Abstract
Introduction
To investigate the efficacy and safety of pulsatile gonadotropin-releasing hormone pump therapy in male infants with congenital hypogonadotropic hypogonadism.
Methods
Seven male infants with congenital hypogonadotropic hypogonadism who were treated in a single center between 2019 and 2022 were included. Each patient was treated by subcutaneous infusion of 5 μg/90 min gonadorelin via a pulsatile gonadotropin-releasing hormone pump for 3–5 months. Data including age, drug dose, penile length, testicular volume and cryptorchidism were collected. Serum testosterone, follicle-stimulating hormone, luteinizing hormone, anti-Müllerian hormone, inhibin B concentration and liver and kidney functions were also measured. Data were analyzed using paired t-test and rank-sum test.
Results
Penile length increased from 1.27 ± 0.71 cm before treatment to 2.43 ± 0.90 cm after treatment, and testicular volume increased from 0.08 (0.04, 0.14) mL (left) and 0.08 (0.06, 0.12) mL (right) to 0.20 (0.16, 0.20) mL (left) and 0.22 (0.18, 0.30) mL (right). Inhibin B and anti-Müllerian hormone increased from 53.86 ± 11.54 pg/mL and 34.25 ± 12.48 ng/mL to 218.46 ± 32.34 pg/mL and 72.84 ± 9.24 ng/mL after treatment, respectively. At the end of the treatment, the testes of some children descended (6/13, 46.1%). During follow-up, the testes of two patients re-ascended to the inguinal region. No obvious adverse reactions were found in all patients before and after treatment.
Conclusion
Pulsatile gonadotropin-releasing hormone pump therapy can increase penile length, testicular volume, anti-Müllerian hormone levels and serum inhibin B levels in infants with congenital hypogonadotropic hypogonadism without adverse effects. However, its long-term efficacy and safety require further follow-up.
Introduction
Congenital hypogonadotropic hypogonadism (CHH) is caused by abnormal development of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus or by defects in the synthesis, secretion or action of GnRH, leading to reduced secretion of gonadotropins from the pituitary and consequently resulting in gonadal insufficiency (1). The infantile hypothalamic-pituitary-gonadal (HPG) axis becomes active, and in male infants, this activity lasts for about 6 months. This period is referred to as mini-puberty. Premature infants also experience this postnatal HPG activity, and it is often more pronounced and of longer duration (2). However, in children with CHH, the characteristic feature is the failure of HPG hormone levels to rise, resulting in the absence of mini-puberty. The main indicators in male infants include micropenis and cryptorchidism (3, 4). Based on whether the child has an abnormal sense of smell, CHH can be classified into Kallmann syndrome, characterized by an abnormal sense of smell and CHH with a normal sense of smell (nCHH). The overall incidence of CHH is one in 100,000, with a higher prevalence in males than in females (5). In males, CHH affects approximately one in 4,400 to one in 30,000 live births (3). The diagnosis of CHH is complex and challenging by the relative inactivity of the gonadal axis during childhood combined with the difficulties associated with assessing the olfactory capabilities of infants. Currently, hormone replacement therapy is widely used for the treatment of CHH, with testosterone being the most commonly used drug (6). Some studies have also employed the use of rFSH/rLH to treat CHH patients in infancy. In addition, recent research has investigated the efficacy of GnRH pump therapy for CHH. The initial testis size is a critical factor influencing the induction of spermatogenesis during puberty. The larger the initial testis volume, the higher the success rate (7, 8, 9). Early hormone replacement therapy aims to mimic the emergence of mini-puberty, which is associated with spermatogenic function and fertility (6, 10, 11). Several studies have investigated gonadotropin therapy in infantile CHH (12, 13, 14, 15, 16, 17, 18). The assessment criteria included penile length, testicular volume, as well as the levels of serum testosterone, anti-Müllerian hormone (AMH) and inhibin B. However, to date, only a few studies have explored the use of pulsatile GnRH pump therapy in infantile CHH patients (19, 20). Therefore, in this study, we aimed to investigate the efficacy and safety of pulsatile GnRH pump therapy in boys with infantile CHH.
Materials and methods
Patients
Seven male children diagnosed with CHH and treated at the Department of Endocrine Genetic Metabolism of Henan Provincial Children’s Hospital from 2019 to 2022 were included in the study.
Inclusion criteria: i) male, age less than 3 years at presentation, with a male chromosomal karyotype (46,XY) and SRY positive; ii) diagnosed with CHH based on the following criteria: (A) presence of micropenis and/or cryptorchidism (particularly bilateral) , along with the absence of penile erections. (B) Serum luteinizing hormone (LH) levels consistently monitored within the first 3 months after birth must be less than 1.00 U/L (minimum of two measurements 14 days apart). If both criteria are met, this represents a clinical diagnosis of CHH, but genetic testing is recommended to further clarify the etiology. If only one criterion is met, then (C) a family history of CHH and/or the presence of cleft lip or palate or hearing impairment are required (1); iii) brain magnetic resonance imaging (MRI) findings: normal or exhibiting olfactory bulb and tract dysplasia; iv) genetic testing results that support the diagnosis.
Exclusion criteria: i) any known causes of external genitalia abnormalities, including chromosomal abnormalities, trauma, surgery, congenital adrenal hyperplasia, NR5A1-related disorders of sexual development, Prader–Willi syndrome and multiple pituitary hormone deficiencies. ii) Prior treatment with exogenous gonadotropins or their analogs, testosterone or other medications before initiating GnRH therapy. iii) Presence of GnRHR gene variants. iv) MRI findings suggestive of sella region abnormality.
Design
All children received a subcutaneous infusion of gonadotropin-releasing hormone (Maanshan Fengyuan Pharmaceutical Co., Ltd, China) at an initial dose of 5 μg/90 min via a pulsatile GnRH pump (Shanghai minimally invasive Life Technology Co., Ltd, China) (21). The dose of the GnRH pump was adjusted based on the blood testosterone level to achieve a target testosterone level of 3.0 ± 2.0 ng/mL. The maximum dose of the GnRH pump should not exceed 10 μg/90 min. The clinical data of the children, including age at the beginning of treatment, dose, penile length at the beginning and end of treatment, and testicular volume and position, were collected. The biochemical data included plasma testosterone, follicle-stimulating hormone (FSH), LH, inhibin B, AMH concentration and liver and kidney function before and after treatment.
Penile length was defined as the distance from the root of the pubic symphysis to the tip (excluding the length of the prepuce) in a non-erect state, as measured by an endocrinologist. The testicular volume formula, based on testicular ultrasound, is length × width × height × 0.71 (22).
Plasma LH, FSH and testosterone levels were detected by electrochemiluminescence using Cobas e801 (Roche, Germany). The lower detection limits for LH, FSH and testosterone are 0.30 mIU/mL, 0.30 mIU/mL and 0.025 ng/mL, respectively, with variability of less than 5%.
Chemiluminescence was performed to detect inhibin B and AMH using Kaeser2000 (Guangzhou Kangrun, China) and Kaeser6600 (Guangzhou Kangrun). The reagents used were an inhibin B determination kit (Guangzhou Kangrun) and an AMH kit (Guangzhou Kangrun). The lower limit of detection for inhibin B is 10 pg/mL and for AMH it is 0.01 ng/mL, with variability <5%.
Liver and kidney functions were assessed using an AU5811 automatic biochemical analyzer (Beckman Coulter, USA).
Whole‐exome sequencing (WES) was conducted in patients to identify the underlying genetic variants. The candidate variants were confirmed by Sanger sequencing. WES tests were completed by we-health Biopharmaceutical Co., Ltd (we-health.com.cn).
Statistical analysis
Normally distributed data are expressed as mean ± standard deviation, and non-normally distributed data are represented using the interquartile method. The paired t-test is used when the data for pre-treatment, post-treatment and their differences are all normally distributed; otherwise, the Wilcoxon signed-rank test is used. Using two-sided statistics, statistical significance was set at P < 0.05.
Ethics
Studies involving humans were approved by the Medical Ethics Committee of the Children’s Hospital affiliated with Zhengzhou University on November 27, 2023 (ethics batch number: 2023-k-163). The study was conducted in accordance with local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians or next of kin.
Results
Patients’ ages at the beginning of treatment (6.4 ± 4.4 months), penile length and testicular position are shown in Supplementary Table 1 (see section on Supplementary materials given at the end of the article). Before treatment, only the left testis could be palpated in the scrotum of patient 5, and no testes were palpable in the scrotums of the other patients. Patient 1 also had hypospadias. Brain MRI of two patients with CHH revealed that the olfactory bulbs were small, and no obvious abnormalities were found in the remaining patients. Patient 6 had a testosterone level of 0.051 ng/mL after 1 month of treatment, and the GnRH pump dosage was adjusted to 7 μg/90 min. After 3 months, the testosterone level was 0.826 ng/mL, and the GnRH pump dosage was further adjusted to 8 μg/90 min. Patient 6 had low testosterone levels during the first month of GnRH therapy, so the treatment duration was extended. After 3 months of GnRH pump therapy, patients 1 and 7 extended their treatment duration because their penile length had not reached the level of their peers. Treatment was stopped for patients when their penile length reached the level of their peers, even though some patients still had undescended testes.
Patients 2, 3, 4 and 5 stopped using the pulsatile GnRH pump after 3 months of treatment. Patient 6 was treated for 4 months, and patients 1 and 7 discontinued treatment after 5 months.
After 3 months of treatment, the penile length increased from 1.27 ± 0.71 to 2.43 ± 0.90 cm (P < 0.05), and the testicular volume (in four cases) increased from 0.08 (0.04, 0.14) mL on the left and 0.08 (0.06, 0.12) mL on the right to 0.20 (0.16, 0.20) mL on the left and 0.22 (0.18, 0.30) mL on the right after treatment (Table 1). In four cases, the levels of AMH and INB increased significantly from 34.25 ± 12.42 ng/mL and 53.86 ± 11.54 pg/mL before treatment to 72.84 ± 9.24 ng/mL and 218.46 ± 32.34 pg/mL after treatment (P < 0.05).
Comparison of test results before and after treatment.
| n | Before treatment | n | After treatment | P | ||
|---|---|---|---|---|---|---|
| Penile length/cm | 7 | 1.27 ± 0.71 | 7 | 2.43 ± 0.90 | <0.05 | |
| Testicular volume/mL | ||||||
| Left | 4 | 0.08 (0.04, 0.14) | 4 | 0.20 (0.16, 0.20) | >0.05 a | |
| Right | 4 | 0.08 (0.06, 0.12) | 4 | 0.22 (0.18, 0.30) | >0.05 a | |
| FSH mIU/mL | 7 | <0.30 | 7 | 8.43 ± 3.59 | ||
| LH mIU/mL | 7 | <0.30 | 7 | 11.46 ± 8.29 | ||
| T ng/mL | 7 | <0.03 | 7 | 3.79 ± 3.22 | ||
| Inhibin B pg/mL | 4 | 53.86 ± 11.54 | 4 | 218.46 ± 32.34 | 0.004 b | |
| AMH ng/mL | 4 | 34.25 ± 12.48 | 4 | 72.83 ± 9.24 | 0.037 b |
LH, luteinizing hormone; FSH, follicle-stimulating hormone; AMH, anti-Müllerian hormone; T, testosterone.
At the end of the treatment, only four patients underwent a follow-up ultrasound examination. The Wilcoxon signed-rank test was used to analyze changes in testicular volume before and after treatment for these patients.
After treatment, inhibin B and AMH were re-examined in four patients, and the results were calculated.
When GnRH pump therapy was stopped, the testicles of five patients, comprising patients 2 (right), 3 (right), 4 (bilateral), 5 (right) and 6 (right) descended into the scrotum. The testicles of patients 1 and 7 remained unchanged.
During treatment, a skin rash appeared at the application site in patient 4, which improved after changing the wearing site. No other serious adverse reactions, such as liver or kidney function abnormalities, were observed in any patient during treatment. Patients 4 and 5 were not followed up after stopping the GnRH pump, while the other patients were followed up at the Department of Endocrine Genetics and Metabolism, Henan Children’s Hospital.
During follow-up after discontinuation of GnRH pump treatment, the testicles of patients 3 (3 months later, right side) and 6 (22 months after drug withdrawal, right side) re-ascended to the inguinal area. Patients 1 (bilateral), 2 (left), 3 (bilateral), 6 (bilateral) and 7 (bilateral) underwent orchidopexy at Henan Children’s Hospital.
Discussion
This study describes the efficacy and safety of pulsatile GnRH pump therapy in the treatment of male infants with CHH. Seven children with CHH received pulsed GnRH pump therapy for 3–5 months in this study. Their penile length, serum testosterone, inhibin B and AMH levels, as well as testicular volume, were significantly higher than before treatment. Only one child developed a rash during treatment. However, during the follow-up period, in two children, the testicles that had descended to the scrotum during treatment again ascended to the groin area.
Pulsed GnRH secretion from the hypothalamus is important for initiating and maintaining human gonadal development and maturation. The fetal hypothalamus begins to secrete GnRH in pulses in the 12th week of gestation (23). Children with CHH experience a reduction in the secretion of pituitary gonadotropins, which also affects the Leydig cells in the testes, leading to decreased production of testosterone and INSL-3. Both testosterone and INSL-3 play crucial roles in the descent of the fetal testes and are closely related to penile growth and development (24). The growth of Sertoli cells is regulated by FSH secreted by the pituitary gland. Sertoli cells and spermatogonia constitute the main components of the testis, and testicular volume may be related to adult fertility. There is a positive association between testicular volume before spermatogenesis induction and sperm count after treatment (7, 8, 25, 26). Therefore, patients with CHH often present with micropenis, small testes or cryptorchidism (25). In addition, studies have shown that executive function, attention and visual and psychomotor development lag in untreated adult patients with CHH compared to healthy controls (27).
The diagnosis of CHH remains challenging, particularly in infants, for whom genetic testing is often required for detection. In this study, three cases carried variants in the ANOS1 gene, two carried variants in the FGFR1 gene, one carried a variant in the CHD7 gene and one carried a variant in the TCF12 gene. Consistent with previous studies, all of these genetic variants have been confirmed to cause CHH (28).
Current perspectives suggest that the primary goal of CHH treatment in newborns or infants is to improve penile length by supplementing with androgens to promote penile growth. However, recent research suggests that early gonadotropin therapy can increase both testicular volume and penile length in infants with CHH (2, 3, 5, 20, 21). The method is to supplement the hypothalamic hormone GnRH or pituitary hormones LH, FSH. The infant CHH study was initially conducted in a 7.9-month-old patient. Main and Schmidt treated this child with FSH and LH. At the end of treatment, the testicular volume increased from the lowest 31–84 mm3, penile length increased from 1.6 to 2.4 cm, and serum inhibin B levels increased (29). Thereafter, several studies have shown that injected or pulsed gonadotropins can increase penile length, testicular volume and increase serum testosterone, inhibin B and AMH levels in infants with CHH (12, 13, 14, 15, 16, 17, 18) (Supplementary Table 2).
Compared with gonadotropins, the use of pulsed GnRH is more consistent with the physiological characteristics of healthy individuals. A study comparing the efficacy of a pulsatile GnRH pump and hCG in adolescent males with CHH found that the group treated with the pulsatile GnRH pump had significantly higher levels of reproductive hormones (LH, FSH and testosterone) and a greater increase in testicular volume than the hCG group (30). Subsequent studies on adolescent patients with CHH (31, 32) also showed that treatment with a GnRH pump could increase sex hormone levels and testicular volume, with no significant adverse reactions during treatment.
Before our study, there was already a research project focused on the use of GnRH pumps for treating CHH in infants and young children (19). In that study, five patients were treated with GnRH pumps for 3–6 months, resulting in significant improvements in penile length, INH-B and AMH at the end of the treatment period. In addition, the study compared the efficacy of HCG+HMG with that of the GnRH pump, but no significant differences were observed between the two treatments. The frequency of GnRH secretion in healthy males is 7–17 times per day, with a short half-life of only 2–4 min (33). A study showed that reducing the frequency of GnRH administration can increase the amplitude and the area under the curve of gonadotropin pulses (34). In our study, we used GnRH administration every 90 min to treat CHH and observed significant increases in penile length, serum testosterone, AMH and inhibin B following pulsatile GnRH pump therapy.
In addition, it was also observed that gonadotropin therapy may have a beneficial impact on cryptorchidism. In Lambert et al.’s study (14), cryptorchidism in eight children descended to the scrotum after treatment, with no testicular re-ascent noted. In Papadimitriou’s study (16), the testes of ten children descended after treatment; however, one case showed testicular re-ascent and required surgical intervention. In a study by Avril et al. (18), 11 patients in the injection group had cryptorchidism before treatment; five patients had testicular descent to the scrotum by the end of treatment. Nine patients in the pump group had cryptorchidism before treatment, and five patients had testicular descent to the scrotum by the end of treatment, without testicular re-ascent. In addition to the studies mentioned above, other relevant research has been consolidated in a recent review. The review notes that 73% of patients demonstrate partial or complete testicular descent following treatment (35). In our study, 13 testes were not located within the scrotum in seven patients before treatment (with the exception of patient 5, whose left testicle was already in the scrotum before treatment). After pulsatile GnRH pump treatment, testicular descent occurred in five cases, and a total of six testes descended. During follow-up, two patients had testicular re-ascent, and only four testes remained descended after excluding the re-ascended testes (4/13, 30%). The issue of cryptorchidism in patients persisted, which is inconsistent with the findings of Ren et al. (19). We speculate that this may be related to testosterone levels. In the study by Ren et al. the testosterone level at the end of treatment was approximately 7.37 ± 4.1 ng/mL, which was higher than that in our study (3.79 ± 3.22 ng/mL).
The present study has some important limitations that must be acknowledged. First, our study is retrospective in nature, which may introduce more biases compared to prospective studies, such as incomplete examination results. Second, the number of patients included in this study is small, and the follow-up period is short. It is necessary to conduct studies with larger sample sizes and longer follow-up periods in the future. Although this study showed improvements in penile length, testosterone levels and testicular volume in children treated with GnRH, it remains unclear whether it offers an advantage over gonadotropin therapy. In addition, the cost of the GnRH pump is higher, and it is not widely available in many countries.
In summary, after seven children with CHH were treated with a pulsatile GnRH pump, the penile length, testicular volume and inhibin B and AMH levels increased to varying degrees, and no serious adverse reactions were observed during treatment. The results showed that pulsatile GnRH pump therapy had a limited effect on testicular descent. However, owing to the limited sample size and short treatment duration, its long-term efficacy and safety need to be confirmed in a larger cohort of children with CHH with long-term follow-up.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0655.
Declaration of interest
The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.
Funding
The author(s) declare that they received financial support for the research, authorship and publication of this article. This study was supported by the Zhengzhou Science and Technology Huimin Program (grant number: 2022KJHM00005).
Author contribution statement
XW contributed to the conceptualization, formal analysis and methodology of the study, wrote the original draft and participated in the review and editing process. ZZ performed formal analysis and investigation and contributed to writing the original draft. JC participated in formal analysis, review and editing. DF contributed to formal analysis and participated in the review and editing process. MD carried out investigation and participated in the review and editing process. YC contributed to conceptualization, methodology, project administration and supervision, as well as review and editing. HW participated in the review and editing process.
Acknowledgments
We would like to acknowledge Editage (https://www.editage.com/) for the English language editing.
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