Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a complex condition that affects women of reproductive age, is characterized by ovulatory dysfunction and androgen excess. Women with PCOS present higher prevalence of obesity, central adiposity, and dyslipidemia, and face increased risk of type 2 diabetes. PCOS is closely linked to functional derangements in adipose tissue. Adipocytes seem to be prone to hypertrophy when exposed to androgen excess, as experienced by women with PCOS, and both adipose tissue hypertrophy and hyperandrogenism are related to insulin resistance. Hypertrophic adipocytes are more susceptible to inflammation, apoptosis, fibrosis, and release of free fatty acids. Disturbed secretion of adipokines may also impact the pathophysiology of PCOS through their influence on metabolism and on sex steroid secretion. Chronic low-grade inflammation in PCOS is also related to hyperandrogenism and to the hypertrophy of adipocytes, causing compression phenomena in the stromal vessels, leading to adipose tissue hypoperfusion and altered secretion of cytokines. Lifestyle changes are the first-line intervention for reducing metabolic risks in PCOS and the addition of an insulin-sensitizing drug might be required. Nevertheless, there is not sufficient evidence in favor of any specific pharmacologic therapies to directly oppose inflammation. Further studies are warranted to identify an adipokine that could serve as an indirect marker of adipocyte production in PCOS, representing a reliable sign of metabolic alteration in this syndrome.

CYP19 gene expression in subcutaneous adipose tissue is associated with blood pressure in women with polycystic ovary syndrome.

In polycystic ovary syndrome (PCOS), hypertension has been linked to androgen excess and insulin resistance. Aromatase, an enzyme encoded by the CYP19 gene, affects androgen metabolism and estrogen synthesis, influencing the androgen to estrogen balance. We characterized CYP19 gene expression in subcutaneous adipose tissue of women with PCOS and normal controls and evaluated the association between subcutaneous fat CYP19 mRNA, circulating hormone levels, and blood pressure. This case-control study was carried out with 31 PCOS patients and 27 BMI-matched normotensive non-hirsute women with regular cycles. Participants underwent anthropometric measurements, collection of blood samples, and adipose tissue biopsy (28 PCOS and 19 controls). Hypertension was defined as systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg. PCOS patients were divided into normotensive and hypertensive. Main outcome measures were serum estrogen and androgen levels, estrogen-to-androgen ratio, and CYP19 gene expression in subcutaneous fat. Subcutaneous CYP19 mRNA was higher in hypertensive PCOS than in control and normotensive PCOS women (p = 0.014). Estrogen-to-androgen ratio was lower in hypertensive PCOS than controls (p < 0.003). Estrogen-to-androgen ratio ≤ 0.06 (median for the three groups) was observed in 91% of hypertensive PCOS women, vs. 37% and 61% in the control and normotensive PCOS groups (p = 0.011). CYP19 gene expression in subcutaneous fat of PCOS patient correlated positively with systolic (p = 0.006) and diastolic blood pressure (p = 0.009). Androgen excess and hyperinsulinemia may play a role in the molecular mechanisms that activate aromatase mRNA transcription in abdominal fat tissue.

c-fos gene and protein expression in pelvic endometriosis: a local marker of estrogen action.

Endometriosis is an estrogen-dependent disease, causing pelvic pain and infertility. c-fos is an early transcription factor that has been reported to be related to estradiol-dependent cell proliferation. The aim of the present study was to assess the c-fos gene and protein expression in pelvic endometriotic implants in comparison to normal endometrium from infertile women. An open, prospective and controlled study included 15 infertile women with endometriosis and 19 control infertile women. Endometrial and endometriotic biopsies were performed at the follicular phase and the samples were processed for RT-PCR and immunohistochemistry. ERalpha mRNA levels were similar in the endometriotic implants/eutopic endometrium from women with endometriosis and in normal tissue (P = 0.649). The aromatase gene, however, was not expressed in the eutopic endometrium from either control or endometriosis groups, and was only expressed in 50% of endometriotic implants (P = 0.044). c-fos gene expression was higher in endometriotic implants (1.32 +/- 0.13; P = 0.011) than in eutopic endometrium from patients with endometriosis (0.97 +/- 0.11) or from the control group (0.91 +/- 0.05). In addition, immunohistochemistry showed a more abundant distribution of c-Fos in the stroma of endometriotic tissue compared to eutopic endometrium. These data suggest that c-fos may play a role in the molecular mechanisms of estrogen action on the induction, promotion or progression of endometriosis.

Expression of 17beta-hydroxysteroid dehydrogenase type 2 in pelvic endometriosis.

Lack of expression or a deficiency of 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2), a key enzyme in estradiol inactivation, could be involved in the pathophysiology of endometriosis. The aim of the present study was to evaluate expression of the gene (17beta-Hsd2) encoding 17beta-HSD2 in eutopic and ectopic endometrial tissues of women with endometriosis. Thirty-four infertile women were divided into a control group, without any clinical or laparoscopic evidence of endometriosis (n = 19), and a group with pelvic endometriosis (n = 15). Diagnosis was confirmed by histological examination of the endometriotic lesions. 17beta-Hsd2 mRNA expression was detected by reverse transcription-polymerase chain reaction in the control group (54% of the samples), in the eutopic endometrium of patients with endometriosis (83% of the specimens analyzed) and in all endometriotic lesions. The semi-quantitative analysis of 17beta-Hsd2 mRNA showed a significantly higher gene expression in the endometriotic implants compared with the intrauterine endometrium of the control group (p < 0.05). 17beta-HSD2 protein was localized to the glandular epithelium of both eutopic endometrium and endometriotic implants. The present results refute the hypothesis of lower or absent 17beta-HSD2 expression in pelvic endometriosis; therefore further studies are needed to assess other potential mechanisms leading to increased estrogenic activity within endometriotic implants.

Androgen-dependent expression of c-jun and c-fos in human non-transformed epithelial prostatic cells: association with cell proliferation.

OBJECTIVE: To assess the effect of dihydrotestosterone (DHT) on the gene expression of C-FOS and C-JUN and on the proliferation of human non-transformed epithelial prostatic (HNTEP) cells. METHODS: Cell proliferation (MTT) and C-FOS and C-JUN mRNA expression (RT-PCR) were determined in cells treated with DHT (10(-8), 10(-10), and 10(-13)M) or with control medium. RESULTS: DHT 10(-13) M had a significant stimulatory effect on cell proliferation (p < 0.05) and C-FOS and C-JUN gene expression when compared to cells treated with higher concentrations of this hormone (10(-10) and 10(-8)M) or with the control group. CONCLUSIONS: Our data demonstrate that the increase in C-FOS and C-JUN expression and cell growth in HNTEP cells is maximal with the lowest DHT concentration (10(-13)M). These proto-oncogenes may play a role in the control of hormone responsiveness and cell proliferation in HNTEP cells.