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Objective: To assess the effect of contemporary menopausal hormone therapy on the risk of cardiovascular disease according to the route of administration and combination of hormones., Design: Nationwide register based emulated target trial., Setting: Swedish national registries., Participants: 919 614 women aged 50-58 between 2007 and 2020 without hormone therapy use in the previous two years, identified from the Swedish population., Interventions: 138 nested trials were designed, starting each month from July 2007 until December 2018. Using the prescription registry data for that specific month, women who had not used hormone therapy in the previous two years were assigned to one of eight treatment groups: oral combined continuous, oral combined sequential, oral unopposed oestrogen, oral oestrogen with local progestin, tibolone, transdermal combined, transdermal unopposed oestrogen, or non-initiators of menopausal hormone therapy., Main Outcome Measures: Hazard ratios with 95% confidence intervals were estimated for venous thromboembolism, as well as for ischaemic heart disease, cerebral infarction, and myocardial infarction separately and as a composite cardiovascular disease outcome. Treatment effects were estimated by contrasting initiators and non-initiators in observational analogues to "intention-to-treat" analyses and continuous users versus never users in "per protocol" analyses., Results: A total of 77 512 women were initiators of any menopausal hormone therapy and 842 102 women were non-initiators. 24 089 women had an event recorded during the follow-up: 10 360 (43.0%) had an ischaemic heart disease event, 4098 (17.0%) had a cerebral infarction event, 4312 (17.9%) had a myocardial infarction event, and 9196 (38.2%) had a venous thromboembolic event. In intention-to-treat analyses, tibolone was associated with an increased risk of cardiovascular disease (hazard ratio 1.52, 95% confidence interval 1.11 to 2.08) compared with non-initiators. Initiators of tibolone or oral oestrogen-progestin therapy had a higher risk of ischaemic heart disease (1.46 (1.00 to 2.14) and 1.21 (1.00 to 1.46), respectively). A higher risk of venous thromboembolism was observed for oral continuous oestrogen-progestin therapy (1.61, 1.35 to 1.92), sequential therapy (2.00, 1.61 to 2.49), and oestrogen-only therapy (1.57, 1.02 to 2.44). Additional results in per protocol analyses showed that use of tibolone was associated with a higher risk of cerebral infarction (1.97, 1.02 to 3.78) and myocardial infarction (1.94, 1.01 to 3.73)., Conclusions: Use of oral oestrogen-progestin therapy was associated with an increased risk of heart disease and venous thromboembolism, whereas the use of tibolone was associated with an increased risk of ischaemic heart disease, cerebral infarction, and myocardial infarction but not venous thromboembolism. These findings highlight the diverse effects of different hormone combinations and administration methods on the risk of cardiovascular disease., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: funding for the study as detailed above; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Breakthrough bleeding (BTB) is a common side effect of hormonal contraception and is thought to impact adherence to combined oral contraceptives (COCs) but respective dose-response relationships are not yet fully understood. Therefore, the objective of this model-based meta-analysis (MBMA) was to establish dose-response for COCs containing different progestin/EE combinations using BTB as the pharmacodynamic endpoint. Data from 25 studies containing BTB information of 4 progestins (desogestrel, drospirenone, gestodene, and levonorgestrel) in combination with ethinyl estradiol (EE) at various dose levels was used for this analysis. The results of our MBMA show that BTB is significantly increased upon initiation of COC use but subsides over time. The time needed for BTB to return to baseline depends on the EE dose and differs marginally between progestins during the initial months of use at the same EE dose. BTB typically returns to baseline within 3 months at the highest (30 μg) dose, whereas it can take significantly longer to reestablish a regular bleeding pattern at lower EE doses (15 and 20 μg), irrespective of the progestin used. The dose-response relationships established for BTB across different progestin/EE combinations can now be used to support the selection of optimal COC dosing/treatment regimens and serve as the scientific basis for evaluating the impact of clinically relevant factors, including drug-drug interactions and demographics, on BTB., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Postmenopausal dyspareunia and vulvar pain are common complaints, affecting about 60% of women within a few years after hormone levels begin to decline (such as estrogen and androgen). Atrophic changes mainly located in the vulvar vestibule and vulnerability to vulvovaginal infections in postmenopause could be predisposing factors to the development of vulvar burning/pain and introital dyspareunia (vestibulodynia secondary to atrophy). Tibolone is the most effective and safe alternative for treating menopausal symptoms. The role of Lactobacilli and lactoferrin shows its effectiveness in the treatment of vaginal microbiota dysbiosis. The aim of the present study was to assess the efficacy of the combination of tibolone and an oral-specific Lactobacilli mixture in combination with bovine lactoferrin as synergistic therapy for the treatment of vestibulodynia related to atrophy., Methods: In this study, we included 35 postmenopausal women with at least 1 year of amenorrhea, affected by vulvar burning/pain and introital dyspareunia. All participants received treatment with open-label, oral Tibolone 2.5 mg and Lactobacilli mixture (5 × 10 9 CFU per capsule) in combination with bovine lactoferrin (Respecta ® ). Each product was taken once daily for 90 days., Results: After 90 d of therapy with TIB+ Respecta ® , in 30 women that completed the treatment, there was a statistically significant decrease from the baseline in the mean of the Visual Analog Scale for vulvar burning/pain and a reduction in scores in the pain evaluation test., Conclusions: This study provides evidence that the combination of TIB+ Respecta ® was effective in reducing symptoms related to vestibular pain and hypersensitivity in a postmenopausal setting.

We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18-45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and - 0.11 (95% CI: - 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7-9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001 ., (© 2024. The Author(s).)

Importance: Menopausal hormone therapy (HT) includes a wide variety of hormonal compounds, and its effect on blood pressure is still uncertain., Objective: The aim of this study was to assess evidence regarding the effect of HT on blood pressure in postmenopausal women and its association with arterial hypertension., Evidence Review: This systematic review and meta-analysis included randomized clinical trials and prospective observational studies. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and the incidence of hypertension were assessed. All stages were independently performed by two reviewers. For blood pressure outcome, standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated as effect measures. Heterogeneity was assessed using the I2 statistic. The results are presented based on the HT type. The incidence of hypertension was compared using descriptive analyses., Findings: Eleven studies were included with 81,041 women evaluated, of which 29,812 used HT. The meta-analysis, conducted with 8 studies and 1,718 women, showed an increase in SBP with the use of oral conjugated equine estrogens plus progestogen (SMD = 0.60 mm Hg, 95% CI = 0.19 to 1.01). However, oral or transdermal use of estradiol plus progestogen (SMD = -2.00 mm Hg, 95% CI = -7.26 to 3.27), estradiol alone, and tibolone did not show any significant effect. No significant effect on DBP was observed for any formulation. Women who used oral estrogen plus progestogen had a higher risk of incident hypertension than those who never used it., Conclusions and Relevance: The effect of HT on blood pressure is influenced by the formulation used, especially the type of estrogen. The combined formulations of conjugated equine estrogens plus progestogen increased SBP and the risk of hypertension, which was not observed among estradiol plus progestogen, estradiol alone, and tibolone users., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2024 by The Menopause Society.)

Activation of progesterone receptor (PR) facilitates lordosis 40 hr after estradiol treatment, but induces concurrent inhibition (CI) when given with estradiol, or sequential inhibition (SI) when given subsequent to the faciliatory time interval. Tibolone (TBL) is a broad spectrum gonadal steroid agonist that facilitates lordosis when given after estradiol and in place of progesterone (P). The present experiment examined whether it can also induce CI or SI of lordosis behavior in rats as a means of determining its dominant receptor mechanism of action. Subcutaneous (SC) injections of estradiol benzoate (EB), TBL, or P were varied in time to examine whether P induced CI in females pre-treated with TBL or EB, or whether P or TBL induced CI when injected prior to EB (Experiment 1); whether P or TBL induced SI after EB treatment (Experiment 2); and whether P induced SI after TBL treatment (Experiment 3). In Experiment 1, P injected 1 h before EB induced CI after a second P administration 40 h later. However, the same treatment of P to females primed with TBL did not induce CI. In Experiment 2, injections of P or TBL 40 h after EB or TBL induced lordosis within 4 h (facilitation test); however, a second injection of P, 24 h later, induced significant lordosis in rat pretreated with TBL, but not in rats pretreated with P (inhibition test). In Experiment 3, P injected 40 hs after different doses of TBL induced intense lordosis behavior (facilitation test); however, a second dose of P injected 64 h later induced SI, but not in females primed with the highest dose of TBL (inhibition test). Unlike P, TBL did not induce CI or SI. This suggests that TBL likely induces its facilitation of lordosis by an action that is independent of PR., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although menopausal hormone therapy (MHT) seemingly increases the risk of ovarian cancer, evidence is insufficient whether the risk varies between various MHT formulations, regimens and administration modes. With the aim of filling these knowledge gaps, we investigated the effect of different MHT treatment options on the risk of ovarian cancer. This prospective Swedish population-based matched-cohort study included all women ≥40 years having used systemic MHT between 2005 and 2012 (288,950 ever-users), group-level matched (1:3) to 866,546 nonusers. MHT use was ascertained from the Swedish Prescribed Drug Registry and data was linked to several national health data registries. Multivariable conditional logistic regression provided odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for parity, and comorbidities. Current EP-MHT use was associated with a modestly increased risk of ovarian cancer (OR = 1.38, 95% CI 1.18-1.62), while no consistent risk was found among past users (OR = 1.00, 95% CI 0.84-1.18). Current continuous testosterone derived (OR = 1.50, 95% CI 1.15-1.96) regimens increased the risk whereas progesterone derived (OR = 1.48, 95% CI 1.00-2.21) regimens increased the risk marginally. Nonsignificant positive associations were observed for sequential regimens (OR = 1.87, 95% CI 0.70-5.08; OR = 1.54, 95% CI 0.96-2.47, respectively). An inverse relationship was observed for all E-MHT use (OR = 0.25, 95% CI 0.22-0.29), but this association might partly be explained by underreporting of oophorectomies or tubal ligations. Current cutaneous EP-MHT (OR = 1.28, 95% CI 0.81-2.02) suggested a possibly lower risk than oral MHT (OR = 1.48, 95% CI 1.25-1.75). In conclusion EP-MHT, notably continuous regimens, were associated with a modestly increased risk of ovarian cancer. The role of E-MHT requires further clarification., (© 2019 UICC.)

To determine the effectiveness of quick starting combined oral contraception (COC) contain 2.5 mg nomegestrol acetate and 1.5 mg estradiol (NOMAC/E2) comparing with 0.075 mg gestodene and 0.02 mg ethinyl estradiol (GS/EE) on ovarian ovulation inhibition rate, we conducted a non-inferiority randomized controlled trial involving 69 healthy female volunteers aged 18-40 years who had normal menstrual history and were randomized at a 2:1 ratio to take one pack of COC containing either NOMAC/E2 (study group) or GS/EE (control group) starting on menstrual cycle Day7-9. The ovarian activity was assessed by using Hoogland and Skouby grading. Forty-six and 23 participants were randomized to NOMAC/E2 and GS/EE groups, respectively. Baseline characteristics were similar between groups. No significant difference was observed between the study and control groups for ovulation inhibition rate (93.4% vs. 95.6%, risk difference: -2.2%, 95% CI: -13.1, 8.8), ovarian quiescence rate (91.2% vs. 91.2%, P = 1.000), persistent cyst rate (2.2% vs. 4.4%, P = 1.000), and ovulation rate (6.6% vs. 4.4%, P = 1.000). Quick starting COC during day7-9 of menstrual cycle can inhibit ovulation for more than 90%. The quick starting NOMAC/E2 is non-inferior to GS/EE for preventing ovulation and suppressing follicular growth.

Hormonal replacement therapy (HRT) is effective in treating the symptoms of menopause. Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity with a tendency towards invasion and infiltration. Being an estrogen-dependent disease, it tends to regress after menopause. Nevertheless, it affects up to 2.2% of postmenopausal women. Conclusive data are not available in the literature on the appropriateness of HRT in women with endometriosis or a past history of the disease. The hypothesis that exogenous estrogen stimulation could reactivate endometriotic foci has been proposed. The aim of this state-of-the-art review was to revise the current literature about endometriosis in perimenopause and menopause and to investigate the possible role of HRT in this setting of patients. An electronic databases search (MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, Sciencedirect, the Cochrane Library at the CENTRAL Register of Controlled Trials, Scielo) was performed, with the date range of from each database's inception until May 2019. All of the studies evaluating the impact of different HRT regimens in patients with a history of endometriosis were selected. 45 articles were found: one Cochrane systematic review, one systematic review, five narrative reviews, two clinical trials, two retrospective cohort studies, 34 case reports and case series. Some authors reported an increased risk of malignant transformation of endometriomas after menopause in patients assuming HRT with unopposed estrogen. Low-quality evidence suggests that HRT can be prescribed to symptomatic women with a history of endometriosis, especially in young patients with premature menopause. Continuous or cyclic combined preparations or tibolone are the best choices. HRT improves quality of life in symptomatic post-menopausal women, who should not be denied the replacement therapy only due to their history of endometriosis. Based on low-grade literature evidence, we recommend to prescribe combined HRT schemes; tibolone could be considered.

Objective:  To analyze the effects of estrogen alone or in combination with progestogens and tibolone (TIB) on the expression of the extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), of perlecan, and of heparanase (HPSE) of the vascular walls of the carotid arteries., Methods:  A total of 30 250-day-old ovariectomized Wistar rats were orally treated for 5 weeks with: a) 1 mg/kg of estradiol benzoate (EB); b) EB + 0.2 mg/kg of medroxyprogesterone acetate (MPA); c) EB + 0.2mg/kg of norethisterone acetate (NETA); d) EB + 2 mg/kg of dydrogesterone (DI); e) 1 mg/kg of TIB; f) placebo (CTR). Following treatment, the expression of mRNA for MMP-2, MMP-9, and HPSE was analyzed by real-time polymerase chain-reaction (PCR), and the expression of MMP-2, of MMP-9, of tissue inhibitor of metalloproteinase 2 (TIMP-2), and of perlecan was quantified by immunohistochemistry in the carotid arteries., Results:  The groups showed significant differences on mRNA HPSE expression ( p  = 0.048), which was higher in the EB, EB + MPA, and TIB groups. There was no statistically significant difference in mRNA MMP-2 or MMP-9 expression. The immunohistochemical expression of MMP-2, of TIMP-2, of MMP-9, of HPSE, and of perlecan showed no differences between groups., Conclusion:  Estradiol alone or associated with MPA and TIB treatment can increase mRNA HSPE expression of the walls of the carotid arteries in ovariectomized rats., Competing Interests: The authors have no conflicts of interests to declare., (Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.)

Importance: Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial., Objective: To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills., Design, Setting, and Participants: A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018., Main Outcomes and Measures: Electrocardiographic changes 3 hours after sotalol administration., Results: A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P = .005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P = .005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n = 13 of 61 [21.0%]) than those taking levonorgestrel (n = 20 of 137 [14.6%]) or women taking no OCs (n = 24 of 207 [11.6%]; P = .01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P = .01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P < .001)., Conclusions and Relevance: Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.

Hyperandrogenism is a condition affecting 5-10% of adolescents. The aim of this study was to evaluate the efficacy of very low dose of flutamide in the treatment of hyperandrogenism in adolescence. One hundred and fifty-eight patients, presenting severe acne and/or hirsutism, received 62.5 mg/day of flutamide + ethinylestradiol + gestodene for 18 months. The patients were subjected to assessments of hepatic enzymes levels. Thirty subjects treated with drospirenone + ethinylestradiol represented the control group. After 18 months of treatment, it was obtained a decrease of hirsutism (-39.9%), an almost recovery of acne (98% of patients) with better results of those obtained in control group. Only one case of light hypertransaminasemia was recorded, regressed spontaneously. Very low dose of flutamide was successful and safe and in the treatment of hyperandrogenism in adolescence.

We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet ® ) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration ( C max ), extended time to reach the C max and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration-time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: To compare the effects on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the lumbar spine, the femoral neck and the total hip following 2 years of treatment with a low-dose combined hormone therapy (HT) comprised of 1 mg estradiol and 0.5 mg norethisterone acetate (E2/NETA) versus 2.5 mg tibolone in postmenopausal women. Additionally, quantitative ultrasonometry (QUS) of the os calcaneus and of the phalanges was performed., Methods: Changes in BMD, QUS and side-effects were assessed at baseline, 6, 12 and 24 months in 50 postmenopausal women who received either E2/NETA (n = 26) or tibolone (n = 24) for 2 years., Results: Compared to women on tibolone, women receiving E2/NETA showed a significant increase in BMD from baseline to 12 and 24 months at the lumbar spine (3.07%, 3.86%; p < 0.01 vs. 1.13%, 2.23%; p < 0.05), and at the total hip (1.33%, 1.69%; p < 0.01 vs. 0.76%, 0.70%) and at the femoral neck from baseline to 24 months (1.10%; p < 0.05). QUS indices only showed a significant change with the ultrasound bone profile index with E2/NETA at 6 months (-2.32%; p < 0.001)., Conclusions: Low-dose E2/NETA showed a significantly higher increase in BMD compared to tibolone. QUS measurement was not considered to comprise beneficial effects in monitoring drug-induced bone changes.

Preparation and in vitro/in vivo evaluation of gestodene (GEST) intravaginal ring (IVR) formulations which can release a constant dose of GEST during 3 weeks were investigated. In present study a reservoir gestodene intravaginal ring, including a gestodene silicone elastomer core and the non-active silicone layer, was reported, which was manufactured by reaction injection moulding at 80°C for 20 min. The raw materials compatibility experiments showed that the silicone elastomer core carrier wouldn't interact with drugs. In vitro release samples were determined by HPLC and the experiment was performed under sink conditions. The equation of cumulative release verse time was Y=64.76χ+5.44 (r=0.9998), performing zero-order release at about the target dose of 60 µg/day over 21 days. Drug release increased with temperature elevating from 45 to 55°C, which could be attributed to optimizing the prescription. In addition, the pharmacokinetic and safety studies of gestodene intravaginal ring were evaluated in female New Zealand White rabbits. The GEST in plasma was analyzed by LC-MS/MS and the results proved that the correlation between in vitro and in vivo was relatively well.

Background: In recent years, several new oral contraceptives have become available. In some ways, they represent an evolution in terms of individualization and compliance on the part of women. The new formulations make it increasingly possible to prescribe a specific hormonal contraceptive on an individual basis., Methods: A systematic literature search of PubMed was performed using the following combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptive'. Only English-language papers published between January 2000 and July 2014 were included in our analysis. The present review analyzes all aspects of the choice of oral contraceptives in the different phases of a woman's life in detail., Results: Regarding the estrogen component, lowering the dose of ethinylestradiol (EE) helped reduce associated side effects. Natural estradiol is now available and represents a valid alternative to EE. And regarding progestins, the dose has changed over time, as well as the endocrine and metabolic characteristics. These are the fruit of much research into improvement of old products (19-nor-progesterone-derived progestins) with androgenic effects and testing of new molecules with improved metabolic neutrality in terms of insulin sensitivity and lipid parameters. New progestins were a genuine turning point because they greatly reduced major side effects, such as water retention, and their anti-androgenic properties made them indicated for all forms of hyperandrogenism associated with acne and mild hirsutism. The associations of estradiol/dienogest and estradiol/nomegestrol acetate are the most suitable contraceptives for women with abundant menstrual bleeding and can increase the number of potential users of hormonal contraception., Conclusion: Progress in the provision of new oral contraceptives has improved the risk/benefit ratio, by increasing benefits and reducing risks. The present challenge is to tailor contraceptives to individual needs in terms of efficacy and protection of reproductive health., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: A prospective randomized controlled trial was conducted to evaluate the effect of low dose of tibolone on the histology, expression of estrogen (ER) and progesterone receptors (PR) and Bcl-2 protein, in endometrium of postmenopausal women., Method: Forty postmenopausal women consented to treatment and were allocated into two groups of 20 women: Group 1 (Control) without hormone replacement therapy (HRT); Group 2 (Tibolone) treatment at the dose of 1.25 mg/day of oral tibolone administered for a 24-week period. The effect on the endometrium was assessed by histology and the apoptosis marker Bcl-2. The immunoexpression of ER and PR were also measured., Results: Tibolone group showed higher expression of ER, PR and Bcl-2 protein in glandular epithelium and stroma compared to control group., Conclusion: Tibolone in a daily dose of 1.25 mg during 24 weeks demonstrated endometrial action that resulted in low proliferation and was shown to lead to atrophic endometrium. It had favorable effects on the postmenopausal endometrium due to its higher immunoexpression of PR and Bcl-2 protein in endometrial glandular epithelium, thereby creating a balance between pro-apoptotic and anti-apoptotic actions.

Objective To evaluate the effect of short-term hormone replacement therapy with tibolone 2.5 mg daily on endothelial function of healthy postmenopausal women, using flow-mediated dilation (FMD) of the brachial artery. Methods We performed a randomized, double-blinded, placebo-controlled study. A total of 100 healthy postmenopausal women were randomly allocated to receive tibolone (n = 50) or placebo (n = 50) for 28 days. Measurement of the FMD of the brachial artery was performed before and after the use of tibolone and placebo. Results A total of 31 women completed the study in the tibolone group, and 32 women completed the study in the control group. The results of the FMD measurements obtained from the women in the two groups before treatment were similar (0.018 and 0.091, for tibolone and placebo, p = 0.57). The values of the FMD in women who used tibolone and placebo, before and after the treatment, were similar in both groups. The numbers of women who presented an increase in the values of the FMD in both groups were also similar. Conclusion Our results demonstrate that the administration of 2.5 mg tibolone to healthy postmenopausal women for 28 days does not promote endothelial-dependent vasodilation, measured by FMD of the brachial artery.

Introduction: All medical treatments for endometriosis are equally effective in relieving pain. However, all of them alleviate pain symptoms for as long as they are used, but pain always relapses when medication is discontinued. Therefore, medications need to be used in the long term., Areas Covered: Formulations of estro-progestins that contain less than 50 µg of estrogen are associated with a low risk of venous thrombosis, myocardial infarction and stroke. When considering the neoplastic effects, data suggest that the overall risk of invasive cancer by age 60 is not increased in previous users of hormonal contraceptives. The use of progestins for contraception has never been associated with an increased risk of breast cancer, venous thromboembolism or bone fractures. Although more data on long-term therapy with progestins are needed, treatment of endometriosis with progestins may be feasible in women with metabolic or cardiovascular contraindications to estroprogestin. The other medications for the treatment of pain associated with endometriosis are less appropriate for long term administration because of side effects (danazol and GnRH analogues), costs (aromatase inhibitors and GnRH agonists) or necessity of complex regimens of associations (GnRH agonists and add back therapy or aromatase inhibitors plus progestins)., Expert Opinion: Progestins and estroprogestins are safe drugs to use in the long term. Adherence to these medications may be high because, being a contraceptive, they are perceived less as a medication for the treatment of a disease. The annual cost of therapy compares favorably with other available medications. Progestins and estroprogestins represent the first-line medications for the treatment of endometriosis associated pain.

Pharmacokinetic (PK) interactions between the cytochrome P450 3A4 (CYP3A4) pathway and transdermally administered ethinyl estradiol (EE) and gestodene (GSD) were investigated. This paper reports the findings of three open-label, intra-individual, one-way crossover, Phase I trials. In two studies, women used a novel contraceptive patch for 3 weeks during two 4-week study periods; in the second period, the CYP3A4 inhibitors erythromycin (Study 1) or ketoconazole (Study 2) were administered concurrently. In a third study, women received single doses of the CYP3A4 model substrate midazolam, alone and after 3 weeks of concurrent patch application. In each period, the EE/GSD patch (delivering low EE and GSD doses resulting in the same systemic exposure as a combined oral contraceptive containing 0.02 mg EE and 0.06 mg GSD) was applied once weekly for 3 weeks, with one patch-free week. Erythromycin, ketoconazole, and midazolam were administered orally. Main outcome measures were area under the curves (AUCs) and maximum plasma concentration (C max) of EE, and total and unbound GSD (Studies 1 and 2). AUC and C max of midazolam (Study 3). Co-administration of CYP3A4 inhibitors did not affect EE metabolism, and had only weak effects on the PK of total and unbound GSD. The patch had no clinically relevant effect on metabolism of the CYP3A4 substrate midazolam.

Background: Several agents have been advocated for breast cancer primary prevention. However, few of them appear effective, the associated severe adverse effects limiting their uptake., Methods: We performed a comprehensive search for randomized controlled trials (RCTs) reporting on the ability of chemoprevention agents (CPAs) to reduce the incidence of primary breast carcinoma. Using network meta-analysis, we ranked CPAs based simultaneously on efficacy and acceptability (an inverse measure of toxicity). All statistical tests were two-sided., Results: We found 48 eligible RCTs, enrolling 271 161 women randomly assigned to receive either placebo or one of 21 CPAs. Aromatase inhibitors (anastrozole and exemestane, considered a single CPA class because of the lack of between-study heterogeneity; relative risk [RR] = 0.468, 95% confidence interval [CI] = 0.346 to 0.634), arzoxifene (RR = 0.415, 95% CI = 0.253 to 0.682), lasofoxifene (RR = 0.208, 95% CI = 0.079 to 0.544), raloxifene (RR = 0.572, 95% CI = 0.372 to 0.881), tamoxifen (RR = 0.708, 95% CI = 0.595 to 0.842), and tibolone (RR = 0.317, 95% CI = 0.127 to 0.792) were statistically significantly associated with a therapeutic effect, which was restricted to estrogen receptor-positive tumors of postmenopausal women (except for tamoxifen, which is active also during premenopause). Network meta-analysis ranking showed that the new selective estrogen receptor modulators (SERMs) arzoxifene, lasofoxifene, and raloxifene have the best benefit-risk ratio. Aromatase inhibitors and tamoxifen ranked second and third, respectively., Conclusions: These results provide physicians and health care regulatory agencies with RCT-based evidence on efficacy and acceptability of currently available breast cancer CPAs; at the same time, we pinpoint how much work still remains to be done before pharmacological primary prevention becomes a routine option to reduce the burden of this disease., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

In this open-label, randomized study, 36 women (18-45 years) applied an ethinyl estradiol/gestodene contraceptive patch once-weekly for 3 weeks followed by a 1-week, patch-free interval, in 3 treatment periods. The primary objective was to evaluate the pharmacokinetics of ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise. The secondary objective was to evaluate patch adhesion under the same conditions. Weeks 1 and 2 of each period comprised "standardized normal activity" (SNA); in week 3, SNA continued or women used a sauna, whirlpool, swimming pool, or performed an exercise combination. Thirty-one women completed the study; 23 yielded evaluable pharmacokinetic data. Analyses were exploratory and conducted using an analysis of variance. Area under the concentration-time curve from 0 to 168 hours (AUC0-168 ) for gestodene and ethinyl estradiol during sauna, swimming, and whirlpool was equivalent to previous SNA recordings. For exercise combination, the gestodene AUC0-168 was 12% lower compared with SNA, albeit not considered clinically relevant. Two women lost a total of 3 patches during sporting activities; other detachments during this week were not correlated with sporting activity. Overall, hormone delivery using the ethinyl estradiol/gestodene patch under conditions of heat, humidity, and exercise corresponded to delivery under normal conditions., (© 2015, The American College of Clinical Pharmacology.)

Introduction: The first contraceptive patch with ethinyl estradiol (EE) and norelgestromin in the United States demonstrated that there was a tremendous interest in topical methods, which could provide patient convenience, steady-state hormonal levels and reassurance of ongoing coverage, while maintaining efficacy and good bleeding patterns. Unfortunately, concerns about increased risk of venous thromboembolism (VTE) risk diminished its popularity. Another version in Europe and Canada had slightly lower estrogen doses, but questions were raised about its VTE risk too based on its progestin. To fill that gap, two new contraceptive patches with lower estrogen levels have been developed and extensively tested., Areas Covered: This article provides a short overview of the first set of patches followed by discussions of the pharmacokinetics of the two experimental patches as well as the results of their clinical trials, including information about efficacy, bleeding patterns and tolerability., Expert Opinion: Given the recent increased use of first tier contraceptive methods (Intrauterine devices and implants), there may be interest in new patches. Price will influence their popularity. However, a new nondaily delivery system with lower estrogen levels will provide an important option to women.

Objective(s): The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG)., Study Design: In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18-45 years (smokers aged 18-35 years) received either the EE/GSD patch and a placebo tablet (n=171), or a placebo patch and the COC (n=175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods., Results: Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (p>.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (p>.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (p<.01). Intracyclic bleeding was comparable between groups., Conclusion(s): Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC., Implications Statement: The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective(s): To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN)., Study Design: In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods., Results: In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding., Conclusion(s): Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch., Implications Statement: The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of heparanase (HSPE), extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), perlecan and proliferating cell nuclear antigen (PCNA) in normal breast tissue., Methods: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expressions of mRNA for HSPE, MMP-2 and MMP-9 were analyzed by real-time PCR and the protein expressions of HSPE, MMP-2, MMP-9, perlecan and PCNA were quantified by immunohistochemistry., Results: There was a statistically significant difference among the groups for the expression of HSPE mRNA due to high levels in the tibolone group. The groups differed in terms of PCNA, with lower levels found in the tibolone group followed by the estradiol benzoate + dydrogesterone group. A statistically significant positive correlation was observed for PCNA versus perlecan and MMP-9., Conclusions: There was no difference in the effects of combinations of estradiol and different progestogens on extracellular matrix components, and breast cell proliferation was associated with increases in perlecan and MMP-9.

Aim: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue., Methods: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging., Results: There was a statistically significant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate + dydrogesterone; however, estradiol benzoate + dydrogesterone showed the greatest rate of apoptosis., Conclusions: The various progestogens can have more or less proliferative and pro-apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol + dydrogesterone combination resulted in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation.

Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2)., Materials: Participants were healthy, nonobese women aged 18 - 45 years (study 1) or 18 - 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch)., Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P-M-E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M-P-E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval)., Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 - 1.16), indicating average daily delivery similar to oral administration of 0.019 - 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 - 0.885), indicating average daily delivery from the patch of 0.057 - 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0-168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 - 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies., Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives.

This Phase III, uncontrolled, open-label, multicenter study was conducted to investigate the contraceptive efficacy, bleeding pattern, and cycle control of a novel once-a-week contraceptive patch, delivering low-dose ethinyl estradiol (EE) and gestodene (GSD) at the same systemic exposure seen after oral administration of a combined oral contraceptive containing 0.02 mg EE/0.06 mg GSD. Participants were women aged 18 to 35 years, all of whom received the EE/GSD patch for 13 cycles each of 21 treatment days (one patch per week for 3 weeks) followed by a 7-day, patch-free interval. The primary efficacy variable was the occurrence of unintended pregnancies during the study period as assessed by life table analysis and the Pearl Index. Secondary efficacy variables were days with bleeding during four 90-day reference periods and during 1 treatment year, bleeding pattern, and cycle control. The Kaplan-Meier probability of contraceptive protection after 364 treatment days was 98.8% and the adjusted Pearl Index was 0.81. The percentage of participants with intracyclic bleeding/spotting decreased over time, from 11.4% to 6.8% in cycles 1 and 12, respectively. Almost all participants (range: 90.8%-97.6%) experienced withdrawal bleeding across the study period. Compliance was very high (mean: 97.9%; median: 100%). The most frequent adverse events were headache (9.5%) and application site reaction (8.5%); no clinically significant safety concerns were observed. Results suggest the EE/GSD patch is highly effective in preventing pregnancy. Menstrual bleeding pattern was favorable and within the ranges expected of a healthy female population. The patch was well tolerated and treatment compliance was high., (© The Author(s) 2014.)

Objectives: A novel once-a-week contraceptive patch delivers the same systemic exposure seen with a combined oral contraceptive pill containing 0.02 mg ethinyl estradiol (EE) and 0.06 mg gestodene (GSD). This study evaluated the relative bioavailability of EE and GSD after application of this patch to three different sites., Methods: In this phase I, open-label, randomized, intra-individual comparison, crossover study, 43 women (aged 18 - 45 years) were randomized to one of six treatment sequences. Patches were applied to two test sites (buttocks and outer, upper arm) and one comparator site (lower abdomen). In each treatment period, four patches were worn for 7 days each, followed by a 7-day, patch-free interval. The primary objective was to investigate the relative bioavailability of transdermally administered EE and GSD between test and comparator sites using the primary variable area under the concentration- time curve (AUC(0-168)) during week 4 of each period., Results: Of the 43 women who were randomized, 43 were included in the set for safety evaluation and 40 were included in the set for pharmacokinetic (PK) analysis. Three subjects were excluded from the PK analysis as they failed to complete the study. AUC(0-168) for EE and GSD were equal when the patch was applied to buttocks or abdomen (AUC(0-168) ratios: EE, 1.07 (94% confidence interval, CI: 0.994 - 1.16); GSD, 1.02 (94% CI: 0.946 - 1.10)). Relative bioavailabilities for EE and GSD were 31% and 24% higher, respectively, for arm vs. abdomen. AUC(0-168) 94% CI for the arm/abdomen ratio exceeded the pre-defined bioequivalence range of 80 - 125% (EE: 1.21 - 1.42; GSD: 1.15 - 1.34). Other PK parameters were correspondingly higher for arm vs. buttocks or abdomen. Patch adhesion and tolerability were good, with no relevant differences between sites., Conclusion: Differences in systemic EE/GSD exposure following patch application to the outer, upper arm vs. lower abdomen and buttocks are unlikely to be clinically relevant, and there were no relevant safety concerns.

Objectives: To assess the patterns of use of reimbursed systemic hormone therapy (HT) and vaginal estrogen preparations among women aged 45 and older in Finland., Study Design: Reimbursed purchases of prescribed systemic HT and vaginal estrogen preparations for the years 2003-2012 were obtained from a nationwide prescription registry. Systemic preparations included estrogen patches, gels and tablets, tibolone, continuous combination preparations and sequential combination preparations. Prescribed vaginal estrogens included a vaginal ring and vaginal tablets., Main Outcome Measures: Annual period prevalence for systemic HT and vaginal estrogen use., Results: The total prevalence of prescribed HT use remained relatively constant (at 26-27%) throughout the studied period, but the share of women using systemic preparations decreased from 21% to 12%, while the share of women using vaginal estrogens increased from 9% to 19%. Decreases were observed for all classes of systemic preparations, although the decrease was largest for sequential combination preparations (from 4.9% to 1.6%) and estrogen tablets (from 5.2% to 2.9%). Continuous combination preparations remained the most commonly used types of systemic preparation (5.4-4.2%). Systemic HT use decreased most among 45-49 year old women (9.5-4.3%), while the use of vaginal estrogens increased most among those aged 65 and over., Conclusions: Based on the register data, the trends in HT use indicate changed prescribing patterns in accordance with clinical guidelines. It is notable that since 2009, vaginal estrogen was more commonly prescribed than systemic HT., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To examine the impact of subject characteristics on efficacy as measured by the Pearl Index (PI) in clinical trials and to make study populations similar by matching., Methods: Our analysis used US data from four large Phase III studies. We compared results from one fertility control patch study with pooled data from three studies with virtually identical design on oral hormonal contraceptives. First, we identified three characteristics that had the most impact on the PI. Second, we used these three variables and matched subjects from the patch study with those from the oral contraceptive (OC) studies. Finally, we calculated the PIs for matched and unmatched subjects from both the patch study and the OC studies., Results: A total of 3706 subjects were included in our analysis. The variables 'Hispanic ethnicity', 'previous pregnancy' and 'previous use of hormonal contraceptives' had the most impact on the PI. The PIs for the matched patch cohort and the matched OC cohort were 2.97 and 2.48, respectively. Those for the unmatched patch cohort and the unmatched OC cohort were 10.17 and 0.90, respectively., Conclusion: Subject characteristics strongly influence the PI in clinical studies of hormonal contraceptives. In particular, Hispanic ethnicity, previous pregnancies and no previous use of hormonal contraceptives result in a higher PI., Implications: PIs from different clinical trials cannot be meaningfully compared unless subject characteristics that have most impact on the PI are similar or are made to be similar statistically as we did here by matching., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

This study taking gestodene (GEST) as a model, investigated the factors affecting reservoir-type intravaginal ring (IVR)'s drug release. This paper reported a gestodene intravaginal ring of reservoir design, comprising a gestodene silicone elastomer core encased in a non-medicated silicone sheath, separately manufactured by reaction injection moulding at 80 degrees C and heating vulcanization at 130 degrees C is reported. The test investigated the factors affecting drug release through a single variable method, taking the drug release rates of 21 days as standards. When changing the thickness of the controlling sheath outside, the ratio of the first day of drug release and mean daily release (MDR), named the relatively burst effect, is closing to 1 with the thickness of controlling sheath increasing, while the 1.25 mm sheath corresponding to 1.04 controlled the burst release effectively; a positive correlation (r = 0.992 2) existed between the average drug release (Q/t) and drug loading (A) within a certain range. The C6-165 controlling sheath with high solubility of GEST is easier to achieve controlled release of the drug; GEST crystalline power is more effective to implement controlled release of drugs among difficent states of the drug. A 1/4 fractional segment core gives a relatively burst effect of 1.76, while the 1/1 and 1/2 are 1.93 and 1.87 separately, at the same drug loading, concluding that use of a fractional segment core would allow development of a suitable GEST reservoir IVR. In summary, GEST reservoir-type IVR could be adjusted by the thickness of controlling sheath, the loading of drug, the material properties of controlling sheath, the dispersion state of drug, the additive composition and structure of intravaginal ring, to control the drug release behavior and achieve the desired drug release rate.

Aim: This study aims to investigate the effect of a transdermal contraceptive patch containing ethinyl estradiol and gestodene on endometrial proliferation over 1 year., Materials & Methods: In this open-label, uncontrolled, Phase IIb study, women (aged 18-35 years) used the patch for 13 cycles of 28 days. The primary variable was histologic endometrial effects at cycle 13. Secondary objectives included contraceptive efficacy and safety., Results: Overall, 89 women were treated. At all visits, endometrial biopsies were devoid of any abnormalities. One woman became pregnant. The patch was well tolerated, with no safety concerns., Conclusion: The ethinyl estradiol and gestodene patch had an endometrial effect consistent with suppression of endometrial proliferation in most patients. No endometrial abnormalities or other concerns were reported; compliance was good.

Background: This study aimed to evaluate the effect of long-term high-dose tibolone on the bladders and urethras of ovariectomized rats., Methods: Bilateral ovariectomy was performed in 14 young adult rats randomly divided into 2 groups. Experimental rats (n = 9) received 1 mg/day of tibolone orally; control rats (n = 6) received a placebo. After 150 days, the bladders and urethras were removed. Bladder cell proliferation was analyzed by Ki-67 immunohistochemistry. A histomorphometric analysis was performed for epithelial thickness and the percent areas of collagen fibers and blood vessels. Data were compared using a Mann-Whitney test (significance level at p < 0.05)., Results: Urothelial thickness and the percent area of collagen fibers and blood vessels were not significantly different between the tibolone and control groups in the bladder and urethra. In addition, urothelium cell proliferation in the bladder showed a low immunopositivity in both groups. Furthermore, the glycogen and glycoprotein contents in urethral epithelium were slightly modified by tibolone and no change was observed in the bladder., Conclusion: Long-term administration of tibolone has no effect on urothelial trophism, collagen fibers, the number of vessels, or cell proliferation in the urethra and bladder of the ovariectomized rat., (© 2014 S. Karger AG, Basel.)

Medical treatment of functional cysts and endometriomas, and the risk of developing functional ovarian cysts in different therapeutic situations are assessed. The available literature regarding the treatment of functional cysts is limited both by the number of studies and the variability of criteria used to define cysts. There is no evidence to support any efficiency of a medical treatment (LE1). However, oral contraceptive use reduces the risk of development of functional cysts (LE2). Using a second generation combination is recommended as a first-line option in order to reduce thromboembolic risk (LE1). Tamoxifen is significantly associated with an increased risk of developing unilocular cysts before menopause (LE2). For endometriomas, GnRH-agonists are not recommended before cystectomy in order to facilitate surgery (grade C) or to prevent recurrence (grade B). After surgery of endometriomas, the use of an intrauterine device with levonorgestrel or oral contraceptives significantly reduces the volume of the cyst in case of recurrence (LE3); oral contraceptives reduce the recurrence rate of endometriomas (LE2); the use of a low-dose oral contraceptive decreases the frequency and severity of long-term dysmenorrhea (LE1)., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

A new method was developed for the quantitation of 3-α-hydroxy tibolone, in human plasma, after oral administration of a tablet formulation containing tibolone (2.5 mg). 3-α-Hydroxy tibolone was extracted by a liquid-liquid procedure, using cyproterone acetate as internal standard and chlorobutane as extraction solvent. After extraction, samples were submitted to a derivatization step with p-toluenesulfonyl isocyanate. A mobile phase consisting of acetonitrile and water (72:28 v/v) was used and chromatographic separation was achieved using Agilent XDB C18 column (100 × 4.6 mm i.d.; 5 µm particle size), at 40°C. Mass spectrometric detection was performed using atmospheric pressure chemical ionization in negative mode for 3-α-hydroxy tibolone and in positive mode for cyproterone acetate. The fragmentation transitions were m/z 510.2 → m/z 170.1 and m/z 417.0 → m/z 357.1 for 3-α-hydroxy tibolone and cyproterone acetate, respectively. Calibration curves were constructed over the range 100-30,000 pg/mL and the method was shown to be specific, precise and accurate, with a mean recovery rate of 94.2% for 3-α-hydroxy tibolone. No matrix effect or carry-over was detected in the samples. The validated method was applied in a pharmacokinetic study with a tibolone formulation in healthy female volunteers., (Copyright © 2013 John Wiley & Sons, Ltd.)

The Pill has undergone many changes since its first appearance some 50 years ago. Key developments included the reduction of ethinylestradiol doses and the synthesis of new progestins in order to increase safety, compliance and efficiency. Low-dose combined oral contraceptives (COCs) are currently the preferred option for millions of women. Due to this widespread use, it has been argued that the safety of COCs should be even better, raising the threshold for excellence. Yet in spite of major improvements, there is still an associated risk of venous thromboembolism (VTE). The next step in COCs' evolution should take total estrogenicity and hepatic estro-androgenic balance into account. The focus on the estrogen component--which has not changed in 50 years--has yielded a new class of natural estrogen pills. Following the introduction of a first quadriphasic pill, a monophasic estradiol pill based on the concept of "natural balance" was subsequently made available. These recent achievements could represent a step forward in the evolution of COCs and pave the way for better safety.

Background: Hormone replacement therapy (HRT) with tibolone used in the management of menopause has low rates of acceptance and compliance in the first year. Few studies analyze the reasons for abandoning the use of tibolone., Objective: To analyze the reasons for abandoned tibolone hormone replacement therapy in postmenopausal women and the effects of the drug through the years in the treatment., Material and Methods: In a cross-sectional study, were included 261 menopausal women between 40 and 60 year old who attended their disease control at the Gynaecological Endocrinology serving in the National Medical Center Northwest in Obregon City, Sonora, Mexico during 2010-2011. The variables studied included: age, type of menopause, time of use of HRT with tibolone, abandonment reason, development of hypertension, dyslipidemia, hypothyroidism and diabetes mellitus., Results: A total of 21 women discontinued treatment (8.60%, 95% CI -3 to 19), p=0.0001. The reasons for abandonment included, 42.9% gynecological reasons (23.8% breast disease, 14.3% and 4.8% cervical condition ovarian pathology, p=0.0001). Liver disease and vascular occurred in 28.6%, p=0.050., Conclusion: The women studied have adequate adherence to treatment with tibolone (>90%). We don't show an increased risk of cardiovascular or metabolic disease in women studied. Further studies are needed to explore the long-term clinical course, therapeutic response and complications in menopausal patients who use HRT with tibolone.

Background: Transdermal delivery of contraceptives offers several advantages over combined oral contraceptives (COCs), including effective absorption and the provision of relatively constant serum concentrations. Ethinyl estradiol (EE) and the progestin gestodene are well-absorbed through the skin and, therefore, well-suited for use in a transdermal contraceptive patch., Objective: The objective of this study was to investigate the impact of a once-weekly transparent, transdermal patch delivering low doses of EE and gestodene equivalent to a COC containing 0.02 mg EE and 0.06 mg gestodene on hemostasis parameters compared with a monophasic COC containing 0.03 mg EE and 0.15 mg levonorgestrel., Methods: In this single-center, open-label, randomized, crossover study, 30 women (aged 18-35 years) received three cycles of each treatment, separated by a two-cycle washout period. The primary outcome measure was the absolute change from baseline in prothrombin fragments 1 + 2 and D-dimer., Results: For both treatments, prothrombin fragments 1 + 2 remained stable during the first treatment period, and increased only slightly in the second period (mean absolute change 0.025 and 0.028 nmol/L in the novel Bayer patch and COC groups, respectively). Increases in D-dimer were observed in both periods (mean absolute change 107.0 ± 147.2 ng/L for the novel Bayer patch and 113.7 ± 159.0 ng/L for the COC). There were no statistically significant treatment differences in prothrombin 1 + 2 or D-dimer (p = 0.667 and p = 0.884, respectively) and no statistically significant treatment sequence or period effects., Conclusion: A COC containing 0.03 mg EE and 0.15 mg levonorgestrel and the novel Bayer patch have comparable influence on hemostatic endpoints. Both treatments were well-tolerated by subjects.

Objective: To compare the effects of low and conventional doses of tibolone in brachial artery flux parameters among postmenopausal women., Methods: Between March 2011 and September 2012, 24 postmenopausal women attending Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Mexico City, for hormone replacement therapy were consecutively recruited. The women were alternately assigned to receive a daily dose of either 2.5mg (n=11) or 1.25mg (n=13) of oral tibolone. Before and after treatment, all women underwent a brachial artery Doppler ultrasound. The arterial diameter was measured, and the pulsatility index (PI) and the resistance index (RI) were calculated. A hyperemic stimulus was then induced and these parameters were measured again., Results: Among the 24 women, the time since menopause ranged from 16 to 24 months, and the median treatment duration was 3 months. Both groups showed a significant increase in arterial diameter after treatment. There was no significant difference between the groups in arterial diameter, PI, and RI. The arterial diameter after hyperemic stimulus was significantly lower after treatment than before treatment in both groups., Conclusion: Low and conventional doses of tibolone induced similar changes in brachial artery flux parameters among postmenopausal women., (Copyright © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To investigate the effect of tibolone and raloxifene on the serum apoptotic markers soluble Fas (sFas), soluble Fas ligand (sFasL) and cytochrome-c (cyt-c) in postmenopausal women., Methods: A total of 89 healthy postmenopausal women, attending the University Menopause Clinic, were randomly allocated to tibolone (n =30), raloxifene (n =29) or no treatment (n =30). Serum apoptotic markers sFas, sFasL and cyt-c were measured at baseline and at 6 months., Results: Serum sFasL decreased significantly in women receiving tibolone (baseline: 53.8±28.3 pg/ml, 6 months: 40.45±19.2 pg/ml, p =0.001), whilst sFas levels did not significantly change in this group. Serum sFas or sFasL did not change either in the raloxifene group or in the control group. Serum cyt-c concentrations were under the detection limit of the assay in all women assessed., Conclusions: Tibolone use resulted in a significant decrease in serum sFasL, but not in serum sFas. Raloxifene had no effect on either sFas or sFasL. These results may indicate that tibolone use is associated with a decrease in receptor-mediated apoptosis.

Objective: To determine the effects of tibolone or oestradiol (E(2) )/norethisterone acetate (NETA) hormone replacement therapy on glucose and insulin metabolism in postmenopausal women., Design: Single-centre double-blind placebo-controlled randomized clinical trial., Subjects/methods: We randomized 105 healthy postmenopausal women to tibolone 2·5 mg daily, continuous combined oral E(2) 2 mg/NETA 1 mg daily or placebo over a 2-year study. We performed intravenous glucose tolerance tests (IVGTT) with measurements of plasma glucose, insulin and C-peptide concentrations and the IVGTT glucose elimination rate, k. Mathematical modelling was performed to determine measures of insulin sensitivity, S(i) , pancreatic insulin secretion and hepatic and plasma insulin elimination., Results: Tibolone decreased S(i) to 53-63% and k to 72-79% of baseline values but increased IVGTT phase 2 C-peptide concentrations 1·6-1·8-fold and pancreatic insulin secretion 2·2-2·4-fold, so overall IVGTT glucose concentrations were unaffected. Similar, but for k, significantly smaller changes in insulin and C-peptide secretion were seen with E(2) /NETA, also with no effect on overall IVGTT glucose concentrations., Conclusions: Tibolone reduces insulin sensitivity. Healthy postmenopausal women seem able to compensate for this and maintain normal postload glucose concentrations, but it may not be advisable to prescribe tibolone to women with, or at increased risk for, diabetes., (© 2012 Blackwell Publishing Ltd.)

Objective: The aim of this prospective randomized controlled cross sectional study was to evaluate the effect of a six month tibolone treatment in healthy postmenopausal women on biochemical CVD markers by calculating the changes of the blood serum levels of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (Tg), high-sensitivity C-reactive protein (hsCRP), homocysteine (Hcy), and endothelin-1 (ET-1) at the beginning of the treatment and after six months., Materials and Methods: Fifty-two healthy postmenopausal women were enrolled in a prospective, randomized, case-controlled outpatient trial. Group 1 (n = 26) received 2,5 mg/d tibolone for six months, while Group 2 (n = 26) received no treatment. Serum levels ofTC, LDL, HDL, Tg, hsCRP, Hcy, and ET-1 were evaluated at baseline and after six months., Results: The two groups did not statistically differ at baseline characteristics. In Group 1 tibolone treatment decreased significantly TC (p = 0.01), HDL (p < 0.001), and Tg (p < 0.001) serum levels while a significant increase ofhsCRP (p < 0.001) was observed. Finally no changes were noticed on LDL, Hcy, and ET-1 serum levels. Regarding Group 2, no changes were observed., Conclusion: Short-term tibolone treatment in healthy postmenopausal women exerts a mixed action, acting beneficially in some markers (TC, LDL, Tg, Hcy, and ET-1) where as detrimentally in others (HDL, hsCRP).

Objective: Thyroid gland dysfunction is associated with menstrual cycle disturbances, infertility, and increased risk of miscarriage, but the mechanisms are poorly understood. However, little is known about the regulation of these receptors in the uterus. The aim of this study was to determine the effects of long-term treatment with steroid hormones on the expression, distribution, and regulation of the receptors for thyrotropin-releasing hormone (TRHR) and thyroid-stimulating hormone (TSHR), thyroid hormone receptor α1/α2 (THRα1/α2), and THRβ1 in the uterus of surgically menopausal monkeys., Methods: Eighty-eight cynomolgus macaques were ovariectomized and treated orally with conjugated equine estrogens (CEE; n = 20), a combination of CEE and medroxyprogesterone acetate (MPA; n = 20), or tibolone (n = 28) for 2 years. The control group (OvxC; n = 20) received no treatment. Immunohistochemistry was used to evaluate the protein expression and distribution of the receptors in luminal epithelium, glands, stroma, and myometrium of the uterus., Results: Immunostaining of TRHR, TSHR, and THRs was detected in all uterine compartments. Epithelial immunostaining of TRHR was down-regulated in the CEE + MPA group, whereas in stroma, both TRHR and TSHR were increased by CEE + MPA treatment as compared with OvxC. TRHR immunoreactivity was up-regulated, but THRα and THRβ were down-regulated, in the myometrium of the CEE and CEE + MPA groups. The thyroid-stimulating hormone level was higher in the CEE and tibolone groups as compared with OvxC, but the level of free thyroxin did not differ between groups., Conclusions: All receptors involved in thyroid hormone function are expressed in monkey uterus, and they are all regulated by long-term steroid hormone treatment. These findings suggest that there is a possibility of direct actions of thyroid hormones, thyroid-stimulating hormone and thyrotropin-releasing hormone on uterine function.

Objective: To investigate the impact of low- and ultralow-dose regimens of flutamide on liver function of young hyperandrogenic females., Design: A 10-year surveillance study., Setting: University teaching hospital., Patient(s): Two hundred three hyperandrogenic young females (mean age: 20.9 ± 4.9 years)., Intervention(s): Inclusion criterion was receiving low- or ultralow-dose of flutamide as antiandrogenic treatment. Patients were categorized into Groups A and B, according to the administered dose (Group A = 62.5 mg/daily, Group B = 125 mg/daily). The two groups were further subdivided into subgroups (A1, A2, B1, B2) depending on the coadministration of estroprogestagen oral contraceptives (OCs) (A2, B2)., Main Outcome Measure(s): Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were periodically evaluated and used as markers of hepatotoxicity., Result(s): Mild-to-severe increase of circulating AST/ALT was detected in 19 (9.4%; 95% CI = 5.9%-14.4%) patients during the first year of treatment (mild = 16 [7.9%, 95% CI = 4.7%-12.7%], moderate = 2 [0.9%, 95% CI = 0.1%-3.9%], severe = 1 [0.5%, 95% CI = 0.0%-3.1%]). No statistical differences were observed in relation to flutamide dose regimens and coadministration of OC. The median time to hypertransaminasemia was 12 weeks (range: 2-48) with no difference between Group A and Group B. A significant correlation was observed between hepatotoxicity and pretreatment BMI, ALT basal level, and AST basal level., Conclusion(s): Hepatotoxicity is a rare but possible event using low- and ultralow-dose regimens of flutamide. We need larger study populations in order to identify risk patterns for hepatotoxicity development., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Aim: We aimed to study 2-h estrogen kinetics in smoking versus non-smoking postmenopausal women receiving estrogen therapy. Moreover, we wished to study estrogen concentrations over 2 years in smokers using ten or fewer cigarettes daily versus non-smokers in postmenopausal women on estrogen treatment., Method: We used post-hoc analyses from two randomized trials. In study I, we included 150 women from three groups receiving therapies containing 1 or 2 mg 17β-estradiol, where trough and 2-h blood samples was collected in cycles 1, 7 and 13. In study II, we included 94 completing women who had received either placebo or a regimen containing 1 mg 17β-estradiol., Results: In study I, 35% were smokers. At 2 h post tablet intake, serum estrone and estradiol concentrations were significantly lower in smokers as compared to non-smokers, i.e. mean serum estrone was 212 pg/ml (95% confidence interval (CI) 177-247 pg/ml) in smokers as opposed to 318 pg/ml (95% CI 278-359 pg/ml) in non-smokers on 1 mg estradiol (p = 0.0002). In study II, 19% were smokers. In the estrogen group, smoking lead to significantly lower levels of both serum estrone and serum estradiol at all post-randomization time points. No differences between smokers and non-smokers were seen on placebo., Conclusion: We conclude that smoking reduces serum estrogens at both trough and after 2 h in postmenopausal women on estrogen treatment. The effect of smoking on estrogen concentrations is fully expressed in women smoking ten or less cigarettes daily. These findings indicate that the influence of smoking upon the metabolism of estrogen therapy is constant and without dose-response for standard smoking intensities.

Background: The Norwegian "Women and cancer" study has shown that when combination hormone replacement products were used for more than five years the relative risk of breast cancer was almost tripled. The population attributable risk was 27 %. In a nested case-control study we have updated the risk estimates for hormone replacement therapy in post-menopausal women since 2002., Material and Method: We selected an age-matched control for each of the 589 women (aged 46-63) who were found in the period 2004-8 to have invasive breast cancer or cancer in situ. These women responded in 2003-6 to a questionnaire on menstruation and the use of hormone replacement therapy. The data from this and earlier questionnaires were compared and analysed using logistical regression., Results: 226 (26 %) of the women were using hormone replacement at the time of the survey. The average time of use was ten years. Current users had a higher risk of breast cancer than never-users: adjusted OR 2.1 (95 % CI 1.5-3.0). The use of combination therapy for more than five years resulted in the highest risk: OR 3.0 (95 % CI 1.9-4.7). Earlier use of oestrogen products did not result in a higher risk. Neither oestradiol nor tibolon caused a statistically significant increase in risk. 232 cases of breast cancer (17 %) in women aged 45-64 could be attributed to the use of hormones., Interpretation: Long-term use of combination products increases the risk of breast cancer. Relative risk estimates have undergone little change since the previous study, but population attributable risk has fallen along with the decline in new users.