PURPOSE: Diabetes profoundly and negatively impacts all domains of female sexual function, however, the underlying pathophysiological mechanisms remain unknown. To date, limited studies have been published on the effects of type 1 & type 2 diabetes on female genital sexual arousal and how this may impact overall sexual function. The aim of this review is to discuss the effects of diabetes on female sexual function and insights from laboratory studies on the underlying pathophysiology. MATERIALS AND METHODS: Using PubMed, we reviewed and evaluated the literature published between 1970 and 2009 and data from our laboratories and others investigating the effects of type 1 and type 2 diabetes on genital sexual arousal responses. RESULTS: Women with diabetes experience diminished genital arousal, reduced vaginal lubrication, vaginal atrophy, dyspareunia, and increased vaginal infections. Also, a number of studies using type 1 and type 2 diabetic animal models have reported reduced plasma estradiol levels and marked physiological, biochemical and histological changes in genital tissues. In animal studies, diabetes alters genital tissue structure and attenuates expression of the estrogen, progesterone and androgen receptors and alters vaginal and clitoral hemodynamics. Importantly, treatment of diabetic animals with estradiol in the face of persistent hyperglycemia can restore vaginal structure and sex steroid receptor expression. CONCLUSIONS: Type 1 & type 2 diabetic complications produce significant structural and functional disruptions in genital organs and attenuate genital hemodynamics. In the type 2 animal model, estradiol treatment ameliorates diabetic-induced pathophysiological alterations in genital tissues, such as the vagina. This suggests that estrogen supplementation may be beneficial in restoring diabetes-induced genital pathology.
Animals ; Arousal ; Atrophy ; Clitoris ; Diabetes Complications ; Diabetes Mellitus ; Dyspareunia ; Estradiol ; Estrogens ; Female ; Genitalia ; Hemodynamics ; Humans ; Hyperglycemia ; Lubrication ; Models, Animal ; Plasma ; Progesterone ; Receptors, Androgen ; Receptors, Steroid ; Testosterone ; Vagina

OBJECTIVE: The fallopian tubes play a critical role in the early events of fertilization. The rapid innate immune defense is an important part of the fallopian tubes. Toll-like receptor 3 (TLR3), as a part of the innate immune system, plays an important role in detecting viral infections. In this basic and experimental study, the effect of sex hormones on the function of TLR3 in the OE-E6/E7 cell line was investigated. METHODS: The functionality of TLR3 in this cell line was evaluated by cytokine measurements (interleukin [IL]-6 and IL-1b) and the effects of sex hormones on TLR3 were tested by an enzyme-linked immunosorbent assay kit. Additionally, TLR3 small interfering RNA (siRNA) and a TLR3 function-blocking antibody were used to confirm our findings. RESULTS: The production of IL-6 significantly increased in the presence of polyinosinic-polycytidylic acid (poly(I:C)) as the TLR3 ligand. Using a TLR3-siRNA-ransfected OE-E6/E7 cell line and function-blocking antibody confirmed that cytokine production was due to TLR3. In addition, 17-β estradiol and progesterone suppressed the production of IL-6 in the presence and absence of poly(I:C). CONCLUSION: These results imply that sex hormones exerted a suppressive effect on the function of TLR3 in the fallopian tube cell line when different concentrations of sex hormones were present. The current results also suggest that estrogen receptor beta and nuclear progesterone receptor B are likely to mediate the hormonal regulation of TLR3, as these two receptors are the main estrogen and progesterone receptors in OE-E6/E7 cell line.
Cell Line ; Enzyme-Linked Immunosorbent Assay ; Epithelial Cells* ; Estradiol ; Estrogen Receptor beta ; Estrogens ; Fallopian Tubes* ; Female ; Fertilization ; Gonadal Steroid Hormones* ; Immune System ; Immunity, Innate ; Interleukin-6 ; Poly I-C ; Progesterone ; Receptors, Progesterone ; RNA, Small Interfering ; Toll-Like Receptor 3* ; Toll-Like Receptors*

OBJECTIVE: The object of this study was to provide a better understanding of the roles played by sex hormones in ovarian carcinogenesis. METHODS: 1) The expressions of estrogen receptor-alpha and -beta, progesterone receptor A and B, androgen receptor in normal ovarian tissue, benign, borderline, and malignant ovarian tumor were analyzed using immunohistochemical stains. 2) Expression of mRNA of sex hormone receptors of cell lines from postmenopausal normal surface epithelial cells, ovarian cancer, and breast cancer were studied using real time quantitative PCR methods. 3) Expression of PR isoforms after treatment with estradiol, expression of AR after treatment with testosterone were analyzed using RT-PCR and immunoblotting methods. 4) Apoptosis after treatment with levonorgestrel in cell lines from ovarian cancer were analyzed using flowcytometry. RESULTS: There was no significant difference in results shown by immunohistochemical staining between sex hormonal receptors of normal ovarian tissue (n=8), benign tumor (n=10), borderline tumor (n=8) and malignant tumor (n=24) according to malignant change. But, PRA was significantly reduced in epithelial ovarian cancer. 1) Expressions of ER-alpha and ER-beta, PRA, PRB and AR mRNA were seen in normal ovarian epithelial cells. 2) Deletion of exons of ER-alpha, ER-alpha wild type and variant, ER-beta variant were seen in many cell lines. 3) Down regulation of PR mRNA isoforms (especially PRA) in cell lines of ovarian cancer. 4) Flowcytometry showed that apoptotic cells markedly increased during exposure of progestins in ovarian cancer cell lines. CONCLUSION: These results suggest that down-regulation of ER-alpha and PRA is associated with the development of ovarian epithelial carcinoma. Progestins can activate the apoptotic pathway in the ovarian epithelium for protection of normal tissue from neoplastic transformation suggests that progestins deserve further evaluation as potential ovarian cancer preventive agents.
Apoptosis ; Breast Neoplasms ; Carcinogenesis ; Cell Line ; Coloring Agents ; Down-Regulation ; Epithelial Cells ; Epithelium ; Estradiol ; Estrogens* ; Exons ; Gonadal Steroid Hormones ; Humans* ; Immunoblotting ; Levonorgestrel ; Ovarian Neoplasms ; Polymerase Chain Reaction ; Progesterone* ; Progestins ; Protein Isoforms ; Receptors, Androgen* ; Receptors, Progesterone* ; RNA Isoforms ; RNA, Messenger ; Testosterone

We studied the status of estrogen(ER) and progesterone(PR) receptors in meningiomas removed from 32 patients, using immunoperoxidase(IP) assays. PR were detected in 72% of the cases & ER were detected in 31%. The possible correlation between age, sex, histological type, ploidy pattern and proliferation index values with steroid receptor activity were discussed. The date suggest that the majority of meningiomas contain high affinity receptors for progesterone, that estrogen receptors are present in only a few meningiomas.
Estrogens* ; Humans ; Meningioma* ; Ploidies ; Progesterone* ; Receptors, Estrogen ; Receptors, Progesterone* ; Receptors, Steroid

Corticosterone is known to modulate GABAergic synaptic transmission in the hypothalamic paraventricular nucleus. However, the underlying receptor mechanisms are largely unknown. In the anterior hypothalamic area (AHA), the sympathoinhibitory center that project GABAergic neurons onto the PVN, we examined the expression of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) of GABAergic neurons using intact GAD65-eGFP transgenic mice, and the effects of corticosterone on the burst firing using adrenalectomized transgenic mice. GR or MR immunoreactivity was detected from the subpopulations of GABAergic neurons in the AHA. The AHA GABAergic neurons expressed mRNA of GR (42%), MR (38%) or both (8%). In addition, in brain slices incubated with corticosterone together with RU486 (MR-dominant group), the proportion of neurons showing a burst firing pattern was significantly higher than those in the slices incubated with vehicle, corticosterone, or corticosterone with spironolactone (GR-dominant group; 64 vs. 11~14%, p<0.01 by chi2-test). Taken together, the results show that the corticosteroid receptors are expressed on the GABAergic neurons in the AHA, and can mediate the corticosteroid-induced plasticity in the firing pattern of these neurons. This study newly provides the experimental evidence for the direct glucocorticoid modulation of GABAergic neurons in the AHA in the vicinity of the PVN.
Animals ; Anterior Hypothalamic Nucleus ; Brain ; Corticosterone ; Fires ; GABAergic Neurons ; Mice ; Mice, Transgenic ; Mifepristone ; Neurons ; Paraventricular Hypothalamic Nucleus ; Plastics ; Receptors, Glucocorticoid ; Receptors, Mineralocorticoid ; Receptors, Steroid ; RNA, Messenger ; Spironolactone ; Synaptic Transmission

OBJECTIVEAIM To establish a drug screening model based on transcriptional regulation of estrogen responsive element (ERE) and use it to screen compounds for discovering new ligands of estrogen receptor (ER) subtypes.

METHODA recombinant reporter vector pERE-TAL-SEAP was constructed by inserting a synthetic sequence composed of five tandem copies of EREs upstream of promoter of the reporter vector pTAL-SEAP. The pERE-TAL-SEAP and the internal control plasmid pCMV were transiently co-transfected into Hela cells expressing ER subtype or ER subtype, and the effects of pure ER agonists 17estradiol, phytoestrogen genistein and pure ER antagonist ICI182, 780 on reporter gene SEAP expression were observed.

RESULTIn the Hela cells expressing ER alpha or ER beta subtype, the expression of SEAP gene were induced in a dose dependent manner by 17-estrodiol with a maximal effect at approximately 10 nmol.L-1 and with EC50 of (80.58 +/- 8.51) pmol.L-1 and (103.90 +/- 5.29) pmol.L-1, respectively, so done by phytoestrogen genistein with a maximal effect at 1 mumol.L-1 and with EC50 of (10.86 +/- 0.75) nmol.L-1 and (39.38 +/- 2.26) nmol.L-1, respectively. The maximal level induced by estrodiol and genistein were about 7-14 fold higher than that of vehicle. The pure antiestrogen ICI182, 780 at concentration of 1 mumol.L-1 completely blocked the inductions of 17-estrodiol and genistein.

CONCLUSIONThe cellular drug screening model can be established by transfecting reporter vector pERE-TAL-SEAP in Hela cell lines expressing ER alpha or ER beta. The cell lines can be used to screen compounds with estrogenicity by testing SEAP activity in the culture media of cells growing in microtitier wells. The system should provide an efficient model for screening and analyzing the activity of large numbers of ligands of ER.

Drug Evaluation, Preclinical ; methods ; Estradiol ; pharmacology ; Estrogen Receptor alpha ; Estrogen Receptor beta ; Gene Expression Regulation ; drug effects ; Genes, Reporter ; Genistein ; pharmacology ; HeLa Cells ; Humans ; Ligands ; Promoter Regions, Genetic ; Receptors, Estrogen ; genetics ; Transfection

PURPOSE: Estrogen receptor (ER) is the key therapeutic target in breast cancer. ERbeta has recently been identified to be distinct from ERalpha. In contrast to ERalpha, the functions of ERbeta in breast cancer are still unclear. We sought to determine whether the expression of ERbeta can be used as a predictive marker for endocrine therapy for patients with ERalpha-negative breast cancer. METHODS: Formalin-fixed, paraffin-embedded tumor specimens from 52 patients with ER-/PR+ invasive breast cancer were immunostained for their ERbeta expression. These patients were treated with adjuvant tamoxifen. The results were correlated with various clinicopathological variables and the follow-up data. The expressions of p53 and HER-2/neu were also analyzed and correlated with the ERbeta status. RESULTS: An ERbeta expression was observed in 53.8% (28/52) of the breast cancer samples. There was no correlation between the ERbeta expression and the other clinicopathologic factors (age, tumor size, histologic type, nodal status, histological grade, stage, therapeutic modality, progesterone receptor (PR) expression, p53 expression and HER-2/neu expression). Recurrence was present in 7.7% (2/26) of the patients whose tumors had an ERbeta expression, as compared to the presence of recurrence in 36.4% (8/22) of the patients whose tumors had no ERbeta expression (p<0.05). The patients with ERbeta negative-tumors revealed lower disease free survival rate than those with ERbeta positive-tumors (p<0.05). Of the 52 patients, 10 (19.2%) were p53 positive, and 11 (21.2%) were HER-2/neu positive. No significant correlations were observed between ERbeta and p53 or HER-2/neu. CONCLUSION: These results suggest that ERbeta might be a predictive marker of a response to endocrine therapy in patients with ER-/PR+ invasive breast cancer, although this needs to be confirmed by additional studies.
Breast ; Breast Neoplasms ; Disease-Free Survival ; Estrogen Receptor alpha ; Estrogen Receptor beta ; Estrogens ; Follow-Up Studies ; Humans ; Progesterone ; Receptors, Progesterone ; Recurrence ; Tamoxifen

BACKGROUND: In order to improve the efficacy of endometrial carcinoma (EC) treatment, identifying prognostic factors for high risk patients is a high research priority. This study aimed to assess the relationships among the expression of estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, and the different histopathological prognostic parameters in EC and to assess the value of these in the management of EC. METHODS: We examined 109 cases of EC. Immunohistochemistry for ER, PR, HER2, and Ki-67 were evaluated in relation to age, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and grade, depth of infiltration, cervical and ovarian involvement, lymphovascular space invasion (LVSI), and lymph node (LN) metastasis. RESULTS: The mean age of patients in this study was 59.8 ± 8.2 years. Low ER and PR expression scores and high Ki-67 expression showed highly significant associations with non-endometrioid histology (p = .007, p < .001, and p < .001, respectively) and poor differentiation (p = .007, p < .001, and p <. 001, respectively). Low PR score showed a significant association with advanced stage (p = .009). Low ER score was highly associated with LVSI (p = .006), and low PR scores were associated significantly with LN metastasis (p = .026). HER2 expression was significantly related to advanced stages (p = .04), increased depth of infiltration (p = .02), LVSI (p = .017), ovarian involvement (p = .038), and LN metastasis (p = .038). There was a close relationship between HER2 expression and uterine cervical involvement (p = .009). Higher Ki-67 values were associated with LN involvement (p = .012). CONCLUSIONS: The over-expression of HER2 and Ki-67 and low expression of ER and PR indicate a more malignant EC behavior. An immunohistochemical panel for the identification of high risk tumors can contribute significantly to prognostic assessments.
Endometrial Neoplasms ; Female ; Gynecology ; Humans ; Immunohistochemistry ; Lymph Nodes ; Neoplasm Metastasis ; Obstetrics ; Prognosis ; Receptor, Epidermal Growth Factor ; Receptors, Estrogen ; Receptors, Progesterone ; Receptors, Steroid

Androgen receptor (AR) is a steroid receptor transcriptional factor for testosterone and dihydrotestosterone consisting of four main domains, the N-terminal domain, DNA-binding domain, hinge region, and ligand-binding domain. AR plays pivotal roles in prostate cancer, especially castration-resistant prostate cancer (CRPC). Androgen deprivation therapy can suppress hormone-naïve prostate cancer, but prostate cancer changes AR and adapts to survive under castration levels of androgen. These mechanisms include AR point mutations, AR overexpression, changes of androgen biosynthesis, constitutively active AR splice variants without ligand binding, and changes of androgen cofactors. Studies of AR in CRPC revealed that AR was still active in CRPC, and it remains as a potential target to treat CRPC. Enzalutamide is a second-generation antiandrogen effective in patients with CRPC before and after taxane-based chemotherapy. However, CRPC is still incurable and can develop drug resistance. Understanding the mechanisms of this resistance can enable new-generation therapies for CRPC. Several promising new AR-targeted therapies have been developed. Apalutamide is a new Food and Drug Administration-approved androgen agonist binding to the ligand-binding domain, and clinical trials of other new AR-targeted agents binding to the ligand-binding domain or N-terminal domain are underway. This review focuses on the functions of AR in prostate cancer and the development of CRPC and promising new agents against CRPC.
Androgen Antagonists ; Castration ; Dihydrotestosterone ; Drug Resistance ; Drug Therapy ; Humans ; Point Mutation ; Prostate ; Prostatic Neoplasms ; Receptors, Androgen ; Receptors, Steroid ; Testosterone

There exist many controversial debates on the presence of estrogen and progesterone receptor in neuroepithelial tumors. The receptors of these two female sex steroid hormones, i.e; estrogen and progesterone receptors, were examined in 24 neuroepithelial tumors. Using a dextran-coated chacoal(DCC) assay, high affinity binding sites were found in the cytosolic fraction with mean capacities of 3.42 and 4.71fmol/mg cytosol protein, respectively for progesterone receptors with stained positively for estrogen receptors and only 2 cases of tumor were stained positively for progesterone receptors with immunohistochemical technique. In addition, the most convincing evidence for the absence of estrogen and progesterone receptors was obtained by reverse transcription polymerase chain reaction(RT-PCR) and Southern blot hybridization using oligo nucleotide probes which is complementary to the fragments of the human estrogen and progesteone recepotrs messenger ribo nucleic acid(mRNA). In 24 neuroepithelial tumors, we were not able to find any expression of mRNAs coding for the estrogen and progesteone receptors. From the present study, it is concluded that estrogen and progesteone receptors are geneally absent in neuoepithelial tumors. This study suggests that estrogen and progesteone receptors would not be involved in neuroepithelial tumors and therefore have no current significance as makers for adjuvant medical therapy of most neuroepithelial tumors.
Binding Sites ; Blotting, Southern ; Clinical Coding ; Cytosol ; Estrogens* ; Female ; Gonadal Steroid Hormones ; Humans ; Neoplasms, Neuroepithelial* ; Progesterone* ; Receptors, Estrogen ; Receptors, Progesterone* ; Reverse Transcription ; RNA, Messenger