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Enclomiphene is a nonsteroidal estrogen receptor antagonist that enhances gonadotropin-dependent testosterone production by the testes.

It has been shown to demonstrate high levels of efficacy for the treatment of secondary hypogonadism.

The classic drug clomiphene (Clomid) was first approved by the FDA in 1967 for the treatment of female infertility specifically as an ovulation inducer. There are two isomers that make up clomiphene: zuclomiphene and enclomiphene. Zuclomiphene was found to have several side effects including unwanted elevations in estrogens and an associated extended half-life (30 days) which contributed to symptoms in men such as emotional lability, erectile dysfunction, and vision abnormalities amongst others.

In contrast, enclomiphene has a shorter half-life (10 hours), was found to raise luteinizing hormone (LH) and follicle-stimulating hormone (FSH), effectively signaling to the testicles to naturally raise testosterone levels without the unwanted estrogenic side effects.


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Enclomiphene has very little efficacy in the treatment of primary hypogonadism as seen with medical diagnoses of testicular insufficiency, testicular injury, or genetic predisposition.

This is critical to understand when this medication is prescribed for testosterone deficiency. In cases of testosterone replacement for extended periods of time, excessive use of testosterone replacement at higher levels, or steroid abuse, we will see irreversible insult to the testicular tissue. In these cases, enclomiphene will have very little effect. In some cases, it’s recommended to start with enclomiphene only to establish what the patient’s maximum baseline will be. If initial labs show a testosterone deficiency, the use of enclomiphene prior to starting testosterone replacement therapy can diagnose whether the cause is primary or secondary hypogonadism. While not the standard for traditional testosterone replacement, this practice can provide much-needed clarity to avoid unnecessary medications that would have very little efficacy.

Secondary hypogonadism is defined as a disruption of the hypothalamus-pituitary-gonadal (HPG) axis. Within the hypothalamus and the anterior pituitary gland, there are estrogen receptors. These receptors are responsible for monitoring excess levels of androgens. The assumption is, evolutionarily speaking, when there is excess estrogen, there is also excess testosterone. When there is systemic inflammation due to alcohol use, obesity and insulin resistance as seen with type-2 diabetes, poor diet, exposure to plastics and other toxic industrial chemicals, there will be an activation of these receptors. The estrogenic receptors then communicate via the hypothalamus pituitary axis to decrease or even shut down the production of gonadotropin-releasing hormone (GNRH). GNRH is responsible for communicating to the anterior pituitary gland to produce follicle-stimulating hormone and luteinizing hormone which then communicates to the testicles to produce testosterone and maintain sperm viability. When there is a significant disruption to this axis, the testicles will cease to produce testosterone, resulting in testosterone deficiency. If the systemic inflammatory effects are felt for a long enough time, this can lead to testicular atrophy in the loss of viable tissue; therefore, making the diagnosis one of primary hypogonadism neutralizing the potential positive effects of enclomiphene. As previously described, an enclomiphene only trial at the onset can diagnose this.

Enclomiphene and TRT

Enclomiphene can be used as a stand-alone treatment for secondary hypogonadism or as an adjunct therapy with exogenous testosterone. Studies have shown a high rate of success amongst men who have viable testicular tissue that has been suppressed by previously mentioned systemic inflammatory conditions.

The most recent study in 2014 demonstrated significant elevations of testosterone without being supraphysiologic after just 14 days. Men demonstrated a 2-to-4-fold increase in testosterone with enclomiphene alone with minimal dihydrotestosterone (DHT) conversion as compared to topical testosterone. Of note, although no studies have been conducted regarding this, enclomiphene may be an appropriate alternative therapy for women who experience high DHT conversion with topical testosterone associated with increased hair growth, clitoromegaly, hair loss, and other unwanted symptoms.

Enclomiphene can also be used while utilizing exogenous testosterone products such as topicals,
injectables, and pellets. Once testicular viability has been proven, enclomiphene can be prescribed as an adjunct therapy to ensure there is no disruption of the hypothalamic pituitary axis with supraphysiologic levels of testosterone that can be seen transiently with testosterone replacement. This adjunct therapy will preserve testicular tissue, sperm viability, and alleviate fertility concerns with younger testosterone-deficient patients.