V. Daniel Castracane

Detecting Insulin Resistance in Polycystic Ovary Syndrome: Purposes and Pitfalls

Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and “normal” insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to explain the pathophysiology of insulin resistance, to list the factors that affect insulin sensitivity, and to outline the various methods used to assess insulin sensitivity.

Leptin in Pregnancy

Abstract Leptin is a polypeptide hormone that aids in the regulation of body weight and energy homeostasis and is linked to a variety of reproductive processes in both animals and humans. Thus, leptin may help regulate ovarian development and steroidogenesis and serve as either a primary signal initiating puberty or as a permissive regulator of sexual maturation. Perhaps significantly, peripheral leptin concentrations, adjusted for adiposity, are dramatically higher in females than in males throughout life. During primate pregnancy, maternal levels that arise from adipose stores and perhaps the placenta increase with advancing gestational age. Proposed physiological roles for leptin in pregnancy include the regulation of conceptus growth and development, fetal/placental angiogenesis, embryonic hematopoiesis, and hormone biosynthesis within the maternal-fetoplacental unit. The specific localization of both leptin and its receptor in the syncytiotrophoblast implies autocrine and/or paracrine relationships in this endocrinologically active tissue. Interactions of leptin with mechanisms regulating pre-eclampsia and maternal diabetes have also been suggested. Collectively, therefore, reports suggest that a better understanding of the regulation of leptin and its role(s) throughout gestation may eventually impact those causes of human perinatal morbidity and mortality that are exacerbated by intrauterine growth retardation, macrosomia, placental insufficiency, or prematurity.

Leptin in Pregnancy: An Update

Abstract Leptin influences satiety, adiposity, and metabolism and is associated with mechanisms regulating puberty onset, fertility, and pregnancy in various species. Maternal hyperleptinemia is a hallmark of mammalian pregnancy, although both the roles of leptin and the mechanisms regulating its synthesis appear to be taxa specific. In pregnant humans and nonhuman primates, leptin is produced by both maternal and fetal adipose tissues, as well as by the placental trophoblast. Specific receptors in the uterine endometrium, trophoblast, and fetus facilitate direct effects of the polypeptide on implantation, placental endocrine function, and conceptus development. A soluble isoform of the receptor may be responsible for inducing maternal leptin resistance during pregnancy and/or may facilitate the transplacental passage of leptin for the purpose of directly regulating fetal development. The steroid hormones are linked to the regulation of leptin and the leptin receptor and probably interact with other pregnancy-specific, serum-borne factors to regulate leptin dynamics during pregnancy. In addition to its effects on normal conceptus development, leptin is linked to mechanisms affecting a diverse array of pregnancy-specific pathologies that include preeclampsia, gestational diabetes, and intrauterine growth restriction. Association with these anomalies and with mechanisms pointing to a fetal origin for a range of conditions affecting the individuals health in adult life, such as obesity, diabetes mellitus, and cardiovascular disease, reiterate the need for continued research dedicated to elucidating leptins roles and regulation throughout gestation.

Leptin and exercise

Short-term exercise (<60 min) studies suggest that leptin concentrations are not acutely affected in healthy males and females. Most reports of reductions in serum leptin may be attributed to circadian rhythms or hemoconcentration. For long-term (≥60 min) exercise, a reduction in leptin concentrations reported from 1 to 3 hr of running or cycling has been attributed to diurnal reduction in circulating leptin, independent of exercise. Exercise that produces a sufficient energy imbalance (kilocalorie intake versus kilocalorie expenditure) suppresses 24-hr mean and amplitude of the diurnal rhythm of leptin in women. Suppression of leptin concentrations may be counterbalanced by feeding and may explain consistent reports of reductions in leptin concentrations following extreme bouts of exercise such as marathons or ultramarathons. In addition, leptin concentrations are reduced 48 hr after long-term aerobic exercise and long-term resistance exercise is associated with delayed leptin reduction 9 hr postexercise. Training studies have documented that short-term exercise training (≤12 weeks) does not affect leptin levels, with the exception of patients with type 2 diabetes. Exercise training protocols that result in reduced fat mass will lower leptin concentrations, thus, most investigators have reported leptin concentrations after accounting for fat loss. There are disparate findings concerning long-term (>12 weeks) training studies, with a number of studies finding no effect of training on leptin concentrations other than effects induced by fat loss, and other studies finding reductions in leptin concentrations after accounting for fat loss. Exercise training-induced reductions in leptin levels have been attributed to alterations in energy balance, improvements in insulin sensitivity, alterations in lipid metabolism, and unknown factors. Hormone replacement does not seem to affect leptin adaptations to training. Patients with type 2 diabetes show delayed effects of short-term resistance exercise on leptin concentrations, reduced leptin levels with long-term training, and appear to be more sensitive to training-induced leptin adaptations than other populations.

Serum leptin concentration in women: effect of age, obesity, and estrogen administration

OBJECTIVE To compare serum leptin levels in normally cycling reproductive females (20-35 years old) with those in age-matched males, in women who were receiving oral contraceptives, and in older (postmenopausal) women (50-65 years old) who were or who were not receiving hormone replacement therapy. DESIGN Case-control study. SETTING Obstetrics and Gynecology Clinic, Texas Tech University Health Sciences Center-Amarillo, or the Exercise Physiology Laboratory at Southeastern Louisiana University. PATIENT(S) Normally cycling women between the ages of 20-35 years and age-matched controls who were receiving oral contraceptives. Postmenopausal women between the ages of 50-65 years who were or who were not receiving hormone replacement therapy. MAIN OUTCOME MEASURE(S) Serum leptin concentration. RESULT(S) In all groups, serum leptin concentrations were correlated significantly with body mass index. Leptin levels were significantly higher in young women than young men (P <.001), but no other statistically significant differences were found for the other three comparisons. CONCLUSION(S) Serum leptin concentrations expressed as a measure of adiposity (body mass index) are greater in young normally cycling females (20-35 years old) than in age-matched males. There is no difference in levels of serum leptin between young and postmenopausal (50-65 years old) women. Estrogen administration, either in young women who are receiving estrogen-progestin oral contraceptives or in postmenopausal women who are receiving hormone replacement therapy, does not effect serum leptin concentrations.

Exercise and Humoral Mediators of Peripheral Energy Balance: Ghrelin and Adiponectin

Ghrelin and adiponectin are recently discovered peptides that are both associated with energy homeostasis and insulin action. In addition, circulating levels of both peptides are altered in obese populations and are associated with poor health. Moreover, expression of ghrelin and adiponectin returns to normal levels following weight loss in obese patients. Because exercise training improves the health status of obese individuals and is associated with reduction of body weight, there is interest in the effects of exercise on adiponectin and ghrelin and whether these peptides may provide better understanding of how exercise improves health. Ghrelin levels do not increase in response to acute running and cycling in humans, and therefore ghrelin does not appear to regulate growth hormone (GH) release during exercise. There is some evidence that ghrelin levels are suppressed following resistance exercise of moderate intensity and are lower with higher GH concentrations during aerobic exercise. It has been suggested that negative feedback from elevated GH produces the reductions, but why these responses have not been consistently found in other studies and whether postexercise reduction in ghrelin affects appetite warrants further investigation. There are a few studies (but not all) that suggest long-term chronic exercise produces increases in ghrelin levels when weight loss is produced. Ghrelin levels are much higher in amenorrheic athletes than in ovulating exercisers or in female exercisers with a luteal phase defect, suggesting an association with reproductive function. Adiponectin concentrations do not change in response to moderate and strenuous running or low- and moderate- intensity cycling. Most studies have revealed that chronic exercise that improves fitness levels, increases insulin sensitivity, and reduces body weight, will increase resting adiponectin levels. However, it does not appear that changes in insulin sensitivity brought about by moderate exercise training are attributable to adiponectin.

Adiponectin responses to continuous and progressively intense intermittent exercise.

PURPOSE Adiponectin is a recently discovered adipocyte protein that is lower in patients with coronary artery disease and in Type II diabetics who have insulin resistance. Regular exercise is known to be a preventative factor in the development of atherosclerosis and Type II diabetes. Acute exercise increases insulin sensitivity; however, it also increases beta-adrenergic and glucocorticoid activities that may suppress adiponectin expression. Two experiments were conducted to determine whether acute exercise affects adiponectin concentrations. METHODS In the first experiment, six healthy male subjects completed 30 min of heavy continuous running exercise at 79% of VO (2max). In the second experiment, well-trained runners completed strenuous intermittent exercise consisting of treadmill running at 60, 75, 90, and 100% VO (2max). A resting control trial for the second experiment was also conducted. RESULTS Glucose and insulin were not altered significantly in the first experiment, but both increased significantly (P < 0.05) in the second experiment. A significant increase (P < 0.05) in adiponectin in the first experiment was no longer significant after correction for plasma volumes shifts. In the second experiment, there were significant (P < 0.05) changes in adiponectin concentrations over time but not a significant difference between adiponectin responses in exercise and control trials. CONCLUSIONS The data suggest that 30 min of heavy continuous running or more strenuous intermittent running does not stimulate an increase in production and release of adiponectin, and small increases in adiponectin concentrations resulting from the exercise may be attributed to normal plasma volume shifts.

Hormonal responses from concentric and eccentric muscle contractions

UNLABELLED Intense resistance exercise can acutely increase testosterone (T), free testosterone (FT), and growth hormone (GH) concentrations, but there are few investigations concerning acute endocrine responses to concentric (CON) and eccentric (ECC) contractile actions. PURPOSE The purpose of the study was to compare acute anabolic hormonal responses to bouts of dynamic CON and ECC contractions from multiple exercises at the same absolute load. METHODS Ten young men (age: 24.7 +/- 1.2 yr, weight: 85.45 +/- 24.2 kg, and height: 178 +/- 0.2 cm) completed two trials in counterbalanced fashion consisting of only CON or ECC contractions at the same absolute workload. Subjects performed four sets of 12 repetitions of bench press, leg extension, military press, and leg curl at 80% of a 10-repetition maximum with 90-s rest periods. Blood samples were collected pre-, post-, and 15-min postexercise. RESULTS There were significant increases in GH, T, and FT and lactate for both trials, but only GH and lactate were greater for the CON trial. CONCLUSION CON exercise increases GH concentrations to a much greater extent than ECC exercise at the same absolute load, and it is likely that greater GH responses were related to intensity rather than mode of contraction. Also, CON and ECC dynamic contraction trials at the same absolute workload elicited similar small but significant increases in T and FT, indicating that the greater metabolic stress produced by during the CON trial did not affect these hormone responses.

Endocrine and metabolic differences among phenotypic expressions of polycystic ovary syndrome according to the 2003 Rotterdam consensus criteria

OBJECTIVE The Rotterdam criteria extend the phenotypic spectrum of polycystic ovary syndrome (PCOS). We characterized endocrine and metabolic differences among women meeting the National Institutes of Health (NIH) definition for PCOS vs two novel phenotypes established by the European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine definition. STUDY DESIGN Endocrine and metabolic data from a retrospective analysis of 160 age- and weight-matched women with PCOS and 23 controls were compared. Insulin sensitivity indices were correlated with androgens, gonadotropins, and lipids within each phenotype. RESULTS Ovarian and adrenal androgens were highest in the NIH-defined PCOS group, lowest in the nonhyperandrogenic PCOS group, and intermediate in the hyperandrogenic ovulatory PCOS population. Insulin sensitivity indices, gonadotropins, and lipids were similar across all PCOS phenotypes. The magnitude of insulin resistance correlated with free testosterone only in the NIH-defined group. CONCLUSION Androgen levels are the major distinguishing endocrine feature differentiating phenotypic expressions of PCOS. Hyperinsulinemia correlates with free testosterone levels only in traditional NIH-defined women with PCOS.

Rpe, pain, and physiological adjustment to concentric and eccentric contractions

PURPOSE The purpose of the study was to compare perceptual (RPE and pain), cardiac (heart rate), lactate, and endocrine (cortisol) responses with concentric (CON) and eccentric (ECC) resistance exercise protocols using the same absolute workload. METHODS Eight healthy men with resistance-training experience participated in the study. Subjects completed two experimental trials consisting of either CON contractions or ECC contractions at the same absolute workload for each of four exercises: bench press, leg extension, military press, and leg curl. Subjects performed four sets of 12 repetitions at 80% of 10-RM with 90-s rest periods. Blood samples were taken before, immediately after, and 15-min postexercise. RESULTS There was a significant trial effect for RPE, with CON exercise eliciting a higher RPE than ECC exercise (6.71 +/- 0.51 and 4.10 +/- 0.27, respectively). A significant trial effect was also demonstrated for pain, with CON exercise producing a higher pain rating than ECC exercise (5.59 +/- 0.41 and 3.23 +/- 0.27, respectively). Significantly higher heart rates and lactates were also demonstrated during the CON trial. For cortisol, a significant interaction was revealed between the pre- and immediate posttrial measures but not an overall trial effect. Correlational analyses revealed a significant relationship between RPE and pain for both trials. CONCLUSIONS CON exercise elicits greater perceptual (higher RPE and pain rating), cardiac, lactate and cortisol response than ECC exercise at the same absolute workload. Data demonstrate that relative to absolute load, RPE and pain respond to resistance exercise in a similar fashion. Additionally, physiological cues are consistent with these perceptual data.