Role of FSHR polymorphism p.N680S in the therapy with FSH in patients who underwent varicocele surgery
Follice-stimulating hormone (FSH) receptor (FSHR) polymorphism p.N680S mediates different responses to FSH in vitro (1), and this polymorphism is associated with the ovarian response in controlled ovarian hyperstimulation. In the last years, FSHR gene polymorphisms have been studied as potential risk factors for spermatogenetic failure. The analysis of this gene represents a valid pharmacogenetic approach to the treatment of male infertility, confirming also the importance of strict criteria for the selection of patients to be treated with FSH. Selice et al. (2011) demonstrate in a group of oligozoospermic subjects with hypospermatogenesis and normal FSH levels, that only subjects with at least one serine in position 680 had a statistically significant improvement of seminal parameters (2).
The aim of our study was to evaluate the influence of the polymorphism p.N680S in the adjuvant therapy with recombinant FSH (rFSH) after surgical repair of varicocele (3).
Materials and Methods
From January 2016 and June 2016, twenty-two patients whose underwent subinguinal microsurgical varicocelectomy (Marmar technique) and with a morphologic aspect of hypospermatogenesis at testicular cytology were enrolled. At the 3th post-operative month the patients underwent a semen analyses and then they started the adjuvant recombinant therapy with follitropin alfa 150UI i.m. 3 times/week for three month . After the therapy the patients had a semen analyses, and the FSHR gene polymorphism p.N680S characterization (Ser-Ser, Ser-Asn, Asn-Asn) with PCR in high resolution melting HRM from DNA extracted by a simple blood sample. Mean values with standard deviations (±SD) were computed and reported for all items. Statistical significance was achieved if p-value was ≤0.05 (two-sides).
The mean age of the patients was 27,45±3,79. 8 out of 22 patients (36.36%) had the Ser-Ser polymorphism, 8 out of 22 patients (36.36%) had the Ser-Asn polymorphism and 6 out of 22 patients (27.27%) had the Asn-Asn polymorphism. The adjuvant therapy did not significantly improve semen volume (p=0.1890).
After 3 months of treatment, we observed significant increase in total sperm count (p = 0.0272), sperm concentration (p =0.0044), percentage of normal morphology forms (p = 0.0001) and progressive motility (0.0013) in the Ser-Ser group.
After 3 months of treatment, we observed significant increase in percentage of normal morphology forms (p = 0.0001) but we did not observe significant increase in total sperm count (p = 0.0514), sperm concentration (p =0.0531) and progressive motility (0.0571) in the Ser-Asn group.
After 3 months of treatment, we did not observe significant increase in total sperm count (p = 0.8326), sperm concentration (p =0.964), in percentage of normal morphology forms (p=0.1271) and progressive motility (0.1986) in the Asn-Asn group.
Our findings demonstrate that only subjects with two serine in position 680 had a statistically significant improvement of seminal parameters except for the percentage of normal morphology forms that is also increased in Ser-Asn group. A positive trend was seen for the others parameters in the Ser-Asn group even if the statistical significance was not reached. The patients with at least one serine in position 680 probably have lower sensitivity to FSH. In these subjects, their FSH basal levels are not sufficient for optimal stimulation of spermatogenesis that is improved by additional FSH. This is not possible for the patients of Asn-Asn group because the same FSH basal levels are already operating at their maximal potential on stimulation of spermatogenesis (2). A limitation of this study is the small cohort of patients.
Which FSHR polymorphism can benefit from FSH treatment is clinically very important, in particular for what regards nonidiopathic patients. It is also relevant from a pharmacoeconomic point of view. We expect to increase our sample size in order to better analyze the role of FSHR gene polymorphism p.N680S in the adjuvant therapy with rFSH after surgical repair of varicocele.
1-Casarini L, Moriondo V, Marino M, Adversi F, Capodanno F, Grisolia C, La Marca A, La Sala GB, Simoni M. FSHR polymorphism p.N680S mediates different responses to FSH in vitro. Mol Cell Endocrinol. 2014 Aug 5;393(1-2):83-91.
2-Selice R, Garolla A, Pengo M, Caretta N, Ferlin A, Foresta C. The response to FSH treatment in oligozoospermic men depends on FSH receptor gene polymorphisms. Int J Androl. 2011 Aug;34(4):306-12.
3-Amirzargar MA, Yavangi M, Basiri A, Hosseini Moghaddam SM, Babbolhavaeji H, Amirzargar N, Amirzargar H, Moadabshoar L. Comparison of recombinant human follicle stiumulating hormone (rhFSH), human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) on semen parameters after varicocelectomy: a randomized clinical trial. Iran J Reprod Med. 2012 Sep;10(5):441-52.Argomenti: andrologia