madman
Super Moderator
Abstract: Hypogonadotropic hypogonadism (HH) is caused by a dysfunction in the hypothalamus and/or the pituitary gland and it can be congenital or acquired. This condition is biochemically characterized by low or inappropriately normal gonadotropin levels along with low total testosterone levels. If fertility is not an issue, testosterone therapy is the treatment of choice to induce and maintain secondary sexual characteristics and sexual function. Spermatogenesis is frequently impaired in patients with HH, but usually responsive to hormonal therapy such as gonadotropin therapy or GnRH supplementary/replacement therapy. When gonadotropins are the choice of treatment, conventional therapy includes human chorionic gonadotropin (hCG) along with different FSH formulations: human menopausal gonadotropins (hMG), highly purified urinary FSH preparations (hpFSH) (e.g., urofollitropin) or recombinant FSH (rFSH). The combination of FSH and hCG demonstrated to be associated with better outcomes than single compounds, whereas similar results were obtained with different FSH preparations in male individuals; both regarding the ability to stimulate spermatogenesis and eventually inducing physiology pregnancy. Gonadotropins can be administered either subcutaneously or intramuscularly. The combination therapy with hCG and FSH for a period of 12-24 months was found to promote testicular growth in almost all patients, spermatogenesis in approximately 80%, and pregnancy rates in the range of 50%. Gynecomastia is the most common side effect of gonadotropin therapy and is due to hCG stimulation of aromatase causing increased secretion of estradiol. The therapeutic success is higher in patients with post-pubertal HH, in those without previously undescended testes, in patients with higher baseline testicular volume, who underwent repeated cycles of therapy, and in patients with higher baseline inhibin B serum concentrations. Reversal of hypogonadism can occur in up to 10% of patients but its physiopathologic mechanism has yet to be elucidated. In conclusion, gonadotropin therapy is effective in promoting puberty and in supporting spermatogenesis onset and preservation in HH patients with either hypothalamic or pituitary conditions.
1. INTRODUCTION AND BACKGROUND
The hypothalamic-pituitary-gonadal (HPG) axis is essential in a number of processes related to the development, maturation, and aging of the male [1]. Through a pulsatile secretion of gonadotropin-releasing hormone (GnRH), the hypothalamus stimulates the biosynthesis of gonadotropins — namely, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) — which is controlled by extremely sophisticated positive and negative feedback. Of gonadotropins, LH stimulates testicular endocrine function by activating Leydig cells hosted in the interstitial space of the testicle, with a consequent activity in terms of male genital development and differentiation, throughout human sexual determination [2]. Instead, FSH sustains testicular exocrine function led by Sertoli cells through spermatogenesis. Both testosterone synthesis and male fertility result from the delicate coordination throughout the HPG axis, thus assuring normal testicular function. In this context, congenital or acquired disturbances at any level of the HPG axis can lead to an impairment of reproductive function and the clinical syndrome of hypogonadism.
Hypogonadism can be caused by a primary testicular pathology (i.e., primary hypogonadism, otherwise known as hypergonadotropic hypogonadism) resulting from a malfunction at the level of the testes themselves. On the contrary, hypothalamic and/or pituitary failures are responsible for secondary hypogonadism (also called central hypogonadism or hypogonadotropic hypogonadism), which is most often caused by genetic defects, neoplasm, or infiltrative disorders [3]. More recently, Grossmann & Matsumoto [4] proposed a classification of male hypogonadism based on the distinction between functional and organic hypogonadism. Accordingly, functional hypogonadism relies on the absence of any recognized organic alterations in the HPG axis and should be treated, firstly, just by resolving or improving the associated comorbidities. On the contrary, organic hypogonadism is characterized by any proven pathology affecting the HPG axis and should be treated with conventional medications (i.e., gonadotropins or testosterone, accordingly) [4].
This narrative review is devoted to discussing the topic of gonadotropin treatment for infertile males with hypogonadotropic hypogonadism (HH).
2. METHODS
2.1. Search Strategy
2.2. Exclusion Criteria
3. RESULTS
3.1. Evidence Synthesis
3.2. Treatment
3.3. Induction of Spermatogenesis
From the early 1970s, several studies dealing with fertility promotion and preservation in HH patients have been published. As discussed, irrespective of etiology, HH is one of the few causes of male infertility effectively treatable with hormone replacement; in that aim, both gonadotropin therapy and GnRH may induce the appearance of sperm in the ejaculate [23,24] and ultimately restore fertility in men with HH [18]. Overall, the vast majority of patients (>80%) have been treated with subcutaneous combined gonadotropin injections [18,11,25]. Indeed, although pulsatile GnRH is an effective therapy to induce spermatogenesis in the absence of pituitary defect, the preferential use of gonadotropins may indicate that GnRH therapy is not available in every country and that this therapy is expensive and likely less comfortable than gonadotropin injections given the long period (i.e., 1 to 3 years) needed to promote testicular maturation [18]. When gonadotropins are the choice of treatment, FSH preparations along with a pharmacological compound to stimulate intratesticular testosterone production by the Leydig cells are usually required. Since there is a lack of LH preparations currently approved for male HH, generally patients are treated with hCG preparations which have similar, but not identical, bioactivity [26]. In this context, some studies also showed that hCG treatment without FSH may stimulate spermatogenesis, particularly in patients with a large testicular volume (>4 ml) and no history of cryptorchidism [27].
Conventional therapy uses hCG along with different FSH formulations: human menopausal gonadotropins (hMG), highly purified urinary FSH (hpFSH) preparations (e.g., urofollitropin [28]) or recombinant FSH (rFSH) [23]. Human menopausal gonadotropins had been the first preparation developed to treat HH. They are produced from the urine of postmenopausal women and have both FSH and LH activity. More in-depth, FSH activity is predominant and LH activity is so low that a combination with hCG is almost mandatory to achieve fertility. Subsequently, hpFSH compounds were developed, showing greater specific activity compared to hMG. Lastly, in the early 1990s, rFSH formulations were launched on the market, with even greater purity and specific activity than any of the urinary preparations and no intrinsic LH activity [29-31].
In everyday clinical practice, traditional treatment includes the administration of hCG (1000–1500 IU) and FSH (75–150 IU) 2 to 3 times per week [23] (Figs. 1 and 2). Unfortunately, no large, randomized controlled trials (RCTs) have ever been conducted to compare the efficacy of recombinant (any) or hpFSH with the urinary hMG preparations in males. Therefore the efficacy of the various FSH preparations in men with HH is “arbitrarily” considered to be comparable, both regarding the ability to stimulate spermatogenesis and eventually inducing physiology pregnancy [32-37]. Likewise, no ideal pharmaceutical dosage for HH treatment has been clearly established, as well as the success rate of treatment and its influencing factors [24,38,25].
3.4. Human Menopausal Gonadotropins
MacLeod et al. reported the first experience of FSH treatment in HH patients using hMG in a 37-year-old patient who underwent complete hypophysectomy in 1963 [39,40]. Since then, hMG plus hCG has been extensively proposed to several HH patients to stimulate spermatogenesis and restore fertility. Büchter et al. [41] analyzed data from 21 patients with HH due to pituitary disorders and treated with 30 courses of hMG in combination with hCG. They found that gonadotropin therapy-induced spermatogenesis in 90% of treatment courses in patients with hypothalamic disorder. In such a case, the timing for sperm detection in the ejaculate while on treatment was quite variable, with an average treatment time of 4 months and 6 months in patients with pituitary and hypothalamic disorder, respectively. Similarly, the duration of time until the induction of pregnancy of the female partner in patients with pituitary disorders was 10 months, whereas of 8 months in men with hypothalamic disorders [41,42].
3.5. FSH in Combination with Recombinant hCG or LH
So far, no adequate studies have been published comparing these preparations with hMG in men. A combination of rFSH with either recombinant LH (rLH) or hCG in one injection pen would allow easier self-administration, more fine-tuning of individual therapy, higher compliance, and maybe higher treatment efficacy. In addition, it could be speculated that LH instead of hCG therapy in combination with FSH could lead to much better clinical efficacy in terms of spermatogenesis stimulation and pregnancy rate in HH males [26,43]. Therefore, injection pens with recombinant LH are still only approved to treat female patients.
3.6. Long-acting FSH
In a recent phase III multicenter clinical trial of corifollitropin alfa in azoospermic men with HH, it was demonstrated that administration of 150 µg of a long-acting FSH preparation, given every second week leads to a significant increase of testicular volume and induction of spermatogenesis, comparable to the effects seen with short-acting rFSH preparations [37,44].
3.7. Routes of Administration
Gonadotropins can be administered either subcutaneously or intramuscularly. The subcutaneous route of administration is as effective as the intramuscular one but significantly increases patient compliance. Some HH patients can restore sperm production and fertility even using hCG alone, with a standard dosage of 500 - 2500 IU injection 2 to 3 times weekly [23]. The dose of hCG can be reduced over time as the testicular size eventually increases. However, when sperm concentration in the ejaculate is lower than 10 million/ml or once there is a plateau in the response to hCG, which typically occurs at 6 months, FSH therapy (in one of the three forms described above) should be added at a dose of 75 IU on alternate days. If sperm production and testicular growth remain suboptimal, the dose of FSH can be gradually increased up to 150 IU daily. A number of evidences have shown that adding FSH (any forms) to hCG was associated with a significantly better outcome as compared with hCG alone [24] (Fig. 2). The use of this combined therapy for a period of 12-24 months induces testicular growth in almost all patients, spermatogenesis in approximately 80%, and pregnancy rates in the range of 50% [24,41,32,45].
Furthermore, it has also been shown that induction of spermatogenesis achieved by FSH plus hCG treatment in HH can be maintained qualitatively, but not quantitatively in most of the patients with hCG alone [46]. Along this line, a sequential therapy with 3 months of treatment with FSH plus hCG alternated by hCG therapy alone for another 3 months has been proposed to reduce the relatively high costs of gonadotropin therapy [28]. However, it is still not known if this dosing regimen has the same high efficacy on the primary outcome i.e. clinical pregnancy rate.
3.8. Factors Influencing the Efficacy of Treatment
3.9. Induction of Androgenization
3.10. Reversal
4. GONADOTROPIN TREATMENT FOR IDIOPATHIC MALE INFERTILITY
4.1. Gonadotropins for Late-Onset Hypogonadism
The effectiveness of gonadotropin therapy has been extensively studied in prepubertal onset HH, while their role in adulthood for the treatment of late-onset hypogonadism (LOH) has been scarcely investigated [3]. In an RCT involving 40 LOH subjects, Liu et al. [82,21] showed that, compared to the placebo-treated arm, body weight and lean mass significantly increased in the rhCG-treated patients, whereas fat mass decreased [82,21]. Besides body composition, lipid profile also improved, with a significant decrease in total and low-density lipoprotein (LDL) cholesterol as well as triglycerides [21]. No concomitant improvement of sexual function was observed [21]. Concerning bone metabolism, the treatment arm had a higher level of neo-formation markers, without differences in bone resorption markers [83]. Similar results were reported by Tsujimura et al. [22], who evaluated the effects of hCG in 77 HH men, aged 50-79 years, complaining of consistent sexual, physical, or psychological symptoms. During follow-up, a significant improvement in sexual, physical, and psychological symptoms was observed. However, no actual improvement of erectile functioning was detected. In addition, no difference in total or high-density lipoprotein (HDL) cholesterol, as well as triglycerides, was shown after hCG treatment [22]. Accordingly, total and calculated free testosterone levels, measured after therapy, although significantly higher compared to baseline levels, were barely above the lower limit of the normal range. Hence, data on hCG treatment of LOH are still scanty and studies effectively comparing TTh and gonadotropin therapy are not yet available.
CONCLUSION
Gonadotropin therapy is effective in inducing spermatogenesis in HH patients with either hypothalamic or pituitary conditions. This approach is effective both in promoting puberty and in supporting spermatogenesis onset and preservation. The combination of FSH and hCG demonstrated to be associated with better outcomes, whereas similar results were obtained with different FSH preparations (hpFSH or rFSH) in male individuals. Several positive and negative predictors of treatment outcomes have been identified but not with a unanimous agreement between studies. Reversal of hypogonadism can occur in up to 10% of patients but its physiopathologic mechanism has yet to be elucidated. FSH therapy has shown positive effects on sperm parameters and pregnancy rate in men with altered sperm parameters and normal FSH levels, but data is too heterogeneous to draw definitive conclusions. If fertility is not an issue, TTh is advised. In contrast to TTh for congenital forms of HH, TTh of LOH is still controversial, because of unclear indications for replacement and potential risks in older individuals that have been widely and often harshly debated, without a definitive conclusion.
1. INTRODUCTION AND BACKGROUND
The hypothalamic-pituitary-gonadal (HPG) axis is essential in a number of processes related to the development, maturation, and aging of the male [1]. Through a pulsatile secretion of gonadotropin-releasing hormone (GnRH), the hypothalamus stimulates the biosynthesis of gonadotropins — namely, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) — which is controlled by extremely sophisticated positive and negative feedback. Of gonadotropins, LH stimulates testicular endocrine function by activating Leydig cells hosted in the interstitial space of the testicle, with a consequent activity in terms of male genital development and differentiation, throughout human sexual determination [2]. Instead, FSH sustains testicular exocrine function led by Sertoli cells through spermatogenesis. Both testosterone synthesis and male fertility result from the delicate coordination throughout the HPG axis, thus assuring normal testicular function. In this context, congenital or acquired disturbances at any level of the HPG axis can lead to an impairment of reproductive function and the clinical syndrome of hypogonadism.
Hypogonadism can be caused by a primary testicular pathology (i.e., primary hypogonadism, otherwise known as hypergonadotropic hypogonadism) resulting from a malfunction at the level of the testes themselves. On the contrary, hypothalamic and/or pituitary failures are responsible for secondary hypogonadism (also called central hypogonadism or hypogonadotropic hypogonadism), which is most often caused by genetic defects, neoplasm, or infiltrative disorders [3]. More recently, Grossmann & Matsumoto [4] proposed a classification of male hypogonadism based on the distinction between functional and organic hypogonadism. Accordingly, functional hypogonadism relies on the absence of any recognized organic alterations in the HPG axis and should be treated, firstly, just by resolving or improving the associated comorbidities. On the contrary, organic hypogonadism is characterized by any proven pathology affecting the HPG axis and should be treated with conventional medications (i.e., gonadotropins or testosterone, accordingly) [4].
This narrative review is devoted to discussing the topic of gonadotropin treatment for infertile males with hypogonadotropic hypogonadism (HH).
2. METHODS
2.1. Search Strategy
2.2. Exclusion Criteria
3. RESULTS
3.1. Evidence Synthesis
3.2. Treatment
3.3. Induction of Spermatogenesis
From the early 1970s, several studies dealing with fertility promotion and preservation in HH patients have been published. As discussed, irrespective of etiology, HH is one of the few causes of male infertility effectively treatable with hormone replacement; in that aim, both gonadotropin therapy and GnRH may induce the appearance of sperm in the ejaculate [23,24] and ultimately restore fertility in men with HH [18]. Overall, the vast majority of patients (>80%) have been treated with subcutaneous combined gonadotropin injections [18,11,25]. Indeed, although pulsatile GnRH is an effective therapy to induce spermatogenesis in the absence of pituitary defect, the preferential use of gonadotropins may indicate that GnRH therapy is not available in every country and that this therapy is expensive and likely less comfortable than gonadotropin injections given the long period (i.e., 1 to 3 years) needed to promote testicular maturation [18]. When gonadotropins are the choice of treatment, FSH preparations along with a pharmacological compound to stimulate intratesticular testosterone production by the Leydig cells are usually required. Since there is a lack of LH preparations currently approved for male HH, generally patients are treated with hCG preparations which have similar, but not identical, bioactivity [26]. In this context, some studies also showed that hCG treatment without FSH may stimulate spermatogenesis, particularly in patients with a large testicular volume (>4 ml) and no history of cryptorchidism [27].
Conventional therapy uses hCG along with different FSH formulations: human menopausal gonadotropins (hMG), highly purified urinary FSH (hpFSH) preparations (e.g., urofollitropin [28]) or recombinant FSH (rFSH) [23]. Human menopausal gonadotropins had been the first preparation developed to treat HH. They are produced from the urine of postmenopausal women and have both FSH and LH activity. More in-depth, FSH activity is predominant and LH activity is so low that a combination with hCG is almost mandatory to achieve fertility. Subsequently, hpFSH compounds were developed, showing greater specific activity compared to hMG. Lastly, in the early 1990s, rFSH formulations were launched on the market, with even greater purity and specific activity than any of the urinary preparations and no intrinsic LH activity [29-31].
In everyday clinical practice, traditional treatment includes the administration of hCG (1000–1500 IU) and FSH (75–150 IU) 2 to 3 times per week [23] (Figs. 1 and 2). Unfortunately, no large, randomized controlled trials (RCTs) have ever been conducted to compare the efficacy of recombinant (any) or hpFSH with the urinary hMG preparations in males. Therefore the efficacy of the various FSH preparations in men with HH is “arbitrarily” considered to be comparable, both regarding the ability to stimulate spermatogenesis and eventually inducing physiology pregnancy [32-37]. Likewise, no ideal pharmaceutical dosage for HH treatment has been clearly established, as well as the success rate of treatment and its influencing factors [24,38,25].
3.4. Human Menopausal Gonadotropins
MacLeod et al. reported the first experience of FSH treatment in HH patients using hMG in a 37-year-old patient who underwent complete hypophysectomy in 1963 [39,40]. Since then, hMG plus hCG has been extensively proposed to several HH patients to stimulate spermatogenesis and restore fertility. Büchter et al. [41] analyzed data from 21 patients with HH due to pituitary disorders and treated with 30 courses of hMG in combination with hCG. They found that gonadotropin therapy-induced spermatogenesis in 90% of treatment courses in patients with hypothalamic disorder. In such a case, the timing for sperm detection in the ejaculate while on treatment was quite variable, with an average treatment time of 4 months and 6 months in patients with pituitary and hypothalamic disorder, respectively. Similarly, the duration of time until the induction of pregnancy of the female partner in patients with pituitary disorders was 10 months, whereas of 8 months in men with hypothalamic disorders [41,42].
3.5. FSH in Combination with Recombinant hCG or LH
So far, no adequate studies have been published comparing these preparations with hMG in men. A combination of rFSH with either recombinant LH (rLH) or hCG in one injection pen would allow easier self-administration, more fine-tuning of individual therapy, higher compliance, and maybe higher treatment efficacy. In addition, it could be speculated that LH instead of hCG therapy in combination with FSH could lead to much better clinical efficacy in terms of spermatogenesis stimulation and pregnancy rate in HH males [26,43]. Therefore, injection pens with recombinant LH are still only approved to treat female patients.
3.6. Long-acting FSH
In a recent phase III multicenter clinical trial of corifollitropin alfa in azoospermic men with HH, it was demonstrated that administration of 150 µg of a long-acting FSH preparation, given every second week leads to a significant increase of testicular volume and induction of spermatogenesis, comparable to the effects seen with short-acting rFSH preparations [37,44].
3.7. Routes of Administration
Gonadotropins can be administered either subcutaneously or intramuscularly. The subcutaneous route of administration is as effective as the intramuscular one but significantly increases patient compliance. Some HH patients can restore sperm production and fertility even using hCG alone, with a standard dosage of 500 - 2500 IU injection 2 to 3 times weekly [23]. The dose of hCG can be reduced over time as the testicular size eventually increases. However, when sperm concentration in the ejaculate is lower than 10 million/ml or once there is a plateau in the response to hCG, which typically occurs at 6 months, FSH therapy (in one of the three forms described above) should be added at a dose of 75 IU on alternate days. If sperm production and testicular growth remain suboptimal, the dose of FSH can be gradually increased up to 150 IU daily. A number of evidences have shown that adding FSH (any forms) to hCG was associated with a significantly better outcome as compared with hCG alone [24] (Fig. 2). The use of this combined therapy for a period of 12-24 months induces testicular growth in almost all patients, spermatogenesis in approximately 80%, and pregnancy rates in the range of 50% [24,41,32,45].
Furthermore, it has also been shown that induction of spermatogenesis achieved by FSH plus hCG treatment in HH can be maintained qualitatively, but not quantitatively in most of the patients with hCG alone [46]. Along this line, a sequential therapy with 3 months of treatment with FSH plus hCG alternated by hCG therapy alone for another 3 months has been proposed to reduce the relatively high costs of gonadotropin therapy [28]. However, it is still not known if this dosing regimen has the same high efficacy on the primary outcome i.e. clinical pregnancy rate.
3.8. Factors Influencing the Efficacy of Treatment
3.9. Induction of Androgenization
3.10. Reversal
4. GONADOTROPIN TREATMENT FOR IDIOPATHIC MALE INFERTILITY
4.1. Gonadotropins for Late-Onset Hypogonadism
The effectiveness of gonadotropin therapy has been extensively studied in prepubertal onset HH, while their role in adulthood for the treatment of late-onset hypogonadism (LOH) has been scarcely investigated [3]. In an RCT involving 40 LOH subjects, Liu et al. [82,21] showed that, compared to the placebo-treated arm, body weight and lean mass significantly increased in the rhCG-treated patients, whereas fat mass decreased [82,21]. Besides body composition, lipid profile also improved, with a significant decrease in total and low-density lipoprotein (LDL) cholesterol as well as triglycerides [21]. No concomitant improvement of sexual function was observed [21]. Concerning bone metabolism, the treatment arm had a higher level of neo-formation markers, without differences in bone resorption markers [83]. Similar results were reported by Tsujimura et al. [22], who evaluated the effects of hCG in 77 HH men, aged 50-79 years, complaining of consistent sexual, physical, or psychological symptoms. During follow-up, a significant improvement in sexual, physical, and psychological symptoms was observed. However, no actual improvement of erectile functioning was detected. In addition, no difference in total or high-density lipoprotein (HDL) cholesterol, as well as triglycerides, was shown after hCG treatment [22]. Accordingly, total and calculated free testosterone levels, measured after therapy, although significantly higher compared to baseline levels, were barely above the lower limit of the normal range. Hence, data on hCG treatment of LOH are still scanty and studies effectively comparing TTh and gonadotropin therapy are not yet available.
CONCLUSION
Gonadotropin therapy is effective in inducing spermatogenesis in HH patients with either hypothalamic or pituitary conditions. This approach is effective both in promoting puberty and in supporting spermatogenesis onset and preservation. The combination of FSH and hCG demonstrated to be associated with better outcomes, whereas similar results were obtained with different FSH preparations (hpFSH or rFSH) in male individuals. Several positive and negative predictors of treatment outcomes have been identified but not with a unanimous agreement between studies. Reversal of hypogonadism can occur in up to 10% of patients but its physiopathologic mechanism has yet to be elucidated. FSH therapy has shown positive effects on sperm parameters and pregnancy rate in men with altered sperm parameters and normal FSH levels, but data is too heterogeneous to draw definitive conclusions. If fertility is not an issue, TTh is advised. In contrast to TTh for congenital forms of HH, TTh of LOH is still controversial, because of unclear indications for replacement and potential risks in older individuals that have been widely and often harshly debated, without a definitive conclusion.
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