Is hormone replacement therapy appropriate for treating depression, anxiety, and weight‑loss resistance in an adult patient?

Hormone Replacement Therapy for Depression, Anxiety, and Weight Loss Resistance

Hormone replacement therapy is not appropriate as a primary treatment for depression, anxiety, or weight loss resistance in the general adult population, and should only be considered for depression in perimenopausal or early postmenopausal women (within 10 years of menopause onset or under age 60) who also have concurrent vasomotor symptoms. 1

Depression and HRT: When It May Be Appropriate

HRT can be considered for depression only in a very specific clinical window:

• The American College of Obstetricians and Gynecologists recommends HRT for treating depression in perimenopausal and early postmenopausal women with concurrent vasomotor symptoms, but explicitly not as a primary antidepressant treatment for general depression or for women beyond this therapeutic window 1

• HRT must be initiated within 10 years of menopause onset or before age 60 to maintain a favorable risk-benefit profile, as starting HRT more than 10 years after menopause or after age 60 increases cardiovascular risks that outweigh any mood benefits 1

• Critical pitfall: Recent Danish registry data (2022) found that systemically administered HT was associated with a higher risk of subsequent depression diagnosis, especially in the year after initiation (HR 2.03 for estrogen alone, HR 2.01 for estrogen combined with progestin) 2. This directly contradicts the use of HRT as a depression treatment in most contexts.

For women outside this narrow window or without vasomotor symptoms, conventional antidepressants should be used instead. 1

Anxiety and HRT: Not Recommended

• The American College of Obstetricians and Gynecologists recommends that women with high anxiety-related personality traits, history of premenstrual syndrome, and lower life satisfaction should be cautious when using combined estrogen-progestin therapy, as it may worsen mood symptoms 1

• There is no guideline support for using HRT as a primary treatment for anxiety disorders in any population 1

Weight Loss Resistance and HRT: Limited Role

HRT is not indicated for weight loss resistance as a primary indication. However, specific hormone deficiencies may contribute to weight management challenges:

Testosterone Deficiency in Men with Obesity

• Testosterone replacement in men with obesity and confirmed hypogonadism (morning free testosterone frankly low on at least 2 separate assessments) has been associated with weight loss, improvements in fasting plasma glucose, insulin resistance, triglyceride levels, lean body mass, and waist circumference 3

• Assessment should include morning total testosterone (drawn between 8-10 AM), free testosterone by equilibrium dialysis, and sex hormone-binding globulin in patients with obesity who have signs and symptoms of hypogonadism (decreased energy, libido, muscle mass, body hair, hot flashes, gynecomastia, infertility) 3

• If testosterone levels are low with concomitantly low LH/FSH (secondary hypogonadism), further evaluation is needed to rule out etiologies unrelated to obesity before initiating testosterone replacement 3

Pharmacotherapy for Obesity Takes Priority

• For weight loss resistance, evidence-based pharmacotherapy options include liraglutide 3.0 mg daily (achieving 8.0% weight loss vs 1.8% placebo) or other FDA-approved obesity medications 3

• These medications are appropriate for patients who report inadequate meal satiety, have type 2 diabetes, prediabetes, or impaired glucose tolerance 3

Absolute Contraindications to HRT

Never initiate HRT in patients with: 4, 5

• History of breast cancer or hormone-sensitive malignancies
• Active or history of venous thromboembolism or stroke
• Coronary heart disease or myocardial infarction
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Unexplained abnormal vaginal bleeding
• Age >60 years or >10 years past menopause (for new initiation)

Clinical Algorithm for Decision-Making

Step 1: Identify the primary complaint

• Depression alone → Use conventional antidepressants 1
• Anxiety alone → Use appropriate anxiolytics or SSRIs 1
• Weight loss resistance alone → Consider obesity pharmacotherapy or evaluate for hypogonadism in men 3

Step 2: If depression is present, assess menopausal status

• Perimenopausal or <10 years postmenopausal AND has vasomotor symptoms → Consider HRT 1

• 10 years postmenopausal OR age >60 OR no vasomotor symptoms → Use conventional antidepressants 1

Step 3: If considering HRT, screen for absolute contraindications

• Any contraindication present → Do not use HRT 4, 5
• No contraindications → May proceed with HRT for appropriate indication

Step 4: If weight loss resistance in men, evaluate for hypogonadism

• Check morning testosterone, free testosterone, SHBG 3
• If confirmed hypogonadism after workup → Consider testosterone replacement 3
• If normal testosterone → Focus on obesity pharmacotherapy and lifestyle 3

Important Caveats

• The U.S. Preventive Services Task Force gives a Grade D recommendation (recommends against) routine HRT use for prevention of chronic conditions, as harmful effects exceed benefits in most women 3, 5

• Micronized progesterone is strongly preferred over synthetic progestins as it has lower rates of mood disturbance while still providing endometrial protection 1

• For gender-affirming hormone therapy in transgender individuals, the evidence consistently shows improvements in depression (20% decrease after 1 year) and quality of life, which is a distinct clinical context from cisgender menopausal hormone therapy 1