Most cases of secondary hypogonadism appear to respond to selective estrogen receptor modulator (SERM) therapy. However, intolerance to SERMs is common or they may cause unwanted side effects, according to Paul Turek, MD, director of the Turek Clinic in Beverly Hills and San Francisco, California. 

“I would say there is sea of change in the way we treat hypogonadotropic hypogonadism (HH) lately,” Dr Turek told Endocrinology Advisor. “This is because reproductive urologists have become more comfortable using SERMs off-label for men, and endocrinologists are now learning how effective SERMs can be to help men wean off anabolic steroids. This class of agents is truly ‘bioidentical’ for testosterone replacement, as they augment native or endogenous testosterone levels rather than replacing them with exogenous testosterone.”

SERMs can also help preserve fertility and testicular size, he noted.

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Until now, it has been reported that HH is a rare cause of male infertility. However, the exact incidence is uncertain, and some clinicians believe the rate may be substantially higher than historically reported, according to Dr Turek.

“There are no good studies on the prevalence of secondary infertility. However, given that it is a consequence of stress of all kinds, it is likely to be very common among reproductive-age men,” he said.

Benefits of Clomiphene Citrate

Clinicians now often empirically treat idiopathic oligospermia with clomiphene citrate to increase luteinizing hormone (LH) and subsequently intratesticular testosterone. The known side effects include gynecomastia, weight gain, visual problems, and acne. 

A 3-year study of 46 men with baseline serum testosterone levels of 228 ng/dL showed that clomiphene citrate resulted in significant improvements in several parameters.1 The mean follow-up testosterone levels were 612 ng/dL at 1 year, 562 ng/dL at 2 years, and 582 ng/dL at 3 years. Mean femoral neck and lumbar spine bone density scores also significantly improved.

Dr Turek and his colleagues have also been prospectively studying how clomiphene citrate affects semen quality. Their study included 23 men with total testosterone <250 ng/dL, normal or low LH levels, and clinical symptoms including erectile dysfunction, infertility, and low libido.

The men were given 12.5 mg to 25 mg of clomiphene citrate daily. Hormone response was assessed 3 weeks later, and the agent was titrated to achieve testosterone levels in the range of 400 ng/dL to 700 ng/dL.

Researchers found that 86% of patients had a greater than 50% increase in testosterone. Among a subset of 11 men with infertility who had pretreatment and post-treatment semen analysis available for comparison, 7 (64%) had a greater than50% increase in total motile sperm count.2

“The biggest thing is a new pure version of clomiphene citrate (enclomiphene) for secondary hypogonadism in men,” said Dr Turek, noting that the drug was up for review by the US Food and Drug Administration (FDA) in 2015.

“Clomiphene citrate, although only FDA-approved for women in the United States, increases pituitary gland drive to the testicle to make more testosterone,” he explained. “It’s a pill and works great for some men.”

The FDA was scheduled to decide whether or not to approve enclomiphene, formerly known as Androxal, on November 30, 2015. A meeting of the agency’s Bone, Reproductive, and Urologic Drugs Advisory Committee, which would have helped guide the FDA’s decision, was also scheduled for November 5, 2015. However, the meeting was canceled, with a notice posted to the FDA’s website stating that “outside, expert advice is no longer needed.”3

In a press release, enclomiphene’s manufacturer, Repros Therapeutics, noted that the meeting was canceled “due to questions that arose late in the review regarding the bioanalytical method validation that could affect interpretability of certain pivotal study data.”4

At this time, the FDA has not ruled on the approval of enclomiphene.

Causes of Secondary Hypogonadism

While clinicians have improved medical therapies for treating secondary hypogonadism, Dr Turek stressed the importance of addressing the whole patient by identifying and treating based on specific detectable pathology.

He noted that when treating these men, it is vital to consider how stress may be affecting their overall health. He recommended that when treating low libido, clinicians should consider individualized therapies, such as regular exercise, massage, acupuncture, and yoga, that help rest and restore the nervous system. He noted that a stressed, unhealthy body is a testosterone depressant.