Jennifer L. Scheid

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.

Elevated PYY is associated with energy deficiency and indices of subclinical disordered eating in exercising women with hypothalamic amenorrhea.

The purpose of this study was twofold: (1) to determine if gastrointestinal hormones, associated with energy intake and energy balance, are altered in exercising women with hypothalamic amenorrhea and (2) to assess the association between gastrointestinal hormones and behavioural indicators of subclinical disordered eating in exercising women with hypothalamic amenorrhea. This cross-sectional study analyzed serum ghrelin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), menstrual status (by E1G and PdG), resting energy expenditure (REE), and subclinical eating behaviours in sedentary ovulatory (SedOv), exercising ovulatory (ExOv), and exercising amenorrheic (ExAmen) women. Groups were similar with respect to age (23.8+/-0.6 years) and BMI (21.4+/-0.3 kg/m(2)). The ratio of REE to predicted REE (REE:predicted REE) was 0.94+/-0.02, 0.94+/-0.02, and 0.88+/-0.02 in the SedOv, ExOv, and ExAmen groups, respectively. The REE:predicted REE in the ExAmen group was consistent with an energy deficiency. LogPYY, ghrelin, dietary cognitive restraint, and drive for thinness were elevated in the ExAmen group compared to other groups. GLP-1 concentrations were similar among groups. LogPYY correlated with drive for thinness and REE/FFM. In conclusion, fasting PYY and ghrelin concentrations are elevated in exercising women with FHA and both gastrointestinal peptides may serve as a proxy indicator of energy deficiency in this population.

Cognitive dietary restraint : Impact on bone, menstrual and metabolic status in young women

We compared bone mineral density (BMD) and content (BMC), menstrual and metabolic status between physically active women with 1) high cognitive dietary restraint (High-CDR) (score > or = 9, n=38) and Normal-CDR (score<9, n=46) and 2) across quartiles of CDR scores. Eighty-four physically active (500+/-35 min wk(-1)) premenopausal women participated and were categorized according to their CDR score. Primary outcomes included, BMD, BMC, menstrual status, estrone-3-glucuronide (E1G) and pregnanediol-3-glucuronide (PdG) area under the curve (AUC). Secondary outcomes included resting energy expenditure (REE), total triiodothyronine, and ghrelin. Measures of body mass (59.2+/-1.1 vs. 58.5+/-1.0 kg) and percent body fat (24.7+/-1.2 vs. 23.7+/-0.7%) were similar between women with Normal-CDR and High-CDR, however the High-CDR group had lower total body (1.140+/-0.011 vs. 1.179+/-0.010 g cm(-2); p=0.015) and lumbar spine (1.114+/-0.019 vs. 1.223+/-0.022 g cm(-2); p=0.001) BMD. The prevalence of oligo-amenorrhea was higher in the High-CDR group and became increasingly greater across the CDR quartiles. There were no differences in metabolic characteristics between the High-CDR and Normal-CDR groups, however REE and the ratio of measured to predicted REE were lower in the fourth quartile (CDR scores > or = 13) compared to the second and third quartiles. Our results provide evidence that high CDR scores are associated with reduced lumbar spine and total body BMD in physically active premenopausal women. A greater frequency of menstrual disturbances in women with higher CDR scores likely played a role in the reduced total body and lumbar spine BMD.

Estrogen and peptide YY are associated with bone mineral density in premenopausal exercising women.

BACKGROUND In women with anorexia nervosa, elevated fasting peptide YY (PYY) is associated with decreased bone mineral density (BMD). Prior research from our lab has demonstrated that fasting total PYY concentrations are elevated in exercising women with amenorrhea compared to ovulatory exercising women. PURPOSE The purpose of this study was to assess the association between fasting total PYY, average monthly estrogen exposure and BMD in non-obese premenopausal exercising women. METHODS Daily urine samples were collected and assessed for metabolites of estrone 1-glucuronide (E1G) and pregnandiol glucuronide (PdG) for at least one menstrual cycle if ovulatory or a 28-day monitoring period if amenorrheic. Fasting serum samples were pooled over the measurement period and analyzed for total PYY and leptin. BMD and body composition were assessed by dual-energy X-ray absorptiometry. Multiple regression analyses were performed to determine whether measures of body composition, estrogen status, exercise minutes, leptin and PYY explained a significant amount of the variance in BMD at multiple sites. RESULTS Premenopausal exercising women aged 23.8±0.9years with a mean BMI of 21.2±0.4kg/m(2) exercised 346±48min/week and had a peak oxygen uptake of 49.1±1.8mL/kg/min. Thirty-nine percent (17/44) of the women had amenorrhea. Fasting total PYY concentrations were negatively associated with total body BMD (p=0.033) and total hip BMD (p=0.043). Mean E1G concentrations were positively associated with total body BMD (p=0.033) and lumbar spine (L2-L4) BMD (p=0.047). The proportion of variance in lumbar spine (L2-L4) BMD explained by body weight and E1G cycle mean was 16.4% (R(2)=0.204, p=0.012). The proportion of variance in hip BMD explained by PYY cycle mean was 8.6% (R(2)=0.109, p=0.033). The proportion of variance in total body BMD explained by body weight and E1G cycle mean was 21.9% (R(2)=0.257, p=0.003). CONCLUSION PYY, mean E1G and body weight are associated with BMD in premenopausal exercising women. Thus, elevated PYY and suppressed estrogen concentrations are associated with, and could be directly contributing to, low BMD in exercising women with amenorrhea, despite regular physical activity.

Ghrelin but not peptide YY is related to change in body weight and energy availability.

PURPOSE The aim of this study was to examine changes in fasting total peptide YY (PYY) and ghrelin in nonobese premenopausal women after an exercise and diet program with and without weight loss. METHODS Body composition, energy balance parameters, ghrelin, and PYY were measured before and after a 3-month intervention in nonexercising controls (n = 7) and exercising women who either remained weight stable (n = 5) or lost weight (n = 10). At baseline, subjects were 20.6 ± 2.2 yr, weighed 58.0 ± 4.8 kg, and had 27.2% ± 4.9% body fat. Supervised exercise training occurred five times a week for up to 90 min at 70%-80% of maximum HR. Subjects were fed a controlled diet. RESULTS Body weight (-3.2 ± 0.8 kg) and fat mass (-2.6 ± 0.7 kg) decreased significantly in the weight-loss exercise group. Neither fasting ghrelin nor PYY changed in response to exercise training in the absence of weight loss, and PYY did not change with exercise and weight loss. Fasting ghrelin did reveal a significant time × experimental group interaction (P = 0.025). The change in ghrelin was inversely correlated with the change in body weight, body mass index, fat-free mass, and energy availability. CONCLUSIONS Neither fasting ghrelin nor fasting PYY seem to play a role in the adaptive changes associated with exercise training when exercise occurs in the absence of weight loss. Fasting ghrelin concentrations increase when body weight is lost and may respond to even smaller changes in energy availability. However, fasting PYY does not seem to play a key role in the regulation of energy balance during diet- and exercise-associated weight loss.

Menstrual Irregularities and Energy Deficiency in Physically Active Women: The Role of Ghrelin, PYY and Adipocytokines

Menstrual cycle irregularities are often observed among physically active women and athletes who participate in physical activity ranging from recreational to competitive exercise training. Further, such irregularities have been casually linked to an energy deficiency where caloric intake is inadequate for exercise energy expenditure resulting in a suppressive effect on growth and reproduction. Adaptations consistent with chronic energy deficiency, including reductions in resting energy expenditure and total triiodothyronine, have been observed in exercising women with functional hypothalamic amenorrhea (FHA). Gut peptides and adipocytokines also appear to be altered in exercising women with FHA and have been hypothesized to be involved in the etiology of FHA. Ghrelin concentrations are elevated in exercising women with FHA. Interestingly, while fasting ghrelin, an orexigenic peptide, is elevated in women with FHA, PYY, an orexigenic peptide, is paradoxically also elevated in women with anorexia nervosa and exercising women with FHA. Leptin, an adipocytokine, is also suppressed in FHA associated with exercise and anorexia. A critical leptin concentration threshold is suggested to be necessary for regular menses to occur. Ghrelin, PYY, and leptin all have the ability to cross the blood brain barrier and, in the hypothalamus, can modulate appetite and food intake, and are hypothesized to affect the hypothalamic-pituitary-ovarian axis. Future studies are needed to determine if ghrelin, PYY, or leptin play a direct role in the regulation of the hypothalamic-pituitary-ovarian axis, and if these signals can be altered by improving energy status secondary to increasing caloric intake and initiate the reversal of amenorrhea.

The effect of exercise and estrogen on osteoprotegerin in premenopausal women.

BACKGROUND The benefits of exercise are widely recognized, however physically active women can develop exercise associated menstrual cycle disturbances such as amenorrhea (i.e., estrogen deficiency) secondary to a chronic energy deficiency. OBJECTIVE To assess the effects of exercise status and estrogen deficiency on osteoprotegerin (OPG) and its relationship to bone resorption in premenopausal exercising women. DESIGN Cross-sectional study of serum OPG, urinary c-telopeptides (uCTX), urinary estrone 3-glucuronide (E1G), urinary pregnanediol 3-glucuronide (PdG) and bone mineral density (BMD) measured on multiple occasions in 67 women. Volunteers were retrospectively grouped: 1) sedentary menstruating group (SedMen n=8), 2) exercising menstruating group (ExMen, n=36), and 3) exercising amenorrheic group (ExAmen, n=23). One-way ANOVAs were performed, and LSD post-hoc tests were performed when differences were detected. RESULTS Subjects were similar with respect to age (24.2+/-1.0 years), weight (57.8+/-1.7 kg), and height (164.3+/-1.3 cm) (p>0.05). ExMen and ExAmen groups were more aerobically fit (p=0.003) and had less body fat (p=0.002) than the SedMen group. Resting energy expenditure/fat free mass was lowest (p=0.001) in the ExAmen groups. Mean E1G across the measurement period (p<0.001) and overall E1G exposure as assessed by E1G area under the curve (AUC) (p<0.001) were lower in the ExAmen group vs. the SedMen and ExMen groups. U-CTX-I was elevated (p=0.033) in the ExAmen group (281.8+/-40.3 microg/L/mmCr), compared with the SedMen and ExMen groups (184.5+/-22.4, 197.2+/-14.7 microg/L/mmCr, respectively). OPG was suppressed (p=0.005) in the ExAmen group (4.6+/-0.2 pmol/L) vs. ExMen group (5.2+/-0.2 pmol/L), and OPG was lower in the SedMen group (4.1+/-0.3 pmol/L) compared with the ExMen group. Findings were translated to BMD; the ExAmen group had suppressed total body BMD (p=0.014) and L2-L4 BMD (p=0.015) vs. the ExMen group. CONCLUSIONS Our results suggest that OPG responds to the bone loading effect of exercise, and that suppressed OPG may play a role in the etiology of increased bone resorption observed in exercising women with chronic estrogen deficiency secondary to hypothalamic amenorrhea.

Decreased luteinizing hormone pulse frequency is associated with elevated 24-hour ghrelin after calorie restriction and exercise in premenopausal women.

Elevated ghrelin has been shown to be associated with reduced luteinizing hormone (LH) pulsatility in Rhesus monkeys, rats, men, and recently women. We previously reported that 24-h ghrelin concentrations are elevated in women following a 3-mo exercise and diet program leading to weight loss. We investigated whether the elevations in ghrelin following an ~3-mo exercise and diet program leading to weight loss are associated with a decrease in LH pulsatility. The nonexercising control group (Control, n = 5) consumed a controlled diet that matched energy needs, whereas energy intake in the exercise group (Energy Deficit, n = 16) was reduced from baseline energy requirements and supervised exercise training occurred five times per a week. Significant decreases in body weight (-3.0 ± 0.6 kg), body fat (-2.9 ± 0.4 kg) and 24-h LH pulse frequency (-0.18 ± 0.08 pulses/h), and a significant increase in 24-h mean ghrelin were observed in only the Energy Deficit group. The pre-post change in LH pulse frequency was negatively correlated with the change in mean 24-h ghrelin (R = -0.485, P = 0.030) and the change in peak ghrelin at lunch (R = -0.518, P = 0.019). Interestingly, pre-post change in night LH pulse frequency was negatively correlated with the change in mean day ghrelin (R = -0.704, P = 0.001). Elevated total ghrelin concentrations are associated with the suppression of LH pulsatility in premenopausal women and may play a role in the suppression of reproductive function following weight loss.

The Role of PYY in Eating Behavior and Diet

Peptide YY (PYY) is a gastrointestinal peptide secreted from the endocrine L cells of the intestine in response to food intake. PYY3–36 is the active form of PYY and is the major form of circulating PYY after a meal. PYY, once released from the intestine to the circulation, can cross the blood brain barrier and act centrally at the level of the arcuate nucleus in the hypothalamus to contribute to eating behavior. PYY3–36’s ability to bind to the Y2 receptor in the arcuate nucleus indicates the key pivotal role of this peptide in body weight regulation. Circulating PYY concentrations rise in response to a caloric load after a meal and peak PYY concentrations are achieved in proportion to the amount of calories ingested and are affected by the macronutrient content of the meal. Fasting and post-prandial PYY concentrations are chronically elevated in populations of energy-deficient women, including women with anorexia nervosa. Fasting PYY concentrations are also elevated in exercising women with functional hypothalamic amenorrhea (FHA). Elevated PYY in the presence of elevated ghrelin may cause a relative ghrelin resistance in women with anorexia nervosa or FHA. Fasting PYY concentrations are suppressed in most studies of obese patients and circulating PYY concentrations are consistently suppressed in obese individuals compared to lean individuals after a meal. Peripherally administered PYY3–36 decrease appetites and 24 h food intake in obese individuals and indicates that administration of PYY3–36 may be a future weight loss aid, by decreasing caloric intake during meal. The PYY response to macronutrients differs between lean and obese individuals and a high-protein diet may be beneficial for obese individuals, potentially increase satiety, and assist with weight control or weight loss.