Paul Kaplowitz

Link Between Body Fat and the Timing of Puberty

Several recent studies suggest that the timing of the onset of puberty in girls has become earlier over the past 30 years, and there is strong evidence that the increasing rates of obesity in children over the same time period is a major factor. This article reviews studies from the United States that examined the age of menarche and the age of onset of breast development and pubic hair as a function of body mass index, which is a good surrogate measure of body fat. These studies are nearly all cross-sectional, so many questions remain unanswered. However, at least several studies show that girls who have relatively higher body mass index are more likely to have earlier menses, as well as a relationship between body mass index and other measures of pubertal onset. The evidence published to date suggests that obesity may be causally related to earlier puberty in girls rather than that earlier puberty causes an increase in body fat. In contrast, few studies have found a link between body fat and earlier puberty in boys. A growing body of evidence from both rodent and human studies suggests that leptin may be the critical link between body fat and earlier puberty. Leptin-deficient mice and humans fail to enter puberty unless leptin is administered, and rodent studies indicate that very low levels of leptin stimulate gonadotropin secretion both at the hypothalamic and the pituitary level. Current evidence indicates that leptin appears to play a permissive role rather than act as the critical metabolic signal initiating puberty. The linkage between body fat and the reproductive axis in girls may have evolved in mammals as a mechanism for ensuring that pregnancy will not occur unless there are adequate fat stores to sustain both the mother and the growing fetus.

Reexamination of the age limit for defining when puberty is precocious in girls in the United States : Implications for evaluation and treatment

In 1997 a study from the Pediatric Research in Office Settings network, based on pubertal staging of >17 000 girls between 3 and 12 years of age, indicated that breast and pubic hair development are occurring significantly earlier than suggested by our current guidelines, especially in African-American girls. In response to this article, the Lawson Wilkins Pediatric Endocrine Society undertook a comprehensive review of this topic. The primary conclusions of this review are: 1.  The current recommendation that breast development before age 8 is precocious is based on outdated studies. Until 1997, no data were available on pubertal staging in US girls that could have documented a trend to earlier maturation. 2.  The 1997 study indicates that stage 2 of breast and pubic hair development is being achieved ∼1 year earlier in white girls and 2 years earlier in African-American girls than previous studies have shown. 3.  Concerns that girls with moderately precocious puberty will be significantly short adults are overstated; most have adult height within the normal range. 4.  Therapy with gonadotropin-releasing hormone agonists has not been proven to have a substantial effect on adult height in most girls whose puberty starts between 6 and 8 years of age. 5.  New guidelines propose that girls with either breast development or pubic hair should be evaluated if this occurs before age 7 in white girls and before age 6 in African-American girls. No changes in the current guidelines for evaluating boys (signs of puberty at younger than 9 years) can be made at this time. normal puberty, breast development, pubic hair.

Subclinical Hypothyroidism in Children: Normal Variation or Sign of a Failing Thyroid Gland?

Subclinical hypothyroidism (SCH), defined by a normal total or free T4 level and a mildly elevated TSH (typically 5–10 mU/L), is common in children, but there is currently no consensus on management. Several recent pediatric studies indicate that progression of SCH to overt hypothyroidism (OH) is uncommon and that over a period of several years, elevated TSH usually either normalizes or persists but does not increase. The etiology appears to be multifactorial, with some cases representing minor developmental abnormalities, some related to obesity, some to mild autoimmune thyroiditis, and some associated with mutations in the gene for the TSH-receptor. There are no pediatric studies showing clinical benefit of treating these children with thyroid hormone, but additional studies in this area are needed. Since few cases of pediatric SCH progress to OH, treatment can be deferred, and periodic follow-up testing may be the preferred strategy, with elevated thyroid antibodies or a goiter being considered risk factors for eventual OH.

Altered blood pressure reactivity in adolescent diabetics

OBJECTIVE We examined hemodynamic responses to a variety of physiologic stimuli in 14 normotensive adolescents with type I diabetes and 45 healthy controls to determine whether structural vascular changes contribute to a reduced vasodilator capacity in adolescent diabetics. We asked, in adolescents with type I diabetes: (1) Are structural vascular changes present? (2) Are changes in the systemic vascular bed reflected in abnormal blood pressure regulation? and (3) Is abnormal vascular reactivity associated with either diabetes duration or control? METHODOLOGY Diabetic subjects were outpatients treated at the Medical College of Virginia, ages 13 to 18 years. Diabetes duration averaged 7.5 years. Each subject underwent an echocardiogram, dynamic and isometric exercise testing, and forearm plethysmography. RESULTS Compared to controls, diabetic subjects had (1) higher systolic and diastolic blood pressure during dynamic and handgrip exercise, (2) decreased forearm vasodilator capacity in response to ischemia, and (3) an increased aortic peak velocity. Group diastolic filling abnormalities were found, but these did not persist after adjustment for heart rate. The following variables were related to both diabetes duration and control (average glycosylated hemoglobin): (1) diastolic blood pressure during dynamic exercise, (2) resting forearm vascular resistance, and (3) forearm vascular reactivity. In addition, diabetes duration correlated with isometric exercise diastolic blood pressure, and diabetes control correlated with resting diastolic blood pressure. CONCLUSION In young diabetics we found that (1) abnormalities of the resistance vessels of the forearm may be present, (2) the degree of vascular change is related to diabetes duration and control, and (3) aortic distensibility may be impaired.

Update on Precocious Puberty: Girls are Showing Signs of Puberty Earlier, but Most Do Not Require Treatment

P recocious puberty is one of the most common endocrine disorders seen by primary care physicians and continues to be a major source of concern for both parents and providers. Since the author’s previous review on this subject in Advances In Pediatrics in 2004 [1], there have been several reports that have added to the knowledge base and confirmed that signs of puberty in girls are appearing earlier than in the past in the United States as well as in other countries. In this article, the author reviews what pediatricians should know about the physical findings seen during normal puberty and their hormonal basis. The evidence that signs of puberty are appearing earlier than 30 to 40 years ago, at least in girls, and the major theories about why this might be occurring are also discussed. However, the key point to be made is that pediatricians should be able to recognize the benign causes of early breast and pubic hair development, which are, at least in the United States, far more common than the cases that might benefit from treatment. The current state of knowledge concerning the diagnosis and treatment of central (true) precocious puberty (CPP) and the red flags that might point toward one of the rare causes of gonadotropin-independent precocious puberty (GIPP) are then reviewed.

Evaluation and Referral of Children With Signs of Early Puberty

Concerns about possible early pubertal development are a common cause for referral to pediatric medical subspecialists. Several recent studies have suggested that onset of breast and/or pubic hair development may be occurring earlier than in the past. Although there is a chance of finding pathology in girls with signs of puberty before 8 years of age and in boys before 9 years of age, the vast majority of these children with signs of apparent puberty have variations of normal growth and physical development and do not require laboratory testing, bone age radiographs, or intervention. The most common of these signs of early puberty are premature adrenarche (early onset of pubic hair and/or body odor), premature thelarche (nonprogressive breast development, usually occurring before 2 years of age), and lipomastia, in which girls have apparent breast development which, on careful palpation, is determined to be adipose tissue. Indicators that the signs of sexual maturation may represent true, central precocious puberty include progressive breast development over a 4- to 6-month period of observation or progressive penis and testicular enlargement, especially if accompanied by rapid linear growth. Children exhibiting these true indicators of early puberty need prompt evaluation by the appropriate pediatric medical subspecialist. Therapy with a gonadotropin-releasing hormone agonist may be indicated, as discussed in this report.

Navigating Recent Articles on Girls' Puberty: Where Should Our Patients Go for Evaluation?

first day. This can cause hypernatremia, which, similar to hyponatremia, results in brain injury or death (as pediatricians active 40 years ago vividly remember). To restore ECF before maintenance therapy is begun, many emergency departments initially give isotonic saline, 5 mL/kg per hour for 6 to 12 hours. After this, maintenance needs often can be met by oral fluids, but they will be safely met by IV maintenance therapy when given in recommended amounts. We proposed the more robust response of giving isotonic saline at a rate of 10 mL/kg per hour for 2 to 4 hours. This rapidly and safely expands ECF, suppresses ADH if elevated, and initiates normal urine flow.

Is There a Role for Metformin in the Treatment of Childhood Obesity

Childhood obesity often seems like an intractable problem, with a rising incidence, especially of severe obesity, over the last few decades and few effective treatment options. Lifestyle changes, including dietary modification and exercise, are effective only in a minority of patients, with significant and sustained weight loss most likely to occur in the setting of costly multidisciplinary programs. Thus, clinicians often turn to pharmacotherapy. Currently there is only 1 medication, orlistat, that is approved for childhood obesity, but its effect on weight is modest and its acceptability is limited by side effects related to decreased fat absorption. Metformin is the mainstay of treatment of type 2 diabetes in both children and adults, with effects mainly on improving insulin sensitivity and decreasing hepatic glucose output. Since 2000, there have been a large number of studies that have examined the use of metformin as a weight-loss drug in children with obesity. Although each study has been unique in its size, design, and the patient populations studied, the theme that emerges, as summarized in a systematic review in 2014 based on 14 randomized clinical trials,1 is that “metformin provides a statistically significant, but very modest reduction in BMI when combined with lifestyle interventions over the short term.” The latest addition to this literature, published in this issue of Pediatrics , is a study from Spain, “Metformin for obesity in prepubertal and pubertal children: A Randomized Controlled Trial,”2 which offers some benefit compared with previous clinical trials but leaves more questions unanswered … Address correspondence to Paul Kaplowitz, MD, Division of Endocrinology, Children’s National Health System, 111 Michigan Ave NW, Washington, DC 20010. E-mail: pkaplowi{at}childrensnational.org

Characteristics of children with the best and poorest first- and second-year growth during rhGH therapy: data from 25 years of the Genentech national cooperative growth study (NCGS)

BackgroundModels assessing characteristics contributing to response to recombinant human growth hormone (rhGH) response rarely address growth extremes in both years 1 and 2 or examine how children track from year to year. Using National Cooperative Growth Study (NCGS) data, we determined characteristics contributing to responsiveness to rhGH and the pattern of change from years 1 to 2.Patients and methodsHeight velocity standard deviation score (HV SDS) for 2 years for prepubertal children with idiopathic GH deficiency (IGHD) (n = 1899) and idiopathic short stature (ISS) (n = 1186) treated with similar doses for two years were computed. Group 1 = HV SDS < −1; 2 = HV SDS −1 to +1; 3 = HV SDS > +1.ResultsFor IGHD, mean age was 7.5 years and similar in all groups. Year 1 HV SDS was associated with greater body mass index (BMI) SDS, lower pre-treatment HV, baseline height SDS, greater target height SDS minus height SDS, and lower maximum stimulated GH (P <0.0001). Year 2, 172/271 (73%) in group 1 moved to either group 2 (n = 156) or 3 (n = 16). Year 2 HV SDS was associated with greater year 1 HV SDS (r = 0.045, P <0.0001), greater BMI SDS, taller parents and lower peak GH.For ISS, year 1 HV SDS was associated with greater BMI SDS and lower pre-treatment HV (P ≤0.0001). 109/169 (64%) in group 1 moved to group 2 (n = 90) or group 3 (n = 19). Greater year 2 HV SDS was related to year 1 HV SDS (r = 0.27, P <0.0001).ConclusionFor IGHD, multiple characteristics contributed to best first-year response but for ISS, best first-year HV SDS was associated only with BMI SDS and inversely with pre-treatment HV. For both GHD and ISS, year 1 HV SDS was not a strong enough predictor of year 2 HV SDS to use first-year HV alone to determine GH continuation.

Case report: rapid spontaneous recovery from severe hypothyroidism in 2 teenage girls

BackgroundWhile it is recognized that patients sometimes recover from autoimmune hypothyroidism, little is known about how rapidly this may occur.Case reportsTwo 13 year old girls had severe primary hypothyroidism (total T4 14.2 nmol/L with TSH 468 miU/L and total T4 7.7 nmol/L with TSH 183 miU/L) accompanied by goiter and positive thyroid peroxidase antibodies. There were delays in starting thyroid hormone replacement, and complete reversal of hypothyroidism was documented within 2 months in both cases. One of the girls had recurrence of severe hypothyroidism after being euthyroid for 18 months.Review of literatureThere are few published studies which have looked systematically at reversibility of acquired hypothyroidism, but one Japanese study found that recovery from autoimmune hypothyroidism may occur within weeks. Other causes of primary hypothyroidism (TSH-blocking antibodies, iodine excess, medications) seem less likely, so this probably represents rapid spontaneous reversal of autoimmune hypothyroidism.ConclusionPatients with severe autoimmune hypothyroidism may have spontaneous normalization of thyroid tests within weeks to months after diagnosis. This suggests that reevaluating the need for thyroid hormone replacement in selected patients with persistently normal TSH during therapy should be considered.