madman
Super Moderator
Gonadotropin Therapy Once a Week for Spermatogenesis in Hypogonadotropic Hypogonadism (2021)
Wanlu Ma, MD, Jiangfeng Mao, MD, Min Nie, PhD, Xi Wang, MD,Junjie Zheng, MD, Zhaoxiang Liu, MD, Bingqing Yu, MD, Shuyu Xiong, MD, Ming Hao, MD, Yinjie Gao, MD, Wen Ji, MD, Qibin Huang, MD, Rui Zhang, MD, Shuying Li, MD, Yaling Zhao, MD, Bang Sun, MD, Xueyan Wu, MD
Abstract
Objective: Hypogonadotropic hypogonadism (HH) can be caused by congenital HH (CHH), pituitary stalk interruption syndrome (PSIS), and pituitary injury (acquired HH). Gonadotropin therapy, typically administered every other day or twice a week, is commonly used to promote spermatogenesis. The aim of this retrospective study was to evaluate the efficacy of weekly gonadotropin therapy on spermatogenesis in patients with HH (n = 160).
Methods: The patients’ diagnoses include Kallmann syndrome (KS) (n = 61), normosmic CHH (nCHH) (n = 34), PSIS (n = 48), and acquired HH (n = 17). The rate of successful spermatogenesis and median time to achieve spermatogenesis among these 4 subgroups were compared as well as between a weekly group (n = 95) and a twice-a-week group (n = 223) of CHH patients.
Results: Once-a-week gonadotropin therapy resulted in 74% (119/160) of HH patients achieving spermatogenesis with significantly increased testicular volume and total testosterone levels (P < .001). The median period of spermatogenesis was 13 (interquartile range[IQR] 11.4-14.6) months. Larger basal testicular volume (P = .0142) was an independent predictor for earlier sperm appearance. Six spontaneous pregnancies occurred. Compared with the twice-a-week regimen for spermatogenesis, the weekly injection group had a similar median time of sperm appearance (14 [IQR, 11.6-16.4] vs 15 [IQR, 13.5-16.5] months), success rate (78% [74/95] vs 64% [143/223]), sperm concentration (20.9 [IQR, 5.0-46.3] vs 11.7 [IQR, 2.1-24.4] million/mL), and progressive sperm motility (40.8 ± 27.3% vs 36.9% ± 20.2%).
Conclusion: Weekly gonadotropin therapy is effective in inducing spermatogenesis, similar to that of twice-a-week therapy. A larger basal testicular size was a favorable indicator for earlier spermatogenesis.
Introduction
Infertility is a global issue that occurs at a prevalence of 15%, of which 50% to 60% of cases are males.1 Male hypogonadism may result in failure to produce normal physiologic concentrations of testosterone and/or sperm. Hypogonadotropic hypogonadism (HH), one of few types of hypogonadism that could be treated, includes congenital HH (CHH), congenital hypopituitarism, and acquired HH.2
CHH is a genetic disorder caused by gonadotropin-releasing hormone (GnRH) deficiency and/or resistance and is divided into normosmic CHH (nCHH) and Kallmann syndrome (KS) based on the presence of olfactory disorders.3,4 Congenital hypopituitarism predominantly consists of pituitary stalk interruption syndrome (PSIS), in which multiple pituitary hormones are deficient. Acquired HH results from tumors, radiation, infiltrative diseases, apoplexy, surgery, head trauma, and subarachnoid hemorrhage.2
Pulsatile GnRH and gonadotropin therapy may promote testicular development, testosterone synthesis, and spermatogenesis.
Studies have confirmed that the combined therapy of human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG), 2 or 3 times a week, had an overall success rate of 75% to 85% in achieving spermatogenesis.5-7 No guidelines on the regimens of gonadotropin therapy have been agreed upon. Typical doses for HCG vary from 500 to 2500 IU, whereas HMG varies from 75 to 225 IU two to three times a week.8-10
Twice-a-week injections may be inconvenient for young adults occupied with school and work on weekdays, especially for students living in school dormitories. Thus, injection of gonadotropin once a week on weekends would be more convenient and manageable, especially for young adults. It may also reduce the psychological pressure of being noticed by peers. However, it is unclear whether gonadotropin injection once a week would be effective in inducing spermatogenesis. Drugs with a long half-life (t1/2), such as long-acting recombinant growth hormone (t1/2= 34.0 ± 8.1 h)11,12 and dulaglutide (t1/2= 4.7-5.5 d),13 are administered once a week. After intramuscular injection, the t1/2 of serum HCG is 31 ± 3 hours, and that of HMG is 37 h. The serum testosterone peak appears at 72 hours after HCG injection,14 suggesting gonadotropin treatment could be provided once a week. Therefore, this study evaluated the efficacy of once-a-week HMG/HCG therapy on spermatogenesis of male HH patients.
Methods
Patients
Male HH patients were included in this retrospective study. Before treatment, they had not received pulsatile GnRH therapy and were azoospermic. The inclusion criteria were as follows:
1. Criteria for CHH: men aged >18 years without pubertal development, total testosterone (TT) <100 ng/dL (3.5 nmol/L) with low or normal levels of gonadotropins,5 normal levels of other pituitary hormones, and negative findings in sellar magnetic resonance imaging (MRI). No systemic diseases that could cause hypogonadism were detected.
2. Criteria for PSIS: pituitary MRI suggests pituitary dysplasia, and/ or pituitary stalk interruption, and/or ectopic posterior pituitary; no history of trauma, inflammation, or tumors; laboratory tests show multiple pituitary hormone deficiencies, including hypogonadism (TT <100 ng/dL).
3. Criteria for acquired HH: defects of multiple pituitary and/or posterior pituitary hormones, including hypogonadism (TT <100 ng/dL), and history of trauma, inflammation, tumor, surgery, or radiotherapy in the sellar region. The specific diagnosis and initial age at diagnosis and treatment of the 17 patients with acquired HH were included in the analysis (Supplementary Table 1).
From January 2005 to September 2019, a total of 542 male HH patients seeking fertility were treated with HCG/HMG. We excluded 159 cases due to poor compliance or incomplete medical data. We analyzed and compared 4 subgroups (KS, nCHH, PSIS, and acquired HH). The spermatogenesis outcomes were compared between 95 CHH patients treated with HCG/HMG once a week and 223 CHH patients treated with HCG/HMG twice a week (The data of the 223 CHH patients treated with HCG/HMG twice a week were retrospectively extracted from our previous study15).
Clinical presentation, cryptorchidism, medical history, and family history were recorded. Serum gonadotropins and testosterone levels were evaluated before and during treatment with HCG/HMG. MRIs of the pituitary gland and olfactory nerve was performed. The testicular volume and the median period of achieving sperm production were recorded. Inhibin B levels could not be assessed in our hospital.
Study Approval and Patient Consent
This study was approved by the Institutional Review Board of Peking Union Medical College Hospital (SK1196). All procedures were performed in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from each patient after the purposes of both studies were fully explained.
Treatment and Follow-up
If used, patients discontinued androgen therapy for at least 3 months before starting gonadotropin therapy. For patients with congenital and acquired hypopituitarism, thyroid and adrenal hormones were returned to normal levels before HCG/HMG treatment. For patients with central diabetes insipidus, desmopressin use was continued during the spermatogenic treatment. HCG 5000 U and HMG 150 U (Livzon Pharmaceutical Co) were intramuscularly injected once a week, and the dosing was the same throughout the study. Regular follow-up was conducted at an interval of 3 to 6 months during the therapy. For the twice-a-week week group, twice-weekly intramuscular injections of HCG (2000-3000 U) and HMG (75-150 U) were given for 6 months.
Luteinizing hormone (LH), follicle-stimulating hormone (FSH), testicular size, testosterone, and sperm count were measured at each visit. LH, FSH, and testosterone levels were measured by a chemiluminescent method using a commercial kit on an ACS: 180 Automated Chemiluminescence System (Bayer). Testosterone levels were measured 48 hours after HCG injection. The testicular size was measured using a Prader orchidometer, and the mean value of bilateral testicular volume was used in data analysis. Semen samples were collected by masturbation and analyzed according to the standard World Health Organization (WHO) method.16 Sperm motility was classified as (A) fast progressive sperm, (B) slow progressive sperm, (C) nonprogressive sperm, or (D) immotile sperm. The proportion of each of the 4 motility categories was assessed.
Outcomes
The primary outcome was successful spermatogenesis, defined as the observation under microcopy of 1 sperm in concentrifuged seminal fluid. The period for spermatogenesis was from the start of HCG/HMG treatment to the time when sperm was first detected during the semen analysis.
Secondary outcomes were specific sperm concentrations and conception. Four sperm thresholds (>0 million/mL, any sperm that was observed under microscopy; >5 million/mL; >10 million/mL; and >15 million/mL) were recorded according to the sperm concentration. Self-reported pregnancy was noted. According to the WHO criteria, a sperm concentration >15 million/mL is above the reference range threshold for adult males.16
Safety Evaluation
During the period of study, gynecomastia developed in 5% (8/ 160) of the subjects. Acne occurred in 2% (3/160) of the patients. No hepatorenal impairment or allergic reactions were reported.
Discussion
This is the first study to investigate the efficacy of weekly gonadotropin therapy on spermatogenesis in HH patients. We found that the general success rate was 74% (119/160), the median time for achieving the first sperm was 13 months, and basal testicular size was a favorable predictor for earlier spermatogenesis.
Various regimens of gonadotropin treatment have been used in clinical practice. Typically, HCG/HMG is administered 2 or 3 times a week.8-10 In clinical practice, many patients are high school or college students, and therefore, injections 2 or 3 times a week are often inconvenient, time-consuming, and difficult to adhere to. Earlier studies have confirmed that patients administered medication once a day have better compliance than patients administered medication 2 to 3 times a day.17 Similarly, weekly injections of long-acting human recombinant growth hormones also significantly improved patient adherence and compliance compared with daily injections.11 Therefore, it is believed that weekly gonadotropin treatment may promote therapy adherence and compliance.
Among CHH patients, 78% (74/95) succeeded in spermatogenesis with gonadotropin treatment once a week. This result was similar to the twice-a-week regimen, which had a success rate of 75% to 85%.5-7 Compared with the 2 times a week strategy, the weekly injection group had a similar rate of spermatogenesis, the median time of sperm appearance, sperm concentration, and sperm progressive motility. These results seem inconsistent with previous studies suggesting multiple low-dose HCG administration, in contrast to a single high dose, enhances Leydig cell steroidogenesis.18 However, patients in the weekly group had a larger basal testicular volume, earlier age at diagnosis and initial treatment, a lower percentage of cryptorchidism, prior androgen treatment, and a higher percentage of previous gonadotropin treatment compared with the twice-a-week regimen, which may have predisposed this group to greater success in the weekly treatment. Further cohorts with similar baselines are needed to better illustrate this question,
*However, our study pointed out the possibility of gonadotropin therapy with a lower injection frequency.
Among these factors, larger basal testicular size has been associated with earlier spermatogenesis.10-20. The success rate of spermatogenesis varies according to the etiology. For instance, acquired HH seemed more prone to successful spermatogenesis due to larger testicular size.21,22 Our study showed a similar spermatogenesis rate between nCHH, PSIS, and acquired HH, possibly due to the small patient number in the acquired HH group.
Our study showed that serum testosterone gradually increased with weekly injection therapy, similar to the twice-a-week injection.23-25 After treatment, the KS and nCHH groups had similar testosterone levels. Weekly fluctuation of testosterone levels, caused by HCG weekly injection, may cause periodic erectile function and physical strength. However, our patients did not have symptoms or complaints in this regard.
The median time for sperm appearance in patients treated weekly was 13 months. This result was similar to the median of 6 to 11 months that occurred with gonadotropin therapy administered 2 or 3 times a week.10,23-25 Comparable with previous studies, acquired HH patients needed the shortest time to achieve spermatogenesis (13 months). Acquired HH patients often experience complete pubertal development and have a relatively good testicular condition, thus providing greater potential for spermatogenesis.21,22 Consistent with previous studies, there was no significant difference between the KS and nCHH groups.26 The time to achieve sperm production was similar between the PSIS and CHH groups, indicating that both groups have similar spermatogenesis potential.21,27
The testicular volume increased from 3.1 ± 3.19 mL to 10.85 ± 5.1 mL (P < .001) with weekly gonadotropin treatment, and there was no significant difference between the 4 subgroups. Basal testicular volume has been consistently predicted as a key indicator for successful spermatogenesis.5,10,19,28 Favorable factors usually associated with spermatogenesis, such as lower BMI,5 less previous androgen exposure,19 and previous gonadotropin use,19,20 were not confirmed to be key indicators for successful spermatogenesis in our study
Cryptorchidism is often identified as an adverse factor of spermatogenesis in pulsatile GnRH treatment and gonadotropin treatment.27-34 In our study, the median time for the emergence of sperm was 23.7 months in CHH patients with cryptorchidism that have achieved spermatogenesis (n =9), which was significantly longer than that of total CHH patients (n =74, 14 months). The average sperm concentration was lower than the average sperm concentration of total CHH patients (17.56 vs 20.9 million/mL). These results indicate that cryptorchidism may be associated with longer periods to achieve spermatogenesis and lower sperm concentration. However, the Cox-related analysis and multivariate linear regression model did not conclude that cryptorchidism was negatively associated with spermatogenesis in our study. The spermatogenesis group and nonspermatogenesis group did not show a significant difference in the proportion of patients with cryptorchidism (7.56% [9/119] vs 9.76% (4/41); P =0.74). However, our model to determine whether cryptorchidism affects spermatogenesis may be underpowered by the small number of patients with cryptorchidism in our cohort.
During this study, 6 spontaneous pregnancies occurred, and 3 healthy children were delivered. Our study showed a large variation in sperm concentration in those patients that successfully impregnated their partners. Sperm concentration is not the dominant factor for pregnancy because spontaneous pregnancy can even occur with a very low sperm concentration.35 In a study where 22 CHH patients impregnated their partners, 5 of the patients had a sperm count <1 million/mL.35
*No severe adverse events were observed during gonadotropin therapy. Acne and gynecomastia occurred in 5% of the patients. Acne is caused by increased serum testosterone, and gynecomastia is induced by estrogen aromatization from increased testosterone levels. Thus, gonadotropin therapy is considered safe for patients with HH.24
There are certain limitations to our study. First, as a retrospective study, patients who had a poor response to gonadotropin therapy may have been lost during the follow-up, causing an increased rate of successful spermatogenesis. Second, the success rate of spermatogenesis could have been influenced by the limited number of participants, especially for patients with acquired HH. Third, gene mutations in CHH patients were not investigated, which may have significantly influenced the effect of gonadotropin-induced spermatogenesis. Fourth, the heterogeneous baseline of the weekly and twice-a-week groups may have caused bias in our outcomes, and therefore, prospective clinical studies are required to control for confounding factors. High school students or college students are more likely to choose weekly therapy because they live in the school dormitory and find weekly intramuscular injections at weekends much more convenient, which could possibly cause the patients in the weekly group to be younger at initial treatment and finally achieve a better spermatogenesis rate. Fifth, the increased weekly fluctuation of testosterone levels may cause erectile dysfunction and psychological pressure, which may need further investigation in the future. It is possible that patients with mild gonadal axis dysfunction may be more suitable for weekly therapy.
Conclusions
In summary, compared with the traditional twice-a-week regime, weekly gonadotropin therapy had similar efficacy in achieving spermatogenesis in male HH patients. Therefore, weekly gonadotropin therapy provides a more convenient therapeutic option for HH patients.
Wanlu Ma, MD, Jiangfeng Mao, MD, Min Nie, PhD, Xi Wang, MD,Junjie Zheng, MD, Zhaoxiang Liu, MD, Bingqing Yu, MD, Shuyu Xiong, MD, Ming Hao, MD, Yinjie Gao, MD, Wen Ji, MD, Qibin Huang, MD, Rui Zhang, MD, Shuying Li, MD, Yaling Zhao, MD, Bang Sun, MD, Xueyan Wu, MD
Abstract
Objective: Hypogonadotropic hypogonadism (HH) can be caused by congenital HH (CHH), pituitary stalk interruption syndrome (PSIS), and pituitary injury (acquired HH). Gonadotropin therapy, typically administered every other day or twice a week, is commonly used to promote spermatogenesis. The aim of this retrospective study was to evaluate the efficacy of weekly gonadotropin therapy on spermatogenesis in patients with HH (n = 160).
Methods: The patients’ diagnoses include Kallmann syndrome (KS) (n = 61), normosmic CHH (nCHH) (n = 34), PSIS (n = 48), and acquired HH (n = 17). The rate of successful spermatogenesis and median time to achieve spermatogenesis among these 4 subgroups were compared as well as between a weekly group (n = 95) and a twice-a-week group (n = 223) of CHH patients.
Results: Once-a-week gonadotropin therapy resulted in 74% (119/160) of HH patients achieving spermatogenesis with significantly increased testicular volume and total testosterone levels (P < .001). The median period of spermatogenesis was 13 (interquartile range[IQR] 11.4-14.6) months. Larger basal testicular volume (P = .0142) was an independent predictor for earlier sperm appearance. Six spontaneous pregnancies occurred. Compared with the twice-a-week regimen for spermatogenesis, the weekly injection group had a similar median time of sperm appearance (14 [IQR, 11.6-16.4] vs 15 [IQR, 13.5-16.5] months), success rate (78% [74/95] vs 64% [143/223]), sperm concentration (20.9 [IQR, 5.0-46.3] vs 11.7 [IQR, 2.1-24.4] million/mL), and progressive sperm motility (40.8 ± 27.3% vs 36.9% ± 20.2%).
Conclusion: Weekly gonadotropin therapy is effective in inducing spermatogenesis, similar to that of twice-a-week therapy. A larger basal testicular size was a favorable indicator for earlier spermatogenesis.
Introduction
Infertility is a global issue that occurs at a prevalence of 15%, of which 50% to 60% of cases are males.1 Male hypogonadism may result in failure to produce normal physiologic concentrations of testosterone and/or sperm. Hypogonadotropic hypogonadism (HH), one of few types of hypogonadism that could be treated, includes congenital HH (CHH), congenital hypopituitarism, and acquired HH.2
CHH is a genetic disorder caused by gonadotropin-releasing hormone (GnRH) deficiency and/or resistance and is divided into normosmic CHH (nCHH) and Kallmann syndrome (KS) based on the presence of olfactory disorders.3,4 Congenital hypopituitarism predominantly consists of pituitary stalk interruption syndrome (PSIS), in which multiple pituitary hormones are deficient. Acquired HH results from tumors, radiation, infiltrative diseases, apoplexy, surgery, head trauma, and subarachnoid hemorrhage.2
Pulsatile GnRH and gonadotropin therapy may promote testicular development, testosterone synthesis, and spermatogenesis.
Studies have confirmed that the combined therapy of human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG), 2 or 3 times a week, had an overall success rate of 75% to 85% in achieving spermatogenesis.5-7 No guidelines on the regimens of gonadotropin therapy have been agreed upon. Typical doses for HCG vary from 500 to 2500 IU, whereas HMG varies from 75 to 225 IU two to three times a week.8-10
Twice-a-week injections may be inconvenient for young adults occupied with school and work on weekdays, especially for students living in school dormitories. Thus, injection of gonadotropin once a week on weekends would be more convenient and manageable, especially for young adults. It may also reduce the psychological pressure of being noticed by peers. However, it is unclear whether gonadotropin injection once a week would be effective in inducing spermatogenesis. Drugs with a long half-life (t1/2), such as long-acting recombinant growth hormone (t1/2= 34.0 ± 8.1 h)11,12 and dulaglutide (t1/2= 4.7-5.5 d),13 are administered once a week. After intramuscular injection, the t1/2 of serum HCG is 31 ± 3 hours, and that of HMG is 37 h. The serum testosterone peak appears at 72 hours after HCG injection,14 suggesting gonadotropin treatment could be provided once a week. Therefore, this study evaluated the efficacy of once-a-week HMG/HCG therapy on spermatogenesis of male HH patients.
Methods
Patients
Male HH patients were included in this retrospective study. Before treatment, they had not received pulsatile GnRH therapy and were azoospermic. The inclusion criteria were as follows:
1. Criteria for CHH: men aged >18 years without pubertal development, total testosterone (TT) <100 ng/dL (3.5 nmol/L) with low or normal levels of gonadotropins,5 normal levels of other pituitary hormones, and negative findings in sellar magnetic resonance imaging (MRI). No systemic diseases that could cause hypogonadism were detected.
2. Criteria for PSIS: pituitary MRI suggests pituitary dysplasia, and/ or pituitary stalk interruption, and/or ectopic posterior pituitary; no history of trauma, inflammation, or tumors; laboratory tests show multiple pituitary hormone deficiencies, including hypogonadism (TT <100 ng/dL).
3. Criteria for acquired HH: defects of multiple pituitary and/or posterior pituitary hormones, including hypogonadism (TT <100 ng/dL), and history of trauma, inflammation, tumor, surgery, or radiotherapy in the sellar region. The specific diagnosis and initial age at diagnosis and treatment of the 17 patients with acquired HH were included in the analysis (Supplementary Table 1).
From January 2005 to September 2019, a total of 542 male HH patients seeking fertility were treated with HCG/HMG. We excluded 159 cases due to poor compliance or incomplete medical data. We analyzed and compared 4 subgroups (KS, nCHH, PSIS, and acquired HH). The spermatogenesis outcomes were compared between 95 CHH patients treated with HCG/HMG once a week and 223 CHH patients treated with HCG/HMG twice a week (The data of the 223 CHH patients treated with HCG/HMG twice a week were retrospectively extracted from our previous study15).
Clinical presentation, cryptorchidism, medical history, and family history were recorded. Serum gonadotropins and testosterone levels were evaluated before and during treatment with HCG/HMG. MRIs of the pituitary gland and olfactory nerve was performed. The testicular volume and the median period of achieving sperm production were recorded. Inhibin B levels could not be assessed in our hospital.
Study Approval and Patient Consent
This study was approved by the Institutional Review Board of Peking Union Medical College Hospital (SK1196). All procedures were performed in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from each patient after the purposes of both studies were fully explained.
Treatment and Follow-up
If used, patients discontinued androgen therapy for at least 3 months before starting gonadotropin therapy. For patients with congenital and acquired hypopituitarism, thyroid and adrenal hormones were returned to normal levels before HCG/HMG treatment. For patients with central diabetes insipidus, desmopressin use was continued during the spermatogenic treatment. HCG 5000 U and HMG 150 U (Livzon Pharmaceutical Co) were intramuscularly injected once a week, and the dosing was the same throughout the study. Regular follow-up was conducted at an interval of 3 to 6 months during the therapy. For the twice-a-week week group, twice-weekly intramuscular injections of HCG (2000-3000 U) and HMG (75-150 U) were given for 6 months.
Luteinizing hormone (LH), follicle-stimulating hormone (FSH), testicular size, testosterone, and sperm count were measured at each visit. LH, FSH, and testosterone levels were measured by a chemiluminescent method using a commercial kit on an ACS: 180 Automated Chemiluminescence System (Bayer). Testosterone levels were measured 48 hours after HCG injection. The testicular size was measured using a Prader orchidometer, and the mean value of bilateral testicular volume was used in data analysis. Semen samples were collected by masturbation and analyzed according to the standard World Health Organization (WHO) method.16 Sperm motility was classified as (A) fast progressive sperm, (B) slow progressive sperm, (C) nonprogressive sperm, or (D) immotile sperm. The proportion of each of the 4 motility categories was assessed.
Outcomes
The primary outcome was successful spermatogenesis, defined as the observation under microcopy of 1 sperm in concentrifuged seminal fluid. The period for spermatogenesis was from the start of HCG/HMG treatment to the time when sperm was first detected during the semen analysis.
Secondary outcomes were specific sperm concentrations and conception. Four sperm thresholds (>0 million/mL, any sperm that was observed under microscopy; >5 million/mL; >10 million/mL; and >15 million/mL) were recorded according to the sperm concentration. Self-reported pregnancy was noted. According to the WHO criteria, a sperm concentration >15 million/mL is above the reference range threshold for adult males.16
Safety Evaluation
During the period of study, gynecomastia developed in 5% (8/ 160) of the subjects. Acne occurred in 2% (3/160) of the patients. No hepatorenal impairment or allergic reactions were reported.
Discussion
This is the first study to investigate the efficacy of weekly gonadotropin therapy on spermatogenesis in HH patients. We found that the general success rate was 74% (119/160), the median time for achieving the first sperm was 13 months, and basal testicular size was a favorable predictor for earlier spermatogenesis.
Various regimens of gonadotropin treatment have been used in clinical practice. Typically, HCG/HMG is administered 2 or 3 times a week.8-10 In clinical practice, many patients are high school or college students, and therefore, injections 2 or 3 times a week are often inconvenient, time-consuming, and difficult to adhere to. Earlier studies have confirmed that patients administered medication once a day have better compliance than patients administered medication 2 to 3 times a day.17 Similarly, weekly injections of long-acting human recombinant growth hormones also significantly improved patient adherence and compliance compared with daily injections.11 Therefore, it is believed that weekly gonadotropin treatment may promote therapy adherence and compliance.
Among CHH patients, 78% (74/95) succeeded in spermatogenesis with gonadotropin treatment once a week. This result was similar to the twice-a-week regimen, which had a success rate of 75% to 85%.5-7 Compared with the 2 times a week strategy, the weekly injection group had a similar rate of spermatogenesis, the median time of sperm appearance, sperm concentration, and sperm progressive motility. These results seem inconsistent with previous studies suggesting multiple low-dose HCG administration, in contrast to a single high dose, enhances Leydig cell steroidogenesis.18 However, patients in the weekly group had a larger basal testicular volume, earlier age at diagnosis and initial treatment, a lower percentage of cryptorchidism, prior androgen treatment, and a higher percentage of previous gonadotropin treatment compared with the twice-a-week regimen, which may have predisposed this group to greater success in the weekly treatment. Further cohorts with similar baselines are needed to better illustrate this question,
*However, our study pointed out the possibility of gonadotropin therapy with a lower injection frequency.
Among these factors, larger basal testicular size has been associated with earlier spermatogenesis.10-20. The success rate of spermatogenesis varies according to the etiology. For instance, acquired HH seemed more prone to successful spermatogenesis due to larger testicular size.21,22 Our study showed a similar spermatogenesis rate between nCHH, PSIS, and acquired HH, possibly due to the small patient number in the acquired HH group.
Our study showed that serum testosterone gradually increased with weekly injection therapy, similar to the twice-a-week injection.23-25 After treatment, the KS and nCHH groups had similar testosterone levels. Weekly fluctuation of testosterone levels, caused by HCG weekly injection, may cause periodic erectile function and physical strength. However, our patients did not have symptoms or complaints in this regard.
The median time for sperm appearance in patients treated weekly was 13 months. This result was similar to the median of 6 to 11 months that occurred with gonadotropin therapy administered 2 or 3 times a week.10,23-25 Comparable with previous studies, acquired HH patients needed the shortest time to achieve spermatogenesis (13 months). Acquired HH patients often experience complete pubertal development and have a relatively good testicular condition, thus providing greater potential for spermatogenesis.21,22 Consistent with previous studies, there was no significant difference between the KS and nCHH groups.26 The time to achieve sperm production was similar between the PSIS and CHH groups, indicating that both groups have similar spermatogenesis potential.21,27
The testicular volume increased from 3.1 ± 3.19 mL to 10.85 ± 5.1 mL (P < .001) with weekly gonadotropin treatment, and there was no significant difference between the 4 subgroups. Basal testicular volume has been consistently predicted as a key indicator for successful spermatogenesis.5,10,19,28 Favorable factors usually associated with spermatogenesis, such as lower BMI,5 less previous androgen exposure,19 and previous gonadotropin use,19,20 were not confirmed to be key indicators for successful spermatogenesis in our study
Cryptorchidism is often identified as an adverse factor of spermatogenesis in pulsatile GnRH treatment and gonadotropin treatment.27-34 In our study, the median time for the emergence of sperm was 23.7 months in CHH patients with cryptorchidism that have achieved spermatogenesis (n =9), which was significantly longer than that of total CHH patients (n =74, 14 months). The average sperm concentration was lower than the average sperm concentration of total CHH patients (17.56 vs 20.9 million/mL). These results indicate that cryptorchidism may be associated with longer periods to achieve spermatogenesis and lower sperm concentration. However, the Cox-related analysis and multivariate linear regression model did not conclude that cryptorchidism was negatively associated with spermatogenesis in our study. The spermatogenesis group and nonspermatogenesis group did not show a significant difference in the proportion of patients with cryptorchidism (7.56% [9/119] vs 9.76% (4/41); P =0.74). However, our model to determine whether cryptorchidism affects spermatogenesis may be underpowered by the small number of patients with cryptorchidism in our cohort.
During this study, 6 spontaneous pregnancies occurred, and 3 healthy children were delivered. Our study showed a large variation in sperm concentration in those patients that successfully impregnated their partners. Sperm concentration is not the dominant factor for pregnancy because spontaneous pregnancy can even occur with a very low sperm concentration.35 In a study where 22 CHH patients impregnated their partners, 5 of the patients had a sperm count <1 million/mL.35
*No severe adverse events were observed during gonadotropin therapy. Acne and gynecomastia occurred in 5% of the patients. Acne is caused by increased serum testosterone, and gynecomastia is induced by estrogen aromatization from increased testosterone levels. Thus, gonadotropin therapy is considered safe for patients with HH.24
There are certain limitations to our study. First, as a retrospective study, patients who had a poor response to gonadotropin therapy may have been lost during the follow-up, causing an increased rate of successful spermatogenesis. Second, the success rate of spermatogenesis could have been influenced by the limited number of participants, especially for patients with acquired HH. Third, gene mutations in CHH patients were not investigated, which may have significantly influenced the effect of gonadotropin-induced spermatogenesis. Fourth, the heterogeneous baseline of the weekly and twice-a-week groups may have caused bias in our outcomes, and therefore, prospective clinical studies are required to control for confounding factors. High school students or college students are more likely to choose weekly therapy because they live in the school dormitory and find weekly intramuscular injections at weekends much more convenient, which could possibly cause the patients in the weekly group to be younger at initial treatment and finally achieve a better spermatogenesis rate. Fifth, the increased weekly fluctuation of testosterone levels may cause erectile dysfunction and psychological pressure, which may need further investigation in the future. It is possible that patients with mild gonadal axis dysfunction may be more suitable for weekly therapy.
Conclusions
In summary, compared with the traditional twice-a-week regime, weekly gonadotropin therapy had similar efficacy in achieving spermatogenesis in male HH patients. Therefore, weekly gonadotropin therapy provides a more convenient therapeutic option for HH patients.
