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4/28/2015Prader Willi Syndrome andHypogonadismKathryn Anglin, MSN, BSN, RNPediatric Endocrine Clinical Nurse SpecialistNationwide Children’s HospitalColumbus, Ohio . .No Conflict of Interest to Disclose . .Objectives Identify the clinical features of hypogonadism andincomplete / delayed puberty in a male with PraderWilli syndrome (PWS) Understand the role of hCG in evaluation andtreatment of hypogonadism in PWS Discuss expert recommendations for the treatment ofhypogonadism in males with PWS1

4/28/2015Introduction PWS is a multisystem genetic disorder (15q11.2-q13) Complex phenotype likely caused by hypothalamicdysfunction leading to hormonal dysfunction and theabsence of satiety Hypotonia and hypogonadism are the firstmanifestations of a primitive hypothalammicalteration, which many believe is the basis of PWSIntroduction Hypogonadism is a common clinical feature of PWSwhich confirms the importance of hypogonadism asa major diagnostic criterion of PWS Patients with PWS commonly fail to spontaneouslyinitiate or complete puberty However, many have premature adrenarche Precocious puberty is more rareCase Study Hypogonadisn in PWSCurrently 19 year old maleHistory: Diagnosed clinically at age 2 years, and at 6 yearsbased on methylation studies; Consistent withimprinting abnormality* Hypotonia and poor feeding in the newborn periodDevelopmental delay and hyperphagia in the earlychildhood years Seen at outside institution, on GH for 6 months, buttherapy stopped due to hyperglycemia Lost to follow up until age 14 years, when referred byPCP regarding micropenis and crypto-orchidism2

4/28/2015Case Study Hypogonadisn in PWSStatureRestarted GH at 18 years ofageCase Study Hypogonadisn in PWSWeightHospitalized at Pittsburgh for medicalweight loss program at 16 years ofageCase Study Hypogonadisn in PWSConcurrent Health Issues ObesitySleep apnea- on CPAP*A lot of daytime tiredness and fell asleep easilyHistory of strabismus (wears corrective lenses)History of behavioral problemsVitamin D insufficiency 21 ng/mL, improved to 29ng/mL after taking 2000 units daily from AprilNovember 2013 Normal Ca, Phos, Alk Phos Diabetes T23

4/28/2015Case Study Hypogonadisn in PWSInitial Evaluation in Endocrine Clinic Age 14 years; clinic visit after lost to follow up Acanthosis nigricans BMI: 41kg / m2 Tanner 2 PH, large suprapubic fat pad, stretchedpenile length difficult to measure but was 3.5 cm,testicles not palpable Plan to obtain gonadotropin and testosterone bloodwork, bone age, refer to urology and PWS clinicCase Study Hypogonadisn in PWSResultsPre-pubertal Testosterone, LH, FSHRanges FSH: Tanner1, 0.26 – 3 T: Tanner 1, 3 - 10 LH: Tanner 1, 0.02 - 0.3 Free T: Adult Males: 52 280 Free T %: Adult Males:1.5 - 3.2 SHBG: Pubertal Males:16 - 100Case Study Hypogonadisn in PWSResultsBone Age Reading Chronological age 14 years 1 monthBone age 16 years Previously on GH therapy at outside institution, wasstopped due to hyperglycemia4

4/28/2015Case Study Hypogonadisn in PWS 15 years Very prominent suprapubic fat pad which completelyengulfed his penis; circumcised but fairly small insize Scattered thin pubic hair Testicles were difficult to feel. Possibly palpatedright testicle higher up above the scrotum; could notpalpate left testicle Referred to UrologyCase Study Hypogonadisn in PWSScrotal UltrasoundTestes not identifiedCase Study Hypogonadisn in PWSUrology Plan“Because this is a much older child and he is morbidlyobese, I think that it may be helpful to obtain a scrotalultrasound to locate the testicles and assess their sizePerforming orchidopexy in this young man would beextremely difficult because of his age and size inaddition to the anesthetic risks because of his obesityThere is no guarantee that the testicles would functionproperly, even after surgeryDiscuss the situation with endocrinology”5

4/28/2015Case Study Hypogonadisn in PWS Plan to do hCG stimulation testing, monitor for risein testosterone indicating presence of testes, thenrepeat scrotal ultrasound with anticipatedenlargement of testes* Administer hCG, 1500 units/m2 (3000 units) twice perweek Draw total testosterone 3 days after every otherhCG injection For example, hCG Monday, hCG on Friday, then hCGinjection and testosterone level on Monday Continue for up to 6 weeks. Stop test if testosteronelevel reaches 300 ng / dlCase Study Hypogonadisn in PWSResultshCG Stimulation Test ResultsRise in testosterone, but overall below reference range100-500 ng / dLCase Study Hypogonadisn in PWSRepeat Scrotal UltrasoundTestes identified6

4/28/2015Case Study Hypogonadisn in PWSScrotal Ultrasound Report On US he had small, ovoid hypoechoic structures ininguinal canals bilaterally No vascularity on doppler Essentially, testes were present, but small andatropicCase Study Hypogonadisn in PWSCase ManagementLaparotomy Diagnostic laparotomy performed February 2013with potential for orchidopexy, age 17 years Orchiectomy was performed Pathology report showed infantile, atrophicchanges with no evidence of spermatogenesisCase Study Hypogonadisn in PWSCase ManagementTestosterone Dosing IM (Q month) Testosterone 50 mg started in April 2013 Increased to 100 mg in Novemeber 2013 Increased to 150 mg in June 2014 Increased to 200 mg in February 20157

4/28/2015Case Study Hypogonadisn in PWSCase ManagementResponse to Testosterone At testosterone dose of 100 mg monthly:Penis increased to 6 cm x 2 cmTanner stage 4 pubic hairAxillary hair present At testosterone dose of 150 mg monthly:Noted voice changeNoted increased assertivenessNo noted aggression or angerCase Study ConclusionHCGStimulationRefer to icular USSurgeryTesticular USUrology23Hypogonadism in Males with PWS Cryptorchidism in 80-100%Small testes 76%Scrotal hypoplasia 69%Incomplete, delayed, or disordered pubertaldevelopmentPremature adrenarche common 14%Premature puberty can occur 3%No reports of paternity from PWS menTestosterone levels often subnormal but lower SHBGcan raise free testosterone(Goldstone AP et al, 2008)8

4/28/2015Hypogonadism in Males with PWSPrevalence of genital abnormalities and pubertal findingsin PWS subjects(Crino et al, 2003)Hypogonadism in Males with PWSWhat about hCG?TREATNOT TO TREATØRole of Hcg in Treatment ofMales with PWSDiagnostic Management of CryptorchidismAmerican Urological Association : Guideline Statement 3 Refer infants with a history of cryptorchidism (detected atbirth) who do not have spontaneous testicular descent by sixmonths * Testes that remain undescended by six months are unlikelyto descend spontaneously The rationale for referral for orchidopexy by six months isthe low probability of spontaneous descent and theprobable continued damage to testes that remain in a non‐scrotal location.(American Urological Association, 2014)9

4/28/2015Role of hCG in Treatment ofMales with PWSTreatment Management of CryptorchidismAmerican Urological Association : Guideline Statement 10 Providers should not use hormonal therapy toinduce testicular descent as evidence shows lowresponse rates and lack of evidence for long-termefficacy Studies show a significant risk of recurrence. Anindividual study may show a reasonable effect ininducing testicular descent, the overall review of allavailable studies fails to document long-term(American Urological Association, 2014)efficacyRole of hCG in Treatment ofMales with PWSDr Jennifer Miller, “ Approach to the child withPrader- Willi syndrome” Treatment with hCG is recommended for infantmales with undescended testes because it may helpwith testicular descent, “more than in typical maleswith cryptochidism” And it improves the size of the scrotal sac iforchiopexy is needed(Crino et al, 2003;Goldstone et al, 2008; Miller, 2012)Hypogonadism in Males with PWShCG may be beneficial to assess function of the testes,but may not be beneficial for treatment of undescendedtestesØ10

4/28/2015Experts on Hypogonadism in PWS Cryptorchidism: Address during the first or thesecond year, particularly because there is evidenceof both primary and central hypogonadism Rare cases of testicular cancer have been reportedin PWS* Scrotal hypoplasia and obesity can make surgerydifficult if delayed until a later age and could requirerepeated surgical interventions(Cassidy, et al, 2011; Goldstone, et al, 2008)Experts on Hypogonadism in PWS Rare cases of testicular cancer have been reportedin PWS(Pediatric Research, 1999)Hypogonadism inMales with PWS Children with PWS display a specific form ofcombined Hypothalamic (low LH) and peripheral (low inhibin Band high FSH) Hypogonadism, suggesting a primary defect inSertoli and / or germ cell Maturation or an early germ cell loss. hCG therapystimulates testosterone production and virilization(J Clinical Endocrinology Metabolism, 2006)11

4/28/2015Hypogonadism in Males with PWSTesticular Failure After Puberty Onset Boys have normal inhibin B levels until age 10 yrs,but after puberty onset inhibin B levels declined to 5% tile and FSH increased to 95 % tile Testosterone increased with puberty but remained 5% tile LH increased but not above 95 % tile Major cause is primary hypogonadism(Siemensma EP et al, 2012)Normal Puberty(Myer, date unknown)Effects of Hypogonadism in PWS Males Likely contributes to decrease in bone and musclemass and increase in body fat Severe obesity in PWS contributes to mortality anddecreased quality of life12

4/28/2015What about TestosteroneReplacement?What about TestosteroneReplacement?Japanese Study with PWS MalesJapanese study of 22 PWS male patients age 16 and 48years; serum Testosterone 300Patients with existing modified overt aggression scale 4 excludedExample: Threatens violence toward self or other; repeatedly ordeliberately Sets fires; throws objects dangerously Inflicts major injury on self or makes a suicide attempt Attacks others, causing serious injury (fracture, loss of teeth,deep cuts, loss of consciousness, etc)(Kido et al, 2013)13

4/28/2015Japanese Study with PWS Males Measurements prior to testosterone replacementand 1 month after last injection Testosterone 125 mg IM monthly Measurements: pubertal stage, body hair, T, LH, FSH,HGB/HCT, HDL, AST/ALT, Chol, Trigs, LDL, BG, A1C Measured erectile dysfunction, ejaculation,spermatogenesis Measured DEXA, BMI, % body fat MOAS- aggression scale(Kido et al, 2013)Japanese Study with PWS MalesAfter Two Years Increased pubic hair 16/22 patients Emergence of erectile function 8/22 patients Ejaculation 3/22 patients– No sperm in samples 1 month post-injection Testosterone levels all 300 Improvement in DEXA and body composition No change in aggression Non-significant increase in HGB/HCT Non-significant decrease in HDL(Kido et al, 2013)Treatment for Hypogonadism inPWSRecommendations: Expert care meeting on PWS 2008 No standardized protocols for sex hormonetreatment nor prevention of osteoporosis Benefits of treatment include prevention ofosteoporosis and fracture14

4/28/2015Expert Treatment of Hypogonadismin PWSHormone replacement: Low dose testosterone (injections, transdermalpatch or gel) using escalating doses every 3- 6months to allow testosterone to get to normal levelor HCG injections(Cassidy, et al, 2011;Goldstone, et al, 2008)Expert Treatment of Hypogonadismin PWS Monitor androgen status annually duringadolescence and adulthood DEXA as clinically indicated Consider gonadal hormone replacement(Cassidy, et al, 2011;Goldstone, et al, 2008)Body Image and Sexual Interests inPWSPWS FYI: Half of patients reported having been on a date andkissing romantically All males and 64% females wished to marry 77% of males wanted hormonal treatment toincrease phallic size 43% of females wanted hormonal treatment toachieve regular menstruation No correlation between hormonal levels and sexualinterests(Gross-Tsur et al, 2011)15