What sex steroids, such as fractionated estrogens and total testosterone, are used for hormone replacement therapy?

Sex Steroids in Hormone Replacement Therapy

When discussing sex steroids for hormone replacement therapy, we are referring to 17β-estradiol (not fractionated estrogens) and total testosterone (with consideration of free testosterone index when SHBG is elevated), administered as bioidentical hormones through specific routes of delivery. 1

Estrogen Formulations for HRT

The term "sex steroids" in hormone replacement specifically refers to:

For Women

• 17β-estradiol (17βE) is the primary estrogen used, NOT fractionated or conjugated estrogens 1
• Transdermal 17β-estradiol at 50-100 micrograms daily is the preferred first-line formulation 1, 2
• Oral 17β-estradiol at 1-2 mg daily serves as a second-line option when transdermal is contraindicated 1, 2
• Conjugated equine estrogens (0.625-1.25 mg daily) are mentioned in older literature but are NOT the preferred bioidentical option 1, 3

The critical distinction: Transdermal 17β-estradiol mimics physiological serum concentrations, avoids hepatic first-pass metabolism, minimizes impact on hemostatic factors, and provides superior effects on lipid profiles, inflammation markers, and blood pressure compared to oral formulations 1, 2. It also achieves better bone mineral density outcomes than ethinylestradiol-based contraceptives 1.

Progestin Component (for women with intact uterus)

• Micronized progesterone 200 mg daily for 12-14 days per month is the preferred first choice 2
• Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month is an alternative, though it has less favorable cardiovascular and metabolic effects 1, 2
• Dydrogesterone 10 mg for 12-14 days per month is another option 2
• Critical caveat: Avoid progestins with anti-androgenic effects as they may worsen hypoandrogenism 2

Testosterone Formulations for HRT

For Men

• Total testosterone is measured, but interpretation requires context 1
• When SHBG is elevated (common in alcoholics), the ratio of total testosterone/SHBG (free testosterone index) <0.3 indicates hypogonadism 1
• Morning serum testosterone levels should be obtained due to significant diurnal variation 1
• Transdermal testosterone is the preferred delivery method for hypogonadal men 1

For Women

• Total testosterone levels are assessed when there is menstrual irregularity or evidence of hypogonadism 1
• Free testosterone is a better index of gonadal status than total testosterone, but measurement availability varies by laboratory 1
• Low-dose testosterone gel (50 mg weekly transdermal) combined with estrogen may improve sexual function in postmenopausal women 4

Key Clinical Algorithm

Step 1: Measure morning total testosterone (men) or assess in context of hypogonadism symptoms (women) 1

Step 2: If SHBG is elevated, calculate free testosterone index (total testosterone/SHBG ratio) 1

Step 3: For estrogen replacement:

• First choice: Transdermal 17β-estradiol 50-100 mcg/day 1, 2
• Second choice: Oral 17β-estradiol 1-2 mg/day 1, 2
• Add micronized progesterone if uterus present 2

Step 4: For testosterone replacement:

• Men: Transdermal testosterone (dose adjusted to normalize levels) 1
• Women: Consider low-dose testosterone gel only after estrogen optimization 4

Common Pitfalls to Avoid

• Do not use conjugated equine estrogens as first-line therapy when bioidentical 17β-estradiol is available, as it lacks the superior safety profile of transdermal 17β-estradiol 1, 3
• Do not rely solely on total testosterone in men with elevated SHBG without calculating the free testosterone index 1
• Do not add progestins to women who have undergone hysterectomy (except in cases of residual intra-peritoneal endometriosis) 1
• Do not measure testosterone at random times of day in men, as diurnal variation significantly affects results 1