Christopher R. McCartney

Obesity and the pubertal transition in girls and boys

Childhood obesity has become a major health concern in recent decades, especially with regard to metabolic abnormalities that impart a high risk for future cardiovascular disease. Recent data suggest that excess adiposity during childhood may influence pubertal development as well. In particular, excess adiposity during childhood may advance puberty in girls and delay puberty in boys. Obesity in peripubertal girls may also be associated with hyperandrogenemia and a high risk of adolescent polycystic ovary syndrome. How obesity may perturb various hormonal aspects of pubertal development remains unclear, but potential mechanisms are discussed herein. Insulin resistance and compensatory hyperinsulinemia may represent a common thread contributing to many of the pubertal changes reported to occur with childhood obesity. Our understanding of obesitys impact on pubertal development is in its infancy, and more research into pathophysiological mechanisms and longer-term sequelae is important.

Maturation of Luteinizing Hormone (Gonadotropin-Releasing Hormone) Secretion across Puberty: Evidence for Altered Regulation in Obese Peripubertal Girls

CONTEXTnPeripubertal obesity (body mass index-for-age >or= 95%) in girls is associated with hyperandrogenemia. LH likely contributes to this relationship, but overnight LH secretion in obese girls is poorly characterized.nnnOBJECTIVEnThe aim of the study was to evaluate LH pulse characteristics in obese girls throughout pubertal maturation.nnnDESIGNnWe conducted a cross-sectional analysis.nnnSETTINGnThe study was performed in a general clinical research center.nnnPARTICIPANTSnEight nonobese and five obese Tanner 1-2 girls participated, as well as 32 nonobese and 12 obese Tanner 3-5 girls.nnnINTERVENTIONnBlood samples were collected every 10 min overnight (from 1900 to 0700 h).nnnMAIN OUTCOME MEASURESnLH pulse frequency, amplitude, and mean LH were measured in three 4-h time blocks (block 1, 1900-2300 h; block 2, 2300-0300 h; and block 3, 0300-0700 h).nnnRESULTSnTanner stage 1-2 nonobese girls demonstrated nocturnal increases of LH frequency (P < 0.01, block 1 vs. 2) and mean LH (P < 0.05, block 1 vs. 2 and 3). Obese Tanner 1-2 girls had lower 12-h LH frequency and LH amplitude (P < 0.05 for both), with no overnight changes of LH pulse parameters. Compared to normal, LH frequency was elevated in Tanner 3-5 obese girls (P < 0.01 in all blocks), whereas LH amplitude was low (P < 0.05 in all blocks). Overnight increases of LH amplitude were observed in nonobese Tanner 3-5 girls (P < 0.0001), but not in obese Tanner 3-5 girls.nnnCONCLUSIONSnObesity in prepubertal and early pubertal girls is associated with reduced LH secretion and reduced nocturnal changes of LH. In later pubertal girls, obesity is linked with reduced LH amplitude, but elevated LH frequency; the latter may reflect effects of hyperandrogenemia.

Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation

CONTEXTnAdult women with polycystic ovary syndrome (PCOS) have decreased GnRH pulse generator sensitivity to progesterone (P)-mediated slowing. This defect is androgen mediated because it is reversed with androgen receptor blockade. Adolescent hyperandrogenism often precedes PCOS.nnnOBJECTIVEnThe aim of the study was to evaluate GnRH pulse generator sensitivity to P-mediated slowing in normal and hyperandrogenic girls.nnnDESIGNnWe conducted a controlled interventional study.nnnSETTINGnThe study was conducted in a general clinical research center.nnnPARTICIPANTSnA total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied.nnnINTERVENTIONnFrequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P.nnnMAIN OUTCOME MEASUREnWe measured the slope of the percentage reduction in LH pulse frequency as a function of d 7 P (slope).nnnRESULTSnOverall, Tanner 3-5 HA subjects were less sensitive to P-mediated slowing than Tanner 3-5 NC (slope, 4.7 +/- 3.4 vs. 10.3 +/- 7.7; P = 0.006). However, there was variability in the responses of HA subjects; 15 had P sensitivities within the range seen in NC, whereas nine were relatively P insensitive. The two groups had similar testosterone levels. Fasting insulin levels were higher in P-insensitive HA girls (39.6 +/- 30.6 vs. 22.2 +/- 13.9 microIU/ml; P = 0.02), and there was an inverse relationship between fasting insulin and P sensitivity in HA girls (P = 0.02). Tanner 1-2 NC had lower testosterone levels and were more P sensitive than Tanner 3-5 NC (slope, 19.3 +/- 5.8; P = 0.04).nnnCONCLUSIONSnHyperandrogenism is variably associated with reduced GnRH pulse generator sensitivity to P-mediated slowing during adolescence. In addition to androgen levels, insulin resistance may modulate P sensitivity.

Polycystic Ovary Syndrome in Adolescence

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive‐aged women and is characterized by hyperandrogenemia, menstrual dysfunction, and polycystic ovarian morphology. The hormonal abnormalities inherent in PCOS often begin in adolescence and include hyperinsulinemia and rapid luteinizing hormone (LH) pulse frequency, both of which mediate ovarian and adrenal overproduction of androgens. Although differences exist regarding the diagnostic criteria for PCOS, we believe that hyperandrogenemia is the final common pathway for the development of adolescent PCOS, and we propose a hypothesis to illustrate such. Recognizing and reducing androgen levels in adolescence is critical given their association with the metabolic syndrome (MBS), diabetes, and infertility in adulthood.

Childhood obesity and its impact on the development of adolescent PCOS.

Obesity exacerbates the reproductive and metabolic manifestations of polycystic ovary syndrome (PCOS). The symptoms of PCOS often begin in adolescence, and the rising prevalence of peripubertal obesity has prompted concern that the prevalence and severity of adolescent PCOS is increasing in parallel. Recent data have disclosed a high prevalence of hyperandrogenemia among peripubertal adolescents with obesity, suggesting that such girls are indeed at risk for developing PCOS. Obesity may impact the risk of PCOS via insulin resistance and compensatory hyperinsulinemia, which augments ovarian/adrenal androgen production and suppresses sex hormone-binding globulin (SHBG), thereby increasing androgen bioavailability. Altered luteinizing hormone (LH) secretion plays an important role in the pathophysiology of PCOS, and although obesity is generally associated with relative reductions of LH, higher LH appears to be the best predictor of increased free testosterone among peripubertal girls with obesity. Other potential mechanisms of obesity-associated hyperandrogenemia include enhanced androgen production in an expanded fat mass and potential effects of abnormal adipokine/cytokine levels. Adolescents with PCOS are at risk for comorbidities such as metabolic syndrome and impaired glucose tolerance, and concomitant obesity compounds these risks. For all of these reasons, weight loss represents an important therapeutic target in obese adolescents with PCOS.

Maturation of Sleep–Wake Gonadotrophin-Releasing Hormone Secretion Across Puberty in Girls: Potential Mechanisms and Relevance to the Pathogenesis of Polycystic Ovary Syndrome

Neuroendocrine mechanisms underlying the progression of sleep–wake gonadotrophin‐releasing hormone (GnRH) pulse secretion across puberty have remained enigmatic. Here, the changes of sleep–wake luteinising hormone (LH) (and, by inference, GnRH) pulse secretion across puberty in normal girls are reviewed, primarily focusing on available human data. It is suggested that the primary control of GnRH pulse frequency changes across puberty, with sex steroid feedback exerting minimal control during childhood, but primary control during adulthood. A working model is proposed regarding how such a transfer of GnRH pulse frequency control may partly account for the prominent day–night differences of GnRH pulse frequency characteristic of puberty. How this model may be relevant to the genesis of abnormal GnRH secretion in peripubertal girls with hyperandrogenaemia is then described.

Decision Analysis of Discordant Thyroid Nodule Biopsy Guideline Criteria

CONTEXTnRecently published guidelines are discordant regarding diagnostic approaches to small (10-14 mm) thyroid nodules.nnnOBJECTIVEnThe objective of the study was to explore the relative desirability of alternative diagnostic approaches to small thyroid nodules using decision analysis.nnnDESIGNnFour diagnostic approaches to a 10- to 14-mm thyroid nodule are modeled: 1) observation only, consistent with American Thyroid Association guidelines; 2) routine fine-needle aspiration biopsy (FNAB), an approach traditionally chosen by many endocrinologists and consistent with American Thyroid Association guidelines; 3) FNAB only when microcalcifications are present, as recommended by Society of Radiologists in Ultrasound guidelines; and 4) FNAB only when the nodule is hypoechoic and has at least one other ultrasonographic risk factor, as endorsed by American Association of Clinical Endocrinologists guidelines.nnnMAIN OUTCOME MEASURESnMeasures included expected values; a priori likelihoods of prespecified outcomes; and two-way sensitivity analyses based on the utility of observation only in the setting of thyroid cancer and thyroid surgery for benign, asymptomatic thyroid disease.nnnRESULTSnExpected values (EVs) were similar among decision alternatives modeling Society of Radiologists in Ultrasound guidelines, American Association of Clinical Endocrinologists guidelines, and routine observation (EVs from 0.912 to 0.927). Routine FNAB had the lowest EV (0.757-0.861), primarily related to a high a priori likelihood of having surgery for a benign nodule.nnnCONCLUSIONSnAs a general approach to 10- to 14-mm thyroid nodules, routine FNAB appears to be the least desirable. This analysis offers additional data that physicians can use when choosing diagnostic approaches to small thyroid nodules based on perceived risks of delayed cancer diagnosis and unnecessary thyroid surgery.

Blunted Day-Night Changes in Luteinizing Hormone Pulse Frequency in Girls With Obesity: the Potential Role of Hyperandrogenemia

CONTEXTnPuberty is marked by sleep-associated changes in LH pulse frequency and amplitude. Early pubertal girls with obesity exhibit blunted day-to-night changes in LH secretion; whether this occurs in late pubertal obese girls is unknown.nnnOBJECTIVEnThe objective of the study was to test two hypotheses: 1) blunted day-to-night changes in LH secretion occur in both early and late pubertal obese girls, and 2) such alterations are specifically associated with hyperandrogenemia.nnnDESIGNnThis was a cross-sectional analysis.nnnSETTINGnThe study was conducted at a clinical research center.nnnPATIENTS OR OTHER PARTICIPANTSnTwenty-seven early pubertal, premenarcheal girls (12 of whom were obese) and 63 late pubertal (postmenarcheal) girls (27 of whom were obese) participated in the study.nnnINTERVENTIONnBlood samples were taken every 10 minutes from 7:00 pm to 7:00 am.nnnMAIN OUTCOME MEASUREnChange in LH pulse frequency [LH interpulse interval (IPI)] from daytime hours (7:00 pm-11:00 pm, while awake) to nighttime hours (11:00 pm to 7:00 am, while generally asleep).nnnRESULTSnBoth nonobese and obese postmenarcheal girls demonstrated significant day-to-night decreases in LH pulse frequency (IPI increases of 33% and 16%, respectively), but day-to-night changes were blunted in obese girls (P = .004, obese vs nonobese). Day-to-night LH pulse frequency decreased significantly in postmenarcheal obese subjects with normal T concentrations (26% IPI increase) but not in those with hyperandrogenemia. Similar differences were evident for LH pulse amplitude. Nonobese and obese early pubertal girls exhibited nonsignificant differences in day-night LH pulse frequency (day to night IPI increase of 26% vs decrease of 1%, respectively).nnnCONCLUSIONSnDay-to-night changes in LH pulse secretion are blunted in postmenarcheal obese adolescent girls. This phenomenon may in part reflect hyperandrogenemia.

Differential Sleep-Wake Sensitivity of Gonadotropin-Releasing Hormone Secretion to Progesterone Inhibition in Early Pubertal Girls

Context: Early pubertal luteinizing hormone (LH), and by inference gonadotropin-releasing hormone (GnRH), pulse secretion is marked by high nocturnal but low daytime frequency; however, the underlying mechanisms remain unclear. Plasma concentrations of progesterone, the major regulator of GnRH frequency in women, increase in the early morning in early pubertal girls and may help slow daytime GnRH frequency. Objective: To evaluate the effect of progesterone on LH pulse frequency in early to mid-pubertal girls. Design: Controlled interventional study. Setting: General clinical research center. Participants: Eighteen non-obese, non-hyperandrogenemic Tanner 1–3 girls. Intervention: Twelve-hour (19:00–07:00 h) blood sampling with or without oral progesterone administration (25–50 mg at 16:00 and 20:00 h). Main Outcome Measure: LH pulse frequency. Results: Girls receiving progesterone (n = 5) exhibited lower 12-hour LH pulse frequency than controls (n = 13), but this difference was not statistically significant (average interpulse intervals 196.0 ± 61.9 and 160.4 ± 67.1 min, respectively; p = 0.2793). In contrast to controls, however, girls receiving progesterone exhibited no LH pulses during waking hours (19:00–23:00 h; estimated interpulse interval 326.0 ± 52.7 vs. 212.0 ± 120.9 min; p = 0.0376), while nighttime (23:00–07:00 h) interpulse intervals were similar (174.8 ± 62.0 vs. 167.5 ± 76.9 min, respectively; p = 0.7750). Conclusions: Exogenous progesterone acutely suppressed daytime, but not nocturnal, LH pulse frequency in early to mid-pubertal girls, suggesting that GnRH pulse frequency is differentially regulated by progesterone depending on sleep status.

Cardiovascular risk and combined oral contraceptives: clinical decisions in settings of uncertainty.

Although generally safe, combined oral contraceptives (COCs) are associated with risks, including an estimated 2-fold increased relative risk of cardiovascular events. For most women taking COCs for contraception, absolute cardiovascular risks are very low, and the overall risks of COCs are outweighed by the risks of unwanted pregnancy. Nonetheless, risks of COCs may be excessive in some women, and both the American College of Obstetricians (ACOG) and the World Health Organization (WHO) have offered contraindications for COC use. Complicating this issue, COCs are commonly used for reasons other than contraception (eg, polycystic ovary syndrome, which is associated with subfertility and cardiovascular risk factors). Thus, in some clinical scenarios, ACOG and WHO guidelines may offer incomplete guidance regarding whether COC use would be associated with an unacceptable risk-benefit ratio. We propose that cardiovascular risk calculators may be helpful in some patients, as an adjunct to ACOG and WHO guidelines, by allowing physicians to estimate the attributable risk of COC-related cardiovascular events.