Prolactinoma Course and Management in Transgender Women: case report and systematic review

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In transgender women, gender-affirming hormone therapy (GAHT) usually combines high doses of oestrogen and anti-androgen therapy, both of which can elevate serum prolactin levels. Whether GAHT influences tumor behaviour in patients with pre-existing prolactinomas remains unclear. Design and methods Case report illustrating the clinical challenges in managing a prolactinoma in the context of GAHT initiation combined with a systematic review of all published cases and available guidelines of GAHT in the prolactinoma context. Results A 22-year-old female (46,XY; assigned male at birth) with untreated gender dysphoria and hypogonadism was diagnosed with a macroprolactinoma (39.9 mm; serum prolactin 285x upper limit of normal (ULN)). Cabergoline therapy reduced prolactin levels to 27.3xULN within one year. Pituitary apoplexy with acute visual field and acuity deterioration required emergency transsphenoidal debulking. Two months postoperatively, prolactin levels were 8.6xULN with total hypopituitarism and small irresectable remnants. Initiation of oestrogen therapy led to unexpected biochemical (128.4xULN) and radiological progression despite cabergoline reintroduction and dose escalation, necessitating oestrogen withdrawal to stabilize disease. Subsequent radiotherapy allowed safe oestrogen reintroduction. To date, 24 prolactinomas in transgender women (including this case) have been reported, most diagnosed after GAHT initiation and lacking baseline prolactin data. Current clinical guidelines provide no specific recommendations for pituitary tumors in this population. Conclusions GAHT initiation might induce rapid progression and concomitant dopamine-agonist resistance in residual macroprolactinoma. Individualized, multidisciplinary management is needed. Development of dedicated clinical guidelines is essential to combine tumor control with gender-affirming care. Pathology Endocrinology & Metabolism Oncology Gender Studies transgender transgender medicine oestrogen prolactinoma lactotroph PitNET gender-affirming therapy transition Figures Figure 1 Figure 2 Figure 3 Significance Statement This study highlights the unique clinical challenges of managing prolactinomas in transgender women undergoing gender-affirming hormone therapy (GAHT). Oestrogen and cyproterone acetate may influence tumour behaviour, including reduction of dopamine-agonist responsiveness, yet no specific guidelines exist for this patient population. Clinical principles derived from cisgender care, such as the safety of oestrogen-containing contraceptives in microprolactinomas, cannot be directly applied. Baseline prolactin assessment before GAHT, prompt evaluation of symptoms, radiological evaluation of hyperprolactinemia and multidisciplinary care are essential. When medical therapy is insufficient, surgical debulking and radiotherapy may allow safe continuation of GAHT. Development of clinical guidelines or consensus statements dedicated to the management of pituitary conditions and GAHT, and further research are needed to optimise tumour control while preserving gender-affirming care. Introduction Prolactinomas are the most common functioning pituitary neuroendocrine tumor (PitNET), accounting for ~ 40% of all PitNETs, and typically present with symptomatic hyperprolactinemia (1). Clinical and biological features show sexual dimorphism: in cis-women prolactinomas often cause menstrual irregularities and infertility, whereas cis-men present with hypogonadism, including pubertal delay, sexual dysfunction, higher serum prolactin levels, and larger invasive tumours (2, 3). Galactorrhoea can occur in both sexes. The first-line treatment can be dopamine agonist therapy or surgery, depending on tumor size, clinical factors, and patient preference (4). In patients with gender dysphoria, the diagnosis and treatment of prolactinomas are more complex. Guidelines for gender-affirming hormone therapy (GAHT) outline how to transition individuals with typical male (46,XY) or female (46,XX) karyotypes and intact gonadal development to the opposite ends of the sex spectrum, not addressing intersex individuals. GAHT for transgender women (male-to-female, MtF) generally consists of oestrogen supplementation, often combined with the antiandrogen cyproterone acetate (CPA) before gender affirming surgery (GAS, orchidectomy) (5–7). This combination induces feminizing physiological changes (8). Because estradiol stimulates pituitary lactotrophs, baseline and periodic serum prolactin measurements are recommended by several GAHT guidelines (5–7, 9, 10). Mild hyperprolactinemia may occur during GAHT and usually resolves after reducing or discontinuing oestrogen or CPA (6), though this may conflict with gender-affirming goals. CPA is strongly linked to elevated serum prolactin levels (4, 11–14). Persistent prolactin elevation despite stable or reduced oestrogen levels should prompt radiological evaluation for prolactinoma. Several cases of transgender women on supraphysiologic oestrogen doses presenting with prolactinomas have fuelled debate on whether GAHT can trigger prolactinoma formation (12, 15, 16). However, there is no convincing evidence for increased incidence of symptomatic prolactinomas in transgender women (12). The Pituitary Society consensus statement on the management of prolactin-secreting pituitary adenomas includes a section on transgender women but lacks specific treatment recommendations [4]. Current strategies therefore rely on clinical expertise, and little is known about presentation, treatment, and biology of prolactinomas including pathophysiology of prolactin-axis in this population. This study aims to summarize all reported cases and present an alerting case with difficult management because of acute expansion of tumour mass and apoplexy. This surgically treated invasive macroprolactinoma that demonstrated unexpected tumour regrowth and rising prolactin levels upon oestrogen treatment, and (2) to highlight the gaps in current treatment guidance for prolactinomas in transgender women. Case Presentation We describe the clinical trajectory of a transgender woman with a prolactinoma in three parts: Clinical diagnosis of prolactinoma and initial treatment; Apoplectic complication and emergency surgery, including the initiation of GAHT; and Considerations in follow up including clinical course after radiotherapy. The overall timeline of the disease is illustrated in Fig. 1 , while biochemical parameters and medication are summarized in Table 1 – 3 . I. Clinical diagnosis and initial treatment A 22-year-old adolescent with a female habitus, presented with a female voice, gynaecomastia (Tanner stage 2), prepubertal testicular volume (5 ml), underdeveloped external genitalia, and no evidence of androgen-dependent hair development (T = 0, in months). Because of gender dysphoria and female appearance, referral to a clinical geneticist was initiated. Genetic testing showed a 46,XY karyotype. Biochemical evaluation revealed marked hyperprolactinemia (285xULN) accompanied by secondary hypogonadism (luteinizing and follicle-stimulating hormones suppressed and testosterone < 0.5 nmol/L) and secondary hypothyroidism. Dedicated pituitary MRI demonstrated (Fig. 2 A ) a large pituitary mass (39.9 mm) with suprasellar extension and complete (360°) encasement of the left internal carotid artery. Visual field testing showed no deficits. Left panels : T2-weighted MRI. Right panels : T1-weighted MRI, unless stated otherwise. A Baseline (T = 0), prolactin 285xULN. B Preoperative imaging (T = 13) after cabergoline therapy, obtained following new onset symptoms compatible with pituitary apoplexy (T = 13), prolactin 15.2xULN. Right panel shows CT imaging. No interval imaging had been performed since cabergoline initiation to assess interim tumor shrinkage under therapy. C Tumour remnants beneath the optic chiasm confirmed on first postoperative imaging (T = 15). Prolactin 8.6xULN. D Tumour remnant progression with rising prolactin levels following oestrogen initiation (T = 18), refractory to cabergoline reintroduction and dose escalation, prompting radiotherapy (T = 18). Prolactin 128.4xULN. E Stable tumour remnants after oestrogen withdrawal (T = 20). Prolactin 43.6xULN. F Stable tumour remnants after radiotherapy and oestrogen reintroduction (T = 33). Prolactin 5.5xULN After initiation of cabergoline treatment (T = 1) and decrease in prolactin values from initial 285xULN to 3.3xULN, the patient reported depressive symptoms and mood fluctuations related to distress over ongoing physical changes, including spontaneous erections, and fear of further virilization. In this context, cyproterone acetate (CPA) was added at a low dose of 10 mg (T = 3) to suppress male pubertal development upon recovering hypogonadism. Following cabergoline dose escalation, serum prolactin levels decreased markedly but did not normalize, reaching a nadir of 15xULN at a dose of 2 mg/week (T = 12–13). At T = 13, the patient presented to the emergency department with progressive visual disturbances over 3–4 days, and headache for one week, raising suspicion of apoplexy or volume expansion. Ophthalmological assessment revealed severe bilateral visual field loss with reduced visual acuity on the left side, without other neurological deficits. MRI demonstrated lower T2 signal intensity within the tumour compared to prior imaging (Fig. 2 B ) . The lesion measured 37.3 mm and appeared slightly smaller, without clear radiological evidence of apoplexy. Because no interval MRI had been performed between cabergoline initiation and presentation, interim tumor shrinkage could not be assessed. In the context of acute symptoms and a sudden decline in serum prolactin levels, pituitary apoplexy was clinically suspected, suggesting acute volume expansion after prior tumor reduction. The patient was urgently referred for emergency endoscopic transsphenoidal surgery. Table 1 Clinical parameters prior to referral (regional hospital) T= (months) 0 1 4 6 7 8 9 10–11 12 13 Prolactin, xULN 285 3.3 68.5 77.2 34.5 38.9 27.3 15.2 Testosterone, nmol/L < 0.5 - 1.4 1.3 1.0 0.8 1 < 0.5 Cabergoline, mg/week 0.5 to 1 1 1 1 1 1.5 1.5 2 2 Cyproterone acetate, mg/day 10 10 10 10 10 10 10 MRI tumour size, mm 39.9 37.3 Abbreviations: MRI magnetic resonance imaging, ULN upper limit of normal II. Emergency Surgery (T = 13) and Commencement of Gender-Affirming Hormone Therapy Pituitary apoplexy was suspected by pituitary care team based on the acute onset of visual field loss and reduced visual acuity, new corticotropic axis deficiency, and a sudden decline in serum prolactin levels. During endoscopic transsphenoidal surgery, intraoperative findings confirmed intratumoral haemorrhage consistent with an apoplexy. The tumour infiltrated the dura and the left cavernous sinus and was markedly adherent to the left optic nerve and the inferior surface of the optic chiasm. Because of firm adhesion to critical neurovascular structures, a small remnant was intentionally left adjacent to the left posterior communicating artery and the underside of the optic chiasm. Resection within the left cavernous sinus was attempted but could not be safely completed. Histopathological examination (Fig. 3 ) confirmed a lactotroph pituitary neuroendocrine tumour (PitNET) of PIT1-lineage with extensive haemorrhage and dopamine agonist-related changes such as stromal hyalinization, fibrosis, patchy immunohistochemical prolactin expression, and altered nuclear-cytoplasmic ratio. Ki-67 proliferation index was < 1%. There was no co-expression of other pituitary hormones, and tumour granulation subtype could not be determined. A Vital and relatively intact tumour morphology with bleeding in the background (x40). B Therapy changes as seen after therapy with dopamine agonists: stroma hyalinization, hyperchromatic nuclei and disrupted cytonuclear ratio (1). C Strong nuclear positivity for PIT1. D Patchy heterogeneously cytoplasmatic expressed prolactin. E Sporadic weak tot moderately strong nuclear ERα expression. F Ki-67 proliferation index is low. G Copy number variation (CNV) analysis revealed a complex pattern of chromosomal alterations as expected for prolactinomas (17). There were balanced gains of chromosomes 5, 7 and 9 with extrapolated genotypes AABB. There were imbalances due to copy number gain on chromosomes 1p; 3, 8, 12, 14, 15, 17, 18, 19, and 20 with extrapolated genotypes AAB/ABB. Loss of heterozygosity (LOH) was observed on chromosomes 16 due to whole chromosome loss with extrapolated genotype A0/B0 and copy number neutral LOH of chr. 21, genotype AA or BB. Chromosome X showing normal genotype A0/B0 as seen in male chromosomal sex. Two months after surgery, the first postoperative MRI (T = 15, Fig. 2 C) confirmed small tumour remnants in the left cavernous sinus (6x6 mm) and beneath the optic chiasm (1x4 mm). Serum prolactin remained mildly elevated (8.6xULN). In shared decision-making, considering side effects and concerns regarding testosterone rebound, cabergoline therapy – stopped pre-operatively – was not reintroduced. Following this evaluation, transdermal oestradiol therapy was initiated (100 µg patches, twice weekly) to induce feminization in accordance with the patient’s wishes. Three months later (T = 18), prolactin levels had increased to 128.4xULN, and ophthalmologic assessment revealed progression of visual field defects compared to T = 15 but still improved relative to preoperative findings at T = 13. MRI (Fig. 2 D) showed marked growth of the suprasellar tumour remnant (8x18 mm) compressing the left optic tract and slight volume increase of the residual lesion in the left cavernous sinus. Cabergoline therapy was reintroduced (0.5 mg twice weekly, increased to three times weekly), but prolactin reduction was insufficient (74.7xULN). Oestradiol therapy was therefore discontinued (T = 19). One month later (T = 20), prolactin levels declined to 43.6xULN, and MRI confirmed stable tumour remnants without further growth (Fig. 2 E). Pathologic reassessment was requested. The tumour showed variable ERα expression (Fig. 3 E) and was negative for progesterone receptor (not shown). No areas with increased Ki-67 proliferation index were identified. Oncomine comprehensive Array Plus detected a pathogenic inactivating variation in ARID1A c.4005-2A > G and no alterations in TP53 , SF3B1 , SDH x, DAXX , MEN1 , or PRKAR1A . The tumour had low tumour mutational burden (TMB), was microsatellite stable (MSS) and homologous-recombination proficient (HRP). Copy-number variation analysis revealed a complex pattern of chromosomal alterations (Fig. 3 G). Table 2 Clinical parameters pre- and postoperatively and prior to radiotherapy T= (months) 13 14 15 18 19 20 21 23 Prolactin, xULN 2.2–2.6 2.7–4.8 8.6–14.3 128.4–49.6 65.0–74.7 60.3–43.6 40.5–44.8 20.0 MRI Confirmation of tumour remnants: left sinus cavernosus (6x6 mm) and suprasellar on chiasma (1x4 mm) Suprasellar remnant enlarged to 8x18 mm, the left sinus cavernosus remnant slightly enlarged. No tumour growth Clinical management Stop CBG. TSS. Stop CPA Start E2 Reintroduction of CBG Stop E2 Referral to radiotherapy Cabergoline, mg/week 1 1.5 0.5 0.5 0.5 Cyproterone acetate, mg/day 10 Estradiol plaster, µg/24 hours 100 100 Abbreviations: CBG cabergoline, CPA cyproterone acetate, E2 estradiol, MRI magnetic resonance imaging, TSS transsphenoidal surgery, pre-op preoperatively, post-op postoperatively, ULN upper limit of normal III. Considerations in follow-up After oestradiol withdrawal, prolactin levels declined but remained elevated (nadir 20xULN) on cabergoline 0.5 mg/week. Because of severe cabergoline-related side effects and the patient’s wish to resume oestrogen therapy, radiotherapy was considered, given the relative contraindication to oestrogen reinitiation due to prior tumour growth. Antiandrogen therapy was unnecessary due to pituitary-gonadal axis failure. Fractionated radiotherapy was administered to a total dose of 50.4 Gy in 28 fractions of 1.8 Gy (T = 24–26), while cabergoline was continued at 0.5 mg/week. Serum prolactin levels remained stable following treatment (16xULN directly post-radiotherapy; 19.7xULN one month later). The first post-radiotherapy MRI (T = 28) demonstrated unchanged residual tumour volumes. Based on these findings, transdermal oestradiol was cautiously reintroduced (50 µg/24 hours). Prolactin levels initially increased (38.2xULN at one month, 43xULN at two months) – but subsequently stabilized (27.9xULN) three months after reinitiation. A follow-up MRI performed five months after oestradiol reintroduction (T = 33, Fig. 2 F) showed no evidence of tumour growth. Table 3 Clinical parameters during and after the radiotherapy and oestrogen therapy reintroduction T= (months) 24 26 27 28 29 30 31 33 Prolactin xULN 24.2 16.0 19.7 38.2 43.0 27.9 35.5 MRI No tumour growth No tumour growth No tumour growth Clinical management RT 50.4 Gy divided in 28 fractions of 1.8 Gy RT completed Reinitiation E2 Cabergoline, mg/week 0.5 0.5 0.5 0.5 0.5 Oestradiol plaster, µg/24 hours 50 50 50 50 50 Abbreviations: E2 oestradiol, MRI magnetic resonance imaging, PRL serum prolactin, RT radiotherapy, ULN upper limit of normal Literature review A systematic literature search was performed in PubMed/MEDLINE and Google Scholar to identify previously reported cases of prolactinoma in transgender women. The search was conducted up to November 2025 using combinations of full terms or root words including “prolactinoma” or “pituitary adenoma” and “transgender” or “transsexual”. The terms “recommendations,” “guidelines” or “management” were additionally used to identify publications addressing clinical management strategies for prolactinoma in transgender women. Reference lists of relevant articles were screened to identify additional eligible reports. Summary of the previously reported cases To date, 24 transgender women diagnosed with prolactinoma have been reported (Table 4 a, 4 b, 4 c), including the present case. Notably, the patient reported by Serri et al. is an individual with Klinefelter syndrome. The vast majority of cases were diagnosed during GAHT treatment (Table 4 a, 4 b). The current patient and a patient reported by Gersey et al. (18), had known macroprolactinoma prior GAHT (Table 4 c). In most (19/24) cases, prolactin levels prior to GAHT-initiation were unknown. Although symptomatology suggests, it is impossible to determine whether these patients already had hyperprolactinemia or asymptomatic prolactinoma prior GAHT. Most individuals had received long-term GAHT, with regimens including high-dose oestrogens and antiandrogens, predominantly CPA at very high doses (100–150 mg), far exceeding current recommendations. The time to prolactinoma diagnosis varied from a few months to several decades after initiation of GAHT. Fourteen of twenty-two prolactinomas were detected because of symptomatic hyperprolactinemia, six were asymptomatic and were detected by biochemical screening. The symptomatic status was not reported in two patients. Seven of ten macroadenomas and seven of twelve microprolactinomas were symptomatic. Sixteen patients were treated with dopamine agonists following diagnosis. Among them, five continued GAHT upon DA initiation (12, 15, 16, 19, 20) and five discontinued GAHT with reported reintroduction in four patients (15, 16, 21, 22), and one did not re-introduce GAHT (23). For six patients, it was not specified whether GAHT was discontinued at the time of dopamine-agonist initiation (12, 24, 25). One of the patients continuing GAHT upon DA therapy showed persistent tumour growth despite falling prolactin levels (20). This patient underwent elective total resection surgery, normalizing prolactin levels, and she continued GAHT. Six patients did not receive DA. All had small lesions (< 10 mm), of whom half were asymptomatic. One symptomatic patient discontinued GAHT prior to TSS, with lactotroph hyperplasia identified on histopathological examination (26). Postoperative prolactin levels were not reported, and it remains unknown whether GAHT was reinitiated. Three patients were managed conservatively (wait-and-see), including two patients with symptomatic and one patient with asymptomatic hyperprolactinemia (12). In one asymptomatic patient, oestrogen cessation was the only intervention. In another patient, thyroid hormone substitution was initiated for hypothyroidism, a potential cause of hyperprolactinemia (12). No follow-up data were reported for the latter five patients. Beside current study, three patients were operated, and histopathology was reported in varying detail (18, 20, 26). The review of previous reported cases illustrates the baseline heterogeneity of clinical parameters and further management strategies. Table 4 a. Prolactinomas in transgender women: normal prolactin levels prior initiation of gender affirming hormone therapy (GAHT). Author, year Age Gender affirming therapy details Prolactinoma diagnosis Management of prolactinoma Serum prolactin upon GAHT Symptoms Radiology Decision Results Gooren et al.,1988 (23) 26 10 months : CPA 100 mg/day, EE 100 µg p.o./day ~ 6–10 months : surreptitiously E17U 100 mg, i.m. 2x/week 17xULN Not reported At 9.5 months CT:10 mm height with suprasellar extension Discontinuation of all E. Plasma E2 from 2.8 to 0.77 nmol/L PRL 21xULN. BRC 2.5 mg twice daily. PRL1.4xULN. CT after 5 months: reduction in tumour size. BRC stop, E not resumed. + 4 months: plasma E2 0.08 nmol/L, PRL 15xULN Bunck et al., 2009 (19), Nota et al., 2018 (12) 36 Start : CPA 100 mg/day, EE 100 µg/day. 2.5 years : GAS, stop CPA. 17bE 50 µg/day, topical patches. 5 years : skin irritation, switch to p.o. CEE 1.25 mg/day. 7 years : chloasma, CEE reduction to 0.625 mg/day. In the first year : up to 3.3xULN, normalized 6 months after. At 15 years : 6.1xULN. During investigation (E pause): 7.6xULN. Asymptomatic MRI: 8 mm lesion, no chasm compression. Quinagolide 75 µg/day Undetectable PRL At 19th year: quinagolide stop FU 20 years: normal PRL. Garcia-Malpartida et al., 2010 (21) 33 CPA 100 mg/day CEE 2.5 mg/day 3 months : 3.5xULN 6 months : 6.4-6.9x ULN Mastodynia, migraine, asthenia, b/l galactorrhoea MRI: sellar floor erosion, 5x4x4 mm lesion with decreased uptake that displaced the carotid siphon. Interruption of GAHT. 2 months later: PRL 5.4xULN, gradual reduction of the symptoms. Start CBG 0.5 mg 2x/week. 6 months later: normal PRL. MRI: tumour size reduction. Cessation of CBG. 3 months later: PRL 3.7xULN E2 31 pg/mL. MRI: stabilization of the tumour size. Re-start CBG. GAS. 3 months later: normal PRL. Stop DA after GAS. GAHT resumed: low-dose transdermal E2 patches, no CPA. Asymptomatic, PRL: normal to 1.6 ULN, appropriate 17bE and testosterone. MRI: stable. Abbreviations: b/l bilateral, BRC bromocriptine, CBG cabergoline, CEE conjugated equine oestrogens, CPA cyproterone acetate, DA dopamine agonist, E oestrogen not other specified, E2 oestradiol not other specified, E17bE oestradiol 17b-enanthate, E17U oestradiol-17-undecanoate, EE ethinyl oestradiol, E2V oestradiol valerate, FU follow up, GAS gender-affirming surgery, GDX gonadectomy, GAHT gender-affirming hormone therapy, HPRL hyperprolactinemia, i.m. intramuscular, LT4 L-thyroxine, MPA medroxyprogesterone acetate, MRI magnetic resonance imaging, n/a not available, p.o. per os (peroral), PRL serum prolactin, SPL spironolactone, TSS transsphenoidal surgery Table 4 b. Prolactinomas in transgender women: Prolactin levels pre-GAHT unknown Author, year Age Gender affirming therapy details Prolactinoma diagnosis Management of prolactinoma Serum prolactin upon GAHT Symptoms Radiology Decision Results Kovacs et al., 1994 (20) 33 Diethylstilbesterol starting at 16 years. 4 years later : GAS, switch to conjugated p.o. E 0.625 mg/day. 5.7xULN. B/l galactorrhoea at time of GAS CT: 9 mm BRC upon E, intolerance above 2.5mg daily. + 10 months: PRL1.9xULN, the tumour size increased despite BRC. MRI: 12 x 10 mm on the left side Selective TSS Post-op: Normal PRL. EE 40 µg/day 1-year post-op: PRL remained normal. Serri et al., 1996 (26) 32 At age of 20 : Klinefelter syndrome diagnosis. GAS. Post-GAS, 4 years : EE 1.5 mg/day, CPA 150 mg/day. n/a Last 3 years: 9 kg weight gain, headache, fatigue, b/l galactorrhoea MRI: 4 mm left sided lesion Cessation of E. At 3–10 days: 24xULN TSS: nodular lesion 3–4 mm fragment. Microscopy: hyperplasia with intact reticuline. Futterweit, 1998 (27) 30 Unknown 4.2xULN Not reported 20 mm Initiation of BRC and SPL. Follow-up MRI: no evidence of tumour. Normal PRL. Bunck et al., 2009 (19) 69 EE 50 µg/day, 30 years. 133xULN Sudden onset of double vision. Right sided III palsy, no visual field defect. MRI: large tumour with right cavernous sinus invasion and contact to chiasma. CBG 0.25 mg/2x week. LT4 50 µg/day. + 10 days: PRL 22 ULN III nerve palsy resolved, tumour shrank, no invasion of chiasmatic cistern and the right cavernous sinus. Refused to stop EE treatment, continued CBG Serum PRL returned to normal and remained normal for 8 years FU, the tumour has never increased in size again. Stop CBG, EE Normal PRL Cunha et al., 2015 (15) 41 Referred for GAHT and GAS. Non-supervised E treatment since age of 23 years: contraceptive pill EE 35 µg/day, CPA 2 mg/day, i.m. E2V 5 mg/week alternating with i.m. E17bE 10 mg/week, total 8 doses. Then, i.m. E17bE 10 mg every 15 days for 16 years. 35xULN Spontaneous galactorrhoea b/l. MRI: 8 mm left-sided lesion, without diffuse enlargement of the pituitary gland CBG 0.5 mg twice weekly At 3 months: normal PRL E reintroduction (no information of pause timepoint): CEE 0.625 mg/day. MRI 8 months after start CBG: lesion identical to the pre-treatment image. Normal PRL. Cunha et al., 2015 (15) 42 Referral for GAHT and GAS. Since the age of 17 years: E17bE 10 mg i.m. every 15 days 35xULN Mild galactorrhoea b/l. MRI: 15 x 13 mm lesion with a central cystic area CBG 1 mg/week + 5 months, normal PRL under continuous use of CEE 1.25 mg/day. CBG FU 1 year MRI: slight reduction of the tumour size, especially in the cystic central area. CBG continued for 2 years. Normal PRL. MRI: normal dimensions, delayed contrast uptake in dynamic sequence, suggesting a microadenoma. Jehangir, 2016 (24) 22 GAS incl. E pellet breast and buttock implants. E injections for 2 years. Ca. 57xULN Breast tenderness, galactorrhoea. MRI: 25 x 22 x 23 mm. CBG (dose n/a) + 3 months: PRL ca. 4.8xULN Nota et al., 2018 (12) 32 ± 4 years CPA 100 mg/day, E2 injection 100 mg/2weeks, GAS. HPRL Asymptomatic “microadenoma” Stop E Not reported Nota et al., 2018 (12) 39 ± 14 years CPA 100 mg/day, conjugated E 2.5 mg/day, GAS. HPRL Hypothyroidism “microadenoma” LT4 Not reported Nota et al., 2018 (12) 27 ± 13 years CPA and E2 injection (doses n/a), no GAS. HPRL Galactorrhoea “microadenoma” DA Not reported Nota et al., 2018 (12) 46 ± 5.5 years CPA 100 mg/day, EE 100 mg/day, no GAS. HPRL Asymptomatic “microadenoma” Wait-and-see Not reported Nota et al., 2018 (12) 24 GAHT duration probably > 9 months. CPA 100 mg/day, no GAS. HPRL Asymptomatic “microadenoma” DA Not reported Nota et al., 2018 (12) 47 ± 7.5 years CPA 100 mg/day, EE 100 mg/day, GAS. HPRL Galactorrhoea “microadenoma” Wait-and-see Not reported Nota et al., 2018 (12) 29 ± 12 years EE 50–100 mg/day, GAS. HPRL Galactorrhoea “microadenoma” Wait-and-see Not reported Nota et al., 2018 (12) 28 ± 11 years CPA 50 mg/day, E2V 2 mg/day, GAS. HPRL Galactorrhoea “macroadenoma” DA Not reported Raven et al., 2021 (16) 23 5-years prior: subdermal E2 implants 6–12 monthly, MPA and SPL. No GAS. 27xULN, Within 3-months of GAHT : elevated PRL. Next 18 months : low-level HPRL, then exponential increase. Spontaneous galactorrhoea after 2-years of GAHT GAHT reduction /temporary suspension PRL: 10.6xULN A right sided 10×6mm lesion within the sella. A second lesion 5 × 3 mm in the left lobe. Cystic changes within both lesions CBG 0.5 mg/week. MPA and SPL re-start. Following 3 months: PRL within normal limits, galactorrhoea resolved. Raven et al., 2021 (16) 53 30 years prior: combination of EE and CPA (doses n/a). At referral: E2 50 µg topical patch 2x/week. CPA 50 mg/day. No GAS. 20xULN. > 10 years: persistent HPRL independent of serum E2 concentrations. Galactorrhoea b/l 11.7 × 12 mm within the sella. CBG 0.5 mg/week, GAHT uninterrupted. Following 3 months: normal PRL, galactorrhoea resolved. Harned and Harper, 2021 (25) 50 E p.o. for six years (dose n/a). 27xULN Galactorrhoea b/l. New onset: tunnel vision, extremity paraesthesia for one day. Visual fields intact. 4 x 13 x 13 mm. BRC 5mg/day. 3 months later: galactorrhoea resolved, normal PRL. MRI (at 1 and 3 years): no significant decrease in tumour size. Chow and Rajpal, 2025 (22) 48 E2 8 mg/day, progesterone 200 mg/day, and SPL 400 mg/day for the last 10 years. 13.7xULN on routine evaluation Asymptomatic 11 mm pituitary tumour abutting the right cavernous sinus E2 and progesterone discontinuation. 6 months: PRL 6xULN. Evaluation by neurosurgery – deferred intervention. CBG initiation gradually up titrated to 0.25mg x3 weekly. MRI 6 months after initial presentation: tumour shrinkage to 0.6 cm. Repeatedly undetectable PRL levels 2 months after CBG initiation. Re-initiation E2 2mg/day. Plan to closely monitor PRL levels and repeat MRI 6–9 months afterwards. b/l bilateral, BRC bromocriptine, CBG cabergoline, CEE conjugated equine oestrogens, CPA cyproterone acetate, DA dopamine agonist, E oestrogen not other specified, E2 oestradiol not other specified, E17bE oestradiol 17b-enanthate, E17U oestradiol-17-undecanoate, EE ethinyl oestradiol, E2V oestradiol valerate, FU follow up, GAS gender-affirming surgery, GDX gonadectomy, GAHT gender-affirming hormone therapy, HPRL hyperprolactinemia, i.m. intramuscular, LT4 L-thyroxine, MPA medroxyprogesterone acetate, MRI magnetic resonance imaging, n/a not available, p.o. per os (peroral), PRL serum prolactin, SPL spironolactone, TSS transsphenoidal surgery. Table 4 c. Prolactinomas in transgender women: prolactinomas diagnosed prior to GAHT initiation Author, year Age Gender affirming therapy details Prolactinoma diagnosis Management of prolactinoma Baseline serum prolactin Regimen Serum prolactin upon GAHT Symptoms Radiology Decision Results Gersey at al., 2025 (18) 49 104xULN Low libido, erectile dysfunction, hot flashes, fatigue, breast tenderness, hypogonadotropic hypogonadism. 22 × 17 × 15 mm CBG initiation: 0.25 mg twice weekly Side effects Transition to BRC 1.25 mg/d At one month: PRL 19xULN BRC to 2.5 mg/d PRL 6.6xULN BRC to 5 mg/d Nadir PRL 1.6xULN. After 6 months: PRL remained elevated, the tumour size decreased. High-dose weekly i.m. E2V + finasteride 5 mg/d Up to 8.8xULN Adjusted E therapy, transition from finasteride to SPL 50 mg/x2d Range 8.8–17xULN E reduction Continuous rise, peak 31xULN BRC to 7.5 mg twice daily 17 × 12 × 12 mm with slight CS extension BRC stop. CBG initiation and stop (severe side effects). Persistent PRL elevation, the patient opted for TSS with medial CS wall resection after multidisciplinary discussion. 2 weeks pre-op: SPL and E stop. 5 days pre-op: BRC stop. A total tumour resection with the medial wall of the left CS. Post-op day 1: normal PRL, discharged home. Post-op day 7: PRL 1.1xULN. 2 weeks post-op: SPL and E reinitiation, PRL levels and imaging monitoring (whether BRC reinitiation was necessary). Two months after resuming E and SPL: PRL 3.1xULN. PRL monitoring, no treatment. No symptoms. MRI at 3 months: no residual tumour. By 4 months: PRL up to 5.1xULN. E pause for GAS PRL dropped to 2xULN. Resume E PRL up to 3.5 ULN. This study See Fig. 1 and Table 1 – 3 b/l bilateral, BRC bromocriptine, CBG cabergoline, CPA cyproterone acetate, CS cavernous sinus E oestrogen not other specified, E2 estradiol not other specified, E2V estradiol valerate, GAS gender-affirming surgery, GAHT gender-affirming hormone therapy, i.m. intramuscular, MRI magnetic resonance imaging, p.o. per os (peroral), post-op postoperatively, PRL serum prolactin, pre-op preoperatively, SPL spironolactone, TSS transsphenoidal surgery, ULN upper limit of normal Summary of the guidelines and recommendations As oestrogen may increase prolactin levels, measurement of baseline serum prolactin before initiating GAHT is universally recommended in the context of initial endocrinological assessment. Oestrogen combined with CPA is associated with higher prolactin levels, an effect not observed when oestrogens are combined with GnRH agonists or spironolactone (7). CPA alone is associated with dose-dependent prolactin elevation (12, 28). In recent years, antiandrogen therapy increasingly shifts from CPA toward GnRH agonists or spironolactone, and when CPA is used, substantially lower doses (typically 10–25 mg daily) are now recommended. Mild, transient, and asymptomatic hyperprolactinemia has no clinical consequence. International standards of transgender care advise clinicians to make individualized decisions based on hormone regimen and symptoms of hyperprolactinemia or a pituitary tumour (7). Prolactin levels should be evaluated at baseline along with other relevant laboratory parameters. This assessment may be challenging when hormone therapy is initiated via online sources or remote consultations without comprehensive endocrine evaluation. (Inter)national guidelines differ on monitoring frequency and thresholds for imaging or intervention: Endocrine Society (USA): baseline prolactin measurement, then annually during transition and every two years thereafter (6). MRI is indicated for rising prolactin despite stable or reduced oestrogen levels. French Society of Paediatric Endocrinology and Diabetology Consensus: baseline prolactin measurement, then every 12 months or every 6 months after each dose adjustment, monitoring may stop after several stable results (10). MRI is considered when hyperprolactinemia worsens over successive controls. Canadian Standards of Care: baseline and annual prolactin measurement when CPA is used; more frequent measurements if prolactin is elevated and 6–8 weeks after medication adjustments (9). For levels > 2.4-2.8xULN switch to spironolactone before reducing oestrogen; imaging if persistent > 3.2xULN or symptomatic. UCSF (University of California, San Francisco) Guidelines: no routine screening in asymptomatic patients; testing only for new onset headaches, visual disturbances, or excessive galactorrhoea (29). Australian Approach: confirm hyperprolactinemia with repeat testing and exclude other causes (30). For mild hyperprolactinemia (1.2-4xULN), lower CPA or switch to alternative anti-androgen and re-assess. Pituitary MRI and/or workup is advised when prolactin reaches 4–6xULN. The Pituitary Society International Consensus Statement (4) on diagnosis and management of prolactin-secreting pituitary tumours acknowledges mild prolactin elevation in transgender women on GAHT but does not provide specific treatment recommendations for transgender women with prolactinomas. Discussion Prolactinomas – histologically corresponding to a lactotroph PitNET – are the most common hormonally active PitNET and typically express ERα (1). Baseline prolactinoma prevalence differs between sexes, and transgender women (assigned male at birth) may, upon oestrogen therapy, adopt a risk profile more closely resembling that of cisgender women. GAHT and new-onset hyperprolactinemia Elevations in serum prolactin during feminizing GAHT are well documented and are generally attributed to oestrogen and CPA effects rather than de novo tumorigenesis (31–35). Elevations of serum prolactin are observed in up to 20% of transgender women receiving oestrogens, sometimes accompanied by pituitary enlargement (6). These changes are often biochemical and are not accompanied by radiological evidence of adenoma. Earlier antiandrogen regimens frequently included high-dose CPA (≥ 100 mg/day), which is independently associated with dose-dependent prolactin elevation. Contemporary practice favours GnRH agonists or spironolactone, and when CPA is used, substantially lower doses (typically 10–20 mg daily) are recommended, potentially reducing the incidence of hyperprolactinemia. GAHT, prolactinoma detection, and incidence The association between feminizing GAHT and prolactinoma formation remains uncertain. Existing literature consists mostly of isolated case reports, often involving supraphysiologic oestrogen exposure. The largest study to date, conducted by Nota et al.(12), identified nine prolactinomas over 23,935 person-years (risk of 0.04% per person-year). While this incidence appears higher than in the general male population, it was comparable to female incidence when adjusted for symptomatic presentation. These findings suggest that intensified biochemical monitoring in transgender women likely contributes to increased prolactinoma detection. To date, 24 prolactinoma cases have been reported in transgender women, including the present case. Notably, six patients were asymptomatic, and symptom documentation lacked in two, supporting the hypothesis of incidental detection through routine monitoring. However, the absence of baseline prolactin measurements in many reports limits conclusions regarding whether hyperprolactinemia or asymptomatic prolactinomas predated GAHT. GAHT and pre-existing prolactinomas In cisgender women with microprolactinomas, combined oestrogen–progestogen contraceptives are generally considered safe and involve relatively low oestrogen doses (36). Feminizing GAHT differs fundamentally from contraceptive exposure, resembling high-dose oestrogen replacement rather than cyclic low-dose contraception. Therefore, clinical experience from contraceptive use in cisgender women cannot be directly extrapolated to transgender women receiving GAHT including oestrogens. Sex-specific characteristics of prolactinomas further complicate the comparison (2, 3, 37, 38). Cisgender women typically present with microprolactinomas, whereas cisgender men often develop macroprolactinomas. Accordingly, micro- and macroprolactinomas may require different management strategy reflecting variation in tumour behaviour, dopamine agonist responsiveness, and treatment duration. Our case highlights the potential effects of feminizing GAHT on prolactinoma tumour behaviour. Specifically, symptomatic regrowth of residual macroprolactinoma (heterogeneously ERα-positive) and marked prolactin elevation shortly after oestrogen initiation, despite cabergoline reinitiation, suggest oestrogen sensitivity of tumour cells. Only three prior histopathologically documented prolactinomas in transgender women have been reported (18, 20, 26). Kovacs et al. described high ER mRNA expression with weak dopamine receptor mRNA expression and continuous growth under bromocriptine during GAHT (20). Gersey at al. reported a weak-to-moderate ERα-positive lactotroph tumour with low Ki-67 proliferation index (18). Serri et al. observed lactotroph hyperplasia (26). Management upon GAHT may be challenging, as GAHT is considered essential for psychological well-being yet may exacerbate tumour activity. At present, no guidelines specifically address prolactinoma management in the setting of feminizing GAHT. Review of published cases suggests that prolactinomas diagnosed during GAHT often follow a mild clinical course, with stabilization or normalization of prolactin levels under conservative management in many patients, allowing discontinuation of dopamine agonists and/or GAHT reintroduction. However, these observations must be interpreted cautiously given incomplete follow-up, heterogeneous treatment regimens, and evolving standards of hormone therapy. Symptomatic hyperprolactinemia in transgender women may also occur less frequently in the future due to the shift from CPA use to GnRH or spironolactone. Endoscopic endonasal/transsphenoidal surgery (EES/TSS) is an effective alternative to dopamine agonists (39). Gersey et al. proposed expanding surgical indications when GAHT exacerbates symptomatic hyperprolactinemia or tumour growth, thereby enabling uninterrupted continuation of GAHT (18). Surgery also may allow discontinuation or marked dose reduction of dopamine-agonists in the setting of intolerance or tumour resistance. However, complete resection is not always feasible, particularly in invasive or near-giant tumours – as in our patient. In this context, radiotherapy may represent a valuable adjuvant treatment strategy, as illustrated by our case, where tumour remained stable after reintroduction of oestrogen therapy post-radiotherapy. Multidisciplinary decision-making is essential to balance surgical morbidity, tumour control, and gender-affirming goals. In conclusion, this study underscores the complex interplay between feminizing GAHT and prolactinoma pathophysiology in transgender women. Oestrogen therapy may influence tumour behaviour in these individuals, necessitating individualized multidisciplinary management strategies. Given the current lack of dedicated recommendations for this patient population, multidisciplinary decision-making is essential to ensure both tumour control and continuity of gender-affirming care. Learning Points This case illustrates that oestrogen treatment in the setting of GAHT can induce progression of a pre-existing prolactinoma, with apparent reduced dopamine-agonist responsiveness, requiring multimodal management. There are currently no recommendations for prolactinoma management in transgender women receiving GAHT. Multidisciplinary management is essential. Close coordination among endocrinologists, neurosurgeons, radiotherapists, and gender-care specialists is required to balance tumour control with gender-affirming goals. Radical endoscopic endonasal/transsphenoidal surgery (EES/TSS) may enable continuation of GAHT when medical therapy is insufficient or poorly tolerated. Radiotherapy may stabilize residual disease and allow cautious reintroduction of GAHT. Baseline endocrine evaluation, including serum prolactin measurement, is essential prior to GAHT initiation to identify pre-existing hyperprolactinemia or occult prolactinomas. In the absence of baseline assessment, causality between GAHT and subsequent prolactinoma detection cannot be determined. Galactorrhoea, headache, or visual disturbances in transgender patients on GAHT should prompt prolactin evaluation and pituitary MRI. GAHT differs fundamentally from oestrogen exposure in cisgender women using contraceptives, therefore management principles derived from cisgender populations (e.g., safety of oestrogen-containing contraceptives in women with microprolactinomas) cannot be directly applied to transgender women. Available case-based literature suggests that many prolactinomas detected during GAHT follow a mild clinical course and may be identified incidentally through routine biochemical monitoring. However, the evidence base is limited by detection bias, heterogeneous hormone regimens, and incomplete follow-up. Declarations Funding No public or commercial funding. Disclosures None declared. Informed Patient Consent for Publication Signed informed consent obtained directly from the patient. Data Availability Statement Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. References WHO Classification of Tumours Editorial Board. Endocrine and neuroendocrine tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2025 02 23]. (WHO classification of tumours series, 5th ed.; vol. 10). Available from: https://tumourclassification.iarc.who.int/chapters/53. Delgrange E, Vasiljevic A, Wierinckx A, François P, Jouanneau E, Raverot G, et al. Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth. Eur J Endocrinol. 2015;172(6):791–801. Andereggen L, Christ E, Stieger A, Luedi MM, Huber M. Gender differences in prolactin thresholds and their association with lactotroph adenoma invasiveness for potential treatment considerations. Scientific Reports. 2025;15(1):9598. Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol. 2023;19(12):722 − 40. Prince JCJ, Safer JD. Endocrine treatment of transgender individuals: current guidelines and strategies. Expert Rev Endocrinol Metab. 2020;15(6):395–403. Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2017;102(11):3869 − 903. Coleman E, Radix AE, Bouman WP, Brown GR, de Vries ALC, Deutsch MB, et al. Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. Int J Transgend Health. 2022;23(Suppl 1):S1-s259. Santos RB, Lemos C, Saraiva M. Gender-Affirming Hormone Therapy: Physical and Sociopsychological Effects, Impact and Satisfaction. Cureus. 2023;15(3):e36484. Ontario RH. 4th edition Sherbourne's guidelines for gender-affirming primary care with trans and non-binary patients.2019 February 12, 2025. Available from: https://www.rainbowhealthontario.ca/product/4th-edition-sherbournes-guidelines-for-gender-affirming-primary-care-with-trans-and-non-binary-patients/. Brezin F, Busiah K, Leroy C, Fiot E, Bensignor C, Amouroux C, et al. Endocrine management of transgender adolescents: Expert consensus of the french society of pediatric endocrinology and diabetology working group. Archives de Pédiatrie. 2024. McFarlane T, Zajac JD, Cheung AS. Gender-affirming hormone therapy and the risk of sex hormone-dependent tumours in transgender individuals-A systematic review. Clin Endocrinol (Oxf). 2018;89(6):700 − 11. Nota NM, Wiepjes CM, de Blok CJM, Gooren LJG, Peerdeman SM, Kreukels BPC, et al. The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment. Brain. 2018;141(7):2047-54. Moltz L, Römmler A, Post K, Schwartz U, Hammerstein J. Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men. Contraception. 1980;21(4):393–413. Valenti G, Vescovi PP, Gerra G, Rastelli G, Butturini U. Activation of PRL secretion by combined treatment with cyproterone acetate and ethinylestradiol. Journal of Endocrinological Investigation. 1985;8(3):269 − 72. Cunha FS, Domenice S, Câmara VL, Sircili MH, Gooren LJ, Mendonça BB, et al. Diagnosis of prolactinoma in two male-to-female transsexual subjects following high-dose cross-sex hormone therapy. Andrologia. 2015;47(6):680-4. Raven LM, Guttman-Jones M, Muir CA. Hyperprolactinemia and association with prolactinoma in transwomen receiving gender affirming hormone treatment. Endocrine. 2021;72(2):524-8. Jentus MM, Bakker L, Verstegen M, Pelsma I, van Wezel T, Ruano D, et al. Chromosomal alteration patterns in PitNETs: massive losses in aggressive tumors. Endocr Relat Cancer. 2025;32(1). Gersey ZC, Vargas AF, Leung JH, Fazeli PK, Zenonos GA, Gardner PA. Prolactinoma Resection in a Transgender Woman on Gender-affirming Hormone Therapy. JCEM Case Rep. 2025;3(8):luaf120. Bunck MC, Debono M, Giltay EJ, Verheijen AT, Diamant M, Gooren LJ. Autonomous prolactin secretion in two male-to-female transgender patients using conventional oestrogen dosages. BMJ Case Rep. 2009;2009. Kovacs K, Stefaneanu L, Ezzat S, Smyth HS. Prolactin-producing pituitary adenoma in a male-to-female transsexual patient with protracted estrogen administration. A morphologic study. Arch Pathol Lab Med. 1994;118(5):562-5. García-Malpartida K, Martín-Gorgojo A, Rocha M, Gómez-Balaguer M, Hernández-Mijares A. Prolactinoma induced by estrogen and cyproterone acetate in a male-to-female transsexual. Fertil Steril. 2010;94(3):1097.e13-5. Chow B, Rajpal A. MON-048 Proactive on Prolactin: Hyperprolactinemia Management in Transgender Patients. Journal of the Endocrine Society. 2025;9(Supplement_1). Gooren LJ, Assies J, Asscheman H, de Slegte R, van Kessel H. Estrogen-induced prolactinoma in a man. J Clin Endocrinol Metab. 1988;66(2):444-6. Jehangir W. P-B1 Prolactinoma in a transgender Male-To-Female HIV positive adult-A rare occurrence & A therapeutic dilemma. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2016;71:72. Harned LK, Harper RJ. Prolactinoma in a Male to Female Transgender Woman on Gender Affirming Hormone Therapy. Journal of the Endocrine Society. 2021;5(Supplement_1):A795-A. Serri O, Noiseux D, Robert F, Hardy J. Lactotroph hyperplasia in an estrogen treated male-to-female transsexual patient. J Clin Endocrinol Metab. 1996;81(9):3177-9. Futterweit W. Endocrine therapy of transsexualism and potential complications of long-term treatment. Arch Sex Behav. 1998;27(2):209 − 26. Kuijpers SME, Wiepjes CM, Conemans EB, Fisher AD, T'Sjoen G, den Heijer M. Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study. J Clin Endocrinol Metab. 2021;106(10):e3936-e45. Deutsch M. Guidelines for the primary and genderaffirming care of transgender and gender nonbinary people [Internet]. Available from:. Centre of Excellence for Transgender Health. 2016. Nolan BJ, Accatino MI, Angus LM, Cheung AS. Approach to prolactin monitoring and hyperprolactinaemia in transgender and gender-diverse individuals undergoing gender affirming hormone therapy. Front Endocrinol (Lausanne). 2025;16:1608108. Asscheman H, Gooren LJ, Assies J, Smits JP, de Slegte R. Prolactin levels and pituitary enlargement in hormone-treated male-to-female transsexuals. Clin Endocrinol (Oxf). 1988;28(6):583-8. Boekhout-Berends ET, Wiepjes CM, Nota NM, Schotman HH, Heijboer AC, den Heijer M. Changes in laboratory results in transgender individuals on hormone therapy - a retrospective study and practical approach. Eur J Endocrinol. 2023. Wilson LM, Baker KE, Sharma R, Dukhanin V, McArthur K, Robinson KA. Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review. Int J Transgend Health. 2020;21(4):391–402. Nota NM, Dekker M, Klaver M, Wiepjes CM, van Trotsenburg MA, Heijboer AC, et al. Prolactin levels during short- and long-term cross-sex hormone treatment: an observational study in transgender persons. Andrologia. 2017;49(6). Gooren LJ, Harmsen-Louman W, van Kessel H. Follow-up of prolactin levels in long-term oestrogen-treated male-to-female transsexuals with regard to prolactinoma induction. Clin Endocrinol (Oxf). 1985;22(2):201-7. CEU F. FSRH CEU Statement: Contraceptive Options for Women with Prolactinoma (September 2012) 2012 [Available from: https://www.cosrh.org/Public/Documents/fsrh-ceu-statement-prolactinoma-sep-2012.aspx. Delgrange E, Trouillas J, Maiter D, Donckier J, Tourniaire J. Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab. 1997;82(7):2102-7. Yoo F, Chan C, Kuan EC, Bergsneider M, Wang MB. Comparison of Male and Female Prolactinoma Patients Requiring Surgical Intervention. J Neurol Surg B Skull Base. 2018;79(4):394–400. van Trigt VR, Bakker LEH, Pelsma ICM, Zandbergen IM, Jentus MM, Kruit MC, et al. The Changing Treatment Paradigm for Prolactinoma-A Prospective Series of 100 Consecutive Neurosurgical Cases. J Clin Endocrinol Metab. 2025;110(6):e1833-e44. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9008671","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":599197966,"identity":"63c5e276-940d-46c4-9a6e-69dd7a920b0b","order_by":0,"name":"Maaia Margo Jentus","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArElEQVRIiWNgGAWjYHCCBDDJzw7hyRCpBYgkmyE8HuItMjhMrBbdBoaHjwt/HLY3PsxjuuEHwzbCWswOMCQbz0g4nLjtMI/ZzR6G20RpSZPmSTicYAbUcpuBSC3pv4Fa7I2bSdCSxgzUwriBmWgthxmSpXnS0hNnHGYru9ljQIyW4z2Jn3lsrO3525u33fhRcVuOoBYGoKuQeAaENQAB+wGilI2CUTAKRsEIBgASWDZoek23DQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5724-7643","institution":"Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands","correspondingAuthor":true,"prefix":"","firstName":"Maaia","middleName":"Margo","lastName":"Jentus","suffix":""},{"id":599200587,"identity":"57834f90-a13a-4de1-95de-003d8fe47762","order_by":1,"name":"Iris Pelsma","email":"","orcid":"","institution":"Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; 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The three parts of clinical course are indicated with background colours. Abbreviations: CBG cabergoline, CPA cyproterone acetate, E2 oestradiol, MRI magnetic resonance imaging, PRL prolactin, RT radiotherapy, ULN upper limit of normal\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9008671/v1/2a83819006f96064fdb9a30e.png"},{"id":104178056,"identity":"afe14943-4384-492e-9848-3815e86f904c","added_by":"auto","created_at":"2026-03-08 16:51:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1881737,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCoronal pituitary imaging illustrating the prolactinoma changes over time.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLeft panels:\u003c/strong\u003e T2-weighted MRI. \u003cstrong\u003eRight panels:\u003c/strong\u003e T1-weighted MRI, unless stated otherwise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e Baseline (T=0), prolactin 285xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e Preoperative imaging (T=13) after cabergoline therapy, obtained following new onset symptoms compatible with pituitary apoplexy (T=13), prolactin 15.2xULN. Right panel shows CT imaging. No interval imaging had been performed since cabergoline initiation to assess interim tumor shrinkage under therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e Tumour remnants beneath the optic chiasm confirmed on first postoperative imaging (T=15). Prolactin 8.6xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e Tumour remnant progression with rising prolactin levels following oestrogen initiation (T=18), refractory to cabergoline reintroduction and dose escalation, prompting radiotherapy (T=18). Prolactin 128.4xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003e Stable tumour remnants after oestrogen withdrawal (T=20). Prolactin 43.6xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e Stable tumour remnants after radiotherapy and oestrogen reintroduction (T=33). Prolactin 5.5xULN\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9008671/v1/07ad1f06e4a8c9d0ef9be618.png"},{"id":104178057,"identity":"2e7c2410-4f71-4001-9383-5a529bb75437","added_by":"auto","created_at":"2026-03-08 16:51:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3615080,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHistopathology (Panels A-F) and Genome-Whole Imbalance-LOH-CNV plot (Panel G) of the prolactinoma.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA \u003c/strong\u003eVital and relatively intact tumour morphology with bleeding in the background (x40).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e Therapy changes as seen after therapy with dopamine agonists: stroma hyalinization, hyperchromatic nuclei and disrupted cytonuclear ratio (1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC \u003c/strong\u003eStrong nuclear positivity for PIT1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e Patchy heterogeneously cytoplasmatic expressed prolactin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE \u003c/strong\u003eSporadic weak tot moderately strong nuclear ERα expression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e Ki-67 proliferation index is low.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eG\u003c/strong\u003e Copy number variation (CNV) analysis revealed a complex pattern of chromosomal alterations as expected for prolactinomas (17). There were balanced gains of chromosomes 5, 7 and 9 with extrapolated genotypes AABB. There were imbalances due to copy number gain on chromosomes 1p; 3, 8, 12, 14, 15, 17, 18, 19, and 20 with extrapolated genotypes AAB/ABB. Loss of heterozygosity (LOH) was observed on chromosomes 16 due to whole chromosome loss with extrapolated genotype A0/B0 and copy number neutral LOH of chr. 21, genotype AA or BB. Chromosome X showing normal genotype A0/B0 as seen in male chromosomal sex.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-9008671/v1/a9a821a947ec335dd91befbd.png"},{"id":104403598,"identity":"2ee3d96b-2297-4226-ab7b-a8ceb118295a","added_by":"auto","created_at":"2026-03-11 12:18:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6997799,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9008671/v1/d73ae909-bebd-40aa-93b0-a8469402b837.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eProlactinoma Course and Management in Transgender Women: case report and systematic review\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Significance Statement ","content":"\u003cp\u003eThis study highlights the unique clinical challenges of managing prolactinomas in transgender women undergoing gender-affirming hormone therapy (GAHT). Oestrogen and cyproterone acetate may influence tumour behaviour, including reduction of dopamine-agonist responsiveness, yet no specific guidelines exist for this patient population. Clinical principles derived from cisgender care, such as the safety of oestrogen-containing contraceptives in microprolactinomas, cannot be directly applied. Baseline prolactin assessment before GAHT, prompt evaluation of symptoms, radiological evaluation of hyperprolactinemia and multidisciplinary care are essential. When medical therapy is insufficient, surgical debulking and radiotherapy may allow safe continuation of GAHT. Development of clinical guidelines or consensus statements dedicated to the management of pituitary conditions and GAHT, and further research are needed to optimise tumour control while preserving gender-affirming care.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eProlactinomas are the most common functioning pituitary neuroendocrine tumor (PitNET), accounting for ~\u0026thinsp;40% of all PitNETs, and typically present with symptomatic hyperprolactinemia (1). Clinical and biological features show sexual dimorphism: in cis-women prolactinomas often cause menstrual irregularities and infertility, whereas cis-men present with hypogonadism, including pubertal delay, sexual dysfunction, higher serum prolactin levels, and larger invasive tumours (2, 3). Galactorrhoea can occur in both sexes. The first-line treatment can be dopamine agonist therapy or surgery, depending on tumor size, clinical factors, and patient preference (4).\u003c/p\u003e \u003cp\u003eIn patients with gender dysphoria, the diagnosis and treatment of prolactinomas are more complex. Guidelines for gender-affirming hormone therapy (GAHT) outline how to transition individuals with typical male (46,XY) or female (46,XX) karyotypes and intact gonadal development to the opposite ends of the sex spectrum, not addressing intersex individuals. GAHT for transgender women (male-to-female, MtF) generally consists of oestrogen supplementation, often combined with the antiandrogen cyproterone acetate (CPA) before gender affirming surgery (GAS, orchidectomy) (5\u0026ndash;7). This combination induces feminizing physiological changes (8). Because estradiol stimulates pituitary lactotrophs, baseline and periodic serum prolactin measurements are recommended by several GAHT guidelines (5\u0026ndash;7, 9, 10). Mild hyperprolactinemia may occur during GAHT and usually resolves after reducing or discontinuing oestrogen or CPA (6), though this may conflict with gender-affirming goals. CPA is strongly linked to elevated serum prolactin levels (4, 11\u0026ndash;14). Persistent prolactin elevation despite stable or reduced oestrogen levels should prompt radiological evaluation for prolactinoma.\u003c/p\u003e \u003cp\u003eSeveral cases of transgender women on supraphysiologic oestrogen doses presenting with prolactinomas have fuelled debate on whether GAHT can trigger prolactinoma formation (12, 15, 16). However, there is no convincing evidence for increased incidence of symptomatic prolactinomas in transgender women (12).\u003c/p\u003e \u003cp\u003eThe Pituitary Society consensus statement on the management of prolactin-secreting pituitary adenomas includes a section on transgender women but lacks specific treatment recommendations [4]. Current strategies therefore rely on clinical expertise, and little is known about presentation, treatment, and biology of prolactinomas including pathophysiology of prolactin-axis in this population.\u003c/p\u003e \u003cp\u003eThis study aims to summarize all reported cases and present an alerting case with difficult management because of acute expansion of tumour mass and apoplexy. This surgically treated invasive macroprolactinoma that demonstrated unexpected tumour regrowth and rising prolactin levels upon oestrogen treatment, and (2) to highlight the gaps in current treatment guidance for prolactinomas in transgender women.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eWe describe the clinical trajectory of a transgender woman with a prolactinoma in three parts:\u003c/p\u003e\n\u003col style=\"list-style-type: upper-roman;\"\u003e\n \u003cli\u003eClinical diagnosis of prolactinoma and initial treatment;\u003c/li\u003e\n\u003c/ol\u003e\n\u003col style=\"list-style-type: upper-roman;\" start=\"2\"\u003e\n \u003cli\u003eApoplectic complication and emergency surgery, including the initiation of GAHT; and\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003col style=\"list-style-type: upper-roman;\" start=\"3\"\u003e\n \u003cli\u003eConsiderations in follow up including clinical course after radiotherapy.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe overall timeline of the disease is illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, while biochemical parameters and medication are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003cstrong\u003eI. Clinical diagnosis and initial treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 22-year-old adolescent with a female habitus, presented with a female voice, gynaecomastia (Tanner stage 2), prepubertal testicular volume (5 ml), underdeveloped external genitalia, and no evidence of androgen-dependent hair development (T\u0026thinsp;=\u0026thinsp;0, in months). Because of gender dysphoria and female appearance, referral to a clinical geneticist was initiated. Genetic testing showed a 46,XY karyotype. Biochemical evaluation revealed marked hyperprolactinemia (285xULN) accompanied by secondary hypogonadism (luteinizing and follicle-stimulating hormones suppressed and testosterone\u0026thinsp;\u0026lt;\u0026thinsp;0.5 nmol/L) and secondary hypothyroidism. Dedicated pituitary MRI demonstrated (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA\u003cstrong\u003e)\u003c/strong\u003e a large pituitary mass (39.9 mm) with suprasellar extension and complete (360\u0026deg;) encasement of the left internal carotid artery. Visual field testing showed no deficits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLeft panels\u003c/strong\u003e: T2-weighted MRI. \u003cstrong\u003eRight panels\u003c/strong\u003e: T1-weighted MRI, unless stated otherwise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e Baseline (T\u0026thinsp;=\u0026thinsp;0), prolactin 285xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e Preoperative imaging (T\u0026thinsp;=\u0026thinsp;13) after cabergoline therapy, obtained following new onset symptoms compatible with pituitary apoplexy (T\u0026thinsp;=\u0026thinsp;13), prolactin 15.2xULN. Right panel shows CT imaging. No interval imaging had been performed since cabergoline initiation to assess interim tumor shrinkage under therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e Tumour remnants beneath the optic chiasm confirmed on first postoperative imaging (T\u0026thinsp;=\u0026thinsp;15). Prolactin 8.6xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e Tumour remnant progression with rising prolactin levels following oestrogen initiation (T\u0026thinsp;=\u0026thinsp;18), refractory to cabergoline reintroduction and dose escalation, prompting radiotherapy (T\u0026thinsp;=\u0026thinsp;18). Prolactin 128.4xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003e Stable tumour remnants after oestrogen withdrawal (T\u0026thinsp;=\u0026thinsp;20). Prolactin 43.6xULN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e Stable tumour remnants after radiotherapy and oestrogen reintroduction (T\u0026thinsp;=\u0026thinsp;33). Prolactin 5.5xULN\u003c/p\u003e\n\u003cp\u003eAfter initiation of cabergoline treatment (T\u0026thinsp;=\u0026thinsp;1) and decrease in prolactin values from initial 285xULN to 3.3xULN, the patient reported depressive symptoms and mood fluctuations related to distress over ongoing physical changes, including spontaneous erections, and fear of further virilization. In this context, cyproterone acetate (CPA) was added at a low dose of 10 mg (T\u0026thinsp;=\u0026thinsp;3) to suppress male pubertal development upon recovering hypogonadism. Following cabergoline dose escalation, serum prolactin levels decreased markedly but did not normalize, reaching a nadir of 15xULN at a dose of 2 mg/week (T\u0026thinsp;=\u0026thinsp;12\u0026ndash;13).\u003c/p\u003e\n\u003cp\u003eAt T\u0026thinsp;=\u0026thinsp;13, the patient presented to the emergency department with progressive visual disturbances over 3\u0026ndash;4 days, and headache for one week, raising suspicion of apoplexy or volume expansion. Ophthalmological assessment revealed severe bilateral visual field loss with reduced visual acuity on the left side, without other neurological deficits. MRI demonstrated lower T2 signal intensity within the tumour compared to prior imaging (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB\u003cstrong\u003e)\u003c/strong\u003e. The lesion measured 37.3 mm and appeared slightly smaller, without clear radiological evidence of apoplexy. Because no interval MRI had been performed between cabergoline initiation and presentation, interim tumor shrinkage could not be assessed. In the context of acute symptoms and a sudden decline in serum prolactin levels, pituitary apoplexy was clinically suspected, suggesting acute volume expansion after prior tumor reduction. The patient was urgently referred for emergency endoscopic transsphenoidal surgery.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical parameters prior to referral (regional hospital)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"10\"\u003e\n \u003cp\u003eT= (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e10\u0026ndash;11\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProlactin, xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e285\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTestosterone, nmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCabergoline, mg/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5 to 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCyproterone acetate, mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI tumour size, mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"11\"\u003eAbbreviations: MRI magnetic resonance imaging, ULN upper limit of normal\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eII. Emergency Surgery (T\u0026thinsp;=\u0026thinsp;13) and Commencement of Gender-Affirming Hormone Therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePituitary apoplexy was suspected by pituitary care team based on the acute onset of visual field loss and reduced visual acuity, new corticotropic axis deficiency, and a sudden decline in serum prolactin levels.\u003c/p\u003e\n\u003cp\u003eDuring endoscopic transsphenoidal surgery, intraoperative findings confirmed intratumoral haemorrhage consistent with an apoplexy. The tumour infiltrated the dura and the left cavernous sinus and was markedly adherent to the left optic nerve and the inferior surface of the optic chiasm. Because of firm adhesion to critical neurovascular structures, a small remnant was intentionally left adjacent to the left posterior communicating artery and the underside of the optic chiasm. Resection within the left cavernous sinus was attempted but could not be safely completed.\u003c/p\u003e\n\u003cp\u003eHistopathological examination (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) confirmed a lactotroph pituitary neuroendocrine tumour (PitNET) of PIT1-lineage with extensive haemorrhage and dopamine agonist-related changes such as stromal hyalinization, fibrosis, patchy immunohistochemical prolactin expression, and altered nuclear-cytoplasmic ratio. Ki-67 proliferation index was \u0026lt;\u0026thinsp;1%. There was no co-expression of other pituitary hormones, and tumour granulation subtype could not be determined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e Vital and relatively intact tumour morphology with bleeding in the background (x40).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e Therapy changes as seen after therapy with dopamine agonists: stroma hyalinization, hyperchromatic nuclei and disrupted cytonuclear ratio (1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e Strong nuclear positivity for PIT1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e Patchy heterogeneously cytoplasmatic expressed prolactin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003e Sporadic weak tot moderately strong nuclear ER\u0026alpha; expression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e Ki-67 proliferation index is low.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eG\u003c/strong\u003e Copy number variation (CNV) analysis revealed a complex pattern of chromosomal alterations as expected for prolactinomas (17). There were balanced gains of chromosomes 5, 7 and 9 with extrapolated genotypes AABB. There were imbalances due to copy number gain on chromosomes 1p; 3, 8, 12, 14, 15, 17, 18, 19, and 20 with extrapolated genotypes AAB/ABB. Loss of heterozygosity (LOH) was observed on chromosomes 16 due to whole chromosome loss with extrapolated genotype A0/B0 and copy number neutral LOH of chr. 21, genotype AA or BB. Chromosome X showing normal genotype A0/B0 as seen in male chromosomal sex.\u003c/p\u003e\n\u003cp\u003eTwo months after surgery, the first postoperative MRI (T\u0026thinsp;=\u0026thinsp;15, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC) confirmed small tumour remnants in the left cavernous sinus (6x6 mm) and beneath the optic chiasm (1x4 mm). Serum prolactin remained mildly elevated (8.6xULN). In shared decision-making, considering side effects and concerns regarding testosterone rebound, cabergoline therapy \u0026ndash; stopped pre-operatively \u0026ndash; was not reintroduced. Following this evaluation, transdermal oestradiol therapy was initiated (100 \u0026micro;g patches, twice weekly) to induce feminization in accordance with the patient\u0026rsquo;s wishes.\u003c/p\u003e\n\u003cp\u003eThree months later (T\u0026thinsp;=\u0026thinsp;18), prolactin levels had increased to 128.4xULN, and ophthalmologic assessment revealed progression of visual field defects compared to T\u0026thinsp;=\u0026thinsp;15 but still improved relative to preoperative findings at T\u0026thinsp;=\u0026thinsp;13. MRI (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD) showed marked growth of the suprasellar tumour remnant (8x18 mm) compressing the left optic tract and slight volume increase of the residual lesion in the left cavernous sinus. Cabergoline therapy was reintroduced (0.5 mg twice weekly, increased to three times weekly), but prolactin reduction was insufficient (74.7xULN). Oestradiol therapy was therefore discontinued (T\u0026thinsp;=\u0026thinsp;19). One month later (T\u0026thinsp;=\u0026thinsp;20), prolactin levels declined to 43.6xULN, and MRI confirmed stable tumour remnants without further growth (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eE).\u003c/p\u003e\n\u003cp\u003ePathologic reassessment was requested. The tumour showed variable ER\u0026alpha; expression (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eE) and was negative for progesterone receptor (not shown). No areas with increased Ki-67 proliferation index were identified. Oncomine comprehensive Array Plus detected a pathogenic inactivating variation in \u003cem\u003eARID1A\u003c/em\u003e c.4005-2A\u0026thinsp;\u0026gt;\u0026thinsp;G and no alterations in \u003cem\u003eTP53\u003c/em\u003e, \u003cem\u003eSF3B1\u003c/em\u003e, \u003cem\u003eSDH\u003c/em\u003ex, \u003cem\u003eDAXX\u003c/em\u003e, \u003cem\u003eMEN1\u003c/em\u003e, or \u003cem\u003ePRKAR1A\u003c/em\u003e. The tumour had low tumour mutational burden (TMB), was microsatellite stable (MSS) and homologous-recombination proficient (HRP). Copy-number variation analysis revealed a complex pattern of chromosomal alterations (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eG).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical parameters pre- and postoperatively and prior to radiotherapy\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003eT= (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProlactin, xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.2\u0026ndash;2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.7\u0026ndash;4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.6\u0026ndash;14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e128.4\u0026ndash;49.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.0\u0026ndash;74.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60.3\u0026ndash;43.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40.5\u0026ndash;44.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConfirmation of tumour remnants: left sinus cavernosus (6x6 mm) and suprasellar on chiasma (1x4 mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuprasellar remnant enlarged to 8x18 mm, the left sinus cavernosus remnant slightly enlarged.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo tumour growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical management\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStop CBG.\u003c/p\u003e\n \u003cp\u003eTSS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStop CPA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStart E2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReintroduction of CBG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStop E2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReferral to radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCabergoline, mg/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCyproterone acetate, mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEstradiol plaster, \u0026micro;g/24 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eAbbreviations: CBG cabergoline, CPA cyproterone acetate, E2 estradiol, MRI magnetic resonance imaging, TSS transsphenoidal surgery, pre-op preoperatively, post-op postoperatively, ULN upper limit of normal\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eIII. Considerations in follow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter oestradiol withdrawal, prolactin levels declined but remained elevated (nadir 20xULN) on cabergoline 0.5 mg/week. Because of severe cabergoline-related side effects and the patient\u0026rsquo;s wish to resume oestrogen therapy, radiotherapy was considered, given the relative contraindication to oestrogen reinitiation due to prior tumour growth. Antiandrogen therapy was unnecessary due to pituitary-gonadal axis failure.\u003c/p\u003e\n\u003cp\u003eFractionated radiotherapy was administered to a total dose of 50.4 Gy in 28 fractions of 1.8 Gy (T\u0026thinsp;=\u0026thinsp;24\u0026ndash;26), while cabergoline was continued at 0.5 mg/week. Serum prolactin levels remained stable following treatment (16xULN directly post-radiotherapy; 19.7xULN one month later). The first post-radiotherapy MRI (T\u0026thinsp;=\u0026thinsp;28) demonstrated unchanged residual tumour volumes.\u003c/p\u003e\n\u003cp\u003eBased on these findings, transdermal oestradiol was cautiously reintroduced (50 \u0026micro;g/24 hours). Prolactin levels initially increased (38.2xULN at one month, 43xULN at two months) \u0026ndash; but subsequently stabilized (27.9xULN) three months after reinitiation. A follow-up MRI performed five months after oestradiol reintroduction (T\u0026thinsp;=\u0026thinsp;33, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eF) showed no evidence of tumour growth.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical parameters during and after the radiotherapy and oestrogen therapy reintroduction\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003eT= (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProlactin xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo tumour growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo tumour growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo tumour growth\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical management\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRT 50.4 Gy divided in 28 fractions of 1.8 Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRT completed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReinitiation E2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCabergoline, mg/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOestradiol plaster, \u0026micro;g/24 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eAbbreviations: E2 oestradiol, MRI magnetic resonance imaging, PRL serum prolactin, RT radiotherapy, ULN upper limit of normal\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eLiterature review\u003c/h2\u003e\n \u003cp\u003eA systematic literature search was performed in PubMed/MEDLINE and Google Scholar to identify previously reported cases of prolactinoma in transgender women. The search was conducted up to November 2025 using combinations of full terms or root words including \u0026ldquo;prolactinoma\u0026rdquo; or \u0026ldquo;pituitary adenoma\u0026rdquo; and \u0026ldquo;transgender\u0026rdquo; or \u0026ldquo;transsexual\u0026rdquo;. The terms \u0026ldquo;recommendations,\u0026rdquo; \u0026ldquo;guidelines\u0026rdquo; or \u0026ldquo;management\u0026rdquo; were additionally used to identify publications addressing clinical management strategies for prolactinoma in transgender women. Reference lists of relevant articles were screened to identify additional eligible reports.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSummary of the previously reported cases\u003c/h3\u003e\n\u003cp\u003eTo date, 24 transgender women diagnosed with prolactinoma have been reported (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea, \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb, \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ec), including the present case. Notably, the patient reported by Serri et al. is an individual with Klinefelter syndrome.\u003c/p\u003e\n\u003cp\u003eThe vast majority of cases were diagnosed during GAHT treatment (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea, \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb). The current patient and a patient reported by Gersey et al. (18), had known macroprolactinoma prior GAHT (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ec).\u003c/p\u003e\n\u003cp\u003eIn most (19/24) cases, prolactin levels prior to GAHT-initiation were unknown. Although symptomatology suggests, it is impossible to determine whether these patients already had hyperprolactinemia or asymptomatic prolactinoma prior GAHT. Most individuals had received long-term GAHT, with regimens including high-dose oestrogens and antiandrogens, predominantly CPA at very high doses (100\u0026ndash;150 mg), far exceeding current recommendations. The time to prolactinoma diagnosis varied from a few months to several decades after initiation of GAHT. Fourteen of twenty-two prolactinomas were detected because of symptomatic hyperprolactinemia, six were asymptomatic and were detected by biochemical screening. The symptomatic status was not reported in two patients. Seven of ten macroadenomas and seven of twelve microprolactinomas were symptomatic.\u003c/p\u003e\n\u003cp\u003eSixteen patients were treated with dopamine agonists following diagnosis. Among them, five continued GAHT upon DA initiation (12, 15, 16, 19, 20) and five discontinued GAHT with reported reintroduction in four patients (15, 16, 21, 22), and one did not re-introduce GAHT (23).\u003c/p\u003e\n\u003cp\u003eFor six patients, it was not specified whether GAHT was discontinued at the time of dopamine-agonist initiation (12, 24, 25).\u003c/p\u003e\n\u003cp\u003eOne of the patients continuing GAHT upon DA therapy showed persistent tumour growth despite falling prolactin levels (20). This patient underwent elective total resection surgery, normalizing prolactin levels, and she continued GAHT.\u003c/p\u003e\n\u003cp\u003eSix patients did not receive DA. All had small lesions (\u0026lt;\u0026thinsp;10 mm), of whom half were asymptomatic.\u003c/p\u003e\n\u003cp\u003eOne symptomatic patient discontinued GAHT prior to TSS, with lactotroph hyperplasia identified on histopathological examination (26). Postoperative prolactin levels were not reported, and it remains unknown whether GAHT was reinitiated. Three patients were managed conservatively (wait-and-see), including two patients with symptomatic and one patient with asymptomatic hyperprolactinemia (12). In one asymptomatic patient, oestrogen cessation was the only intervention. In another patient, thyroid hormone substitution was initiated for hypothyroidism, a potential cause of hyperprolactinemia (12). No follow-up data were reported for the latter five patients.\u003c/p\u003e\n\u003cp\u003eBeside current study, three patients were operated, and histopathology was reported in varying detail (18, 20, 26).\u003c/p\u003e\n\u003cp\u003eThe review of previous reported cases illustrates the baseline heterogeneity of clinical parameters and further management strategies.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ea. Prolactinomas in transgender women: normal prolactin levels prior initiation of gender affirming hormone therapy (GAHT).\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAuthor, year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGender affirming therapy details\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eProlactinoma diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eManagement of prolactinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum prolactin upon GAHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRadiology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecision\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eResults\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eGooren et al.,1988 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e10 months\u003c/span\u003e: CPA 100 mg/day,\u003c/p\u003e\n \u003cp\u003eEE 100 \u0026micro;g p.o./day\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e~\u0026thinsp;6\u0026ndash;10 months\u003c/span\u003e: surreptitiously E17U 100 mg, i.m. 2x/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e17xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eAt 9.5 months CT:10 mm height with suprasellar extension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinuation of all E.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlasma E2 from 2.8 to 0.77 nmol/L\u003c/p\u003e\n \u003cp\u003ePRL 21xULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC 2.5 mg twice daily.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePRL1.4xULN.\u003c/p\u003e\n \u003cp\u003eCT after 5 months: reduction in tumour size.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC stop, E not resumed.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u0026thinsp;4 months: plasma E2 0.08 nmol/L, PRL 15xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eBunck et al., 2009 (19), Nota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStart\u003c/span\u003e: CPA 100 mg/day, EE 100 \u0026micro;g/day.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e2.5 years\u003c/span\u003e: GAS, stop CPA.\u003c/p\u003e\n \u003cp\u003e17bE 50 \u0026micro;g/day, topical patches.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e5 years\u003c/span\u003e: skin irritation, switch to\u003c/p\u003e\n \u003cp\u003ep.o. CEE 1.25 mg/day.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e7 years\u003c/span\u003e: chloasma, CEE reduction to 0.625 mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eIn the first year\u003c/span\u003e: up to 3.3xULN, normalized 6 months after.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAt 15 years\u003c/span\u003e: 6.1xULN.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eDuring investigation\u003c/span\u003e (E pause): 7.6xULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMRI: 8 mm lesion, no chasm compression.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQuinagolide\u003c/p\u003e\n \u003cp\u003e75 \u0026micro;g/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUndetectable PRL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAt 19th year: quinagolide stop\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFU 20 years: normal PRL.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"5\"\u003e\n \u003cp\u003eGarcia-Malpartida et al., 2010 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"5\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCPA 100 mg/day\u003c/p\u003e\n \u003cp\u003eCEE 2.5 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e3 months\u003c/span\u003e: 3.5xULN\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e6 months\u003c/span\u003e: 6.4-6.9x ULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMastodynia, migraine, asthenia, b/l\u003c/p\u003e\n \u003cp\u003egalactorrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI: sellar floor erosion, 5x4x4 mm lesion with decreased uptake that displaced the carotid siphon.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInterruption of GAHT.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 months later: PRL 5.4xULN, gradual reduction of the symptoms.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\" rowspan=\"4\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStart CBG 0.5 mg 2x/week.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months later: normal PRL.\u003c/p\u003e\n \u003cp\u003eMRI: tumour size reduction.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCessation of CBG.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 months later: PRL 3.7xULN\u003c/p\u003e\n \u003cp\u003eE2 31 pg/mL.\u003c/p\u003e\n \u003cp\u003eMRI: stabilization of the tumour size.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRe-start CBG. GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 months later: normal PRL.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStop DA after GAS. GAHT resumed: low-dose transdermal E2 patches, no CPA.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsymptomatic, PRL: normal to 1.6 ULN, appropriate 17bE and testosterone. MRI: stable.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003eAbbreviations: b/l bilateral, BRC bromocriptine, CBG cabergoline, CEE conjugated equine oestrogens, CPA cyproterone acetate, DA dopamine agonist, E oestrogen not other specified, E2 oestradiol not other specified, E17bE oestradiol 17b-enanthate, E17U oestradiol-17-undecanoate, EE ethinyl oestradiol, E2V oestradiol valerate, FU follow up, GAS gender-affirming surgery, GDX gonadectomy, GAHT gender-affirming hormone therapy, HPRL hyperprolactinemia, i.m. intramuscular, LT4 L-thyroxine, MPA medroxyprogesterone acetate, MRI magnetic resonance imaging, n/a not available, p.o. per os (peroral), PRL serum prolactin, SPL spironolactone, TSS transsphenoidal surgery\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eb. Prolactinomas in transgender women: Prolactin levels pre-GAHT unknown\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAuthor, year\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGender affirming therapy details\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eProlactinoma diagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eManagement of prolactinoma\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSerum prolactin upon GAHT\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRadiology\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDecision\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eResults\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eKovacs et al., 1994 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eDiethylstilbesterol starting at 16 years.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e4 years later\u003c/span\u003e: GAS, switch to conjugated p.o. E 0.625 mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e5.7xULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003eB/l galactorrhoea at time of GAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT: 9 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC upon E, intolerance above 2.5mg daily.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u0026thinsp;10 months: PRL1.9xULN, the tumour size increased despite BRC.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI: 12 x 10 mm\u003c/p\u003e\n \u003cp\u003eon the left side\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSelective TSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-op: Normal PRL.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEE 40 \u0026micro;g/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1-year post-op: PRL remained normal.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eSerri et al., 1996 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAt age of 20\u003c/span\u003e: Klinefelter syndrome diagnosis.\u003c/p\u003e\n \u003cp\u003eGAS.\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePost-GAS, 4 years\u003c/span\u003e:\u003c/p\u003e\n \u003cp\u003eEE 1.5 mg/day,\u003c/p\u003e\n \u003cp\u003eCPA 150 mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003en/a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003eLast 3 years: 9 kg weight gain, headache, fatigue, b/l galactorrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMRI: 4 mm left sided lesion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCessation of E.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAt 3\u0026ndash;10 days: 24xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTSS: nodular lesion 3\u0026ndash;4 mm fragment.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMicroscopy: hyperplasia with intact reticuline.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFutterweit, 1998 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.2xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInitiation of BRC and SPL.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFollow-up MRI: no evidence of tumour.\u003c/p\u003e\n \u003cp\u003eNormal PRL.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eBunck et al., 2009 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eEE 50 \u0026micro;g/day, 30 years.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e133xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" rowspan=\"3\"\u003e\n \u003cp\u003eSudden onset of double vision. Right sided III palsy, no visual field defect.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eMRI: large tumour with right cavernous sinus invasion and contact to chiasma.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG 0.25 mg/2x week.\u003c/p\u003e\n \u003cp\u003eLT4 50 \u0026micro;g/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u0026thinsp;10 days: PRL 22 ULN\u003c/p\u003e\n \u003cp\u003eIII nerve palsy resolved, tumour shrank, no invasion of chiasmatic cistern and the right cavernous sinus.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRefused to stop EE treatment, continued CBG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum PRL returned to normal and remained normal for 8 years FU, the tumour has never increased in size again.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStop CBG, EE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal PRL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCunha et al., 2015 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eReferred for GAHT and GAS. Non-supervised\u003c/p\u003e\n \u003cp\u003eE treatment since age of 23 years: contraceptive pill EE 35 \u0026micro;g/day, CPA 2 mg/day, i.m. E2V 5 mg/week alternating with i.m. E17bE 10 mg/week, total 8 doses. Then, i.m. E17bE 10 mg every 15 days for 16 years.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e35xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003eSpontaneous galactorrhoea b/l.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eMRI: 8 mm left-sided lesion,\u003c/p\u003e\n \u003cp\u003ewithout diffuse enlargement of\u003c/p\u003e\n \u003cp\u003ethe pituitary gland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG 0.5 mg twice weekly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAt 3 months: normal PRL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eE reintroduction (no information of pause timepoint): CEE 0.625 mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI 8 months after start CBG: lesion identical to the pre-treatment image.\u003c/p\u003e\n \u003cp\u003eNormal PRL.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eCunha et al., 2015 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReferral for GAHT and GAS.\u003c/p\u003e\n \u003cp\u003eSince the age of 17 years: E17bE 10 mg i.m. every 15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMild galactorrhoea b/l.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI: 15 x 13 mm lesion with a central cystic area\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG 1 mg/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u0026thinsp;5 months, normal PRL under continuous use of CEE 1.25 mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG FU 1 year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI: slight reduction of the tumour size, especially in the cystic central area.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG continued for 2 years.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal PRL.\u003c/p\u003e\n \u003cp\u003eMRI: normal dimensions, delayed contrast uptake in dynamic sequence, suggesting a microadenoma.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJehangir, 2016 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGAS incl. E pellet breast and buttock implants. E injections for 2 years.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCa. 57xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBreast tenderness, galactorrhoea.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI: 25 x 22 x 23 mm.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG (dose n/a)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u0026thinsp;3 months: PRL ca. 4.8xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026plusmn;\u0026thinsp;4 years CPA 100 mg/day, E2 injection 100 mg/2weeks, GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;microadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStop E\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026plusmn;\u0026thinsp;14 years CPA 100 mg/day, conjugated E 2.5 mg/day, GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;microadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLT4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026plusmn;\u0026thinsp;13 years CPA and E2 injection (doses n/a), no GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGalactorrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;microadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026plusmn;\u0026thinsp;5.5 years CPA 100 mg/day, EE 100 mg/day, no GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;microadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWait-and-see\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGAHT duration probably\u0026thinsp;\u0026gt;\u0026thinsp;9 months. CPA 100 mg/day, no GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;microadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026plusmn;\u0026thinsp;7.5 years CPA 100 mg/day, EE 100 mg/day, GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGalactorrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;microadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWait-and-see\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026plusmn;\u0026thinsp;12 years EE 50\u0026ndash;100 mg/day, GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGalactorrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;microadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWait-and-see\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNota et al., 2018 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026plusmn;\u0026thinsp;11 years CPA 50 mg/day, E2V 2 mg/day, GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHPRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGalactorrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ldquo;macroadenoma\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eRaven et al., 2021 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e5-years prior: subdermal E2\u003c/p\u003e\n \u003cp\u003eimplants 6\u0026ndash;12 monthly, MPA and SPL. No GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e27xULN,\u003c/p\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eWithin 3-months of GAHT\u003c/span\u003e: elevated PRL. \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eNext 18 months\u003c/span\u003e: low-level HPRL, then exponential increase.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003eSpontaneous\u003c/p\u003e\n \u003cp\u003egalactorrhoea after 2-years of GAHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGAHT reduction\u003cem\u003e/temporary\u003c/em\u003e suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePRL: 10.6xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA right sided\u003c/p\u003e\n \u003cp\u003e10\u0026times;6mm lesion within the sella. A second lesion 5 \u0026times; 3 mm in the left lobe. Cystic changes within both lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG 0.5 mg/week.\u003c/p\u003e\n \u003cp\u003eMPA and SPL re-start.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFollowing 3 months: PRL within normal limits, galactorrhoea resolved.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRaven et al., 2021 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 years prior: combination of EE and CPA (doses n/a).\u003c/p\u003e\n \u003cp\u003eAt referral: E2 50 \u0026micro;g topical patch 2x/week. CPA 50 mg/day. No GAS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20xULN.\u003c/p\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;10 years: persistent HPRL independent\u003c/p\u003e\n \u003cp\u003eof serum E2 concentrations.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGalactorrhoea b/l\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.7 \u0026times; 12 mm within the sella.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG 0.5 mg/week, GAHT uninterrupted.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFollowing 3 months: normal PRL, galactorrhoea resolved.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHarned and Harper, 2021 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eE p.o. for six years (dose n/a).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGalactorrhoea b/l.\u003c/p\u003e\n \u003cp\u003eNew onset: tunnel vision, extremity\u003c/p\u003e\n \u003cp\u003eparaesthesia for one day. Visual fields intact.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 x 13 x 13 mm.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC 5mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 months later: galactorrhoea resolved, normal PRL.\u003c/p\u003e\n \u003cp\u003eMRI (at 1 and 3 years): no significant decrease in tumour size.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eChow and Rajpal, 2025 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eE2 8 mg/day, progesterone 200 mg/day, and SPL 400 mg/day for the last 10 years.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.7xULN on\u003c/p\u003e\n \u003cp\u003eroutine evaluation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e11 mm pituitary tumour abutting\u003c/p\u003e\n \u003cp\u003ethe right cavernous sinus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eE2 and progesterone discontinuation.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months: PRL 6xULN. Evaluation by neurosurgery \u0026ndash; deferred intervention.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG initiation gradually up titrated to 0.25mg x3 weekly.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMRI 6 months after initial presentation: tumour shrinkage to 0.6 cm.\u003c/p\u003e\n \u003cp\u003eRepeatedly undetectable PRL levels 2 months after CBG initiation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRe-initiation E2 2mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlan to closely monitor PRL levels and repeat MRI 6\u0026ndash;9 months afterwards.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"9\"\u003e\n \u003cp\u003eb/l bilateral, BRC bromocriptine, CBG cabergoline, CEE conjugated equine oestrogens, CPA cyproterone acetate, DA dopamine agonist, E oestrogen not other specified, E2 oestradiol not other specified, E17bE oestradiol 17b-enanthate, E17U oestradiol-17-undecanoate, EE ethinyl oestradiol, E2V oestradiol valerate, FU follow up, GAS gender-affirming surgery, GDX gonadectomy, GAHT gender-affirming hormone therapy, HPRL hyperprolactinemia, i.m. intramuscular, LT4 L-thyroxine, MPA medroxyprogesterone acetate, MRI magnetic resonance imaging, n/a not available, p.o. per os (peroral), PRL serum prolactin, SPL spironolactone, TSS transsphenoidal surgery.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ec. Prolactinomas in transgender women: prolactinomas diagnosed prior to GAHT initiation\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAuthor, year\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eGender affirming therapy details\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eProlactinoma diagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eManagement of prolactinoma\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline serum prolactin\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRegimen\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSerum prolactin upon GAHT\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRadiology\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDecision\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eResults\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGersey at al., 2025 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e104xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\" rowspan=\"4\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003eLow libido, erectile dysfunction, hot flashes, fatigue, breast tenderness, hypogonadotropic hypogonadism.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e22 \u0026times; 17 \u0026times; 15 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBG initiation: 0.25 mg twice weekly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSide effects\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\" rowspan=\"12\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTransition to BRC 1.25 mg/d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAt one month: PRL 19xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC to 2.5 mg/d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePRL 6.6xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC to 5 mg/d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNadir PRL 1.6xULN.\u003c/p\u003e\n \u003cp\u003eAfter 6 months: PRL remained elevated, the tumour size decreased.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh-dose weekly i.m. E2V\u0026thinsp;+\u0026thinsp;finasteride 5 mg/d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUp to 8.8xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"4\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdjusted E therapy, transition from finasteride to SPL 50 mg/x2d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRange 8.8\u0026ndash;17xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eE reduction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eContinuous rise, peak 31xULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC to 7.5 mg twice daily\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 \u0026times; 12 \u0026times; 12 mm with slight CS extension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRC stop.\u003c/p\u003e\n \u003cp\u003eCBG initiation and stop (severe side effects).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePersistent PRL elevation, the patient opted for TSS with medial CS wall resection after multidisciplinary discussion.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"5\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 weeks pre-op: SPL and E stop.\u003c/p\u003e\n \u003cp\u003e5 days pre-op: BRC stop.\u003c/p\u003e\n \u003cp\u003eA total tumour resection with the medial wall of the left CS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-op day 1: normal PRL, discharged home.\u003c/p\u003e\n \u003cp\u003ePost-op day 7: PRL 1.1xULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 weeks post-op: SPL and E reinitiation, PRL levels and imaging monitoring (whether BRC reinitiation was necessary).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTwo months after resuming E and SPL: PRL 3.1xULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePRL monitoring, no treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo symptoms. MRI at 3 months: no residual tumour. By 4 months: PRL up to 5.1xULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eE pause for GAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePRL dropped to 2xULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eResume E\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePRL up to 3.5 ULN.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThis study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003eSee Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"9\"\u003e\n \u003cp\u003eb/l bilateral, BRC bromocriptine, CBG cabergoline, CPA cyproterone acetate, CS cavernous sinus E oestrogen not other specified, E2 estradiol not other specified, E2V estradiol valerate, GAS gender-affirming surgery, GAHT gender-affirming hormone therapy, i.m. intramuscular, MRI magnetic resonance imaging, p.o. per os (peroral), post-op postoperatively, PRL serum prolactin, pre-op preoperatively, SPL spironolactone, TSS transsphenoidal surgery, ULN upper limit of normal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eSummary of the guidelines and recommendations\u003c/h3\u003e\n\u003cp\u003eAs oestrogen may increase prolactin levels, measurement of baseline serum prolactin before initiating GAHT is universally recommended in the context of initial endocrinological assessment. Oestrogen combined with CPA is associated with higher prolactin levels, an effect not observed when oestrogens are combined with GnRH agonists or spironolactone (7). CPA alone is associated with dose-dependent prolactin elevation (12, 28). In recent years, antiandrogen therapy increasingly shifts from CPA toward GnRH agonists or spironolactone, and when CPA is used, substantially lower doses (typically 10\u0026ndash;25 mg daily) are now recommended. Mild, transient, and asymptomatic hyperprolactinemia has no clinical consequence.\u003c/p\u003e\n\u003cp\u003eInternational standards of transgender care advise clinicians to make individualized decisions based on hormone regimen and symptoms of hyperprolactinemia or a pituitary tumour (7). Prolactin levels should be evaluated at baseline along with other relevant laboratory parameters. This assessment may be challenging when hormone therapy is initiated via online sources or remote consultations without comprehensive endocrine evaluation.\u003c/p\u003e\n\u003cp\u003e(Inter)national guidelines differ on monitoring frequency and thresholds for imaging or intervention:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eEndocrine Society (USA): baseline prolactin measurement, then annually during transition and every two years thereafter (6). MRI is indicated for rising prolactin despite stable or reduced oestrogen levels.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eFrench Society of Paediatric Endocrinology and Diabetology Consensus: baseline prolactin measurement, then every 12 months or every 6 months after each dose adjustment, monitoring may stop after several stable results (10). MRI is considered when hyperprolactinemia worsens over successive controls.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eCanadian Standards of Care: baseline and annual prolactin measurement when CPA is used; more frequent measurements if prolactin is elevated and 6\u0026ndash;8 weeks after medication adjustments (9). For levels\u0026thinsp;\u0026gt;\u0026thinsp;2.4-2.8xULN switch to spironolactone before reducing oestrogen; imaging if persistent\u0026thinsp;\u0026gt;\u0026thinsp;3.2xULN or symptomatic.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eUCSF (University of California, San Francisco) Guidelines: no routine screening in asymptomatic patients; testing only for new onset headaches, visual disturbances, or excessive galactorrhoea (29).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eAustralian Approach: confirm hyperprolactinemia with repeat testing and exclude other causes (30). For mild hyperprolactinemia (1.2-4xULN), lower CPA or switch to alternative anti-androgen and re-assess. Pituitary MRI and/or workup is advised when prolactin reaches 4\u0026ndash;6xULN.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe Pituitary Society International Consensus Statement (4) on diagnosis and management of prolactin-secreting pituitary tumours acknowledges mild prolactin elevation in transgender women on GAHT but does not provide specific treatment recommendations for transgender women with prolactinomas.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eProlactinomas \u0026ndash; histologically corresponding to a lactotroph PitNET \u0026ndash; are the most common hormonally active PitNET and typically express ERα (1). Baseline prolactinoma prevalence differs between sexes, and transgender women (assigned male at birth) may, upon oestrogen therapy, adopt a risk profile more closely resembling that of cisgender women.\u003c/p\u003e\n\u003ch3\u003eGAHT and new-onset hyperprolactinemia\u003c/h3\u003e\n\u003cp\u003eElevations in serum prolactin during feminizing GAHT are well documented and are generally attributed to oestrogen and CPA effects rather than de novo tumorigenesis (31\u0026ndash;35). Elevations of serum prolactin are observed in up to 20% of transgender women receiving oestrogens, sometimes accompanied by pituitary enlargement (6). These changes are often biochemical and are not accompanied by radiological evidence of adenoma.\u003c/p\u003e \u003cp\u003eEarlier antiandrogen regimens frequently included high-dose CPA (\u0026ge;\u0026thinsp;100 mg/day), which is independently associated with dose-dependent prolactin elevation. Contemporary practice favours GnRH agonists or spironolactone, and when CPA is used, substantially lower doses (typically 10\u0026ndash;20 mg daily) are recommended, potentially reducing the incidence of hyperprolactinemia.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGAHT, prolactinoma detection, and incidence\u003c/h2\u003e \u003cp\u003eThe association between feminizing GAHT and prolactinoma formation remains uncertain. Existing literature consists mostly of isolated case reports, often involving supraphysiologic oestrogen exposure. The largest study to date, conducted by Nota et al.(12), identified nine prolactinomas over 23,935 person-years (risk of 0.04% per person-year). While this incidence appears higher than in the general male population, it was comparable to female incidence when adjusted for symptomatic presentation.\u003c/p\u003e \u003cp\u003eThese findings suggest that intensified biochemical monitoring in transgender women likely contributes to increased prolactinoma detection. To date, 24 prolactinoma cases have been reported in transgender women, including the present case. Notably, six patients were asymptomatic, and symptom documentation lacked in two, supporting the hypothesis of incidental detection through routine monitoring. However, the absence of baseline prolactin measurements in many reports limits conclusions regarding whether hyperprolactinemia or asymptomatic prolactinomas predated GAHT.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGAHT and pre-existing prolactinomas\u003c/h3\u003e\n\u003cp\u003eIn cisgender women with microprolactinomas, combined oestrogen\u0026ndash;progestogen contraceptives are generally considered safe and involve relatively low oestrogen doses (36). Feminizing GAHT differs fundamentally from contraceptive exposure, resembling high-dose oestrogen replacement rather than cyclic low-dose contraception. Therefore, clinical experience from contraceptive use in cisgender women cannot be directly extrapolated to transgender women receiving GAHT including oestrogens.\u003c/p\u003e \u003cp\u003eSex-specific characteristics of prolactinomas further complicate the comparison (2, 3, 37, 38). Cisgender women typically present with microprolactinomas, whereas cisgender men often develop macroprolactinomas. Accordingly, micro- and macroprolactinomas may require different management strategy reflecting variation in tumour behaviour, dopamine agonist responsiveness, and treatment duration.\u003c/p\u003e \u003cp\u003eOur case highlights the potential effects of feminizing GAHT on prolactinoma tumour behaviour. Specifically, symptomatic regrowth of residual macroprolactinoma (heterogeneously ERα-positive) and marked prolactin elevation shortly after oestrogen initiation, despite cabergoline reinitiation, suggest oestrogen sensitivity of tumour cells. Only three prior histopathologically documented prolactinomas in transgender women have been reported (18, 20, 26). Kovacs et al. described high ER mRNA expression with weak dopamine receptor mRNA expression and continuous growth under bromocriptine during GAHT (20). Gersey at al. reported a weak-to-moderate ERα-positive lactotroph tumour with low Ki-67 proliferation index (18). Serri et al. observed lactotroph hyperplasia (26).\u003c/p\u003e \u003cp\u003eManagement upon GAHT may be challenging, as GAHT is considered essential for psychological well-being yet may exacerbate tumour activity. At present, no guidelines specifically address prolactinoma management in the setting of feminizing GAHT. Review of published cases suggests that prolactinomas diagnosed during GAHT often follow a mild clinical course, with stabilization or normalization of prolactin levels under conservative management in many patients, allowing discontinuation of dopamine agonists and/or GAHT reintroduction. However, these observations must be interpreted cautiously given incomplete follow-up, heterogeneous treatment regimens, and evolving standards of hormone therapy. Symptomatic hyperprolactinemia in transgender women may also occur less frequently in the future due to the shift from CPA use to GnRH or spironolactone.\u003c/p\u003e \u003cp\u003eEndoscopic endonasal/transsphenoidal surgery (EES/TSS) is an effective alternative to dopamine agonists (39). Gersey et al. proposed expanding surgical indications when GAHT exacerbates symptomatic hyperprolactinemia or tumour growth, thereby enabling uninterrupted continuation of GAHT (18). Surgery also may allow discontinuation or marked dose reduction of dopamine-agonists in the setting of intolerance or tumour resistance. However, complete resection is not always feasible, particularly in invasive or near-giant tumours \u0026ndash; as in our patient. In this context, radiotherapy may represent a valuable adjuvant treatment strategy, as illustrated by our case, where tumour remained stable after reintroduction of oestrogen therapy post-radiotherapy. Multidisciplinary decision-making is essential to balance surgical morbidity, tumour control, and gender-affirming goals.\u003c/p\u003e \u003cp\u003eIn conclusion, this study underscores the complex interplay between feminizing GAHT and prolactinoma pathophysiology in transgender women. Oestrogen therapy may influence tumour behaviour in these individuals, necessitating individualized multidisciplinary management strategies. Given the current lack of dedicated recommendations for this patient population, multidisciplinary decision-making is essential to ensure both tumour control and continuity of gender-affirming care.\u003c/p\u003e\n\u003ch3\u003eLearning Points\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThis case illustrates that oestrogen treatment in the setting of GAHT can induce progression of a pre-existing prolactinoma, with apparent reduced dopamine-agonist responsiveness, requiring multimodal management.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThere are currently no recommendations for prolactinoma management in transgender women receiving GAHT.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMultidisciplinary management is essential. Close coordination among endocrinologists, neurosurgeons, radiotherapists, and gender-care specialists is required to balance tumour control with gender-affirming goals.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eRadical endoscopic endonasal/transsphenoidal surgery (EES/TSS) may enable continuation of GAHT when medical therapy is insufficient or poorly tolerated.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eRadiotherapy may stabilize residual disease and allow cautious reintroduction of GAHT.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eBaseline endocrine evaluation, including serum prolactin measurement, is essential prior to GAHT initiation to identify pre-existing hyperprolactinemia or occult prolactinomas. In the absence of baseline assessment, causality between GAHT and subsequent prolactinoma detection cannot be determined.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eGalactorrhoea, headache, or visual disturbances in transgender patients on GAHT should prompt prolactin evaluation and pituitary MRI.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eGAHT differs fundamentally from oestrogen exposure in cisgender women using contraceptives, therefore management principles derived from cisgender populations (e.g., safety of oestrogen-containing contraceptives in women with microprolactinomas) cannot be directly applied to transgender women.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAvailable case-based literature suggests that many prolactinomas detected during GAHT follow a mild clinical course and may be identified incidentally through routine biochemical monitoring. However, the evidence base is limited by detection bias, heterogeneous hormone regimens, and incomplete follow-up.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eFunding\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eNo public or commercial funding.\u003c/p\u003e\n\u003ch3\u003eDisclosures\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003ch3\u003eInformed Patient Consent for Publication\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eSigned informed consent obtained directly from the patient.\u003c/p\u003e\n\u003ch3\u003eData Availability Statement\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eWHO Classification of Tumours Editorial Board. Endocrine and neuroendocrine tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2025 02 23]. (WHO classification of tumours series, 5th ed.; vol. 10). Available from: https://tumourclassification.iarc.who.int/chapters/53.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDelgrange E, Vasiljevic A, Wierinckx A, Fran\u0026ccedil;ois P, Jouanneau E, Raverot G, et al. Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth. Eur J Endocrinol. 2015;172(6):791\u0026ndash;801.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAndereggen L, Christ E, Stieger A, Luedi MM, Huber M. Gender differences in prolactin thresholds and their association with lactotroph adenoma invasiveness for potential treatment considerations. Scientific Reports. 2025;15(1):9598.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePetersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol. 2023;19(12):722\u0026thinsp;\u0026minus;\u0026thinsp;40.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePrince JCJ, Safer JD. Endocrine treatment of transgender individuals: current guidelines and strategies. Expert Rev Endocrinol Metab. 2020;15(6):395\u0026ndash;403.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2017;102(11):3869\u0026thinsp;\u0026minus;\u0026thinsp;903.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eColeman E, Radix AE, Bouman WP, Brown GR, de Vries ALC, Deutsch MB, et al. Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. Int J Transgend Health. 2022;23(Suppl 1):S1-s259.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSantos RB, Lemos C, Saraiva M. Gender-Affirming Hormone Therapy: Physical and Sociopsychological Effects, Impact and Satisfaction. Cureus. 2023;15(3):e36484.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eOntario RH. 4th edition Sherbourne\u0026apos;s guidelines for gender-affirming primary care with trans and non-binary patients.2019 February 12, 2025. Available from: https://www.rainbowhealthontario.ca/product/4th-edition-sherbournes-guidelines-for-gender-affirming-primary-care-with-trans-and-non-binary-patients/.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBrezin F, Busiah K, Leroy C, Fiot E, Bensignor C, Amouroux C, et al. Endocrine management of transgender adolescents: Expert consensus of the french society of pediatric endocrinology and diabetology working group. Archives de P\u0026eacute;diatrie. 2024.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMcFarlane T, Zajac JD, Cheung AS. Gender-affirming hormone therapy and the risk of sex hormone-dependent tumours in transgender individuals-A systematic review. Clin Endocrinol (Oxf). 2018;89(6):700\u0026thinsp;\u0026minus;\u0026thinsp;11.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eNota NM, Wiepjes CM, de Blok CJM, Gooren LJG, Peerdeman SM, Kreukels BPC, et al. The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment. Brain. 2018;141(7):2047-54.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMoltz L, R\u0026ouml;mmler A, Post K, Schwartz U, Hammerstein J. Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men. Contraception. 1980;21(4):393\u0026ndash;413.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eValenti G, Vescovi PP, Gerra G, Rastelli G, Butturini U. Activation of PRL secretion by combined treatment with cyproterone acetate and ethinylestradiol. Journal of Endocrinological Investigation. 1985;8(3):269\u0026thinsp;\u0026minus;\u0026thinsp;72.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCunha FS, Domenice S, C\u0026acirc;mara VL, Sircili MH, Gooren LJ, Mendon\u0026ccedil;a BB, et al. Diagnosis of prolactinoma in two male-to-female transsexual subjects following high-dose cross-sex hormone therapy. Andrologia. 2015;47(6):680-4.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRaven LM, Guttman-Jones M, Muir CA. Hyperprolactinemia and association with prolactinoma in transwomen receiving gender affirming hormone treatment. Endocrine. 2021;72(2):524-8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eJentus MM, Bakker L, Verstegen M, Pelsma I, van Wezel T, Ruano D, et al. Chromosomal alteration patterns in PitNETs: massive losses in aggressive tumors. Endocr Relat Cancer. 2025;32(1).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGersey ZC, Vargas AF, Leung JH, Fazeli PK, Zenonos GA, Gardner PA. Prolactinoma Resection in a Transgender Woman on Gender-affirming Hormone Therapy. JCEM Case Rep. 2025;3(8):luaf120.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBunck MC, Debono M, Giltay EJ, Verheijen AT, Diamant M, Gooren LJ. Autonomous prolactin secretion in two male-to-female transgender patients using conventional oestrogen dosages. BMJ Case Rep. 2009;2009.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKovacs K, Stefaneanu L, Ezzat S, Smyth HS. Prolactin-producing pituitary adenoma in a male-to-female transsexual patient with protracted estrogen administration. A morphologic study. Arch Pathol Lab Med. 1994;118(5):562-5.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a-Malpartida K, Mart\u0026iacute;n-Gorgojo A, Rocha M, G\u0026oacute;mez-Balaguer M, Hern\u0026aacute;ndez-Mijares A. Prolactinoma induced by estrogen and cyproterone acetate in a male-to-female transsexual. Fertil Steril. 2010;94(3):1097.e13-5.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChow B, Rajpal A. MON-048 Proactive on Prolactin: Hyperprolactinemia Management in Transgender Patients. Journal of the Endocrine Society. 2025;9(Supplement_1).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGooren LJ, Assies J, Asscheman H, de Slegte R, van Kessel H. Estrogen-induced prolactinoma in a man. J Clin Endocrinol Metab. 1988;66(2):444-6.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eJehangir W. P-B1\u0026emsp;Prolactinoma in a transgender Male-To-Female HIV positive adult-A rare occurrence \u0026amp; A therapeutic dilemma. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2016;71:72.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHarned LK, Harper RJ. Prolactinoma in a Male to Female Transgender Woman on Gender Affirming Hormone Therapy. Journal of the Endocrine Society. 2021;5(Supplement_1):A795-A.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSerri O, Noiseux D, Robert F, Hardy J. Lactotroph hyperplasia in an estrogen treated male-to-female transsexual patient. J Clin Endocrinol Metab. 1996;81(9):3177-9.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFutterweit W. Endocrine therapy of transsexualism and potential complications of long-term treatment. Arch Sex Behav. 1998;27(2):209\u0026thinsp;\u0026minus;\u0026thinsp;26.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKuijpers SME, Wiepjes CM, Conemans EB, Fisher AD, T\u0026apos;Sjoen G, den Heijer M. Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study. J Clin Endocrinol Metab. 2021;106(10):e3936-e45.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDeutsch M. Guidelines for the primary and genderaffirming care of transgender and gender nonbinary people [Internet].\u0026nbsp;\u003c/span\u003e\u003cspan\u003eAvailable from:. Centre of Excellence for Transgender Health. 2016.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eNolan BJ, Accatino MI, Angus LM, Cheung AS. Approach to prolactin monitoring and hyperprolactinaemia in transgender and gender-diverse individuals undergoing gender affirming hormone therapy. Front Endocrinol (Lausanne). 2025;16:1608108.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAsscheman H, Gooren LJ, Assies J, Smits JP, de Slegte R. Prolactin levels and pituitary enlargement in hormone-treated male-to-female transsexuals. Clin Endocrinol (Oxf). 1988;28(6):583-8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBoekhout-Berends ET, Wiepjes CM, Nota NM, Schotman HH, Heijboer AC, den Heijer M. Changes in laboratory results in transgender individuals on hormone therapy - a retrospective study and practical approach. Eur J Endocrinol. 2023.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWilson LM, Baker KE, Sharma R, Dukhanin V, McArthur K, Robinson KA. Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review. Int J Transgend Health. 2020;21(4):391\u0026ndash;402.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eNota NM, Dekker M, Klaver M, Wiepjes CM, van Trotsenburg MA, Heijboer AC, et al. Prolactin levels during short- and long-term cross-sex hormone treatment: an observational study in transgender persons. Andrologia. 2017;49(6).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGooren LJ, Harmsen-Louman W, van Kessel H. Follow-up of prolactin levels in long-term oestrogen-treated male-to-female transsexuals with regard to prolactinoma induction. Clin Endocrinol (Oxf). 1985;22(2):201-7.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCEU F. FSRH CEU Statement: Contraceptive Options for Women with Prolactinoma (September 2012) 2012 [Available from: https://www.cosrh.org/Public/Documents/fsrh-ceu-statement-prolactinoma-sep-2012.aspx.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDelgrange E, Trouillas J, Maiter D, Donckier J, Tourniaire J. Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab. 1997;82(7):2102-7.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eYoo F, Chan C, Kuan EC, Bergsneider M, Wang MB. Comparison of Male and Female Prolactinoma Patients Requiring Surgical Intervention. J Neurol Surg B Skull Base. 2018;79(4):394\u0026ndash;400.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003evan Trigt VR, Bakker LEH, Pelsma ICM, Zandbergen IM, Jentus MM, Kruit MC, et al. The Changing Treatment Paradigm for Prolactinoma-A Prospective Series of 100 Consecutive Neurosurgical Cases. J Clin Endocrinol Metab. 2025;110(6):e1833-e44.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Leiden University Medical Center","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"transgender, transgender medicine, oestrogen, prolactinoma, lactotroph PitNET, gender-affirming therapy, transition","lastPublishedDoi":"10.21203/rs.3.rs-9008671/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9008671/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eProlactinomas are the most common functioning pituitary neuroendocrine tumours (PitNETs). In transgender women, gender-affirming hormone therapy (GAHT) usually combines high doses of oestrogen and anti-androgen therapy, both of which can elevate serum prolactin levels. Whether GAHT influences tumor behaviour in patients with pre-existing prolactinomas remains unclear.\u003c/p\u003e\u003ch2\u003eDesign and methods\u003c/h2\u003e \u003cp\u003eCase report illustrating the clinical challenges in managing a prolactinoma in the context of GAHT initiation combined with a systematic review of all published cases and available guidelines of GAHT in the prolactinoma context.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA 22-year-old female (46,XY; assigned male at birth) with untreated gender dysphoria and hypogonadism was diagnosed with a macroprolactinoma (39.9 mm; serum prolactin 285x upper limit of normal (ULN)). Cabergoline therapy reduced prolactin levels to 27.3xULN within one year. Pituitary apoplexy with acute visual field and acuity deterioration required emergency transsphenoidal debulking. Two months postoperatively, prolactin levels were 8.6xULN with total hypopituitarism and small irresectable remnants. Initiation of oestrogen therapy led to unexpected biochemical (128.4xULN) and radiological progression despite cabergoline reintroduction and dose escalation, necessitating oestrogen withdrawal to stabilize disease. Subsequent radiotherapy allowed safe oestrogen reintroduction. To date, 24 prolactinomas in transgender women (including this case) have been reported, most diagnosed after GAHT initiation and lacking baseline prolactin data. Current clinical guidelines provide no specific recommendations for pituitary tumors in this population.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eGAHT initiation might induce rapid progression and concomitant dopamine-agonist resistance in residual macroprolactinoma. Individualized, multidisciplinary management is needed. Development of dedicated clinical guidelines is essential to combine tumor control with gender-affirming care.\u003c/p\u003e","manuscriptTitle":"Prolactinoma Course and Management in Transgender Women: case report and systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 16:51:47","doi":"10.21203/rs.3.rs-9008671/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d0a771a4-d90b-4288-ab62-ffa4b6d9abce","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63757890,"name":"Pathology"},{"id":63757891,"name":"Endocrinology \u0026 Metabolism"},{"id":63757892,"name":"Oncology"},{"id":63757893,"name":"Gender Studies"}],"tags":[],"updatedAt":"2026-03-08T16:51:47+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 16:51:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9008671","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9008671","identity":"rs-9008671","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}