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. Myo-inositol in patients with polycystic ovary syndrome: A novel method for ovulation induction Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study. Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial. Metformin treatment of polycystic ovary syndrome improves health-related quality-of-life, emotional distress and sexuality. Androgen excess in women: experience with over 1000 consecutive patients. Induction of menstrual disorders by strenuous exercise in untrained women. Induction and prevention of low-T3 syndrome in exercising women. No effect of menstrual cycle phase on glucose and glucoregulatory endocrine responses to prolonged exercise Effects of metformin therapy on hyperandrogenism in women with polycystic ovarian syndrome A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome. Polycystic ovaries are inherited as an autosomal dominant trait: analysis of 29 polycystic ovary syndrome and 10 control families.
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 Background . Polycystic ovary syndrome ( PCOS ) is often characterized by chronic oligo- or anovulation ( usually manifested as oligo- or amenorrhea ) , and hyper and rogenism . In addition , 30–40 % of PCOS women have impaired glucose tolerance , and a defect in the insulin signaling pathway ( inositol-containing phosphoglycan mediators ) seems to be implicated in the pathogenesis of insulin resistance . PCOS patients are subfertile as a consequence of such ovulatory disorders and often need drugs , such as clomiphene citrate or follicle-stimulating hormone , for ovulation induction , which increases the risk of multiple pregnancy and ovarian hyperstimulation syndrome . We hypothesized that the administration of an isoform of inositol ( myo-inositol ) , belonging to the vitamin B complex , would improve the insulin-receptor activity , restoring normal ovulatory function . Material s and methods . Twenty-five PCOS women of childbearing age with oligo- or amenorrhea were enrolled in the study . Ovulatory disorder due to PCOS was apparently the only cause of infertility ; no tubal defect or deficiency of male semen parameters was found . Myo-inositol combined with folic acid ( Inofolic ® ) 2 g twice a day was administered continuously . During an observation period of 6 months , ovulatory activity was monitored with ultrasound scan and hormonal profile , and the numbers of spontaneous menstrual cycles and eventually pregnancies were assessed . Results . Twenty-two out of the 25 ( 88 % ) patients restored at least one spontaneous menstrual cycle during treatment , of whom 18 ( 72 % ) maintained normal ovulatory activity during the follow-up period . A total of 10 singleton pregnancies ( 40 % of patients ) were obtained . Nine clinical pregnancies were assessed with fetal heart beat at ultrasound scan . Two pregnancies evolved in spontaneous abortion . Conclusion . Myo-inositol is a simple and safe treatment that is capable of restoring spontaneous ovarian activity and consequently fertility in most patients with PCOS . This therapy did not cause multiple pregnancy Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome , consisting of hyper and rogynism , infertility , menstrual irregularities , and elevated LH levels . This is generally considered secondary to poor control of the congenital adrenal hyperplasia . However , our experience led us to suspect that ovarian hyper and rogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy . Therefore , we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyper and rogenism . We studied eight women with congenital adrenal virilizing disorders , seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age . We also studied six women with late-onset 21-hydroxylase deficiency , without signs of congenital virilization . An ovarian source of and rogens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist ( nafarelin ) test . Five women with congenital adrenal virilizing disorders ( four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma ) and one women with late-onset 21-hydroxylase deficiency had ovarian hyper and rogenism as determined by subnormal suppression of free testosterone after dexamethasone and /or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone . All women with congenital adrenal virilization and ovarian hyper and rogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin , which suggests that LH excess is the cause of their ovarian hyper and rogenism . This was not the case for the late-onset 21-hydroxylase-deficient woman . Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty . This is postulated to frequently cause ovarian hyper and rogenism even when adrenal and rogen excess is subsequently controlled by glucocorticoid therapy 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 CONTEXT Metformin is successfully used in the treatment of cycle disorders and anovulation in women with polycystic ovary syndrome ( PCOS ) . No data of the exact point and the impact of insulin resistance ( IR ) on metformin 's efficacy exist . OBJECTIVE The objective of the study was to evaluate the early potential effects of metformin treatment , their time of onset , and the role of IR on metformin 's efficacy . DESIGN This was a prospect i ve r and omized , double-blind , placebo-controlled trial . SETTING The study was conducted at the University of Heidelberg , Heidelberg , Germany . PATIENTS The patient population was 45 oligo-/anovulatory PCOS women with typical ovaries . INTERVENTIONS Women were stratified for IR ( 32 of 13 ) and then r and omly allocated to receive either metformin ( n = 22 ) or placebo ( n = 23 ) and were assessed before and every 4 wk within a treatment period of 12 wk . MAIN OUTCOME MEASURES Menstrual disturbance and markers of insulin metabolism were measured . RESULTS The main outcome criterion menstrual disturbance was successfully improved in the metformin-treated group , depending on IR ( 12 of 15 vs. three of 17 ) , whereas women without IR ( four of seven vs. four of six ) had no significant amelioration of their menstrual irregularities ( P < 0.05 ) . Estradiol levels increased continuously only in the treatment group ( P < 0.005 ) , indicating an improvement of ovulatory function . Sixty-seven percent of metformin-treated women had at least one ovulation , compared with only 45 % in the placebo group , shown by biphasic body temperature curves . Insulin sensitivity improved within 4 wk after beginning of metformin as shown by an increased area under the curve glucose to insulin ratio , compared with baseline ( P < 0.005 ) . CONCLUSIONS IR is a baseline predictor of clinical efficacy in metformin treatment in PCOS women measured by improved menstrual cyclicity and ovulatory function BACKGROUND In polycystic ovary syndrome ( PCOS ) , changes in physical appearance , menstrual disturbances and infertility result in psychological distress and reduced quality -of-life .  Metformin improves biochemical , clinical and reproductive parameters in PCOS women . In a prospect i ve , observational study , we analysed the effects of metformin treatment on health-related quality -of-life ( HRQL ) , emotional well-being and sexuality in PCOS . No placebo-treated control group was included . METHODS Before , during and after 6 months of treatment , changes in clinical and endocrine parameters , quality -of-life , psychological disturbances and sexuality were assessed in 64 PCOS patients using vali date d question naires ( SF-36 , SCL-90-R ) and visual analogue scales . Patients were also compared with published normative data for the vali date d question naires . RESULTS During treatment , HRQL , particularly the psychosocial aspects ( indicated by significant increases in SF-36 scales Vitality , Social Function , Emotional Role Function , Mental Health , Psychological Sum scale ) and emotional well-being ( reflected by significant lowering of SCL-90-R scales ) improved . These improvements in HRQL were significantly correlated with a reduction in body weight and significantly more pronounced in patients with normalized menstrual cycles . In addition , PCOS women were significantly more satisfied with their sex life and reported higher frequencies of sexual intercourse following treatment . CONCLUSION Treatment can improve the psychosocial , emotional and psychosexual situation of PCOS patients . Although at least some of these effects may be related to the reduction of individual clinical symptoms ( i.e. weight loss , normalization of menstrual disturbances , improvement of acne ) , this observational study does not allow us to clearly discern the role of symptom constellation and does not preclude non-specific and /or placebo effects . Nevertheless , emotional distress and reduced quality -of-life are clearly not an inevitable consequence of PCOS and should be considered as adjunct treatment goals in future studies The objective of the present study was to estimate the prevalence of the different pathological conditions causing clinical ly evident and rogen excess and to document the degree of long-term success of suppressive and /or anti and rogen hormonal therapy in a large consecutive population of patients . All patients presenting for evaluation of symptoms potentially related to and rogen excess between October 1987 and June 2002 were evaluated , and the data were maintained prospect ively in a computerized data base . For the assessment of therapeutic response , a retrospective review of the medical chart was performed , after the exclusion of those patients seeking fertility therapy only , or with inadequate follow-up or poor compliance . A total of 1281 consecutive patients were seen during the study period . Excluded from analysis were 408 patients in whom we were unable to evaluate hormonal status , determine ovulatory status , or find any evidence of and rogen excess . In the remaining population of 873 patients , the unbiased prevalence of and rogen-secreting neoplasms was 0.2 % , 21-hydroxylase-deficient classic adrenal hyperplasia ( CAH ) was 0.6 % , 21-hydroxylase-deficient nonclassic adrenal hyperplasia ( NCAH ) was 1.6 % , hyper and rogenic insulin-resistant acanthosis nigricans ( HAIRAN ) syndrome was 3.1 % , idiopathic hirsutism was 4.7 % , and polycystic ovary syndrome ( PCOS ) was 82.0 % . Fifty-nine ( 6.75 % ) patients had elevated and rogen levels and hirsutism but normal ovulation . A total of 257 patients were included in the assessment of the response to hormonal therapy . The mean duration of follow-up was 33.5 months ( range , 6 - 155 ) . Hirsutism improved in 86 % , menstrual dysfunction in 80 % , acne in 81 % , and hair loss in 33 % of patients . The major side effects noted were irregular vaginal bleeding ( 16.1 % ) , nausea ( 13.0 % ) , and headaches ( 12.6 % ) ; only 36.6 % of patients never complained of side effects . In this large study of consecutive patients presenting with clinical ly evident and rogen excess , specific identifiable disorders ( NCAH , CAH , HAIRAN syndrome , and and rogen-secreting neoplasms ) were observed in approximately 7 % of subjects , whereas functional and rogen excess , principally PCOS , was observed in the remainder . Hirsutism , menstrual dysfunction , or acne , but not alopecia , improved in the majority of patients treated with a combination suppressive therapy ; although more than 60 % experienced side effects 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 To investigate the influence of exercise on thyroid metabolism , 46 healthy young regularly menstruating sedentary women were r and omly assigned to a 3 x 2 experimental design of aerobic exercise and energy availability treatments . Energy availability was defined as dietary energy intake minus energy expenditure during exercise . After 4 days of treatments , low energy availability ( 8 vs. 30 kcal.kg body wt-1.day-1 ) had reduced 3,5,3'-triiodothyronine ( T3 ) by 15 % and free T3 ( fT3 ) by 18 % and had increased thyroxine ( T4 ) by 7 % and reverse T3 ( rT3 ) by 24 % ( all P < 0.01 ) , whereas free T4 ( fT4 ) was unchanged ( P = 0.08 ) . Exercise quantity ( 0 vs. 1,300 kcal/day ) and intensity ( 40 vs. 70 % of aerobic capacity ) did not affect any thyroid hormone ( all P > 0.10 ) . That is , low-T3 syndrome was induced by the energy cost of exercise and was prevented in exercising women by increasing dietary energy intake . Selective observation of low-T3 syndrome in amenorrheic and not in regularly menstruating athletes suggests that exercise may compromise the availability of energy for reproductive function in humans . If so , athletic amenorrhea might be prevented or reversed through dietary reform without reducing exercise quantity or intensity Introduction Prolonged exercise requires increased utilization of blood glucose and adjustment of glucoregulatory hormones . Estrogen can reduce hepatic gluconeogenesis which could affect insulin concentrations . Amylin is co-secreted with insulin and controls influx of glucose into the blood . Purpose To determine the effect of menstrual cycle stage on glucose , leptin , and pancreatic hormone responses to prolonged ( 90 min ) exercise . Methods Five healthy , eumenorrheic women ( 24.6 ± 5.1 years ; 67.4 ± 1 kg ) were monitored for 3 months to determine menstrual cycle length . Subjects completed a preliminary session to determine exercise workloads and , in a fasted condition , completed two r and omized 90-min treadmill exercise trials at 60 % VO2max during the early follicular ( EFX ) and mid-luteal phase ( MLX ) of their menstrual cycle . Blood sample s were analyzed for glucose , insulin , C-peptide , amylin , glucagon , leptin , and cortisol concentrations at rest ( −30 and 0 min ) , during exercise ( 18 , 36 , 54 , 72 , and 90 min ) and after 20 min of recovery . Results No changes in amylin , leptin , or cortisol occurred for EFX and MLX trials . A significant ( p < 0.05 ) time effect occurred for glucose , insulin , and glucagon with reduced insulin across the exercise trial and increases in glucose and glucagon later in the trial , but there were no differences between the EFX and MLX trials . Conclusions Menstrual cycle stage does not affect glucose , insulin , C-peptide , amylin , glucagon , cortisol , and leptin responses  to prolonged exercise ; however , the exercise reduces insulin and increases glucose and glucagon concentrations . This is the first study to determine acute effects of exercise on amylin and other glucoregulatory hormone responses in women Polycystic ovarian syndrome ( PCOS ) is one of the most common endocrine diseases in women . This syndrome is characterized by hyper and rogenism , chronic anovulation , infertility and obesity . The association between PCOS-related hyper and rogenemia and insulin resistance is well documented in the literature . Insulin resistance and the result ing raised plasma levels of insulin are reported to be responsible for the high and rogen concentration observed in patients with PCOS . In this prospect i ve study , blood sample s for levels of testosterone ( T ) , dehydroepi and rosterone sulfate ( DHEAS ) , luteinizing hormone ( LH ) , follicle-stimulating hormone ( FSH ) , LH/FSH , prolactin and fasting blood sugar ( FBS ) before starting metformin administration were obtained r and omly from 40 women who were apparently obese , had PCOS and had been referred to a university hospital .  Metformin was then given at a dose of 500 mg three times a day for 8 weeks , after which time the pretreatment study was repeated . Clinical symptoms of PCOS , including acne and hirsutism score and body mass index ( BMI ) , were assessed before and after the treatment cycle . Metformin therapy result ed in a significant decrease in total testosterone levels and FBS . There was also a significant decline in BMI , length of the menstrual cycle , acne and hirsutism score . There were no significant changes in the levels of DHEAS , prolactin , FSH or LH , or in LH/FSH . The effect of metformin on subjects with elevated DHEAS levels was different to that on individuals with normal DHEAS levels . In the latter group there were only significant improvements in the length of the menstrual cycle , BMI and testosterone and DHEAS levels . It is concluded that metformin therapy in subjects with PCOS results in a decrease in fasting blood sugar and testosterone levels , and leads to a significant improvement in the clinical manifestation of hyper and rogenism . These responses also related to the level of adrenal function 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 The aim of this study was to obtain evidence for the genetic basis of polycystic ovaries ( PCO ) and premature male pattern baldness ( PMPB ) by screening first-degree relatives of women affected by polycystic ovary syndrome ( PCOS ) . Because of the high prevalence of PCO in the general population , we also studied first-degree relatives of ten asymptomatic control volunteers of reproductive age . The prob and s were recruited prospect ively from infertility and endocrine clinics , where they presented with various clinical symptoms of PCOS . Each had PCO , on transvaginal ultrasound scan . The families of 29 prob and s and 10 volunteers agreed to take part in the study .  Clinical , ultrasound , and biochemical parameters were used to define PCO/PCOS . All female relatives had an ovarian ultrasound scan and hormone profile performed . History was used to assign status in postmenopausal women . All male relatives were assessed for early onset ( < 30 yr old ) male pattern baldness , by photographs . All relatives were assigned affected ( PCO/PMPB ) or nonaffected status , and segregation analysis was performed . Of the relatives of 29 PCOS prob and s , 15 of 29 mothers ( 52 % ) , 6 of 28 fathers ( 21 % ) , 35 of 53 sisters ( 66 % ) , and 4 of 18 brothers ( 22 % ) were assigned affected status . First-degree female relatives of affected individuals had a 61 % chance of being affected . Of the first-degree male relatives , 22 % were affected . Of a total of 71 siblings of PCOS prob and s , 39 were affected , giving a segregation ratio of 39/32 ( 55 % ) , which is consistent with autosomal dominant inheritance for PCO/PMPB . In the control families , 1 of 10 prob and s ( 10 % ) , 1 of 10 mothers ( 10 % ) , no fathers , 2 of 13 sisters ( 15 % ) , and 1 of 11 brothers ( 9 % ) were affected . Of a total of 24 siblings , 3 were affected ( 13 % ) , giving a segregation ratio ( observed/expected ) of 3/12 , which was significantly different from autosomal dominant inheritance . The inheritance of PCO and PMPB is consistent with an autosomal dominant inheritance pattern in PCOS families , perhaps caused by the same gene . There was no such genetic influence in families of women without PCOS . Sisters of PCOS prob and s with polycystic ovarian morphology were more likely to have menstrual irregularity and had larger ovaries and higher serum and rostenedione and dehydroepi and rosterone-sulfate levels than sisters without PCO . This suggests a spectrum of clinical phenotype in PCOS families . Men with PMPB had higher serum testosterone than those without . Collectively , these data are consistent with a role for genetic differences in and rogen synthesis , metabolism , or action in the pathogenesis of PCOS
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 .