By Dr. Steven Long, DO, MHA, CPT
Beyond Health | Precision Medicine for High-Performance Living
From Controversy to Clarity
Testosterone replacement therapy (TRT) has evolved from a controversial intervention to a well-studied and increasingly accepted treatment for male hypogonadism. Historically, fears about cardiovascular disease and prostate cancer cast a long shadow over testosterone use. But in early 2025, a major regulatory shift occurred: the FDA removed its black box warning for cardiovascular risk associated with testosterone products, citing the robust results of the TRAVERSE trial. TRT, while not without risks, is now viewed through a more evidence-based lens.
In this post, we cover:
Testosterone Therapy: What It Does and Who It’s For
TRT is indicated for men with confirmed hypogonadism (low serum testosterone on two morning labs plus symptoms) and a clear etiology. It is not approved for age-related testosterone decline alone, though this remains a gray area in clinical practice. Benefits of TRT may include improved energy, libido, mood, muscle mass, bone density, insulin sensitivity, and fat distribution.
However, exogenous testosterone suppresses the hypothalamic-pituitary-gonadal (HPG) axis, often impairing spermatogenesis and reducing fertility. For younger men or those seeking to preserve fertility, this is a critical consideration.
FDA Removes Cardiovascular Risk Warning: What the TRAVERSE Trial Showed
The 2023 TRAVERSE trial enrolled over 5,000 men with hypogonadism and heightened cardiovascular risk and followed them for major adverse cardiovascular events (MACE) including heart attack, stroke, and death. The results: testosterone therapy was non-inferior to placebo, with no increased risk of MACE (Hazard Ratio 0.96, 95% CI 0.78–1.17) (Anawalt et al., 2023).
However, TRT did lead to a slight increase in atrial fibrillation and pulmonary embolism. Most notably, it raised ambulatory systolic blood pressure by 1–2 mmHg. Based on these findings, the FDA removed the cardiovascular boxed warning but added a class-wide blood pressure warning to all testosterone labels (FDA, 2025).
Forms of Testosterone Therapy
Testosterone can be delivered in several forms:
Each form offers tradeoffs in pharmacokinetics, adherence, and side effect profile.
Clomiphene Citrate: The HPG-Sparing Alternative
Clomiphene citrate is a selective estrogen receptor modulator (SERM) that increases endogenous testosterone by blocking estrogen feedback at the hypothalamus and pituitary, thereby increasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This preserves fertility and often improves sperm counts.
In a 2020 review by Herzog et al., clomiphene was shown to increase testosterone levels in men with secondary hypogonadism while maintaining fertility and presenting an overall favorable safety profile. Common side effects include mood changes, visual disturbances, and gynecomastia. It remains off-label for male hypogonadism in the U.S. but is frequently used in practice.
Enclomiphene: The Purified Isomer with a Targeted Effect
Clomiphene is a racemic mixture of two isomers: zuclomiphene (with weak estrogenic effects) and enclomiphene (a more potent estrogen antagonist). Enclomiphene has been investigated as a purer, more targeted option for increasing endogenous testosterone.
A 2014 study published in Fertility and Sterility compared enclomiphene to transdermal testosterone and found that while both increased testosterone, only enclomiphene preserved normal sperm counts (Wiehle et al., 2014).
Despite early promise, enclomiphene has not received FDA approval and is not widely available as of 2025. It remains an experimental but conceptually appealing option for younger men.
Pregnenolone: A Precursor Without Proof
Pregnenolone is the first steroid hormone derived from cholesterol and serves as a precursor for all downstream steroids including DHEA, testosterone, progesterone, and cortisol. However, supplementing pregnenolone has not been shown to reliably increase testosterone levels in humans.
In a 2023 study on shift workers, men with lower pregnenolone also had lower testosterone, suggesting correlation. But trials administering pregnenolone (typically 50–100 mg orally) have failed to produce consistent increases in serum testosterone (Bracci et al., 2023).
Pregnenolone remains popular in the supplement world but lacks solid evidence for testosterone modulation.
Clinical Recommendations
Conclusion: Smarter, More Personalized Hormonal Care
The removal of the cardiovascular black box warning marks a new chapter in the story of testosterone therapy. While the pendulum has swung toward greater acceptance, careful selection and monitoring are still vital. For many men, especially younger ones, clomiphene or future agents like enclomiphene may offer a way to optimize hormonal health without sacrificing fertility.
At Beyond Health, we prioritize precision, personalization, and evidence. Testosterone is a powerful hormone—and when used wisely, it can be part of a transformative approach to long-term health and performance.
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