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J T Jensen, A B Edelman, B A Chen, D F Archer, K T Barnhart, M A Thomas, A E Burke, C L Westhoff, L S Wan, R Sitruk-Ware, N Kumar, B Variano, D L Blithe
BACKGROUND: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2 ) doses. STUDY DESIGN: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2 , either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles...
February 2, 2018: Contraception
Katharine B Simmons, Narender Kumar, Marlena Plagianos, Kevin Roberts, Elena Hoskin, Leo Han, Mohcine Alami, George Creasy, Bruce Variano, Ruth Merkatz
OBJECTIVES: To evaluate the effects of concurrent administration of three vaginal miconazole nitrate formulations on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol from a novel contraceptive vaginal ring (NES/EE CVR). STUDY DESIGN: This was an open-label, randomized, crossover, drug-drug interaction study conducted over three menstrual cycles in healthy women with regular menses. We compared systemic exposure to NES and EE by determining area under the curve (AUC8-21d ) with CVR only and CVR with each miconazole treatment...
March 2018: Contraception
Renate Louw-du Toit, Meghan S Perkins, Janet P Hapgood, Donita Africander
Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel. We show that the progestins bind to the androgen receptor (AR) with similar affinities to each other and progesterone, while none bind estrogen receptor (ER)-β, and only norethisterone acetate, levonorgestrel and gestodene bind ERα...
September 9, 2017: Biochemical and Biophysical Research Communications
M Zitzmann, J Rohayem, J Raidt, S Kliesch, N Kumar, R Sitruk-Ware, E Nieschlag
Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone® (NES), all in combination with transdermal testosterone (T)...
May 2017: Andrology
Narender Kumar, Jerôme Fagart, Philippe Liere, Scott J Mitchell, Alanah R Knibb, Isabelle Petit-Topin, Marion Rame, Martine El-Etr, Michael Schumacher, Jeremy J Lambert, Marie-Edith Rafestin-Oblin, Regine Sitruk-Ware
Nestorone® (NES) is a potent nonandrogenic progestin being developed for contraception. NES is a synthetic progestin that may possess neuroprotective and myelin regenerative potential as added health benefits. In receptor transactivation experiments, NES displayed greater potency than progesterone to transactivate the human progesterone receptor (PR). This was confirmed by docking experiments where NES adopts the same docking position within the PR ligand-binding domain (LBD) as progesterone and forms additional stabilizing contacts between 17α-acetoxy and 16-methylene groups and PR LBD, supporting its higher potency than progesterone...
January 1, 2017: Endocrinology
Renate Louw-du Toit, Meghan S Perkins, Jacky L Snoep, Karl-Heinz Storbeck, Donita Africander
Progestins used in contraception and hormone replacement therapy are synthetic compounds designed to mimic the actions of the natural hormone progesterone and are classed into four consecutive generations. The biological actions of progestins are primarily determined by their interactions with steroid receptors, and factors such as metabolism, pharmacokinetics, bioavailability and the regulation of endogenous steroid hormone biosynthesis are often overlooked. Although some studies have investigated the effects of select progestins on a few steroidogenic enzymes, studies comparing the effects of progestins from different generations are lacking...
2016: PloS One
Giovanni Grandi, Antonella Napolitano, Angelo Cagnacci
INTRODUCTION: Is the replacement of ethinyl-estradiol (EE) with estradiol (E2) in combined hormonal contraceptives (CHCs) associated with fewer metabolic effects, leading to a further improvement on safety of hormonal contraceptives? AREAS COVERED: This is a narrative review paper including all available data on the metabolic impact of CHCs containing E2 published in English up to December 2015. Modification of a metabolic variable of interest during the first months of treatment was considered as an outcome...
July 2016: Expert Opinion on Drug Metabolism & Toxicology
D F Archer, M A Thomas, J Conard, R B Merkatz, G W Creasy, K Roberts, M Plagianos, D Blithe, R Sitruk-Ware
OBJECTIVES: Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150mcg Nestorone® (NES) and 15mcg ethinyl estradiol (EE). STUDY DESIGN: A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers)...
January 2016: Contraception
Yongmei Huang, Ruth B Merkatz, Sharon L Hillier, Kevin Roberts, Diana L Blithe, Régine Sitruk-Ware, Mitchell D Creinin
BACKGROUND: A contraceptive vaginal ring (CVR) containing Nestorone® (NES) and ethinyl estradiol (EE) that is reusable for 1- year (13 cycles) is under development. This study assessed effects of this investigational CVR on the incidence of vaginal infections and change in vaginal microflora. METHODS: There were 120 women enrolled into a NES/EE CVR Phase III trial and a microbiology sub-study for up to 1- year of cyclic product use. Gynecological examinations were conducted at baseline, the first week of cycle 6 and last week of cycle 13 (or during early discontinuation visits)...
2015: PloS One
Vivian Brache, Ruth Merkatz, Narender Kumar, Cristian Jesam, Heather Sussman, Elena Hoskin, Kevin Roberts, Mohcine Alami, Deshawn Taylor, Aidelis Jorge, Horacio Croxatto, Ellen Lorange, Daniel R Mishell, Regine Sitruk-Ware
OBJECTIVE: This study aims to determine the lowest effective of three Nestorone (NES)/estradiol (E2) transdermal gel doses to ensure ovulation suppression in 90-95% of cycles. METHODS: This was a randomized, open-label, three-treatment-period cross-over study to evaluate the effects of NES/E2 transdermal gel on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters. The doses were low (1.5 mg NES/0.5 mg E2), medium (3.0 mg NES/1.0 mg E2) and high (4...
October 2015: Contraception
Laura Garay, Maria Claudia Gonzalez Deniselle, Regine Sitruk-Ware, Rachida Guennoun, Michael Schumacher, Alejandro F De Nicola
Progesterone plays a protective role in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Besides spinal cord neuropathology, MS patients present a dysfunctional hippocampus. In this work we studied the therapeutic effects of the progestin Nestorone in the brain of mice with chronic EAE. Nestorone decreased clinical grade and enhanced motor behavior. In addition, it increased cell proliferation and doublecortin positive neuroblasts in the hippocampus, increased GABAergic interneurons and attenuated the number of Iba1+ microglia/macrophages, events possibly linked to enhancement of neurogenesis...
November 15, 2014: Journal of Neuroimmunology
Martine El-Etr, Marion Rame, Celine Boucher, Abdel M Ghoumari, Narender Kumar, Philippe Liere, Antoine Pianos, Michael Schumacher, Regine Sitruk-Ware
Multiple Sclerosis affects mainly women and consists in intermittent or chronic damages to the myelin sheaths, focal inflammation, and axonal degeneration. Current therapies are limited to immunomodulators and antiinflammatory drugs, but there is no efficient treatment for stimulating the endogenous capacity of myelin repair. Progesterone and synthetic progestins have been shown in animal models of demyelination to attenuate myelin loss, reduce clinical symptoms severity, modulate inflammatory responses and partially reverse the age-dependent decline in remyelination...
January 2015: Glia
Ruth B Merkatz, Marlena Plagianos, Elena Hoskin, Michael Cooney, Paul C Hewett, Barbara S Mensch
OBJECTIVES: Develop and test a theoretical acceptability model for the Nestorone®/ethinyl estradiol contraceptive vaginal ring (CVR); explore whether domains of use within the model predict satisfaction, method adherence and CVR continuation. STUDY DESIGN: Four domains of use were considered relative to outcome markers of acceptability, that is, method satisfaction, adherence and continuation. A questionnaire to evaluate subjects' experiences relative to the domains, their satisfaction (Likert scale) and adherence to instructions for use was developed and administered to 1036 women enrolled in a 13-cycle Phase 3 trial...
November 2014: Contraception
Mara Y Roth, Grace Shih, Niloufar Ilani, Christina Wang, Stephanie T Page, William J Bremner, Ronald S Swerdloff, Regine Sitruk-Ware, Diana L Blithe, John K Amory
OBJECTIVE: Fifty percent of pregnancies in the United States are unintended despite numerous contraceptive methods available to women. The only male contraceptive methods, vasectomy and condoms, are used by 10% and 16% of couples, respectively. Prior studies have shown efficacy of male hormonal contraceptives in development, but few have evaluated patient acceptability and potential use if commercially available. The objective of this study is to determine if a transdermal gel-based male hormonal contraceptive regimen, containing testosterone and Nestorone® gels, would be acceptable to study participants as a primary contraceptive method...
October 2014: Contraception
M Y Roth, N Ilani, C Wang, S T Page, W J Bremner, R S Swerdloff, C Dart, R Sitruk-Ware, N Kumar, D Blithe, J K Amory
Development of a male hormonal contraceptive has been challenging ascribable to the failure to adequately suppress spermatogenesis in 5-10% of men. Methods to identify incomplete suppressors early in treatment might identify men most responsive to male hormonal contraceptives. We hypothesized that serum hormone and gonadotropin concentrations after 4 weeks of transdermal treatment with testosterone and Nestorone in a contraceptive trial would be associated with suppression of sperm concentrations to <1 million/mL after 24 weeks...
November 2013: Andrology
R Sitruk-Ware, M El-Etr
Progesterone is a steroid hormone that is essential for the regulation of reproductive function. The main physiological roles of this hormone have been widely described. Progesterone and progestins have been approved for a number of indications including the treatment of irregular and anovulatory menstrual cycles and, when combined with estrogen, for contraception, and the prevention of endometrial hyperplasia in postmenopausal hormonal replacement therapy (HRT) regimens. Lack of understanding between the differences in categories of the progestins as well as with the physiological hormone has resulted in considerable controversy surrounding the use of progestins for HRT regimens...
August 2013: Climacteric: the Journal of the International Menopause Society
Vivian Brache, Luis José Payán, Aníbal Faundes
Contraceptive vaginal rings (CVR) offer a new, effective contraceptive option, expanding the available choices of hormonal contraception. Various ring prototypes have been evaluated: progestin-only rings and combined progestin-estrogen rings, as well as different combination of progestins and estrogens. The progestin-only ring is intended for continuous use, whereas the combined ring has been designed for cyclic 3-week in/1-week out use, although several studies have explored alternative schemes of extended use...
March 2013: Contraception
Mandana Rad, Jacobus Burggraaf, Regine L Sitruk-Ware, Marieke L de Kam, Adam F Cohen, Cornelis Kluft
UNLABELLED: OBJECTIVE & STUDY DESIGN: In a parallel design, 23 and 22 healthy pre-menopausal women were randomly administered a contraceptive vaginal ring (CVR) delivering 150/15 μg Nestorone®/ethinyl estradiol (EE) daily or an oral contraceptive (OC) containing levonorgestrel and EE (150/30 μg) for three cycles, to compare the effects on C-reactive protein and other markers of inflammation. ANCOVA was performed with baseline values as covariate. RESULTS: The CVR caused [estimate of difference (95% CI), 109% (16-275%)] higher levels of CRP than the OC, while no difference was observed for leukocyte 1% (-13/+17%) and monocyte counts 6% (-9/+23%)...
November 2012: Steroids
Niloufar Ilani, Mara Y Roth, John K Amory, Ronald S Swerdloff, Clint Dart, Stephanie T Page, William J Bremner, Regine Sitruk-Ware, Narender Kumar, Diana L Blithe, Christina Wang
CONTEXT: Combinations of testosterone (T) and nestorone (NES; a nonandrogenic progestin) transdermal gels may suppress spermatogenesis and prove appealing to men for contraception. OBJECTIVE: The objective of the study was to determine the effectiveness of T gel alone or combined with NES gel in suppressing spermatogenesis. DESIGN AND SETTING: This was a randomized, double-blind, comparator clinical trial conducted at two academic medical centers...
October 2012: Journal of Clinical Endocrinology and Metabolism
Ailing Liu, Isabelle Margaill, Shaodong Zhang, Florencia Labombarda, Bérard Coqueran, Brigitte Delespierre, Philippe Liere, Catherine Marchand-Leroux, Bert W O'Malley, John P Lydon, Alejandro F De Nicola, Regine Sitruk-Ware, Claudia Mattern, Michel Plotkine, Michael Schumacher, Rachida Guennoun
Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5α-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage...
August 2012: Endocrinology
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