Emma O'Donnell

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.

Estrogen Status and the Renin Angiotensin Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) is integrally involved in multiple cardiovascular physiological processes including arterial blood pressure (BP) regulation. Over activity of the RAAS has been implicated in the pathogenesis of a number of cardiovascular disease entities, including hypertension. Several lines of evidence suggest estrogen favorably modulates the RAAS. Conversely, estrogen deficiency due to menopause may contribute to over activity of the RAAS. Of importance, estrogen deficiency in women is not exclusive to the postmenopausal period. Functional hypothalamic amenorrhea is a reversible cause of premenopausal hypoestrogenemia. In contrast to postmenopausal women (PMW), premenopausal women with exercise-associated functional hypothalamic amenorrhea demonstrate decreased, not increased, resting BP compared with their estrogen-replete eumenorrheic counterpart. In this review we briefly examine the effects of estrogen status on the RAAS and present the hypothesis that the RAAS is altered in physically active women with functional hypothalamic amenorrhea.

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.

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.

Aerobic exercise training in healthy postmenopausal women: effects of hormone therapy

Objective:We investigated the influence of hormone therapy (HT) on submaximal central and peripheral function in healthy postmenopausal women after 12 weeks of endurance training. Methods:A randomized, double-blind, placebo-controlled study in a research and clinical facility was conducted. All participants (N = 23) underwent 12 weeks of aerobic exercise training (walking 5 d/wk at 70%-80% peak heart rate [HR]). Eleven participants received HT; 12 received placebo. HT consisted of daily 17&bgr;-estradiol (1 mg) with cyclic micronized progesterone (200 mg) or placebo for 10 days per month. Participants were tested before and after exercise training. Primary outcome measures were submaximal stroke volume, cardiac output, and total peripheral resistance measured during cycling at 30W, 45W, and 60W. Secondary outcome measures were ventilatory threshold, peak oxygen uptake (VO2 peak), and resting and peak-ischemic calf blood flow. Results:At baseline, HT and placebo groups were similar (P > 0.05) in age (mean ± SEM, 57 ± 1 y), height (162 ± 2 cm), weight (72 ± 4 kg), VO2 peak (21.5 ± 1.4 mL · kg−1 · min−1), and all cardiovascular measures. Posttraining oxygen consumption and HR decreased (P < 0.05) within groups during each submaximal exercise workload. Stroke volume, cardiac output, and total peripheral resistance remained unaltered (P > 0.05). VO2 peak and oxygen consumption at the ventilatory threshold increased (P < 0.05) within groups. Resting and postischemic blood flow were unaltered. HT did not influence any of the cardiovascular responses. Conclusions:These findings suggest that in healthy postmenopausal women, 12 weeks of aerobic training is effective in eliciting favorable cardiovascular adaptations, regardless of the presence of short-term HT.

Impaired Vascular Function in Physically Active Premenopausal Women With Functional Hypothalamic Amenorrhea Is Associated With Low Shear Stress and Increased Vascular Tone

INTRODUCTION Exercise-trained hypoestrogenic premenopausal women with functional hypothalamic amenorrhea (ExFHA) exhibit impaired endothelial function. The vascular effects of an acute bout of exercise, a potent nitric oxide stimulus, in these women are unknown. METHODS Three groups were studied: recreationally active ExFHA women (n = 12; 24.2 ± 1.2 years of age; mean ± SEM), and recreationally active (ExOv; n = 14; 23.5 ± 1.2 years of age) and sedentary (SedOv; n = 15; 23.1 ± 0.5 years of age) ovulatory eumenorrheic women. Calf blood flow (CBF) and brachial artery flow-mediated dilation (FMD) were evaluated using plethysmographic and ultrasound techniques, respectively, both before and 1 hour after 45 minutes of moderate-intensity exercise. Endothelium-independent dilation was assessed at baseline using glyceryl trinitrate. Calf vascular resistance (CVR) and brachial peak shear rate, as determined by the area under the curve (SRAUCpk), were also calculated. RESULTS FMD and glyceryl trinitrate responses were lower (P < .05) in ExFHA (2.8% ± 0.4% and 11.6% ± 0.7%, respectively) than ExOv (8.8% ± 0.7% and 16.7% ± 1.3%) and SedOv (8.0% ± 0.5% and 17.1% ± 1.8%). SRAUCpk was also lower (P < .05) in ExFHA. Normalization of FMD for SRAUCpk (FMD/SRAUCpk) did not alter (P > .05) the findings. CBF was lower (P < .05) and CVR higher (P < .05) in ExFHA. After exercise, FMD and SRAUCpk were augmented (P < .05), but remained lower (P < .05), in ExFHA. FMD/SRAUCpk no longer differed (P > .05) between the groups. CBF in ExFHA was increased (P < .05) and CVR decreased (P < .05) to levels observed in ovulatory women. CONCLUSIONS Acute dynamic exercise improves vascular function in ExFHA women. Although the role of estrogen deficiency per se is unclear, our findings suggest that low shear rate and increased vasoconstrictor tone may play a role in impaired basal vascular function in these women.

After-exercise heart rate variability is attenuated in postmenopausal women and unaffected by estrogen therapy.

Objective:Delayed heart rate (HR) recovery in the immediate postexercise period has been linked to adverse cardiovascular prognosis. The after effects of an acute bout of exercise on HR modulation in postmenopausal women (PMW) and the influence of estrogen therapy are unknown. Methods:In 13 sedentary PMW (54 ± 2 y, mean ± SEM), we assessed HR variability (HRV) —an index of HR modulation—and the influence of estrogen therapy on HRV. HRV in the frequency domain was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes, at 60% VO2peak. PMW were studied before and after 4 weeks of oral estradiol. To obtain reference values for the after effects of exercise on HRV in healthy young women, 14 premenopausal women (PreM) completed the identical exercise protocol. Results:Compared with PreM, PMW demonstrated lower high frequency (vagal modulation) and total HRV (P < 0.05) at rest. In PreM, all HRV values were similar before and after exercise. In contrast, in PMW after exercise, despite having identical HR to PreM, high frequency and total HRV were all lower (all P ⩽ 0.01) compared with pre-exercise HRV values. Estrogen therapy had no effect on pre or postexercise values for HRV. Conclusions:When compared with PreM, PMW have identical HR, but lower vagal HR modulation at rest and delayed HRV recovery after exercise. Estrogen does not restore baseline HRV or accelerate HRV recovery postexercise, suggesting aging rather than estrogen deficiency per se may lower HRV in PMW.

Augmented vagal heart rate modulation in active hypoestrogenic pre-menopausal women with functional hypothalamic amenorrhoea

Compared with eumenorrhoeic women, exercise-trained women with functional hypothalamic amenorrhoea (ExFHA) exhibit low heart rates (HRs) and absent reflex renin-angiotensin-system activation and augmentation of their muscle sympathetic nerve response to orthostatic stress. To test the hypothesis that their autonomic HR modulation is altered concurrently, three age-matched (pooled mean, 24 ± 1 years; mean ± S.E.M.) groups of women were studied: active with either FHA (ExFHA; n=11) or eumenorrhoeic cycles (ExOv; n=17) and sedentary with eumenorrhoeic cycles (SedOv; n=17). Blood pressure (BP), HR and HR variability (HRV) in the frequency domain were determined during both supine rest and graded lower body negative pressure (LBNP; -10, -20 and -40 mmHg). Very low (VLF), low (LF) and high (HF) frequency power spectra (ms(2)) were determined and, owing to skewness, log10-transformed. LF/HF ratio and total power (VLF + LF + HF) were calculated. At baseline, HR and systolic BP (SBP) were lower (P<0.05) and HF and total power were higher (P<0.05) in ExFHA than in eumenorrhoeic women. In all groups, LBNP decreased (P<0.05) SBP, HF and total power and increased (P<0.05) HR and LF/HF ratio. However, HF and total power remained higher (P<0.05) and HR, SBP and LF/HF ratio remained lower (P<0.05) in ExFHA than in eumenorrhoeic women, in whom measures did not differ (P>0.05). At each stage, HR correlated inversely (P<0.05) with HF. In conclusion, ExFHA women demonstrate augmented vagal yet unchanged sympathetic HR modulation, both at rest and during orthostatic stress. Although the role of oestrogen deficiency is unclear, these findings are in contrast with studies reporting decreased HRV in hypoestrogenic post-menopausal women.