madman
Super Moderator
ABSTRACT
Introduction
According to estimates by the World Health Organization, about 17.5% of the adult population – roughly 1 in 6 globally – experience infertility. The causes of male infertility remain poorly understood and have yet to be fully evaluated. Follicle-stimulating hormone (FSH) represents an available and useful therapeutic strategy for the treatment of idiopathic infertility.
Areas covered
We provide here an overview of the molecular mechanisms by which FSH stimulates Sertoli cells and the schemes, dosages, and formulations of FSH most prescribed so far and reported in the literature. We also evaluated the possible predictor factors of the response to FSH administration and the indications of the latest guidelines on the use of FSH for the treatment of male infertility.
Expert opinion
FSH therapy should be considered for infertile male patients with oligoasthenoteratozoospermia and normal serum FSH levels to quantitatively and qualitatively improve sperm parameters and pregnancy and birth rates. The grade of evidence is very low to low, due to the limited number of randomized controlled studies and patients available, the heterogeneity of the studies, and the limited effect size. To overcome these limitations, preclinical and clinical research is needed to evaluate the most effective dose and duration of FSH administration.
The therapies currently available for the treatment of male infertility include surgical and medical approaches.
As far as surgical options, these include diagnostic procedures, such as multi-site fine needle aspiration (or ‘testicular mapping’) and open testicular biopsy, or therapeutic techniques, performed to correct existing diseases to improve in sperm production (varicocele repair, hydrocelectomy, reverse vasectomy – vasectomy, vasoepididymostomy), procedures aimed at removing the cause of the obstruction in cases of obstructive azoospermia (i.e. transurethral resection of ejaculatory ducts) and sperm retrieval by percutaneous epididymal sperm aspiration (PESA), epididymal microscopic sperm aspiration (MESA), testicular aspiration (TESA), extraction (TESE), ormicroTESE [11].
Regarding medical treatment, according to the American Urological Association (AUA)/American Society for Reproductive Medicine (ASRM) guidelines, physicians may benefit from the use of human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or a combination thereof for infertile patients with low serum testosterone (T) levels [12]. Although some data suggest the usefulness of antioxidants and vitamins for the treatment of male infertility (Calogero et al., 2017) [13], patients should be informed of their limited clinical efficacy, as the evidence is not robust enough to provide a recommendation in favor of their use [12]. Finally, treatment with follicle-stimulating hormone (FSH) can be considered for idiopathic infertility [12]. Because of its LH-like effect, hCG is used to promote or restore the increase of intratesticular concentration and to induce spermatogenesis. It can be prescribed alone or together with FSH in patients with hypogonadotropic hypogonadism. It can also be used in patients with late-onset hypogonadism and a desire for fatherhood[14]. Furthermore, hCG therapy has been shown to improve spermatogenesis in men undergoing T-replacement therapy[15]. This occurs because, when injective T is administered, LH secretion is suppressed, which in turn results in a cessation of Leydig cell activity [14].
Drugs such as SERMs and AIs, while acting on different targets, share the same mechanism of action, which consists of blocking the negative feedback exerted by estrogens on the hypothalamic-pituitary-gonadal axis. This blockade causes an increase in the secretion of gonadotropin-releasing hormone(GnRH) and gonadotropins. By blocking the action of aromatase, AIs prevent the conversion of androgens to estrogens. Thus, they reduce the negative feedback of estrogens on the hypothalamic-pituitary-testicular axis, increasing intratesticular T levels and spermatogenesis [16,17]. Overall, the choice of therapy will depend on the underlying cause of infertility and should therefore be determined after a careful clinical evaluation of the patient. SERM administration is associated with a 3-fold improvement in the chance of pregnancy [odd ratio(OR) 3.42, 95% CI: 1.37–8.52] [18], which is similar to the efficacy of the therapy with FSH, as discussed in section 3.3. However, the latter drug is more expensive. Due to its efficacy and low cost, clomiphene is the most used drug in the empirical medical management of idiopathic male infertility, at least in the United States [19].
In addition to hypogonadotropic hypogonadism, FSH can also be used to achieve an increase in sperm concentration in cases of idiopathic infertility or oligozoospermia in patients with normal serum of gonadotropins. Several studies have shown that FSH therapy positively has a positive impact on sperm parameters such as concentration, motility, morphology, and DNA fragmentation [18]. However, the role of FSH in the treatment of idiopathic infertility is still debated. Despite supporting evidence conducted primarily in Caucasian cohorts, its use is still not recognized in clinical practice worldwide. Therefore, the purpose of this review was to provide an evidence-based state of the art of the use of FSH for male infertility. We will first discuss the physiology and molecular signaling pathways of FSH; then we will cover the indications for treatment in detail.
2. Physiology and molecular signaling
*Effects of FSH on Sertoli cells and spermatogenesis
FSH regulates gametogenesis by acting on target cells in the gonads. Its biosynthesis is regulated by the pulsatile release of GnRH, which stimulates its secretion from gonadotropic cells located in the anterior pituitary gland into the systemic circulation to control the development, maturation, and function of gonads [20]. It is a 35.5 kDa dimeric glycoprotein, which shares the same αsubunit with LH, thyroid-stimulating hormone, and hCG, while the ß-subunit is specific for each hormone and gives to FSH and its specific biological activity, performed by binding to its receptor[21]. Furthermore, FSH promotes the growth and maturation of Sertoli cells and supports spermatogenesis [21].
Sertoli cells proliferate during the fetal and neonatal periods, ceasing proliferation during puberty when they begin their terminal differentiation into the adult form. During embryonic-testicular development, fetal Sertoli cells aggregate and encase male precursor germ cells, called gonocytes, to form testicular cords that eventually become seminiferous tubules in the adult testis [22]. In neonatal life and childhood, Sertoli cells are the most represented cell types in the testis, accounting for most pre-pubertal testicular volume. In this phase, while the levels of LH, FSH, and T are very low, the Sertoli cells secrete a high amount of AMH [23,24]. Therefore, this hormone has been suggested as a useful marker of testicular function in prepubertal age [25]. More specifically, the measurement of AMH and inhibin B can be useful for the early diagnosis of puberty disorders and the presence of possible primary testicular damage. Indeed, low levels of these hormones have been found in children with primary testicular disorders. By measuring their levels, it may also be possible to discriminate between conditions such as congenital hypogonadotropic hypogonadism, constitutional delay in growth and puberty, or when precocious puberty is clinically suspected [25,26]
Spermatogenesis involves multiple autocrine, paracrine, and hormonal stimuli, as well as nutrients that support germ cell development through the mechanisms of mitotic development, meiotic recombination, and sperm morphological maturation. Once spermatogenesis is initiated by FSH, it can be qualitatively maintained with T alone [27].Gametogenesis results from fine-tuning between cell growth and survival and cross-linked steroidogenic signals for apoptosis. The interaction between the different components and the consequent negative feedback exerted by the T and the inhibin B produced by Sertoli cells is essential in the first place for the regulation of the feedback and the secretion of GnRH and gonadotropins for the maintenance of the correct homeostasis of the hypothalamus-pituitary testicular axis [28].
*FSHR expression and signaling
3. Indications
3.1. Puberty induction
3.2. Hypogonadotropic hypogonadism
In the case of the post-pubertal onset of hypogonadotropic hypogonadism (testicular volume ≥4 ml), the EAU guidelines for sexual and reproductive health suggest treatment with (250 IU x 2/week to 2000 IU x 2/week). The dose can be adjusted according to the serum T levels that should be maintained at least in half of the normal range. Semen analysis should be requested every 3 months. FSH could be prescribed concurrently or subsequently, at a dose ranging from 75 to 150 IU x 3/week [50].
3.3. Idiopathic infertility
4. Conclusion
Male infertility represents one of the greatest challenges of modern medicine. Studies have shown that its prevalence is steadily increasing. The reasons behind this are still not entirely clear and often we are faced with a diagnosis of idiopathic infertility. While on the one hand, for some well-defined causes, there are therapeutic protocols that can help restore fertility, this is not fully true in the case of idiopathic infertility. Further research is therefore needed to understand the etiology and treatment of these forms of infertility.
Therapies that can be considered for male infertility treatment include surgical and medical approaches. As far as medical approaches are concerned, more and more importance is being given to FSH-based therapy. It is available in two formulations: the so-called purified human FSH obtained and then purified from the urine of post-menopausal women, and other formulations obtained by in vitro recombinant technology. The most used scheme in the treatment of infertile patients is the administration of FSH at a dose of 150 IU three times a week, even if there is evidence that more prolonged therapies or at different doses may have greater efficacy. Furthermore, several parameters have been called into play to predict the response to FSH administration, and, among all, the guidelines cite testicular cytology and the presence of spermatids as predictors of treatment efficacy [83]. Furthermore, exciting new evidence is progressively expanding our understanding of the molecular mechanisms in which FSH is involved, with clinical implications.
In conclusion, FSH-based therapies can represent a valid support in a selected cohort of patients presenting well-defined characteristics, such as idiopathic oligozoospermia, normal serum levels of FSH and inhibin B, presence of hypospermatogenesis but not a testicular cytology picture of germ-cell maturation arrest.
Introduction
According to estimates by the World Health Organization, about 17.5% of the adult population – roughly 1 in 6 globally – experience infertility. The causes of male infertility remain poorly understood and have yet to be fully evaluated. Follicle-stimulating hormone (FSH) represents an available and useful therapeutic strategy for the treatment of idiopathic infertility.
Areas covered
We provide here an overview of the molecular mechanisms by which FSH stimulates Sertoli cells and the schemes, dosages, and formulations of FSH most prescribed so far and reported in the literature. We also evaluated the possible predictor factors of the response to FSH administration and the indications of the latest guidelines on the use of FSH for the treatment of male infertility.
Expert opinion
FSH therapy should be considered for infertile male patients with oligoasthenoteratozoospermia and normal serum FSH levels to quantitatively and qualitatively improve sperm parameters and pregnancy and birth rates. The grade of evidence is very low to low, due to the limited number of randomized controlled studies and patients available, the heterogeneity of the studies, and the limited effect size. To overcome these limitations, preclinical and clinical research is needed to evaluate the most effective dose and duration of FSH administration.
The therapies currently available for the treatment of male infertility include surgical and medical approaches.
As far as surgical options, these include diagnostic procedures, such as multi-site fine needle aspiration (or ‘testicular mapping’) and open testicular biopsy, or therapeutic techniques, performed to correct existing diseases to improve in sperm production (varicocele repair, hydrocelectomy, reverse vasectomy – vasectomy, vasoepididymostomy), procedures aimed at removing the cause of the obstruction in cases of obstructive azoospermia (i.e. transurethral resection of ejaculatory ducts) and sperm retrieval by percutaneous epididymal sperm aspiration (PESA), epididymal microscopic sperm aspiration (MESA), testicular aspiration (TESA), extraction (TESE), ormicroTESE [11].
Regarding medical treatment, according to the American Urological Association (AUA)/American Society for Reproductive Medicine (ASRM) guidelines, physicians may benefit from the use of human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or a combination thereof for infertile patients with low serum testosterone (T) levels [12]. Although some data suggest the usefulness of antioxidants and vitamins for the treatment of male infertility (Calogero et al., 2017) [13], patients should be informed of their limited clinical efficacy, as the evidence is not robust enough to provide a recommendation in favor of their use [12]. Finally, treatment with follicle-stimulating hormone (FSH) can be considered for idiopathic infertility [12]. Because of its LH-like effect, hCG is used to promote or restore the increase of intratesticular concentration and to induce spermatogenesis. It can be prescribed alone or together with FSH in patients with hypogonadotropic hypogonadism. It can also be used in patients with late-onset hypogonadism and a desire for fatherhood[14]. Furthermore, hCG therapy has been shown to improve spermatogenesis in men undergoing T-replacement therapy[15]. This occurs because, when injective T is administered, LH secretion is suppressed, which in turn results in a cessation of Leydig cell activity [14].
Drugs such as SERMs and AIs, while acting on different targets, share the same mechanism of action, which consists of blocking the negative feedback exerted by estrogens on the hypothalamic-pituitary-gonadal axis. This blockade causes an increase in the secretion of gonadotropin-releasing hormone(GnRH) and gonadotropins. By blocking the action of aromatase, AIs prevent the conversion of androgens to estrogens. Thus, they reduce the negative feedback of estrogens on the hypothalamic-pituitary-testicular axis, increasing intratesticular T levels and spermatogenesis [16,17]. Overall, the choice of therapy will depend on the underlying cause of infertility and should therefore be determined after a careful clinical evaluation of the patient. SERM administration is associated with a 3-fold improvement in the chance of pregnancy [odd ratio(OR) 3.42, 95% CI: 1.37–8.52] [18], which is similar to the efficacy of the therapy with FSH, as discussed in section 3.3. However, the latter drug is more expensive. Due to its efficacy and low cost, clomiphene is the most used drug in the empirical medical management of idiopathic male infertility, at least in the United States [19].
In addition to hypogonadotropic hypogonadism, FSH can also be used to achieve an increase in sperm concentration in cases of idiopathic infertility or oligozoospermia in patients with normal serum of gonadotropins. Several studies have shown that FSH therapy positively has a positive impact on sperm parameters such as concentration, motility, morphology, and DNA fragmentation [18]. However, the role of FSH in the treatment of idiopathic infertility is still debated. Despite supporting evidence conducted primarily in Caucasian cohorts, its use is still not recognized in clinical practice worldwide. Therefore, the purpose of this review was to provide an evidence-based state of the art of the use of FSH for male infertility. We will first discuss the physiology and molecular signaling pathways of FSH; then we will cover the indications for treatment in detail.
2. Physiology and molecular signaling
*Effects of FSH on Sertoli cells and spermatogenesis
FSH regulates gametogenesis by acting on target cells in the gonads. Its biosynthesis is regulated by the pulsatile release of GnRH, which stimulates its secretion from gonadotropic cells located in the anterior pituitary gland into the systemic circulation to control the development, maturation, and function of gonads [20]. It is a 35.5 kDa dimeric glycoprotein, which shares the same αsubunit with LH, thyroid-stimulating hormone, and hCG, while the ß-subunit is specific for each hormone and gives to FSH and its specific biological activity, performed by binding to its receptor[21]. Furthermore, FSH promotes the growth and maturation of Sertoli cells and supports spermatogenesis [21].
Sertoli cells proliferate during the fetal and neonatal periods, ceasing proliferation during puberty when they begin their terminal differentiation into the adult form. During embryonic-testicular development, fetal Sertoli cells aggregate and encase male precursor germ cells, called gonocytes, to form testicular cords that eventually become seminiferous tubules in the adult testis [22]. In neonatal life and childhood, Sertoli cells are the most represented cell types in the testis, accounting for most pre-pubertal testicular volume. In this phase, while the levels of LH, FSH, and T are very low, the Sertoli cells secrete a high amount of AMH [23,24]. Therefore, this hormone has been suggested as a useful marker of testicular function in prepubertal age [25]. More specifically, the measurement of AMH and inhibin B can be useful for the early diagnosis of puberty disorders and the presence of possible primary testicular damage. Indeed, low levels of these hormones have been found in children with primary testicular disorders. By measuring their levels, it may also be possible to discriminate between conditions such as congenital hypogonadotropic hypogonadism, constitutional delay in growth and puberty, or when precocious puberty is clinically suspected [25,26]
Spermatogenesis involves multiple autocrine, paracrine, and hormonal stimuli, as well as nutrients that support germ cell development through the mechanisms of mitotic development, meiotic recombination, and sperm morphological maturation. Once spermatogenesis is initiated by FSH, it can be qualitatively maintained with T alone [27].Gametogenesis results from fine-tuning between cell growth and survival and cross-linked steroidogenic signals for apoptosis. The interaction between the different components and the consequent negative feedback exerted by the T and the inhibin B produced by Sertoli cells is essential in the first place for the regulation of the feedback and the secretion of GnRH and gonadotropins for the maintenance of the correct homeostasis of the hypothalamus-pituitary testicular axis [28].
*FSHR expression and signaling
3. Indications
3.1. Puberty induction
3.2. Hypogonadotropic hypogonadism
In the case of the post-pubertal onset of hypogonadotropic hypogonadism (testicular volume ≥4 ml), the EAU guidelines for sexual and reproductive health suggest treatment with (250 IU x 2/week to 2000 IU x 2/week). The dose can be adjusted according to the serum T levels that should be maintained at least in half of the normal range. Semen analysis should be requested every 3 months. FSH could be prescribed concurrently or subsequently, at a dose ranging from 75 to 150 IU x 3/week [50].
3.3. Idiopathic infertility
4. Conclusion
Male infertility represents one of the greatest challenges of modern medicine. Studies have shown that its prevalence is steadily increasing. The reasons behind this are still not entirely clear and often we are faced with a diagnosis of idiopathic infertility. While on the one hand, for some well-defined causes, there are therapeutic protocols that can help restore fertility, this is not fully true in the case of idiopathic infertility. Further research is therefore needed to understand the etiology and treatment of these forms of infertility.
Therapies that can be considered for male infertility treatment include surgical and medical approaches. As far as medical approaches are concerned, more and more importance is being given to FSH-based therapy. It is available in two formulations: the so-called purified human FSH obtained and then purified from the urine of post-menopausal women, and other formulations obtained by in vitro recombinant technology. The most used scheme in the treatment of infertile patients is the administration of FSH at a dose of 150 IU three times a week, even if there is evidence that more prolonged therapies or at different doses may have greater efficacy. Furthermore, several parameters have been called into play to predict the response to FSH administration, and, among all, the guidelines cite testicular cytology and the presence of spermatids as predictors of treatment efficacy [83]. Furthermore, exciting new evidence is progressively expanding our understanding of the molecular mechanisms in which FSH is involved, with clinical implications.
In conclusion, FSH-based therapies can represent a valid support in a selected cohort of patients presenting well-defined characteristics, such as idiopathic oligozoospermia, normal serum levels of FSH and inhibin B, presence of hypospermatogenesis but not a testicular cytology picture of germ-cell maturation arrest.
