Exercise decreases anti-müllerian hormone in anovulatory overweight women with polycystic ovary syndrome: a pilot study. Magnitude of daily energy deficit predicts frequency but not severity of menstrual disturbances associated with exercise and caloric restriction. Estrogen and progesterone exposure is reduced in response to energy deficiency in women aged 25-40 years. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. Menstrual disorders in girls with systemic lupus erythematosus treated with cyclophosphamide. Impact of electro-acupuncture and physical exercise on hyperandrogenism and oligo/amenorrhea in women with polycystic ovary syndrome: a randomized controlled trial. Serum antimüllerian hormone in response to dietary management and/or physical exercise in overweight/obese women with polycystic ovary syndrome: secondary analysis of a randomized controlled trial. Acupuncture for ovulation induction in polycystic ovary syndrome: a randomized controlled trial. Effects of exercise and nutritional counseling in women with polycystic ovary syndrome. Vitamin D Decreases Serum VEGF Correlating with Clinical Improvement in Vitamin D-Deficient Women with PCOS: A Randomized Placebo-Controlled Trial Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium.
Polycystic ovary syndrome ( PCOS ) is a common condition in women associated with menstrual irregularity and anovulation . While obesity worsens and weight loss or exercise improves reproduction function in PCOS , the mechanism for this is unclear . The aim of this study was to examine the effect of exercise on ovarian hormones [ anti-Müllerian hormone ( AMH ) ] and menstrual and ovulatory function in women with and without PCOS . Overweight women with ( n=7 ) and without ( n=8 ) PCOS of comparable age , weight and BMI undertook a 12-week intensified endurance exercise training program ( 1 h 3 times/week ) with no structured energy restriction . Primary outcomes were AMH , ovulation ( weekly urinary pregnanediol ) and menstrual regularity . Secondary outcomes were insulin resistance ( euglycemic hyperinsulinemic clamp ) and body composition ( computed tomography and dual X-ray absorptiometry ) . Exercise  decreased BMI , total and and roid fat mass and improved insulin sensitivity for all women . AMH was significantly higher in women with PCOS compared to controls before ( p<0.001 ) and after exercise ( p=0.001 ) . There was a significant interaction between AMH changes with exercise and PCOS status ( p=0.007 ) such that women without PCOS had no change in AMH ( + 1.4±5.2 pmol/l , p=0.48 ) while women with PCOS had a decrease in AMH ( - 13.2±11.7 pmol/l , p=0.025 ) . Exercise is associated with improvements in ovarian hormones in women with abnormal ovarian function . This suggests that mechanisms associated with ovarian dysfunction can be improved by exercise in PCOS We assessed the impact of energy deficiency on menstrual function using controlled feeding and supervised exercise over four menstrual cycles ( 1 baseline and 3 intervention cycles ) in untrained , eumenorrheic women aged 18 - 30 yr . Subjects were r and omized to either an exercising control ( EXCON ) or one of three exercising energy deficit ( ED ) groups , i.e. , mild ( ED1 ; -8 ± 2 % ) , moderate ( ED2 ; -22 ± 3 % ) , or severe ( ED3 ; -42 ± 3 % ) . Menstrual cycle length and changes in urinary concentrations of estrone-1-glucuronide , pregnanediol glucuronide , and midcycle luteinizing hormone were assessed . Thirty-four subjects completed the study . Weight loss occurred in ED1 ( -3.8 ± 0.2 kg ) , ED2 ( -2.8 ± 0.6 kg ) , and ED3 ( -2.6 ± 1.1 kg ) but was minimal in EXCON ( -0.9 ± 0.7 kg ) . The overall sum of disturbances ( luteal phase defects , anovulation , and oligomenorrhea ) was greater in ED2 compared with EXCON and greater in ED3 compared with EXCON AND ED1 . The average percent energy deficit was the main predictor of the frequency of menstrual disturbances ( f = 10.1 , β = -0.48 , r(2 ) = 0.23 , P = 0.003 ) even when weight loss was included in the model . The estimates of the magnitude of energy deficiency associated with menstrual disturbances ranged from -22 ( ED2 ) to -42 % ( ED3 ) , reflecting an energy deficit of -470 to -810 kcal/day , respectively . This is the first study to demonstrate a dose-response relationship between the magnitude of energy deficiency and the frequency of exercise-related menstrual disturbances ; however , the severity of menstrual disturbances was not dependent on the magnitude of energy deficiency BACKGROUND Alterations in circulating steroids are believed to be important mediators of the impact that diet and exercise have on breast cancer risk and changes in bone density . This study aim ed to test the hypothesis that moderate exercise training combined with caloric restriction would produce significant menstrual disturbances and alterations in ovarian steroids in premenopausal women . METHODS Sedentary premenopausal women ( 25 - 40 years ; body mass index : 23.6 + /- 0.6 kg/m(2 ) ) assigned to either a light conditioning ( LC , n = 9 ) or an exercise combined with caloric restriction group ( EX + CR , n = 24 ) were studied for one screening , one baseline and four intervention periods equivalent to the length of subjects ' menstrual cycles . Exercise consisted of supervised training sessions , i.e. two LC or four EX + CR times per week , 30 - 60 min at a moderate intensity . The EX + CR group was prescribed a diet representing a caloric restriction of 20 - 35 % below baseline energy requirements , whereas the LC group remained eucaloric . Ovarian steroid exposure was determined with daily urinary estrone-1- and pregnanediol glucuronides ( E1 G and PdG , respectively ) and mid-cycle urinary LH measures . Fitness , body composition , and serum sex hormone binding globulin ( SHBG ) and serum estradiol ( E2 ) were assessed repeatedly . RESULTS The intervention produced significant increases in VO(2 ) max and decreases in both body weight ( -3.7 + /- 0.5 kg ; ranged from -8.8 to + 1.8 kg ) and percent body fat ( -4.5 + /- 0.7 % ; ranged from -12 to + 0.3 % ) , which were attributable primarily to changes in the EX + CR subjects ( time x group ; P < 0.05 ) . Serum E2 and urinary E1 G and PdG concentrations declined significantly across the intervention period ( time ; P < 0.05 ) , whereas SHBG increased transiently ( time ; P < 0.05 ) in the EX + CR subjects , with no significant changes observed in the LC group . The decrease in E1 G area under the curve was significantly related to the daily energy deficit ( R = 0.61 ; P = 0.003 ) , not the amount of weight lost . There was no significant impact of the intervention on menstrual cyclicity or the incidence of menstrual disturbances in either group . CONCLUSIONS A moderate aerobic exercise training program combined with modest weight loss in accordance with recommended guidelines produces significant reductions in ovarian steroid exposure without disrupting menstrual cyclicity in premenopausal women aged 25 - 40 years . Exposure to a daily energy deficit is a stronger predictor of the decline in estrogen exposure than decreases in body weight 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 To study the ovarian toxicity associated with cyclophosphamide in girls with systemic lupus erythematosus ( SLE ) , we retrospectively review ed the charts of 30 SLE girls aged 16 yr or younger at diagnosis , followed at three university hospitals . Gynaecological history was extracted from the charts or obtained prospect ively . Ten had not received cyclophosphamide therapy , six were treated with daily oral cyclophosphamide , 10 with intravenous pulses and four with daily oral and intravenous pulses . Median oral cyclophosphamide dose was 38 g ( inter-quartile range 75 ) and median intravenous dose 12.95 g ( inter-quartile range 6.2 ) . Six girls had oligomenorrhoea ( 20 % ) and one amenorrhoea ( 3 % ) . Two treated with oral cyclophosphamide had oligomenorrhoea ( 33 % ) and one amenorrhoea ( 17 % ) , two treated with both oral and intravenous pulses had oligomenorrhoea ( 50 % ) , and none of those treated with intravenous pulses alone had menstrual disturbances ( 50 % oral vs 0 % intravenous pulses ; P = 0.016 ) . Girls who had menstrual disturbances had received higher doses of cyclophosphamide than those who did not ( medians : 63 vs 15 g ; P < 0.05 ) . In summary , menstrual disturbances in SLE girls treated with cyclophosphamide are related to the total dose and perhaps to the administration method Polycystic ovary syndrome ( PCOS ) , the most common endocrine disorder in women of reproductive age , is characterized by hyper and rogenism , oligo/amenorrhea , and polycystic ovaries . We aim ed to determine whether low-frequency electro-acupuncture ( EA ) would decrease hyper and rogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention . We r and omized 84 women with PCOS , aged 18 - 37 yr , to 16 wk of low-frequency EA , physical exercise , or no intervention . The primary outcome measure changes in the concentration of total testosterone ( T ) at week 16 determined by gas and liquid chromatography-mass spectrometry was analyzed by intention to treat . Secondary outcome measures were changes in menstrual frequency ; concentrations of and rogens , estrogens , and rogen precursors , and glucuroni date d and rogen metabolites ; and acne and hirsutism . Outcomes were assessed at baseline , after 16 wk of intervention , and after a 16-wk follow-up . After 16 wk of intervention , circulating T decreased by -25 % , and rosterone glucuronide by -30 % , and and rostane-3α,17β-diol-3-glucuronide by -28 % in the EA group ( P = 0.038 , 0.030 , and 0.047 , respectively vs. exercise ) ; menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group ( P = 0.018 vs. exercise ) . After the 16-wk follow-up , the acne score decreased by -32 % in the EA group ( P = 0.006 vs. exercise ) . Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention . Low-frequency EA and physical exercise improved hyper and rogenism and menstrual frequency more effectively than no intervention in women with PCOS . Low-frequency EA was superior to physical exercise and may be useful for treating hyper and rogenism and oligo/amenorrhea OBJECTIVE To investigate whether r and omized diet and /or physical exercise influence serum levels of antimüllerian hormone ( AMH ) in obese women with polycystic ovary syndrome ( PCOS ) . DESIGN R and omized , 4-month trial with three interventions . SETTING Women 's health clinical research unit at a university hospital . PATIENT(S ) Fifty-seven overweight/obese women with PCOS . INTERVENTION(S ) Diet , physical exercise , or both , using programs individually adapted and supervised by a dietician and /or a physiotherapist . MAIN OUTCOME MEASURE(S ) Serum AMH levels before and after the interventions and correlations to reproductive function , body composition , and endocrine and metabolic variables . RESULT ( S ) After intervention , serum levels of AMH were significantly decreased only in the diet group , and the levels were significantly lower than in the exercise group . The strongest predictor of decreased AMH was a decrease in free T , whereas weight loss had no significant influence . Normalized levels of AMH were associated with improvements in menstrual cyclicity and hyper and rogenism but not in metabolic variables . CONCLUSION ( S ) This r and omized study supports that diet reduces serum AMH in association with decreased and rogen levels in obese women with PCOS . Increased serum AMH may be used as a marker of ovulatory dysfunction and hyper and rogenism but not as a marker of insulin resistance . CLINICAL TRIAL REGISTRY NUMBER IS RCT N48342048 Acupuncture has been demonstrated to improve menstrual frequency and to decrease circulating testosterone in women with polycystic ovary syndrome ( PCOS ) . Our aim was to investigate whether acupuncture affects ovulation frequency and to underst and the underlying mechanisms of any such effect by analyzing LH and sex steroid secretion in women with PCOS . This prospect i ve , r and omized , controlled clinical trial was conducted between June 2009 and September 2010 . Thirty-two women with PCOS were r and omized to receive either acupuncture with manual and low-frequency electrical stimulation or to meetings with a physical therapist twice a week for 10 - 13 wk . Main outcome measures were changes in LH secretion patterns from baseline to after 10 - 13 wk of treatment and ovulation frequency during the treatment period . Secondary outcomes were changes in the secretion of sex steroids , anti-Müllerian hormone , inhibin B , and serum cortisol . Ovulation frequency during treatment was higher in the acupuncture group than in the control group . After 10 - 13 wk of intervention , circulating levels of estrone , estrone sulfate , estradiol , dehydroepi and rosterone , dehydroepi and rosterone sulfate , and rostenedione , testosterone , free testosterone , dihydrotestosterone , and rosterone glucuronide , and rostane-3α,17β-diol-3-glucuronide , and and rostane-3α,17β-diol-17-glucuronide decreased within the acupuncture group and were significantly lower than in the control group for all of these except and rostenedione . We conclude that repeated acupuncture treatments result ed in higher ovulation frequency in lean/overweight women with PCOS and were more effective than just meeting with the therapist . Ovarian and adrenal sex steroid serum levels were reduced with no effect on LH secretion This pilot study assessed the effects of exercise and nutritional counseling on hormonal , menstrual , and reproductive function in women with polycystic ovary syndrome ( PCOS ) . Twelve females with a clinical , biochemical , and ultrasonographic diagnosis of PCOS were r and omly assigned to endurance and resistance exercise plus nutritional counseling ( EN ) or nutritional counseling only ( N ) for a period of 12 weeks . Anthropometry , resting metabolic rate ( RMR ) , selected hormones , and ovarian follicle population were measured pre and post-intervention . Following the 12 week intervention , greater decreases in sum of 2 skinfolds ( p = 0.002 ) and a greater increase in estimated VO2 max ( p = 0.017 ) occurred in the exercise group . Significant decreases in waist girth ( p = 0.001 ) and insulin levels ( p = 0.03 ) occurred in both groups . Hormonal changes were not statistically significant ; however , a trend towards an improved hormonal profile , specifically sex-hormone binding globulin ( EN , 39 % increase ; N , 8 % increase ) and lutenizing hormone : follicle-stimulating hormone ( LH : FSH ) ( EN , 9 % decrease ; N , 27 % decrease ) occurred in the absence of weight loss . These findings suggest exercise and nutritional counseling may benefit the metabolic and reproductive abnormalities associated with PCOS Vascular endothelial growth factor ( VEGF ) has been suggested to play a role in the pathophysiology of polycystic ovary syndrome ( PCOS ) and may contribute to increased risk of ovarian hyperstimulation syndrome ( OHSS ) in affected individuals .  Vitamin D ( VitD ) supplementation improves multiple clinical parameters in VitD-deficient women with PCOS and decreases VEGF levels in several other pathologic conditions . Unveiling the basic mechanisms underlying the beneficial effects of vitamin D on PCOS may enhance our underst and ing of the pathophysiology of this syndrome . It may also suggest a new treatment for PCOS that can improve it through the same mechanism as vitamin D and can be given regardless of vitamin D levels . Therefore , we aim ed to explore the effect of VitD supplementation on serum VEGF levels and assess whether changes in VEGF correlate with an improvement in characteristic clinical abnormalities of PCOS . This is a r and omized placebo-controlled trial conducted between October 2013 and March 2015 . Sixty-eight VitD-deficient women with PCOS were recruited . Women received either 50,000 IU of oral VitD3 or placebo once weekly for 8 weeks . There was a significant decrease in serum VEGF levels ( 1106.4 ± 36.5 to 965.3 ± 42.7 pg·mL–1 ; p < 0.001 ) in the VitD group . Previously reported findings of this trial demonstrated a significant decrease in the intermenstrual intervals , Ferriman-Gallwey hirsutism score , and triglycerides  following VitD supplementation . Interestingly , ∆VEGF was positively correlated with ∆triglycerides ( R2 = 0.22 ; p = 0.02 ) following VitD supplementation . In conclusion , VitD replacement significantly decreases serum VEGF levels correlating with a decrease in triglycerides in women with PCOS . This is a novel molecular explanation for the beneficial effects of VitD treatment . It also suggests the need to investigate a potential role of VitD treatment in reducing the incidence or severity of OHSS in VitD-deficient women with PCOS The endometrium of reproductive aged women undergoes cyclic developmental changes in preparation for implantation in response to estrogen and progesterone . These steroids and their receptors are tightly regulated throughout the menstrual cycle , and their actions are facilitated by the presence of steroid receptor coactivators of the p160 family . In this study using immunohistochemistry and Western blot analysis , we characterize the expression patterns of three coactivators , steroid receptor coactivator-1 , amplified in breast cancer-1 ( AIB1 ) , and transcriptional intermediary factor-2 in human endometrium obtained prospect ively from normal fertile women throughout the menstrual cycle . With the exception of gl and ular AIB1 , which increased in the late secretory phase , none of the coactivators changed significantly during the menstrual cycle . We compared coactivator expression patterns in fertile endometrium to the endometrium of anovulatory ( proliferative ; n = 3 ) and clomiphene-induced ovulatory ( secretory ; n = 13 ) women with polycystic ovarian syndrome ( PCOS ) , a group that have a higher likelihood of developing estrogen-induced endometrial hyperplasia and cancer . To control for the effect of clomiphene citrate , an additional group was included consisting of ovulatory women treated with clomiphene citrate for " male factor " infertility . Compared with both fertile and infertile controls , PCOS women exhibited elevated levels of AIB1 and transcriptional intermediary factor-2 expression in both epithelial and stromal cells . We postulate that increased coactivator expression may render the endometrium more sensitive to estrogen . In support of this , we describe an increased expression of ERalpha ( an estrogen-induced gene product ) during the menstrual cycle in PCOS endometrium compared with fertile controls . In summary , we demonstrate that the expression of p160 coactivators are regulated in endometrium during the menstrual cycle in normal fertile women but are overexpressed in the endometrium of women with PCOS . Based on these findings , we suggest a possible mechanism to explain the poor reproductive performance observed in PCOS and the increased incidence of endometrial hyperplasia and cancer noted in this group of women
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 .
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 .