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Polycystic ovary syndrome (PCOS) is commonly characterised by obesity, insulin resistance (IR), hyperandrogenemia and hirsutism. Nesfatin-1 a recently discovered hormone, acts upon energy balance, glucose metabolism, obesity and probably gonadal functions. This study was to evaluate the circulating levels of nesfatin-1 in patients with PCOS (n= 30) and in age and body mass index (BMI)-matched controls (n=30). PCOS patients had significantly lower levels of nesfatin-1 (0.88 ± 0.36 ng/mL) than healthy controls (2.22 ± 1.14 ng/mL). PCOS patients also had higher gonadotropin and androgen plasma concentrations, Ferriman–Gallwey scores, blood glucose levels and a homeostasis model of assessment-IR index (HOMA-IR) index than in healthy women. Correlation tests in PCOS subjects detected a negative correlation between nesfatin-1 levels and BMI, fasting blood glucose, insulin levels and a HOMA-IR index. Lower nesfatin-1 concentration may plays a very important role in the development of PCOS.Polycystic ovary syndrome (PCOS) is commonly characterised by obesity, insulin resistance (IR), hyperandrogenemia and hirsutism. Nesfatin-1 a recently discovered hormone, acts upon energy balance, glucose metabolism, obesity and probably gonadal functions. This study was to evaluate the circulating levels of nesfatin-1 in patients with PCOS (n= 30) and in age and body mass index (BMI)-matched controls (n=30). PCOS patients had significantly lower levels of nesfatin-1 (0.88 ± 0.36 ng/mL) than healthy controls (2.22 ± 1.14 ng/mL). PCOS patients also had higher gonadotropin and androgen plasma concentrations, Ferriman–Gallwey scores, blood glucose levels and a homeostasis model of assessment-IR index (HOMA-IR) index than in healthy women. Correlation tests in PCOS subjects detected a negative correlation between nesfatin-1 levels and BMI, fasting blood glucose, insulin levels and a HOMA-IR index. Lower nesfatin-1 concentration may plays a very important role in the development of PCOS.

A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues.

Estrogen is an extremely potent mitogen for endometrium and endometriosis. Progesterone, on the other hand, inhibits the mitogenic action of estrogen on endometrium and enhances differentiation. These antiproliferative and differentiative effects of progesterone are less pronounced on endometriosis tissue compared with endometrium. Thus, endometriosis is, at least in part, resistant to progesterone action. The product of a single gene named aromatase synthesizes estrogen. The potent estrogen estradiol is metabolized and thus inactivated by an enzyme termed 17β-hydroxysteroid dehydrogenase (HSD) type 2 that is normally induced by progesterone in endometrium. Progesterone action is mediated by its receptor subtypes progesterone receptor (PR)-A and PR-B. We found a number of abnormalities in the expression of aromatase, 17β-HSD type 2, and the PR-B/PR-A ratio in endometriosis tissue. These abnormalities and their functional consequences are discussed in this review article.

We investigated the regulation of prostaglandin production in normal endometrial stromal cells (ESC) by malignant endometrial epithelial cells. We found that cyclooxygenase (COX)-2 mRNA and protein levels and prostaglandin (PG)E2production in ESC were significantly increased by Ishikawa malignant endometrial epithelial cell conditioned medium (MECM). By using transient transfection assays, we found that the −360/−218-bp region of the COX-2promoter gene was critical for MECM induction of promoter activity. This MECM-responsive region contained a variant nuclear factor (NF)-κB site at −222 to −213 that, when mutated, completely abolished COX-2promoter activation by MECM. Employing electrophoretic mobility shift assays, we further demonstrated that binding of NF-κB p65 to this NF-κB-binding site is, in part, responsible for the COX-2promoter activation by MECM. To investigate further the potential effects of MECM onCOX-2mRNA stability, ESC were treated with MECM in the absence or presence of actinomycin D, a general transcription inhibitor. We found that MECM significantly increased COX-2mRNA stability. Intriguingly, we found that PGE2was one of the major factors in MECM, which was responsible for up-regulating COX-2 expression in ESC. ECC-1 and HEC-1A malignant endometrial epithelial cell lines also produced significantly increased quantities of PGE2. In conclusion, malignant endometrial epithelial cells secrete PGE2that induces COX-2 expression in normal endometrial stromal cells in a paracrine fashion through activation of transcription and stabilization of COX-2mRNA.

Aromatase activity is absent in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis, which gives rise to strikingly high levels of aromatase activity in this tissue. Both aromatase expression and activity are stimulated by PGE2. This results in local production of estrogen, which induces PGE2formation and establishes a positive feedback cycle. Another abnormality in endometriosis, that is, deficient 17?-HSD type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor.

Endometriosis is one of the most common causes of infertility and chronic pelvic pain and affects 1 in 10 women in the reproductive-age group. Although existence of this disease has been known for over 100 years, our current knowledge of its pathogenesis, the pathophysiology of related infertility, and its spontaneous evolution is limited. Several reasons contribute to our lack of knowledge, the most critical being the difficulty in carrying out objective long-term studies in women. Thus, we and others have developed the baboon as an appropriate nonhuman primate to study the etiology of this disease. We suggested that endometriosis develops in two distinct phases. Phase I is invasive and dependent on ovarian steroids. Phase II, which is the active phase of the disease, is characterized by endogenous estrogen biosynthesis. Following inoculation with menstrual endometrial tissues in two consecutive menstrual cycles, baboons develop lesions that are similar to those seen in humans. Laparoscopy at 1, 4, and 10 months revealed a preponderance of red raised nodules at the first month, while both red lesions and reddish-blue proliferative endometriotic lesions were evident at 4 and 10 months. The presence of glandular tissue and stromal fibroblasts in these lesions was confirmed by histology. Lesions obtained at 1 and 4 months expressed estrogen receptor ? (ER?), matrix metalloproteinase-7 (MMP-7), and vascular endothelial growth factor (VEGF) predominantly. However, aromatase expression was only readily evident at 10 months, although some lesions obtained at 4 months expressed low levels of aromatase. Therefore, our preliminary data suggest that endometriosis can be artificially induced in baboons, and the role of exogenous and endogenous estradiol in proliferation, angiogenesis, and immune modulations can now be evaluated in a potentially systemic manner.