Differentiating Polycystic Ovary Syndrome from Adrenal Disorders.

Although polycystic ovary syndrome (PCOS) is primarily considered a hyperandrogenic disorder in women characterized by hirsutism, menstrual irregularity, and polycystic ovarian morphology, an endocrinological investigation should be performed to rule out other hyperandrogenic disorders (e.g., virilizing tumors, non-classical congenital adrenal hyperplasia (NCAH), hyperprolactinemia, and Cushing's syndrome) to make a certain diagnosis. PCOS and androgen excess disorders share clinical features such as findings due to hyperandrogenism, findings of metabolic syndrome, and menstrual abnormalities. The diagnosis of a woman with these symptoms is generally determined based on the patient's history and rigorous clinical examination. Therefore, distinguishing PCOS from adrenal-originated androgen excess is an indispensable step in diagnosis. In addition to an appropriate medical history and physical examination, the measurement of relevant basal hormone levels and dynamic tests are required. A dexamethasone suppression test is used routinely to make a differential diagnosis between Cushing's syndrome and PCOS. The most important parameter for differentiating PCOS from NCAH is the measurement of basal and ACTH-stimulated 17-OH progesterone (17-OHP) when required in the early follicular period. It should be kept in mind that rapidly progressive hyperandrogenic manifestations such as hirsutism may be due to an androgen-secreting adrenocortical carcinoma. This review discusses the pathophysiology of androgen excess of both adrenal and ovarian origins; outlines the conditions which lead to androgen excess; and aims to facilitate the differential diagnosis of PCOS from certain adrenal disorders.

The investigation of diverse physiological and therapeutic impact of cellular-based products derived from human cumulus cells.

Particular somatic cells, namely cumulus cells (CCs) that support the oocyte maturation, fertility, and viability by providing the nutrients and energy to the oocyte envelop the mammalian oocyte. In this study, discarded human cumulus tissues were used to reveal the value of hyaluronic acid-rich CCs on several cellular events, including differentiation. Conditioned media, recovered from the primary culture of CCs, were introduced to the human nucleus pulposus cells (hNPCs) which were functionally distorted because of the loss of chondrogenecity. Enlightening the impact of cumulus conditioned media (CCM) on wound healing and angiogenesis was also investigated. In line with these goals, differentiation of hNPCs into chondrocytes with CCM as the basal medium containing traditional differentiation agents was induced upon isolation and characterization of hCCs and hNPCs. The effects were detected by differentiation-specific cell stains and gene expression analyses. Scratch and tube formation assays were performed to detect the effect of CCM on wound healing and angiogenesis. Our results showed that cumulus cell-conditioned media promoted the chondrogenesis and osteogenesis of hNPCs. A significant increase in angiogenesis and ability for wound closure was detected only in groups cultured in CCM compared to the control. These findings demonstrated that CCM might be used in therapeutics.

Identification of miR-16-5p and miR-155-5p microRNAs differentially expressed in circulating leukocytes of pregnant women with polycystic ovary syndrome and gestational diabetes.

INTRODUCTION: Pregnant women with polycystic ovary syndrome (PCOS) are at increased risk of gestational diabetes (GDM). We aimed to assess the expressions of candidate microRNAs (miRs) in leukocytes of pregnant women with PCOS and GDM. Methods: Using real-time quantitative PCR method, miR-16-5p and miR-155-5p were examined from PCOS (n = 17), GDM (n = 14), GDM + PCOS (n = 11), and controls (n = 27). The relative expression levels of the candidate miRNAs were compared between patient and control samples. The results were calculated as relative quantification values (RQ). Results: After adjusting for potential confounding variables using ANCOVA, no significant differences were observed in miR-16-5p (p = .154) and miR-155-5p (p = .702) expressions among four groups. We found significantly upregulated miR-16-5p expression in PCOS patients (RQ = 12.97 ± 1.94; p = .0001), compared to controls (RQ = 2.32 ± 1.46). Decreased miR-155-5p was found in GDM women (RQ = 0.80 ± 0.36; p = .04), compared to controls (RQ = 1.78 ± 0.25). Body mass index had a positive correlation with 155-5p in the GDM group (r = 0.55; p = .038). We found strong positive correlation between 1-hour glucose and miR-155-5p in PCOS patients (r = 0.71; p = .001). Fasting glucose (r= -0.63, p = .03) presented significant inverse association with miR-16-5p in the GDM + PCOS group. Discussion: The present study shows for the first time that increased miR-16-5p expression is associated with PCOS in pregnancy. Moreover, downregulated miR-155-5p expression was found in relation with GDM.

Association between endometriosis and increased arterial stiffness.

BACKGROUND: Endometriosis is a common gynecologic disease associated with systemic inflammation and atherogenic risk factors. Therefore, women with endometriosis may have increased cardiovascular risk. AIMS: We aimed to evaluate arterial stiffness using cardio-ankle vascular index (CAVI) in women with and without endometriosis. METHODS: We enrolled 44 patients with endometriosis and 76 age­matched controls without endometriosis.Endometriosis was diagnosed based on histopathologic examination or magnetic resonance imaging. Arterial stiffness was evaluated using CAVI in all study participants. RESULTS: No differences were observed between patients and controls in terms of age (median [interquartile range, IQR], 30 [24.25-5] years and 26 years [24-35] years, respectively), body mass index (median [IQR], 23.31 [20.82-24.98] kg/m2 and 23.74 [21.13-26.78] kg/m2, respectively), or waist circumference (median [IQR], 69 [64-75] cm and 72 [65-81.25] cm, respectively). C­reactive protein levels were higher in women with endometriosis than in controls (median [IQR], 0.27 [0.14-0.68] mg/dl vs 0.12 [0.06-0.24] mg/dl; P <0.001). Left ventricular ejection fraction, left ventricular mass index (LVMI), relative wall thickness, as well as systolic and diastolic blood pressures were similar in both groups. Women with endometriosis had higher CAVI than controls (mean [SD], 5.961 [0.644] vs 5.554 [0.654]; P = 0.001). Elevated arterial stiffness was observed in the endometriosis group also after adjustment for age and LVMI. CONCLUSIONS: Our results indicate increased arterial stiffness measured by CAVI in women with endometriosis. Therefore,clinicians should be aware that these patients may be at increased cardiovascular risk.

Experimental treatments of endometriosis.

Endometriosis is defined as the presence of endometrial gland and stroma outside the uterine cavity. It is an estrogen-dependent disease and is associated with chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. The treatment of endometriosis is conservative or radical surgery, medical therapies or their combination. All currently used hormonally active treatments are effective in the treatment of endometriosis; however, the adverse effects of these hormonal treatments limit their long-term use. Moreover, recurrence rates are high after cessation of therapy, and the treatments have no benefit in endometriosis-associated infertility. Therefore, researchers are working on new treatment modalities with improved side effects, mainly focusing on the molecular targets involved in etiopathogenesis of endometriosis. Here we summarized these novel treatments modalities.

Estrogen receptor alpha (Esr1) regulates aromatase (Cyp19a1) expression in the mouse brain.

OBJECTIVES: Local estrogen production in the brain regulates critical functions including neuronal development, gonadotropin secretion and sexual behavior. In the mouse brain, a 36 kb distal promoter (l.f) regulates the Cyp19a1 gene that encodes aromatase, the key enzyme for estrogen biosynthesis. In vitro, promoter l.f interacts with estrogen receptor alpha (Esr1) to mediate Cyp19a1 mRNA expression and enzyme activity in mouse hypothalamic neuronal cell lines. The in vivo mechanisms that control mammalian brain aromatase expression during fetal and adult development, however, are not thoroughly understood. Our aim was to elucidate the basis of the in vivo connection between Esr1 and Cyp19a1. METHODS: Pregnant mice were sacrificed at gestational days 9, 11, 13, 15, 16, 19, 21 and the brain tissues of the fetuses were harvested along with five newborns at the age of postnatal day 2. Esr1KO (female) were also sacrificed and their hypothalamus were excised out. Then both fetuses and adults RNA were isolated, reverse transcribed and amplified employing primers specific for Esr1 and Cyp19a1 with Real time PCR. RESULTS: In the fetal mouse brain, Cyp19a1 mRNA levels are inversely correlated with estrogen receptor alpha (Esr1) mRNA levels in a temporal manner. Moreover, Cyp19a1 mRNA levels increased in the hypothalamus of estrogen receptor-alpha knockout female mice (Esr1KO). CONCLUSION: Taken together, our findings might indicate that Esr1 has crucial roles in the in vivo regulation of aromatase expression in the brain during fetal and adult life.

Role of estrogen receptor-ß in endometriosis.

Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local aromatase expression. The question remains, then, what mediates estradiol action. Because estrogen receptor (ER)ß levels in endometriosis are >100 times higher than those in endometrial tissue, this review focuses on this nuclear receptor. Deficient methylation of the ERß promoter results in pathological overexpression of ERß in endometriotic stromal cells. High levels of ERß suppress ERα expression. A severely high ERß-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor and increased cyclo-oxygenase-2 levels contributing to progesterone resistance and inflammation. ERß-selective estradiol antagonists may serve as novel therapeutics of endometriosis in the future.

Outcomes of pregnancies complicated by hyperemesis gravidarum.

OBJECTIVES: To evaluate maternal and fetal outcomes among women with hyperemesis gravidarum (HG). METHODS: In a university hospital and a research and training hospital, a retrospective cohort study was conducted among women with singleton deliveries between 2003 and 2011. Maternal outcomes evaluated included gestational diabetes, pregnancy-induced hypertension, cesarean delivery. Neonatal outcomes also determined were 5-min Apgar score of less than 7, low birth weight, small for gestational age (SGA), preterm delivery, fetal sex, and stillbirth. RESULTS: There were no statistical differences in the mean of age, parity, the number of artificial pregnancy, and smoking between two groups. Infants from HG pregnancies manifested similar birth weight (3,121.5 ± 595.4 vs. 3,164 ± 664.5 g) and gestational age (38.1 ± 2.3 vs. 38.1 ± 2.6 weeks), relative to infants from the control group (p = 0.67 and 0.91, respectively). In addition, no statistical significant differences were found in the rates of SGA birth, preterm birth, gestational diabetes, pregnancy-induced hypertension, and adverse fetal outcome between two groups (p > 0.05). Cesarean delivery rates were similar in two groups (31.9% in hyperemesis group vs. 27% in control group, p = 0.49). Comparing the gender of the newborn baby and Apgar scores less than 7 at 5 min, there were no statistically significant differences between two groups (p = 0.16 and 0.42, respectively). CONCLUSION: Hyperemesis gravidarum is not associated with adverse pregnancy outcomes.

Cyclooxygenase-2 gene and epithelial ovarian carcinoma risk.

In this study, we aimed to investigate a possible association of the COX-2 polymorphisms (-765G→C and -1195A→G) and with the risk of developing epithelial ovarian carcinoma (EOC). COX-2 gene polymorphisms was investigated in 111 healthy women and 57 patients with EOC. Individuals who had -765 CG, -1195 AA genotype, and -765 C allele had increased risk for ovarian carcinoma (P < 0.01) and individuals with -765 GG, -1195 AG genotypes and -1195 G allele seem to be protected from ovarian carcinoma (P < 0.01). Haplotype analysis confirmed the association of COX-2 gene variants with ovarian carcinoma and revealed that the frequencies of -765C: -1195A haplotype frequencies was significantly higher in patients as compared with those of controls (P = 0.048). We state that there appears to be a modulating role for the COX-2 -1195A→G and -765G→C polymorphisms in the development of EOC. To the best of our knowledge, this is the first study to show such an association.

Genetic variants of vascular endothelial growth factor and risk for the development of endometriosis.

BACKGROUND/AIMS: Endometriosis is regarded as a complex disese, in which genetic and environmental factors contribute to the disease phenotype. Whether vascular endothelial growth factor (VEGF) -460 C/T and +405 G/C polymorphisms are associated with susceptibility to endometriosis was investigated. PATIENTS AND METHODS: Diagnosis of endometriosis was made on the basis of laparoscopic findings. Stage of endometriosis was determined according to the Revised American Fertility Society classification. Sixty out of the 112 women enrolled had no endometriosis, 11 had mild or early-stage endometriosis and 41 had severe endometriosis. Polymerase chain reaction (PCR), restriction fragment length polymorphism and agarose gel electrophoresis techniques were used to determine the -460 C/T and +405 G/C genotypes. RESULTS: The VEGF +405 G/C genotype frequencies among the cases and controls were CC 55.8% and 35%; GC 30.8% and 50.0%; GG 13.5% and 15.0%, respectively. The allelic frequencies were C 71.15% (cases) and 60.0% (controls) and G 28.8% (cases) and 40% (controls). Patients with endometriosis had a higher incidence of the VEGF +405 CC genotype compared with the controls (p=0.027). Women with VEGF +405 CC genotype had 2.3-fold higher risk for endometriosis. VEGF +405 GC genotype and G allele in the control group was higher than the endometriosis group (p=0.039, p=0.027 respectively). The VEGF -460 C/T genotype frequencies among the cases were CC 21.2%, CT 26.9% and TT 51.9%; the C and T allelic frequencies were 34.6% and 65.3%, respectively. The VEGF -460 genotype frequencies among the controls were CC 31.70%, CT 18.3% and TT 50.0%; the C and T allelic frequencies were 40.8% and 59.1%, respectively (p>0.05). There was linkage disequilibrium between VEGF -460 C/T and +405 G/C polymorphisms (D': 0.197, r(2)=0.013). We observed that the VEGF 460T/405C haplotype frequency was significantly higher in patients compared to controls (p=0.011). CONCLUSION: Our data suggest that the CC genotype of VEGF +405 and 460T/405C haplotypes of VEGF may be associated with the risk of endometriosis, but the G allele of VEGF +405 appears to be protective against endometriosis.

Association of CCL2 and CCR2 gene variants with endometrial cancer in Turkish women.

Chemokines and their receptors play diverse roles in malignant tumor progression, particularly as key mediators of tumor stroma interactions. C-C motif chemokine ligand 2 (CCL2) also called monocyte chemoattractant protein-1 (MCP-1), belongs to the C-C motif chemokine sub-family and is currently believed to mediate its actions through one receptor, C-C motif chemokine receptor 2 (CCR2). CCL2 has been identified as a major chemokine inducing the recruitment of macrophages in human tumors, including those of the bladder, cervix, ovary, lung and breast. In this study of Turkish women, the association of CCL2 A2518G and CCR2 V64I polymorphisms with endometrial cancer was investigated using 50 endometrial cancer patients and 211 controls. In our study, individuals with CCL2 A2518G GG genotype showed a 6.7-fold increased risk for endometrial cancer (p<0.0001) and individuals with CCL2 A2518G A allele had a 7.14-fold lower risk of endometrium cancer (p<0.0001). Individuals carrying the CCR2 64I/64I genotype had a 4.13-fold increased risk for endometrial cancer (p<0.0001). We also found that individuals carrying the CCR2 wt allele had a 4.16-fold lower risk for endometrial cancer (p=0.005). We observed that the CCL2 G: CCR2 64I haplotype frequency was significantly higher in patients compared to controls (p=0.019). In conclusion, we state that there appears to be an association between polymorphism of CCL2 and its receptor CCR2 and endometrial cancer. To the best of our knowledge, this is the first study to show such an association.

Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis.

Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)beta promoter resulting in pathologic overexpression of ERbeta in endometriotic stromal cells. We speculate that alterations in the relative levels of ERbeta and ERalpha in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERalpha-tauomicron-ERbeta ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERbeta and ERalpha leading to PR loss and progesterone resistance in endometriosis.

Association of interleukin 1beta gene (+3953) polymorphism and severity of endometriosis in Turkish women.

Endometriosis is regarded as a complex trait, in which genetic and environmental factors contribute to the disease phenotype. We investigated whether the interleukin (IL) 1beta (+3953) polymorphism is associated with the severity of endometriosis. Diagnosis of endometriosis was made on the basis of laparoscopic findings. Stage of endometriosis was determined according to the Revised American Fertility Society classification. 118 women were enrolled in the study. 78 women did not have endometriosis, 6 women had stage I, 3 had stage II, 13 had stage III and 18 had stage IV endometriosis. Polymerase Chain Reaction (PCR), Restriction Fragment Length Polymorphism (RFLP), and agarose gel electrophoresis techniques were used to determine the IL 1beta (+3953) genotype. Frequencies of the IL-1beta (+3953) genotypes in the control group were: CC, 0.397; TT, 0.115; CT, 0.487. Frequencies of the IL-1beta (+3953) genotypes in cases were: CC, 0.375; TT, 0.225; CT, 0.400. We found a 2.22 fold increase in TT genotype in the endometriosis group. However, the difference was not statistically significant (P > 0.05). We also observed an increase in the frequency of IL-1beta (+3953) T allele in the endometriosis group. However, the difference was not statistically significant. We also investigated the association between IL-1beta (+3953) polymorphism and the severity of endometriosis. The frequencies of CC+CT genotypes in stage I, III and IV endometriosis patients were 83.3, 84/6 and 72.2%, respectively; and TT genotypes were 16.7, 15.4 and 27.8%, respectively. We observed a statistically insignificant increase in TT genotype in stage IV endometriosis (P > 0.05). We suggest that IL-1beta (+3953) polymorphism is not associated with endometriosis in Turkish women.

Effect of vascular endothelial growth factor on sperm motility and survival.

Vascular endothelial growth factor (VEGF) and its receptors are present in both male and female reproductive systems. In this experimental study, the effect of different concentrations of VEGF on sperm motility and survival in vitro was investigated. Human spermatozoa, collected from voluntary, proven fertile donors, were incubated in sperm washing medium containing different concentrations of VEGF (5, 10, 15, 20 ng/ml) for 24 h in a university reproductive endocrinology laboratory setting. Assessment of VEGF action on sperm motion characteristics was evaluated using a computer-assisted semen analyser. Sperm survival was determined by hypo-osmotic swelling and eosin-Y dye tests. VEGF had a positive effect on some parameters of sperm motility in a concentration-dependent manner. Maximal effect was observed at a concentration of 15 ng/ml; motility, progression, straight-line velocity and curvilinear velocity of VEGF-exposed spermatozoa were significantly increased (P < 0.05) at this concentration. However, sperm viability was not prolonged at any concentration of VEGF as shown by hypo-osmotic swelling and eosin-Y dye tests. VEGF may increase some sperm motility parameters, but not survival, in a concentration-dependent manner in vitro.

Steroidogenic factor-1 and endometriosis.

Endometriosis is a common and chronic disease characterized by persistent pelvic pain and infertility. Estradiol is essential for growth and inflammation in endometriotic tissue. The complete cascade of steroidogenic proteins/enzymes including aromatase is present in endometriosis leading to de novo estradiol synthesis. PGE(2) induces the expression of the genes that encode these enzymes. Upon PGE(2) treatment, coordinate recruitment of the nuclear receptor SF-1 to the promoters of these steroidogenic genes is the key event for estradiol synthesis. SF-1 is the key factor determining that an endometriotic cell will respond to PGE(2) by increased estradiol formation. The presence of SF-1 in endometriosis and its absence in endometrium is determined primarily by the methylation of its promoter. The key steroidogenic enzyme in endometriosis is aromatase encoded by a single gene because its inhibition blocks all estradiol biosynthesis. Aromatase inhibitors diminish endometriotic implants and associated pain refractory to existing treatments in affected women.

Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis.

CONTEXT: Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E2 (PGE2) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream-transcription factor (COUP-TF) and Wilms' tumor-1 (WT1) in endometrium. OBJECTIVE: The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE2-stimulated estrogen production in endometriotic cells and endometrium. RESULTS: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells. CONCLUSION: Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.

Use of hematopoietic stem cells in obstetrics and gynecology.

Stem cells can be used in different areas of obstetrics and gynecology. Adult stem cells are specialized cells found within many tissues of the body where they function in tissue homeostasis and repair. In vitro they have been shown to differentiate into a wide variety of cell types. Hematopoietic stem cells (HSC) have been used to set up therapeutic strategies for the treatment of gynecological solid tumors such as ovarian cancer. Stem cells can be used for prenatal transplantation and in utero gene therapy. Also stem cells can be used in infertility and IVF for research and treatment.

Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis.

Local estrogen biosynthesis is a major factor in the pathogenesis of endometriosis. Aberrant expression of steroidogenic acute regulatory protein (StAR) and aromatase in endometriotic tissue leads to an up-regulation of estrogen production. The transcription factor steroidogenic factor-1 (SF-1) activates the promoters of both StAR and aromatase in endometriotic tissue. We investigated differences in SF-1 expression in endometriotic tissue and normally located endometrium to elucidate the mechanism underlying increased StAR and aromatase activities in endometriosis. Serial deletion and site-directed mutants of the SF-1 promoter showed that an E-box sequence was critical for its activity in endometriotic stromal cells. EMSAs showed that the upstream stimulatory factor (USF) 1 and 2 in nuclear extracts from endometrial and endometriotic stromal cells bound to the E-box. Chromatin-immunoprecipitation-PCR assay, however, demonstrated in intact cells that binding activity of USF2 to the SF-1 promoter was strikingly higher than that of USF1 in endometriotic stromal cells and that USF1 or USF2 binding activity was hardly detectable in endometrial stromal cells. Moreover, knockdown of USF2 but not USF1 resulted in robust and consistent down-regulation of SF-1 and its target genes StAR and aromatase in endometriotic stromal cells. USF2 but not USF1 mRNA and protein levels were significantly higher in endometriotic vs. endometrial stromal cells. In vivo, USF2 mRNA and immunoreactive USF2 levels in endometriotic tissues were strikingly higher than those in endometrium. Taken together, the elevated levels of USF2 in endometriosis account for, in part, the aberrant expression of SF-1 and its target gene StAR and aromatase.

Aromatase excess in cancers of breast, endometrium and ovary.

Pathogenesis and growth of three common women's cancers (breast, endometrium and ovary) are linked to estrogen. A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less clear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kb 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. In cancers of breast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter I.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE(2) via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE(2) secreted by malignant epithelial cells, PKC is also activated, and this potentiates cAMP-PKA-dependent induction of aromatase. Thus, inflammatory substances such as PGE(2) may play important roles in inducing local production of estrogen that promotes tumor growth.

Letrozole versus human menopausal gonadotrophin in women undergoing intrauterine insemination.

This pilot study was conducted to compare the results of intrauterine insemination (IUI) under ovarian stimulation with either letrozole (Femara) or human menopausal gonadotrophin (HMG). A randomized controlled trial was conducted. Eighty women aged 20-35 years with unexplained infertility of at least 2 years' duration were randomized according to a computer-generated randomization list into the letrozole group and the HMG group. Letrozole was administered at 5 mg/day from day 3 to day 7 of the IUI cycle. HMG injections were started on day 3 at a dose of 75 IU for women under 30 years old and 150 IU for women over 30 years old and monitored periodically by vaginal ultrasound and oestradiol concentrations. The variables selected for analysis were clinical pregnancy rate, endometrial thickness, length of follicular phase and number of preovulatory follicles. No statistically significant difference in clinical pregnancy rates per cycle was found for patients in the letrozole or HMG group (18.4 versus 15.7%). Cost was significantly higher in the HMG stimulation cases (P < 0.001) and no injections were required in the letrozole group. In conclusion, letrozole offers a new treatment regimen in ovarian stimulation regimens for IUI that is cost effective, simple and convenient for the patients.