Estradiol Acetate Research Articles

An evaluation of relugolix/estradiol/norethindrone acetate for the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women

ABSTRACT Introduction Uterine Fibroids (UFs) are the most predominant benign tumor in women who are coming of reproductive age, and causes intense economic load priced in billions of US dollars. Historically, surgery has been the main definitive treatment, albeit less attractive nowadays, especially for women with future fertility plans. Therefore, studies to explore the pharmacological treatment options are increasing especially as those that are currently available are limited for short-term use only. Areas covered This drug evaluation features the clinical results from previous and ongoing studies of relugolix, in combination with the add back therapy of estradiol (E2) and norethindrone acetate (NETA), as a novel, orally administered, nonpeptide antagonist of gonadotropin-releasing hormone (GnRH) for the management of heavy menstrual bleeding (HMB) in premenopausal women with UFs. Expert opinion The combination of relugolix/E2/NETA is an encouraging, well-tolerated and noninvasive pharmacological option for UFs patients. Relugolix induced a concentration-dependent decrease in HMB. However, it should be used with hormonal add-back therapy (E2+ NETA) to avoid induced hypoestrogenic side effects, importantly bone mineral density loss. Moreover, symptoms will likely resume shortly after the termination of the relugolix combination administration.

A stability indicating RP-HPLC- PDA method for simultaneous estimation of segesterone acetate and ethinyl estradiol in tablet dosage form

A simple, accurate, precise method was developed for the simultaneous estimation of the Segesterone acetate and Ethinyl estradiol in a tablet dosage form. The chromatogram was run through Discovery C18 150 x 4.6mm, 5mm column and mobile phase containing buffer 0.01N KH2PO4: Acetonitrile taken in the ratio 50:50 was pumped through the column at a flow rate of 1 ml/min. The temperature was maintained at 30°C. The optimized wavelength selected was 240.0 nm. Ethinyl estradiol and Segesterone acetate were eluted at 2.348 min and 3.855 min respectively.

186 Hormone content of anabolic implants differentially affects plasma and liver trace mineral concentrations

Abstract Forty-eight commercial Angus steers (327 ± 25 kg) were utilized to determine effects of varying implant hormone composition on liver and plasma trace mineral concentrations. Implant (IMP) treatments (n = 12/treatment) included: no implant (CON), estradiol (E2; Compudose; 25.7 mg estradiol; Elanco Animal Health; Greenfield, IN), trenbolone acetate (TBA; Finaplix H; 200 mg trenbolone acetate; Merck Animal Health; Madison, NJ), and a combination of estradiol and trenbolone acetate (ETBA Revalor-S; 24 mg estradiol + 120 mg trenbolone acetate; Merck Animal Health). Cattle were fed forage-based step up rations throughout the sampling period. Plasma samples were collected on d 0, 2, 10 and 30, with liver biopsies collected on d 2 and 10. Data were analyzed with ProcMixed of SAS with fixed effect of IMP. Contrast statements for each treatment vs CON were developed. Plasma trace mineral analysis utilized repeated measures (repeated effect = day). No IMP × Day effects (P ≥ 0.18) on plasma trace mineral were observed. Day 2 liver Zn and Cu and d 10 liver Mn were lesser (P ≤ 0.04) for TBA implanted steers than CON and d 2 liver Mn tended to be lesser (P = 0.06). The Mn response may reflect changes in protein metabolism due to TBA. However, E2 and ETBA tended to have greater (P ≤ 0.07) d 10 liver Fe concentrations than CON while plasma Fe was unaffected (P ≥ 0.75) by E2, TBA, or ETBA. Both d 2 liver and plasma Zn were lesser for ETBA than CON (P ≤ 0.04) likely driven by the TBA in the implant. Implant contrasts did not affect (P ≥ 0.13) other plasma or liver trace mineral concentrations. These data indicate implant strategies, and thus hormones differentially influence trace mineral metabolism in feedlot steers, which may have implications for diet formulation.

Premature ovarian insufficiency – novel hormonal approaches in optimizing fertility

Premature ovarian insufficiency (POI) is a delicate medical problem in young women. This condition is not unchangeable and permanent but is associated with intermittent and unpredictable ovarian activity, resulting in low conception rate. Over the period of 8 years, the evaluation of secondary amenorrhea was conducted in 90 patients below the age of 40 who wished to restore fertility. Having confirmed the diagnosis and investigated the etiology of POI, hormone replacement therapy was applied (sequential administration of estradiol and norethisterone acetate) in the first 30 patients (group A). Estrogen–progestogen therapy with daily supplementation of 25 mg of micronized oral dehydroepiandrosterone (DHEA) was conducted in 44 patients (group B), whereas a combined regime (estrogen–progestogen therapy, DHEA supplementation in daily dose of 25 mg, and melatonin supplementation in daily dose of 3 mg) was conducted in 16 patients (group C). In the course of our study, 16 pregnancies were realized (18% of all cases: 17% in group A; 18% in group B; 19% in group C) 6 to 20 months after the initiation of hormone therapy, and there have been 13 completed term pregnancies so far with normal fetal growth and development. We concluded that estrogen–progestogen therapy combined with DHEA and melatonin could optimize fertility and lead to successful pregnancy in POI patients.

Information Gaps in Package Inserts Cause Insufficient Patient Information on Correct Handling of Transdermal Patches

The multi-step administration process of transdermal patches requires sufficient knowledge and skills of patients to prevent administration errors. The package insert is an easily accessible information source that reaches the patient automatically with drug dispensing. However, information gaps potentially limit their suitability as appropriate patient information material. Package inserts of all transdermal patches available on the German drug market were analyzed for medication administration recommendations. In total, 81 package inserts were analyzed including buprenorphine (N = 13), fentanyl (N = 33), granisetron (N = 1), glyceroltrinitrate (N = 2), nicotin (N = 4), oxybutynin (N = 1), rivastigmin (N = 10), rotigotin (N = 2), scopolamin (N = 1), and hormone preparations with estradiol, estradiol hemihydrate, ethinyl estradiol, gestodene, levonorgestrel, norelgestromin, and norethindrone acetate (N = 14). None of the package inserts included all 28 administration recommendations that were previously identified as relevant through a systematic literature search. In particular, information was lacking on transdermal patch-specific characteristics such as mechanism of drug absorption, monitoring, storage, and disposal. The package inserts insufficiently inform patients on correct transdermal patch administration and thus, comprehensive patient education by healthcare professionals is required. In the long-term, regulatory requirements for package inserts should include standardized and dosage form-specific recommendations for correct medication administration.

A RASH FROM PROGESTERONE, ESTROGEN, OR IRON: OCPs HAVE THEM ALL BUT WHO'S TO BLAME

Introduction Progesterone hypersensitivity (PH) is a poorly understood condition that was initially thought to be secondary to premenstrual progesterone exposure. However, few cases have been reported to exogenous sources of progestogens. We present a case of PH secondary to the use of a combined oral contraceptive pill (OCP). Case Description 18-year-old female with history of anxiety reported a maculopapular non-pruritic rash on her neck and chest, throat closing sensation, and chest tightness after completing a 6-week treatment with a combined OCP ordered by her gynecologist for contraception. The medication contained ferrous fumarate, ethinyl estradiol, and norethindrone acetate. Symptoms resolved within 3 days of treatment with diphenhydramine. Physical exam was noncontributory. Skin testing for the different components of the medication was performed. Testing was positive for progesterone (intradermal [0.005 mg/mL]), ferrous fumarate (intradermal [6 mg/mL]), and combined OCP (intradermal [pill dissolved in 1 mL]). The patient was advised to avoid these medications and to use estrogen-only contraceptive methods. Four months later, the patient was required to start iron replacement therapy due to anemia. An open oral challenge to iron-containing multivitamin was performed without adverse reactions. Discussion There are different sources of progestins including oral and implantable contraceptives, long-acting depot preparations, emergency contraception, and intrauterine devices. Exogenous sources of progestogens are an important and growing consideration in diagnosing PH. Progesterone skin testing has not been validated; a negative result does not exclude PH.

A comparison of combined oral contraceptives containing chlormadinone acetate versus drospirenone for the treatment of acne and dysmenorrhea: a randomized trial

BackgroundOral contraceptives (OCs), aside from contraceptive efficacy, have been widely known for their non-contraceptive benefits. Different progestogens component of the OCs have been shown to improve the skin, hair, menstrual cycle related disorders and dysmenorrhoeic pain. Thus, we compared the efficacy of OCs containing ethinyl estradiol (EE) and chlormadinone acetate (CMA) versus OCs containing EE and drospirenone (DRSP) for the treatment of acne and dysmenorrhea.MethodsThis study was an investigator-blinded, randomized, parallel group study conducted at the Family Planning Clinic, Department of Obstetrics and Gynaecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Women aged between 18 and 45 years were randomly assigned into two treatment groups, either EE/CMA at the dosage of 30 mcg/2 mg once daily (OD) or EE/DRSP at the dosage of 30 mcg/3 mg OD. The subjects were evaluated for the OC’s efficacy for the treatment of acne and dysmenorrhea at baseline visit and after 1, 3, and 6 months of treatment.ResultsA total of 180 women were randomized into the study. Each group had 90 women. Baseline characteristics between both groups were comparable. At Month 6, there was a significantly greater reduction of total acne lesion in the EE/CMA group than EE/DRSP (72.2% vs 64.5%; p = 0.009). As per the investigator’s global assessment of acne treatment, a higher proportion of the subjects from the EE/CMA group was rated “excellent” than those from the EE/DRSP (75.3% vs 49.4%). More subjects from the EE/CMA group had graded their improvement in acne as “excellent” compared to the EE/DRSP group (66.3% vs 48.3%). A higher proportion of the subjects in the EE/CMA group reported a decrease in dysmenorrhoeic pain as “much decrease” and “decrease”. The absence of dysmenorrhea pain was more frequently found in the EE/CMA group and significantly seen as early as Month 1 also in the EE/CMA group compared to EE/DRSP (47.2% vs 27.3%, respectively). The treatments were generally well-tolerated in both groups. There were no significant differences between both groups for adverse events.ConclusionsEE/CMA is more effective for the treatment of acne and dysmenorrhea in women with mild to moderate acne vulgaris and dysmenorrhea than EE/DRSP.Trial registrationThai Clinical Trial Registry ID: TCTR20170518001 (date of registration: May 17, 2017; retrospectively registered).

Effects of tibolone and hormone therapy (estradiol and medroxyprogesterone acetate) on the late toxic effects of radiotherapy in cervical cancer survivors: a prospective, double-blind, randomized, placebo-controlled trial

Effects of tibolone and hormone therapy (estradiol and medroxyprogesterone acetate) on the late toxic effects of radiotherapy in cervical cancer survivors: a prospective, double-blind, randomized, placebo-controlled trial

Body composition and psychological improvement in healthy premenopausal women assuming the oral contraceptive containing micronized estradiol (E2) and nomegestrol acetate (NOMAC)

This observational study was conducted in healthy premenopausal women, who presented themselves for contraceptive advice at the outpatient Family Planning Clinics of the Department of Obstetrics and Gynecology of the University of Cagliari, Hospital–University of Cagliari (Italy). After a screening period of three menstrual cycles, 48 women without contraindications to estroprogestin contraceptives (OCs) were included in the study. The primary purposes of the study were to evaluate whether a 12-month-treatment with the combined OC containing micronized estradiol (1.5 mg, E2) plus nomegestrol acetate (2.5 mg, NOMAC) (E2/NOMAC) interfere on anthropometric indices (AI), body composition (BC) and psychological status (PS). In subjects with dysmenorrhea (#36), its intensity was evaluated using the visuo analogic scale (VAS), both before and during the 12-month-treatment with E2/NOMAC. E2/NOMAC did not modify neither AI nor BC in the 40 subjects who concluded the study. The PS and the VAS of dysmenorrhea were significantly (p < 0.0001) improved from the first cycle of treatment and throughout the E2/NOMAC treatment in comparison with basal values. The study suggests that E2/NOMAC is devoid of negative effects on AI and BC, with additional benefits on PS and dysmenorrhea.

Proteomic-coupled-network analysis of T877A-androgen receptor interactomes can predict clinical prostate cancer outcomes between White (non-Hispanic) and African-American groups.

The androgen receptor (AR) remains an important contributor to the neoplastic evolution of prostate cancer (CaP). CaP progression is linked to several somatic AR mutational changes that endow upon the AR dramatic gain-of-function properties. One of the most common somatic mutations identified is Thr877-to-Ala (T877A), located in the ligand-binding domain, that results in a receptor capable of promiscuous binding and activation by a variety of steroid hormones and ligands including estrogens, progestins, glucocorticoids, and several anti-androgens. In an attempt to further define somatic mutated AR gain-of-function properties, as a consequence of its promiscuous ligand binding, we undertook a proteomic/network analysis approach to characterize the protein interactome of the mutant T877A-AR in LNCaP cells under eight different ligand-specific treatments (dihydrotestosterone, mibolerone, R1881, testosterone, estradiol, progesterone, dexamethasone, and cyproterone acetate). In extending the analysis of our multi-ligand complexes of the mutant T877A-AR we observed significant enrichment of specific complexes between normal and primary prostatic tumors, which were furthermore correlated with known clinical outcomes. Further analysis of certain mutant T877A-AR complexes showed specific population preferences distinguishing primary prostatic disease between white (non-Hispanic) vs. African-American males. Moreover, these cancer-related AR-protein complexes demonstrated predictive survival outcomes specific to CaP, and not for breast, lung, lymphoma or medulloblastoma cancers. Our study, by coupling data generated by our proteomics to network analysis of clinical samples, has helped to define real and novel biological pathways in complicated gain-of-function AR complex systems.

The Effects of Long-Term Treatment with Estradiol and Medroxyprogesterone Acetate on Tyrosine Hydroxylase Fibers and Neuron Number in the Medial Prefrontal Cortex of Aged Female Rats

Menopausal women often initiate hormone treatment to alleviate the symptoms of menopause. Research suggests that these treatments also affect cognition, and studies in young animals indicate that hormone treatment can alter several neuroanatomical measures. However, very little is known about the effects of long-term hormone treatment on the aging female brain. This study investigated the effects of hormone treatment on neuron number and tyrosine hydroxylase (TH) in the rat medial prefrontal cortex (mPFC). Female Long Evans rats were ovariectomized at middle age (12-13 months) and placed in one of four groups: no replacement (NR) (n = 12), 17β-estradiol (E(2)) (n = 12), E(2) and progesterone (n = 7), or E(2) and medroxyprogesterone acetate (MPA) (n = 10). Animals were euthanized at 20 months, and the brains were Nissl stained; a subset was immunostained for TH [NR (n = 5); E(2) (n = 6); E(2) + MPA (n = 4); E(2) + progesterone (n = 6)]. E(2) was administered through the drinking water, and progestagens were administered via pellets inserted at the nape of the neck. Neuron number and TH fiber density were quantified in the mPFC. Hormone treatment did not alter neuron number. Treatment with E(2) and MPA resulted in greater TH densities than NR in layer 1 (P < 0.05). In layers 2/3, animals receiving E(2) had greater TH densities than NR animals (P < 0.01). These results indicate that long-term hormone treatments alter dopaminergic fibers and potentially the functioning of the aging mPFC.

Abstract 3726: Postmenopausal hormone therapy use and mammographic density in Norwegian women

Abstract While studies have shown that the use of post-menopausal hormone therapy increases mammographic density, certain aspects of this association remain unclear. We examined whether mammographic density differs according to the type of hormone therapy used, dose, duration of use, time since last use, as well as whether the effects are modified by age and body mass index (BMI). We used a cross-sectional design and recruited 2265 post-menopausal women, aged 50-69 who participated in the Norwegian Breast Cancer Screening Program in 2004. Mammographic density was assessed with the computer-assisted method (Madena), and we estimated mean percent mammographic density, controlling for possible confounding factors. Statistical analyzes were performed for all women combined and by age and BMI. Mammographic density was higher among current hormone therapy users (percent density: 20.8%; 95% CI: 19.6-21.9%), than among former (18.7%; 18.1-19.3%) or never HT users (16.7%; 15.8-17.6%). Ever users of combined estrogen-progestogen therapy (EPT) had higher percent density (20.0%; 19.1-20.9%) than estrogen-only (ET) users (18.3%, 17.7-18.9%) and never users (16.7%, 15.8-17.6%), and the highest density was seen in current EPT users (21.4%; 20.1-22.6%). Time since last use was significantly associated with density, with women who quit more than 3 years ago having density similar to never users. Mammographic density declined with increasing age and BMI. In analyses stratified by BMI, we found higher densities with EPT use in all categories, with somewhat smaller differences between ever and never EPT users in women with BMI of 26 and higher. When stratifying analyses by age, mammographic density was similar in EPT users and never users in women aged 55 and below. However, this was not true in leaner women (BMI of 23 or less). Among these young women (55 or less) with low BMI (23 or less), EPT users had higher percent density than never users. The percent density was 26.8% (23.7-29.8%) in never users, and 31.7% (28.0-35.4%) in ever users. No statistically significant difference in density was found in women older than 62 years old with a BMI of 26 and above, with percent density of 6.8% (5.3-8.3%), and 9.3% (6.9-11.6%) in never and ever users, respectively. Higher mammographic density was seen in ever users of estradiol and norethisterone acetate regimens (Activelle and Kliogest) compared to other EPT. Mammographic density was higher in women using high rather than low doses of estradiol and progestogen. In conclusion, the highest mammographic density was found in EPT users compared to ET and never users, particularly in users of the norethisterone acetate regimens. This increase was bigger in women taking high rather than low EPT doses. The association between EPT use and mammographic density was modified by age and BMI. These results have important implications and should be considered when, for example, deciding on which type and dose of hormones to prescribe. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3726. doi:10.1158/1538-7445.AM2011-3726

An open-label study of subdermal implants of estradiol-only versus subdermal implants of estradiol plus nomegestrol acetate: effects on symptom control, lipid profile and tolerability

Objective. To compare the effects of continuous 17-β estradiol-only silastic implants with those of continuous 17-β estradiol plus continuous nomegestrol acetate silastic implants on symptom control, lipid profile and tolerability in postmenopausal women.Methods. This was an open-label, parallel-group study. Women with and without uterus and no contraindications to hormone therapy (HT) in this study, we consider as HT the replacement of Estrogens-only and Estrogens + Progestogens Therapy, were enrolled. Each subject was assigned to receive four 17-β estradiol-only silastic implants (women without uterus), or four 17-β estradiol plus one nomegestrol acetate silastic implant (women with intact uterus), for 1 year.Results. A total of 40 subjects were enrolled and received, the silastic implants of which 40 (100.0%) subjects completed the study (n = 20, estradiol only; n = 20, estradiol plus nomegestrol acetate). The incidence of postmenopausal symptoms decreased significantly. No significant decreases in total cholesterol (1.3%), low-density lipoprotein cholesterol (1.1%), triglycerides (1.2%) and fasting glucose ((1.3%) serum levels were observed in both groups, whereas high-density lipoprotein (HDL) cholesterol increased significantly (2.8%), during the study in both groups. The incidences of adverse events were similar in both treatment groups.Conclusions. Women treated with 17-β estradiol-only silastic implants or 17-β estradiol plus nomegestrol acetate silastic implants showed significant improvement of postmenopausal symptoms, including urogenital and sexual health symptoms and a significant increase in HDL cholesterol and no significant differences in other lipid profiles and tolerability.

Postmenopausal hormone therapy with estradiol and norethisterone acetate and mammographic density: findings from a cross-sectional study among Norwegian women

Background Although a number of studies have evaluated the associations between use of postmenopausal hormone therapy (HT) and mammographic density, few have assessed the effects of the medications containing estradiol (E2) plus norethisterone acetate (NETA). In particular, there are few data on the effects of the low-dose E2/NETA regimen.Methods We included data from 724 women, aged 50–70 years, residing in south-east Norway, who participated in a cross-sectional study conducted within the Norwegian Breast Cancer Screening Program. We assessed mammographic density using a previously validated computer-assisted method.Results After adjusting for age at screening, number of children and body mass index, women who currently used HT had 6.0% higher percent mammographic density than never-users, p < 0.0001. Women who used either low- or high-dose continuous combined E2/NETA regimens had 7.7% (p < 0.0001) and 8.8% (p < 0.0001) higher percent mammographic density than never-users, respectively.Conclusion Our study suggests that the effect of E2/NETA regimens on mammographic density could be at least as detrimental to the breast tissue as several other estrogen + progestin regimens. Our results suggest that both low- and high-dose E2/NETA influence mammographic density, but there were some indications in our analyses that the effect of low-dose E2/NETA could be slightly lower than that of the older high-dose regimen.

Determination of natural and synthetic estrogens and their conjugates in sewage sludge by pressurized liquid extraction and liquid chromatography–tandem mass spectrometry

In this study we present a pressurized liquid extraction/liquid chromatography–tandem mass spectrometry (PLE/LC–MS–MS) method to determine a group of estrogens and conjugated estrogens in sewage sludge. Parameters that affect the extraction step such as extraction solvent, temperature, pressure, static extraction time, number of cycles, purge time and flush volume have been optimized. In the LC–MS–MS system, electrospray ionization and a triple quadrupole analyzer have been used, and the multiple reaction monitoring mode has enabled low levels of target analytes to be detected. All recoveries were higher than 81% except for estrone 3-glucoronide and estradiol 17-glucoronide which were not extracted and consequently, they were not considered in the present study. The repeatability and reproducibility between days expressed as %RSD ( n = 3), were lower than 6% and 9%, respectively. The method developed allowed the target analytes to be quantified at low levels of μg/kg. The limits of detection were lower than 26 μg/kg of dry weight (d.w.) of sewage sludge, except for 17α-estradiol, 17β-estradiol, 17α-ethinylestradiol and estradiol 17-acetate whose values were between 150 and 175 μg/kg (d.w.). The method was applied to determine these compounds in sewage sludge from two domestic sewage treatment plants. Estrone 3-sulfate, estradiol 3-sulfate, diethylstilbestrol, estrone and estriol were determined in some samples and estriol showed the highest value (406 μg/kg d.w.).

Effects of estradiol and medroxyprogesterone acetate on expression of the cell cycle proteins cyclin D1, p21 and p27 in cultured human breast tissues

Estrogen and progesterone are key regulators of normal breast epithelial cell proliferation and differentiation. They are also involved in the initiation and progression of breast tumorigenesis. Several experimental studies have demonstrated that steroid hormones affect cell cycle proteins associated with tumor initiation and progression. Hormone replacement therapy (HT) is widely used to alleviate climacteric symptoms among postmenopausal women. Little is known, however, about cell cycle protein regulation during hormonal treatment of human breast tissue (HBT). In this study we aimed to evaluate the effects of 17β-estradiol (E2) and medroxyprogesterone acetate (MPA) on cultured HBTs representing samples from reduction mammoplasty of premenopausal (pre-HBT) and postmenopausal (postm-HBT) women, and from peritumoral tissue (peritum-HBT) after breast tumor surgery among postmenopausal patients. Explants of HBT were cultured for 14 days in medium supplemented with E2, MPA or E2+MPA. Expression of cyclin D1, p21 and p27 was assessed by immunohistochemical staining of explants cultured for 2 and 14 days. Further, Ki-67 staining was performed to evaluate correlation between proliferation and cell cycle regulatory protein expression. Our results showed that HBTs studied were positive for ERα, ERβ and PR (≥10% of the cells stained). The level of p21 was lower (p

A comparison of hormone therapies on the urinary excretion of prostacyclin and thromboxane A2

Objective To evaluate the effect of estradiol, estradiol and norethisterone acetate (NETA), raloxifene and tibolone on the prostacyclin (PGI2)/thromboxane A2 (TxA2) ratio in postmenopausal women after 8 weeks of treatment.Design This was a randomized, double-blind, cross-over study. Each patient took 8-week courses of estradiol 2 mg, estradiol 2 mg + NETA 1 mg, tibolone 2.5 mg, and raloxifene 60 mg; there was an 8-week placebo wash-out between each different intervention. All volunteers took all four treatment options and were randomized to one of three possible sequences. Urine was collected and frozen at each visit. Urinary metabolites of PGI2 and TxA2 were then assessed at the end of the study.Results The ratio of PGI2/TxA2 was significantly increased for raloxifene. No other treatments showed statistically significant changes.Conclusions The relationship between cardiovascular risk and hormone replacement therapy remains poorly understood. Raloxifene may have additional cardioprotective effects that the other treatments did not demonstrate, and none of the treatments statistically worsened the PGI2/TxA2 ratio. This ratio may be under-utilized as a marker of net effect on cardiovascular health, but more research is needed to link it to health outcomes.

Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density

Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density

Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density

Objective To compare the effects of two different ultra-low doses of continuous combined hormone therapy and placebo on mammographic breast density in postmenopausal women.Methods A subpopulation of 255 postmenopausal women from the CHOICE trial were randomly assigned to 0.5 mg 17β-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA, or placebo. Women using hormone replacement therapy (HRT) up to 2 months prior to the study were excluded; 154 women fulfilled the inclusion criteria. Mammograms were performed at baseline and after 6 months. Breast density was evaluated by visual classification scales and a computer-assisted digitized technique.Results No significant differences were detected between the active treatment groups and the placebo group in the digitized quantification. The mean baseline values for density around 20% were unchanged after 6 months. Also, visual classifications showed no increase in breast density in any study group.Conclusion In contrast to currently available bleed-free regimens, the new ultra-low-dose combination of 0.5 mg E2 and 0.1 mg NETA seems to have very little or even a neutral effect on the breast. Both digitized quantification and visual assessment of breast density were unchanged after 6 months. Larger prospective studies should be performed to confirm this new finding.

Thrombin inhibits GnRH receptor (GnRHR) gene expression in first trimester decidual stromal cells

TRIMESTER DECIDUAL STROMAL CELLS ERROL NORWITZ, FREDERICK SCHATZ, HEE JOONG LEE, VICTORIA SNEGOVSKIKH, MICHAEL PAIDAS, CATALIN BUHIMSCHI, IRINA BUHIMSCHI, CHARLES LOCKWOOD, JOSEPH HUANG, Yale University, Ob/Gyn, New Haven, Connecticut OBJECTIVE: Hypothalamic GnRH (GnRH-I) is critical in regulating mammalian reproduction. GnRH-I, a second isoform (GnRH-II), and their cognate receptor (GnRHR) are produced also by extra-hypothalamic tissues (placenta and decidua) and have local autocrine/paracrine functions. Decidual GnRH appears to regulate trophoblast invasion. Decidual hemorrhage (abrupion) is associated with adverse pregnancy outcome. This study investigates the effects of thrombin on GnRH-I, GnRH-II, and GnRHR gene expression in first trimester decidual stromal cells (DSCs). STUDY DESIGN: First trimester decidua was identified from pregnancy termination tissues (n=3). DSCs were isolated by enzymic digestion, purified, and depleted of leukocytes. Cells were pretreated with estradiol (10-8 M [E2]) and medroxyprogesterone acetate (10-7 M [MPA]) for 7 days. After 6h incubation with or without thrombin (2.5 U/mL), RNA was extracted, cDNA synthesized and purified, and cRNAs prepared and hybridized on Affymetrix HG_U133 Plus 2.0 human chips (which screens for 47,400 human genes and ESTs) followed by fluorescence labeling and optical scanning. Raw data of 3 separate experiments without normalization were generated using Affymetrix GeneChip Operating Software v. 1.1.1 (Santa Clara, CA) and analyzed by GeneSpring software 6.1 (Silicon Genetics, Redwood City, CA). Gene readouts were normalized to 50th percentile of the distribution of all measurements in each chip. Fold ratios were derived by comparing normalized data between different groups. Data are expressed as mean (SEM). RESULTS: DSCs expressed mRNA for GnRH-I, GnRH-II, and GnRHR. Thrombin did not alter GnRH-I or -II mRNA, but significantly downregulated GnRHR gene expression by 5.5-fold (P!0.01) (Figure).