Journal of Endocrinological Investigation https://doi.org/10.1007/s40618-018-0843-y CONSENSUS STATEMENT The use of follicle stimulating hormone (FSH) for the treatment of the infertile man: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS) A. Barbonetti1 · A. E. Calogero2 · G. Balercia3 · A. Garolla4 · C. Krausz5 · S. La Vignera2 · F. Lombardo6 · E. A. Jannini7 · M. Maggi5 · A. Lenzi6 · C. Foresta4 · A. Ferlin4,8 Received: 28 November 2017 / Accepted: 27 January 2018 © Italian Society of Endocrinology (SIE) 2018 Abbreviations RCT​ Randomized controlled trial ART​ Assisted reproductive technologies rhFSH Recombinant human follicle stimulating FSH Follicle stimulating hormone hormone FSHR FSH receptor GnRH-a Gonadotropin-releasing hormone agonist hCG Human chorionic gonadotropin Introduction hMG Human menopausal gonadotropin hpFSH Highly purifed follicle stimulating hormone Infertility refers to the inability of a couple to conceive after ICSI Intracytoplasmic sperm injection 12 months of regular unprotected sexual intercourse [1, 2] IUI Intrauterine insemination and afects about 10–15% of couples of reproductive age IVF In vitro fertilization [3–5]. Male factor alone is responsible for approximately IVF-ET In vitro fertilization-embryo transfer 30% of cases of infertility, while a combination of male and OAT Oligo/astheno/teratozoospermia female factors afects another 20%. Therefore, overall, the pFSH Purifed follicle stimulating hormone male factor would be involved in 50% of infertile couples [2, 3, 6]. In about 30% of cases of male infertility, no obvious cause for subnormal semen parameters can be found after a careful diagnostic workup (2, 3). Indeed, this condition, * A. Ferlin which is referred to as “idiopathic infertility”, represents [email protected] the most commonly observed form of infertility in clini- 1 Casa di Cura San Rafaele Sulmona, Sulmona, AQ, Italy cal practice, but unfortunately, rational treatment are lack- 2 ing. Although intracytoplasmic sperm injection (ICSI) is Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy regarded as an appropriate treatment for infertile men with 3 severe oligo/astheno/teratozoospermia (OAT), sperm struc- Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, Ancona, ture and quality may afect its outcome [7]. Therefore, the Polytechnic University of Marche, Ancona, Italy justifed enthusiasm for ICSI as the treatment of choice for 4 Unit of Andrology and Reproductive Medicine, Department severe male factor infertility should not discourage attempts of Medicine, University of Padova, Padua, Italy to better understand pathophysiology, to provide when pos- 5 Department of Biomedical, Experimental and Clinical sible an etiological diagnosis, and to improve sperm quality. Sciences ‘Mario Serio’, University of Florence, Florence, As gonadotropins are needed for testis physiology and Italy represent a successful treatment in hypogonadotropic hypo- 6 Laboratory of Seminology‑Sperm Bank “Loredana Gandini”, gonadism [8], they have been also ofered to men with idi- Department of Experimental Medicine, University of Rome opathic infertility based on the hypothesis that spermatogen- “La Sapienza”, Rome, Italy esis could be stimulated by increasing gonadotropin levels. 7 Department of Systems Medicine, Chair of Endocrinology Available follicle stimulating hormone (FSH) preparations and Medical Sexology (ENDOSEX), University of Rome Tor are those extracted and purifed from the urine of postmen- Vergata, Rome, Italy 8 opausal women, the so-called purifed FSH (pFSH) and Present Address: Department of Clinical and Experimental highly purifed FSH (hpFSH) [9], as well as those obtained Sciences, University of Brescia, Brescia, Italy Vol.:(0123456789)1 3 Journal of Endocrinological Investigation from recombinant in vitro technology (rhFSH) [10]. Combi- Efects of FSH on conventional sperm nation strategies with human chorionic gonadotropin (hCG) parameters can be used in men with hypogonadotropic hypogonadism to restore intratesticular testosterone concentrations and Recommendations induce spermatogenesis [11]. The addition of rhFSH to hCG treatment protocols results in normal testicular growth 1. We recommend not prescribing FSH treatment for and hastens the induction of spermatogenesis in young men improving sperm parameters in all infertile men before with hypogonadotropic hypogonadism [12]. These strate- a specifc diagnostic workup (1 ØØØØ). gies seem to be efective even in men with late-onset hypog- 2. We recommend not using FSH treatment in azoospermic onadism [13]. On the contrary, FSH administration as single men and in men with obstructive/sub-obstructive forms therapy is usually considered in men with idiopathic infertil- of infertility (1 ØØØØ). ity and gonadotropins within the normal range. 3. We suggest the use of FSH (either purifed or recom- Actually, results obtained in idiopathic infertility seem to binant) to increase sperm concentration and motility in be still controversial. In fact, the efectiveness of FSH ther- infertile normogonadotropic men with idiopathic oligo- apy in improving semen parameters in idiopathic male-factor zoospermia or OAT (2 ØØØO). infertility has not been demonstrated by some authors [7, 14–24], whereas others have reported signifcant improve- Evidence ments in sperm quality and/or pregnancy rates after FSH treatment [15, 16, 20, 21, 24–41]. A meta-analysis by the Several studies have shown that FSH treatment improves Cochrane Collaboration [42], only including randomized conventional sperm parameters in oligozoospermic men controlled trials (RCTs), showed that infertile men who with gonadotropin levels within the normal range (gener- received FSH had a signifcant increase in spontaneous ally 1–8 IU/l) [36]. A meta-analysis showed a signifcant pregnancy rate per couple with respect to patients receiving improvement of sperm concentration after FSH administra- placebo or no treatment, whereas no signifcant diference tion, with a mean improvement of 2.66 × 106/ml (95% CI between the two groups in terms of pregnancy rate after 0.47, 4.84; p = 0.02, n = 520) and a non-signifcant improve- assisted reproductive technologies (ART) was observed. ment of concentration of sperm with progressive motility, More recently, in another meta-analysis [43], including all with a mean raise of 1.22 × 106/ml (95% CI − 0.07, 2.52; available controlled clinical trials, when compared to pla- p = 0.06, n = 332) [43]. The efcacy of FSH treatment has cebo or untreated controls, men receiving FSH showed a been associated with FSH dose and duration of the treatment signifcant improvement in sperm concentration and qual- [24] (Table 1), and with the molecule specifcally used (e.g. ity and exhibited a signifcant increase in spontaneous and rhFSH, pFSH, hpFSH) (Table 2). ART-related pregnancy rate. Concerning the dosage, the evidence from the literature sur- The aim of the present article was to analyse the state of vey suggests that it depends on the type of FSH prescribed. the art regarding the clinical evidence on the efectiveness Several observational studies described the efcacy of hpFSH of FSH therapy in male infertility and to provide a position administered at weekly cumulative doses ≤ 450 IU (e.g. statement on its use from the Italian Society of Andrology 150 IU three times a week, 75 IU on alternate days, etc.) for and Sexual Medicine (SIAMS). In particular, three major 3 months (Table 2). With this type and dosage of FSH, a sig- outcomes were assessed: improvement of conventional nifcant improvement of the sperm concentration was showed sperm parameters, improvement of sperm DNA integrity, in all the studies and most of them reported a benefcial efect and improvement of pregnancy rate. The suitability of on sperm motility as well [29–32, 34, 40, 41, 45]. Data on the available possible predictors of response to FSH treatment efcacy of hpFSH on sperm morphology are less consistent has been also assessed according to the Evidence-Based [20]. In contrast to hpFSH, rhFSH, administered at a weekly Medicine (EBM) criteria. The task force used the following cumulative dose ≤ 450 IU, resulted to be less efective. In internationally shared coding system [44]: (1) “we recom- more detail, one randomized controlled trial (RCT) [23] and mend” indicates a strong recommendation; (2) “we suggest” one observational study [33] reported contrasting results on denotes a weak recommendation. As far as the evidence sperm concentration, motility and morphology following treat- grading is concerned: ØOOO denotes very low-quality evi- ment with αfollitropin. In the study by Colacurci et al. [23], dence; ØØOO, low quality; ØØØO, moderate quality; and the administration of 150 IU on alternate days for 3 months ØØØØ, high quality. did not signifcantly improve conventional sperm parameters, whereas the administration of 150 IU three times a week for 3 months was able to improve sperm concentration, motility and morphology [33]. According to one RCT [46] and one 1 3 Journal of Endocrinological Investigation Journal ofEndocrinological Table 1 Efects of FSH treatment on conventional sperm parameters in normogonadotropic infertile men Author Cohort Dosage Outcome Low-dose therapy (weekly cumulative dose ≤ 450 IU) Acosta et al. [15] 24 men with OAT vs 26 matched controls with pFSH; 150 IU three times a week for 3 months No signifcant change in sperm concentration, Observational study OAT