What is the efficacy of high-dose versus and low-dose estrogen therapy?

Updated: Oct 16, 2018
  • Author: Janice L Bacon, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Data also indicate that low-dose preparations are effective in reducing the severity and number of hot flashes compared with commonly prescribed doses, though a dose-response relationship may be observed (see the image below). [23] Low-dose estrogen is often considered to be 0.3mg or less of conjugated estrogen, 0.5mg or less of oral micronized estradiol, 2.5μg or less of ethinyl estradiol, or 25μg or less of transdermal estradiol.

Mean daily number of hot flashes by week for vario Mean daily number of hot flashes by week for various doses of conjugated estrogen (CEE) alone or combined with medroxyprogesterone acetate (MPA). (Utian, 2001) A) Placebo and CEE groups; B) Placebo and CEE-MPA groups. Difference vs placebo was significant from weeks *2-12 or †3-12. ‡Difference between CEE 0.45mg/day and CEE 0.45mg/day7 with MPA 2.5mg/day was significant at weeks 3, 4, 5, and 9. §Difference between CEE 0.625 vs 0.45mg/day was significant from weeks 2-12. llDifference between CEE 0.625 and 0.3mg/day was significant at weeks 4, 5, 6, 9, 10, and 12.

Differences in symptom response between high- and low-dose preparations tend to be greatest at 4 weeks after the start of hormone therapy and are reduced after 8-12 weeks. Low-dose preparations are desirable because they may be safer than high-dose forms in terms of cardiovascular disease (CVD), venous thromboembolism, stroke, and breast cancer. In addition, they also decrease unacceptable adverse effects, such as irregular bleeding and breast tenderness.

Women who are starting low-dose estrogen therapy should be counseled that it may take 8-12 weeks for their vasomotor symptoms to be relieved. [24, 25] If a low-dose estrogen is selected, a low dose of progestogen can also be prescribed. However, low doses of oral medroxyprogesterone acetate (ie, 1.5mg/day), when combined with low doses of oral conjugated estrogen (0.30-0.45mg/day), provide adequate endometrial protection. [26] Likewise, a low dose of norethisterone acetate (0.125mg/day), when combined with estradiol (0.025mg/day) in a transdermal preparation, also provides endometrial protection. [27]

Furthermore, if low-dose estrogens are used with cyclic progestogen regimens, intervals between progestogen use can be lengthened without significantly compromising endometrial protection. Examples of this approach include using medroxyprogesterone acetate 10mg/day for 14 days every 3 months [24] or every 6 months. [28]

The combination product of bazedoxifene, a SERM, with a small dose of conjugated estrogens (CEs) was approved by the FDA in October 2013. Combining a SERM with a low dose of CEE lowers the risk of uterine hyperplasia... This combination significantly reduced the number and severity of hot flashes at weeks 4 and 12 (P < 0.001). At week 12, bazedoxifene/CEE reduced hot flashes from baseline by 74% (10.3 hot flashes [baseline] vs 2.8) compared with 51% (10.5 vs 5.4) for placebo. [29] Bazedoxifene/CE is FDA-approved for prevention of osteoporosis and treatment of vasomotor symptoms in postmenopausal women.

The North American Menopause Society (NAMS) and The Endocrine Society (ES) suggest a “shared decision-making approach” to decide on the appropriate hormonal dose, route of administration, and to discuss each individual’s risks, treatment goals, and duration of therapy. [112, 113] This updates the concept of “the smallest dose for the shortest length of time” as that may provide insufficient care or even be harmful to some women if HT is curtailed prematurely.

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