Estradiol stimulates cell growth and secretion of procathepsin D and a 120-kilodalton protein in the human ovarian cancer cell line BG-1.

Ovarian cancers are highly invasive. In a first attempt to define the hormones and factors involved in the control of tumor invasion and metastasis, we have used the human ovarian cancer cell line BG-1 which contains both estrogen and progesterone receptors. Protein synthesis and secretion was assayed by [35S]methionine incorporation and polyacrylamide gel electrophoresis followed by fluorography. Three responses to estradiol were found: 1) procathepsin D secretion was increased, whereas the corresponding intracellular proteins were not significantly affected; 2) an abundant but nonidentified 120-kilodalton (kDa) estrogen-induced secreted glycoprotein, different from CA125, was detected for the first time; and 3) the number of cells as determined by DNA assay was markedly stimulated, reaching a higher level of confluency. The antiestrogen OH-tamoxifen was weakly agonist at low concentrations to stimulate cell growth but was a pure antagonist on the 120-kDa protein. The steroid specificity of these responses strongly suggests that they are mediated by the estrogen receptor. We conclude that cathepsin D secretion is specifically stimulated by estrogen in this ovarian cancer cell line as it is in estrogen receptor-positive breast cancer cells. Both cathepsin D and a newly described 120-kDa secreted glycoprotein are potential markers of hormone responsiveness and/or aggressiveness which deserve to be further studied in clinical ovarian cancers.

Obesity and pregnancy: complications and cost.

The prevalence of obesity is currently rising in developed countries, making pregravid overweight one of the most common high-risk obstetric situations. Although the designs and populations of published studies vary widely, most authors agree that pregravid overweight increases maternal and fetal morbidity. Even moderate overweight is a risk factor for gestational diabetes and hypertensive disorders of pregnancy, and the risk is higher in subjects with overt obesity. Compared with normal weight, maternal overweight is related to a higher risk of cesarean deliveries and a higher incidence of anesthetic and postoperative complications in these deliveries. Low Apgar scores, macrosomia, and neural tube defects are more frequent in infants of obese mothers than in infants of normal-weight mothers. The regional distribution of fat modulates the effects of weight on carbohydrate tolerance, hemodynamic adaptation, and fetal size. Maternal obesity increases perinatal mortality. Long-term complications include worsening of maternal obesity and development of obesity in the infant. The average cost of hospital prenatal and postnatal care is higher for overweight mothers than for normal-weight mothers, and infants of overweight mothers require admission to neonatal intensive care units more often than do infants of normal-weight mothers. Preconception counseling, careful prenatal management, tight monitoring of weight gain, and long-term follow-up could minimize the social and economic consequences of pregnancies in overweight women.

Hemostasis parameters during ovarian stimulation for in vitro fertilization: results of a prospective study.

OBJECTIVE: To evaluate the effect of IVF-ET on the hemostatic system. DESIGN: Prospective clinical study. SETTING: Apparently healthy age-matched women of the hospital staff at various stage of the menstrual cycle. PATIENT(S): Twenty-five women involved in a IVF-ET program at the Department of Obstetrics and Gynecology, Montpellier University Hospital. INTERVENTION(S): Twenty-six hemostasis parameters evaluated repeatedly in patients undergoing IVF-ET. MAIN OUTCOME MEASURE(S): Blood cell-dependent hemostasis parameters and plasmatic coagulation factors, determined at pituitary desensitization, maximal E2 level, and P plateau. RESULT(S): Activation of the hemostatic system is evidenced at the P plateau, when D-dimers and fragments 1 + 2 of the prothrombin levels rose dramatically. At E2 peak, no significant modification of hemostasis markers was noted. CONCLUSION(S): The present results indicate that ovarian hyperstimulation may induce hemostasis activation at the P plateau. The role of supraphysiologic sex hormone levels on the hemostatic system requires further investigation.

[Obesity and pregnancy]. / Obésité et grossesse.

As the prevalence of obesity is currently increasing in Western countries, maternal obesity is one of the most frequently encountered high-risk obstetrical situations. Pregnancies in obese women are characterized by a high incidence of maternal (gestational diabetes, hypertensive disorders) and fetal (macrosomia, neural tube defects, late fetal deaths) complications. Because of those complications, cesarean sections rate is higher in obese women than in lean women. The occurrence of materno-fetal complications parallels the level of obesity, but even moderate overweight amplifies the risk. Long-term complications include worsening of maternal obesity, type 2 diabetes in the mother, and development of childhood obesity. Prenatal care should include a tight monitoring of weight gain and screening for gestational diabetes. Long term follow-up is necessary.

[Obstetrical complications of maternal overweight]. / Complications obstétricales du surpoids maternel.

Overweight is associated with a higher risk of cardiovascular and metabolic disease. Pregnancy in obese women frequently results in an increased incidence of maternal complications (gestational diabetes, hypertension, toxemia) and adverse perinatal outcome (macrosomia, perinatal mortality). Cesarean deliveries are also more frequent in obese women, mainly because of cephalopelvic dysproportion due to macrosomia. Optimal treatment for gestational diabetes is difficult to achieve, although hyperglycemia further impairs maternofoetal prognosis. The incidence of intrauterine growth retardation is not increased in obese pregnancy. A successful obstetrical outcome may be achievable through multidisciplinary antenatal management.

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.

Obesity and breast cancer risk.

Being overweight appears to be associated with a higher risk of post-menopausal breast cancer in most studies. Although the relative risk of breast cancer related to Quetelet's index is generally weak (range 1.1-1.9 in the major cohort studies), some studies have found that timing of weight gain and body fat distribution could be more significant factors of an increased risk. Conversely, obesity appears to be slightly correlated with a decreased risk of breast cancer in pre-menopausal women. These contrasting effects of excess weight on breast cancer incidence according to menopausal status, and the lack of a strong association between obesity and breast cancer in some studies, could be due to a number of confounding factors. Among these factors, age, country of origin, family history, alcohol consumption, nutrition, and hormonal treatment could account for the differences observed, and are reviewed in the present study. Obesity and central fat distribution are believed to act through endocrine intermediates such as hyperinsulinaemia and steroid hormones. Since obesity is one of the few breast cancer risk factors that can be modified, the influence of weight loss, particularly in women at high risk, deserves to be further investigated.

[Prognostic value of high FSH concentrations]. / Valeur pronostique des FSH élevées.

Ovarian age is a major determinant of success in assisted reproductive technologies. The number and quality of oocytes retrieved directly depend upon the ovarian reserve. The evaluation of FSH concentration during the first days of the menstrual cycle provides a simple and accurate means of assessing ovarian reserve. Plasma FSH value is correlated with cancellation rate, peak estradiol, number of oocytes retrieved and of the resulting embryos, pregnancy rate, outcome of cryopreservation. However, a poor response to the stimulation treatment is unpredictable in a subgroup of women whose FSH concentration remain within the normal range. Ovarian aging begins several years before any clinical or endocrinological modification. Recurrent FSH determinations may help in predicting a poor response, as a large intercycle FSH variability is correlated with ovarian failure. The value of ovarian reserve tests is presently not fully established.

[How to assess ovarian reserve in 1999?]. / Comment évaluer la réserve ovarienne en 1999?

Fertility and results of infertility therapies are submitted to amajor drop in relation with the age of the female patient and her so-called ovarian reserve. Although there is no clear definition of what is exactly the ovarian reserve, the consequence of its decline is a greater difficulty to produce ovocytes with a capacity of becoming living embryos after fertilization. Several tests have been developed to assess the ovarian reserve in order to evaluate the prognosis of spontaneous fertility, the results of infertility therapy and assisted procreation techniques, and to make necessary technical adaptations. Basal determinations of FSH, estradiol and inhibin B at day 3 of the cycle an all reflect the ovarian potential, but only FSH reflects a decline infecundability reliable enough to be used as a screening test. Challenge tests such as the clomiphene citrate, the exogenous FSH or the GnRH challenge tests have the purpose to reveal an exaggerated liberation of FSH or an insufficient secretion of estradiol after stimulation. None of these tests have demonstrated a better sensibility together with a higher specificity and they should be considered as evaluating tools in specific cases only. In conclusion, assessing the ovarian reserve has become a clinical necessity in the following situations: ovulation defect, unexplained infertility, before undergoing ovarian stimulation for assisted procreation, in particular in women above the age of 35. This assessment can be made by determining the basal FSH level on day 3 of a cycle and should be renewed every year.

Vascular complications of diabetes mellitus: what role for phospholipid-binding antibodies?

Vascular complications are the main cause of morbidity in diabetes mellitus. However, the risk factors for vascular disease remain incompletely elucidated. It has been previously suggested that factors other than glycemia may contribute to the development of vasculopathy. In this study we determined the prevalence of phospholipid-binding antibodies in uncomplicated and complicated diabetes. We studied 53 uncomplicated diabetic patients, with type 1 (n = 32) or type 2 (n = 21) diabetes; 23 diabetic patients with proliferative retinopathy; 28 diabetic patients with an overt nephropathy; 37 diabetic patients with macroangiopathy and 22 non diabetic control patients. Both lupus anticoagulant and anticardiolipin antibodies were determined. Other risk factors for macroangiopathy were analysed. The prevalence of phospholipid-binding antibodies was similar in uncomplicated diabetic patients and in controls (type 1 diabetes: 9.4%; type 2 diabetes: 9.5%; control group: 4.6%; P= 0.76). In complicated diabetes, the frequency of these antibodies was increased only in patients with overt nephropathy (32.1%, P=0.01) or with macroangiopathy (32.4%, P=0.01) while patients with isolated retinopathy were comparable with uncomplicated diabetic patients (4.3%, P= 0.66). Uncomplicated diabetes was not associated with phospholipid-binding antibodies. We found a higher prevalence of these antibodies in diabetic patients with macroangiopathy or nephropathy. These results suggest a potential role of phospholipid-binding antibodies in the progression of vascular complications in diabetes mellitus.

Weight excess before pregnancy: complications and cost.

OBJECTIVE: To investigate the incidence of pregnancy complications and the cost of prenatal care in patients with pregravid overweight. DESIGN: Retrospective study of patients dispatched into four groups: normal weight, moderate overweight, obesity, massive obesity. SETTING: Department of Obstetrics and Gynecology of Montpellier. SUBJECTS: One hundred and twelve pregnancies among 89 overweight women, compared with 54 healthy normal weight controls. MAIN OUTCOME MEASURES: Incidence of maternal complications, complications of labor, duration of hospitalization. RESULTS: Hypertension, toxemia, gestational diabetes, insulin treatment, urinary tract infections and macrosomia were positively correlated with maternal pregravid weight excess. Mean duration of hospitalization and overall cost were also strongly related to maternal weight. Cesarean section rate increased only in morbidly obese women. No materno-fetal mortality was observed in our study. CONCLUSION: Even moderate overweight is a significant risk factor for obstetrical complications and needs a multidisciplinary antenatal management in order to prevent materno-fetal complications.

Ovarian reserve test with the gonadotrophin-releasing hormone agonist buserelin: correlation with in-vitro fertilization outcome.

A gonadotrophin-releasing hormone agonist stimulation test determination of follicle stimulating hormone (FSH) concentrations before and 2 h after buserelin injection was carried out in 78 in-vitro fertilization cycles, and compared with basal FSH concentrations to predict ovarian response. Ovarian response was quantified by the ratio of peak oestradiol concentration divided by the total dose of human menopausal gonadotrophin (HMG) administered, the most reproducible parameter in 11 patients who underwent two treatment cycles. Stimulation outcome was highly related to the buserelin test, the best prognostic indicator being the sum of FSH concentrations. However, basal FSH concentration achieved similar correlations, even in those patients aged > 35 years. Sensitivity, specificity, positive and negative predictive values of basal FSH concentration and sum of FSH concentrations were similar. Low basal concentration and sum of FSH concentrations were both associated with a better ovarian response. Construction of receiver operator characteristic curves demonstrated that basal FSH concentration was more informative than the sum of FSH concentrations. Finally, the sum of FSH concentrations did not increase the prediction of ovarian response variability. We conclude that the buserelin test is strongly predictive of stimulation outcome, but is no more informative than the usual screening. We suggest that the performance of other stimulation tests should be clearly compared with that of basal FSH concentration.

TSH suppression combined with carbimazole for Graves' disease: effect on remission and relapse rates.

OBJECTIVE: We studied the influence of TSH suppressive therapy combined with carbimazole (CBZ) on treatment outcome in Graves' disease. DESIGN: Open non-randomized prospective study. SETTING: University Hospital of Montpellier, France. SUBJECTS: Sixty-six consecutive patients without prior treatment were included. All the patients were treated initially with 30 mg of CBZ. After 1 month of treatment, one group continued CBZ alone (n = 23), another group received a combination of CBZ plus T3 (n = 19) and a third group received CBZ and 3,5,3'-triiodothyroacetic acid (Triac, n = 24). Therapy was stopped when remission was obtained based on clinical euthyroidism, normalization of FT4 and of early radioiodine uptake. Nine patients with medical treatment failure or major side effects requiring to stop antithyroid drugs underwent surgery or radioiodine therapy. Nine patients were lost to follow-up. The remaining 48 patients were available for analysis of both remission and relapse. RESULTS: The median duration of therapy was 18 months (range, 4-41 months). Based on clinical examination, goitre size at 4 months decreased more in the CBZ + T3 and CBZ + Triac groups than in the CBZ group (P = 0.02). The overall remission rate tended to be higher in the groups treated with CBZ + T3 and CBZ + Triac than in the group treated with CBZ alone, but the difference did not reach statistical significance (P = 0.17). No difference in the relapse rate was observed between the three groups. CONCLUSION: TSH suppression combined with CBZ has little or no effect on remission and relapse rates in Graves' disease patients.

Androgen receptor gene mutation in male breast cancer.

We screened thirteen male breast cancers for the presence of germline mutations in exons 2 and 3 encoding the DNA-binding domain of the androgen receptor. These two exons were amplified from genomic DNA extracted from patients' white blood cells. In one of these thirteen patients, single strand conformation polymorphism and direct sequencing detected a guanine-adenine point mutation at nucleotide 2185 that changes Arg608 into Lys in a highly conserved region of the second zinc finger of the androgen receptor. This mutation occurred in a 38 year old man with partial androgen insensitivity syndrome and normal androgen-binding capacity in cultured genital skin fibroblasts. To our knowledge, only one germline Arg to Gln androgen receptor gene mutation has been previously reported at position 607 in male breast cancer. This androgen receptor mutation along with the Arg608 into Lys mutation we describe, suggests that this genetic abnormality is not fortuitous: a decrease in androgen action within the breast cells could account for the development of male breast cancer by the loss of a protective effect of androgens on these cells. Activation of estrogen regulated genes by the change of DNA-binding characteristics of the mutant androgen receptor cannot, however, be ruled out.

[Perspectives in the treatment of type 2 diabetes. Role of insulin therapy?]. / Perspectives dans le traitement du diabète de type 2. Place de l'insulinotherapie?

Independently of its initial mechanism, Type 2 diabetes associates in various degrees disorders in insulin sensibility and secretion. The dissociated insulin resistance among tissues explains the predictable imperfection of insulin therapy in this disease due to frequent weight increase and the potential risks of insulin on atherogenesis raised on the basis of experimental studies. All diabetic subjects are not equally insulin resistant and do not have the same insulin secretory capacity evaluated in practice by means of the response of insulin or C peptide plasma levels to various secreting agents. Intensity and duration of hyperglycaemia, muscular mass, physical activity and way of life, age, weight and fat patterning, the presence of complications, acceptance, education feasibility and compliance are essential in selecting towards insulin therapy. Meanwhile, as the results of the prospective studies in progress become available, it seems that insulin should be restricted to the smallest useful dosage possible and that weight change should be carefully checked within the weeks following initiation of insulin. The future of insulin therapy in Type 2 diabetes requires (1) better selection of patients showing a demonstrated beneficial effect of insulin, (2) the association of insulin with new molecules capable of reducing its dosage and preventing its deleterious effects, (3) a change in the mode of insulin administration, with an appropriate balance between comfort and efficacy, (4) change in the insulin structure towards analogues or compounds related to insulin but with less perverted effects.