Gonadotropin-Releasing Hormone Deficiency in Adults Clinical Presentation

Updated: Feb 17, 2022
  • Author: Vaishali Popat, MD, MPH; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Presentation

History

The age of onset, whether congenital or acquired, and the severity, whether complete or partial, determines the phenotypic expression.

During the neonatal period, boys present with micropenis. The incomplete descent of the testes and immaturity of the external genitalia are due to failure of the hypothalamic-pituitary-gonadal axis to activate in the late fetal and neonatal periods. In the embryonic and early fetal periods, fetal testosterone is required for full sexual and external genital development, which is stimulated by maternal human chorionic gonadotropin (hCG) and does not require the stimulation of fetal pituitary gonadotropins. Newborn girls have no obvious abnormalities. Cryptorchidism has been reported in as many as 50% of males with idiopathic hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS), and microphallus is present in as many as 30% of affected individuals.

During childhood, anosmia is the only manifestation in patients with KS.

In most cases, diagnosis is made much later, with absence of pubertal development. Histologically, the ovaries of affected women rarely possess follicles matured past the primordial stages. Hence, most of these women present with primary amenorrhea.

Some patients undergo early pubertal development but subsequently develop hypogonadism, leading to infertility and sexual dysfunction. [39]

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Physical Examination

Most physical findings are related to failure of sexual maturation. These patients have eunuchoidal body habitus, with arm-span greater than height by 5 cm or more. Secondary sexual characteristics are often absent. Women have little or no breast development, and men have little or no facial hair. In both genders, pubic hair may be present, as adrenarche may not be affected. Gynecomastia is not a typical feature. Gonadotropin-releasing hormone (GnRH) deficiency results in decreased testosterone as well as estrogen production.

Many affected individuals are unaware of their loss of olfaction, especially those with partial defects. Testing with graded dilutions of pure scents is often necessary to identify the impaired olfaction. The magnitude of GnRH deficiency appears to correlate to the severity of anosmia. In cases where KS or IHH is suspected but cryptorchidism and microphallus are absent, an MRI may reveal olfactory bulbs, although normal olfactory bulbs have been demonstrated in only 25% of males with KS.

Along with the anosmia, another interesting neurological finding is that of mirror movements related to cerebellar defects. Present in as many as 85% of patients with KS, mirroring is the involuntary movements in a limb that mirror the voluntary movements of the contralateral limb.

Many associated defects have been reported in patients with KS. These can be defined as sporadic and include uterine malformation, congenital heart defects, and dental agenesis. X-linked KS can be associated with another X-linked disorder known as ichthyosis (steroid sulfatase disorder). The finding of renal agenesis/hypoplasia has been noted in some individuals with X-linked KS. Colquhoun-Kerr et al (1999) described an Australian family with a high frequency of renal agenesis in the presence or absence of the KAL1 mutation, suggesting an autosomal dominant or X-linked gene, which may independently or codependently contribute to renal agenesis. [40]

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