Follicle stimulating and leutinizing hormones, estradiol and testosterone in Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a classic genomic imprinting disorder in which affected individuals display hypotonia, failure to thrive, feeding difficulties, developmental delays and hypogenitalism/ hypogonadism in infancy.At approximately2–3years of age, hyperphagia, central obesity, short stature, small hands and feet, behavioral problems and characteristic facial features are present [Cassidy, 1984; Butler, 1990; Bittel and Butler, 2005; Butler et al., 2006]. The genetic causes are generally due to a paternal deletion of the chromosome 15q11–q13 region (about 70%), maternal disomy 15 (UPD) (about 25%), or imprinting defects or translocations involving chromosome 15 (about 5%) [Bittel and Butler, 2005]. The characteristic findings of hyperphagia, central obesity, short stature, cryptorchidism and hypogonadism are consistent with endocrine and/or metabolic abnormalities involving the hypothalamic–pituitary axis. While some studies have examined specific hormonal levels in Prader–Willi syndrome [Nagai et al., 1998; Burman et al., 2001; Eiholzer and Lee, 2006; Eiholzer et al., 2006; Butler et al., 2007], a comprehensive examination of follicle stimulating hormone (FSH), leutinizing hormone (LH), estradiol and testosterone levels is lacking in individuals with Prader–Willi syndrome with known genetic subtypes. Thus, we report FSH, LH, estradiol and testosterone levels in a relatively large cohort of males and females (16 years of age and older) with Prader–Willi syndrome as a function of genetic subtype and obesity status. The regulation of FSH and LH secretion and subsequent estradiol (female) and testosterone (male) secretion is highly integrated involving multiple signaling pathways, receptor systems and signaling molecules such as inhibin and ghrelin [Ojeda et al., 2006]. In females, FSH levels vary throughout the menstrual cycle peaking at mid-cycle while LH levels peak prior to ovulation. Both FSH and LH levels increase dramatically after menopause. Hypothalamic hypogonadism subjects are characterized by lowFSH, LHand sexhormone levelswhile normal or elevated FSH levels indicate a gonadal origin. Elevated LH levels are seen in females with ovarian failure while low levels are seen in pituitary failure. Inmales, there is a prominent neonatal surge of LH, FSH and testosterone that begins shortly after birth and peaks at 6–8 weeks of age before gradually waning over 4–6 months [Veldhuis et al., 2006]. This early rise in FSH and LH is not observed in females. At 10 years of age for females and at 11 years of age in males, adrenarche usually occurs as defined by the appearance of pubic and axillary hair and increased apocrine sweat gland activity. This event is triggered by increased adrenal productionof dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione but not cortisol [Veldhuis et al., 2006]. However, maturation of the testes and ovaries (gonadarche) requires the orderly activation of the hypothalamic–pituitary–gonadal axis. The initiation of this process remains poorly defined but involves increased pulsatile secretion of gonadotropin releasing hormone (GnRH) that subsequently controls FSH and LH secretion from the anterior pituitary [Veldhuis et al., 2006]. This orderly