Increased serum adiponectin concentrations in amenorrheic physically active women are associated with impaired bone health but not with estrogen exposure.

BACKGROUND: The role of adiponectin in mediating gonadal status and bone health in weight-stable healthy adult female athletes with secondary amenorrhea has not yet been described. METHODS: Using a prospective observational study, age-matched premenopausal women were studied, including 1) sedentary ovulatory women (SedOv; n=10), 2) exercising ovulatory women (ExOv; n=15), and 3) exercising amenorrheic women (ExAmen; n=9). Primary outcome measures included serum total adiponectin and daily urinary estrogen (E1G) levels, expressed as area under the curve (AUC), body fat distribution, and bone mineral density (BMD). Serum leptin, ghrelin, total triiodothyronine (TT3), insulin, and resting energy expenditure (REE) were also determined. RESULTS: The women in this study did not differ in age (25.3±1.4 years; mean ± SEM), height (164±1 cm), weight (57.7±1.0 kg) and BMI (21.5±0.4 kg/m(2)). Exercising women had a higher fat free mass (FFM), lower fat mass (FM) and lower serum leptin concentrations (p<0.05) compared to sedentary women. Adiponectin and ghrelin levels were higher (p<0.05), and TT3 (p=0.019), urinary E1G AUC (p=0.002) lower in ExAmen compared with ExOv and SedOv. Total and L1-L4 BMD were lower (p<0.05) in ExAmen compared with ExOv. Stepwise linear regression identified trunkal FM as the strongest predictor of log adiponectin adjusted for FM (F=23.54, p<0.001). L1-L4 BMD was predicted by log adiponectin and E1G AUC (F=9.856, p=0.045). Total BMD was predicted by log adiponectin (F=7.948, p=0.009). TT3 was the strongest predictor of E1G AUC (F=9.885, p=0.004). CONCLUSIONS: Hypoestrogenic adult female athletes with secondary amenorrhea demonstrate elevated circulating adiponectin relative to FM in association with impaired bone health. Estrogen exposure was predicted by TT3, but not adiponectin. These findings suggest that nutritionally regulated hormones may mediate gonadal status, and that adiponectin and estrogen, either independently or in combination, may mediate bone health in adult amenorrheic physically active women

The cardiovascular effects of chronic hypoestrogenism in amenorrhoeic athletes: a critical review.

In premenopausal women, the most severe menstrual dysfunction is amenorrhoea, which is associated with chronic hypoestrogenism. In postmenopausal women, hypoestrogenism is associated with a number of clinical sequelae related to cardiovascular health. A cardioprotective effect of endogenous oestrogen is widely supported, yet recent studies demonstrate a deleterious effect of hormone replacement therapy for cardiovascular health. What remain less clear are the implications of persistently low oestrogen levels in much younger amenorrhoeic athletes. The incidence of amenorrhoea among athletes is much greater than that observed among sedentary women. Recent data in amenorrhoeic athletes demonstrate impaired endothelial function, elevated low- and high-density lipoprotein levels, reduced circulating nitrates and nitrites, and increased susceptibility to lipid peroxidation. Predictive serum markers of cardiovascular health, such as homocysteine and C-reactive protein, have not yet been assessed in amenorrhoeic athletes, but are reportedly elevated in postmenopausal women. The independent and combined effects of chronic hypoestrogenism and exercise, together with subclinical dietary behaviours typically observed in amenorrhoeic athletes, warrants closer examination. Although no longitudinal studies exist, the altered vascular health outcomes reported in amenorrhoeic athletes are suggestive of increased risk for premature cardiovascular disease. Future research should focus on the presentation and progression of these adverse cardiovascular parameters in physically active women and athletes with hypoestrogenism to determine their effects on long-term health

Relationships between vascular resistance and energy deficiency, nutritional status and oxidative stress in oestrogen deficient physically active women.

OBJECTIVE: Oestrogen deficiency contributes to altered cardiovascular function in premenopausal amenorrheic physically active women. We investigated whether other energy deficiency-associated factors might also be associated with altered cardiovascular function in these women. DESIGN: A prospective observational study was completed at a research facility at the University of Toronto. PARTICIPANTS: Thirty-two healthy premenopausal women (18-35 years old) were studied; 9 sedentary and ovulatory; 14 physically active and ovulatory; and 8 physically active and amenorrheic. MEASUREMENTS: We measured calf vascular resistance, resting heart rate, dietary energy intake, resting energy expenditure and serum measures of homocysteine, high-sensitivity C-reactive protein, oxidized low-density lipoproteins, total T(3), ghrelin, leptin and insulin. RESULTS: Groups were similar (P > 0.05) in age (25.1 +/- 0.8 years; mean +/- SEM), weight (57.3 +/- 1.1 kg), and BMI (21.4 +/- 0.3 kg/m(2)). Resting vascular resistance and ghrelin were highest (P 0.05, main effect) among the groups, and were unrelated to cardiovascular measures. CONCLUSION: Altered resting vascular resistance in premenopausal oestrogen deficient physically active amenorrheic women is not associated with vascular inflammation or oxidative stress, but rather with parameters that reflect metabolic allostasis and dietary intake, suggesting a potential role for chronic energy deficiency in vascular regulation

On a secant Dirichlet series and Eichler integrals of Eisenstein series

In estrogen deficient postmenopausal women, osteoporosis share s a common lin k with cardiovascular disease risk, including endothelial dysfunction. The current study sought to examine associations between bone mineral density (BMD) and endothelial function in estrogen deficient premenopausal women with exercise -associated menstrual disturbances. Recreationally trained women (24.3±0.8 years; overall mean±SEM) who were estrogen deficient (amenorrheic or eumenorrheic anovulatory cycles; E2Def; n=13) or estrogen replete (eumenorrheic ovulatory cycles; E2Rep; n=14) were studied . Total body and lumbar BMD (L1 -L4) were determined using dual energy X -ray absorptiometry. Serum markers of oxidative stress (oxidised low -density lipoprotein; OxLDL), energy deficiency (triiodothyronine ) , and bone turnover (osteocalcin, c -telopeptide X, P1NP) were assessed. Estrogen exposure was determined by assessing daily urinary estrone - 3 -glucuronide (E1G) across a monitoring period. Calf blood flow (CBF), an index of endothelial function, was measured using strain -gauge plethysmography. CBF, total body and L1 -L4 BMD, triiodothyronine and E1G were lower (p<0.05), and c -telopeptide crosslinks higher (p<0.05) in E2Def. Osteocalcin and OxLDL did not differ (p>0.05) between groups. L1 -L4 BMD, osteocalcin and E1G were the strongest predictors of CBF ( R 2 =0.615, p<0.001). CBF was the strongest predictor of L1 -L4 BMD ( R 2 =0.478, p<0.001). L1 -L4 (r=0.558, p=0.008) and CBF (r=0.534, p=0.004) were independently correlated with E1G. In young recreationally trained premenopausal women with anovulatory menstrual disturbances, low CBF predicts decreased lumbar BMD, suggesting impaired peripheral endothelial function may predict early unfavorable changes in bone metabolism . This finding may be of relevance in the early detection of cardiovascular and bone health decrements in otherwise healthy estrogen deficient premenopausal women

Long-term estrogen deficiency lowers regional blood flow, resting systolic blood pressure, and heart rate in exercising premenopausal women.

The cardiovascular consequences of hypoestrogenism in premenopausal women are unclear. Accordingly, the influence of menstrual status and endogenous estrogen (E(2)) exposure on blood pressure (BP), heart rate (HR), and calf blood flow in young (18-35 yr) regularly exercising premenopausal women with exercise-associated menstrual aberrations was investigated. Across consecutive menstrual cycles, daily urinary ovarian steroid levels were analyzed, and the area under the curve was calculated to determine menstrual status and E(2) exposure. BP, HR, blood flow, vascular conductance, and resistance were measured at baseline and following ischemic calf exercise. Exercising subjects consisted of 14 ovulatory (ExOv), 10 short-term (anovulatory and 100 days amenorrhea; LT-E(2) Def) E(2)-deficient women. Nine sedentary ovulatory subjects (SedOv) were also studied. All groups were similar in age (24.8 +/- 0.7 yr), height (164.8 +/- 1.3 cm), weight (57.9 +/- 0.9 kg), and body mass index (21.3 +/- 0.3 kg/m(2)). E(2)-deficient groups had lower (P < 0.002) E(2) exposure compared with ovulatory groups. Resting systolic BP, HR, blood flow, and vascular conductance were lower (P < 0.05) and vascular resistance higher (P < 0.05) in LT-E(2) Def compared with both ovulatory groups. Peak ischemic blood flow, vascular conductance, and HR were also lower (P < 0.05) and vascular resistance higher (P < 0.05) in LT-E(2) Def compared with all other groups. Our findings show that exercising women with long-term E(2) deficiency have impaired regional blood flow and lower systolic BP and HR compared with exercising and sedentary ovulatory women. These cardiovascular alterations represent markers of altered vascular function and autonomic regulation of which the long-term effects remain unknown

Misunderstanding the female athlete triad: refuting the IOC consensus statement on relative energy deficiency in sport (RED-S).

Misunderstanding the female athlete triad: refuting the IOC consensus statement on relative energy deficiency in sport (RED-S)

Fasting ghrelin levels in physically active women: relationship with menstrual disturbances and metabolic hormones.

Recent findings support a role for ghrelin in the regulation of energy homeostasis and possibly reproductive function. The primary purpose of this study was to test whether differences in fasting ghrelin levels exist in exercising women with differing menstrual and metabolic status. Menstrual cycle status was defined as sedentary ovulatory (SedOvul; n = 10, cycles = 26), exercising ovulatory (ExOvul; n = 11, cycles = 22), exercising luteal phase defect/anovulatory (ExLPD/Anov; n = 11, cycle = 27), and exercising amenorrheic (ExAmen; n = 8, cycle = 16). Subjects were 27.7 +/- 1.2 yr of age, weighed 60.2 +/- 3.3 kg, and had menstrual cycle lengths of 28.4 +/- 0.9 d. Blood was collected during the follicular phase (d 2-9) of each menstrual cycle and analyzed for total ghrelin, insulin, total T(3), and leptin. Ghrelin was significantly elevated by approximately 85% in the ExAmen category (725.5 +/- 40.8 pmol/liter) when compared with all other categories (P < 0.001; SedOvul = 393.6 +/- 32.0 pmol/liter, ExOvul = 418.9 +/- 34.8 pmol/liter, and ExLPD/Anov = 381.1 +/- 314 pmol/liter). Leptin levels were lower in all groups vs. SedOvul (P < 0.001). Insulin was lower in both the ExLPD/Anov and ExAmen categories vs. SedOvul and ExOvul (P < 0.018), and total T(3) was lower in ExAmen compared with all other groups (P < 0.001), with concentrations in ExLPD/Anov and ExOvul exceeding those in SedOvul (P < 0.05). These data clearly indicate a metabolic hormonal profile consistent with chronic energy deficiency in exercising women across a range in menstrual status and introduces ghrelin as a potential supplementary indicator that uniquely discriminates amenorrheic athletes from athletes with other menstrual disturbances

High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures.

BACKGROUND: The identification of subtle menstrual cycle disturbances requires daily hormone assessments. In contrast, the identification of severe menstrual disturbances, such as amenorrhea and oligomenorrhea, can be established by clinical observation. The primary purpose of this study was to determine the frequency of subtle menstrual disturbances, defined as luteal phase defects (LPD) or anovulation, in exercising women, with menstrual cycles of 26-35 days, who engage in a variety of sports, both recreational and competitive. Secondly, the prevalence of oligomenorrhea and amenorrhea was also determined via measurement of daily urinary ovarian steroids rather than self report alone. METHODS: Menstrual status was documented by daily measurements of estrone and pregnanediol glucuronide and luteinizing hormone across two to three consecutive cycles and subsequently categorized as ovulatory (Ovul), LPD, anovulatory (Anov), oligomenorrheic (Oligo) and amenorrheic (Amen) in sedentary (Sed) and exercising (Ex) women. RESULTS: Sed (n = 20) and Ex women (n = 67) were of similar (P > 0.05) age (26.3 +/- 0.8 years), weight (59.3 +/- 1.8 kg), body mass index (22.0 +/- 0.6 kg/m2), age of menarche (12.8 +/- 0.3 years) and gynecological maturity (13.4 +/- 0.9 years). The Sed group exercised less (P < 0.001) (96.7 +/- 39.1 versus 457.1 +/- 30.5 min/week) and had a lower peak oxygen uptake (34.4 +/- 1.4 versus 44.3 +/- 0.6 ml/kg/min) than the Ex group. Among the menstrual cycles studied in the Sed group, the prevalence of subtle menstrual disturbances was only 4.2% (2/48); 95.8% (46/48) of the observed menstrual cycles were ovulatory. This finding stands in stark contrast to that observed in the Ex group where only 50% (60/120) of the observed menstrual cycles were ovulatory and as many as 50% (60/120) were abnormal. Of the abnormal cycles in the Ex group, 29.2% (35/120) were classified as LPD (short, inadequate or both) and 20.8% (25/120) were classified as Anov. Among the cycles of Ex women with severe menstrual disturbances, 3.5% (3/86) of the cycles were Oligo and 33.7% (29/86) were Amen. No cycles of Sed women (0/20) displayed either Oligo or Amen. CONCLUSIONS: This study suggests that approximately half of exercising women experience subtle menstrual disturbances, i.e. LPD and anovulation, and that one third of exercising women may be amenorrheic. Estimates of the prevalence of subtle menstrual disturbances in exercising women determined by the presence or absence of short or long cycles does not identify these disturbances. In light of known clinical consequences of menstrual disturbances, these findings underscore the lack of reliability of normal menstrual intervals and self report to infer menstrual status

12-months of increased dietary intake does not exacerbate disordered eating-related attitudes, stress, or depressive symptoms in women with exercise-associated menstrual disturbances: the REFUEL randomized controlled trial

Disordered eating-related attitudes are a leading cause of energy deficiency and menstrual disturbances in exercising women. Although treatment recommendations include psychological counseling with increases in dietary intake, a key concern is whether increased dietary intake may exacerbate negative eating behaviors. Objective: To determine the effects of a 12-month nutritional intervention on eating-related attitudes and psychological characteristics in exercising women with oligomenorrhea/amenorrhea (Oligo/Amen). Methods: Intent-to-treat analysis of the REFUEL randomized controlled trial (#NCT00392873) in 113 exercising women (age [mean±SEM]:] 21.9±0.4 yrs; BMI: 20.9±0.2 kg/m2). Women were randomized to increase energy intake 20-40% above baseline energy needs (Oligo/Amen+Cal, n=40) or maintain energy intake (Oligo/Amen Control, n=36) while maintaining their exercise behaviors. A reference group of ovulatory women (OVref, n=37) maintained diet and exercise behaviors. Body composition, eating behavior, stress, and depressive symptoms were assessed at baseline and every 3 months. Results: At baseline, the Oligo/Amen groups had higher drive for thinness, cognitive restraint, and eating disorder risk than OVref group (p Discussion: Long-term nutritional intervention consisting of modest increases in dietary intake with guidance from a registered dietician and a psychologist increases body and fat mass without increasing disordered eating-related attitudes, stress, or depressive symptoms in exercising women with Oligo/Amen.</p