Does testosterone replacement cause weight gain in an older postmenopausal woman receiving 100 mg subcutaneous testosterone pellets, estrogen therapy, and weekly semaglutide?

Testosterone Replacement Does Not Cause Weight Gain in Postmenopausal Women

Testosterone replacement therapy in postmenopausal women does not cause significant weight gain; in fact, the limited evidence suggests it may increase lean body mass without substantially affecting total body weight. 1

Evidence from Women Receiving Testosterone

The most relevant data comes from studies of testosterone supplementation in women with HIV wasting, where testosterone at doses of 150 mg/day showed positive effects on muscle mass and strength but no significant weight gain or muscle mass gain overall 1. A meta-analysis of testosterone therapy demonstrated only minimal differences in total body weight between testosterone and placebo groups, with a difference of just 1.04 kg (0.01-12.10) by random effect models 2.

In postmenopausal women specifically, a 3-month trial of testosterone undecanoate (40 mg every other day) showed that body weight increased by approximately 1 kg, but total body fat did not increase significantly 3. The weight gain was primarily attributable to increased lean body mass rather than fat accumulation 3.

Body Composition Changes Rather Than Weight Gain

The key distinction is that testosterone affects body composition rather than causing overall weight gain:

• Lean body mass increases: Testosterone treatment, particularly when combined with estrogen, significantly increases lean body mass in postmenopausal women 3
• Fat mass remains stable or decreases: Despite modest increases in total weight, fat mass does not increase proportionally 3
• Muscle mass and strength improve: Women receiving testosterone show improvements in muscle mass strength without corresponding increases in total body weight 1

Your Patient's Specific Context

In your patient receiving 100 mg subcutaneous testosterone pellets, estrogen therapy, and weekly semaglutide, several factors work against weight gain:

Semaglutide's Dominant Effect

Semaglutide produces substantial weight loss in postmenopausal women, with studies showing 5.8-5.9% total body weight loss after 4 months at 1 mg weekly 4. Importantly, postmenopausal women on hormone therapy (estrogen) actually demonstrate superior weight loss response to semaglutide compared to those not on hormone therapy, with 16% vs 12% total body weight loss at 12 months 5.

Estrogen's Interaction with Testosterone

Your patient is receiving estrogen therapy, which has important metabolic interactions:

• Oral estrogen increases sex hormone-binding globulin (SHBG), which reduces free testosterone concentrations 6
• This means the bioavailable testosterone reaching tissues is lower than the administered dose would suggest 6
• The combination of testosterone plus estrogen in one study increased lean body mass but still resulted in only 1 kg total weight gain over 3 months 3

Metabolic Concerns with Testosterone

While testosterone does not cause weight gain per se, it does have metabolic effects that warrant monitoring:

• Insulin resistance: Testosterone treatment reduces insulin-induced glucose disposal by approximately 20% in postmenopausal women 3
• Adverse lipid profile: HDL-cholesterol decreases significantly with testosterone treatment 3
• These effects occur even when body weight and fat mass remain stable 3

Clinical Algorithm for Your Patient

If weight gain occurs:

1. Attribute it to factors other than testosterone: Given the powerful weight-loss effect of semaglutide (which is enhanced by concurrent estrogen therapy 5), any weight gain is unlikely due to testosterone
2. Evaluate dietary intake and adherence: Semaglutide's effectiveness depends on continued use and dietary modification
3. Check for fluid retention: Testosterone can cause modest fluid retention, which may manifest as 1-2 kg weight increase without true fat gain 3
4. Monitor body composition: Use DEXA scanning or bioimpedance to distinguish lean mass gain (beneficial) from fat mass gain (concerning) 3, 4

If metabolic parameters worsen:

1. Monitor fasting glucose and HbA1c: Testosterone reduces insulin sensitivity by ~20%, which may counteract some metabolic benefits of weight loss 3
2. Check lipid panel: Expect HDL-cholesterol to decrease with testosterone; this may require adjustment of lipid management 3
3. Consider testosterone dose reduction: If metabolic parameters deteriorate significantly, reducing testosterone dose may be necessary 3

Common Pitfalls to Avoid

• Do not assume weight gain is from testosterone: In a patient on semaglutide plus estrogen, weight gain is far more likely due to dietary non-adherence, medication discontinuation, or other factors 4, 5
• Do not ignore body composition changes: A stable weight may mask beneficial increases in lean mass offset by fat loss 3, 4
• Do not overlook metabolic effects: Even without weight gain, testosterone causes insulin resistance and adverse lipid changes that require monitoring 3
• Do not forget the estrogen interaction: Oral estrogen reduces free testosterone levels, potentially attenuating both beneficial and adverse effects 6

Expected Outcome in Your Patient

Given the combination of therapies, your patient should experience:

• Net weight loss or stability: Semaglutide's effect (enhanced by estrogen) will dominate over any minimal weight effect of testosterone 4, 5
• Improved body composition: Potential increase in lean mass from testosterone, with fat mass reduction from semaglutide 3, 4
• Metabolic trade-offs: Possible insulin resistance from testosterone partially offset by weight loss from semaglutide 3, 4