Towards an individualized management of pubertal induction in girls with hypogonadism: insight into the best replacement outcomes from a large multicentre registry.

OBJECTIVE: An evidence-based pubertal induction scheme in hypogonadal girls is still to be established. Interestingly, literature data report a suboptimal uterine longitudinal diameter (ULD) in >50% of treated hypogonadal women, negatively influencing their pregnancy outcomes. This study aims to investigate auxological and uterine outcomes of pubertal induction in girls in the light of underlying diagnosis and therapeutic schemes used. DESIGN: Retrospective analysis of longitudinal data from a multicentric registry. METHODS: Auxological, biochemical, and radiological data were collected at baseline and during follow-up in 95 hypogonadal girls (chronological age > 10.9 years, Tanner stage ≤ 2) treated with transdermal 17ß-oestradiol patches for at least 1 year. Induction was started at a median dose of 0.14 mcg/kg/day with a 6-monthly increase and was considered completed for 49/95 patients who started progesterone with a concomitant oestrogen adult dose. RESULTS: At the end of induction, the achievement of the complete breast maturation was associated with a 17ß-oestradiol dose at progesterone introduction. ULD showed a significant correlation with a 17ß-oestradiol dosage. Final ULD was >65 mm in only 17/45 girls. At multiple regression analysis, pelvic irradiation represented the major determinant of reduced final ULD. After correction for uterine irradiation, ULD was associated with the 17ß-oestradiol dose at progesterone introduction. Final ULD was not significantly different from the one assessed after progesterone introduction. CONCLUSIONS: Our results provide evidence that progestins, hampering further changes in uterine volume and breast development, should be introduced only in the presence of a concomitant adequate 17ß-oestradiol dose and an appropriate clinical response.

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

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.