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The Role of Prior Pubertal Development, Biochemical Markers of Testicular Maturation, and Genetics in Elucidating the Phenotypic Heterogeneity of Idiopathic Hypogonadotropic Hypogonadism

Reproductive Endocrine Unit, Department of Medicine, National Center for Infertility Research, Pediatric Surgical Research Laboratory, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Nelly Pitteloud, M.D., Reproductive Endocrine Unit and National Center for Infertility Research, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: npitteloud{at}partners.org

As our knowledge of the molecular mechanisms underlying idiopathic hypogonadotropic hypogonadism (IHH) expands, it becomes increasingly important to define the phenotypic spectrum of IHH. In this study we examined historical, clinical, biochemical, histological, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. We hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context.

Thirty-eight percent of the population had Kallmann syndrome (KS; IHH with anosmia), 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, KS represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty).

Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Comparing IHH patients according to the absence (68%) or presence (24%) of some prior pubertal development revealed significant differences in testicular size (3.3 ± 0.2 vs. 11.8 ± 1.2 ml; P < 0.001), incidence of cryptorchidism (40% vs. 5%; P < 0.05), microphallus (21% vs. 0%; P < 0.05), inhibin B levels (45 ± 4 vs. 144 ± 20 pg/ml; P < 0.0001), and Mullerian inhibitory substance levels (9.8 ± 1.4 vs. 2 ± 0.5 ng/ml). Most familial cases had no pubertal development (95% vs. 5%; P < 0.001); males with mutations in the KAL gene displayed the most severe phenotype.

Mean gonadotropins levels (LH, 1.8 ± 0.1 vs. 2.9 ± 0.4 IU/liter; FSH, 2.2 ± 0.2 vs. 3.3 ± 0.3 IU/liter; P < 0.05) and the finding of apulsatile LH secretion based on frequent sampling (80% vs. 55%; P < 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive.

The use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism, and microphallus), biochemical markers of testicular growth and differentiation (inhibin B and Mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. Viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability.

This work was supported by Grants R01-HD-15788, and M01-RR-01066 and by the NICHHD/NIH through Cooperative Agreements U54-HD-28138 and U54-DK-07028-24 as part of the Specialized Cooperative Centers Program in Reproduction Research.

Abbreviations: AHH, Acquired idiopathic hypogonadotropic hypogonadism after completion of puberty; BMI, body mass index; CV, coefficient of variation; HPG, hypothalamic-pituitary-gonadal; I_B, inhibin B; IHH, idiopathic hypogonadotropic hypogonadism; 2nd IRP, Second International Reference Preparation; KS, Kallmann syndrome; MIS, Mullerian inhibitory substance; nIHH, normosmic idiopathic hypogonadotropic hypogonadism; TV, testicular volume; X-KS, X-linked form of Kallmann syndrome.

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