Distinguishing Self-limited Delayed Puberty From Permanent Hypogonadotropic Hypogonadism: How and Why?

Pediatric endocrinologists frequently encounter youth with delayed puberty. After the history, physical examination, and initial lab tests are completed, hypergonadotropic hypogonadism and an underlying condition causing functional or acquired hypogonadotropic hypogonadism are often eliminated. The endocrinologist is then left with 2 possibilities: constitutional delay of growth and puberty (CDGP) and congenital hypogonadotropic hypogonadism (CHH) (1). These youth are more commonly male and, in some cases, a tentative diagnosis is supported by findings suggestive of an associated syndrome, a history of cryptorchidism, or testes volume ≤ 1 cc (1). However, such features do not make the diagnosis of CHH certain, nor does a family history of self-limited delayed puberty confirm the diagnosis of CDGP. The inability to distinguish CHH from CDGP can lead to anxiety among patients and caregivers, impede counselling, lead to (unnecessary) additional testing, and affect treatment decisions. We reviewed the available clinical tests in 2012 and concluded “current literature does not allow for recommendation of any diagnostic test for routine clinical use, making this an important area for future investigation” (2). One wonders: where is the field 9 years later? Over the ensuing years, 2 of the more promising tests have not been fully supported. The first was basal inhibin B, which had offered the potential of a simple first-line test to distinguish CHH from CDGP. The rationale was that inhibin B, whose secretion from sertoli and granulosa cells is stimulated by follicle-stimulating hormone (FSH), would be lower in those with lifelong CHH. Subsequent studies have verified that inhibin B levels are significantly lower in patients with CHH but have also reported a 5-fold variation in the threshold concentration of inhibin B needed to distinguish CHH from CDGP (3). The lowest inhibin B concentrations have high specificity for CHH, particularly among patients with high pretest probability based upon features such as cryptorchidism, low testicular volume, or syndromic characteristics. However, in youth without such clinical features, where clinicians are reliant on laboratory investigations to provide diagnostic clarity, basal inhibin B has lower sensitivity, potentially limiting its utility. Genetic testing was another promising discriminator. An ever-increasing number of genes have been identified to cause CHH, and some genetic causes of CDGP have also been identified. The genetic profiles of CDGP and CHH have some overlap but are largely distinct (4). However, for genetic testing to have greatest utility, even more causative genes need to be identified, as currently diagnostic variants are identified in only approximately 50% of cases of CHH. Yield can be increased by guiding testing based on presence of phenotypic features such as synkinesia or hearing loss, but doing so utilizes sequencing more as a confirmatory test instead of a discriminator for the cases where when no diagnostic clues are present. A newly proposed test is kisspeptin stimulated luteinizing hormone (LH) levels (5). Utilizing a stimulus upstream of gonadotropin-releasing hormone, the authors hypothesized that response to kisspeptin stimulation could identify youth with the innate ability to secrete gonadotropin-releasing hormone and subsequently LH (CDGP) from those without (CHH). In a study of 15 youth, a kisspeptin stimulated LH level of ≤0.4 mIU/mL identified youth with CHH with 100% sensitivity and specificity (5). These results are promising but need replication with diagnostic thresholds validated before advocating routine use. The test is also complicated, requiring access to intravenous kisspeptin and multiple blood draws over 4 h; perhaps future iterations can be simplified, decreasing a potential barrier to its routine use. Chaudhary et al now present the latest test, FSH-stimulated inhibin B concentrations (FSH-iB) (6). Recognizing the potential limitations of basal inhibin B, they hypothesized that low FSH -stimulated inhibin B would better identify youth with CHH. The authors analyzed a cohort of 42 individuals (adults with CHH and youth who underwent spontaneous puberty) to determine proposed diagnostic cutoffs and then examined the robustness of the cutoffs in 19 youth with delayed puberty. This 2-step approach is a strength of the study, and the authors report that a FSH-iB concentration of 116.14 pg/mL is able to distinguish youth with self-limited delayed puberty, who stimulated above this value, from those with CHH. Interestingly, the authors include cases of youth with multiple pituitary hormone deficiencies, in which a possible diagnosis of CHH is refuted by the FSH-iB level and subsequent endogenous puberty. The results also need replication with thresholds validated, but FSH-iB represents another promising diagnostic test. As with all diagnostic tests proposed so far, determining performance of this test in the most clinically challenging scenario is critical—the ability to separate the 12- to 13-year-old female or 13- to 14-year-old male with CDGP from those with CHH without clinical features suggestive of the underlying diagnosis. The FSH-iB test does have advantages over the proposed kisspeptin testing in that FSH is more readily available; however, it requires 3 injections over 3 to 5 days, which may hinder use. Concerns aside, these new developments raise the exciting possibility of distinguishing CDGP from CHH in the clinical setting. If so, obvious benefits would accrue, such as providing youth and caregivers a diagnosis, limiting additional testing, and making informed decisions about starting sex steroid supplementation and what regimen to use (1). While being careful not to medicalize variations in growth and development, it is increasingly appreciated that delayed puberty is associated with increased risk of negative psychosocial, educational, and medical impacts (7). If one knew that a youth had CHH, why not start supplementation at an earlier age that allows puberty to occur in concert with peers? Future considerations may also depend on the ability to distinguish CDGP from CHH. For example, were aromatase inhibitors to emerge as a preferred therapy for CDGP in males (8), one would need to identify and exclude those with CHH for whom the therapy would be inappropriate. Current studies do not demonstrate that initial testosterone therapy impairs future fertility in boys with CHH (1); however, if new studies were to demonstrate superiority of early gonadotropin treatment, one would need to identify youth with CHH to guide therapy. Thus, the ongoing quest to identify an inexpensive, easily administered, and generalizable diagnostic test for delayed puberty remains an important one. Disclosures: The authors have no conflicts of interest to disclose. Financial Support: None. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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