madman
Super Moderator
ABSTRACT
Context. Despite the new opportunities provided by assisted reproduction techniques, male infertility treatment is far from being optimized. One possibility, based on pathophysiological evidence, is to stimulate spermatogenesis with gonadotropins.
Evidence Acquisition. We conducted a comprehensive systematic PubMed literature review, up to January 2020, of studies evaluating the genetic basis of FSH action, the role of FSH in spermatogenesis, and the effects of its administration in male infertility. Manuscripts evaluating the role of genetic polymorphisms and FSH administration in women undergoing assisted reproduction were considered whenever relevant.
Evidence Synthesis. FSH treatment has been successfully used in hypogonadotropic hypogonadism, but with questionable results in idiopathic male infertility. A limitation of this approach is that schemes for male infertility have been borrowed from hypogonadism, without daring to overstimulate, as is done in women undergoing assisted reproduction. FSH effectiveness does not depend only on its serum levels, but also on the individual, genetic variants able to determine hormonal levels, activity, and receptor response. Single-nucleotide polymorphisms (SNPs) in FSHB and FSHR genes have been described, some of them impacting testicular volume and sperm output. The FSHR p.N680S and the FSHB -211G>T variants could be genetic markers to predict FSH response.
Conclusions. FSH may be helpful to increase sperm production in infertile men, even if the evidence to recommend the use of FSH in this setting is weak. Placebo-controlled clinical trials, considering FSHB-FSHR haplotype, are needed to define the most effective dosage, the best treatment length, and the criteria to select candidate responder patients.
Since spermatogenesis is regulated by hormones, the question arises whether gonadotropins can be used to improve sperm output and function in male idiopathic infertility; and a new approach was recently proposed (14). In this review, we summarize the state-of-the-art, pinpointing the critical issues and suggesting possible future strategies concerning the use of gonadotropins, focusing on factors that one should carefully consider before planning future studies in this field.
2. Use of gonadotropins for male infertility
The endocrine regulation of spermatogenesis by gonadotropins is a well-established topic, extensively reviewed (15-17). Gonadotropins are effectively used to stimulate sperm production in patients with hypogonadotropic hypogonadism (HH). In this setting, the administration of exogenous gonadotropins of pulsatile gonadotropin-releasing hormone (GnRH) induces the increase of intratesticular and serum testosterone, the development of secondary sexual characteristics, and the appearance of sperm in the ejaculate (18,19). Pulsatile GnRH therapy is the physiological approach, restoring endogenous gonadotropin secretion by the pituitary (20-22), but its use has been almost abandoned. More often, testicular stimulation in HH is obtained by the administration of exogenous gonadotropins, using human chorionic gonadotropin (hCG) either alone or in combination with follicle-stimulating hormone (FSH) (19). hCG alone is able to stimulate spermatogenesis (23), although FSH addition increases the final sperm number (24-26). This synergic action results in sperm production in the vast majority of HH men (69-81%) (24,26), although the time required is quite variable, ranging from 3 to 19 months, and semen parameters rarely achieve WHO normal ranges (24). Although treatment of HH by gonadotropins is pathophysiologically solid, it remains only empirical, and no evidence-based clinical guidelines, reporting the most appropriate scheme regimen and duration of the replacement therapy, have been produced so far. Reviews and opinion papers suggest the use of hCG 1000-2500 IU twice a week and of FSH 75-225 IU, three times a week (19,27) but no randomized prospective trials to find the best regimen have been carried out so far. In addition, even if hCG is able to induce the necessary intratesticular testosterone increase, it does not constitute the physiological hormone in human adults. hCG is used for practical convenience, due to its relatively long half-life and to the low number of injections required for sustaining the therapy, as well as to the lack of pharmacological LH preparations registered for this indication. Currently, recombinant LH is available but no clinical experience in males exists. Given that LH and hCG interact with the same receptor (the LHCGR) but activate different molecular pathways (28-30), and that hCG was shown to be pro-inflammatory in the testis (31), the effect of clinical treatments with LH in HH men would be worthy of investigation. On the other hand, the use of urinary and recombinant FSH molecules in HH men has led to a similar improvement of semen parameters and pregnancy rate, although evidence is limited (32-35).
3. Pathophysiological rationale of FSH treatment of male idiopathic infertility
3.1 The concept of gonadotropin efficacy
3.2 FSH is a highly heterogeneous hormone
3.3 Mechanism of FSH action
3.4 Effect of FSH in the primate, adult testis
3.5 Pharmacogenetics of FSH action
3.6 Clinical studies with FSH based on pharmacogenetics of FSH action
4. FSH for male idiopathic infertility: Prospects and needs
Overall it appears that FSH treatment of male infertility might have a rationale in the hormone capability to stimulate and increase sperm output. The case is clear in HH. In the case of idiopathic infertility, existing data suggest that FSH may be helpful to improve sperm parameters in some patients but not in all of them. This might depend on the etiology of OAT, unknown by definition, and/or on the genetic background impacting FSH action, but this statement remains speculative in the absence of well-powered, controlled studies.
5. Conclusions
There is an increasing interest in the treatment of male infertility. The recent advances in the understanding of the molecular mechanism of action of FSH, the transgenic mouse models, and the effects of genetic mutations/polymorphisms of the FSHB and FSHR genes contributed substantially to our current knowledge about the role of FSH on human spermatogenesis and the impact of the genetic background on FSH levels and action. However, too few clinical studies have been performed so far and the existing meta-analyses are based only on a few hundred patients (37,39). In some patients, FSH might be effective in improving sperm parameters, although clear-cut selection criteria must be established a priori. The FSHB-FSHR haplotype might be one of such criteria, but this issue should be further tested by statistically powerful clinical trials designed with the aim of attaining testicular overstimulation by FSH doses which is high enough to improve sperm output (14). Should such an approach work, at least in a subset of patients, it would not matter that the therapy is not etiological, since its rationale is to obtain a boost in spermatogenesis independently of the cause of its fault. This proof-of-principle trial can be implemented using any of the current, registered FSH preparations. If successful, novel biologicals with very long-acting FSH activity could be engineered to reduce the burden of the injections.
Another question is whether FSH is the best hormonal strategy. Given the preponderant role of LHCGR-mediated androgen production in supporting human spermatogenesis, as demonstrated by the efficacy of the treatment of HH with hCG alone, it would be interesting to investigate whether mild overstimulation of the Leydig cell compartment has any effect on sperm production. A modest but significant reduction of serum testosterone was demonstrated in men with idiopathic infertility for the first time in 2004 (146) and was repeatedly confirmed thereafter (147-149). Although still within the physiological range, testosterone and the testosterone/LH ratio are lower, while estradiol and the estradiol/testosterone ratio are higher in infertile than fertile men (150- 152). This suggests that LH-induced stimulation of aromatase activity or testosterone production (or secretion into the bloodstream) is less efficient in infertile men. On the other hand, no studies evaluated the clinical effect of FSH + LH co-administration, neither those of LH alone, in male idiopathic infertility so far, and therefore this aspect deserves investigation. The short half-life of LH might be advantageous in this case, since the aim would not be to increase serum testosterone levels but, rather, to moderately rise Leydig cell activity. Some studies based on clomiphene citrate and other selective estrogen receptor modulators or aromatase inhibitors would suggest some benefit for a sub-group of patients (153,154), although insufficient data for achieving clear-cut indications exist at this point.
In conclusion, the genetic background influencing FSH action appears to be a very promising tool for tailoring FSH therapy of male idiopathic infertility, an issue which awaits a very much needed ad hoc clinical trial.
Context. Despite the new opportunities provided by assisted reproduction techniques, male infertility treatment is far from being optimized. One possibility, based on pathophysiological evidence, is to stimulate spermatogenesis with gonadotropins.
Evidence Acquisition. We conducted a comprehensive systematic PubMed literature review, up to January 2020, of studies evaluating the genetic basis of FSH action, the role of FSH in spermatogenesis, and the effects of its administration in male infertility. Manuscripts evaluating the role of genetic polymorphisms and FSH administration in women undergoing assisted reproduction were considered whenever relevant.
Evidence Synthesis. FSH treatment has been successfully used in hypogonadotropic hypogonadism, but with questionable results in idiopathic male infertility. A limitation of this approach is that schemes for male infertility have been borrowed from hypogonadism, without daring to overstimulate, as is done in women undergoing assisted reproduction. FSH effectiveness does not depend only on its serum levels, but also on the individual, genetic variants able to determine hormonal levels, activity, and receptor response. Single-nucleotide polymorphisms (SNPs) in FSHB and FSHR genes have been described, some of them impacting testicular volume and sperm output. The FSHR p.N680S and the FSHB -211G>T variants could be genetic markers to predict FSH response.
Conclusions. FSH may be helpful to increase sperm production in infertile men, even if the evidence to recommend the use of FSH in this setting is weak. Placebo-controlled clinical trials, considering FSHB-FSHR haplotype, are needed to define the most effective dosage, the best treatment length, and the criteria to select candidate responder patients.
Since spermatogenesis is regulated by hormones, the question arises whether gonadotropins can be used to improve sperm output and function in male idiopathic infertility; and a new approach was recently proposed (14). In this review, we summarize the state-of-the-art, pinpointing the critical issues and suggesting possible future strategies concerning the use of gonadotropins, focusing on factors that one should carefully consider before planning future studies in this field.
2. Use of gonadotropins for male infertility
The endocrine regulation of spermatogenesis by gonadotropins is a well-established topic, extensively reviewed (15-17). Gonadotropins are effectively used to stimulate sperm production in patients with hypogonadotropic hypogonadism (HH). In this setting, the administration of exogenous gonadotropins of pulsatile gonadotropin-releasing hormone (GnRH) induces the increase of intratesticular and serum testosterone, the development of secondary sexual characteristics, and the appearance of sperm in the ejaculate (18,19). Pulsatile GnRH therapy is the physiological approach, restoring endogenous gonadotropin secretion by the pituitary (20-22), but its use has been almost abandoned. More often, testicular stimulation in HH is obtained by the administration of exogenous gonadotropins, using human chorionic gonadotropin (hCG) either alone or in combination with follicle-stimulating hormone (FSH) (19). hCG alone is able to stimulate spermatogenesis (23), although FSH addition increases the final sperm number (24-26). This synergic action results in sperm production in the vast majority of HH men (69-81%) (24,26), although the time required is quite variable, ranging from 3 to 19 months, and semen parameters rarely achieve WHO normal ranges (24). Although treatment of HH by gonadotropins is pathophysiologically solid, it remains only empirical, and no evidence-based clinical guidelines, reporting the most appropriate scheme regimen and duration of the replacement therapy, have been produced so far. Reviews and opinion papers suggest the use of hCG 1000-2500 IU twice a week and of FSH 75-225 IU, three times a week (19,27) but no randomized prospective trials to find the best regimen have been carried out so far. In addition, even if hCG is able to induce the necessary intratesticular testosterone increase, it does not constitute the physiological hormone in human adults. hCG is used for practical convenience, due to its relatively long half-life and to the low number of injections required for sustaining the therapy, as well as to the lack of pharmacological LH preparations registered for this indication. Currently, recombinant LH is available but no clinical experience in males exists. Given that LH and hCG interact with the same receptor (the LHCGR) but activate different molecular pathways (28-30), and that hCG was shown to be pro-inflammatory in the testis (31), the effect of clinical treatments with LH in HH men would be worthy of investigation. On the other hand, the use of urinary and recombinant FSH molecules in HH men has led to a similar improvement of semen parameters and pregnancy rate, although evidence is limited (32-35).
3. Pathophysiological rationale of FSH treatment of male idiopathic infertility
3.1 The concept of gonadotropin efficacy
3.2 FSH is a highly heterogeneous hormone
3.3 Mechanism of FSH action
3.4 Effect of FSH in the primate, adult testis
3.5 Pharmacogenetics of FSH action
3.6 Clinical studies with FSH based on pharmacogenetics of FSH action
4. FSH for male idiopathic infertility: Prospects and needs
Overall it appears that FSH treatment of male infertility might have a rationale in the hormone capability to stimulate and increase sperm output. The case is clear in HH. In the case of idiopathic infertility, existing data suggest that FSH may be helpful to improve sperm parameters in some patients but not in all of them. This might depend on the etiology of OAT, unknown by definition, and/or on the genetic background impacting FSH action, but this statement remains speculative in the absence of well-powered, controlled studies.
5. Conclusions
There is an increasing interest in the treatment of male infertility. The recent advances in the understanding of the molecular mechanism of action of FSH, the transgenic mouse models, and the effects of genetic mutations/polymorphisms of the FSHB and FSHR genes contributed substantially to our current knowledge about the role of FSH on human spermatogenesis and the impact of the genetic background on FSH levels and action. However, too few clinical studies have been performed so far and the existing meta-analyses are based only on a few hundred patients (37,39). In some patients, FSH might be effective in improving sperm parameters, although clear-cut selection criteria must be established a priori. The FSHB-FSHR haplotype might be one of such criteria, but this issue should be further tested by statistically powerful clinical trials designed with the aim of attaining testicular overstimulation by FSH doses which is high enough to improve sperm output (14). Should such an approach work, at least in a subset of patients, it would not matter that the therapy is not etiological, since its rationale is to obtain a boost in spermatogenesis independently of the cause of its fault. This proof-of-principle trial can be implemented using any of the current, registered FSH preparations. If successful, novel biologicals with very long-acting FSH activity could be engineered to reduce the burden of the injections.
Another question is whether FSH is the best hormonal strategy. Given the preponderant role of LHCGR-mediated androgen production in supporting human spermatogenesis, as demonstrated by the efficacy of the treatment of HH with hCG alone, it would be interesting to investigate whether mild overstimulation of the Leydig cell compartment has any effect on sperm production. A modest but significant reduction of serum testosterone was demonstrated in men with idiopathic infertility for the first time in 2004 (146) and was repeatedly confirmed thereafter (147-149). Although still within the physiological range, testosterone and the testosterone/LH ratio are lower, while estradiol and the estradiol/testosterone ratio are higher in infertile than fertile men (150- 152). This suggests that LH-induced stimulation of aromatase activity or testosterone production (or secretion into the bloodstream) is less efficient in infertile men. On the other hand, no studies evaluated the clinical effect of FSH + LH co-administration, neither those of LH alone, in male idiopathic infertility so far, and therefore this aspect deserves investigation. The short half-life of LH might be advantageous in this case, since the aim would not be to increase serum testosterone levels but, rather, to moderately rise Leydig cell activity. Some studies based on clomiphene citrate and other selective estrogen receptor modulators or aromatase inhibitors would suggest some benefit for a sub-group of patients (153,154), although insufficient data for achieving clear-cut indications exist at this point.
In conclusion, the genetic background influencing FSH action appears to be a very promising tool for tailoring FSH therapy of male idiopathic infertility, an issue which awaits a very much needed ad hoc clinical trial.
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