medwireNews: An international study of men with congenital hypogonadotropic hypogonadism (CHH) has revealed two distinct classes of spontaneous reversal of the condition, as well as several individual phenotypic and genetic predictors.
The findings “could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder,” write Andrew Dwyer (Boston College, Massachusetts, USA) and co-authors in The Lancet Diabetes & Endocrinology.
They explain that around 10–15% of men with CHH undergo spontaneous reversal but the process is poorly understood.
To address this, the researchers studied data for 195 men from six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. CHH was defined as absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic–pituitary–gonadal (HPG) axis dysfunction.
The cohort included 87 men with CHH reversal, defined as spontaneous recovery of HPG axis function when exogenous hormone treatment was stopped.
Using statistical modelling, Dwyer and colleagues identified two distinct reversal classes based on mean testicular volume, the presence of cryptorchidism or micropenis, and serum follicle-stimulating hormone (FSH) concentration.
Most patients (86%) had class 1 characteristics, which were suggestive of a more severe gonadotrophin-releasing hormone (GnRH) deficiency. These included the presence of cryptorchidism (15% vs 0% of class 2), micropenis (27 vs 0%), significantly smaller mean testicular volume (4.0 vs 13.8 cm3), and significantly lower mean FSH concentration (1.8 vs 2.7 IU/mL).
The characteristics of participants in class 2 (larger testicular volume, no micropenis, and higher FSH concentration) were consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH, the researchers note.
Dwyer et al found that individuals with CHH reversal were significantly less likely than the 108 men who did not to have Kallmann syndrome (35 vs 65%), cryptorchidism (13 vs 32%), complete absence of puberty (testicular volume <4 cm³; 49 vs 67%), and two or more rare genetic variants (29 vs 59%).
In a subset of patients who underwent genetic testing, rare pathogenic ANOS1 variants associated with Kallmann syndrome were detected in none of the 75 individuals with CHH reversal but were present in 11% of the 95 patients without CHH reversal.
This suggests that genetic testing “could inform management,” the investigators remark. They add: “If a patient is found to have an ANOS1 variant, they would have an extremely low likelihood of reversal, and therefore clinical management should focus on maintaining adherence to lifelong hormone therapy.”
Conversely, the researchers found that the identification of rare variants in GNRHR was more common among the participants with versus without reversal (12 vs 3%).
“As such, our findings identify the first use of genetic testing to tailor disease management strategies for male patients with CHH,” Dwyer et al remark.
They continue: “In settings where genetic testing is not feasible, family history and detailed clinical examination can provide clues suggestive of variants in ANOS1 (ie, X-linked inheritance pattern) and GNRHR (ie, Pasqualini syndrome subtype).
“A phenotype-first approach with careful history (ie, cryptorchidism or micropenis as signs of absent minipuberty) and clinical phenotyping (ie, testicular volume), followed by genetic testing (where available), can effectively target male patients with CHH for surveillance of reversal.”
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Lancet Diabetes Endocrinol 2024; doi:10.1016/S2213-8587(24)00028-7