Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome.

BACKGROUND: Insulin-sensitizing drugs (ISDs) have recently been advocated as possibly a safer and more effective long-term treatment than the oral contraceptive pill (OCP) in women with polycystic ovary syndrome (PCOS). It is important to directly compare the efficacy and safety of ISDs versus OCPs in the long-term treatment of women with PCOS. OBJECTIVES: To assess the effectiveness and safety of ISDs versus the OCP (alone or in combination) in improving clinical, hormonal, and metabolic features of PCOS. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (September 2005), Cochrane Central Register of Controlled Trials (CENTRAL (Ovid), third quarter 2005), MEDLINE (1966 to September 2005), CINAHL (1982 to September 2005), and EMBASE (1988 to September 2005). References of the identified articles were handsearched, and pharmaceutical companies and experts in the field were also contacted for additional relevant studies. SELECTION CRITERIA: Randomised controlled trials which compared ISDs versus the OCP (alone or in combination). DATA COLLECTION AND ANALYSIS: Performed independently by two review authors. MAIN RESULTS: Six trials were included for analysis, four of which compared metformin versus OCP (104 participants) and two of which compared OCP combined with metformin versus OCP alone (70 participants). Limited data demonstrated no evidence of difference in effect between metformin and the OCP on hirsutism and acne. There was either insufficient or no data on the relative efficacy of metformin or the OCP (alone or in combination) for preventing the development of diabetes, cardiovascular disease, or endometrial cancer. Metformin was less effective than the OCP in improving menstrual pattern (Peto odds ratio (OR) 0.08, 95% CI 0.01 to 0.45). Metformin resulted in a higher incidence of gastrointestinal (Peto OR 7.75, 95% CI 1.32 to 45.71), and a lower incidence of non-gastrointestinal (Peto OR 0.11, 95% CI 0.03 to 0.39), severe adverse effects requiring stopping of medication. Metformin was less effective in reducing serum androgen levels (total testosterone: weighted mean difference (WMD) 0.54, 95% CI 0.22 to 0.86; free androgen index: WMD 3.69, 95% CI 2.56 to 4.83). Metformin was more effective than the OCP in reducing fasting insulin (WMD -3.46, 95% CI -5.39 to -1.52) and not increasing triglyceride (WMD -0.48, 95% -0.86 to -0.09) levels, but there was insufficient evidence regarding comparative effects on reducing fasting glucose or cholesterol levels. AUTHORS' CONCLUSIONS: Up to 12-months treatment with the OCP is associated with an improvement in menstrual pattern and serum androgen levels compared with metformin; but metformin treatment results in a reduction in fasting insulin and lower triglyceride levels than with the OCP. Side-effect profiles differ between the two drugs. There is either extremely limited or no data on important clinical outcomes such as the development of diabetes, cardiovascular disease, or endometrial cancer. There are no data comparing ISDs other than metformin (that is rosiglitazone, pioglitazone, and D-chiro-inositol) versus OCPs (alone or in combination).

Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment.

The content of estrogen and progesterone receptors (ER, PR) is higher in fibroid tissue than in homologous myometrium, and both receptors seem to be regulated by the levels of circulating sex steroids. Myometrial and fibroid tissues were recovered from women undergoing gynecological operations during different phases of the menstrual cycle and during treatment with an analogue of GnRH (GnRHa). Contents of ER and PR in the tissue cytosol were determined by enzyme immunoassay. The ER levels were significantly higher in fibroid tissue than in homologous myometrium in all the endocrine conditions. During the secretory phase, when luteal progesterone production is prominent, the ER levels in the myometrium and fibroids were lower than during the proliferative phase. During GnRHa treatment, the ER levels in both tissues were similar to those in the proliferative phase but significantly higher than in the secretory phase. The PR levels were also significantly higher in fibroids than in myometrium in all the different endocrine conditions. In both tissues, the PR levels were lower in the secretory phase and during GnRHa treatment, compared with the proliferative phase. Our data suggest that, in these categories of women, both ER and PR are overexpressed in fibroid tissue. Apparently, high progesterone levels down-regulate the ER in both fibroids and myometrium, whereas estrogen mediates the up-regulation of the PR during the proliferative phase. Increased knowledge about the mechanisms by which sex steroids regulate their own receptors in uterine tissues might provide a basis for development of new treatment strategies for women with fibroid disease.

Serum FSH levels in women with polycystic ovary syndrome during ovulation induction using down-regulation and urofollitropin.

OBJECTIVE: To evaluate retrospectively the use of serum FSH levels and to correlate them with follicular growth in a clinical ovulation induction program. METHODS: Twenty women with infertility due to anovulation associated with polycystic ovary syndrome (PCOS) were studied. The patients were down-regulated with a long GnRH agonist protocol and stimulated with purified urofollitropin, using a low-dose step-up regimen. Repeated serum samples were drawn and transvaginal ultrasound scans were-performed. During the exogenous FSH therapy serum FSH levels resulting in continuous follicular growth were analyzed, as well as the rates of ovulation, pregnancy, cancellation and conversion to in vitro fertilization (JVF). RESULTS: Thirty-two out of fifty treatment cycles led to ovulation, resulting in five term pregnancies. Eight cycles were converted to IVF/embryo transfer due to multiple follicular growth. They resulted in two pregnancies. Ten cycles were cancelled because of impaired follicular growth. The serum FSH levels (median 6 IU/I) resulting in continuous growth of the follicles were relatively stable within patients (variation 15%) but varied considerably between patients (45%). The relationship between FSH dose and serum level was different for lean and obese PCOS patients after subcutaneously injected urofollitropin CONCLUSIONS: There seems to be a difference in resorption/metabolism between lean and obese PCOS patients with regard to s.c. injected FSH. The intra-patient coefficient of variation (C.V.) of the serum FSH response level was quite low, as was the C.V. of the FSH dose at the response level. This allowed a more rapid dose adjustment in subsequent cycles. Analysis of serum FSH during induction of ovulation with gonadotropins seems to be of limited value in clinical programs.

Persistent trophoblast after conservative treatment of tubal pregnancy: prediction and detection.

The incidence of persistent trophoblast and risk of second surgical intervention after conservative treatment of tubal pregnancy are substantial. The preoperative and postoperative hCG patterns in patients with tubal pregnancy were studied to see whether this information could predict and detect persistent trophoblast at an early stage. Ninety-eight women with tubal pregnancy underwent conservative surgical treatment by laparoscopy or laparotomy. Eight developed postoperative complications necessitating a second operation, and seven of them had both biochemical and histologic evidence of persistent trophoblastic activity. In seven of 31 patients with preoperative hCG above 3000 IU/L, a second operation was necessary, whereas in 67 with preoperative hCG levels below 3000 IU/L, only one such intervention was necessary. Eight of the 22 patients with hCG above 1000 IU/L on the second day after surgery and seven of 11 patients with hCG above 1000 IU/L on the seventh day after surgery later needed a second surgical procedure. In contrast, 86 of 87 women with hCG below 1000 IU/L on the seventh day after surgery had an uneventful convalescence. We conclude that pre- and postoperative hCG measurements can identify patients at risk of developing persistent trophoblast. Further, in patients with preoperative hCG titers below 3000 IU/L, we recommend conservative surgery followed by measurement of hCG 1 week postoperatively.

Prediction of persistent ectopic pregnancy after laparoscopic salpingostomy.

OBJECTIVE: To evaluate whether preoperative measurements of progesterone and hCG in serum can predict the risk of needing a second therapeutic intervention after laparoscopic salpingostomy. METHODS: In 158 patients with unruptured tubal pregnancies smaller than 4 cm, serum progesterone and hCG levels were measured in two venous blood samples taken preoperatively. Fourteen complicated cases, in which a second therapeutic intervention was necessary, were compared with 144 uncomplicated cases. RESULTS: Eleven of the 14 complicated cases (79%) had preoperative progesterone values exceeding 35 nmol/L, whereas this was true for only 15 (10%) of the uncomplicated cases. Among the complicated cases, 12 (86%) had preoperative daily hCG changes above 100 IU/L, compared to 44 (31%) of the uncomplicated cases. Cases with a progesterone level above 35 nmol/L and a daily hCG change exceeding 100 IU/L had a 61% risk for a second therapeutic intervention, whereas with a progesterone value below 35 nmol/L and/or a daily hCG change of less than 100 IU/L, the risk was only 2%. CONCLUSION: The risk for a second therapeutic intervention after laparoscopic salpingostomy for ectopic pregnancy can be predicted by the combined use of two sequential serum hCG samples and one serum progesterone sample, the last of each taken within 24 hours preoperatively.

Combined use of progesterone and human chorionic gonadotropin determinations for differential diagnosis of very early pregnancy.

Progesterone (P) level and daily change in human chorionic gonadotropin (hCG) were determined in the serum of 307 patients with suspected ectopic pregnancy (EP). Of the viable intrauterine pregnancies (IUP), 99% had P values above 30 nmol/L, whereas 75% of the EP and 81% of the spontaneous abortions had P values less than 30 nmol/L. Among the viable IUP, 95% had normal hCG increases, whereas 89% of the EP and 99% of the spontaneous abortions had abnormal hCG increases. A P value less than 30 nmol/L combined with an abnormal hCG increase had a positive predictive value for pathological pregnancy of 1.0. Consequently, in such cases, further invasive diagnostic or therapeutic measures can be taken with a low risk of jeopardizing a viable IUP.

Are women with polycystic ovary syndrome at an increased risk of pregnancy-induced hypertension and/or preeclampsia?

OBJECTIVE: To study whether there is an increased risk of glucose intolerance and hypertensive complications during pregnancy in women with polycystic ovary syndrome (PCOS) and if there is an adverse pregnancy outcome. METHODS: In a retrospective case-control study, pregnancies and neonatal outcome were compared in 33 women with PCOS and 66 women without PCOS. The women were treated at Huddinge University Hospital; antenatal care was given at associated outpatient units. MAIN OUTCOME MEASURES: Blood glucose and blood pressure during the different trimesters. Pregnancy outcome in terms of gestational length, birth weight, and need for neonatal intensive care. RESULTS: No significant differences were found in blood glucose levels between the groups. There were also no differences in blood pressure during the first and second trimester. However, during the third trimester and labor, the PCOS group had a significantly higher blood pressure than the control group. Apart from a tendency toward reduced growth of twins in PCOS mothers, the babies were healthy, overall, with few problems in the neonatal period. CONCLUSIONS: No major differences with regard to perinatal outcome in pregnant women with and without PCOS were found. An increased risk of hypertensive disorders in the third trimester and during labor was demonstrated in the PCOS group. This suggests that in the antenatal care of women with PCOS, attention should focus on blood pressure in order to reduce the risks of morbidity associated with hypertension.

Microalbuminuria, but not reduced eGFR, is associated with cardiovascular subclinical organ damage in type 2 diabetes.

AIM: This study explored the association between reduced estimated glomerular filtration rate (eGFR) and microalbuminuria vs. subclinical organ damage in patients with type 2 diabetes. METHODS: Data from middle-aged patients with type 2 diabetes (n=706) treated in primary care were analyzed for microalbuminura, defined as a urinary albumin/creatinine ratio (uACR)≥3.0mmol/mol, and reduced eGFR, defined as<60mL/min/1.73m(2), in relation to blood pressure, pulse wave velocity (PWV), left ventricular mass index (LVMI), and carotid intima-media thickness (IMT) and lumen diameter (LD). RESULTS: Patients with microalbuminuria had significantly higher 24-h ambulatory systolic blood pressure (ASBP) compared with subjects with uACR<3mg/mmol: 137 vs. 128mmHg (P<0.001). There were no differences in ASBP in patients with eGFR<60mL/min/1.73m(2). However, patients with vs. without microalbuminuria had increased PWV (11.4 vs. 10.1m/s; P<0.001), LVMI (134.4 vs. 118.6g/m(2); P<0.001), LD (7.01±0.93 vs. 6.46±0.74mm; P<0.001) and IMT (0.78 vs. 0.74mm; P=0.047), respectively. The associations between uACR vs. PWV and LVMI were more robust after adjusting for age, diabetes duration, ASBP, HbA1c, LDL-cholesterol, and antihypertensive and lipid-lowering therapy compared with uACR vs. IMT. There were no statistically significant differences in PWV, LVMI or IMT between patients with reduced (<60mL/min/1.73m(2)) vs. normal eGFR. CONCLUSION: Levels of urinary albumin excretion, but not reduced eGFR, were associated with increased arterial stiffness, left ventricular mass and atherosclerosis in patients with type 2 diabetes.

Power Doppler ultrasound assessment of follicular vascularity in the early follicular phase and its relationship with outcome of in vitro fertilization.

OBJECTIVE: To determine whether ovarian perifollicular blood flow (PFBF) in the early follicular phase (EFP) was associated with treatment outcome. DESIGN: Retrospective longitudinal cohort study. SETTING: Tertiary referral centre/university hospital. PATIENTS: Thirty-four women underwent 37 IVF cycles, which resulted in 35 embryo transfers. INTERVENTIONS: Serial transvaginal scans using power Doppler ultrasound during the follicular phase. Ovarian PFBF of follicles > or =5 mm was subjectively assessed using a modified grading system (grades 0-4). MAIN OUTCOME MEASURES: Ovarian PFBF and pregnancy. RESULTS: Treatment cycles were retrospectively divided into two groups: Group 1 (n=20) had cycles with at least one small (5-10 mm) or medium (11-14 mm) size follicle(s) of high grade (2-4) PFBF on cycle day 5 or 6 or 7; and Group 2 (n=17), had cycles that did not. Group 1 had a significantly higher proportion of high grade large follicles in the late follicular phase (35% vs. 21%) (OR 2.0; 95% CI 1.1-3.7) and higher clinical pregnancy rate (47% vs. 12%) (OR 6.3; CI 1.1-35.7) compared to Group 2. CONCLUSION: High grade ovarian PFBF in the EFP during IVF is associated with both high grade PFBF in the late follicular phase and a higher clinical pregnancy rate.

Stimulation of in vitro fertilization in mice with 17 beta-estradiol.

The effect of various concentrations of estradiol on in vitro fertilization frequency was studied. Fertilization was stimulated by 5 X 10(-9) M 17 beta-estradiol but not by 5 X 10(-9) M 17 alpha-estradiol. At 5 X 10(-6), 5 X 10(-7), 5 X 10(-8), and 5 X 10(-10) M 17 beta-estradiol there was no difference in the fertilization frequency between test and control samples. It is suggested that stimulation of the acrosome reaction is instrumental in increasing the fertilization rate.

A follow-up study of sperm preparation for IVF by swim-up in a solution of hyaluronate.

Spermatozoa prepared for in-vitro fertilization (IVF) by swim-up in a balanced salt solution containing hyaluronate gave rates of fertilization, cleavage and pregnancy which were not significantly different from those obtained with sperm prepared by swim-up in standard IVF medium followed by centrifugation. However, the content of prostaglandin F2alpha in the final sperm suspension was higher using hyaluronate but this seemed to be of no consequence for IVF. Thus, preparation of normal sperm samples for IVF may be simplified by performing swim-up in a balanced salt solution containing hyaluronate.

On the diagnostic value of the hypoosmotic sperm swelling test in an in vitro fertilization (IVF) program.

The ability of the hypoosmotic sperm swelling (HOS) test to identify nonfertilizing sperm samples in a group of 50 couples undergoing in vitro fertilization (IVF) was investigated. The findings indicate that the HOS test is not significantly more useful than any of the standard semen variables for this purpose.

A possible mechanism of action of 17 beta-estradiol in stimulation of fertilization in vitro.

The effects of 17 beta-estradiol (E2) on sperm-egg interactions in the mouse were investigated. It was shown that E2 induces adhesiveness of the sperm head, expressed as sperm-sperm and sperm-egg binding. Since the concentration dependence of this process was similar to that observed for stimulation of in vitro fertilization by E2, it is suggested that induction of adhesiveness or initiation of processes that cause adhesiveness of the sperm head are of biological significance as preparatory steps for fertilization. Finally, the content of E2 in mouse eggs was determined and found to be 0.2 pg/egg, equally distributed between the oocyte together with the zona pellucida and the follicular cells with their associated intercellular matrix. The intra-ovum concentration is estimated as 10(-6) M.

Effects of lead on the male mouse as investigated by in vitro fertilization and blastocyst culture.

Long-term exposure of male mice to inorganic lead (lead chloride, 1 g/liter) in the drinking water reduces their fertility. The cause of this reduction, expressed as a decrease in the number of mated females showing implantations, was investigated, using an in vitro fertilization method. It was found that spermatozoa from lead-exposed males had a significantly lower ability to fertilize mouse eggs than those from unexposed males. Preimplantation embryos, isolated from uterine horns of mice mated with lead-exposed males, were examined. No morphologically abnormal embryos were found. However, when cultured in vitro over the implantation period, blastocysts of the group mated with lead-exposed males showed an increased frequency of delayed hatching from the zona pellucida or an inability to hatch. Among blastocysts from this group a decreased frequency of inner cell mass development was also found.

Serial human chorionic gonadotropin determinations by fluoroimmunoassay for differentiation between intrauterine and ectopic gestation.

A new means for differentiation between ectopic and early intrauterine pregnancy--the human chorionic gonadotropin score--is described. The score relates the rate of serum hCG rise per day to the initial human chorionic gonadotropin level. The positive predictive value for ectopic pregnancy was 94.7%, based on human chorionic gonadotropin scores from 41 women with increasing human chorionic gonadotropin levels in the range of 10 to 4000 IU/L. The method may be useful for identification of ectopic pregnancy in a category of women in whom ultrasonography is of limited diagnostic value.