The Microbiota and Transgenomic Networks: Potential Implications for Maternal-Fetal Medicine.

The maternal microbiota has long been considered a potential cause for adverse perinatal outcomes. Gene expression regulators in prokaryotic and eukaryotic cells are influenced by changes in their microenvironments. We propose the novel idea that during in utero development, an adaptive and dynamic gene-regulatory cross talk might exist between the host genome and the maternal microbiota. Understanding these cross talks could increase the appreciation for the discovery of new diagnostics and therapeutics in maternal-fetal medicine.

No effect of menstrual cycle phase on glucose and glucoregulatory endocrine responses to prolonged exercise.

INTRODUCTION: Prolonged exercise requires increased utilization of blood glucose and adjustment of glucoregulatory hormones. Estrogen can reduce hepatic gluconeogenesis which could affect insulin concentrations. Amylin is co-secreted with insulin and controls influx of glucose into the blood. PURPOSE: To determine the effect of menstrual cycle stage on glucose, leptin, and pancreatic hormone responses to prolonged (90 min) exercise. METHODS: Five healthy, eumenorrheic women (24.6 ± 5.1 years; 67.4 ± 1 kg) were monitored for 3 months to determine menstrual cycle length. Subjects completed a preliminary session to determine exercise workloads and, in a fasted condition, completed two randomized 90-min treadmill exercise trials at 60 % VO2max during the early follicular (EFX) and mid-luteal phase (MLX) of their menstrual cycle. Blood samples were analyzed for glucose, insulin, C-peptide, amylin, glucagon, leptin, and cortisol concentrations at rest (-30 and 0 min), during exercise (18, 36, 54, 72, and 90 min) and after 20 min of recovery. RESULTS: No changes in amylin, leptin, or cortisol occurred for EFX and MLX trials. A significant (p < 0.05) time effect occurred for glucose, insulin, and glucagon with reduced insulin across the exercise trial and increases in glucose and glucagon later in the trial, but there were no differences between the EFX and MLX trials. CONCLUSIONS: Menstrual cycle stage does not affect glucose, insulin, C-peptide, amylin, glucagon, cortisol, and leptin responses to prolonged exercise; however, the exercise reduces insulin and increases glucose and glucagon concentrations. This is the first study to determine acute effects of exercise on amylin and other glucoregulatory hormone responses in women.

Maternal serum leptin in the pregnant rat: fetal-placental implantation number and progesterone.

PURPOSE: This study was designed to determine whether there is a role of the placenta in the regulation of maternal serum leptin levels in the pregnant rat. METHODS: We have adjusted the number of fetal-placental implants on day 9 in the pregnant rat by aspirating fetal-placental units to adjust the number to 1-2, 4-5 per rat or >10 in controls. Serum levels of leptin and progesterone were determined by radioimmunoassay. A separate group of pregnant rats were ovariectomized and maintained with progesterone silastic capsules (10, 20 or 40 mm). RESULTS: In the pregnant rats with varied fetal-placental implant numbers, the maternal serum leptin were greatest in the group with the smallest number (1-2) of implants; intermediate in the midgroup (4-5 implants); and lowest in the group with a full complement of implantations (>10) (p < 0.001). Serum progesterone levels are lowest in the 1-2 implantation group. In the ovariectomized rats there was a stepwise decline in serum leptin (p < 0.05) as the dose of progesterone increased (p < 0.01). Both of these studies suggest that progesterone suppressed maternal serum leptin levels. CONCLUSIONS: Increasing placental mass is not associated with increasing maternal serum leptin levels in the pregnant rat; the contrary condition is observed with the least placental implants having the highest leptin levels. Progesterone seems to suppress serum leptin levels in several physiological models.

Serum magnesium concentrations and metabolic variables in polycystic ovary syndrome.

OBJECTIVE: Hypomagnesemia is associated with diabetes mellitus type 2 and other components of the metabolic syndrome in older patients. Whether serum magnesium concentrations correlate with insulin resistance, obesity, hypertension, dyslipidemia, or other components of metabolic syndrome in younger women with polycystic ovary syndrome (PCOS) is currently unknown. DESIGN: Cross-sectional analysis. SETTING: Academic medical center. POPULATION: 100 consecutive women with PCOS by the Rotterdam criteria and 20 age- and BMI-matched normal women. METHODS: Statistical analysis of the relationship between magnesium levels and a variety of physical, endocrine, and metabolic variables. The STROBE guidelines for a cross-sectional analysis were followed. MAIN OUTCOME MEASUREMENTS: Serum magnesium levels, insulin sensitivity indices, and glucose assessments. BMI, waist circumference, blood pressure, and lipids served as secondary endpoint measurements. RESULTS: No patient demonstrated hypomagnesemia. Magnesium levels did not differ between women with and those without insulin resistance, glucose intolerance, or hypertension. Magnesium levels were similar across PCOS phenotypes and WHO-defined BMI categories. Multiple regression analysis did not suggest that serum magnesium concentrations correlated with any physical, metabolic, or endocrine variable. CONCLUSIONS: Magnesium levels do not correspond with age, BMI, waist circumference, insulin sensitivity, glycemic levels, blood pressure, or lipid levels in reproductive-age women with PCOS. Magnesium concentrations are similar across PCOS phenotypes and indistinguishable from women without PCOS.

Stress reactivity to repeated low-level challenges: a pilot study.

The purpose of this study was to examine the effects of a mental challenge on cardiovascular and endocrine [epinephrine (EPI), norepinephrine (NE), and cortisol (CORT)] responses to subsequent low-intensity physical exertion. Twelve males (23.25±0.45 years) completed three sessions, including a graded exercise test on a cycle ergometer and two counter-balanced mental stress trials. In the mental challenge-control condition (MC), participants sat quietly for 20 min following a 20 min mental challenge whereas in the mental challenge-exercise condition (MEC) subjects cycled at 35% of maximal oxygen consumption (VO2max) following the mental challenge. Repeated-measures ANOVAs were used to assess state anxiety (SAI), cardiovascular variables, EPI, NE, and CORT levels across time between conditions. Participants reported significantly greater increases in SAI scores immediately after the mental challenge, which then decreased post-challenge in both conditions. Neither EPI or NE demonstrated an alteration in levels in either condition, but CORT significantly increased after the mental challenge in both conditions and then maintained a significantly greater level during the MEC compared to the MC condition from midexercise through 15 min of recovery. Area-under-the-curve calculations for CORT was significantly greater in the MEC compared to the MC. Results suggest that the initial mental challenge may have acted to enhance the overall adrenal response to the subsequent anticipation of and actual participation in the low-level physical challenge.

Perils of prolonged ovarian suppression and hypoestrogenism in the treatment of breast cancer: Is the risk of treatment worse than the risk of recurrence?

Premenopausal breast cancer is usually estrogen receptor positive, and hence, prolonged ovarian suppression by medical or surgical means to prevent recurrence has become standard of management to improve disease-free survival. Ten-year adjuvant tamoxifen therapy is associated with 3.5% fewer recurrences compared to five years. The SOFT trial demonstrated small but statistically significant incremental improvements in long-term disease-free survival by the addition of gonadotropin-releasing hormone analog treatment (triptorelin) to an aromatase inhibitor (exemestane). Profound hypoestrogenism in the premenopausal age group may not be well tolerated due to a host of bothersome side effects (primarily vasomotor symptoms, musculoskeletal complaints, genitourinary syndrome of menopause, and mood disorders). Prolonged hypoestrogenism in younger women is associated with premature development of cardiovascular disease, bone loss, cognitive decline, and all-cause mortality. This paper explores multi-system consequences of prolonged hypoestrogenism in premenopausal women derived from studies of women with and without breast cancer. Pretreatment counseling in estrogen receptor positive breast cancer should emphasize the benefit of prolonged estrogen suppression on breast cancer recurrence and established risks of lifelong hypoestrogenism on quality of life and all-cause mortality. Future genomic research may help identify the best candidates for extended ovarian suppression to avoid treating many women when only a minority benefit.

Endocrine factors associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome: do androgens play a role?

OBJECTIVE: To characterise the metabolic profile of women with polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD) and to determine whether circulating androgens differ in PCOS women with NAFLD compared to PCOS subjects without NAFLD. METHODS: Retrospective study of 21 women with PCOS, elevated liver enzymes and ultrasound evidence of hepatic steatosis matched with 32 PCOS women with normal liver enzymes. Extensive demographic, endocrine and metabolic data were compared. Pearson's correlation coefficients were calculated to assess for potential relationships between the free androgen index (FAI) and other dependent variables. RESULTS: PCOS subjects with NAFLD demonstrate greater insulin resistance but have similar circulating androgen levels. CONCLUSION: In this pilot study, insulin resistance was the most prominent feature characterising NAFLD complicating PCOS. Total testosterone, FAI, DHEAS and 17-hydroxyprogesterone levels were similar between patients with PCOS and without NAFLD.

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.

Load rather than contraction type influences rate of perceived exertion and pain.

The purpose of the study was to determine whether muscle contraction type (concentric [CON] or eccentric [ECC]) or loading (relative or absolute) has a greater impact on the perceptual and metabolic responses to conventional resistance exercise. Additionally, overall effort, pain sensations, and specific pain descriptors were compared with physiological responses. Seven healthy men (mean +/- SE, 25.71 +/- 2.17 years) with resistance training experience completed 2 one-repetition maximum (1-RM) trials. Subsequently, 2 randomized, counterbalanced, experimental sessions were completed consisting of 4 sets of 10 repetitions for 6 exercises. These sessions were performed at 65% CON 1-RM for CON only contractions or 65% CON 1-RM + 20% for ECC contractions. Blood samples were taken pre, post, and 15 minutes postexercise. OMNI-RPE (OMNI-Res), CR-10 pain rating, McGill pain ratings, and heart rate (HR) were recorded after each set. A significant time effect occurred for OMNI-Res, pain, lactate, and HR (p < 0.05). No significant pattern emerged for the contraction type, except for higher HR and lactate immediately postexercise for the CON contractions. Physiological measures were not significantly related to perceptual measures. When considered with previous data, muscle loading rather than contraction type plays the primary role in perceptual alterations of effort sense and pain. Practical applications of the investigation are that strength and conditioning professionals may be able to load CON and ECC contractions in a relative fashion by increasing loads in the ECC portion by 20% above the CON load that would result in comparable perceptual experiences.

Adipose tissue and reproductive health.

The understanding of adipose tissue role has evolved from that of a depot energy storage organ to a dynamic endocrine organ. While genetics, sexual phenotype and sex steroids can impact the mass and distribution of adipose tissue, there is a counter-influence of white adipocytes on reproduction. This primarily occurs via the secretion of adipokines, the most studied of which- leptin and adiponectin- are highlighted in this article. Leptin, the "satiety hormone" primarily acts on the hypothalamus via pro-opiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AgRP) neurons to translate acute changes in nutrition and energy expenditure, as well as chronic adipose accumulation into changes in appetite and potentially mediate insulin resistance via shared pathway and notably impacting reproductive health via influence on GnRH secreting neurons. Meanwhile, adiponectin is notable for its action in mediating insulin sensitivity, with receptors found at every level of the reproductive axis. Both have been examined in the context of physiologic and pathologic reproductive conditions. Leptin has been shown to influence puberty, pregnancy, hypothalamic amenorrhea, and lipodystrophy, and with a potential therapeutic role for both metabolic and reproductive health. Adiponectin mediates the relative state of insulin resistance in pregnancy, and has been implicated in conditions such as polycystic ovary syndrome and reproductive malignancies. There are numerous other adipokines, including resistin, visfatin, chemerin and retinol binding protein-4, which may also play roles in reproductive health and disease states. The continued examination of these and other adipokines in both normal reproduction and reproductive pathologies represents an important avenue for continued study. Here, we seek to provide a broad, yet comprehensive overview of many facets of these relationships and highlight areas of consideration for clinicians and future study.

Understanding vitamin D metabolism in pregnancy: From physiology to pathophysiology and clinical outcomes.

This critical time frame of intrauterine life development is considered of major importance on the metabolic imprinting of overall health of the offspring, in later life. This requires a delicate immune balance that nurtures the allogeneic fetus, while maintaining reactivity against pathogens. Dysregulation of these tightly controlled biophenomena at a systemic and placental level, have been considered as a potential mechanism mediating pathogenesis of preeclampsia and spontaneous birth. In this context, vitamin D has been considered as a significant regulator of both innate and adaptive immunity by regulating cell proliferation, differentiation and apoptosis. Vitamin D metabolism during pregnancy manifests striking differences as compared to the non-pregnant state. Calcitriol is increasing >2-3 fold in the first weeks of pregnancy whereas maternal 25-hydroxyvitamin D crosses the placental barrier and represents the main pool of vitamin D in the fetus. Moreover, during pregnancy, vitamin D receptor and regulatory metabolic enzymes are expressed in the placenta and decidua, indicating a potential critical point in the immunomodulation at the maternal-fetal interface. Considering these effects, maternal hypovitaminosis D during pregnancy has been associated with pregnancy related disorders. This review focuses on the mechanistic basis of these adaptive changes, as a background for the development of pregnancy related disorders, with a discourse on the pathophysiology relating hypovitaminosis D and clinical outcomes.

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.

Comparison of hormone responses following light resistance exercise with partial vascular occlusion and moderately difficult resistance exercise without occlusion.

Previous studies of contracting muscle with low loading and partial vascular occlusion demonstrated hypertrophy and strength adaptations similar to and exceeding those observed with traditional moderate to high resistance (Shinohara M, Kouzaki M, Yoshihisa T, and Fukunaga T. Eur J Physiol 77: 189-191, 1998; Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, and Ishii N. J Appl Physiol 88: 2097-2106, 2000; Takarada Y, Sato Y, and Ishii N. Eur J Physiol 86: 308-314, 2002). The purpose of the study was to determine the anabolic and catabolic hormone responses to light resistance exercise combined with partial vascular occlusion. Three experimental conditions of light resistance with partial occlusion (LRO), moderate resistance with no occlusion (MR), and partial occlusion without exercise (OO) were performed by eight healthy subjects [mean 21 yr (SD 1.8)]. Three sets of single-arm biceps curls and single-leg calf presses were completed to failure with 1-min interset rest periods. Workloads of 30 and 70% one repetition maximum for each exercise were lifted for the LRO and MR trials, respectively. Blood samples were taken preexercise, postexercise, and 15 min postexercise for each experimental condition. Lactate increased significantly in the LRO and MR trials and was not significantly different from each other at any time point. Growth hormone (GH) increased significantly by fourfold from pre- to postexercise in the LRO session but did not change significantly during this time period in the MR and OO trials (8.3 +/- 2.3 vs. 2.1 +/- 1.2 and 2.6 +/- 0.94 microg/l; respectively, P < 0.05). There were no changes in resting total testosterone [T; mean 15.7 +/- 1.6 (SE) nmol/l], free testosterone (FT; 54.1 +/- 4.5 pmol/l), or cortisol (267.6 +/- 22 nmol/l) across all trials and times. In conclusion, with similar lactate responses, light exercise combined with partial vascular occlusion elicits a greater GH response than moderate exercise without occlusion but does not affect T, FT, or cortisol.

Detection of gestational diabetes mellitus by homeostatic indices of insulin sensitivity: a preliminary study.

OBJECTIVE: We investigated whether homeostatic indices of insulin sensitivity might suitably screen for gestational diabetes mellitus. STUDY DESIGN: One hundred twenty-three pregnant women who were between 24 and 28 weeks of gestation completed a 3-hour 100-g oral glucose challenge test and fasting insulin level in a nested case-control study design. Insulin sensitivity indices were calculated and tested for their ability to detect gestational diabetes mellitus. RESULTS: Fasting glucose demonstrated the best overall accuracy, but the homeostasis model assessment and quick insulin sensitivity check index were also sensitive screening techniques for gestational diabetes mellitus when either the National Diabetes Data Group or Carpenter-Coustan criteria were used. CONCLUSION: Homeostasis model assessment, quick insulin sensitivity check index, and fasting glucose are sensitive screening tests for gestational diabetes mellitus and can avoid oral administration of glucose-containing solutions.

Interrelationships of serum estradiol, estrone, and estrone sulfate, adiposity, biochemical bone markers, and leptin in post-menopausal women.

OBJECTIVE: The aim of this study was to examine the relationships between endogenous estrogens and adiposity, bone markers, and leptin in post-menopausal (PM) women. DESIGN: Seventy-three post-menopausal (PM) women participated in a clinical correlational study. Weight, height, waist-hip ratio, fasted morning serum and first morning voided urine samples were obtained to compare body mass index (BMI), waist-hip ratio, endogenous estrogens, leptin, and bone markers. Serum estradiol, estrone (E1), estrone sulfate (E1S), leptin, osteocalcin, and urinary deoxypyridinoline (Dpd) were determined. RESULTS: Significant positive relationships were found between BMI and estradiol, E1, and E1S (r = 0.52, 0.38, and 0.29; P < or = 0.001, 0.001, and 0.013 respectively). Significant relationships between leptin and estrogens were revealed, but were not significant when BMI was used as a covariate. Although many subjects revealed elevated bone marker levels, no correlation between estrogens or BMI and bone markers (Dpd and osteocalcin) was found. CONCLUSIONS: There are significant positive correlations between estrogens and BMI in PM women. Increasing levels of estradiol, E1, and E1S with increasing BMI may be an indicator of adiposity, but are without effect as a stimulatory factor on leptin production. Waist-hip ratio did not significantly affect leptin concentrations when accounting for BMI. Due to assay sensitivity in the present study, data represent a more precise representation of these relationships. The lack of correlation between estrogens and bone marker levels may have been due to low estrogen levels in PM women.

Effects of partial vascular occlusion on irisin responses to loaded muscle contractions.

The purpose of the study was to determine the effects of partial vascular occlusion on irisin responses. Eight males completed trials of light (30% 1-repetition maximum (1RM)) resistance exercise (single biceps curls and calf presses) with partial vascular occlusion (LRO), moderate resistance (70% 1RM) with no occlusion (MR), and occlusion only (OO). Blood was collected before, after, and 15 min after exercise. Changes in circulating irisin were more affected during LRO than MR and OO trials.

Plasma cell-free mitochondrial DNA declines in response to prolonged moderate aerobic exercise.

Increased plasma cell-free mitochondrial DNA (cf-mDNA), a damage-associated molecular pattern (DAMP) produced by cellular injury, contributes to neutrophil activation/inflammation in trauma patients and arises in cancer and autoimmunity. To further understand relationships between cf-mDNA released by tissue injury, inflammation, and health benefits of exercise, we examined cf-mDNA response to prolonged moderate aerobic exercise. Seven healthy moderately trained young men (age = 22.4 ± 1.2) completed a treadmill exercise trial for 90 min at 60% VO2 max and a resting control trial. Blood was sampled immediately prior to exercise (0 min = baseline), during (+18, +54 min), immediately after (+90 min), and after recovery (R40). Plasma was analyzed for cf-mDNA, IL-6, and lactate. A significant difference in cf-mDNA response was observed between exercise and control trials, with cf-mDNA levels reduced during exercise at +54 and +90 (with or without plasma volume shift correction). Declines in cf-mDNA were accompanied by increased lactate and followed by an increase in IL-6, suggesting a temporal association with muscle stress and inflammatory processes. Our novel finding of cf-mDNA decline with prolonged moderate treadmill exercise provides evidence for increased clearance from or reduced release of cf-mDNA into the blood with prolonged exercise. These studies contrast with previous investigations involving exhaustive short-term treadmill exercise, in which no change in cf-mDNA levels were reported, and contribute to our understanding of differences between exercise- and trauma-induced inflammation. We propose that transient declines in cf-mDNA may induce health benefits, by reducing systemic inflammation.

Serum leptin in nonpregnant and pregnant women and in old and new world nonhuman primates.

Leptin is a hormone that is produced during mammalian pregnancy in the placental trophoblast and other tissues, including! fetal and maternal adipocytes. Synthesis of the polypeptide and the presence of its specific receptors throughout the human maternal fetoplacental unit suggest direct effects on conceptus growth and development. However, both the physiologic roles of leptin and the mechanisms regulating leptin synthesis in human pregnancy differ from those in laboratory and domestic species, necessitating the development of non-human primate research models. Therefore, we compared serum leptin concentrations in nonpregnant and pregnant women with those in both old world nonhuman primates (i.e., baboon, rhesus monkey, cynomolgus monkey) and new world nonhuman primates (i.e., squirrel monkey, titi monkey). As expected, maternal leptin levels were elevated in human and baboon pregnancies (P < 0.05 and P < 0.001, respectively). Levels in both species of old world monkeys were also greatly enhanced (P < 0.001). Although maternal serum concentrations were slightly elevated compared to nonpregnant levels in both species of new world monkeys, overall concentrations were dramatically lower than for either old world primates or humans. Results provide comparisons of serum leptin concentrations in pregnant and nonpregnant humans and baboons with those in both old and new world monkeys and further characterize these nonhuman primates as models for the investigation of leptin dynamics in pregnancy.

Endocrine alterations from concentric vs. eccentric muscle actions: a brief review.

Resistance exercise has a positive effect on many tissues, including heart, bone, skeletal muscle, and nervous tissue. Eccentric muscle actions offer a unique and a potentially beneficial form of exercise for maintaining and improving health. During resistance exercise, the effects of gravity, and mechanical properties of the sarcomere and connective tissue in skeletal muscle allow a greater muscle load during an eccentric (lengthening) muscle contraction than a concentric (shortening) muscle contraction. Consequently, older patients, patients with muscle or limb movement limitations or injuries, as well as cancer patients may be able to benefit from isolated eccentric muscle actions. There are specific physiological responses to eccentric muscle contractions. This review will describe the effects of different eccentric muscle contraction protocols on endocrine responses that could have positive effects on different tissues and recommend direction for future research.

Changes in circulating leptin, leptin receptor, and gonadal hormones from infancy until advanced age in humans.

We determined developmental changes in circulating levels of the soluble leptin receptor (sOB-R), leptin, and gonadal hormones in human subjects. In both sexes the rise in leptin with age was associated with a decline in sOB-R, and age-related changes in both parameters preceded the pubertal rise in gonadal hormones. Leptin levels above 10 ng/ml were a strong predictor of sOB-R concentrations, but this predictive value decreased as leptin declined. In young subjects there were no gender differences in serum leptin, but boys had higher sOB-R levels. In adults neither leptin nor sOB-R changed with age, but serum leptin was higher and sOB-R was lower in women than men. There was a significant negative correlation between sOB-R and leptin in women, but not men. The data suggest that bioavailable leptin in the circulation may be increasing more rapidly during development than indicated by total leptin levels, and that these changes may serve as one of the signals to the central nervous system that metabolic conditions are adequate to support pubertal development. Furthermore, the study provides suggestive evidence that leptin regulates the secretion of its own binding protein, but it also appears that an additional gender-specific, leptin-independent, regulatory mechanism is functional before puberty.