Myla's notebook

A Detailed Analysis of the Negative Effects of Feminizing HRT

Hey everyone. I'm about to start HRT in the following weeks and my endocrinologist pointed out possible negative effects, but without any sources or actual quantitative data. I decided to search more about it and tested ChatGPT's Deep Research option, which makes detailed reports with lots of citations included (you can see them listed at the end). I believe the result was actually extremely informative!

Negative Effects of Feminizing Hormone Therapy (Transfeminine HRT)

Hormone therapy for transfeminine individuals (male at birth, female gender identity) can profoundly alter physiology. Along with its benefits, it carries certain risks. Below we analyze key negative effects, comparing transfeminine individuals on HRT to cisgender women (and cisgender men where relevant), and discuss mechanisms and evidence. We also review strategies to mitigate these risks.

Breast Cancer Risk

Incidence and Comparison: Transfeminine individuals on long-term estrogen therapy do face a risk of breast cancer, but data suggest it remains markedly lower than in cisgender women. A large Dutch cohort found transfeminine patients had a 46-fold higher breast cancer incidence than cis men, yet only about 30% of the risk observed in cis women (Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands - PubMed). In that study (median 18 years of HRT), 15 breast cancer cases occurred in ~2,260 trans women, yielding a standardized incidence ratio (SIR) of 0.3 relative to cis women (Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands - PubMed). This means trans women’s breast cancer risk, while elevated above cis men’s (who rarely develop breast cancer), is substantially lower than a cis female’s lifetime risk.

Mechanisms: The development of breast tissue under estrogen stimulation is the primary driver. Exogenous estrogen (often with an anti-androgen or progestin) promotes ductal growth and breast cell proliferation, which over years can lead to malignant changes (Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands - PubMed). Notably, tumors seen in trans women are usually estrogen receptor (ER) and progesterone receptor positive (Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands - PubMed), similar to typical postmenopausal breast cancers. The reduced overall risk compared to cis women may reflect later age of breast development (adult onset of breast tissue under HRT) and possibly lower cumulative estrogen exposure over the lifespan.

Evidence and Guidelines: Because risk is not negligible, many experts recommend breast cancer screening for trans women on HRT akin to cis women, especially after many years on estrogen or over age ~50. Current guidelines suggest following cisgender female screening protocols (e.g. mammography starting at age 50 or earlier if risk factors), given documented cases (Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands - PubMed). Ongoing research is examining if specific regimens (e.g. inclusion of progestins) influence tumor risk. Overall, while feminizing HRT raises breast cancer risk above male baseline, it still appears lower than in cis females, and routine monitoring can help early detection.

Venous Thromboembolism (VTE: DVT and Pulmonary Embolism)

Risk Level: Estrogen has well-known pro-thrombotic effects. Transfeminine hormone therapy is associated with an increased risk of venous thromboembolism (blood clots in deep veins and lungs). Multiple studies show higher VTE rates in trans women on estrogen compared to both cis men and cis women. For example, a large cohort analysis found trans women on oral estrogen had about a 2.7-fold higher hazard of VTE compared to cisgender women ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ). Similarly, relative to cis men, the risk may be several-fold higher; one analysis noted VTE occurred in ~5% of trans women after ~7.7 years of estrogen, equating to ~355% higher risk than in cis men (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)). In absolute terms, the incidence is modest (e.g. ~2 events per 1000 person-years in one meta-analysis ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC )), but clearly elevated on a relative basis.

Contributing Factors: The route and type of estrogen play a significant role. Older regimens using ethinyl estradiol (a synthetic oral estrogen once used for transgender care) had especially high thrombotic risk. After clinics shifted to bioidentical 17β-estradiol, VTE rates dropped significantly (Overview of feminizing hormone therapy | Gender Affirming Health Program). Even with estradiol, oral administration undergoes first-pass liver metabolism, increasing production of clotting factors and lowering anticoagulant proteins ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ) ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ). This pro-coagulant shift (elevated factors II, VII, IX, XI and decreased protein C, S, antithrombin) promotes thrombosis ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). By contrast, transdermal estrogen (patches/gels) avoids high liver first-pass concentrations and appears to minimize VTE risk – data in menopausal women show no significant clot risk with transdermal estradiol (Overview of feminizing hormone therapy | Gender Affirming Health Program), and transgender studies similarly report no VTE increase on transdermal formulations ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ).

Other factors include dosage (higher estrogen levels correlate with more risk), additional medications (the anti-androgen cyproterone can independently raise clot risk (Cyproterone acetate and the risk of meningioma)), and baseline patient risk factors (age, obesity, smoking, genetic thrombophilia). Notably, smoking synergistically increases estrogen’s thrombotic risk. All trans women who smoke should be counseled on tobacco cessation at every visit, as smoking while on estrogen further elevates VTE and cardiovascular risk (Overview of feminizing hormone therapy | Gender Affirming Health Program). Still, guidelines note that smoking status shouldn’t categorically bar someone from HRT, but rather prompt risk mitigation (e.g. using transdermal estrogen and encouraging quitting) (Overview of feminizing hormone therapy | Gender Affirming Health Program).

Clinical Manifestations: The VTE risk on feminizing hormones most commonly presents as deep vein thrombosis (DVT) in the legs or pulmonary embolism (PE). Symptoms like unilateral leg swelling/pain or sudden shortness of breath in a trans woman on HRT should raise suspicion. Fortunately, while the relative risk is higher, the absolute risk remains low for most individuals ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ). For perspective, one meta-analysis of ~11,500 transfeminine patients on oral estrogen found an incidence around 2 events per 1000 person‐years ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ). This is comparable to or lower than clot risk seen in cisgender women on oral contraceptives or postmenopausal HRT. Nonetheless, providers remain vigilant: estrogen-related VTE is one of the most common serious complications in transfeminine care ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ) ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ).

Mechanism: Estrogen induces a hypercoagulable state. Within a year of starting HRT, studies document increases in clotting Factors (like IX, XII) and reductions in anticoagulants (protein C, antithrombin) ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ) ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). These changes mirror those in cis women on the Pill or pregnancy. Additionally, estrogen can raise levels of fibrinogen and plasminogen activator inhibitor, tilting the balance toward clot formation. This mechanism explains why risk is higher with oral estrogen (greater hepatic impact). The form of estrogen matters too: ethinyl estradiol is potent in liver effect (and is now generally avoided in transfeminine therapy due to this), whereas transdermal 17β-estradiol has minimal impact on coagulation proteins (Overview of feminizing hormone therapy | Gender Affirming Health Program).

In summary, transfeminine HRT roughly doubles to triples VTE risk relative to cis women (and even more so relative to cis men) ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ) (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)). The risk is driven by estrogen’s pro-thrombotic effects, especially with oral dosing. Proper route selection and patient counseling can greatly mitigate this risk (detailed under Risk Mitigation).

Cardiovascular Disease: Stroke and Myocardial Infarction

Ischemic Stroke: Estrogen-related clotting and possibly blood pressure changes can also increase the risk of ischemic stroke (cerebral infarction). Current evidence suggests transfeminine individuals on hormones have a modestly higher stroke incidence than cisgender peers. A recent meta-analysis reported about a 1.3-fold higher incidence of stroke in trans women vs. cis men (95% CI up to 1.8) (Importance of Sex and Gender Differences in Enrollment and ...). Similarly, compared to cis women, trans women may have ~1.8 times the risk of stroke ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). For example, one cohort observed an ischemic stroke rate of ~4.8 per 1000 in trans women, corresponding to an ~80% higher risk than cis men (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)). Another U.S. study (Kaiser Permanente cohort) initially found no overall stroke difference versus controls over ~4 years on average, but in those who had initiated HRT, stroke rates became more pronounced over longer follow-up (Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study - PubMed) (Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study - PubMed). This suggests that cumulative estrogen exposure over many years might be needed to significantly impact stroke risk.

Myocardial Infarction (Heart Attack): The effect of feminizing hormones on heart attack risk is complex. Some data show trans women have more MIs than cis women, but not more than cis men. In one large study, trans women had a hazard ratio of ~1.8 for MI compared to cisgender women (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)). However, their MI risk was similar to cisgender men (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)) (who inherently have higher heart attack rates than cis women). In other words, a trans woman’s cardiovascular risk profile tends to resemble the male baseline from which she started. After transition, her risk may remain closer to her birth sex’s risk or in between male and female norms. A 2019 study in Circulation likewise found trans women had about 2.5 times higher MI risk than cis women, but no significant increase versus cis men ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). This suggests estrogen therapy does not completely negate the prior lifetime effects of testosterone, cholesterol, etc., that influence male-pattern cardiac risk.

Mechanisms: Several mechanisms could contribute to increased stroke and MI risk in transfeminine people:

Because of these mixed influences, the net cardiovascular risk in trans women is an evolving picture. Early research (with short follow-ups) showed minimal differences, but newer long-term data indicate heightened risk of cardiovascular events (stroke, heart attack) after 5–10+ years of HRT (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)) (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)). It’s important to emphasize that even if relative risk is elevated, many trans women will not experience these events, especially if preventive care is in place. The presence of traditional cardiac risk factors (smoking, diabetes, hypertension, family history) likely plays a bigger role in an individual’s MI/stroke risk than HRT itself. Still, clinicians are advised to monitor blood pressure, lipids, and glucose during therapy, and manage them aggressively to offset any hormone-related increase in cardiovascular risk.

Metabolic Effects and Diabetes Risk

Feminizing hormone therapy induces significant metabolic changes. Key among these are effects on body composition and insulin-glucose metabolism, which can influence diabetes risk.

Body Composition: Estrogen plus androgen suppression causes a shift toward a typically female body composition. Transfeminine patients experience decreased lean muscle mass and increased fat mass over time ( Effects of gender-affirming hormone therapy on insulin resistance and body composition in transgender individuals: A systematic review - PMC ). Prospective studies show loss of muscle bulk (on average a few kilograms of lean mass in the first year) and a relative increase in body fat percentage. In fact, trans women’s body fat percentage tends to rise into the range of cis women, while muscle mass drops partway toward female norms ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). For example, one study found adolescent trans women on estradiol had ~31% body fat vs ~28% pre-HRT (and cis men ~20%, cis women ~35%) ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). This redistribution (more subcutaneous fat on hips/thighs, less visceral abdominal fat) can have mixed metabolic implications: more subcutaneous fat is metabolically benign, but loss of muscle can reduce basal metabolism and glucose uptake.

Insulin Sensitivity: Evidence suggests feminizing HRT can worsen insulin sensitivity in many patients. A systematic review reported that 5 of 8 studies on trans women found increased insulin resistance after starting estrogen (the others found no change) ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). In one controlled experiment, insulin sensitivity (measured by glucose tolerance tests) decreased in trans women on estrogen ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). Trans women have been found to be significantly more insulin resistant than cis men; one study noted a lower insulin sensitivity index in trans women vs male controls (0.078 vs 0.142 mL/μU, P = 0.011) ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). The likely causes are the reduction in muscle mass (a major site of glucose disposal) and gain in fat mass, along with direct hormonal effects. Estrogen can affect how muscle and liver respond to insulin – some data from cisgender research suggest high doses of estrogen may impair insulin’s action on muscle. Additionally, use of certain anti-androgens (like high-dose cyproterone) might contribute to weight gain and insulin resistance, though data are limited.

Glucose and Diabetes Risk: With increased insulin resistance, the risk of developing type 2 diabetes could rise for trans women on long-term HRT. However, hard outcomes data are still emerging. Some population studies hint at a trend toward higher diabetes prevalence in transfeminine cohorts, but confounders (like weight and lifestyle) are hard to parse. It’s noteworthy that testosterone (in cis men) tends to promote insulin resistance, whereas estrogen in cis women is generally insulin-sensitizing – yet in trans women, the scenario is unique because the intervention (adding estrogen + blocking testosterone) is abrupt and often leads to weight gain. The World Professional Association for Transgender Health (WPATH) notes that metabolic syndrome features should be monitored during feminizing therapy. Clinicians often check fasting glucose or A1c periodically. While no dramatic spike in diabetes incidence has been proven, early studies indicate a potential uptick in risk ( Cardiovascular Risk in Transgender People With Gender-Affirming Hormone Treatment - PMC ). For instance, one analysis observed higher odds of metabolic syndrome components in trans women on HRT, including elevated fasting glucose and triglycerides (though not always reaching diabetic range).

Lipid Profile: As a brief aside, estrogen’s effect on blood lipids in trans women appears generally favorable:

In summary, feminizing HRT may reduce insulin sensitivity and increase body fat, potentially elevating the long-term risk of type 2 diabetes. It’s recommended to monitor weight, blood sugar, and cholesterol during therapy. Encouraging a healthy diet and regular exercise is important to counteract these metabolic shifts. Some trans women actually improve their lifestyle (diet/exercise) during transition, which can offset HRT effects. Thus, with good preventive care, many metabolic changes can be managed such that the net health impact is minimized.

Hyperprolactinemia and Prolactinoma

Prolactin Changes: Estrogens stimulate the pituitary gland’s lactotroph cells. Many trans women on HRT develop elevated prolactin levels (hyperprolactinemia), especially when high estrogen doses are used in combination with certain antiandrogens. Typical physiologic prolactin in adult males is relatively low; under estrogen exposure, prolactin often rises into the female reference range or above. Studies have documented prolactin increases of over 100% from baseline in trans women on estradiol, particularly when combined with cyproterone acetate (a potent antiandrogen with progestogenic activity) ( Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review - PMC ) ( Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review - PMC ). For example, one study observed median prolactin jumping from ~8 ng/mL to ~19 ng/mL (a 149% increase) over 12 months with estrogen + cyproterone, whereas estrogen + spironolactone caused only a ~35–45% increase ( Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review - PMC ) ( Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review - PMC ). This indicates cyproterone amplifies prolactin elevation relative to other blockers.

Prolactinoma Risk: The critical question is whether these prolactin rises lead to prolactinomas – benign pituitary tumors. Fortunately, prolactinomas in transfeminine individuals are rare. Current guidelines (WPATH and Endocrine Society) note that only a few case reports of prolactinomas in trans women have been published, and no increase in tumor incidence was seen in large cohorts (). In one series from the Netherlands involving thousands of trans women on long-term HRT, clinically significant prolactinomas were not observed, despite hyperprolactinemia being common in those on cyproterone. As the Endocrine Society states: “Given that only a few case studies reported prolactinomas, and prolactinomas were not reported in large cohorts of estrogen-treated persons, the risk is likely to be very low.” (). In other words, while many trans women get elevated blood prolactin, it usually does not progress to a pituitary adenoma.

Cases and Severity: The few documented cases of prolactinoma in transfeminine patients typically involved high-dose estrogen use over many years (often non-standard doses or older estrogen formulations) or the combination of estrogen + cyproterone. These patients presented with symptoms like headaches, visual field changes (from optic chiasm compression), or galactorrhea (milk discharge), similar to prolactinoma presentations in other populations (Prolactinoma in a Male to Female Transgender Woman on Gender ...). Treatment (dopamine agonists like bromocriptine or surgery in large tumors) has been successful in the reported cases. The prolactinomas were generally benign microadenomas. So far, no evidence suggests that trans women develop more aggressive prolactin tumors than cisgender women – if anything, the overall incidence is lower than might be expected given the degree of prolactin elevation.

Monitoring: Even though the risk is low, guidelines recommend periodic prolactin monitoring in trans women on estrogen, especially if also on cyproterone or if symptoms occur ( Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review - PMC ). A common practice is to check prolactin at baseline, then annually for a few years. Mildly elevated prolactin without symptoms (e.g. <100 ng/mL) is usually observed. If levels rise substantially or symptoms of a tumor appear, an MRI of the pituitary is warranted. In practice, significant hyperprolactinemia is more frequently an issue with cyproterone. One study showed prolactin elevations returned to baseline after stopping cyproterone (post-orchiectomy), reinforcing the link ( Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study - PMC ). Trans women on spironolactone or GnRH analogues plus estradiol rarely get very high prolactin levels.

Bottom Line: Prolactin elevation is a known side effect of feminizing HRT. However, clinically relevant prolactinomas are exceedingly rare (). The risk is low, but prudent monitoring is advised. Patients should report any unexplained headaches, vision changes, or nipple discharge. Overall, fears of prolactinoma should not deter appropriate HRT use, given the low incidence – just something to be mindful of during long-term care.

Meningioma Risk with Cyproterone Acetate

Cyproterone acetate (CPA) is a powerful antiandrogen often used in transfeminine regimens (particularly in Europe). It is essentially a synthetic progestogen with anti-testosterone effects. Long-term use of high-dose cyproterone has been linked to meningiomas, which are usually benign tumors of the brain lining (meninges). This association has come to light in recent years through large epidemiological studies.

Risk Magnitude: A French nationwide cohort study in 2021 (covering over 250,000 cyproterone users) demonstrated a clear dose-dependent risk of intracranial meningioma (Cyproterone acetate and the risk of meningioma). Women who accumulated ≥3 grams of CPA (equivalent to >25 mg/day for 6+ months) had a significantly higher incidence of meningiomas than those on lower doses (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed) (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed). The incidence among high-dose users was about 23.8 per 100,000 person-years vs 4.5 per 100,000 in low-dose users (a more than fivefold difference) (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed). After adjusting for confounders, the hazard ratio was ~6.6-fold for the exposed group vs controls (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed). Moreover, extremely high cumulative exposure (>60 g total) drove the risk even further – with an HR of ~21.7 in that subset (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed). In practical terms, using 50–100 mg of cyproterone daily for several years markedly raises one’s risk of developing a meningioma.

Even transfeminine-specific data reflects this risk. In the French study, a subgroup of about 10,000 trans women on CPA showed a similarly elevated meningioma incidence (~20.7 per 100,000 person-years) (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed). Meningiomas were especially noted in certain locations (skull base regions rich in hormone receptors) in CPA users (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed).

Mechanism: The biological mechanism is thought to be related to progesterone receptor activation in meningeal tissues. Meningiomas often express progesterone receptors, and cyproterone, being a progestin, can strongly stimulate these receptors (Cyproterone acetate and the risk of meningioma) (Cyproterone acetate and the risk of meningioma). This hormonal stimulation likely promotes growth of latent meningioma cells. In essence, CPA “feeds” the meningioma much like progesterone can. This is analogous to rare cases of meningioma growth seen with other high-dose progestins (some contraceptives and hormone therapies). The risk is dose and duration dependent – which is why it’s mainly seen at CPA doses ≥25 mg/day and long treatment spans (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA)) (Cyproterone acetate and the risk of meningioma). Low-dose CPA (1–2 mg in birth control pills) has not shown this risk (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA)).

Significance: While meningiomas are usually benign and slow-growing, they can cause serious issues (seizures, neurological deficits) and often require surgery or radiation if symptomatic. Thus, this risk is clinically significant. The observed frequency in high-dose CPA users (on the order of 1 in 4,000 users per year at highest doses (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed)) is considered rare but noteworthy. European regulators now warn that “the occurrence of (multiple) meningiomas is associated with longer-term use of cyproterone at doses of 25 mg/day or higher” (High-dose cyproterone acetate: potential risk of (multiple ... - GOV.UK) (Cyproterone acetate and the risk of meningioma). France and other countries have even restricted CPA’s indications and recommend annual neurological monitoring for those on high doses.

What Transfeminine Patients Should Know: Trans women taking cyproterone should be informed of this risk. Signs of meningioma can include headaches, changes in vision or hearing, or memory problems (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA)) (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA)). If such symptoms arise, imaging (MRI) is indicated. Guidelines now suggest using the lowest effective CPA dose or considering alternative blockers (see Risk Mitigation). If a trans woman on CPA is diagnosed with a meningioma, CPA must be permanently discontinued (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA)) (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA)), as tumors often stabilize or even regress off the drug.

In summary, prolonged high-dose CPA use confers a clear meningioma risk. Mechanistically it’s tied to progestogenic stimulation of meningeal cells. The risk is “very low” in absolute terms (estimated between 1–10 cases per 10,000 people (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA)) (Restrictions in use of cyproterone due to meningioma risk | European Medicines Agency (EMA))), but given the seriousness, it warrants caution. Many clinics have shifted to other antiandrogens or reduced CPA dosing as a result.

Bone Health (Bone Density and Osteoporosis)

Sex hormones are crucial for bone density maintenance. In transfeminine individuals, the removal or suppression of testosterone combined with estrogen therapy creates a new hormonal milieu for bones. The net effect on bone mineral density (BMD) can vary depending on treatment details, but with proper management estrogen can protect bone health similarly to how it does in cisgender women.

Baseline Factors: Some studies suggest trans women may enter HRT with suboptimal bone metrics. One study found transfeminine patients had lower physical activity, muscle strength, and vitamin D levels than cis men (Bone health and osteoporosis | Gender Affirming Health Program) – all factors that could predispose to lower BMD even before treatment. Another analysis noted trans women had somewhat lower bone mass and cortical bone size than cis men prior to HRT, possibly due to lifelong differences in weight-bearing exercise or nutrition (Managing skeletal issues in transgender and gender ... - Mayo Clinic). These pre-existing factors mean bone health is an important consideration from the start.

Effect of HRT on BMD: Research has shown mixed outcomes:

A systematic review encompassing various regimens found conflicting results, likely because of those protocol differences (timing of estradiol start, dosing, length of follow-up) (Bone health and osteoporosis | Gender Affirming Health Program). On balance, estrogen appears to preserve bone density in transfeminine people, akin to its role in postmenopausal HRT, provided levels are in the female physiologic range.

Critical Risk Factor – Hormone Gaps: The greatest risk to bone health is under-supply of estrogen. Known risk factors for osteoporosis in trans women include prolonged periods without hormones after gonad removal, or use of puberty blockers/androgen blockers without concomitant estrogen (Bone health and osteoporosis | Gender Affirming Health Program). If a trans woman undergoes orchiectomy (removal of testes) and either stops or significantly reduces estrogen (for instance, due to cost or other issues), she essentially enters an acute menopause and can lose bone rapidly. Similarly, a trans woman on a GnRH analog or high-dose blocker who delays starting estradiol will have low sex hormones and likely bone loss. WPATH advises avoiding any long gaps in hormone therapy for this reason.

Studies confirm that GnRH analogues alone (without estradiol) cause a drop in BMD over time (Bone health and osteoporosis | Gender Affirming Health Program). However, when estrogen is added or blockers are stopped, bone density tends to return to normal (Bone health and osteoporosis | Gender Affirming Health Program). In trans women who adhere to therapy, BMD generally remains comparable to cisgender women of the same age. In fact, small studies show trans women on stable estrogen have BMD in the osteopenic range no more frequently than cis women. Trans women also tend to have had the higher peak bone mass from male puberty, which may offer some advantage.

Comparison to Cisgender People: Compared to cis men (who have higher bone density on average), trans women’s BMD will usually decrease somewhat with transition, trending toward female norms. Compared to cis women, trans women’s bone density is similar or slightly higher (owing to larger bone size from male development). Importantly, estrogen is the key hormone for bone in all sexes – cis men rely on aromatization of testosterone to estrogen for bone maintenance. Thus, once a trans woman is on estrogen, her bone metabolism is supported much like a cis woman’s. If estrogen levels are in the normal female range, significant bone loss is not expected. Indeed, one long-term Dutch study found osteoporosis rates in older trans women were not higher than in cis women, provided they were consistently on estrogen.

Guidelines: There are no unique bone screening rules for trans people yet, but experts recommend standard osteoporosis screening (DEXA scans) by age 65 for all, and earlier (50–64) if risk factors exist (Bone health and osteoporosis | Gender Affirming Health Program). A trans woman who had an orchidectomy and then went several years without HRT should be considered high-risk and get a bone density test regardless of age (Bone health and osteoporosis | Gender Affirming Health Program). Lifestyle measures (calcium, vitamin D, exercise) are advised similar to the general population. Overall, with continuous estrogen therapy, bone mass is preserved in transfeminine individuals – interrupted or inadequate hormone therapy is the main threat to bone health (Bone health and osteoporosis | Gender Affirming Health Program).

Other Health Risks and Considerations

Beyond the major categories above, a few additional risks and observations from recent research are worth noting:

It’s clear that current research continues to refine our understanding of transfeminine health risks. Most risks are manageable with proper medical supervision. Importantly, the quality-of-life and mental health benefits of gender-affirming hormone therapy are significant and must be weighed against these medical risks ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ) ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ). Informed consent and personalized care enable most trans women to navigate these risks safely.

Risk Mitigation Strategies

Despite the above risks, there are effective ways to minimize health dangers while allowing transfeminine individuals to reap the benefits of HRT. Key strategies involve optimizing the hormone regimen and addressing modifiable risk factors:

Adjust Hormone Dosages to the Lowest Effective Level

Prefer Safer Routes and Medication Options

Lifestyle and Preventive Health Interventions

In conclusion, risk mitigation is about smart prescribing and holistic care. By using safer hormone regimens (correct dose, route, and medications) (Overview of feminizing hormone therapy | Gender Affirming Health Program) and addressing lifestyle factors, providers can significantly lower the risks of feminizing hormone therapy. Modern medical guidelines emphasize that with proper oversight, hormone therapy for transfeminine individuals can be administered safely and effectively, with risks comparable to those of cisgender hormone therapies (Overview of feminizing hormone therapy | Gender Affirming Health Program). The goal is to maximize gender-affirming benefits while minimizing adverse outcomes – something very much achievable with today’s knowledge and a proactive approach.

Sources:

  1. de Blok CJM et al. (2019). Breast cancer risk in transgender people receiving hormone treatment: Nationwide cohort study. BMJ, 365, l1652. – Incidence of breast cancer in trans women vs cis men/women (Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands - PubMed).
  2. Wierckx K et al. (2013). Venous thrombosis and changes in coagulation profile during cross-sex hormone therapy in trans people. J Sex Med, 10(12), 3129-37. – Highlights estrogen-induced VTE risk and importance of route (transdermal vs oral) ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ) (Overview of feminizing hormone therapy | Gender Affirming Health Program).
  3. Getahun D et al. (2018). Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons. Ann Intern Med, 169(4), 205-213. – Cohort study on VTE, stroke, MI in trans populations (trans women had higher VTE; stroke/MI risk differed vs cis men/women) (Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study - PubMed) (Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients | GE HealthCare (United States)).
  4. Baker KE et al. (2021). Hypercoagulability and Cardiovascular Risk during Gender-Affirming Hormone Therapy. Clin Chem, 67(1), 132-142. – Review of thrombosis mechanisms in GAHT; notes oral estrogen ~3-fold VTE risk vs cis women, transdermal no increase ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ).
  5. Hembree WC et al. (2017). Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 102(11), 3869-3903. – Standard guidelines; advise prolactin monitoring and note prolactinoma risk is very low (only rare cases reported) ().
  6. Nota NM et al. (2019). Prolactin in transgender women after orchiectomy. Andrologia, 51(10), e13404. – Found prolactin levels drop to baseline after stopping cyproterone post-orchiectomy ( Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study - PMC ). Confirms CPA’s role in elevating prolactin.
  7. Donato D et al. (2020). Cyproterone acetate and risk of intracranial meningioma. BMJ, 371, m4457. – French cohort: dose-dependent meningioma risk with CPA (HR ~6 for >3g; ~22 for >60g cumulative) (Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study - PubMed). Led to EU warnings (Cyproterone acetate and the risk of meningioma).
  8. UCSF Transgender Care Guidelines (2016). Primary Care Protocol for Transgender Patient Care. – Recommends transdermal estrogen for those >40 or with VTE risk, and tobacco cessation counseling for all trans women on HRT (Overview of feminizing hormone therapy | Gender Affirming Health Program) (Overview of feminizing hormone therapy | Gender Affirming Health Program). Also discusses bone health screening and maintaining post-gonadectomy hormones (Bone health and osteoporosis | Gender Affirming Health Program).
  9. World Prof. Assoc. for Transgender Health (WPATH) Standards of Care, 8th Version (2022). – Emphasizes need for ongoing monitoring (lipids, glucose, prolactin) and risk reduction in hormone therapy. Notes benefits outweigh risks when managed properly ( Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk - PMC ).
  10. Cheung AS et al. (2020). Effects of GAHT on insulin resistance and body composition in transgender individuals: Systematic review. World J Diabetes, 11(3), 66-77. – Summarizes that trans women on HRT lose lean mass, gain fat, and may worsen insulin resistance ( Effects of gender-affirming hormone therapy on insulin resistance and body composition in transgender individuals: A systematic review - PMC ), underlining need to watch metabolic health.

#en #hr #other