Relationship of age at menarche and serum leptin with the metabolically unhealthy phenotype in adolescents.

INTRODUCTION: Objective: to analyze the relationship of age at menarche and leptin with the metabolically healthy (MH) and metabolically unhealthy (MUH) phenotypes in adolescent girls in different body mass index (BMI) categories. Method: an observational and cross-sectional study consisting of 139 female adolescents attended to at the Adolescent Reference Center in Macaé, Rio de Janeiro. Menarche was classified as early (EM) when the first menstruation occurred at or before 11 years of age; normal menarche (NM) was categorized at ages 12 to 14; menarche was considered late (LM) when it occurred at age 15 or older. The factors required to ascertain the subjects' phenotype, as well as their leptin levels, weight, and height, were measured and their BMIs were calculated. The girls were classified as MH or MUH based on the NCEP-ATP III criteria as adapted for children and adolescents. Results: 82 % (n = 114) of the girls were classified as MH and 18 % (n = 25) as MUH. Mean age at menarche was 11.79 ± 1.39 years. There was a higher prevalence of MUH amongst the girls who had EM (p = 0.04). A higher inadequacy of serum leptin concentrations was found in girls who had EM (p = 0.05) and in those classified as MUH (p = 0.01). The adolescents who were severely obese exhibited inadequate leptin levels (p < 0.01) and had gone through EM (p = 0.02). A total of 8.1 % (n = 7) of the normal-weight girls were classified as MUH, and 29.4 % (n = 5) of those who were severely obese were classified as MH (p < 0.01). Conclusion: early menarche and high serum leptin concentrations are related with the MUH phenotype in adolescent girls in different BMI categories.

INTRODUCCIÓN: Objetivo: analizar la relación de la edad de la menarquia y los niveles de leptina con los fenotipos metabólicamente saludables (MS) y metabólicamente no saludables (MNS) en adolescentes de diferentes categorías de índice de masa corporal (IMC). Método: estudio observacional y transversal compuesto por 139 adolescentes de sexo feminino, atendidas en el Centro de Referencia para Adolescentes de Macaé, Río de Janeiro. La menarquia se clasificó como precoz (MP) cuando se produjo la primera menstruación a o antes de los 11 años de edad; la menarquia normal (MN) se clasificó como aquella sucedida a la edad de 12 a 14 años; la menarquia se consideró tardía (MT) cuando ocurrió a los 15 años o más. Se midieron los factores necesarios para determinar el fenotipo de los sujetos, y se midieron sus niveles de leptina, peso y altura, y se calculó su IMC. Las adolescentes se clasificaron como MS y MNS según los criterios de NCEP-ATP III, adaptados para niños y adolescentes. Resultados: el 82 % (n = 114) de las adolescentes se clasificaron como MH y el 18 % (n = 25) como MUH. La edad media de la menarquia fue de 11,79 ± 1,39 años. Hubo una mayor prevalencia de MUH entre las adolescentes que tenían MP (p = 0,04). Se encontró una mayor insuficiencia de las concentraciones séricas de leptina en las adolescentes que tenían MP (p = 0,05) y en aquellas clasificadas como MNS (p = 0,01). Las adolescentes que eran severamente obesas exhibieron niveles inadecuados de leptina (p < 0,01) y habían pasado por una MP (p = 0,02). El 8,1 % (n = 7) de las adolescentes de peso normal se clasificaron como MNS y el 29,4 % (n = 5) de las que eran severamente obesas se clasificaron como MS (p < 0,01). Conclusión: la menarquia temprana y las altas concentraciones séricas de leptina están relacionadas con el fenotipo MNS en las adolescentes de diferentes categorías de IMC.

The association between second to fourth digit ratio, reproductive and general health among women: findings from an Israeli pregnancy cohort.

The ratio between the length of second and fourth digits (2D:4D) is a putative biomarker for prenatal testosterone and estrogen exposure. The aim of the study was to examine the association between 2D:4D and women's general and reproductive health. This analysis was conducted within a prospective pregnancy cohort study. The study population included 187 women. 2D:4D was measured directly in both hands using a digital caliper. Multivariable linear and logistic models were used to study the associations between digit ratio and the studied health characteristics. Mean age of the participants was 30.7 ± 4.9 years. The mean age at menarche was 12.9 ± 1.4 years. Right hand 2D:4D mean ± SD was 0.965 ± 0.03. Left hand 2D:4D mean ± SD was 0.956 ± 0.03. An association was found between right 2D:4D and age at menarche, with older age in women with 2D:4D ≥ mean versus 2D:4D < mean (13.2 ± 1.5 and 12.8 ± 1.3 respectively, b = 0.48, 95%CI:0.06-0.91) while controlling for ethnicity. Higher 2D:4D was also associated with heavier menses bleeding and dysmenorrhea. There is an association between 2D:4D and sub optimal reproductive characteristics, including later age at menarche, heavier menses bleeding and dysmenorrhea. These findings support the association between the intrauterine period and reproductive characteristics. Further studies are required to support our findings.

Migraine: navigating the hormonal minefield.

Migraine affects 959 million people worldwide,1 with the highest prevalence being in women of childbearing age. The interplay between female hormones and migraine can be a challenging area to navigate since issues relating to pregnancy, contraception and the menopause are often out of the neurology comfort zone. This review aims to help the neurologist to manage women with migraine, from menarche to menopause.

Sex Hormone Phenotypes in Young Girls and the Age at Pubertal Milestones.

CONTEXT: The age of pubertal onset is influenced by many variables in young girls. Previous studies have not examined sex hormones longitudinally around the time of breast development and their relationship to pubertal onset. OBJECTIVE: We sought to use an unbiased statistical approach to identify phenotypes of sex hormones in young girls and examine their relationship with pubertal milestones. DESIGN AND SETTING: Longitudinal observational study. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 269 girls, serum concentrations of steroid sex hormones [estradiol (E2), estrone, testosterone, and dehydroepiandrosterone sulfate] were measured by HPLC-mass spectrometry at time points before, at, and after thelarche. Girls were classified into four hormone phenotypes using objective principal components and cluster analyses of longitudinal hormone data. The association between the identified phenotypes and age of pubertal milestones was estimated using Cox proportional hazards modeling. RESULTS: Mean ages at thelarche, pubarche, and menarche were 9.02, 9.85, and 12.30 years, respectively. Girls with low levels of all four hormones, phenotype 3b, were youngest at thelarche (8.67 years); those in phenotype 2, with the highest E2 levels and E2 surge 6 months after thelarche, were youngest at menarche (11.87 years) with shortest pubertal tempo. When controlling for race, maternal age of menarche, caregiver education, and body mass, different phenotypes were associated with the age of pubertal events. CONCLUSIONS: Hormone phenotypic clustering can identify clinically relevant subgroups with differing ages of thelarche, pubarche, and menarche. These findings may enhance the understanding of timing of pubertal milestones and risk of adult disease.

Mendelian randomization analysis using mixture models for robust and efficient estimation of causal effects.

Mendelian randomization (MR) has emerged as a major tool for the investigation of causal relationship among traits, utilizing results from large-scale genome-wide association studies. Bias due to horizontal pleiotropy, however, remains a major concern. We propose a novel approach for robust and efficient MR analysis using large number of genetic instruments, based on a novel spike-detection algorithm under a normal-mixture model for underlying effect-size distributions. Simulations show that the new method, MRMix, provides nearly unbiased or/and less biased estimates of causal effects compared to alternative methods and can achieve higher efficiency than comparably robust estimators. Application of MRMix to publicly available datasets leads to notable observations, including identification of causal effects of BMI and age-at-menarche on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI on the risk of major depressive disorder.

Potential risk factors of ovarian cancer and analysis of CA125, a biomarker used for its monitoring and diagnosis.

Ovarian cancer (OC) is the fourth most common cancer among Pakistani, Scottish and Chinese women. The aim of the present study was to determine the association of potential risk factors with OC and analysis of Cancer Antigen 125 (CA125) in its monitoring and diagnosis. A total of 200 patients diagnosed with OC were included in this study. All the patients were interviewed and 54 OC patients (case group) and 35 age-matched healthy subjects (control group) gave their blood for analysis of CA125. The blood of case and control groups was subjected to an ELISA test for the evaluation of CA125 levels. Majority of the patients were of 40-50 years of age and most of the patients were diagnosed at this period of life. The majority of the patients experienced their first menarche and menopause at the age of 13-14 and 40-50 years respectively. There is no significant association between early menarche and OC family history, nor between late menopause and OC family history. There is a significant association between family history of breast cancer (BC) and age of menarche (P = 0.005). An OC patient with an age of menarche of 13 years or younger has 2.8 times the odds of having a family history of BC than those whose age of menarche is more than 13 years. Eleven percent of patients diagnosed with OC received no intervention. All other patients underwent treatment options including hysterectomy (69.5%), radiotherapy (39%) and chemotherapy (95%). The profiles of the patients showed that those who had a family history of OC were more likely to provide blood samples (OR = 3.87, P = 0.025), and similarly for those with a history of breast cancer (OR = 2.83, P = 0.022) in comparison to those who were not willing to provide blood for testing of biomarker. The distribution of CA125 for OC patients and control group showed that CA125 values were significantly higher (P = 0.034) in the case patients compared with the control group. The decrease in CA125 levels indicated the positive response to treatment, whereas increase in CA125 values showed resistant and disease progression. 52% of the patients with OC were correctly diagnosed as having OC (based on the optimal cut-point of CA125), while 83% of those without OC were also correctly diagnosed (with 48% of OC patients and 17% of non-OC patients incorrectly diagnosed). We concluded that there is significant association between family history of breast cancer and OC history and use of CA125 as a biomarker is not an ideal diagnostic and monitoring test as it has low sensitivity and high specificity.

Does the age of seizure onset relate to menarche and does it matter?

PURPOSE: To determine whether there is a relationship between the age of seizure onset and the age of menarche. METHODS: 1144 women with epilepsy (WWE) in the community, ages 18-47 years, provided web-based survey data. We compared the frequencies of the individual differences between their ages of seizure onset and menarche to each other and chance. We determined whether the age of menarche is a predictor of the age of seizure onset and the percentage of the variance that menarche explains. We used two-step cluster analysis to auto-identify a cluster of years relative to the age of menarche that showed the greatest predilection for seizure onset. RESULTS: Average age of menarche was 12.55 [95% CI: 12.45-12.65]. It was greater in WWE who developed seizures before versus after menarche (12.70 [12.54-12.86] v 12.42 [12.30-12.54], p = 0.006). More WWE had seizure onset during the year of menarche than during any other year (8.3% v expected 2.1%; p < 0.0001). Menarche, however, explained only 1% of the variance. Seizure onset frequencies were greatest for an auto-identified cluster that spanned 2 years before to 6 years after menarche and subsumed 49.3% of seizure onset. CONCLUSION: Although the results indicate a significant relationship between the age of seizure onset and the age of menarche, the broader auto-identified perimenarchal cluster that subsumes 49.3% of seizure onset suggests that research target the potential role of the great increase in adrenarchal, as well as gonadarchal, neuroactive steroids that modulate neuronal excitability and seizures during that span.

Effect of Interaction between Early Menarche and Genetic Polymorphisms on Triglyceride.

Early menarche has been associated with increased risk of metabolic syndrome. Therefore, investigating the association of each component of metabolic syndrome with age at menarche, and interactions between them, might lead to a better understanding of metabolic syndrome pathogenesis. In this study, we evaluated age at menarche for risk of metabolic syndrome and associations with its components. As a result, the risk of MetS incidence was significantly increased only at ≤12 years of age at menarche (OR = 1.91, P < 0.05). Women with early menarche (≤12 years) had significantly higher levels of triglycerides (ß coefficient = 37.83, P = 0.02). In addition, hypertriglyceridemia was significantly increased at early menarche with 1.99 (95% CI: 1.16-3.41, P < 0.01). With GWAS-based pathway analysis, we found the type 2 diabetes mellitus, stress-activated protein kinase signaling, and Jun amino-terminal kinase cascade pathways (all nominal P < 0.001, all FDR < 0.05) to be significantly involved with early menarche on triglyceride levels. These findings may help us understand the role of early menarche on triglyceride and interaction between gene and early menarche on triglyceride for the development of metabolic syndrome.

Distinctive Reproductive Phenotypes in Peripubertal Girls at Risk for Polycystic Ovary Syndrome.

CONTEXT: Increased testosterone (T) levels are a cardinal feature of polycystic ovary syndrome (PCOS). Female relatives of affected women, including premenarchal daughters, have elevated T levels supporting a genetic susceptibility to this phenotype. Girls with obesity (OB-g) also have increased T levels throughout puberty, which may indicate risk for PCOS. OBJECTIVE: We tested the hypothesis that premenarchal daughters of women affected with PCOS (PCOS-d) have distinctive phenotypic features compared with OB-g. DESIGN, SETTING, AND PARTICIPANTS: Forty-eight PCOS-d, 30 OB-g, and 22 normal weight (NW-g) premenarchal girls were studied. Mothers of OB-g and NW-g had no evidence for PCOS. MAIN OUTCOME MEASURES: Reproductive hormones were measured. RESULTS: Body mass index differed by design, was highest in OB-g, followed by PCOS-d (P > 0.001). PCOS-d and OB-g had similar increases in free T levels compared with NW-g (PCOS-d vs NW-g, P = 0.01; OB-g vs NW-g, P = 0.0001). Sex hormone binding globulin levels were lowest in OB-g and lower in PCOS-d than in NW-g (PCOS-d vs NW-g, P = 0.005; OB-g vs NW-g, P < 0.0001; PCOS-d vs OB-g, P < 0.0001). Anti-Müllerian hormone (AMH) levels in PCOS-d were significantly increased compared with OB-g, who tended to have lower AMH levels than NW-g (PCOS-d vs OB-g, P < 0.0001; PCOS-d vs NW-g, P = 0.10). CONCLUSIONS: Despite similarly elevated free T levels, PCOS-d had increased AMH levels compared with OB-g. This finding suggests that OB-g lack alterations in ovarian folliculogenesis, a key reproductive feature of PCOS. Causal mechanisms may differ in PCOS-d or OB-g, or elevated T in OB-g may not be an early marker for PCOS.

Higher luteinizing hormone levels associated with antimüllerian hormone in postmenarchal daughters of women with polycystic ovary syndrome.

OBJECTIVE: To study the reproductive and metabolic differences between daughters of women with polycystic ovary syndrome (PCOSd) and control women (Cd) after menarche. DESIGN: Case-control study. SETTING: Clinical endocrinology unit. PATIENT(S): We studied 43 PCOSd and 28 Cd 1.5-6 years after menarche. INTERVENTION(S): Determination of anthropometry, pubertal development, hirsutism, oral glucose tolerance test, and GnRH analogue test. MAIN OUTCOME MEASURE(S): Ferriman score, sex steroids, gonadotropins, antimüllerian hormone (AMH), ovarian volumes, and glucose and insulin levels. RESULT(S): The groups were similar in chronologic, gynecologic, and menarchal ages and anthropometric variables. Ferriman score, ovarian volumes, and AMH were higher in PCOSd. Propensity score analysis showed that there were significant differences in LH, LH-FSH ratio, T and free androgen index, post-stimulated LH and LH-FSH ratio, and 2-hour insulin that could be attributed only to the fact of being a PCOS daughter. The generalized linear model showed that higher LH levels were positively associated with AMH and T levels. CONCLUSION(S): We found that higher LH, androgen, and insulin levels are present in PCOSd during the postmenarchal period, which may establish the basis for the development of PCOS during adulthood. Moreover, LH levels were associated with AMH levels, which supports that the neuroendocrine feedback proposed for AMH and LH is present in humans and that this feature is probably programed in utero, as recently shown in mice.

Impact of zinc on sexual maturation of female sickle cell anemia (SCA) children in Enugu, Southeast Nigeria.

Adolescence is an important developmental period of childhood. Good health and adequate nutrition consisting major food constituents and trace elements like zinc are fundamental for optimal sexual maturation. To determine the relationship between zinc levels and pattern of breast and pubic hair development, as well as menarcheal age of female SCA children aged 6-18 years and their matched controls with hemoglobin genotype AA. Cross sectional, case-control study. Information on biodata, age at menarche, medical and drug history as well as 24-hour dietary recall was documented using interviewer administered questionnaire. Sexual maturation was assessed using Tanner staging and zinc levels determined using Atomic absorption spectrophotometer. Eighty-one subjects were compared with 81 controls. There was significant delay in the mean age of attainment of various Tanner stages of breast and pubic hair in the subjects. Mean age of 14.81 ± 1.07 years at menarche in subjects was significantly higher than 12.62 ± 1.18 years in controls (p = 0.001). Serum zinc of 58.01 ± 10.58 µg/dl in subjects was significantly lower than 68.37 ± 8.67 µg/dl in controls (p = 0.001). Serum zinc levels were found to have a significant positive relationship with stages of sexual maturation and mean age at menarche. Reduced serum zinc in children with SCA was associated with delayed sexual maturation.

Micronutrient status in middle childhood and age at menarche: results from the Bogotá School Children Cohort.

Childhood intake of animal foods is associated with age at first menstrual period (menarche). It is unknown whether the micronutrients present in these foods could explain this association. Our objective was to investigate the associations of micronutrient status biomarkers in middle childhood with age at menarche. We quantified circulating Hb, ferritin, mean corpuscular volume, Zn, vitamin B12, erythrocyte folate and retinol in 1464 pre-menarcheal girls aged 5-12 years in Bogotá, Colombia, and followed them for a median 5·7 years for the occurrence and date of menarche. We estimated median age at menarche and hazard ratios (HR) with 95 % CI by levels of each biomarker with use of Kaplan-Meier survival probabilities and Cox regression, respectively. Median age at menarche was 12·4 years. Middle childhood Hb was inversely related to age at menarche whereas plasma ferritin was positively associated with this outcome in a linear manner. HR of menarche for every 1 sd of Hb (11 g/l) and ferritin (23·2 µg/l) were 1·11 (95 % CI 1·04, 1·18; P=0·001) and 0·94 (95 % CI 0·88, 0·99; P=0·02), respectively, after adjustment for baseline age, C-reactive protein concentration, maternal age at menarche and parity and socioeconomic status. The association with ferritin was stronger in girls aged 9-10 years at baseline. Additional adjustment for baseline height- and BMI-for-age did not change the results. We conclude that higher Fe status in middle childhood is related to later age at menarche whereas Hb concentrations are inversely associated with age at onset of menses.

Association Between Menopausal Factors and the Risk of Seronegative and Seropositive Rheumatoid Arthritis: Results From the Nurses' Health Studies.

OBJECTIVE: To investigate whether menopausal factors are associated with the development of serologic rheumatoid arthritis (RA) phenotypes. METHODS: Data were analyzed from the Nurses' Health Studies (NHS; 1976-2010 and NHSII 1989-2011). A total of 120,700 female nurses ages 30-55 years in the NHS, and a total of 116,430 female nurses ages 25-42 years in the NHSII, were followed via biennial questionnaires on lifestyle and disease outcomes. In total, 1,096 incident RA cases were confirmed by questionnaire and chart review. Seropositive RA was defined as rheumatoid factor positive (RF) or antibodies to citrullinated protein antigen (ACPA) positive, and seronegative RA was defined as RF negative and ACPA negative. We used Cox proportional hazards models to obtain multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) of seropositive/seronegative RA associated with menopausal status, age at menopause, type of menopause, ovulatory years, and postmenopausal hormone therapy (PMH) use. RESULTS: Postmenopausal women had a 2-fold increased risk of seronegative RA, compared with premenopausal women (NHS: HR 1.8 [95% CI 1.1-3.0], NHSII: HR 2.4 [95% CI 1.4-3.9], and pooled HR 2.1 [95% CI 1.4-3.0]). Natural menopause at early age (≤44 years) was associated with an increased risk of seronegative RA (pooled HR 2.4 [95% CI 1.5-4.0]). None of the menopausal factors was significantly associated with seropositive RA. We observed no association between PMH use and the risk of seronegative or seropositive RA, except that PMH use of ≥8 years was associated with increased risk of seropositive RA (pooled HR 1.4 [95% CI 1.1-1.9]). CONCLUSION: Postmenopause and natural menopause at an early age were strongly associated with seronegative RA, but only marginally with seropositive RA, suggesting potential differences in the etiology of RA subtypes.

Impact of BMI on gonadorelin-stimulated LH peak in premenarcheal girls with idiopathic central precocious puberty.

OBJECTIVE: To clarify the impact of body mass index (BMI) on luteinizing hormone (LH) secretion in response to gonadorelin (GnRH) stimulation testing in girls diagnosed with idiopathic central precocious puberty (ICPP). METHODS: Retrospective single-center cohort study was carried out in 865 confirmed ICPP girls who underwent GnRH stimulation tests. Pubertal development according to Tanner, sex hormone parameters, and LH secretion in response to GnRH-stimulation was compared. RESULTS: Around 609 girls were of normal weight (70.4%), while 168 children (19.4%) were overweight, and 88 (10.2%) were obese. Peak LH levels after GnRH were much higher in the normal-weight group, with a median of 9.1 mIU ml(-1) (interquartile 5.2-13.1), compared with the median peak LH in the overweight and obese groups (8.5 mIU ml(-1), interquartile 5.3-11.6, and 6.2 mIU ml(-1), interquartile 5.3-11.0, respectively P < 0.001 for all comparisons). Peak LH/FSH ratio was also lower in the obese group (median 0.6, interquartile 0.68-0.90) compared with the normal-weight (median 0.8, interquartile 0.61-1.11) and overweight (median 0.8, interquartile 0.64-0.92) groups. CONCLUSIONS: Higher BMI is associated with lower LH response to GnRH-stimulation testing in girls with ICPP. It is recommended that BMI should be considered when interpreting GnRH-stimulation tests.

Pubertal development in children diagnosed with diabetes mellitus type 1 before puberty.

STUDY OBJECTIVE: To investigate an association between pubertal development and timing of menarche with glycemic control, disease duration, and body mass index (BMI) in patients diagnosed with diabetes mellitus type 1 (DM1) before puberty. DESIGN: Retrospective study. SETTING: The study was performed at the diabetes outpatient clinic of Instituto de Puericultura e Pediatria Martagão Gesteira--IPPMG of the Federal University of Rio de Janeiro--UFRJ. PARTICIPANTS: A total of 131 children, 61 girls and 70 boys, diagnosed with DM1 before puberty participated in the study. MAIN OUTCOME MEASURES: The study investigated how age at puberty onset relates to mean glycated hemoglobin (HbA1c) before puberty, BMI percentile, and disease duration; how puberty duration relates to mean HbA1c before and during puberty and to disease duration; and how timing of menarche relates to mean HbA1c before puberty, BMI percentile, and disease duration. RESULTS: Age at puberty onset was positively correlated with mean HbA1c before puberty (r = 0.204, R(2) = 0.042; P = .019) and disease duration (r = 0.451, R(2) = 0.203; P < .0001), and negatively correlated with BMI percentile (r = -0.289, R(2) = 0.084; P = .001). Timing of menarche was negatively correlated with BMI percentile (r = -0.556, R(2) = 0.310; P < .001). CONCLUSIONS: Children with longer disease duration began puberty later than those diagnosed more recently. Girls in higher BMI percentiles reached menarche sooner.

Blunted day-night changes in luteinizing hormone pulse frequency in girls with obesity: the potential role of hyperandrogenemia.

CONTEXT: Puberty 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. OBJECTIVE: The 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. DESIGN: This was a cross-sectional analysis. SETTING: The study was conducted at a clinical research center. PATIENTS OR OTHER PARTICIPANTS: Twenty-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. INTERVENTION: Blood samples were taken every 10 minutes from 7:00 pm to 7:00 am. MAIN OUTCOME MEASURE: Change 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). RESULTS: Both 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). CONCLUSIONS: Day-to-night changes in LH pulse secretion are blunted in postmenarcheal obese adolescent girls. This phenomenon may in part reflect hyperandrogenemia.

Cluster analysis of cardiovascular and metabolic risk factors in women of reproductive age.

OBJECTIVE: To study the association between endocrine disturbances and metabolic complications in women seeking gynecologic care. DESIGN: Retrospective study, cluster analysis. SETTING: Outpatient clinic, university medical center. PATIENT(S): 573 women, including 384 at low risk and 189 at high risk of cardiometabolic disease. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cardiovascular and metabolic parameters and clinical and biochemical characteristics. RESULT(S): Risk factors for metabolic disease are associated with a low age of menarche, high levels of high-sensitivity C-reactive protein and liver enzymes, and low levels of sex hormone-binding globulin. Overweight/obese status, polycystic ovary syndrome, oligo/amenorrhea, and hyperandrogenism were found to increase the risk of cardiometabolic disease. However, hyperprolactinemia and premature ovarian failure were not associated with the risk of cardiometabolic disease. In terms of androgens, the serum total testosterone level and free androgen index but not androstenedione or dehydroepiandrosterone sulfate (DHEAS) were associated with cardiometabolic risk. CONCLUSION(S): Although polycystic ovary syndrome is associated with metabolic risk, obesity was the major determinant of cardiometabolic disturbances in reproductive-aged women. Hyperprolactinemia and premature ovarian failure were not associated with the risk of cardiovascular and metabolic diseases. CLINICAL TRIAL REGISTRATION NUMBER: NCT01826357.

Earlier age at menarche is associated with higher diabetes risk and cardiometabolic disease risk factors in Brazilian adults: Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

OBJECTIVES: Early menarche has been linked to higher risk of type 2 diabetes in Western and Asian societies, yet whether age at menarche is associated with diabetes in Latin America, where puberty and diabetes may have different life courses, is unknown. We tested the hypothesis that earlier menarche is associated with higher diabetes risk in Brazilian adults. METHODS: We used data from 8,075 women aged 35-74 years in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) who had complete information on age at menarche, diabetes status, and covariates. Diabetes was defined based on self-reported physician diagnosis, medication use, and laboratory variables (fasting glucose, 2-hour glucose, and glycated hemoglobin). Poisson regression was used to generate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Menarche onset < 11 years [vs. 13-14 years (referent)] was associated with higher risk of diabetes (RR = 1.34; 95% CI: 1.14-1.57) after adjusting for sociodemographic factors, maternal education, maternal and paternal diabetes, and birth weight. This persisted after further control for BMI at age 20 years and relative leg length. Additionally, among those not taking diabetes medications, earlier menarche [<11 years vs. 13-14 years (referent)] was associated with higher % glycated hemoglobin (p < 0.001), alanine aminotransferase (p < 0.001), triglycerides (p < 0.001), C-reactive protein (p = 0.003), waist circumference (p < 0.001), and BMI measured at baseline exam (p < 0.001). CONCLUSION: These findings support the hypothesis that earlier menarche is associated with greater risk for adult diabetes and cardiometabolic disease in the Brazilian context.

Higher levels of IGF-I and adrenal androgens at age 8 years are associated with earlier age at menarche in girls.

CONTEXT: Earlier age at menarche is associated with rapid infancy weight gain and childhood obesity. The role of hormone levels in mediating these associations is unclear. OBJECTIVE: The aim of this study was to identify childhood hormone levels at age 8 yr that are associated with early menarche, independent of body size. DESIGN, SETTINGS, AND SUBJECTS: A total of 329 girls from a prospective United Kingdom birth cohort study provided blood samples at mean age 8.1 yr (range, 8.0-8.5) for hormone measurements and were followed longitudinally to establish age at menarche. MAIN OUTCOME MEASURES: Fasting plasma levels of IGF-I, androstenedione, dehydroepiandrosterone sulfate (DHEAS), leptin, insulin, IGF binding protein-1, and SHBG were measured. Age at menarche was reported by questionnaire and categorized as before 12.0, 12.0-13.0, or later than 13 yr. RESULTS: Earlier menarche was associated with greater body weight, height, and body mass index at age 8 yr (all P-trend <0.001). Before adjustment for body size, earlier menarche was associated with higher levels of IGF-I, androstenedione, DHEAS, leptin, and fasting insulin, and with lower levels of IGF binding protein-1 and SHBG at age 8 yr (all P < 0.01). After adjustment for body mass index and height at age 8 yr, only IGF-I (P = 0.004), androstenedione (P = 0.01), and DHEAS (P = 0.01) remained associated with earlier menarche. CONCLUSIONS: Associations between higher levels of IGF-I and adrenal androgens at age 8 yr with earlier menarche, independent of body size, support functional roles of these hormones in regulating puberty timing in girls. Higher levels of these hormones reported in children who exhibited rapid weight gain during infancy may indicate their role in developmental pathways leading to earlier sexual maturation.

Serum PBDEs and age at menarche in adolescent girls: analysis of the National Health and Nutrition Examination Survey 2003-2004.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs), widely used as flame retardants since the 1970s, have exhibited endocrine disruption in experimental studies. Tetra- to hexa-BDE congeners are estrogenic, while hepta-BDE and 6-OH-BDE-47 are antiestrogenic. Most PBDEs also have antiandrogenic activity. It is not clear, however, whether PBDEs affect human reproduction. OBJECTIVES: The analysis was designed to investigate the potential endocrine disruption of PBDEs on the age at menarche in adolescent girls. METHODS: We analyzed the data from a sample of 271 adolescent girls (age 12-19 years) in the National Health and Nutrition Examination Survey (NHANES), 2003-2004. We estimated the associations between individual and total serum BDEs (BDE-28, -47, -99, -100, -153, and -154, lipid adjusted) and mean age at menarche. We also calculated the risk ratios (RRs) and 95% confidence intervals (CI) for menarche prior to age 12 years in relation to PBDE exposure. RESULTS: The median total serum BDE concentration was 44.7ng/g lipid. Higher serum PBDE concentrations were associated with slightly earlier ages at menarche. Each natural log unit of total BDEs was related to a change of -0.10 (95% CI: -0.33, 0.13) years of age at menarche and a RR of 1.60 (95% CI: 1.12, 2.28) for experiencing menarche before 12 years of age, after adjustment for potential confounders. CONCLUSION: These data suggest high concentrations of serum PBDEs during adolescence are associated with a younger age of menarche.