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
122 drug discovery papers about Isolated congenital hypogonadotropic hypogonadism, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
122 drug discovery papers about Isolated congenital hypogonadotropic hypogonadism, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-02-09 | Association of self-stigma, impulsivity, and insomnia with anxiety and depression in patients with Kallmann syndrome.
Kallmann syndrome (KS) is a rare inherited disorder characterized by congenital hypogonadotropic hypogonadism and reduced or absent olfactory function. In addition to gonadal dysgenesis and structural abnormalities, KS patients may present with extensive psychosocial dysfunction and behavioral changes. This study aims to evaluate the effects of self-stigma, impulsivity, and insomnia on anxiety and depression in KS patients and to explore the interrelationships among these factors. A total of 206 patients with confirmed KS were recruited from the Xiangya Hospital and Henan Provincial People's Hospital. Multivariable Logistic regression analysis was used to identify independent factors associated with anxiety and depression, and a serial multiple-mediator model was applied to characterize pathway effects. The cohort of KS patients demonstrated substantial psychological and social burden, including self-stigma, impulsivity, insomnia, loneliness, anxiety, depression, and overall social isolation tendencies. Logistic regression analysis indicated that self-stigma (OR=1.112, P=0.003), loneliness (OR=1.198, P=0.007), and insomnia (OR=1.098, P=0.017) were independent factors the presence of anxiety and depression in KS patients. Mediation-effect modeling further showed that impulsivity and insomnia significantly mediated the effect of self-stigma on anxiety and depression in KS (indirect effect 3=0.013, P=0.008; 95% CI 0.004 to 0.024; c'=0.147, P<0.001; 95% CI 0.091 to 0.201). This study preliminarily identified the major modifiable factors associated with anxiety and depression in KS patients, including self-stigma, loneliness, and insomnia. Impulsivity and insomnia demonstrated significant serial mediation effects linking self-stigma to affective outcomes. Multidimensional intervention strategies targeting stigma reduction, impulsivity regulation, and sleep-quality improvement may help alleviate anxiety-depression symptoms and ultimately improve overall quality of life in patients with KS.
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.
2025-05-08 | ‘’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.
2026-02-09 | Association of self-stigma, impulsivity, and insomnia with anxiety and depression in patients with Kallmann syndrome.
Kallmann syndrome (KS) is a rare inherited disorder characterized by congenital hypogonadotropic hypogonadism and reduced or absent olfactory function. In addition to gonadal dysgenesis and structural abnormalities, KS patients may present with extensive psychosocial dysfunction and behavioral changes. This study aims to evaluate the effects of self-stigma, impulsivity, and insomnia on anxiety and depression in KS patients and to explore the interrelationships among these factors. A total of 206 patients with confirmed KS were recruited from the Xiangya Hospital and Henan Provincial People's Hospital. Multivariable Logistic regression analysis was used to identify independent factors associated with anxiety and depression, and a serial multiple-mediator model was applied to characterize pathway effects. The cohort of KS patients demonstrated substantial psychological and social burden, including self-stigma, impulsivity, insomnia, loneliness, anxiety, depression, and overall social isolation tendencies. Logistic regression analysis indicated that self-stigma (OR=1.112, P=0.003), loneliness (OR=1.198, P=0.007), and insomnia (OR=1.098, P=0.017) were independent factors the presence of anxiety and depression in KS patients. Mediation-effect modeling further showed that impulsivity and insomnia significantly mediated the effect of self-stigma on anxiety and depression in KS (indirect effect 3=0.013, P=0.008; 95% CI 0.004 to 0.024; c'=0.147, P<0.001; 95% CI 0.091 to 0.201). This study preliminarily identified the major modifiable factors associated with anxiety and depression in KS patients, including self-stigma, loneliness, and insomnia. Impulsivity and insomnia demonstrated significant serial mediation effects linking self-stigma to affective outcomes. Multidimensional intervention strategies targeting stigma reduction, impulsivity regulation, and sleep-quality improvement may help alleviate anxiety-depression symptoms and ultimately improve overall quality of life in patients with KS.
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.
2025-05-08 | ‘’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.
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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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