Hypogonadism in females with Prader–Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction

Abstract

Objective: The variable hypogonadism in Prader-Willi syndrome (PWS) has generally been attributed to hypothalamic dysfunction. Recent studies have documented primary testicular dysfunction in PWS males. Our aims were to characterize sexual development and reproductive hormones in PWS females and to investigate the etiology of hypogonadism. Design: A cross-sectional study. Methods: Physical examination was performed on 45 PWS females (aged 6 weeks to 32 years) and blood samples were obtained for hormonal analyses. Results: Age of onset and progression of puberty varied; most adults had incomplete sexual development. Spontaneous menarche was reported in four (aged 15-30 years) but all had subsequently developed secondary amenorrhea or oligomennorrhea. Anti-Mullerian hormone levels were within the normal range in all age groups. Inhibin B was consistently low or undetectable; only five women had levels in the low-normal range (20-54 pg/ml). LH was normal in most children, but low (!1.0 IU/l) in 9 of 15 adults. FSH was within the normal range for age in most children, but low (!0.5 IU/l) in 10 and high in four adults. Estradiol levels were normal-low and androgen levels were normal in the majority. Conclusions: Pubertal development in PWS females, as in males, is characterized by normal adrenarche, pubertal arrest, and hypogonadism due to variable combinations of a unique primary gonadal defect and hypothalamic dysfunction.

Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility

“…Consequently, plasma levels of estradiol were reduced by 35% in mir-7a2 KO female mice ( Figure 2F). Furthermore, as in male mice, gonadal fat pad weights were increased and dual energy x-ray absorptiometry (DEXA) measurements of fat and lean body mass revealed increased fat and decreased lean mass in 16-week-old mir-7a2 KO mice compared with WT littermate mice (Supplemental Figure 1, K-M), consistent with the hypogonadal-induced obesity observed in mice and humans (30,31). Together, these data illustrate that loss of mir-7a2, but not mir-7a1 or mir-7b, is sufficient to induce hypogonadism and infertility in mice.…”

Prader-Willi syndrome

“…Although the hypogonadism in PWS has long been believed to be entirely hypothalamic, resulting in low gonadotropins and subsequent low gonadal hormones, recent studies have suggested that there is a combination of hypothalamic and primary gonadal deficiencies. [30][31][32] That conclusion was largely based on absence of hypogonadotropism and abnormally low inhibin B in both sexes. In a recent study, all 20 individuals with PWS who were evaluated had brain abnormalities that were not found in 21 sibs or 16 individuals with early-onset morbid obesity who did not have PWS.…”

Characterization of Minipuberty in Infants with Prader-Willi Syndrome

“…and a blood sample was taken for hormone assays. We previously reported hormonal data on 3 of the male infants and 1 of the female infants [11,17]. Written informed consent was obtained from the parents.…”

“…Until recently, the etiology of hypogonadism in PWS was attributed to hypothalamic dysfunction resulting in decreased secretion of gonadotropins from the pituitary [6,7]. However, we and others found that a primary defect in gonadal function is the major contributor to hypogonadism, especially in PWS adult men [8,9,10,11,12,13,14,15]. …”

“…There are no published studies of minipuberty in PWS infant girls. Although reproductive hormone levels have been described in cross-sectional and longitudinal studies of older PWS children and adults [10,11,12,13,14], full reproductive hormone profiles, including inhibin B, AMH, and sex hormone-binding globulin (SHBG), in a larger cohort of young PWS infants have not been reported.…”