The benefits of estetrol addition to drospirenone for contraception.

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

The drospirenone (DRSP)-only pill: clinical implications in the daily use.

OBJECTIVES: Progestins used in contraception are either components of combined hormonal contraceptives or are used as a single active ingredient. Progestins are highly effective in long-term contraception and have a very good safety profile with very few contraindications. METHODS: An oestrogen-free ovulation inhibitor POP has been authorised in the USA and the EU. It contains 4 mg of drospirenone (DRSP). The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular- phase levels, preventing oestrogen deficiency. RESULTS: Clinical trials have demonstrated high contraceptive effectiveness, a very low risk of cardiovascular risk events and a favourable bleeding pattern. Due to the long half-life of DRSP (30-34 h), the effectiveness is maintained even in case of a forgotten pill on a single occasion. Studies involving deliberate 4 days in one cycle 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. CONCLUSIONS: This review article will describe the clinical impact in the daily use of the 4 mg DRSP only pill and the resulting data on the effectiveness and safety of this hormonal contraceptive.

The 4 mg drospirenone-only pill improves the bleeding profile in comparison to 0.075 mg desogestrel and achieves high contraceptive efficacy even with a 24 h missed pill window.

A novel estetrol-containing combined oral contraceptive: European expert panel review.

PURPOSE: Despite considerable advances in recently developed combined oral contraceptives (COCs), resulting in lower rates of adverse events while maintaining contraceptive efficacy, there is interest in further innovation. MATERIALS AND METHODS: Estetrol (E4), a native oestrogen, and progestin drospirenone (DRSP) were combined in a new COC. A European expert panel reviewed the pharmacology, efficacy, and safety and tolerability of this combination. Their findings are presented as a narrative review. RESULTS: E4 15 mg/DRSP 3 mg in a 24/4 regimen provided effective contraception with good cycle control, characterised by a predictable regular bleeding pattern and minimal unscheduled bleeding, together with a good safety profile. The combination was associated with high user satisfaction, well-being, and minimal changes in body weight. The effects on endocrine and metabolic parameters were limited, and the combination was found to have a limited impact on liver function and lipid and carbohydrate metabolism. Moreover, its effect on several haemostatic parameters was lower than that of comparators containing ethinyl oestradiol (EE) 20 µg/DRSP 3 mg and EE 30 µg/levonorgestrel 150 µg. CONCLUSION: E4 15 mg/DRSP 3 mg provides safe and effective contraception, with high user satisfaction and predictable bleeding. Further research will evaluate the long-term safety of the COC.

Invasive cervical cancer after treatment of CIN.

INTRODUCTION: A historical audit of 30 post-treatment cervical cancers (10% of 289 cancers, 1999-2016) compared with a one-year-equivalent control group treated for cervical intraepithelial neoplasia (CIN) grade 3 (n = 164). MATERIALS AND METHODS: We compared history and follow up of cancer patients and controls and reviewed initial excision biopsies preceding cancer and, in 41% of controls, high-grade recurrence (n = 17) or consistently negative follow-up (n = 51). RESULTS: Either abnormal post-excision cytology without high-risk human papillomavirus (hrHPV) tests or immediate re-excision was recorded in 70% (19 of 27) of patients with squamous cell carcinoma (SCC). Negative investigations including cytology, colposcopy, re-excision, hysteroscopy, hrHPV, and/or treatment default were recorded in 83% (25 of 30) of all cancers. The mean interval between initial excision and cancer diagnosis was 79.8 ± 30.1 months versus 11.2 ± 30.1 months for CIN3 recurrence. Eight, 13, and 9 patients with cancer had initial excision at age 20-34, 35-49, and 50+ years, respectively, compared with 71%, 23%, and 5% of controls. CIN3 more often preceded SCC than CIN2 (22:1); 5 of 30 initial excisions were originally reported as negative after severe dyskaryosis. No SCC or CIN3 recurrence followed complete excision. Depth of CIN3 2+ mm (20 of 82 reviewed) was strongly associated with cancer/high-grade recurrence or early stromal invasion on review (18 of 20; 90%). Discrepancies were found on review in 10% of biopsies and as occasional abnormal cells in 9 of 34 cytology slides. CONCLUSIONS: Residual disease may be inconspicuous or absent on cytology, colposcopy, and/or histology. Management taking account of risk of recurrence (age, CIN3 depth, incomplete initial excision) could avoid some post-treatment cancers.

Cervical screening: why young women should be encouraged to be screened.

BACKGROUND: The English National Health Service Cervical Screening Programme (NHSCSP) recommendation not to offer cervical screening to women aged 20-24 years is considered in the context of national rates of cervical intraepithelial neoplasia grade 3 (CIN3) and invasive cervical carcinoma, falling screening coverage in young women, detection of screen-detected invasive cancers and risks of excisional treatment of CIN. METHODS: Registrations of invasive and in situ cervical carcinoma were obtained from the Office for National Statistics, data on screening coverage and cytology results from the NHSCSP website and data on screen-detected cancers from an audit at Guy's & St Thomas' NHS Foundation Trust (GSTFT). RESULTS: Before and after the introduction of organised screening in England, CIN3 was primarily detected in women aged 20-39 years. Increasing rates of CIN3 were recorded in women aged 20-24 years during the last decade (3000-4000 cases per year) despite falling screening coverage. The peak incidence of invasive cancer in screening age groups is now 35-39 years. At GSTFT in 1999-2006, 24 of 32 cancers (75%) in women aged 20-34 years were screen-detected and that percentage declined in subsequent 15-year age bands (p < or =0.0001). DISCUSSION AND CONCLUSIONS: Delaying the age for screening eligibility carries a risk of CIN becoming more extensive, and therefore more difficult to excise, as well as a risk of progression. The NHSCSP should reconsider its decision and encourage young women to be screened, not excluding those aged 20-24 years. Facilities for taking the tests should be made more convenient. Women should be informed that low-grade CIN is potentially reversible and may safely be monitored. Cervical screening also provides an opportunity for education on healthy lifestyles and safer sex while treatment should be reserved for high-grade CIN.

Human papillomavirus testing with conventional Pap smear screening in three inner London community clinics.

BACKGROUND AND METHODOLOGY: This observational study aimed to establish prevalence of high-risk human papillomaviruses (hrHPV) in women attending three inner London community clinics for routine screening and to pilot hrHPV testing in the triage of either borderline or negative cytology after previous abnormalities. Hybrid Capture 2 was carried out on brush samples taken alongside conventional smears from 1434 women aged 20-49 years. hrHPV positivity prompted earlier referral of women with previous abnormalities and either low-grade or negative cytology. Outcome at colposcopy was compared with the records of 1871 women aged 20-49 years attending colposcopy during the same period of time (routine colposcopies). RESULTS: hrHPV was detected in 111/161 (68.9%) women with abnormal cytology, 76/460 (16.5%) with negative cytology after previous abnormalities and 105/813 (12.9%) with negative cytology and no previous abnormalities. Overall, hrHPV was detected in 292/1434 (20.4%) women in the study (95% CI 18.3-22.5). hrHPV prevalence increased with severity of cytological abnormality (p<0.001) and decreased with age both with negative and low-grade cytology (p<0.001). High-grade cervical intraepithelial neoplasia (CIN) biopsies were found more frequently in women in the study groups with low-grade (p<0.001) or negative cytology than in routine colposcopies, but more women in the study groups attended colposcopy (8.2% compared with 4.1% routine colposcopies, p<0.001). CONCLUSIONS: hrHPV positivity increased detection of high-grade CIN in the study groups at the expense of more colposcopies. hrHPV negativity could reduce the need for investigation of low-grade cytology in women aged over 35 years and for surveillance after previous abnormalities.

Long-term use of contraceptive depot medroxyprogesterone acetate in young women impairs arterial endothelial function assessed by cardiovascular magnetic resonance.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) inhibits proliferation of ovarian follicles, resulting in anovulation and a decrease in circulating estrogen; the latter action is potentially disadvantageous to cardiovascular health. We therefore investigated the vascular effects of long-term contraceptive DMPA in young women. METHODS AND RESULTS: Endothelium-dependent (hyperemia-induced flow-mediated dilatation [FMD]) and -independent (glyceryl trinitrate [GTN]) changes in brachial artery area were measured using cardiovascular magnetic resonance in 13 amenorrheic DMPA users (>1 year use; mean age 29+/-4 years) and in 10 controls (mean age 30+/-4 years, P=0.25) with regular menstrual cycles after validation of the technique. FMD and GTN responses were measured just before repeat MPA injection and 48 hours later (n=12) in DMPA users and during menstruation and midcycle (n=9) in controls. Serum-estradiol levels (S-estradiol) were measured at both visits. FMD was reduced in DMPA users compared with controls during menstruation (1.1% versus 8.0%, respectively P<0.01) without differences in GTN responses. S-estradiol levels in DMPA users were significantly lower than in controls during menstruation (58 versus 96 pmol/L, P<0.01). High levels of circulating MPA 48 hours after injection were not linked to an additional impairment in FMD (2.0% versus 3.1%, P=0.23). Estradiol levels were significantly correlated to FMD (r=0.43, P<0.01). CONCLUSIONS: Endothelium-dependent arterial function measured by cardiovascular magnetic resonance is impaired in chronic users of DMPA, and hypoestrogenism may be the mechanism of action. DMPA might adversely affect cardiovascular health, and in particular its use in women with cardiovascular disease should be additionally evaluated.