Steroid sulfatase is increased in the placentas and whole blood of women with early-onset preeclampsia.

INTRODUCTION: Preeclampsia is a serious complication of pregnancy affecting 5% of pregnancies. Our team identified 137 genes highly expressed in placenta relative to other human tissues. Here, we have explored a role for steroid sulfatase (STS) in preeclampsia by characterising STS expression and the functional effects of STS on primary placental trophoblasts. METHODS: Characterisation of STS was performed on preterm preeclamptic and gestation-matched normotensive preterm controls who delivered at <34 weeks gestation. We characterised placental and maternal whole blood STS mRNA and placental protein expression via qRT-PCR, immunohistochemistry and Western Blot. To assess whether STS is involved in sFlt1 secretion and syncytialisation, we administered siRNA to silence STS in primary trophoblasts before measuring sFlt1 and hCG secretion and E-Cadherin expression. RESULTS: A custom array containing 45 placental specific genes identified 10 genes significantly altered in the placentas of preeclamptic patients relative to normotensive gestation-matched controls. Of these genes, qRT-PCR and western blot on a larger cohort confirmed that the expression of STS was significantly elevated in preeclamptic placentas (n = 44) relative to gestation matched controls (n = 26). Given placental RNA leaks in to the maternal circulation, we also assessed STS mRNA expression in the whole blood of patients with preeclampsia and found it was significantly increased relative to normotensive controls. siRNA knockdown of STS in primary trophoblast resulted in a modest but significant reduction in sFlt1 secretion, but had no affect on hCG secretion or E-Cadherin protein expression. DISCUSSION: STS is increased in preeclamptic placentas and maternal whole blood. Our data suggests that STS may affect sFlt1 secretion by regulating sFlt1-i13 transcription, and not via alterations in syncytialisation.

Synergistic effects of E2MATE and norethindrone acetate on steroid sulfatase inhibition: a randomized phase I proof-of-principle clinical study in women of reproductive age.

The combination of a progestin such as norethindrone acetate (NETA) reducing the ovarian estrogen production with a steroid sulfatase (STS) inhibitor (STS-I) decreasing the local estrogen production could result in a new treatment option for endometriosis. The study reported was a randomized, double-blind, and placebo-controlled study to investigate the pharmacodynamics, pharmacokinetics, and safety of the STS-I PGL2001 (E2MATE) and NETA. A total of 24 healthy women of reproductive age were treated with weekly doses of PGL2001 or daily doses of NETA or a combination of both compounds for 4 weeks. Four weeks of treatment with PGL2001 or PGL2001 + NETA reduced the STS activity in the endometrium by 91% (±3%) and 96% (±4%), respectively, and comparable values were observed 1 month after the treatment was stopped. The combined treatment of PGL2001 + NETA led to significantly higher STS inhibition at both times (P < .01 and P < .05, respectively). This study showed that administration of PGL2001 alone at 4 mg/week or combined with NETA to healthy women of reproductive age led to STS inhibition and changes in functional STS biomarkers in the endometrium, resulting in synergistic effects of PGL2001 and NETA on STS activity.

[Androgen and 17-hydroxyprogesterone concentrations in blood serum versus menstrual patterns in women with polycystic ovary syndrome (PCOS)]. / Stezenie hormonów androgennych oraz 17-hydroksyprogesteronu w surowicy krwi a wzorzec miesiaczkowania u pacjentek z zespolem policystycznych jajników.

THE AIM OF THE STUDY: to evaluate correlation between androgen and 17-hydroxyprogetserone concentrations in blood serum and menstrual patterns of women with polycystic ovary syndrome. MATERIAL AND METHODS: 227 patients with polycystic ovarian syndrome (PCOS), aged 18 to 35 years, hospitalized at the Department of Gynecological Endocrinology All patients with PCOS presented clinical and biochemical evidence of hyperandrogenism with oligoovulation and/or ultrasonographic appearance of polycystic ovaries. PCOS was diagnosed according to the Rotterdam Criteria after excluding reasons such as: congenital adrenal hyperplasia, adrenal and ovarian tumors, hyperprolactinemia and hypo- hyperthyreosis. The following hormone concentrations were measured in each patient: total testosterone (TT), androstendione (A), dehydroepiandrosterone sulphate (DHEAS) and 17-hydroxyprogesterone (17-OHP). The patients were divided into 4 groups: I--eumenorrhoeic (n = 66), II--polymenorrhoeic (n = 32), III--oligomenorrhoeic (n = 93), IV--with secondary amenorrhea (n = 36). The control group consisted of 40 patients with normal regular menstrual cycles and no clinical/biochemical sings of hyperandrogenism. Statistical analysis was performed using one-way Anova and NIR test. P < 0.05 were considered to be statistically significant. RESULTS: The mean TT concentrations were as follows: Group I-- 0.91 +/- 0.56 ng/ml, II--0.91 +/- 0.22, III--0.91 +/- 0.48, IV--1.66 +/- 1.78 ng/ml; Androstendione: I-- 3.34 +/- 1.32, II--2.77+/- 0.75 ng/ml, III--3.28 +/- 1.00 ng/ml, IV--4.29 +/- 2.18 ng/ ml, 17-OHP: I--1.08 +/- 1.61 ng/ml, II-- 0.89 +/- 0.62ng/ml, III--0.94 +/ - 0.37 ng/ml; IV--1.68 +/-1.28 ng/ml and DHEAS: I--5.69 +/- 2.49 micromol/, II-- 6.11 +/- 3.11 micromol/l, III--6.04 +/- 3.00 micromol/l, IV-- 6.12 +/- 3.25 micromol/l respectively. The hormone concentrations in the control group were as follows: TT--0.58 +/- 0.35 ng/ml, A--2.33 +/- 0.52 ng/ml, 17-OHP--0.67 +/- 0.30 ng/ml, DHEAS--5.24 +/- 2.33 micromol/I. We found significantly higher TT A, 17-OHP concentrations in all PCOS subgroups than in the healthy subjects (p < 0.05). The PCOS group analysis revealed that all the mentioned hormone concentrations were significantly higher in women with secondary amenorrhea (group IV) than in the remaining 3 groups (p < 0.05). We found no significant difference in DHEAS concentrations between the study and the control group. CONCLUSIONS: Higher total testosterone, androstendione and 17-hydroxyprogesterone concentrations, longer menstrual cycles in women with PCOS.

[Insulin resistance and serum concentrations of ovarian and adrenal androgen in obese women without additional disease and with policystic ovary syndrome]. / Insulinoopornosc a stezenie androgenów jajnikowych i nadnerczowych w surowicy otylych kobiet bez chorób towarzyszacych i z zespolem policystycznych jajników.

THE AIM: of the present study was to evaluate serum concentrations of adrenal and ovarian androgens and sex hormone-binding globulin in obese women without additional diseases and in obese women with polycystic ovary syndrome with and without insulin resistance. MATERIAL AND METHODS: The study group involved 73 obese women (39 with PCOS--A and 34 obese without additional diseases--B). The serum concentration of glucose and insulin were measured and the study group was divided on the basis of HOMA index into two subgroups: A I-PCO without insulin resistance (n=18, mean age 27.2+/-5.9 yr; BMI 33.2+/-3.5 kg/m2); AII-PCO with insulin resistance (n=21, mean age 27.5+/-7.1 yr; BMI 37.6+/-6.5 kg/m2); B I-obese without insulin resistance (n=8, age 33.5+/-7.5 yr; BMI 35.2+/-4.8 kg/m2); B II-obese with insulin resistance (n=24, age 30.3+/-5.2 yr; BMI 36.4+/-5.8 kg/m2). Body mass and height were measured and body mass index was calculated with formula. Body composition was measured using bioimpedance method. The serum concentrations of FSH, LH, total and free testosterone, androstendione, DHEAS, SHBG and insulin were determined by RIA method and glucose was determined by enzymatic procedure. RESULTS: We observed significantly higher body mass, fat mass and BMI in AII subgroup when compared to AI, BI and BII subgroups. Only serum concentration of free testosterone was significantly higher in AII subgroup when compared to AI subgroup. We observed a positive correlation between serum concentrations of insulin and free testosterone in both groups A and B, moreover we observed positive correlations between serum concentrations of insulin and both DHEAS and LH in group B. CONCLUSIONS: It seems that insulin resistance plays a key role in the development of hyperandrogenism in obese women. However mechanisms leading to hyperandrogenism in PCOS are still unrevealed and seem to be more complex.

The influence of parturition on the level and synthesis of sulfated and free neurosteroids in rats.

Alterations in neurosteroid levels may play a role in affective disorders including those related to changes in the levels of ovarian steroids. The effects of pregnancy and delivery on circulatory and brain levels of dehydroepiandrosterone (DHEA), pregnenolone (PN), their sulfate esters and the enzymatic activities of sulfatase and sulfotransferase were examined in rats. Our findings indicate an increase, not reflected in the brain cortex, in serum DHEA levels, at the end of pregnancy with a partial decrease following delivery. DHEA sulfate levels in the cortex and PN levels in both serum and cortex decreased following delivery with no changes in its sulfated form. Sulfatase levels were high both before and after delivery with no changes noted in sulfotransferase levels, compared to controls. We speculate that changes in the level or ratio of sulfated and free neurosteroids may play a role in postpartum behavioral disorders due to their antagonistic GABA(A) modulatory effect.