The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most ...frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM).
In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively.
After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P < 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P < 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P < 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants.
The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.
With the aim to shorten the time for diagnosis and accelerate access to correct management, a non-invasive diagnostic test for endometriosis was developed and validated. The IVD test combines an ...ELISA test kit to quantify CA125 and BDNF concentrations in serum and a data treatment algorithm hosted in medical software processing results from the ELISA test and responses to six clinical variables. Serum samples and clinical variables extracted from psychometric questionnaires from 77 patients were collected from the Oxford Endometriosis CaRe Centre biobank (UK). Case/control classification was performed based on laparoscopy and histological verification of the excised lesions. Biomarkers serum concentrations and clinical variables were introduced to the software, which generates the qualitative diagnostic result (“positive” or “negative”). This test allowed the detection of 32% of cases with superficial endometriosis, which is an added value given the limited efficacy of existing imaging techniques. Even in the presence of various confounding medical conditions, the test maintained a specificity of 100%, supporting its suitability for use in patients with underlying medical conditions.
This study aimed to identify vaginal discomfort in the form of dryness, itching, burning, and dyspareunia, which remains an inadequately addressed clinical problem for many postmenopausal women, and ...to describe the age or menopause-related dysfunction of the female urethral tract, which is prevalent.
Medical literature on the incidence and treatment of vulvovaginal symptoms in postmenopausal women was reviewed.
Urogenital atrophy should not be considered an inevitable consequence of menopause because various hormonal and nonhormonal products are available to relieve symptoms. Estrogen deficiency is the primary cause of atrophic urogenital changes, and postmenopausal estrogen therapy is the most logical choice for treatment. All available low-dose local estrogen formulations are effective, but the optimal dose and preferred mode of estrogen administration to achieve symptom relief can vary from woman to woman. Individualization of therapy is the key to balancing the desired local effects of topical vaginal estrogens with potential systemic effects, which may or may not be desired.
This article reviews the use of products for the management of urogenital atrophy in terms of their efficacy, safety, and other characteristics that may influence prescribing and woman's preference.
Estetrol (E4) has emerged as a novel and highly promising estrogen for therapeutic use. E4 is a weak natural estrogen produced only in pregnancy. Because of its novelty, there is considerable ...interest by clinicians in how it is produced in pregnancy. Although the fetal liver plays a key role in its production, the placenta is also involved. A current view is that estradiol (E2) formed in the placenta enters the fetal compartment and is then rapidly sulfated. E2 sulfate then undergoes 15α-/16α-hydroxylation in the fetal liver thereby forming E4 sulfate (phenolic pathway). However, another pathway involving 15α,16α-dihydroxy-DHEAS formed in the fetal liver and converted to E4 in the placenta also plays a significant role (neutral pathway). It is not known which pathway predominates, but both pathways appear to be important in E4 biosynthesis. In this commentary, we summarize the well-established pathways in the formation of estrogens in the nonpregnant and pregnant female. We then review what is known about the biosynthesis of E4 and describe the 2 proposed pathways involving the fetus and placenta.
•Estetrol (E4) biosynthesis in pregnancy is usually attributed to a phenolic pathway.•This pathway involves E4 formation in fetal liver from placental estradiol.•A neutral pathway contributes significantly to E4 biosynthesis as well.•It involves placental aromatization of fetal 15α-/16α-hydroxylated androgens.
This study aimed to compare contraceptive efficacy and safety of drospirenone 4 mg in a 24/4-day regimen in nonobese and obese users and describe pharmacokinetics according to bodyweight.
We analyzed ...data from three drospirenone 4 mg trials (2 European and 1 United States) to report outcomes in nonobese (body mass index <30 kg/m2) and obese (body mass index ≥30 kg/m2) users. We used data from the US trial to calculate the Pearl Index (pregnancies per 100 woman-years) in nonbreastfeeding participants aged ≤35 years at enrollment for confirmed pregnancies. We assessed safety outcomes from all trials based on reported treatment-emergent adverse events. We evaluated pharmacokinetics by bodyweight in the US trial.
The three trials combined comprised 2152 nonobese and 425 obese participants, including 590 nonobese and 325 obese participants in the US trial. Eight nonobese and four obese participants had confirmed pregnancies in the US trial, resulting in Pearl Indices of 3.0 (95% CI: 1.3–5.8) and 2.9 (95% CI: 0.8–7.3), respectively. Two-hundred forty-four (11.3%) nonobese and 39 (9.2%) obese participants discontinued due to a treatment-emergent adverse event. The pharmacokinetic analysis included 814 participants with a median weight of 73 (interquartile range 61–89) kg and median plasma drospirenone exposure (AUC0–24ss) of 661.3 (interquartile range 522–828) ng∙h/mL. Changing bodyweight from the median to the fifth percentile (51 kg) or 95th percentile (118 kg) changed drospirenone exposure (AUC0–24,ss) by 22.2% and –23.6%, respectively.
Drospirenone 4 mg demonstrated similar contraceptive efficacy for both nonobese and obese users despite a difference in exposure based on bodyweight.
Our limited comparison between obese and nonobese users of drospirenone-only oral contraception demonstrated no evidence that efficacy or discontinuation for adverse events differs between groups. Serum drospirenone levels vary by bodyweight and may correlate with bleeding outcomes.
Abstract The need to seek improved combined oral contraceptive (COC) efficacy, with fewer health risks and better acceptability, has been ongoing since the introduction of COCs more than 50 years ...ago. New progestin formulations combined with lower doses of ethinyl estradiol (EE), the predominant estrogenic component of COCs, have reduced the incidence of venous thromboembolism and other negative outcomes of COC treatment. Previous attempts to use endogenous 17β-estradiol (E2 ) instead of EE were limited primarily by poor cycle control. The recent introduction of E2 -based formulations has renewed interest to determine if there are potential benefits of using E2 in COCs. These formulations have been shown to have similar efficacy and cycle control as EE-based COCs. This review provides a brief summary of the pharmacology of EE and E2 , including metabolism, pharmacokinetics and pharmacodynamics, as well as adverse effects of these estrogens.
•Dehydroepiandrosterone an intravaginal ovule improved vulvovaginal atrophy.•Dehydroepiandrosterone intravaginal ovules improved dyspareunia.•Intravaginal dehydroepiandrosterone improves libido in ...postmenopausal women.•Dehydroepiandrosterone conversion to estradiol in the vagina results in efficacy.
The effects of intravaginal administration of dehydroepiandrosterone (DHEA) for the management of symptomatic vulvovaginal atrophy are reviewed.
A literature search related to vulvovaginal atrophy, vaginal atrophy, atrophic vaginitis, estrogen, dehydroepiandrosterone, vulvar itching, burning, dryness, dyspareunia, and libido was performed. Relevant articles addressing the incidence, management, and outcome of DHEA therapy were identified and used for this Expert Opinion.
DHEA compared to a placebo is an effective treatment improving symptoms of vaginal atrophy: dyspareunia, burning, itching, and dryness. Objective parameters of vaginal atrophy, specifically pH, vaginal maturation index (VMI), and investigator-evaluated changes in the vagina: moisture, epithelia integrity and color were improved compared to baseline and placebo. There were significant improvements in libido and dyspareunia with the intravaginal use of DHEA that contribute to improved quality of life for postmenopausal women.
Dehydroepiandrosterone administered intravaginally on a daily basis is an effective treatment for symptoms, and signs of vulvovaginal atrophy along with libido in postmenopausal women.
This article is part of a Special Issue entitled ‘Essential role of DHEA’.
Drospirenone (DRSP) is a fourth-generation progestin that interacts with the progesterone receptor (PR) and androgen receptor (AR) in addition to uniquely interacting to the mineralocorticoid ...receptor (MR). The known effects of DRSP via the mineralocorticoid receptor (MR) are limited. This study seeks to determine if DRSP alters plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in human immortalized endometrial endothelial cells (HEEC) and if such changes in the plasminogen activator system (PAS) are mediated through the MR or AR. The in vitro cell culture experiments utilizing an immortalized human endometrial endothelial cell line evaluated two concentrations of DRSP on PAI-1 and tPA levels in the culture media using specific enzyme-linked immunoassays (ELISA). Experiments adding DRSP with an androgen receptor blocker, flutamide, or a mineralocorticoid receptor agonist, aldosterone, were performed to elucidate which receptor(s) mediated the PAS effects. DRSP 10 μM significantly decreased both HEEC levels of PAI-1 and tPA to 0.75 ± 0.04 and 0.82 ± 0.05 of control, respectively. These direct effects were blunted by flutamide, an AR antagonist. PAI-1 and tPA were not changed by the MR agonist, aldosterone. DRSP significantly decreased both PAI-1 and tPA in the HEECs via the androgen receptor.
Objective To evaluate the safety and efficacy of elagolix vs. placebo and elagolix with low-dose E2 /progestogen add-back therapy. Design Proof-of-concept, dose-ranging, multiple-cohort study. ...Setting Forty-five US clinics. Patient(s) Premenopausal women with fibroids and heavy menstrual bleeding (menstrual blood loss MBL >80 mL per cycle). Intervention(s) Three months' treatment with elagolix alone: 100 mg twice daily (BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 200 mg BID plus continuous low-dose E2 0.5 mg/norethindrone acetate 0.1 mg or elagolix 300 mg BID plus E2 1 mg continuously and cyclical P 200 mg. Main Outcome Measure(s) Least-squares mean percentage change in MBL; adverse events (AEs). Result(s) Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment period. The MBL percentage change from baseline to last 28 days was significantly greater with elagolix alone (range, −72% to −98%; dose-dependent reduction was highest with 300 mg BID) vs. placebo (range, −8% to −41%); mean percentage changes with add-back regimens were −80% to −85%. Overall AEs were dose independent (elagolix alone, 70.0%–81.3%) but lower with placebo (56.0%) and add-back regimens (55.6%–70.6%). Hot flush was the most common AE (elagolix alone, 45.5%–62.5%; placebo, 12.0%; add-back regimens, 18.5%–26.5%). Conclusion(s) Elagolix significantly reduced heavy menstrual bleeding in women with fibroids. Low-dose add-back regimens substantially reduced flushing. Clinical Trial Registration Number NCT01441635.
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