Congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic condition of central hypogonadism that results in absent or incomplete pubertal development and reproductive immaturity. It has an estimated incidence of between 1 in 15,000 and 1 in 50,000, and a male-to-female predominance of 3.6 to one. It has been linked to variants in over 50 genes.

CHH is characterised by low concentrations of circulating sex steroids, which is caused by a deficiency of pituitary gonadotrophins – namely luteinising hormone (LH) and follicle-stimulating hormone (FSH).

Deficiency of pituitary gonadotrophins is most commonly caused by a failure of gonadotrophin-releasing hormone (GnRH) production from the hypothalamus or, alternatively, by GnRH resistance or an inherent pituitary anomaly.

Classification

CHH is broadly classified into three subgroups:

• idiopathic hypogonadotropic hypogonadism;
• Kallmann syndrome, which is the association of CHH with anosmia; and
• CHH as part of a wider syndrome.

CHH often presents with delayed, absent or arrested puberty in adolescence. It may also be indicated by the presence of ‘red-flag’ features such as:

• anosmia;
• synkinesis (mirror movements);
• sensorineural hearing loss;
• midline anomalies such as cleft palate, cleft lip, hypodontia and renal agenesis;
• digit or limb anomalies, such as ectrodactyly; and
• cryptorchidism (undescended testes) and/or micropenis. (These will be apparent in male infants and may lead to the diagnosis of CHH being made in early childhood. In older children and adults, there may be a history of surgical orchidopexy to correct cryptorchidism.)

Post puberty

After puberty, the CHH diagnosis may be missed until later in adult life, when patients may present with hypogonadism, lack of libido, reduced energy levels and reduced bone density. It may also be diagnosed during investigations for infertility.

In women

CHH is less prevalent in women and can be more challenging to diagnose due to an overlap with features of hypothalamic amenorrhoea and polycystic ovary syndrome, such as oligomenorrhea or amenorrhoea.

Partial CHH

A partial CHH can be seen in both male and female patients. The phenomenon of reversibility (in which patients recover their reproductive endocrine capacity and are able to stop hormonal treatment) is observed in up to one in five CHH patients – though they may later relapse.

Syndromic CHH

CHH may occur as part of a wider genetic syndrome, involving phenotypes such as:

• other pituitary hormone deficiencies (including combined pituitary hormone deficiency (CPHD));
• septo-optic dysplasia;
• obesity;
• neurodevelopmental disorders (such as Coffin-Siris syndrome or peripheral demyelinating sensorimotor polyneuropathy); and
• other non-reproductive phenotypes (such as in CHARGE syndrome).

Diagnosis of CHH requires both biochemical and radiological investigations, as detailed in tables 1 and 2 respectively. Note that the red-flag signs identified above may be present throughout life. Micropenis and/or cryptorchidism are particularly notable features in males with severe CHH.

Table 1: Biochemistry investigations for diagnosis of CHH

Please note that:

• stimulation testing (either with GnRH to assess LH response, or with human chorionic gonadotropin (hCG) to assess testosterone response) is used commonly in paediatric practice in mini-puberty and puberty, but is rarely used in adult practice; and
• mini-puberty is the period of hypothalamic-pituitary-gonadal axis stimulation, from about one to five months of age, when GnRH pulsatility leads to detectable LH and sex steroids in male and female infants. It is thought to be important for gonadal development and is a window of opportunity for diagnosis of CHH.

Table 2: Radiological investigations for diagnosis of CHH

More than 50 genes have been implicated in the aetiology of CHH. These genes have roles in the development and function of the GnRH neurons in the hypothalamus and the pituitary’s response to GnRH. There is an overlap between those genes that may cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

The current version of the R148 Hypogonadotropic hypogonadism panel (April 2023) includes over 20 genes, all of which are rated green, meaning that they are reportable for clinical practice (table 3). For patients with CPHD or septo-optic dysplasia, many additional genes have been identified that contribute to the aetiology. They are captured in a separate gene panel: R159 Pituitary hormone deficiency.

For information about testing, see Presentation: Patient aged 18 with delayed puberty.

In addition to monogenic inheritance and oligogenic transmission, incomplete penetrance has also been observed in CHH pedigrees. Despite the clear genetic heterogeneity, recent studies in large cohorts with CHH or Kallmann syndrome show that an underlying variant of interest can be identified in 21%–51% of patients.

Autosomal dominant, autosomal recessive and X-linked patterns of inheritance have been identified, as well as rare cases of uniparental isodisomy. Evidence of phenotype-genotype correlation can aid targeted genomic testing – for example if syndromic features are present, such as sensorineural hearing loss (associated with ANOS1), severe obesity (LEP/LEPR) or skeletal anomalies (FGFR1).

Table 3: Genes included in the R148 Hypogonadotropic hypogonadism gene panel and associated phenotypes

The goals of hormonal therapy in patients with CHH are:

• physical maturation with secondary sexual characteristics and optimisation of adult height;
• achievement of optimal bone mass and body composition;
• normal psychosocial development; and
• fertility.

Sex steroid replacement has been used for a long time in nearly all forms of hypogonadism in order to achieve most of these outcomes, although fertility cannot be achieved with sex steroid therapy alone. Gonadotropin or GnRH treatment is required for patients with CHH to enable the potential for fertility.

Genetic diagnoses also influence the outcome of treatment and can guide therapy. For example, the treatment of patients with ANOS1 variants can be more difficult because they may have anomalies at several levels of the hypothalamus-pituitary-gonadal axis. Another example is that patients with CHH due to GnRHR variants will be better treated with gonadotropins than pulsatile GnRH.

As up to 20% of CHH patients have sustained reversal after treatment is stopped, a ‘trial off treatment’ can be used intermittently to assess requirements for maintenance therapy.

In both genders, optimisation of vitamin D and calcium intakes are advisable to help bone mineral density acquisition. Bone density should be regularly monitored by dual energy X-ray absorptiometry scanning. Counselling around fertility and psychological support is important in this patient group.

Management recommendations for hypogonadism (up to adolescence) have been published, and reference ranges have been released for:

• inhibin B, LH, FSH and testosterone levels in healthy males by age;
• inhibin B, LH, FSH and testosterone levels in healthy females by age;
• inhibin B, LH, FSH and oestradiol levels in healthy females by Tanner stage and stage of the menstrual cycle; and
• AMH levels in healthy males and females by age.

For clinicians

• British Society of Paediatric Endocrinology and Diabetes: BSPED guideline: Testosterone therapy in infancy and adolescence (PDF, 11 pages)
• British Society of Paediatric Endocrinology and Diabetes: Guidance statement: Hormone supplementation for pubertal induction in girls (PDF, 21 pages)
• British Society of Paediatric Endocrinology and Diabetes: Protocol for induction of puberty with gonadotropins in adolescent males with GnRH or gonadotropin deficiency (PDF, five pages)
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels resource
• NHS England: National Genomic Test Directory

References:

• Bergada I, Rojas G, Ropelato G and others. ‘Sexual dimorphism in circulating monomeric and dimeric inhibins in normal boys and girls from birth to puberty‘. Clinical Endocrinology, 1999: volume 51, issue 4, pages 455–460. DOI: 10.1046/j.1365-2265.1999.00814.x
• Boehm U, Bouloux PM, Dattani MT and others. ‘European Consensus Statement on congenital hypogonadotropic hypogonadism–pathogenesis, diagnosis and treatment‘. Nature Reviews Endocrinology 2015: volume 11, issue 9, pages 547–564. DOI: 10.1038/nrendo.2015.112
• Butz H, Nyiro G, Kurucz PA and others. ‘Molecular genetic diagnostics of hypogonadotropic hypogonadism: From panel design towards result interpretation in clinical practice‘. Human Genetics 2021: volume 140, issue 1, pages 113–134. DOI: 10.1007/s00439-020-02148-0
• Howard SR and Dunkel L. ‘Management of hypogonadism from birth to adolescence‘. Best Practice & Research Clinical Endocrinology & Metabolism 2018: volume 32, issue 4, pages 355–372. DOI: 10.1016/j.beem.2018.05.011
• Jopling H, Yates A, Burgoyne N and others. ‘Paediatric anti-Müllerian hormone measurement: Male and female reference intervals established using the automated Beckman Coulter Access AMH assay‘. Endocrinology, Diabetes & Metabolism 2018: volume 1, issue 4, article e00021. DOI: 10.1002/edm2.21
• Sehested A, Juul AA, Andersson AM and others. ‘Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels‘. Journal of Clinical Endocrinology & Metabolism 2000: volume 85, issue 4, pages 1634–1640. DOI: 10.1210/jcem.85.4.6512

For patients

• Kallmann Syndrome & Congenital Hypogonadotropic Hypogonadism
• Kallmann syndrome: Delayed or absent puberty (UK patient experience blog)
• Patient video: What is hypogonadotropic hypogonadism and Kallmann syndrome? (video, four minutes)