Abstract
Objective: This study aimed to evaluate the effects of TX-001HR (17β-estradiol [E2] and progesterone [P4] in a single oral capsule) on cardiometabolic markers and outcomes.
Methods: Four E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) were compared with placebo in menopausal women with vasomotor symptoms (VMS) and a uterus in the phase 3 REPLENISH (ClinicalTrials.gov, NCT01942668) trial. Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months as well as cardiovascular events are summarized.
Results: A total of 1835 participants took ≥1 capsule of daily E2/P4; 1684 received E2/P4 and 151 received placebo. No clinically significant changes in lipid parameters, coagulation factors, or glucose were observed between treatment groups. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1–4%, 6–11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). One episode of deep venous thrombosis and three cases of cardiovascular disease were observed, similar to expected rates of these events in the general population.
Conclusions: In the REPLENISH trial, postmenopausal women with VMS treated with E2/P4 had no clinically meaningful effects on lipids, glucose, or coagulation parameters compared with placebo.
摘要
目的：该研究旨在评估TX-001HR（17β-雌二醇[E2]和孕酮[P4]在单一口服胶囊中）对心脏代谢指标和预后的影响。
方法：三期补充（临床试验.gov, NCT01942668）试验中, 在有血管舒缩症状(VMW)的有子宫妇女中, 对四种剂量的E2/P4组 (1mg/100mg, 0.5mg/100mg, 0.5mg/50mg, 0.25mg/50mg)和安慰剂组进行比较。对6个月、9个月和12个月时基线水平的血脂、凝血指标和血糖的变化以及心血管事件进行总结。
结果：总共1835名受试者每天服用≥1粒胶囊；1684名服用E2/P4, 151名服用安慰剂。治疗组间脂质代谢、凝血因子和血糖未见明显临床改变。在第12个月时, 总胆固醇, 甘油三酯和血糖有了具有潜在临床意义的最低增加, E2/P4组(分别是1–4%, 6–11%和1%), 安慰剂组(分别是3%, 7%, 和2%)。观察到一例深静脉血栓形成和三例心血管疾病, 其发生率与普通人群的预期发病率相似。
结论：在补充实验中, 与服用安慰剂相比, 有VMS的绝经后女性使用E2/P4治疗, 对脂质、血糖、和凝血指标无临床影响。
Introduction
Many postmenopausal women experience bothersome symptoms during menopause, including vasomotor symptoms (VMS) and vulvovaginal atrophyCitation1–Citation3. Symptoms have been shown to negatively impact quality of lifeCitation1,Citation4, sleepCitation1,Citation5, and work productivityCitation4,Citation6 of these women. VMS can be effectively treated with oral hormone therapy (HT), which reduces the frequency and severity of hot flushesCitation7. However, HT can be associated with an increased risk of adverse events (AEs), such as cardiovascular disease (CVD) and venous thromboembolism (VTE)Citation8–Citation10.
CVD, which encompasses hypertensive diseases, coronary heart disease (CHD), and stroke, is the leading cause of death among American women, accounting for approximately one of every three female deathsCitation11. The incidence of CVD generally rises quickly with age after menopause, such that after menopause 70% of women develop CVD according to the American Heart Association. HT in younger women close to menopause is thought to be protective for coronary disease and total mortalityCitation12; however, there are several possible mechanisms for this observation, and changes in lipids and coagulation markers have not been linked to beneficial events or AEs. Well-known metabolic changes with some oral HT formulations include decreases in total cholesterol and low-density lipoprotein-cholesterol (LDL), and increases in high-density lipoprotein-cholesterol (HDL) and triglyceridesCitation13–Citation16. Some oral HT formulations also cause an imbalance in hemostatic factors leading to blood coagulation activation and a hypercoagulable stateCitation13–Citation17. Some progestogens attenuate the beneficial effects of estrogens on lipid metabolism, those with greater androgenicity having more impactCitation18–Citation21. Furthermore, some evidence suggests that progesterone (P4), compared with synthetic progestins used in HT, may not negatively affect VTE risk or cardiovascular outcomesCitation22–Citation24.
TX-001HR (TherapeuticsMD, Boca Raton, FL, USA) combines 17β-estradiol (E2) and P4 in a single, oral, softgel capsuleCitation25. The 1 mg E2/100 mg P4 dose was approved by the US Food and Drug Administration (FDA) as Bijuva™ (TherapeuticsMD)Citation26 for the treatment of moderate to severe VMS in postmenopausal women with a uterus in October 2018, the first, combined E2/P4 oral formulation approved by the FDA. The safety and efficacy of four daily doses of E2/P4 (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) were evaluated in the REPLENISH trial for the treatment of moderate to severe VMS in menopausal women with a uterus. The two highest E2/P4 doses (1 mg/100 mg and 0.5 mg/100 mg) met the study’s prespecified, four coprimary endpoints, with significantly greater improvements than placebo in the frequency and severity of moderate to severe VMS from baseline to week 4 (all, p < 0.05) and to week 12 (all, p < 0.001)Citation25, with demonstrated endometrial protection as defined by the FDACitation27.
The objective of this analysis was to determine the effects of E2/P4 on cardiometabolic risk parameters and evaluate CVD outcomes in the REPLENISH trial.
Materials and methods
Study design and participants
The REPLENISH trial (ClinicalTrials.gov, NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated four doses of E2/P4 versus placebo for the treatment of moderate to severe VMS. TX-001HR is an oral product that combines E2/P4 in a single softgel capsule. Details of the trial, including inclusion and exclusion criteria, have been reported previouslyCitation25. Briefly, women with moderate to severe hot flushes (≥7/day or ≥50/week) were included in a VMS substudy and were randomized 1:1:1:1:1 to daily doses of oral E2/P4 (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) or placebo for 12 months. Women not meeting VMS substudy eligibility were randomized 1:1:1:1 to the same active E2/P4 doses only, as part of the primary safety endpoint analysis of endometrial hyperplasia and general safety analysisCitation25. Overall, women were randomized ∼11:1 for E2/P4 to placebo. Randomization was performed at each site using a reproducible, computer-generated, block randomization schedule; all study investigators and participants were blinded to treatment. A double-dummy blinding technique was used because different doses were presented as two different capsule sizes, hence all women took two capsules daily (with food at bedtime). The study protocol was approved by central or local Institutional Review Boards and the study was conducted in accordance with Good Clinical Practice. Written informed consent was required before study participation.
Postmenopausal women seeking relief for VMS associated with menopause were eligible to participate in the study if they were 40–65 years of age, had an intact uterus, and had a body mass index ≤34 kg/m2. Women were characterized as postmenopausal if they had ≥12 months of spontaneous amenorrhea, or ≥6 months of spontaneous amenorrhea with serum follicle-stimulating hormone levels >40 mIU/ml, or ≥6 weeks postsurgical bilateral oophorectomy. Participants had to abstain from using products that contained estrogens or progestogens during the study. Eligible women also had to be generally healthy with a normal or non-clinically significant physical examination.
Women were excluded from the study if they had a history of thromboembolic disorder; coronary artery or cerebrovascular disease; chronic liver or kidney disorder; malabsorption disorder; gallbladder disorder; malignancies; and uterine/endometrial disorders, including undiagnosed vaginal bleeding. Women with a history of diabetes, thyroid disease, or any other endocrinological disease were excluded, with the exception of those with diet-controlled diabetes or controlled hypothyroid disease at screening. Women were also excluded if they had any of the following clinical laboratory values: fasting triglyceride ≥300 mg/dl and/or total cholesterol ≥300 mg/dl, positive for Factor V Leiden mutation, aspartate aminotransferase or alanine aminotransferase ≥1.5 times the upper limit of normal, or fasting glucose >125 mg/dl. Stable medications to lower cholesterol, such as statins, were permitted. Participants were included in the safety study population if they had taken at least one capsule of study treatment.
The primary efficacy and safety endpoints of the REPLENISH trial were changes from baseline to weeks 4 and 12 in the frequency and severity of moderate to severe VMS in the VMS substudy with E2/P4 versus placebo, and the incidence of endometrial hyperplasia at 12 months with E2/P4. Additional safety endpoints were to evaluate the effects of TX-001HR on cardiometabolic parameters and CVD outcomes.
Safety assessments
Blood samples for chemistry and coagulation testing were collected at baseline, week 12, and months 6, 9, and 12 (or early termination) under fasting (≥8 h) conditions and sent to a central laboratory. Blood chemistry tests included total cholesterol, HDL, LDL, triglycerides, and glucose. Coagulation factors measured included the prothrombin time, the activated partial thromboplastin time (aPTT), fibrinogen, protein C (factor XIV), protein S, antithrombin III, and factor V Leiden (screening only).
Observed values for each time point and changes from baseline for clinical laboratory data were summarized (including mean and standard deviation [SD], median, minimum, and maximum) and analyzed by analysis of covariance. Missing or invalid data were not imputed. If a participant had multiple visits (scheduled or unscheduled) in a defined visit interval, repeated values obtained within 30 days of the first value for that visit were used in the analysis. Potentially clinically important (PCI) changes were prespecified as an increase from baseline ≥50 mg/dl (≥1.29 mmol/l) and above the normal range for total cholesterol and triglycerides, and ≥126 mg/dl (≥7.0 mmol/l) for glucose. Lipid and glucose levels were also analyzed by time since last menstrual period (<6 years vs. ≥6 years) and by use of lipid-lowering agents. Analyses were performed with SAS® 9.2 (SAS Institute Inc, Cary, NC, USA).
AEs occurring during the study were collected through 15 days after the last dose of study medication for non-serious AEs and through 30 days for serious AEs, unless considered possibly or probably related to the study medication. Intensity of AEs was rated as mild, moderate, or severe. Causality of AEs with the study medication was characterized as not related, possible, probable, or definite. The total number and proportion of subjects who experienced AEs were computed by dose.
Results
Disposition and demographics
A total of 1845 women were randomized; 1835 were included in the safety population, and 1275 (69.5%) completed the study at 52 weeks. Overall, 1684 women received one of the four E2/P4 doses (1 mg/100 mg [n = 415], 0.5 mg/100 mg [n = 424], 0.5 mg/50 mg [n = 421], 0.25 mg/50 mg [n = 424]) and 151 women received placebo. The most common reasons for discontinuations at 52 weeks were AEs (8.9%), withdrawal of consent (8.2%), lack of efficacy (7.9% for placebo vs. 1.4% for E2/P4), and lost to follow-up (7.5%). Five women taking E2/P4 had treatment-emergent AEs of changes in lipids or coagulation factors that led them to discontinue the study. Four of the women were taking 0.25 mg E2/50 mg P4: one had an increase in lipids (LDL, cholesterol, and HDL) at day 86, two had prolonged aPTT, and one had a decrease in blood fibrinogen. One woman taking 1 mg E2/100 mg P4 had an increase in blood glucose but had slightly elevated glucose levels at baseline.
Participants’ mean age was 54.6 years (range, 40‒66 years) and mean body mass index was 26.7 kg/m2 (range, 14.0‒34.5 kg/m2); most were white (65.4%) or African American (32.1%). Comparable participant demographics and baseline characteristics were observed across treatment groups (). Women in the study were generally healthy, with a mean Framingham 10-year risk of CHD score of ∼2.5%; 14–19% of women were taking a lipid-lowering agent at baseline.
Table 1. Participant demographics and baseline characteristics of the safety population.
Lipid and glucose parameters
Mean percent changes in fasting total cholesterol, LDL, HDL, and triglyceride levels from baseline to month 12 with E2/P4 were not significantly different from those observed with placebo (). Overall, total cholesterol, LDL, HDL, and triglyceride levels remained within or close to their respective normal ranges. Women not taking lipid-lowering agents had no significant differences in mean percent changes in lipid and glucose levels between E2/P4 and placebo groups ().
Table 2. Blood chemistry parameters by treatment.
When analyzed by time since last menstrual period (<6 years vs. ≥6 years), no significant mean percent differences between baseline and month 12 were observed in any of the lipid parameters measured. Women ≥6 years versus those <6 years from their last menstrual period had slightly greater reduction in cholesterol (–2.3% vs. –1.1%) and LDL (–4.5% vs. –3.3%) levels and smaller increases in HDL (1.0% vs. 1.3%) and triglyceride (10.1% vs. 12.4%) levels.
Individual PCI increases in cholesterol (≥50 mg/dl and above normal) from baseline were observed in 2.8% (33/1178) of women in the E2/P4 groups at month 12, with similar proportions in the placebo group (3.3%, 3/91). PCI increases in triglycerides (≥50 mg/dl and above normal) were also observed in 8.9% (105/1178) of women with E2/P4 doses versus 6.6% (6/91) with placebo at month 12.
Fasting glucose levels were similar to baseline at month 12, and remained within the normal range, with no significant differences in mean percent changes between the E2/P4 and placebo groups (). PCI increases in glucose (≥7.0 mmol/l) occurred in 1.0% (12/1178) of women who took E2/P4 and in 2.2% (2/91) of women who took placebo.
Coagulation factors
Coagulation outcomes are presented in . No significant differences between any E2/P4 dose and placebo were observed from baseline to month 12 in mean percent changes for aPTT, protein S, and protein C. At month 12, significant changes from baseline in antithrombin activity and in prothrombin time were observed with the three highest E2/P4 doses, in prothrombin international normalized ratio with the second highest E2/P4 dose, and in fibrinogen with the lowest E2/P4 dose compared with placebo. However, all mean values at month 12 remained near or within their respective normal ranges at month 12.
Table 3. Coagulation parameters by treatment group.
CVD outcomes
A total of four vascular AEs occurred during the study. Three cases of CHD were reported in the trial. The sole case of deep vein thrombosis occurred in one woman in the 0.5 mg E2/50 mg P4 group and was deemed possibly related to treatment; this participant had a family history of deep vein thrombosis. No other treatment-related CVD events were reported.
Discussion
In the REPLENISH trial of postmenopausal women with VMS and a uterus with 12 months of treatment, the TX-001HR combination of E2/P4 had no clinically significant effects on lipid parameters, coagulation factors, or glucose levels compared with placebo, and the incidence of cardiovascular AEs was low.
The use of some oral estrogens has well-established effects on lipids, such as decreases in total cholesterol and LDL and increases in triglycerides and HDL. While trends were observed with TX-001HR, there were no significant changes versus placebo. While the neutral effects of TX-001HR on triglyceride levels found in our study are in contrast to the significant increases in triglycerides observed with conjugated equine estrogens alone or with continuous medroxyprogesterone acetate, cyclical medroxyprogesterone acetate, or cyclical P4 (range, 11.4–13.7 mg/dl vs. placebo –3.2 mg/dl) in the Postmenopausal Estrogen/Progestin Interventions (PEPI) studyCitation14, they are similar to the neutral effects with E2 and/or P4 in other studies.
In the 4-year Kronos Early Estrogen Prevention Study (KEEPS)Citation28, women (without prior CVD events and low coronary artery calcium scores) using a weekly E2 patch with cyclical P4 had triglyceride levels similar to placebo (–0.1 mg/dl vs. –2.0 mg/dl), although women taking oral conjugated equine estrogens/cyclical P4 had significant increases in triglycerides compared with placebo (13.1 mg/dl vs. –2.0 mg/dl). Triglyceride levels also remained similar to placebo in the longitudinal data from the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) of women randomized to unopposed oral 1 mg E2 daily (and not taking lipid-lowering agents)Citation29. In another study, postmenopausal women with VMS using oral P4 had no significant changes from baseline to 3 months in triglyceride levelsCitation30. Collectively, these data suggest that both TX-001HR and transdermal E2 with oral P4 do not increase triglyceride levels more than placebo in postmenopausal women, as observed in the REPLENISH trial.
However, the neutral effects of TX-001HR on HDL levels found in our study are in contrast to what has been observed in the PEPICitation14 and EPATCitation29 studies. In both trials, each active treatment significantly increased mean HDL greater than placeboCitation14,Citation29. Changes in HDL levels could be explained by differences in baseline levels, which are known to influence the degree of change. In the EPATCitation29, the mean level of HDL for the E2 group was 54 mg/dl, while it was higher (62.5 mg/dl) in women receiving TX-001HR (E2/P4) in the REPLENISH trial. It is also possible that daily continuous P4 attenuated some of the rise in HDL observed here, in contrast to EPAT, which also studied 1 mg of E2 but with no progestogen. Nevertheless, E2 is known to exert a beneficial arterial effect, independent of lipid changesCitation31,Citation32. CVD mortality and overall mortality were decreased in a Finnish study that used E2 therapy; and this effect was not attenuated with added progestogenCitation33. Our data also showed only minor changes in some of the coagulation parameters when compared to placebo; and these changes largely remained within the normal ranges.
Although the REPLENISH trial lacked statistical power to assess cardiovascular outcomes or events such as stroke, VTE, and CHD, the incidence of these endpoints was as expected for a menopausal population. For example, the observed rate for CHD events of 2/1684 in this trial was slightly less than the expected annual rate of 2–3/1000Citation34, and the observed VTE rate of 1/1684 was slightly less than the expected annual rate of 1.7/1000Citation35, reported for US women of this age. Additionally, no stroke events were reported.
Since the publication of the Women’s Health Initiative results, many women have stopped taking FDA-approved HT due to concerns regarding breast cancer or cardiovascular eventsCitation36. Subsequently, many women have switched to pharmacy-compounded products containing bio-identical E2/P4 hormones, believing that they are saferCitation37,Citation38. Consequently, use of unapproved, compounded HT formulations in the USA has risenCitation37–Citation40, reaching an estimated 39 million prescriptions filled annuallyCitation41. Unfortunately, most compounded HT products have not been rigorously studiedCitation42–Citation46, and many may not provide sufficient endometrial protection or appropriate relief of menopausal VMS, possibly due to non-standardized hormone preparationsCitation41. Historically, the combination of E2/P4 in a single oral capsule has been challengingCitation47. At this time, only the 1 mg E2/100 mg P4 dose has been approved by the FDA for the treatment of moderate to severe VMS in postmenopausal women with a uterus. For women who prefer to use bio-identical hormones, this new formulation may provide a well-studied and FDA-approved option that has demonstrated clinical effectiveness in improving the frequency and severity of VMS in postmenopausal women with a uterus, with a documented safety profile, including endometrial safetyCitation25,Citation48. Furthermore, data from the REPLENISH trial showed significant improvements in quality of lifeCitation49 and sleep outcomesCitation50 with E2/P4. Finally, the combination of E2/P4 in a single oral capsule may be more convenient and possibly increase adherence as seen in other therapeutic areasCitation51,Citation52.
While the REPLENISH trial was a well-designed, randomized controlled trial that evaluated the efficacy and endometrial safety of E2/P4, one limitation is that it was not powered to detect events, such as CVD, that occur with a low incidence in relatively recently menopausal women. Also, generalization of the results is limited to white and African American women who are healthy and reside in the USA.
In conclusion, 12-month data from the REPLENISH trial showed that the approved E2/P4 formulation (Bijuva™ [1 mg E2/100 mg P4]), which combines bio-identical hormones in a single capsule for the treatment of moderate to severe VMS in postmenopausal women with a uterusCitation26, did not cause clinically meaningful changes, as determined by cardiometabolic disease risk markers and cardiovascular events.
Potential conflict of interest
R. A. Lobo has received research grants (to Columbia University) from TherapeuticsMD, Bayer Healthcare, and Ogeda and has served as a consultant (in the last 3 years) to Allergan, AMAG, Mithra Sojournix, and TherapeuticsMD. A. M. Kaunitz has served as a consultant to or on the advisory board of AMAG and Mithra, and has received research support (to University of FL) from Allergan, Bayer Healthcare, and TherapeuticsMD. N. Santoro has served on the advisory board of Astellas/Ogeda and Menogenix with stock options in Menogenix. S. Graham, B. Bernick, and S. Mirkin are current full-time employees of TherapeuticsMD with stock/stock options. B. Bernick is also a board member of TherapeuticsMD.
Source of funding
TherapeuticsMD sponsored the REPLENISH study and funded the medical writing support provided by Dominique J. Verlaan, PhD of Precise Publications, LLC (Bedminster, NJ, USA).
Acknowledgements
The authors acknowledge the writing assistance provided by Dominique J. Verlaan, PhD of Precise Publications, LLC (Bedminster, NJ, USA) and the statistical analysis provided by Chao Wang, PhD of Pharma Data Associates (New York City, NY, USA).
References
- Blumel JE, Chedraui P, Baron G. A large multinational study of vasomotor symptom prevalence, duration, and impact on quality of life in middle-aged women. Menopause 2011;18:778–85
- Hunter MS, Gentry-Maharaj A, Ryan A, et al. Prevalence, frequency and problem rating of hot flushes persist in older postmenopausal women: impact of age, body mass index, hysterectomy, hormone therapy use, lifestyle and mood in a cross-sectional cohort study of 10,418 British women aged 54–65. BJOG 2012;119:40–50
- Duffy OK, Iversen L, Hannaford P. The impact and management of symptoms experienced at midlife: a community-based study of women in northeast Scotland. BJOG 2012;119:554–64
- Whiteley J, Wagner JS, Bushmakin A, Kopenhafer L, Dibonaventura M, Racketa J. Impact of the severity of vasomotor symptoms on health status, resource use, and productivity. Menopause 2013;20:518–24
- Blumel JE, Cano A, Mezones-Holguin E, et al. A multinational study of sleep disorders during female mid-life. Maturitas 2012;72:359–66
- Kleinman NL, Rohrbacker NJ, Bushmakin AG, Whiteley J, Lynch WD, Shah SN. Direct and indirect costs of women diagnosed with menopause symptoms. J Occup Environ Med 2013;55:465–70
- The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause 2017;24:728–53
- Henderson VW, Lobo RA. Hormone therapy and the risk of stroke: perspectives 10 years after the Women's Health Initiative trials. Climacteric 2012;15:229–34
- Renoux C, Dell'Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost 2010;8:979–86
- Hale GE, Shufelt CL. Hormone therapy in menopause: an update on cardiovascular disease considerations. Trends Cardiovasc Med 2015;25:540–9
- Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322
- Lobo RA, Pickar JH, Stevenson JC, Mack WJ, Hodis HN. Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis 2016;254:282–304
- Lobo RA, Bush T, Carr BR, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001;76:13–24
- Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1995;273:199–208
- Scarabin PY, Hemker HC, Clement C, Soisson V, Alhenc-Gelas M. Increased thrombin generation among postmenopausal women using hormone therapy: importance of the route of estrogen administration and progestogens. Menopause 2011;18:873–9
- Terauchi M, Honjo H, Mizunuma H, Aso T. Effects of oral estradiol and levonorgestrel on cardiovascular risk markers in postmenopausal women. Arch Gynecol Obstet 2012;285:1647–56
- Canonico M. Hormone therapy and hemostasis among postmenopausal women: a review. Menopause 2014;21:753–62
- Lobo RA. Clinical review 27: effects of hormonal replacement on lipids and lipoproteins in postmenopausal women. J Clin Endocrinol Metab 1991;73:925–30
- Miller VT, Muesing RA, LaRosa JC, Stoy DB, Phillips EA, Stillman RJ. Effects of conjugated equine estrogen with and without three different progestogens on lipoproteins, high-density lipoprotein subfractions, and apolipoprotein A-I. Obstet Gynecol 1991;77:235–40
- Hirvonen J, Blom M, Tuominen U, et al. Health-related quality of life in patients waiting for major joint replacement. A comparison between patients and population controls. Health Qual Life Outcomes 2006;4:3
- Jiang Y, Tian W. The effects of progesterones on blood lipids in hormone replacement therapy. Lipids Health Dis 2017;16:219
- Mirkin S. Evidence on the use of progesterone in menopausal hormone therapy. Climacteric 2018;21:346–54
- Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. ATVB 2010;30:340–5
- Canonico M, Carcaillon L, Plu-Bureau G, et al. Postmenopausal hormone therapy and risk of stroke: impact of the route of estrogen administration and type of progestogen. Stroke 2016;47:1734–41
- Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2018;132:161–70
- Bijuva™ (Estradiol and Progesterone) Capsules, for Oral Use Prescribing Information. Boca Raton, FL: TherapeuticsMD; 2018
- Lobo RA, Liu J, Stanczyk FZ, et al. Estradiol and progesterone bioavailability for moderate to severe vasomotor symptom treatment and endometrial protection with the continuous-combined regimen of TX-001HR (oral estradiol and progesterone capsules). Menopause 2019;26:720
- Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women. Ann Intern Med 2014;161:249–60
- Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939–53
- Prior JC, Elliott TG, Norman E, Stajic V, Hitchcock CL. Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women. PLoS One 2014;9:e84698
- Mikkola TS, Savolainen-Peltonen H, Venetkoski M, Ylikorkala O. New evidence for cardiac benefit of postmenopausal hormone therapy. Climacteric 2017;20:5–10
- Reslan OM, Khalil RA. Vascular effects of estrogenic menopausal hormone therapy. Rev Recent Clin Trials 2012;7:47–70
- Mikkola TS, Tuomikoski P, Lyytinen H, et al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause 2015;22:976–83
- Lobo RA. Evaluation of cardiovascular event rates with hormone therapy in healthy, early postmenopausal women: results from 2 large clinical trials. Arch Intern Med 2004;164:482–4
- Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573–80
- Steinkellner AR, Denison SE, Eldridge SL, Lenzi LL, Chen W, Bowlin SJ. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women's Health Initiative. Menopause 2012;19:616–21
- Gass ML, Stuenkel CA, Utian WH, et al. Use of compounded hormone therapy in the United States: report of the North American Menopause Society Survey. Menopause 2015;22:1276–84
- Fishman JR, Flatt MA, Settersten RA Jr. Bioidentical hormones, menopausal women, and the lure of the ‘natural’ in U.S. anti-aging medicine. Soc Sci Med 2015;132:79–87
- American College of Obstetricians and Gynecologists. Compounded bioidentical menopausal hormone therapy. Committee opinion no. 532. Obstet Gynecol 2012;120:411–15
- Manson JE, Kaunitz AM. Menopause management – getting clinical care back on track. N Engl J Med 2016;374:803–6
- Pinkerton J, Santoro N. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women. Menopause 2015;22:926–36
- Pinkerton JV, Pickar JH. Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy. Menopause 2016;23:215–23
- Eden JA, Hacker NF, Fortune M. Three cases of endometrial cancer associated with ‘bioidentical’ hormone replacement therapy. Med J Aust 2007;187:244–5
- Davis R, Batur P, Thacker HL. Risks and effectiveness of compounded bioidentical hormone therapy: a case series. J Womens Health (Larchmt) 2014;23:642–8
- Dezman VL, Gersak MZ, Gersak K. Two cases of atypical endometrial hyperplasia associated with ‘bioidentical’ hormone replacement therapy: IGCS-0084 uterine cancer, including Sarcoma. Int J Gynecol Cancer 2015;25: Suppl 1:71
- Stuenkel C, Manson J. Compounded bioidentical hormone therapy: does the regulatory double standard harm women?. JAMA Intern Med 2017;177:1719–20
- Pickar JH, Bon C, Amadio JM, Mirkin S, Bernick B. Pharmacokinetics of the first combination 17beta-estradiol/progesterone capsule in clinical development for menopausal hormone therapy. Menopause 2015;22:1308–16
- Constantine G, Revicki DA, Kagan R, Simon J, Graham S, Mirkin S. TX-001HR is associated with a clinically meaningful effect on vasomotor symptoms. Menopause 2017;24:1428
- Simon JA, Kaunitz A, Kroll R, Graham S, Bernick B, Mirkin S. Oral 17β-estradiol-progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms. Menopause 2019;26:506–12
- Kagan R, Constantine G, Kaunitz A, Gasper G, Bernick B, Mirkin S. TX-001HR improved the Medical Outcomes Study-Sleep (MOS-Sleep) questionnaire in menopausal women with vasomotor symptoms (S-17). Menopause 2017;24:1431
- Sutton SS, Hardin JW, Bramley TJ, D'Souza AO, Bennett CL. Single- versus multiple-tablet HIV regimens: adherence and hospitalization risks. Am J Manag Care 2016;22:242–8
- Coca A, Agabiti-Rosei E, Cifkova R, Manolis AJ, Redón J, Mancia G. The polypill in cardiovascular prevention: evidence, limitations and perspective – position paper of the European Society of Hypertension. J Hypertens 2017;35:1546–53