What are the potential adverse effects of bioidentical testosterone (intramuscular (IM)/subcutaneous (SQ)/topical), oral progesterone, and topical/subcutaneous estrogen?

Adverse Effects of Bioidentical Hormones: Testosterone, Progesterone, and Estrogen

Bioidentical hormone therapy carries significant risks including cardiovascular events, erythrocytosis, liver toxicity, and fertility impairment, with commercially manufactured FDA-approved products being safer than compounded formulations.

Testosterone Adverse Effects

Administration Route-Specific Effects

• Topical testosterone preparations carry a significant risk of secondary exposure to women and children, potentially causing virilization, precocious puberty, and hyperandrogenism 1
• Transdermal patches cause skin reactions (erythema, pruritus) in up to 66% of users, while gel preparations cause similar reactions in about 5% of users 1
• Intramuscular injections can cause local pain, soreness, bruising, erythema, swelling, nodules, or furuncles at the injection site 1
• Subcutaneous administration shares similar local site reactions as intramuscular injections 1

Cardiovascular Effects

• Testosterone therapy should not be initiated for 3-6 months after cardiovascular events 1
• Some postmarketing studies have shown increased risk of myocardial infarction and stroke with testosterone replacement therapy 2
• Fluid retention can occur, which is generally mild but should be used cautiously in patients with congestive heart failure or renal insufficiency 1

Hematologic Effects

• Erythrocytosis (elevated hematocrit) is a common adverse effect, with higher risk from injections (43.8%) than topical preparations (15.4%) 1
• Risk increases with higher testosterone doses and can potentially lead to increased blood viscosity, which may aggravate vascular disease 1

Reproductive Effects

• Testosterone therapy significantly impairs fertility by interrupting normal spermatogenesis, potentially causing severe oligospermia or azoospermia 1
• Testicular size and consistency often diminish during therapy 1
• Breast tenderness and swelling may occur in some men 1

Other Effects

• Sleep apnea may be exacerbated or develop newly, particularly in men with existing risk factors 1
• Minor effects include acne, oily skin, increased body hair, and flushing 1
• Hypertension is rarely reported 1

Estrogen Adverse Effects (Topical/Subcutaneous)

Cardiovascular Effects

• Increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) 3
• Increased risk of stroke, particularly in women over 50 years 3
• Potential increase in blood pressure 3

Reproductive/Genitourinary Effects

• Abnormal uterine bleeding or spotting 3
• Vaginal candidiasis and other vaginal infections 3
• Application site reactions including burning and irritation with topical preparations 3
• Genital pruritus 3
• Risk of endometrial hyperplasia and endometrial cancer 3

Breast Effects

• Breast tenderness, enlargement, pain, and nipple discharge 3
• Increased risk of breast cancer 3

Other Effects

• Skin reactions: chloasma (may persist after discontinuation), rash 3
• Headache, migraine, dizziness 3
• Mental depression, mood disturbances, irritability 3
• Edema and arthralgias 3

Oral Progesterone Adverse Effects

Cardiovascular Effects

• When combined with estrogen, progesterone may have a less favorable effect on HDL cholesterol compared to estrogen alone 4
• However, micronized progesterone has a more favorable effect on HDL cholesterol than synthetic progestins 4

Reproductive Effects

• When used appropriately with estrogen in women with intact uterus, progesterone prevents the endometrial hyperplasia associated with unopposed estrogen 4
• May cause irregular bleeding patterns 4

Other Effects

• Drowsiness and dizziness (particularly with oral micronized progesterone) 5
• Headaches 5
• Breast tenderness 5
• Mood changes 5

Important Monitoring Considerations

For Testosterone Therapy

• Baseline and follow-up measurements of PSA and hematocrit/hemoglobin levels 1
• Digital rectal examination at baseline and follow-up 1
• Assessment of voiding symptoms and sleep apnea 1
• Initial follow-up at 1-2 months, then every 3-6 months for the first year, and yearly thereafter 1
• Testosterone levels should be measured every 6-12 months while on therapy 1

For Estrogen/Progesterone Therapy

• Regular blood pressure monitoring 3
• Breast examinations 1
• Assessment for signs of thromboembolism 3
• Monitoring for mood changes 3

Important Considerations and Cautions

• Commercially manufactured testosterone products should be prescribed rather than compounded testosterone whenever possible due to quality and potency concerns with compounded products 1
• FDA has not approved any "bioidentical hormone therapy" for prevention of chronic diseases in postmenopausal women 1
• There is a lack of evidence supporting marketing claims that bioidentical hormones are safer or more effective than FDA-approved hormone medications 6
• Compounded bioidentical hormone therapy should not be routinely prescribed when FDA-approved formulations exist 6
• Alkylated oral testosterone should not be prescribed due to risk of liver toxicity 1

Special Populations

• Testosterone therapy should be used with extreme caution in men with existing cardiovascular disease 1
• Estrogen therapy carries higher risks in women over 50 years of age 3
• Testosterone therapy should not be used in men trying to conceive 1
• Careful monitoring is needed when using testosterone in men with sleep apnea risk factors 1