A novel machine-learning framework based on early embryo morphokinetics identifies a feature signature associated with blastocyst development.

BACKGROUND: Artificial Intelligence entails the application of computer algorithms to the huge and heterogeneous amount of morphodynamic data produced by Time-Lapse Technology. In this context, Machine Learning (ML) methods were developed in order to assist embryologists with automatized and objective predictive models able to standardize human embryo assessment. In this study, we aimed at developing a novel ML-based strategy to identify relevant patterns associated with the prediction of blastocyst development stage on day 5. METHODS: We retrospectively analysed the morphokinetics of 575 embryos obtained from 80 women who underwent IVF at our Unit. Embryo morphokinetics was registered using the Geri plus® time-lapse system. Overall, 30 clinical, morphological and morphokinetic variables related to women and embryos were recorded and combined. Some embryos reached the expanded blastocyst stage on day 5 (BL Group, n = 210), some others did not (nBL Group, n = 365). RESULTS: The novel EmbryoMLSelection framework was developed following four-steps: Feature Selection, Rules Extraction, Rules Selection and Rules Evaluation. Six rules composed by a combination of 8 variables were finally selected, and provided a predictive power described by an AUC of 0.84 and an accuracy of 81%. CONCLUSIONS: We provided herein a new feature-signature able to identify with an high performance embryos with the best developmental competence to reach the expanded blastocyst stage on day 5. Clear and clinically relevant cut-offs were identified for each considered variable, providing an objective tool for early embryo developmental assessment.

The effect of extended cryo-storage following vitrification on embryo competence: a systematic review and meta-analysis.

PURPOSE: Few studies explored whether prolonged cryo-storage after vitrification affects embryo competence and perinatal outcomes. This systematic review and meta-analysis aims at highlighting any putative impact of cryo-storage duration on cryo-survival, miscarriage, live birth and major malformations. METHODS: A systematic review was performed using MEDLINE (PubMed), ISI Web of Knowledge, Scopus and Embase databases up to June 2021. Data were combined to obtain a pooled OR, and meta-analysis was conducted using a random effects model. Out of 1,389 screened abstracts, 22 papers were assessed for eligibility, and 5 studies were included (N = 18,047 embryos). Prolonged cryo-storage was defined as > 12 months (N = 3389 embryos). Subgroup analysis was performed for untested vitrified cleavage stage embryos (N = 1739 embryos) and for untested and euploid vitrified blastocysts (N = 13,596 and 2712 embryos, respectively). RESULTS: Survival rate, miscarriage, live birth and major malformation rates were all similar in the two groups. CONCLUSION: These data further support the safety of long-term cryo-storage of human embryos beyond 12 months. This is reassuring for good prognosis patients with surplus embryos, couples seeking a second child from supernumerary embryos and women postponing the transfer for clinical or personal reasons.

Human recombinant FSH induces chemoresistance in human breast cancer cells via HIF-1α activation†.

Breast cancer patients under 40 years of age who are candidate to chemotherapy with alkylating drugs may undergo controlled ovarian stimulation (COS) with recombinant human follicle-stimulating hormone (rhFSH) in order to get fertility preservation by mature oocyte cryostorage. The direct effect(s) of exogenous rhFSH on the chemosensitivity of breast cancer is currently unknown. To clarify this issue, we incubated four different breast cancer cell lines with rhFSH (10 IU/L, 24 h) and then we exposed them to doxorubicin (DOX) or cyclophosphamide (CPA). The effect(s) of rhFSH on human breast cancer cells treated with DOX or CPA was measured in terms of (1) cell viability, (2) cytotoxicity, (3) multidrug resistance (MDR) genes and proteins expression and activities, and (4) hypoxia-inducible factor 1-alpha (HIF-1α) activation. Pretreatment with rhFSH significantly increased the viability of breast cancer cells after treatment with DOX or CPA, and reduced the lactate dehydrogenase leakage and reactive oxygen species production. Moreover, after preincubation with rhFSH, the MDR proteins (Pgp, MPR1, and BCRP) expression and activity resulted upregulated and the HIF-1α pathway activated. In addition, the use of a widely used HIF-1α inhibitor, the 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), prevented the rhFSH effect on the onset of MDR. Taken together, these observations suggest that a short exposure to rhFSH induces chemoresistance to DOX and CPA in human breast cancer cells via HIF-1α activation.

Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer.

OBJECTIVE: To compare in a randomized, non-inferiority trial the embryo transfer (ET) technique based on uterine length measurement before transfer (ULMbET) with transabdominal ultrasound-guided embryo transfer (TA-UGET) in a large population of patients undergoing in-vitro fertilization (IVF). METHODS: Patients undergoing IVF with ET with cleaving fresh embryos were randomized to receive ULMbET or TA-UGET. The transfer of one to three embryos on day 2-3 of culture was performed using a soft catheter either under transabdominal ultrasound guidance (TA-UGET group) or after measurement of the uterine cavity by transvaginal ultrasound and calculation of the discharge site (ULMbET group). The primary outcome measures were clinical pregnancy rate, ongoing pregnancy rate and implantation rate, and secondary outcomes included patient discomfort during ET. RESULTS: A total of 1648 patients undergoing IVF were randomized to receive ULMbET (n = 828) or TA-UGET (n = 820) and were included in the analysis. Comparable clinical pregnancy rate (38.2% vs 38.9%), implantation rate (24.8% vs 25.2%) and ongoing pregnancy rate (33.1% vs 34.8%) were observed in ULMbET and TA-UGET groups. The discomfort intensity score and the proportion of patients with moderate-to-severe discomfort during ET were significantly higher in the TA-UGET group (2.6 vs 1.5 visual analog scale points and 19.8% vs 1.2%; P = 0.045 and P = 0.003, respectively). CONCLUSION: The ULMbET technique leads to IVF results comparable to those obtained with UGET, but is better tolerated than is TA-UGET and is technically easier to perform for a single operator. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

TD-UAPO diffracted field evaluation for penetrable wedges with acute apex angle.

This study deals with the time domain (TD) diffraction phenomenon related to a penetrable acute-angled dielectric wedge. The transient diffracted field originated by an arbitrary function plane wave is evaluated via a convolution integral involving the TD diffraction coefficients, which are determined here in closed form, starting from the knowledge of the frequency domain counterparts. In particular, the inverse Laplace transform is applied to the uniform Asymptotic physical optics diffraction coefficients valid for the internal region of the wedge and the surrounding space. Diffraction by penetrable wedges in the TD framework is a challenging problem from the analytical point of view, and no other expressions are available in closed form for the diffraction coefficients associated with the considered problem.

Diffraction by 90° penetrable wedges with finite conductivity.

This study concerns the diffraction problem relevant to a plane wave normally incident with respect to a 90° wedge. A penetrable material with finite conductivity forms the structure. A high-frequency solution is here obtained by adopting a physical optics approximation for the equivalent electric and magnetic surface currents involved in the radiation integrals used to represent the fields scattered in the inner region of the wedge and the surrounding space. Uniform asymptotic evaluations of such integrals lead to closed form expressions for the diffraction coefficient in terms of the transition function of the uniform theory of diffraction and the Fresnel coefficients for the reflection and transmission mechanisms. No limitation exists on the loss tangent of the medium. Comparisons with numerical tools assess the effectiveness of the proposed solutions for the field diffracted in the inner and outer regions.

Plane-wave diffraction by an obtuse-angled dielectric wedge.

Uniform high-frequency solutions in closed form are derived for the diffraction of a plane wave normally impacting on a penetrable wedge having an obtuse apex angle and arbitrary dielectric permittivity. The approach used here takes advantage of a physical optics approximation for the electric and magnetic equivalent surface currents in the scattering integrals related to the inner region of the wedge and the surrounding space. Numerical tests and comparisons with finite-difference time-domain results demonstrate the accuracy and effectiveness of the proposed solutions.

Construction of an evidence-based integrated morphology cleavage embryo score for implantation potential of embryos scored and transferred on day 2 after oocyte retrieval.

BACKGROUND: Evidence-based morphological embryo scoring models for ranking of implantation potential are still scarce, and the need for a precise model increases when aiming for singleton pregnancies. METHODS: Prospectively, 2266 IVF/ICSI double-embryo, day 2 transfers were studied. The five variables scored in 3- to 5-step scales for the embryos transferred are blastomere number (BL), fragmentation, blastomere size variation ('equality', EQ), symmetry of the cleavage and mononuclearity in the blastomeres (NU). The scoring results of embryos with an individual traceability from scoring to implantation, i.e. treatments resulting in either no implantation (n=1385) or twin implantation (n=228), were studied for prognostic potential. RESULTS: Although all five variables correlated highly with implantation potential, only BL, NU and EQ remained independently significant after regression analysis. The equation thus derived formed the basis for a 10-point integrated morphology cleavage (IMC) embryo score. A table with the scoring point for each possible combination of the embryo variables is presented. The scoring model was statistically validated on the singleton pregnancy group (n=653). CONCLUSIONS: We suggest that this IMC embryo scoring, incorporating cleavage stage and information on the variation in blastomere size and the number of mononucleated blastomeres, may optimize embryo ranking and selection for day 2 transfers.

[Leptin as a possible marker of augmented metabolic risk during pregnancy]. / La leptina come possibile marker di aumentato rischio metabolico in gravidanza.

AIM: Leptin is a proteic hormone, isolated in 1994, mainly synthetized in the white adipose tissue. Aim of this study was to compare leptin concentrations in normal pregnancies with those measured in pregnancies complicated by gestational diabetes or gestational hypertension or pre-eclampsia. METHODS: We enrolled 48 pregnant women: 18 with uncomplicated pregnancy, 11 with gestational diabetes, 19 with gestational hypertension or pre-eclampsia. Leptin concentrations were measured in maternal serum at enrollment, together with insulin and cortisol, at delivery and in the immediate postpartum. At delivery serum leptin was calculated in the cord blood too. RESULTS: Fasting plasma leptin and insulin were higher in the group of patients with gestational hypertension, than in the other groups. Third-trimester maternal leptin concentrations correlated significantly with insulin levels in the group of women with gestational diabetes and in the group with gestational hypertension or pre-eclampsia, but not in the women with an uncomplicated pregnancy. CONCLUSIONS: Leptin concentrations in pregnancies complicated by hypertensive disorders are significantly higher than in normal pregnancies. The increased leptin concentrations are independent of associated proteinuria, as women with simple gestational hypertension and preeclampsia showed comparable third-trimester leptin concentrations. In both women with gestational diabetes and women with hypertensive disorders, serum leptin correlated closely with serum insulin, suggesting that the association between leptin and insulin resistance is preserved in pregnancy. Whatever the reasons for an increased maternal leptin production in pregnancies complicated by hypertension, maternal leptin homeostasis does not seem to influence foetal serum leptin concentrations, which seems to be mainly related to birth weight.

Preserved insulin sensitivity and {beta}-cell activity, but decreased glucose effectiveness in normal-weight women with the polycystic ovary syndrome.

Insulin resistance and hyperinsulinemia are often considered intrinsic features of the polycystic ovary syndrome (PCOS). Nevertheless, conflicting results of insulin sensitivity and secretion have been obtained in the subgroup of normal-weight women with PCOS. Differences in body composition, ethnicity, and diet composition and a family history of metabolic diseases may act as confounding variables in women with PCOS. In the present study, insulin sensitivity and secretion were estimated by an iv glucose tolerance test (IVGTT), analyzed by minimal models, in 20 normal-weight healthy women with PCOS and no family history of type 2 diabetes mellitus and in 20 normally ovulating women, matched for age and body mass index. Insulin sensitivity [mean (95% confidence intervals); PCOS 4.0 (2.8-5.1) vs. controls 4.5 (3.5-5.4) 10(-4) min(-1)/microU.ml], and insulin secretion, expressed as the acute insulin response to glucose [PCOS 3.7 (3.3-4.2) vs. controls 3.7 (3.4-4.0) microU/ml] were similar in the two groups. The women with PCOS showed an increased proportion of total body fat (PCOS 29% vs. controls 27.2%; P < 0.01). They also showed decreased glucose effectiveness, i.e. the proportion of glucose uptake independent from insulin activity [PCOS 2.6 (2.1-3.0) vs. controls 3.8 (3.0-4.6) mg x 100 min(-1); P = 0.01]. The levels of insulin sensitivity and of glucose effectiveness did not correlate in either group. Whether the isolated finding of decreased glucose effectiveness could reflect an early stage in the development of the metabolic aberrations often associated with the syndrome remains to be clarified.

Salpingoscopic and laparoscopic investigations in relation to fertility outcome.

STUDY OBJECTIVE: To evaluate the correlation between salpingoscopic and laparoscopic findings and their relation to reproductive outcomes. DESIGN: Prospective study (Canadian Task Force classification II-2). SETTING: University-affiliated hospital. PATIENTS: Ninety-one infertile women. INTERVENTION: Salpingoscopy and laparoscopy. MEASUREMENTS AND MAIN RESULTS: Salpingoscopic findings were expressed according to a widely used classification. Tubal morphology at laparoscopy was defined as regular (normal morphology), convoluted (any kind of distortion or adhesion), or hydrosalpinx. Laparoscopic and salpingoscopic findings did not correlate. Seventeen pregnancies occurred within 1 year from the procedures. According to life table analysis, the cumulative pregnancy rate was significantly higher in women with endotubal morphology showing minimal or no tubal damage, than in women with higher grades of endotubal damage. Conversely, tubal morphology at laparoscopy was not able to predict pregnancy outcome. CONCLUSION: Laparoscopy alone might not be sufficient to predict tubal integrity. Performing salpingoscopy with laparoscopy could significantly increase accuracy in predicting short-term fertility outcome. Given its low complication rate and brief duration, salpingoscopy should have a primary role in management of infertility.

Prediction models for insulin resistance in the polycystic ovary syndrome.

Women with the polycystic ovary syndrome (PCOS) have a high prevalence of insulin resistance, with consequent increased risk of metabolic diseases later in life. An early metabolic screening would therefore be of clinical relevance. By using stepwise regression analysis on several variables obtained in 72 women with PCOS, we constructed simple and reliable mathematical models predicting insulin sensitivity, as measured by the euglycaemic hyperinsulinaemic clamp. The normal ranges of insulin sensitivity were calculated from 81 non-hirsute, normally menstruating women with normal ovaries, and similar body mass index (BMI) and age as the women with PCOS. Measured variables included BMI, waist and hip circumferences, truncal-abdominal skin folds, circulating concentrations of gonadotrophins, androgens, sex hormone-binding globulin (SHBG), triglycerides, total cholesterol and cholesterol subfractions, fasting insulin, C-peptide and free fatty acids. The three best prediction models included waist circumference, together with insulin (model I: R(2) = 0.77), serum triglycerides (model II: R(2) = 0.65), and the subscapularis skin fold (model III: R(2) = 0. 64). Using reference limits for insulin sensitivity obtained in the 81 normal pre-menopausal women, the models identify insulin resistant women with PCOS. These simple and inexpensive models are potentially useful in clinical practice as an early screening in women with PCOS.

Response of the pituitary-adrenal axis to hypoglycemic stress in women with the polycystic ovary syndrome.

The role of the adrenals in the polycystic ovary syndrome (PCOS) is debated. Both single steroid-converting enzyme abnormalities and increased adrenal activity have received support. The conventional Synacthen test using pharmacological doses of ACTH results in unphysiological levels of ACTH. Therefore, we used insulin-induced hypoglycemia (0.15 IU/kg BW) to asses the responses of ACTH, cortisol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, and androstenedione in 18 women with PCOS and in 17 normal women of similar age and body mass index. The blood glucose concentration at 30 min was 2 mmol/L or less in all women, i.e. well below the threshold of the hormonal counterregulatory response. The women with PCOS showed a lower ACTH response, expressed as the maximum increment above basal [mean (95% confidence interval): PCOS, 11.1 (6.9-15.3); controls, 19.9 (13.8-26) pmol/L; P < 0.05], but a quantitatively comparable [PCOS, 207.2 (148.5-266.5); controls, 167.1 (100.6-233.2) nmol/L; P = NS] and more prompt cortisol response than the controls (by chi2 test, P < 0.05), resulting in a higher molar ratio between the maximum increments of cortisol and ACTH [PCOS, 13.9 (8.7-19); controls, 8.8 (5.7-12); P < 0.05]. The women with PCOS did, however, show a more rapid decline in cortisol levels than the controls (P < 0.05 at 120 and 180 min). The responses of the androgens and intermediate adrenal steroids were similar in women with PCOS and controls. The findings suggest an adaptation to increased adrenal reactivity to endogenous ACTH in women with PCOS. Exposure to hypoglycemia as a model of stress was not followed by hypersecretion of adrenal androgens and revealed no signs of steroid enzyme disturbances in women with PCOS.

Is there a role for leptin in the endocrine and metabolic aberrations of polycystic ovary syndrome?

Immunoreactive serum leptin was analysed in 49 women with polycystic ovary syndrome (PCOS) distributed on a wide range of body mass index (BMI; kg/m2) and in 32 normally menstruating women with comparable age, BMI, physical activity and dietary habits. All women with PCOS had increased androgen concentrations and obese women with PCOS (BMI > or = 25, n=24) also showed decreased insulin sensitivity and a preferential accumulation of truncal-abdominal body fat. Anthropometric and hormonal variables, insulin sensitivity, and pancreatic beta-cell activity were investigated in all women. Percentage body fat was calculated using gender-specific regression equations based on skinfold measurements. Serum leptin concentrations were higher in obese than in non-obese women (P < 0.001), but did not differ between the women with PCOS and controls, nor did they differ between glucose intolerant and glucose tolerant, or hirsute and non-hirsute women with PCOS. Both groups showed strong correlations between serum leptin concentrations and percentage body fat, BMI, body fat distribution, fasting plasma insulin and C-peptide, early insulin secretion, the free androgen index (FAI), and the degree of insulin resistance. After correcting for percentage body fat, only the FAI in the women with PCOS remained significant (P < 0.05). However, in a multiple regression analysis with both percentage body fat and the FAI as independent variables, the FAI increased only minimally (2%) the explained variation in leptin concentrations. Thus, serum leptin concentrations are almost exclusively determined by the total amount of body fat, independent of its location, and do not confirm the hypothesis that leptin is involved in the development of the hormonal and metabolic abnormalities in the PCOS.

High prevalence of polycystic ovaries and associated clinical, endocrine, and metabolic features in women with previous gestational diabetes mellitus.

The prevalence of polycystic ovaries, according to ultrasonography, and associated clinical, endocrine, and metabolic features were investigated in women with previous gestational diabetes mellitus (GDM). Thirty-four women with GDM 3-5 yr before the investigation and 36 controls with uncomplicated pregnancies, selected for similar age, parity, and date of delivery, were investigated. The women with previous GDM showed a higher prevalence of polycystic ovaries [14 of 34 (41%) vs. 1 of 36 (3%); P < 0.0001], hirsutism (P < 0.01), irregular menstrual cycles (P < 0.01), and a higher body mass index (BMI; P < 0.001) than the controls. Five women (15%) with previous GDM had developed manifest diabetes (excluded in comparisons of metabolic variables). After dividing the women with previous GDM into subgroups according to ovarian appearance, the 2 subgroups showed similar glucose tolerance and prevalence of diabetes, whereas the women with polycystic ovaries were younger (mean +/- SD, 33.3 +/- 1.4 vs. 38.2 +/- 1.1; P < 0.01), had higher truncal-abdominal/femoral fat ratio according to skin folds (P < 0.05), had higher concentrations of androstenedione (P < 0.01) and testosterone (P < 0.01), and had a higher LH/FSH ratio (P < 0.01), lower levels of GH (P < 0.01), higher levels of triglycerides (P < 0.05) and cholesterol (P < 0.05) in very low density lipoprotein, all independent of age and BMI, and had a higher prevalence of pregnancy-induced hypertension (50% vs. 15%; P < 0.05) during the index pregnancy compared with the women with normal ovaries. The group of women with GDM showed a lower early insulin release after glucose (i.v. glucose tolerance test) for their degree of insulin resistance (euglycemic hyperinsulinemic clamp) compared with controls (P < 0.05). In the two subgroups, insulin sensitivity was lower in the polycystic ovaries group, independent of BMI (P < 0.05), than in the group with normal ovaries. In conclusion, ultrasonographic, clinical and endocrine signs of polycystic ovary syndrome were much increased in women with a history of GDM. Compared with the women with normal ovaries and previous GDM, those with polycystic ovaries formed a distinct subgroup that may be more prone to develop various features of the insulin resistance syndrome. Both groups showed a similarly disturbed balance between beta-cell activity and insulin sensitivity, but in women with polycystic ovaries, insulin resistance may be the dominant component.

The counterregulatory response to hypoglycaemia in women with the polycystic ovary syndrome.

OBJECTIVE: The pathogenetic mechanisms behind insulin resistance in polycystic ovary syndrome (PCOS) are far from fully elucidated. Aberrant counterregulatory responses to hypoglycaemia have been reported in patients with insulin resistance, and recent reports suggest that plasma glucose may be regulated at lower levels in women with PCOS. In this study we investigated the complete hormonal counterregulatory response to hypoglycaemia in women with PCOS. DESIGN: Prospective cross-sectional study. PATIENTS: Eight obese (BMI > or = 25) and 10 non-obese (BMI < 25) women with PCOS, diagnosed by means of ultrasonography and clinical signs of chronic anovulation. Eight obese and 9 non-obese controls. MEASUREMENTS: Hypoglycaemia was induced by an intravenous bolus of soluble insulin (0.15 IU/kg body weight). The counterregulatory responses of cortisol, GH, catecholamines, glucagon, chromogranin A (CGA), and neuropeptide Y (NPY) were studied together with symptoms of hypoglycaemia. RESULTS: The obese women with PCOS had a more pronounced truncal-abdominal body fat distribution (waist hip ratio, WHR) and were hyperinsulinaemic, compared with the obese controls. All the women exhibited blood glucose levels (< 2 mmol/l) well below the threshold for the hormonal counterregulatory response and for the appearance of clinical symptoms. The non-obese women with PCOS showed a greater increase in serum concentrations of GH than the lean controls. The obese women with PCOS exhibited blunted responses of noradrenaline and NPY, but similar increases of adrenaline and CGA, compared with the obese controls. They also showed a lower symptom score during hypoglycaemia. The response of noradrenaline to hypoglycaemia correlated inversely with fasting insulin levels in the women with PCOS. Among all the obese women (PCOS and controls pooled) basal levels of noradrenaline correlated inversely with the WHR. CONCLUSIONS: All the women with PCOS, independent of BMI, body fat distribution and insulin levels, showed preserved counterregulatory responses to hypoglycaemia. The reduced plasma levels of noradrenaline and the lower perception of hypoglycaemic symptoms in the obese women with PCOS could both reflect a lower activation of the sympathetic nervous system. This aberration seems related to truncal-abdominal obesity and hyperinsulinaemia. The finding of an increased response of GH in the lean women with PCOS could support previous suggestions of an altered activity of the GH/IGF-I system in these women.

Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state?

The aim of this study was to evaluate office and 24 h blood pressures in women with polycystic ovary syndrome (PCOS) and normal controls in relation to insulin sensitivity. Office blood pressure, insulin sensitivity (euglycaemic hyperinsulinaemic clamp) and body fat distribution (skin-folds, waits:hip ratio) were investigated in 36 women with PCOS and 55 controls [body mass index (BMI) for PCOS patients, mean (confidence interval) 26.3 (24.6-28.2); controls, 25.1 (24.0-26.9)], and ambulatory 24 h blood pressure was recorded in representative subgroups of 17 and 16 women respectively. Compared with the controls, the women with PCOS had higher day-time systolic (mean +/- SD, 126 +/- 11 versus 119 +/- 12 mm Hg, P < 0.05) and mean arterial blood pressures (92 +/- 7 versus 86 +/- 7 mm Hg, P < 0.05) in ambulatory recordings, and greater increases in pulse rate (70%; P < 0.05) from night to day-time recordings, whereas the groups did not differ significantly in day-time diastolic blood pressure (74 +/- 6 versus 70 +/- 6 mm Hg, P = 0.05) or in night-time recordings. The women with PCOS had a more pronounced truncal-abdominal fat distribution (P < 0.05) and a lower insulin-mediated glucose disposal (P < 0.01) during the clamp. The increased day-time blood pressures in women with PCOS persisted after adjusting for BMI, body fat distribution and insulin resistance. It is concluded that women with PCOS have an increased prevalence of labile blood pressure, which may indicate a pre-hypertensive state, adding a further risk factor for cardiovascular disease in these women.

Climacteric symptoms and control of the cycle in women aged 35 years or older taking an oral contraceptive with 0.150 mg desogestrel and 0.020 mg ethinylestradiol.

In a multicenter prospective trial, 58 healthy women aged between 35 and 49 years were studied for one year (639 cycles) while taking an oral contraceptive (OC) containing desogestrel 0.150 mg and ethinylestradiol (EE) 0.020 mg. Efficacy, control of the cycle, side effects, complaints, and climacteric symptoms were monitored after 3, 6, 9 and 12 cycles. No pregnancies occurred during the study period. Spotting gradually decreased from 29.3% in cycle 1 to 4.2% in cycle 12, while breakthrough bleeding (BTB) disappeared after cycle 7. One case of superficial thrombophlebitis and 3 cases of minor side effects were registered. With regard to the complaints, breast tenderness, headache, and depression gradually decreased during the study (basal vs. 12-month data: 50.9% vs. 31.2%, 48.3% vs. 18.7%, 39.6% vs. 20.8%, respectively), while nausea disappeared after three months. A significant treatment-dependent reduction of climacteric symptoms was obtained after cycle 3 and this tendency was maintained up to cycle 12. No changes were registered in body mass index (BMI) or blood pressure.

The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women.

OBJECTIVE: To investigate the basal levels of gonadotrophins and sex steroids, with special reference to the effects of obesity and body fat distribution, in premenopausal women, both those with polycystic ovary syndrome (PCOS) and those with normal ovaries and regular menstrual cycles. DESIGN: Cross-sectional study. The separate effects of obesity (and body fat distribution and fasting insulin levels) and PCOS on endocrine variables were evaluated by means of analysis of covariance. PATIENTS: Sixty-seven women with anovulatory menstrual cycles and polycystic ovaries according to ultrasonography and 59 women with normal ovaries and regular cycles, both groups covering a wide range of body mass index (BMI, PCOS, 17.6-37.4, mean 25.7 kg/m2; controls, 18.8-40.9, mean 25.1 kg/m2). MEASUREMENTS: Serum levels of gonadotrophins, sex steroid hormones, prolactin and GH obtained in the early follicular phase in the controls, fasting insulin levels, anthropometric measures (BMI, skinfolds, waist hip ratio). RESULTS: Mean serum concentrations of LH, androstenedione, testosterone, the free androgen index (FAI; all P < 0.0001) and DHEAS (P < 0.01) were higher, and serum FSH (P < 0.01) and serum SHBG levels lower (P < 0.0001), in the PCOS group than in the controls. Women with PCOS had a more pronounced upper body fat distribution and higher fasting insulin levels than the controls. Independent of PCOS, BMI was positively associated with serum levels of FSH (P < 0.001) and negatively with levels of LH (P < 0.05), LH/FSH ratio (P < 0.0001), SHBG (P < 0.0001) and androstenedione (P < 0.01), whereas for levels of testosterone, FAI and DHEAS the impact of obesity differed significantly between the groups. Thus, in the PCOS group, testosterone levels (P < 0.05) and the FAI (P < 0.001) were positively associated with BMI, whereas they were constant throughout the entire range of BMI in the controls. DHEAS levels were positively associated with BMI in the PCOS group (P < 0.05) and negatively in the controls (P < 0.01). Measures of upper body fat were related to testosterone and FAI levels, independent of BMI. CONCLUSIONS: Lower FSH levels were found in women with PCOS than during the early follicular phase of normally ovulating women, suggesting a role in anovulation in PCOS. Obesity itself exerted effects on endocrine variables, with the net result of a reduced LH/FSH ratio and lower serum levels of androstenedione and SHBG in both groups; obesity was associated with increased levels of DHEAS, testosterone and FAI exclusively in the women with PCOS. The results underline the endocrine impact of obesity and body fat distribution and the necessity of applying reference values of BMI matched subjects when establishing the endocrine profile of women with PCOS.

An open prospective study on the effects on carbohydrate metabolism of an oral monophasic contraceptive containing gestodene (WL-70).

The effects of a monophasic oral contraceptive (gestodene 75mcg + ethinylestradiol 30 mcg) on plasma glucose (PG) and insulin (IRI) responses to an oral glucose load (OGTT) and on glycosylated haemoglobin Alc (HbAlc), fructosamine (Fr), total cortisol (FT) and transcortin (CBG) were studied in 30 healthy women. Blood samples were taken before treatment and after 6 and 12 cycles. After 6 and 12 months, OGTT-PG and IRI levels showed substantially unchanged values; for HbAlc and Fr the same behaviour was seen with the exception of the latter between 6 and 12 months; FT and CBG showed significant rises. All recorded values were in the normal range. The basal and dynamic PG and IRI behaviour failed to show any significant variations between pre-treatment values and those after 6 and 12 months of OC administration. Other data showed a substantial neutrality for this oral contraceptive containing gestodene.