Rowland AS, Baird DD, Long S, Wegienka G, Harlow SD, Alavanja M, Sandler DP.
Influence of medical conditions and lifestyle factors on the menstrual cycle.
Epidemiology. 2002 Nov;13(6):668-74. doi: 10.1097/00001648-200211000-00011.
Abstract/Text
BACKGROUND: Few studies have described medical and lifestyle factors associated with various menstrual cycle characteristics.
METHODS: We analyzed cross-sectional data collected from 3941 premenopausal women from Iowa or North Carolina participating in the Agricultural Health Study between 1994 and 1996. Eligible women were age 21-40, not taking oral contraceptives, and not currently pregnant or breast feeding. We examined four menstrual cycle patterns: short cycles (24 days or less), long cycles (36 days or more), irregular cycles, and intermenstrual bleeding.
RESULTS: Long and irregular cycles were less common with advancing age and more common with menarche after age 14, with depression, and with increasing body mass index. The adjusted odds of long cycles increased with increasing body mass index, reaching 5.4 (95% confidence interval [CI] = 2.1-13.7) among women with body mass indexes of 35 or higher compared with the reference category (body mass index of 22-23). Smoking was associated with short cycles. Long cycles, irregular cycles, and intermenstrual bleeding were associated with a history of infertility. Having long cycles was associated with a doubling in the adjusted odds of having a fetal loss among women who had been pregnant within the last 5 years (odds ratio = 2.3; 95% CI = 0.9-5.7).
CONCLUSIONS: Menstrual patterns are influenced by a number of host and environmental characteristics. Factors that perturb menstruation may increase a woman's risk of other reproductive disorders.
Golden NH, Jacobson MS, Schebendach J, Solanto MV, Hertz SM, Shenker IR.
Resumption of menses in anorexia nervosa.
Arch Pediatr Adolesc Med. 1997 Jan;151(1):16-21. doi: 10.1001/archpedi.1997.02170380020003.
Abstract/Text
OBJECTIVE: To determine factors associated with resumption of menses (ROM) in adolescents with anorexia nervosa.
DESIGN: Cohort study with 2-year follow-up.
SETTING: Tertiary care referral center.
PATIENTS: Consecutive sample of 100 adolescent girls with anorexia nervosa.
INTERVENTIONS: Body weight, percent body fat, and luteinizing hormone, follicle-stimulating hormone, and estradiol levels were measured at baseline and every 3 months until ROM (defined as 2 or more consecutive spontaneous menstrual cycles). Treatment consisted of a combination of medical, nutritional, and psychiatric intervention aimed at weight gain and resolution of psychological conflicts.
MAIN OUTCOME MEASURES: Body weight, body composition, and hormonal status at ROM.
RESULTS: Menses resumed at a mean (+/-SD) of 9.4 +/- 8.2 months after patients were initially seen and required a weight of 2.05 kg more than the weight at which menses were lost. Mean (+/-SD) percent of standard body weight at ROM was 91.6% +/- 9.1%, and 86% of patients resumed menses within 6 months of achieving this weight. At 1-year follow-up, 47 (68%) of 69 patients had resumed menses and 22 (32%) remained amenorrheic. No significant differences were seen in body weight, body mass index, or percent body fat at follow-up in those who resumed menses by 1 year compared with those who had not. Subjects who remained amenorrheic at 1 year had lower levels of luteinizing hormone (P < .001) and follicle-stimulating hormone (P < .05) at baseline and lower levels of luteinizing hormone (P < .01) and estradiol (P < .001) at follow-up. At follow-up, a serum estradiol level of more than 110 pmol/L (30 pg/mL) was associated with ROM (relative risk, 4.6; 95% confidence interval, 1.9-11.2).
CONCLUSIONS: A weight approximately 90% of standard body weight was the average weight at which ROM occurred and is a reasonable treatment goal weight, because 86% of patients who achieved this goal resumed menses within 6 months. Resumption of menses required restoration of hypothalamic-pituitary-ovarian function, which did not depend on the amount of body fat. Serum estradiol levels at follow-up best assess ROM.
Nakamura Y, Yoshimura Y, Oda T, Katayama E, Kamei K, Tanabe K, Iizuka R.
Clinical and endocrine studies on patients with amenorrhoea associated with weight loss.
Clin Endocrinol (Oxf). 1985 Dec;23(6):643-51. doi: 10.1111/j.1365-2265.1985.tb01125.x.
Abstract/Text
Two hundred and forty-three patients with amenorrhoea associated with weight loss were studied. At the onset of amenorrhoea, regardless of percentage weight loss, basal levels of LH were low and LH responses to LHRH were impaired. However, both basal and stimulated levels of FSH were comparable to normal. With resumption of menstruation, the basal and stimulated levels of LH were found to rise to normal, while FSH responses continued to exceed normal. However, 16.6% of 66 unimproved cases had normal responses but remained amenorrhoeic. Furthermore, amenorrhoea persisted in 71% of 31 patients with complete recovery of body weight. No significant correlation was noted between percentage weight loss and responsiveness to LHRH, nor between recovery of body weight and resumption of menstruation. Return to normal weight is desirable for resumption of normal cyclic menstruation and hypothalamic-pituitary function, but is not always effective.
Grinspoon S, Miller K, Coyle C, Krempin J, Armstrong C, Pitts S, Herzog D, Klibanski A.
Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea.
J Clin Endocrinol Metab. 1999 Jun;84(6):2049-55. doi: 10.1210/jcem.84.6.5792.
Abstract/Text
Reduced bone density is observed in over half of women with anorexia nervosa (AN), in whom the risk of fracture is significantly increased even at a young age. It is unknown to what extent low bone density in AN differs from other conditions of premenopausal osteoporosis and is related to estrogen deficiency and/or other factors, such as nutritional status. We therefore investigated bone loss in nutritionally replete and nutritionally deplete amenorrheic women by comparing patients with AN (n = 30) to age-matched subjects with hypothalamic amenorrhea (HA; n = 19) in whom duration of amenorrhea, prior estrogen use, and age of menarche were comparable. Healthy, age-matched, eumenorrheic women were studied as a control group (NL; n = 30). Weight and nutritionally dependent factors including (body mass index, 20.7 +/- 0.3 vs. 16.7 +/- 0.3 kg/m2; P < 0.0001), insulin-like growth factor I (270 +/- 18 vs. 203 +/- 17 ng/mL; P < 0.01), percent body fat (26% vs. 19%; P < 0.0001), and lean body mass (38.7 +/- 1.1 vs. 34.3 +/- 0.8, P < 0.01) were significantly different between the HA and AN groups, respectively. The bone densities of the anterior-posterior (AP) spine, total hip, and total body measured by dual energy x-ray absortiometry were reduced in both amenorrheic groups compared to those in control subjects, but were significantly lower in women with AN than in those with HA. The t scores for AP spine and hip were -1.80 +/- 0.15 (AN), -0.80 +/- 0.22 (HA), and 0.28 +/- 0.19 SD (NL) for the AP spine and -1.62 +/- 0.17 (AN), -0.51 +/- 0.21 (HA), and 0.25 +/- 0.16 (NL) for the total hip, respectively (P < 0.01 for all comparisons). Among the amenorrheic subjects, duration of amenorrhea, age of menarche, and N-telopeptide were inversely correlated with bone density at all sites, whereas body mass index, insulin-like growth factor I, lean body mass, and fat intake were positively correlated with bone density at all sites measured. In multivariate regression analyses, bone density was most significantly related to lean body mass (P = 0.05 and P = 0.03 for the spine and hip, respectively), but not to the duration of amenorrhea or other indexes of estrogen status among patients with AN. In contrast, bone density of the lumbar spine was significantly related to weight and duration of amenorrhea among patients with HA. These data demonstrate that the severity of osteopenia in AN is greater than that in patients with HA and is critically dependent upon nutritional factors in addition to the degree or duration of estrogen deficiency itself. Lean body mass, independent of the duration or severity of estrogen deficiency, is an important predictor of bone loss among women with AN.
Vescovi JD, Jamal SA, De Souza MJ.
Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature.
Osteoporos Int. 2008 Apr;19(4):465-78. doi: 10.1007/s00198-007-0518-6. Epub 2008 Jan 8.
Abstract/Text
UNLABELLED: Functional hypothalamic amenorrhea (FHA) impairs the attainment of peak bone mass and as such can increase the risk of fractures later in life. To document available treatment strategies, we conducted a systematic review of the literature. We report that hormonal therapies have limited effectiveness in increasing bone mass, whereas increased caloric intake resulting in weight gain and/or resumption of menses is an essential strategy for restoring bone mass in women with FHA.
INTRODUCTION: Women with functional hypothalamic amenorrhea (FHA) may not achieve peak bone mass (PBM), which increases the risk of stress fractures, and may increase the risk of osteoporotic fractures in later life.
METHODS: To identify effective treatment strategies for women with FHA, we conducted a systematic review of the literature. We included randomized controlled trials (RCTs), cross-sectional studies, and case studies that reported on the effects of pharmacological and non-pharmacological interventions on bone mineral density (BMD) or bone turnover in women with FHA.
RESULTS: Most published studies (n=26) were designed to treat the hormonal abnormalities observed in women with FHA (such as low estrogen, leptin, insulin-like growth factor-1, and DHEA); however none of these treatments demonstrated consistent improvements in BMD. Therapies containing an estrogen given for 8-24 months resulted in variable improvements (1.0-19.0%) in BMD, but failed to restore bone mass to that of age-matched controls. Three studies reported on the use of bisphosphonates (3-12 months) in anorexic women, which appear to have limited effectiveness to improve BMD compared to nutritional treatments. Another three investigations showed no improvements in BMD after androgen therapy (DHEA and testosterone) in anorexic women. In contrast, reports (n=9) describing an increase in caloric intake that results in weight gain and/or the resumption of menses reported a 1.1-16.9% increase in BMD concomitant with an improvement in bone formation and reduction in bone resorption markers.
CONCLUSIONS: Our literature review indicates that the most successful, and indeed essential strategy for improving BMD in women with FHA is to increase caloric intake such that body mass is increased and there is a resumption of menses. Further long-term studies to determine the persistence of this effect and to determine the effects of this and other strategies on fracture risk are needed.
Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS.
Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial.
J Clin Endocrinol Metab. 2002 Nov;87(11):4935-41. doi: 10.1210/jc.2002-020545.
Abstract/Text
Young women with anorexia nervosa (AN) have subnormal levels of dehydroepiandrosterone (DHEA) and estrogen that may be mechanistically linked to the bone loss seen in this disease. The purpose of this study was to compare the effects of a 1-yr course of oral DHEA treatment vs. conventional hormonal replacement therapy (HRT) in young women with AN. Sixty-one young women were randomly assigned to receive oral DHEA (50 mg/d) or HRT (20 micro g ethinyl estradiol/0.1 mg levonorgestrel). Anthropometric, nutrition, and exercise data were acquired every 3 months, and bone mineral density (BMD) and body composition were measured by dual energy x-ray absorptiometry (DXA) every 6 months over 1 yr. Serum samples were obtained for measurements of hormones, proresorptive cytokines, and bone formation markers, and urine was collected for determinations of bone resorption markers at each visit. In initial analyses, total hip BMD increased significantly and similarly (+1.7%) in both groups. Hip BMD increases were positively correlated with increases in IGF-I (r = 0.44; P = 0.030) and the bone formation marker, bone-specific alkaline phosphatase increased significantly only in the DHEA treatment group (P = 0.003). However, both groups gained significant amounts of weight over the year of therapy, and after controlling for weight gain, no treatment effect was detectable. There was no significant change in lumbar BMD in either group. Both bone formation markers, bone-specific alkaline phosphatase and osteocalcin, increased transiently at 6-9 months in those subjects receiving DHEA compared with the estrogen-treated group (P < 0.05). Both DHEA and HRT significantly reduced levels of the bone resorption markers, urinary N-telopeptides (P < 0.05). There was a positive correlation between changes in IGF-I and changes in weight, body fat determined by DXA, and estradiol for both groups. In addition, patients receiving DHEA exhibited improvement on three validated psychological instruments (Eating Attitudes Test, Anorexia Nervosa Subtest, and Spielberger Anxiety Inventory). Both DHEA and HRT had similar effects on hip and spinal BMD. Over the year of treatment, maintenance of both hip and spinal BMD was seen, but there was no significant increase after accounting for weight gain. Compared with HRT, DHEA appeared to have anabolic effects, evidenced by the positive correlation between increases in hip DXA measurements and IGF-I and significant increases in bone formation markers. Both therapies significantly decreased bone resorption. Replicating results from studies of the elderly, DHEA resulted in improvements in specific psychological parameters in these young women.
Strokosch GR, Friedman AJ, Wu SC, Kamin M.
Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study.
J Adolesc Health. 2006 Dec;39(6):819-27. doi: 10.1016/j.jadohealth.2006.09.010.
Abstract/Text
PURPOSE: To evaluate the effect of an oral contraceptive (OC) on bone mineral density (BMD) in adolescent females with anorexia nervosa (AN) or eating disorder not otherwise specified (EDNOS).
METHODS: Females 11-17 years of age with AN or EDNOS entered the study. Subjects were randomized equally to treatment with a triphasic OC containing norgestimate (NGM) 180-250 microg and ethinyl estradiol (EE) 35 microg or placebo for 13 28-day cycles. Dual energy x-ray absorptiometry scans (DXA) of the lumbosacral spine (LS) and hip were obtained at baseline and after 6 and 13 cycles.
RESULTS: Demographic characteristics of the 112 subjects (NGM/EE 53; Placebo 59) who received study drug and had at least one on-treatment DXA were similar between groups for age (mean: 15 years in each group) and body mass index (mean: NGM/EE 17.9 kg/m2; Placebo 17.6 kg/m2). At the end of Cycle 6, there was a significant increase in the mean LS BMD in the NGM/EE group compared with placebo (.020 g/cm2 vs. .008 g/cm2; p = .021); however, at the end of Cycle 13 the mean increase in LS BMD in the NGM/EE group compared with placebo was no longer significant (.026 g/cm2 vs. .019 g/cm2, p = .244). There was no significant difference in change in hip BMD between groups. The incidence of adverse events was similar between groups.
CONCLUSIONS: In a group of adolescent females with AN or EDNOS, treatment with a triphasic OC for 13 cycles did not have a statistically significant effect on LS or hip BMD.
Viapiana O, Gatti D, Dalle Grave R, Todesco T, Rossini M, Braga V, Idolazzi L, Fracassi E, Adami S.
Marked increases in bone mineral density and biochemical markers of bone turnover in patients with anorexia nervosa gaining weight.
Bone. 2007 Apr;40(4):1073-7. doi: 10.1016/j.bone.2006.11.015. Epub 2007 Jan 19.
Abstract/Text
Anorexia nervosa (AN) is a life-threatening eating disorder characterized by an inability to maintain a normal body weight and amenorrhoea, often associated with osteoporosis and increased risk of fragility fractures. Bone metabolism, including markers of bone turnover (serum total alkaline phosphatase, bone alkaline phosphatase [bone AP], osteocalcin [OC] and type I collagen C-telopeptide breakdown products [sCTX]) and bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) at the spine and at the hip, were evaluated in 55 consecutive women with AN undergoing a 3-month intensive nutritional rehabilitation program. The control group was constituted of 25 healthy young medical students. In AN patients body weight increased during the 3-month nutritional program from 37.8+/-5.1 (mean+/-SD) to 51.5+/-4.5 kg. The corresponding BMI rose to values >17.5 kg/m(2) in all patients. Mean BMD significantly rose by 2.6+/-3.5% and 1.1+/-3.6% at the hip and at the spine, respectively. The markers of bone formation, serum bone AP and osteocalcin, significantly rose by two-folds, while sCTX decreased by 16%. The changes in hip BMD were positively related (p<0.005) to changes in body weight and in bone AP (p<0.02) while the changes in spine BMD were positively related to changes in serum osteocalcin (p<0.05). In the 25 patients who attended the 12-month posttreatment control, mean body weight significantly decreased by 3.6+/-6.0 kg and this was not associated with any significant change in BMD values. In the patients in whom BMI fell again below 17.5 kg/m(2) hip BMD values decreased significantly. On the contrary, in the patients who maintained BMI >17.5 kg/m(2), BMD values continued to rise up to values over the 15-month observation of 4.8+/-6.2 and 7.1+/-12.1 at the spine and hip, respectively. In conclusion, we have demonstrated that substantial gains in weight in women with chronic AN are associated with remarkable increases in BMD at both the hip and the spine. If weight is maintained, the overall improvement approach 1 SD within 1 year. The changes in both weight and BMD are correlated with improvements in bone formation markers and diminutions in a marker of bone resorption.
Dominguez J, Goodman L, Sen Gupta S, Mayer L, Etu SF, Walsh BT, Wang J, Pierson R, Warren MP.
Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses.
Am J Clin Nutr. 2007 Jul;86(1):92-9. doi: 10.1093/ajcn/86.1.92.
Abstract/Text
BACKGROUND: Recovery from osteoporosis in anorexia nervosa (AN) is uncertain.
OBJECTIVE: The purpose of this study was to understand the changes in bone mineral density (BMD) in women with AN and the mechanisms of recovery from osteopenia.
DESIGN: We studied BMD and markers of bone formation and resorption, osteocalcin and N-telopeptide (NTX), in patients with AN (n=28) who were following a behavioral weight-gain protocol.
RESULTS: Anorexic patients experienced significant percentage increases in BMD (4.38 +/- 7.48% for spine; 3.77 +/- 8.8% for hip; P<0.05 for both) from admission until recovery of 90% ideal body weight, achieved over 2.2 mo. NTX concentrations were higher in patients with AN at admission than in healthy control subjects (n=11; 69.0 +/- 31.09 and 48.3 +/- 14.38 nmol/mmol creatinine, respectively; P<0.05) and in reference control subjects (n=30; 69.0 +/- 31.09 and 37.0+/-6.00 nmol/mmol creatinine, respectively; P<0.001). In weight-recovered subjects with AN, osteocalcin increased (from 8.0 +/- 3.05 to 11.2 +/- 6.54 ng/mL; P<0.05), whereas NTX remained elevated (from 69.0 +/- 31.09 to 66.7 +/- 45.5 nmol/mmol creatinine; NS). A decrease in NTX (from 70.7 +/- 40.84 to 45.9 +/- 22.72 nmol/mmol creatinine; NS) occurred only in the subgroup of subjects who regained menses with weight recovery.
CONCLUSIONS: Nutritional rehabilitation induces a powerful anabolic effect on bone. However, a fall of NTX and a shift from the dominant resorptive state, which we postulate involves full recovery, may involve a hormonal mechanism and require a return of menses. Nutritional rehabilitation appears to be critical to bone recovery and may explain the ineffectiveness of estrogen treatment alone on BMD in the cachectic state.
Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ.
Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment.
Hum Reprod. 1998 Jun;13(6):1502-5. doi: 10.1093/humrep/13.6.1502.
Abstract/Text
Obesity affects ovulation, response to fertility treatment, pregnancy rates and outcome. In this prospective study, a weight loss programme was assessed to determine whether it could help obese infertile women, irrespective of their infertility diagnosis, to achieve a viable pregnancy, ideally without further medical intervention. The subjects underwent a weekly programme aimed at lifestyle changes in relation to exercise and diet for 6 months; those that did not complete the 6 months were treated as a comparison group. Women in the study lost an average of 10.2 kg/m2, with 60 of the 67 anovulatory subjects resuming spontaneous ovulation, 52 achieving a pregnancy (18 spontaneously) and 45 a live birth. The miscarriage rate was 18%, compared to 75% for the same women prior to the programme. Psychometric measurements also improved. None of these changes occurred in the comparison group. The cost savings of the programme were considerable. Prior to the programme, the 67 women had had treatment costing a total of A$550,000 for two live births, a cost of A$275,000 per baby. After the programme, the same women had treatment costing a total of A$210,000 for 45 babies, a cost of A$4600 per baby. Thus weight loss should be considered as a first option for women who are infertile and overweight.
Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, Oelsner G, Freedman L, Mashiach S, Lunenfeld B.
Cancer incidence in a cohort of infertile women.
Am J Epidemiol. 1998 Jun 1;147(11):1038-42. doi: 10.1093/oxfordjournals.aje.a009397.
Abstract/Text
Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval (CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded.
Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E.
Clomiphene and anti-oestrogens for ovulation induction in PCOS.
Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. doi: 10.1002/14651858.CD002249.pub4. Epub 2009 Oct 7.
Abstract/Text
BACKGROUND: Subfertility due to anovulation is a common problem in women. First-line oral treatment is with anti-oestrogens, for example clomiphene citrate, but resistance (failure to ovulate) may be apparent with clomiphene. Alternative and adjunctive treatments have been developed such as tamoxifen, dexamethasone, and bromocriptine.
OBJECTIVES: To determine the relative effectiveness of anti-oestrogen agents alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome (PCOS).
SEARCH STRATEGY: A search was conducted using the Cochrane Menstrual Disorders and Subfertility Group Trials Register (May 2009), CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to May 2009), and EMBASE (1980 to May 2009) for identification of relevant randomised controlled trials (RCTs). The United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs were searched.
SELECTION CRITERIA: RCTs comparing oral anti-oestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility were considered. Insulin sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility were excluded.
DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were done independently by two review authors. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, overstimulation, ovarian hyperstimulation syndrome, and women reported adverse effects.
MAIN RESULTS: This is a substantive update of a previous review. Fifteen RCTs were included. One trial reported live birth. Miscarriage, multiple pregnancy rates and adverse events were poorly reported.Clomiphene was effective in increasing pregnancy rate compared to placebo (OR 5.8, 95% CI 1.6 to 21.5) as was clomiphene plus dexamethasone treatment (OR 9.46, 95% CI 5.1 to 17.7) compared to clomiphene alone. No evidence of a difference in effect was found between clomiphene versus tamoxifen or clomiphene in conjunction with human chorionic gonadotrophin (hCG) versus clomiphene alone.The remaining results had only one study in each comparison. A significant improvement in the pregnancy rate was reported for clomiphene plus combined oral contraceptives versus clomiphene alone. No evidence of a difference in effect on pregnancy rate was found with any of the other comparisons.
AUTHORS' CONCLUSIONS: This review shows evidence supporting the effectiveness of clomiphene citrate and clomiphene in combination with dexamethasone for pregnancy rate only. There is limited evidence on the effects of these drugs on outcomes such as miscarriage. Evidence in favour of these interventions is flawed due to the lack of evidence on live births.
