Recombinant luteinizing hormone induces increased production of ovarian follicular adiponectin in vivo: implications for enhanced insulin sensitivity.

OBJECTIVE: To determine in vivo whether LH supplementation during the late follicular phase induces increased production of ovarian follicle adiponectin in humans. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Academic tertiary care medical center. PATIENT(S): Twenty infertile, healthy women (aged 18-39 years) undergoing IVF. INTERVENTION(S): Administration of recombinant FSH after down-regulation and equal randomization of subjects to receive recombinant LH 75 IU/day or placebo when two or more follicles reached a mean diameter of 14 mm. MAIN OUTCOME MEASURE(S): Follicular fluid (FF) adiponectin levels were measured. RESULT(S): Adiponectin FF levels were significantly higher in the recombinant LH group compared with the placebo group, and these differences were unaltered after correction to estrogen (E) levels and number of follicles in each cycle. CONCLUSION(S): This is the first demonstration of in vivo induction of adiponectin by gonadotropins in the human ovary. The addition of recombinant LH during the late follicular phase may enhance follicular insulin sensitivity, resulting in decreased androgen levels through a cascade mediated by increased production of adiponectin.

Regulation of vascular endothelial growth factor-A and its soluble receptor sFlt-1 by luteinizing hormone in vivo: implication for ovarian follicle angiogenesis.

OBJECTIVE: To determine in vivo whether LH supplementation during the late follicular phase induces ovarian follicle angiogenesis in humans, as reflected by vascular endothelial growth factor (VEGF)-A, its soluble receptor sFlt-1, and placental growth factor (PlGF) expression. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Academic tertiary care medical center. PATIENT(S): Twenty infertile, healthy women (aged 18-39 years) undergoing IVF. INTERVENTION(S): Administration of recombinant FSH after down-regulation and equal randomization of subjects to receive recombinant LH 75 IU/day or placebo when two or more follicles reached a mean diameter of 14 mm. MAIN OUTCOME MEASURE(S): Serum and follicular fluid (FF) VEGF-A, sFlt-1, and PlGF protein levels were measured. RESULT(S): Recombinant LH increased both the FF VEGF-A/sFlt-1 ratio statistically significantly and PlGF/sFlt-1 insignificantly. Recombinant LH did not affect the serum VEGF/sFlt-1 ratio. Plasma levels of PlGF were undetectable. CONCLUSIONS: This in vivo study demonstrates for the first time in humans that LH induces ovarian follicular angiogenesis via modulation of VEGF-A and its soluble receptor sFlt-1 expression. A constant VEGF-A/sFlt-serum ratio may prevent adverse effects of VEGF-A. Because angiogenesis is essential during the periovulatory period, recombinant LH supplementation during the late follicular phase may improve ovulation induction outcome.

[Long-term health consequences of polycystic ovaries syndrome: metabolic, cardiovascular and oncological aspects].

The polycystic ovary syndrome (PCOS), then called the Stein-Leventhal syndrome, was first described in 1935. Originally, diagnosis required pathognomonic ovarian findings and the clinical triad of hirsutism, amenorrhea, and obesity. During fertility years, women with PCOS are often seen for immediate concerns such as infertility, menstrual irregularity, and symptoms of androgen excess. During the past two decades, however, such patients have been observed to have increased risk of cardiovascular disease, dyslipidaemia, hypertension and diabetes and increased risk for endometrial cancer. The management of polycystic ovary syndrome is now complex and includes life style modifications, dietary-induced weight loss, oral contraceptives, clomiphene citrate, gonadotropins, antiandrogens and insulin-sensitising agents. These observations have led to a unique clinical perspective about PCOS--one that recognizes the need to address the immediate issues of irregular bleeding, hirsutism, and infertility, but also emphasizes the long-term goals of preventing diabetes, heart disease, and cancer.

Time-independent approximations for periodically driven systems with friction.

The classical dynamics of a particle that is driven by a rapidly oscillating potential (with frequency omega) is studied. The motion is separated into a slow part and a fast part that oscillates around the slow part. The motion of the slow part is found to be described by a time-independent equation that is derived as an expansion in orders of omega(-1) (in this paper terms to the order omega(-3) are calculated explicitly). This time-independent equation is used to calculate the attracting fixed points and their basins of attraction. The results are found to be in excellent agreement with numerical solutions of the original time-dependent problem.

Undiagnosed systemic lupus erythematosus in a cohort of infertile women.

PROBLEM: Systemic lupus erythematosous (SLE) is a chronic disease with a broad spectrum of clinical and immunological manifestations, therefore, this condition may be frequently misdiagnosed. The current study was conducted to determine the prevalence of undiagnosed SLE among a cohort of infertile women. METHOD OF STUDY: Screening was performed using sequential (two stage) testing, which included a self-completed questionnaire followed by an antinuclear antibody (ANA) test. The Liang screening questionnaire was distributed to 143 consecutive infertile patients, aged 24-42 years (mean, 33.6 +/- 4.7 years), who were receiving in-vitro fertilization (IVF) treatment. Patients who completed the questionnaire with three or more positive answers, were sent for ANA testing; those who tested positive (>or=1:40) were referred to the Clinical Immunology Unit for anti-double-stranded DNA (dsDNA) antibody test and clinical assessment. RESULTS: A total of 136 women (95.1%) completed the questionnaire. Thirteen patients (9.6%) answered yes to three or more questions. Of these, five patients (3.7%) were ANA-positive and two (1.5%) had undiagnosed SLE. CONCLUSIONS: A 1.5% prevalence of undiagnosed SLE was found in our cohort of infertile women. Additional investigations should be performed as to the role of SLE screening in infertile female population; a high-risk group with regard to ovulation induction treatments.

Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2.

During placental development, vessel formation occurs initially by vasculogenesis and subsequently by branching and nonbranching angiogenesis. We investigated vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang)-1 and -2 transcript profiles, and the protein products that they encode in placentas from normotensive pregnancies throughout pregnancy. In addition, we compared these genes in placentas from normotensive women and those with preeclampsia during the third trimester. Quantitative real-time PCR analysis demonstrated that VEGF-A and Ang1 mRNA increased in a linear pattern by 2.5 (not significant) and 2.8%/wk (P = 0.034), respectively, whereas Ang2 decreased logarithmically by 3.5%/wk (P = 0.0003). Ang2 mRNA was 400- and 100-fold higher than Ang1 and VEGF-A, respectively, in the first trimester and declined to 20-fold and 7-fold in the third. Ang2 protein (ELISA) decreased by 4.7%/wk (P = 0.0001), whereas Ang1 and VEGF-A were undetectable. In preeclampsia compared with normotensive pregnancy, only VEGF-A mRNA increased significantly, by 3-fold (P = 0.006). This increase may be related to low oxygen tension, as VEGF-A is up-regulated by hypoxia. In situ hybridization and immunohistochemical studies revealed that VEGF-A was localized in cyto- and syncytiotrophoblast and perivascular cells, whereas Ang1 and Ang2 were only in syncytiotrophoblast and perivascular cells in the immature intermediate villi during the first and second trimesters, and mature intermediate and terminal villi during the third trimester. These data suggest that these molecules may play important roles in placental biology and chorionic villus vascular development and remodeling in an autocrine/paracrine manner. The tight correlation between Ang2 mRNA and protein indicates that regulation of placental vascular development occurs at the transcriptional, and not translational, level.