In an older woman receiving subcutaneous testosterone pellets (total 100 mg), the GLP‑1 receptor agonist semaglutide, and estrogen supplementation, why is she not losing weight and what management steps should be taken?

Why Weight Loss May Be Stalled Despite Semaglutide, Testosterone, and Estrogen

The most likely explanation is that semaglutide's weight loss efficacy is significantly reduced in postmenopausal women not on hormone therapy, and the testosterone pellet dose (100mg total) may be insufficient or improperly timed to provide synergistic metabolic benefits. Additionally, several medication-specific and patient factors require immediate evaluation.

Primary Issue: Hormone Therapy Timing and Semaglutide Response

Postmenopausal women on hormone therapy achieve significantly greater weight loss with semaglutide compared to those without HT. In a recent study, women on HT had 16% total body weight loss at 12 months versus only 12% in women without HT when treated with semaglutide 1. The difference was evident as early as 3 months (7% vs 5%) and persisted throughout treatment 1.

Critical Questions to Address:

• What is the estrogen formulation, dose, and route? Oral versus transdermal estrogen may have different metabolic effects 1
• When was estrogen initiated relative to semaglutide? The synergistic effect requires concurrent use 1
• Is the estrogen dose adequate? Subtherapeutic dosing may not provide metabolic benefits 1

Testosterone Pellet Considerations

The 100mg testosterone pellet dose and delivery method require scrutiny. While research suggests potential synergistic effects between sex hormones and GLP-1 agonists on weight reduction 2, several factors may limit effectiveness:

Testosterone-Specific Issues:

• Pellet absorption variability: Subcutaneous pellets have unpredictable release kinetics; serum testosterone levels should be measured to confirm therapeutic range 2
• Dosing inadequacy: 100mg total may be insufficient for metabolic effects in obesity; typical female replacement ranges from 50-100mg every 3-4 months 2
• Timing since last pellet insertion: If >3 months, testosterone levels may have declined below therapeutic threshold 2

Recommendation: Obtain serum total and free testosterone levels immediately. If subtherapeutic, consider increasing pellet dose or switching to more predictable delivery methods 2.

Semaglutide Optimization Assessment

Verify Adequate Dosing and Duration:

Is she on the full 2.4mg weekly maintenance dose? Semaglutide achieves 14.9% weight loss at 68 weeks only at the full 2.4mg dose 3. Lower doses (1.0mg or 1.7mg) produce substantially less weight loss 3.

• Titration schedule: Should have reached 2.4mg after 16 weeks of gradual escalation 4
• Duration at maintenance dose: Requires minimum 12-16 weeks at 2.4mg to assess efficacy 3
• If <5% weight loss after 3 months at therapeutic dose, consider treatment failure 3

Rule Out Medication Non-Adherence:

• Weekly injection compliance: Missed doses significantly reduce efficacy 4
• Proper injection technique: Subcutaneous administration in abdomen, thigh, or upper arm 5
• Storage conditions: Refrigeration required; improper storage degrades medication 4

Concomitant Medication Review

Several medications promote weight gain and may counteract semaglutide's effects 6:

High-Priority Culprits:

• Antidepressants: Mirtazapine, amitriptyline, paroxetine—consider switching to bupropion or sertraline 6
• Antipsychotics: Olanzapine, quetiapine—consider alternatives 6
• Corticosteroids: Even low-dose prednisone impairs weight loss 6
• Beta-blockers: Propranolol, metoprolol—consider switching to carvedilol 6
• Insulin or sulfonylureas: May promote weight gain; consider discontinuation or dose reduction 5

Action: Systematically review and optimize all medications to eliminate weight-promoting agents 6.

Lifestyle and Dietary Factors

Semaglutide requires concurrent lifestyle modifications to achieve optimal results 3, 7:

Essential Components Often Missing:

• Caloric deficit: Minimum 500-kcal reduction below daily requirements 7
• Physical activity: Minimum 150 minutes/week of moderate activity 7
• Resistance training: Critical to preserve lean body mass and maintain metabolic rate 6, 8

Common Pitfalls:

• Compensatory eating: Patients may unconsciously increase caloric intake despite reduced appetite 6
• Liquid calories: Alcohol, sweetened beverages, protein shakes can sabotage weight loss 6
• Inadequate protein intake: Should target 1.2-1.6 g/kg ideal body weight to preserve muscle mass 6, 8

Recommendation: Refer to registered dietitian nutritionist for comprehensive dietary assessment and structured meal planning 6.

Metabolic and Medical Barriers

Screen for Underlying Conditions:

• Hypothyroidism: TSH should be <2.5 mIU/L for optimal metabolic function; even subclinical hypothyroidism impairs weight loss 9
• Insulin resistance severity: Patients with severe insulin resistance (HOMA-IR >5) may have blunted response 2
• Sleep apnea: Untreated OSA impairs weight loss through metabolic dysregulation 7
• Polycystic ovary syndrome (PCOS): May require additional interventions beyond GLP-1 agonists 9

Body Composition Changes vs. Scale Weight:

Semaglutide may be working despite stable scale weight if body composition is improving 8:

• Muscle preservation with fat loss: Resistance training can maintain lean mass while reducing fat mass 8
• Fluid shifts: Initial weight loss includes significant water loss; later plateaus may reflect fluid reaccumulation 8
• Obtain DEXA scan or bioimpedance analysis to assess body composition changes 8

Algorithmic Approach to Management

Step 1: Immediate Laboratory Assessment

• Serum testosterone (total and free)
• Estradiol level
• TSH and free T4
• Fasting glucose and HbA1c
• Comprehensive metabolic panel
• Lipid panel

Step 2: Medication Optimization

• If testosterone <30 ng/dL: Increase pellet dose or switch delivery method 2
• If estradiol <50 pg/mL: Increase estrogen dose or optimize formulation 1
• If semaglutide <2.4mg weekly: Complete titration to full dose 3, 4
• Review and eliminate weight-promoting medications 6

Step 3: Lifestyle Intervention Intensification

• Structured dietary program: 500-kcal deficit with high protein (1.2-1.6 g/kg) 6
• Resistance training: Minimum 2-3 sessions/week to preserve muscle mass 6, 8
• Aerobic activity: 150-300 minutes/week moderate intensity 7

Step 4: Consider Treatment Escalation (if Steps 1-3 fail)

• Switch to tirzepatide 15mg weekly: Superior efficacy (20.9% vs 14.9% weight loss) 3, 7
• Add SGLT2 inhibitor: Complementary weight loss mechanism 9
• Refer for metabolic surgery evaluation if BMI ≥35 with comorbidities 3

Critical Monitoring Points

Reassess at 12-16 weeks after optimization 3:

• If <5% weight loss: Consider treatment failure; escalate to tirzepatide or alternative strategies 3
• If 5-10% weight loss: Continue current regimen with lifestyle intensification 7
• If >10% weight loss: Maintain current approach; monitor for adverse effects 3

Common Pitfalls to Avoid

• Assuming semaglutide alone is sufficient: Requires concurrent lifestyle modifications and hormone optimization 1, 6
• Ignoring hormone therapy timing: Estrogen and testosterone must be at therapeutic levels concurrently with semaglutide 1, 2
• Overlooking medication-induced weight gain: Systematically review all concomitant medications 6
• Neglecting resistance training: Critical to preserve lean mass and metabolic rate during weight loss 6, 8
• Premature discontinuation: Requires minimum 12-16 weeks at therapeutic dose to assess efficacy 3