#291 ‒ The role of testosterone in males and females, performance-enhancing drugs, sustainable fat loss, supplements, and more | Derek, More Plates More Dates Pt.2

Episode Summary

Executive Summary: Peter Attia and Derek from More Plates More Dates discuss hormone replacement and performance pharmacology, focusing on testosterone, DHT, DHEA, progesterone, Clomid, HCG, and peptides. They emphasize careful candidate selection, the risks of over-optimizing women’s testosterone, the limits of Clomid/HCG as long-term solutions, the FDA’s peptide crackdown, and practical fat-loss strategies that still prioritize diet, training, sleep, and sustainability.

Main Topics: Testosterone, DHT, and androgen biology (Priority: 5/5): They review how testosterone and DHT act through androgen receptors, why DHT is more androgenic, and how these hormones shape muscle growth, sexual differentiation, and virilization risk. Female hormone replacement and over-treatment risks (Priority: 5/5): A major theme is that women are often pushed to supraphysiologic testosterone levels, which can cause acne, voice changes, clitoral enlargement, and other masculinizing effects, especially when compounded dosing is imprecise. DHEA and progesterone in men and women (Priority: 4/5): They debate DHEA’s limited utility in men but possible value in women on oral contraceptives, and discuss progesterone’s calming, sleep-supportive metabolites and possible use in both sexes. TRT decision-making, labs, and fertility preservation (Priority: 5/5): The conversation covers how to evaluate low testosterone, the role of SHBG, free testosterone testing, HCG as a diagnostic/therapeutic tool, and why Clomid or HCG may be preferable in some fertility-preserving scenarios. FDA peptide restrictions and gray-market compounds (Priority: 4/5): They interpret the FDA’s Category 2 peptide actions as a major warning signal that increases legal and compounding risk, while noting that research-chemical sellers continue operating in a gray market. Myostatin, folistatin, and performance-enhancement hype (Priority: 4/5): They examine folistatin/myostatin inhibition, the modest human data so far, and the gap between dramatic animal phenotypes and underwhelming real-world human outcomes. Bodybuilding-style fat loss and appetite suppression (Priority: 5/5): The latter half shifts to practical dieting: food swaps, calorie tracking, protein targets, creatine, caffeine, yohimbine, carnitine, and the importance of gradual deficits and movement for sustainable fat loss.

Key Arguments: Testosterone is a natural hormone with major anabolic and psychoactive effects in both sexes, but the dose-response and side-effect profile differ dramatically between men and women. DHT is a more potent androgen than testosterone and is central to masculinization; excessive exposure in women can cause rapid, sometimes irreversible virilizing changes. Many women on hormone replacement are likely being dosed too high; targets like 200-300 ng/dL total testosterone are described as far above physiologic female ranges. DHEA appears largely unhelpful in men, but in women—especially those on combined oral contraceptives—it may restore testosterone and free testosterone meaningfully. Progesterone may have value beyond reproduction because its metabolites can reduce anxiety and support sleep; however, dosing is highly individual and can have anti-androgenic or suppressive effects. Clomid and enclomiphene can raise testosterone by blocking estrogen feedback, but long-term use may be problematic because they interfere with estrogen signaling in multiple tissues and may affect mood and lipids. HCG is useful for assessing testicular responsiveness and preserving fertility, but it does not provide the same pituitary information as Clomid and is not a simple long-term monotherapy for everyone. The FDA’s peptide actions likely reflect safety and approval concerns, but the market remains active through research-chemical and compounding channels. Myostatin inhibition sounds powerful in theory, but current human folistatin data appear modest and may be confounded by marketing, lighting, and other physique manipulation. For fat loss, the most reliable tools remain calorie control, adequate protein, resistance training, sleep, and gradual titration; supplements and drugs are secondary and often marginal. Creatine remains the strongest OTC performance supplement, while caffeine is the most reliable appetite/energy aid; yohimbine is more situational and can be too stimulating for stressed individuals. Rapid dieting and aggressive deficits can worsen endocrine function and adherence; slower, measured weight loss is more sustainable and preserves lean mass better.

Data Points: Testosterone in men vs women: ~10x higher in men - Derek states men produce testosterone in significantly greater quantities than women. Female testosterone dosing error: 10x the intended dose for ~1 month - Peter describes a female patient who accidentally took a male-physiologic testosterone dose. Female testosterone target criticized: 200-300 ng/dL total testosterone - Discussed as an excessively high target for women on TRT. Female physiologic testosterone example: ~10-20 ng/dL - Peter cites a symptomatic woman with very low testosterone before treatment. DHEA dose in women on OCs: 50 mg/day - Derek cites a study where DHEA restored testosterone while women remained on combined oral contraceptives. Testosterone restoration with DHEA: ~60 ng/dL from ~15 ng/dL - In women on oral contraceptives, DHEA reportedly restored total testosterone to baseline. TRT search interest: Google Trends has skyrocketed over the past decade - Used to illustrate rising public interest in TRT. Clomid dose commonly used: ~50 mg - Derek describes common real-world dosing for men. HCG/Clomid fertility recovery window: Weeks to months; most recover within 1-2 years - Discussing recovery after androgen suppression, even in some abusers. Equilibrium dialysis: Gold standard free testosterone test - Used to contrast with calculated or immunoassay-based estimates. Peter’s testosterone assay discrepancy: 502 vs 381 - Immunoassay testosterone read higher than LCMS in Peter’s bloodwork. Peter’s estradiol assay discrepancy: 41.3 vs 18.3 - Immunoassay estradiol was more than 2x higher than LCMS. Caffeine upper limit: 400 mg/day - Referenced as the FDA’s commonly cited safe threshold. Bodybuilder calorie deficit: ~300 kcal/day - Suggested as a sustainable starting deficit for fat loss. Protein target in a cut: 1 g per lb body weight - Presented as a standard bodybuilding rule to preserve lean mass. Typical stage-lean calories: <2000 kcal/day for sub-200 lb naturals; ~2500-2600 kcal/day for 260 lb pros - Illustrates how body size changes absolute intake even in severe cuts. Testosterone-only non-training study: 600 mg/week - Referenced as a study showing testosterone increased lean mass even without training. Folistatin human effect: ~2 lb lean mass gain and ~1% body fat reduction - Discussed as modest results from early human data. Mature mouse myostatin block: >99% mRNA deletion produced ~25% muscle gain - Used to show that adult intervention may be less dramatic than knockout at birth. Creatine use: Continued through contest prep - Bodybuilders do not necessarily stop creatine before stage. L-carnitine oral bioavailability: ~10-15% - Explains why injectable forms are popular among some users.

Pivotal Quotes: "HRT is serious business." — Peter Atiyah: Peter summarizes the need for caution and competent medical oversight in hormone replacement. "If you are mindful of fertility, it's worth consideration of HCG concurrently with whatever you're going to be using." — Derek: Derek explains why HCG may be important for men who want to preserve fertility while on TRT. "You do not achieve even the outcomes from anabolics without the support of a great infrastructure of diet and training and sleep." — Derek: He emphasizes that drugs cannot substitute for fundamentals in physique development.

Implications: Listeners should treat hormone therapy and peptides as high-stakes interventions, not optimization hacks. The industry is moving toward tighter regulation, while sustainable body composition still depends mostly on diet, training, sleep, and careful medical supervision.