corin badiu - endocrine obesity in pws joi

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 Endocrine Endocrine obesityobesity in PWS patient in PWS patient 

C. Badiu, G. Madaras

National Institute of EndocrinologyBucharest

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 Prader  Prader--Willi Syndrome...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.

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 Diagnosis«

 Diagnosis«

Prenatal= reduced fetal movement and polyhydramnios

= genetic testing (chorionic villous sampling)

= amniocentesis

Postnatal= clinical features

= confirmed by genetic testing

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 Endocrine Endocrine

obesity disordersobesity disordersin PWS in PWS 

short stature p high BMI

delayed puberty & hypogonadism osteoporosis

excessive appetite morbid obesity

Low GH q lipolysis

central hypocorticism could be associated

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 Etiology of  Etiology of 

endocrine obesityendocrine obesityin PWS 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

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CRH/ACTHCRH/ACTH -- What can go wrong?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

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 F ood intake F ood intake -- What can go wrong?What can go wrong?

Highly significant decrease inthe number of OXT neurons of  the PVN nucleus which inhibitfood intake seem to be good

candidates for playing a physiological role in ingestive behavior ("satiety neurons³)

Vigorous control of the food

environment

Regular exercise is essential tomanage hyperphagia and obesity

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 F rom genes to behavior  F rom genes to behavior 

G. Lucignani et al. / NeuroImage 22 (2004) 22±28

Del 15q11 ±13 loss of EFK SU - GABAA rec

 Alterations of the G ABAergic system have a relevant role in the pathogenesis of 

 symptoms commonly observed in PWS.

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GHRH/GH GHRH/GH -- What can go wrong?What can go wrong?

low spontaneous GHsecretion

low peak GH response tostimulation tests

low serum IGF

-I levels

low levels of IGF-binding protein 3

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GHRH/GH GHRH/GH  -- What can go wrong?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

T he 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.

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W hat we should do?W hat 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

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T he HypothalamicT he Hypothalamic--Pituitary Pituitary--Gonadal  AxisGonadal  Axis

 H  ypogonadism:

GnRH deficiency

(central)

 primary gonadaldamage (peripheral)

retarded or incompletesexual development

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 Puberty in PWS  Puberty in PWS 

no/delayed/incompletepuberty

almost all subjects will requirehormonal treatment for induction, promotion, or maintenance of puberty

no consensus as to the most

appropriate regimen in PWS

the chosen therapy, the dosingand timing should reflect as far as possible the process of normal puberty

precocious puberty (4%)*

* GnRH analogs is not needed (early

 puberty not usually sustained)

isolated prematurepubarche (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 androgenswhen there is associated advancementof bone age

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Sex hormone steroid replacement in adultsSex 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  B MD assessed as indicated by dual-energy  x-ray photon absorptiometry

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What should we do?

cryptorchidism (80%)

orchidopexy

human chorionicgonadotropin (hCG)

testosterone patches andgel preparations*

* when transdermal preparations are

not tolerated initial low dose of imtestosterone preparations (one third tohalf the recommended dose for  hypogonadal adults) with incrementsas tolerated

estrogen therapy

(transdermal andnonsynthetic) should beconsidered if:

amenorrhea/oligomenorrhea

low-normal BMD

reduced estradiol levels

aware of the possible needfor contraceptives (fewreports of pregnancy inPWS women)

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 E ndocrine obesity E ndocrine obesityMortality & 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

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 E ndocrine obesity E ndocrine obesity

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

mTOR 

AMPK 

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 E ndocrine obesity E ndocrine obesity

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

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GhrelinGhrelinControl 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

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 Intervention 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

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 Bariatric surgery Bariatric surgeryBilio-pancreatic diversion

+ Sleeve gastrectomy

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

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 Bariatric surgery Bariatric surgery

Pa avramidis et al., J Pediatric Sur er 2006 41, 1153± 1158

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