madman
Super Moderator
Male hypogonadism is often associated with impaired fertility. In special cases, treatment with gonadotropins can induce, maintain, or augment spermatogenesis. Patients responsive to such regimens are men with secondary hypogonadism, lacking gonadotropin secretion due to pituitary disorders or hypothalamic insufficiency. Such diseases may be inherited or acquired. Available substances are recombinant follicle-stimulating hormone and human chorionic gonadotropin (substituting activity of luteinizing hormone). Recommendation based on current research is that treatment should last at least 2 years. Successful induction of spermatogenesis is more likely in men with pituitary disorders than in those lacking hypothalamic GnRH secretion (e.g. patients with Kallman Syndrome).
Introduction
Testicular dysfunction often comprises both productions of testosterone and spermatogenesis. These functions are dependent on gonadotropin action in men, with LH stimulating testosterone production in Leydig cells and FSH supporting spermatogenesis by stimulating Sertoli cell function.
While hypogonadism as such is usually treated with testosterone applied by various methods, for achieving fertility – possible in the hypogonadotropic forms – temporary treatment with gonadotropins or their clinical substitutes are required, i.e. human chorionic gonadotropin (hCG) in combination with human menopausal gonadotropin (hMG) or purified urinary follicle-stimulating hormone (FSH) or recombinant human FSH (rhFSH) or, alternatively to gonadotropins, pulsatile GnRH application. Once paternity has been achieved, the treatment scheme should switch back to the more convenient and cost-effective testosterone substitution. Information about the state of the art of gonadotropin treatment in infertile men with hypogonadotropic hypogonadism will be given in the following.
Hormone Replacement by Pulsatile GnRH Application or Gonadotropin Substitution in General
In hypogonadotropic hypogonadism the origin of the disease influences the choice of treatment to achieve fertility.
GnRH substitution is only effective in hypothalamic disorders; a pituitary insufficiency always requires administration of gonadotropins (either the conventional choice of human chorionic gonadotropin and human menopausal gonadotropin, or purified urinary FSH, or more recently, recombinant human FSH) [1]. FSH plays a pivotal role in the initiation and maintenance of spermatogenesis. The induction of proliferation of Sertoli cells and spermatogonia depends on this gonadotropin [2].
For completely normal spermatogenesis, FSH and testosterone are important, and the intratesticular location/action of testosterone is pivotal. Thus for treating infertility in hypogonadal men, there is a need for high intratesticular testosterone levels to initiate spermatogenesis. This was demonstrated by treating men with hypogonadotropic hypogonadism with purified FSH and testosterone and comparing its effectiveness to hCG/hMG therapy [1]. The latter was able to induce spermatogenesis while the FSH/testosterone regimen failed [7].
Pulsatile GnRH Therapy
Treatment with GnRH requires subcutaneous pulsatile application using a portable pump and a butterfly needle placed in the abdominal wall and changed every 2 days. The dose ranges from 5 to 20 µg/ 120 min, or 100–400 ng/kg body weight per 120 min. Low-dose pulsatile GnRH therapy (2 µg/150 min) may not elicit a sufficient pituitary response, reflecting different degrees of central maturation [16]. In most cases, the induction of spermatogenesis is evidenced by the appearance of sperm in the ejaculate. Therapy lasts on average 4 months, as shown in six of seven GnRH therapy cycles in patients with idiopathic hypogonadotropic hypogonadism or Kallman syndrome [10]. Sperm counts were below the normal range of 1.2–15.3 mill/ml.
When pulsatile GnRH treatment fails, a mutation of the GnRH receptor gene can be the cause. These defects have been described and are probably transmitted as an autosomal recessive trait. A variable degree of hypogonadism in an affected kindred was seen: a male showed no response to pulsatile administration of GnRH, which was effective in his two sisters, all showing clinical patterns of hypogonadotropic hypogonadism [19].
Another cause for failure of pulsatile GnRH treatment was observed in a patient who formed anti-GnRH antibodies during intravenous administration. This was associated with deterioration of testosterone and gonadotropin levels [20].
Gonadotropin Therapy
In order to achieve fertility in cases of pituitary lesions or GnRH receptor gene defects, the regimens using gonadotropins must be applied, but they are also a useful option in hypothalamic disorders. Historical therapy used hCG and hMG, both purified extractions from urine. In recent years, however, purified urinary FSH and recombinant human FSH have replaced hMG in most countries for various reasons [1].
Treatment with hCG/hMG
As the subunits of hCG and LH are structurally very similar, they act on the same receptor located on Leydig cells. This effect is used to substitute LH with purified urinary hCG or recombinant hCG. Human menopausal gonadotropin contains both LH- and FSH-activity. However, a dose that provides adequate FSH-activity does not maintain Leydig cell function because the LH-activity is low. Thus a combination with hCG is required to achieve fertility.
95% of hMG consists of co-purified proteins that lack LH or FSH activity and is believed to cause the hypersensitivity reactions occasionally observed under hMG therapy, but not under highly purified FSH or recombinant FSH [22–24].
HCG may also induce antibody formation [25], which may neutralize hCG bioactivity [26–28].
Therapy in men is initiated by the administration of hCG alone, which is given intramuscularly or subcutaneously. The usual dose is 1500–3000 IU applied twice per week (Monday and Friday) for a period of 8–12 weeks; adjustments have to be made to achieve testosterone levels within the normal range. In some cases sperm can be found in the ejaculate by then, due to residual FSH secretion [11, 31, 32].
Following the induction phase, hMG or rhFSH is administered intramuscularly at a dose of 75–150 IU thrice weekly (Monday, Wednesday, Friday). Sometimes it may be necessary to reduce the hCG dose due to increasing testosterone levels or development of gynecomastia caused by increased levels of testosterone which are aromatized to estradiol. A review of 9 patients with IHH, 9 patients with Kallmann syndrome (group A) and 21 patients with hypopituitarism (group B) treated with this regimen showed the appearance of first sperm in the ejaculate after an average period of 6 months (1–18 months) in group A, and 4 months (2–16 months) in group B. Sperm concentrations were 1.2 mill/ml (0.1–9.0 mill/ml) in group A, and 8.1 mill/ml (0.1–180 mill/ml) in group B [10].
As mentioned above, the duration of therapy depends on the initial testicular size and the patients’ history of uni- or bilateral maldescensus. Pregnancies were induced in 5 of 10 patients belonging to group A (time to pregnancy on average 8 months), and in 17 of 21 patients of group B (time to pregnancy on average 10 months). Testicular size increased from 4.4 ± 2.86 to 15.3 ± 7.4 ml (group A), and from 14.0 ± 8.7 to 28.3 ± 10.9 ml (group B; [10]).
Treatment with hCG/Highly Purified Urinary Human FSH (Urinary-hFSH)
Improved purification methods have provided highly purified urinary FSH with an enhanced specific activity in comparison to hMG (10,000 IU/mg of protein vs. 150 IU: mg of protein for hMG). A study including 28 men with hypogonadotropic hypogonadism examined the effects of hCG 2000 IU twice weekly for 3–6 months followed by 18 months of additional subcutaneous administration of highly purified urinary FSH. Twenty-five patients achieved spermatogenesis, 18 of them with a sperm density of more than 1.5 mill/ml. The median time to initiation of spermatogenesis (appearance of sperm in the ejaculate) was 9 months. Mean testicular volume increased from 3.6 ± 1.7 to 10.5 ± 4.1 ml. The partner of one patient seeking fertility conceived a child. The effectiveness was comparable to regimens using hCG and hMG [33].
Treatment with hCG/Recombinant Human FSH (r-hFSH)
rhFSH has advantages over urinary preparations in terms of purity, specific activity, consistent composition, and constant supply. Multiple-dose pharmacokinetics showed an elimination half-life of 48 ± 5 h and proved that serum FSH is increased in a dose-proportional fashion. No intrinsic LH activity was detected [36].
A combined analysis of data from 4 studies using rFSH/hCG to induce spermatogenesis in men with hypogonadotropic hypogonadism (n = 100) revealed that spermatogenesis could be achieved in 68 men after a maximal duration of treatment of 18 months [40].
Use of Recombinant Human LH (rhLH)
Recombinant hLH is available for stimulation purposes in cycles of assisted reproduction and used in women to induce ovulation [41]. Whilst hCG is effective for 36 hours, rhLH would have to be administered daily for substitution in men. Its use may therefore be limited, but longer comparative studies in men are lacking. A recent in vitro study suggests that, although human luteinizing hormone (hLH) and chorionic gonadotropin (hCG) act on the same receptor, they may nevertheless elicit a different cellular and molecular response in COS-7 and hGL5 cells [42].
Comparison of GnRH and Gonadotropin Therapy
There is still some degree of uncertainty regarding the optimal treatment modality in patients with hypogonadotropic hypogonadism caused by disorders at the hypothalamic level. Our group reported 42 cases of men with hypogonadotropic hypogonadism treated for infertility, comprising 24 patients with IHH or Kallmann syndrome. Six of these received pulsatile GnRH treatment, the other 18 the conventional hCG/hMG regimen. No statistically significant differences in terms of the first appearance of sperm in the ejaculate or time to pregnancy was seen, nor was the increment of testicular size significantly different [10].
Another study with 36 patients with disorders at the hypothalamic level (IHH or Kallmann syndrome), divided into groups of 18, reported no significant difference in effectiveness with respect to sperm counts. With GnRH therapy increment of testicular volume occurred more rapidly and was significantly more pronounced than under a gonadotropin regimen. Five patients with the latter therapy developed gynecomastia, probably due to the significantly higher testosterone concentrations in that group [18]. A 2- year comparison including 16 patients showed no advantage of either therapy concerning acceleration and/or enhancement of testicular growth, the onset of spermatogenesis, or increment of sperm output [17].
Hormonal Treatment of Normogonadotropic Oligoasthenotheratozoospermia
Outlook: Pharmacogenetic Implications
Conclusion
Gonadotropin substitution therapy is highly effective in men with hypogonadotropic hypogonadism to achieve both androgenization and fertility. Up to now, the use of gonadotropins, especially FSH, in normogonadotropic infertile men cannot be recommended generally. However, clearly predefined patients might benefit from this therapy.
Introduction
Testicular dysfunction often comprises both productions of testosterone and spermatogenesis. These functions are dependent on gonadotropin action in men, with LH stimulating testosterone production in Leydig cells and FSH supporting spermatogenesis by stimulating Sertoli cell function.
While hypogonadism as such is usually treated with testosterone applied by various methods, for achieving fertility – possible in the hypogonadotropic forms – temporary treatment with gonadotropins or their clinical substitutes are required, i.e. human chorionic gonadotropin (hCG) in combination with human menopausal gonadotropin (hMG) or purified urinary follicle-stimulating hormone (FSH) or recombinant human FSH (rhFSH) or, alternatively to gonadotropins, pulsatile GnRH application. Once paternity has been achieved, the treatment scheme should switch back to the more convenient and cost-effective testosterone substitution. Information about the state of the art of gonadotropin treatment in infertile men with hypogonadotropic hypogonadism will be given in the following.
Hormone Replacement by Pulsatile GnRH Application or Gonadotropin Substitution in General
In hypogonadotropic hypogonadism the origin of the disease influences the choice of treatment to achieve fertility.
GnRH substitution is only effective in hypothalamic disorders; a pituitary insufficiency always requires administration of gonadotropins (either the conventional choice of human chorionic gonadotropin and human menopausal gonadotropin, or purified urinary FSH, or more recently, recombinant human FSH) [1]. FSH plays a pivotal role in the initiation and maintenance of spermatogenesis. The induction of proliferation of Sertoli cells and spermatogonia depends on this gonadotropin [2].
For completely normal spermatogenesis, FSH and testosterone are important, and the intratesticular location/action of testosterone is pivotal. Thus for treating infertility in hypogonadal men, there is a need for high intratesticular testosterone levels to initiate spermatogenesis. This was demonstrated by treating men with hypogonadotropic hypogonadism with purified FSH and testosterone and comparing its effectiveness to hCG/hMG therapy [1]. The latter was able to induce spermatogenesis while the FSH/testosterone regimen failed [7].
Pulsatile GnRH Therapy
Treatment with GnRH requires subcutaneous pulsatile application using a portable pump and a butterfly needle placed in the abdominal wall and changed every 2 days. The dose ranges from 5 to 20 µg/ 120 min, or 100–400 ng/kg body weight per 120 min. Low-dose pulsatile GnRH therapy (2 µg/150 min) may not elicit a sufficient pituitary response, reflecting different degrees of central maturation [16]. In most cases, the induction of spermatogenesis is evidenced by the appearance of sperm in the ejaculate. Therapy lasts on average 4 months, as shown in six of seven GnRH therapy cycles in patients with idiopathic hypogonadotropic hypogonadism or Kallman syndrome [10]. Sperm counts were below the normal range of 1.2–15.3 mill/ml.
When pulsatile GnRH treatment fails, a mutation of the GnRH receptor gene can be the cause. These defects have been described and are probably transmitted as an autosomal recessive trait. A variable degree of hypogonadism in an affected kindred was seen: a male showed no response to pulsatile administration of GnRH, which was effective in his two sisters, all showing clinical patterns of hypogonadotropic hypogonadism [19].
Another cause for failure of pulsatile GnRH treatment was observed in a patient who formed anti-GnRH antibodies during intravenous administration. This was associated with deterioration of testosterone and gonadotropin levels [20].
Gonadotropin Therapy
In order to achieve fertility in cases of pituitary lesions or GnRH receptor gene defects, the regimens using gonadotropins must be applied, but they are also a useful option in hypothalamic disorders. Historical therapy used hCG and hMG, both purified extractions from urine. In recent years, however, purified urinary FSH and recombinant human FSH have replaced hMG in most countries for various reasons [1].
Treatment with hCG/hMG
As the subunits of hCG and LH are structurally very similar, they act on the same receptor located on Leydig cells. This effect is used to substitute LH with purified urinary hCG or recombinant hCG. Human menopausal gonadotropin contains both LH- and FSH-activity. However, a dose that provides adequate FSH-activity does not maintain Leydig cell function because the LH-activity is low. Thus a combination with hCG is required to achieve fertility.
95% of hMG consists of co-purified proteins that lack LH or FSH activity and is believed to cause the hypersensitivity reactions occasionally observed under hMG therapy, but not under highly purified FSH or recombinant FSH [22–24].
HCG may also induce antibody formation [25], which may neutralize hCG bioactivity [26–28].
Therapy in men is initiated by the administration of hCG alone, which is given intramuscularly or subcutaneously. The usual dose is 1500–3000 IU applied twice per week (Monday and Friday) for a period of 8–12 weeks; adjustments have to be made to achieve testosterone levels within the normal range. In some cases sperm can be found in the ejaculate by then, due to residual FSH secretion [11, 31, 32].
Following the induction phase, hMG or rhFSH is administered intramuscularly at a dose of 75–150 IU thrice weekly (Monday, Wednesday, Friday). Sometimes it may be necessary to reduce the hCG dose due to increasing testosterone levels or development of gynecomastia caused by increased levels of testosterone which are aromatized to estradiol. A review of 9 patients with IHH, 9 patients with Kallmann syndrome (group A) and 21 patients with hypopituitarism (group B) treated with this regimen showed the appearance of first sperm in the ejaculate after an average period of 6 months (1–18 months) in group A, and 4 months (2–16 months) in group B. Sperm concentrations were 1.2 mill/ml (0.1–9.0 mill/ml) in group A, and 8.1 mill/ml (0.1–180 mill/ml) in group B [10].
As mentioned above, the duration of therapy depends on the initial testicular size and the patients’ history of uni- or bilateral maldescensus. Pregnancies were induced in 5 of 10 patients belonging to group A (time to pregnancy on average 8 months), and in 17 of 21 patients of group B (time to pregnancy on average 10 months). Testicular size increased from 4.4 ± 2.86 to 15.3 ± 7.4 ml (group A), and from 14.0 ± 8.7 to 28.3 ± 10.9 ml (group B; [10]).
Treatment with hCG/Highly Purified Urinary Human FSH (Urinary-hFSH)
Improved purification methods have provided highly purified urinary FSH with an enhanced specific activity in comparison to hMG (10,000 IU/mg of protein vs. 150 IU: mg of protein for hMG). A study including 28 men with hypogonadotropic hypogonadism examined the effects of hCG 2000 IU twice weekly for 3–6 months followed by 18 months of additional subcutaneous administration of highly purified urinary FSH. Twenty-five patients achieved spermatogenesis, 18 of them with a sperm density of more than 1.5 mill/ml. The median time to initiation of spermatogenesis (appearance of sperm in the ejaculate) was 9 months. Mean testicular volume increased from 3.6 ± 1.7 to 10.5 ± 4.1 ml. The partner of one patient seeking fertility conceived a child. The effectiveness was comparable to regimens using hCG and hMG [33].
Treatment with hCG/Recombinant Human FSH (r-hFSH)
rhFSH has advantages over urinary preparations in terms of purity, specific activity, consistent composition, and constant supply. Multiple-dose pharmacokinetics showed an elimination half-life of 48 ± 5 h and proved that serum FSH is increased in a dose-proportional fashion. No intrinsic LH activity was detected [36].
A combined analysis of data from 4 studies using rFSH/hCG to induce spermatogenesis in men with hypogonadotropic hypogonadism (n = 100) revealed that spermatogenesis could be achieved in 68 men after a maximal duration of treatment of 18 months [40].
Use of Recombinant Human LH (rhLH)
Recombinant hLH is available for stimulation purposes in cycles of assisted reproduction and used in women to induce ovulation [41]. Whilst hCG is effective for 36 hours, rhLH would have to be administered daily for substitution in men. Its use may therefore be limited, but longer comparative studies in men are lacking. A recent in vitro study suggests that, although human luteinizing hormone (hLH) and chorionic gonadotropin (hCG) act on the same receptor, they may nevertheless elicit a different cellular and molecular response in COS-7 and hGL5 cells [42].
Comparison of GnRH and Gonadotropin Therapy
There is still some degree of uncertainty regarding the optimal treatment modality in patients with hypogonadotropic hypogonadism caused by disorders at the hypothalamic level. Our group reported 42 cases of men with hypogonadotropic hypogonadism treated for infertility, comprising 24 patients with IHH or Kallmann syndrome. Six of these received pulsatile GnRH treatment, the other 18 the conventional hCG/hMG regimen. No statistically significant differences in terms of the first appearance of sperm in the ejaculate or time to pregnancy was seen, nor was the increment of testicular size significantly different [10].
Another study with 36 patients with disorders at the hypothalamic level (IHH or Kallmann syndrome), divided into groups of 18, reported no significant difference in effectiveness with respect to sperm counts. With GnRH therapy increment of testicular volume occurred more rapidly and was significantly more pronounced than under a gonadotropin regimen. Five patients with the latter therapy developed gynecomastia, probably due to the significantly higher testosterone concentrations in that group [18]. A 2- year comparison including 16 patients showed no advantage of either therapy concerning acceleration and/or enhancement of testicular growth, the onset of spermatogenesis, or increment of sperm output [17].
Hormonal Treatment of Normogonadotropic Oligoasthenotheratozoospermia
Outlook: Pharmacogenetic Implications
Conclusion
Gonadotropin substitution therapy is highly effective in men with hypogonadotropic hypogonadism to achieve both androgenization and fertility. Up to now, the use of gonadotropins, especially FSH, in normogonadotropic infertile men cannot be recommended generally. However, clearly predefined patients might benefit from this therapy.
