Roy Homburg

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. This paper describes, on the basis of the currently available evidence, the consensus reached by a group of experts regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counselling should be provided emphasizing the importance of life style, especially weight reduction and exercise in overweight women, smoking and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotrophins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotrophins is associated with increased chances for multiple pregnancy and, therefore, intense monitoring of ovarian response is required. LOS alone is usually effective in <50% of women and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC, gonadotrophin paradigm) is reported to be highly effective with a cumulative singleton live birth rate of 72%. Recommended third-line treatment is in vitro fertilization. More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-, second- or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.

In vitro fertilization and embryo transfer for the treatment of infertility associated with polycystic ovary syndrome

OBJECTIVEnTo examine the outcome of treatment with IVF-ET of women with polycystic ovarian syndrome (PCOS) who failed to conceive on conventional treatment.nnnDESIGNnRetrospective analysis with an age-matched control group.nnnSETTINGnUniversity hospital infertility clinic and IVF unit. PATIENTS.nnnINTERVENTIONSnSixty-eight women with PCOS who had failed to conceive on treatment with clomiphene citrate and during six ovulatory cycles on gonadotropins underwent 208 cycles of IVF-ET. An age-matched group of 68 women with a tubal mechanical factor who received 143 treatment cycles during the same period served as controls.nnnMAIN OUTCOME MEASURESnCumulative conception rates, the cumulative livebirth rates, and IVF-ET data were compared between the two groups. Results of treatment with and without GnRH agonist (GnRH-a) within the groups were also compared.nnnRESULTSnA comparison of PCOS and mechanical factor (control) groups showed almost identical results at 6 months for cumulative conception rate (82% versus 85%) and cumulative livebirth rate (69% versus 65%). Significantly more oocytes were retrieved but a smaller percentage fertilized in PCOS, and the pregnancy rate per ET did not differ between the two groups (23% versus 26%). Treatment with GnRH-a and gonadotropins as opposed to gonadotropins alone improved the cumulative conception rate, miscarriage rate, and cumulative livebirth rate in the PCOS but not in the control group and improved fertilization rates in both groups.nnnCONCLUSIONSnFor patients with PCOS who fail to conceive with gonadotropin treatment, IVF-ET is a successful treatment alternative, producing results equal to those for women with a mechanical tubal factor. Better results were achieved with GnRH-a in women with PCOS but made no difference to those with a mechanical tubal factor compared with treatment with gonadotropins alone.

Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnancies achieved in women with polycystic ovarian syndrome

OBJECTIVEnTo compare the effect of treatment with gonadotropin-releasing hormone agonist (GnRH-a) and human menopausal gonadotropins (hMG) with that of gonadotropins only, on the cumulative livebirth rate and miscarriage rate of pregnancies achieved in women with polycystic ovarian syndrome (PCOS).nnnDESIGNnRetrospective analysis of the outcome of 97 pregnancies according to the treatment protocol, with or without GnRH-a. Calculation of miscarriage rate and cumulative livebirth rate by life-table analysis.nnnSETTINGnInfertility clinic and in vitro fertilization (IVF) unit.nnnPATIENTSnWomen with polycystic ovaries (n = 239) who were clomiphene citrate failures and received either GnRH-a/hMG (n = 110) or gonadotropins only (n = 129) for ovulation induction (n = 138) or superovulation for IVF (n = 101).nnnINTERVENTIONSnFor ovulation induction, hMG was given in a step-up, individually adjusted dose scheme. For IVF, three ampules of pure follicle-stimulating hormone were given for 3 days followed by three ampules per day hMG and then individual dose adjustment. Gonadotropin-releasing hormone agonist (Decapeptyl, D-Trp6, microcapsules, 3.75 mg) was given in a single dose 2 weeks before gonadotropin treatment.nnnMAIN OUTCOME MEASURESnThe rate of early miscarriages (< 12 weeks) per pregnancies achieved was analyzed, and the cumulative livebirth rate for each treatment group was calculated by life-table analysis.nnnRESULTSnMiscarriage rates after treatment in ovulation induction with (16.7%) and without GnRH-a (39.4%) and in IVF with (18.2%) and without GnRH-a (38.5%) were almost identical and were therefore analyzed together. Of pregnancies achieved with GnRH-a, 17.6% miscarried compared with 39.1% of those achieved with gonadotropins alone. Cumulative livebirth rate after four cycles for GnRH-a was 64% compared with 26% for gonadotropins only.nnnCONCLUSIONSnCotreatment with GnRH-a/hMG for anovulatory women with PCOS reduces the miscarriage rate and improves the livebirth rate compared with treatment with gonadotropins alone.

A comparative prospective study of conventional regimen with chronic low-dose administration of follicle-stimulating hormone for anovulation associated with polycystic ovary syndrome

OBJECTIVEnTo compare efficiency of conventional and chronic low-dose regimens for treatment of anovulation associated with polycystic ovary syndrome (PCOS).nnnDESIGNnFifty participants divided into two equal groups. The first group was treated with urinary human FSH using a conventional stepwise protocol and the second group was treated with a regimen of chronic low-dose and small incremental rises with urinary human FSH or with recombinant human FSH for a maximum of three cycles.nnnSETTINGnTertiary referral university hospital fertility unit.nnnPATIENTSnFifty infertile women with clomiphene citrate-resistant anovulation associated with PCOS.nnnMAIN OUTCOME MEASURESnPattern of follicular development, amount of FSH required, serum E2 concentrations, cycle fecundity, cumulative conception, and live birth rates. Multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) rates.nnnRESULTSnCompared with the conventional dose protocol, the chronic low-dose regimen yielded slightly improved pregnancy rates (40% versus 24%) while completely avoiding OHSS and multiple pregnancies, which were prevalent (11% and 33%, respectively) with conventional therapy. Monofollicular development was induced in 74% versus 27% of cycles, and the total number of follicles > 16 mm and E2 concentrations were half those observed on conventional therapy.nnnCONCLUSIONSnFor women with PCOS, a chronic low-dose regimen of FSH eliminated complications of OHSS and multiple pregnancies while maintaining a satisfactory pregnancy rate. This modality, thus, has distinct advantages and could well replace conventional gonadotropin therapy for these patients.

PCOS Forum: research in polycystic ovary syndrome today and tomorrow.

Objectiveu2002 To summarize promising areas of investigation into polycystic ovary syndrome (PCOS) and to stimulate further research in this area.

Health and fertility in World Health Organization group 2 anovulatory women

BACKGROUNDnDisruption of ovulation occurs in different types of clinical infertility. The World Health Organization (WHO) has provided a classification of ovulation disorders. This review focuses on WHO group 2 anovulation.nnnMETHODSnSearches were performed in Medline/PubMed and EMBASE. Each subject summary was presented to the European Society of Human Reproduction and Embryology (ESHRE) Workshop Group, where omissions or disagreements were resolved by discussion.nnnRESULTSnDisorders resulting in ovulatory disturbances are a relatively common cause of infertility. They occur most frequently in the context of WHO group 2 anovulation as reflected, for example, in the polycystic ovary syndrome (PCOS). The aetiology of PCOS remains unclear but evidence exists for a multifactorial origin with a genetic predisposition. Women with PCOS show an increased time to pregnancy but their eventual family size is not necessarily reduced. Also their frequency of miscarriage does not appear increased. Clomiphene citrate is still the first-line treatment in subfertile anovulatory patients with PCOS, with gonadotrophins and laparoscopic ovarian surgery as second-line options. Aromatase inhibitors show promising results.nnnCONCLUSIONSnLong-term health risks in patients with WHO group 2 anovulation demand their general health be monitored, even after their reproductive needs have been fulfilled. Metabolic and cardiovascular risk prevention in women with PCOS should start as early as possible. It is not easy to analyse the possible role of PCOS, independent of obesity, metabolic syndrome, insulin resistance and diabetes, on long-term health.

Recurrent spontaneous ovarian hyperstimulation syndrome associated with polycystic ovary syndrome

Ovarian hyperstimulation syndrome (OHSS) is the most serious potentially life-threatening iatrogenic complication of ovulation induction. Presented here is the first reported case of recurrent severe OHSS which developed spontaneously in a women with polycystic ovary syndrome, diagnosed early in her second pregnancy, and necessitated intensive fluid and colloid therapy.

Polycystic ovary syndrome — loss of the apoptotic mechanism in the ovarian follicles?

Polycystic ovary syndrome (PCOS) is the most prevalent female endocrinopathy and the largest single cause of anovulatory infertility. The PCOS is characterized by multiple small antral follicles arrested in their development but nonatretic and viable. The hyperexpression of some growth factors (e.g. EGF/TGF alpha) in PCOS, considered to be survival or antiapoptotic factors, led to the hypothesis of their involvement in the blocking of apoptosis and atresia leading to an accumulation of multiple small antral follicles. Diminished FSH stimulation and accumulation of androgens could explain the arrest of progress to the preovulatory stage. Further investigation of the pathogenesis of PCOS is needed on the modulation of tumour suppressor and apoptosis genes such as p53, BAX or the APO/FAS system and the over expression of survival genes such as BCL2.

3 Adverse effects of luteinizing hormone on fertility: fact or fantasy

High tonic serum concentrations of luteinizing hormone (LH) in the follicular phase, frequently witnessed in polycystic ovary syndrome, have been associated with decreased reproductive function. Impaired rates of fertilization, conception and miscarriage are obtained when LH levels are high before oocytes are collected, during ovulation induction or in women with regular cycles. Conversely, treatment that decreases LH concentrations, such as gonadotrophin-releasing hormone analogue or laparoscopic ovarian puncture, eases induction of ovulation and pregnancy and improves miscarriage rates. Tonic hypersecretion of LH appears to induce premature oocyte maturation, causing the problems with fertilization and miscarriage.

The influence of estradiol/follicle and estradiol/oocyte ratios on the outcome of controlled ovarian stimulation for in vitro fertilization

Objective. The aim of the study was to evaluate the influence of the ratios of estradiol (E2) to either the number of follicles >14 mm on the day of human chorionic gonadotropin administration (E2/follicle) or the number of oocytes retrieved (E2/oocytes) during controlled ovarian hyperstimulation (COH) with gonadotropin-releasing hormone (GnRH)-agonist (agonist group) and GnRH-antagonist (antagonist group), on the outcome of in vitro fertilization (IVF) cycles. Patients and methods. All consecutive women aged <35 years admitted to our IVF unit during a 6-year period with normal to high response to COH were retrospectively studied. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryos transferred and pregnancy rate were assessed. Results. Six hundred and ninety consecutive IVF cycles were evaluated, 301 in the agonist group and 389 in the antagonist group. The ratios of E2/follicle and E2/oocyte were significantly higher in the agonist group (p < 0.001 for both). Moreover, while pregnancy rates within E2/oocyte ratio of 100–200 pg/ml were comparable between the agonist and antagonist groups, when E2/oocyte ratios were <100 pg/ml or >200 pg/ml, pregnancy rates were significantly higher in the agonist group. Furthermore, no difference in pregnancy rates was observed within the agonist group between different E2/oocytes ratios, while within the antagonist group, higher pregnancy rates were observed when comparing those with E2/oocyte ratio of 100–200 pg/ml with those with E2/oocyte ratio <100 pg/ml or >200 pg/ml. Conclusion. While E2/oocyte ratio cannot predict the success of GnRH-agonist protocol, patients undergoing GnRH-antagonist protocol should reach E2/oocyte ratio within the 100–200 pg/ml range in order to achieve the best IVF outcome.