Can the health impacts of cross-sex hormones be permanent?

Health Impacts of Cross-Sex Hormones: Permanence and Reversibility

Cross-sex hormone therapy produces both reversible and permanent physical changes, with the permanence depending on the specific effect, duration of treatment, and timing of exposure—particularly whether hormones are administered during critical developmental periods. 1

Permanent Changes from Feminizing Hormone Therapy (Estradiol)

The following changes are generally permanent and persist after hormone discontinuation:

• Voice changes do NOT occur with feminizing therapy—the laryngeal prominence and lowered voice pitch from prior male puberty remain unchanged and permanent 1
• Bone structure changes from prior male puberty are permanent and do not reverse with estrogen therapy 1
• Breast tissue development is permanent once established, though some regression may occur if hormones are stopped 1, 2
• Fertility impairment may be permanent after prolonged treatment, though the exact threshold is unclear 1
• Testicular atrophy is likely permanent after extended treatment 1

Reversible changes that resolve after stopping estrogen:

• Decreased muscle mass and strength (returns toward baseline) 1, 2
• Skin softening 1
• Decreased libido and erectile function 1
• Body fat redistribution 2

Permanent Changes from Masculinizing Hormone Therapy (Testosterone)

The following changes are permanent and persist after testosterone discontinuation:

• Voice deepening is permanent due to irreversible thickening of vocal cords 1, 3
• Facial and body hair growth is largely permanent, though some reduction may occur after stopping 1, 3
• Clitoral enlargement is permanent 3
• Male pattern baldness (androgenic alopecia) is permanent if it develops 3
• Bone structure changes are permanent once established 1

Reversible changes that resolve after stopping testosterone:

• Increased muscle mass and strength (gradually returns toward baseline) 1, 3
• Menstrual suppression (menses typically resume within months) 3
• Increased libido 1, 3
• Acne (typically improves) 3
• Body fat redistribution 1

Critical Concept: Organizational vs. Activational Effects

The permanence of hormonal effects depends fundamentally on whether they are "organizational" (permanent developmental changes) or "activational" (temporary functional changes):

• Organizational effects occur during critical developmental periods (prenatal, early postnatal, or puberty) and cause permanent structural changes to tissues, including the brain 1
• Activational effects occur in adulthood and are reversible upon hormone withdrawal 1
• Animal studies demonstrate that postnatal androgens at ages 1-6 months can permanently masculinize brain development and behavior patterns 1
• Gonadal hormones acting during early development create long-lasting "organizational" effects that persist even after gonadectomy, while adult hormone exposure primarily causes reversible "activational" effects 1

Cardiovascular and Metabolic Risks: Persistence After Discontinuation

Cardiovascular risks are primarily present during active treatment but may have lasting consequences:

• Trans women on estrogen have elevated risk of venous thromboembolism, ischemic stroke, and myocardial infarction compared to cisgender individuals 1, 2, 4
• Current ethinyl estradiol use (not past use) is associated with threefold increased cardiovascular death risk, suggesting risk diminishes after discontinuation 5
• Trans women have 51% higher total mortality than general population, primarily from suicide, AIDS, cardiovascular disease, and drug abuse—not all hormone-related 5
• Osteoporosis risk in trans women is permanent without continued hormone therapy after gonadectomy, with 25% developing osteoporosis at lumbar spine and radius 6
• Trans men show no significantly increased mortality or serious morbidity related to testosterone treatment 7, 8, 5

Fertility Considerations

Fertility impacts may be permanent but are not universally irreversible:

• Trans men have successfully achieved pregnancy after testosterone discontinuation, with studies showing primordial follicles preserved even after >1 year of androgen treatment 1
• One case report documented successful oocyte retrieval and live birth in a trans man while still on testosterone 1
• Trans women face likely permanent fertility impairment after prolonged estrogen therapy, though specific thresholds are poorly defined 1
• Fertility preservation (oocyte/sperm banking) should occur before initiating hormones when future biological parenthood is desired 1, 3

Bone Health: Permanent Consequences Without Continued Treatment

Continuous hormone therapy is required to prevent osteoporosis after gonadectomy:

• Profound hypogonadal state after surgical sex reassignment necessitates lifelong hormone replacement to maintain bone density 8
• Discontinuing hormones after gonadectomy leads to accelerated bone loss and osteoporosis 8, 6
• This represents a permanent dependency rather than a reversible effect 8

Clinical Implications for Counseling

When counseling patients about permanence of effects:

• Emphasize that voice changes, bone structure, and certain secondary sex characteristics are permanent depending on which hormone is used 1, 3
• Explain that muscle and fat changes are largely reversible, but structural changes to larynx, skeleton, and hair follicles are not 1, 2, 3
• Discuss fertility preservation before initiating therapy, as permanent infertility may result 1, 3
• Clarify that cardiovascular risks are primarily present during active treatment but may have lasting consequences if events occur 5, 6
• Stress that lifelong hormone therapy is required after gonadectomy to prevent osteoporosis and maintain health 8, 6