madman
Super Moderator
Abstract
Background: Compared to adult studies, studies that involve the treatment of pediatric congenital hypogonadotropic hypogonadism (CHH) are limited and no universal treatment regimen is available. The aim of this study was to evaluate the feasibility of human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) therapy for treating male adolescents with CHH.
Methods: Male adolescent CHH patients were treated with hCG/hMG (n = 20) or a gonadotropin-releasing hormone (GnRH) pump (n = 21). The treatment was divided into a study phase (0–3 months) and a follow-up phase (3–12 months). The testicular volume (TV), penile length (PL), penis diameter (PD), and sex hormone levels were compared between the two groups. The TV and other indicators between the groups were analyzed using a t-test (equal variance) or a rank-sum test (unequal variance).
Results: Before treatment, there was no statistical difference between the two groups in terms of biochemistry, hormones, and other demographic indicators. After 3 months of treatment, the TV of the hCG/hMG and GnRH groups increased to 5.1 ± 2.3 mL and 4.1 ± 1.8 mL, respectively; however, the difference was not statistically significant (P > 0.05, t = 1.394). The PL reached 6.9 ± 1.8 cm and 5.1 ± 1.6 cm (P < 0.05, t = 3.083), the PD reached 2.4 ± 0.5 cm and 2.0 ± 0.6 cm (P < 0.05, t = 2.224), respectively, in the two groups. At the end of 6 months of treatment, biomarkers were in the normal range in the two groups. Compared with the GnRH group, the testosterone (T) level and growth of PL and PD were significantly greater in the hCG/hMG group (all P < 0.05). While the TV of both groups increased, the difference was not statistically significant (P > 0.05, t = 0.314). After 9 to 12 months of treatment, the T level was higher in the hCG/hMG group. Other parameters did not exhibit a statistical difference.
Conclusions: The hCG/hMG regimen is feasible and effective for treating male adolescents with CHH. The initial 3 months of treatment may be a window to optimally observe the strongest effects of therapy. Furthermore, results from the extended-time period showed positive outcomes at the 1-year mark; however, the long-term effectiveness, strengths, and weaknesses of the hCG/hMG regimen require further research.
Introduction
Congenital hypogonadotropic hypogonadism (CHH) is a disorder that results from the insufficient release and secretion of gonadotropin-releasing hormone (GnRH).[1] Two subtypes of CHH exist; they are Kallmann syndrome (KS), which is associated with olfactory dysfunction, and normosmic idiopathic hypogonadotropich hypogonadism (nIHH), which retains intact olfactory function without other intracranial pathologies. The incidence of CHH is in the range of 1 to 10/100,000 and the male to female ratio is 5:1.[2] There are many clinical treatment options for CHH, the most common among which involves the usage of a GnRH pump, the combination of human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) (follicle-stimulating hormone [FSH]), and testosterone replacement.[3] Notably, testosterone replacement can promote the development of secondary sexual characteristics in patients but unfortunately cannot improve fertility. Obtaining fertility is a very high priority for Chinese patients; however, our previous therapeutic experience indicates that the application of hCG alone is not sufficient to ensure this outcome.[4] On the other hand, hCG/hMG injection and GnRH pump treatment can promote the production of testosterone and sperm in the testes.[5,6] Compared to patients with acquired hypogonadism, gonadotropin deficiency occurs in the fetal period for CHH patients, and abnormalities such as cryptorchidism, a small penis, and scrotal dysplasia can be observed at birth.[7] CHH patients also usually show a poor response to the application of spermatogenic therapy when they are in adulthood.[8] Nevertheless, the dose of hCG for CHH pre-treatment may also predict future therapeutic effects.[9] Recombinant human follicle-stimulating hormone (r-hFSH) has been approved for CHH treatment in many countries because exogenous FSH can stimulate Sertoli cells and spermatogonia, increase levels of antiMüllerian hormone (AMH) and elevate the testicular volume (TV) and sperm density.[1,5,10] However, there may still be testicular dysfunction in children with CHH, and if FSH is initially applied, the testes may not develop in some children. Considering the high cost of FSH in China, we chose to use hCG pre-treatment in the clinic and combined it with monitoring of testosterone levels. If testicular function appears normal, hMG (or FSH) may be applied to further induce puberty.
Compared to adult studies, those involving the treatment of pediatric CHH are limited and no universal treatment regimen is available. A multicenter study in Germany in 60 children aged 14 to 22 years indicated that subcutaneous injection of hCG/r-hFSH may be a safe and valid treatment option based on the positive therapeutic effects, compared to testosterone treatment.[11] Despite these positive results, the details of the same therapy in each treatment center are generally dissimilar.[11] Some scholars propose a treatment protocol that begins with low doses of gonadotropin at a timing that is closer to the onset of puberty (namely, a timing that coincides with entrance into junior high school).[12] However, this idea is not easily adherent because puberty is a complicated and long process, and proof for the effectiveness of treatments that involve low dose gonadotropin administration cannot be expected in a short time period. In addition, it is not easy to effectively compare or summarize treatment effects because the treatment regimen varies across patients according to individual needs.
Regarding the pituitary hormone pump, the cost is high, it is inconvenient and difficult to conceal, and it does not offer much privacy. For these reasons, many adolescent patients prefer hCG/hMG injection over the pituitary hormone pump. Therefore, the goal of this study was to establish a standardized, simple hCG/hMG treatment scheme for adolescent males with CHH. This regimen is simple and effective over a short time period and can aid in increasing adherence.
Furthermore, puberty development in boys begins at the age of 9 to 14 years, with 12 years being the median age for full development. Patients with CHH at this age have been subject to preliminary study at the Beijing Children’s Hospital, National Center for Children’s Health, Beijing.[4] We hope that through therapeutic research, the treatment age of CHH can be extended to 12 years old; doing so would ensure that penile development in similarly-aged children are similar and can reduce the psychological burden of such children and their parents. In this retrospective cohort study, we therefore also compared the efficacy and safety, as well as the impact on growth and development, of the two previously mentioned treatment regimens in an adolescent population.[13,14]
Treatment regimen
Patients in the two groups were followed up every 3 months. Height and body weight were recorded every 6 months during the course of treatment. Treatment effectiveness was assessed with TV, sex hormones, the occurrence of a nocturnal emission, penile length (PL), and change of scrotal skin. The treatment regimen was designed and modified based on “Expert consensus on the diagnosis and treatment of idiopathic hypogonadotropic hypogonadism.”[5] We referred to studies that recommended adult hCG doses in the range of 4000 to 6000 U per week, combined with 75 to 150 U of hMG 2 to 3 times per week.[1,4,5] The actual total dose was less than the recommended dose for adults because multiple low doses were more in line with physiological needs. For the hCG/hMG group, hCG was injected muscularly as follows: for the first 3 months (pre-treatment phase), 1000 to 2000 U of hCG was injected intramuscularly once every other day or twice per week. This injection volume was started at a low dose and was gradually increased until the testosterone level reached 200 ng/dL. Following this, and to start the formal therapeutic stage, hMG containing 75 U of FSH and 75 U of LH was administered once per day. In practice, the dosage of hCG was adjusted to maintain the testosterone value at 200 to 500 ng/dL to the extent possible.
The GnRH group was continuously treated with a GnRH pump. The dose of GnRH was chosen according to adult hypogonadotropic hypogonadism (HH) guidelines and our previous research.[1,4] Briefly, 8 to 10 mg of GnRH (200 mg/mL) were subcutaneously injected every 90 min via an injection pump. If side effects (described below) occurred, the dose of the GnRH was reduced.
During treatment, we carefully monitored adverse reactions, such as breast development, self-perceived excessive acne, frequent (>1 time per day) penile erection, erectile pain, skin infection and discomfort at the injection site, liver dysfunction, renal dysfunction, electrolyte abnormalities, and other autonomic reactions.
In short, 3 months of treatment with hCG/hMG provides a safe and effective treatment window for inducing puberty in male adolescent CHH patients. It can be used as an alternative option to hCG for inducing puberty and fertility, especially for those patients who have pituitary lesions. Treatment using a GnRH pump is still effective for patients with MPHD; however, it is thought that such patients still retain some pituitary gonadotropin cells that can be stimulated by GnRH. Thus, this treatment may be able to restart pituitary testicular axis function.
The price of the pituitary hormone pump is still high and inconvenient. For privacy protection, many adolescent patients prefer hCG/hMG injection instead of wearing a pituitary hormone pump. This study suggests a different treatment scheme for adolescent CHH, that has similar efficacy and safety as the hormone pump and that provides more data and choice for clinicians to treat various patients.
This study compared the therapeutic effect and safety, as well as the impact on growth and development, of two treatment options in an adolescent CHH population. The target population of this study was adolescents since similar work in adults has been previously reported. While the ultimate goal of this work is to help CHH patients simulate normal puberty development and to fill their psychological and physiological needs, various limitations of the current work must be addressed in the future. First, the observation duration period of the current study was short and without semen analysis. Second, the sample size was small and an extended phase is necessary to validate these results. These data will be gradually supplemented and improved in future research.
Background: Compared to adult studies, studies that involve the treatment of pediatric congenital hypogonadotropic hypogonadism (CHH) are limited and no universal treatment regimen is available. The aim of this study was to evaluate the feasibility of human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) therapy for treating male adolescents with CHH.
Methods: Male adolescent CHH patients were treated with hCG/hMG (n = 20) or a gonadotropin-releasing hormone (GnRH) pump (n = 21). The treatment was divided into a study phase (0–3 months) and a follow-up phase (3–12 months). The testicular volume (TV), penile length (PL), penis diameter (PD), and sex hormone levels were compared between the two groups. The TV and other indicators between the groups were analyzed using a t-test (equal variance) or a rank-sum test (unequal variance).
Results: Before treatment, there was no statistical difference between the two groups in terms of biochemistry, hormones, and other demographic indicators. After 3 months of treatment, the TV of the hCG/hMG and GnRH groups increased to 5.1 ± 2.3 mL and 4.1 ± 1.8 mL, respectively; however, the difference was not statistically significant (P > 0.05, t = 1.394). The PL reached 6.9 ± 1.8 cm and 5.1 ± 1.6 cm (P < 0.05, t = 3.083), the PD reached 2.4 ± 0.5 cm and 2.0 ± 0.6 cm (P < 0.05, t = 2.224), respectively, in the two groups. At the end of 6 months of treatment, biomarkers were in the normal range in the two groups. Compared with the GnRH group, the testosterone (T) level and growth of PL and PD were significantly greater in the hCG/hMG group (all P < 0.05). While the TV of both groups increased, the difference was not statistically significant (P > 0.05, t = 0.314). After 9 to 12 months of treatment, the T level was higher in the hCG/hMG group. Other parameters did not exhibit a statistical difference.
Conclusions: The hCG/hMG regimen is feasible and effective for treating male adolescents with CHH. The initial 3 months of treatment may be a window to optimally observe the strongest effects of therapy. Furthermore, results from the extended-time period showed positive outcomes at the 1-year mark; however, the long-term effectiveness, strengths, and weaknesses of the hCG/hMG regimen require further research.
Introduction
Congenital hypogonadotropic hypogonadism (CHH) is a disorder that results from the insufficient release and secretion of gonadotropin-releasing hormone (GnRH).[1] Two subtypes of CHH exist; they are Kallmann syndrome (KS), which is associated with olfactory dysfunction, and normosmic idiopathic hypogonadotropich hypogonadism (nIHH), which retains intact olfactory function without other intracranial pathologies. The incidence of CHH is in the range of 1 to 10/100,000 and the male to female ratio is 5:1.[2] There are many clinical treatment options for CHH, the most common among which involves the usage of a GnRH pump, the combination of human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) (follicle-stimulating hormone [FSH]), and testosterone replacement.[3] Notably, testosterone replacement can promote the development of secondary sexual characteristics in patients but unfortunately cannot improve fertility. Obtaining fertility is a very high priority for Chinese patients; however, our previous therapeutic experience indicates that the application of hCG alone is not sufficient to ensure this outcome.[4] On the other hand, hCG/hMG injection and GnRH pump treatment can promote the production of testosterone and sperm in the testes.[5,6] Compared to patients with acquired hypogonadism, gonadotropin deficiency occurs in the fetal period for CHH patients, and abnormalities such as cryptorchidism, a small penis, and scrotal dysplasia can be observed at birth.[7] CHH patients also usually show a poor response to the application of spermatogenic therapy when they are in adulthood.[8] Nevertheless, the dose of hCG for CHH pre-treatment may also predict future therapeutic effects.[9] Recombinant human follicle-stimulating hormone (r-hFSH) has been approved for CHH treatment in many countries because exogenous FSH can stimulate Sertoli cells and spermatogonia, increase levels of antiMüllerian hormone (AMH) and elevate the testicular volume (TV) and sperm density.[1,5,10] However, there may still be testicular dysfunction in children with CHH, and if FSH is initially applied, the testes may not develop in some children. Considering the high cost of FSH in China, we chose to use hCG pre-treatment in the clinic and combined it with monitoring of testosterone levels. If testicular function appears normal, hMG (or FSH) may be applied to further induce puberty.
Compared to adult studies, those involving the treatment of pediatric CHH are limited and no universal treatment regimen is available. A multicenter study in Germany in 60 children aged 14 to 22 years indicated that subcutaneous injection of hCG/r-hFSH may be a safe and valid treatment option based on the positive therapeutic effects, compared to testosterone treatment.[11] Despite these positive results, the details of the same therapy in each treatment center are generally dissimilar.[11] Some scholars propose a treatment protocol that begins with low doses of gonadotropin at a timing that is closer to the onset of puberty (namely, a timing that coincides with entrance into junior high school).[12] However, this idea is not easily adherent because puberty is a complicated and long process, and proof for the effectiveness of treatments that involve low dose gonadotropin administration cannot be expected in a short time period. In addition, it is not easy to effectively compare or summarize treatment effects because the treatment regimen varies across patients according to individual needs.
Regarding the pituitary hormone pump, the cost is high, it is inconvenient and difficult to conceal, and it does not offer much privacy. For these reasons, many adolescent patients prefer hCG/hMG injection over the pituitary hormone pump. Therefore, the goal of this study was to establish a standardized, simple hCG/hMG treatment scheme for adolescent males with CHH. This regimen is simple and effective over a short time period and can aid in increasing adherence.
Furthermore, puberty development in boys begins at the age of 9 to 14 years, with 12 years being the median age for full development. Patients with CHH at this age have been subject to preliminary study at the Beijing Children’s Hospital, National Center for Children’s Health, Beijing.[4] We hope that through therapeutic research, the treatment age of CHH can be extended to 12 years old; doing so would ensure that penile development in similarly-aged children are similar and can reduce the psychological burden of such children and their parents. In this retrospective cohort study, we therefore also compared the efficacy and safety, as well as the impact on growth and development, of the two previously mentioned treatment regimens in an adolescent population.[13,14]
Treatment regimen
Patients in the two groups were followed up every 3 months. Height and body weight were recorded every 6 months during the course of treatment. Treatment effectiveness was assessed with TV, sex hormones, the occurrence of a nocturnal emission, penile length (PL), and change of scrotal skin. The treatment regimen was designed and modified based on “Expert consensus on the diagnosis and treatment of idiopathic hypogonadotropic hypogonadism.”[5] We referred to studies that recommended adult hCG doses in the range of 4000 to 6000 U per week, combined with 75 to 150 U of hMG 2 to 3 times per week.[1,4,5] The actual total dose was less than the recommended dose for adults because multiple low doses were more in line with physiological needs. For the hCG/hMG group, hCG was injected muscularly as follows: for the first 3 months (pre-treatment phase), 1000 to 2000 U of hCG was injected intramuscularly once every other day or twice per week. This injection volume was started at a low dose and was gradually increased until the testosterone level reached 200 ng/dL. Following this, and to start the formal therapeutic stage, hMG containing 75 U of FSH and 75 U of LH was administered once per day. In practice, the dosage of hCG was adjusted to maintain the testosterone value at 200 to 500 ng/dL to the extent possible.
The GnRH group was continuously treated with a GnRH pump. The dose of GnRH was chosen according to adult hypogonadotropic hypogonadism (HH) guidelines and our previous research.[1,4] Briefly, 8 to 10 mg of GnRH (200 mg/mL) were subcutaneously injected every 90 min via an injection pump. If side effects (described below) occurred, the dose of the GnRH was reduced.
During treatment, we carefully monitored adverse reactions, such as breast development, self-perceived excessive acne, frequent (>1 time per day) penile erection, erectile pain, skin infection and discomfort at the injection site, liver dysfunction, renal dysfunction, electrolyte abnormalities, and other autonomic reactions.
In short, 3 months of treatment with hCG/hMG provides a safe and effective treatment window for inducing puberty in male adolescent CHH patients. It can be used as an alternative option to hCG for inducing puberty and fertility, especially for those patients who have pituitary lesions. Treatment using a GnRH pump is still effective for patients with MPHD; however, it is thought that such patients still retain some pituitary gonadotropin cells that can be stimulated by GnRH. Thus, this treatment may be able to restart pituitary testicular axis function.
The price of the pituitary hormone pump is still high and inconvenient. For privacy protection, many adolescent patients prefer hCG/hMG injection instead of wearing a pituitary hormone pump. This study suggests a different treatment scheme for adolescent CHH, that has similar efficacy and safety as the hormone pump and that provides more data and choice for clinicians to treat various patients.
This study compared the therapeutic effect and safety, as well as the impact on growth and development, of two treatment options in an adolescent CHH population. The target population of this study was adolescents since similar work in adults has been previously reported. While the ultimate goal of this work is to help CHH patients simulate normal puberty development and to fill their psychological and physiological needs, various limitations of the current work must be addressed in the future. First, the observation duration period of the current study was short and without semen analysis. Second, the sample size was small and an extended phase is necessary to validate these results. These data will be gradually supplemented and improved in future research.
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