Effects of Estradiol and Cyproterone Acetate on Prolactin in Transfeminine Hormone Therapy
Introduction
Transfeminine (MTF) hormone therapy typically combines 17β-estradiol (the main feminizing estrogen) with an antiandrogen to suppress testosterone. One commonly used antiandrogen, cyproterone acetate (CPA), is a progestogenic androgen blocker. Both estradiol and CPA can influence prolactin secretion, a pituitary hormone. Elevated prolactin (hyperprolactinemia) and even rare prolactin-secreting adenomas (prolactinomas) have been reported in transgender women on hormone therapy[1][2]. This report examines how each drug – estradiol and CPA – independently affects prolactin levels, as well as their combined effects, drawing on clinical studies, reviews, and guidelines. Differences related to estradiol administration routes (especially transdermal vs. oral or injectable) are also discussed.
Estradiol’s Impact on Prolactin
Mechanism: Estrogen is known to stimulate the growth and activity of lactotroph cells in the pituitary. In fact, estrogens are “powerful stimulators” of prolactin synthesis and release[3]. Thus, introducing estradiol in a transfeminine individual can lead to some increase in serum prolactin.
Magnitude of Prolactin Increase: Clinical evidence indicates that estradiol therapy alone tends to cause a mild to moderate rise in prolactin levels, usually within or just above the female-reference range. For example, in one 2-year study of 39 transfeminine patients (most on estradiol plus an antiandrogen), mean prolactin rose from about 14 ng/mL pre-treatment to 23.5 ng/mL post-treatment (an increase of ~9 ng/mL)[4]. This change was statistically significant (p=0.02) and represents roughly a sixty- to seventy-percent increase, but importantly all values remained in a relatively moderate range (averaging ~24 ng/mL, which is near the upper limit of female-normal in many labs)[4]. None of these patients developed a prolactinoma during the observation period[5]. Similarly, other cohort data have shown that estradiol-alone regimens rarely cause prolactin levels to exceed the normal female range. In a large 12-month study of 882 trans women, no cases of prolactin above 600 mIU/L (upper-normal) were observed in those treated with estradiol without cyproterone[6]. This suggests that bioidentical estradiol by itself, at typical doses, only modestly elevates prolactin and uncommonly induces frank hyperprolactinemia[7].
Clinical Guidelines Perspective: Due to estrogen’s known effect on prolactin, older guidelines recommended periodic prolactin monitoring in trans women on estradiol therapy as a precaution[8]. However, accumulating evidence indicates that estradiol-induced prolactin elevations are usually mild. The UCSF Transgender Care guidelines note that prolactinomas under modern estradiol regimens are only a theoretical risk, with several case reports in the literature but no clear evidence of a higher incidence than in cisgender women[9]. As a result, routine prolactin screening in asymptomatic patients on estradiol is often not recommended; many experts now check prolactin only if symptoms of hyperprolactinemia arise (e.g. unexplained galactorrhea or headache/visual changes)[10]. The latest WPATH Standards of Care (2022) similarly do not mandate routine prolactin monitoring, instead advising individualized decision-making based on the regimen and patient symptoms[11].
Estradiol Dose and Route Considerations: An important question is whether the route of estradiol administration (transdermal vs. oral vs. intramuscular injectable) affects prolactin response. There is limited direct comparative research on this in transfeminine populations, but available evidence suggests no major difference in prolactin elevation between routes when achieving similar estradiol levels. In the aforementioned 39-patient study, about one-third were on transdermal patches and two-thirds on oral estradiol, yet no separate difference in prolactin outcomes was reported – overall prolactin rose modestly in the cohort regardless of route[12][4]. Similarly, an Endocrine Society practice study found no correlation between estradiol blood levels and prolactin levels in trans women on standard estrogen therapy[13], implying that higher systemic estrogen (such as from injected or high-dose oral estradiol) did not necessarily produce higher prolactin than moderate levels (transdermal tends to give steadier moderate levels). Notably, oral ethinyl estradiol (a synthetic estrogen used in older protocols) was linked historically to higher prolactin surges and a few prolactinoma cases[14]. However, ethinyl estradiol is now avoided in gender-affirming therapy due to its thrombosis risks, and modern use of transdermal or micronized estradiol is thought to be safer for prolactin as well. In summary, transdermal estradiol does not appear to uniquely minimize prolactin elevations – all bioidentical estradiol routes cause some mild prolactin rise, but the key driver of marked prolactin increases in transfeminine therapy is usually not estradiol itself but concurrent cyproterone acetate (as discussed next)[7][15].
Cyproterone Acetate’s Impact on Prolactin
Cyproterone acetate (CPA) is a potent antiandrogen with progestogenic properties. CPA has a well-documented tendency to raise prolactin levels in transgender women on estrogen therapy[16]. The mechanism is thought to involve CPA’s progestin activity and a reduction in hypothalamic dopamine tone[16]. (Dopamine normally inhibits prolactin release; CPA may lessen this inhibition, thus increasing prolactin secretion.) Several clinical studies have quantified CPA’s effect on prolactin:
- Systematic Review Findings: A 2020 systematic review compiled data from 17 studies and found that adding CPA was associated with prolactin increases of over 100% (more than doubling the level) on average in trans women, whereas by comparison another antiandrogen (spironolactone) was associated with a more modest ~45% increase[17]. Notably, the review authors cautioned that most trans women in these studies were on both estrogen and an antiandrogen, so isolating CPA’s independent effect was difficult[18]. Nonetheless, the disproportionate rise in the CPA groups suggests CPA is a major contributor to prolactin elevation.
- Prospective Cohort Data (Short-Term): In a Dutch study of 61 transgender women, the introduction of estradiol + CPA (50 mg/day) caused mean prolactin to jump from ~150 mIU/L at baseline to ~440 mIU/L by 3 months[19]. By 12 months, prolactin remained elevated (~440–460 mIU/L on average), with 30% of patients exceeding the normal reference upper limit (~600 mIU/L)[19]. Importantly, when CPA was discontinued after gonadectomy (while continuing estradiol), prolactin levels fell back to baseline (~160 mIU/L)[20]. This reversal strongly implicates CPA as the cause of the prior prolactin rise, since estradiol alone (post-gonadectomy) did not sustain the elevation.
- Prospective Cohort Data (Longer-Term): A Belgian study of 107 trans women on estradiol + CPA 50 mg showed a similar pattern. Mean prolactin increased from ~200 mIU/L at baseline to ~500 mIU/L after 12 months on therapy[21]. In those who underwent orchiectomy and stopped CPA, prolactin dropped back near baseline (~216 mIU/L)[22]. In those who continued CPA beyond 12 months (no gonadectomy), prolactin at 18 months was somewhat lower (~300 mIU/L) but still above the starting baseline[23]. These findings confirm a CPA-associated prolactin rise of roughly 2- to 2.5-fold within the first year, plateauing thereafter.
- Dose-Dependency: The degree of prolactin elevation correlates with CPA dosage. A large 12-month study (882 trans individuals) found no hyperprolactinemia at all in estradiol-only patients, but among those on CPA, higher doses led to higher prolactin incidence[6]. Hyperprolactinemia (PRL >600 mIU/L) occurred in ~9% of patients on low-dose CPA (10 mg/day), ~12–14% on moderate doses (25–50 mg), and ~14% on high dose (100 mg)[7]. Similarly, a retrospective analysis comparing mean CPA ~12 mg vs. ~62 mg showed prolactin rose in both groups over 12 months, but ended significantly higher in the high-dose CPA group (even after adjusting for estradiol levels)[24]. These data illustrate a clear dose-response: higher CPA doses cause greater prolactin elevations.
- Comparison to Other Antiandrogens: Notably, CPA’s prolactin effect is stronger than that of spironolactone or GnRH agonists. Randomized trials have directly compared CPA vs. spironolactone in feminizing regimens and consistently found higher prolactin levels with CPA[25]. Even at a low CPA dose (12.5 mg/day), prolactin rose (though remained under twice the ULN over 6 months) while spironolactone produced no significant change[26]. Likewise, retrospective studies show CPA users have higher PRL than those on GnRH analogues (e.g. leuprolide)[27]. In one such comparison, mean prolactin climbed from ~237 to 574 mIU/L in 1 year with CPA, versus a negligible change (260 to 313) with leuprolide[27]. Only 5% of CPA patients in that study developed prolactin above the normal range (none had extreme elevations)[28]. Taken together, these findings underscore that CPA – more so than other antiandrogens – tends to elevate prolactin, likely due to its unique pharmacologic actions.
In summary, cyproterone acetate frequently causes moderate hyperprolactinemia in transfeminine individuals. The typical pattern is a doubling or tripling of baseline prolactin levels within a few months of starting CPA, especially at higher doses[17][19]. While this rise often plateaus below the threshold of clinical concern (e.g. usually <1000 mIU/L in most cases), mild elevations are common. CPA’s effect is reversible – stopping CPA (such as after gender-affirming surgery) usually brings prolactin back down to baseline[20].
Combined Effects and Comparative Analysis
In practice, transfeminine patients are often on combined estradiol + CPA therapy, so it’s useful to consider their interaction on prolactin levels. The evidence indicates that estradiol and CPA together have an additive (or synergistic) effect, with CPA being the dominant contributor to elevated prolactin:
- Estradiol Alone vs. With CPA: On estradiol monotherapy (or estradiol + a non-CPA blocker), prolactin tends to increase only slightly or not at all above the female-normal range[6][29]. But when CPA is added, prolactin levels rise more markedly. For example, in one cohort the mean prolactin on estradiol + spironolactone (no CPA) remained essentially unchanged over time and did not exceed reference norms[29]. By contrast, with estradiol + CPA, the mean prolactin in comparable patients was higher and often above the cis-female reference interval[30]. One analysis noted that the CPA group’s mean prolactin was above the normal range, whereas the spironolactone group’s was not, suggesting CPA (rather than estrogen) was the key factor in the elevation[30]. In short, combined estradiol–CPA therapy produces significantly higher prolactin levels than estradiol alone.
- Clinical Significance of Prolactin Elevation: The mild-to-moderate prolactin elevations seen with estradiol+CPA are usually asymptomatic. Most reported prolactin values in studies (e.g. ~20–30 ng/mL, or 400–600 mIU/L) are below the typical threshold that causes symptoms like galactorrhea. However, a subset of patients on high-dose estrogen and CPA in older studies did develop more pronounced hyperprolactinemia and even prolactinomas. The largest series (2,555 trans women, many from eras of higher dosing) found 9 cases of prolactinoma (~0.35% incidence), mostly microadenomas; only 5 of these had any symptoms (galactorrhea or hypothyroid from pituitary effect)[2]. This corresponded to a standardized incidence ratio (SIR) about 4-fold higher than cisgender women[2]. When only clinically significant (symptomatic) prolactinomas were considered, the incidence in trans women was not statistically different from the general population (SIR ~2.4, 95% CI overlapping 1)[31]. Thus, prolactinoma remains a rare complication. Most cases reported involved older hormone regimens (e.g. very high estrogen doses or ethinyl estradiol plus high-dose CPA) that are no longer standard[14][32]. Current feminizing protocols using moderate-dose 17β-estradiol (100–200 pg/mL levels) and lower CPA doses have not been clearly linked to new prolactinoma formation in the short-to-mid term, though long-term vigilance is warranted.
- Guideline Recommendations: Reflecting the above data, medical guidelines take a balanced approach. The Endocrine Society (2017) suggests checking prolactin at baseline, annually during the first few years of feminizing therapy, and every 2 years thereafter[8]. This conservative stance accounts for the potential (albeit low) risk. In contrast, many experienced clinicians and other guidelines (e.g. an Italian consensus, WPATH SOC8) do not recommend routine prolactin monitoring in the absence of symptoms[33]. They argue that mild prolactin elevations are expected on estrogen+CPA and usually benign, and that indiscriminate monitoring could lead to unnecessary imaging and anxiety[8][34]. Instead, the focus is on symptom-triggered evaluation. If a patient on feminizing hormones develops signs of hyperprolactinemia (nipple discharge, breast milk production, headaches or vision changes suggesting a pituitary mass), then prolactin is measured and appropriate workup (e.g. MRI) done. Absent symptoms, a modest prolactin elevation (for example, 600–1500 mIU/L) can often be managed by observation or by adjusting the hormone regimen (such as lowering the CPA or estradiol dose and rechecking levels)[35][36]. Only markedly high prolactin levels (e.g. >2000–3000 mIU/L, roughly >100–150 ng/mL) raise strong suspicion for prolactinoma and warrant imaging in a patient without symptoms[37][38]. Fortunately, in studies of trans women on estradiol+CPA, prolactin rarely exceeds those levels[19][39].
Bottom Line – Comparative Summary: Estradiol and cyproterone acetate each influence prolactin, but CPA’s effect is much more pronounced. Estradiol alone typically causes a slight rise in prolactin (often staying within normal female range)[7]. Cyproterone acetate, especially at higher doses and in combination with estrogen, frequently drives prolactin to elevated levels (often 2× or more above baseline)[17][19]. The two together can yield prolactin levels in the upper-normal to mildly high range for many trans women on therapy. This is usually a benign, transient phenomenon – after gender-affirming surgery when CPA is stopped, prolactin levels tend to normalize[20]. The risk of true prolactinomas appears very low, and mainly associated with old high-dose regimens[2]. Modern management focuses on achieving feminization goals with the lowest effective estradiol and CPA doses (to minimize side effects)[40], and on being vigilant for symptoms rather than chasing laboratory prolactin numbers in the absence of clinical signs. In summary, transdermal estradiol (or other routes) causes modest prolactin increases, whereas CPA adds a significant additional effect on prolactin. Clinicians tailor monitoring and therapy accordingly, recognizing that mild prolactin elevation is a common side effect of feminizing hormone therapy, particularly with CPA[16][6].
References
- Deutsch MB. Overview of Feminizing Hormone Therapy. UCSF Transgender Care Guidelines (2016). – Discusses estrogen and antiandrogen use, noting prolactinomas as a theoretical risk with estrogen therapy[9][34].
- Nolan BJ et al. “Approach to prolactin monitoring and hyperprolactinaemia in transgender individuals undergoing GAHT.” Front Endocrinol (2025). – Comprehensive review of prolactin in trans women, including CPA’s impact (doubling prolactin), dose-dependent effects, and monitoring recommendations[19][6].
- Wilson LM et al. “Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review.” Int J Transgend Health 21(4):391-402 (2020). – Found CPA raises prolactin ~100% vs. ~45% with spironolactone, though could not fully separate estrogen vs antiandrogen effects[17]. Concluded prolactin may increase on E+AA therapy and called for studies comparing estrogen alone to combination regimens[18].
- Hayon M et al. “Prolactin concentration in male-to-female transsexual subjects following cross-sex hormone therapy.” Endocrine Abstracts 56:P975 (2018). – A 2-year study: estradiol (oral or patch) plus CPA led to a modest prolactin rise (~14→23 ng/mL) with no prolactinomas observed[4]. Confirms estrogens typically cause mild prolactin elevation[3].
- Asscheman H et al. “Prolactin levels and pituitary enlargement in hormone-treated male-to-female transsexuals.” Clin Endocrinol (Oxf) 41(4): 428-435 (1994). – Older study reporting incidence of significant hyperprolactinemia and some pituitary changes in trans women on high-dose conjugated estrogens and CPA (historical interest; not cited above but provides context for prolactinomas in past regimens).
- Bisson JR et al. “Prolactin levels do not rise among transgender women treated with estradiol and spironolactone.” Endocr Pract 24(7):646–651 (2018). – Found no significant prolactin increase in trans women on estradiol + spironolactone over several years, and no correlation between estradiol levels and prolactin[29]. Highlights that estrogen therapy without CPA is not strongly hyperprolactinemic.
- Simoncini T et al. “Prolactinoma induced by estrogen and cyproterone acetate in a transgender woman.” Fertil Steril 94(4):e37–e40 (2010). – Case report of a prolactin-secreting microadenoma after 2 years of high-dose conjugated equine estrogen plus CPA[41]. Illustrates the extreme end of prolactin effects, underscoring the importance of today’s safer dosing practices.
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