Hypogonadism in Prader–Willi syndrome from birth to adulthood: a 28-year experience in a single centre

Abstract

Background: Hypogonadism is a key feature of Prader-Willi syndrome (PWS) but clear strategies for hormone replacement are lacking. Objective: To evaluate gonadal status and outcome in patients attending a Scottish PWS clinic from 1991-2019. Methods: In 93 (35F:56M) patients, median follow-up 11.2 years, gonadal and pubertal status were assessed clinically. Pelvic ultrasound findings and basal/stimulated gonadotrophins were compared with age-matched controls. Results: Females: Of 22 patients aged >11, 9 had reached B4-5, while 5 were still at B2-3, and 6 remained prepubertal. Eight patients experienced menarche aged 9.8-21.4 years, none with a normal cycle. Uterine length and ovarian volumes were normal but uterine configuration remained immature, with low follicular counts. Gonadotrophins were unremarkable, serum estradiol 129 (70 – 520) pmol/L. Only 5 patients received oestrogen replacement. Males: Fifty-four (96%) patients were cryptorchid (9 unilateral). Weekly hCG injections resulted in unilateral/bilateral descent in 2/1 of 25 patients. Of 37 boys aged >11, 14 (9 with failed/untreated bilateral cryptorchidism) failed to progress beyond G1, 15 arrested at G2-3 (testes 3-10 ml), and 8 reached G4-5. Gonadotrophins were unremarkable except in boys at G2-5 in whom FSH was elevated: 12.3/27.3 vs 3.25/6.26 U/L in controls (p<0.001). In males aged >13, testosterone was 3.1 (0.5-8.4) nmol/L. Androgen therapy, given from 13.5-29.2 years, was stopped in 4/24 patients owing to behavioural problems. Conclusion: Despite invariable hypogonadism, few females and only half the males with PWS in this study received hormone replacement. Double-blind placebo-controlled crossover trials of sex steroids are required to address unproven behavioural concerns.

Single‐center real‐life experience with testosterone treatment in adult men with Prader–Willi syndrome

“…Increasing behavioral disturbance was noted in one of eight individuals following testosterone treatment. Similarly, 4 of 24 individuals ceased testosterone treatment due to increasing behavioral disturbance in a recent analysis in people with PWS (Kherra et al, 2021), whereas another analysis reported behavioral disturbance in one-third of individuals (Pellikaan et al, 2021). Few behavioral problems were attributed to testosterone treatment in a questionnaire of practitioners experienced in care of individuals with PWS (Eiholzer et al, 2021), and are not commonly reported in the literature following initiation of testosterone treatment (Noordam et al, 2021).…”

Prader–Willi Syndrome and Weight Gain Control: From Prevention to Surgery—A Narrative Review

“…PWS males have a normal mini-puberty during infancy with normally elevated luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels within the first few months of life [ 25 , 31 , 32 , 33 ]. After this mini-puberty, gonadotropins and testosterone decrease to pre-pubertal levels.…”

“…After this mini-puberty, gonadotropins and testosterone decrease to pre-pubertal levels. Typically, males develop a delayed or incomplete puberty and consequently commonly become infertile in adulthood [ 25 , 31 , 32 , 33 ]. Cryptorchidism (either unilateral or bilateral) is almost universal in PWS males, ranging from 66% to 100% of newborns with PWS, and it requires orchiopexy to reposition the testicles in their correct anatomical location.…”

“…Cryptorchidism (either unilateral or bilateral) is almost universal in PWS males, ranging from 66% to 100% of newborns with PWS, and it requires orchiopexy to reposition the testicles in their correct anatomical location. However, many studies have demonstrated that an early treatment with human chorionic gonadotropin (hCG) may promote spontaneous testicular descent and also increase penile length and scrotal size [ 25 , 31 , 32 , 33 ]. In clinical practice, testosterone injections started at 15–16 ages at lower doses until doses were tolerated well and under close supervision of an endocrinologist [ 25 , 31 , 32 , 33 , 34 , 35 ].…”

“…However, many studies have demonstrated that an early treatment with human chorionic gonadotropin (hCG) may promote spontaneous testicular descent and also increase penile length and scrotal size [ 25 , 31 , 32 , 33 ]. In clinical practice, testosterone injections started at 15–16 ages at lower doses until doses were tolerated well and under close supervision of an endocrinologist [ 25 , 31 , 32 , 33 , 34 , 35 ]. Other formulations of testosterone exist which are more expensive and require a daily administration.…”