GLP-1 Drugs & Testosterone: The Overlooked Connection
GLP-1 receptor agonists—semaglutide, tirzepatide, and retatrutide (the “tides”). The “tides” have changed the game in obesity medicine. They blunt appetite, improve insulin sensitivity, and produce astonishing fat loss. But that metabolic magic comes with a tradeoff few clinicians address: catabolism.
When caloric intake plummets and protein turnover falters, lean mass melts right along with the fat. That’s where testosterone—the body’s master anabolic hormone—steps in. Understanding how GLP-1–induced catabolism interacts with testosterone-driven anabolism is essential to prevent muscle wasting, metabolic slowdown, and the post-GLP-1 “crash” so many men experience once the novelty wears off.
GLP-1 Drugs: Metabolic Reset or Catabolic Overdrive?
GLP-1 receptor agonists activate incretin pathways that:
Enhance glucose-dependent insulin release
Suppress glucagon
Delay gastric emptying
Blunt hypothalamic hunger signals
All good news for fat loss, but the same mechanisms create a semi-fasted metabolic state. Chronic caloric deficit shifts the body toward gluconeogenesis and proteolysis (lean muscle breakdown) to maintain glucose homeostasis—especially when dietary protein is insufficient.
Studies show up to 30–40% of total weight lost on GLP-1 therapy can come from lean tissue unless anabolic signaling (testosterone, resistance training, protein intake) is preserved.
Kaltoft et al., “Glucagon‐like peptide‐1 receptor agonist-based agents and weight loss composition” (2024) — review reports ~20%-40% of total weight loss is fat-free mass loss with GLP-1RA use. PubMed
“Changes in lean body mass with glucagon‐like peptide-1-based therapies” (Dom-pubs / Wiley) — notes heterogeneity but some trials show lean mass reductions of 40-60% of total weight loss. PubMed+1
Testosterone: The Counterbalance to Catabolism
Testosterone’s anabolic effects extend far beyond libido and mood. Testosterone:
Increases muscle protein synthesis via mTOR activation
Decreases myostatin, the muscle-growth inhibitor
Enhances IGF-1 signaling in skeletal muscle
Promotes satellite cell proliferation and repair
Maintains basal metabolic rate through mitochondrial biogenesis
In other words, testosterone preserves the engine while GLP-1 turns down the fuel supply.
Without adequate testosterone, that caloric deficit turns destructive—sacrificing muscle mass, lowering resting energy expenditure, and setting the stage for rebound weight gain once the peptide stops.
The Hormonal Tug-of-War: GLP-1 vs. the HPG Axis
GLP-1 agonists indirectly affect the hypothalamic-pituitary-gonadal (HPG) axis. Rapid fat loss and declining leptin levels signal “energy scarcity,” suppressing GnRH and reducing LH/FSH output. This transient secondary hypogonadism can manifest as:
Fatigue
Diminished libido
Poor exercise recovery
Plateaued weight loss despite ongoing caloric deficit
In contrast, restoring or maintaining physiological testosterone during GLP-1 therapy preserves the anabolic environment necessary for healthy recomposition.
The Anabolic Advantage: GLP-1 + Testosterone Synergy
When used together, GLP-1 and testosterone therapy form a metabolic one-two punch:
GLP-1 reduces visceral adiposity and improves insulin sensitivity.
Testosterone maintains lean muscle mass, nitrogen balance, and resting metabolic rate.
The combination produces a higher fat-to-lean loss ratio, improving aesthetics, strength, and long-term metabolic stability.
Clinically, men on TRT who start GLP-1 therapy retain far more muscle mass during rapid weight loss and recover faster post-cycle. The reverse is also true—men with low testosterone on GLP-1s often plateau early, feel drained, and rebound once treatment stops.
Protein Synthesis, Recovery, and Metabolic Permanence
Muscle tissue isn’t vanity—it’s metabolic armor. Each pound of muscle burns ~6 kcal/hour even at rest, supports glucose uptake independent of insulin, and provides amino acid reserves for immune and endocrine function.
Testosterone directly upregulates muscle-specific transcription factors (Myogenin, MRF4, and IGF-1Ea) that protect against sarcopenia and cachexia. In contrast, GLP-1–induced caloric suppression without anabolic support promotes loss of contractile proteins and declines in basal metabolic rate.
Hence, pairing GLP-1 therapy with testosterone—and emphasizing protein intake (≥1.5 g/kg) and resistance training—is not “optional optimization.” It’s the difference between fat loss and muscle loss.
In Practice: Balancing the Scales
For men initiating GLP-1 therapy:
Assess baseline testosterone.
If low or borderline, optimize levels before or alongside GLP-1 initiation.
Track body composition, not just weight. DEXA or InBody scans > scale numbers.
Prioritize resistance training at least 3–4x weekly.
Maintain adequate protein and hydration to support nitrogen balance. Shoot for minimum of 0.5 - 0.8 grams of protein per pound of body weight daily.
Mehrtash F. et al., JAMA Internal Medicine (2025): Recommends 1.0–1.5 g/kg body weight (~0.45–0.7 g/lb) during GLP-1–induced weight loss.
🔗 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2836527“Nutritional Priorities to Support GLP-1 Therapy for Obesity” — AJCN (2025): Recommends ~1.5 g/kg of lean mass (~0.7 g/lb FFM).
🔗 https://ajcn.nutrition.org/article/S0002-9165%2825%2900240-0/fulltext
Our goal here is preserving the endocrine and musculoskeletal systems that sustain the new metabolic baseline.
The Functional Medicine View: Repair, Not Replacement
GLP-1s reset the metabolic thermostat. Testosterone rebuilds the frame around it.
In functional medicine, the goal isn’t indefinite pharmacologic maintenance—it’s restoration of natural homeostasis. When used together strategically:
GLP-1 reverses metabolic inflexibility.
Testosterone repairs anabolic signaling pathways.
Nutrition and resistance training lock the gains in place.
That’s what creates a permanent physiologic recalibration, not another yo-yo cycle.
Key Takeaways
GLP-1 therapy without anabolic support can lead to muscle loss and metabolic slowdown.
Testosterone preserves protein synthesis, lean mass, and energy expenditure during GLP-1 treatment.
Combined therapy yields superior recomposition—greater fat loss, better metabolic outcomes, and improved quality of life.
The goal isn’t just weight loss—it’s functional restoration of the male metabolic engine.
Final Word
GLP-1s suppress appetite. Testosterone builds resilience.
Used independently, each has limits. Together, they create a metabolic environment where fat melts, muscle stays, and energy returns. In a world obsessed with shrinking bodies, let’s not forget the importance of maintaining the machinery that keeps them alive.
Let Mars Ascend Men’s Health help you keep the “tides” from turning on you during your weight loss journey!
Authored and Medically Reviewed by
Jay Marsolan, NP-C, PhD, IFMCP
Board-Certified Nurse Practitioner | Functional Medicine Certified Practitioner
Founder, Mars Ascend Men’s Health
With over 30 years in emergency and functional medicine, Jay helps men optimize hormones, metabolism, and performance through evidence-based, personalized care.