Publications by authors named "Attia G"

51 Publications

Anejaculatory infertility due to multiple sclerosis.

Andrologia 2012 May 2;44 Suppl 1:833-5. Epub 2011 Aug 2.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Miami Miller School of Medicine, Miami, FL, USA.

There are few reports of pregnancy outcomes in couples with anejaculatory infertility secondary to multiple sclerosis and no longitudinal reports of semen quality in this population. We report our experience with one such case. The couple achieved two live births from spermatozoa obtained with electroejaculation: the first by intrauterine insemination and the second by in vitro fertilisation with intracytoplasmic sperm injection of donor oocytes. Linear regression analysis showed no progressive decline in semen parameters across 26 semen retrievals performed over 7.7 years. Years of disease do not appear to cause progressive decline in semen quality.
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http://dx.doi.org/10.1111/j.1439-0272.2011.01208.xDOI Listing
May 2012

Pregnancy outcomes by intravaginal and intrauterine insemination in 82 couples with male factor infertility due to spinal cord injuries.

Fertil Steril 2011 Aug 31;96(2):328-31. Epub 2011 May 31.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Miami Miller School of Medicine, Miami, Florida, USA.

Objective: To report our center's pregnancy rates (PR) by intravaginal insemination (IVI) or intrauterine insemination (IUI) in 82 couples with male partners with spinal cord injuries.

Design: Retrospective analysis.

Setting: Major medical center.

Patient(s): Male patients with spinal cord injuries and their female partners.

Intervention(s): Intravaginal insemination and IUI.

Main Outcome Measure(s): Pregnancy and live birth outcomes.

Result(s): Overall, 31 of the 82 couples (37.8% PR) achieved 39 pregnancies. Sperm were obtained by masturbation, penile vibratory stimulation, or electroejaculation in 4 men (4.9%), 42 men (51.2%), and 36 men (43.9%), respectively. Intravaginal insemination, performed mostly at home by selected couples, was undertaken in 45 couples, 17 of whom (37.8% PR) achieved 20 pregnancies. Intrauterine insemination was performed in 57 couples, 14 of whom (24.6% PR) achieved 19 pregnancies, with a cycle fecundity of 7.9%. Eighteen and 21 live births occurred by IVI and IUI, respectively.

Conclusion(s): The methods of IVI and IUI are reasonable options for this patient population. These methods warrant consideration before proceeding to assisted reproductive technologies (ART).
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http://dx.doi.org/10.1016/j.fertnstert.2011.05.019DOI Listing
August 2011

Virilization from partner's use of topical androgen in a reproductive-aged woman.

Am J Obstet Gynecol 2011 Sep 2;205(3):e3-4. Epub 2011 Apr 2.

Department of Obstetrics and Gynecology, University of Miami, Miller School of Medicine, Miami, FL, USA.

A woman presented with virilization symptoms and elevated testosterone; however, a neoplastic source of excess androgen was not found on imaging. Eventually, the patient revealed she was exposed to transdermal testosterone used by her partner. This case highlights the importance of considering exogenous androgens in the differential diagnosis of virilization.
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http://dx.doi.org/10.1016/j.ajog.2011.02.017DOI Listing
September 2011

Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.

Obstet Gynecol 2010 Oct;116(4):865-875

From the Carolina Women's Research and Wellness Center, Durham, North Carolina; Xanodyne Pharmaceuticals, Inc., Newport, Kentucky; the Department of Obstetrics and Gynecology, University of Kentucky, Lexington, Kentucky; the New Age Medical Research Corporation, Miami, Florida; the Cleveland Clinic Fertility Center, Canfield, Ohio; the Department of Obstetrics and Gynecology, Danderyds Hospital, Stockholm, Sweden; the University of Alabama at Birmingham, Birmingham, Alabama; The Center for Women's Health & Wellness, LLC, Plainsboro, New Jersey; the University of Miami, Miami, Florida; the University of Washington, Seattle, Washington; and ARSTAT Analysis, Flemington, New Jersey.

Objective: To assess the efficacy and safety of an oral formulation of tranexamic acid for the treatment of heavy menstrual bleeding.

Methods: Adult women with heavy menstrual bleeding (mean menstrual blood loss 80 mL or more per cycle) were enrolled in a double-blind, placebo-controlled study. After two pretreatment menstrual cycles, women were randomized to receive tranexamic acid 3.9 g/d or placebo for up to 5 days per menstrual cycle through six cycles. To meet the prespecified three-component primary efficacy end point, mean reduction in menstrual blood loss from baseline with tranexamic acid treatment needed to be 1) significantly greater than placebo, 2) greater than 50 mL, and 3) greater than a predetermined meaningful threshold (36 mL or higher). Health-related quality of life was measured using a validated patient-reported outcome instrument.

Results: Women who received tranexamic acid (n=115) met all three primary efficacy end points: first, a significantly greater reduction in menstrual blood loss of -69.6 mL (40.4%) compared with -12.6 mL (8.2%) in the 72 women who received placebo (P<.001); reduction of menstrual blood loss exceeding a prespecified 50 mL; and last, reduction of menstrual blood loss considered meaningful to women. Compared with women receiving placebo, women treated with tranexamic acid experienced significant improvements in limitations in social or leisure and physical activities, work inside and outside the home, and self-perceived menstrual blood loss (P<.01). The majority of adverse events were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo.

Conclusion: In this study, a new oral tranexamic acid treatment was well tolerated and significantly improved both menstrual blood loss and health-related quality of life in women with heavy menstrual bleeding.

Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386308.

Level Of Evidence: I.
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http://dx.doi.org/10.1097/AOG.0b013e3181f20177DOI Listing
October 2010

Impact of obstructive sleep apnea on global myocardial performance in children assessed by tissue Doppler imaging.

Pediatr Cardiol 2010 Oct 7;31(7):1025-36. Epub 2010 Aug 7.

Pediatrics Department (Pediatric Cardiology Unit), Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.

This study aimed to assess the impact of obstructive sleep apnea (OSA) due to adenotonsillar hypertrophy (ATH) on the global myocardial performance in children using tissue Doppler imaging (TDI) and to evaluate the reversibility of the disorder after adenotonsillectomy (AT). The study included 42 children with OSA due to ATH (mean age, 5 ± 3.14 years) as the study group and 45 age- and sex-matched healthy children (mean age, 5.2 ± 3.08 years) as the control group. Polysomnography and echocardiography were performed. Indexed left ventricular mass (LVMi), pulmonary artery systolic pressure, mean pulmonary artery pressure (mPAP), and pulmonary vascular resistance (PVR) were calculated by echocardiography. Tissue Doppler imaging was used to determine the left ventricular and right ventricular myocardial performance index (MPI) of patients and control subjects before and after AT. The patients were classified into mild OSA (apnea-hypopnea index [AHI] 1-5; n = 18)] and moderate to severe OSA (AHI >5; n = 24) according to polysomnography findings. All the children in the control group had an AHI less than 1. They were treated using AT, then reevaluated by polysomnography and echocardiographic examination 6 to 8 months after surgery. Results are described as mean ± standard deviation. The patients with OSA had higher pulmonary artery systolic pressure, mPAP, PVR, LVMi, and right ventricular diastolic diameter than the control subjects. The patients with moderate to severe OSA showed more prominent changes than the patients with mild OSA, but the latter still differed significantly from the control subjects. The TDI-derived right ventricular MPI and left ventricular MPI measurements of the patients with OSA were higher (mean, 0.40 ± 0.08 vs 0.28 ± 0.01; p < 0.001) than those of the control subjects and (0.45 ± 0.05 vs 0.32 ± 0.05; p < 0.001) and correlated well with AHI and mPAP. In addition, mPAP was significantly correlated with AHI. Postoperatively, relief of OSA was validated by polysomnography, and a repeat of the echocardiographic parameters showed no significant differences between the patients and the control subjects. Tissue Doppler imaging can detect the subtle, subclinical changes in cardiac performance that occur in OSA due to adenotonsillar hypertrophy. Such changes generally are reversible after surgical treatment.
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http://dx.doi.org/10.1007/s00246-010-9755-0DOI Listing
October 2010

Evaluation of serum DNA integrity as a screening and prognostic tool in patients with hepatitis C virus-related hepatocellular carcinoma.

Int J Biol Markers 2010 Apr-Jun;25(2):79-86

Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt.

Background: Hepatocellular carcinoma (HCC) is a common malignancy in Egypt due to the high frequency of hepatitis C virus (HCV) infection among the general population. Circulating free DNA is a potential molecular marker for the diagnosis and prognosis of malignant tumors. DNA released from apoptotic cells usually consists of short uniform fragments while DNA released from cancer cells is longer. The ratio of long DNA fragments to total DNA (DNA integrity) may be a potential marker for early detection of HCC and its progression in HCV patients.

Methods: Sera from 25 patients with HCV-related HCC, 25 patients with chronic HCV infection, and 15 healthy volunteers were examined for Alu repeats by quantitative real-time PCR (qPCR) using 2 sets of primers of 115 and 247 base pairs. DNA integrity was calculated as the ratio of 247-bp to 115-bp Alu fragments.

Results: Compared with healthy volunteers and HCV patients, significantly higher DNA integrity was found in HCC patients. DNA integrity was associated with tumor size, TNM stage, vascular invasion, lymph node involvement, and distant metastasis. DNA integrity had a higher sensitivity and specificity in discriminating HCC from HCV patients than total DNA. Patients with high DNA integrity had a significantly shorter overall survival and high DNA integrity was shown to be an independent prognostic factor for survival in HCV-related HCC.

Conclusions: DNA integrity is a promising molecular biomarker for detecting HCC in patients with chronic HCV infection; it reflects the progression and metastatic potential of the tumor, and high DNA integrity is associated with short overall survival in HCV-related HCC.
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September 2010

Myocardial performance in asphyxiated full-term infants assessed by Doppler tissue imaging.

Pediatr Cardiol 2010 Jul 9;31(5):634-42. Epub 2010 Feb 9.

Pediatric Cardiology Unit, Mansoura University Children's Hospital, Mansoura, Egypt.

The aim of this study was to assess myocardial performance of full-term infants with perinatal asphyxia using Doppler tissue imaging (DTI) and to correlate it with serum cardiac troponin T (cTnT) concentrations. Twenty-five asphyxiated and 20 nonasphyxiated term infants were investigated. Serum cTnT concentrations were measured between 12 and 24 h of life. Conventional two-dimensional Doppler echocardiography and DTI were done during the first 72 h of life. Right ventricular (RV) and left ventricular (LV) Tei indexes were significantly higher in asphyxiated neonates (mean +/- SD: 0.45 +/- 0.05 vs. 0.28 +/- 0.05, P < 0.001 and 0.51 +/- 0.04 vs. 0.38 +/- 0.04, P < 0.001, respectively). Mitral and tricuspid systolic (Sm) velocities were significantly lower in asphyxiated neonates (mean +/- SD: 5.06 +/- 0.89 vs. 6.89 +/- 0.94 cm/s, P < 0.001 and 5.78 +/- 0.58 vs. 6.69 +/- 0.87 cm/s, P < 0.001, respectively). cTnT concentrations were significantly higher in asphyxiated neonates [median (range): 0.17 (0.05-0.23) vs. 0.03 (0-0.07) microg/l, P < 0.001)], and they correlated positively with the LV Tei index (r = 0.67, P < 0.001) and the RV Tei index (r = 0.68, P < 0.001) and negatively with the mitral systolic (Sm) velocity (r = -0.68, P < 0.001) and tricuspid systolic (Sm) velocity (r = -0.41, P = 0.01). A higher cTnT was a significant predictor of mortality, whereas fractional shortening (FS) and DTI measurements did not show any significant predictive value. The DTI technique appears to be more sensitive than conventional echocardiography in the early detection of myocardial dysfunction induced by perinatal asphyxia in full-term infants.
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http://dx.doi.org/10.1007/s00246-010-9661-5DOI Listing
July 2010

Conventional (2D) Versus Conformal (3D) Techniques in Radiotherapy for Malignant Pediatric Tumors: Dosimetric Perspectives.

J Egypt Natl Canc Inst 2009 Dec;21(4):309-14

The Departments of Radiation Oncology, Faculty of Medicine, Cairo University.

Objectives: In pediatric radiotherapy, the enhanced radiosensitivity of the developing tissues combined with the high overall survival, raise the possibility of late complications. The present study aims at comparing two dimensional (2D) and three dimensional (3D) planning regarding dose homogeneity within target volume and dose to organs at risk (OARs) to demonstrate the efficacy of 3D in decreasing dose to normal tissue.

Material And Methods: Thirty pediatric patients (18 years or less) with different pediatric tumors were planned using 2D and 3D plans. All were CT scanned after proper positioning and immobilization. Structures were contoured; including the planning target volume (PTV) and organs at risk (OARs). Conformal beams were designed and dose distribution analysis was edited to provide the best dose coverage to the PTV while sparing OARs using dose volume histograms (DVHs) of outlined structures. For the same PTVs conventional plans were created using the conventional simulator data (2-4 coplanar fields). Conventional and 3D plans coverage and distribution were compared using the term of V95% (volume of PTV receiving 95% of the prescribed dose), V107% (volume of PTV receiving 107% of the prescribed dose), and conformity index (CI) (volume receiving 90% of the prescribed dose/PTV). Doses received by OARs were compared in terms of mean dose. In children treated for brain lesions, OAR volume received 90% of the dose (V90%) and OAR score were calculated.

Results: The PTV coverage showed no statistical difference between 2D and 3D radiotherapy in terms of V95% or V107%. However, there was more conformity in 3D planning with CI 1.43 rather than conventional planning with CI 1.86 (p-value <0.001). Regarding OARs, 3D planning shows large gain in healthy tissue sparing. There was no statistical difference in mean dose received by each OAR. However, for brain cases, brain stem mean dose and brain V90% showed better sparing in 3D planning (brain stem mean dose was 61% in 2D and 51% in 3D (pvalue 0.0001) and Brain V90% was 17.6 in 2D and 8.6 in 3D (p-value 0.001). Similarly, there was overall significant decrease in doses receive by healthy tissues in term of OARs score which was 0.24 in 3D and 0.40 in 2D planning (p-value 0.0001).

Conclusion: This study confirms that 3D conformal radiotherapy is more effective than 2D conventional radiotherapy in decreasing dose to normal tissue without compromising dose distribution, homogeneity and dose coverage to PTV.

Key Words: Conformal radiation therapy - Pediatric tumors - Dosimetry.
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December 2009

Heterotopic uterus transplantation in a swine model.

Transplantation 2009 Aug;88(4):465-9

Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.

Background: The aim of our study was to examine the feasibility of allogeneic uterine transplantation in a large animal model.

Methods: We performed heterotopic uterine transplants in genetically defined mini-pigs. Immunosuppression was tacrolimus administered intravenously for the first 12 days posttransplantation followed by oral cyclosporine maintenance immunosuppression. The graft was transplanted heterotopically in the lower abdominal cavity of the recipient. The vaginal vault was exteriorized as a stoma in the lower right abdominal wall. The uterine grafts were followed with endoscopies and biopsies.

Results: Ten transplants were performed. Follow-up was until July 2008. At the end of the follow-up period, 5 animals were alive and healthy, 0.5 to 12 months posttransplantation. There were 5 deaths due to pneumonia (n=1), intussusception of the graft (n=1), cardiorespiratory arrest during anesthesia (n=1), and complications of the stoma (n=2). Acute rejections of the graft presented during the 2nd and 3rd month posttransplantation were treated successfully with increase of the maintenance immunosuppression and steroids. Other complications included prolapse and infections of the graft stoma. Pathological changes seen in the endometrial biopsies included acute rejection and acute endometritis.

Conclusion: These findings demonstrate that successful uterus transplantation in a large animal model (miniature swine) is feasible using this heterotopic model, and it can be useful for the study of these transplants.
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http://dx.doi.org/10.1097/TP.0b013e3181b07666DOI Listing
August 2009

Induction Docetaxel and Cisplatin Followed by Weekly Docetaxel and Cisplatin with Concurrent Radiotherapy in Locally Advanced Stage III Non Small Cell Lung Cancer (LA-NSCLC)-A Phase II Study.

J Egypt Natl Canc Inst 2007 Mar;19(1):15-20

The Departments of Clinical Oncology,Faculty of Medicine, Tanta University.

Purpose: The objective of this phase II study was to document the activity and to evaluate the toxicity of docetaxel and cisplatin as induction chemotherapy followed by concurrent docetaxel and cisplatin with thoracic radiation in locally advanced stage III non small cell lung cancer.

Patients And Methods: Twenty-seven patients with stage III locally advanced non-small cell lung cancer received induction chemotherapy with two cycles of docetaxel 75mg/m2 and cisplatin 75mg/m2 D1 every 3 weeks. Patients without disease progress after induction chemotherapy were assigned to concurrent chemoradiotherapy 20mg/m2 docetaxel&25mg/m2 cisplatin administrated on day 1 every week for 6 weeks along with concurrent radiotherapy at a dose of 60Gy in 30 fractions (2 Gy/fraction and 5 fractions per week). The primary endpoint was to determine the overall response rate (ORR), the secondary endpoint was to evaluate time to progression (TTP) and safety profile.

Results: After induction chemotherapy, the overall response rate (ORR) was 44.4%, 23 patients without disease progress were assigned to concurrent treatment with an overall response rate of 65%. Median survival time was 17 months, time to progression was 11.5 months and the one-year survival was 58%. Neutropenia was the most common toxicity during induction therapy (26% expressed grade 3-4) whereas esophagitis was the most common toxicity during concurrent phase (17.3% expressed grade 3-4); toxicities were manageable.

Conclusion: Induction chemotherapy by docetaxel and cisplatin followed by weekly docetaxel and cisplatin with concurrent thoracic radiation therapy is feasible and tolerable. These results warrant further large randomized studies to document and confirm the effectiveness of this regimen. Key Words: Lung cancer , Docetaxel , Cisplatin , Concurrent chemoradiotherapy.
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March 2007

Current trends in the treatment of infertility in men with spinal cord injury.

Fertil Steril 2006 Oct 11;86(4):781-9. Epub 2006 Sep 11.

Department of Urology, University of Ioannina, Ioannina, Greece.

Objective: To determine current use of penile vibratory stimulation (PVS), electroejaculation (EEJ), and intrauterine insemination (IUI) in treatment of infertility in men with spinal cord injury (SCI).

Design: Prospective survey, retrospective chart review, and literature review.

Setting: Major university medical center.

Patient(s): Male SCI patients and female partners.

Intervention(s): A survey administered to professionals determined current treatment methods for infertility in couples with SCI male partners.

Main Outcome Measure(s): Sperm retrieval methods, ejaculation success rates, total motile sperm (TMS), IUI application, and IUI outcomes.

Result(s): Twenty-eight percent of surveyed professionals do not retrieve sperm from ejaculates of SCI patients, relying instead on retrieval from reproductive tissues. Reasons for not offering PVS or EEJ were lack of familiarity, training, or equipment. Thirty-four percent do not offer IUI to these couples. Chart review showed that semen could be retrieved by PVS or EEJ in 95% of patients. Fifty-three percent and 43% of trials had TMS >5 and >10 x 10(6), respectively. Of survey respondents performing IUI, 42% lacked enough data to estimate pregnancy rates (PRs) in these couples. Literature review showed IUI PRs between 9% and 18% per cycle and 30% and 60% per couple.

Conclusion(s): Based on ejaculation success rates, TMS yields, and IUI outcomes, the methods of PVS, EEJ, and IUI warrant consideration in centers not currently offering these options for couples with SCI male partners.
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http://dx.doi.org/10.1016/j.fertnstert.2006.01.060DOI Listing
October 2006

The orphan nuclear receptor, liver receptor homolog-1, regulates cholesterol side-chain cleavage cytochrome p450 enzyme in human granulosa cells.

J Clin Endocrinol Metab 2005 Mar 21;90(3):1678-85. Epub 2004 Dec 21.

Division of Reproductive Endocrinology and Infertility, Cedars Medical Center, 1400 NW 12th Avenue, East Building 4th floor, Miami, Florida 33136, USA.

After ovulation, there is a shift in ovarian steroidogenesis from an estrogen-producing ovarian follicle to a progesterone-producing corpus luteum. The first step in human ovarian steroidogenesis is catalyzed by cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme. Steroidogenic factor-1 is an orphan nuclear receptor that regulates several steroidogenic enzymes, including CYP11A1. Liver receptor homolog-1 (LRH-1) is another orphan nuclear receptor that is expressed in the human ovary. After ovulation there is a down-regulation in steroidogenic factor-1, which is associated with an up-regulation of LRH-1 expression. These changes coincide with increased level of CYP11A1 expression in human corpus luteum. In this study, we examined the role of LRH-1 in the regulation of human granulosa cell CYP11A1 expression. Cotransfection of human granulosa cell tumor cells with CYP11A1 promoter and LRH-1 expression vector resulted in a significant increase in CYP11A1 expression. Deletion analysis revealed two putative LRH-1 binding sites at -1580 and -40, which was confirmed by EMSA. Dosage-sensitive sex-reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene-1 inhibited LRH-1 stimulated CYP11A1 expression, and that was not overcome by the presence of PKA agonist. We conclude that CYP11A1 expression in human granulosa cells is regulated by LRH-1. We propose that LRH-1 could be the major transcription factor for the post-ovulatory surge in human ovarian steroidogenesis.
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http://dx.doi.org/10.1210/jc.2004-0374DOI Listing
March 2005

Liver receptor homolog-1 regulates the expression of steroidogenic acute regulatory protein in human granulosa cells.

J Clin Endocrinol Metab 2004 Jun;89(6):3042-7

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032, USA.

Steroidogenic acute regulatory protein (StAR) plays a critical role in the initial step of steroid hormone synthesis. In the present study, we investigated the role of liver receptor homolog-1 (LRH-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX-1) in the regulation of StAR gene expression in human granulosa cell tumor cells. We also examined the effect of protein kinase A (PKA) signaling pathway on the expression of StAR in the presence of LRH-1 and DAX-1. Cell transfection, mutation analysis, and EMSA were performed. LRH-1 significantly induced StAR promoter activity in a concentration-dependent manner. This induction was further augmented in the presence of PKA agonist. Using deletion analysis, we demonstrated LRH-1 binding site at -105/-95. Mutation of this site resulted in a significant decrease in the StAR promoter activity. Using EMSA, the ability of this cis-element to bind LRH-1 was confirmed. DAX-1 inhibited LRH-1-stimulated StAR promoter activity in a concentration-dependent manner. This inhibition was also maintained in the presence of PKA stimulation. Our results demonstrated that LRH-1 plays a critical role in the induction of StAR gene expression. We hypothesize that LRH-1 could be the major transcription factor responsible for the rapid and significant increase in ovarian StAR gene expression after ovulation.
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http://dx.doi.org/10.1210/jc.2003-031599DOI Listing
June 2004

The role of the orphan nuclear receptor, liver receptor homologue-1, in the regulation of human corpus luteum 3beta-hydroxysteroid dehydrogenase type II.

J Clin Endocrinol Metab 2003 Dec;88(12):6020-8

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas Texas 75390-9032, USA.

After ovulation, ovarian 3beta-hydroxysteroid dehydrogenase type II (HSD3B2) expression increases to enhance the shift of steroidogenesis toward progesterone biosynthesis. Steroidogenic factor-1 (SF-1) is a transcription factor for several genes encoding steroidogenic enzymes. However, the level of SF-1 expression decreases in the human corpus luteum (CL) after ovulation. Liver receptor homolog-1 (LRH-1) is another member of the orphan nuclear receptor family. We hypothesize that LRH-1, rather than SF-1, plays an essential role in the regulation of corpus luteum steroidogenesis. Semiquantitative RT-PCR and real-time PCR were performed to quantify the level of LRH-1 expression and correlate with HSD3B2 level. Cell transfection, mutation analysis, and EMSA were performed to examine the role of LRH-1 in the regulation of HSD3B2. LRH-1 expression was higher in CL, compared with mature ovarian follicles. Cotransfection of granulosa cells with HSD3B2 and LRH-1 resulted in a 10-fold increase of transcription. DAX-1 inhibited LRH-1-stimulated HSD3B2, which was maintained in the presence of dibutyryl cAMP. Mutation of the either of the two putative LRH-1 binding sites, which were confirmed by EMSA, in the HSD3B2 promoter decreased LRH-1 stimulation. Our findings suggest that LRH-1 is highly expressed in CL, and it plays an essential role in the regulation of HSD3B2.
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http://dx.doi.org/10.1210/jc.2003-030880DOI Listing
December 2003

Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome.

Fertil Steril 2003 Mar;79(3):469-81

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, 75235, USA.

Objective: Metformin has been used as a treatment in many studies of the infertility associated with polycystic ovary syndrome (PCOS). We will review the literature on this topic as it specifically relates to changes in body mass index (BMI), improvement in menstrual cyclicity, and effects on ovulation and pregnancy rates.

Design: Review of studies addressing biochemical and clinical changes in women with PCOS on metformin.

Main Outcome Measure(s): Changes in BMI, menstrual cyclicity, ovulation rate, and pregnancy rate.

Result(s): Metformin has been shown to produce small but significant reductions in BMI. Multiple observational studies have confirmed an improvement in menstrual cyclicity with metformin therapy. The studies addressing the concomitant use of metformin with clomiphene citrate initially predicted great success, but these have been followed by more modest results. There is little data in the literature concerning the use of metformin and hMGs.

Conclusion(s): Some (but not all) women with PCOS have improvements in their menstrual cycles while on metformin. The data supporting the use of metformin in ovulation induction with clomiphene citrate and hMG remain to be confirmed by large, randomized, prospective studies.
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http://dx.doi.org/10.1016/s0015-0282(02)04800-8DOI Listing
March 2003

Liver receptor homologue-1 is expressed in human steroidogenic tissues and activates transcription of genes encoding steroidogenic enzymes.

J Endocrinol 2002 Sep;174(3):R13-7

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

In the current study we test the hypothesis that liver receptor homologue-1 (LRH; designated NR5A2) is involved in the regulation of steroid hormone production. The potential role of LRH was assessed by first examining expression in human steroidogenic tissues and second by examining effects on transcription of genes encoding enzymes involved in steroidogenesis. LRH is closely related to steroidogenic factor 1 (SF1; designated NR5A1), which is expressed in most steroidogenic tissues and regulates expression of several steroid-metabolizing enzymes. LRH transcripts were expressed at high levels in the human ovary and testis. Adrenal and placenta expressed much lower levels of LRH than either ovary or liver. To examine the effects of LRH on steroidogenic capacity we used reporter constructs prepared with the 5'-flanking region of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage (CYP11A1), 3beta hydroxysteroid dehydrogenase type II (HSD3B2), 17alpha hydroxylase, 17,20 lyase (CYP17), 11beta hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2). Co-transfection of these reporter constructs with LRH expression vector demonstrated that like SF1, LRH enhanced reporter activity driven by flanking DNA from StAR, CYP11A1, CYP17, HSD3B2, and CYP11B1. Reporter constructs driven by CYP11A1 and CYP17 were increased the most by co-transfection with LRH and SF1. Of the promoters examined only HSD3B2 was more sensitive to LRH than SF1. The high level of ovarian and testicular LRH expression make it likely that LRH plays an important role in the regulation of gonadal function.
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http://dx.doi.org/10.1677/joe.0.174r013DOI Listing
September 2002

Metformin directly inhibits androgen production in human thecal cells.

Fertil Steril 2001 Sep;76(3):517-24

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9032, USA.

Objective: To examine the direct effect of metformin on thecal cell androgen production.

Setting: Basic science research laboratory, University of Texas Southwestern, Dallas, Texas.

Intervention(s): Human ovarian theca-like tumor cells were treated with various concentrations of metformin in the presence and absence of forskolin for 48 hours.

Main Outcome Measure(s): Media were collected, and radioimmunoassay (RIA) for progesterone, 17 alpha-hydroxyprogesterone (17OHP), androstenedione, and testosterone was performed. The effect of metformin on the expression of various enzymes involved in theca cell steroidogenesis was examined.

Result(s): Metformin (50 microM and 200 microM) significantly inhibited androstenedione production from both forskolin-stimulated and unstimulated theca cells. Testosterone production was also significantly inhibited in forskolin-treated cells in the presence of 200 microM of metformin-treated compared with forskolin-only-treated cells. Western blot analysis revealed that metformin significantly inhibited the expression of steroidogenic acute regulatory (StAR) protein and 17 alpha-hydroxylase (CYP17) expression in cells stimulated with forskolin compared with forskolin treatment alone. There was no significant change in either 3beta-hydroxysteroid dehydrogenase (3 beta HSD) or cholesterol side-chain cleavage (CYP11A1) protein expression. Northern analysis revealed a significant decrease in the expression of CYP17 mRNA in forskolin-stimulated cells treated with metformin (200 microM) compared with forskolin-only-treated cells, however, there was no significant change in steroidogenic acute regulatory protein mRNA expression.

Conclusion(s): Our results suggest that metformin may have a direct effect on thecal cells' androgen production.
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http://dx.doi.org/10.1016/s0015-0282(01)01975-6DOI Listing
September 2001

Transforming growth factor beta inhibits steroidogenic acute regulatory (StAR) protein expression in human ovarian thecal cells.

Mol Cell Endocrinol 2000 Dec;170(1-2):123-9

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

In this study, we investigated the effects of TGFbeta1 on steroidogensis and expression of the steroidogenic acute regulatory (StAR) protein which regulates an important early step in the steroidogenic pathway. We utilized a human ovarian thecal like tumor (HOTT) cell model and investigated the effects of activin-A, inhibin-A, or TGFbeta1 in the presence of forskolin and the effect of dibutyryl cyclic AMP (dbcAMP) on steroid accumulation in the culture medium. Cells were also treated with different concentration of TGFbeta1 in the presence of forskolin, combined steroid production was measured at the end of 48 h and after 3 h incubation with 22R-hydroxycholesterol. In the presence of TGFbeta1 there was a dose-dependent inhibition of androstenedione production. Inhibition in combined steroid production was apparent at the highest concentration of TGFbeta1 tested. In the presence of 22R-hydroxycholesterol, combined steroid production was significantly inhibited at lower concentrations. TGFbeta1 inhibited StAR protein expression in a concentration dependent manner. There was also a similar inhibition in StAR mRNA. These results suggest that the effect of TGFbeta1 on steroid production and possibly follicular development may be in part due to its effects on StAR expression.
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http://dx.doi.org/10.1016/s0303-7207(00)00335-xDOI Listing
December 2000

Bone morphogenetic protein inhibits ovarian androgen production.

J Clin Endocrinol Metab 2000 Sep;85(9):3331-7

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, 75235-9032, USA.

Bone morphogenetic proteins (BMPs), members of the transforming growth factor beta superfamily, were recently shown to be expressed and to regulate steroidogenesis in rat ovarian tissue. The purpose of this study was to investigate the effect of BMP-4 on androgen production in a human ovarian theca-like tumor (HOTT) cell culture model. We have previously demonstrated the usefulness of these cells as a model for human thecal cells. HOTT cells respond to protein kinase A agonists by increased production of androstenedione and with an induction of steroid-metabolizing enzymes. In this investigation, HOTT cells were treated with forskolin or dibutyryl cyclic AMP (dbcAMP) in the presence or absence of various concentrations of BMP-4. The accumulation of androstenedione, progesterone, and 17alpha-hydroxyprogesterone (17OHP) in the incubation medium was measured by RIA. The expression of 17alpha-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase (3betaHSD), cholesterol side-chain cleavage (CYP11A1), and steroidogenic acute regulatory (StAR) protein was determined by protein immunoblotting analysis using specific rabbit polyclonal antibodies. We also examined the expression of BMP receptor subtypes in our HOTT cells using RT-PCR. In cells treated with medium alone, steroid accumulation and steroid enzyme expression was unchanged. In cells treated with BMP alone there was a modest decrease in androstenedione secretion. In the presence of forskolin, HOTT cell production of androstenedione, 17OHP, and progesterone increased by approximately 4.5-, 35-, and 3-fold, respectively. In contrast, BMP-4 decreased forskolin-stimulated HOTT cell secretion of androstenedione and 17OHP by 50% but increased progesterone production 3-fold above forskolin treatment alone. Forskolin treatment led to an increase in CYP17, CYP11A1, 3betaHSD, and StAR protein expression. BMP-4 markedly inhibited forskolin stimulation of CYP17 expression but had little effect on 3betaHSD, CYP11A1, or StAR protein levels. Similar results were observed with the cAMP analog dbcAMP. In addition, BMP-4 inhibited basal and forskolin stimulation of CYP17 messenger RNA expression as determined by RNase protection assay. Other members of the transforming growth factor beta superfamily, including activin and inhibin, had minimal effect on androstenedione production in the absence of forskolin. In the presence of forskolin, activin inhibited androstenedione production by 80%. Activin also inhibited forskolin induction of CYP17 protein expression as determined by Western analysis. We identified the presence of messenger RNA for three BMP receptors (BMP-IA, BMP-IB, and BMP-II) in the HOTT cells model. In conclusion, BMP-4 inhibits HOTT cell expression of CYP17, leading to an alteration of steroidogenic pathway resulting in reduced androstenedione accumulation and increased progesterone production. These effects of BMP-4 seem similar to those caused by activin, another member of the transforming growth factor-beta superfamily of proteins.
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http://dx.doi.org/10.1210/jcem.85.9.6835DOI Listing
September 2000

Progesterone receptor isoform A but not B is expressed in endometriosis.

J Clin Endocrinol Metab 2000 Aug;85(8):2897-902

Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas 75235, USA.

We previously demonstrated that 17beta hydroxysteroid dehydrogenase type 2, the enzyme that inactivates estradiol to estrone, is expressed in luteal eutopic endometrium in response to progesterone but not in simultaneously biopsied peritoneal endometriotic tissue. This molecular evidence of progesterone resistance, together with the clinical observation of resistance of endometriosis to treatment with progestins, led us to determine the levels of progesterone receptor (PR) isoforms PR-A and PR-B in eutopic endometrial and extra-ovarian endometriotic tissues. It was proposed that progesterone action on target genes is mediated primarily by homodimers of PR-B, whereas the truncated variant PR-A acts as a repressor of PR-B function. Immunoprecipitation, followed by Western blot analysis, was performed to detect bands specific for PR-A and PR-B in paired samples of endometriotic and eutopic endometrial tissues simultaneously biopsed from 18 women undergoing laparoscopy during various phases of the menstrual cycle. PR-B was present in 17 of 18 eutopic endometrial samples, and its level increased in the preovulatory phase, as expected, whereas PR-A was detected in all samples (n = 18) with a similar, but less prominent, cyclic variation in its levels. In endometriotic samples, however, no detectable PR-B could be demonstrated, whereas PR-A was detected in all samples (n = 18), albeit in much lower levels and without any cyclic variation in contrast with the eutopic endometrium. Levels of PR-A and PR-B in endometriotic and eutopic endometrial tissues were determined and compared after normalization to total protein and estrogen receptor-alpha levels. Using RNase protection assay, we also demonstrated indirectly that only PR-A transcripts were present in endometriotic tissue samples (n = 8), whereas both PR-A and PR-B transcripts were readily detectable in all eutopic endometrial samples (n = 8). This was indicative that failure to detect PR-B protein in endometriotic tissues is due to the absence of PR-B transcripts. We conclude that progesterone resistance in endometriotic tissue from laboratory and clinical observations may be accounted for by the presence of the inhibitory PR isoform PR-A and the absence of the stimulatory isoform PR-B.
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http://dx.doi.org/10.1210/jcem.85.8.6739DOI Listing
August 2000
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