Genetic and phenotypic differences between sexes in congenital hypogonadotropic hypogonadism (CHH): Large cohort analysis from a single tertiary centre

Abstract

Background: Congenital hypogonadotropic hypogonadism (CHH) is a condition with a strong genetic background, caused by a deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Published data on CHH cohorts indicate a male predominance, although this is not supported by our current understandings.

Aims: In order to unravel the possible causes or contributors to such epidemiological sex difference, the aim of our study is to investigate differences in genetic background and clinical presentation between males and females in a large cohort of CHH patients.

Materials and methods: We enrolled 338 CHH patients with absent or arrested pubertal development, referred to our Center from 01/2016. Data collection included clinical assessment at diagnosis and genetic analysis performed by next generation sequencing (NGS), employing a custom panel of 28 candidate genes.

Results: Among 338 patients 94 were female (F) and 244 male (M), with a ratio of 1:2.6. We found that 36.09% (122/338) of patients harbored potentially pathogenic rare genetic variants (RVs) with no significant differences between sexes; on the other hand, a significantly higher frequency of oligogenicity was observed in females (F 9,57% 9/94 vs M 3,69% 9/244, P = 0.034). The prevalence of non-reproductive phenotypic features was significantly higher (P = 0.01) in males (53/228, 23.2%) than in females (10/93, 10.8%): in particular, kidney abnormalities affected only male patients and midline defects had a significantly higher prevalence in males (P = 0.010). Finally, BMI SDS was -0.04 ± 1.09 in females and 0.69 ± 1.51 in males, with a statistically significant difference between groups (P = <0.001).

Conclusion: Our data confirm the male predominance in CHH and identify some differences with regard to the clinical presentation between males and females that could indicate a variable expression of genetic rare variants and a dimorphic modulation of phenotype according to metabolic/behavioral factors, which will need to be substantiated and investigated by further studies.

Keywords: GnRH (gonadotropin releasing hormone); congenital hypogonadotropic hypogonadism (CHH); female; genetics; phenotype [mesh]; sex.

Figure 1

Biology and genetic background of the GnRH neuronal system. GnRH, gonadotropin-releasing hormone; LH, Luteinizing Hormone; FSH: Follicle-Stimulating Hormone; Glu, glutamate; GABA, gamma-amino-butyric acid; NPY, neuropeptide Y; POA, preoptic area; KISS, Kisspeptin; NKB, neurokinin B; Dyn, dynorphin; CRH, cortitropin releasing hormone; ARC, arcuate nucleus; INS, insulin.

Figure 2

Prevalence of rare genetic variants in female (A) and male (B) cohort of patients according to their genetic assortment. RVs, rare genetic variants. Comparison between male and female patients using Fisher’s exact test: *P = <0.05.

Figure 3

Prevalence of rare genetic variants in each candidate gene. RVs, rare genetic variants.

Figure 4

Prevalence of “red flags” and each “non-reproductive” defects in the study cohort Red flags: cryptorchidism, microphallus, deafness, kidney abnormalities, midline defects and bimanual synkinesis; Non-reproductive red flags: deafness, kidney abnormalities, midline defects and bimanual synkinesis. Comparison between male and female patients using Fisher’s exact test: **P = <0.01.

Figure 5

Prevalence of “non-reproductive” defects in the study cohort. Comparison between male and female patients using Fisher’s exact test: **P = <0.01.

Figure 6

Frequency distribution of BMI SDS in female (A) and male (B) patients. Comparison between male and female cohorts using t-test: **P = <0.01.

Figure 7

Distribution of female CHH patients for Breast Tanner Stages (A) and Pubic hair Tanner Stage (B).

Figure 8

Basal and stimulated values of gonadotropins according Breast Tanner Stage. Value of basal LH (A), difference between basal LH and LH peak (DLH) after stimulation test (B), LH peak after stimulation test (C), basal FSH (D), difference between basal FSH and FSH peak (DFSH) after stimulation test (E), FSH peak after stimulation test (F) compared according to Breast Tanner Stage. Pairwise comparison: *P = <0.05.