Short-term oestrogen as a strategy to prevent postpartum depression in high-risk women: protocol for the double-blind, randomised, placebo-controlled MAMA clinical trial

IntroductionPostpartum depression affects 10%–15% of women and has a recurrence rate of 40% in subsequent pregnancies. Women who develop postpartum depression are suspected to be more sensitive to the rapid and large fluctuations in sex steroid hormones, particularly estradiol, during pregnancy and postpartum. This trial aims to evaluate the preventive effect of 3 weeks transdermal estradiol treatment immediately postpartum on depressive episodes in women at high risk for developing postpartum depression.Methods and analysisThe Maternal Mental Health Trial is a double-blind, randomised and placebo-controlled clinical trial. The trial involves three departments of obstetrics organised under Copenhagen University Hospital in Denmark. Women who are singleton pregnant with a history of perinatal depression are eligible to participate. Participants will be randomised to receive either transdermal estradiol patches (200 µg/day) or placebo patches for 3 weeks immediately postpartum. The primary outcome is clinical depression, according to the Diagnostic and Statistical Manual of Mental Disorders-V criteria of Major Depressive Disorder with onset at any time between 0 and 6 months postpartum. Secondary outcomes include, but are not limited to, symptoms of depression postpartum, exclusive breastfeeding, cortisol dynamics, maternal distress sensitivity and cognitive function. The primary statistical analysis will be performed based on the intention-to-treat principle. With the inclusion of 220 participants and a 20% expected dropout rate, we anticipate 80% power to detect a 50% reduction in postpartum depressive episodes while controlling the type 1 error at 5%.Ethics and disseminationThe study protocol is approved by the Regional Committees on Health Research Ethics in the Capital Region of Denmark, the Danish Medicines Agency and the Centre for Data Protection Compliance in the Capital Region of Denmark. We will present results at scientific meetings and in peer-reviewed journals and in other formats to engage policymakers and the public.Trial registration numberNCT04685148.

Feminizing Hormone Therapy Prescription Patterns and Cardiovascular Risk Factors in Aging Transgender Individuals in Australia

ContextThe safety and efficacy of feminizing hormone therapy in aging transgender (trans) individuals is unclear. Current recommendations suggest transdermal estradiol beyond the age of 45 years, especially if cardiometabolic risk factors are present.ObjectiveTo evaluate feminizing hormone therapy regimens and cardiovascular risk factors in aging trans individuals.DesignRetrospective cross-sectional analysis.SettingPrimary care and endocrine specialist clinic in Melbourne, Australia.ParticipantsTrans individuals on feminizing therapy for ≥6 months.Main Outcomes MeasuresFeminizing hormone regimens and serum estradiol concentrations by age group: (a) ≥45 years, (b) <45 years, and prevalence of cardiometabolic risk factors in individuals ≥45 years.Results296 individuals were stratified by age group: ≥45 years (n=55) and <45 years (n=241). There was no difference in median estradiol concentration between groups (328 nmol/L vs. 300 nmol/L, p=0.22). However, there was a higher proportion of individuals ≥45 years treated with transdermal estradiol (31% vs. 8%, p<0.00001). Of those treated with oral estradiol, the median dose was lower in the ≥45 years group (4mg vs. 6mg, p=0.01). The most prevalent cardiometabolic risk factor in the ≥45 years group was hypertension (29%), followed by current smoking (24%), obesity (20%), dyslipidaemia (16%) and diabetes (9%).ConclusionsA greater proportion of trans individuals ≥45 years of age were treated with transdermal estradiol. Of those who received oral estradiol, the median dose was lower. This is important given the high prevalence of cardiometabolic risk factors in this age group, however cardiovascular risk management guidelines in this demographic are lacking.

Hormonal Replacement Therapy in Premenopausal Women With Hypogonadism: An Analysis of Prescriber Practices

Introduction: Estrogen replacement therapy in premenopausal women with hypogonadism is important for reducing risk of osteoporosis, cardiovascular disease, and urogenital atrophy. Numerous formulations of estrogen are available and there is limited evidence to guide management. We conducted a preliminary retrospective study to determine prescribing practices of hormonal replacement therapy (HRT) in premenopausal women with hypogonadism and frequency of DEXA scan screening. Methods: Using ICD 10 and billing codes, females ages 18-51 with a diagnosis of hypogonadism were identified. Patients with a diagnosis of prolactinoma, breast or endometrial cancer, and significant thrombotic disease as well as patients without clinical data were excluded. Information regarding etiology of hypogonadism, age of diagnosis, type/dose of estrogen and progesterone prescribed, prescriber specialty [obstetrics and gynecology (OB/GYN), endocrinology (ENDO), primary care (PCP), or other], and DEXA results was recorded. Prescriptions for estrogen and progesterone were compared in women with primary vs secondary hypogonadism and among specialties. For bone density, we analyzed the frequency of DEXA scan ordering. Statistical analysis was performed using Fisher’s Exact Test. Results: Out of 1,306 patients identified, 150 met criteria for analysis. 99 (66%) had primary hypogonadism, 47 (31%) had secondary hypogonadism, and 4 (3%) had mixed or unknown type. OB/GYN was the most common prescriber (n=88, 59%) followed by ENDO (n=39, 26%) and PCP/other (n=23, 15%). For all patients, type of estrogen prescribed differed by specialty (p=0.041) with ENDO most commonly prescribing transdermal estradiol (47%), OB/GYN either transdermal estradiol (30%) or oral ethinyl estradiol (30%), and PCP/other oral estradiol (45%). Patients with primary, but not secondary hypogonadism, were prescribed more transdermal estradiol by ENDO as compared to OB/GYN (68% vs 27%, p=0.039). In patients with secondary hypogonadism on oral ethinyl estradiol, mean daily dose (mcg) differed among providers ((ENDO 27 ± 6, OB/GYN 35 ± 8, PCP/other 10 ± 0, p=0.04). There was no difference in dosing of other types of estrogen, prescribing practices for progesterone, or frequency of DEXA scans among providers. DEXA scans were performed at least once in 59 (39%) and more than once in 20 (13%) patients. Conclusions: Overall, premenopausal women with hypogonadism seeing ENDO as compared to other providers were more frequently prescribed transdermal estradiol as compared to oral estradiol and/or other types of estrogen. Only dosages of oral ethinyl estradiol differed by provider. Despite an increased risk of osteoporosis, a minority of patients underwent DEXA scans. This study highlights heterogeneity in prescribing practices and underscores the need for further research to guide management of premenopausal women with hypogonadism.

A Clinical Experience of Pubertal Induction in Female Patients With Congenital Hypogonadotropic Hypogonadism (CHH) From an Endo-ERN Referral Center

Female congenital hypogonadotropic hypogonadism (CHH) is a rare condition, with a strong genetic background, characterized by absent or incomplete pubertal development, for which inductive treatment with sex-hormone is required. Although the available data, mostly coming from studies in patients with Turner syndrome, indicate transdermal estradiol (TDE) as the first-choice formulation, no internationally validated therapeutic schemes are currently available. Furthermore, data on CHH patients are certainly lacking and there is no standard of care for pubertal induction in this specific population. The aim of our work was the retrospective analysis of the data from a collection of case reports of pubertal induction in CHH patients referred to our Center. Six patients underwent induction with transdermal estradiol (TDE) at the starting dose of 0.1µg/kg/day (night-time for the first 4-6 months), increased every 4-6 months up to the adult dose, for a mean period of 2.86 ± 0.45 ys. Micronized progesterone (200 mcg) was introduced at reaching of 50µg dose or if breakthrough bleeding occurred. Treatment was monitored through clinical and anthropometric evaluations at each dose modification. The average age of induction was 17.25 ± 1.41 ys, with each bone age> 13 ys. Three out of six patients already had a Tanner B2 stage at diagnosis. The mean times of pubertal advancement were respectively 1.3 ± 0.46 ys for the achievement of B3, 2.13 ± 0.29 ys for the B4 and 2.35 ± 0.77 ys for menarche; all the patients reached an adult breast conformation (B5) in 2.81 ± 0.28 ys. These data are consistent with physiological pubertal progress. All of them achieved adequate uterine development (medium longitudinal diameter 72.2 ± 3.37mm), except one patient with suboptimal development (54mm). The final height (FH) was adequate in all patients, with SDS FH +1.6 (-0.43 - +3.38), in spite of an average growth of 4.11 cm (2.5-6) ​​during the induction period and a growth rate > 2cm/year only in 50% of patients. No side effects were reported, and individual compliance and satisfaction were quite high. This clinical experience suggests that the adopted regimen, consistent with current literature, guarantees excellent efficacy and safety. However, further studies are needed to identify the optimal treatment in adolescents with CHH, taking into account their higher age at the start of induction, the modest impact on growth and final stature, to focus on the specific clinical objectives in these patients

Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study

Background: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. Objective: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. Methods: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. Results: Recruitment was stopped prematurely due to slow inclusions ( n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58–1.39), placebo = 0.97 (0.63–1.50) ( p = 0.79)). Conclusion: POPARTMUS failed showing efficacy of a NOMAc–E2 combination in preventing post-partum relapses.