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Efficacy of laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: relationships with chronological and ovarian age.

BACKGROUND: Laparoscopic ovarian diathermy (LOD) has been used successfully as a first-, second- and third-line treatment for ovulation induction in women with polycystic ovary syndrome (PCOS). However, little is known about the predictors for LOD efficacy. The aim of the present study was to evaluate reproductive outcomes in clomiphene citrate (CC)-resistant PCOS patients treated with LOD according to ovarian and chronological age. METHOD: A total of 60 non-obese, primary infertile, CC-resistant women with PCOS were enrolled and treated with LOD. During the following 6 months, all patients underwent ovulation monitoring and timed intercourse. If spontaneous ovulation did not occur within 3 months from surgery, CC (100 mg/day) was administered for 5 days from day 3 of the remaining cycles. The ovulation, abortion and pregnancy rates were assessed and analyzed with patients categorized according to chronological age (group A, <25 years; group B, 25-30 years; group C, 30-35 years; group D, >35 years) and ovarian age (group 1, follicle stimulating hormone (FSH) < 10 mIU/ml; group 2, FSH > 10 mIU/ml). RESULTS: At the end of the study, total ovulation, pregnancy and abortion rates were 57.1, 13.0 and 18.2%, respectively. No difference in all reproductive outcomes was observed between groups A, B and C, whereas the efficacy of LOD was significantly lower in group D. A significant difference in all clinical endpoints was detected between groups 1 and 2. CONCLUSIONS: Our data show that chronological age >35 years and basal FSH value > 10 mIU/ml are related to poor reproductive prognosis in CC-resistant PCOS patients treated with LOD.

Abortion, Spontaneous↗

Mutation analysis of the WNT-4 gene in patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of childbearing age and is characterized by chronic anovulation with either oligomenorrhea or amenorrhea and hyperandrogenism. The etiology of this entity remains unknown. It has been suggested that genomic variants in genes related to the regulation of androgen biosynthesis and function could be involved in genetic predisposition to PCOS. WNT-4 is a member of the WNT family of secreted molecules. Studies on female Wnt-4 knockout mice have suggested that this gene suppresses gonadal androgen synthesis in normal females. We investigated if 25 women with PCOS presented mutations in WNT-4 as the cause of their disorder. Direct sequencing of all five exons demonstrated no mutant alleles in any patient. This study demonstrates that, at least in the population studied, mutations of the open reading frame of WNT-4 gene or its intron/exon junctions are not the cause of PCOS. However, the present data do not rule out the possible existence of causative mutations in the WNT-4 gene promoter region.

Adolescent↗

Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer.

AIM: The combination of gonadotropin-releasing hormone (GnRH) antagonist and gonadotropin represents a valid alternative to the classical protocol with GnRH agonist for ovulation induction in patients with polycystic ovary syndrome (PCOS). The use of metformin is of benefit to women with PCOS. The aim of the present study was to compare the stimulation characteristics and in vitro fertilization (IVF)-embryo transfer (ET) outcomes of the standard short GnRH antagonist protocol for ovarian stimulation with or without metformin. MATERIALS AND METHODS: We recruited 40 PCOS patients. The population studied was divided into two groups (A and B). Group A was pretreated for 2 months with metformin 1.5 g/day (Glucophage(R); Merck Pharm), and then stimulated with recombinant follicle-stimulating hormone (rFSH) 150 UI/day (Gonal F(R) 75 UI; Serono). GnRH antagonist, cetrorelix acetate 0.25 mg/day (Cetrotide(R); Serono), was started when the leading follicle reached 14 mm diameter on ultrasound scan. Group B was treated only with rFSH 150 UI/day and GnRH antagonist 0.25 mg/day when the leading follicle was >or=14 mm in diameter. RESULTS: In group A we found a statistically significant (p < 0.05) decrease in the number of ampoules of rFSH (A vs. B: 18+/-6 vs. 24+/-8) and estradiol levels (A vs. B: 2400+/-600 vs. 3370+/-900 pg/ml) (all values mean+/-standard deviation). Group A had significantly fewer cancelled cycles (A vs. B: 1 vs. 3; p < 0.05). The incidence of ovarian hyperstimulation syndrome was 5% in group A and 15% in group B (p < 0.05). In patients treated with metformin, the total number of follicles on the day of human chorionic gonadotropin treatment (23+/-1.2 vs. 33+/-2.6) was decreased with no change in the number of follicles >or=14 mm in diameter (A vs. B: 18+/-1.2 vs. 19+/-1.7). However, the mean number of mature oocytes (A vs. B: 8.4+/-1.5 vs. 5.0+/-1.5) was increased with metformin treatment (p < 0.05). No difference was found in the number of cleaved embryos (A vs. B: 2.5+/-0.5 vs. 2.2+/-0.3). CONCLUSIONS: The use of metformin with GnRH antagonist improves the outcome of ovarian stimulation in IVF-ET cycles in PCOS patients.

Chorionic Gonadotropin↗

Metformin therapy in the management of polycystic ovary syndrome: endocrine, metabolic and reproductive effects.

Polycystic ovary syndrome (PCOS) is a convergence of multisystem endocrine derangements. Impairment in insulin metabolism is a prominent feature of the syndrome and appears to play a key pathogenetic role precipitating the cascade of other disorders associated with PCOS. Recent studies report that insulin-sensitizing agents, such as metformin, reduce hyperinsulinemia, reverse the endocrinopathy of PCOS and normalize endocrine, metabolic and reproductive functions, leading to the resumption of menstrual cyclicity and ovulation. In this review, we report the most recent evidence regarding metformin usage in women with PCOS.

Endocrine System↗

The genetic basis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Familial clustering of cases suggests that genetic factors play an important part in its aetiology. A number of studies of families with several cases of PCOS have produced results suggesting an autosomal dominant trait. Detailed analysis of a large number of affected families has, however, cast some doubt about the mode of inheritance. An autosomal dominant trait remains possible but a more complex aetiology seems more likely. The results of our recent studies support the concept of an oligogenic disorder in which genes affecting metabolic pathways in glucose homeostasis and steroid biosynthesis are both involved. We review evidence for an important role for the insulin gene minisatellite in the aetiology of anovulatory PCOS and for the gene coding for P450 cholesterol side chain cleavage (CYP11a) in the mechanism of excessive androgen secretion in women with polycystic ovaries. We propose that the heterogeneity of clinical and biochemical features in PCOS can be explained by the interaction of a small number of key genes with environmental, particularly nutritional, factors.

Cholesterol Side-Chain Cleavage Enzyme↗

Insulin regulation of human ovarian androgens.

Hyperinsulinaemic insulin resistance is characteristic of many, if not all, women with polycystic ovary syndrome (PCOS). We will review evidence suggesting that hyperinsulinaemia promotes hyperandrogenism in PCOS by two distinct and independent mechanisms: (i) by increasing circulating ovarian androgens; and (ii) by directly reducing serum sex hormone-binding globulin concentrations. The net result of these actions is to increase circulating free testosterone concentrations. It appears likely that an inherent (probably genetically determined) ovarian defect need be present in women with PCOS, which makes the ovary susceptible to insulin stimulation of androgen production. Limited evidence suggests that hyperinsulinaemia might also promote ovarian androgen production by influencing pituitary release of gonadotrophins. This latter possibility, however, has not been critically evaluated. The clinical implication of these findings is that amelioration of hyperandrogenism in women with PCOS may be achieved by interventions which improve insulin sensitivity and reduce circulating insulin. Such measures might include, but are not limited to, weight loss, dietary modification, and insulin-sensitizing medications.

Female↗

Choice of stimulation in polycystic ovarian syndrome: the influence of obesity.

Obesity modifies insulin sensitivity and gonadotrophins dynamics, and is associated with disorders of spontaneous ovulation. High concentrations of leptin are possibly a link between weight and spontaneous ovulation. Weight excess in polycystic ovary syndrome (PCOS) patients increases hyperinsulinaemia, which may result in altered follicular maturation. Obese PCOS women are characterized by a decreased efficiency of the different stimulation treatments. Although clomiphene resistance is not associated with obesity, the dose of clomiphene required to achieve ovulation is positively correlated with body weight. Obese PCOS women also require higher doses of gonadotrophins than their lean counterparts, with ultimately poorer results in pulsatile gonadotrophin releasing hormone-stimulated cycles. The first stage in the optimal management of obese PCOS anovulatory women is a weight loss programme, which helps to correct the clinical and endocrine abnormalities.

Clomiphene↗

High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.

This preliminary report reviews our experience with 18 infertile patients with clomiphene-resistant polycystic ovary syndrome (PCOS). In the first treatment cycle, troglitazone was administered alone. During cycles 2-5, clomiphene was added with increments of 50 mg (up to 200 mg/day) if the previous cycle was anovulatory. Basal body temperature charts and serum progesterone were obtained to confirm ovulation. In a total of 66 treatment cycles, ovulation occurred in 44 (67%) and pregnancy in seven (11%). There were no significant changes in body weight, waist:hip ratio or liver enzymes during treatment. Troglitazone, alone or with clomiphene, induced ovulation in 15 of 18 patients (83%) and seven (39%) of them achieved pregnancy. This is the first report on ovulatory rates in clomiphene-resistant women with PCOS when troglitazone was used alone or with clomiphene. Recently, metformin and clomiphene were successfully used in women with PCOS. However, our patients represent a more resistant population of women with PCOS, with each patient serving as her own historical control by previous resistance to clomiphene. Although the pregnancy rate (39%) was promising for clomiphene-resistant women with polycystic ovary syndrome, it does not seem to have a definite advantage over gonadotrophins.

Adult↗

Effect of ovarian suppression on glucose metabolism of young lean women with and without ovarian hyperandrogenism.

Gonadal steroids are believed to influence glucose metabolism, oestrogens inducing an improvement and androgens or progestins a deterioration. At baseline and after 3 months of ovarian suppression with a gonadotrophin-releasing hormone analogue (GnRHa: goserelin depot 3.75 mg/28 days), glucose metabolism was evaluated in eight lean women affected by ovarian hyperandrogenism (PCOS) and six age-weight-matched non-hyperandrogenic women (controls) by using both an oral glucose tolerance test (75 g; OGTT) and the minimal model method. The latter method allows calculation of peripheral insulin sensitivity (Si) and glucose dependent glucose utilization (Sg). In PCOS, higher fasting concentrations (P < 0.05) of insulin and C-peptide, and lower Sg (P < 0.05) and Si (P < 0.01) were found. GnRHa did not significantly modify glucose metabolism of controls, while in women with PCOS it decreased fasting glucose (P < 0.05) and significantly increased Si (P < 0.03) up to control values. The present data indicate that strong suppression of ovarian activity improves Si in lean women with PCOS, while it is without relevant effects on glucose metabolism of non-hyperandrogenic women.

Adult↗

Comparison of follicle steroidogenesis from normal and polycystic ovaries in women undergoing IVF: relationship between steroid concentrations, follicle size, oocyte quality and fecundability.

Studies of ovarian stimulation for IVF have suggested a relationship between follicle size and pregnancy rates. Furthermore the follicular endocrine environment is correlated with oocyte quality. The aim of this study was first to verify the relationship between follicular steroid content, follicular size, oocyte maturity and fertilization outcome in women with normal ovaries following recombinant human FSH (rhFSH). Secondly this study was extended to women with polycystic ovarian syndrome (PCOS). Fifty-nine patients (31 normal, 28 PCOS) underwent conventional IVF with rhFSH induction. Follicular diameter was classified as small (8-13 mm) or large (>14 mm) and sex steroid content was analysed for each group. Oocyte maturity was studied according to nuclear maturation the day after fertilization. In both ovulation groups, 17 beta-oestradiol and progesterone concentration were significantly higher in large follicles with meiotically competent oocytes compared with those containing meiotically incompetent oocytes. Testosterone levels were increased in PCOS follicles compared with normal patients, with no difference between corresponding sub-groups of follicles with meiotically competent oocytes. The relationship between follicle size and embryo development showed that 14 mm could be a threshold value following rhFSH induction in normal or PCOS women.

Adult↗

Predictive value of serum and follicular fluid leptin concentrations during assisted reproductive cycles in normal women and in women with the polycystic ovarian syndrome.

Leptin is an adipocyte-derived hormone which plays a central role in the regulation of body weight and energy homeostasis and in signalling to the brain that adequate energy stores are available for reproduction. Although leptin may affect reproduction by regulating the hypothalamic-pituitary-gonadal axis, recent in-vitro observations indicate that leptin may also have direct intra-ovarian actions. Leptin concentrations were measured in women who succeeded in becoming pregnant within three cycles of in-vitro fertilization (IVF) or gamete intra-fallopian transfer (n = 53), in women who failed to become pregnant within three cycles (n = 50), and in women with polycystic ovarian syndrome (PCOS) (n = 22). It was found that lower follicular fluid leptin concentrations were a marker of assisted reproduction treatment success in normal women. Women with PCOS had higher leptin concentrations than women without such a diagnosis, but this was due to their higher body mass index (BMI). After adjustment for age and BMI, women with PCOS who became pregnant tended to have lower mean follicular fluid leptin concentrations than women with PCOS who did not succeed at becoming pregnant. Further studies exploiting the strengths of the IVF model are needed to assess whether the prognostic role for follicular fluid leptin in human reproduction is independent of other factors, and to elucidate the underlying mechanisms.

Adult↗

Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome.

The aim of the study was to determine the prevalence of non-insulin dependent diabetes mellitus (NIDDM), arterial hypertension, coronary artery disease and the risk factors for these diseases in perimenopausal women with a history of polycystic ovary syndrome (PCOS) treatment. A group of 28 women was selected from a large group of patients who had undergone wedge ovarian resection. A total of 752 controls was selected by age (45-59 years) from a random female population sample. There was no difference between the two groups in body mass index, waist circumference or waist-hip ratio. Both groups were found to have identical family histories of NIDDM, hypertension, and coronary artery disease and identical smoking habits. We did not find a difference between the mean concentrations of lipids and fasting glucose. The two groups did not differ in the proportions of women with elevated lipid concentrations. The prevalence of NIDDM and coronary artery disease was significantly higher in PCOS women. In conclusion, women in the general population have the same level of risk factors at perimenopausal age as PCOS women. Patients with markedly expressed clinical symptoms of PCOS made up a subgroup in the general population at high risk for developing NIDDM and coronary artery disease.

Coronary Disease↗

Immunolocalization of Fas and Fas ligand in the ovaries of women with polycystic ovary syndrome: relationship to apoptosis.

Both Fas (APO-1, CD95), an apoptosis-inducing receptor, and its ligand, Fas ligand (FasL, CD95L), have been localized to the ovary. Granulosa cell apoptosis occurs in antral follicular atresia. In polycystic ovary syndrome (PCOS), antral follicles accumulate with some atretic features. The ovarian expression of Fas and FasL was examined in PCOS by immunohistochemistry and correlated with immunodetection of apoptotic cells. Fas immunostaining was present in pre-antral follicle oocytes, some primary and secondary pre-antral follicle granulosa cells, and both granulosa and theca of antral follicles. Thecal staining persisted with advancing atresia, while granulosa staining declined. In antral follicles, abundant Fas-positive cells co-localized with scattered nuclei immunopositive for apoptosis. Ovarian vascular myocytes were strongly Fas-immunopositive. FasL immunostaining was present in pre-antral follicles in oocytes and variably in granulosa. In antral follicles, granulosa and thecal FasL staining increased with advancing atresia. Normal control ovaries showed follicular Fas and FasL staining patterns similar to those in PCOS, but vascular staining was less prominent. In one healthy follicle, Fas immunostaining was seen in the oocyte and weakly in mural granulosa and theca interna. The results suggest that in PCOS, an alteration in Fas-mediated apoptosis, does not cause abnormal folliculogenesis, but may promote ovarian vascular remodelling.

Adult↗

Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome.

BACKGROUND: Cross-sectional studies have shown a high frequency of impaired glucose tolerance (IGT) and non-insulin dependent diabetes mellitus (NIDDM) in women with polycystic ovarian syndrome (PCOS). However, little is known about the change in glucose tolerance that occurs over a period of several years in women with PCOS. METHODS: Sixty-seven women with PCOS received a 75 g glucose tolerance test and measurement of lipids at baseline and at follow-up after an average time of 6.2 years. All women followed prospectively had normal glucose tolerance (n = 54) or IGT (n = 13) at the start of the study. RESULTS: Change in glycaemic control from baseline was frequent, with 5/54 (9%) of normoglycaemic women at baseline developing IGT and a further 4/54 (8%) moving directly from normoglycaemic to NIDDM. For women with IGT at baseline, 7/13 (54%) had NIDDM at follow-up. Body mass index (BMI) at baseline was an independent significant predictor of adverse change in glycaemic control. CONCLUSIONS: Women with PCOS, particularly those with a high BMI, should be reviewed regularly with respect to IGT or NIDDM, as the frequency of impaired glycaemic control is high, and that the rate of conversion from normal glucose tolerance to IGT or NIDDM, or from IGT to NIDDM is substantial.

Adult↗

Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome.

BACKGROUND: The endocrine-metabolic status of non-obese, young women with polycystic ovary syndrome (PCOS) is normalized more effectively by combined treatment with flutamide and metformin than by either of these drugs in monotherapy. In this follow-up study, we assess whether the endocrine-metabolic benefits of combined flutamide-metformin treatment are maintained in the presence of a low-dose oral contraceptive (OC). METHODS: To a population of non-obese, young PCOS women already receiving flutamide-metformin (125 mg/day and 1275 mg/day), a low-dose OC (ethinyl estradiol 20 microg + gestodene 75 microg) was administered to reduce the risk of pregnancy. A total of 12 women elected to receive the OC and this subgroup (OC+) was matched to a subgroup continuing on flutamide-metformin alone (OC-), for a total study population of 24 women (mean age +/- SEM 18.7 +/- 0.3 years; body mass index, 21.8 +/- 0.5 kg/m(2)). Endocrine-metabolic indices were assessed before any treatment (0 months), on flutamide-metformin (12 months), and again after a further 6 months with or without additional OC (18 months). RESULTS: In OC- and OC+ women, the beneficial effects of flutamide-metformin on hyperandrogenaemia, hyperinsulinaemia and dyslipidaemia were maintained. In OC+ women, there was an additional increase in sex hormone-binding globulin (SHBG), and thus a further drop in the free androgen index. CONCLUSION: When a low-dose OC is administered with a low-dose flutamide-metformin combination in women with PCOS, the beneficial effects are maintained on hyperinsulinaemia-dyslipidaemia, which are key determinants of long-term complications. Hence, in daily practice, such a low-dose quatuor may become a therapeutic option of first choice for young women with PCOS.

Adult↗

Ultrasound examination of polycystic ovaries: is it worth counting the follicles?

BACKGROUND: This study revisited the ultrasonographic diagnostic criteria of polycystic ovary syndrome (PCOS) and studied the relationship between the major hormonal and metabolic features of PCOS and the follicle number per ovary (FNPO). METHODS: This prospective study included 214 women with PCOS compared with 112 women with normal ovaries. Main clinical, biological and ultrasonographic markers of PCOS were assessed during the early follicular phase. RESULTS: The mean FNPO of follicles 2-5 mm in size was significantly higher in polycystic ovaries than in controls, while it was similar within the 6-9 mm range. Setting the threshold at 12 for the 2-9 mm FNPO offered the best compromise between specificity (99%) and sensitivity (75%). Within the 2-5 mm follicular range, we found significant positive relationships between the FNPO and androgens. The FNPO within the 6-9 mm range was significantly and negatively related to body mass index and fasting insulin serum level. CONCLUSIONS: We propose to modify the definition of polycystic ovaries by adding the presence of > or =12 follicles measuring 2-9 mm in diameter (mean of both ovaries). Also, our findings strengthen the hypothesis that the intra-ovarian hyperandrogenism promotes excessive early follicular growth and that further progression cannot proceed normally because of hyperinsulinism and/or other metabolic influence linked to obesity.

Adult↗

Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study.

BACKGROUND: Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome (PCOS) scheduled for IVF stimulation. METHODS: Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria: hyperandrogenaemia, elevated LH/FSH ratio, hyperinsulinism, decreased SHBG levels or hirsutism, were studied. Normal weight and overweight patients were randomized separately in a prospective, randomized, double blind study. All patients were treated for at least 16 weeks with metformin (1000 mg bid) or placebo ending on the day of HCG injection. RESULTS: No differences were found in the primary end-points: duration of FSH stimulation 14.4 (13.1-15.7) versus 14.2 (12.6-15.7) days or estradiol on the day of HCG injection 6.8 (5.3-8.2) versus 7.6 (5.6-9.6) nmol/l in the metformin and placebo groups, respectively. The secondary end-points number of oocytes, fertilization rates, embryo quality, pregnancy rates and clinical pregnancy rates were equal. However, in the normal weight subgroup (BMI <28 kg/m(2), n = 27), pregnancy rates following IVF were 0.71 (0.63-0.79) versus 0.23 (0.15-0.31) in the metformin and placebo groups, respectively (P = 0.04). Overall clinical pregnancy rates were equal: 0.51 (0.34-0.68) versus 0.44 (0.27-0.62) in the metformin and placebo groups, respectively. However, in the normal weight subgroup, clinical pregnancy rates were 0.67 (0.43-0.91) and 0.33 (0.06-0.60), respectively (P = 0.06). CONCLUSIONS: Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome. However, among normal weight PCOS women, pre-treatment with metformin tends to improve pregnancy rates. Further studies in subgroups of PCOS women are required.

Adult↗

Flutamide-metformin plus an oral contraceptive (OC) for young women with polycystic ovary syndrome: switch from third- to fourth-generation OC reduces body adiposity.

BACKGROUND: Low-dose flutamide-metformin has been developed as a background therapy for non-obese adolescents and young women with hyperinsulinaemic hyperandrogenism, a variant of polycystic ovary syndrome (PCOS). We verified whether the lipolytic efficacy of flutamide-metformin in women with PCOS is enhanced by giving an oral contraceptive (OC) co-therapy that contains drospirenone, instead of gestodene, as progestin. METHODS: An open-labelled study was carried out in which non-obese women with PCOS (n = 29; age approximately 20 years), who had been on a combination of flutamide (62.5 mg/day), metformin (850 mg/day) and ethinylestradiol-gestodene for 8-15 months, were randomized for replacement of the gestodene OC by a drospirenone OC. Assessments of endocrine-metabolic state and body composition (by dual-energy X-ray absorptiometry) were performed at randomization and after 6 months. RESULTS: The switch to drospirenone OC was accompanied by a reduction of total and abdominal fat (mean -0.8 and -0.5 kg) and by an increment of lean body mass (+0.6 kg; all P < 0.01), so that body adiposity was strikingly reduced without changing body weight. CONCLUSION: In non-obese women with PCOS, low-dose flutamide-metformin reduces total and abdominal fat excess more effectively if contraceptive co-therapy contains drospirenone, instead of gestodene, as progestin.

Abdomen↗