Obesity: Endocrine Issues as the Cause and as the Effect Angela Lennon MD Assistant Professor, Pediatrics University of Kansas Medical Center April 22, 2016 Disclosure I have no relevant financial relationships with the manufacturers(s) of any commercial products(s) and/or provider of commercial services discussed in this CME activity. I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation. Outline Discuss endocrine causes of obesity - Cushing s disease, GH deficiency, Hypothyroidism Pseudohypoparathyroidism Type 1a Discuss endocrine complications of obesity - Type 2 DM and insulin resistance - Polycystic ovary syndrome - Growth and puberty 1
Endocrine Causes of Obesity Endocrine causes of obesity Seen in identified in less than 1 percent of children and adolescents with obesity. Most children with these problems have short stature and/or hypogonadism. Klish, W, UpToDate. Cushing s syndrome Result of chronic exposure to excess glucocorticoids. Weight gain with growth retardation; the latter may be the first indication of steroid excess. ETIOLOGY : Iatrogenic Cushing's syndrome: - most common cause - can be from any source of steroids Pituitary or adrenal tumors Ectopic ACTH syndrome http://www.uptodate.com/contents/epidemiology and clinicalmanifestations of cushings syndrome 2
Signs and symptoms Central fat distribution Moon face, suprascapular fat pad Dermatologic manifestations: Skin atrophy, easy bruisability, purple striae Hirsutism, acne Menstrual irregularities Hypertension, hyperglycemia Diagnosis 24-hour urine for free cortisol Midnight salivary cortisol levels Blood cortisol levels- afternoon levels Dexamethasone suppression test Growth hormone deficiency Features: Growth deceleration Excess subcutaneous fat, accelerated weight gain Cherubic face Delayed physical maturation Work up: IGF-1 level; Definitive diagnosis by GH hormone stimulation testing 3
Hypothyroidism Features: decreased linear growth, mild accelerated weight gain (mostly due to fluid retention), fatigue, constipation, altered school performance. Most common cause : Autoimmune disease (Hashimoto s hypothyroidism) Diagnosis: TSH (thyroid-stimulating hormone) Free T4, T3 Microsomal Ab/ Thyroid Peroxidase Ab Thyroglobulin Ab / Pseudohypoparathyroidism (PHP Type 1a) Also called Albright's hereditary osteodystrophy PTH resistance, along with characteristic phenotypic appearance Molecular defects in the gene (GNAS1) encoding the alpha subunit of the stimulatory G protein (Gsα) Autosomal dominant, also associated with other hormone resistance Abraham, M. Pseudohypoparathyroidism Accessed in emedicine.medscape.com PHP Type 1a Characteristic phenotype: Obesity Short stature Developmental delay Brachymetacarpals/ tarsals Soft tissue calcification Paresthesias, carpopedal spasm, or seizure Lab: Low Ca, High Phos, high PTH Analysis of the GNAS1 gene 4
Endocrine Effects of Obesity Insulin resistance Impaired response to the physiologic effect of insulin on carbohydrate, fat and protein metabolism, and effects on vascular endothelial function. Core defect in the development of T2DM. Haffner et al. Diabetes Care, 1999 Insulin Resistance: Associated Conditions Atherosclerosis Type 2 DM/ Impaired glucose tolerance Fatty liver Dyslipidemia Insulin Resistance PCOS Hypertension Chronic inflammation Adapted from Consensus Development Conference of the American Diabetes Association. Diabetes Care 1998;21:310-314. 5
TYPE 2 DIABETES Epidemiology of T2DM In 1994: T2DM accounted for <5% of newly diagnosed DM in youth. In 2008-2009, T2DM accounted for about 20% of newly diagnosed DM in youth National Diabetes Statistics Report, 2014 Screening for DM The American Diabetes Association recommends screening with a fasting glucose test when a child is overweight and has 2 additional risk factors: 1 Family history of diabetes 2. African American, Hispanic, or Native American background 3. Other related conditions, such as polycystic ovary syndrome, acanthosis nigricans, or cardiovascular risk factors Screening should begin at puberty or 10 years of age and should be performed every 2 years. American Diabetes Association. Diabetes Care. 2015;38 6
Diagnosis of Type DM Normal Pre-diabetes Diabetes Fasting glucose < 100 mg/dl 100-126 mg/dl > 126 mg/dl 2 hr post-prandial < 140 mg/dl > 140 but < 200 mg/dl > 200 mg/dl HgA1c < 5.7 % > 5.7% but <6.5 % > 6.5 % Random glucose > 200 mg/dl Pre-diabetes: PCP can follow up Lifestyle modification and weight loss; follow up every 6 months. Metformin if PCP is comfortable. Diabetes: Refer to Endocrine First line treatment is still lifestyle modification. Insulin levels change with glucose intake Time (min) Glucose (mg/dl) Insulin (uu/ml) 0 65-109 <17 30 64-178 6-86 60 53-153 8-112 90 53-134 5-68 120 51-113 5-55 150 42-108 3-46 180 60-98 3-20 240 62-106 <15 300 71-106 <8 Metformin First line medication for the treatment of Type 2 DM. Also used in prediabetes, and PCOS. Well-studied in adults and children; safe and effective. Approved for pediatric use in diabetes for >10 yrs. Mechanism of action - Suppression of hepatic glucose output - Decreases intestinal absorption of glucose - Increasing peripheral glucose uptake and utilization. - Decrease lipids. Prescrire international 23 (154): 269 72. Nov 2014. 7
Metformin Side effects: nausea, anorexia, diarrhea, abdominal pain, usually lessen in 2-3 wks. Rare: lactic acidosis. Rarely causes hypoglycemia. Weight neutral/weight loss. Start 500mg/day (in 1-2 divided doses increasing every 1-2 weeks to full dose of 2000mg/day. - Regular tablets: divided BID, - Extended release form: can be given once daily; don t split Insulin Ultimately, some patients with T2DM will be markedly insulinopenic, and only insulin will treat this defect. Not generally considered first line therapy for type 2 DM, unless HgbA1C >9%. Side effects: Hypoglycemia, weight gain, difficulty in management POLYCYSTIC OVARIAN SYNDROME 8
Diagnosis of PCOS Endocrine Society Clinical Practice Guideline. (Legro, et al. JCEM 2013 98:12, 4565-4592) Recommend Rotterdam criteria: Presence of 2 of the following: 1. Androgen excess: Clinical: hirsutism, alopecia, acne OR Biochemical: elevated free and total testosterone 2. Ovulatory dysfunction 3. Polycystic ovaries on US Require exclusion of other causes of hyperandrogenism. Risks of PCOS Confers a 5- to 10-fold increased risk of developing T2DM. Risk of infertility, first trimester miscarriage, sleep apnea, cardiovascular disease. Chronic anovulation associated with an increased risk of endometrial hyperplasia and carcinoma. Caveats in Adolescents Adolescents can have irregular menses 2-3 years after menarche. Ultrasound usually is not needed: - Multifollicular ovaries are a feature of normal puberty that subsides with onset of regular menstrual cycling. Hyperandrogenism is key in PCOS diagnosis of teens! 9
Typical PCOS findings: Work Up Elevated free and total testosterone. Sex hormone binding globulin is low. Elevated LH/FSH ratio >3. Mildly elevated DHEAS and androstenedione. * Testosterone >150ng/dl and DHEAS levels >700 mcg/dl suggestive of adrenal tumor. Estrada, et al. Child Obese Aug; Vol 10, No. 4 :3D4-17 Legro, R. et al. JCEM 2013 98:12, 4565-4592 Diagnosis of exclusion Late onset CAH: Prolactinoma: Thyroid dysfunction: Pregnancy: Cushing s disease: 17-OH Progesterone Prolactin TSH and Free T4 Beta HCG 24 hr urine cortisol, salivary cortisol OGTT to screen for IGT and T2DM. Consider using HgbA1c if a patient is unable or unwilling to complete an OGTT. Ultrasound of a typical polycystic ovary - Presence of 12 or more follicles 2-9mm in diameter, and/or increased ovarian volume >10ml in either ovary - Pearl necklace sign: follicles oriented in the periphery 10
Management Options for PCOS FIRST line of treatment: Lifestyle modifications if obese or overweight Diet, exercise, weight loss Weight loss may is beneficial for both reproductive and metabolic dysfunction. Medical Therapy FIRST line: Hormonal contraceptives (pills, patch, vaginal ring) -OCPs reduce ovarian androgen production. -Induce regular menses, also help with hirsutism and acne. -Progestin choice is important: Avoid preparations that have norgestrel and levonorgestrel because of their androgenic activity. Drosperinone have anti androgenic effects. Badawy A, Elnashar A. International Journal of Women s Health. 2011;3:25-35. Polycystic Ovarian Syndrome. Medscape. Richard Lucidi, MD, FACOG Side effects of OCPs Nausea in first 1-2 mos, alteration in insulin action, hypercoagulation. Don t use in patients with family history of clotting disorder, smoking. 1 No strong evidence exists to support the common belief that they cause weight gain. Usually associated with high-dose estrogen used in the past. 2-1 Polycystic Ovarian Syndrome. Medscape. Richard Scott Lucidi, MD 2 Gallo MF, et al. Cochrane Database Syst Rev. 2014 11
Treatment of Hirsutism and Acne Hirsutism: Mechanical/ temporary: shaving, plucking, waxing Mechanical/ permanent: electrolysis, laser Acne: may use topical solutions - Benzoyl peroxide, Tretinoin, Adapalene, Erythromycin, Clindamycin, Sodium Sulfacetamide. May consider anti androgens: Flutamide, Finasteride, Spironolactone (cause menstrual irregularity and risk of feminizing a male fetus when used alone. Usually used with OCPs) Metformin If with glucose/insulin abnormalities, consider Metformin. Metformin itself may increase menstrual cyclicity, improved ovulation, and a reduction in circulating androgen levels. May be more useful in the treatment of adolescents than adults with PCOS. Legro, et al. JCEM 2013 98:12, 4565-4592 GROWTH AND PUBERTY 12
Obesity may be accompanied by modest overgrowth and early onset of puberty, especially in girls. Bone age may be advanced, so that final adult height is not increased. Adolescents often attain normal adult height. Richmond, E, et al. Up ToDate References Klish, W, Definition; epidemiology; and etiology of obesity in children and adolescents. In UpToDate, Accessed on Mar 27, 2016. Klish, W. Comorbities and Complications of obesity in children and adolescents. In UptoDate. American Diabetes Association. Standards of medical care in diabetes 2015. Diabetes Care. 2015;38(suppl 1):S1-S93 Prescrire international 23 (154): 269 72. Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects."november 2014 Richard S. Legro,], et al. Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Cinical Practice Guidline. The Journal of Clinical Endocrinology & Metabolism 2013 98:12, 4565-4592 13
E Estrada, et al. Children s Hospital Association Consensus Statements for Comorbidities of Childhood Obesity. Child Obese Aug; Volume 10, Number 4 :3D4-17 Polycystic Ovarian Syndrome. Medscape. Richard Scott Lucidi, MD, FACOG; Chief Editor: Richard Scott Lucidi, MD, FACOG Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. International Journal of Women s Health. 2011;3:25-35. Haffner SM, et al. Diabetes Care. 1999;22:562-568. Consensus Development Conference of the American Diabetes Association. Diabetes Care. 1998;21:310-314. Gallo MF, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2014 Richmond, E, et al. The child with tall stature and/or abnormally rapid growth. In: Up ToDate, Accessed on Mar 27, 2016) 14