ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2021 Aug 18;106(9):e3495-e3505. doi: 10.1210/clinem/dgab357. PMID: 34010394https://academic.oup.com/jcem/article-abstract/106/9/e3495/6278376

Brief Summary: This prospective interventional study evaluates the stimulation of inhibin B by exogenous FSH as a promising predictor of spontaneous puberty onset.

The diagnostic approach to delayed puberty (DP) is still difficult and differential diagnosis between self-limited DP and Isolated Hypogonadotropic Hypogonadism (IHH) remains a major challenge. Recently, inhibin B levels seemed promising, but diagnostic thresholds are variable and overlapping [3]–[6]. The main stimulus to inhibin B is FSH, but inhibin B stimulation as a diagnostic tool had not been studied so far [7]. This study evaluate inhibin B stimulation by exogenous FSH as a predictor for puberty onset.

Two cohorts were studied: an exploratory cohort of healthy pubertal subjects (Group 1- 18 M/8 F) or IHH patients (Group 2 - 8 M/8 F), and a validation cohort of 19 subjects (11 M/8 F) followed for DP. To confirm the diagnosis, the validation group had been followed up until age 18 years. All subjects underwent an FSH stimulation test and a triptorelin stimulation test. In the exploratory cohort, Group 1 showed higher levels of basal inhibin B (219 pg/ml M - 100.35 pg/ml F) than Group 2 (29.32 pg/ml M vs 36.38 pg/ml F). This was confirmed and amplified for stimulated-inhibin B (FSH-ib) (408 pg/ml in Group 1 M vs 45.96 pg/ml in Group 2 M; 1165.75 pg/ml in Group 1 F vs 45.16 pg/ml in Group 2 F). A cut-off value of FSH-ib of 116.14 pg/mL in M and 116.50 pg/mL in F showed 100% sensitivity and specificity to identify puberty onset. FSHib was superior to baseline and stimulated LH levels (54.5%-87.5% diagnostic accuracy) and baseline inhibin B (81.8% - 87.5% diagnostic accuracy).

This study, although conducted in a limited sample size, reveals that inhibin B can be stimulated by exogenous FSH only in subjects with a functioning hypothalamic-pituitary-gonadal axis, making this a promising tool for diagnostic purposes. This test, compared to combined GnRH-analogue- and hCG or kisspeptin stimulation tests [8][9], requires fewer injections, shorter duration and no hospitalization.

References: 1. Lee PA. (1980) “Normal ages of pubertal events among American males and females.,” J Adolesc Health Care; 1(1): 26–9. 2. Sedlmeyer IL, Palmert MR. (2002) “Delayed puberty: analysis of a large case series from an academic center.,” J Clin Endocrinol Metab; 87(4): 1613–20. 3. Rohayem J, Nieschlag E, Kliesch S, Zitzmann M. 2015 “Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism,” Androl; 3(5):882–7. 4. Coutant R, Biette-Demeneix E, Bouvattier C, Bouhours-Nouet N, Gatelais F, Dufresne S, Rouleau S, Lahlou N. (2010) “Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty.” J Clin Endocrinol Metab; 95(12):5225–32. 5. Binder G, Schweizer R, Blumenstock G, Braun R. (2015) “Inhibin B plus LH vs GnRH agonist test for distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism in boys,” Clin Endocrinol; 82(1):100–5. 6. Adan L, Lechevalier P, Couto-Silva AC, Boissan M, Trivin C, Brailly-Tabard S, Brauner R. (2010) “Plasma inhibin B and antimüllerian hormone concentrations in boys: discriminating between congenital hypogonadotropic hypogonadism and constitutional pubertal delay.” Med Sci Monit; 16(11):CR511–7. 7. Anderson RA, Sharpe RM (2000) “Regulation of inhibin production in the human male and its clinical applications,” Int J Androl; 23(3):136–44. 8. Chan YM, Lippincott MF, Sales Barroso P, Alleyn C, Brodsky J, Granados H, Roberts SA, Sandler C, Srivatsa A, Seminara SB. (2020) “Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay.” J Clin Endocrinol Metab; 105(8):e2717–25. 9. Segal TY, Mehta A, Anazodo A, Hindmarsh PC, Dattani MT. (2009) “Role of Gonadotropin-Releasing hormone and human chorionic gonadotropin stimulation tests in differentiating patients with hypogonadotropic hypogonadism from those with constitutional delay of growth and puberty,” J Clin Endocrinol Metab; 94(3):780–5.