Is breast cancer risk the same for all progestogens?

The population-based case–control study CECILE investigated the impact of various menopausal hormone therapy (MHT) products on breast cancer (BC) risk in 1,555 postmenopausal women [1]. The case group (n = 739) included incident cases of in situ (!) or invasive BC in postmenopausal women. The control group (n = 816) included women from the general population within predefined quotas by age and socio-economic status (SES). While quotas by age were applied to obtain similar distributions by age among controls and among cases, quotas by SES in control women were applied to reflect the distribution by SES of women in the general population in the study area. Data of participants were obtained by a structured questionnaire during in-person interviews, and from pathology reports if applicable, respectively. Women were divided into current and past MHT user. MHTs were classified in estrogen-only therapy (ET), estrogen combined with progestin therapy (EPT) and tibolone. EPT was subdivided in three subtypes according to the progestogen constituent: natural micronized progesterone, progesterone derivatives, and testosterone derivatives. In comparison to never MHT users, any current or past MHT use (ET, EPT, tibolone) was not associated with an increased BC risk. However, in subanalysis BC risk was significantly increased for current use of EPT for 4 or more years (n = 73 cases and n = 56 controls, adjusted OR 1.55; 95 % CI 1.02–2.36). Within the group of current EPT users for 4 or more years, 14 cases had used estrogens combined with micronized progesterone (n = 17 controls), and 55 a combination with a synthetic progestogen (n = 34 controls), respectively. Compared to never MHT use, current use of EPT containing a synthetic progestogen for 4 or more years was associated with a significantly increased BC risk (adjusted OR 2.07; 95 % CI 1.26–3.39), but EPT containing micronized progesterone was not (adjusted OR 0.79; 95 % CI 0.37–1.71). 73 % of current MHT users started treatment within the first year of onset of menopause. Early EPT (n = 52 cases and n = 38 controls, adjusted OR 1.65; 95 % CI 1.02–2.69), but not early ET, starters had a significantly higher BC risk compared to never MHT users. In contrast, MHT initiation beyond 1 year after menopause was not associated with an increased BC risk. The authors concluded that: (1) ET and EPT containing natural progesterone did not increase BC risk whereas, (2) BC risk was increased in users of tibolone or EPT containing a synthetic progestogen, respectively, and that (3) MHT use early after onset of menopause was associated with an increased BC risk as compared to women who delay MHT beyond 1 or more years.

Association of hormone therapy and incident gout: population-based case-control study

OBJECTIVE This study aims to assess the odds of developing incident gout in association with the use of postmenopausal estrogen-progestogen therapy, according to type, timing, duration, and route of administration of estrogen-progestogen therapy. METHODS We conducted a retrospective population-based case-control analysis using the United Kingdom-based Clinical Practice Research Datalink. We identified women (aged 45 y or older) who had a first-time diagnosis of gout recorded between 1990 and 2010. We matched one female control with each case on age, general practice, calendar time, and years of active history in the database. We used multivariate conditional logistic regression to calculate odds ratios (ORs) with 95% CIs (adjusted for confounders). RESULTS The adjusted OR for gout with current use of oral formulations of opposed estrogens (estrogen-progestogen) was 0.69 (95% CI, 0.56-0.86) compared with never use. Current use was associated with a decreased OR for gout in women without renal failure (adjusted OR, 0.71; 95% CI, 0.57-0.87) and hypertension (adjusted OR, 0.62; 95% CI, 0.44-0.87) compared with never use. Tibolone was associated with a decreased OR for gout (adjusted OR, 0.77; 95% CI, 0.63-0.95) compared with never use. Estrogens alone did not alter the OR for gout. CONCLUSIONS Current use of oral opposed estrogens, but not unopposed estrogens, is associated with a decreased OR for incident gout in women without renal failure and is more pronounced in women with hypertension. Use of tibolone is associated with a decreased OR for incident gout. The decreased OR for gout may be related to the progestogen component rather than the estrogen component.

Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet

Aims The major aims of the study were to compare the safety of a continuous low-dose estradiol-releasing vaginal ring (ESTring) to that of a vaginal estradiol tablet (Vagifem®) on the endometrium and the relief of subjective symptoms and signs of urogenital estrogen deficiency. Quality of life and acceptability of treatment delivery were also assessed. Study design A prospective, randomized study in which women were assigned in a 2: 1 ratio to ESTring and Vagifem and followed for 12 months. The primary endpoint was endometrial safety, based on the results of ultrasound measurement of endometrial thickness and a progestogen challenge test at baseline and week 48. Efficacy was determined by subjective assessment of urogenital estrogen deficiency symptoms at baseline and weeks 3, 12, 24, 36 and 48 and assessment of signs of vaginal epithelial atrophy by the clinician at baseline, 12 and 48 weeks. In addition, pelvic floor strength, vaginal cytological evaluation and pH, bacteruria and patient acceptability were assessed. Quality of life was assessed using a menopause-specific quality-of-life questionnire and a 2-day bladder diary at baseline and 12 and 48 weeks. The comparability of the two groups was assessed using ANOVA, χ(2) or Fisher's exact tests. Results A total of 126 women were randomized to ESTring and 59 to Vagifem. There was no statistical difference between the groups in the alleviation of symptoms and signs of urogenital estrogen deficiency. Maturation indices increased in both groups, from generally atrophic at baseline to proliferative or highly proliferative at 48 weeks. After 48 weeks of treatment, there was no statistically significant difference in endometrial thickness between the two groups. A statistically smaller proportion of bleeding/spotting occurred in the ESTring group (n = 0) compared to the Vagifem users (n = 4). Estradiol and total estrone serum levels increased during treatment in both groups but remained within the normal postmenopausal range. General health status in both groups was unchanged but the urogenital component of health burden was significantly improved in both groups. Bladder diary variables showed no differences between treatment groups. Conclusion Equivalent endometrial safety and efficacy in the relief of the symptoms and signs of urogenital estrogen deficiency were demonstrated for the 12 months' use of a low-dose estradiol-releasing vaginal ring and a vaginal estradiol tablet.

A study of the effects of orally administered female hormones on the volume and composition of lacrimal fluid related to the toleration of corneal contact lenses

This study was designed to evaluate the effects of certain orally active contraceptive steroids on the eye, related to the tolerance of a corneal contact lens. An oestrogen, ethinyloestradiol BP. 0.05 mg, a progestogen, norethisterone acetate BP. 2.50 mg and a control tablet (vitamin C, 50 mg) were utilised. The effect of these preparations on corneal curvature, lacrimal fluid volume and protein composition and directly on corneal lens tolerance was monitored in a group of 23 volunteer patients. The progestogen was found to produce a significant (P≥ 0.05) decrease in tear volume as measured by a 3 minute Schirmer test. A smaller volume reduction was observed with ethinyloestradiol. A normal cornea appears unaffected, within the measurement limits available, by the use of either hormone. However, in the presence of a corneal lens, oestrogen was found to induce substantial corneal steepening, indicative of tissue oedema, during the initial 2-3 weeks of medication. Progestogen occasionally produced a similar effect, which could recur with either hormone shortly after the end of the treatment period. A new method of acrylamide gel electrophoresis was developed for examination of the protein concentration and composition of lacrimal fluid. This allowed much greater resolution of microquantities of unconcentrated fluid than anything previously reported. Quantitation by densitometry has permitted the recording of medication and lens-induced changes in the protein pattern. Tear albumin has been shown to differ from serum albumin and to consist of up to 3 subfractions, 7 further protein fractions may also be resolved. The concentration and probable origin of these proteins have been established and the overall effects of hormone administration described. Individual idiosyncratic responses are also discussed. The study has established tbenature of some effects of contraceptive steroids on the anterior eye, and the probable reasons for resultant corneal lens intolerance.

Levonorgestrel intrauterine system versus medical therapy for menorrhagia

ABSTRACT: Menorrhagia is a common problem that interferes with a woman’s physical, emotional, and social life. Evidence to guide physicians for decision about therapy for heavy menstrual bleeding is lacking. One treatment option, the levonorgestrel-releasing intrauterine system (levonorgestrel-IUS), has been available in the United States since 2009. Updated meta-analyses comparing the levonorgestrel-IUS with nonhormonal and hormonal treatments showed that the levonorgestrel-IUS produced a greater reduction in menstrual blood loss at 3 to 12 months of follow-up. It is not clear whether these short-term benefits persist. Moreover, the rates of discontinuation of the levonorgestrel-IUS at 2 years are as high as 28%, and effects on bleeding-related quality of life are not known. This pragmatic, multicenter, randomized trial compared the effectiveness of the levonorgestrel-IUS with that of usual medical treatment among women with menorrhagia in a primary care setting. A total of 571 women with menorrhagia were randomized to treatment with levonorgestrel-IUS (n = 285) or usual medical treatment (n = 286). Usual treatment was tranexamic acid, mefenamic acid, combined estrogen-progestogen, or progesterone alone. The primary study outcome measure was the patient-reported score on the condition-specific Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period. The MMAS scores range from 0 to 100, with lower scores indicating greater severity. Summary MMAS scores were assessed at 6, 12, and 24 months. Secondary outcome measures included general health-related quality of life, sexual-activity scores, and surgical intervention. There was a significant improvement in total MMAS scores from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group; the mean increase was 32.7 and 21.4 points, respectively; P < 0.001 for both comparisons. Over the 2-year follow-up, improvements were maintained in both groups but were significantly greater in the levonorgestrel-IUS group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9–16.9; P < 0.001). Significantly greater improvements in all MMAS domains (practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships) occurred with the levonorgestrel-IUS than with the usual treatment (P < 0.001 with the use of a test for trend). This was also found for 7 of the 8 quality-of-life domains. At the 2-year end point, almost twice as many women were still using the levonorgestrel-IUS than were those receiving the usual medical treatment (64% vs 38%, P < 0.001). No significant between-group differences were noted in the rates of surgical intervention or sexual-activity scores as well as in the frequency of serious adverse events. These data show that levonorgestrel-IUS is more effective than usual medical treatment in improving the quality of life of women with menorrhagia in a primary care setting.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia:the ECLIPSE trial

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena(®), Bayer) compared with usual medical treatment, with exploration of women's perspectives on treatment. DESIGN: A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING: Women who presented in primary care. PARTICIPANTS: A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS: LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES: The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS: The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS: The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in women's assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86566246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information.

Randomised trial of levonorgestrel intrauterine system compared to usual medical treatment for heavy menstrual bleeding:the ECLIPSE Trial

Objective: Heavy menstrual bleeding (menorrhagia) is a common problem, yet evidence is limited to inform therapeutic decisions.We compared the levonorgestrel-releasing intrauterine system(LNG-IUS) to usual medical treatment in a pragmatic randomised trial in primary care. Methods: We randomly assigned 571 women consulting their primary care providers with menorrhagia to LNG-IUS or to usual medical treatment as clinically appropriate (tranexamic acid, mefenamic acid, combined estrogen/progestogen or progestogen only). The primary outcome was a patient-reported measure ofimpact of menorrhagia, the validated Menorrhagia Multi-Attribute Scale (MMAS), assessed over 2 years. Secondary measures included generic quality of life (SF-36), sexual activity and surgical intervention.Results MMAS scores improved from baseline in both the LNG-IUS and usual medical treatment groups by 6 months (mean increases 32.7 points versus 21.4 points, respectively; P < 0.001for both) and were maintained over 2 years, but improvements were significantly greater with LNG-IUS (mean between-group difference 13.4 points, 95%CI, 9.9–16.9; P < 0.001).All domains of MMAS (practical difficulties, social life, family life,work/daily routine, psychological well being and physical health)improved significantly more with LNG-IUS, as were seven of the eight domains of SF-36. More women were still using LNG-IUSthan usual medical treatment at 2 years (64% versus 38%,P < 0.001). There were no significant between-group differences in surgical intervention rates or sexual activity scores. There were no serious adverse events in either group.Conclusions Among women presenting to primary care providers with menorrhagia, LNG-IUS was more effective than usual medical treatment at reducing the impact of this problem on their quality of life. In practice therefore, conventional treatments, such as tranexamic and mefenamic acid, remain helpful choices in women for whom LNG-IUS is considered unsuitable, or due to individual preference. For other women, LNG-IUS can be confidently recommended as an effective initial medical therapy for menorrhagia. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 02/06/02)