Effect of Peri- and Postmenopausal Hormone Replacement Therapy on Body Weight

A Cochrane review [Abstract] 1 included 22 studies. No statistically significant difference was found in mean weight gain between those using unopposed oestrogen and those not using hormone replacement therapy (HRT) (0.66 kg, 95% CI -0.62, 1.93). No significant difference was found in mean weight gain between those using oestrogen/progestogen therapy and non-HRT users (-0.47 kg, 95% CI -1.63, 0.69). Insufficient data exist to enable meta-analysis of the effect of unopposed oestrogen on BMI. The reviewers found no statistically significant difference in mean BMI increase between those using oestrogen/progestogen and non-HRT users (-0.50, 95% CI -1.06, 0.06). Insufficient data exist to enable meta-analysis of the effect of HRT on waist-hip ratio, fat mass or skinfold thickness.

• Study quality: High
• Applicability: Moderate
• Comment: This very large RCT and long-term follow-up confirm the previous evidence. The study findings may not apply to perimenopausal HRT users because the mean age at randomization was 63 y. Conjugated equine estrogen is not used in Finland.

A 6-year follow-up sub-study 3 from the Women's Health Initiative hormone trials evaluated the effects of postmenopausal estrogen plus progestogen therapy (EP) or estrogen therapy (E) alone on age-related changes in lean body mass. Postmenopausal women (50 to 79 years) were randomly (block randomization) assigned to either EP (n = 543) or control (n = 471) and E (n = 453) or control (n = 474). Treatment arms received 0.625 mg conjugated equine estrogen alone or combined with 2.5 mg medroxyprogesterone acetate. Body composition, weekly recreational energy expenditure and other covariates were analyzed at baseline and at 3 and 6 years. Fat mass change was not significantly different between intervention and control groups at any of the time points examined. Lean body mass loss was significantly less in both of the active intervention arms of the E and EP trials compared with their respective placebo groups at 3 years. At 6 years post randomization, lean body mass change did not differ between E and control group (-0.44 kg, SD 2.28 kg vs. -0.5 kg, SD 2.45 kg, P=0.72, respectively) or between EP and control group (-0.29 kg, SD 1.9 kg vs. -0.4 kg, SD 2.15 kg, P=0.46, respectively). Despite early preservation of lean body mass with HRT (3 y), HRT did not ameliorate long-term (6 y) loss in lean body mass with aging.

• Study quality: High
• Applicability: Moderate
• Comment: This very large RCT and long-term follow-up confirm the previous evidence. The study findings may not apply to perimenopausal HRT users because the mean age at randomization was 63 y. Conjugated equine estrogen is not used in Finland.
• General comment: Neither estrogen/progestogen nor estrogen only HRT regimens do modify postmenopausal BMI change or long term changes in lean body mass or fat mass.

A 12-month randomized controlled phase-3 trial 4 (n=1272) assessed the effects of oral, single-capsule of combined bioidentical 17b-estradiol (E2) and natural progesterone at 4 different doses on postmenopausal changes in body mass index. Demographic characteristics were similar between all groups (mean age of 54.6 years, mean weight of 72.0 kg, mean BMI of 26.7 kg/m², average of 5.8 years since menopause). All active treatment groups were compared to non-users/control (n=93), who showed a weight loss of -0.3 kg (SD ± 4.3). Group I used 1 mg/day E2 + 100 mg/day progesterone (n=282), with a weight gain of +0.3 kg (SD ± 4.4, P=0.249); group II received 0.5 mg/day E2 + 100 mg/day progesterone (n=305) and showed a weight gain of +0.7 kg (SD ± 4.4, P=0.133); group III with 0.5 mg/day E2 + 50 mg/day progesterone (n=312), showed a weight gain of +0.5 kg (SD ± 4.3, P=0.133); group IV was given 0.25 mg/day E2 + 50 mg/day progesterone (n=280) and showed a weight gain of +0.3 kg (SD ± 4.2, P=0.113).

• Study quality: High
• Applicability: Good
• Comment: This large RCT has rather short follow-up but comparisons of different E2 doses reinforce the concept that E2 does not significantly contribute to postmenopausal weight gain. The mean changes from baseline in active groups were not significantly different versus placebo, except for the 0.5mg/100mg E2/P4 group, which could be a result of random variations by chance, as the changes showed no trends and the significant difference with 0.5mg/100mg E2/P4 was not observed at other time points during the study.

A prospective, randomized, and placebo-controlled trial 5 tested the clinical effect of HRT with estradiol valerate (1 mg) combined with 2 different progestins in metabolism. Postmenopausal women with climacteric symptoms received for 12 months orally, either placebo (n=20), 1mg estradiol (E) plus 0.5mg noretisterone acetate (NETA; n=40), or 2mg drospirenone (DRSP; n=40) in double blinded fashion. The mean age and BMI in placebo, E/DRSP, and E/NETA groups were 51.6±2.8, 50.9±4.2, 50.6±4.6 years, and 60.9±7.8, 59.6±8.1, 60.0±8.3 kg/m², respectively. Weight declined only during E/DRSP (p<0.04 versus placebo). Fat mass decreased similarly during E/NETA (p<0.003 vs. placebo) and E/DRSP group (p<0.019 vs. placebo).

• Study quality: High
• Applicability: Good
• Comment: This RCT is rather small and has a short follow-up but comparisons of 2 different progestins with fixed E2 dose against placebo reinforce the concept that E2 does not significantly contribute to postmenopausal weight gain and suggests minor improvements in fat free mass.

A study 2 assessed changes in obese HRT-users in resting energy expenditure (REE), autonomic asset, and assessment of oxidative stress in comparison with obese premenopausal women and post-menopausal women without HRT (n= 50 in each 3 groups). The mean age and BMI in HRT group and in control group 9were 50.6 ± 3.4 vs. 50.9 ± 3.8 years and 30.8 ± 0.7 30.8 ± 0.08 kg/m², respectively. In the HRT-group a significant increase of the sympathetic activity and resting energy expenditure was described. Finally this group showed a notable increment of oxidative stress compared with the others, and utilizing Body Impedance Analysis (BIA) instrument, the free fat mass was increased as compared to of obese postmenopausal women without HRT (ANOVA p < 0.01 and post-hoc test showed a difference between HRT and post-menopause women). respect to the fat mass of obese women.

• Study quality: Low
• Applicability: Moderate
• General comment: The enrollment of 150 sedentary, obese women is not fully enclosed. Those in HRT group had had HRT-treatment at least for 2 years and the treatment consisted of estrogen and progesterone (estrogen = 0.625 mg/day, progesterone = 2.5 mg/day). The study is a cross sectional analysis but the methods to study REE are adequately described.

References

• 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;(2):CD001018. [PubMed]
• Monda V, Salerno M, Fiorenzo M et al. Role of SexHormones in the Control of Vegetative and Metabolic Functions of Middle-Aged Women. Front Physiol 2017;(8):773. [PubMed]
• Bea JW, Zhao Q, Cauley JA, et al. Effect of hormone therapy on lean body mass, falls, and fractures: 6-year results from the Women's Health Initiative hormone trials. Menopause 2011;18(1):44-52[PubMed]
• Black DR, Minkin MJ, Graham S, et al. Effects of combined 17β-estradiol and progesterone on weight and blood pressure in postmenopausal women of the REPLENISH trial. Menopause 2020;28(1):32-39 [PubMed]
• Paoletti AM, Cagnacci A, Di Carlo C, et al. Clinical effect of hormonal replacement therapy with estradiol associated with noretisterone or drospirenone. A prospective randomized placebo controlled study. Gynecol Endocrinol 2015;31(5):384-7 [PubMed]