Treatment With a Nonaromatizable Androgen for Transgender Man With a Hormone-sensitive Ovarian Cancer

A 51-year-old transgender man had first presented in 2015 at the age of 43 years seeking GAHT for marked and persistent life-long gender incongruence. He was otherwise in good physical and mental health, apart from mild asthma and morbid obesity (body mass index, 42 kg/m 2 ). He used no regularly prescribed or over-the-counter medications. He was a life-long nonsmoker or drinker. He could not recall onset of menarche but reported regular menstrual cycle without dysmenorrhea or menorrhagia. He was not sexually active and had never been pregnant. There was absence of any benign or malignant gynecological condition in the family. Short-acting intramuscular testosterone enanthate (Primoteston 250 mg) at 2 to 3 weekly intervals was commenced in November 2015 and switched to longer acting intramuscular testosterone undecanoate (Reandron 1000 mg, 12 weekly) a few months later. Cessation of menses occurred 4 months into testosterone and other desired physical changes including deepening of his voice, self-reported body fat redistribution, and mild acne were observed. Because of the shape and size of the nipples and breasts on a background of obesity, he was recommended to first undergo nipple reduction and chest liposuction in October 2016, followed by bilateral mastectomies in May 2017. He was pleased with the surgical outcome and continued intramuscular testosterone undecanoate with clinical reviewed every 6 months. In November 2017, he reported recurrence of almost daily menstrual spotting for about 6 weeks, which eventually ceased spontaneously. A suggested gynecological referral was not taken up. In January 2019, the spotting recurred lasting for 1 day. A diagnosis of diverticular disease was also made at the time based on clinical symptoms and radiographic evidence of diverticular disease. A gynecology referral was again sought with a view to hysterectomy.

Hormone-related cancer remains a serious but uncommon issue in transgender and gender diverse individuals. Its rarity is partly attributable to the relatively younger age of this population, lack of consistent screening strategy and uptake as well as limited therapeutic alternatives to conventional gender-affirming hormone therapy (GAHT), which may be contraindicated in certain cases. The decision to maintain or discontinue GAHT, particularly testosterone in transgender men following a diagnosis of hormone-sensitive cancer, is complex and requires careful consideration of alternative options by both the patient and multidisciplinary team. Here, we report a case of a transgender man who developed recurrent hormone-sensitive, low-grade endometroid ovarian cancer and outline the challenges encountered in management.

The patient continued to do well at last review in May 2024, without evidence of disease recurrence clinically, biochemically, and radiologically. The dose of nandrolone was uptitrated to 150 mg every 2 weeks based on clinical symptoms; the patient did not report any undesirable adverse effects. Table 1 summarized serial laboratory results throughout his treatment. Serial laboratory profile and timeline over the course of our patient's treatment Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CA 125, cancer antigen 125; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDH, lactate dehydrogenase; LDL, low-density lipoprotein;TAH-BSO, total abdominal hysterectomy, bilateral salpingo-oophorectomy. a Serum estradiol measured by liquid chromatography-mass spectrometry.

Ovarian cancer can occur in transgender men, but diagnosis and management present unique challenges. As in cisgender women, there are no established screening guidelines for ovarian cancer. However, in transgender men, health care avoidance may further complicate early detection. Maintaining clinical awareness and a high index of suspicion is crucial for timely diagnosis. The impact of discontinuing gender-affirming testosterone therapy requires careful discussion. Risks and benefits must be evaluated in a multidisciplinary team setting, taking into account the patient's quality of life, mental health, and the risk of hormone-sensitive cancer recurrence. Nandrolone is a plausible alternative gender-affirming masculinizing therapy. It may help avoid androgen deficiency symptoms while maintaining bone and muscle health and reduce the risk of hormone-sensitive cancer recurrence compared to testosterone therapy.

The patient underwent laparotomic excision of pelvic masses and omentectomy in March 2021. The histopathology showed metastatic well-differentiated adenocarcinoma in the resected pelvic nodules ( Fig. 1A ), with no evidence of malignancy in the omentum. Immunohistochemistry of the pelvic nodules was negative for estrogen, progesterone, androgen receptors, and caudal type homeobox transcription factor 2. The adenocarcinoma was only patchy positive for special AT-rich sequence binding protein immunostaining ( Figure 1B ). A differential diagnosis between recurrent ovarian endometrioid adenocarcinoma and primary colorectal adenocarcinoma was raised. Consensus agreement at a multidisciplinary tumor board meeting favored a final diagnosis of recurrent ovarian endometrioid adenocarcinoma based on clinical history and normal colonoscopy. (A) Metastatic adenocarcinoma from pelvic nodule recurrence (hematoxylin and eosin stain). (B) Pelvic nodule recurrence demonstrated negative staining with androgen receptor immunohistochemistry. Unfortunately, an abdominal computed tomography scan 2 months postoperatively detected a residual nodule measuring 30 × 29 mm in the left pelvic wall, consistent with recurrence. Tumor markers were negative. The recommended treatment modality was endocrine therapy with local pelvic radiotherapy. Because aromatization of injectable testosterone would produce estradiol with potential to stimulate the hormone-sensitive cancer, testosterone therapy was discontinued in May 2021. Endocrine therapy with oral medroxyprogesterone 200 mg daily was commenced. Pretreatment serum estradiol measured by liquid chromatography–mass spectrometry at 29.7 pg/mL (109 pmol/L) (normal reference range: 9.8-42 pg/mL; 36-155 pmol/L). Throughout the follow-up review, he had no disease recurrence but struggled with progressive weight gain, lethargy, and deterioration in bone mineral density, effects considered likely due to untreated hypogonadism with lack of testosterone. A decision was made to commence injectable 19-nortestosterone (nandrolone decanoate) starting at 50 mg every 2 weeks in February 2023.

The patient underwent hysteroscopy with uterine dilation and curette in November 2019, which revealed a benign endometrial polyp on histology. Imaging identified a left ovarian mass, and he underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathological examination of the left ovary confirmed The International Federation of Gynaecology and Obstetrics (FIGO) grade 1 endometrioid carcinoma, with carcinoma extending to the ovarian serosal surface. No malignancy was identified elsewhere. Immunohistochemistry revealed strong nuclear staining for estrogen and progesterone receptors in approximately 5% to 10% of tumor cells. He recovered well from surgery. He was considered surgically cured and did not require adjuvant therapy. He continued on intramuscular testosterone undecanoate 1000 mg every 14 weeks. In February 2021, at routine review, he reported abdominal pain. Colonoscopy and abdominal computed tomography scan confirmed diverticular disease but also 3 soft tissue nodules in the pelvis. A positron emission tomography scan detected intensely avid uptake in the nodules with maximum standardized uptake value 15.2 without significant activity elsewhere. The case was reviewed at gynecological cancer multidisciplinary meeting and thought to represent recurrent disease.

Epithelial ovarian cancer is a rare malignancy, with an estimated lifetime risk of 1.2% for Australian women to be diagnosed before the age of 85 years [ 1 ]. Among the subtypes, endometrioid ovarian cancer represents a distinct form, accounting for approximately 10% to 13% of all epithelial ovarian cancers [ 2 ]. This subtype can be associated with endometriosis and tends to present at an earlier stage, compared to other epithelial ovarian cancers, which may contribute to its generally more favorable prognosis. However, outcomes can vary depending on factors such as tumor grade and extent of disease at diagnosis. The symptoms of ovarian cancer are often nonspecific and can be mistaken for other conditions, specifically gastrointestinal problems, not dissimilar to our patient. A retrospective population-based study examined the factors impacting the time to diagnosis based on prespecified classic symptoms (abdominal/pelvic pain, bloating, urinary symptoms, and difficulty eating) [ 3 ]. A total of 18 693 women were identified as having stage II to IV primary epithelial ovarian cancer. Of these, 74.2% (13 872 women) had codes for at least 1 prespecified symptom. The time to diagnosis differed significantly by first symptom, number of symptoms, and first physician specialty seen. This highlights the importance of being vigilant to screen for ovarian cancer in the presence of nonspecific symptoms and appropriate referral to gynecologist. The treatment of ovarian carcinomas is highly dependent on the subtypes, with emerging evidence for targeted molecular therapies [ 4 ]. In endometrioid ovarian carcinoma, surgery remains the cornerstone of treatment, with primary objectives to achieve complete cytoreduction and accurate staging [ 5 ]. The role of adjuvant therapy in low-grade endometrioid ovarian cancer is nuanced. In early-stage disease, observation of regular follow up is generally recommended. In advanced-stage disease, the decision to administer chemotherapy or endocrine therapy is individualized, taking into account factors such as residual disease postsurgery and patient comorbidities. For recurrent disease, endocrine therapy offers a treatment option, especially in patients with hormone receptor-positive disease, by exerting an antiestrogenic effect, inducing cellular differentiation, apoptosis, and anti-inflammation. The prevalence of ovarian cancer in transgender men remains very low and reported in either case reports or case series only. In a systematic review published in 2018 on breast and reproductive cancers in transgender population, only 5 cases of ovarian cancers were reported [ 6 ]. We have further identified an additional 6 cases since then and summarized all reported cases to date in Table 2 [ 7-16 ]. The sole unifying observation is the much younger age of ovarian cancer in transgender population compared with cisgender women but the paucity of reported malignant cases highlighted the limited screening and management strategies available for such patients. Ovarian tumor (malignant and nonmalignant) in transgender men—published case reports (terminology used directly adopted from respective case reports) Reference ranges: CA125—cancer antigen 125 (0-35 kU/L; 0-35 U/mL); CA 15.3—cancer antigen 15.3 (reference range <30 kU/L; <30 U/mL). Abbreviations: AR, androgen receptor; BSO, bilateral salpingo-oophorectomy; EGF-R, epidermal growth factor receptor; ER, estrogen receptor; FIGO, The International Federation of Gynaecology and Obstetrics; HPV, human papillomavirus; MRI, magnetic resonance imaging; PR, progesterone receptor; RP, regulatory peptides; TAH, total abdominal hysterectomy; US, ultrasound; VEGF, vascular endothelial growth factor; WT1, Wilms’ Tumor Gene 1. There is no convincing direct association between testosterone and development of ovarian cancer in transgender population. However, there is potential implication of androgen receptor signalling in ovarian tumorigenesis and malignant transformation [ 9 , 17 ]. Our patient is unique in that although androgen receptor status was negative, he had estrogen and progesterone receptor positivity in the original tumor, making the ongoing use of aromatizable testosterone as gender-affirming care risky for cancer recurrence. Yet the discontinuation of testosterone led to worsening underlying gender dysphoria and hypogonadal symptoms. Hence, after careful consideration, testosterone treatment was discontinued and eventually switched to intramuscular injectable 19-nortestosterone (nandrolone decanoate) following treatment for the ovarian disease. Nandrolone is one of the most commonly used androgens, as a derivatives of testosterone lacking the C19 methyl group (=19-nor) with the injectable pro-drug product in the form of an ester of decanoic acid in an oil vehicle [ 18 ]. Nandrolone is metabolized by the 5α-reductase enzyme into 5α-dihydro 19-nortestosterone, a weakened androgen unlike the 5α reduction of testosterone to the more potent, pure, (nonaromatizable) androgen dihydrotestosterone ( Fig. 2 ). Nandrolone is also metabolized to 19-norandrosterone and 19-noretiocholanolone, which are inactive androgen metabolites. Pathways of action between testosterone and nandrolone. Nandrolone has been used in various clinical conditions with catabolic state such as burns, anemia, chronic kidney disease, osteoporosis, sarcopenia, and HIV associated wasting syndrome [ 18 ], but its virilizing properties largely preclude its use in women and children. It is also among the most frequent androgens abused in sports doping and body building [ 19 ]. The therapeutic dose for humans can be 0.4 mg/kg/day [ 18 ] but is usually administered as 50 mg every 1 to 3 times weekly. Although 19-nortestosterone is an intermediate in the aromatization reaction converting testosterone to estradiol in the aromatase enzyme complex, paradoxically, exogenous nandrolone is not converted to estradiol in men [ 20 ]. It is this nonaromatizable characteristic that prompted the use of nandrolone as an alternative gender-affirming masculinizing therapy in our patient to maintain the androgen effects but without generating estradiol by aromatization that may promote cancer recurrence while also improving androgen deficiency symptoms and maintaining bone density and muscle mass. In summary, this case highlights the challenges in balancing provision of gender-affirming care for better psychosocial well-being when a hormone-sensitive cancer occurs, which precludes using aromatizable testosterone for risk of promoting tumor recurrence. It provides an opportunity for use of nandrolone as an alternative masculinizing hormone as GAHT and relief for androgen deficiency symptoms while maintaining androgen effects on muscle, bone, and brain without risking recurrence of a hormone-sensitive cancer. It also emphasizes a coordinated multidisciplinary team is essential for optimal patient outcome.

All authors made individual contributions to authorship. S.L., L.C., and Y.C.L. were involved in diagnosis and management of the patient. D.J.H. suggested the use of nandrolone as alternative treatment. S.L., R.P., and D.J.H. were involved in manuscript drafting. K.T. was involved in histopathology reporting and preparation of the histology images. All authors approved the final manuscript.