Oestrogens in oral contraception: considerations for tailoring prescription to women's needs.

BACKGROUND: The oestrogenic component of combined oral contraceptives (COCs) has changed over years with the aim of reducing oestrogen-related side effects and risks, whilst maintaining oestrogen beneficial effects, particularly on cycle control. PURPOSE: To describe the pharmacological profiles of different oestrogens commonly used in COCs to provide insights on contraceptive prescription tailored to women's needs. RESULTS: All COCs ensure a high contraceptive efficacy. COCs containing the natural oestrogens oestradiol (E2), oestradiol valerate (E2V) and estetrol (E4) have limited impact on liver metabolism, lipid and carbohydrate metabolism, haemostasis and sex hormone binding globulin levels, compared with ethinylestradiol (EE). COCs with E2 and E2V appear also to entail a lower elevation of the risk of venous thromboembolism vs. EE-containing pills. No epidemiological data are available for E4-COC. E2- and E2V-containing COCs seem to exert a less stabilising oestrogenic effect on the endometrium compared with EE-COCs. The E4-COC results in a predictable bleeding pattern with a high rate of scheduled bleeding and minimal unscheduled bleeding per cycle. Based on in vitro and in vivo animal data, E4 seems to be associated with a lower effect on cell breast proliferation. CONCLUSION: Today various COCs contain different oestrogens. Prescribers must be familiar with the different properties of each oestrogen for a tailored contraceptive recommendation, considering their safety and contraceptive efficacy, as well as women's needs and preferences.

For contraceptive pills physicians can choose among different oestrogens, besides many progestins. Natural oestrogens have less metabolic impact vs EE, while EE and E4 seem to provide a better cycle control. Knowing the different oestrogen characteristics is crucial for adjusting pill prescription to women's needs and desires.

Multidisciplinary care of peripartum heart failure: A scientific statement of the Heart Failure Association of the ESC.

Heart failure is the most common cardiovascular complication during pregnancy and the postpartum period. It is associated with increased risk of maternal morbidity and mortality as well as potentially life-threatening foetal pathology. Management of heart failure in pregnancy requires expert knowledge of cardiovascular disease as well as obstetrics which underscores the importance of multidisciplinary cardio-obstetrics teams in order to optimize diagnosis, treatment and outcome. This includes counselling of women at risk before and during the course of pregnancy in order to strengthen the relationship between medical specialists and patients, as well as to allow patient-centred delivery of care and improve quality of life.

A review of the pharmacology, clinical outcomes, and real-world effectiveness, safety, and non-contraceptive effects of NOMAC/E2.

Selecting an appropriate oral contraceptive can be challenging for healthcare professionals due to the abundance of marketed contraceptive options with different clinical and real-world effectiveness and safety profiles. Nomegestrol acetate + 17ß-estradiol (NOMAC/E2) is a combined oral contraceptive (COC) that inhibits ovulation by suppressing ovarian function by a 17-hydroxy-progesterone derivative and an estrogen identical to that endogenously produced by the ovaries. This narrative review examines clinical and real-world studies of NOMAC/E2 based on a background literature search using PubMed and Google Scholar. The review outlines the pharmacology of NOMAC/E2, including its progestational activity, pharmacokinetics, and effects on carbohydrate metabolism, lipid metabolism, and coagulation parameters, and summarizes key clinical efficacy and safety data that led to the approval of NOMAC/E2 in Europe, Brazil, and Australia. To help elucidate how NOMAC/E2 clinical trial data translate into a real-world setting, this review describes the effectiveness and safety of NOMAC/E2 in prospective studies that include over 90,000 users (half of whom received NOMAC/E2), outlining its effects on risk of thrombosis, menstrual bleeding patterns, weight, mood, acne, bone health, and patient quality of life. Non-contraceptive benefits of NOMAC/E2 for women with endometriosis, dysmenorrhea, or pre-menstrual dysphoric disorder are also discussed. These data demonstrate that NOMAC/E2 has a long half-life and rapid absorption, is effective at preventing unwanted pregnancies, and exhibits a favorable safety profile in both clinical trials and real-world settings. Importantly, NOMAC/E2 is not associated with increased risk of venous thromboembolism, a major safety concern of healthcare professionals for women receiving hormonal contraceptives. This review highlights NOMAC/E2 as a differentiated option among COCs and could help inform oral contraceptive choice to ultimately improve patient management and outcomes in real-world settings.

Is the multinational, surveillance PRO-E2 study informative for all countries? The Italian data on VTE and contraceptive effectiveness.

PURPOSE: To evaluate whether the thromboembolic risk and contraceptive effectiveness of NOMAC-E2 observed in the PRO-E2 study can be extended to each participating country, as lifestyle, cardiovascular risk factors and prescribing habits may differ geographically. This analysis was performed on the PRO-E2 Italian subpopulation, where smoking habit and women over 35 years were more prevalent compared with the overall study population. MATERIALS AND METHODS: Data from NOMAC-E2 or levonorgestrel-containing COCs (COCLNG) new users were descriptively analysed. Incidence rates of thrombosis (events/10,000 women-years [WY]) and the Pearl Index (pregnancies/100 WY) were calculated. RESULTS: Overall, 11,179 NOMAC-E2 and 8,504 COCLNG users were followed up to 2 years (34,869 WY). The NOMAC-E2 cohort included more women over 35 vs. COCLNG (37.7% vs. 31.8%; p = 0.001). A comparable low risk of combined deep venous thrombosis of lower extremities (DVT) and pulmonary embolism (PE) was observed in NOMAC-E2 (1.7/10,000 WY; 95% CI: 0.21-6.2) and COCLNG users (6.6/10,000 WY; 95% CI: 2.4-14.4). Similar results were obtained by considering all thromboembolic events (VTE). Unintended pregnancies did not differ between NOMAC-E2 (0.12/100 WY; 95% CI: 0.06-0.21) and COCLNG (0.15/100 WY; 95% CI: 0.08-0.26) cohorts. CONCLUSION: Despite the higher age and tobacco use, findings from the Italian subpopulation were broadly consistent with overall PRO-E2 results, confirming a similar low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 and COCLNG. SHORT CONDENSATION: This subgroup analysis of the PRO-E2 study provides comprehensive epidemiological data on the use of combined oral contraceptives in a large Italian cohort, with a higher prevalence of women over 35 years and smokers. The study confirms the low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 pill.

NOMAC-E2 shows a better contraceptive effectiveness than LNG combined oral contraceptives in women under 25: real-world PRO-E2 study.

Objective: To investigate unintended pregnancy and changes in mood, acne, and weight in NOMAC-E2 vs levonorgestrel-containing COC (COCLNG) users under 25 years.Methods: In this large, observational study, new users (first-ever users of an eligible COC or restarting with the same or a new eligible COC after a break of at least 2 months) of NOMAC-E2 and COCLNG were recruited in 12 countries in Europe, Australia, and Latin America and followed up via questionnaires for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 women-years). Crude (HRcrude) and adjusted hazard ratios (HRadj) were calculated. Mood and acne changes were defined as change of score from baseline. Weight change was defined as percent change of body weight.Results: Overall, 12,829 NOMAC-E2 users and 17,095 COCLNG users under 25 were followed-up. The risk of unintended pregnancy was statistically significantly lower in the NOMAC-E2 cohort; confirmed events: 30 NOMAC-E2 (PI 0.24; 95% CI, 0.16-0.35) vs 94 COCLNG (PI 0.51; 95% CI, 0.41-0.62). The HRcrude for unintended pregnancy comparing NOMAC-E2 to COCLNG was 0.47 (95% CI, 0.31-0.71) and the HRadj was 0.52 (95% CI, 0.34-0.78). No differential effect on acne, mood, and weight was observed between cohorts.Conclusions: NOMAC-E2 shows a significantly better contraceptive effectiveness in young women and has no differential effect on acne, mood, and weight compared to COCLNG.

NOMAC-E2 compares to LNG combined oral contraceptives in women over forty: real-world PRO-E2 study.

OBJECTIVE: To investigate safety and effectiveness of NOMAC-E2 and levonorgestrel-containing COCs (COCLNG) in users over 40. METHODS: In this large, observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed-up via questionnaires. Incidence of venous thromboembolism (VTE) was expressed as incidence rate (IR; events/104 women-years [WY]). Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 WY). Mood and weight changes were defined as mean changes in mood score and percentage of body weight. RESULTS: Overall, 7,762 NOMAC-E2 and 6,059 COCLNG users over 40 were followed-up. NOMAC-E2 showed no increased VTE risk compared to COCLNG; confirmed events: 5 NOMAC-E2 (IR 5.9; 95% CI, 1.9-13.7) vs 4 COCLNG (IR 5.9; 95% CI, 1.6-15.1). Unintended pregnancy did not differ substantially between cohorts; confirmed events: 4 NOMAC-E2 (PI 0.05; 95% CI, 0.01-0.13) vs 5 COCLNG (PI 0.08; 95% CI, 0.03-0.18). No differential effect on mood and weight was observed between cohorts. CONCLUSIONS: NOMAC-E2 can be considered a valid alternative to COCLNG in perimenopausal women.

COVID-19, gender and estroprogestins, what do we know?

The new coronavirus disease-19 (COVID-19) pandemic has rapidly spread all around the world, eliciting many questions and doubts about the pathogenesis of the disease and treatment. Mortality has been related to a prothrombotic state. Risk factors for the infection and for severe forms of COVID-19 have still to be defined. According to data collected, women appear to be less prone to severe forms of the disease and their mortality was lower than for men. The role of female hormones in the modulation of inflammation may be the reason behind this gender gap.Considering the prothrombotic state activated by the virus, hormone therapies have been placed under investigation as possible increasing risk factors for severe forms. Moreover, new vaccines and their rare thrombotic side effects have increased the concern about this issue.The goal of this review is to go over the mechanisms that lead up to thrombosis during COVID-19, trying to explain the possible reasons why women seem to be naturally protected. The expert opinions about whether to continue/discontinue hormonal therapies are reviewed. Moreover, available data about the so-called 'vaccine induced immune thrombotic thrombocytopaenia' caused by vaccines against COVID-19 are discussed.

Estetrol: A New Choice for Contraception.

Estetrol (E4) is a natural estrogenic steroid that is normally produced by human fetal liver. Recent research has demonstrated that it is a potent, orally bioavailable, natural selective estrogen receptor modulator; it has a moderate affinity for both human estrogen receptor alpha (ERα) and ERß, with a preference for ERα. Clinical studies have demonstrated possible use as an estrogen in combined oral contraceptives (COC). COCs containing E4 and drospirenone (DRSP) showed a high acceptability, tolerability, and user satisfaction also when compared to COCs containing ethinylestradiol (EE). E4/DRSP effectively inhibits ovulation, with a similar effect on endometrium thickness than that of EE-containing COCs. Low doses (15 mg) of E4 with DRSP (3 mg) showed promising results in term of bleeding pattern and cycle control, also when compared to other COCs containing synthetic estrogens. Moreover, the association has limited effects on serum lipids, liver, SHBG levels, and carbohydrate metabolism. This combination also could drive a lower risk of venous thromboembolism than EE-containing COCs. In this review, we will summarize the actual knowledge about the new E4-containing contraceptive. Further large-scale studies in the full target population are needed to provide more insights into the cardiovascular safety profile and user satisfaction of E4/DRSP.

Characterization of a novel mutation V136L in bone morphogenetic protein 15 identified in a woman affected by POI.

BACKGROUND: Premature ovarian insufficiency (POI) is an ovarian defect characterized by primary or secondary amenorrhea, hypergonadotropism and hypoestrogenism which occurs before the age of 40 years with a major genetic component. In this study we performed clinical evaluation and genetic analysis of a group of 18 patients with POI. The study involved 18 consecutive women with POI. Karyotiping and genetic analysis for research of mutations in GDF9 (Growth Differentation Factor 9) and BMP15 (Bone morphogentic protein 15) genes and FMR1 (Fragile X Mental Retardation 1) premutation were carried out. In vitro functional study of the novel BMP15 mutation was performed using COV434 (Human ovarian granulosa tumour cells 434) cells of ovarian granulosa, which consistently express BMP responsive element, and luciferase reporter assay. RESULTS: Three patients (17%) had a family history of POI. Ten patients (56%) had a family history of autoimmune diseases and nine patients (50%) showed a personal history of one or more autoimmune diseases. Of patients for whom morphological assessment was available, almost half (44%) had poor follicle assets or small ovaries's size at pelvic US. Two patients (13%) showed reduced bone density at DEXA (Dual Energy X-ray Absorptiometry). All the women had normal female kariotype and no mutations in the GDF-9 gene or FMR1 premutations were found. A novel heterozygous mutation c.406G > C (V136L) of BMP15 gene was identified in one patient. After transfection in COV434 cells, BMP15 variant showed a significantly reduced luciferase activity compared to wild type. CONCLUSIONS: POI is a multifactorial disease with several health implications. Autoimmunity and genetics represent the most common aetiology. We identified and characterized a novel BMP15 mutation, providing an additional elucidation of molecular basis of this complex disorder.

Estro-progestin Contraceptives and Risk of Cervical Cancer: A Debated Issue.

Steroid contraceptive hormones may promote human papilloma virus (HPV) - DNA integration into the host genome, may bind to specific HPV-DNA sequences within transcriptional regulatory regions, and may modulate cell apoptosis. Most epidemiological studies, reported in this narrative review, have shown that oral contraception is associated with a 1.5-3.3-fold higher relative risk of cervical carcer, but only in users for >5 years and especially in HPV-positive women. The relative risk declines with increasing time since last use and is not different from that of never users after >10 years. Ten-year oral contraceptive use from the age of 20 years is associated with an increase in the cumulative incidence of invasive cervical cancer at the age of 50 years of approximately 1 case per 1,000. Oral contraception has a very small negative impact on the absolute risk of cancer of the uterine cervix.

Hormonal Contraception and Depression: Updated Evidence and Implications in Clinical Practice.

Hormonal contraceptives are used worldwide by more than 100 million women. Some studies have been published about the possible appearance of depressive symptoms when using hormonal contraceptives, but this link is still a matter of debate. The purpose of this review is to provide an update of the literature on this issue, and to investigate the possible explanations of this problem based on animal and human studies. The main pathway responsible for menstrual cycle-related mood changes is the γ-aminobutyric acid pathway, which is sensitive to changes in the levels of progesterone and of its metabolites, the neurosteroids. In particular, allopregnanolone is a potentiating neurosteroid with anxiolytic and anti-convulsant effects whose levels change during a normal menstrual cycle together with progesterone levels. Progestins have different effects on allopregnanolone, mainly owing to their diverse androgenicity. Moreover, they might affect brain structure and function, even though the meaning of these changes has yet to be clarified. It is important to define the groups of women in which negative mood disorders are more likely to occur. Adolescence is a critical period and this age-specific vulnerability is complex and likely bidirectional. Moreover, women with a history of mood affective disorders or premenstrual dysphoric syndrome are at a higher risk when taking contraceptives. In this review, we aim to provide clinicians with advice on how to approach these difficult situations.

Clinical and Metabolic Effects of Alpha-Lipoic Acid Associated with Two Different Doses of Myo-Inositol in Women with Polycystic Ovary Syndrome.

The aim of this retrospective study was to evaluate the effects of a treatment with α-lipoic acid (ALA) associated with two different doses of myo-inositol (MI) on clinical and metabolic features of women with polycystic ovary syndrome (PCOS). Eighty-eight women received the treatment, and 71 among them had complete clinical charts and were considered eligible for this study. All women were treated with 800 mg of ALA per day: 43 patients received 2000 mg of MI and 28 received 1000 mg of MI per day. Menstrual cyclicity, BMI, FSH, LH, estradiol, testosterone, androstenedione, fasting insulin, HOMA-IR, and insulin response to a 2 h OGTT were evaluated before and after 6 months of treatment. The presence of diabetic relatives (DRs) was investigated. Cycle regularity was improved in 71.2% of women. The improvement of menstrual cyclicity occurred regardless of the state of IR and the presence of DRs of the patients. Women with IR mainly showed a significant improvement of metabolic parameters, while those without IR had significant changes of reproductive hormones. Patients with DRs did not show significant changes after the treatment. 85.7% of women taking 2000 mg of MI reported a higher improvement of menstrual regularity than those taking 1000 mg of MI (50%; p < 0.01). In conclusion, ALA + MI positively affects the menstrual regularity of women with PCOS, regardless of their metabolic phenotype, with a more evident effect with a higher dose of MI. This effect seems to be insulin independent. The presence of IR seems to be a predictor of responsivity to the treatment in terms of an improvement of the metabolic profile.

Long-term treatment with α-lipoic acid and myo-inositol positively affects clinical and metabolic features of polycystic ovary syndrome.

The aim of this retrospective study was to evaluate the effects of a long-term treatment with α-lipoic acid (ALA) combined with myo-inositol (MI) on clinical and metabolic features of women with polycystic ovary syndrome (PCOS). Fifty-seven women with PCOS and a history of oligoamenorrhea were treated with MI and ALA (800 mg + 2000 mg per day). Forty-four of them had complete clinical charts and were considered eligible for the study. Information about cycle length and body mass index (BMI) was checked after 6, 12, and 24 months. After 12 months ovarian volume, total testosterone plasma levels and changes in hirsutism were also evaluated. The metabolic parameters were evaluated in 16 women after 6 and 18 months of the treatment. Cycle length was significantly reduced at 6 (p < .001), 12, and 24 months of treatment (p < .01). BMI showed a reduction only at 6 months (p < .05), thereafter returning similar to the basal values. No changes of testosterone and ovarian volume were observed. HOMA-IR and fasting insulin were unchanged, but the insulin response to a 3 h OGTT was improved after 6 (p < .01) and 18 months (p < .05) of treatment. No individual suffered from any adverse event. In conclusion, the combination of ALA and MI showed to be useful as long-term therapy in PCOS women, providing a normalization of the menstrual cycle and an amelioration of insulin levels with a high tolerability.

Contraception with estradiol valerate and dienogest: adherence to the method.

Purpose: The aim of the study was to examine the discontinuation rate of hormonal contraception with estradiol valerate (E2V) and dienogest (DNG). Patients and methods: We collected data at the Family Planning Clinics of the Departments of Obstetrics and Gynecology of Pisa and Cagliari. We included in the analysis 354 consecutive women using oral contraceptive pills containing E2V and DNG. We analyzed the rate and the reason for discontinuation, classifying the reasons in 5 categories: 1) minor side effects, 2) adverse events, 3) other events not directly caused by the drug or conditions for which the pill could represent a risk factor, 4) no compliance with the method and 5) no further need. Results: Of the 354 women examined, 50.8% had discontinued E2V/DNG pill. Excluding women who stopped the pill because of no further need (10.5%), 27.4% discontinued because of minor side effects, 1.7% discontinued for adverse events, 9.9% because of other events not directly caused by the drug or conditions for which the pill could represent a risk factor and 1.4% because of difficulties with compliance. Irregular bleedings were the main reasons reported for discontinuation. The time to discontinuation for irregular bleedings was significantly (p<0.02) longer in adults than in adolescents and slightly but not significantly longer in women who received information about this possible effect. Conclusion: Unacceptable cycle control was the principal cause of discontinuation of pill with E2V and DNG. An appropriate information about this possible effect may improve adherence to this combined oral contraceptive.

Treatment with d-chiro-inositol and alpha lipoic acid in the management of polycystic ovary syndrome.

To evaluate the effects of the combination of d-chiro inositol and alpha lipoic acid on menstrual cycles and insulin sensitivity in women with polycystic ovary syndrome (PCOS). Forty-one women with PCOS and 31 controls have been enrolled in the study. The menstrual cycle, BMI, homeostasis model assessment index (HOMA-I), and insulin secretion in response to an OGTT were evaluated before and after 6 months of treatment. During the observation period, the patients have been asked to not modify their diet and physical activity. The menstrual cycle length improved in 76.7% of the women. Ovulation was restored in 40%. During treatment, BMI significantly decreased (p<.002). The HOMA-I and insulin secretion were unchanged by treatment. However, when women were divided according to the presence of insulin resistance (IR; HOMA-I > 2.5), in those with IR the HOMA-I and the insulin secretion significantly decreased (p<.05 and p<.006). The association of d-chiro-inositol and alpha lipoic acid improves menstrual cycle length, restoring ovulation in the majority of women. Insulin sensitivity improved in women with IR only, confirming that in presence of IR the d-chiro-inositol has a role in restoring the insulin action overcoming the inactivity of epimerase in transforming myo-inositol to d-chiro inositol.

Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives?

OBJECTIVE: Estradiol (E2)-based hormonal contraceptives impact less than ethinylstradiol (EE) contraceptives on venous thromboembolism (VTE) in comparison to formulations with EE. STUDY DESIGN: In this article, the pharamacologic data of EE and E2 were briefly reviewed, along with the induced biologic effect. These data were then related to a recent large international prospective, controlled, non-interventional cohort active surveillance study, on the cardiovascular risk of users of different types of combined estroprogestin contraceptive (CEPC). RESULTS: The crude HR for E2-valerate (E2V)/dienogest vs other CEPCs with EE was 0.8 (95% CI, 0.4-1.6), but when the data were corrected for age, body mass index, duration of use, and family history of VTE, the corresponding adjusted HR was 0.5 (95% CI, 0.2-1.0). A comparison of the E2V/dienogest and EE/levonorgestrel groups showed that the two contraceptives induced a similar VTE risk with the crude and adjusted VTE HRs of 0.7 (95% CI, 0.3-1.8) and 0.5 (95% CI, 0.2-1.3), respectively. Similar results were obtained when the observation was prolonged to January 2017. CONCLUSIONS: The reduced impact of E2 vs EE on coagulation translates into the epidemiologic evidence of a reduced number of events in E2V vs EE users, when progestins other than levonorgestrel are used. However, E2 may continue to negatively impact on the risk of VTE, and this should not be forgotten at the time of prescription. Family history of VTE or thrombophilia, age, and obesity are risk factors for VTE too. If these risk factors are not taken into consideration and excluded, they can overcome or hide the higher safety of E2 vs CEPCs with EE.