Secondary Hypogonadism: Causes and Potential Treatment

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.

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.

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.

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.

The use of testosterone therapy among young men has also dramatically risen during the last decade. Reproductive endocrinologists are seeing increasing numbers of men who are infertile due to anabolic steroid use.

"The diagnosis of secondary hypogonadism is being missed and treated as primary hypogonadism," said Dr Turek. "While spontaneous recovery of spermatogenesis may occur following the use of anabolic steroids, studies have shown that treatments, which include SERMs, human chorionic gonadotropin, and aromatase inhibitors, may speed that recovery."

In 2014, the Endocrine Society issued a scientific statement on the use of anabolic steroids and adverse health outcomes to highlight what it sees as an education gap.5 The society stated that media attention has been mostly focused on the high prevalence of performance-enhancing drug use by elite athletes and not on the overall health risks. Subsequently, there appears to be a widespread misperception that performance-enhancing drug use is safe and that adverse effects are manageable.

"There is indeed an increase in anabolic steroid use, and because exogenous testosterone suppresses the hypothalamic‐pituitary-testicular axis (HPT), this results in drug-induced HH. That is a different entity than pathologic HH," said Rebecca Sokol, MD, MPH, professor of medicine and obstetrics and gynecology at the Keck School of Medicine at the University of Southern California in Los Angeles.

"Another cause of drug-induced HH is the increasing use of heroin, naltrexone, and codeine and codeine-like derivatives. Opiates suppress the hypothalamic-pituitary system, dramatically dropping testosterone levels."

Peter Kolettis, MD, professor of urology at the University of Alabama at Birmingham, said the rise in HH due to steroid and testosterone use is a growing problem.

According to Dr Kolettis, studies have shown that replacement testosterone has a strong negative effect on sperm production, and anabolic steroids can harm male fertility in a similar manner.

"More research could be helpful to better understand this problem. It is important to educate men and care providers about the risks these drugs pose to fertility. It is important for men of reproductive age to know that there are risks to their fertility if they use steroids or testosterone," Dr Kolettis told Endocrinology Advisor.

Kenan Omurtag, MD, assistant professor of reproductive endocrinology and infertility at Washington University School of Medicine in Saint Louis, Missouri, said endocrinologists need to speak out on this issue. Not only do endocrinologists need to educate their patients, but they should also discuss the effects of what many may view as harmless supplementation.

"You can listen to any sports radio ads and they are just inundating men about testosterone replacement therapy," Dr Omurtag told Endocrinology Advisor. "They are targeting 30- to 40-year-old men, and many of these men are trying to have a child or a second or third child. There is a misconception that it does not affect their sperm count and some mistakenly think it improves their sperm count."