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Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)

Authors
Nelly Pitteloud, MD
William F Crowley, Jr, MD
Ravikumar Balasubramanian, MBBS, PhD, MRCP(UK)
Section Editors
Peter J Snyder, MD
Alvin M Matsumoto, MD
Deputy Editor
Kathryn A Martin, MD

INTRODUCTION

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD), also referred to as idiopathic hypogonadotropic hypogonadism (IHH), is a family of genetic disorders that are associated with defects in the production and/or action of hypothalamic peptide that controls human reproduction, GnRH. IHH can occur either with normal olfaction (normosmic IHH) or with anosmia. This latter clinical presentation of IHH with anosmia is referred to as Kallmann syndrome (KS) [1]. The pathogenesis, genetics, clinical presentation, and management of isolated GnRH deficiency (IGD or IHH) will be discussed here [2,3]. Other causes of hypogonadotropic hypogonadism (HH) are reviewed separately. (See "Causes of secondary hypogonadism in males" and "Evaluation and management of secondary amenorrhea".)

TERMINOLOGY

Patients with IHH often have clinical features that are present at birth (cryptorchidism, microphallus, and/or biochemical evidence of low gonadotropins and sex steroids during the three to six months of the neonatal period referred to as "mini-puberty"). Some experts consider this to be a congenital disorder and refer to it in the literature as "congenital hypogonadotropic hypogonadism." However, more often, these neonatal features are absent and the age of onset or its precise etiology cannot be determined, and thus, the term "idiopathic" is used. Regardless of the terminology, this disorder is characterized by hypogonadotropic hypogonadism (HH).

IHH is differentiated from primary gonadal failure (ie, primary hypogonadism) by the demonstration of inappropriately low/normal serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the setting of prepubertal levels of gonadal steroids (while high levels of LH and FSH are seen with primary gonadal failure). The diagnosis of IHH is thus a presumptive nomenclature and can only be confirmed by normal radiologic studies of the hypothalamic-pituitary region and the absence of any of the other diagnostic testing indicating another etiology. Hence, testing of other anterior pituitary endocrine function should always be undertaken to assure that the defect is isolated, affecting only the hypothalamic gonadotropin-releasing hormone (GnRH)-pituitary-gonadal axis. In addition, hemochromatosis should be ruled out biochemically using iron levels.

The major diagnostic problem is distinguishing this disorder from constitutional delay of puberty or functional hypogonadotropic hypogonadism (FHH) prior to age 18 years.

PATHOGENESIS

The lack of endogenous hypothalamic gonadotropin-releasing hormone (GnRH) secretion/action in patients with IHH cannot be proven by direct assay of GnRH in the portal circulation but can be reasonably inferred by two findings:

                       

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Literature review current through: Jul 2017. | This topic last updated: Jun 30, 2017.
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