Gonadotropin-Releasing Hormone Deficiency in Adults Differential Diagnoses

Updated: Jan 09, 2017
  • Author: Vaishali Popat, MD, MPH; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Diagnostic Considerations

Differentiating between gonadotropin-releasing hormone (GnRH) deficiency and delayed puberty is difficult. A definitive diagnosis of GnRH deficiency is not made before age 18 years in most cases. Constitutional delay of puberty is more common compared with GnRH deficiency. Various clinical clues and follow up over a period of time helps clarify the diagnosis.

A detailed family history is helpful. GnRH, anosmia, or presence of associated congenital abnormalities in the family is suggestive of GnRH deficiency. On the other hand, a family history of delayed puberty, late development of breast or testes, or stalled puberty are suggestive of constitutional delay of puberty. However, some families of patients with idiopathic hypogonadotropic hypogonadism (IHH) report a history of delayed puberty within the family. In a series of 106 patients with isolated GnRH deficiency, 12% reported family members with a history of delayed puberty without any physical features of IHH. Certainly, the finding of delayed puberty and isolated GnRH deficiency within the same family may represent 2 ends of a phenotypic spectrum of GnRH deficiency. [11] The incidence of delayed puberty in the general population is less than 1%.

Pubic hair may be present in GnRH deficiency because adrenarche occurs normally, but in delayed puberty, both, adrenarche and sexual development are attenuated.

Other CNS clinical syndromes associated with hypogonadism may result in diagnostic confusion. A brief review of the clinical manifestations of these disorders is as follows:

Laurence-Moon-Biedl (LMB) syndrome is characterized by obesity, mental retardation, renal abnormalities, polydactyly, pigmented retinal dystrophy, and spastic paraparesis. The Bardet-Biedl form is the same as LMB, but these individuals do not have the spastic paraparesis.

Prader-Willi syndrome (PWS) includes neonatal hypotonia, obesity, mental retardation, and short stature. The extent of sexual maturation in PWS is variable.

Moebius syndrome is characterized by congenital oculofacial paralysis, eye movement disorders, gait disorders, and mental retardation.

Lowe syndrome is composed of oculocerebral-renal disorders, the inheritance of which is X-linked.

LEOPARD syndrome is an acronym for lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retarded growth, and deafness.

Carpenter syndrome is associated with obesity, acrocephaly, agenesis of the hands and feet, and craniosynostosis. Besides the obvious differences in clinical manifestation, the serum levels of steroids and gonadotropins can exclude these syndromes from Kallmann syndrome (KS).

CHARGE syndrome is an arrhinencephalic disease characterized by one of more of the following: coloboma of the eye, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, external ear anomalies and deafness. Patients with CHARGE syndrome may also have anosmia due to olfactory bulb hypoplasia or aplasia and hypogonadotropic hypogonadism, making this syndrome clinically similar to KS. This may lead to diagnostic confusion, particularly when few of the classic features of CHARGE syndrome are present.

Further complicating the distinction between KS and CHARGE syndrome, the mutations that define most cases of CHARGE syndrome, mutations in the CHD7 gene, have also been identified in patients with KS. [40] Further, in both syndromes, hypogonadism results from defective migration of GnRH neurons. [41] Thus, patients with hypogonadotropic hypogonadism and anosmia should also be screened for clinical features of CHARGE syndrome and for the CHD7 mutation if any CHARGE syndrome features are present.

Adult-onset IHH has been reported in men. Normal puberty is followed by a decline in libido and fertility. Testicular size is nearly normal. The biochemical profile includes pulsatile luteinizing hormone (LH) secretion but low serum testosterone and, in 90% of cases, normal restoration of the reproductive axis with exogenous GnRH administration.

Unlike hypothalamic amenorrhea in women, neither an identifiable factor such as stress, exercise or weight loss that would impair GnRH secretion, nor any spontaneous waxing or waning of LH pulsatility, has been observed in men with adult-onset IHH. The "fertile eunuch syndrome" was described in 1950 as a clinical entity of eunuchoid body type and normal secondary sexual characteristics, including developed testes containing sperm, but often with oligoasthenozoospermia and thus reduced fertility.

This syndrome is considered to be a mild phenotypic variant of IHH. Men with the fertile eunuch syndrome possess the pubertal sleep-augmented GnRH–induced LH pattern; however, as adults they require treatment with testosterone or human chorionic gonadotropin (hCG) therapy to achieve fertility. Based on their response to exogenous GnRH, the abnormality was identified as hypothalamic in origin and was later specifically identified as an isolated LH deficiency due to disturbed hypothalamic GnRH secretion. This syndrome is thought to represent an incomplete form of GnRH deficiency, although the pathophysiology has still not been fully elucidated. Additional candidate mechanisms include mutations in the beta subunit of LH, [42] altered function of Leydig cells, [43] and mutations in gonadotroph GnRH receptors. [44, 45]

Differential Diagnoses