Secondary Logo

Journal Logo

Original Studies

Effects of combined 17β-estradiol and progesterone on weight and blood pressure in postmenopausal women of the REPLENISH trial

Black, Denise R. MD, FRCSC1; Minkin, Mary Jane MD2; Graham, Shelli PhD3; Bernick, Brian MD3; Mirkin, Sebastian MD3

Author Information
doi: 10.1097/GME.0000000000001659
  • Open

Abstract

Although aging in women is often accompanied by increases in body weight, hormonal changes at menopause can have added effects, especially with central adipose distribution and abdominal obesity.1-3 Many women choose not to initiate or discontinue hormone therapy (HT) due to their fear of undesired weight gain.4,5 However, reviews of clinical studies generally show a neutral to beneficial effect of some HT formulations on body weight and fat distribution during menopause.2,5-8 In fact, several studies showed that HT slowed down weight gain due to aging, as less weight gain was observed in postmenopausal women using some HT formulations compared with nonusers,9-14 and some studies even reported weight loss in women using HT.15-17

Aging is also associated with elevated blood pressure (BP).18,19 Hypertension is one of the major risk factors for cardiovascular morbidity and mortality in postmenopausal women.19-21 Hypertension was found to be more prevalent in older women, especially in those aged 60 years or more,19,20 and associated with being overweight.19 A positive relationship between hypertension and menopausal status in women has been suggested.22,23 Estrogen deficiency in women may contribute to the rising BP during menopause.20,21 Data regarding the effect of HT on BP are inconsistent, although most of the reported effects on BP are either neutral or beneficial.6,18,21 Synthetic progestin in combined HT has been suggested to counteract the vasodilatory effects of estrogen, whereas natural progesterone (P4) may have a positive effect of lowering BP.21

An oral, single-capsule of combined bioidentical 17β-estradiol (E2) and P4, TX-001HR (TherapeuticsMD, Boca Raton, FL), was developed to treat moderate to severe vasomotor symptoms (VMS) in postmenopausal women with a uterus. Of the four different doses of TX-001HR (E2/P4: 1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, and 0.25 mg/50 mg) evaluated for safety and efficacy in the REPLENISH trial, the 1 mg/100 mg and 0.5 mg/100 mg doses significantly reduced the frequency and severity of moderate to severe VMS from baseline, meeting all co-primary endpoints, without negative impacts on endometrial safety24 or cardiovascular outcomes.25 Quality of life and sleeping profiles in postmenopausal women also improved with TX-001HR.26,27 In addition, an easy-to-use, oral, single-capsule formulation may facilitate adherence in women.28-30 The 1 mg E2/100 mg P4 dose was FDA approved as Bijuva ([E2 and P4] capsules, TherapeuticsMD, Boca Raton, FL) for the treatment of moderate to severe VMS in postmenopausal women with a uterus.

To address women's concern of weight gain when using menopausal HT, this paper reports weight and BP changes in women who used TX-001HR in the REPLENISH study and examines the possible influence of body mass index (BMI) on the efficacy of TX-001HR in treating VMS.

METHODS

Study design and participants

REPLENISH (NCT01942668) was a multicenter, randomized, placebo-controlled, double-blind, phase-3 trial evaluating TX-001HR for the treatment of moderate to severe VMS in postmenopausal women with a uterus. The trial was conducted in accordance with Good Clinical Practice at 117 US sites, with the study protocol approved by a central or local institutional review board at each study site. Healthy women with menopausal VMS and aged 40-65 years with an intact uterus, BMI ≤34 kg/m2, and sitting BP ≤140/90 mm Hg were eligible to enroll. Postmenopausal women were characterized as those who had spontaneous amenorrhea for ≥12 months or a screening serum follicle-stimulating hormone level >40 mIU/mL for ≥6 months, or bilateral oophorectomy 6 weeks or more prior to screening. Major exclusion criteria included having contraindication or allergy to estrogen and/or P4, heavy smoking (≥15 cigarettes/d), and recent use of medications that could alter P4 or estrogen activity. Women with a history of thromboembolic disorder, coronary artery or cerebrovascular disease, chronic liver or kidney disorder, diabetes, or other endocrinological diseases were also excluded. Women who used medications that could affect the outcome of the VMS endpoints within 28 days before screening were not eligible for the VMS substudy. Additional key inclusion and exclusion criteria, typical for menopausal HT studies, have been described elsewhere.24 Written informed consent was obtained for all participants.

A reproducible, computer-generated block schedule was used to randomize participants to four daily, oral doses of E2 (mg)/P4 (mg) (1/100, 0.5/100, 0.5/50, 0.25/50) for 12 months.24 Enrolled participants who had ≥7 moderate to severe hot flushes per day or ≥50 per week at screening were assigned into four active treatment groups and one placebo group equally in a modified-intent-to-treat VMS (MITT-VMS) substudy. The remaining participants were randomized to the four active doses at 1:1:1:1. The safety population included all participants who took at least one dose of the study drug for analysis of drug safety. To ensure study blind, a double-dummy design was used.24,25

Efficacy and safety endpoints

Primary efficacy endpoints of the study were changes in frequency and severity of moderate to severe VMS from baseline to weeks 4 and 12 in the VMS substudy. Daily diaries of participating women were used to collect weekly hot flush frequency data (total number of moderate and severe hot flushes in the last 7 d) and a weekly hot flush severity score (calculated as [(number of mild hot flushes) × 1 + (number of moderate hot flushes) × 2 + (number of severe hot flushes) × 3] / (total number of mild, moderate, and severe hot flushes)] over 7 d).

The primary safety endpoint was incidence of endometrial hyperplasia in women who completed the 12-month treatment, as previously reported.24 Further safety assessments included vital signs (sitting BP, heart rate, respiratory rate, and body temperature), physical examination findings, body weight, and BMI.

In the safety population, vital signs and adverse events (AEs) were monitored throughout the study. Sitting BP was measured at screening, weeks 4, 8, and 12, and months 6, 9, and 12, whereas body weight was measured at screening, week 4, and months 6 and 12. Clinically significant worsening from baseline or new findings in vital signs were considered AEs. All nonserious AEs were collected after informed consent was signed through 15 days following the last dose and serious AEs were collected through 30 days after the last dose. Treatment-emergent adverse events (TEAEs) were collected from the time of the first dose through 15 days after the last dose, and were assessed for severity and causality with the study drug. Treatment compliance was assessed at week 12 for the MITT-VMS population and at month 12 for the safety population, and was calculated for all women regardless whether the woman completed or discontinued the study during the time periods. A compliant woman was defined as one who took ≥80% of the capsules expected to be taken for the respective time periods (over the first 12 weeks or throughout the 1-year study). Compliance rates were determined as proportions of compliant women in the specific populations.

Statistical analysis

The overall sample size in this study was determined based on the target of achieving 1% or less incidence of endometrial hyperplasia after the 12-month therapy with an upper bound of 95% confidence of 4% or less. The size of the VMS substudy was based on the hypothesized changes in the frequency and severity of VMS from baseline to weeks 4 and 12. Demographic characteristics were summarized descriptively. Changes from baseline at screening to month 12 for sitting BP and body weight were analyzed for each time point and compared between each active treatment group versus placebo. Incidence of potentially clinically important (PCI) change was defined as the proportion of women who had BP or weight changes meeting the PCI criteria (Table 1). Mean changes in frequency and severity of VMS were analyzed by a mixed model for repeated measures method, where treatment, week, and treatment-by-week interaction as factors, baseline as covariate, and participant as repeated measures unit. Influence of BMI on VMS treatment response was analyzed across baseline BMI tertiles (<25 kg/m2, ≥25 and <30 kg/m2, and ≥30 kg/m2). Statistical analysis was performed with SAS v9.2 or higher (SAS Institute, Cary, NC).

TABLE 1 - Criteria for potentially clinically important (PCI) changes in vital signs and weight
Variable Criteria a
Sitting BP (Systolic) Increase or decrease from baseline of ≥20 mm Hg with absolute value of ≥160 or ≤90 mm Hg
Sitting BP (Diastolic) Increase or decrease from baseline of ≥15 mm Hg with absolute value of ≥90 or ≤60 mm Hg
Body weight Increase or decrease from baseline of ≥15% and ≥11.3 kg
BP, blood pressure.
aBaseline was defined as the last value prior to treatment.

RESULTS

Participants disposition and demographics

The safety population included all 1,835 participants who took at least one dose of the study drug during the study. The overall ratio of women who received E2/P4 vs women who received placebo was approximately 11:1 (Fig. 1). Demographic characteristics were similar between all groups (Table 2). Women had a mean age of 54.6 years, mean weight of 72.0 kg, mean BMI of 26.7 kg/m2, and an average of 5.8 years since menopause. The majority (65.4%) of women were white and one-third (32.1%) African American (Table 2). At baseline, sitting BP measures were comparable across all groups, with mean systolic BP ranging from 118.9 to 120.5 mm Hg and mean diastolic BP 75.7 to 76.3 mm Hg.

FIG. 1
FIG. 1:
Disposition of participants in the safety population and the MITT-VMS substudy. E2, 17β-estradiol; MITT-VMS, modified intent-to-treat vasomotor symptoms substudy; P4, progesterone.
TABLE 2 - Demographic and baseline characteristics
E2 (mg)/P4 (mg)
Characteristic 1/100 (n = 415) 0.5/100 (n = 424) 0.5/50 (n = 421) 0.25/50 (n = 424) Placebo (n = 151) Total (n = 1,835)
Age, y 54.7 ± 4.4 54.5 ± 4.5 54.9 ± 4.3 54.4 ± 4.0 54.5 ± 4.3 54.6 ± 4.3
Race, n (%)
 White 271 (65.3) 281 (66.3) 276 (65.6) 273 (64.4) 100 (66.2) 1,201 (65.4)
 Black or African American 134 (32.3) 136 (32.1) 133 (31.6) 140 (33.0) 46 (30.5) 589 (32.1)
 Other a 10 (2.4) 7 (1.6) 12 (2.8) 11 (2.6) 5 (3.3) 45 (2.4)
Weight, kg 72.1 ± 12.3 71.7 ± 13.1 72.2 ± 11.8 72.1 ± 11.9 71.4 ± 11.5 72.0 ± 12.2
BMI, kg/m2 26.8 ± 4.1 26.7 ± 4.3 26.7 ± 4.0 26.7 ± 4.0 26.6 ± 3.9 26.7 ± 4.1
Years since last menstrual period, y 5.8 ± 4.9 6.0 ± 5.1 5.7 ± 4.6 5.6 ± 4.9 6.0 ± 5.3 5.8 ± 4.9
Baseline BP n = 415 n = 423 n = 421 n = 423 n = 151 n = 1,833
 Systolic BP, mm Hg 119.5 ± 12.0 120.3 ± 11.7 120.5 ± 11.9 119.8 ± 11.2 118.9 ± 10.9
 Diastolic BP, mm Hg 75.7 ± 8.2 76.2 ± 8.0 76.3 ± 8.1 76.2 ± 8.1 75.9 ± 7.7
Baseline VMS (MITT-VMS; BMI <25 kg/m2) n = 54 n = 49 n = 52 n = 58 n = 46 n = 259
 Weekly frequency 80.4 ± 45.4 69.0 ± 21.4 75.9 ± 23.3 82.4 ± 35.3 73.0 ± 20.8
 Weekly severity 2.53 ± 0.25 2.53 ± 0.27 2.49 ± 0.23 2.59 ± 0.28 2.48 ± 0.27
Baseline VMS (MITT-VMS; BMI ≥25 and <30 kg/m2) n = 56 n = 55 n = 64 n = 65 n = 61 n = 301
 Weekly frequency 73.5 ± 23.1 70.3 ± 30.3 76.5 ± 30.8 72.0 ± 26.2 70.5 ± 25.4
 Weekly severity 2.61 ± 0.24 2.46 ± 0.25 2.48 ± 0.23 2.43 ± 0.21 2.54 ± 0.24
Baseline VMS (MITT-VMS; BMI ≥30 kg/m2) n = 31 n = 45 n = 31 n = 31 n = 28 n = 166
 Weekly frequency 65.6 ± 32.3 77.6 ± 30.3 74.6 ± 30.3 77.5 ± 27.9 75.7 ± 22.7
 Weekly severity 2.44 ± 0.50 2.56 ± 0.21 2.56 ± 0.24 2.54 ± 0.27 2.55 ± 0.23
Data are mean ± SD unless noted otherwise.BMI, body mass index; BP, blood pressure; E2, 17β-estradiol; MITT-VMS, modified intent-to-treat vasomotor symptoms substudy; P4, progesterone; SD, standard deviation; VMS, vasomotor symptoms.
aOther includes: Other (20), Asian (12), American Indian or Alaska Native (6), Native Hawaiian or Pacific Islander (5), and Unknown (2).

A total of 726 women were included in the MITT-VMS substudy (efficacy population). The demographic characteristics of the VMS substudy were similar to those in the safety population.24 Baseline mean VMS frequency ranged from 65.6 to 82.4 hot flushes per week. Baseline mean VMS severity scores were similar and ranged from 2.43 to 2.61 across treatment groups.

The compliance rate was 89.5% for the MITT-VMS population over the first 12 weeks and 76.3% for the safety population over the 1-year study period.

Changes in body weight

With 12-month use of study drug, mean body weight remained nearly unchanged compared with baseline in all treatment groups (Fig. 2A). In general, no statistically significant differences were observed in mean changes from baseline to month 12 with E2/P4 versus placebo; mean changes in all groups were <1 kg and not considered clinically meaningful, albeit statistically significant in the 0.5 mg/100 mg E2/P4 group (Table 3).

FIG. 2
FIG. 2:
Changes in weight from baseline to month 12. (A) Comparison of mean body weight at baseline and at month 12. (B) Comparison of incidence of PCI weight change in different treatment groups. E2, 17β-estradiol; P4, progesterone; PCI, potentially clinically important.
TABLE 3 - Changes from baseline to month 12 in body weight and blood pressure
E2 (mg)/P4 (mg)
Measurement at month 12 1/100 (n = 415) 0.5/100 (n = 424) 0.5/50 (n = 421) 0.25/50 (n = 424) Placebo (n = 151) Total (n = 1,835)
Body weight n = 282 n = 305 n = 312 n = 280 n = 93 n = 1,272
 Mean change ± SD, kg 0.3 ± 4.4 0.7 ± 4.4 0.5 ± 4.3 0.3 ± 4.2 −0.3 ± 4.3
   P value (vs placebo) 0.249 0.032 0.133 0.113
 PCI change, n (%) 7 (2.5) 8 (2.6) 6 (1.9) 3 (1.1) 2 (2.2) 26 (2.0)
 PCI increase, n (%) 4 (1.4) 5 (1.6) 3 (1.0) 1 (0.4) 0 13 (1.0)
 PCI decrease, n (%) 3 (1.1) 3 (1.0) 3 (1.0) 2 (0.7) 2 (2.2) 13 (1.0)
Systolic BP n = 284 n = 305 n = 312 n = 281 n = 93 n = 1,275
 Mean change ± SD, mm Hg 1.0 ± 12.9 1.3 ± 12.9 0.2 ± 13.2 0.2 ± 13.0 1.2 ± 10.9
   P value (vs placebo) 0.679 0.993 0.528 0.577
 PCI change, n (%) 3 (1.1) 1 (0.3) 2 (0.6) 3 (1.1) 1 (1.1) 10 (0.8)
 PCI increase, n (%) 1 (0.4) 1 (0.3) 1 (0.3) 2 (0.7) 1 (1.1) 6 (0.5)
 PCI decrease, n (%) 2 (0.7) 0 1 (0.3) 1 (0.4) 0 4 (0.3)
Diastolic BP n = 284 n = 305 n = 312 n = 281 n = 93 n = 1,275
 Mean change ± SD, mm Hg 0.3 ± 8.8 0.4 ± 8.7 0.3 ± 9.6 −0.4 ± 8.6 0.2 ± 9.1
   P value (vs placebo) 0.745 0.911 0.965 0.568
 PCI change, n (%) 4 (1.4) 8 (2.6) 13 (4.2) 10 (3.6) 3 (3.2) 38 (3.0)
 PCI increase, n (%) 1 (0.4) 5 (1.6) 5 (1.6) 3 (1.1) 2 (2.2) 16 (1.3)
 PCI decrease, n (%) 3 (1.1) 3 (1.0) 8 (2.6) 7 (2.5) 1 (1.1) 22 (1.7)
BP, blood pressure; E2, 17β-estradiol; P4, progesterone; PCI, potentially clinically important; SD, standard deviation.

Similar percentages of women in the active (1.1%-2.6%) and placebo (2.2%) groups had changes in body weight meeting PCI criteria (Table 1) at month 12, with half of them having PCI weight gain and the other half having PCI weight loss (Table 3). In addition, the number of women having PCI weight gain was similar to that of women having PCI weight loss within each E2/P4 group (Table 3; Fig. 2B).

Changes in blood pressure

Mean sitting BPs (both systolic and diastolic) at month 12 were similar to those at baseline for any treatment group (Fig. 3A and B). Mean changes from baseline to month 12 ranged from 0.2 to 1.3 mm Hg in systolic BP and −0.4 to 0.4 mm Hg in diastolic BP, without showing any dose dependence in either measure (Table 3).

FIG. 3
FIG. 3:
Changes in sitting BP from baseline to month 12. Comparison of mean BP at baseline and at month 12 for systolic BP (A) and diastolic BP (B). Comparison of incidence of PCI changes in systolic BP (C) and diastolic BP (D). BP, blood pressure; E2, 17β-estradiol; MITT-VMS, modified intent-to-treat vasomotor symptoms substudy; P4, progesterone; PCI, potentially clinically important.

At month 12, no difference was found in the proportions of women having PCI changes in systolic or diastolic BP with E2/P4 vs placebo (1.4%-4.2% vs 3.2% for diastolic BP and 0.3%-1.1% vs 1.1% for systolic BP; Table 3). Both PCI increases and PCI decreases were observed within each treatment group for both systolic and diastolic BP, except for no PCI decrease in systolic BP in the 0.5 mg/100 mg E2/P4 and the placebo groups (Fig. 3C and D).

Discontinuation due to weight gain or hypertension

Related TEAEs of weight gain (E2/P4 vs placebo: 1.4%-2.6% vs 1.3%) and hypertension (0.2%-1.2% vs 0%) were reported in a small number of women during the study. Discontinuation rates due to these TEAEs were low. Among the 502 women who discontinued E2/P4, weight gain was the primary reason to withdraw for eight women (1.6%) and hypertension for three (0.6%).

Effect of BMI on VMS treatment efficacy

At week 12, both severity and frequency of VMS in E2/P4 groups decreased from baseline, with changes in some active groups statistically significant versus placebo within each BMI subgroup (Fig. 4). The efficacy profile did not vary by BMI (Fig. 4). The 1 mg/100 mg and 0.5 mg/100 mg E2/P4 doses showed numerically greater improvement than placebo in terms of VMS frequency and severity at weeks 4 and 12 for all BMI subgroups, except for a similar decrease in severity for 1 mg/100 mg E2/P4 versus placebo at week 4 in the BMI ≥30 kg/m2 subgroup.

FIG. 4
FIG. 4:
Mean changes (±SD) from baseline in frequency (A) and severity (B) of moderate to severe VMS in different BMI subgroups at week 12. P value was calculated for each active dose versus placebo. BMI, body mass index; E2, 17β-estradiol; P4, progesterone; PCI, potentially clinically important; VMS, vasomotor symptoms.

DISCUSSION

In the REPLENISH trial, mean changes in weight and BP at month 12 relative to baseline with E2/P4 were modest, without statistically significant differences in general, or clinically meaningful differences, when compared with placebo. The overall changes in each treatment groups were not substantial enough to be deemed clinically meaningful. Treatment-related TEAEs of weight gain or hypertension were reported at low frequencies and led to few study discontinuations. In addition, efficacy profiles of E2/P4 for relieving VMS within each BMI subgroup were found consistent with previous observation24 and did not vary by BMI.

A common belief of women is that HT may bring undesired weight gain. Small gains in weight appear to be common in midlife women. Among women of 42-52 years who were participating in the Study of Women's Health Across the Nation, an average 2.1-kg increase in body weight over 3 years was observed.31 In other randomized, controlled trials of HT in postmenopausal women, the observed mean weight gain was on average 0.4 to 1.6 kg in the placebo groups.10,11,13 Mean weight of participants in REPLENISH remained relatively constant in all groups after 12 months of treatment. The mean changes from baseline in active groups were not significantly different versus placebo, except for the 0.5 mg/100 mg E2/P4 group, which could be a result of random variations by chance, as the changes showed no trends and the significant difference with 0.5 mg/100 mg E2/P4 was not observed at other time points during the study (data not shown).

Discontinuation due to weight gain occurred in a small percentage of the women (1.6%) who stopped using E2/P4. This is in contrast to HT with the more androgenic progestins, which have been postulated to be associated with weight gain in postmenopausal women.32 The results of no clinically meaningful weight gain after one year of TX-001HR use are consistent with previous systematic reviews showing no effect on body weight with combined estrogen and progestogen.7,8

Data in the Study of Women's Health Across the Nation study reported that higher BMI was associated with increased VMS in premenopausal or perimenopausal women.33 However, such a correlation was not observed at baseline in the present study. The VMS substudy in REPLENISH excluded women with low levels of VMS and therefore may not be able to reflect any relationship between BMI and VMS. Effectiveness of HT with exogenous estrogen could also be modified by BMI. In the present study, the efficacy profile for relieving VMS among BMI subgroups was consistent with the primary analyses,24 with the 1 mg/100 mg and 0.5 mg/100 mg E2/P4 mostly showing significant reductions in both frequency and severity of moderate to severe symptoms at weeks 4 and 12. This is in agreement with a previous observation in the Women's Health, Osteoporosis, Progestin, Estrogen study, which showed no significant impact of BMI on effectiveness in reducing VMS with conjugated estrogens/medroxyprogesterone acetate when the participants were grouped by BMI <25 kg/m2 and BMI ≥25 kg/m2 (P = 0.66 for frequency and P = 0.14 for severity).13

BP is one of the risk factors for cardiovascular diseases.6,34,35 Elevated BP is responsible for 51% of deaths from stroke and 45% from coronary heart disease according to the 2012 WHO World Health Statistics.36 Therefore, prevention of unfavorable increases in BP is important for postmenopausal women. TX-001HR was not associated with changes in either systolic or diastolic BP in REPLENISH. This contrasts with the finding of a numerically small (1.35 mm Hg higher) but statistically significant difference in mean systolic BP between conjugated estrogens/medroxyprogesterone acetate and placebo arms at year 1 in the Women's Health Initiative study.37 The results here for REPLENISH are similar to those of the randomized, controlled postmenopausal estrogen/progestin interventions study, which found small increases in systolic BP with no significant differences among treatment groups including placebo.9 In the large, randomized, controlled Danish Osteoporosis Prevention study of 17β-estradiol with or without norethisterone acetate, similar reductions in BP were observed in both HT users and nonusers,38 whereas an observational cohort study in Australia showed an association of HT with significantly higher odds of having high BP.39 Differences in design, sample size, type of hormones, or methods used for BP measurements could contribute to the inconsistency among these studies.21

Surrogate markers of cardiovascular disease risk include BP, weight, and lipids. Previous analyses reported from the REPLENISH study showed no clinically significant changes in risk parameters, including total cholesterol, triglycerides, and glucose, at month 12 with E2/P4 compared with placebo.25 Together with the results on weight and BP from this analysis, the REPLENISH trial demonstrated that E2/P4 does not have adverse effects on cardiovascular disease risk factors.

One limitation of the study is that no data on waist-to-hip ratio or body composition were collected. Although weight gain might be mainly from aging, it is believed that hormonal changes during menopause transition result in a redistribution of body fat from lower body to central body.1,2,40 The present analysis lacks the ability to evaluate counteracting effects by TX-001HR on menopause-related changes in adipose distribution. The study is also limited in that weight-affecting factors, such as diet, nutrition, and physical activity, were not controlled or evaluated in the study, although this is typical for trials evaluating HT. Nevertheless, the current analysis suggests that there were no clinically meaningful changes in weight and BP, adding to the safety information available for TX-001HR.

CONCLUSION

Data from the randomized, placebo-controlled, phase 3 REPLENISH trial revealed no overall clinically significant changes in body weight and sitting BP in all groups, showing no impact of TX-001HR on these cardiovascular disease risk factors. Together with previously reported efficacy and safety data,24,25 the results of this analysis on weight and BP add to the efficacy and safety profile for the approved 1 mg/100 mg E2/P4 dose, which is an option for postmenopausal women with a uterus and moderate to severe VMS.

Acknowledgments

The authors would like to acknowledge the medical writing assistance of Hui Zhang, PhD and Kathleen Ohleth, PhD of Precise Publications, LLC, which was supported by TherapeuticsMD.

REFERENCES

1. Davis SR, Castelo-Branco C, Chedraui P, et al. Understanding weight gain at menopause. Climacteric 2012; 15:419–429.
2. Karvonen-Gutierrez C, Kim C. Association of mid-life changes in body size, body composition and obesity status with the menopausal transition. Healthcare (Basel) 2016; 4:
3. Kapoor E, Collazo-Clavell ML, Faubion SS. Weight gain in women at midlife: a concise review of the pathophysiology and satrategies for management. Mayo Clin Proc 2017; 92:1552–1558.
4. Goldman GA, Kaplan B, Leiserowitz DM, Pardo Y, Amster R, Fisch B. Compliance with hormone replacement therapy in postmenopausal women. A comparative study. Clin Exp Obstet Gynecol 1998; 25:18–19.
5. van Seumeren I. Weight gain and hormone replacement therapy: are women's fears justified? Maturitas 2000; 34: (suppl 1): S3–S8.
6. Casanova G, Bossardi Ramos R, Ziegelmann P, Spritzer PM. Effects of low-dose versus placebo or conventional-dose postmenopausal hormone therapy on variables related to cardiovascular risk: a systematic review and meta-analyses of randomized clinical trials. J Clin Endocrinol Metab 2015; 100:1028–1037.
7. Coquoz A, Gruetter C, Stute P. Impact of micronized progesterone on body weight, body mass index, and glucose metabolism: a systematic review. Climacteric 2019; 22:148–161.
8. Norman RJ, Flight IH, Rees MC. Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution. Cochrane Database Syst Rev 2000; CD001018.
9. 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.
10. Espeland MA, Stefanick ML, Kritz-Silverstein D, et al. Effect of postmenopausal hormone therapy on body weight and waist and hip girths. Postmenopausal Estrogen-Progestin Interventions Study Investigators. J Clin Endocrinol Metab 1997; 82:1549–1556.
11. Gambacciani M, Ciaponi M, Cappagli B, et al. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal women. J Clin Endocrinol Metab 1997; 82:414–417.
12. Yuksel H, Odabasi AR, Demircan S, et al. Effects of oral continuous 17beta-estradiol plus norethisterone acetate replacement therapy on abdominal subcutaneous fat, serum leptin levels and body composition. Gynecol Endocrinol 2006; 22:381–387.
13. Utian WH, Gass ML, Pickar JH. Body mass index does not influence response to treatment, nor does body weight change with lower doses of conjugated estrogens and medroxyprogesterone acetate in early postmenopausal women. Menopause 2004; 11:306–314.
14. Jensen LB, Vestergaard P, Hermann AP, et al. Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study. J Bone Miner Res 2003; 18:333–342.
15. Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. AnnInternMed 2003; 138:1–9.
16. Cicinelli E, de Ziegler D, Alfonso R, Nicoletti R, Bellavia M, Colafiglio G. Endometrial effects, bleeding control, and compliance with a new postmenopausal hormone therapy regimen based on transdermal estradiol gel and every-other-day vaginal progesterone in capsules: a 3-year pilot study. Fertil Steril 2005; 83:1859–1863.
17. Cicinelli E, de Ziegler D, Galantino P, et al. Twice-weekly transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy in postmenopausal women: a 1-year prospective study. Am J Obstet Gynecol 2002; 187:556–560.
18. Cannoletta M, Cagnacci A. Modification of blood pressure in postmenopausal women: role of hormone replacement therapy. IntJWomens Health 2014; 6:745–757.
19. Wenger NK, Arnold A, Bairey Merz CN, et al. Hypertension across a woman's life cycle. J Am Coll Cardiol 2018; 71:1797–1813.
20. Kawecka-Jaszcz K, Czarnecka D, Olszanecka A, Rajzer M, Jankowski P. The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension. J Hum Hypertens 2002; 16:509–516.
21. Issa Z, Seely EW, Rahme M, El-Hajj Fuleihan G. Effects of hormone therapy on blood pressure. Menopause 2015; 22:456–468.
22. Staessen JA, Ginocchio G, Thijs L, Fagard R. Conventional and ambulatory blood pressure and menopause in a prospective population study. J Hum Hypertens 1997; 11:507–514.
23. Zanchetti A, Facchetti R, Cesana GC, et al. Menopause-related blood pressure increase and its relationship to age and body mass index: the SIMONA epidemiological study. J Hypertens 2005; 23:2269–2276.
24. 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; 132:161–170.
25. Lobo RA, Kaunitz AM, Santoro N, Bernick B, Graham S, Mirkin S. Metabolic and cardiovascular effects of TX-001HR in menopausal women with vasomotor symptoms. Climacteric 2019; 22:610–616.
26. Mirkin S, Graham S, Revicki DA, Bender RH, Constantine G. Relationship between vasomotor symptom improvements and quality of life and sleep outcomes in menopausal women treated with oral, combined 17β-estradiol/progesterone. Menopause 2019; 26:637–642.
27. Kagan R, Constantine G, Kaunitz AM, Bernick B, Mirkin S. Improvement in sleep outcomes with a 17β-estradiol-progesterone oral capsule (TX-001HR) for postmenopausal women. Menopause 2019; 26:622–628.
28. 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; 22:242–248.
29. Coca A, Agabiti-Rosei E, Cifkova R, Manolis AJ, Redon J, Mancia G. The polypill in cardiovascular prevention: evidence, limitations and perspective - position paper of the European Society of Hypertension. J Hypertens 2017; 35:1546–1553.
30. Bailey CJ, Day C. Fixed-dose single tablet antidiabetic combinations. Diabetes, obesity & metabolism 2009; 11:527–533.
31. Sternfeld B, Wang H, Quesenberry CP Jr, et al. Physical activity and changes in weight and waist circumference in midlife women: findings from the Study of Women's Health Across the Nation. Am J Epidemiol 2004; 160:912–922.
32. Black D, Messig M, Yu CR, et al. The effect of conjugated estrogens/bazedoxifene therapy on body weight of postmenopausal women: pooled analysis of five randomized, placebo-controlled trials. Menopause 2016; 23:376–382.
33. Gold EB, Block G, Crawford S, et al. Lifestyle and demographic factors in relation to vasomotor symptoms: baseline results from the Study of Women's Health Across the Nation. Am J Epidemiol 2004; 159:1189–1199.
34. Karmali KN, Lloyd-Jones DM. Global risk assessment to guide blood pressure management in cardiovascular disease prevention. Hypertension 2017; 69:e2–e9.
35. Kshirsagar AV, Carpenter M, Bang H, Wyatt SB, Colindres RE. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. Am J Med 2006; 119:133–141.
36. World Health Organization. World Health statistics: a snapshot of global health. Available at: https://www.who.int/gho/publications/world_health_statistics/2012/en/. Accessed December 3, 2019.
37. Shimbo D, Wang L, Lamonte MJ, et al. The effect of hormone therapy on mean blood pressure and visit-to-visit blood pressure variability in postmenopausal women: results from the Women's Health Initiative randomized controlled trials. J Hypertens 2014; 32:2071–2081.
38. Vestergaard P, Hermann AP, Stilgren L, et al. Effects of 5 years of hormonal replacement therapy on menopausal symptoms and blood pressure-a randomised controlled study. Maturitas 2003; 46:123–132.
39. Chiu CL, Lujic S, Thornton C, et al. Menopausal hormone therapy is associated with having high blood pressure in postmenopausal women: observational cohort study. PLoS One 2012; 7:e40260.
40. Donato GB, Fuchs SC, Oppermann K, Bastos C, Spritzer PM. Association between menopause status and central adiposity measured at different cutoffs of waist circumference and waist-to-hip ratio. Menopause 2006; 13:280–285.
Keywords:

Blood pressure; Body mass index; Body weight; Estradiol; Progesterone; Vasomotor symptoms

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.