RARE DISEASE
Isolated congenital hypogonadotropic hypogonadism
Isolated congenital hypogonadotropic hypogonadism
Isolated congenital hypogonadotropic hypogonadism
Synonyms: Gonadotropic deficiency, Isolated congenital gonadotropin deficiency, Isolated gonadotropin-releasing hormone deficiency
Synonyms: Gonadotropic deficiency, Isolated congenital gonadotropin deficiency, Isolated gonadotropin-releasing hormone deficiency
Synonyms: Gonadotropic deficiency, Isolated congenital gonadotropin deficiency, Isolated gonadotropin-releasing hormone deficiency
Drug discovery
1
drug
With orphan designation
Overview
Isolated congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by deficient gonadotropin-releasing hormone (GnRH) secretion or action, resulting in impaired puberty and infertility. It presents as normosmic CHH or Kallmann syndrome (with anosmia). Over 25 genetic causes have been identified, with variable penetrance and complex inheritance patterns. Diagnosis involves hormonal profiling (low sex steroids and gonadotropins) and exclusion of structural hypothalamic-pituitary lesions [1][2][6][12].
Burden
Physical: Osteoporosis, metabolic syndrome, and 20–30% treatment resistance in severe cases [3][12][18].
Psychological: Reduced quality of life due to delayed puberty, body image concerns, and infertility [8][18].
Genetic: Oligogenic inheritance in 15–30% of cases; lifelong monitoring for reversibility (~10% spontaneous recovery) [6][7][14].
Categories: rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders
Research Papers
123 drug discovery papers about Isolated congenital hypogonadotropic hypogonadism, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
123 drug discovery papers about Isolated congenital hypogonadotropic hypogonadism, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-11-06 | Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior, and fertility in male and female mice.
Reproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that selenoprotein T (SELENOT), a newly described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuroendocrine regulation in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These changes were reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time to our knowledge the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a redox effector of GnRH neuron activity impacting both male and female reproductive function.
2025-10-01 | Congenital Hypogonadotropic Hypogonadism in Saudi Arabia: A Single-Center Case Series and Literature Review Across Both Sexes
Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder of absent or incomplete puberty due to deficient gonadotropin-releasing hormone action. The Kallmann variant is associated with anosmia or hyposmia. In Saudi Arabia, reports are limited to isolated familial cases, including a KISS1R mutation in a consanguineous family. Broader clinical and genetic data remain scarce. We present a multi-patient series to highlight phenotypic diversity, genetic findings, and treatment outcomes. Case Description: We reviewed nine patients (seven males and two females) presenting primarily in late adolescence or early adulthood. Anosmia or hyposmia was present in eight, cryptorchidism in five, and micropenis in two. Dysmorphic features included syndactyly, dental agenesis, and gynecomastia in select cases. Imaging revealed hypoplastic testes or uterus, with absent olfactory bulbs in one female. Baseline gonadotropins and sex steroids were consistently low (median LH: 0.2 IU/L, FSH: 0.2 IU/L, testosterone: 0.9 nmol/L). Genetic testing identified ANOS1 and FGFR1 variants most frequently, alongside CHD7, PROKR2, and GNRHR; one patient carried an Xp22 microdeletion encompassing ANOS1/STS. Pathogenic or likely pathogenic variants were confirmed in several patients, while others had variants of uncertain significance. Management strategies included testosterone replacement in males, gonadotropins (hCG ± recombinant FSH) for fertility induction, and stepwise estrogen induction in females. Eight of nine patients achieved partial or complete pubertal development, with improved virilization or feminization, normalized sex steroid levels, and better quality of life. Fertility outcomes remain pending, though early hormonal responses were promising. Conclusion: This case series provides the first multipatient description of CHH from Saudi Arabia. Patients exhibited typical features, genetic heterogeneity, and responded well to therapy. Pubertal induction was successful in most, but spermatogenesis and pregnancy were not achieved. These findings highlight both the benefits and persistent reproductive challenges in CHH, emphasizing the need for early recognition, sustained follow-up, and access to fertility care. Publication History Article published online: 29 December 2025 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
2025-05-08 | ‘’Benefit of Pulsatile GnRH Therapy in Treatment of Functional Hypothalamic Amenorrhea (FHA) and Congenital Hypogonadotropic Hypogonadism(CHH) in Infertile Patients Over Canonical Gonadotropins with IVF –A Short Communication’’
Normoprolactinemic hypogonadotropic hypogonadismis (HH) a germanely frequent etiology of anovulation. It originates from pituitary and /or suprapituitary structures. Besides hyperprolactinemia, ovulation induction by gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) delivery might be posited in women who want pregnancy. The choice of ovulation induction medications are based on the region of the gonadotropic axis impacted: pulsatiledelivery of GnRH might just be taken into account in suprapituitary etiologes, while injectable gonadotropins possess the capacity of getting utillized in both suprapituitary and pituitary etiologes. Hypothalamic anovulation is usually categorized into congenital and acquired etiologies .In case of acquired normoprolactinemic HH, organic etiologies are compared to functional hypothalamic amenorrhea (FHA). FHA takes place by diminished pulsatilityof GnRH leading to a diminished frequency and amplitude of luteinizing hormone (LH) pulses. Restriction of fat intake and/or increased physical activity is implicated in such diminished pulsatility. The phenotypic expression of suprapituitary congenital hypogonadotropic hypogonadism (CHH) might differ. An escalating number of genes are implicated in the migration of GnRH neurons at the time of intrauterine life in addition to / or in the homeostasis of the gonadotropic axis are isolated. Till now, practically 50%of corroborated cases of CHH continue to be idiopathic subsequent to genetic evaluation.No studies have contrasted the efficacy of pulsatile GnRH delivery as per the etiology of suprapituitary anovulation or tried to isolate prognostic factors for the success of this treatment. Recently in a retrospective cohort study at France, the ongoing pregnancy rate per initiated cycle amongst FHA and CHH patients was contrasted subsequent to treatment with pulsatile GnRH delivery aiming for monofollicular ovulation. Comparable outcome were seen in FHA and CHH, advocating its superiority over gonadotropins and IVF.
2025-03-26 | Neurokinin 3 receptor agonist senktide stimulates GnRH release in isolated hypogonadotropic hypogonadism mice.
Isolated hypogonadotropic hypogonadism (IHH) is caused by defective gonadotropin-releasing hormone (GnRH) secretion or action, resulting in absent or incomplete pubertal development and infertility. However, the pathogenesis mechanism of IHH is not fully understood. This study utilized PROK2/PROKR2 knockdown mice and GT1-7 cells to investigate the effects and potential mechanismsof the NK3R agonist senktide on GnRH deficiency and related syndromes. In this investigation, PROK2/PROKR2 knockdown resulted in a deficiency of GnRH neurons, reduced levels of LSH, FSH, and E2, and the inhibition of the MAPK/ERK and PI3K/AKT pathways in mice. However, this effect was reversed by senktide. Furthermore, the inhibition of MAPK/ERK or PI3K/AKT signaling pathways counteracted the remission of the GnRH insufficiency and associated syndrome by senktide in mice with PROK2/PROKR2 knockdown. In summary, NK3R agonist senktide alleviated the GnRH insufficiency and related syndromes caused by PROK2/PROKR2 knockdown via the MAPK/ERK pathway and the PI3K/AKT pathway.
2025-03-14 | An Effective Outcome Despite Delayed Treatment Initiation in a Female With Kallmann Syndrome: A Case Report.
Kallmann syndrome (KS) is an idiopathic hypogonadotropic hypogonadism with anosmia due to isolated gonadotropin-releasing hormone deficiency. In females, the diagnosis often occurs around age 15 due to primary amenorrhea, prompting hormone replacement therapy (HRT) initiation. However, limited data exists on the effectiveness of delayed HRT in females with KS. Here, we describe a case involving a female with KS who began treatment at the age of 27. Following HRT initiation, the patient showed increases in uterine size, bone mineral density, and growth of breasts over a two-year period. Delayed diagnosis of KS in females, as in this case, is extremely rare, and this case demonstrates two important clinical issues. First, HRT can still be effective in females with KS even if treatment initiation is delayed, and, second, therapeutic benefits become apparent within two years following initiation of treatment. These findings may be applicable to other patients with congenital hypogonadotropic hypogonadism whose treatment initiation was delayed.
2025-11-06 | Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior, and fertility in male and female mice.
Reproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that selenoprotein T (SELENOT), a newly described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuroendocrine regulation in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These changes were reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time to our knowledge the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a redox effector of GnRH neuron activity impacting both male and female reproductive function.
2025-10-01 | Congenital Hypogonadotropic Hypogonadism in Saudi Arabia: A Single-Center Case Series and Literature Review Across Both Sexes
Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder of absent or incomplete puberty due to deficient gonadotropin-releasing hormone action. The Kallmann variant is associated with anosmia or hyposmia. In Saudi Arabia, reports are limited to isolated familial cases, including a KISS1R mutation in a consanguineous family. Broader clinical and genetic data remain scarce. We present a multi-patient series to highlight phenotypic diversity, genetic findings, and treatment outcomes. Case Description: We reviewed nine patients (seven males and two females) presenting primarily in late adolescence or early adulthood. Anosmia or hyposmia was present in eight, cryptorchidism in five, and micropenis in two. Dysmorphic features included syndactyly, dental agenesis, and gynecomastia in select cases. Imaging revealed hypoplastic testes or uterus, with absent olfactory bulbs in one female. Baseline gonadotropins and sex steroids were consistently low (median LH: 0.2 IU/L, FSH: 0.2 IU/L, testosterone: 0.9 nmol/L). Genetic testing identified ANOS1 and FGFR1 variants most frequently, alongside CHD7, PROKR2, and GNRHR; one patient carried an Xp22 microdeletion encompassing ANOS1/STS. Pathogenic or likely pathogenic variants were confirmed in several patients, while others had variants of uncertain significance. Management strategies included testosterone replacement in males, gonadotropins (hCG ± recombinant FSH) for fertility induction, and stepwise estrogen induction in females. Eight of nine patients achieved partial or complete pubertal development, with improved virilization or feminization, normalized sex steroid levels, and better quality of life. Fertility outcomes remain pending, though early hormonal responses were promising. Conclusion: This case series provides the first multipatient description of CHH from Saudi Arabia. Patients exhibited typical features, genetic heterogeneity, and responded well to therapy. Pubertal induction was successful in most, but spermatogenesis and pregnancy were not achieved. These findings highlight both the benefits and persistent reproductive challenges in CHH, emphasizing the need for early recognition, sustained follow-up, and access to fertility care. Publication History Article published online: 29 December 2025 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
2025-05-08 | ‘’Benefit of Pulsatile GnRH Therapy in Treatment of Functional Hypothalamic Amenorrhea (FHA) and Congenital Hypogonadotropic Hypogonadism(CHH) in Infertile Patients Over Canonical Gonadotropins with IVF –A Short Communication’’
Normoprolactinemic hypogonadotropic hypogonadismis (HH) a germanely frequent etiology of anovulation. It originates from pituitary and /or suprapituitary structures. Besides hyperprolactinemia, ovulation induction by gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) delivery might be posited in women who want pregnancy. The choice of ovulation induction medications are based on the region of the gonadotropic axis impacted: pulsatiledelivery of GnRH might just be taken into account in suprapituitary etiologes, while injectable gonadotropins possess the capacity of getting utillized in both suprapituitary and pituitary etiologes. Hypothalamic anovulation is usually categorized into congenital and acquired etiologies .In case of acquired normoprolactinemic HH, organic etiologies are compared to functional hypothalamic amenorrhea (FHA). FHA takes place by diminished pulsatilityof GnRH leading to a diminished frequency and amplitude of luteinizing hormone (LH) pulses. Restriction of fat intake and/or increased physical activity is implicated in such diminished pulsatility. The phenotypic expression of suprapituitary congenital hypogonadotropic hypogonadism (CHH) might differ. An escalating number of genes are implicated in the migration of GnRH neurons at the time of intrauterine life in addition to / or in the homeostasis of the gonadotropic axis are isolated. Till now, practically 50%of corroborated cases of CHH continue to be idiopathic subsequent to genetic evaluation.No studies have contrasted the efficacy of pulsatile GnRH delivery as per the etiology of suprapituitary anovulation or tried to isolate prognostic factors for the success of this treatment. Recently in a retrospective cohort study at France, the ongoing pregnancy rate per initiated cycle amongst FHA and CHH patients was contrasted subsequent to treatment with pulsatile GnRH delivery aiming for monofollicular ovulation. Comparable outcome were seen in FHA and CHH, advocating its superiority over gonadotropins and IVF.
2025-03-26 | Neurokinin 3 receptor agonist senktide stimulates GnRH release in isolated hypogonadotropic hypogonadism mice.
Isolated hypogonadotropic hypogonadism (IHH) is caused by defective gonadotropin-releasing hormone (GnRH) secretion or action, resulting in absent or incomplete pubertal development and infertility. However, the pathogenesis mechanism of IHH is not fully understood. This study utilized PROK2/PROKR2 knockdown mice and GT1-7 cells to investigate the effects and potential mechanismsof the NK3R agonist senktide on GnRH deficiency and related syndromes. In this investigation, PROK2/PROKR2 knockdown resulted in a deficiency of GnRH neurons, reduced levels of LSH, FSH, and E2, and the inhibition of the MAPK/ERK and PI3K/AKT pathways in mice. However, this effect was reversed by senktide. Furthermore, the inhibition of MAPK/ERK or PI3K/AKT signaling pathways counteracted the remission of the GnRH insufficiency and associated syndrome by senktide in mice with PROK2/PROKR2 knockdown. In summary, NK3R agonist senktide alleviated the GnRH insufficiency and related syndromes caused by PROK2/PROKR2 knockdown via the MAPK/ERK pathway and the PI3K/AKT pathway.
2025-03-14 | An Effective Outcome Despite Delayed Treatment Initiation in a Female With Kallmann Syndrome: A Case Report.
Kallmann syndrome (KS) is an idiopathic hypogonadotropic hypogonadism with anosmia due to isolated gonadotropin-releasing hormone deficiency. In females, the diagnosis often occurs around age 15 due to primary amenorrhea, prompting hormone replacement therapy (HRT) initiation. However, limited data exists on the effectiveness of delayed HRT in females with KS. Here, we describe a case involving a female with KS who began treatment at the age of 27. Following HRT initiation, the patient showed increases in uterine size, bone mineral density, and growth of breasts over a two-year period. Delayed diagnosis of KS in females, as in this case, is extremely rare, and this case demonstrates two important clinical issues. First, HRT can still be effective in females with KS even if treatment initiation is delayed, and, second, therapeutic benefits become apparent within two years following initiation of treatment. These findings may be applicable to other patients with congenital hypogonadotropic hypogonadism whose treatment initiation was delayed.
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Drug Discovery Landscape
1 orphan drug designation for Isolated congenital hypogonadotropic hypogonadism, including 1 approved therapy.
1 orphan drug designation for Isolated congenital hypogonadotropic hypogonadism, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Gonadorelin acetate [Lutrepulse] | small molecules | FDA | 1987-04-22 | 1989-10-10 | Ferring Laboratories, Inc. |
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