Successful management of refractory hyperprolactinemia secondary to ectopic prolactin-secreting disseminated peritoneal leiomyomatosis via surgical resection and postoperative leuprorelin therapy: a rare case report

Background Hyperprolactinemia is a syndrome characterized by elevated serum prolactin levels and manifests with symptoms such as amenorrhea, galactorrhea, and infertility. Physiological hyperprolactinemia may occur during pregnancy, lactation, or nipple stimulation in women, whereas pathological causes mainly involve hypothalamic-pituitary disorders and medication use. Dopamine agonists (DAs), such as cabergoline and bromocriptine, are the primary pharmacological treatment (1). However, for patients who do not respond to this pharmacotherapy, comprehensive screening is imperative to rule out ectopic prolactin-secreting lesions (2). Disseminated peritoneal leiomyomatosis (DPL) is a rare benign condition characterized by the diffuse proliferation of small smooth muscle nodules throughout the abdominal and pelvic cavities. Although it predominantly affects women of reproductive age, isolated cases have also been reported in males in the medical literature. A subset of patients has a history of exogenous hormonal exposure, most commonly oral contraceptive use or hormone replacement therapy (3). Most affected individuals are asymptomatic, and the condition is often incidentally detected during abdominal surgery or, less frequently, at autopsy (4,5). Given the limited number of reported cases (fewer than 200 to date), the true incidence of DPL remains unclear (6). Although the etiological mechanisms underlying DPL are not fully understood, hormonal influences and iatrogenic factors are thought to play a role. Due to its rarity, no standardized treatment protocols have been established. Current management primarily involves surgical resection and endocrine therapy (7). Rationale and knowledge gap Although previous studies have shown that the uterine myometrium and uterine leiomyomas can secrete prolactin, and a small number of case reports have described hyperprolactinemia caused by leiomyomas, these cases have rarely provided immunohistochemical evidence regarding whether the leiomyomas themselves secrete prolactin or whether prolactin receptors (PRLRs) are present (1-3,6). Furthermore, the optimal treatment for such conditions remains unclear.

We report a rare case of hyperprolactinemia in a female patient caused by DPL that was unresponsive to DAs. Following surgical resection, we observed a rapid decline in serum prolactin levels, and immunohistochemical analysis of the resected lesions confirmed prolactin expression. To our knowledge, this is the first reported case of ectopic prolactin secretion originating from DPL. By presenting this case and conducting a literature review, we aim to explore potential approaches for clinical management. We present this article in accordance with the CARE reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-18/rc). Case presentation All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. An 18-year-old female underwent an open myomectomy at a local general hospital in May 2022, after which she did not attend any follow-up visits. In October 2023, she presented with symptoms suggestive of amenorrhea, galactorrhea, and occasional mild abdominal distension. Laboratory tests at the local facility revealed elevated prolactin levels, whereas other hormone levels were within normal ranges. Brain magnetic resonance imaging (MRI) indicated slight enlargement of the pituitary gland, and pelvic ultrasound examination showed no abnormalities. Subsequently, she was administered oral bromocriptine at a dosage of 2.5 mg per day for 2 months. Midway through this treatment, monitoring revealed no reduction in prolactin levels, leading to an adjustment of the dosage to 5 mg daily for 4 months. Despite this adjustment, her symptoms remained unresolved, and her abdominal distension worsened. Consequently, she sought further examination and treatment at our hospital. Upon arrival at our facility, a gynecological examination was performed, revealing no abnormalities; however, a hard mass with indistinct boundaries was noted in the left abdomen. Repeat brain MRI showed a 0.5 cm × 0.6 cm × 0.7 cm nodular lesion in the left pituitary, slightly hypointense on T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI), with mild delayed enhancement, which may represent a pituitary microadenoma. Laboratory findings showed a prolactin level exceeding 200 ng/mL (normal range: <29.2 ng/mL). Pelvic ultrasound demonstrated irregular hypoechoic masses with poorly defined margins adjacent to both sides of the uterus, suggestive of possible uterine leiomyomas. A subsequent abdominal MRI revealed diffuse infiltrations within the pelvic and abdominal cavity, exhibiting partial fusion. The largest lesion was observed in the left epigastrium (Figure 1). Based on these findings, DPL was suspected, leading to the decision to perform an exploratory laparotomy. Intraoperatively, multiple nodules were observed on the peritoneal surfaces, greater omentum, mesentery, intestines, bladder, and uterine surfaces. The diameters of these nodules ranged from 0.5 to 10 cm, with some exhibiting fusion together. The ovaries and fallopian tubes appeared normal. The nodules were characterized by their small size, round shape, firm consistency, and well-defined boundaries (Figures 2,3). Intraoperative frozen section pathology indicated a leiomyoma. To minimize residual lesions, the nodules were removed as completely as possible, making the entire procedure arduous yet ultimately successful. The patient demonstrated a favorable recovery trajectory. Postoperative pathology confirmed the diagnosis of DPL. Immunohistochemistry revealed positive staining for progesterone and estrogen receptors, along with positive staining for prolactin and weakly positive staining for PRLRs (Figure 4). The proliferation index (Ki67) was exceedingly low at 1%. The prolactin level normalized immediately following the procedure. To address any potential residual microscopic implants, a postoperative regimen of leuprorelin (3.75 mg administered subcutaneously every 28 days) was initiated and continued for 6 months. To date, the patient’s prolactin levels have remained within the normal range, with no evidence of recurrence. The alterations in prolactin levels and corresponding therapeutic interventions are illustrated in Figure 5.

Prolactin is mainly produced by pituitary lactotrophs, but it is also expressed in various peripheral tissues, where its transcription, translation, and function differ from pituitary prolactin. Although extrapituitary prolactin shows tissue-specific regulation, both forms share the same primary, secondary, and tertiary structures and act through the same receptor (8). Uterine myomas are hormone-sensitive, typically growing in response to elevated estrogen and progesterone. However, prolactin-producing leiomyomas—though extremely rare—can actively synthesize and secrete prolactin (9). In this case, the patient received bromocriptine for hyperprolactinemia, but serum prolactin levels paradoxically increased after treatment initiation and further rose with dose escalation. Complete resection of the intra-abdominal lesions led to a rapid prolactin decline. Histopathology confirmed prolactin production by the lesions, establishing them as the cause of hyperprolactinemia. A review of the English-language literature identified seven cases of hyperprolactinemia caused by benign leiomyomas (2,10-15). These cases, along with the present case, are summarized in Table 1. All patients were treated with DAs, either cabergoline or bromocriptine; however, prolactin levels remained unresponsive, and their primary complaints persisted. Patients with a history of uterine leiomyomas exhibited enlargement of these lesions. Ultimately, all patients underwent surgical intervention, which included either hysterectomy or myomectomy. Postoperatively, prolactin levels rapidly normalized in all patients. The majority of cases either omitted prolactin immunostaining data or showed negative results and only one (2) demonstrated focal, punctate staining. In striking contrast, our case exhibited diffuse, robust prolactin positivity spanning the entire lesion. Table 1 | Reference | Age (years) | Initial symptoms | Peak PRL level before surgery (ng/mL) | Size of leiomyoma before DA (cm) | Size of leiomyoma after DA (cm) | Mode of operation | Immunostaining for prolactin | PRL level after surgery (ng/mL) | |---|---|---|---|---|---|---|---|---| | Sachdev et al. (2) | 47 | Amenorrhea | 224 | 9.8 | 13.9 | Hysterectomy | Positive | 2.5 | | Galactorrhea | |||||||| | Herzog (10) | 36 | Migraine | >100 | 5.5 | Enlarged | Myomectomy | Not available | Normal range | | Irregular menstruation | |||||||| | Galactorrhea | |||||||| | Cordiano V (11) | 44 | Amenorrhea | >200 | Not available | 8 | Hysterectomy | Not available | 15 | | Sato et al. (12) | 45 | Amenorrhea | 75.5 | 6.6 | 9 | Hysterectomy | Negative | 0.8 | | Galactorrhea | |||||||| | Sendur et al. (13) | 25 | Amenorrhea | Not available | Not available | 8 | Myomectomy | Negative | 3.43 | | Galactorrhea | |||||||| | Infertility | |||||||| | Upreti et al. (14) | 41 | Amenorrhea | 278.3 | 6.4 | 8.8 | Myomectomy | Negative | Normal range | | Galactorrhea | |||||||| | Estrogen deficiency symptoms | |||||||| | Barry et al. (15) | 37 | Irregular menstrual cycle | 87.5 | 10.5 | 15.2 | Myomectomy | Negative | 0.32 | | Galactorrhea | |||||||| | This case | 18 | Amenorrhea | 284.2 | Not detected | 10 | Myomectomy | Positive | 7.2 | | Galactorrhea | The peak prolactin level was 5,900 mU/L in reference 14 and 1,856 mIU/L in reference 15. To maintain uniformity in this table, all prolactin units are standardized to ng/mL (1 ng/mL =21.2 mIU/L). DA, dopamine agonist; PRL, prolactin. Myometrial and leiomyoma smooth muscle cells are capable of expressing PRLR mRNA, enabling prolactin to act as an autocrine or paracrine growth factor that may promote tumor progression (16). Baban et al. (17) examined PRLR expression in 53 leiomyomas and matched myometrium, compared with myometrium from 40 healthy pregnant women, and found that PRLR was present in all tissues but showed stronger and more heterogeneous staining in leiomyomas, indicating increased receptor expression in fibroids. Moreover, DiMauro et al. demonstrated that prolactin activates STAT5 and MAPK signaling in uterine smooth muscle cells, promoting their trans-differentiation into a myofibroblast-like, fibrotic phenotype (18). To our knowledge, PRLR expression has not been previously assessed in similar cases. Here, we report weak but detectable PRLR immunoreactivity, implicating prolactin autocrine signaling as a potential contributor to lesion progression. Prolactinomas, the most common cause of pathological hyperprolactinemia and up to 50% of pituitary adenomas, secrete prolactin autonomously due to lactotroph monoclonal proliferation and impaired D2 receptor signaling (19). Non-functioning pituitary adenomas (NFPAs) are hormonally inert and often incidentally detected. When hyperprolactinemia occurs, it is typically due to stalk compression. On contrast-enhanced T1 MRI, NFPAs appear hypointense owing to delayed enhancement, and pharmacological treatment is generally ineffective (20). Although MRI suggested a possible pituitary microadenoma in our patient, we classified the lesion as non-functioning based on imaging features, lack of response to medical therapy, and rapid postoperative normalization of prolactin. Surgical resection was therefore appropriate for symptom relief. It is plausible that the patient’s condition was initially missed due to diagnostic limitations: (I) inadequate evaluation of abdominal symptoms; (II) use of transabdominal rather than transvaginal ultrasound, owing to the patient’s asexual status; (III) suboptimal ultrasound capabilities at the local facility. Collectively, these factors increase the risk of delayed or missed diagnosis and emphasize the need for thorough, individualized assessments. Remarkably, the leiomyoma observed in our patient was DPL, an exceptionally rare condition. Given its rarity, the precise incidence and underlying etiology of DPL remain poorly understood. The underlying pathophysiological mechanisms of DPL include: (I) unconfined utilization of power morcellation during laparoscopic surgeries; (II) origination from metaplastic changes in primitive and multipotent mesenchymal subcoelomic stem cells, driven by hormonal factors. Additionally, a hereditary component may also be a potential etiological factor in DPL (21). Chen et al. (22) analyzed 13 DPL cases, all occurring after laparoscopic surgery with uncontained morcellation, supporting an association between DPL and iatrogenic causes. Ordulu et al. (23) further elucidated DPL pathobiology through molecular cytogenetic analysis, demonstrating that these lesions likely originate from implanted uterine leiomyoma cells that subsequently evolve following the initial procedure. Ma et al. (24) indicated that DPL with and without prior morcellation may have distinct pathogenic pathways. Their findings showed that in patients with a history of morcellation use, the MED12 mutation status and loss of heterozygosity (LOH) at a specific locus were consistent between the original uterine leiomyomas and subsequent DPL lesions, supporting a common clonal origin. While microsatellite instability and LOH analysis in patients without prior morcellation indicated that the peritoneal/pelvic tumors were genetically distinct from uterine leiomyomas, this supported the hypothesis that this type of DPL likely originates from the secondary Müllerian system. Furthermore, for this form of DPL, tumor regression or stabilization has been observed after the cessation of hormonal stimulation. Interestingly, Halama et al. (25) described six members of a family diagnosed with DPL, including three men. They proposed a hypothesis suggesting a potential genetic component in the etiology of DPL. In this case, the patient had a history of uterine leiomyoma and had previously undergone open myomectomy without the use of a power morcellator. This finding appears to support the metaplasia theory; however, we do not exclude the possibility that unrestricted power morcellation could contribute to DPL in other cases. Given the unclear etiology of DPL, genetic testing to investigate potential causes is warranted. Rein et al. (26) examined gonadotropin-releasing hormone agonists (GnRH-a)’s effects on prolactin secretion in uterine leiomyomata versus myometrium using explant cultures from 17 patients. They found that GnRH-a significantly suppressed fibroid prolactin secretion (P<0.001), likely through indirect mechanisms (e.g., induced hypoestrogenism) rather than direct action (ineffective in vitro). Given the positive estrogen receptor status and the ability of GnRH-a to reduce prolactin levels in leiomyomas, postoperative treatment with leuprorelin was administered for 6 months, resulting in a favorable prognosis. In such cases, administration of GnRH-a is typically recommended for patients. This study reports a case of hyperprolactinemia caused by ectopic prolactin secretion from DPL. The patient achieved rapid hormonal normalization following surgical resection, with long-term remission maintained on leuprolide therapy. While this unique case provides preliminary insights that may inform the management of similar presentations, two limitations merit consideration: first, the single-case design limits generalizability; second, the absence of genetic profiling precludes investigation of potential mutation-driven pathogenesis, as only immunohistochemical analysis was performed.

The clinical implications of this case are threefold: (I) when pharmacological treatment for hyperprolactinemia fails, clinicians should prioritize patient symptoms, perform thorough physical examinations, and initiate comprehensive imaging to identify potential ectopic prolactin-secreting lesions; (II) for DPL associated with ectopic prolactin secretion, the preferred management strategy involves surgical resection followed by maintenance therapy with GnRH-a; (III) genetic testing should be considered to elucidate potential underlying genetic contributors. Acknowledgments None. Footnote Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-18/rc Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-18/prf Funding: None. Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-18/coif). Y.S. serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from May 2023–December 2025. X.H. serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from June 2024–December 2025. The other author has no conflicts of interest to declare. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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