Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)
- Nelly Pitteloud, MD
Nelly Pitteloud, MD
- Professor in Medicine
- Lausanne University Switzerland
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
- Section Editors
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
- Alvin M Matsumoto, MD
Alvin M Matsumoto, MD
- Section Editor — Male Reproductive Endocrinology
- Professor of Medicine
- University of Washington School of Medicine
Isolated gonadotropin-releasing hormone (GnRH) deficiency (or idiopathic hypogonadotropic hypogonadism [IHH] with normal smell [normosmic IHH (nIHH)] or anosmia [Kallmann syndrome (KS)]) is associated with defects in the production or action of hypothalamic GnRH. The pathogenesis, genetics, clinical presentation, and management of isolated GnRH deficiency will be discussed here. Other causes of hypogonadotropic hypogonadism (HH) are reviewed separately. (See "Causes of secondary hypogonadism in males" and "Evaluation and management of secondary amenorrhea".)
Often this condition has evidence of being present from birth (eg, cryptorchidism and microphallus, or low gonadotropins and sex steroids during the "mini-puberty" of the neonatal period) and can therefore be viewed as congenital. However, more often, its age of onset cannot be determined and thus the term "idiopathic" is also used. By either terminology, this defect results in hypogonadotropic hypogonadism.
Idiopathic hypogonadotropic hypogonadism (IHH) is differentiated from primary gonadal failure by the demonstration of low serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the setting of castrate levels of gonadal steroids. The diagnosis is presumptive, however, and can only be confirmed by normal radiologic studies of the hypothalamic-pituitary region. Testing of other anterior pituitary endocrine function should also be undertaken to assure that the defect in gonadotropin secretion is isolated. The major diagnostic problem is distinguishing this disorder from constitutional delay of puberty prior to age 18 years.
The lack of endogenous GnRH secretion in patients with congenital GnRH deficiency cannot be proven by direct assay but can be reasonably inferred by two findings:
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- KAL1 gene
- PROK2 and PROKR2
- - KISS1
- TAC3 and TAC3R
- SOX10 (SRY-box 10 gene)
- Digenic and oligogenic mutations
- CLINICAL PRESENTATION
- Physical findings
- Differential diagnosis
- Hormone replacement
- - Girls and women
- - Boys and men
- - Ovulation induction in women
- - Induction of spermatogenesis in men
- PROGNOSIS AND OUTCOME
- Reversal of IHH
- SUMMARY AND RECOMMENDATIONS