medwireNews: Measuring levels of testosterone, inhibin B and anti-Müllerian hormone (AMH) at different time points over the first year of life may help diagnose congenital hypogonadotropic hypogonadism (CHH) in infant boys with minor abnormalities of the external genitalia, French researchers say.
“We have highlighted significant differences in circulating hormone levels of the HPG [hypothalamic–pituitary–gonadal] axis between subjects with CHH and those with idiopathic micropenis or cryptorchidism, even out of the period of mini-puberty”, report Regis Coutant (University Hospital, Angers) and co-workers.
“This could lead to early diagnosis, interventions, and counseling that may improve outcomes for these infants”, they write in The Journal of Clinical Endocrinology & Metabolism.
The team explains that absence of a testosterone increase during mini-puberty between 1 and 3 months of age is the “gold standard” for CHH diagnosis, but hormone evaluation is not always possible at this time, and genital abnormalities associated with CHH during mini-puberty also occur in around 5% of newborn boys. CHH diagnosis is therefore more common at the end of adolescence or early adulthood following incomplete pubertal virilisation, testis growth, and low levels of gondatropins and testosterone.
To investigate thresholds at which hormone levels may discriminate CHH in the first year of life, the researchers measured levels of inhibin B, AMH, testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) in 138 male infants attending French university hospitals with micropenis and/or cryptorchidism between 2000 and 2022.
Hormone levels were assessed between days 1 and 4 of life, during early mini-puberty between days 15 and 65, late mini-puberty between days 66 and 179 and after mini-puberty, on days 180–365.
The study involved 58 boys with isolated (i)CHH who were diagnosed at mini-puberty or a later date based on anosmia or lack of puberty, including 28 with a molecular diagnosis, and 32 boys with CHH as part of combined pituitary hormone deficiency (CPHD) who were diagnosed at mini-puberty, including 17 with an ectopic posterior pituitary and six with pituitary hypoplasia. Their hormone levels were compared with those of 48 controls who were diagnosed with isolated micropenis and/or cryptorchidism during mini-puberty.
Coutant et al report significant differences in the clinical and hormonal characteristics of boys with iCHH or CHH as part of CPHD compared with the controls during all the study periods, whereas the iCHH and CPHD infants were comparable, and analyses for these two patient populations were combined.
“We did not find any combination of HPG hormones significantly associated with a better prediction of CHH than the single hormone measurements”, comment Coutant and co-authors.
Between days 1 and 4, the best hormone for discriminating between CHH and controls was inhibin B. Using a cutoff of 150 pg/mL the measure was 100% sensitive and 75% specific for CHH diagnosis, while using a cutoff of 85 pg/mL the values were 89% and 100%, respectively.
During days 15–65, a testosterone level below 2.4 nmol/L was 100% sensitive and specific for identification of children with CHH, followed by LH at a cutoff of less than 1.20 IU/L (100% and 97%, respectively) or less than 0.85 IU/L (97% and 100%, respectively).
For days 66–179, the researchers report that testosterone was the most effective hormone for identifying CHH. Using a lower cutoff than during early mini-puberty of less than 1.1 nmol/L, testosterone was 100% sensitive and 91% specific, while the corresponding values at a cutoff of less than 0.72 nmol/L were 95% and 100%.
Finally, between days 180 and 365, inhibin B was the most effective measure for discriminating CHH, with 100% sensitivity and specificity at a cutoff of 100 pg/mL, followed by AMH at a threshold of less than 600 pmol/L, which had 100% sensitivity and 92% specificity.
“[S]ince mini-puberty is associated with the second wave of multiplication of Sertoli and germ cells, it has been proposed to treat male boys with CHH in the first months of life with recombinant gonadotropins to mimic mini-puberty, with the hope of favoring later fertility”, the team concludes.
“Our findings, namely the proposed hormone cutoffs for diagnosis of CHH before 1 year of age, if confirmed in a validation cohort, may help identify infants who could benefit from early treatment.”
By Lynda Williams
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