Follicle stimulating hormone (FSH) is a glycoprotein secreted by the pituitary gland under the control of the pulsatile gonadotropin hormone-releasing hormone (GnRH) secretion, of the activinfollistatin-inhibin B loop, and of testosterone, which modulates its oligosaccharide complexity that affects the FSH receptor affinity at the target organ. FSH plays a crucial role in the hormonal control of spermatogenesis in humans: it determines the number of Sertoli cells at neonatal and peripubertal age, modulates the expression of a great number of Sertoli cell genes, is a survival factor for spermatogonia and increases their differentiation and proliferation, seems to be involved in the pubertal onset of spermatogenesis, and although its action on spermatogenesis is limited to the progression of meiosis until the pachytene spermatocytes stage, experimental studies suggest that it may also influence the process of spermiation and of sperm chromatin condensation.
FSH treatment has been proven effective in promoting spermatogenesis in men with hypogonadotropic hypogonadism, who may achieve pregnancies mostly by natural conception, regardless of the final sperm concentrations reached. This has prompted the experimental use of FSH treatment in infertile patients with normal hypothalamic and pituitary function. According to the latest Cochrane systematic review on this matter, this treatment significantly improves the spontaneous pregnancy rate per couple, but it does not affect the IUI or IVF pregnancy rate. A more recent meta-analysis, however, which included both randomized and non-randomized controlled clinical trials, found that the treatment improved the IVF pregnancy rate compared to no treatment; the number needed to treat (NNT) was, however, high (10 patients to be treated to achieve one spontaneous pregnancy and 18 to achieve an IVF pregnancy). When, however, higher FSH dose was used (300 UI on alternate days), the NNT decreased to 12 and 6 for spontaneous and ART pregnancies, respectively. This latter study suggests that patients who did not respond to FSH treatment in previous studies probably did not receive a sufficiently high FSH dose for a sufficient time to stimulate spermatogenesis.
The identification of responders to FSH treatment has been the matter of several studies. The basal serum FSH levels alone are insufficient to predict response in idiopathic infertile men, and the socalled “pharmacogenetic approach to male infertility”, which identifies the possible responders to treatment based on the discovery of single nucleotide polymorphisms in FSH beta subunit or FSH receptor gene, has produced conflicting results. On the other hand, the identification, among infertile men with oligozoospermia, of distinct epigenetic biomarkers in FSH-responders compared to non-responders to FSH treatment, suggests that epigenetic diagnostics may be applied to select the optimal candidates for such a treatment.
Written by:
- Ettore Caroppo, MD, Asl Bari, Reproductive Unit, Andrology Outpatients Clinics, Conversano, Italy
- Craig Niederberger, MD, Department of Urology, University of Illinois at Chicago, Chicago, Illinois