Prolactinoma Resection in a Transgender Woman on Gender-affirming Hormone Therapy

Abstract

The management of prolactinoma in the setting of gender-affirming hormone therapy (GAHT) is lacking in the literature. We present the case of a transgender woman who was found to have prolactinoma prior to initiating GAHT. Initially, medication effectively managed prolactin levels; however, upon starting GAHT, maintaining control of these levels became challenging. Opting to sustain GAHT without disruption and gain control over symptomatic hyperprolactinemia, the patient underwent endoscopic endonasal surgery, resulting in gross total tumor resection including the medial wall of the cavernous sinus. Postoperative assessments revealed normal prolactin levels without dopamine agonist medication, allowing uninterrupted continuation of GAHT; in the following months, prolactin has minimally increased with plans for monitoring without treatment for now due to intolerance of oral antidopaminergics and lack of visible lesion on follow-up magnetic resonance imaging.

Introduction

Gender dysphoria significantly impacts individuals whose gender identity and expression differ from their sex assigned at birth, often leading to increased rates of self-harm, suicidality, and functional impairment [1]. Advances in transgender healthcare have enabled more individuals to seek gender-affirming hormone therapy (GAHT) to align their physical characteristics with their gender identity, improving psychological well-being [2, 3]. However, GAHT also raises concerns about potential health risks associated with exogenous hormone treatments.

For transgender women, GAHT typically involves estradiol administration and androgen blockade (eg, spironolactone or cyproterone) to promote secondary female sex characteristics [2]. Studies linked GAHT to an increased risk of brain tumors, including meningiomas and possibly prolactinomas, though the contributions of estrogen vs antiandrogens remain unclear. In cisgender women, cyproterone use significantly increases meningioma risk in a dose-dependent manner, with some reduction after discontinuation [4]. Similarly, transgender women on GAHT have a higher risk of brain tumors compared to controls.

The link between GAHT and prolactinomas or hyperprolactinemia remains uncertain, largely due to the concurrent use of estrogen and antiandrogens. The Endocrine Society's 2017 guideline weakly recommends periodic prolactin monitoring in transgender women on estrogen, citing concerns about estrogen-induced pituitary lactotroph growth. A 2020 systematic review found limited data on prolactinoma incidence, with only 1 study, which had a serious risk of bias due to confounding and missing data, reporting no cases in 98 patients on estradiol and spironolactone [5, 6]. In contrast, studies have consistently shown a dose-dependent increase in prolactin levels with cyproterone acetate (CPA) [7, 8]. Spironolactone and leuprolide show minimal or inconsistent effects on prolactin levels, leading to reduced CPA doses in some regions and debate over routine prolactin monitoring where CPA use is limited [9-11].

Pituitary adenomas, including prolactinomas, are among the most common benign brain neoplasms, with prolactinomas accounting for approximately 40% of pituitary adenomas [12]. These tumors arise from lactotroph cells, causing excessive prolactin secretion. Estrogen, such as estradiol—a key component of GAHT—may promote the growth of prolactin-producing tumors [6, 13]. This case report highlights a transgender woman with a preexisting prolactinoma undergoing GAHT who achieved tumor control through an endoscopic endonasal surgery (EES).

Case Presentation

A 49-year-old then male-identifying patient, previously treated for hypogonadism with testosterone, presented with decreased energy, low libido, erectile dysfunction, hot flashes, fatigue, and breast tenderness and was diagnosed with hypogonadotropic hypogonadism.

Diagnostic Assessment

Laboratory tests revealed a prolactin level of 1578 ng/mL (68.6 nmol/L) (normal reference range: 4.0-15.2 ng/mL; 0.2-0.66 nmol/L), and pituitary magnetic resonance imaging (MRI) (Fig. 1) showed a 22 × 17 × 15 mm macroadenoma consistent with a macroprolactinoma. All other endocrinologic laboratory values were within normal limits, and symptomatology was not consistent with a secreting adenoma; therefore, no further confirmatory tests were pursued. Cabergoline treatment was initiated at 0.25 mg twice weekly, but the patient experienced significant side effects including nausea, dizziness, headaches, and fatigue. He was transitioned to bromocriptine at 1.25 mg daily. One month later, his prolactin level was 288 ng/mL (12.52 nmol/L), bromocriptine was increased to 2.5 mg daily, and the prolactin level decreased to 101 ng/mL (4.39 nmol/L). Bromocriptine was subsequently increased to 5 mg daily with a nadir prolactin of 24 ng/mL (1.04 nmol/L). After 6 months of treatment with bromocriptine, prolactin levels remained elevated with a decrease in the size of the pituitary adenoma.

Figure 1.

Initial MRI revealing a pituitary adenoma (red dashed line). (A) Coronal T1-weighted MRI with contrast. (B) Sagittal T1-weighted MRI with contrast.

Abbreviation: MRI, magnetic resonance imaging.

Treatment

The patient later initiated hormone therapy to affirm as a transgender woman. High-dose weekly intramuscular estradiol valerate and finasteride 5 mg daily were started, resulting in a prolactin increase to 134 ng/mL (5.83 nmol/L). Despite adjustments to estradiol therapy and transitioning from finasteride to spironolactone 50 mg twice daily, her prolactin levels ranged between 133 ng/mL (5.78 nmol/L) and 255 ng/mL (11.09 nmol/L). Following endocrinology consultation, estradiol was reduced, and bromocriptine was increased to 7.5 mg twice daily, but prolactin levels continued to rise, peaking at 472 ng/mL (20.52 nmol/L). Due to the continual rise in prolactin levels, bromocriptine was discontinued, and a trial of cabergoline therapy was initiated but later was discontinued due to significant adverse effects of nausea, dizziness, headaches, and fatigue. A follow-up MRI revealed a pituitary lesion (1.7 × 1.2 × 1.2 cm) with slight cavernous sinus extension (Fig. 2). Given the persistent prolactin elevation and the need to continue GAHT, the patient opted for EES with medial cavernous sinus wall resection for definitive tumor control after multidisciplinary discussion.

Figure 2.

Preoperative MRI showing a slightly smaller pituitary adenoma with left cavernous sinus invasion (yellow arrow). (A) Coronal T1-weighted MRI with contrast. (B) Axial T1-weighted MRI with contrast.

Abbreviation: MRI, magnetic resonance imaging.

Spironolactone and estradiol were stopped 2 weeks before surgery. Bromocriptine was stopped 5 days before surgery. The plan was to reinitiate spironolactone and estradiol 2 weeks after surgery and to monitor prolactin levels and imaging postoperatively to determine whether reinitiation of bromocriptine was necessary.

The patient underwent general anesthesia in a supine position with a 3-pin Mayfield placed for cranial immobilization. The otolaryngology team performed initial exposure of the sphenoid sinus with preservation of the right vascular pedicle and sacrifice of the left pedicle to allow access to the left cavernous sinus. The bone overlying the sella was carefully removed and then extended to expose the left parasellar and upper paraclival carotid artery. The dura was opened and the interface between the gland and tumor identified. The tumor was dissected in an extra-capsular manner until it was removed en bloc. The anterior face of the cavernous sinus was then opened, exposing the medial wall of the cavernous sinus. The inferior parasellar, caroticoclinoidal, and superior parasellar ligaments were cut, and the inferior hypophyseal artery was coagulated and cut. The medial cavernous sinus wall was removed in 1 piece. Meticulous hemostasis was performed, a free mucosal graft was placed for reconstruction, and absorbable nasal packing was placed to conclude the surgery.

Outcome and Follow-up

A gross total resection of the tumor was accomplished along with the medial wall of the left cavernous sinus. The patient recovered well from surgery and was discharged home on postoperative day 1 with a prolactin level of 10.8 ng/mL (0.47 nmol/L) (Fig. 3). Pathology results showed overgrowth of monotonous cells with round nuclei and salt and pepper chromatin consistent with a pituitary adenoma. The neoplastic cells were positive for prolactin, estrogen receptor, and PIT1, confirming the diagnosis of prolactinoma. Ki67 proliferation index was approximately 1%. Tumor involvement of the medial cavernous sinus wall was confirmed (Fig. 4).

Figure 3.

Summary of prolactin levels throughout the patient's treatment course.

Abbreviations: DA, dopamine agonist; GAHT, gender-affirming hormone therapy.

Figure 4.

Pathology slides demonstrating the patient's pituitary adenoma as well as invasion of the medial cavernous sinus wall. (A) Hematoxylin and eosin. (B). Pituitary adenoma (yellow arrows) invading the fibrous connective tissue (yellow dashed line) of the medial cavernous sinus wall. (C) PIT1 immunostain showing a PIT1-positive tumor. (D) Prolactin immunostain confirming a prolactin staining adenoma.

Her immediate postoperative prolactin nadir was 10.8 ng/mL (0.47 nmol/L). On postoperative day 7, while off estradiol and spironolactone, prolactin was 17.2 ng/mL (0.75 nmol/L). Two months later, after resuming her preoperative regimen of estradiol and spironolactone, prolactin increased to 46.5 ng/mL (2.02 nmol/L). At 3 months, MRI showed no residual tumor (Fig. 5), though prolactin rose to 76.9 ng/mL (3.34 nmol/L) by 4 months. Given the normal imaging and absence of symptoms, the prolactin was monitored without treatment. After holding hormones for gender-affirming surgery, prolactin dropped to 30.9 ng/mL (1.34 nmol/L). Upon resuming estradiol, prolactin increased to 52.5 ng/mL (2.28 nmol/L), consistent with estrogen therapy as the primary driver of prolactin elevation, rather than tumor recurrence, as confirmed by MRI.

Figure 5.

Postoperative MRI showing no residual pituitary adenoma with the mucosal free graft (yellow arrow). (A) Coronal T1-weighted MRI with contrast. (B) Sagittal T1-weighted MRI with contrast.

Abbreviation: MRI, magnetic resonance imaging.

Discussion

This report presents a case of a transgender woman with a prolactinoma who underwent endoscopic endonasal resection due to GAHT conflict, highlighting a novel indication for prolactinoma surgery. Initially, dopamine agonist (DA) therapy controlled both tumor size and prolactin levels. However, after starting GAHT, her prolactin levels rose despite dose optimization and DA augmentation. While supratherapeutic estradiol initially explained the prolactin increase, levels continued to rise even on therapeutic doses. The tumor's estrogen receptor positivity likely contributed, as prolactin dropped when estradiol was paused and rose again postoperatively upon its resumption. Although MRI showed no residual tumor, the prolactin variability may suggest microscopic residual disease, necessitating long-term monitoring of labs and imaging.

Prolactinomas are typically managed successfully with medication alone, and surgery is infrequently considered [14]. However, when patients exhibit resistance to medical treatment, typically characterized by persistent elevation of prolactin levels despite escalating doses of DA therapy, surgical intervention becomes a viable option. This is particularly pertinent in cases where achieving control through medications proves challenging. Surgery becomes an essential consideration when prolactinomas exhibit aggressive growth patterns, leading to compression of surrounding structures or causing neurological symptoms despite treatment with DA therapy. In such cases, the goal of surgical resection is not only to control prolactin levels but also to alleviate the mass effect, mitigating symptoms and preserving neurological function [15].

A small percentage of patients can be intolerant of DAs, either due to gastrointestinal side effects or the increasingly more recognized psychiatric side effects [16]. In addition, DAs are relatively contraindicated in pregnancy. Although DAs are classified as Category B by the Food and Drug Administration—indicating that animal studies have not demonstrated fetal harm, but adequate human studies are lacking—there is a standard practice of discontinuing these agents during pregnancy due to the absence of robust human safety data. This can create the occasional surgical indication of relief of mass effect in preparation for likely regrowth of large tumors in proximity of the optic apparatus, prior to initiating pregnancy. In any of these scenarios, surgery can provide cure or dramatically reduce tumor burden, allowing for optimized management of prolactinomas [17].

Finally, when there is uncertainty about the nature of the pituitary adenoma or suspicion of a nonfunctioning tumor, surgery may be recommended for diagnostic purposes. The histopathological analysis of the tumor tissue obtained during surgery can provide valuable insights, aiding in the accurate diagnosis and informing subsequent treatment strategies [18].

Resection of the medial wall of the cavernous sinus in pituitary adenoma surgery has been documented as a safe and effective procedure, exhibiting minimal morbidity while demonstrating commendable rates of both resection and remission [19]. Notably, Pontes et al emphasized the feasibility and favorable outcomes associated with the removal of the medial cavernous wall in their systematic review and meta-analysis of 8 studies that included patients undergoing EES for functional adenomas. This study demonstrates that medial cavernous sinus wall resection was safe (carotid injury rate of 0.5%) and leads to good outcomes with endocrinological remission in 63.3% of cases [20].

It should be noted that some resistant prolactinomas can be invasive to the point of being unresectable by invading beyond the medial cavernous wall to involve the adventitia of the internal carotid artery or lateral cavernous sinus. In these cases, a balance must be struck between surgical morbidity and tumor control, with the final solution often requiring a combination treatment whereby a dramatically reduced tumor burden allows for a significant reduction in DA dose. Additional therapeutic options such as stereotactic radiosurgery and systemic therapy with temozolomide have been utilized, particularly in cases with high proliferative indices (Ki-67 > 3%) and/or o(6)-methylguanine-DNA methyltransferase promoter methylation status suggesting responsiveness to alkylating agents [21, 22]. While these modalities may be appropriate for unresectable or refractory tumors, this patient achieved disease control through surgical resection, and adjunctive therapies were not required at this time. Long-term follow-up will be necessary to monitor for potential recurrence requiring further intervention.

For transgender women, estradiol treatment to induce secondary female characteristics may be pivotal in their gender affirmation. In case reports of transgender women with prolactinomas, optimizing their estrogen regimen or DA medication can typically be used to control their disease [13, 23-25]. In rare cases where DA therapy alone is insufficient, potentially due to estrogen receptor expression on the prolactinoma-promoting growth, management becomes more complex. Here we present a novel indication for EES for prolactinoma, providing a safe and effective treatment option. This surgical intervention allows patients to seamlessly continue with their GAHT, addressing the unique complexities associated with prolactinoma management in this specific demographic.

Learning Points

• A comprehensive evaluation should be performed before initiating hormone replacement therapy to identify potential underlying causes of hypogonadism, such as prolactinoma, which may require alternative management strategies.

• Prolactin levels should be measured before initiating GAHT to rule out a preexisting prolactinoma, as routine prolactin monitoring during GAHT is not necessary in the absence of an adenoma.

• EES can be an effective solution for prolactinomas resistant to dopamine agonist therapy, particularly when hormonal therapy exacerbates prolactin levels or when patients experience significant side effects from medical treatment.

• EES allows for uninterrupted continuation of GAHT, addressing both medical and psychological needs of transgender patients.

• Long-term monitoring of prolactin levels and imaging is essential postsurgery to ensure tumor control and manage potential microscopic residual disease.

Contributors

All authors made individual contributions to authorship. Z.C.G., J.H.L., P.K.F., and P.A.G. were involved in the diagnosis and management of this patient. Z.C.G. and A.F.V. were involved in manuscript preparation and drafting. Z.C.G., A.F.V., J.H.L., P.K.F., G.A.Z., and P.A.G. were involved in manuscript review and editing. Z.C.G. and P.A.G. were responsible for the patient's surgeries. Z.C.G. and P.A.G. were involved in manuscript submission. All authors reviewed and approved the final draft.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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 analyzed during the current study.