Estrogens: Using Lower Doses and Alternative Delivery Systems

In light of the Women’s Health Initiative results, many physicians are re-evaluating the need and indications for menopausal hormone therapy. One option is to give reduced doses, and a second option is to consider alternative routes of delivery for hormones.

At a session held during the Annual Meeting of the ASRM, a panel of experts explored these options.

This program was supported by an unrestricted educational grant from Solvay Pharmaceuticals, Inc.

Recommendations for Hormone Therapy by National Organizations and their Implications for the Practitioner

David F. Archer, MD, Profes-sor, Department of Obstetrics and Gynecology, and Director, CONRAD Clinical Research Center, Eastern Virginia Medical School, Norfolk, began his presentation by discussing results from the estrogen/progestin arm of the Women’s Health Initiative (WHI) study.

He emphasized that the increased incidence of breast cancer among estrogen/progestin recipients was small and took three or four years to appear. According to the 2003 updated analysis of the data, the hazard ratio for invasive breast cancer was 1.24 (1.01-1.54). (Chlebowski RT et al. JAMA 2003;289: 3243-3253).

Shortly after these data were published, the Million Women Study from the United Kingdom reported that women taking estrogen or estrogen plus progestin had an increased incidence of breast cancer (Lancet. 2003;362:419-427). However, the study also found that women who had taken hormone therapy (HT) and then stopped had no increased risk of breast cancer, regardless of when they stopped the hormones.

“This is a justification for arguing that HT is not an inducer of neoplasia, but rather is a growth factor that reverts to a lower level of stimulation or growth of the existing neoplasm when the medication is discontinued,” said Dr. Archer.

Dr. Archer next presented the updated 2003 analysis from the WHI study on coronary heart disease (CHD), conducted by Manson et al., which found that there was an increase in CHD events in the first year, which leveled off thereafter (N Engl J Med. 2003;349:523-534). The overall hazard ratio for CHD among estrogen/progestin recipients was 1.24, which was not statistically significant. The hazard ratio for CHD when broken down by year was 1.81 in the first year, followed by a decline down to 0.70 after six years.

This raises a possible counter argument to the WHI study, according to Dr. Archer. “If we were to evaluate younger women, prior to the development of atherosclerosis, and give them estrogen or estrogen/progestin, there may be a preventive health advantage by retarding development of atherosclerotic plaque,” he said.

The updated analysis of WHI stroke data was conducted by Wassertheil-Smoller and associates, who found an increased occurrence of stroke in women taking estrogen/progestin, which began after about two years and increased each year over placebo (JAMA. 2003; 289:2673-2684). The hazard ratio for ischemic stroke was 1.44, which was statistically significant, and for hemorrhagic stroke it was 0.82, which was not statistically significant.

Another update of the WHI data looked at probable dementia and mild cognitive impairment (MCI) in women, all of whom were over age 65 when they were enrolled in the study (Shumaker et al. JAMA. 2003;289:2651-2662). After two years of estrogen/progestin use, the hazard ratio for probable dementia was 2.05 and for MCI it was 1.07. The data for probable dementia broken down by five year age bands was only significant in the participants who were over age 75.

Dr. Archer next discussed recommendations for use of postmenopausal HT from the North American Menopause Society (NAMS), the American Association of Clinical Endocrinologists (AACE), the American College of Obstetrics and Gynecology (ACOG), and the American Society of Reproductive Medicine (ASRM). Each organization emphasizes the need to individualize therapy based on the patient’s risk/benefit profile.

NAMS recommends HT for relief of menopausal symptoms, given for the shortest possible duration of therapy, with the consideration of lower than standard doses. They suggest local estrogen for vulvar and vaginal atrophy in some cases. HT for osteoporosis prevention should be used only after weighing the risks and benefits versus alternative therapies.

According to NAMS, estrogen plus progestin therapy is not indicated for primary or secondary prevention of CHD or to prevent dementia in women over age 65. Breast cancer risk is increased with estrogen and to a greater extent with estrogen plus progestin use beyond five years.

NAMS also states that the absolute risks and benefits are small and that extended use of HT is acceptable for symptom relief when benefits outweigh the risks, for women with moderate-to-severe menopausal symptoms or in women with high risk for osteoporotic fractures, and for prevention of osteoporosis in high-risk women when alternative therapies are not appropriate.

The position of the AACE is that the “WHI results are limited to the type of preparation used and the study population (i.e., women who are older, more likely to have CHD, and less symptomatic).” Menopausal needs should be individualized.

ASRM recommends use of HT for symptomatic women after carefully discussing risks and benefits and weighing the alternatives. At the patient’s annual visit, her current medical status and reason for HT should be used to decide on continuation of HT.

Use of Progestins and their Effects

James A. Simon, MD, Clinical Professor of Obstetrics and Gynecology, George Washington University School of Medicine, Washington, DC, discussed the impact of progestogens on breast cancer, osteoporosis, and senile dementia.

“In an attempt to put the WHI breast cancer data into perspective, I want to emphasize that relatively few women use hormone therapy for prolonged periods of time, and most studies show that fewer than 10% of women who start hormone therapy take it longer than five years,” said Dr. Simon. He also stressed that breast cancer risk with HT isn’t new information; past epidemiologic data demonstrated that long-term use of HT slightly increased the risk of breast cancer. The primary difference with the WHI is that it was a randomized, placebo-controlled trial.

He also pointed out that other factors, besides HT, can increase a woman’s risk for breast cancer. For example, delaying childbearing, drinking alcohol, and obesity are independent risk factors.

He also noted that over 12,000 of the 16,608 women in the WHI had no prior use of HT, and among this group there was no increase in breast cancer even with 5.2 years of use. “Women who had used hormones prior to entering the WHI drove the statistical significance of the overall study findings toward an association of breast cancer with hormone therapy,” he said.

The Million Women Study found a statistically significant increase in breast cancer with estrogen alone and an even greater increase with estrogen plus progestogen (Lancet 2003;362:419-427). However, discontinuation of hormones led to a reduction of relative risk back to baseline. “Current users had greater risk than prior users,” said Dr. Simon.

The added risk from progestin included all the types mentioned in the study: medroxyprogesterone acetate, norethisterone (norethindrone in the U.S.), and progestins in the norgestrel and levonorgestrel group. “Conspicu-ously absent were data on micronized progesterone, used commonly around the world, but not included in this study,” said Dr. Simon. “The findings were similar for sequential and continuous combination therapy, with a suggestion that long-term use of continuous combined therapy may have more risk, although this comparison was not very robust,” he added.

Effects of HT on Osteoporosis
On the topic of HT for osteoporosis prevention, Dr. Simon reviewed results of the Postmenopausal Estrogen/ Progestin Interventions (PEPI) trial, in which postmenopausal women were randomized to receive CEE, CEE plus MPA (continuous), CEE plus MPA (cyclic), CEE plus micronized progesterone (cyclic), or placebo. (JAMA 1996;276: 1389-1396).

In all active treatment groups, there was an improvement in bone mineral density (BMD) of about 4% to 5% from baseline, and there was a loss in BMD of 2% to 3% in the placebo group.

The Women’s HOPE Study, a two-year randomized, placebo-controlled trial, examined whether lower doses of CEE (0.45 and 0.3 mg compared to 0.625 mg) would also prevent loss of BMD (Utian WH, et al. Fertil Steril. 2001;75:1065-1079).

“All doses of CEE plus MPA significantly improved BMD relative to placebo and baseline,” said Dr. Simon.

One of the positive findings from the WHI study was the reduction in hip fractures among women taking estrogen/progestin. Dr. Simon found this finding “amazing,” because the women in the study were not in the high risk category for hip fractures and yet they had a statistically significant reduction in this fracture. The average age was 63 at baseline (young for hip fractures); they were at low risk of falling; and 70% of them were overweight (a negative risk factor for osteoporosis).

HT and Cognitive Decline
“It has been shown that women with the highest levels of bioavailable estradiol as they age have the lowest risks of cognitive decline,” Dr. Simon continued. And yet, the Women’s Health Initiative Memory Study (WHIMS) found an increase in dementia among women taking estrogen/progestin vs. placebo, but no change in mild cognitive impairment (JAMA 2003;289:2651-2662). In contrast, Dr. Simon cited data from the Cache County Study, an epidemiologic study, which found that women who used hormones in the past had a reduction in Alzheimer’s disease (JAMA. 2002;288:2123-2129).

In conclusion, Dr. Simon stated that “progestins appear to increase the risk for breast cancer to a greater extent than estrogen alone. Whether the increase is due to promotion of existing disease or induction of new lesions remains to be determined. HT reduces the risk of osteoporotic fractures, and adding some but not all progestogens appears to increase BMD to a greater extent than estrogen alone. Contrary to epidemiologic data, the WHI found that HT increases the incidence of Alzheimer’s disease and other forms of dementia.”

Vivian Lewis, MD, Director, Strong Fertility and Reproductive Science Center, University of Rochester Medical Center, New York, discussed lower doses of HT for menopausal symptoms and different modes of delivery.

According to a study by Maartens et al., 50% to 80% of women in the transition period between perimenopause and postmenopause experience vasomotor symptoms (Fam Pract. 2001;18: 189-194). “These are effectively treated with HT,” said Dr. Lewis.

The Women’s HOPE Study compared women on conventional doses of CEE (0.625 mg) with or without MPA to women receiving 0.3 mg or 0.45 mg CEE with or without a lower dose of MPA (Fertil Steril. 2001;75:1065-1079).

“All of the doses of estrogen effectively reduced vasomotor symptoms in the severely symptomatic group, from an average of 10 hot flashes a day to
one to four a day,” said Dr. Lewis. “The addition of progestins, regardless of the dose, seemed to potentiate that effect,” she added.

Lower doses of other types of estrogen are also effective for treatment of menopausal symptoms. Dr. Lewis cited studies showing that 0.3 mg of esterified estrogens reduced vasomotor symptoms and sleep problems (Climacteric. 2000; 3:176-182), as did oral micronized 17-beta estradiol (Obstet Gynecol. 2000; 95:726-731). She noted that transdermal 17-beta estradiol has also been shown to be effective at lower doses, citing a study comparing 100 mcg to 25 mcg, both of which reduced the percent of patients experiencing moderate-to-severe hot flashes (Am J Obstet Gynecol. 1999;181:71-79).

Another common symptom of women in the menopause is vaginal dryness, which can cause itchiness, pain with intercourse, and sometimes frequent UTIs. A longitudinal study by Denner-stein and colleagues found that about half of all women complained of vaginal dryness three years after their last menstrual period (Obstet Gynecol. 2000;96: 351-358).

Vaginal dryness can be assessed clinically with a physical examination by checking vaginal pH, looking for signs of mucosal thinning, and using the vaginal maturation index—a tool in which the ratio of parabasal cells is compared to superficial cells on a smear from the lateral fornix of the vagina.

The Women’s HOPE Study used the vaginal maturation index to assess vaginal atrophy and found that all doses of CEE, with or without MPA, had a positive effect on the index.

“It isn’t necessary to give hormone therapy systemically to see an effect on vaginal atrophy,” said Dr. Lewis. She described a study by Nilsson et al. using low-dose 17 beta-estradiol vaginal tablets at 10 mcg or 25 mcg, which showed an improvement in the maturation index and in symptoms (Maturitas. 1992;15: 121-127). In another study, women were treated with either conjugated estrogen cream or 17 beta-estradiol tablets. Both forms improved symptoms of vaginal atrophy, but 2.5% of women treated with the cream had endometrial hyperplasia, whereas none of those treated with the tablets did.

“When using the cream, patients may have a little more latitude than you would like in terms of delivering an accurate dose,” said Dr. Lewis.

A slow release ring is also available that delivers a very low dose of 17 beta-estradiol, which is effective for vaginal atrophy. In a study by Pinkerton, women with vaginal atrophy who were taking raloxifene (a selective estrogen receptor modulator) still had effective relief of vaginal symptoms and improvement in maturation value, vaginal pH, mucosal thinning, and dryness with concomitant use of the vaginal ring. (Menopause. 2003;10:45-52).

“Low dose systemic HT can relieve signs and symptoms of vulvovaginal atrophy,” said Dr. Lewis. Vaginal administration of estrogen allows further lowering of the dose, even if the patient is taking a SERM.

Sexuality and hormones
“Sexual functioning is a complex matter, and the extent to which it is influenced by hormones is yet to be determined,” continued Dr. Lewis. Factors that can influence it include the nature of intimate relationships, sexual attitudes, health of the partners, medications, and libido.

Nonetheless, she reviewed evidence that estrogen and androgen replacement can influence sexuality. The Melbourne Women’s Mid-Life Health Project used a sexual dysfunction scale to evaluate over 200 women in their 40s and 50s, and found sexual dysfunction was present in 42% of women in early menopause, rising to 88% in postmenopausal women (Fertil Steril. 2002; 77:S42-S48). “They found no effect on sexual functioning of total or free testosterone or DHEAS,” said Dr. Lewis. However, they did find an effect of estradiol on sexual responsivity and libido.

In contrast, several studies have suggested a role for androgen replacement therapy in improving sexual function. “The major problem with these studies is they often deliver supraphysiologic amounts of testosterone,” said Dr. Lewis.

An advantage of using methyltestosterone for androgen replacement is the ability to give it orally, she said, adding that three studies using methyltestosterone doses of 1.25 to 5 mg have all showed some benefit.

The testosterone patch, currently only available in doses suitable for men, is being studied in women. In one study, 75 surgically menopausal women were pretreated with CEE (0.625 mg) daily and then received one of two doses of the testosterone patch. Only the high dose showed efficacy for improving sexual function (N Engl J Med. 2000;343: 682).

“It’s important to replace estrogen, especially if the patient has menopausal symptoms and vulvovaginal atrophy,” said Dr. Lewis, adding that “the androgens have the potential to be helpful, but their role is less clear.”

Dr. Lewis continued with a discussion of safety issues of HT. “As people are looking to use HT for short periods of time, there is growing interest in using unopposed estrogens,” she said. To counter the possible objection regarding the association of unopposed estrogen with endometrial hyperplasia and cancer, she explained that “the incidence of hyperplasia is dose related and selected patients may not have an increased risk with short-term use.”

“When treating patients with unopposed estrogen, monitor the endometrium and do an individualized risk assessment,” she said. In addition, various types of progestogen are effective at preventing endometrial hyperplasia, including norethindrone acetate, medroxyprogesterone acetate (both continuous and cyclic), and micronized progesterone.

The other safety issue Dr. Lewis discussed was risk for venous thromboembolic disease. All of the adverse effects reported with HT have been with oral forms. At least one study has suggested that the risk for thromboembolic disease is due to a first pass effect (Lancet. 2003;362:428-432). In this case-controlled study, women using estrogen via the transdermal patch had the same risk for venous thromboembolism as non-hormone-users, while women taking oral estrogen replacement therapy had a three- to four-fold increased risk.

Therefore, delivery forms other than oral, such as transdermal patches, rings, and new formulations as gels, may be safer.

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