Progestogen should be added to estrogen therapy (ET) in all postmenopausal women with an intact uterus to prevent the elevated risk of estrogen-induced endometrial hyperplasia and adenocarcinoma. All U.S. Food and Drug Administration (FDA)-approved progestogen formulations will provide endometrial protection if the dose and duration are adequate. Evidence is lacking to recommend topical progesterone preparations for preventing estrogen-induced endometrial hyperplasia.
EPT Regimens
The clinical goal of estrogen plus progestogen therapy (EPT) regimens is to provide uterine protection, maintain estrogen benefits, and minimize side effects (particularly uterine bleeding, which is annoying to many women and often reduces compliance), although there is no consensus on how to accomplish this goal. Regimens may be classified into the following types: cyclic, cyclic-combined, continuous-cyclic, continuous long-cycle, continuous-combined, and intermittent-combined (refer to Table 4 in the original guideline document for details on the definitions of EPT regimens).
Standard EPT regimens provide adequate endometrial protection. There is less long-term experience with intermittent-combined and continuous long-cycle regimens, and more study is required to fully ascertain efficacy and safety. Some cyclic regimens may be less effective than continuous regimens in inhibiting the development of uterine cancer. With cyclic and continuous-cyclic regimens, withdrawal uterine bleeding occurs in about 80% of women when progestogen is stopped, although many women on continuous-cyclic regimens become amenorrheic within 12 months. Continuous-combined regimens avoid withdrawal bleeding, but breakthrough uterine bleeding occurs in nearly 40% of women during the first 6 months. Nearly 90% of women on this regimen become amenorrheic within 12 months. Persistent breakthrough bleeding with continuous-combined EPT may necessitate switching to another regimen. Pulsed regimens have 1-year amenorrhea rates of nearly 80%. Some women using a cyclic ET regimen experience hot flashes during the estrogen-free period; regimens with continuous estrogen administration usually avoid hot flashes.
Effects on other Organ Systems
Cardiovascular System
Because of clinical trials (primarily the Women’s Health Initiative [WHI] and the Heart and Estrogen/Progestin Replacement Study [HERS]) reporting significantly increased risks with EPT, The North American Menopause Society (NAMS) recommends not initiating any ET or EPT regimen for the primary or secondary prevention of coronary heart disease (CHD), although the effect of ET on CHD is not yet clear. However, observational studies have shown that ET has beneficial effects on atherosclerosis, vasodilation, plasma lipids, arterial response to injury, and insulin sensitivity. Although adding some progestogens may diminish these beneficial effects, in general, they do not eliminate them. Selecting a metabolically neutral progestogen for EPT, such as micronized progesterone or norgestimate, is recommended to maintain higher plasma high-density lipoprotein cholesterol (HDL-C). In animal studies, progestins with a higher androgenic potency reduce more of the beneficial effects of estrogens on vasodilation; progesterone and 19-norpregnane derivatives have less of an adverse effect. For women with diabetes mellitus (DM) who are using EPT to treat acute menopausal symptoms, continuous-cyclic EPT regimens are recommended to minimize progestogen exposure; low-dose oral micronized progesterone is also recommended.
Skeleton
Although adding 2.5 mg medroxyprogesterone acetate (MPA) or 1 mg norethindrone acetate (NETA) to ET slightly enhances estrogen’s ability to prevent bone mineral density (BMD) loss in early postmenopausal women, estrogen alone is adequate to maintain BMD. EPT reduces spine and hip fractures, but the role of progestogen in this effect is not known. The decision to add progestogen to ET should not be based on its skeletal impact.
Breast
Breast cancer risk is not decreased when progestogen is added to hormone therapy, and emerging data suggest that there may be an increased risk with standard doses. However, the overall risk (approximately 30% increase) does not seem to affect mortality. Mammographic density is increased with progestogen use, although this effect will reverse with discontinuation of use. Breast discomfort and pain may increase with progestogen use.
Central Nervous System
Negative effects on mood can occur when progestogen is added to hormone therapy. Data are inadequate to recommend specific progestogens or EPT regimens for minimal adverse effects.
Therapeutic Management
The clinical goal of progestogen therapy when added to ET is to provide endometrial protection while minimizing unwanted side effects. As with any pharmaceutical agent, therapy should be tailored to a woman’s individual needs. The only menopause-related indication for chronic progestogen use seems to be endometrial protection from unopposed estrogen therapy. NAMS recommends that clinicians prescribe adequate progestogen for all postmenopausal women with an intact uterus who are using ET; postmenopausal women without a uterus should not be prescribed a progestogen.
Studies have better defined the necessary dose and duration of the progestogen course to oppose the estrogen-induced risk of endometrial hyperplasia and adenocarcinoma. All of the FDA-approved progestogen formulations will provide endometrial protection if the dose and duration are adequate (refer to Table 5 of the original guideline document for the minimum progestogen dosing requirements for endometrial protection with standard estrogen dosing). Larger or smaller estrogen doses may require larger or smaller progestogen doses, respectively. However, the risk for endometrial cancer is never eliminated in women with a uterus, as women not using hormones can develop this disease. Long-term surveillance is necessary, even in women receiving appropriate doses of progestogen. Because of concern that adding progestogen may increase breast cancer risk and may attenuate some benefits of ET, the lowest appropriate dose of progestogen should be used. Use of EPT should be limited to the shortest duration consistent with treatment goals, benefits, and risks for the individual woman.
Side Effects
While using EPT, some women may experience uterine bleeding for months or years. Bleeding may be partially due to anatomic conditions (e.g., polyps, fibroids). If bleeding on continuous-combined or pulsed EPT persists beyond 6 months, endometrial cancer must be ruled out through tissue evaluation and/or hysteroscopy. Endometrial thickness measured by ultrasonography does not always correlate with histology of the endometrium obtained from a biopsy, although an endometrial thickness of less than 4 mm on vaginal ultrasound can be reassuring if endometrial biopsy cannot be performed.
In general, the side effects of adding progestogen to estrogen therapy are mild, although they may be severe in a small percentage of women. By tailoring progestogen type, dosage, or rate of administration, or the EPT regimen, most women who require therapy can obtain benefits with minimal side effects.
Hormone-related headaches may be lessened or eliminated by reducing estrogen fluctuation (e.g., switching from a cyclic to a continuous-combined regimen or switching from an oral to a transdermal product). In women whose headaches are exacerbated by progestogen, a better choice may be progesterone or a 19-norpregnane.
Low doses of transdermal, vaginal, or intrauterine progestogen formulations may have metabolic advantages over higher doses or oral progestogens, especially progestins derived from 19-nortestosterone. If oral therapy is preferred, the 19-norpregnanes seem to be free from metabolic side effects.
During initial progestogen therapy (particularly with oral micronized progesterone), bedtime dosing is advised to avoid the dizziness and/or drowsiness that some women experience.
Summary
The primary role of progestogen in hormone therapy is to protect the endometrium from hyperplasia and adenocarcinoma associated with unopposed estrogen therapy (ET). Adding the appropriate dose and duration of progestogen (either as progestin or progesterone) to ET has been shown to lower that risk to the level found in never-users of ET. The clinical goal of progestogen in hormone therapy is to provide endometrial protection while maintaining estrogen benefits and minimizing progestogen-induced side effects, particularly uterine bleeding. All FDA-approved progestogen formulations will provide endometrial protection if the dose and duration are adequate. There are not enough data to recommend topical progesterone for this use.
A wide variety of progestogen types, routes of administration, and dosage regimens are available, each having distinct side effects, as well as different actions on the endometrium and other organ systems. Some progestogens may diminish the beneficial effects of ET on coronary heart disease and may negatively affect mood. Data on the association between progestogen use and an increased risk of breast cancer are inconsistent and controversial, but it is clear that adding progestogen to ET does not decrease breast cancer risk. Progestogen has limited effect on the bone-enhancing action of ET.
Uterine bleeding is the primary adverse effect associated with EPT. Higher rates of EPT discontinuance correlate with more uterine bleeding, and women with more days of amenorrhea have higher rates of continuance. In general, the other side effects of added progestogen are mild, although they may be severe in a small percentage of women.
There is no consensus on the preferred regimen; however, by changing the progestogen type, route, or regimen, clinicians can help minimize any attenuation of estrogen’s benefits, decrease side effects, and lessen uterine bleeding while providing adequate endometrial protection.
