What is the recommended treatment for an adult woman with clinically significant low testosterone (low free or bioavailable testosterone, normal estrogen, symptoms of reduced libido, fatigue, or diminished well‑being)?

Treatment of Low Testosterone in Adult Women

For adult women with clinically significant low testosterone (low free or bioavailable testosterone, normal estrogen, symptoms of reduced libido, fatigue, or diminished well-being), testosterone replacement therapy is recommended as an adjunct to estrogen therapy, particularly in surgically menopausal women or those with premature ovarian failure. 1, 2

Diagnostic Confirmation Required

Before initiating treatment, confirm the diagnosis with:

• Measure free testosterone or calculate bioavailable testosterone using total testosterone divided by sex hormone-binding globulin (SHBG), targeting values in the lower one-third of the female reproductive range 1, 3
• Verify adequate estrogen status through clinical assessment and serum estradiol measurement, as testosterone therapy should be given to estrogen-replete women 1, 4
• Document specific symptoms: diminished libido, persistent unexplained fatigue, decreased sense of well-being, or reduced sexual receptivity and pleasure 1, 4
• Exclude other contributing factors such as depression, relationship issues, medications, or medical conditions that could explain symptoms 4

Primary Treatment Options

Testosterone Formulations for Women

Oral methyltestosterone combined with estrogen is the most commonly approved product in the United States, typically dosed as 1.25 mg esterified estrogen plus 2.5 mg methyltestosterone, or half-strength at 0.625 mg estrogen plus 1.25 mg methyltestosterone 5

Alternative formulations include:

• Testosterone implants for sustained release 4
• Testosterone creams compounded for women 4
• Transdermal patches and sprays (in development or available in some countries) 4, 3

Dosing Considerations

• Use physiological replacement doses designed specifically for women, as products developed for men produce androgen levels that are too high and unsafe 3, 5
• Target testosterone levels in the mid-normal female range, avoiding supraphysiological concentrations 4, 5
• Monitor free testosterone levels rather than total testosterone alone, especially in women on oral estrogen which increases SHBG and reduces bioavailable testosterone 1, 3

Expected Treatment Outcomes

Women receiving appropriate testosterone replacement can expect:

• Significant improvement in libido and sexual function, with enhanced interest in initiating sexual activity and improved response to sexual stimulation 1, 2
• Improved sense of well-being and reduced anxiety and depression 1, 2
• Relief from persistent fatigue and increased energy 1, 2, 4
• Symptom improvement typically occurs within weeks to months of achieving physiological testosterone levels 2, 4

Special Populations

Surgically Menopausal Women

Women who have undergone oophorectomy are among those most likely to benefit from testosterone therapy, as testosterone and androstenedione levels decline by approximately 50% after ovarian removal 1, 3

• These women often experience more severe androgen deficiency symptoms than naturally menopausal women 1
• Combined estrogen-androgen therapy offers additional benefits including improved vasomotor stability and reduced triglyceride levels 5

Women on Oral Estrogen Therapy

Oral estrogen administration significantly increases SHBG, which reduces free testosterone and estradiol, potentially worsening androgen deficiency 1, 3

• Consider switching to transdermal estrogen delivery to minimize SHBG elevation 3
• If oral estrogen must be continued, testosterone supplementation becomes even more important 3

Age-Related Androgen Decline

Androgen levels decline by 50% from the early 20s to mid-40s in normal women, meaning age-related androgen insufficiency may occur in women in their late 30s and 40s, not just postmenopausally 4

Safety Monitoring and Adverse Effects

Low-Dose Testosterone Safety Profile

When used at appropriate physiological doses (1.25 mg methyltestosterone or equivalent), adverse effects are minimal 5

• Liver dysfunction is unlikely with low-dose therapy 5
• Adverse lipid effects are minimal, and the regimen may actually reduce triglycerides 5
• Virilization risk is low when maintaining physiological testosterone concentrations 4, 5

Required Monitoring

• Monitor for signs of androgen excess: acne, hirsutism, voice deepening, clitoral enlargement 4, 5
• Check lipid profiles periodically, noting that estrogen-androgen combinations typically reduce triglycerides 5
• Assess liver function if using oral methyltestosterone, though dysfunction is rare at recommended doses 5
• Add progestogen if the uterus is intact to prevent endometrial hyperplasia from unopposed estrogen 5

Cardiovascular and Bone Effects

• Estrogen-androgen therapy offers beneficial cardiovascular effects, primarily through improved lipid profiles and vasodilation 5
• Positive effects on bone density have been demonstrated 2, 5
• The marked reduction in triglycerides is particularly important for surgically menopausal women who have elevated baseline triglyceride levels 5

Critical Pitfalls to Avoid

• Do not use testosterone products formulated for men, as these produce supraphysiological levels unsafe for women 3, 5
• Do not initiate testosterone without confirming adequate estrogen status, as testosterone is an adjunct to estrogen therapy, not a replacement 1, 4
• Do not rely on total testosterone alone in women taking oral estrogen, as elevated SHBG masks true androgen deficiency; always assess free or bioavailable testosterone 1, 3
• Do not attribute symptoms solely to psychosocial factors without biochemical assessment, as true androgen deficiency is frequently overlooked 2, 4
• Do not forget progestogen in women with intact uteri receiving estrogen-androgen therapy 5

Treatment Algorithm Summary

1. Confirm low free or bioavailable testosterone (lower one-third of female range) with sensitive assay 1, 4, 3
2. Verify adequate estrogen status and document specific symptoms (libido, fatigue, well-being) 1, 4
3. Exclude other causes of symptoms through comprehensive evaluation 4
4. Initiate low-dose testosterone (e.g., 1.25 mg methyltestosterone with estrogen or equivalent transdermal/implant formulation) 4, 3, 5
5. Monitor response at 3-6 months: assess symptom improvement, free testosterone levels, and adverse effects 2, 4
6. Adjust dose to maintain physiological testosterone levels and optimize symptom relief 4, 5
7. Continue long-term monitoring for efficacy and safety, though long-term safety data remain limited 2, 3