Longitudinal Study of Reproductive Hormones in Prader-Willi Syndrome (PWS) from Early Infancy through the Fourth Decade

Background: We previously showed in cross-sectional studies of PWS men (1) and women (2) that the etiology of hypogonadism is heterogeneous, with primary testicular failure common in PWS men and variable combinations of ovarian dysfunction and gonadotropin deficiency in women. Longitudinal studies confirmed these findings in children and adolescents, but few longitudinal data were reported for adults older than age 20 years (3,4).Objectives: Aims of this prospective study were to determine the age at which the type of hypogonadism (hypothalamic or primary gonadal defect) becomes established and if hormonal patterns are consistent throughout adulthood in individual patients. Methods: We assayed 149 blood samples (2-5 per pt) in 49 males (ages 2m-36y) and 190 samples (2-6 per pt) in 57 women (ages 1m-37y) with PWS (61 deletions, 43 UPD, 2 IC defect). Duration of follow-up was 4.0±1.6 (1-6)y. None received androgens or sex hormone replacement during the study period. Samples were assayed for LH, FSH, DHEAS, inhibin B, AMH, testosterone (in men) and estradiol (in women) using assay techniques and reference values as previously described (1,2). Results: In males, LH levels began to rise at age 12-13y and were normal to high in men ages 20-35y. FSH began to rise at 8 years. After age 20y, FSH was markedly high in 6 men (34.4±11.5mIU/ml), but was normal in 4 (3.5±1.6 mIU/ml). Nine boys ages 10-15y had normal testosterone levels for age (2.2±2.7 nmol/l), however all 14 men above age 20y had low levels (5.7±3.4 nmol/l). AMH levels showed the expected normal decrease with age, even though testosterone was low in all adult males. Inhibin B was normal (241±105 pg/ml) in infant males (<1 year), fell to low levels by 2y and remained low to undetectable in most adolescents and adults (65±58 pg/ml). In females, LH was variable during childhood, low in 7 women >20y (0.21±0.18 mIU/ml) and normal in 6 (3.77±1.67 mIU/ml). In women ages 20 – 37y, FSH was low only in 3 (0.71±0.60 mIU/ml) and normal in 10 (6.42±3.78 mIU/ml). Only 7 adult women had estradiol levels (157±133 pmol/l) consistently above the lower limit of detection. AMH was below the normal median in most PWS females, although high levels (3.67±2.66 ng/ml) were measured in 7 girls below age 12y. Inhibin B (19.6±16.8 pg/ml) was low or undetectable in all PWS females. An early and exaggerated rise in DHEAS was seen in some children as early as age 5y, but levels were in the normal ranges for all men and most women. Conclusions: The type of hypogonadism (hypothalamic vs primary gonadal dysfunction) becomes apparent in late adolescence and early adulthood in PWS men and women. Hormonal profiles are consistent and stable in PWS men and women >20y. Primary gonadal dysfunction is a major component of hypogonadism in PWS. Recognition of age-related changes in reproductive hormones is important for tailoring individualized recommendations for hormone replacement and counseling.

(1) Hirsch HJ et al., J Clin Endocrinol Metab 2009; 94:2262. (2) Eldar-Geva et al., Eur J Endocrinol 2010; 162:377. (3) Siemensma EP et al., J Clin Endocrinol Metab 2012; 97:E452. (4) Siemensma EP et al., J Clin Endocrinol Metab 2012; 97:1766