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AAP Endocrinology Newsletter Spring 2003
 

AAP Endocrinology Newsletter Spring 2003

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    AAP Endocrinology Newsletter Spring 2003 AAP Endocrinology Newsletter Spring 2003 Document Transcript

    • The Section on ENDOCRINOLOGY Newsletter Volume 11 Winter/Spring 2003 Chairperson’s Column Inside this Issue Janet Silverstein, MD Editor’s Column As we find ourselves more over-worked and counseling, and social work and Paul Kaplowitz, MD with increasing reliance on ancillary health psychology services. Each of these had 29 care providers to provide care for our or more responses. In addition, there were New Therapeutic Approaches to diabetes and obese patients, we are several other services mentioned, such as Childhood Obesity: Insulin struggling to maintain adequate networking the patient to other resources, Suppressors and Sensitizers reimbursement for the services we provide. filling out paperwork forms, justification of Robert H. Lustig, MD prescriptions, and telephone consultation. A reimbursement survey was sent to 925 Many practices stated that they do not bill Nutritional Endocrinology: A Novel members of the Section on Endocrinology separately for these services but rather Dietary Approach to Childhood and the Lawson Wilkins Pediatric Endo- include all services under the physician’s Obesity crine Society. Seventy-two responses were charge. When asked why services were David S. Ludwig, MD, PhD received of which 59 were valid responses. denied, many stated that the insurers say As we asked for only one response per that the service is not included in the Etiology-Based Treatment of practice, these 59 responses represented insurance plan, others state that Pediatric Obesity: A Plea for Patience 157 pediatric endocrinologists, giving us a reimbursement is received but is down Jack A. Yanovski, MD, PhD 17% return rate. The survey largely coded, and still others state they have discussed reimbursement for obesity and stopped billing these services. Several Risk of Cancer in Former Pituitary for ancillary services for diabetes care, stated that insurers do not pay for an GH Recipients in the UK: A including nutritional counseling, psycho- ancillary service such as diabetes Commentary logical services, and diabetes education. education or psychological counseling on Lillian Meacham, MD the same day as a doctor visit and that if Most respondents stated that they did not two visits are coded on the same day, only Lipid Disorders in Diabetes get reimbursed for the codes for obesity the less expensive visit is covered. Lilliam Gonzalez de Pijem, MD (278.00, 278.01). On the other hand, the majority of respondents stated they When asked what CPT codes are used to Management of the Patient with received reimbursement for acanthosis bill for those services, most people bill at a Intersex: A Middle Way nigricans (701.2), and 16 received 99244 or 99245 level for initial consults and reimbursement for abnormal weight gain 99214 or 99215 level for initial visit. There Jorge Daaboul, MD (783.1). However, others found that are specific codes for ancillary care that are abnormal weight gain was not a variably reimbursed. For instance, a Growth Curves: Are we reimbursable code. Most felt that services dietitian may bill 97802 for a new visit and Missing the Picture? were reimbursed only if a co-morbidity is 97803 for a return, education may bill under Adda Grimberg, MD present, the most commonly used G0108 in ½ hour increments, and 99211 co-morbidities being hypertension, codes may be used for non-MD services, dyslipidemia, glucose intolerance, and but reimbursement rates for these codes acanthosis nigricans. Ten respondents are generally low. Diabetes education, stated that the inclusion of an obesity nutrition education and counseling are code, even in the presence of a generally covered when billed by the co-morbidity, resulted in rejection for hospital. reimbursement. continued on page 9 Among the services provided for the diagnosis and treatment of diabetes which did not receive reimbursement were diabetes education, nutrition education Section on Endocrinology Newsletter Copyright © 2003 American Academy of Pediatrics
    • Editor’s Column I n the fall issue, I wrote a column The patient reported by Dr. Kaplowitz has this case, should result in enough questioning the fairly common multiple findings of GH deficiency. These sex-steroid production to stimulate an practice of prescribing growth include a height of greater than 2 standard increase in linear growth velocity above the hormone for peripubertal short children. deviations below the mean, a significantly prepubertal rate. I gave a specific example of a nearly 15 delayed bone age, low-normal IGF-1 for both Since 1985, recombinant technology has year old boy I had seen who had short age and Tanner stage, and a peak serum provided unlimited GH that is free of parents and a predicted height compat- growth hormone level of only 3 ng/mL. While infectious agents. New indications for ible with his target height. His IGF-1 and we agree that provocative GH tests are not growth hormone treatment have occurred in IGF-BP3 were normal but after testing, the gold standard that they are held to be by children (e.g. small for gestational age, his peak GH was 3 ng/ml. He received GH insurance companies, we dispute Dr. growth failure in Prader-Willi Syndrome) and at the pubertal dosing of 0.7 mg/kg/week Kaplowitz’s contention that the patient had multiple pharmaceutical companies are and grew well while progressing through been diagnosed solely by a provocative GH manufacturing the product. Cost continues puberty, but when I first saw him 15 test. Importantly, he does not state the to be an enormous issue. Perhaps rhGH cost months later, his predicted height had not pretreatment growth rate. We must assume may decrease as additional competition increased. The following commentary on that the growth rate of approximately 10 cm/ arises. In his summary, Dr. Kaplowitz my column was sent to the Section year represents an excellent response to rhGH proposes limiting the use of growth hormone chairperson and is printed in its entirety, and, therefore, might be considered as an- in hopes of preventing further insurance followed by my reply. other indication of GH deficiency. company limitations on its use. This Paul Kaplowitz, MD viewpoint both effectively handcuffs the We also contend that Dr. Kaplowitz did not physicians who should be responsible for We read with great interest Dr. Kaplowitz’s make a strong case for a combination of making the determination of which patients editorial regarding the judicious use of genetic short stature and constitutional de- deserve rhGH therapy and gives the growth hormone in the Summer/Fall 2002 lay. The patient indeed has short parents insurance companies license to continue to Section on Endocrinology Newsletter. and a mid-parental height of only 5’5”. limit or deny coverage. We request that in After doing so, the ten physicians in our However, unless Dr. Kaplowitz has the future, topics with this degree of endocrine section were in disagreement with longitudinal growth data at his disposal, a importance that are published in the AAP’s the author’s opinion. We do not advocate diagnosis of constitutional delay should be Section on Endocrinology Newsletter b e recombinant growth hormone treatment of in question when a Tanner stage 3, nearly presented either as a consensus statement all short children. Those children who 15-year-old male is not yet 150 cm in height. or as a point-counterpoint. Every opinion exhibit a growth pattern most consistent with In this particular case, we believe that it deserves to be heard. constitutional delay or delayed puberty with would have been difficult to continue to wait a normal prepubertal growth velocity are for the child to exhibit a pubertal growth Sincerely, typically followed to determine their course. spurt. What if the growth spurt did not Alexander Karmazin, MD writing for If available, longitudinal growth data are occur while the bone age continued to The Section of Endocrinology carefully reviewed. Those individuals who advance? This patient received pubertal Children’s Mercy Hospital demonstrate abnormal growth rates or dosing (0.7 mg/kg/week) of rhGH. His height Affiliated with the University of deceleration across percentile lines initially increased 13 centimeters in 15 months. A Missouri-Kansas City are screened with a bone age x-ray and similar result might have been achieved with School of Medicine appropriate blood tests to rule out other standard, less costly GH dosing (0.3 mg/kg/ Kansas City, Missouri causes of poor growth. Unless children who week), particularly in light of a bone age that Faculty have subnormal growth rates in our clinic did not indicate a compromise in height Campbell Howard, MD have clear indications for GH therapy (Turner potential. On the other hand, the report of Carol Huseman, MD Syndrome, renal insufficiency, cranial the study of pubertal dosing indicated that Jill Jacobson, MD irradiation), they undergo provocative GH children with the characteristics of this child Wayne Moore, MD, PhD testing with two secretagogues - typically have a better outcome in terms of final adult Jadranka Popovic, MD clonidine and arginine. Those who fail to height. Our general experience is that Miles Yu, MD achieve serum GH levels of 10 ng/mL or adolescents in mid-puberty who respond Fellows greater are prescribed growth hormone. sub-optimally to a standard GH dose improve Joseph Cernich, MD Patients who pass the tests continue to be their height velocity by a dose increase to Alexander Karmazin, MD monitored with stadiometric measurements 0.35-0.4 mg/kg/week. Understanding that the Kurt Midyett, MD to see if growth failure is persistent. Those peak growth velocity in boys occurs late in Angela Turpin, MD with persistent growth failure are later the pubertal process, we contend that a considered candidates for rhGH. gonadal volume of 8 cc, as was present in continued on page 3 Section on Endocrinology Page 2
    • Editors column pubertal and short, without clear evidence predicted height of the boy I presented continued from page 2 of growth acceleration. In each case, I was 168 cm, no better (and even 2 cm explained to the family that it was best to below) that which should have been wait 4-6 months to be sure that the growth predicted at the initial visit. One could Dr. Kaplowitz replies: spurt was kicking in, and at the return visit, argue that this could not have predicted growth rates were in the range of 8-10 cm/ when treatment was started, but I think it I read with interest the letter signed by the year. One of the characteristics which is entirely consistent with what has been entire Pediatric Endocrine division at makes pediatricians different from many reported in the literature. Several studies Children’s Mercy Hospital in Kansas City other specialists is that we have more faith show that height gained during GH and their viewpoint certainly deserves to in the human body. I think my faith that a treatment in short children who are not be heard and responded to. Although generally health boy with physical severely GH-deficient is gained primarily the treating endocrinologist did not feel changes of puberty will in fact have a nice prior to the onset of puberty. I would the child in question had started his growth spurt if we show just have a little encourage readers of this column who growth spurt, the growth chart I received patience is justified. Thus the assumption know of studies that either support or showed that based on PCP measurements, that “the growth rate of 10 cm/year refute this statement to send them to me, height fell further below the 3rd percentile represents an excellent response to rhGH and I will include this information in the between ages 12 ½ and 14 ¼ (as it and might be considered another indica- next issue of this newsletter. typically does in boys with delayed tion of GH deficiency” bothers me a great puberty), and then he grew about 3.7 cm deal. This sounds similar to the reasoning in the 6 months prior to his first pediatric many physicians use when they prescribe endocrine visit. This would suggest that antibiotics for illnesses which are likely to Section on Endocrinology this boy was starting his growth spurt be of viral origin. Does the fact that the Executive Committee before GH was started. Even if one did fever goes away and the child gets better 2002-2003 not have this information, I question the within a few days really suggest that the reluctance to wait for the pubertal growth original infection was bacterial? I would concede the possibility that giving GH to Chairperson spurt in a boy with a pubertal exam non-GH deficient pubertal boys might Janet Silverstein, MD because of the concern that the bone age would advance without a growth spurt. result in a marginal increase in growth rate This ignores the fact that in healthy (perhaps from 9 to 10 or 11 cm/yr), but is Members children, the growth spurt and rapid bone that potential small increase worth the Kenneth Copeland, MD age advancement are tightly coupled cost? events, both related to pubertal increases Inger Hansen, MD in testosterone, estradiol, and GH. If this I would not place much hope in the cost of boy were classically GH-deficient, he GH decreasing any time soon. In fact, we Francine Kaufman, MD might have advanced his bone age are fortunate that compared to other without a growth spurt, but he would also medications whose cost has skyrocketed Susan Rose, MD have been referred for severe short in the past decade, the cost of GH has stature well before age 14 and would have been stable since 1985. However, I see Surendra Varma, MD had unequivocally low levels of IGF-1 and little point in complaining about how IGF-BP3. The claim that an IGF-1 of 222 insurance companies “handcuff the Membership Chairperson ng/ml in a 14 year old early pubertal boy is physician” who wants to determine Kenneth Copeland, MD entirely consistent with GH deficiency without restriction who deserves GH. As suggests that GH deficiency is much more long as health care in this country is Newsletter Committee common in the Kansas City area than in underfunded by both the private and Paul Kaplowitz, MD other parts of the country. public sectors, insurance companies are Liliam Gonzalez de Pijem, MD within their rights to scrutinize the usage It is not clear to me why in a nearly 15 of high cost medications like GH, and it is Nominations Committee year old boy with short parents and a appropriate for them to use pediatric Stephen LaFranchi, MD bone age of 12 ½, the “diagnosis of endocrinologists as outside reviewers. Edward Reiter, MD constitutional growth delay should be in Although I know there are many horror question” because the height was less stories about unreasonable denials for GH, the cases I have reviewed that have been Program Chairperson than 150 cm. I have seen many boys with denied by insurance companies have been Surendra Varma, MD constitutional delay who were as short as this boy at age 15, got 4 monthly test- for the most part very questionable. osterone injections, grew well, and Pediatric Endocrine achieved an adult height compatible with The authors of the letter did not comment Nursing Society Liaision their genetic potential. I have also seen about the fact that after 15 months of high Judy Hartman, RN, BSN, MHS several 14-15 year olds who were clearly dose growth hormone therapy, the Section on Endocrinology Page 3
    • New Directions in Research New New Therapeutic Approaches to Childhood Obesity: and Patient Care in Pediatric Obesity Insulin Suppressors and Sensitizers T he majority of clinical Robert H. Lustig, MD part of the problem, and can be part of the pediatric endocrinologists, I University of California, San Francisco solution. suspect, feel the same sense San Francisco, CA of frustration I do when confronted Leptin resistance and hyperinsulinemia with the typical 10 year old child Leptin, insulin, and energy balance coexist in most obese subjects. What’s the who is already 180% of his or her Think of obesity as energy storage gone connection? Inexplicably, leptin and ideal body weight, and you take one haywire. The root causes are still un- insulin act through different receptors on look at the parents and see exactly known, but the brain’s resistance to the same hypothalamic neurons to activate where it is coming from. The fact signaling by the adipocyte hormone leptin the same second messenger system that primary care physicians is an important component. Leptin tells (Insulin Receptor Substrate/Phosphatidyl continue to refer these patients to your brain how thin you are, not how fat Inositol-3-Kinase) (3), which, in turn, us when we have accomplished little you are. Circulating concentrations of mediates the anorexigenic effects of both with the last few they referred is a leptin increase proportionately with hormones. Could hyperinsulinemia be the testimony to their frustration and increasing body fat. Each individual has proximate cause of leptin resistance? And inability to deal themselves with a their own “personal leptin threshold”, a could reducing the insulinemia improve the fairly insoluble problem. We are all level of circulating leptin, above which leptin resistance and the obesity? aware that research into the tells their hypothalamus that they have pathways which regulate appetite enough peripheral energy storage to burn Insulin suppression and octreotide and body weight have made great energy at their normal Resting Energy Perhaps the most “organic” obesity strides since the discovery of leptin, Expenditure (REE). Levels above this syndrome occurs after hypothalamic but we are impatient for these gains leptin threshold (getting fatter) do not alter damage in patients surviving brain tumors to be translated into drugs we can REE, but going below this leptin threshold or leukemia. “Hypothalamic obesity” is the prescribe for our patients. Until is interpreted by the hypothalamus as a “ultimate” leptin resistance, which leads to then, we continue to counsel state of starvation. REE decreases in an disinhibition of the vagus nerve, which lifestyle changes but rarely see attempt to conserve fuel, making you not stimulates excessive insulin hypersecre- an overweight child make significant want to spend any extra energy on tion at the b-cell (seen on glucose toler- and sustained progress under our activity, and appetite increases to bring ance testing), with resultant increases in care. energy stores, and leptin, back to baseline adipogenesis and energy storage. In these (1). Virtually every obese patient is patients we have studied the effects of There are a few among us who have hyperleptinemic. So why in the obese is a insulin suppression using octreotide, a devoted a major chunk of their time high leptin level interpreted by the somatostatin analog which limits calcium and effort to better understanding hypothalamus as a low level (leptin influx into the b-cell, and prevents insulin the complexities of pediatric obesity resistance), necessitating more energy exocytosis. In a pilot study (4), patients and coming up with novel intake and storage? received subcutaneously administered therapeutic approaches which may octreotide for six months. Insulin re- someday be widely used by the rest Now to insulin. Insulin performs two sponses to glucose were normalized with of us. I have asked three of the top important but opposing roles in energy treatment. Of 8 patients, 3 lost substantial researchers in pediatric obesity, balance. First, insulin is the primary energy (>10%) weight, 2 lost moderate amounts of Robert Lustig, David Ludwig, and storage hormone. Everything insulin does weight, and 3 stabilized weight. The mean Jack Yanovski, to share with our to the adipocyte promotes the uptake of weight loss was –4.8 ± 1.8 kg in 6 months. readers some of their insights into glucose and triglyceride, and the de novo Insulin responses decreased from 281 ± 47 what directions we might want to synthesis of fatty acids to increase energy to 114 ± 35 mU/ml. Weight loss correlated take in our pursuit of effective storage. Second, insulin tells the hypo- with both changes in insulin response and therapy for overweight children, thalamus that energy is being metabolized, with changes in leptin levels (inferring both medical and dietary. which signals the anorexigenic system to improvement in leptin sensitivity). A stop feeding (2). Virtually every obese double-blind, placebo-controlled trial in Paul Kaplowitz, MD, PhD, editor child is also hyperinsulinemic. Initially it children with hypothalamic obesity (5) was thought that the hyperinsulinemia demonstrated weight stabilization (+1.6 ± was a result of the obesity, but now we 0.6 vs. +9.2 ± 1.5 kg) and BMI (-0.2 ± 0.2 understand that in some patients, espe- vs. +2.3 ± 0.5 kg/m2), with suppression of cially children, the reverse is true, that hyperinsulinemia can be a cause. Insulin is continued on page 5 Section on Endocrinology Page 4
    • Lustig Metformin (dimethylbiguanide) has been and the low-glycemic index diet, attempt to continued from page 4 used for more than 40 years for the reduce insulinemia as a therapeutic goal. treatment of children and adults with type The trick is to think of insulin like any 2 diabetes mellitus. Several short-term other hormone, which possesses a U- insulin response, and with increased studies demonstrate a reduction in fasting shaped therapeutic curve. Too little insulin physical activity, which correlated with the insulin and BMI in non-diabetic causes one disease (diabetes mellitus), degree of insulin suppression. hyperinsulinemic adolescents (9-13). Some while too much insulin causes another believe that metformin promotes weight (obesity). Although not yet proven, insulin A small subpopulation of obese adults loss though a primary anorectic effect, as may be an integral part of the behavioral without cranial insult also exhibit insulin initial side-effects of nausea and gas- changes that attend obesity. Normalization hypersecretion (6). In response to the trointestinal distress limit caloric intake of insulinemia should be a primary target in long-acting formulation octreotide-LAR for acutely. More likely, metformin improves the war on childhood obesity. 6 months (7), 8 out of 44 subjects exhibited insulin resistance by acting on the liver to large decrements in weight (-12.6 ± 1.1 kg) reduce hepatic glucose output. As the liver References and BMI (-4.4 ± 0.4 kg/m2). In addition, improves its sensitivity to insulin, the 1. Rosenbaum M, Murphy EM, their caloric intake declined, which was pancreas (by the laws of mass action) Heymsfield SB, Matthews DE, Leibel RL almost entirely explained by cessation of reduces insulin output, and fasting insulin 2002 Low dose leptin administration carbohydrate intake –600 cal/day). The levels fall. This could attenuate or reverse reverses effects of sustained weight degree of pretreatment insulin hypersecre- the adipogenic process. Although mean reduction on energy expenditure and tion was a predictor of the weight re- weight reductions achieved with metformin circulating concentrations of thyroid sponse to octreotide. Lastly, leptin was have been modest (BMI losses of –0.5, – hormones. J Clin Endocrinol Metab also suppressed significantly (-27 ± 2.6, 1.3, -2.2 kg/m2), some individual subjects 87:2391-2394 from 68.2 to 44.7 ng/ml). Between the have demonstrated significant reductions, 2. Lustig RH 2001 The neuroendocrinol- weight loss and the leptin decline, we amounting to as much 10% of their initial ogy of childhood obesity. Ped Clin NA expected to see a decrease in REE, but weight, with corresponding declines in 48:909-930 amazingly the REE stayed exactly the leptin. One particular use for metformin 3. Niswender KD, Morton GJ, Stearns same. This demonstrated to us that these may be to combat the weight gain ob- WH, Rhodes CJ, Myers MG, Schwartz MW patients’ leptin resistance must have served in children taking certain psycho- 2001 Intracellular signalling. Key enzyme in improved. Indeed the improvement in tropic medications, which are known to leptin-induced anorexia. Nature 413:794- leptin sensitivity correlated with the cause massive weight gain. An added 795 degree of insulin suppression (8). Thus, beneficial effect of metformin is a subjec- 4. Lustig RH, Rose SR, Burghen GA, there appears to be a subpopulation of tive increase in spontaneous physical Velasquez-Mieyer P, Broome DC, Smith K, obese children and adults who exhibit activity. By improving insulin sensitivity, Li H, Hudson MM, Heideman RL, Kun LE insulin hypersecretion as the cause of reducing weight, reducing fasting glucose, 1999 Hypothalamic obesity in children both their weight gain and leptin resis- reducing food intake, and increasing caused by cranial insult: altered glucose tance, and in whom insulin suppressive activity, metformin has been promoted as a and insulin dynamics, and reversal by a strategies such as octreotide can be potential pharmacologic preventative somatostatin agonist. J Pediatr 135:162-168 successful. agent for Type 2 diabetes mellitus in 5. Lustig RH, Hinds PS, Smith KR, children (14). However, it should be noted Christensen RK, Kaste SC, Schreiber RE, Insulin sensitization and metformin that cessation of metformin therapy Rai S, Lensing S, Wu S, Xiong X 2003 Conversely, insulin resistance is a primary frequently leads to a rebound Octreotide treatment of pediatric hypotha- entity in some pediatric populations, hypersinsulinemia and rapid weight gain lamic obesity: a double-blind, placebo- particularly minorities. It is associated with (15), negating any beneficial effects seen controlled trial. J Clin Endocrinol Metab (in obesity and the metabolic syndrome during therapy. press) (consisting Type 2 diabetes, dyslipidemia, 6. Sigal RJ, El-Hashimy M, Martin BC, hypertension, and cardiovascular disease). Summary Soeldner JS, Krolewski AS, Warram JH Large amounts of intramyocellular and Reduction in insulinemia (either through 1997 Acute post-challenge intrahepatocellular lipid accumulate, which suppression of insulin hypersecretion with hyperinsulinemia predicts weight gain. correlate with, and may be the proximate octreotide, or through sensitization of Diabetes 46:1025-1029 cause of hepatic and muscle insulin insulin resistance with metformin) is a 7. Velasquez-Mieyer PA, Cowan PA, resistance. Defective muscle and hepatic relatively safe and effective strategy for Buffington CK, Arheart KL, Cowan GSM, glucose uptake and increased hepatic treatment of obesity. Reduction in Connelly BE, Spencer KA, Lustig RH 2003 glucose output and gluconeogenesis are insulinemia may work at the adipocyte to Suppression of insulin secretion promotes seen, which correlate with the degree of reduce the adipogenic stimulus, and at the weight loss and alters macronutrient hyperinsulinemia. However, the adipocyte brain to improve leptin sensitivity. Indeed, preference in a subset of obese adults. Int retains its insulin sensitivity. Thus, the many weight loss paradigms, including J Obesity 27:219-226 hyperinsulinemia of insulin resistance caloric restriction, exercise, the Atkins diet, allows for continued energy storage. continued on page 6 Section on Endocrinology Page 5
    • Lustig continued from page 5 Nutritional Endocrinology: A Novel Dietary Approach to Childhood Obesity 8. Lustig RH, Soberman JE, Velasquez- David S. Ludwig, MD, PhD unpredictable quantity and quality of food Mieyer PA 2003 Improvement in leptin Department of Medicine in nature. In order to maintain energy sensitivity correlates with insulin suppres- Children’s Hospital of Boston homeostasis, very different biological sion in obese subjects. Endocr Soc 85 Boston, MA actions (e.g., gluconeogenesis, glyco- (abstract) genolysis, lipogenesis, lypolysis) must C 9. Freemark M, Bursey D 2001 The onventional approaches to obesity occur depending upon whether an animal effects of metformin on body mass index treatment assume that all calories is feeding or fasting, and if feeding, and glucose tolerance in obese adoles- are alike with regard to body whether carbohydrate, protein or fat has cents with fasting hyperinsulinemia and a weight regulation; to lose weight, one been consumed. These biological actions family history of Type 2 diabetes. Pediat- must simply eat less or exercise more. are regulated by hormones that are, in rics 107:e55 Though appealing in its simplicity, this turn, regulated by diet. 10. Lustig RH, Christensen ML, Tosson notion belies the extraordinary difficulty of HM, Velasquez-Mieyer PA, Arheart KL, maintaining long-term weight loss for most Because of the central role of glucose in Danish RK, Burghen GA 2001 Racial obese patients. In this paper, I will energy homeostasis, dietary factors that dichotomy in the body mass index (BMI) consider the possibility that the hormonal alter blood glucose concentration can response to metformin pharmacotherapy effects of food may be more relevant to exert a particularly important influence on for obesity/insulin resistance in children. obesity treatment, from a practical many hormonal systems, providing the Soc Ped Research 46:550 (abstract) perspective, than calorie content. basis for interest in the glycemic index (3). 11. Lutjens A, Smit JL 1977 Effect of The glycemic index (GI) was proposed in biguanide treatment in obese children. For more than a century, certain hormones 1981 by Jenkins and colleagues as a Helv Paediatr Acta 31:473-480 were known to have profound effects on physiological basis for classifying 12. Ibanez L, Valls C, Potau N, Marcos body composition. Among the earliest carbohydrate-containing foods, describing MV, de Zegher F 2000 Sensitization to effective pharmacological treatments for how a particular food or meal affects blood insulin in adolescent girls to normalize obesity was thyroid extract, commonly glucose concentration in the postprandial hirsutism, hyperandrogenism, oligomenor- prescribed in the 1890s (though, as with state. Because refined starchy foods can rhea, dyslipidemia, and hyperinsulinism most other weight loss medication ever be digested into glucose essentially after precocious adrenarche. J Clin prescribed, unacceptable side effects without rate limitation, most items at the Endocrinol Metab 85:3526-3530 preclude its use for this purpose). In the base of the USDA Food Guide Pyramid 13. Kay JP, Alemzadeh R, Langley G, early 20th century, insulin deficiency was have a very high GI; by contrast, non- D’Angelo L, Smith P, Holshouser S 2001 identified as the cause of the profound starchy vegetables, nuts, legumes and Beneficial effects of metformin in weight loss observed in untreated type 1 fruit tend to have a low GI. normoglycemic morbidly obese adoles- diabetes mellitus. Conversely, primary cents. Metabolism 50:1457-1461 hypersecretion of insulin or exogenous To examine the hormonal effects of GI, we 14. Freemark M 2003 Pharmacologic peripheral insulin administration appears gave obese adolescents three isocaloric approaches to the prevention of Type 2 to promote weight gain (1, 2), as argued by meals in a cross-over fashion: instant diabetes in high risk pediatric patients. J Lustig in the preceding paper. Indeed, oatmeal (high GI), old-fashion oatmeal Clin Endocrinol Metab 88:3-13 numerous classical or newly identified (medium GI) or a vegetable omlet with fruit 15. Lustig RH, Rose SR, Pitukcheewanont hormones can affect energy balance, (low GI). We observed a marked increase P, Broome DC, Blackwell A, Burghen GA including (in addition to insulin and in insulin to glucagon ratio in the plasma 1998 Metformin effects on weight and thyroxin): leptin, cortisol, catecholamines, after the high- compared to the medium- or insulin secretion in adolescent females growth hormone, glucagon, GLP-1, GIP, low- GI meals, comprising a potent with obesity/hyperinsulinemia/acanthosis ghrelin, Peptide PYY, the sex steroids and stimulus for uptake of glucose into liver, nigricans. NCGS 11:9 (abstract) others. Some of these hormones or related muscle and fat. Though initially higher, signal transduction pathways are targets blood glucose dropped to especially low for ongoing obesity drug development. levels 4 to 5 hr after the high GI meal associated with a sharp rise in the counter- Less commonly recognized is that dietary regulatory hormones epinephrine and composition may affect hormone systems growth hormone. Free fatty acids were in fundamental ways. Indeed, the above- suppressed to a greater degree 2.5 to 4.5 hr mentioned hormones may have evolved in after the high GI meal compared to the part to integrate the continuous needs of other meals (4). animals for energy substrate with the continued on page 7 Section on Endocrinology Page 6
    • Ludwig energy balance progressively more 6. Agus MSD, Swain JF, Larson CL, Eckert Continued from page 6 difficult over the long-term, not because of EA, and Ludwig DS. Dietary composition any breakdown in the laws of thermody- and physiologic adaptations to energy This sequence of biological events namics. For this reason, a diet focused on restriction. Am J Clin Nutr 71: 901-907, following consumption of a high GI meal the hormonal effects of food, rather than 2000. may promote weight gain and/or antago- its calorie content, may constitute a more 7. Ludwig DS. Dietary glycemic index and nize weight loss through several mecha- effective approach to obesity prevention obesity. J Nutr 130: 280S-283S, 2000. nisms (3). First, the decreased availability and treatment in the prevailing environ- 8.Leibel RL, Hirsch J, Appel BE, and of circulating metabolic fuels, chiefly ment of food abundance. Checani GC. Energy intake required to glucose and free fatty acids, several hours maintain body weight is not affected by after the meal would be expected to Such a diet might contain abundance wide variation in diet composition. Am J stimulate hunger and food intake, as quantities of low GI foods including non- Clin Nutr 55: 350-355, 1992. occurs after experimental hypoglyemia. starchy vegetables, fruit, nuts and 9.Spieth LE, Harnish JD, Lenders CM, Second, the increased insulin secretion legumes; limited amounts of minimally Raezer LB, Pereira MA, Hangen SJ, and would tend to shunt substrate from processed grains and concentrated sugar; Ludwig DS. A low-glycemic index diet in oxidation in muscle to storage in fat, a adequate protein; and moderate (not low) the treatment of pediatric obesity. Arch notion supported by animal studies (3) fat. An outcomes assessment from our Pediatr Adolesc Med 154: 947-951., 2000. and metabolic balance studies of humans obesity program suggests that this diet is with diabetes receiving exogenous insulin feasible and realistic in practice. We found (5). Third, an energy-restricted high GI that children assigned to an ad libitum low diet may accentuate neuroendocrine GI diet lost about 7 lbs more weight over a adaptations that antagonize weight loss. mean of 4 months than those assigned to a Thus, we observed that resting metabolic conventional reduced-fat, energy-re- rate decreased significantly more in obese stricted diet (9). men treated with weight-reducing high compared to low GI diets (6). Clearly, much more research is needed in Remember to Vote! this young field of “nutritional endocrinol- Section on Endocrinology Though there are no published long-term, ogy,” including feeding studies to examine large scale randomized controlled trials on the mechanisms whereby dietary composi- Elections are open until April 30! the subject, short and medium term tion affects hormones and metabolism, and 1) Log into the AAP Members Only studies provide considerable support for long-term trials to evaluate clinical Channel (www.aap.org/moc). an important role of GI in the regulation of applications. Another fruitful area of feeding and body weight. Fifteen of 16 pursuit may be genotype-phenotype 2) Select the Section on Endocrinology single-day studies found increased interactions as applied to diet. (located on the left-hand side of the satiety, decreased hunger or less volun- screen , under the heading “Members”) tary energy intake after low compared to References by clicking on the section’s name. high GI foods or meals (7). Several cross- 1. Le Stunff C, Fallin D, Schork NJ, and over or parallel design studies of least 1 Bougneres P. The insulin gene VNTR is 3)Select the “2003 Election” link at the top month duration reported decreased associated with fasting insulin levels and of the page and follow the directions on adiposity or greater weight loss among development of juvenile obesity. Nat the ballot page to see a candidate subjects treated with a low compared to Genet 26: 444-446., 2000. biosketch or vote for your candidate of high GI diet (3). 2. Cusin I, Rohner-Jeanrenaud F, Terrettaz choice. J, and Jeanrenaud B. Hyperinsulinemia and This is not to imply that the biological its impact on obesity and insulin resis- Your AAP ID# is required to log into the effects of a low GI diet supercede the laws tance. Int J Obes Relat Metab Disord 16 Members Only Channel. of thermodynamics. Weight loss does Suppl 4: S1-11, 1992. Not sure of your AAP ID#? require establishment of a negative energy 3. Ludwig DS. The glycemic index: balance. Isoenergetic diets varying physiological mechanisms relating to n You can find your ID# on your dramatically in composition have similar obesity, diabetes, and cardiovascular Pediatrics mailing label (eliminate the effects on body weight, at least over the disease. JAMA 287: 2414-2423., 2002. last digit of the 7-digit number). short term, in the setting of a metabolic 4. Ludwig DS, Majzoub JA, Al-Zahrani A, n Contact the Customer Service Center research ward (8). However, this observa- Dallal GE, Blanco I, and Roberts SB. High at 1-866-THE-AAP1 or csc@aap.org. tion may have little direct relevance to glycemic index foods, overeating, and outpatient obesity treatment, where obesity. Pediatrics 103: E26 (6 pages), If you prefer to vote using a print ballot, patients today have virtually unlimited 1999. please contact: access to high energy-dense foods. 5. Carlson MG and Campbell PJ. Intensive Rebecca Marshall Ultimately, diets fail because increasing insulin therapy and weight gain in IDDM. Phone: 800/433-9016, ext 4079 hunger makes maintenance of a negative Diabetes 42: 1700-1707, 1993. E-mail: bmarshall@aap.org Section on Endocrinology Page 7
    • Etiology-Based Treatment of Pediatric Obesity: A Plea for Patience Jack A. Yanovski, MD, PhD producing alpha-MSH, and leading to a mutations disrupting POMC (alpha-MSH) Head, Unit on Growth and Obesity, DEB, beautifully choreographed set of changes processing. Elucidation of humoral NICHD intended to promote intake and decrease defects in other subgroups may soon be National Institutes of Health thermogenesis [5, 6]. Starvation-induced accomplished. Perhaps most intriguing to Bethesda, MD endocrine changes, to name a select few, pediatric endocrinologists are recent include increased cortisol, adrenaline, and findings that patients with the Prader Willi In 1524, Thomas Tusser wrote, “Make growth hormone, decreased thyroid and syndrome, a disorder associated with hunger thy sauce, as a medicine for gonadal hormones, and increased gut- extreme food-seeking behavior, have health.” Whether this advice was salutary derived ghrelin [5-8]. All of these systems higher ghrelin levels than are found in in the 1500s is not clear, but it certainly enable humans to survive periods of patients with other forms of obesity [11- appears to be rarely followed by severely starvation by decreasing energy expendi- 13]. Ghrelin infusions stimulate appetite in overweight children or their parents today. tures and increasing food-seeking behav- humans, at least in the short-term [14], and To the contrary—as the cost of calorie- iors. When faced with an overabundance the development of functional ghrelin dense foods has decreased and food of nutrients, these systems are designed antagonists will certainly be watched with availability has risen in the US, from 3400 not to keep us at an “ideal” body weight, great interest. kcal/d per capita in 1909-1919 to 3700 kcal/ but to store energy, in the form of triglycer- d per capita in 1990-1999 (with fat availabil- ide, for use during future fasts. Now that What these findings suggest is that there ity rising from 120 to 159 g/d per capita) our genomes have enabled us to construct may come a time when therapy for pediat- [1], it appears that hunger is ever more an environment where these stored ric obesity will be based upon an under- infrequent: overweight has become the calories are less frequently needed, the standing of the particular physiological norm for adults, and children are not far inevitable result would appear to be situation of each child. Can we look behind their parents: more than 15% of increasing weight. forward to an era when the full nosology children and adolescents now have a body of obesity will be established, and its mass index (BMI) greater than the 95th But obesity is not, in fact, inevitable for differential diagnosis, evaluation, and percentile (based on norms from the today’s youth—rather there appear to be specific treatments will be recited on 1970s), and 30% today have a BMI above more and less susceptible children and rounds by medical students as readily as the 85th percentile [2, 3]. Greater adiposity adults. The BMI distribution is now more they are now recited for hypocalcemia or has triggered a rise in the prevalence of skewed towards inordinately high values hypothyroidism? All of us impatiently impaired glucose homeostasis during than ever before, but there remain children await the development of an “obesity childhood, and we can expect a tidal wave and adults who by dint of their physiology panel” of hormones and genetic tests that of type 2 diabetes, dyslipidemia, hyperten- and behavior remain of normal weight. will enable us to match treatment to cause. sion, and ultimately cardiovascular disease Understanding the molecular and cellular to inundate the US populace. biology of weight-regulatory systems that The preceding two comments, by Drs. predispose us to obesity may therefore Lustig and Ludwig, present theory-based Although the causes of obesity are also help us deal with the current environ- attempts to modify peripheral insulinemia complex, a major factor in the rise in ment, as we uncover those systems that either pharmacologically or through obesity is likely to be the obesity-promot- help lean individuals stay lean. dietary manipulation in an effort to treat ing environment we have created interact- children with obesity. Other untailored ing with our “thrifty” genome. Our weight Single gene defects promoting weight gain approaches to reverse pediatric obesity regulating systems evolved not to keep us have now been demonstrated in a number that have been tried include decreasing fat lean when we are presented with a surfeit of animal models, and individuals with absorption with orlistat [15], altering of calories, but to promote survival of the mutations affecting gene function have energy expenditure with caffeine and human genome in times of inadequate been found for several of the genes ephedrine [16], and decreasing appetite nutrition. involved in leptin signal transduction. The with chlorphentermine [17]. The difficulty most prevalent of these are heterozygous for each of these approaches is that the The humoral milieu changes dramatically mutations decreasing signal transduction treatments prescribed likely specifically with food restriction: serum levels of of the melanocortin 4 receptor, which may ameliorate the physiologic problem only adipocyte-derived factors such as leptin be present in 1-3% of significantly for a small minority of the children studied. fall along with insulin, the decreases in overweight children and adults [9]. Far less In my opinion, none of the available leptin and insulin affect hypothalamic and common are inactivating mutations of the experimental approaches is ready for use brainstem [4] neurons, stimulating those leptin gene, for which exogenous leptin is by practitioners outside the research that secrete neuropeptide Y and agouti- effective therapy [10], inactivating related peptide and inhibiting those mutations of the leptin receptor, and continued on page 9 Section on Endocrinology Page 8
    • Yanovski, MD hyporesponsiveness, and neuroendocrine/ Most respondents felt that there were Continued from page 8 metabolic dysfunction of human congeni- differences in rejections by payer. When tal leptin deficiency. J Clin Invest, 2002. asked which payers were more likely to setting. Just as even the most intensive 110(8): p. 1093-103. provide reimbursement for diagnosis and behavioral weight management programs 11. Cummings, D.E., et al., Elevated treatment of obesity, over half of the lead to long-term decrements in degree of plasma ghrelin levels in Prader Willi respondents said none. A quarter of them overweight in less than 50% of children syndrome. Nat Med, 2002. 8(7): p. 643-4. said they didn’t know and others stated [18], none of the novel or intensive 12. DelParigi, A., et al., High circulating that they knew of no insurer who would approaches to obesity presently under ghrelin: a potential cause for hyperph- pay for the 278 series of diagnostic codes investigation will work for all. Hence, the agia and obesity in prader-willi syn- (obstructive sleep apnea, localized fat pad) plea for patience in the title of this essay: I drome. J Clin Endocrinol Metab, 2002. but stated that insurers will pay for the 251 believe we must await a better understand- 87(12): p. 5461-4. series (hyperinsulinism, insulin resistance). ing of which therapies help which patients, 13. Haqq, A.M., et al., Serum ghrelin In general, because of differences among lest many children be exposed to the risks levels are inversely correlated with body payers and differences in different of treatments with a very uncertain mass index, age, and insulin concentra- geographic areas, there was a wide variety potential for benefit. tions in normal children and are mark- of answers to the questions of who edly increased in prader-willi syndrome. J reimbursed diabetes education, nutrition References Clin Endocrinol Metab, 2003. 88(1): p. 174- counseling, and psychology services. A 1.Gerrior, S. and L. Bente, Nutrient Content 8. large number of respondents did not know of the U.S. Food Supply, 1909-99: A 14. Wren, A.M., et al., Ghrelin enhances who paid for which services for their Summary Report, in Home Economics appetite and increases food intake in practice and approximately half of the Research Report. 2002, U.S. Department of humans. J Clin Endocrinol Metab, 2001. respondents did not know the laws in the Agriculture, Center for Nutrition Policy 86(12): p. 5992. state regarding insurance reimbursement and Promotion: Washington, DC. p. 1-26. 15. McDuffie, J.R., et al., Three-Month for diabetes education, nutrition counsel- 2. Ogden, C.L., et al., Prevalence and Tolerability of Orlistat in Adolescents ing, or psychological services. trends in overweight among US children with Obesity- Related Comorbid Condi- and adolescents, 1999-2000. Jama, 2002. tions. Obes Res, 2002. 10(7): p. 642-650. It is clear that reimbursement for both 288(14): p. 1728-32. 16. Molnar, D., et al., Safety and efficacy of obesity and diabetes care is inconsistent 3. Flegal, K.M., et al., Prevalence and treatment with an ephedrine/caffeine and inadequate. One potential means of trends in obesity among US adults, 1999- mixture. The first double-blind placebo- improving reimbursement is to improve 2000. Jama, 2002. 288(14): p. 1723-7. controlled pilot study in adolescents. Int J coding. A potential next step is for the 4. Grill, H.J. and J.M. Kaplan, The neu- Obes Relat Metab Disord, 2000. 24(12): p. Section on Endocrinology is to put roanatomical axis for control of energy 1573-8. together a one to two page fact sheet balance. Front Neuroendocrinol, 2002. 17. Rauh, J.L. and R. Lipp, which will include information regarding 23(1): p. 2-40. Chlorphentermine as an anorexigenic the state laws dealing with insurance 5. Schwartz, M.W., et al., Central nervous agent in adolescent obesity. Report of its reimbursement for diabetes education, system control of food intake. Nature, efficacy in a double-blind study of 30 nutrition, and counseling and to provide 2000. 404(6778): p. 661-71. teen-agers. Clin Pediatr (Phila), 1968. 7(3): information as to which CPT codes might 6. Spiegelman, B.M. and J.S. Flier, Obesity p. 138-40. be successfully used for these services. In and the regulation of energy balance. 18. Epstein, L.H., et al., Ten-year outcomes addition, the most commonly used Cell, 2001. 104(4): p. 531-43. of behavioral family-based treatment for reimbursed ICD-9 codes will be listed. 7. Beer, S.F., et al., The effect of a 72-h fast childhood obesity. Health Psychol, 1994. Members will be able to access this on the on plasma levels of pituitary, adrenal, 13(5): p. 373-83. web and it will be included in a future issue thyroid, pancreatic and gastrointestinal of the newsletter. In addition, the American hormones in healthy men and women. J Academy of Pediatrics is putting together Endocrinol, 1989. 120(2): p. 337-50. Chairperson’s Column a task force on obesity. An important 8. Hansen, T.K., et al., Weight loss Continued from page 1 undertaking by this group will be an increases circulating levels of ghrelin in initiative to increase reimbursement for human obesity. Clin Endocrinol (Oxf), 2002. obesity services. 56(2): p. 203-6. Whether or not the full contractual amount 9. Vaisse, C., et al., Melanocortin-4 is paid depends on contractual adjust- We have a long way to go before we receptor mutations are a frequent and ments, Medicare rates, and Medicaid rules. receive adequate reimbursement for the heterogeneous cause of morbid obesity Many physicians are clearly frustrated, services we provide. But, at least, the [see comments]. J Clin Invest, 2000. 106(2): feeling that insurers don’t recognize the journey has begun. p. 253-62. importance of the educational and coun- 10. Farooqi, I.S., et al., Beneficial effects of seling aspects of diabetes care and the leptin on obesity, T cell time and energy it entails; others feel the payment given is completely arbitrary. Section on Endocrinology Page 9
    • Risk of cancer in former pituitary GH recipients in the UK: A Commentary Commentary on a recent provocative occurred more frequently than expected felt that in “not-at-risk” patients, the rates report by with 2 cases observed, 0.18 cases expected for the development of leukemia were not Lillian Meacham, MD with a Standardized Incidence Ratio (SIR) significantly increased ([18], [19], [20], Associate Professor Pediatrics of 11.1 (p=0.03). Mortality from cancer was [21], [22]). Emory University significantly increased for colorectal cancer Atlanta, GA and Hodgkin’s disease. Two subjects died In regard to the report by Swerdlow et al from colorectal cancer and with 0.13 deaths the following points should be consid- Swerdlow et al [1] report the incidence expected for a Standardized Mortality Ratio ered. First, the number of cases of cancer and mortality from cancer in 1,848 patients (SMR) 14.9 (p=0.02) and 2 subjects died reported were few. As the authors treated with human pituitary derived from Hodgkin’s disease with only 0.13 mention, the number of cases were small, growth hormone (GH) in the UK between deaths expected for an SMR 15.3 (p=0.02). with only 2 for Hodgkin’s disease and 2 1959-1985). During this time period, all One of the cases of colorectal cancer may for colorectal cancer. One case of use of human pituitary GH was approved have had a history of polyposis coli. colorectal cancer may have been predis- through a central committee in the UK and posed based on the history of polyposis the end of treatment was reported to the Since growth hormone is a mitogenic and coli. Because so few cases were expected, central authority. Patients were treated antiapoptotic hormone, the safety of its these results reached significance. It will with human pituitary GH with two to three use and the subsequent and perhaps take continuous ongoing monitoring in injections per week with each dose up to related development of cancer has been GH and oncology databases to confirm 10 IU. The cohort included 1209 men and studied over the last half century. There the significance of these observations. 639 women with 39% of the subjects less are three settings in which the question of Secondly the age of the cohort was than 10 years of age and 60% between the GH and cancer have been studied: 1) relatively young at the time of the report. ages of 10-19 at the start of therapy. The patients at risk secondary to a preceding It will be interesting to see if more cases of etiology of GHD was idiopathic in 53% malignancy and its treatment, 2) pathologic cancer emerge as the cohort ages, but of and a CNS tumor in 26% of the patients. excess of GH as in acromegaly, and 3) course more cases will be expected in an In addition there were 22 cases of normal subjects replaced with “normal” older control group as well. Third, the leukemia-lymphoma, 4 cases of chromo- amounts of GH. Several studies now refute dosing regimen used during this era was some fragility syndrome and 2 cases of the concern that GH shortens the event quite different from the dosing schedules glycogen storage disease. Information on free survival in childhood cancer survivors used today. . Dosing was not based on cancer occurrence and death were ([2], [3], [4], [5], [6], [7], [8], [9], [10], [11]). weight and was up to a dose of 10 units obtained from national registries of The lack of increase in rates of recurrence per injection. This would equal approxi- England, Wales, Scotland and Northern or progression is reassuring but Sklar et al mately 3-3.5 mg/dose. It is not clear how Ireland. There were 29,817 person years of recently reported a 3 fold increase in the results from this study, using relatively follow up in the determination of subse- second malignant neoplasms (SMN) in high doses per injection but less frequent quent cancer development which ended in patients enrolled in the childhood cancer dosing, would apply to cancer risk in 1995 and 39,178 person years of followup survivor study (CCSS) who were treated current GH dosing regimens. Fourth, in the mortality analysis which ended in with GH. In the report of the SMNs from although it is logical that exposure to a 2000. There were 12 cancers, 241 deaths the CCSS as in the Swerdlow report, the mitogenic agent might predispose to the with 10 attributable to cancer and 28 cases were too few in number to be sure it development or progression of cancer patients lost to follow up. This cohort was is not a chance finding, but the observa- during the exposure, it is less intuitively fairly young at the age of analysis with tions warrant further close clinical monitor- obvious that exposure years in the past is only 0.6% of the person years being 45 ing ([2]). In acromegaly, there have been relevant to cancer development decades years of age or older. All but one of the reported increased rates of colonic polyps later. Lastly, perhaps it was the clinical cancers and all the deaths occurred in and of gastrointestinal and specifically state of untreated GH deficiency and the patients older than 15 and all of the colo-rectal cancer ([12], [13] [14]). In metabolic syndrome that can be a conse- cancers developed after the GH had been normal subjects with upper quartile IGF-I, quence of GHD that predisposed this discontinued. lower quartile IGF-BP3 and increased IGF-I cohort to increased mortality. There were / IGF-BP3 ratios, there have been increased 241 overall deaths in 1,848 subjects which The data analysis excluded 469 patients rates of breast cancer, prostate and colon would yield 13% overall mortality. In this whose initial diagnosis might have cancer ([15], [16], [17]). Lastly, the concern fairly young cohort, this high mortality predisposed them to the development of a of cancer in “normal- not at risk” subjects rate might also be linked to unreplaced GH malignancy. In the adjusted cohort the treated with GH began in the 1980s with a deficiency. As the authors suggest, only overall risk of cancer was increased but flurry of reports of leukemia. After exten- not significantly. Colorectal cancer sive worldwide analysis of the data it was continued on page 11 Section on Endocrinology Page 10
    • Meacham 2959-64. continued from page 10 12. Pines, A., et al., Gastrointestinal Upcoming Meetings tumors in acromegalic patients. Am J through responsible monitoring by all Gastroenterol, 1985. 80(4): p. 266-9. groups who use GH and a collective 13. Ron, E., et al., Acromegaly and vigilance will we be able to discern the true gastrointestinal cancer. Cancer, 1991. 68(8): p. 1673-7. 2003 long-term risks of growth hormone therapy. 14. Orme, S.M., et al., Mortality and cancer incidence in acromegaly: a 30th European Symposium on retrospective cohort study. United Calcified Tissues References Kingdom Acromegaly Study Group. J Clin May 8-12, 2003 1. Swerdlow, A.J., et al., Risk of cancer in Endocrinol Metab, 1998. 83(8): p. 2730-4. Rome, Italy patients treated with human pituitary 15. Hankinson, S.E., et al., Circulating http://www.ectsoc.org growth hormone in the UK, 1959-85: a cohort study. Lancet, 2002. 360(9329): p. concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet, AAP Section on Endocrinology 273-7. 1998. 351(9113): p. 1393-6. Executive Committee Meeting 2. Sklar, C.A., et al., Risk of disease 16. Chan, J.M., et al., Plasma insulin-like April 30, 2003 recurrence and second neoplasms in growth factor-I and prostate cancer risk: Seattle, WA survivors of childhood cancer treated with growth hormone: a report from the a prospective study. Science, 1998. 279(5350): p. 563-6. LWPES Annual Meeting Childhood Cancer Survivor Study. J Clin 17. Cats, A., et al., Increased epithelial May 2-5, 2003 Endocrinol Metab, 2002. 87(7): p. 3136-41. cell proliferation in the colon of patients Seattle, Washington 3. Packer, R.J., et al., Growth hormone with acromegaly. Cancer Res, 1996. 56(3): www.lwpes.org replacement therapy in children with medulloblastoma: use and effect on tumor p. 523-6. 18. Nishi, Y., et al., Recent status in the AACE 12th Annual Meeting control. J Clin Oncol, 2001. 19(2): p. 480-7. occurrence of leukemia in growth May 14-18, 2003 4. Swerdlow, A.J., et al., Growth hormone hormone-treated patients in Japan. GH San Diego Marriott Hotel & Marina treatment of children with brain tumors Treatment Study Committee of the San Diego, CA and risk of tumor recurrence. J Clin Foundation for Growth Science, Japan. J www.aace.com Endocrinol Metab, 2000. 85(12): p. 4444-9. 5. Arslanian, S.A., et al., Growth hormone Clin Endocrinol Metab, 1999. 84(6): p. 1961- 5. ENDO 2003 therapy and tumor recurrence. Findings 19. Stahnke, N. and H.J. Zeisel, Growth The Endocrine Society’s in children with brain neoplasms and hormone therapy and leukaemia. Eur J 85th Annual Meeting hypopituitarism. Am J Dis Child, 1985. Pediatr, 1989. 148(7): p. 591-6. June 19-22, 2003 139(4): p. 347-50. 20. Stahnke, N., Leukemia in growth- Philadelphia, PA 6. Clayton, P.E., et al., Craniopharyn- hormone-treated patients: an update, www.endo-society.org gioma recurrence and growth hormone therapy [letter]. Lancet, 1988. 1(8586): p. 1992. Horm Res, 1992. 38(Suppl 1): p. 56- 62. American Board of Pediatrics 642. 21. Fradkin, J.E., et al., Risk of leukemia Certifying Examination in Pediatric 7. Ogilvy-Stuart, A.L., et al., Growth after treatment with pituitary growth Endocrinology hormone and tumour recurrence. Bmj, hormone. Jama, 1993. 270(23): p. 2829-32. August 18, 2003 1992. 304(6842): p. 1601-5. 22. Allen, D.B., et al., Risk of leukemia in www.abp.org 8. Ogilvy-Stuart, A.L., Safety of growth hormone after treatment of a childhood children treated with human growth malignancy. Horm Res, 1995. 44(Suppl 3): hormone: review and reanalysis. J Pediatr, p. 73-9. 1997. 131(1 Pt 2): p. S32-6. 9. Moshang, T., Jr., et al., Brain tumor recurrence in children treated with growth hormone: the National Coopera- tive Growth Study experience. J Pediatr, 1996. 128(5 Pt 2): p. S4-7. 10. Corrias, A., et al., Growth hormone treatment in irradiated children with brain tumors. J Pediatr Endocrinol Metab, 1997. 10(1): p. 41-9. 11. Leung, W., et al., Outcomes of growth hormone replacement therapy in survi- vors of childhood acute lymphoblastic leukemia. J Clin Oncol, 2002. 20(13): p. Section on Endocrinology Page 11
    • Lipid Disorders in Diabetes Lilliam Gonzalez de Pijem, MD have a lipid profile done at the time of diagnosis and yearly Department of Pediatrics afterwards. Type 2 diabetics should also have a lipid profile University of Puerto Rico Medical Center done at time of diagnosis, and if there are any lipid abnormalities San Juan, Puerto Rico present then, a repeat profile done to monitor dietary interven- tions. Cardiovascular disease (CVD) is the leading cause of morbidity NCEP Guidelines: The National Cholesterol Education programs and mortality in diabetic subjects. It accounts for approximately established lipid cut points in children and adolescents from 2 to three quarters of all diabetic hospitalizations, and it is the 19 years of age. underlying pathogenesis for macro vascular complications. Lipid Values in mg/dl Diabetes is considered a major risk factor for CVD. Prevalence of Total Cholesterol Diabetes has increased from approximately 2 million affected High > 200 individuals in the 1960’s to 17 million in 2002 and although 5 to Borderline 170 – 199 10% are type 1 diabetics, there is a marked increase of type 2 Acceptable <170 diabetics among children and adolescents. The greatest increase LDL-C has been in minority populations: African-Americans, Latinos, High > 130 Asian-Americans, and native Americans. Borderline 110 – 129 Acceptable <110 Type 1 Diabetes: Most everybody agrees that there is very little HDL – C difference between normal lipid levels and those of a well- Low males male< 35 controlled type 1 diabetic. The hypertriglyceridemia that is seen female<35 in uncontrolled diabetes will return to normal as insulin treatment Triglycerides is reinstated. Mild elevations of LDL Cholesterol and the lowering Quite elevated > 150 of HDL Cholesterol seen in uncontrolled diabetes return to normal Mod. Elevated male - Approx 120 with good diabetic control, as evidenced by lower Hgb A1c female -Approx 130 levels. Children with type 1 diabetes have total cholesterol greater than the 75th and 95th percentile, although no association Medical management: Children and adolescents with type 1 and between TC-CVD risk factor could be observed. Genetic and type 2 diabetes develop the subtle, life-threatening risks at a familial factor are also important in the assessment of lipid levels very early age. Their treatment must include aggressive life in children with diabetes. style changes, including exercise, limiting TV viewing to 2 hrs a day, avoiding other risk factors such as smoking, in order to Nevertheless, type 1 diabetics have an independently higher risk prevent or delay the complications of an increased atherogenic for cardiovascular problems and their disease begins at a much process and cardiovascular events. younger age than adults or adolescents with type 2 diabetes. · Nutritional therapy: Has to take into consideration the Jarvisalo et al, in Finland, using ultrasound techniques to patient’s age, gender, activity, type of diabetes, and other visualize the intima-medial thickness of the carotid and abdominal medical conditions. It should focus on attaining good glycemic aorta Type 1 diabetics found them to be markedly thickened as control – as evidenced by a normal or near normal Hgb A1c – compared to normal controls. and modifying lipid levels. Careful attention should be given to Type 2 Diabetes: Children with type 2 diabetes tend to have the ingestion of cholesterol, saturated fats and trans fats. central obesity and are insulin resistant. Visceral adiposity in · Exercise: Older children with type 1 Diabetes should these patients delivers an excessive load of free fatty acids to the exercise at least 20 – 30 minutes 3 times a week. Metabolic liver where it becomes a substrate for very low density lipopro- control should be assessed before exercising: if blood sugar > tein. Much of this is a consequence of increased caloric intake 250mg – exercise should be avoided until glycemic control is and decreased physical activity. These children have a very achieved; if < 100 mg, extra carbohydrate should be ingested. characteristic lipid pattern: a) increased triglycerides concentra- Adolescents with type 1 or type 2 Diabetes should try to get a 30 tion, b) decreased HDL cholesterol, and c) although LDL choles- – 60 minute exercise period 5 – 6 times a week. The same general terol concentration is normal or only mildly elevated, these LDL rules of blood glucose control apply. The timing of the exercise particle are smaller and denser than typical LDL particles. These period is very important. Avoid exercising late at night. particles are highly atherogenic. This triad is called diabetic · Pharmacological Management: If LDL - C dyslipidemia and it confers a highly increased risk for CVD to • < 110 - counsel patient and parents on a healthy diet type 2 diabetics. Individuals with type 2 diabetes have a much and lifestyle. Reevaluate in 1 year. higher mortality than non-diabetic individual with the same • 110 - 129 – Modified Step 1 diet: Total fat <25%, cholesterol level. Saturated fatty acids < 8 %, Monounsaturated fatty Screening: In our setting we recommend that type 1 diabetics continued on page 13 Section on Endocrinology Page 12
    • Gonzalez, MD Continued from page 12 Management of the Patient with Intersex: A Middle Way acids 10 –15%, Polyunsaturated Jorge Daaboul, MD considerable criticism from social scien- fatty acids 7-10 %, University of Florida tists, psychologists and individuals with Cholesterol <300 mg/d. Repeat Gainesville, FL intersex. They claim that in the past, the lipid profile in 3 months intersexed and their parents have not been • > 130 - Modified Step 1 diet. Editor’s note: The following article is fully informed of their condition. They Monitor lipids in 3 months, if goal also object to the standard model because a condensed version of an article written it has facilitated surgery that, in their not attained: Step 2 diet – as step by Dr JorgeDaaboul and pediatrician opinion, is disfiguring and destructive. 1 except that saturated fatty acids and ethicist Joel Frader, which has been They propose a complete ban on genital < 7 %, and Cholesterol < 200 mg., published in J Ped Endocrinol Metab vol. surgery and hormonal treatments (other if goal not achieved, consider 14, no 9, 1575-1583. I think he presents than that needed for the patients’ medical drug therapy some very thoughtful ideas on how to safety) until the affected person attains the • > 190 or > 160 + 1 risk factor – relate to families in these difficult cases. Step 2 diet; Children < 10 years of capacity to choose what, if anything, he or After reading it, I asked for some clarifica- she wants done cosmetically. Some age – bile acid resin. Avoid tion, and have included his responses to nicotinic acid because it tends to propose that parents should consider my concerns. PBK intersex as a variant of normal gender and raise the blood sugar. Statins have been successfully used in that families should adapt to a situation children. Monitor liver function rather different from their prenatal expecta- before and every 3 – 6 months “...male and female he created them...” tions. while on the statins. Genesis In both cases, the exclusion of parents from decision-making about sex assign- References: Humans hold the belief that there are two ment and gender-of-rearing violates our 1. Lipman TH, Hayman LL, Fabian CV, et sexes and that these sexes differ in biology current understanding of good medical al: Risk Factor for cardiovascular disease and behavior. Although dynamic and care for children. We presume that in children with Type 1 diabetes. 2000 Nurs varied insofar as specifics, all human parents, rather than strangers, best Res 49: 160-6 societies have powerful notions of what represent the current interests and future 2. Abraha A, Schultz , Konopelska-Bahu et constitutes male and female characteristics. prospects of their children. They can and al: Glycaemic control and familial factors Occasionally, nature challenges our should bring to bear their experience and determine hyperlipidaemia in early child- complacency in such matters: in the values on decisions about their children, hood diabetes. Oxford Regional Prospec- process of human fetal sexual differentia- analogous to the way competent patients tive Study of Childhood Diabetes. 1999 tion an individual develops who is not have authority to make choices about their 16:598-604 easily classified as male or female. Al- own care. Physicians should provide 3. Jarvisalo MJ, Nanto Salonen K, Irjala K, though these individuals have been called easily understood information on the risks, et al: Increased aortic intima-media hermaphrodites, current usage favors the benefits, and alternatives to available thickness: a marker of preclincal athero- term intersex or intersexed. In pediatrics, treatment; make what they believe to be sclerosis in high-risk children. 2001 individuals with sexual organs anatomically appropriate recommendations; assure Circulation 104 (24): 2943-7 intermediate between that which we adequate parental understanding of the 4. Jarvisalo ML, Putto-Laurilia A, Jartti L, et customarily call male or female are referred situation; and help parents choose what al: Carotid artery intime-media thickness in to as having “ambiguous genitalia.” best fits the family’s unique circumstances. children with type 1 diabetes. 2002 From this perspective, parents may Diabetes 51(2): 493-8 Over the last ten years the medical ap- permissibly disagree with the sex assign- 5. Haffner SM, Latho S, Ronemaa T et al. proach to intersexed individuals with ment, even when physicians believe their 1998: Mortality from coronary artery ambiguous genitalia has become contro- recommendation is based upon “objec- disease in subjects with type 2 diabetes versial. The standard model of medical tive” facts, logic, and experience. As long and in nondiabetic subjects with and care has held that sex assignment should as no physiologic harm threatens the child, without prior myocardial infarction. N Engl be made on the potential for reproductive choices about reproductive capacity or J Med 339:229-234 and sexual functioning and reconstructive pleasure during intercourse are personal 6. Data from the American Academy of genital surgery has been the norm. In matters, not medical questions to be Pediatrics. National Cholesterol Education practical terms, this model has often had answered by physicians abstracted from Program: Reprot of the Expert Panel on the effect of making sex assignment a the cultural and social milieu of the patient Blood cholesterol Levels in children and decision made by the medical team caring and the family. Under the moral and legal Adolescents. 1992 Pediatrics; 89: 525-584 for the intersexed patient with little parental input. This approach has come under continued on page 14 Section on Endocrinology Page 13
    • Dabooul, MD does the suggestion account for any cal indeterminacy. We need to do much continued from page 13 personal, individual dissonance that might more systematic research, especially develop for the child who perceives his or follow-up studies. Nevertheless, though her genitals differently from those com- systematic follow-up studies will help monly seen in the gender to which he or clarify general biological and behavioural precepts of the doctrine of informed she has been assigned. While biases can trends in intersexed, the data will very consent, health care professionals have change, it is not so clear that intersex likely confirm what we already know: that clear obligations to disclose fully all children should become vulnerable “foot there is enormous variability in how relevant information about diagnosis, soldiers” in a campaign to bring about a individuals with identical intersex condi- treatment options, and expected outcomes. gender-neutral society. Certainly, physi- tions evolve psychologically. There are By contemporary standards, good medical cians and intersex groups can understand conditions such as Complete Androgen decision making is decision making shared and accept parental anxiety about poten- Insensitivity Syndrome (AIS) where with patients and/or their valid surrogates. tially negative social and psychological outcomes are almost universally predict- Some now argue that decisions about consequences of deferring cosmetic able. But for most intersex conditions, the whether to have a poorly lubricated vagina surgery until intersex children can decide psychological outcomes will be so variable that can receive a penis, but will not likely for themselves. that, for each specific case, the outcome contribute to orgasm, or about retaining a Physicians often feel a sense of urgency to will be unpredictable. I would propose small penis which may experience orgasm, assign sex and gender to a newborn, that the appropriate care model is one in but will probably not achieve penetration, coupled with the belief that parents cannot which the focus is shifted away from the can only be made legitimately by individu- understand or tolerate complex medical precise medical diagnosis and towards the als themselves at such a time as they information and uncertainty. However, parents’ conception of what their child develop the cognitive skills and maturity experience in other areas of newborn care has, what they believe their child’s gender to appreciate the implications of the suggests that many parents want to to be, and how they see their child’s future available alternatives. That is, surgery participate in medical decisions and, given in the context of their family and of society should not occur until at least adoles- appropriate education and support, do in general. Each set of parents, with their cence, when the intersexed person can grasp intellectual and emotional ambigu- unique sociocultural beliefs and back- decide what he or she wants to do. In this ities. Many parents of extremely low birth grounds, would then make all decisions view, even parents should not authorize weight premature infants willingly enter regarding the care of their child. These appearance- and sensation-altering dialogues with neonatologists about decisions will be unique to each family and surgery, no matter how well informed they uncertain outcomes and alternative will reflect each family’s unique perspec- become or how well intentioned they are. approaches to care, including decisions to tive on the incredibly complex issues of This is a valid argument up to a point. limit or withdraw life support. Parents of sex and gender. Our task, as pediatric However, in cases where there is extreme infants born with hypoplastic left heart endocrinologists, should be to facilitate dissonance between the child’s assigned syndrome can, if given the opportunity to the parents’ decision making by providing gender and the child’s genitalia, the consider alternatives (the Norwood them with accurate information and clearly parents, as custodians of the child’s best sequence of reconstructive operations, explaining what is known and not known interests, may legitimately choose surgery. heart transplantation, or hospice care), about their child’s condition and the Children vary substantially in how well make informed and loving decisions outcomes of the medical and surgical they respond to others who look or consistent with the medical facts and their therapies used to treat it. behave differently from themselves. The own values and beliefs. Ambiguous variability in response depends, in part, on genitalia generally does not involve the In summary, it is my opinion that when all their personalities as well as what they urgency associated with birth at 23-28 the outcomes data on intersex are collected have been taught. It would not be weeks of gestation or a diagnosis of and analyzed we will discover that there surprising if intersex children became the hypoplastic left heart syndrome, nor does will be no one answer or management victims of harsh teasing and ridicule, if not it carry the weight of life and death protocol per intersex condition, but rather outright abuse, when peers see their decisions. Thus, pediatricians should many answers, each unique to a given genitals in the course of play commonly assume that parents of a newly born infant family. engaged in by preschoolers, or when the with intersex can participate meaningfully children are in school bathrooms or locker in an entirely open and honest discussion EDITOR. My main concern is that while IN rooms. It has been proposed that this of all available options. THEORY, having the parents make the situation could be addressed by having decision on sex of rearing with our parents limiting the social contacts of their The challenges to the treatment of children guidance is the best way, this would often intersex children with atypical genital with intersex have surely helped many to be quite difficult in practice. anatomy who do not have surgery to see how poorly we understand the minimize teasing, abuse and gossip. determinants of sex and gender identity DAABOUL: Actually, in practice parents Unfortunately, this could lead to the and how best to help those born with a usually rely on their physicians’ advice as impoverishment of opportunities for play, substantial degree of anatomic, and to sex of rearing, etc and there is no schooling, involvement in sports, or other sometimes, neurobiological or psychologi- valuable social and cultural activities. Nor continued on page 16 Section on Endocrinology Page 14
    • Growth curves: Are we missing the picture? Adda Grimberg, MD have created a selection pressure for taller It is time for us to encourage our primary Assistant Professor males. Certainly, the dramatic change in care colleagues to rethink their approach Children’s Hospital of Philadelphia human lifestyle makes this selection to growth. By switching our mind-set, we Philadelphia, PA pressure less applicable today than in our should be able to resist the time con- evolutionary past. Instead, cultural mores straints, biologic bias and social pressures have created social pressures that make in order to appreciate the importance of T ime constraints, biology and social pressures…three powerful forces heightism affect men more than women. growth as a fundamental tool in monitoring shape our approach to growth But there is another way to view growth. child health, a tool that is equally impor- failure…and make us miss an important Growth is a vital sign. It is a very sensi- tant in girls and boys. It is unclear if the clue to child health. The prevalent tive, albeit nonspecific, sign of a child’s results of our study suggest that there are paradigm of growth failure uses short over-all health. Growth failure can be the diseases being missed in girls who are not stature as an end-point; growth should be first and only sign of an underlying referred or if the percentage of organic monitored in children because short disease, preceding more classic “organic” disease in boys is being “diluted” by the stature is an undesirable outcome. symptoms by months or even years. It is large numbers of healthy boys who are for this reason that the American Academy referred. Either way, both genders suffer. The time constraints on most clinical of Pediatrics (AAP) and other health Girls may miss out on timely medical care, practices these days really push for organizations world-wide advocate for and healthy boys may undergo unneces- expediency. Physicians and nurses must routine, careful monitoring of child growth sary evaluations and tests that reinforce prioritize issues concerning their patients’ as a screen for child health. the perception that their short (or not so health and tend to them accordingly. tall, yet normal) stature is a problem that Short stature is not a disease. In fact, the Sadly, we are not doing so well in monitor- needs fixing. only direct consequence of short stature ing this key variable. In a survey of may be heightism — psychosocial primary care practices in eight areas across References: prejudice and discrimination against the United States, 10% of pediatric and Lipman TH, Hench K, Logan JD, DiFazio shorter individuals. Is short stature by 40% of family practices did not measure DA, Hale PM, Singer-Granick C. Assess- itself a problem for the child? This subject children at all well visits (Lipman et al, ment of growth by primary health care is hotly debated in the literature. Multiple 2000) despite the recommendations from providers. Journal of Pediatric Health studies demonstrate such prejudice, while the AAP (AAP, 2000). Additional errors Care. 2000;14:166-171. others point out that short individuals can were prevalent in measuring and plotting still achieve normal psychosocial function. techniques (Lipman et al, 2000). Why? American Academy of Pediatrics Policy Furthermore, the vast majority of children Statement - Committee on Practice and with short stature are perfectly healthy. We reviewed the charts of all children Ambulatory Medicine. Recommendations They are short because of ethnic differ- referred to the Children’s Hospital of for Preventive Pediatric Health Care. ences, familial short stature and/or Philadelphia Diagnostic and Research Pediatrics. 2000;105:645. constitutional delay of growth and Growth Center in 2001 for evaluation of puberty. short stature or growth failure (Grimberg et Adda Grimberg, Jessica L. Katz, Andrew J. al.,2003). Almost twice as many boys than Cucchiara, “Gender bias in growth In the primary care setting, close monitor- girls were referred, a significant departure referrals,” The Lawson Wilkins Pediatric ing of growth often assumes a lower from the expected equal proportions given Endocrine Society/Pediatric Academic priority than vigilant screening and that 5% of boys and 5% of girls by Societies’ Meeting, Seattle, WA, May, investigation of signs and symptoms of definition fall “below the curves.” At the 2003; submitted for publication. organic disease, like respiratory changes, time of referral, the height deficit was pain and fever. In contrast to the myriad greater in girls than boys, relative to both laboratory and radiologic tests we rely on, the general population and their parental Visit us on the Web! measuring a child’s growth and plotting it target heights. Yet more girls (41%) than on a growth curve is a freebie; the only boys (15%) were found to have underlying thing it costs is the time to do it. organic disease. Conversely, more boys www.aap.org/sections/ (72%) than girls (48%) were of normal height (height SD = > -2) or short but endocrinology If growth failure seems less important than other health concerns, biology and social healthy. Many of the same errors de- pressures make it seem even less so in scribed in the Lipman study were also girls. Mating patterns in many mammalian found in our review. species, including primates and humans, Section on Endocrinology Page 15
    • Daaboul, MD consented to surgery. Within six months to tell them the downside. I had a very continued from page 14 of the surgery the father had abandoned similar situation with a child of Afghani the family. He said he simply couldn’t parents who had partial AIS with a very stand to look upon his “mutilated” son. small phallus (1 cm), some posterior For the next several years every time the fusion and labioscrotal folds. The parents discordance between the physicians’ mother would come to clinic she would ask were adamant that the child be raised as a recommendation and the parents’ decision. me why we had made her boy into a girl. boy. After much discussion, we accepted For the vast majority of cases the pro- By age 12 the girl was dressing in boy’s the parent’s decision and the child posed recommendations will not represent clothes and telling everyone she was a underwent surgery to close the vaginal a change in sex assignment outcomes. boy. By age 16 she was overtly “male” in opening, etc. her dress and behavior. EDITOR: I would like to think that the I want to emphasize that the model I parents will always pick what they think When I was at Northwestern in Chicago, I propose does not call for the pediatric will be best for the child, but in many was involved in the case of a severely endocrinologist to abstract him/herself cultures, the desire for a son is very virilized CAH girl. The grandfather of the from the decision making process nor to strong, and parents may wish to have the infant was the minister of one of the support a course of action he/she does intersex child raised as a male even in largest African American churches in the not agree with. We can and should bring situations where we would be very city and he felt that God had intended this our experience and knowledge to the uncomfortable with that decision. child to be a boy. Despite our best efforts table. If we feel strongly about an issue to convince him otherwise over a period of we should express it to the parents to the DAABOUL: You’re absolutely correct, but 4 years (social work, psychology were all point that if we disagree strongly enough that is precisely the point of the article. involved), he was convinced that this we are not medically or legally obligated The decisions we make as physicians are infant was a miracle “boy” sent by God to execute the parents’ wishes (e.g. for heavily tainted by our culture and, very and the child’s mother was fully accepting surgery). Having said that, we should specifically, our subculture of pediatric of the grandfather’s vision. We were left and must accept the parents as the endocrinology which emphasizes scientific with two options: Accept the family’s ultimate decision makers and if we cannot rationality. The decisions that we recom- decision or challenge it in court and force abide their decision we are obligated to mend re: sex assignment may function well surgery. Our attorneys felt that we would refer them to another center and not and make sense in our culture and “sub- very likely lose the case based on parental coerce them into doing something they culture” but may make no sense whatso- rights (the best interests rule) and we don’t want to do. Basically, my thesis is ever to someone who does not share our dropped the matter. In the meantime, we that when all is said and done, only the belief system. After all, who is going to be alienated the family thereby compromising parents can medicolegally and ethically raising the child? The pediatric endocrine the child’s care. make the final decision as to sex assign- community or, for example, the lower ment. middle class Latino parents for whom male Lastly, although not necessarily relevant sex is extremely important and removal of to the thread of my argument, increasing One last comment, although no pediatric testes is the most horrific mutilation evidence shows that our previous concep- endocrinologist is obliged to accept/ imaginable (see below). We do not live in tion of sexual preference and gender support parental/patient wishes that he/ their world and what would work very well identity in CAH girls is deeply flawed. she strongly disagrees with, I would in our culture/subculture is potentially Many (up to a third) become lesbians and suggest that in cases where there is disastrous in theirs. an increasing number are stating that they extreme disagreement, pediatric endocri- have true gender dysphoria. nologists need to look beyond the basic EDITOR: Would you apply your reason- biology of the situation and try to ing to the case of a severely virilized EDITOR: What about the child with understand and be more open to the fact female infant with CAH if the parents want partial androgen insensitivity syndrome? that other cultures may not share our a boy? Should we let the family make the call and viewpoints on sex assignment. not bother them with the downside of male DAABOUL: Yes and let me give you a sex rearing (inadequate phallic size at a couple of cases I was personally involved minimum) or do we tell them the downside Statements and opinions in. and then say “But it’s your decision and expressed in this publication During my fellowship a severely virilized 8 we support you whatever you decide.” are those of the authors and day old female with CAH presented to our not necessarily those of the institution. The family was Mexican. We DABOOUL: Years ago we had a child American Academy of Pediatrics. recommended rearing as a female with with partial AIS whom we felt strongly surgical recession of the phallic structure would never be fully functional as a male and vaginoplasty. The family was con- and we tried unsuccessfully to convince vinced the child was a boy and strongly the family to agree to the surgery needed resisted our efforts, but through sheer for female rearing. I think we are obligated pressure the family very grudgingly Section on Endocrinology Page 16