Investigational Treatment of Congenital Hypogonadotropic Hypogonadism in Infants

Keywords

congenital hypogonadotropic hypogonadism - infants - hormone

Introduction

Congenital hypogonadotropic hypogonadism (CHH) is a group of rare disorders characterized by a deficiency in gonadotropin-releasing hormone (GnRH), leading to pituitary gonadotropin deficiencies. This condition typically presents from fetal development and often persists throughout life [1]. Male patients with CHH may have a micropenis and/or cryptorchidism at birth. These patients lack the mini-puberty observed in normal boys after birth, a phenomenon that can be helpful for early diagnosis [2] [3]. Studies on the treatment of adolescent and adult patients have had some positive results, whereas relevant reports on infant CHH are rare [4]. Currently, there are 22 cases of infantile CHH treated in the literature, with the treatment of subcutaneous injection of different doses of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Gonadotropins and internal androgens play important roles in the proliferation of Leydig cells and differentiation of germ cells in the early postnatal period [5] [6]. In addition to prenatal androgen secretion and action, postnatal surges in gonadotropins and sex steroids, known as mini-puberty in normal babies, play a crucial role in genital development after birth where Leydig and Sertoli cells proliferate substantially [7]. Normally, the mini-puberty period lasts 6 months and drives male genital development after birth [8] [9]. The testes position is strongly correlated with Leydig and Sertoli cell functions [10] [11] [12]. In the absence of GnRH activity during fetal life and neonatal-infancy, the diminished proliferation of Sertoli cells and seminiferous tubules, which would normally account for 90% of testicular volume owing to FSH-signaling loss, results in undeveloped testes [13]. Depressed Sertoli cell-derived anti-Müllerian hormone (AMH) and inhibin B (INH-B) levels reflect a sparse Sertoli cell mass, which, in turn, has a huge bearing on future spermatogenic potential if not addressed appropriately [14]. There are many clinical treatment options for CHH, the most common among which involves the usage of a GnRH pump, the combination of human chorionic gonadotropin (HCG)/human menopausal gonadotropin (HMG) and low-dose external testosterone (T). Traditional treatment of congenital micropenis with low-dose external T concurrently inhibits gonadotropin, leading to a decrease in internal T levels and exacerbating testicular dysplasia [15]. The GnRH pump can pulse release gonadotropins, simulating mini-puberty. HCG and HMG can, respectively, stimulate the proliferation of testicular Leydig and Sertoli cells, achieving the goal of simulating mini-puberty. Therefore, an appropriate treatment of CHH should involve gonadotropins in the very early postnatal period to induce testicular growth and improve future fertility potential. This study was designed to mimic the physiological state of mini-puberty in patients with CHH. Our treatment plan was based on our previous experience in treating adolescents with CHH [4] [16].

Participants and Methods

Patients

We collected treatment and follow up data of eight boys with CHH who were treated at the Department of Endocrinology, Beijing Children’s Hospital, Capital Medical University. The clinical characteristics of these patients are displayed in [Table 1]. This study was approved by the Ethics Committee of Beijing Children’s Hospital, Capital Medical University (Clinical trial registration number: NCT02880280). The parents of the patients provided written informed consent.

Table 1 Characteristics of the 8 patients with CHH who received gonadotropins during early infancy.

Patient	Diagnosis	Genetic analysis	Age at treatment initiation months	Therapeutic method	Duration of treatment (months)	Height (cm)		Weight (kg)		PL (cm)		Testis position		Testicular ultrasound testis length (cm)		TV (ml)		T (g/dl)		INH-B (pg/ml)		AMH (ng/ml)		LH (IU/l)		FSH (IU/l)
						Baseline	End	Baseline	End	Baseline	End	Baseline	End	Baseline	End	Baseline	End	Baseline	End	Baseline	End	Baseline	End	Baseline	End	Baseline	End
1	CHH	FGFR1	7 months	HCG+HMG	1	69.5	71.6	9.55	10.5	1.2	3.5	Both inguinal	Both scrotal	ND	ND	1	2	<4.9	478	ND	234	ND	>23	0.67	1.2	0.07	15.4
2	CHH	ANOS1	8 months	GnRH pump	3	71.5	74	11	12	2	3	Both inguinal	Both scrotal	ND	L: 1.3 R: 1.1	<1	1	8.4	745.19	38.6	137	>23	>23	0	4.39	1.3	4.36
3	CHH	negative	8 months	GnRH pump	3	65	67	10	11.2	0	3.3	L: inguinal R: scrotal	Both scrotal	L: 0.9 R: 0.8	L: 0.7 R: 0.9	<1	1	<12.97	ND	ND	85.9	ND	>23	0.03	0.03	0.13	2.29
4	MPHD	negative	8 months	GnRH pump (3 months) →HCG+HMG	6	64.5	69	7.66	9	1.7	4	Both inguinal	Both scrotal	L: 0.8 R: 0.7	L: 1.3 R: 1.2	<1	1	<7	874.92	29.4	125	>23	20.1	0.1	0.1	0.54	14.24
5	CHH	CHD7	1 year	GnRH pump	6	73	75	9.45	10	2	3.5	Both inguinal	Both scrotal	L: 0.8 R: 0.9	L: 1.4 R: 1.4	<1	1	<3	377	19.6	155	>23	>23	0.1	9.68	0.53	9.11
6	CHH	SOX2	2 years	GnRH pump	3	81.3	82	9.4	9.5	2	3.5	Both iliac fossa	Both inguinal	L: 1.0 R: 0.9	L: 1.33 R: 1.3	<1	1	<20	468.5	86.6	245.68	13.71	32.3	0.04	15.85	0.21	9.8
7	CHH	PROKR2	5 months	HCG+HMG	3	68.3	71.8	8.51	9.71	1.6	4	Both inguinal	Both scrotal	ND	L: 1.2 R: 1.2	<1	1	<20	1479	44.68	200	>23	>23	0.177	1.17	0.51	19.5
8	MPHD	ND	11 months	HCG+HMG	3	69.8	74	7	8.5	1	3	Both inguinal	Both scrotal	ND	L: 1.0 R: 1.2	<1	1	0.46	ND	44.39	ND	>23	ND	0.27	ND	0.08	ND
Data summary						70.36±5.30	73.05±4.51	9.07±1.29	10.05±1.15	1.44±0.69	3.48±0.38			L: 0.88±0.10 R: 0.83±0.10	L:1.18±0.25 R:1.1 9±0.16			undetectable	737.1±409.5	47.88±23.03	168.94±59.34			0.17±0.21	4.63±6.01	0.42±0.41	10.67±6.14
p-Value						>0.05		>0.05		<0.0001				L: 0.02 R: 0.001				NA		0.002				0.04		<0.0001

The data are expressed as mean±SD; ND: Not done; NA: Not applicable.

Study design

All infants with CHH were evaluated at baseline and once monthly until the end of treatment. The observation items included penile length (PL), testicular volume (TV) (as evaluated via Prader testicular gauge), serum hormone assays [T, luteinizing hormone (LH), follicle-stimulating hormone (FSH), INH-B, and AMH], and ultrasound to assess testis size and position and record side effects. Each treatment period lasted for 1–3 months, with follow-up assessments conducted for 3–6 months.

The patients were treated with a GnRH pump (2.5–5 μg/90 min) or injected with human chorionic gonadotropin (HCG) 1000 IU combined with human menopausal gonadotropin (HMG) 75 IU (twice or thrice per week) (this drug contains 75IU LH and 75IU FSH). Dose titration and duration were modified according to the T response.

Grouping: We divided the patients into two groups based on a literature review: low-dose group (FSH dosage<100 IU/week) and high-dose group (FSH dosage of 450–1050 IU/week).

Literature search: A search was conducted in the PubMed database using the keywords “congenital hypogonadotropic hypogonadism,” “infants,” and “mini-puberty” to retrieve articles written in the English language published up until October 2023.

Hormone assays

Sample were collected from 8:00–10:00 AM. LH, FSH, and T levels were measured using an enzyme-enhanced chemiluminescence immunoassay (Immulite 2000; Siemens Corporation, Munich, Germany) at baseline and once a month. INH-B was measured using a chemiluminescence immunoassay (Iflash 3000-c chemiluminescence immunoanalyzer; Shenzhen Yahuilong Biotechnology Co., Ltd., Shenzhen, China).

Statistical analysis

Data are expressed as mean±SD. Parametric tests (t-tests and paired tests) were used to evaluate the associations between the variables. Analyses were performed using the SPSS software. Statistical significance was set at p<0.05.

Results

Eight infants [six with isolated CHH and two with multiple pituitary hormone deficiencies (MPHD)] were included in the study, and their main characteristics are presented in [Table 1]. Micropenises and cryptorchidism were diagnosed at birth or shortly after birth. Molecular testing was performed in all patients, and only two patients had negative results ([Table 1]). They were treated at a mean age of 10.4±5.9 months for a mean duration of 4.3±1.5 months. No severe adverse effects were observed.

Clinical features

After 1–3 months of treatment, the height increased from 70.36±5.30 (–2.8 SDS) to 73.05±4.51 cm (–1.3 SDS) (p>0.05), and the weight increased from 9.07±1.29 (–1.3 SDS) to 10.05±1.15 kg (0 SDS) (p>0.05). PL increased from 1.44±0.69 to 3.48±0.38 cm (p<0.0001), and TV increased from<1 ml to 1–2 ml. Ultrasound showed that the testes remained high scrotal or inguinal in seven patients at baseline (cases 1, 2, 3, 4, 5, 7, and 8) and then descended during treatment. The testes in case 6 were located in the iliac fossa at baseline; the patient underwent an orchiopexy ([Table 1]).

Repeated treatment cycles

Two patients (cases 2 and 3) experienced testicular retraction after completing their first course of medication, lasting 3 and 1 month, with follow-up periods of 3 and 5 months, respectively. Case 4, diagnosed with MPHD, showed no significant changes in the penis, testicles, and hormone levels after 3 months of pump treatment. Owing to the impaired pituitary gland function, therapy was switched to HCG+HMG for 3 months, resulting in significant improvement in external genitalia.

Hormone levels

In the first month of treatment, LH, FSH, T, and INH-B levels increased significantly, as depicted in [Fig. 1] and [Table 1]. Patients were divided into the pump treatment group (cases 2, 3, 5, and 6) and the HCG+HMG treatment group (cases 1, 4, 7, and 8). The HCG+HMG treatment group generally had significantly higher FSH levels (p=0.011) than those of the pump treatment group ([Table 2]). No significant differences were noted in the baseline TV or FSH levels between the two groups. However, it is worth considering that the significant increase in FSH levels observed after treatment in the group receiving HCG combined with HMG therapy may be influenced by immediate blood sampling following FSH injection. There were no significant differences in the TV or PL between the two groups.

Fig. 1 Hormone levels and PL changes during treatment.

Table 2 Hormonal and clinical effects of two groups.

	GnRH pump group	HCG+HMG group	p-Value
Baseline TV (ml)	<1	<1	>0.05
Baseline FSH (IU/l)	0.54±0.53	0.30±0.26	>0.05
FSH after treatment (IU/l)	6.39±3.65	16.38±2.76	0.011
LH after treatment (IU/l)	7.49±6.83	0.82±0.63	>0.05
T after treatment (ng/dl)	530.23±191.70	943.97±504.06	>0.05
PL after treatment (cm)	3.33±0.24	3.63±0.48	>0.05
ΔPL (cm)	1.83±1.01	2.25±0.17	>0.05

Literature review

We reviewed 22 cases reported in the literature and supplemented them with the data from our study, which included eight cases. We analyzed their features and presented the data in [Table 3]. Thirty patients were divided into two groups based on dosage. The Δ mean PL in low-dose group (a total of six patients, Main et al. 2002 [20], and Kohva et al. 2019 [21]) after treatment was 1.1 cm, and three patients required orchidopexy. The high dose group (a total of 20 patients from literature and four patients from our study) exhibited a Δ mean PL of 2.2 cm after treatment, and the testis of patients with cryptorchidism descended into the scrotum; only one patient required orchiopexy. In the low-dose group, after 3 months of treatment, some patients still had incomplete testicular descent and required orchidopexy. However, the effect was better in the high-dose group than in the low-dose group, and the duration of course was also shorter. Based on the literature and case studies in this article, we recommend short-term high-dose treatment. No severe adverse reactions were observed.

Table 3 The previous literature on the treatment and effect evaluation of CHH in infancy.

Literature [Ref]	Patient number	Age of starting treatment	Therapeutic dose	Treatment duration	Effect evaluation
		Months		Months	ΔTV (ml)	ΔPL (cm)	Δ Mean T (ng/dl)	Δ Mean INH-B (pg/ml)	Δ mean AMH	Testicular position
Bougnères et al. 2008 [17]	2	0.5–3.5	P1 LH 392 IU/week, FSH 469 IU/week, P2 LH 350IU/week, FSH 875 IU/week	6	1.53, 1.65	1.3, 3.6	218.16, 148.13	685, 378	214 pmol/l, 440 pmol/l	Scrotum → scrotum
Sarfati et al. 2015 [18]	1	1	LH 525 IU/week, FSH 525 IU/week	6	2	2.3	–	–	–	Scrotum → scrotum
Stoupa et al. 2017 [19]	5	4.2±0.9	LH 1050 IU/week, FSH 525 IU/week	3	–	3.2, 3, 2, 2.8, 3.4		374.6	92.4 ng/ml	All 4 cases of cryptorchidism descended to scrotum
Main et al. 2002 [20]	1	7.9	LH 40 IU/week → 80 IU/week, FSH 42.6 IU/week	2	TV increased by 1.7 times	0.8	–	147	–	Scrotum → scrotum
Kohva et al. 2019 [21]	5	0.7–4.2	P1 FSH 33.2 IU/week, P2 FSH 16.6 IU/week, P3 FSH 16.6 IU/week, P4 FSH 22.5 IU/week, P5 FSH 33.4 IU/week, testosterone 25 mg, once a month	3–4.5	–	1.7, 1.4, 0.9, 1.1, 0.7	–	–	–	Two patients with cryptorchidism descended to scrotum, and three patients were surgically fixed
Lambert and Bougnères et al. 2016 [21]	8	0.25–11	LH 350 IU/week, FSH 525–1050 IU/week	6	–	1.2, 0.7, 4, 0.9, 1.5, 2.1, 2.4, 1.7	–	–	–	5 cases of intraabdominal cryptorchidism: 7/10 testes completely decreased; 3/10 testes fell to the high position of scrotum. In the testicles of 3 cases the high position of scrotum decreased completely

Discussion

This is the first case series in China involving 8 patients exploring treatment for infant CHH, with 4 of them being the first worldwide to undergo pituitary pump treatment. The treatment course for our patients ranged from 3 to 6 months, and favorable outcomes were achieved. Our exploratory treatment yielded satisfactory results, with no significant side effects.

This study (cases 2, 3, 5, and 6) represents the first exploration of GnRH pumps for the treatment of infant CHH in comparison with subcutaneous HCG and HMG injections. The dosage administered was approximately half that used for adolescent and adult patients, and the treatment duration was relatively short, typically of 3 months. Nonetheless, we observed improvements in the symptoms of micropenis and cryptorchidism in these patients, with significant increases in T and INH-B levels. No severe adverse reactions were observed. The longest follow-up period in our study was 4 years (case 7), during which we continued to monitor the condition of the testicles and penises. Two patients experienced testicular retraction; however, after the second round of treatment, the testicles descended back into the scrotum. To date, the longest duration of GnRH pump treatment for infant CHH reported in this article is 6 months.

Micropenis was corrected in all patients, and no difference was observed between the outcomes of pump treatment and HMG+HCG treatment. Following the completion of treatment, only one patient still required surgery to correct cryptorchidism; this could be attributed to the initially high position of the testes (located in the iliac fossa) in this patient. Additionally, this patient underwent treatment at the age of 2, and the treatment outcome may not have been as effective as that in younger patients. However, our data were limited, and we could not provide detailed information. Therefore, we recommend initiating treatment soon after diagnosis (preferably before 2 years of age). During the follow-up period, two patients experienced testicular retraction. However, after undergoing a second round of treatment, the testes descended. This observation suggests that an individualized treatment may be necessary, possible requiring intermittent low-dose administration of gonadotropin therapy.

To date, 22 cases of CHH have been treated in infants, with the majority of cases involving adolescents [4] [16] [17] [18] [19] [20] [21] [22] [23]. The reason for focusing on treatment in infancy is the absence of mini-puberty in these patients, which can result in the premature interruption of reproductive system development and poor prognosis for reproduction in adulthood [24]. Mini-puberty plays a crucial role in determining long-term testicular function [24]. Therefore, many pediatricians have begun exploring treatment options for infant CHH.

Cases 1, 7, and 8 were treated with a combination of HCG and HMG, whereas cases 2, 3, 4, 5, and 6 were treated with a GnRH pump. Notably, there was a significant change in the PL of the patients, and after three months of medication, all testicles descended into the scrotum. These observations suggested that the Leydig and Sertoli cells in the testes functioned well, indicating their potential for fertility. However, it is important to note that the true acquisition of fertility potential can only be determined in adulthood. It would be beneficial to conduct comparative cohort studies to assess spermatogenesis ability in these patients. Previous studies have shown promising results in terms of hormone levels, penile growth, and TV in infants treated with a combination of LH and FSH ([Table 3]). Regardless of the dosage, all the symptoms improved. Notably, in the low-dose group (comprising six patients with FSH dosage<100 IU/week) treated for>3 months, the mean increase in PL was only 1.1 cm, and three patients still required surgical fixation of the testes. In contrast, the high-dose group (comprising 16 patients with FSH dosages ranging from 450 to 1050 IU/week) showed a mean increase in PL of 2.2 cm, and the testes of patients with cryptorchidism descended into the scrotum. Therefore, the high-dose group exhibited better outcomes. However, definitive conclusions could not be drawn owing to the limited sample size. The treatment plans used in this study differ from those used in previous studies. Cases 2, 3, 5, and 6 represent the global first instances of the use of a GnRH pump to treat infant CHH. The dosage used was smaller, and the treatment duration was shorter than that used in adolescent and adult patients, typically lasting within 3 months. Nonetheless, improvements in micropenis and cryptorchidism were observed. There were significant increases in T and INH-B levels, and no serious adverse reactions were reported. Simultaneously, we observed that patients in the HCG+HMG treatment group generally exhibited higher FSH levels than those in the pump treatment group, and this difference was statistically significant. However, both groups demonstrated improvements in penile and testicular functions, with no significant differences between them. Previous studies have suggested a relative resistance of postpartum Sertoli cells to FSH in infants with CHH, necessitating high serum FSH concentrations during treatment to achieve normal INH-B and AMH levels. In contrast, adult patients with CHH typically exhibit FSH concentrations of approximately 11–14 IU/l [17], which are sufficient to induce an increase in INH-B and AMH. Our study found that the FSH concentration in the pump-treated group fell within the range of 11–14 IU/l, resulting in a significant increase in INH-B levels and an improvement in both penile and testicular function. This finding further confirms that postpartum Sertoli cells in infants with CHH do not exhibit FSH resistance. It is important to consider that the differences observed between the two groups may be attributed to variations in treatment methods and serum FSH concentrations.

In conclusion, gonadotropin treatment in CHH infants has been shown to promote the growth of the testis and penis, as well as increase INH-B levels. This treatment effectively mimics the physiological state of mini-puberty. Although it appears to be effective, further investigation is required to determine whether early initiation of gonadotropin replacement therapy can enhance the reproductive potential of adult patients with CHH. This study represents the first exploratory treatment for CHH in Chinese infants, and the treatment outcomes were significantly positive. Notably, cases 7 and 8, who are currently 5 and 4 years old, respectively, exhibited normal external genitalia after 4 years of post-treatment follow-up. Nonetheless, long-term follow-up is still necessary to assess any changes in the external genitalia and puberty development after treatment discontinuation.

• References

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