Follicle-Stimulating Hormone and Inequality in Idiopathic Male Infertility

Should FSH be used to treat infertility in men more often?

With Manuela Simoni MD PhD and Nick Tadros MD

A meta-analysis of 15 controlled clinical studies covering over 1200 men with idiopathic infertility where half were given FSH treatment and half were given a placebo or remained untreated found promising results.

Sperm may be the smallest cells in the human body, but their shape, motility, and numbers are products of complex endocrine, paracrine, and autocrine interactions. Although the interactions in the male are no less complex than those that govern ovarian function in women, the level of research and clinical application regarding fertility in women far outweighs that of men. Thus, the term “idiopathic male infertility” has become a common label for men, even if they might have an identifiable cause to their infertility and a potential course of treatment.

Sexual inequality in fertility treatment

It is estimated that between 8-15% of couples are affected by infertility. Infertility of the male partner is estimated to contribute to 50% of those couples, with 20-30% of the infertility due solely to the male partner. This means that in a substantial portion of the couples, the female is fertile, however she bears the larger burden in assisted reproductive therapy (ART) technologies. Infertility therapies do not usually address the male partner, especially if it is idiopathic.

Manuela Simoni MD, PhD, Professor of Endocrinology at the University of Modena and Reggio Emilia, Italy, told EndocrineWeb, “The male ‘part’ in couple's infertility is still under considered. All data demonstrate that both the female and the male of an infertile couple should be investigated and, as the woman is referred to the gynecologist, the man should be referred to the andrologist.” A recent review by Dr. Simoni and colleagues addresses this inequality, reviews the available data, and proposes an option for enhancing sperm production and quality in idiopathic male infertility based on the follicle-stimulating hormone (FSH) and its receptor, FSH-R.

FSH influences fertility

FSH is a gonadotropin hormone released by the pituitary. It independently supports the initial meiotic stages of spermatogenesis, then co-dependently with testosterone matures spermatids into functioning spermatozoa. FSH interacts with FSH receptors expressed on Sertoli cells, the “nurse” cell of the testes, to support sperm quantity and quality. For review see Simoni and Santi, 2019.

In the current Simoni review, the authors point out that FSH treatment has been used with success in men with hypogonadotropic hypogonadism (HH), who fail to produce FSH, luteinizing hormone (LH), and gonadotropin-releasing hormone (GrH). In light of the success observed in HH men, there are no evidence-based guidelines for using hormone treatment in male infertility. Based on clinical reports and meta-analyses, HH men are typically treated with twice-weekly injections of 1000-2500 IU human chorionic gonadotropin (hCG) and thrice weekly injections of 75-225 IU of FSH. The intent in HH men is to stimulate testosterone production, spermatogenesis, and ultimately fertility.

It is argued by Dr. Simoni and others that FSH could be used in men with idiopathic infertility following a similar course of FSH treatment. A meta-analysis of 15 controlled clinical studies covering over 1200 men with idiopathic infertility where half were given FSH treatment and half were given a placebo or remained untreated found promising results. The odds ratio for spontaneous pregnancy after FSH treatment was 4.5 compared to controls. In pregnancies resulting from ART, FSH treatment had only a modest effect, with an odds ratio of 1.6.

In their review, Simoni et al. state that only 30-50% of infertile men experience elevated sperm count in response to FSH treatment, prompting the group to propose a pharmacogenetic approach to male infertility to identify FSH responders and non-responders.

SNPs and the pharmacogenetics of male infertility

Single nucleotide polymorphisms or SNPs occur when one nucleotide in a gene sequence gets exchanged for another. In the FSH receptor gene on chromosome 2 p21, within codon 680 (N680S), a single alanine (A) can be exchanged for a glycine (G), changing an asparagine (Asn) into a serine (Ser) and causing the downstream clinical results to greatly affect fertility in both men and women.

In men, changes in N680S may be related to sperm number. A large prospective study looked at the genetic profile of proven fathers (“fertile”, n=240) to azoospermic (no sperm, n=150) and oligospermic (low sperm; n=120) infertile men. All three groups had statistically similar serum FSH levels. Most men (>= 60%), regardless of status, had no N680S changes, being homozygous asparagine (Asn/Asn).

The heterozygous profile, Asn/Ser, was most often associated in azoospermic males (30.7%) and less often in oligospermic (10.8%) or “fertile” (20.4%) of males. Interestingly, homozygosity for the serine SNP (Ser/Ser), was found in both oligospermic (20.8%) and fertile (15.4%) males more frequently than the azoospermic (6.6%). A single nucleotide exchange in one FSH receptor gene (Asn/Ser) was associated with the complete absence of sperm.

In women, the N680S polymorphisms determine how responsive a woman is to exogenous FSH. Those with a serine SNP in one or both chromosomes (Asn/Ser or Ser/Ser) have been given higher doses of FSH treatment during in vitro fertilization (IVF) to obtain good ovarian response. In females, a pharmacogenetic approach to treating infertility is embraced.

Polymorphisms also occur within the FSH b-subunit gene, where guanine (G) exchanges for thymine (T) near the transcription starting point (-211; FSHB rs10835638). Overall, men are more likely to be homozygous for the major form, G-G, regardless of fertility status. The researchers, though, found a shift in infertile men towards expressing the heterozygous form (G-T) and the minor homozygous form (T-T), more frequently than the population-based cohort. Expression of the T-T genetic profile was also associated with lower serum FSH levels, lower testicular volume, and decrease sperm motility even though sperm count and semen volume were similar.

To summarize these studies, EndocrineWeb turned to Nick Tadros, MD, Director of Men’s Health and Male Infertility at Southern Illinois University. Dr. Tadros said:

“The majority of men with idiopathic or unexplained infertility likely have a genetic basis for their fertility problems, we have just not discovered the specific genes and proteins yet. This paper (Simoni et al, 2020) is a good example of the importance of FSH and the FSH receptor as potential causes and treatment targets in these patients. The more we understand the genetic basis of the pathways, receptors, and proteins in mediating spermatogenesis, the more potential treatment opportunities we will find.”

How do we move forward, equally?

When asked this question, Dr. Simoni answered that “the best would be if the two professionals (gynecologists and andrologists) operated together with the therapeutic approach decided collegially. Furthermore, we should aim for surpassing the necessity of ART when the problem is only on the male side.”

In other words, it takes two to get pregnant. The therapeutic burden should not disproportionately fall on the female partner, especially when there is evidence to support therapeutic interventions for the infertile male partner.

Dr. Tadros leaves us with a view of a brighter future for infertile couples:

“I believe that pharmacogenetics will fundamentally change how we treat infertility. ‘Idiopathic’ male infertility will become a term regulated to history books as we find more specific causes of these men's infertility. This will allow us to offer better, customized treatments to our patients with better results than the treatments we currently have. In addition, more men will want to undergo testing since they know there will be successful treatments available to them.”

Drs. Bjugstad and Tadros report no conflicts with regard to discussing this study. Dr. Simoni reports receiving grants and honoraria from Merck, Ferring and IBSA.

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