Sexual dichotomy of gonadal function in Prader-Willi syndrome from early infancy through the fourth decade.
OBJECTIVE
At what age does the type of hypogonadism, namely hypothalamic or primary gonadal defect, become established in men and women with Prader-Willi syndrome (PWS)?


CONCLUSIONS
The type of hypogonadism becomes established only in late adolescence and early adulthood.


BACKGROUND
The etiology of hypogonadism in PWS is heterogeneous and the clinical expression is variable. Primary testicular failure is common in PWS men, while combinations of ovarian dysfunction and gonadotrophin deficiency are seen in women.


METHODS
This is a prospective study of a cohort of 106 PWS patients followed for a mean duration of 4.5 years. Serial blood samples were obtained and assayed for gonadotrophins, inhibin B, anti-Mullerian hormone (AMH), dehydroepiandrosterone sulfate (DHEAS), testosterone (males), and estradiol (females). Results were compared with normal reference values obtained from the literature. For the purpose of this study, we defined the following age groups: infants <1 year; children 1-10 years; adolescents 11-20 years and adults >20 years.


METHODS
Study participants were 49 males (aged 2 months to 36 years) and 57 females (aged 1 month to 37 years) with genetically confirmed diagnoses of PWS (deletions 60, uniparental disomy 54, imprinting center defect 2) followed in the Israel national multidisciplinary PWS clinic.


RESULTS
Serum LH levels were in the normal range (1.0-6.0 mIU/ml) for 7/10 adult men, and high in 3, while FSH (normal range 1.0-6.1 mIU/ml) was elevated (34.4 ± 11.5 mIU/ml) in 6 and normal (3.5 ± 1.6 mIU/ml) in 4 men. Testosterone was low (5.7 ± 3.4 nmol/l) compared with the normal range of 12.0-34.5 nmol/l in the reference population in all men >20 years. AMH showed a normal decrease with age, despite low testosterone levels. Inhibin B was normal (241 ± 105 pg/ml) in infant boys, but low or undetectable in most adult men. Hormonal profiles were more heterogeneous in women than in men. Estradiol was consistently detectable in only 7/13 adult women. Inhibin B was low or undetectable in all PWS females although occasional samples showed levels within the normal range of 15-95 pg/ml. Vaginal bleeding was reported to occur for the first time in eight women at a median age of 20 years (13-34 years), but only one had regular monthly menses. The type of hypogonadism (primary or secondary) in PWS can be determined only after age 20 years.


CONCLUSIONS
The study cohort was heterogeneous, showing variability in BMI, cognitive disability and medical treatment.


CONCLUSIONS
Demonstration of the natural history of reproductive hormone development in PWS suggests that androgen replacement may be indicated for most PWS boys in mid-adolescence. Recommendations for hormone replacement in PWS women need to be individually tailored, serial measurements of inhibin B should be performed, and contraception should be considered in those women who may have the potential for fertility.
Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem 91031, Israel Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem 91031, Israel hirschmd@gmail.com.
H J
HJ
Hirsch
Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem 91031, Israel Reproductive Endocrinology and Genetics Unit, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center and The Hebrew University School of Medicine, Jerusalem 91031, Israel.
T
T
Eldar-Geva
The Herman Dana Child and Adolescent Psychiatry Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91031, Israel.
F
F
Bennaroch
Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem 91031, Israel The School of Education, The Hebrew University, Jerusalem 91031, Israel.
Y
Y
Pollak
Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem 91031, Israel Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem 91031, Israel The Hebrew University School of Medicine, Jerusalem 91031, Israel.
V
V
Gross-Tsur
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007006:Hypogonadism / Q000097:blood* / Q000209:etiology; D007223:Infant; D008297:Male; D011218:Prader-Willi Syndrome / Q000097:blood* / Q000150:complications; D012737:Sex Factors; D055815:Young Adult
Prader–Willi syndrome; anti-Mullerian hormone; delayed puberty; gonadotrophins; hypergonadotrophic hypogonadism; hypogonadotrophic hypogonadism; inhibin B; primary ovarian insufficiency; primary testicular failure