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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]

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]

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]

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]

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]

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]

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]