Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).

BACKGROUND: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING: UK MRC DCS/DPFS grant MR/J003611/1.

Hormonal regulation of oviductal glycoprotein 1 (OVGP1; MUC9) in the rhesus macaque cervix.

BACKGROUND: Macaques are outstanding animal models for the development of new contraceptives. In women, progestin-only contraceptives often fail to block ovulation and are believed to act by altering cervix physiology. Herein, we assessed oviductal glycoprotein 1 (OVGP1) in the macaque cervix as a marker for progestogen action. MATERIALS: Rhesus macaques were treated with estradiol (E2 ), E2 plus progesterone (P), and E2 plus levonorgestrel (LNG), a contraceptive progestin. Samples consisted of archived blocks of midcervix mucosa (epithelium and lamina propria) and fresh epithelial cells collected non-invasively by cytobrush. OVGP1 was assayed by quantitative real-time PCR and localized by immunocytochemistry. RESULTS: OVGP1 transcript was maximal after E2 and reduced after treatment with E2  + P (P < .05). LNG also reduced OVGP1 expression (P < .05). OVGP1-specific staining localized to epithelial cells, and transcript was quantifiable in cytobrush collected samples. CONCLUSIONS: OVGP1 expression in cytobrush samples of macaque cervix provides a non-invasive indicator of contraceptive progestin action.

Translational In Vivo Models for Women's Health: The Nonhuman Primate Endometrium--A Predictive Model for Assessing Steroid Receptor Modulators.

Macaques and baboons display physiological responses to steroid hormones that are similar to those of women. Herein, we describe various uses of nonhuman primates for preclinical studies on menstruation, endometriosis, and as a model system to evaluate reproductive therapies and contraceptives. Our goal is to outline the strengths of the nonhuman primate model for studies leading to improved therapies for women.

Cyclic remodeling of the nonhuman primate endometrium: a model for understanding endometrial receptivity.

Old World monkeys display physiological responses to steroid hormones that are similar to those of women. In this review, we describe cyclic morphological changes that take place within the uterus of Old World primates during the menstrual cycle. In primates, estrogen stimulates endometrial growth in the follicular phase of the menstrual cycle. Progesterone secreted in the luteal phase acts to induce secretory differentiation, which is required for successful embryo implantation. During the differentiation process, endometrial estrogen receptor-1 (ESR-1) is suppressed, and reduced staining for ESR-1 is a definitive marker of the onset of uterine receptivity. Downregulation of ESR-1 is topographically limited to the functionalis (upper) zones of the endometrium, the zones in which embryo implantation occurs, indicating that zone-specific factors play a role in the differentiation process. Future genomic and proteomic studies are expected to reveal additional markers for diagnosing endometrial receptivity. Due to the distinct zonal response of the endometrium to ovarian steroids, accurate histological characterization will remain necessary to interpret novel targets in the assessment of fertility.

Role of progesterone in nonhuman primate implantation.

Herein we review the morphological and physiological effects of estradiol and progesterone (P) on the nonhuman primate uterus. Progesterone action acts to prepare the endometrium for embryo implantation, which normally occurs only during a brief period in the mid-luteal phase of the menstrual cycle. During this window of implantation, P stimulates secretory morphological differentiation and suppresses estrogen receptor alpha (ERalpha), in the endometrial functionalis zone. Reduced endometrial ERalpha is a definitive physiological marker for the onset of endometrial receptivity in primates. These actions of P are specific for the functionalis zones, and P does not fully inhibit ERalpha in the glands of basalis zone of nonhuman primates. Paradoxically, during the secretory phase of the cycle, progesterone receptor (PR) is also reduced in the glandular epithelium of the progestin-responsive functionalis zone. Therefore, P action on the epithelium in the functionalis zone may be mediated by paracrine factors arising from the PR-positive cells in the stroma. Genomic analysis of the endometrium of women and nonhuman primates has revealed numerous secretory phase genes that may contribute to differentiation of the endometrium. However, the exact nature and function of these putative factors have been elusive. We propose that nonhuman primates, especially macaques, can provide a valuable animal model for experimentally testing the functional role of P-regulated genes on endometrial receptivity.