Endocrine obesity in PWS patient

C. Badiu, G. Madaras
National Institute of Endocrinology
Bucharest
 Prader-Willi Syndrome...

• first described in 1956

• prevalence = 1:12,000 to 15,000
• multisystemic disorder - all races, both sexes

• the cause = unclear

▼▼▼▼▼
Prader A, Labhart A, Willi H. Schweiz. Med. Wochenschr 1956; 86: 1260–1.
 Diagnosis…

• Prenatal
= reduced fetal movement and polyhydramnios
= genetic testing (chorionic villous sampling)
= amniocentesis
• Postnatal
= clinical features
= confirmed by genetic testing
Genetic testing….

• deletion
/other abnormal finding on
chromosome 15q11-q13
= 70% (paternal deletion)

• two maternal chromosome 15s and no paternal 15; impriting defect

= 30 % (maternal uniparental disomy = UPD)
 Endocrine
obesity disorders
in PWS

• short stature  high BMI

• delayed puberty & hypogonadism → osteoporosis
• excessive appetite → morbid obesity
• Low GH   lipolysis
• central hypocorticism could be associated
 Etiology of
endocrine obesity
in PWS

• Reduced GH secretion + hypogonadotropic hypogonadism + abnormal appetite

control + high pain threshold suggest hypothalamic - pituitary dysfunction

• No organic defect of the hypothalamus has been discovered on post mortem

investigation

• Genetic abnormalities in chromosome 15 disrupt the normal functioning of the

hypothalamus
• hypothalamic autopsies:
◘ the PVN nucleus = reduced in size
◘ fewer oxytocin-expressing neurons
◘ reduction in GHRH-releasing neurons in the nc. arcuatus
◘ deficiency in vasopressin
• pituitary hypoplasia frequently observed

• IRM - abnormal bright spot

in the posterior pituitary
CRH/ACTH - What can go wrong?
▼
central adrenal insufficiency (CAI)
• 60% of PWS patients had CAI during
stressful conditions (insufficient ACTH
response during metyrapone test)
• elevated levels of DHEA and its sulfate
(DHEAS)
• more research is required, but at this
moment, it is important to consider
hydrocortisone treatment for PWS
patients during stressful conditions
Food intake - What can go wrong?

• Highly significant decrease in

the number of OXT neurons of
the PVN nucleus which inhibit
food intake seem to be good
candidates for playing a
physiological role in ingestive
behavior ("satiety neurons“)

• Vigorous control of the food

environment

• Regular exercise is essential to

manage hyperphagia and obesity
 From genes to behavior
Del 15q11 –13  loss of  SU - GABAA rec

Alterations of the GABAergic system have a relevant role in the pathogenesis of

symptoms commonly observed in PWS. G. Lucignani et al. / NeuroImage 22 (2004) 22–28
GHRH/GH - What can go wrong?
• low spontaneous GH
secretion

• low peak GH response to

stimulation tests

• low serum IGF-I levels

• low levels of IGF-binding

protein 3
 GHRH/GH - What can go wrong?
Clinical features support the presence of GHD in PWS:
• short stature
• abnormal body composition
• obesity with extra fat deposits over the abdomen
• reduced muscle mass
• decreased bone density
• retarded bone age
The degree of GHD may vary from mild to severe
Theodoro et al. Body composition and fatness patterns in Prader-Willi syndrome:
comparison with simple obesity. Obesity (Silver Spring) 2006; 14(10):1685-1690.
 What we should do?
• starting GH treatment as early as 2 yr
• benefit in starting therapy between 6 and 12
months of age

• recommended dose = 1.0 mg/m2/d

• increases longitudinal growth

• decreases in percent body fat
• increases muscle mass
• improves bone mineral density
The Hypothalamic-Pituitary-Gonadal Axis
Hypogonadism:

► GnRH deficiency
(central)

► primary gonadal
damage (peripheral)

retarded or incomplete
sexual development
 Puberty in PWS
no/delayed/incomplete
puberty
▼ not usually sustained)
• almost all subjects will require
hormonal treatment for
induction, promotion, or
maintenance of puberty
• no consensus as to the most
appropriate regimen in PWS
• the chosen therapy, the dosing
and timing should reflect as far as
possible the process of normal
puberty
precocious puberty (4%)*
* GnRH analogs is not needed (early puberty
isolated premature pubarche
(14%)*
= growth of axillary and pubic hair
probably due to early maturation of
zona reticularis of the adrenal gland
* use of hydrocortisone in premature
pubarche to decrease adrenal androgens
when there is associated advancement of
bone age
 Sex hormone steroid replacement in adults

• known benefits to bone health*

• muscle mass metabolic protection
• possible benefits to mental, emotional, and physical well-
being

* estrogen and androgen status should be monitored yearly during

adolescence and adulthood and BMD assessed as indicated by dual-
energy x-ray photon absorptiometry
 ► What should we do?
♂ ♀
• cryptorchidism (80%) →
orchidopexy
• human chorionic
gonadotropin (hCG)
• testosterone patches and
gel preparations*
* when transdermal preparations are
not tolerated → initial low dose of im
testosterone preparations (one third to
half the recommended dose for
hypogonadal adults) with increments
as tolerated
• estrogen therapy
(transdermal and
nonsynthetic) should be
considered if:
amenorrhea/oligomenorrhea
low-normal BMD
reduced estradiol levels
• aware of the possible need
for contraceptives (few
reports of pregnancy in
PWS women)
 Endocrine obesity
Mortality & morbidity: caused by obesity  MS
(type 2 diabetes mellitus (DM2), arterial hypertension, sleep apnea, respiratory
insufficiency and cardiovascular disease)

Brambilla P et al., Metabolic syndrome in children with Prader Willi syndrome: the effect of
obesity, Nutr Metab Cardiovasc Dis (2009), doi:10.1016/j.numecd.2009.10.004
 Endocrine obesity
mTOR
AMPK

Lenard and Berthoud, Obesity, 16, S3 (2008), S11-S22

Endocrine obesity

Lenard and Berthoud, Obesity, 16, S3 (2008), S11-S22

 Ghrelin
Control of food intake and energy metabolism at central as
well as peripheral levels.
PWS presents higher ghrelin levels, relative
hypoinsulinemia and normal insulin sensitivity.

F. Prodam et al. / Clinical Nutrition 28 (2009) 94–99

 Intervention
• Psychopharmacology: Risperidone
– Araki et al. Successful risperidone treatment for behavioral
disturbances in Prader-Willi syndrome. Pediatr Int 2010; 52(1):e1-e3.

• Vigorous control of the food environment

• Regular exercise is essential to manage

hyperphagia and obesity
 Bariatric surgery
Bilio-pancreatic diversion
+ Sleeve gastrectomy

Papavramidis et al., J Pediatric Surgery (2006) 41, 1153– 1158

Bariatric surgery

Papavramidis et al., J Pediatric Surgery (2006) 41, 1153– 1158

 Reteaua multidisciplinara
ANBRaRo

Kinetoterapeut Asistent Pediatru

Servicii sociale /
educationale

probleme Medic
Familia Copil / Pacient
cotidiene Specialist

Genetician Nutritionist
MS / DSP

Pentru familii: prin ANBRaRo se pot organiza conditii de rezolvare pentru

situatii complexe, care impun o abordare multidisciplinara
Pentru profesionisti: prin ANBRaRo se pot organiza schimbul de know-how şi
dezvoltarea abilitatilor
Functional Genomics