RARE DISEASE
Congenital hypogonadotropic hypogonadism
Congenital hypogonadotropic hypogonadism
Congenital hypogonadotropic hypogonadism
Drug discovery
4
drugs
With orphan designations
Overview
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by insufficient gonadotropin-releasing hormone (GnRH) secretion or action, leading to absent/incomplete puberty and infertility. It manifests as low sex steroids with inappropriately low gonadotropins and may coexist with anosmia (Kallmann syndrome) or non-reproductive anomalies (e.g., cryptorchidism, cleft palate). Genetic mutations in over 30 genes contribute to its pathogenesis, though ~50% of cases remain genetically unresolved [1][4][15].
Therapies
Puberty induction: Gradual testosterone replacement (intramuscular or topical) [3][7].
Fertility restoration: Combined gonadotropin therapy (hCG + FSH) or pulsatile GnRH to stimulate spermatogenesis [3][7].
Infancy interventions: Short-term neonatal gonadotropin therapy to correct micropenis and promote testicular descent [1][7].
Categories: rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders
Research Papers
487 drug discovery papers about Congenital hypogonadotropic hypogonadism, with 1 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
487 drug discovery papers about Congenital hypogonadotropic hypogonadism, with 1 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-24 | A Novel Hemizygous ANOS1 Variant in a Patient With Kallmann Syndrome and Type 2 Diabetes Mellitus: A Case Report.
Kallmann syndrome (KS), a rare genetic disorder, is characterized by congenital hypogonadotropic hypogonadism (CHH) and anosmia or hyposmia. We report a case of KS with type 2 diabetes mellitus (T2DM) associated with a novel hemizygous missense variant in ANOS1 (NM_000216.4; exon 4; c.505G >C;p.(Gly169Arg)). A 33-year-old male presented with persistent hyperglycemia, delayed pubertal development with absent secondary sexual characteristics, and lifelong anosmia. Olfactory testing, magnetic resonance imaging (MRI) of the pituitary region, and a gonadotropin-releasing hormone (GnRH) stimulation test supported a clinical diagnosis of KS. Trio-based exome sequencing (ES) revealed the aforementioned hemizygous variant in ANOS1. Notably, neither parent harbored this variant, supporting a de novo origin, which is consistent with the variant's potential pathogenicity. Multiple sequence alignment showed that Gly169 is highly conserved across species, suggesting it may be functionally important for the protein. Furthermore, a three-dimensional protein model generated using SWISS-MODEL predicted marked conformational changes in the protein attributable to this amino acid substitution at a highly conserved residue, suggesting a potential functional impact. Notably, emerging evidence has linked ANOS1 variants to dysregulated glucose metabolism, supporting a potential association with T2DM in this case. For treatment, insulin and oral hypoglycemic agents were used for glycemic control, and a GnRH pump was initiated. At the sixth follow-up visit, the patient had achieved satisfactory glycemic control; however, serum testosterone levels remained low despite GnRH pump therapy, so testosterone replacement therapy was subsequently initiated. ANOS1 variants are genetically diverse and may contribute to both KS pathogenesis and the development of comorbid T2DM, though further studies are needed to confirm this link. For KS patients, close monitoring of fasting glucose, glycated hemoglobin, and oral glucose tolerance test results is advisable to detect diabetes and prediabetes early.
2026-06-26 | Reversible congenital hypogonadotropic hypogonadism: keys for clinical management.
Congenitalhypogonadotropic hypogonadism (CHH) is characterized by absent/incomplete puberty and a treatable form of male infertility resulting from deficient gonadotropin-releasing hormone (GnRH) secretion/action. Traditionally, CHH has been considered a permanent, lifelong condition. However, evidence indicates a subset men undergo reversal and recover reproductive axis function. We conducted a structured literature search (Medline, PubMed) using keywords to retrieve articles on CHH reversal (1975-2025). We synthesize the literature to provide a high-level overview of CHH and the reversal phenomenon in males. Particular focus is given to clinical aspects of CHH and reversal using a case vignette to highlight keys to management. Approximately 10-15% of males with CHH undergo reversal with sustained normalized testosterone levels and spermatogenesis off treatment. A key sign of reversal is testicular growth while on testosterone replacement therapy. Those men with some degree of spontaneous puberty (i.e., larger testicular volume), detectable follicle stimulating hormone levels , and/or pathogenic variants in GNRHR are more likely to undergo reversal. In contrast, severe GnRH deficiency, pathogenic ANOS1 and/or two or more combined pathogenic variants (oligogenicity) in CHH genes are less likely to recover reproductive axis function. Reversal is not lasting in all cases. The reversal phenomenon challenges the classical dogma that CHH is permanent and lifelong. Reversal cases highlight the plasticity of the neuroendocrine control of reproduction. Clinicians can tailor the approach to men with CHH using reversal predictors to guide supervise washout to identify reversal as well as long-term monitoring to assess potential relapse.
2026-05-18 | Case Report: Homozygous KISS1R mutation associated with congenital hypogonadotropic hypogonadism in two siblings: pulsatile GnRH therapy restores pituitary architecture and induces pubertal development.
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH), the central regulator of the reproductive axis. We report two siblings from a consanguineous family with CHH caused by a homozygous nonsense mutation (c.182C > A; p. Ser 61Ter) in exon 1 of KISS1R gene. The 15-years-old male proband presented with absent puberty, micropenis, and gynecomastia. Endocrine evaluation revealed low gonadotropin levels and brain magnetic resonance imaging (MRI) showed pituitary hypoplasia. His 12-years-old sister exhibited puberty delays, with absent breast development and pubic hair. The male patient received 1 year of pulsatile GnRH therapy, resulting in significant clinical improvements, including markedly increased testicular volume (from 0.9 to 5.6 mL), penile growth, and the resolution of gynecomastia. Notably, follow-up imaging demonstrated morphological recovery of the pituitary gland, with an increase in height from 3.5 to 4.5 mm, accompanied by the successful induction of spermatogenesis. This excellent response to GnRH underscores its efficacy in restoring fertility, particularly when initiated in early adolescence, and highlights the value of genetic diagnosis in consanguineous families.
2026-04-17 | Comparing the response of triple therapy and conventional treatment in male congenital hypogonadotropic hypogonadism: a randomized controlled trial.
This study investigated whether triple therapy with human chorionic gonadotropin (hCG), follicle-stimulating hormone(FSH) and testosterone(T) in congenital hypogonadotropic hypogonadism(CHH) promoted more timely virilization, aiding psychosocial development while reducing hCG requirements, offering a balanced approach to long-term management. An open-label randomized controlled trial (1:1:1) was conducted in adult males with CHH. Group A received triple therapy, Group B received combined hCG and FSH from the outset, and Group C received hCG monotherapy followed by combined FSH and hCG. Initial doses comprised hCG 2,000 IU twice weekly, FSH 75 IU thrice weekly and intramuscular testosterone(T) 100 mg every two weeks. Group A titrated hCG to achieve AMH of 7.4ng/ml; Groups B and C aimed for T normalization. Primary outcomes were hCG/FSH doses required for spermatogenesis induction and the time to spermatogenesis. Forty-five CHH males (mean age 25.8 ± 6.1years) were randomized. Spermatogenesis was achieved in 84.6% of group A participants compared with 69.2% and 75% in groups B and C, respectively(p=0.648). Median hCG dose at spermatogenesis was 7500IU/week in group A and 9000IU/week in groups B and C(p=0.016). The time to spermatogenesis was comparable (Groups A/B:12 months; Group C:15 months;p=0.345). Group A participants achieved an AMH of 3.5(2.31-5.38)ng/ml, comparable to the other groups(p=0.962). Predictors of spermatogenesis included USGmTV cut-off of 1.97ml (sensitivity-86.2%,specificity-62.5%), hCG dose of 9,000 IU/week (sensitivity-79.3%,specificity-87.5%) and an Inh B cut-off of 66.8 pg/ml(sensitivity-92.6%,specificity-100%). Triple therapy provided a better quality of life without compromising spermatogenesis. The AMH and Inh B provided an effective means of monitoring. www.ctri.nic.in, identifier CTRI/2022/05/042795.
2026-03-25 | Clinical Implications of Minipuberty.
Minipuberty refers to a specific period in early postnatal life with high activity of the hypothalamic-pituitary-gonadal (HPG) hormone axis. In infant boys 1 to 3 months of age, high concentrations of follicle-stimulating hormone and luteinizing hormone are released, which results in high levels of gonadal hormones from testicular Leydig cells (testosterone and insulin-like 3) and Sertoli cells (inhibin B and antimüllerian hormone). The HPG axis is also active in infant girls, who have adult levels of follicle-stimulating hormone and luteinizing hormone during this period. Immediately after minipuberty, the HPG axis is silenced for approximately 10 years and is reactivated only with the onset of puberty. Thus, minipuberty represents an early window for diagnosing disorders of sexual differentiation and rare endocrine disorders, such as congenital hypogonadotropic hypogonadism, and may help guide dosing of therapeutic interventions including gonadotropin therapy. Of note, minipuberty predicts adult reproductive capacity.
2026-07-24 | A Novel Hemizygous ANOS1 Variant in a Patient With Kallmann Syndrome and Type 2 Diabetes Mellitus: A Case Report.
Kallmann syndrome (KS), a rare genetic disorder, is characterized by congenital hypogonadotropic hypogonadism (CHH) and anosmia or hyposmia. We report a case of KS with type 2 diabetes mellitus (T2DM) associated with a novel hemizygous missense variant in ANOS1 (NM_000216.4; exon 4; c.505G >C;p.(Gly169Arg)). A 33-year-old male presented with persistent hyperglycemia, delayed pubertal development with absent secondary sexual characteristics, and lifelong anosmia. Olfactory testing, magnetic resonance imaging (MRI) of the pituitary region, and a gonadotropin-releasing hormone (GnRH) stimulation test supported a clinical diagnosis of KS. Trio-based exome sequencing (ES) revealed the aforementioned hemizygous variant in ANOS1. Notably, neither parent harbored this variant, supporting a de novo origin, which is consistent with the variant's potential pathogenicity. Multiple sequence alignment showed that Gly169 is highly conserved across species, suggesting it may be functionally important for the protein. Furthermore, a three-dimensional protein model generated using SWISS-MODEL predicted marked conformational changes in the protein attributable to this amino acid substitution at a highly conserved residue, suggesting a potential functional impact. Notably, emerging evidence has linked ANOS1 variants to dysregulated glucose metabolism, supporting a potential association with T2DM in this case. For treatment, insulin and oral hypoglycemic agents were used for glycemic control, and a GnRH pump was initiated. At the sixth follow-up visit, the patient had achieved satisfactory glycemic control; however, serum testosterone levels remained low despite GnRH pump therapy, so testosterone replacement therapy was subsequently initiated. ANOS1 variants are genetically diverse and may contribute to both KS pathogenesis and the development of comorbid T2DM, though further studies are needed to confirm this link. For KS patients, close monitoring of fasting glucose, glycated hemoglobin, and oral glucose tolerance test results is advisable to detect diabetes and prediabetes early.
2026-06-26 | Reversible congenital hypogonadotropic hypogonadism: keys for clinical management.
Congenitalhypogonadotropic hypogonadism (CHH) is characterized by absent/incomplete puberty and a treatable form of male infertility resulting from deficient gonadotropin-releasing hormone (GnRH) secretion/action. Traditionally, CHH has been considered a permanent, lifelong condition. However, evidence indicates a subset men undergo reversal and recover reproductive axis function. We conducted a structured literature search (Medline, PubMed) using keywords to retrieve articles on CHH reversal (1975-2025). We synthesize the literature to provide a high-level overview of CHH and the reversal phenomenon in males. Particular focus is given to clinical aspects of CHH and reversal using a case vignette to highlight keys to management. Approximately 10-15% of males with CHH undergo reversal with sustained normalized testosterone levels and spermatogenesis off treatment. A key sign of reversal is testicular growth while on testosterone replacement therapy. Those men with some degree of spontaneous puberty (i.e., larger testicular volume), detectable follicle stimulating hormone levels , and/or pathogenic variants in GNRHR are more likely to undergo reversal. In contrast, severe GnRH deficiency, pathogenic ANOS1 and/or two or more combined pathogenic variants (oligogenicity) in CHH genes are less likely to recover reproductive axis function. Reversal is not lasting in all cases. The reversal phenomenon challenges the classical dogma that CHH is permanent and lifelong. Reversal cases highlight the plasticity of the neuroendocrine control of reproduction. Clinicians can tailor the approach to men with CHH using reversal predictors to guide supervise washout to identify reversal as well as long-term monitoring to assess potential relapse.
2026-05-18 | Case Report: Homozygous KISS1R mutation associated with congenital hypogonadotropic hypogonadism in two siblings: pulsatile GnRH therapy restores pituitary architecture and induces pubertal development.
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH), the central regulator of the reproductive axis. We report two siblings from a consanguineous family with CHH caused by a homozygous nonsense mutation (c.182C > A; p. Ser 61Ter) in exon 1 of KISS1R gene. The 15-years-old male proband presented with absent puberty, micropenis, and gynecomastia. Endocrine evaluation revealed low gonadotropin levels and brain magnetic resonance imaging (MRI) showed pituitary hypoplasia. His 12-years-old sister exhibited puberty delays, with absent breast development and pubic hair. The male patient received 1 year of pulsatile GnRH therapy, resulting in significant clinical improvements, including markedly increased testicular volume (from 0.9 to 5.6 mL), penile growth, and the resolution of gynecomastia. Notably, follow-up imaging demonstrated morphological recovery of the pituitary gland, with an increase in height from 3.5 to 4.5 mm, accompanied by the successful induction of spermatogenesis. This excellent response to GnRH underscores its efficacy in restoring fertility, particularly when initiated in early adolescence, and highlights the value of genetic diagnosis in consanguineous families.
2026-04-17 | Comparing the response of triple therapy and conventional treatment in male congenital hypogonadotropic hypogonadism: a randomized controlled trial.
This study investigated whether triple therapy with human chorionic gonadotropin (hCG), follicle-stimulating hormone(FSH) and testosterone(T) in congenital hypogonadotropic hypogonadism(CHH) promoted more timely virilization, aiding psychosocial development while reducing hCG requirements, offering a balanced approach to long-term management. An open-label randomized controlled trial (1:1:1) was conducted in adult males with CHH. Group A received triple therapy, Group B received combined hCG and FSH from the outset, and Group C received hCG monotherapy followed by combined FSH and hCG. Initial doses comprised hCG 2,000 IU twice weekly, FSH 75 IU thrice weekly and intramuscular testosterone(T) 100 mg every two weeks. Group A titrated hCG to achieve AMH of 7.4ng/ml; Groups B and C aimed for T normalization. Primary outcomes were hCG/FSH doses required for spermatogenesis induction and the time to spermatogenesis. Forty-five CHH males (mean age 25.8 ± 6.1years) were randomized. Spermatogenesis was achieved in 84.6% of group A participants compared with 69.2% and 75% in groups B and C, respectively(p=0.648). Median hCG dose at spermatogenesis was 7500IU/week in group A and 9000IU/week in groups B and C(p=0.016). The time to spermatogenesis was comparable (Groups A/B:12 months; Group C:15 months;p=0.345). Group A participants achieved an AMH of 3.5(2.31-5.38)ng/ml, comparable to the other groups(p=0.962). Predictors of spermatogenesis included USGmTV cut-off of 1.97ml (sensitivity-86.2%,specificity-62.5%), hCG dose of 9,000 IU/week (sensitivity-79.3%,specificity-87.5%) and an Inh B cut-off of 66.8 pg/ml(sensitivity-92.6%,specificity-100%). Triple therapy provided a better quality of life without compromising spermatogenesis. The AMH and Inh B provided an effective means of monitoring. www.ctri.nic.in, identifier CTRI/2022/05/042795.
2026-03-25 | Clinical Implications of Minipuberty.
Minipuberty refers to a specific period in early postnatal life with high activity of the hypothalamic-pituitary-gonadal (HPG) hormone axis. In infant boys 1 to 3 months of age, high concentrations of follicle-stimulating hormone and luteinizing hormone are released, which results in high levels of gonadal hormones from testicular Leydig cells (testosterone and insulin-like 3) and Sertoli cells (inhibin B and antimüllerian hormone). The HPG axis is also active in infant girls, who have adult levels of follicle-stimulating hormone and luteinizing hormone during this period. Immediately after minipuberty, the HPG axis is silenced for approximately 10 years and is reactivated only with the onset of puberty. Thus, minipuberty represents an early window for diagnosing disorders of sexual differentiation and rare endocrine disorders, such as congenital hypogonadotropic hypogonadism, and may help guide dosing of therapeutic interventions including gonadotropin therapy. Of note, minipuberty predicts adult reproductive capacity.
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Drug Discovery Landscape
4 orphan drug designations for Congenital hypogonadotropic hypogonadism, including 1 approved therapy.
4 orphan drug designations for Congenital hypogonadotropic hypogonadism, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Leuprorelin acetate | small molecules | EMA | 2017-01-12 | — | Stichting Centre for Human Drug Research (CHDR) |
Follitropin alfa, recombinant [Gonal-F] | proteins | FDA | 1998-12-21 | 2000-05-24 | EMD Serono, Inc. |
Urofollitropin | proteins | FDA | 1997-12-05 | — | EMD Serono, Inc. |
Somatropin | proteins | FDA | 1987-09-01 | — | Novo Nordisk Pharmaceuticals |
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