Metformin increases norepinephrine transporter expression in placenta of patients with polycystic ovary syndrome.

OBJECTIVE: To evaluate the norepinephrine (NE) and placental NE transporter (NET) in women with polycystic ovary syndrome (PCOS) non-treated and treated with metformin during pregnancy. PATIENTS AND METHODS: We studied sixteen pregnant women with PCOS: 8 without metformin treatment during pregnancy (PCOS-M) and 8 treated with metformin during pregnancy (PCOS+M). Sixteen pregnant women of similar age without PCOS were included as controls (Control). At 24th and 35th weeks of pregnancy, blood samples were obtained. Placentas from full-term pregnancies were collected immediately after delivery. They were divided into two samples representative from the region near the chorionic plate (fetal side) and from the region near the basal plate (maternal side). NE plasma concentrations were measured by HPLC with electrochemical detection, and placental NET protein levels were determined by Western blot. RESULTS: At week 24 of gestation, PCOS-M had higher NE plasma levels compared to control women (p < 0.001). Moreover, NET expression was lower in the maternal side of the placenta of PCOS-M compared to controls (p < 0.05). Metformin treatment normalized NE plasma levels at week 24 of gestation and NET expression in the maternal side of the placenta. In the fetal side of the placenta, NET expression was lower in PCOS-M and PCOS+M compared to control women (p < 0.001 and < 0.01, respectively). CONCLUSIONS: Our results strongly suggest that norepinephrine homeostasis is altered in pregnant women with PCOS. Remarkably, metformin administration during pregnancy decreases circulating norepinephrine levels and increases NET expression in the maternal side of placentas from PCOS women.

Obesity during pregnancy affects sex steroid concentrations depending on fetal gender.

BACKGROUND/OBJECTIVE: It is not clear whether maternal obesity along with fetal gender affect sex steroid metabolism during pregnancy. Therefore, we compared sex steroid concentrations and placental expression of steroidogenic enzymes between non-obese and obese pregnant women with non-pathological pregnancies, and investigated the influence of fetal gender on these parameters. METHODS: In 35 normal weight (body mass index (BMI) 20-24.9 kg m-2) (controls) and 36 obese women (BMI 30-36 kg m-2) (obese), a fasting blood sample was obtained at first and at third trimester of gestation to measure progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone and estradiol by liquid chromatography-tandem mass spectrometry and estrone by radioimmunoassay. In a subset of women, placental mRNA and protein expression of steroidogenic enzymes was measured by quantitative PCR and western blot, respectively. The comparisons were primarily made between controls and obese, and then separately according to fetal gender. RESULTS: At first and third trimesters of gestation serum progesterone was lower whereas testosterone was higher in obese women (P<0.05, respectively). Upon analyzing according to fetal gender, lower progesterone levels were present in obese pregnant women with male fetuses at first trimester and with female fetuses at third trimester (P<0.05, respectively). Testosterone was higher in obese women with male fetuses compared to control women with male fetuses (P<0.05). The placental protein expression of P450scc was higher in obese women compared to controls (P<0.05). P450 aromatase was higher in obese women with female fetuses (P=0.009), whereas in obese women with male fetuses P450 aromatase was lower compared to control women (P=0.026). CONCLUSIONS: Obesity in non-pathological pregnancies alters the maternal serum progesterone and testosterone concentrations depending on fetal gender. These changes can be attributed to gender-related placental adaptations, as the expression of P450 aromatase is different in placentas from females compared to males.

Patterns of hormonal response to the GnRH agonist leuprolide in brothers of women with polycystic ovary syndrome: a pilot study.

BACKGROUND: The aim of this study was to evaluate the effect of a single dose of leuprolide acetate on gonadotrophin and gonadal steroid secretion in brothers of women with polycystic ovary syndrome (PCOS), in order to assess P450c17alpha activity. An oral glucose tolerance test (OGTT) and a lipid profile were also performed. METHODS: Twenty-two unrelated brothers of women with PCOS (PCOS(b)) and 14 brothers of normal cycling women (C(b)), matched for age, underwent a leuprolide acetate test (10 microg/kg s.c.) and an OGTT with measurement of circulating concentrations of gonadotrophins, steroid hormones, glucose, insulin and lipids. RESULTS: Clinical and basal hormonal parameters were similar in both groups. After leuprolide administration, PCOS(b) exhibited a significant increase of 17alpha-hydroxyprogesterone (17-OHP) compared to C(b) (P<0.05). However, only 45% of PCOS(b) showed a supranormal increase of 17-OHP (2 SD above the respective control group mean values, P<0.003) with a normal gonadotrophin response (group 1). The other 55% of the PCOS(b) exhibited a normal 17-OHP response to the analogue (group 2). However, in group 2, basal steroid concentrations did not show a uniform pattern: six of the PCOS(b) exhibited high basal androstenedione (2 SD above the respective control group mean values), three were very similar to C(b), and the other three presented lower basal testosterone concentrations (2 SD below the respective control group mean values) than those observed in C(b). CONCLUSIONS: This study shows that different responses to leuprolide in PCOS brothers make evident the heterogeneity of this syndrome in which P450c17alpha activity could be involved.