Testosterone Versus Enclomiphene

In this Unbreakable Podcast episode, host Ben Greenfield sits down with hormone expert Dr. John Crisler to dissect the pros and cons of traditional testosterone therapy versus enclomiphene citrate—a novel, fertility-preserving alternative for men with low testosterone. The discussion opens with an overview of typical exogenous testosterone treatments, including gels, injections, and pellets, and how they effectively raise serum testosterone levels but can shut down the hypothalamic-pituitary-gonadal (HPG) axis. This suppression often leads to reduced endogenous luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production, which in turn can impair sperm production and testicular size. Dr. Crisler then introduces enclomiphene, the trans-isomer of clomiphene citrate, explaining how it selectively antagonizes estrogen receptors at the hypothalamus. By blocking negative feedback from circulating estrogens, enclomiphene stimulates gonadotropin release—boosting LH and FSH secretion—so that the testes resume their own testosterone and sperm production. The pair review the limited clinical trials showing that enclomiphene can normalize testosterone levels while maintaining or even improving markers of fertility, such as sperm count and motility. They compare dosing protocols, noting that enclomiphene is typically administered orally at low daily doses, whereas testosterone requires weekly or biweekly administration and carries risks like erythrocytosis, lipid changes, and prostate tissue stimulation. Dr. Crisler emphasizes the importance of regular lab monitoring—tracking testosterone, estradiol, hematocrit, lipids, and prostate-specific antigen—to fine-tune treatment and avoid adverse effects. The conversation also delves into practical considerations: cost, insurance coverage, off-label prescribing, and patient selection. Ben and Dr. Crisler discuss scenarios in which enclomiphene might be preferred—especially younger men who wish to preserve fertility or those concerned about long-term HPG suppression. They touch on the pharmacology of enclomiphene versus clomiphene’s two isomers, and why enclomiphene’s action may result in fewer side effects and more predictable increases in testosterone. Toward the end, they cover anecdotal patient experiences, address misconceptions about estrogen’s role in men, and outline future research needed—particularly larger, long-term trials comparing enclomiphene directly with various testosterone formulations. The episode concludes with a balanced assessment: while exogenous testosterone remains a powerful tool for symptom relief in hypogonadal men, enclomiphene represents a promising, fertility-friendly approach for those who qualify and are carefully monitored.