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.

Efficacy and Safety of Megestrol in the Hospitalized Older Person.

Objectives To evaluate the efficacy and safety of megestrol for off-label use in older patients with weight loss. Design Retrospective, nonblinded cohort study. Setting Upstate University Hospital is a 420-bed facility and academic medical center with a level 1 trauma center. Upstate Community Hospital is a 314-bed acute care/hospital/ambulatory care center and long-term care hospital that also provides teaching services. Participants Patients 65 years of age and older without malignancy or acquired immunodeficiency syndrome who were initiated and continued megestrol therapy at the Upstate University hospitals for at least two weeks were included. Of the 1,290 patients initially screened, 16 patients on megestrol were evaluated. An age- and gender-matched control group of 16 patients was utilized for comparison of changes in weight and other variables. Interventions Patients in the megestrol group have received daily doses of megestrol between 160 mg to 800 mg for an average duration of 19 days. Patients in the control group had no history or current use of megestrol utilization. Main Outcome Measurements The primary outcome was an increase in weight. Secondary outcome measures included albumin and thromboembolic events. Changes in weight and albumin were also compared with the control group. Results At a mean duration of 19 days, there was no significant difference in weight gain (0.95 kg, OR = 1.33 [95% CI -1.615-3.527]). Albumin decreased by (0.4 g/dL OR = 0.916 [95% CI 0.12-0.78]) and none of the patients developed a thromboembolic event. Conclusion In older hospitalized patients, megestrol did not increase weight, and did not improve albumin. No thromboembolic events were observed, but this may be because of a limited duration of observation of therapy and the routine use of anticoagulation prophylaxis in the inpatient setting.

Preliminary report of patients with meningiomas exposed to Cyproterone Acetate, Nomegestrol Acetate and Chlormadinone Acetate - Monocentric ongoing study on progestin related meningiomas.

INTRODUCTION: The relationship between meningioma and progestins has not been elucidated. Meningioma regression after acetate cyproterone (CA) withdrawal has been reported. Our purpose was to evaluate the meningioma evolution after withdrawal of progestins in patients who underwent long-term exposure to CA, nomegestrol acetate (NA), chlormadinone acetate (ChlA). METHODS: Our study retrospectively included 69 patients with intracranial meningioma and exposed to one of these 3 progestins between December 2006 and March 2019. In each patient, clinico-radiological (MRI) follow-up was performed every 6 months after diagnosis and treatment withdrawal recommendation. Statistical analyses were applied to compare tumor location and respect of prescription rules between the 3 groups. RESULTS: The mean hormonal exposure was 16 years in CA group (n = 46), 16 years in NA group (n = 12) and 9.7 years in ChlA group (n = 11). A higher rate of "out of label" use was observed in the CA group (p = 0.003). Multiple meningiomas were demonstrated in more than 60% of cases in each group. Anterior skull base location was noted in 60.5% of cases in CA group, 25% of cases in NA group and 36.7% of cases in ChlA group (p = 0.05). Incomplete tumor regression was recorded in 11 cases of CA group and in 2 cases of ChlA group. CONCLUSION: In CA group, our results suggest a strong relationship between this treatment and development of intracranial meningioma. In presence of voluminous asymptomatic meningioma, treatment can be delayed due to the potential regression after withdrawal. On the contrary in NA and ChlA groups, further studies are needed.

Association of Megestrol Use With the Development of New Psychiatric Diagnoses.

OBJECTIVE: To analyze the risk of megestrol, a glucocorticoid and progesterone receptor agonist used to enhance appetite, on the development of a new psychiatric diagnosis. DESIGN AND PARTICIPANTS: Deidentified data of megestrol (n = 706) and propensity score-matched comparison (age, gender, and body mass index) patients (n = 2,118) from January 1, 2001 to June 30, 2018 were obtained from the UT Southwestern patient database. Data were analyzed using a series of conditional binary logistic regressions controlling for comorbidities, pre-existing psychiatric disorders, and number of patient encounters. SETTING: A large academic medical center database of megestrol-treated patients and matched comparison patients was used. MEASUREMENTS AND RESULTS: The regression model showed that megestrol was significantly associated with developing a new psychiatric diagnosis (B = 1.28, Wald χ21 = 83.12, odds ratio [OR] = 3.60, p <0.001). In subgroup analyses, development of cognitive (B = 2.42, Wald χ21 = 16.09, OR = 11.30, p <0.001), mood (B = 1.31, Wald χ21 = 40.38, OR = 3.70, p <0.001), and anxiety (B = 1.72, Wald χ21 = 45.28, OR = 5.60, p <0.001) disorders were also associated with megestrol use. CONCLUSIONS: Patients taking megestrol were significantly more likely to develop a new psychiatric diagnosis than comparison patients. Highest risks were associated with the development of cognitive diagnoses. The findings suggest that megestrol, like other glucocorticoid agonists, is associated with an increased risk of developing a psychiatric disorder. This risk should be considered when determining the risk-to-benefit ratio of megestrol use in patients.

Combined hormonal influence of cyproterone acetate and nomegestrol acetate on meningioma: a case report.

Cyproterone acetate (CPA) is an antiandrogenic drug which has recently been recognized to promote the occurrence and growth of intracranial meningiomas. Nomegestrol acetate (NOMAC) is a widely used progestin-like drug that could be suggested as an alternative for patients taking CPA. We report a case of CPA-related meningioma for which relay from CPA to NOMAC led to further tumor growth and cessation of NOMAC-induced tumor shrinkage. We suggest NOMAC can have a similar effect than CPA on meningiomas. The use of NOMAC as replacement for CPA in the presence of a meningioma should be discouraged until further evidence becomes available on the role of NOMAC in such instances.

Ongoing or previous mental disorders predispose to adverse mood reporting during combined oral contraceptive use.

PURPOSE: Previous studies have emphasised that women with pre-existing mood disorders are more inclined to discontinue hormonal contraceptive use. However, few studies have examined the effects of combined oral contraceptives (COC) on mood in women with previous or ongoing mental disorders. MATERIALS AND METHODS: This is a supplementary analysis of an investigator-initiated, double-blinded, randomised clinical trial during which 202 women were treated with either a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo during three treatment cycles. The Mini International Neuropsychiatric Interview was used to collect information on previous or ongoing mental disorders. The primary outcome measure was the total change score in five mood symptoms on the Daily Record of Severity of Problems (DRSP) scale in the intermenstrual phase of the treatment cycle. RESULTS: Women with ongoing or previous mood, anxiety or eating disorders allocated to COC had higher total DRSP Δ-scores during the intermenstrual phase of the treatment cycle in comparison with corresponding women randomised to placebo, mean difference 1.3 (95% CI 0.3-2.3). In contrast, among women without mental health problems, no difference in total DRSP Δ-scores between COC- and placebo users was noted. Women with a risk use of alcohol who were randomised to the COC had higher total DRSP Δ-scores than women randomised to placebo, mean difference 2.1 (CI 95% 1.0-3.2). CONCLUSIONS: Women with ongoing or previous mental disorders or risk use of alcohol have greater risk of COC-induced mood symptoms. This may be worth noting during family planning and contraceptive counselling.

The sexuological impact of hormonal contraceptives based on their route of administration.

Evidence on the effects of hormonal contraceptives on female sexuality is conflicting. We enrolled 556 women, divided into six groups: two composed of subjects using a combined hormonal contraceptive (COC) containing 0.020 ("COC20") and 0.030 ("COC30") mg of ethynyl estradiol (EE), "natural", using COC containing 1.5 mg of estradiol (E2), "ring", using a vaginal ring releasing each day 0.015 mg of EE + 0.120 of etonogestrel, "subcutaneous", using a progestin only subcutaneous contraceptive implant releasing etonogestrel and "controls", using no hormonal contraceptive methods. The subjects were required to answer to the McCoy female sexuality questionnaire and were subjected to a blood test for hormonal evaluation. An ultrasound evaluation of the dorsal clitoral artery was also performed. The higher McCoy sexological value were recorded in the subdermal group; significant differences were recorded among the groups in terms of hormone distribution, with the higher levels of androstenedione in subdermal and control groups. The ultrasound evaluation of dorsal clitoral artery shows a significative correlation between pulsatility and resistance indices and orgasm parameters of McCoy questionnaire. The recorded difference in the sexual and hormonal parameters among the studied hormonal contraceptives may guide toward the personalization of contraceptive choice.

Pooled analysis of two randomized, open-label studies comparing the effects of nomegestrol acetate/17ß-estradiol and drospirenone/ethinyl estradiol on bleeding patterns in healthy women.

OBJECTIVES: To obtain more precise and detailed information regarding the bleeding patterns of nomegestrol acetate (NOMAC)/17ß-estradiol (E2) and drospirenone/ethinyl estradiol (DRSP/EE) and to identify whether baseline demographic characteristics were associated with unscheduled bleeding, absent scheduled bleeding, or amenorrhea. STUDY DESIGN: This analysis pooled results from two pivotal open-label, randomized trials that compared bleeding patterns of NOMAC/E2 and DRSP/EE. In the two studies 4317 women aged 18-50 years from 24 countries across the Americas, Europe, and Asia underwent treatment. RESULTS: 2835 women taking NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen and 938 women taking DRSP/EE (3 mg/30 µg) in a 21/7-day regimen had at least 1 evaluable cycle for vaginal bleeding analyses. The frequency of absent scheduled bleeding was higher (p<.0001) for women using NOMAC/E2 than DRSP/EE across all 11 cycles (cycles 2-12), ranging between 17.6% and 31.6% and between 3.4% and 5.8%, respectively. For women who had absent scheduled bleeding in cycles 2, 3, or 4 the incidence of absent scheduled bleeding in subsequent cycles was high and ranged between approximately 50%-60% for NOMAC/E2 and approximately 40%-50% for DRSP/EE. Amenorrhea increased over time with both regimens, being higher with NOMAC/E2. Both absent scheduled bleeding and amenorrhea with NOMAC/E2 were more common in older women, overweight women, switchers, and smokers; unscheduled bleeding was more common in starters, but had no association with age, body mass index, and smoking. CONCLUSIONS: NOMAC/E2 is associated with a higher prevalence of absent scheduled bleeding compared with DRSP/EE. Absent scheduled bleeding and amenorrhea were associated with age, body weight, switching and smoking. Unscheduled bleeding was more common in starters. IMPLICATIONS: Information about the factors associated with bleeding patterns may help clinicians provide guidance to women considering use of the NOMAC/E2 oral contraceptive.

Effect on quality of life of switching to combined oral contraception based on natural estrogen: an observational, multicentre, prospective phase IV study (ZOCAL Study).

OBJECTIVES: This observational, multicentre, prospective phase IV study examined change in health-related quality of life (QOL) from baseline to 6 months in women initiating combined oral contraception (COC) based on natural estrogen. METHODS: Eligible women attending a baseline and 6-month gynaecology appointment belonged to one of three groups: group 1 used barrier contraception (condoms) and elected to continue this method; group 2 used condoms and elected to switch to COC based on natural estrogen; group 3 used COC based on ethinylestradiol and elected to switch to COC based on natural estrogen. The Spanish Society of Contraception (SEC)-QOL scale assessed health-related QOL. Secondary outcomes included symptoms of premenstrual syndrome, intermenstrual bleeding, duration and intensity of menstrual bleeding, contraception continuation rate, and tolerability. RESULTS: A total of 857 women were enrolled and 785 completed the study. Group 2 (n = 224 completed) had significantly lower SEC-QOL global and dimension scores at baseline and significantly greater increases in SEC-QOL from baseline to 6 months compared with groups 1 (n = 72) and 3 (n = 489). Group 3 reported a similar SEC-QOL score to that of group 1 at baseline but showed significantly greater improvement in SEC-QOL global and psychological scores from baseline to 6 months. Among women receiving COC based on natural estrogen, the contraception continuation rate was 713/780 (91.4%); treatment-related adverse events were reported by 13/780 (1.7%). CONCLUSIONS: Improved SEC-QOL after 6 months was found in women who were dissatisfied with their current contraception at baseline and chose to switch to COC based on natural estrogen.

An update on new orally administered contraceptives for women.

INTRODUCTION: The focus in contraception is shifting from oral contraceptives to more effective methods, such as implants and intrauterine devices. Generics are favored by third-party payors. As a result, potentially exciting developments in branded pills to increase safety or to reduce side effects may have gone unnoticed. AREAS COVERED: This article reviews the features of each of the four new oral contraceptives that have been introduced in the United States and/or Europe in the last few years. The motivation for the development of each product is outlined as is its efficacy, safety, tolerability and the noncontraceptive applications that have been explored are described. EXPERT OPINION: The hypothesis that using estradiol in place of ethinyl estradiol would reduce the risk of venous thromboembolism is still to be proven. However, the stronger progestogens used in these formulations may offer other tangible benefits for selected women. The new products for extended cycle pill use may have less impact. The flexible regimen can be adopted using any pill, but the approved product does provide convenience to patients. Cost will continue to be the determining factor in the acceptance of these new products, unless substantial health benefits can be conclusively proven.

Zoely: a new combined oral contraceptive.

▼Zoely is the second estradiol-containing oral contraceptive formulated as an 'extended regimen' (pill-free interval <7 days) to be licensed in the UK. However, unlike the quadraphasic estradiol-containing contraceptive Qlaira, it is a monophasic preparation.1,2 It is postulated that combined oral contraceptives (COCs) containing synthetic estradiol, which is structurally identical to endogenous oestrogen,3 are potentially safer and better tolerated than those containing ethinylestradiol, the synthetic oestrogen most commonly used in COCs.4 The progestogen in Zoely is nomegestrol acetate, which is structurally related to progesterone,5 in contrast to the majority of progestogens in COCs that are derived from 19-nortestosterone6 and associated with androgenic effects.7 It is suggested that nomegestrol acetate, with its greater specificity for progesterone receptors, may minimise the potential for androgenic, oestrogenic and glucocorticoid effects.7 The company considers Zoely an option for women "who want a contraceptive with hormones similar to her own", and claims that it has a high level of contraceptive efficacy, produces shorter, lighter periods compared with a 21-day regimen of drospirenone 3mg/ethinylestradiol 30µg (Yasmin) and that most women report no negative impact on weight and skin.8 Here we review the effectiveness and place of Zoely.

The effect of therapeutic and supratherapeutic oral doses of nomegestrol acetate (NOMAC)/17ß-estradiol (E2) on QTcF intervals in healthy women: results from a randomized, double-blind, placebo- and positive-controlled trial.

BACKGROUND AND OBJECTIVE: Nomegestrol acetate (NOMAC)/17ß-estradiol (E2) is a monophasic oral contraceptive that contains a progesterone-derived progestogen (NOMAC), and E2, a bio-identical estrogen. The primary objective of this thorough QT/QTc study was to investigate whether once-daily administration of therapeutic (2.5/1.5 mg) and supratherapeutic (12.5/7.5 mg) doses of NOMAC/E2 were associated with prolongation of the mean Fridericia-corrected QT (QTcF) interval in electrocardiograms at steady-state concentrations of NOMAC/E2 versus placebo. The co-primary objective was to establish assay sensitivity after a single dose of moxifloxacin (positive control). METHODS: This was a randomized, double-blind, parallel-group trial comparing 2.5/1.5 mg of NOMAC/E2 (therapeutic dose), 12.5/7.5 mg of NOMAC/E2 (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Double-blind study medication was administered from day -1 to 14. Healthy women aged 18-50 years were randomized. RESULTS: The largest time-matched mean QTcF difference compared with placebo for the therapeutic dose of NOMAC/E2 was 1.6 ms, with an upper limit (UL) of a one-sided 95% confidence interval (CI) of 5.2 ms, and 3.1 ms with an UL 95% CI of 7.0 ms for the supratherapeutic dose. The UL for the time-matched QTcF differences compared with placebo were below the 10 ms threshold defined in the ICH E14 guideline for all time points, both for the therapeutic and the supratherapeutic dose. For moxifloxacin, assay sensitivity was demonstrated. CONCLUSIONS: This thorough QT/QTc study showed that therapeutic and supratherapeutic doses of NOMAC/E2 were not associated with clinically relevant QTc interval prolongation in healthy women after a 2-week period of dosing.

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy.

PURPOSE: The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic ß2-agonist and an appetite stimulant in patients with cancer cachexia. METHODS: Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 µg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥ 4 % or function ≥ 10 %. RESULTS: Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p=0.012; right 1.02 vs. 1.06 L, p=0.004). There was a trend towards an increase in quadriceps and handgrip strength (p>0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p=0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). CONCLUSIONS: In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.

Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk.

Combined hormonal contraceptives (CHCs) contain estrogen and progestin, which can stimulate estrogen-sensitive and/or progesterone-sensitive breast cancer growth. Until recently, ethinylestradiol had been almost the only estrogen used for decades, and its dose has been greatly reduced over time. The first generations of birth control pills contained approximately five times more estrogen and four times more progestin than the latest contraceptives. Newer CHCs also contain steroids that more closely mimic the physiological estradiol (E2) and progesterone effects. The newer CHC formulations are thus expected to have less influence on the breast, although it is very difficult to demonstrate any difference among the recent available preparations in human studies. Recently, nomegestrol acetate (NOMAC), a neutral, nonandrogenic, progesterone-like profile progestin, has become available in combination with the 'natural' estrogen, E2. According to the literature, NOMAC/E2 is expected to have either a lesser stimulating effect or a neutral effect on estrogen-sensitive breast cancers. We performed an analysis of the available studies and a bibliographical review. The endocrine and metabolic effects of NOMAC/E2 formulation might lead to a lesser breast tissue stimulation. The data reported, confirmed through clinical studies, should be considered when choosing a hormonal contraceptive, especially when breast stimulation is a concern.

[Zoely, a combined oral contraceptive, monophasic pill containing estradiol and nomegestrol acetate]. / La médicament du mois. Zoely, une association monophasique d'estradiol et d'acétate de nomégestrol.

A new combined oral contraceptive called Zoely has just been marketed in Belgium. It contains nomegestrol acetate, a progestin known for its high contraceptive reliability based on its antigonadotropic power and long half-life. This progestin is associated with estradiol and Zoely is devoid of ethinyl estradiol, which is the usual component of the majority of combined oral contraceptives and is primarily responsible for thrombotic side effects of the pill. The compositon and type of regimen of this new oral contraceptive contribute to its efficacy and excellent clinical tolerance.