A total of 500 consecutive women (mean age 32.9 years; SD 5 years) presenting with a history of recurrent miscarriages (median 4; range 3-17) were investigated for the presence of antiphospholipid antibodies (APA), polycystic ovaries (PCO), hypersecretion of luteinizing hormone (LH) and chromosome abnormalities in order to detect an underlying cause of their pregnancy losses. All women had details of their previous reproductive history, investigations and treatment documented: 76% of the women had experienced only early pregnancy losses (miscarriage < 13 weeks gestation); 32% had a history of subfertility; and significant parental chromosome rearrangements were present in 3.6% of couples. An ultrasound diagnosis of PCO was made in 56% of women, 58% of whom were demonstrated to hypersecrete LH, based on early morning urinary LH analysis. Circulating APA were found in 14% of women. An underlying cause of recurrent miscarriage--genetic, endocrine or autoimmune--was found in > 50% of couples. Women in the latter two groups are being recruited to randomized treatment trials which are discussed.

Objective To assess the effect of moderate obesity on the outcome of induction of ovulation with low dose gonadotrophin in women with polycystic ovary syndrome (PCOS). Design Retrospective analysis of women with PCOS treated consecutively. An analysis of the impact of obesity on outcome of pregnancy using data from the North West Thames Regional (NWTR) obstetric database was included for comparison. Setting Induction of ovulation clinic at the Samaritan Hospital for Women (St. Mary's Hospital Group). Subjects 100 women with clomiphene‐resistant anovulation associated with PCOS. 75 were of normal weight (BMI 19–24. 9 kg/m2, lean group) and 25 were moderately overweight (BMI 25–27.9 kg/m2, obese group). Interventions Induction of ovulation using low doses of gonadotrophins with small, stepwise increments in dosage as required. Main outcome measures Rates of ovulation, pregnancy and miscarriage; daily and total doses of gonadotrophin required for induction of ovulation. Results The proportion of ovulatory cycles was significantly greater in the lean group (77%) compared with the obese group (57%) (χ2 9.8, P<0.001). Obese women required larger doses of gonadotrophin to achieve ovulation (P <0.001). The proportion of women who achieved at least one pregnancy was similar in the two groups (39%vs 48%) but miscarriage was more frequent in the obese group (60%vs 27%; P<0.05). This difference was independent of the baseline and/or mid‐follicular luteinizing hormone (LH) concentration either before or during treatment. Analysis of data from the North West Thames Health Region obstetric database confirmed an increased risk of miscarriage in moderately obese women which was independent of maternal age. Conclusions Moderate obesity in women with PCOS, treated with low dose gonadotrophin, is associated with an increased risk of miscarriage. This is reflected in the results of analysis of the effect of obesity on outcome of pregnancy in the general population. It is therefore important to encourage weight reduction in obese women with PCOS before considering therapy to induce ovulation.

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Women with anovulation due to polycystic ovary syndrome are likely to develop multiple follicles during gonadotrophin therapy and therefore have a high risk of multiple pregnancy. We have developed a low-dose regimen for use in these women; 100 women with clomiphene-resistant polycystic ovary syndrome were treated. Ninety-five of the women ovulated at least once, 72% of the 401 cycles induced were ovulatory and the majority (73%) of these were uni-ovulatory. The overall cumulative conception rate was 55% at 6 months with only two multiple pregnancies. The rate of early pregnancy loss was 32%, which is similar to that reported by other groups. The prevalence of complications was low with no cases of severe hyperstimulation and less than 5% of cycles were abandoned because of development of multiple follicles. Analysis of baseline and mid-follicular luteinizing hormone levels showed that a raised baseline and/or mid-follicular luteinizing hormone level was associated with a poor response to treatment, i.e. anovulation, ovulation but no conception, or early pregnancy loss. There were no successful pregnancies in the women whose luteinizing hormone levels were persistently raised during ovulatory cycles. Low-dose gonadotrophin therapy is a safe and effective method of inducing ovulation; it is associated with a high incidence of single follicular development and a very low multiple pregnancy rate.

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Objective-To determine whether prepregnancy pituitary suppression of luteinising hormone secretion with a luteinising hormone releasing hormone analogue improves the outcome of pregnancy in ovulatory women with a history of recurrent miscarriage, polycystic ovaries, and hypersecretion of luteinising hormone.Design-Randomised controlled trial. Setting-Specialist recurrent miscarriage clinic.Subjects-106 women with a history of three or more consecutive first trimester miscarriages, polycystic ovaries, and hypersecretion of luteinising hormone.Interventions-Women were randomised before conception to receive pituitary suppression with a luteinising hormone releasing hormone analogue followed by low dose ovulation induction and luteal phase progesterone (group 1) or were allowed to ovulate spontaneously and then given luteal phase progesterone alone or luteal phase placebo alone (group 2). No drugs were prescribed in pregnancy.Main outcome measures-Conception and live birth rates over six cycles.Results-Conception rates in the pituitary suppression and luteal phase support groups were 80% (40150 women) and 82% (46156) respectively (NS). Live birth rates were 65% (26140) and 76% (35146) respectively (NS). In the luteal phase support group there was no difference in the outcome of pregnancy between women given progesterone and those given placebo pessaries. Live birth rates from an intention to treat analysis were 52% (26150 pregnancies) in the group given pituitary suppression and 63% (35/56) in the controls (NS).Conclusions-Prepregnancy suppression of high luteinising hormone concentrations in ovulatory women with recurrent miscarriage and hypersecretion of luteinising hormone does not improve the outcome of pregnancy. The outcome of pregnancy without pituitary suppression is excellent. IntroductionHypersecretion of luteinising hormone is strongly associated with subfertility and early pregnancy failure. Studies from assisted conception cycles have shown an adverse effect of high luteinising hormone concentra-

Polycystic ovary syndrome is the most common cause of anovulatory infertility. Anovulation in polycystic ovary syndrome is characterized by the failure of selection of a dominant follicle with arrest of follicle development at the 5-10 mm stage. In an attempt to elucidate the mechanism of anovulation associated with this disorder we have investigated at what follicle size human granulosa cells from normal and polycystic ovaries respond to LH. Granulosa cells were isolated from individual follicles from unstimulated human ovaries and cultured in vitro in serum-free medium 199 in the presence of LH or FSH. At the end of a 48-h incubation period, estradiol (E2) and progesterone (P) were determined in the granulosa cell-conditioned medium by RIA. In ovulatory subjects (with either normal ovaries or polycystic ovaries), granulosa cells responded to LH once follicles reached 9.5/10 mm. In contrast, granulosa cells from anovulatory women with polycystic ovaries responded to LH in smaller follicles of 4 mm. Granulosa cells from anovulatory women with polycystic ovaries were significantly more responsive to LH than granulosa cells from ovulatory women with normal ovaries or polycystic ovaries (E2, P < 0.0003; P, P < 0.03). The median (and range) fold increase in estradiol and progesterone production in response to LH in granulosa cell cultures from size-matched follicles 8 mm or smaller were E2, 1.0 (0.5-3.9) and P, 1.0 (0.3-2.5) in ovulatory women and E2, 1.4 (0.7-25.4) and P, 1.3 (0.3-7.0) in anovulatory women. Granulosa cells from anovulatory (but not ovulatory) women with polycystic ovaries prematurely respond to LH; this may be important in the mechanism of anovulation in this common endocrinopathy.