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0.625 mg/g; 7-2 g daily x 2 wk, then 7 g daily 7-3 x wk

0.7 mg/g; 2-4 g daily x 2 wk, then 7 g daily 7-3 x wk

0.07 mg/g; 7-2 app qd x 2 wk, then taper to 7-2 x wk

0.025 mg daily x 2 weeks, attempt to discontinue over 3 to 6 mos

0.075 mg/d ring; insert ring vaginally every 90 days

0.05 mg, 0.7 mg/d ring; insert vaginally every 90 days

Reprinted with permission from: Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems: A comparative review. Am J Drug Deliv 2005; 3:7-7 6.


Brand Name

Conjugated equine

Premarin cream

Estrogen cream

Estradiol cream

Estrace cream

Dienestrol cream


Estradiol tablets

Vagifem tablets

Estradiol ring



given neurontin have fewer hot flashes than those given placebo. Low dose progestins are effective in the treatment of menopausal symptoms to a moderate degree, but still a form of hormonal therapy and may be a source of concern in patients with a history of breast cancer. Two antihypertensives, clonidine and methyldopa, have been used to treat vasomotor symptoms, suggesting a role for adrenoreceptors in the physiology of these symptoms. Low dose clonidine, is partially effective in the relief of hot flashes, but for many women, adequate therapy requires substantial doses and severe side effects. Methyldopa, at doses of 500 to 1000 mg/d, has been shown to be twice as effective as placebo for the treatment of hot flashes. Veralipride is a dopam-ine antagonist that has been shown to be active in the hypothalamus, effectively inhibiting flushing at a dose of 100 mg/day. However, it is associated with major side effects such as galactorrhea and mastodynia. Bellergal is a combination of belladonna alkaloids, ergotamine tartrate, and phenobarbital that has been proven to be slightly better than placebo in the treatment of hot flashes, but with significant sedating effects.

Alternative Medicine

This approach includes dietary supplements, which are not considered to be drugs by the Food and Drug Administration (FDA) and therefore are not subject to the strict regulation and safety guidelines imposed on conventional medications. As a result, significant variation can occur in the content and potency of each batch of supplement. Phytoestrogens are plant-derived compounds with estrogen effects soybeans are a particularly rich source of phytoestrogens with approximately 1 to 3 mg of phytoestrogen per gram of soy protein. Since it would be very difficult to consume sufficient soy to alleviate menopausal symptoms in a typical Western diet, some patients opt to take soy supplements. Some (but not all) studies have suggested that isoflavones in soy products reduce the frequency and severity of hot

Table 11.4. WHI absolute risks/benefits*



Heart disease



Invasive breast CA







+ 18


Osteoporotic fracture



Colon CA



*Number of events per 10,000 women/yr compared to placebo.

*Number of events per 10,000 women/yr compared to placebo.

flashes, favorably effect lipid profiles and increase bone mineral density (BMD). Black cohosh or remifemin is another popular herbal medication that has been used to treat menopausal symptoms. Clinical trials show that it is superior to placebo for relief of hot flashes and short term safety data are reassuring. However, many of the efficacy studies are open label and there are no long term safety studies, particularly with respect to effects on breast and endometrium. Finally, vitamin E at a dose of 800 IU daily has been shown to be only slightly more effective than placebo in the treatment of menopausal symptoms. Further study is needed in this area to determine whether there is a definitive benefit from these forms of therapy.


With declining estrogen levels, vaginal pH rises from acidic to basic levels, resulting in the decline of the previously predominant lactobacilli and a newly hospitable environment to previously atypical bacteria colonizing the vagina, most significantly enterobacteria. This is thought to result in an increased risk of urinary tract infections. There are also marked atrophic changes of the urethra, resulting in dysuria and frequency. Atrophy of the vulva and vagina can also be seen in the menopause. Genital symptoms include: decreased lubrication, burning, itching, discharge, dyspareunia, and sexual dysfunction. Urinary symptoms include frequency, dysuria, hematuria, and incontinence. Numerous studies have demonstrated the effectiveness of local, oral, or transdermal estrogen for treating symptoms of vulvar and vaginal atrophy. A review of the literature shows conflicting results regarding the role of estrogen therapy in treating urinary incontinence, including a meta-analysis that concluded that estrogen has only a small effect, if any, on urinary incontinence.

Local Therapy (Vaginal or Topical Administration)

Estrogen creams, estrogen tablets and the estrogen ring are options for localized hormonal therapy, which can allow administration of a lower dose of estrogen, avoiding systemic effects. The low dose estradiol vaginal ring (Estring) is placed in the vagina delivering estrogen associated with no detectable changes in blood estradiol or estrone levels. These alternative methods of localized estrogen therapy offer important alternatives for those women who cannot or choose not to receive oral or transdermal therapy. Localized estrogen therapy primarily addresses symptoms related to vaginal atrophy.


Osteoporosis is defined pathologically as an absolute decrease in the amount of bone, resulting in an increased risk of fracture with minimal trauma. It is a major long-term health risk associated with the loss of estrogen from the menopause. Hip fracture incidence appears to be race dependent, with a lifetime risk of hip fracture of 17.5% in white women, but only of 5.6% in African American women. However, although hip fractures are much less common in nonwhites, they remain a significant problem for all elderly women and men, regardless of race. By extreme old age, one of every three women and one of every six men will have a hip fracture. Of all hip fractures 12 to 20% will be fatal and 50% of survivors will require long-term nursing care, resulting in total annual costs of 6.1 billion dollars in the United States.


The pathophysiology of osteoporosis is based on a disruption of the bone remodeling unit coupling process, which involves osteoclasts, the bone resorbing cells, and osteoblasts, the bone forming cells. In adults 25% of trabecular bone (i.e., vertebrae, forearm) and 3% of cortical bone (i.e., hip) is absorbed and replaced each year. Osteoporosis occurs when bone resorption by osteoclasts is greater than bone formation by osteoblasts. Loss of estrogen in the early menopause can be associated with a significant reduction in bone during the first 5-8 years of the menopause (trabecular, 5%/yr; cortical, 1-2%/yr),

Bone loss in the early postmenopausal period is associated with increased osteo-clast activity with normal osteoblast activity, which primarily affects trabecular bone. In contrast, the later menopausal period is associated with normal osteoclast activity in the face of decreased osteoblast activity, primarily affecting cortical bone. Consistent with these differences, bone loss associated with early menopause occurs primarily in trabecular bone (i.e., vertebral and distal forearm), while the slow progressive bone loss consistent with aging occurs primarily in cortical bone (i.e., hip).

Risk Factors and Diagnosis

Some of the risk factors for osteoporosis include low estrogen, low bone density, trauma, inadequate peak bone mass, family history, low body weight, inactivity, excessive glucocorticoid use or Cushing's syndrome, osteomalacia, long term hep-arin therapy, multiple myeloma, long-term anticonvulsant use, hyperthyroidism, hepatobiliary disease, excessive caffeine intake, smoking, heavy alcohol use and type I diabetes mellitus.

Osteoporosis is generally diagnosed on the basis of low bone mineral density or clinical evidence of bone fragility in a patient who has no other reason for low bone mass (e.g., osteomalacia, myeloma, etc.). Bone mineral density (BMD) is usually measured by dual-energy X-ray absorptiometry (DEXA) which utilizes transmission of two energy beams passed through bone and then compared to a standardized control. Using DEXA, osteoporosis is defined as a BMD greater than 2.5 SD below the mean value of peak bone mass in young normal women (T score of <-2.5). Osteopenia, or low bone mass, is defined as T score between -1 and -2.5. A normal bone mass is defined as T score -1 or higher. DEXA should be performed in all postmenopausal women >60-65 y/o, those 50-60 y/o with one or more risk factors for osteoporosis, and all postmenopausal women with fractures.

Biochemical markers of bone metabolism that reflect bone formation or breakdown may occasionally be useful in the clinical treatment of patients with osteoporosis. The three principle markers of bone formation are alkaline phosphatase, osteocalcin and procollagen I carboxy peptide, while the markers of bone resorption include: hydroxyproline, hydroxylysine glycosides, collagen crosslink molecules and N-telopeptide.

Prevention/Treatment of Osteoporosis Estrogen

Estrogen is useful prevention (i.e., maintaining BMD) or treatment of osteoporosis (reducing the fracture risk). Estrogens typically exert their positive effects on BMD by inhibiting osteoclast activity. Numerous observational and prospective studies have demonstrated the effectiveness of estrogen treatment in increasing BMD. The Women's Health Initiative (WHI) study also demonstrated efficacy for fracture reduction.

Recent data indicates that CEE doses of 0.45 mg/day are equally effective in maintenance of BMD, and that 0.3 mg of CEE has positive effects upon hip and spine BMD compared to placebo. This is also true of lower doses (45-50 |ig) of transdermal estradiol. The lower doses are also effective for treatment of hot flushes or vaginal maturation indices. However, it is important to note that fracture prevention data do not exist for these lower doses.

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs) are an attractive alternative to estrogen for the treatment of postmenopausal osteoporosis. Like estrogens, SERMs act by inhibiting osteoclast activity. Unlike estrogen, SERMs exert mixed effects in different tissues. SERMs have potent estrogen agonist effects in some tissues while exerting estrogen antagonist effects in others. Raloxifene and tamoxifen are two of the best known and most studied SERMs. Tamoxifen (an adjuvant for breast cancer treatment) has been shown to have estrogen agonistic effects on bone, lipid profiles, and endometrial tissue. Therefore, while tamoxifen use is associated with improved bone mass and cholesterol profiles, stimulation of the endometrium results in an increased risk of endometrial hyperplasia and cancer in postmenopausal women.

In contrast, raloxifene has a mixed agonist-antagonist profile that makes it particularly useful for the treatment of osteoporosis. Raloxifene has been shown to have solely estrogen antagonist effects in the breast and endometrium, but with estrogen agonist effects in bone and on lipid profiles, thus mitigating the risk for endometrial hyperplasia and breast cancer. In a prospective randomized, placebo controlled trial, raloxifene treatment significantly reduced the risk of vertebral fracture in patients with existing osteoporosis (RR = 0.5 and 0.7 with 60 mg/day and 120 mg/day, respectively). Interestingly, women treated with Raloxifene had a lower incidence of breast cancer during this study, but an increased risk of venous thromboembolism (VTE) was noted, which is similar to that seen with estrogen use. In women treated with 60 mg/day of Raloxifene, a marked decrease in total cholesterol levels and LDL was noted with a minimal reduction in HDL levels. Multiple studies have illustrated the antiestrogenic effects of raloxifene on endometrial tissue and its safety for use in postmenopausal women. Thus, SERMs appear useful for the treatment of osteoporosis without the increased risk of breast cancer or endometrial hyperplasia and cancer associated with estrogen replacement use.


Bisphosphonates are potent inhibitors of bone resorption that act by exerting a direct inhibitory effect on mature osteoclasts. Bisphosphonates such as alendronate, risedronate, and ibandronate, have a low bioavailability ranging from 1.5% to 3.5%. It is important to take these medications on an empty stomach with no other liquids than water and separate from calcium supplements, and remain upright for 30-60 minutes following administration.

Multiple clinical trials have demonstrated the utility of bisphosphonates in the prevention and treatment of osteoporosis utilizing a variety of treatment regimens. These data include fracture reduction risk at the hip and spine. Such regimens include daily, weekly, or more recently, monthly administration.

Further studies have explored dosing frequency by examining the benefits of once weekly bisphosphonate dosing, to examine potential improved tolerance without compromising efficacy. Overall, both the daily and weekly treatment regimens demonstrated significant increases in BMD, but with fewer serious upper GI adverse experiences among those patients receiving the weekly dosing regimen. Thus, bisphosphonates are an effective alternative treatment for osteoporosis for patients who do not require estrogen therapy.

Other Treatments

Calcitonin is another agent that can be used to prevent osteoporosis and also acts by inhibition of the resorptive activity of osteoclasts. Calcitonin can be given as an intranasal spray at a dose of 200 IU/day. However, there are no data regarding hip fracture prevention with this agent.

Sodium Fluoride has also been shown to increase bone density; however, increased fracture rate associated with increased skeletal fragility suggest that high dose fluoride would be a poor choice for the treatment of osteoporosis. In contrast, lower doses combined with calcium may be beneficial, as suggested in some studies.

Calcium is generally recommended in postmenopausal women with a dietary calcium intake of 1200-1500 mg/d in addition to more specific therapy. It is clear that calcium alone will not adequately prevent bone loss.

Cardiovascular Disease

Cardiovascular disease is the leading cause of death in women over the age of 50 in the United States. Before the age of menopause, cardiovascular disease occurs predominantly in males. However, after menopause, the rate of cardiovascular disease in women increases until it eventually equals that of men by age 70. Numerous observational studies have demonstrated an association between estrogen replacement therapy and low risk of cardiovascular disease. Estrogen replacement therapy has been shown to decrease total cholesterol, low-density lipoprotein, lipo-protein A, and increase high-density lipoprotein levels; which was assumed to be the explanation for this association. Recently, prospective randomized blinded studies like the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Health Initiative (WHI) failed to show any efficacy for either secondary prevention (HERS) or primary prevention (WHI) of coronary artery disease. Because of the prospective, blinded, randomized design of those two studies, they merit a separate discussion.

HERS Study and Secondary Prevention of Cardiovascular Disease

In contrast to the findings of multiple other cohort studies regarding secondary prevention, the findings of the HERS study challenged the concept of estrogen's efficacy for the secondary prevention of cardiovascular disease. In this prospective, randomized clinical trial, estrogen therapy did not change the rate of cardiovascular events among women with established coronary artery disease, despite favorable changes in the lipid profile. The daily use of combination hormone replacement therapy did not reduce the overall risk of nonfatal myocardial infarction or cardiovascular disease related-death. An increased incidence of deep venous thrombosis, pulmonary emboli, and gallbladder disease was noted among women treated with estrogen, consistent with prior observational studies. These results led the investigators to caution against starting women on estrogen therapy for secondary prevention of cardiovascular disease but to suggest its continuation only among women already receiving estrogen therapy.

WHI Study and Primary Prevention of Cardiovascular Disease

The Women's Health Initiative (WHI) trial was a large, placebo controlled randomized multicenter trial looking at the effects of hormone replacement therapy (HRT) or estrogen replacement therapy (ERT) versus placebo in menopausal women. In this study, HRT consisted of conjugated equine estrogens (CEE) 0.625 mg/d combined with medroxyprogesterone acetate (MPA) at a dose of 2.5 mg/d. One arm of the study looked at hysterectomized women on ERT vs. placebo (n = 10,739). Another part of the study compared nonhysterectomized women on HRT vs. placebo (n = 16,608). Study endpoints included MI (fatal and nonfatal, breast cancer, stroke, venous thromboembolic events (VTE), colorectal cancer and hip fracture. Patients in the HRT arm were followed for an average of 5.2 years while patients in the ERT arm were followed for an average of 6.8 years.

Although the goal of the WHI was to address the issue of primary prevention of coronary artery disease, it came to similar conclusions as the HERS study, which addressed secondary prevention. During the first year of use, the relative risk (RR) of cardiac events in users of combined estrogen/progesterone replacement was 1.52 (1.01-2.29). In the estrogen only arm (for women who have had a hysterectomy), there was no increased risk of cardiac events. The main criticism of WHI is that the population studied was an older population with a mean age of 63 years. Such an older population is very likely to have a high prevalence of preexisting subclinical cardiac disease. Table 11.4 lists absolute risk/benefits of both study arms (number of events per 10,000 women/yr compared to placebo). Based upon HERS and the WHI, hormone replacement therapy is no longer an accepted treatment for prevention of cardiovascular disease.

Alzheimer's Disease

Alzheimer's disease (AD) is a significant health problem for aging men and women in the United States. After age 65 the prevalence of Alzheimer's disease exponentially increases with age, with the number of affected persons doubling every five years and commonly affects women far more often than men. Multiple epidemio-logical studies have suggested a beneficial effect of estrogen on AD, while others have shown no benefit. In the WHI memory study (WHIMS), investigators found an increase in all-cause dementia in the HRT arm although this was not seen in the

ERT arm. AD was not addressed separately in this study, and the results are further limited by small numbers of cases. The women in this study were 65 years or older. Based on the current literature, estrogen probably does not slow or improve AD progression, and when HRT is given to older women it may increase the risk of dementia.

Risks of Homone Replacement

Estrogen Replacement Therapy and Breast Cancer

Breast cancer is a leading cause of death in American women 40 to 55 years old and currently, one in nine women will be diagnosed with breast cancer. Of all American women, 12.6% will be diagnosed with breast cancer in their lifetime and 3.5% of all women will die of this disease. Unfortunately, the peak incidence of breast cancer occurs among post-menopausal women, the same women for whom the choice of whether to take HRT becomes an issue, along with its apparent risks and benefits.

Until the results of the Women's Health Initiative trial were published in July of 2002, there was no clear consensus on the relationship of HRT to breast cancer incidence, although some studies showed a small increase with long-term use. The WHI trial showed that there was a statistically significant increase in breast cancer HRT arm (intact uterus) during the fifth year of use only (RR = 1.99, 1.18-3.35), bringing the relative risk among users of the combined estrogen/progesterone to 1.26 (1.00-1.63) over at least 6 years. Interestingly, patients in the estrogen-only arm did not show an increase in invasive breast cancer (RR 0.77{0.59-1.01}) but rather showed a trend toward a decrease in the incidence of invasive breast cancer although this did not achieve statistical significance.

Estrogen Replacement Therapy and Endometrial Cancer

Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer in women. Risk factors for the development of endometrial cancer have traditionally included obesity, nulliparity, and late menopause. Multiple studies have demonstrated a strong correlation between the use of unopposed estrogen and an increased incidence of endometrial cancer. The addition of a progestin induces endometrial regression and stabilization thereby preventing the development of endometrial hyperplasia and cancer. Therefore, the importance of prescribing a combination estrogen and progestin therapy in women with an intact uterus receiving hormone replacement therapy is clear.

Venous Thromboembolic Events

Venous thromboembolic events (VTEs) represent a broad category (including pulmonary embolus and deep venous thrombosis) of potentially life-threatening risks that are associated with ERT/HRT use. Based on prior observational studies, and the results of prospective trials such as HERS I, HERS II, and WHI, it appears that there is a 2-fold increase in the risk of VTE in users of ERT/HRT. Estrogens, particularly those given orally, stimulate hepatic production of clotting factors. Accordingly, some studies suggest that women taking transdermal estrogens are not at greater risk of VTEs. Nonetheless, the use of ERT/HRT would be contraindicated in patients with a prior history of VTEs.

Other Risks of HRT

Observational studies of the risk of stroke among users of HRT have yielded inconsistent results. The WHI study demonstrated an increased risk among combination HRT users as well as users of estrogen alone compared to placebo. A metaanalysis of randomized clinical trial found that oral estrogen use was primarily associated with increased risk of ischemic stroke rather than hemorrhagic stroke or transient ischemic attacks.

HRT appears to increase the risk of gallbladder disease in observational studies as well as randomized clinical trials. Estimates from the WHI suggests that the magnitude of the absolute risk translates into about 3 additional cases per 1000 women. Previous cholecystectomy is not a contraindication to HRT.


Colon Cancer

Colon cancer is the third leading cancer and cause of cancer death in women. Multiple studies (retrospective as well as observational cohort studies like the Nurses Health Study) have suggested an association between HRT and a decreased incidence of colon cancer and were confirmed by recent findings from the WHI. In the WHI trial, patients receiving HRT had a significantly lower incidence of colon cancer compared to placebo. However, there was no such reduction in the ERT arm.

Macular Degeneration

Macular degeneration (MD) is the leading cause of legal blindness in the United States, accounting for 25 to 60% of all new cases. The pathogenesis of MD is unknown and currently there is no effective medical therapy, with surgical photocoagulation being useful in only a limited number of patients. Multiple retrospective studies as well as data from the WHI has suggested that HRT may decrease the incidence of MD.


As postmenopausal women age, there is a linear decrease in skin collagen content of 2.1% and skin thickness of 1.13% per year from premenopausal levels during the initial 15 to 18 postmenopausal years. HRT prevents some of this collagen loss but is not currently an indication for long term estrogen use.

Benefits of Hormone Replacement

There is an increased prevalence of sexual dysfunction following the menopause. Causes include psychogenic, endocrinologic, vascular, neurogenic, muscular, medication-related and infection. Endocrinologic changes associated with loss of estrogen at the menopause include vulvo-vaginal atrophy and possibly decreased desire or arousal. The use of ERT or HRT can improve symptoms of sexual dysfunction by improving genital sensation, as well as decreasing pain and burning during intercourse. Some studies suggest that a combination of estrogen and testosterone may improve libido.

Key Points on HRT Use

In the past, HRT was prescribed for women for a multitude of potential health benefits. It was previously thought that HRT, in addition to its beneficial role in osteoporosis, could protect against cardiac disease, stroke, and Alzheimer's disease. The recent prospective, randomized, and blinded studies have challenged the validity of this. Based on current literature, HRT is indicated today only for the treatment of vasomotor symptoms and vaginal atrophy, and prevention/treatment of osteoporosis. HRT should be prescribed in the lowest effective dose for the shortest period of time. Therefore, bone-specific agents would likely be more appropriate in patients requiring long-term osteoporosis prevention/treatment. Ultimately, the decision regarding whether or not to take hormone replacement therapy is a personal one, to be decided by the patient herself with guidance from her physician.

Suggested Reading

1. Writing group for the women's health initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.

2. Shumaker SA, Legault C, Kuller L et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004; 291:2947-2958.

3. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280:605-613.

4. Anderson GL, Limacher M, Assaf AR et al.Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701-1712.

5. Draper MW. The role of selective estrogen receptor modulators (SERMs) in post-menopausal health. Ann N Y Acad Sci 2003; 997:373-377.

6. Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems: A comparative review. Am J Drug Deliv 2005; 3:7-16.

7. LeBlanc ES, Janowsky J, Chan BK et al. Hormone replacement therapy and cognition: Systematic review and met-analysis. JAMA 2001; 285:1489-1499.

8. Shumaker SA, Legault C, Kuller L et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004; 291:2947-2958.

9. Shumaker SA, Legault C, Rapp SR et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 2003; 289:2651-22662.

10. Lindsay R, Gallagher JC, Kleerekoper M. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002; 287:2668-2676.

11. Utian WH, Shoupe D, Bachmann G et al. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001; 75:1065-1075.

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