title: Induction of menstrual disorders by strenuous exercise in untrained women. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. Menstrual cycle irregularity and risk for future cardiovascular disease. The GnRH pulse generator. Hormonal profile of women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland birth cohort 1966 study. Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Beneficial effects of a three-month structured exercise training program on cardiopulmonary functional capacity in young women with polycystic ovary syndrome. A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome. Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study.
abstract: We performed a prospect i ve study of 28 initially untrained college women with documented ovulation and luteal adequacy to determine whether strenuous exercise spanning two menstrual cycles would induce menstrual disorders . To ascertain the influence , if any , that weight loss might exert , we r and omly assigned the subjects to weight-loss and weight-maintenance groups . Subjects were expected to run 4 miles ( 6.4 km ) per day , progressing to 10 miles ( 16.1 km ) per day by the fifth week , and to engage daily in 31/2 hours of moderate-intensity sports . The normalcy of the menstrual cycles during the period of exercise was judged independently according to clinical and hormonal criteria , the latter comprising serial measurements of gonadotropin and sex-steroid excretion . A higher percentage of abnormalities proved to be detectable by hormonal means ( P less than 0.02 ) . Only four subjects ( three in the weight-maintenance group ) had a normal menstrual cycle during training . In the weight-loss group , the number of women who had luteal abnormalities as compared with those who lost the surge in luteinizing hormone altered significantly over time , the latter occurring more frequently ( P less than 0.01 ) as training progressed . Within six months of termination of the study , all subjects were again experiencing normal menstrual cycles . We conclude that vigorous exercise , particularly if compounded by weight loss , can reversibly disturb reproductive function in women We performed this study to access the changes in glucose tolerance over time in a group of women with polycystic ovary syndrome ( PCOS ) ( n = 71 ) and control women ( n = 23 ) with regular menstrual cycles and baseline normal glucose tolerance . Mean follow-up was between 2 and 3 yr for both groups ( PCOS 2.5 + /- 1.7 yr ; controls 2.9 + /- 2.1 yr ) . Based on World Health Organization glucose tolerance categories , there was no significant difference in the prevalence of glucose intolerance at follow-up in the PCOS group . In the PCOS group , 25 ( 37 % ) had impaired glucose tolerance ( IGT ) and seven ( 10 % ) had type 2 diabetes mellitus at baseline , compared with 30 ( 45 % ) and 10 ( 15 % ) , respectively , at follow-up . There were also no differences within groups ( PCOS or control ) or between groups ( PCOS vs. control ) in the oral glucose tolerance test-derived measure of insulin sensitivity , but in the women with PCOS who converted to either IGT or type 2 diabetes mellitus , there was a significant decrease ( P < 0.0001 ) . At the follow-up visit , the mean glycohemoglobin level was 6.1 + /- 0.9 % in women with PCOS vs. 5.3 + /- 0.7 % in the control women ( P < 0.001 ) . Women with PCOS and baseline IGT had a low conversion risk of 6 % to type 2 diabetes over approximately 3 yr , or 2 % per year . The effect of PCOS , given normal glucose tolerance ( NGT ) at baseline , is more pronounced with 16 % conversion to IGT per year . Our study supports that women with PCOS ( especially with NGT ) should be periodically rescreened for diabetes due to worsening glucose intolerance over time , but this interval may be over several years and not annually We tested two hypotheses about the disruption of luteinizing hormone ( LH ) pulsatility in exercising women by assaying LH in blood sample s drawn at 10-min intervals over 24 h from nine young , habitually sedentary , regularly menstruating women on days 8 , 9 , or 10 of two menstrual cycles after 4 days of intense exercise [ E = 30 kcal.kg lean body mass (LBM)-1.day-1 at 70 % of aerobic capacity ] . To test the hypothesis that LH pulsatility is disrupted by low energy availability , we controlled the subjects ' dietary energy intakes ( I ) to set their energy availabilities ( A = I - E ) at 45 and 10 kcal.kg LBM-1.day-1 during the two trials . To test the hypothesis that LH pulsatility is disrupted by the stress of exercise , we compared the result ing LH pulsatilities to those previously reported in women with similar controlled energy availability who had not exercised . In the exercising women , low energy availability reduced LH pulse frequency by 10 % ( P < 0.01 ) during the waking hours and increased LH pulse amplitude by 36 % ( P = 0.05 ) during waking and sleeping hours , but this reduction in LH pulse frequency was blunted by 60 % ( P = 0.03 ) compared with that in the previously studied nonexercising women whose low energy availability was caused by dietary restriction . The stress of exercise neither reduced LH pulse frequency nor increased LH pulse amplitude ( all P > 0.4 ) . During exercise , the proportion of energy derived from carbohydrate oxidation was reduced from 73 % while A = 45 kcal.kg LBM-1.day-1 to 49 % while A = 10 kcal.kg LBM-1.day-1 ( P < 0.0001 ) . These results contradict the hypothesis that LH pulsatility is disrupted by exercise stress and suggest that LH pulsatility in women depends on energy availability Cross-sectional and short-term prospect i ve studies in humans support the concept that low energy availability , and not other factors associated with exercise , causes the development of exercise-induced reproductive dysfunction . To rigorously test this hypothesis , we performed a longitudinal study , examining the role of low energy availability on both the development and the reversal of exercise-induced amenorrhea , using a monkey model ( Macaca fascicularis ) . Eight adult female monkeys developed amenorrhea ( defined as absence of menses for at least 100 d , with low and unchanging concentrations of LH , FSH , E2 , and P4 ) after gradually increasing their daily exercise to 12.3 + /- 0.9 km/d of running over a 7- to 24-month period . Food intake remained constant during exercise training . To test whether amenorrhea is caused by low energy availability , four of the eight amenorrheic monkeys were provided with supplemental calories ( 138 - 181 % of calorie intake during amenorrhea ) while they maintained their daily training . All four monkeys exhibited increased reproductive hormone levels and reestablished ovulatory cycles , with recovery times for circulating gonadotropin levels ranging from 12 - 57 d from the initiation of supplemental feeding . The rapidity of recovery within the reproductive axis in a given monkey was directly related to the amount of energy that was consumed during the period of supplemental feeding ( r = -0.97 ; P < 0.05 ) . Repeated measurements of plasma T3 concentrations , a marker of cellular energy availability , revealed a tight correlation between the changes in reproductive function and T3 levels , such that T3 significantly decreased ( 27 % ) with the induction and significantly increased ( 18 % ) with the reversal of amenorrhea ( P < 0.05 ) . These data provide strong evidence that low energy availability plays a causal role in the development of exercise-induced amenorrhea Cross-sectional studies suggest that women who have irregular menstrual cycles and hyper and rogenism may be at increased risk for cardiovascular disease ( CVD ) . However , prospect i ve data are lacking on the relationship between menstrual cycle irregularity and subsequent CVD risk . The objective of this study was to assess prospect ively the risk for coronary heart disease ( CHD )  and stroke associated with a history of irregular menstrual cycles . The study design was a prospect i ve cohort study of 82,439 female nurses who provided information in 1982 on prior menstrual regularity ( at ages 20 - 35 yr ) and were followed through 1996 for cardiovascular events . Incident reports of nonfatal myocardial infa rct ion , fatal CHD , and nonfatal and fatal stroke were made . Medical records were review ed for confirmation . During 14 yr ( 1,155,915 person-yr ) of follow-up , there were 1417 incident cases of CHD and 838 incident cases of stroke , including 471 cases of ischemic stroke . Compared with women reporting a history of very regular menstrual cycles , women reporting usually irregular or very irregular cycles had an increased risk for nonfatal or fatal CHD [ age-adjusted relative risks ( RR ) , 1.25 and 1.67 , respectively ; 95 % confidence intervals ( CI ) , 1.07 - 1.47 and 1.35 - 2.06 , respectively ] . Increased risks for CHD associated with prior cycle irregularity remained significant after adjustment for body mass index and several potential confounders . There was a nonsignificant increase in overall stroke risk ( RR , 1.30 ; 95 % CI = 0.97 - 1.74 ) and in ischemic stroke risk ( RR , 1.40 ; 95 % CI = 0.97 - 2.04 ) associated with very irregular cycles . Menstrual cycle irregularity may be a marker of metabolic abnormalities predisposing to increased risk for CVD The notion of an oscillator or signal generator in the central nervous system that controls the rhythmic release of GnRH and , thereby , the pulsatile secretion of the gonadotropic hormones , originated in the finding of strikingly abrupt and rhythmic fluctuations in the concentration of LH in the plasma of ovariectomized monkeys . These oscillations had a period of about one hour when blood sample s were obtained at 10 to 20 minute intervals . I These surprising observations were presaged by reports of seemingly r and om , major fluctuations in plasma gonadotropin concentrations in gonadectomized monkeys " and rats""1 as well as in women . ' In these earlier studies the sampling intervals employed were never less than one hour and unable , therefore , to reveal the orderly , rhythmic events that occur with frequencies of one event per hour , or more . In the original study describing pulsatile LH secretion in ovariectomized monkeys the possibility was considered that the circhoral discharges of LH may be initiated by autoregulatory mechanisms involving long or short feedback loops , but the more likely view that these discharges were due to intermittent signals from the central nervous system unrelated to circulating LH levels that result ed in putative increments in GnRH release was favored . Nevertheless , the possible role of autoregulatory mechanisms in the control of pulsatile LH secretion was repeatedly considered,6 but finally laid to rest in the relatively recent past.7 Conversely , the view that each pulse of LH released from the pituitary gl and is the consequence of a bolus of GnRH secreted into the pituitary portal system has been unequivocally upheld by the demonstration of synchronous increments ofGnRH assessed in the pituitary portal circulation and of LH measured in sample s of peripheral blood obtained simultaneously.s , 9 In any case , the phenomenon of pulsatile gonadotropic hormone secretion was rapidly extended to most vertebrate species studied in this regard , including our own , The hormonal profiles of nested female patients ( n = 500 ) with self-reported symptoms typical of polycystic ovary syndrome ( PCOS ) , oligomenorrhea , and /or hirsutism and their r and omly selected controls ( n = 1026 ) at the age of 31 yr were analyzed in a general population -based Northern Finl and birth cohort 1966 to find out whether the symptomatic women also have the endocrine characteristics of PCOS and could be detected in a general population using simple questions . Higher medians of serum testosterone ( T ) ( 2.10 vs. 1.90 nmol/liter , P < 0.001 ) , LH ( 5.40 vs. 4.85 U/liter , P = 0.005 ) , insulin ( 53.8 vs. 51.66 pmol/liter , P = 0.040 ) , and free and rogen index ( FAI ) ( 4.01 vs. 3.03 , P < 0.001 ) and lower glucose/insulin ratio ( 91.1 x 10(8 ) vs. 94.9 x 10(8 ) , P = 0.048 ) and SHBG ( 52.4 vs. 60.7 nmol/liter , P < 0.001 ) were observed among the cases , but no difference was observed in cortisol and glucose levels between the cases and controls . Of all the women in the cohort , 10.2 % reported only oligomenorrhea and had biochemical findings similar to the whole case group . Those who reported only hirsutism ( 10.4 % ) were in between the case and control groups according to biochemical findings . The subjects who reported both oligomenorrhea and hirsutism ( 3.4 % ) had the highest T , LH , FAI , insulin , and glucose and the lowest SHBG and glucose/insulin ratio , compared with the case group and the groups with either symptom only indicating a dose-response manner in typical endocrine profile of PCOS by adding up symptoms . The levels of T and FAI were higher and SHBG lower in groups with overweight or obesity both at 14 and 31 yr , compared with groups with normal weight at 14 yr and overweight or obesity at 31 yr . In the group with normal weight at 14 and 31 yr and the group with overweight or obesity at 14 yr but normal weight at 31 yr , the levels of T and FAI were lowest and SHBG highest . T and FAI were higher and SHBG lower among the cases than the controls in groups stratified by weight development from adolescence to adulthood . In conclusion , this longitudinal study of a large , stable population indicates that women with self-reported symptoms of hirsutism and /or oligomenorrhea show endocrine characteristics of PCOS and can be detected in a general population using simple questions . These symptoms are markers of the underlying metabolic alterations possibly associated with increased health risks in later life OBJECTIVE We tested the hypothesis that the three clinical phenotypes of polycystic ovary syndrome ( PCOS ) represent forms of the same metabolic disorder . DESIGN Prospect i ve cohort analysis . SETTING University-based tertiary care . PATIENT(S ) Three-hundred sixteen untreated consecutive women diagnosed as having PCOS . INTERVENTION(S ) None . MAIN OUTCOME MEASURE(S ) Each subject underwent an  evaluation of ovulatory function , body habitus , acne , and hirsutism ; serum free and total testosterone ( T ) , 17-hydroxyprogesterone ( 17-HP ) , and DHEAS ; and fasting plasma glucose and insulin levels . Insulin resistance and beta-cell function were assessed using the homeostatic assessment model equation ( HOMA-IR and HOMA-beta-cell , respectively ) . RESULT ( S ) The Oligo+HA+Hirsutism phenotype was present in 48 % of subjects , Oligo+HA in 29 % , and Oligo+Hirsutism in 23 % . The three phenotypes did not differ in mean body mass index , waist-to-hip ratio , racial composition , degree of oligo-ovulation , prevalence of acne , or family history of hyper and rogenic symptomatology . However , subjects demonstrating the Oligo+HA+Hirsutism phenotype were the youngest and had the greatest degrees of hyper and rogenemia , hyperinsulinemia , and beta-cell function ; patients with the Oligo+Hirsutism phenotype where the oldest and had the mildest degrees of hyper and rogenemia , hyperinsulinemia , and beta-cell function . Subjects with the Oligo+HA phenotype demonstrated intermediate degrees of hyper and rogenemia and metabolic dysfunction . CONCLUSION ( S ) We conclude that the three clinical phenotypes of PCOS do not represent forms of the same metabolic disorder and may be the result of varying degrees of metabolic dysfunction ; greater degrees of beta-cell function and circulating insulin levels favored the development of hirsutism and frank hyper and rogenemia CONTEXT Polycystic ovary syndrome ( PCOS ) is an endocrine disease closely related to several risk factors for cardiovascular disease . An impaired cardiopulmonary functional capacity was previously demonstrated in PCOS women . No data regarding the effects of a structured exercise training ( ET ) program on cardiopulmonary functional capacity in PCOS women are available . OBJECTIVE Our objective was to evaluate the effects of a 3-month ET program on cardiopulmonary functional capacity in young PCOS women . DESIGN AND SETTING A prospect i ve baseline-r and omized clinical study was conducted at the University " Federico II " of Naples , School of Medicine ( Italy ) . PATIENTS Ninety young overweight PCOS women were enrolled . MEAN OUTCOME MEASURES Ninety young PCOS women were r and omly subdivided into two groups , each composed of 45 subjects . The PCOS-T ( trained ) group underwent a 3-month structured ET program , whereas the PCOS-UnT ( untrained ) group did not . Hormonal and metabolic profiles and cardiopulmonary and exercise parameters were evaluated . RESULTS After 3-month ET , PCOS-T showed a significant improvement in peak oxygen consumption ( + 35.4 % ; P<0.001 ) and in maximal workload ( + 37.2 % ; P<0.001 ) . In PCOS-T we also observed a significant reduction in body mass index ( -4.5 % ; P<0.001 ) and in C-reactive protein ( -10 % ; P<0.001 ) , and a significant ( P<0.001 ) improvement in insulin sensitivity indexes . After 3 months , no changes were observed in PCOS-UnT. CONCLUSIONS A 3-month structured ET program improves cardiopulmonary functional capacity in young PCOS women OBJECTIVE We performed this study as a pilot experiment to investigate the short term effects of two diets of varying composition on weight loss as the primary outcome in obese women with polycystic ovary syndrome ( PCOS ) seeking fertility . DESIGN R and omized clinical trial . SETTING Academic medical center . PATIENT(S ) Thirty-five obese women with PCOS . INTERVENTION(S ) We examined the effects of a 1-month dietary intervention on the PCOS phenotype . Participants were r and omized to one of two energy-restricted diets ; high protein ( HP : 30 % protein , 40 % carbohydrate , and 30 % fat ) or high carbohydrate ( HC : 15 % protein , 55 % carbohydrate , and 30 % fat ) . The fat content was held constant in both diets . MAIN OUTCOME MEASURE(S ) Primary - change in body weight ; Secondary - biometric , hormonal , lipid and lipoprotein , and markers of glucose homeostasis and energy metabolism . RESULT ( S ) Twenty-six women completed the study . Both the HP ( -3.7 + /- 1.9 kg ) and HC ( -4.4 + /- 1.5 kg ) diets result ed in significant weight loss , but there was no significant difference in mean weight loss between the two groups . There were also no differences between diets on a variety of measures including circulating and rogens , measures of glucose metabolism , and leptin . However , the effects of a hypocaloric diet per se on improving metabolic and reproductive abnormalities in a group of PCOS women were marked by a decline in circulating and rogens ( P=.03 ) , fasting and area under the curve ( AUC ) insulins ( P<.05 ) on a 3-hour oral glucose tolerance test ( OGTT ) , and fasting and AUC leptin levels ( P<.0001 ) . There was a high prevalence of menstrual bleeding during the trial ( 14 out of 26 patients ) . CONCLUSION ( S ) Those who completed the short-term hypocaloric diet had a significant weight loss and a significant improvement in their reproductive and metabolic abnormalities . There was no increased benefit to a high-protein diet . Future diet studies evaluating the ideal composition of a hypocaloric diet in women with PCOS will require a large study population , and will most likely require a multicenter trial BACKGROUND Lifestyle modifications are successfully employed to treat obese and overweight women with polycystic ovary syndrome ( PCOS ) . The aims of the current pilot study were ( i ) to compare the efficacy on reproductive functions of a structured exercise training ( SET ) programme with a diet programme in obese PCOS patients and ( ii ) to study their clinical , hormonal and metabolic effects to eluci date potentially different mechanisms of action . METHODS Forty obese PCOS patients with anovulatory infertility underwent a  SET programme ( SET group , n = 20 ) and a hypocaloric hyperproteic diet ( diet group , n = 20 ) . Clinical , hormonal and metabolic data were assessed at baseline , and at 12- and 24-week follow-ups . Primary endpoint was cumulative pregnancy rate . RESULTS The two groups had similar demographic , anthropometric and biochemical parameters . After intervention , a significant improvement in menstrual cycles and fertility was noted in both groups , with no differences between groups . The frequency of menses and the ovulation rate were significantly ( P < 0.05 ) higher in the SET group than in diet group but the increased cumulative pregnancy rate was not significant . Body weight , body mass index , waist circumference , insulin resistance indexes and serum levels of sex hormone-binding globulin , and rostenedione and dehydroepi and rosterone sulphate changed significantly ( P < 0.05 ) from baseline and were significantly different ( P < 0.05 ) between the two groups . CONCLUSIONS Both SET and diet interventions  improve fertility in obese PCOS patients with anovulatory infertility . We hypothesize that in both interventions an improvement in insulin sensitivity is the pivotal factor involved in the restoration of ovarian function but potentially acting through different mechanisms
target: Although scarce , the data available to date suggest that hyper and rogenism , such as that observed in PCOS , may likely be associated with oligomenorrhoea in exercising women , and may not always represent hypothalamic inhibition secondary to an energy deficiency .
background: To date , the predominant mechanism underlying  menstrual disturbances in exercising women supports an underlying energy deficiency-related aetiology , in which a failure to compensate dietary intake for the energy cost of exercise suppresses reproductive function .
  Increasing evidence demonstrates that energy deficiency plays a causal role in the induction of amenorrhoea in  exercising women , and consistent with this mechanism are findings of glucoregulatory perturbations such as low triiodothyronine , reduced insulin secretion and elevated cortisol , growth hormone and ghrelin levels .
  The menstrual disturbance that may differ in its energetic characteristics and , perhaps in its and rogenic and ovarian steroid environment , is oligomenorrhoea .
  We conducted a systematic review of the literature to begin to underst and whether oligomenorrhoea in  exercising women is a mild sub clinical phenotype of polycystic ovarian syndrome ( PCOS ) in which exercise is conferring beneficial effects in protecting women from the classic PCOS phenotype , or whether oligomenorrhoea is part of the spectrum of menstrual disturbances caused by an energy deficiency that is often reported in exercising women with menstrual disturbances .