Therapeutic effects of a pulsatile GnRH pump on adult male patients with congenital hypogonadotropic hypogonadism (CHH): a retrospective study

Introduction

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive disorder that is primarily caused by gonadotropin-releasing hormone (GnRH) deficiency (1-6). The incidence of male CHH is nearly 1/10,000 live births, with approximately 2/3 of cases suffering from a reduced or absent sense of smell (hyposmia or anosmia, respectively), termed Kallmann syndrome (KS) (1,7-9). Clinically, KS is characterized by abnormally low plasma levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in conjunction with low sex steroids. Its clinical features are abnormalities in secondary sexual development, delays in sexual maturity/terminated adolescence, and spermatogenic dysfunction (10,11). The goal of clinical treatment for CHH is to promote and maintain secondary sexual characteristics, restore normal sexual function and normal spermatogenesis, and obtain normal fertility (3,5,12). As the defect of CHH patients is located in the hypothalamus, it is best to treat this disorder at the hypothalamic level (1). Thus, the use of a pulsatile GnRH pump is considered to be an ideal management strategy for the treatment of CHH, as it emulates the normal physiologic regulatory mechanism within the hypothalamic-pituitary-gonadal (HPG) axis (13-17). However, there are presently few clinical reports available on the use of pulsatile GnRH pumps, their long-term effects, or the variations in results achieved in different CHH populations. We herein summarized promising data on the medium- and long-term efficacy and safety of pulsatile GnRH in the treatment of 54 male patients with CHH. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-199/rc).

Methods

Patients

This study is a clinical trial on patients with congenital CHH, aiming to assess the medium-and long-term efficacy and safety of pulsatile GnRH pump therapy.

Men who visited Affiliated Hospital of Guizhou Medical University between August of 2013 and August of 2022, and who were diagnosed with CHH, were enrolled in the present study (Figure 1). The inclusion criteria for this study were that (I) the patient’s biologic age was over 18 years, with abnormal development of secondary sexual characteristics; (II) testosterone levels (T) were less than 3.47 nmol/L (1 ng/mL), and LH and FSH levels were below the normal range; (III) a GnRH stimulation test (13) confirmed that pituitary function and gonadal reserve were normal, with no mass lesion of the pituitary or hypothalamus on computed tomography or magnetic resonance imaging (MRI); (IV) there was no constitutional delay of growth and puberty (CDP), nor cryptorchidism, systemic disease, or other cause of hypogonadism; (V) patients who had a history of cryptorchidism but which had been corrected by cryptorchidopexy could be included and their history recorded; (VI) patients had not used human chorionic gonadotropin (hCG), androgens, human menopausal gonadotropins (HMG), or other related preparations during the previous 3 months; and (VII) patients agreed to be treated with a subcutaneous injection of GnRH by a pulsatile pump. We excluded patients with the following conditions: (I) accompanied by cryptorchidism (not corrected), age <18 years, or who have received hCG/HMG treatment; (II) LH/FSH peak values after GnRH stimulation test was below three times the baseline; (III) multiple anterior pituitary hormone deficiencies due to hypothalamic-pituitary lesions; (IV) functional hypogonadotropic hypogonadism (mainly seen in chronic systemic diseases, hypothyroidism, malnutrition); (V) hypergonadotropic hypogonadism. (VI) Lost to follow-up, less than three months of follow-up, or inability to adhere to treatment for various reasons. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Affiliated Hospital of Guizhou Medical University (No. 2025-312) and informed consent was obtained from all individual participants.

Figure 1 Flowchart of screening patients. CHH, congenital hypogonadotropic hypogonadism; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, combined human chorionic gonadotropin; HMG, human menopausal gonadotropin; KS, Kallmann syndrome; LH, luteinizing hormone; nCHH, hypogonadotropic hypogonadism with normal olfactory sensation.

Fifty-four patients were enrolled in this study, with a mean age of 22.8±5.8 years (mean ± standard deviation; range, 18–41 years). The general baseline characteristics of the 54 male CHH patients are shown in Table 1. Before treatment, none of the 54 cases showed any beard growth, and all of the patients exhibited a micropenis and small testes. Sixteen cases did not manifest pubic hair, 37 cases had sparse pubic hair, and 1 case exhibited normal adult pubic hair. Only 3 cases had nocturnal emissions (containing no spermatozoa), and the other 51 cases did not produce either nocturnal emissions or ejaculations by masturbation. Seventeen of the 54 men manifested olfactory disorders, including 10 of 17 cases with hyposmia and 7 with anosmia. One patient was reported as having gonadal development similar to that of his younger brother; however, the exact manifestations were not thoroughly evaluated as he was younger than 13 years of age. No other patients had a family history of CHH. Three of the patients (1 CHH and 2 KS) had a history of cryptorchidism, which was corrected by cryptorchidopexy before 3 years of age. Four patients were married, and 50 patients were unmarried (including 2 patients over 40 years of age).

Methods

We collected and recorded clinical features, including birth history, growth history, surgical history, family history of olfactory disorders [patients’ olfaction was tested using the T&T olfactometer test (18)], penile erectile function, which was evaluated with a standardized tool, the Erection Hardness Score (EHS) (19), and nocturnal emission history. Secondary sexual characteristics; flaccid penile length [flaccid length was measured from the root (pubo-penile junction) of the penis to the tip of the glans on the dorsal surface, where the pre-pubic fat pad was pushed to the bone], stretched penile length [stretched length was measured as above while maximally extending the penis (20)], and circumference of the flaccid penis [flaccid circumference was measured at the base or mid-shaft of the penis (21)]; volume of the testis [measured with the Prader testis model comparison, using bilateral mean volume (22)]; and Tanner staging of pubic hair (23), height, weight, etc., were also quantified and recorded.

All of the above measurements were completed by the same andrologist. Given the slight variations in average penile length across different racial and ethnic groups, the definition of a micropenis in this study was based on a systematic review of 15,521 men, which reported an average flaccid length of 9.16 cm and an average stretched length of 13.24 cm (21). According to the micropenis definition of being less than 2.5 standard deviations below the mean (representing 0.14% of the male population), this study defined micropenis as a flaccid length of less than 5.2 cm and a stretched length of less than 8.5 cm. All of the patients included in this group manifested micropenis.

We performed the GnRH stimulation test on all patients. Blood samples were obtained in the supine position after an overnight fast, starting between 8:00 and 9:30 AM. Basic hormone concentrations for LH, FSH, and testosterone were measured before initial GnRH injection, and then gonadorelin acetate (100 µg; Fengyuan Pharmaceutical, Anhui, China) was administered by intravenous injection. The levels of LH and FSH at 25, 45, 90, and 180 minutes after injection were then measured. Most of the peak values for FSH and LH were 3 to 10 times the baseline values, and most of the LH peak values were less than 4 IU/L; this suggested that a prepubertal pattern of gonadotropin secretion was elicited by GnRH stimulation, that there was putative pituitary function, and that the individual would likely respond to GnRH stimulation and was found to be suitable for GnRH pump treatment (24,25).

The GnRH microinjection pump (Shanghai Minimally Invasive Life Technologies), which was connected to the microinjection needle by joining tubing with the microneedle itself, was placed under the skin (Figure 2) to allow pulsatile subcutaneous infusion of gonadorelin. The injection site chosen was usually within 3–5 cm of the umbilicus, where there is abundant fat and muscle tissue. The injection site was changed once every 3–4 days to a location approximately 1cm from the original injection site.

Figure 2 Schematic diagram of GnRH pump for its wearing and usage. (A) The pulsatile GnRH pump; (B) the micro-needle is placed on the left side of the umbilicus; (C) the micro-needle is placed on the right side of the umbilicus; (D) the pump is worn on the waist. GnRH, gonadotropin-releasing hormone.

The pump pulse setting started at 0:00, with the initial dosage of 10 µg/90 min/per pulse (16 pulses/24 h) (17), and the follow-up after treatment was performed every 3 months. All data—including T, FSH, and LH levels, testicular volume, resting penile length, erectile function, and semen quality (if these endpoints could be retrieved)—were detected and recorded by 1 expert when patients came for follow-up. If the patient had already started to exhibit nocturnal emissions and was able to masturbate successfully, the semen test was conducted by masturbation to procure as much semen as possible. We performed semen analysis with a routine computer-aided sperm analysis (CASA) system; and semen volume (mL), sperm concentration, and sperm motility and viability were evaluated based on the 5th Edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen (26).

In our study, the dose of gonadorelin was adjusted according to the LH, FSH, and T levels. If the patient’s response to the initial dose of 10 µg was inadequate, the pulse was adjusted by successive increments of 5 µg to achieve the appropriate GnRH intensity required by individual CHH patients. This dose adjustment strategy is based on multiple clinical studies. They indicate that a 5 µg incremental step helps gradually achieve physiological hormone levels and prevents excessive or inadequate stimulation (27). Research has confirmed that this 5 µg incremental approach is safe in practice, with good patient tolerability and a low incidence of adverse reactions (28). Fertility was also recorded if the patient was married.

To explore the differences in the efficacy of GnRH pumps in improving spermatogenesis in patients with different etiologies, of different primary states, and of different age groups included in this study, patients were further subdivided into a Kallmann group (KS group) and CHH group with a normal sense of smell (nCHH group), according to whether the patients demonstrated olfactory disorders. According to the initial value for testicular volume, the patients were divided into a group with a testicular volume less than 4 mL and a group with testicular volume greater than 4 mL; and according to the different ages exposed to the initial treatment, patients were divided into a subgroup aged ≥28 years and a subgroup aged <28 years. The percentages of spermatogenic recovery for each group were then compared and analyzed.

LH, FSH, and testosterone were measured by chemiluminescence immunoassay (CLIA) (Abbott, USA), with the normal male range for LH being 1.1–8.8 IU/L, for FSH 1.6–6.4 IU/L, and for testosterone 300–1,000 ng/dL (29,30).

In this study, efforts to address potential bias included establishing strict inclusion criteria, having the same andrologist conduct all measurements, obtaining ethical approval and informed consent, using standardized assessment tools, and conducting regular follow-ups.

Statistical analysis

We performed statistical analyses using SPSS version 23.0 software (IBM, Chicago, IL, USA). All of the data were expressed as mean ± standard deviation, with data from the different (sub)groups compared using the one-way analysis of variance (ANOVA), followed by Tukey’s multiple-comparisons post-test. Chi-squared test was used to compare the percentage of spermatogenic recovery between different subgroups. Statistical significance was set at P<0.05.

Results

General characteristics

The majority of patients began to exhibit nocturnal penile erections, with increased pubic hair density and distribution area 3 months after starting treatment. After more than 0.5 year of treatment, all of the patients showed obvious beard growth and significantly increased pubic hair, more frequent nocturnal erections, nocturnal emissions, and ejaculations by masturbation. Tanner staging with respect to pubic hair was significantly increased in most patients, and the pubic hair growth patterns in 61.0% (25/41) of patients treated for 1 year and 88.5% (23/26) of the patients treated for 2 years closely emulated those of normal adult males (Tanner stage ≥ IV). We further evaluated erectile function using a standardized tool, the EHS, and noted that all of the patients treated for more than 1 year experienced an erection score of 4 at least once per week. Patient height was also increased significantly after 1 or 2 years of treatment compared with that before treatment (Table 2).

Sex hormone changes

Before treatment, the serum levels of LH, FSH, and T were 0.65±0.63, 1.03±0.64, and 48±47 ng/dL, respectively, in 54 male patients with CHH—which were much lower than in healthy male adults. The serum LH, FSH, and T levels of patients treated for more than 0.5, 1, and 2 years were, however, significantly improved relative to pre-treatment levels, respectively (P<0.0001). The mean serum T concentration in the 41 cases treated for more than 1 year was 361±117 ng/dL, which was significantly elevated relative to patients treated for 0.5 year (234±143 ng/dL) (P<0.0001). The mean serum T in the 26 cases treated for more than 2 years was 381±68 ng/dL, which was significantly increased compared with treatment for 0.5 year (234±143 ng/dL) (P<0.0001), but was not significantly increased compared with treatment for 1 year (361±117 ng/dL) (P>0.05). While serum LH and FSH levels did not show any statistical significance among the patients treated for the first 0.5, 1, or 2 years (P>0.05) (Table 3), 6 patients suspended their treatment with GnRH pumps for 2 months during the 6-month to 1-year treatment periods, and their LH, FSH, and T levels were significantly attenuated—approaching pre-treatment levels. On resumption of GnRH pump use, LH, FSH, and T levels were subsequently restored to levels observed before the interruption.

Changes in external genitalia

The mean testicular volume, flaccid penile length, stretched length, and circumference of the flaccid penis in the 45 patients treated for 0.5 year, and in the 41 patients treated for 1 year, and 26 patients treated for 2 years were significantly increased compared with the same indices before treatment (P<0.0001). The development of external genitalia in the patients treated for 1 and 2 years was further significantly improved relative to the patients treated for 0.5 year (P<0.0001), but the increased amplitude in the second 0.5 year and second year was reduced compared with the first 0.5 year. Although the development of external genitalia in the patients treated for 2 years showed further enlargement relative to the patients treated for 1 year, this was not statistically significant (Table 4, Figures 3-5). All of the patients exhibited micropenis with an average flaccid length of 3.54±0.92 cm and a mean stretched length of 5.68±1.27 cm before treatment. However, the flaccid and stretched lengths for the majority of patients increased to the normal range with an average flaccid length of 6.08±0.52 cm and a mean stretched length of 9.63±1.07 cm after 2 years of treatment.

Figure 3 Typical case 1: the changes of external genitalia before treatment, 6 months, and 1 year after treatment. (A) Before treatment, the flaccid length of the penis was 3.5 cm, the stretched length of the penis was 5.5 cm, the testicular volume was 5 mL; (B) 6 months after treatment, the flaccid length of the penis was 4.5 cm, the stretched length of the penis was 7.0 cm, the testicular volume was 6–7 mL; (C) 1 year after treatment, the flaccid length of the penis was 6.5 cm, the stretched length of the penis was 10.5 cm, the testicular volume was 9 mL. The patient’s spouse became pregnant.

Figure 4 Typical case 2: the changes of external genitalia before treatment, 6 months, 1 year, and 2 years after treatment. (A) Before treatment, the flaccid length of the penis was 4.0 cm, the stretched length of the penis was 6.0 cm, the testicular volume was 4 mL; (B) 6 months after treatment, the flaccid length of the penis was 5.0 cm, the stretched length of the penis was 8.0 cm, the testicular volume was 6 mL; (C) 1 year after treatment, the flaccid length of the penis was 5.5 cm, the stretched length of the penis was 9.5 cm, the testicular volume was 9 mL; (D) 2 years after treatment, the flaccid length of the penis was 6.0 cm, the stretched length of the penis was 10.0 cm, the testicular volume was 11 mL.

Figure 5 Typical case 3: the changes of external genitalia before treatment, 6 months, 1 year, and 2 years after treatment. (A) Before treatment, the flaccid length of the penis was 4.5 cm, the stretched length of the penis was 7.5 cm, the testicular volume was 3.5 mL; (B) 6 months after treatment, the flaccid length of the penis was 6 cm, the stretched length of the penis was 9 cm, the testicular volume was 6 mL; (C) 1 year after treatment, the flaccid length of the penis was 7 cm, the stretched length of the penis was 11 cm, the testicular volume was 10 mL; (D) 2 years after treatment, the flaccid length of the penis was 7.5 cm, the stretched length of the penis was 11.5 cm, the testicular volume was 11 mL.

Changes in semen quantity and quality

During the follow-up period, all 45 patients treated for more than 0.5 year showed emission phenomena. Our analysis of ejaculates from 34 men who collected their semen by masturbation or electric massage methods showed that 27 patients with over 0.5 year of treatment exhibited sperm in their ejaculates. The treatment efficiency for sperm induction was 79.4%, and sperm emergence time was 6.48±1.84 months in the 27 patients—with the earliest sperm emergence at 3 months of treatment. Thirteen of the 27 patients showed normal or nearly normal semen parameters, and 3 married patients impregnated their spouses naturally during treatment.

Of the 34 patients from whom semen was obtained, partitioning of our statistical analysis for subgroups showed that the percentage of spermatogenic recovery in the KS group was 54.5% (6/11), which was significantly lower than that in the nCHH group (91.3%, 21/23) (P<0.05); and the initial appearance of sperm in the KS group was an average of 9.5 months after treatment, which was later than in the nCHH group (5.6 months). Using subgroup analysis based on testicular volume, we found that the percentage of spermatogenic recovery in the group with an initial testicular volume ≥4 mL was 88.9% (8/9), which was higher than in the group with a testicular volume <4 mL (76.0%, 19/25); however, owing to the small number of samples, we did not achieve statistical significance between the 2 subgroups (P>0.05). The first appearance of sperm in the group with an initial testicular volume of ≥4 mL was an average of 5.4 months after treatment, which was earlier than in the group with an initial testicular volume of <4 mL (6.9 months). Our subgroup analysis based on different age ranges showed that the percentage of spermatogenic recovery in the group with a mean age ≥28 years was 50.0% (3/6), which was lower than in the group aged <28 years (85.7%, 24/28); however, we did not achieve statistical significance between the 2 subgroups (P>0.05). The initial appearance of sperm in the group aged ≥28 years was an average of 8.7 months after treatment, which was later than in the group aged <28 years (approximately 6.2 months).

Safety of GnRH pump treatment and follow-up

During the follow-up period, the infusion dosage and time-interval with respect to the GnRH pump were precisely controlled, and the overall safety was reliable. Needle breakage occurred in 1 patient after strenuous exercise; and 10 patients developed skin irritation at the site of injection, although this disappeared spontaneously or after treatment with antibiotic ointment. The skin irritation was found to be more common in the first week of pump treatment, and 29 patients complained that skin discomfort increased while sweating. Our overall impression was that daily life, work, and study were not affected during the GnRH pump-treatment period.

The mean follow-up time was 15.9 months (range, 3–40 months). Twenty-six patients treated with pulsatile GnRH infusion were followed for over 2 years, 41 patients were followed for over 1 year, 4 cases were followed for 6–12 months, 9 cases were followed for 3–6 months. Among the 28 patients not followed up for more than 2 years, 4 relocated, 5 had unknown reasons, and 19 were lost to follow-up at various stages.

Discussion

Male CHH patients often experience adverse psychologic, emotional, social, and psychosexual effects because of the physical defects related to disrupted puberty, and these seriously affect their normal social activity and marital intimacy—which in turn can result in serious family problems and social burdens (5,31). CHH is a rare, treatable form of infertility (31), and its treatment may be initiated for two purposes: androgenization and fertility (1,32). While the first goal can be reached with testosterone substitution (33-35), the second can only be achieved by gonadotropins (29,36,37) or pulsatile GnRH treatment (17,35,38). In China, hCG treatment is more commonly used in clinics because of its relatively lower cost and ease of management relative to GnRH (17). Studies have shown that treatment with hCG alone or in combination with hMGs (which contain forms of LH and FSH) can increase the levels of T in serum, enlarge testicular volume, and induce sperm production (39-42); however, the optimal strategy for inducing fertility in men with CHH is still equivocal (43). The recent emergence of pulsatile GnRH pump therapy has now provided a more effective treatment model for the hypothalamic-pituitary-gonadal axis in the CHH patient, and can be more suitable in restarting the developmental process of puberty, inducing an increase in testicular volume, penile development, and spermatogenesis. However, there are few extant reports regarding the application of pulsatile GnRH pumps in CHH treatment, and such devices are not currently available in many countries (44).

In the present study, therefore, we evaluated several fertility parameters after treatment with pulsatile GnRH pump therapy, and observed that the levels of LH, FSH, and T; mean testicular volume; and mean flaccid penile length, stretched length, and penile circumference were all rapidly increased; and that pubic hair distribution and erectile function were significantly improved. Sixty-one percent of the men with CHH who were treated for 1 year and 88.5% treated for 2 years obtained nearly normal pubic hair development (Tanner stage ≥ IV), and all of the patients treated for more than 1 year achieved an EHS score of 4 at least once per week. Patients usually achieved obvious testicular and penile size increases, and began to show regular morning erections and nocturnal emissions after treatment for more than 3 months. The average testicular volume increased from 3.19 to 6.22 mL after 6 months of treatment, to 8.90 mL after 1 year of treatment, and to 9.73 mL after 2 years of treatment; and although the latter volume was somewhat below the normal average, 0.5 of the patients ultimately reached the normal range for adult testicular size. The average serum T level increased from 48 to 361 ng/dL after 1 year of treatment, reaching the international standard normal range, and the T concentration was further increased to 381 ng/dL after further extending treatment. The stretched penile length was increased from 5.68 to 9.44 cm after 1 year of treatment and further increased to 9.63 cm after 2 years of treatment. Although this average stretched length was still shorter than the normal average stretched length, the condition was no longer considered to be micropenis (21).

Although the present study is not a controlled study, we did find that the overall results were enhanced and the average time to sperm emergence was earlier than in the majority of the hCG-related treatment studies found in the literature. To our knowledge, there is very limited comparative research on the application of hCG and/or HMG and pulsatile GnRH pump for CHH. The sperm production rate of 79.4% in this study is slightly better than the 75.8% and 76.9% rates reported in multiple hCG studies. More importantly, the 6.48±1.84 months sperm emergence time shown in this study is significantly shorter than the 9–18 months reported in hCG studies (14,17,45). We were not able to obtain every patient’s semen-analysis result at each visit because of the difficulty in producing semen by masturbation or electric massage, and this may have dictated our observed success rate and time to sperm induction as slightly below actual values. Dwyer et al. in fact demonstrated that a sequential treatment protocol using recombinant FSH (rFSH) pretreatment (75–150 IU daily) for 4 months—followed by the administration of 24 months of GnRH therapy—was successful in inducing testicular growth and fertility in CHH men with prepubertal testes (43). These authors additionally recommended that a large, prospective, multicenter study would be required to definitively demonstrate the superiority of this approach (46), and we concur that the optimal approach for the treatment of CHH still requires additional and controlled investigations. We also agreed with the opinion that increased understanding of the arcane genetics underlying CHH may reveal insights into fertility potential and could lead to more personalized approaches to treatment (46).

To explore the differences in the efficacy of GnRH pumps in improving spermatogenesis in patients with different etiologies included in this study, patients with semen-test results were further subdivided into a Kallmann group (KS group) and CHH group with a normal sense of smell (nCHH group), this distinction was made because KS and nCHH may have different pathophysiological mechanisms that could influence the response to GnRH treatment. Age is a significant factor influencing spermatogenic recovery. Younger patients may recover more quickly, while older patients might respond more slowly due to long-standing hypogonadism or age-related complications (47). In this study, patients with semen-test results were also divided into a subgroup aged ≥28 years and a subgroup aged <28 years (younger adult) based on the average age. Since testicular volume is a crucial indicator of gonadal function and impacts gonadotropin secretion, grouping patients based on this volume helps clarify treatment effects across different initial states. Based on the testicular volume stratification reported in a relevant study, the patients were divided into two groups according to their initial testicular volume: the group with testicular volume less than 4 mL and the group with testicular volume greater than 4 mL (48). The percentages of spermatogenic recovery for each group were then compared and analyzed.

Subgroup analysis of the 34 patients with semen-test results showed that the nCHH patients appeared to require a shorter time for the emergence of sperm and exhibited a higher percentage of spermatogenic recovery, while the KS patients achieved less-favorable results. The reason for this apparent discrepancy may be due to the KS patients representing a more severe group of CHH that is characterized by a complete absence of pubertal development (with a testicular volume <4 mL), a smaller micropenis, and complete absence of pubic hair. This speculation has also been confirmed to some extent by further subgroup analysis. The patients with an initial testicular volume <4 mL showed a longer time for the emergence of sperm and a lower spermatogenic recovery percentage compared with the patients with a larger initial testicular volume (≥4 mL at the beginning of treatment). These results are similar to previous literature findings which reported that patients with a small penis and cryptorchidism required longer treatment to resume spermatogenesis (38,49). It is noted that three of our patients had a history of cryptorchidism that was corrected by cryptorchidopexy before they were 3 years old, but it was difficult for us to conclude that cryptorchidism is a negative predictor of spermatogenesis due to the small number of patients.

Our results not only showed that the patients with an initial testicular volume <4 mL showed a longer time for the emergence of sperm and a lower spermatogenic recovery percentage [confirming that the testicular volume (<4 mL) was a critical factor in predicting spermatogenesis], but we also found that the age at initial treatment may affect the treatment results—implying that initiating treatment for CHH at an early age might achieve better results though we did not reach statistical significance between the two subgroups due to the small number of samples. Some younger patients who achieved significant results manifested T concentrations that reached the normal range, and showed testicular volumes and stretched penile lengths that doubled within only 0.5 year of treatment. The reason for the heterogeneity of responses to GnRH pulse treatment during treatment is not entirely clear. In a summary based on several previous reports, Dwyer et al. indicated that initial testicular volume (<4 mL), a history of cryptorchidism, and low inhibin B concentrations (<60 pg/mL) were critical negative predictors of spermatogenesis (46). Thus, with respect to an optimal treatment age for CHH, based on our results and related work (17), we hypothesize that adolescence may be the best age for treatment. It has been suggested that strategies to identify individuals with CHH early in childhood—as well as instituting timely pubertal induction in adolescence—can significantly improve long-term sexual and reproductive function (50).

It was notable that most of our patients showed varying degrees of increased height during treatment. This finding holds significant clinical importance and warrants greater attention in future clinical studies. From a physiological perspective, GnRH pulsatile secretion regulates gonadotropin release, thereby influencing sex hormone levels. These hormones play a crucial role in driving linear growth during puberty (44). Adequate sex hormone stimulation can enhance bone growth and development, consequently affecting height (51). In our study, height increased by an average of more than 6 cm—as a typical 19-year-old patient whose former height was only 145 cm and reached a height of 162 cm—with a height growth of 17 cm by 1 year after treatment. This suggests that the treatment may indirectly promote linear growth by modulating sex hormone levels. In CHH patients, insufficient or abnormal GnRH secretion often leads to low sex hormone levels. Given that sex hormones are essential for epiphyseal closure, delayed bone age closure is prevalent among CHH patients, which may positively impact height growth (52). Research indicates that combining GnRH analogs with growth hormone can be effective in increasing height in short-statured children and tall-statured older males (52,53). This further supports the potential benefits of pulsatile GnRH therapy for height growth. Therefore, GnRH pumps not only restore gonadal development but also effectively improve height. For those male CHH patients with obvious height retardation, this treatment manifests more advantages and constitutes a novel and more ideal treatment option.

Pulsatile GnRH pump therapy can significantly increase LH, FSH, and T levels in CHH patients, promote spermatogenesis, and enhance external genital and secondary sexual characteristic development. However, individual differences and poor treatment adherence can impact efficacy. Some patients respond poorly to GnRH pump therapy, showing minimal hormone increases and poor spermatogenesis. Additionally, some patients have low treatment adherence due to the long treatment duration, high costs, or improper device maintenance. For patients with poor response to GnRH pump therapy, the combination therapy of hCG and hMG can be attempted as an alternative option, as reported in prior studies; for those with a slow response, extending the treatment time may increase the spermatogenesis rate (45,54). However, clinically, we have indeed observed that a small number of patients cannot achieve significant therapeutic effects regardless of the treatment plan used.

Etiologies of CHH are genetically heterogeneous, and we presently know of more than 50 genes acting alone or in synergism with others that have been reported to relate to CHH (55). Genetic testing can identify specific gene mutations, facilitating precise diagnosis and personalized treatment. Regrettably, due to funding constraints, genetic testing was not conducted on any patients in this study. The clinical manifestations of the CHH patients were also diverse and uneven, and the men may have had primary pituitary and/or testicular defects, which would result in atypical responses to the GnRH- or hCG/FSH-related treatments (4). Therefore, there is no consensus regarding an optimal approach to functional recovery therapy in CHH men. However, increasing evidence supports the supposition that pulsatile GnRH therapy is the best option for the development of external genitalia and restoration of spermatogenic function (14,17,43,56,57).

Regarding the adverse effects of GnRH pump treatment, the present study showed discomfort at the site of the indwelling needle because of sweating or to an allergic skin reaction to the bandage, and 1 patient suffered from breakage of the indwelling needle that was related to strenuous exercise. Drugs used in GnRH pumps are GnRH analogs, and the length of time needed for them to reach their peak levels in serum is very short, and their metabolism is rapid. Thus, we used an infusion frequency of 1 pulse every 90 minutes and observed no transfusion complications related to injection of the hormone. We suggest that the dosage of each pulse should be adjusted according to the physiologic response of the patient and his hormone levels, and therefore close follow-up and frequent monitoring of hormone levels are of paramount importance.

As to the choice of time for GnRH pump withdrawal, there is still a lack of consensus at present—ideally, GnRH pump treatment should be maintained throughout one’s lifetime. If patients do not wish to maintain GnRH pump treatment for their entire lives, then their sperm should be obtained and frozen at a time when there is a high sperm count present, and when the patients no longer desire to father children. When patients state that they have tired of GnRH pump treatment and they still only have a small number of sperm and cannot impregnate their wives naturally, assisted reproductive technologies should be employed to help improve the possibility of pregnancy (58,59). Another option for aspermia is testicular microdissection for sperm extraction. When the patients have already fathered children and do not wish further fertility, the treatment strategy could be changed to an alternative treatment regimen of hCG/HMG combination therapy or androgen-replacement therapy.

There are several disadvantages and limitations to our study. As the overall incidence of the disease is low, the number of CHH cases and their long-term follow-up results were limited; this was not a prospective randomized controlled study and no randomized controlled group with traditional gonadotropin treatment was applied; and the data obtained were not complete enough to reflect the integrity of the overall long-term effects after GnRH pump treatment (especially for long-term effects after more than 2 years of treatment).

Conclusions

This study conducted a thorough observation of the medium-and long-term clinical efficacy of pulsatile GnRH pump therapy in 54 adult male CHH patients and carried out a comparative analysis of efficacy differences among various subgroups. The findings revealed that pulsatile GnRH pump therapy for CHH resulted in a significant increase in patients’ LH, FSH, and T levels. It also rapidly promoted the development of pubic hair, penis, and testes, and led to an improvement in spermatogenesis. The therapy proved to be most effective within six months. However, it continued to show potential in promoting the further growth and development of external genitalia after 1 and 2 years of treatment. In addition, the therapy had a positive effect on patients’ height growth. Within this study group, the adult patients experienced an average height increase of 6 cm, with one patient exhibiting a remarkable height increase of 17 cm. This height-promoting effect was found to be more pronounced in younger patients. Follow-up results of different subgroups indicated that GnRH pump therapy yielded better outcomes in nCHH patients with normal olfaction, young patients in early adulthood, and CHH patients with an initial testicular volume exceeding 4 mL. When compared to the combined gonadotrophin therapy used in other studies, GnRH pump therapy demonstrated a faster and more effective promotion of testicular development and restoration of spermatogenesis. The 2-year follow-up data in this study are the most extensive when compared to previously published literature. The varying treatment effects observed among different subgroups offer practical guidance for clinicians. Future multicenter, large-scale, long-term observational studies are anticipated to generate more data on GnRH pulse pump therapy. This will enable the development of more optimal and better personalized treatment strategies for different CHH patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-199/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-199/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-199/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-199/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Affiliated Hospital of Guizhou Medical University (No. 2025-312) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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