SIGIS-SIAMS-SIE position statement of gender affirming hormonal treatment in transgender and non-binary people.

PURPOSE: Gender Incongruence (GI) is a marked and persistent incongruence between an individual's experienced and the assigned gender at birth. In the recent years, there has been a considerable evolution and change in attitude as regards to gender nonconforming people. METHODS: According to the Italian Society of Gender, Identity and Health (SIGIS), the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE) rules, a team of experts on the topic has been nominated by a SIGIS-SIAMS-SIE Guideline Board on the basis of their recognized clinical and research expertise in the field, and coordinated by a senior author, has prepared this Position statement. Later on, the present manuscript has been submitted to the Journal of Endocrinological Investigation for the normal process of international peer reviewing after a first internal revision process made by the SIGIS-SIAMS-SIE Guideline Board. RESULTS: In the present document by the SIGIS-SIAMS-SIE group, we propose experts opinions concerning the psychological functioning, gender affirming hormonal treatment, safety concerns, emerging issues in transgender healthcare (sexual health, fertility issues, elderly trans people), and an Italian law overview aimed to improve gender non-conforming people care. CONCLUSION: In this Position statement, we propose experts opinions concerning the psychological functioning of transgender people, the gender-affirming hormonal treatment (full/partial masculinization in assigned female at birth trans people, full/partial feminization and de-masculinization in assigned male at birth trans people), the emerging issues in transgender health care aimed to improve patient care. We have also included an overview of Italian law about gender affirming surgery and registry rectification.

Weight gain and obesity rates in transgender and gender-diverse adults before and during hormone therapy.

BACKGROUND: Obesity rates and weight changes in adults on gender-affirming hormone therapy are lacking or limited by small sample sizes, duration, and location. SUBJECTS/METHODS: This longitudinal study followed the body mass index and body weights of 470 transgender and gender-diverse adult patients (247 transfeminine and 223 transmasculine; mean age, 27.8 years) seen at a Federally Qualified Health Center and an academic endocrinology practice, both in Washington DC USA. Body weight and body mass index were recorded at baseline and at multiple follow-up clinical visits up to 57 months after the initiation of gender-affirming hormone therapy. The outcomes of this study were the changes to body weight and obesity rates following hormone therapy. RESULTS: Within 2-4 months of starting gender-affirming hormone therapy, the mean body weight increased in the transmasculine group by 2.35 (1.15-3.55) kg and further increased beyond 34 months. Among the transfeminine group, the mean body weight was stable for the first 21 months of hormone therapy and then began to steadily increase, particularly in those under 30 years old. The prevalence of obesity at baseline was 25% in the transfeminine group and 39% in the transmasculine group. Following the initiation of hormone therapy, rates of obesity ranged from 42 to 52% among the transmasculine group and 21 to 30% among transfeminine group. Following 11-21 months of hormone therapy, weight gain ≥5 kg was seen among 21% of transfeminine individuals and 30% of transmasculine individuals. CONCLUSIONS: As compared with transfeminine individuals, transmasculine individuals have greater rates of obesity and weight gain before and during hormone therapy. Body weight and body mass index should be routinely monitored before and after the initiation of gender-affirming hormone therapy. Multidisciplinary weight-reduction interventions should be promoted where appropriate.

Levothyroxine in the treatment of overt or subclinical hypothyroidism: a systematic review and meta-analysis.

The goal of this study was to review relevant randomized controlled trials in order to determine the clinical efficacy of levothyroxine in the treatment of overt or subclinical hypothyroidism. Using appropriate keywords, we identified relevant studies using PubMed, the Cochrane library, and Embase. Key pertinent sources in the literature were also reviewed, and all articles published through December 2019 were considered for inclusion. For each study, we assessed odds ratios (ORs), mean difference (MD), and 95% confidence interval (95%CI) to assess and synthesize outcomes. We included 25 studies with totally 1,735 patients in the meta-analysis. In the patients with hypothyroidism, compared with L-T4, L-T4 plus L-T3 significantly decreased TSH levels and increased FT3 levels. Compared with placebo, L-T4 significantly increased FT4 levels and decreased TSH levels. In patients with subclinical hypothyroidism, compared with placebo, L-T4 significantly decreased SBP, TSH, T3 and TC and increased FT3 and FT4.

Current Evidence of the Oncological Benefit-Risk Profile of Hormone Replacement Therapy.

Hormone replacement therapy (HRT) remains the most effective treatment for menopausal symptoms and has been shown to prevent bone loss and fracture. The progestogen is added to provide endometrial protection in women with an intact uterus. After the publication of the initial WHI (Women's Health Initiative) results in 2002 reporting an overall increased risk of breast cancer, many women discontinued HRT. Despite the re-analysis of the results by subgroups of patients and updates with extended follow-up, much controversy remains, which we will analyze later in the text. Different types of estrogen or progestogen, as well as different formulations, doses, and durations, may play a role in HRT's effects on breast tissue. Evidence states that conjugated equine estrogen (CEE), compared to estro-progestin therapy, shows a better profile risk (HR 0.79, CI 0.65-0.97) and that, among different type of progestins, those structurally related to testosterone show a higher risk (RR 3.35, CI 1.07-10.4). Chronic unopposed endometrial exposure to estrogen increases the risk of endometrial hyperplasia and cancer, whereas the association with progestins, especially in continuous combined regimen, seems to reduce the risk (RR 0.71, CI 0.56-0.90). HRT was also associated with a protective effect on colon cancer risk (HR 0.61, CI 0.42-0.87). Data about ovarian and cervical cancer are still controversial.

Risk-Reducing Bilateral Salpingo-Oophorectomy for BRCA Mutation Carriers and Hormonal Replacement Therapy: If It Should Rain, Better a Drizzle than a Storm.

Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer. The most effective strategy to reduce this risk is the bilateral salpingo-oophorectomy, with or without additional risk-reducing mastectomy. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is recommended between age 35 and 40 and between age 40 and 45 years for women carriers of BRCA1 and BRCA2 mutations, respectively. Consequently, most BRCA mutation carriers undergo this procedure prior to a natural menopause and develop an anticipated lack of hormones. This condition has a detrimental impact on various systems, affecting both the quality of life and longevity; in particular, women carrying BRCA1 mutation, who are likely to have surgery earlier as compared to BRCA2. Hormonal replacement therapy (HRT) is the only effective strategy able to significantly compensate the hormonal deprivation and counteract menopausal symptoms, both in spontaneous and surgical menopause. Although recent evidence suggests that HRT does not diminish the protective effect of RRBSO in BRCA mutation carriers, concerns regarding the safety of estrogen and progesterone intake reduce the use in this setting. Furthermore, there is strong data demonstrating that the use of estrogen alone after RRBSO does not increase the risk of breast cancer among women with a BRCA1 mutation. The additional progesterone intake, mandatory for the protection of the endometrium during HRT, warrants further studies. However, when hysterectomy is performed at the time of RRBSO, the indication of progesterone addition decays and consequently its potential effect on breast cancer risk. Similarly, in patients conserving the uterus but undergoing risk-reducing mastectomy, the addition of progesterone should not raise significant concerns for breast cancer risk anymore. Therefore, BRCA mutation carriers require careful counselling about the scenarios following their RRBSO, menopausal symptoms or the fear associated with HRT use.

The state of testosterone therapy since the FDA's 2015 labelling changes: Indications and cardiovascular risk.

OBJECTIVE: A label change in testosterone (T) products in March 2015 followed a highly publicized FDA advisory committee meeting in September 2014. Changes included a warning of possible increased cardiovascular (CV) risks and restriction of indicated populations to younger men with a limited set of known aetiologies of testosterone deficiency (TD). These changes greatly impacted clinical practice and public perception of T therapy (TTh). Our aim was to review these changes in the light of subsequently published studies. DESIGN: We identified 23 studies through June 2017, including 12 clinical trials and 11 observational studies. The Testosterone Trials included 790 men aged 65 years and older with TD without known aetiology, assigned to 1-year T gel or placebo. RESULTS: Demonstrated benefits of T included sexual activity and desire, physical activity and mood. There were 9 major adverse CV events (MACE) in the T arm and 16 in the placebo arm. No study reported increased MACE with TTh. A 3-year RCT showed no difference in carotid atherosclerosis. Several large observational studies reported reduced CV events with TTh, including one showing progressively reduced CV and mortality risk with greater duration of TTh. Men whose serum T normalized with TTh had reduced risk of MI and death compared with men whose T levels failed to normalize. CONCLUSION: We conclude that existing evidence fails to support increased CV risk with TTh; on the contrary, there is evidence suggestive of real-world CV benefits. Finally, existing evidence provides benefits of TTh in older men without known aetiology for T deficiency.

Hormone therapy and patient satisfaction with treatment, in a large cohort of diverse disorders of sex development.

OBJECTIVES: To describe and investigate the hormone treatments in individuals with different forms of disorders of sex development (DSD) and the patients' own views on their treatment. DESIGN: Multicentre cross-sectional clinical evaluation, dsd-LIFE in 6 European countries from February 2014 to September 2015. PARTICIPANTS: A total of 1040 adolescents and adults (≥16 years) with different DSD conditions. MAIN OUTCOMES MEASURES: Hormone replacement, information received and patient satisfaction. RESULTS: Included were women with Turner syndrome (301), 46,XX GD (n = 20), and women with 45,X/46XY (n = 24). Individuals with Klinefelter syndrome (n = 218), 46,XX males (n = 6), individuals with different forms of 46,XY DSD (n = 243): 46,XY DSD conditions (n = 222), men with 45,X/46XY (n = 21) 46,XX CAH, (n = 226). Oestrogen ± progestin was used by 306 (81%) individuals, 72 (19%) received ethinylestradiol and 198 had testosterone treatment. The overall adherence was good, with 10% of women with oestrogen and 5% of those on testosterone had stopped the medication despite 20% reporting dissatisfaction with the treatment, mostly because of psychological side effects. Glucocorticoid replacement in patients with CAH was very seldom stopped. More than 75% were satisfied with the information about the treatment, but the satisfaction with information about treatment options and side effects was lower. CONCLUSIONS: More than 50% in the total cohort had hormone replacement. Although adherence was generally good, this study shows that hormone replacement therapy may be improved. This may be achieved by better individualization of the treatment and by providing specific information to patients regarding both long-term and short-term hormonal effects and side effects.

Annual report of the Women's Health Care Committee, Japan Society of Obstetrics and Gynecology, 2017.

To improve women's quality of life, the activity of the Women's Health Care Committee over a year up to July 2017 focused upon: (i) breast management; (ii) the influence of gynecological disease therapy on physical condition; (iii) non-surgical management of pelvic organ prolapse; (iv) survey of infectious diseases in obstetrics and gynecology in Japan; (v) health care for female athletes; (vi) a training program for women's health care advisors; (vii) revising the Japanese guidelines on hormone replacement therapy; and (viii) revising the 2016 Japanese guidelines for the proper use of emergency contraceptives. The detailed activity of the eight subcommittees is described herein. This report is based on the Japanese version of our annual report (Acta Obst Gynaec Jpn 2017;69(6):1480-1491), to publicize the activities of our committee.

Use of hormone therapy for menopausal symptoms and quality of life in breast cancer survivors. Safe and ethical?

Breast cancer is the most prevalent cancer in women and presently, the breast cancer survivors are an important group of women that faced the several consequences of estrogen deficiency, which is especially common in women after chemotherapy. The most bothersome is the vasomotor symptoms, which are effectively relieved by hormonal therapy (HT). Also, the increased risk of osteoporosis and coronary artery disease is major problem to be resolved in pos of maintaining a good quality of life. Fearing cancer recurrence, most physicians do not offer HT to women with a history of breast cancer. Over this issue reviews the available evidence of the use of HT and tibolone in women treated for breast cancer.

ITALIAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS STATEMENT-REPLACEMENT THERAPY FOR PRIMARY HYPOTHYROIDISM: A BRIEF GUIDE FOR CLINICAL PRACTICE.

OBJECTIVE: Hypothyroidism requires life-long thyroid hormone replacement therapy in most patients. Oral levothyroxine (LT4) is an established safe and effective treatment for hypothyroidism, but some issues remain unsettled. METHODS: The Italian Association of Clinical Endocrinologists appointed a panel of experts to provide an updated statement for appropriate use of thyroid hormone formulations for hypothyroidism replacement therapy. The American Association of Clinical Endocrinologists' protocol for standardized production of clinical practice guidelines was followed. RESULTS: LT4 is the first choice in replacement therapy. Thyroid-stimulating hormone (TSH) should be maintained between 1.0 and 3.0 mIU/L in young subjects and at the upper normal limit in elderly or fragile patients. Achievement of biochemical targets, patient well-being, and adherence to treatment should be addressed. In patients with unstable serum TSH, a search for interfering factors and patient compliance is warranted. Liquid or gel formulations may be considered in subjects with hampered LT4 absorption or who do not allow sufficient time before or after meals and LT4 replacement. Replacement therapy with LT4 and L-triiodothyronine (LT3) combination is generally not recommended. A trial may be considered in patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism only after co-existent nonthyroid problems have been excluded or optimally managed. LT3 should be administered in small (LT4:LT3 ratio, 10:1 to 20:1) divided daily doses. Combined therapy should be avoided in elderly patients or those with cardiac risk factors and in pregnancy. CONCLUSION: LT4 therapy should be aimed at resolution of symptoms of hypothyroidism, normalization of serum TSH, and improvement of quality of life. In selected cases, the use of liquid LT4 formulations or combined LT4/LT3 treatment may be considered to improve adherence to treatment or patient well-being. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists FT3 = free triiodothyronine FT4 = free thyroxine LT3 = levotriiodothyronine LT4 = levothyroxine MeSH = medicine medical subject headings QoL = quality of life TSH = thyroid-stimulating hormone.

Recommendations for treatment of hypothyroidism with levothyroxine and levotriiodothyronine: a 2016 position statement of the Italian Society of Endocrinology and the Italian Thyroid Association.

Levothyroxine (L-T4) is recommended as lifelong replacement therapy for hypothyroidism. Recent clinical and experimental data support the addition of levotriiodothyronine (L-T3) treatment in some selected hypothyroid patients when their symptoms persist and their quality of life remains impaired despite adequate L-T4 monotherapy. An increase in L-T3 prescriptions has been recently observed in Italy due to availability of different L-T3 formulations, making it possible to clinicians to prescribe L-T3 alone or in combination with L-T4. The aim of the present position statement was to define the correct clinical indications, schedule, duration of treatment and contraindications of combined treatment with L-T4 and L-T3 in hypothyroid patients in an attempt to guide clinicians and to avoid potential adverse effects of overtreatment.

Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Hormone Replacement Therapy.

OBJECTIVE: To provide an overview of the current literature on the use of hormone replacement therapies in pediatric cardiac critical care. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library were searched using keywords relevant to the hormonal therapy, with no limits on language but restricting the search to children 0-18 years old. STUDY SELECTION: All clinical studies believed to have relevance were considered. Where studies in children were sparse, additional evidence was sought from adult studies. DATA EXTRACTION: All relevant studies were reviewed, and the most relevant data were incorporated in this review. DATA SYNTHESIS: All authors of this review contributed to the appraisal of the data extracted. Challenges and revisions by the authors were conducted by group e-mail debate. CONCLUSIONS: Glycemic control: although it is likely that some children could benefit, the routine use of tight glycemic control cannot be recommended in children after cardiac surgery. Thyroid hormone replacement: routine use of thyroid hormone replacement to normalize levels after cardiac surgery cannot be recommended on current evidence. Until further evidence from adequately powered studies is available, therapeutic decisions should be based on individual patient circumstances. Corticosteroids: 1) cardiopulmonary bypass: although studies seem to favor steroid administration during surgery with cardiopulmonary bypass, a large randomized controlled trial is required before strong recommendations can be made; 2) refractory hypotension: the evidence for the use of steroid replacement in refractory hypotension is poor, and no firm recommendations can be made; and 3) abnormal adrenal function after cardiac surgery: there is inadequate evidence on which to make recommendations on the use of corticosteroid replacement in children with critical illness-related corticosteroid insufficiency in children following cardiac surgery.

Does menopausal hormone therapy (MHT), exercise or a combination of both, improve pain and function in post-menopausal women with greater trochanteric pain syndrome (GTPS)? A randomised controlled trial.

BACKGROUND: Greater trochanteric pain syndrome (GTPS) is pathology in the gluteus medius and minimus tendons and trochanteric bursa that causes debilitating tendon pain and dysfunction, particularly in post-menopausal women. Limited evidence in clinical studies suggests hormone changes after menopause may have a negative effect on tendon. This protocol describes a randomised controlled trial comparing the effectiveness of menopausal hormone therapy (MHT) and exercise therapy in reducing pain and dysfunction associated with GTPS in post-menopausal women. METHOD: One hundred and sixteen post-menopausal women will be recruited and randomised to receive one of two exercise programs (sham or targeted intervention exercise) and transdermal creams (MHT cream containing oestradiol 50mcg and norethisterone acetate 140mcg or placebo cream). Interventions will be 12-weeks in duration and outcomes will be examined at baseline, 12-weeks and 52-weeks. The primary outcome measure will be the VISA-G questionnaire and secondary outcomes measures will include three hip pain and function questionnaires (Hip dysfunction and Osteoarthritis Outcome Score, Oxford Hip Score, Lateral Hip Pain questionnaire), a global change in symptom questionnaire (using a 15-point Likert scale) and a quality of life measure (AQoL-8D questionnaire). Data will be analysed using the intention to treat principle. DISCUSSION: This study is the first randomised controlled trial to compare the effectiveness of menopausal hormone therapy therapy alone, and with the combination of exercise therapy, to treat pain and dysfunction associated with GTPS. This study has been pragmatically designed to ensure that the interventions in this study can be integrated into policy and clinical practice if found to be effective in the treatment of GTPS in post-menopausal women. If successful, there is potential for this treatment regimen to be explored in future studies of other persistent tendon conditions in the post-menopausal population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614001157662 Registered 31 October 2014.

Modern Hydrocortisone Replacement Regimens in Adrenal Insufficiency Patients and the Risk of Adrenal Crisis.

The aim of this study was to examine the incidence of adrenal crises (AC) and the prescription of short-acting glucocorticoids (GC) in different geographic areas. To do this we conducted a descriptive study of AC hospitalisations and prescriptions for two GCs (hydrocortisone (HC) and cortisone acetate (CA)), and fludrocortisone acetate (FA), in different geographic areas of Australia between 1999/2000 and 2011/2012, using government databases.There were 2,584 hospital admissions for AC in Australia between 1999/00 and 2011/12 and the corresponding admission rates increased significantly from 7.4 to 11.1/10(6)/year (p<0.001). AC admission rates increased in 5 out of 6 geographic areas. Prescription rates for the combined GCs (HC/CA) increased at an annual rate of between 0.2-2.0% in all areas. All areas had significant (p<0.01) increases in HC prescription rates (4.5% to 13.7% annually) and CA prescription rates decreased in 5 out of the 6 regions (3.5% annual decrease to a 0.5% annual increase). When the geographic areas were combined, there was a significant correlation between the AC admission rates and HC/CA prescription rates (r=0.30, p<0.01). Admissions for AC and GC prescriptions increased significantly in Australia after 1999 and these varied significantly by geographic area. These results suggest that modern recommendations for lower dose, short-acting GC replacement may be of concern and further investigation is warranted.

Outcomes of androgen replacement therapy in adult male hypogonadism: recommendations from the Italian society of endocrinology.

OBJECTIVE: We developed clinical practice guidelines to assess the individual risk-benefit profile of androgen replacement therapy in adult male hypogonadism (HG), defined by the presence of specific signs and symptoms and serum testosterone (T) below 12 nmol/L. PARTICIPANTS: The task force consisted of eight clinicians experienced in treating HG, selected by the Italian Society of Endocrinology (SIE). The authors received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by a systematic review of controlled trials conducted on men with a mean T < 12 nmol/L and by interactive discussions. The guidelines were reviewed and sequentially approved by the SIE Guidelines Commission and Executive Committee. CONCLUSIONS: We recommend T supplementation (TS) for adult men with severely reduced T levels (T < 8 nmol/L) to improve body composition and sexual function. We suggest that TS be offered to subjects with T < 12 nmol/L to improve glycaemic control, lipid profile, sexual function, bone mineral density, muscle mass and depressive symptoms, once major contraindications have been ruled out. We suggest that lifestyle changes and other available interventions (e.g. for erectile dysfunction) be suggested prior to TS. We suggest that TS should be combined with currently available treatments for individuals at high risk for complications, such as those with osteoporosis and/or metabolic disorders. We recommend against using TS to improve cardiac outcome and limited mobility. We recommend against using TS in men with prostate cancer, unstable cardiovascular conditions or elevated haematocrit. The task force places a high value on the timely treatment of younger and middle-aged subjects to prevent the long-term consequences of hypoandrogenism.

Screening and management of hypothyroidism in pregnancy: results of an Asian survey.

Maternal hypothyroidism in pregnancy is associated with several adverse outcomes. The American Thyroid Association and the Endocrine Society Guidelines for the management of thyroid diseases in pregnancy were published in 2011 and 2012, respectively; however, impact of the guidelines in routine clinical practice is unknown. We therefore carried out a survey to study current practices in the screening and management of hypothyroidism in pregnancy. We collected completed questionnaire survey based on clinical case scenarios from 321 members of the Asia-Oceania Thyrpid Association (AOTA). Responses from 310 clinician members (from 21 Asian countries) were analyzed. For a woman with hypothyroidism planning pregnancy, 54% favored testing thyroid function before adjusting the dose, whilst 32% recommended increasing the dose of L-thyroxine (L-T4) as soon as pregnancy is confirmed. For a pregnant woman with newly diagnosed overt hypothyroidism, most responders initiated a full dose of L-T4. One half of responders used serum TSH and free T4 to monitor the dose of L-T4. Although the target of thyroid function tests that responders aimed to achieve with L-T4 was inconsistent, but a majority aim to keep TSH within recommended trimester specific range. Twenty-one % responders or their institutions screened all pregnant women for thyroid dysfunction, 66% performed targeted screening of only the high-risk group, whilst 13% did not carry out systemic screening. Majority of responders practices within recommendations of major professional societies; however, there is wide variation in the clinical practice in the treatment and screening of hypothyroidism during pregnancy in Asia.

Influence of testosterone gel treatment on spermatogenesis in men with hypogonadism.

The prevalence of androgen deficiency in reproductive-aged men is increasing and needs new approach to long-term hypogonadism treatment that can preserve fertility. An open non-controlled pilot study included 18 men with eugonadotropic hypogonadism, who received transdermal testosterone gel treatment for 3 months. Sperm analysis was made before treatment and after 3 month of testosterone therapy. Testosterone level was normalized in all patients, but no negative effect was observed on spermatogenesis. Testosterone gel therapy may be a therapy of choice in hypogonadal men of reproductive age but further studies are needed.

Effectiveness, tolerability and acceptance of an oral estradiol/levonorgestrel formulation for the treatment of menopausal complaints: a non-interventional observational study over six cycles of 28 days.

BACKGROUND: Use of hormone therapy for menopausal complaints is a subject of controversy and increased uncertainty and concerns. This non-interventional study aimed to investigate a marketed oral formulation containing 1 mg estradiol and 0.04 mg levonorgestrel for continuous treatment of menopausal symptoms for approximately 6 months in women visiting gynecological practices in Germany. METHODS: Changes in the menopause rating scale (MRS) total and sub-domain scores after three and six 28-d cycles served as primary endpoint. Skin- and hair-related complaints, quality of sexual life and subjective satisfaction with the treatment were assessed. Adverse drug reactions (ADRs), adverse events (AEs) and vaginal bleeding were evaluated. RESULTS: MRS scores improved significantly above 5 points of clinical relevance as compared to baseline (n = 736, p < 0.0001). Skin- and hair-related symptoms abated; quality of sexual life improved. AEs were registered in 9.9% of the participants. No unexpected ADRs were reported. Bleeding episodes consistently decreased; >75% of the subjects were amenorrheic throughout the study. Medication's effectiveness and tolerability was rated very good/good by >80% of the participants, who also continued treatment. CONCLUSION: This estradiol/low-dose levonorgestrel formulation safely alleviates menopausal symptoms in peri- and postmenopausal women with add-on benefits regarding dermatological and sexual life complaints.

Applying optimal model selection in principal stratification for causal inference.

Noncompliance to treatment allocation is a key source of complication for causal inference. Efficacy estimation is likely to be compounded by the presence of noncompliance in both treatment arms of clinical trials where the intention-to-treat estimate provides a biased estimator for the true causal estimate even under homogeneous treatment effects assumption. Principal stratification method has been developed to address such posttreatment complications. The present work extends a principal stratification method that adjusts for noncompliance in two-treatment arms trials by developing model selection for covariates predicting compliance to treatment in each arm. We apply the method to analyse data from the Esprit study, which was conducted to ascertain whether unopposed oestrogen (hormone replacement therapy) reduced the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction. We adjust for noncompliance in both treatment arms under a Bayesian framework to produce causal risk ratio estimates for each principal stratum. For mild values of a sensitivity parameter and using separate predictors of compliance in each arm, principal stratification results suggested that compliance with hormone replacement therapy only would reduce the risk for death and myocardial reinfarction by about 47% and 25%, respectively, whereas compliance with either treatment would reduce the risk for death by 13% and reinfarction by 60% among the most compliant. However, the results were sensitive to the user-defined sensitivity parameter.