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Abstract: Objectives: The present study aims to establish the levels of acylated ghrelin, desacylated ghrelin, obestatin and preptin, during pregnancy and the postpartum period in pregnant women with Gestational Diabetes Mellitus (GDM) and healthy pregnancy women. Design and methods: The study registered 20 pregnant women with GDM and 20 healthy pregnant women. Fasting venous blood samples were collected from all cases between weeks 24 and 28 of pregnancy and after 24h postpartum. Hormones were analyzed using ELISA method. Results: Serum acylated ghrelin (p:0.001), desacylated ghrelin (p:0.001), obestatin (p:0.006) and preptin (p:0.001) levels were all found statistically higher in both groups during the postpartum period, when compared to the pregnancy period. A positive correlation was established between desacylated ghrelin and acylated ghrelin (p:0.008), desacylated ghrelin and preptin (p:0.012) and preptin and insulin (p:0.039) in the GDM group during pregnancy. Conclusions: The studied hormones (especially desacylated ghrelin and obestatin) are critical in GDM pathophysiology based on the comparison of measure after and before the delivery. [Copyright &y& Elsevier]

To investigate the severity of pain and circadian changes in uterine artery blood flow in primary dysmenorrhea cases. The study included 27 cases diagnosed as primary dysmenorrhea and 25 individuals who had no dysmenorrhea complaint. Bilateral uterine artery systole/diastole rates (S/D), pulsatility indices (PI) and resistance indices (RI) of all cases were measured using transvaginal colour Doppler at 12.00–02.00 p.m. and 12.00–02.00 a.m. Severity of pain was evaluated in dysmenorrhea cases at the same hours using a verbal pain assessment scale. Doppler measurements of dysmenorrhea cases conducted at 12.00–02.00 p.m. showed right uterine artery S/D: 3.37 ± 0.26, RI: 0.73 ± 0.07, PI: 2.38 ± 0.34 and left uterine artery S/D: 3.33 ± 0.37, RI: 0.74 ± 0.14, PI: 2.41 ± 0.15, while measurements carried out at 12.00–02.00 a.m. showed right uterine artery S/D: 3.88 ± 0.12, RI: 0.87 ± 0.14, PI: 2.94 ± 0.21 and left uterine artery S/D: 3.90 ± 0.27, RI: 0.92 ± 0.12, PI: 2.93 ± 0.21. Comparisons revealed significantly higher Doppler indices at night ( P < 0.05) than in the day in dysmenorrhea cases. There was not any significant circadian difference in individuals who did not have dysmenorrhea ( P > 0.05). Pain score in the verbal pain assessment of dysmenorrhea cases was found 3.6 ± 1.4 in the day and 5.8 ± 1.7 at night. The difference was found significant ( P < 0.05). Uterine artery blood flow is reduced at night in dysmenorrhea cases. In correlation with this, the cases feel more pain at night. Our results may be important on the planning of working hours and their quality of life. [ABSTRACT FROM AUTHOR]

To examine the efficacy of venlafaxine, which is used as an antidepressant, in the treatment of stress urinary incontinence. The study was designed as a placebo-controlled, double-blind and randomized clinical study. Patients in Group 1 ( n = 20) were administered 75 mg venlafaxine, those in Group 2 ( n = 20) were administered placebo for 12 weeks. All the cases were evaluated in terms of weekly incontinence episode frequency (IEF), change in void interval (VI), the Incontinence Quality of Life (I-QOL) in weeks 0, 4, 8 and 12. Additionally, PGI-S was assessed at baseline and was followed by PGI-I evaluations in weeks 4, 8 and 12. Evaluations in weeks 0, 4, 8 and 12 did not show any significant difference in IEF, VI, IQOL and PGI-I values of placebo group ( p > 0.05). However, in the patients who were administered venlafaxine declines in IEF and PGI-I values as well as the elevations in VI and IQOL scores showed significant changes parallel to the increasing follow-up period ( p < 0.05). Nausea was observed in 40% of cases in venlafaxine group, and 15% of those in placebo group ( p < 0.05). It was seen in our study that efficacy of venlafaxine started early and the clinical efficacy associated with the use of the drug continued in the following months. Venlafaxine should be considered a clinically efficient alternative drug in the treatment of SUI. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To examine the effects of hysterectomy and bilaterally salpingo-oophorectomy (BSO) on Female Sexual Function Index (FSFI) in the post-menopausal women. Method: This study included 92 women who underwent vaginal hysterectomy (VH) and BSO (n:37) and who underwent abdominal hysterectomy (AH) and BSO (n:55). Estrogen replacement therapy (ERT) was given 21 women who underwent VH and BSO and 28 women who underwent AH and BSO in pre- and postoperative periods. All patients were evaluated preoperatively and postoperative 6th month in terms of FSFI scores. Results: It was found that hysterectomies by abdominal or vaginal routes reduced FSFI scores significantly (P <0.05). The use of ERT were no effect on total score of FSFI in AH and BSO (P >0.05). ERT prevented deterioration of FSFI in women who underwent VH relative to preoperative values but AH. Conclusion: Hysterectomy causes unfavourable effects on sexual functions at least in the first 6 postoperative months and this negative effect can not be repaired by estrogen replacement therapy in AH and BSO. [Copyright &y& Elsevier]

Uterine leiomyomas are the most common benign tumours of the female genital tract, often necessitating hysterectomy. The most common symptoms are dysmenorrhoea, menorrhagia, infertility and abortion. Ovarian hormones seem to play an essential role in pathogenesis, and deprivation of ovarian oestrogen causes leiomyomas to shrink significantly. The purpose of this study was to evaluate the effects of the non-steroidal aromatase inhibitor letrozole on uterine leiomyomas and on bone metabolism. A prospective, open clinical trial was conducted in a university-based hospital. Sixteen premenopausal women with symptomatic uterine leiomyomas were treated with letrozole 5 rag/day orally for 3 months. The main outcome measures of uterine and uterine leiomyoma sizes, serum FSH, LH, oestradiol concentrations, ovarian volumes and myoma-related symptoms were noted at baselines and once a month during treatment. Lumbar spine bone mineral density and biochemical markers of bone metabolism were studied at the beginning and at the end of 3 months. Letrozole significantly decreased uterine leiomyoma sizes (P < 0.01) and promptly benefited women with heavy menstrual bleeding associated with leiomyomas without changing bone mineral density. Aromatase inhibitors may represent a new generation of medications for the treatment of leiomyoma and associated symptoms, Larger clinical trials are needed, however, to fully evaluate their safety and efficacy. [ABSTRACT FROM AUTHOR]

Binding activity of steroidogenic factor-1 (SF-1) to promoters of the majority of steroidogenic genes in response to gonadotropins is a critical mechanism that regulates steroidogenesis in gonads. Thus, the modulation of SF-1 action may be essential for the differential regulation of formation of sex steroids in the ovary. Aromatase P450 (P450arom) is the rate-limiting enzyme for estrogen formation. In this study, we characterize another nuclear receptor half site in the gonadal aromatase promoter which we show to be important for aromatase regulation. We also show herein that the stimulation of P450arom promoter activity by SF-1 in ovarian granulosa, testicular Sertoli and JEG-3 choriocarcinoma cells is inhibited by two transcription factors, Wilms’ tumor suppressor gene (WT1) and dosage sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1). Given the characterized roles of these transcription factors in gonadal development and function, modulation of SF-1 action by WT1 and DAX-1 may represent an important key mechanism in steroidogenesis. [Copyright &y& Elsevier]

Estrogen is produced in a number of human tissues including the ovary, placenta and extraglandular sites such as adipose tissue, skin and the brain. Aromatase is the key enzyme that regulates estrogen formation in these tissues. Aromatase activity is not detectable in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis and is stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, i.e. deficient 17β-hydroxysteroid dehydrogenase (17β-HSD) type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in 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. [Copyright &y& Elsevier]

Abstract: Objectives: The goal of this study was to compare levels of acyl and des-acyl ghrelin, obestatin, nesfatin-1 and leptin in healthy gravidas to hyperemesis gravidarum (HG) patients. Design and methods: Twenty pregnant women with HG and twenty healthy pregnant women all of similar ages, BMI and all at similar pregnancy development comprised the study cohort. Fasting serum samples were obtained and measured for acyl and des-acyl ghrelin, leptin, obestatin and nesfatin-1. Results: Nesfatin-1 concentrations in the HG group were higher compared to the control group whereas; leptin concentrations during pregnancy were lower in the HG group as compared to the control group. The two groups did not differ with regard to acyl and des-acyl ghrelin and obestatin. Conclusion: This pilot study suggests a possible role of leptin and nesfatin-1, which might be involved in the pathology of the disease. [Copyright &y& Elsevier]

Primitive neuroectodermal tumors of uterus (PNET) are extremely rare in tumors of the female genital system and therefore there is no sufficient information about their diagnosis, treatment, and follow-up. The case is a 32-year-old, operated in emergency conditions due to intra-abdominal hemorrhage, and discusses our diagnosis and treatment approaches in the light of literature data. To the best of our knowledge, this is first report of uterine PNET that presented with intraabdominal hemorrhage due to uterine rupture. Despite advances in therapy, the prognosis is poor. The low number of these cases precludes accurate standardization of therapy. [ABSTRACT FROM AUTHOR]

Aim: : To measure obestatin levels in the blood and saliva samples of normal-weight patients with polycystic ovary syndrome (PCOS) in comparison with normal-weight healthy controls, and to determine whether there were relationships between blood and/ or salivary obestatin levels and other measured parameters. Materials and Methods: Fifteen healthy women and 15 patients with PCOS, all of which had normal weight, were included in the study. Participants' age, height, weight, menstrual characteristics, hormone levels, body mass index, waist/hip ratio, and modifed Ferriman-Gallwey (FG) scores were recorded. Obestatin levels were measured in both fasting blood and saliva samples. Homeostasis Model Assessment (HOMA-IR) was used to predict insulin resistance. Results: In the PCOS group, menstrual cycle duration and FG scores were signifcantly higher (P-value, <0.001, <0.001, respectively). The levels of luteinizing hormone, total testosterone and androstenedione were signifcantly higher in the PCOS group than in the control group (P-value, 0.001, 0.009, 0.004, respectively). In the PCOS group, blood obestatin level was 1265.2 ± 221.9 pg/ml, salivary obestatin level was 3095.33 ± 310.2 pg/ml; whereas the control group demonstrated lower levels of 939.66 ± 72.3 pg/ml and 2611.20 ± 217.1 pg/mL, respectively. However, no statistically signifcant difference was found between the PCOS and control groups when comparing obestatin levels in blood or saliva (P-value, 0.218, 0.369, respectively). No correlation was found between blood and salivary obestatin levels in either group. Finally, obestatin levels were not associated with any of the other measured parameters. Conclusion: Our results suggest that increased levels of obestatin, albeit in a small amount that would not be statistically signifcant in normal weight patients with PCOS, may have signifcant effects on weight control in these patients. In addition, our fndings show that saliva sample can be used as an alternative to blood sample in the measurement of obestatin level in patients with PCOS. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a medical case study of a 72-year-old woman who has a basal cell carcinoma and its treatment.

Highlights: [•] The human mammary gland is immunopositive for preptin, salusins and hepcidins. [•] Breast milk contains preptin, salusins and hepcidins. [•] Preptin and hepcidin concentrations are higher during lactation time points in women with gestational diabetes mellitus. [•] Colostrum preptin and hepcidin levels are higher than the corresponding plasma levels. [•] Salusins are lower in gestational diabetes mellitus. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effects of ovulation induction agents on the ovarian surface epithelium in rats. Sixty adult females were randomly divided into six groups, each containing 10 rats. In four of these groups ovulation induction was applied with six cycles of clomiphene citrate, human menopausal gonadotrophin (HMG), recombinant FSH (rFSH) or human chorionic gonadotrophin (HCG), respectively, followed by unilateral oophorectomy, and another six cycles of the same treatment. After a total of 12 cycles of ovulation induction, the remaining ovary was taken out and the alterations in ovarian surface epithelium were examined. No malignancies were observed on the ovarian surface epithelium of the rats that were given clomiphene citrate, rFSH or HMG as ovulation induction agents, while identification rates of histopathological parameters constituting epithelial dysplasia were found to be significant (P < 0.05). There was no significant dysplasia in the epithelium of the group which was given HCG only, relative to control groups. The findings suggest that the ovulation induction agents except for HCG bring about dysplasia in the ovarian surface epithelium. It is not clear whether these dysplasias are precursory lesions of ovarian malignancies. [ABSTRACT FROM AUTHOR]

To determine the prevalence of primary dysmenorrhea and attitudes and behavior toward dysmenorrhea in the female students of an university toward this problem. A total of 1,266 female university students were anonymously surveyed by doctors. It was found that mean age of the surveyed students was 21.02 ± 2.13 years, mean menarche age was 13.3 ± 1.4 years, and menstruation frequency was 32.58 ± 19.8 days. Of the students, 45.3% were found to suffer pain in each menstruation, 42.5% in some and 12.2% in none. Of those with primary dysmenorrhea, 66.9% were established to take analgesic drugs. Prevalence of primary dysmenorrhea was found higher than that cited in the literature. It was established that although the rate of consultation with health professionals about menstruation and related changes was low, use of agents known to be effective in primary dysmenorrhea treatment was highly common. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of inhibiting aromatase activity on endometrial lesion growth and aromatase expression in a baboon model of induced endometriosis.Design: Prospective study.Setting: Primate research institute.Animal(s): Sixteen olive baboons.Intervention(s): Sixteen olive baboons with induced endometriosis were examined with laparoscopy 10 months after disease inoculation. Animals in group 1 (n = 10) were treated with 1.25 mg/d of the aromatase inhibitor (AI) letrozole, and animals in group 2 (n = 6) were given a placebo for a total of 6 months.Main Outcome Measure(s): Total number of endometriotic lesions, morphology, and volume of lesions, as well as semiquantitative reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction for levels of aromatase cytochrome messenger RNA were measured. Ovarian volumes were evaluated before treatment initiation and every 2 months during the study.Result(s): Treatment of group 1 animals with an AI significantly decreased lesion volume from baseline measurements, whereas the placebo-treated animals showed an increase in lesion volume. Aromatase messenger RNA levels in lesions in the AI-treated animals were significantly lower compared with the placebo-treated animals. Ovarian volumes were significantly increased at 6 months of AI treatment compared with pretreatment volumes.Conclusion(s): These findings suggest that suppression of aromatase cytochrome P450 may inhibit the in vivo growth of endometriotic lesions in baboons. [ABSTRACT FROM AUTHOR]

Objective. To determine the effects of Mullerian inhibiting substance (MIS) treatment on endometriosis cells through study of apoptosis and autophagy. Design. Experimental in vitro study. Setting. University research laboratory. Cell Line. CRL-7566 endometriosis cell line. This line was established from a benign ovarian cyst taken from a patient with endometriosis. Interventions. In vitro treatment with MIS. Main Outcome Measures. The main outcome measures were cellular viability, proliferation, cell-cycle arrest, and induction of apoptosis and autophagy in endometriotic cells. Results. MIS treatment inhibited proliferation of endometriosis cells and induced apoptosis, as indicated by Annexin V staining, and induced caspase-9 cleavage and cell-cycle arrest, as evidenced by increased expression of p27 CDK-inhibitor. MIS treatment also induced autophagy in endometriosis cells as demonstrated by a significant increase in LC3-II induction, a hallmark of autophagy. Conclusions. MIS inhibits cell growth and induces autophagy, as well as apoptosis, in ectopic endometrial cell lines. Our results suggest that MIS may have a potential as a novel approach for medical treatment of endometriosis. Further studies may be needed to test the efficacy of MIS treatment in animal models and to develop MIS treatment specifically targeted to the endometriosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate ghrelin and obestatin expression in serous ovarian tumours. Materials and methods: Preparations of deparaffinized blocks obtained from the pathology archives of a total of 47 previously diagnosed cases of benign serous tumour ( n = 20), borderline serous tumour ( n = 7) and malignant serous tumour ( n = 20) were subjected to immunohistochemical examination to find out ghrelin and obestatin expressions. Results: Mean ghrelin expressions decreased significantly in the benign group, relative to the malignant group ( p < 0.05), while there was no significant change in mean obestatin expression. It was established that rates of preparations with moderate and severe ghrelin and obestatin expression displayed a significant increase from benign to malignant ones ( p < 0.05). Conclusion: The fact that rates of preparations with severe expression correlated with an increase in malignancy suggests that ghrelin and obestatin may be effective in the malignant transformation in at least some cases. [ABSTRACT FROM AUTHOR]

Background. Endometrium carcinoma ranks fourth among female carcinomas. Therefore, early diagnosis of endometrium pre-malignant lesions is emphasised, and attempts are made to identify the risk factors. Since hyperplasias, particularly those with atypia, are held responsible for the development of the most common endometrium carcinomas, it is important to definitely distinguish between well-differentiated carcinomas and hyperplasia with atypia. In the present study, we aimed to explore whether ghrelin expression had a role in distinguishing between benign, pre-malignant and malignant lesions of endometrium. Methods. Tissue ghrelin expressions of a total of 60 cases, who were diagnosed in the Pathology Department Laboratory of Fıırat University Medical School, and of whom 10 were in the proliferation phase, 10 had simple hyperplasia without atypia, 10 had simple hyperplasia with atypia, 10 had complex hyperplasia without atypia, 10 had complex hyperplasia with atypia and 10 had endometrioid carcinoma cases, were examined using immunohistochemical method. Additionally, tissue samples were homogenised to analyse tissue ghrelin levels in the supernatants according to RIA method. Samples from the parotid glands were used as positive control for ghrelin. Cells that exhibited cytoplasmic staining with ghrelin antibody were evaluated as positive. Results. Immunohistochemical examination showed that ghrelin expression increased markedly in the proliferation phase, relative to hyperplasias and carcinoma. These results were parallel to ghrelin levels in tissue supernatants. Immunohistochemical and RIA analysis results indicate that ghrelin expression either markedly decreases or is entirely depleted in endometrial carcinomas. Conclusions. Therefore, we think that ghrelin expression can be useful in differentiating not only endometrium carcinomas from benign lesions but also complex hyperplasias with atypia, which pose diagnostic difficulties. [ABSTRACT FROM AUTHOR]

Abstract: 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. PGE2 induces the expression of the genes that encode these enzymes. Upon PGE2 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 PGE2 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. [Copyright &y& Elsevier]

Abstract: Objective: The peptide hormones ghrelin and leptin have been found in blood and breast milk. This study was undertaken to investigate whether breast milk also contains obestatin, which is derived from the same gene as ghrelin but has opposite actions, and to characterize the relations among serum and milk ghrelin, obestatin, and leptin levels in lactating mothers. Methods: Venous blood, colostrum, and mature milk were obtained from healthy lactating women (n = 31) just before suckling. The ghrelin and obestatin concentrations were determined by radioimmunoassay. Leptin levels were measured by enzyme-amplified sensitivity immunoassay. Results: Obestatin levels in colostrum (538.9 pg/mL) and mature milk (528.5 pg/mL) were more than twice the corresponding blood levels (270.3 and 289.4 pg/mL, respectively). In contrast, leptin levels in colostrum (2.01 ng/mL) and mature milk (2.04 ng/mL) were more than five-fold lower than the corresponding blood levels (11.54 ng/mL). There was no correlation between breast milk ghrelin levels and leptin (r = −0.18, P > 0.05). However, there was a positive correlation between leptin levels in breast milk and blood (r = 0.369, P < 0.05). Conclusion: The origin of milk obestatin is not currently known, but it comes from the blood or breast and may drain through the mammary glands into the milk. Ghrelin, obestatin, and leptin in the milk may directly affect appetite and their levels may be related to the regulation of energy balance and the pathogenesis of obesity. [Copyright &y& Elsevier]

Since sex hormones are reported to have important roles in the regulation of immune function, this study was designed to investigate the effects hormone replacement therapy (HRT) and raloxifene (RAL) on serum cytokine concentrations in healthy postmenopausal women. Fifty-three healthy postmenopausal women were randomly assigned and treated by RAL (Group I, [RAL 60 mg daily and continuously], n = 16), HRT (Group II, [2 mg estradiol valerat + 2 mg dienogest, continuously] n = 18) or placebo (Group III, n = 19). Two fasting morning blood samples were obtained from each participant before and 3 months after the treatments. Serum concentration of interleukin (IL)-4 (as a Th2 cytokine) and transforming growth factor-beta (TGF-β)1 (as a Th3 cytokine), were measured by using commercially available enzyme-linked immunosorbent assay kits. Kruskal–Wallis analysis of variance, Mann–Whitney U, and Wilcoxon Signed-Ranks Tests were used as necessary. At the beginning of the study, the chronological ages, menopausal ages, years of amenorrhea, weights, body mass indexes, and blood pressures were not significantly different between groups ( P < 0.05). RAL treatment caused a significant decrease on serum IL-4 concentration ( P < 0.001). Although HRT caused a 14% decrease in serum IL-4 concentration, this decrease was not statistically significant ( P > 0.05). Serum TGF-β1 concentrations were significantly decreased by HRT when compared to basal value ( P < 0.001), and to control ( P < 0.05). RAL treatment has no significant effect on serum TGF-β1 concentration ( P > 0.05). It seems that RAL treatment might cause a decrease in serum IL-4 concentration while valerate plus dienogest treatment as HRT seems to cause a Th3 tendency in healthy postmenopausal women. [ABSTRACT FROM AUTHOR]

Aim. The present study was designed to investigate the effects of two aromatase inhibitors on steroid hormone levels, bone mineral density (BMD) and bone turnover markers in intact female rats. Methods. Letrozole and anastrazole at two different dose levels were investigated for their effect on serum levels of estradiol, androstenedione, testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulfate, BMD of femur and dorsal spine, and osteocalcin and pyridinoline levels as bone turnover markers. Fifty intact female rats were randomly divided in five groups (group 1 (n = 10): control, 2 ml saline; group 2 (n = 10): letrozole 1 mg/kg; group 3 (n = 10): letrozole 2 mg/kg; group 4 (n = 10): anastrazole 0.1 mg/kg; group 5 (n = 10): anastrazole 0.2 mg/kg), and oral gavages were applied for a period of 16 weeks. Results. Both doses of letrozole and anastrazole did not change femoral and vertebral BMD. Serum estradiol levels were reduced significantly at all dose levels by both agents (p < 0.001); all androgen levels were significantly elevated by letrozole (p < 0.05), although anastrazole increased only androstenedione (p < 0.05). The higher dose of letrozole increased osteocalcin levels (p < 0.05), while pyridinoline levels were increased (p < 0.05) by the higher dose of anastrazole. Conclusion. Our results indicate that short-term use of letrozole and anastrazole had no clear effects on BMD in intact rats. Further investigations are needed to understand their effects on bone metabolism in intact females. [ABSTRACT FROM AUTHOR]

Abstract: 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 215bp from each other and are coordinately stimulated by PGE2 via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE2 secreted by malignant epithelial cells, PKC is also activated, and this potentiates cAMP-PKA-dependent induction of aromatase. Thus, inflammatory substances such as PGE2 may play important roles in inducing local production of estrogen that promotes tumor growth. [Copyright &y& Elsevier]

Abstract: Endometrial tissue from uterine disease-free women does not exhibit aromatase activity. In contrast, aromatase enzyme activity and mRNA levels are readily detectable in endometriosis. PGE2 stimulates both aromatase expression and activity in endometriotic stromal cells via promoter II region of the aromatase gene. This results in local production of estradiol, which induces PGE2 formation and establishes a positive feedback cycle. This mechanism seems to contribute to continuous production of estradiol and PGE2. Aromatase mRNA levels and enzyme activity are also present in uterine leiomyomata that are estrogen-dependent benign tumors of the myometrium. Successful treatment of endometriosis and uterine leiomyomata using aromatase inhibitors by recent pilot trials underscores the clinical significance of these molecular studies. [Copyright &y& Elsevier]

To determine the role of P and its nuclear receptor PR in the growth of ectopic uterine tissue of mice with or without a disrupted PR gene.Animal study.Academic medical center.Female wild-type (WT) and transgenic knockout mice for P receptor (PRKO).Endometriosis was induced in the following groups of ovariectomized adult mice: [1] untreated WT, [2] estradiol (E2)-treated WT, [3] P-treated WT, [4] E2 + P-treated WT, [5] untreated PRKO, [6] E2-treated PRKO, and [7] E2 + P-treated PRKO (n = 5 in each group).The size of ectopic uterine tissue in WT and PRKO mice were compared between the groups subjected to treatments with P or E2. Tissue proliferating cell nuclear antigen (PCNA) levels were compared among these groups.Treatment with P only significantly decreased the size of WT ectopic uterine tissue. The untreated PRKO ectopic uterine tissue was significantly larger than WT tissue. Estradiol increased the size of ectopic uterine tissues, and this E2-dependent growth could be suppressed by P in WT tissues but not in PRKO tissues. Finally, the hormone-dependent changes in ectopic uterine tissue size were accompanied by comparable alterations in PCNA levels.Intact PR in ectopic uterine tissue is essential to abolish E2-dependent or -independent proliferation. We also suggest that ectopic uterine tissue is associated with significantly increased resistance to P action and increased predisposition to E2-dependent proliferation in the absence of PR. Overall, these findings support the hypothesis that P resistance in human endometriosis may be due to the absence of sufficient levels of functional PR in this tissue. [Copyright &y& Elsevier]

: ObjectiveTo determine the role of an aromatase inhibitor, letrozole, in the treatment of reproductive-age women with endometriosis and associated chronic pelvic pain.: DesignPhase 2, open-label, nonrandomized proof-of-concept study.: SettingOutpatient tertiary-care center.: Patient(s)Ten patients with endometriosis, all previously treated both medically and surgically, with unsatisfactory results.: Intervention(s)Endometriosis was diagnosed by biopsy and scored from an initial diagnostic laparoscopy performed within 1 month before treatment was begun. Oral administration of letrozole (2.5 mg), the progestin norethindrone acetate (2.5 mg), calcium citrate (1,250 mg), and vitamin D (800 IU) was done daily for 6 months. Within 1–2 months after completion of the treatment, a second-look laparoscopy was performed to score and biopsy endometriosis.: Main outcome measure(s)Changes in American Society for Reproductive Medicine (ASRM) scores for endometriosis, pelvic pain assessed by visual analog scale, serum hormone levels (FSH, LH, E2, and estrone [E1]), and bone density (DEXA scan).: Result(s)No histologically demonstrable endometriosis was present in any patient during the second-look laparoscopy. ASRM and pelvic pain scores decreased significantly in response to treatment. Overall, no significant change in bone density was detected. Gonadotropin levels were not significantly altered by treatment, and although circulating E2 and E1 levels were reduced, the decrease was not statistically significant.: Conclusion(s)The combination of letrozole and norethindrone acetate achieved marked reduction of laparoscopically visible and histologically confirmed endometriosis in all 10 patients and significant pain relief in nine out of 10 patients who had not responded previously to currently available treatments. On this basis, letrozole should be a candidate for the medical management of endometriosis. [Copyright &y& Elsevier]