E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Case presentation:

A 23-year old transfeminine woman was referred for endocrine review of hyperprolactinaemia. Gender affirming hormone therapy (GAHT) had been commenced five-years prior and consisted of subdermal oestradiol 100 mg implants inserted 6-12 monthly, medroxyprogesterone acetate (MPA) 10 mg daily and spironolactone 100 mg daily. She was surgically naïve. Past medical history included depression, well controlled with fluvoxamine 100 mg daily and vitamin D insufficiency treated with cholecalciferol 1000 units daily. There was no significant family history. Physical examination identified gynecomastia (Tanner V) with expressible galactorrhea bilaterally. Resting blood pressure measured 117/80 mmHg and weight measured 97.6 kg, equating to a body mass index of 29.5 kg/m². There was no visual field deficit identified when assessed by confrontation. Hormonal analysis confirmed hyperprolactinaemia with serum prolactin measuring 13,696 mIU/L (normal range; NR 85-500). Magnetic resonance imaging (MRI) of the pituitary identified a right-sided 10.0 x 6.0 mm macroadenoma contained within the sella (Figure 1). A smaller, second adenoma measuring 5.0 x 3.0 mm was visualised within the left pituitary lobe, suggestive of a second adenoma. Cystic changes were present within both adenomas, raising the possibility of previous haemorrhage.

A review of prior results identified that serum prolactin levels had been elevated for several years prior to referral, with mild hyperprolactinaemia first documented three-months after commencement of GAHT. Mild low-level elevations in serum prolactin (<1000 mIU/L) persisted over the following 18-months, after which there was a progressive and exponential increase in serum prolactin to the current level of 13,696 mIU/L (NR 85-500), greater than 25-times the normal upper reference limit (Figure 2). Galactorrhoea had developed in conjunction with the marked increase in serum prolactin. There were no associated headaches or changes to vision or visual fields. Treatment with MPA and spironolactone was temporarily suspended and re-insertion of the next subdermal oestradiol implant was deferred. Prolactin levels decreased by approximately 50% following withdrawal of GAHT, but despite serum oestradiol levels of <300 pmol/L, prolactin remained grossly elevated at 5,307 mIU/L and galactorrhoea persisted.

Treatment with cabergoline was initiated at a dose of 0.5 mg weekly and MPA and spironolactone were recommenced. In place of a subdermal oestradiol implant, topical oestradiol was commenced via 50 mcg patch applied twice weekly. Following three months of treatment, serum prolactin concentrations improved to 140 mIU/L and galactorrhea had resolved.

Discussion:

Prolactin secretion is greater in women than in men. Lactotroph cells of the anterior pituitary are abundant in nuclear estrogen receptor alpha and estrogens are an important stimulator of pituitary lactotroph hyperplasia and prolactin release (1). In animal studies, administration of exogenous estrogens can induce formation of prolactin secreting pituitary tumours. Human data is limited, but also suggest exogenous oestradiol administration plays an important role in prolactin secretion (1).

Approximately one-in-five transgender women will develop hyperprolactinaemia following commencement of GAHT (2). Prolactin levels typically normalise with oestradiol dose reduction, although a subset will develop persistent hyperprolactinaemia with associated pituitary gland hyperplasia (2). In transwomen receiving feminising GAHT, prolactin levels increase in a dose dependent manner following commencement of oestradiol and decrease with dose reduction or oestradiol withdrawal (2, 3). Cyproterone acetate also increases serum prolactin through an unknown mechanism and hyperprolactinaemia can develop in transwomen treated with CPA independent of serum oestradiol concentration (4). Similar elevations in prolactin are not observed when oestradiol is used in combination with spironolactone or when CPA is withdrawn following gonadectomy (4-6). The long term consequences of hyperprolactinaemia in transwomen are unknown, but prolactinomas have been reported in association with GAHT suggesting a possible link between long term oestradiol use and risk of pituitary lactotroph adenomas (7).

Prolactinomas have been reported in multiple transgender women following long-term oestradiol treatment. Prolactinomas are benign functional tumours of the anterior pituitary lactotroph cell and oestrogens are primary regulators of lactotroph cell differentiation and proliferation (1). Transwomen are exposed to lifelong treatment with oestradiol, often at supraphysiologic doses and in conjunction with an anti-androgen. Anti-androgenic agents include cyproterone acetate and spironolactone. The incidence of prolactinoma in transwomen receiving GAHT is higher than in cis-gender women, men and transmasculine individuals, but despite the well-documented association, prolactinomas remain rare among transwomen. Current evidence suggests that risk of incident GAHT-associated prolactinoma is comparable to the increased risk in cis-gender women relative to cis-gender males (7). However, the true prevalence remains unknown and may be higher than reported, as transwomen do not develop typical signs of hyperprolactinaemia (menstrual irregularity) that typically lead to diagnosis in cis-gender women. The relative contribution of oestradiol and other factors to risk of prolactinoma is unknown (8). Whether higher doses and serum concentrations of oestradiol during GAHT proportionally increase risk remains controversial. Ethinyl oestradiol was historically used  as the oestrogen component of GAHT and most reported GAHT-associated prolactinomas have occurred in association with ethinyl oestradiol (7). The relative risk of different oestradiol preparations is not known, although prolactinomas have been reported in association with conjugated oestradiol, oestradiol valerate and intramuscular oestradiol formulations (7). The majority of GAHT-associated prolactinomas have occurred when oestradiol was used in conjunction with CPA (7). Whether CPA exerts a direct effect via progestogenic suppression of hypothalamic dopamine release or acts indirectly via modulation of oestradiol or some alternate mechanism has yet to be determined. Interestingly, there is a clear association between CPA and meningioma, another benign brain tumor (9). However, prolactinoma has not been a prominent feature of CPA use outside of the transgender setting. Prior to this report, GAHT-associated prolactinoma had not been reported in association with alternative anti-androgens such as spironolactone. Spironolactone antagonises the androgen receptor, but unlike CPA does not act centrally to inhibit gonadotrophin releasing hormone secretion. The effect of spironolactone on pituitary lactotrophs is currently unknown, but appears less potent than CPA based on available observational data (4-6).

Predicting prolactin abnormalities is currently not possible and risk factors for development of GAHT-associated hyperprolactinaemia or prolactinoma are not known. Clinical practice guidelines currently recommend periodic monitoring of prolactin levels (10). However, no prolactin cut off has been established as pathogenic for transgender women receiving GAHT and the threshold for further investigation of hyperprolactinaemia remains arbitrary and subject to individual interpretation (10). Although marked hyperprolactinaemia and GAHT-associated prolactinoma are currently uncommon, they may become an increasingly important component of endocrine practice as the number of transwomen seeking GAHT continues to increase. Future research to further elucidate the mechanisms underlying the association between GAHT and hyperprolactinaemia will be important to identify women at risk of hyperprolactinaemia and GAHT-associated prolactinoma.

Take home messages:

• Transwomen receiving GAHT are at risk of hyperprolactinaemia, which can develop early in the course of GAHT
• Transwomen receiving GAHT may be at increased risk for prolactinoma
• Prolactinoma can occur in transwomen receiving spironolactone, and these women should receive similar monitoring to those prescribed CPA as an anti-androgenic agent
• Clinicians should maintain oestradiol at the lowest dose required to suppress testosterone and achieve adequate feminisation to reduce the risk of GAHT-associated hyperprolactinaemia and prolactinoma
• Screening of prolactin levels in transwomen receiving GAHT seems prudent to prevent morbidity related to hyperprolactinaemia and allow for early detection of prolactin secreting pituitary adenomas