Postmenopausal hormone therapy had its beginning in the effort to alleviate specific symptoms associated with the decline in estrogen production at the menopause. There is little question that women who suffer from hot flushes or atrophy of reproductive tract tissues can be relieved of their problems by use of estrogens. However, in the last decade, the focus of postmenopausal hormone therapy has changed from short-term treatment to the preventive health care benefits associated with long-term treatment. It is almost certain that the long-term disabilities of osteoporosis can be largely prevented by therapy with estrogen and progestin. It is increasingly accepted that appropriate doses of estrogen have a beneficial impact on the risk of cardiovascular disease. The long-term impacts on urinary incontinence and cognition remain to be documented, but there is reason to believe there will be benefits in these areas.

The dose of estrogen that is effective in maintaining the axial and peripheral bone mass is equivalent to 0.625 mg of conjugated estrogens.^1,2 The relative potencies of commercially available estrogens are important when prescribing estrogen, and the clinician should be familiar with the potencies listed in Table 1.

TABLE 1 Relative Estrogen Potencies^3–6

The only comparative study of oral estriol concluded that 2 mg of oral estriol was as effective as 0.625 mg of conjugated estrogens in maintaining bone density, although there was no response in follicle-stimulating hormone (FSH) levels with estriol. Esterified estrogens are synthetically prepared from plant precursors and are composed mostly of sodium estrone sulfate with a 6% to 15% component of sodium equilin sulfate. Estradiol valerate is rapidly hydrolyzed to estradiol, and the pharmacology and effects therefore are comparable at similar dosages.⁷

Transdermal Administration

The patches first used for transdermal estrogen administration contained an alcohol reservoir; the estrogen was released through a semipermeable membrane attached to the skin with an adhesive. The current generation of patches has the hormones dissolved and distributed throughout the adhesive matrix. In a study of women who had previously discontinued patches because of skin irritation (contact dermatitis), skin reactions were less common with the newer matrix patches.⁸ The patches are designated according to the amount of estrogen delivered per day: 50 and 100 μg.

The effect of steroids on lipids and lipoproteins is determined by the type of steroid, the dose, and the route of administration. An obstacle to the use of transdermal hormone therapy has been the scarcity of data indicating a beneficial impact on the lipoprotein profile. There has been concern that delivery of estrogen through the skin yields a blood level that might be too low to provide protection against cardiovascular disease, especially because after peak concentrations in the first day after application, there is a progressive decrease that can be relatively rapid. Furthermore, there is marked variation in levels among individuals and within the same individual.

The concentration of estrogen in the portal system after oral administration is four to five times higher than that in the periphery.⁹ Furthermore, the estradiol-estrone ratio differs in the portal system. Thus, the first-pass effect is either significant for the lipoprotein effects, or it is important only in the short-term. For example, short-term studies (6 weeks) could document increased catabolism of low-density lipoprotein and increased production of apoprotein A-I with oral estrogen, but no effect with transdermal estrogen.^10,11 Furthermore, a 2-year study in Los Angeles with a transdermal dose (100 g) detected no significant change in high-density lipoprotein (HDL) cholesterol levels.¹² However, English data indicate that the transdermal administration of 50 g of estradiol twice a week is as effective as 0.625 mg of oral conjugated estrogens, when combined with a progestin in sequential regimens, on bone density and lipids over a duration of 3 years.¹³ Notice that 12% of the women on either the transdermal or oral regimen lost bone from the femoral neck despite documented adequate compliance. The transdermal administration of 100 g of estradiol combined with a progestin not only increases bone density, but also reduces the fracture rate in older women who already have significant osteoporosis.¹⁴

Estradiol Implants

Estradiol pellets are available in doses of 25, 50, and 75 mg for subcutaneous administration twice yearly. The 25-mg pellet provides blood levels in the range of 40 to 60 pg/mL (150 to 220 pmol/L), levels, which are comparable with those obtained with the standard oral dose.¹⁵ However, the effect is cumulative, and after several years the blood levels are two to three times higher. Significant blood levels of estradiol persist for up to 2 years after the last insertion. Progestational treatment is necessary, and because of the higher blood levels, a minimal duration of 14 days each month is advised. We believe that the estradiol pellets confer no advantages over the usual treatment regimens. We further recommend that women receiving pellets be monitored by obtaining blood estradiol levels; levels greater than 200 pg/mL (and, preferably, 100 pg/mL) should be avoided.

Percutaneous Estrogen

Estradiol delivery can be accomplished by applying a gel (estrogel) to the skin, usually over the abdomen or thighs. The preparation produces blood levels of estradiol of approximately 95 to 125 pg/mL (350 to 450 pmol/L), levels which are both higher and more variable than the standard oral regimens.¹⁶ As with pellets, we recommend that blood estradiol levels be monitored and maintained at a level below 100 to 200 pg/mL (370 to 740 pmol/L).

Monitoring the estradiol blood level in postmenopausal women receiving hormone therapy is not as straightforward as it seems. There are two primary difficulties. First, the clinical assays available differ considerably in their technique and quality (laboratory and antibody variations). Second, the various commercial products represent a diverse collection of estrogenic compounds, ranging from estradiol to unique equine estrogens. Although the body interconverts various estrogens into estrone and estradiol, is this process relatively consistent within and between individuals? For example, a highly specific assay for estradiol detects low levels of estradiol in women receiving 0.625 mg of conjugated equine estrogens; however, most clinical assays report a level of 40 to 100 pg/mL (150 to 370 pmol/L) in these women. We find measurement of blood estradiol levels to be useful in selected patients, such as the patient who requests ever-increasing doses of estrogen for the treatment of symptoms, which, in the presence of high blood levels of estradiol, can be diagnosed as psychosomatic. Each clinician must learn which blood level of estradiol, as performed by the local laboratory, is associated with the standard doses of hormone therapy (0.625 of conjugated estrogens, 1 mg of estradiol, 50 g of transdermal estradiol). This range usually is 40 to 100 pg/mL (150 to 370 pmol/L) estradiol. Remember that because FSH is regulated by a factor other than estrogen (i.e., inhibin), FSH levels cannot be used to monitor estrogen dosage. Postmenopausal hormone therapy produces only a 10% to 20% decrease in FSH and luteinizing hormone, and there is great individual variability in the responses.¹⁷

The most common sequential method in the United States involves estrogen administration with 0.625 mg of conjugated estrogens or 1.0 mg of micronized estradiol daily. A daily dose of 5 mg of medroxyprogesterone acetate (MPA) is added for 14 days of every month. One-year randomized trial data indicate that the 5-mg dose protects the endometrium as well as the 10-mg dose.¹⁸ Unfortunately, progestin withdrawal bleeding occurs in 80% to 90% of women on a sequential regimen.^19,20,21 The sequential regimen also can cause adverse symptoms related to the dose of progestin such as breast tenderness, bloating, fluid retention, and depression. Switching from MPA to norethindrone often relieves these complaints.

The Sequential Program

In the sequential regimen (Table 2), the amount of norethindrone equivalent to 10 mg of MPA is 1.0 mg.²² Norethindrone is available in a dose of 0.35 mg in the progestin-only minipill oral contraceptive. In a 3-year randomized trial, 200 mg of micronized progesterone given daily for 12 days each month effectively protected the endometrium against hyperplasia.²¹ The lowest effective dose of micronized progesterone and the proper dose for continuous daily administration are not established; however, a short-term (6-month) study indicates that 100 mg/day was effective.²³ Micronized progesterone is absorbed irregularly, metabolized rapidly, and peaks in blood levels of progesterone, and active metabolites are associated with sedation and other disturbing CNS reactions.

TABLE 2 Sequential Program For Postmenopausal Hormone Therapy

  Daily estrogen

  0.625 mg Conjugated estrogens, or
  1.25 mg Estrone sulfate, or
  1.0 mg Micronized estriadol

  5 mg Medroxyprogesterone acetate, or
  0.7 mg Norethindrone, or
  200 mg Micronized protesterone

  (400 IU in winter and 800 IU for women older than 70 years of age).

The Continuous Combination Program

The continuous/combined method of treatment evolved to improve patient continuance in the presence of bleeding and other symptoms. The continuous activity of progestin allows the use of lower doses that, by virtue of a daily availability, inhibit endometrial growth. This approach involves the continuous daily use of the estrogen-progestin combinations listed in Table 3.

TABLE 3 Continuous Combination Program For Postmenopausal Hormone Therapy

  Daily estrogen

  0.625 mg Conjugated estrogens, or
  1.25 mg Estrone sulfate, or
  1.0 mg Micronized estriadol

  2.5 mg Medroxyprogesterone acetate, or
  0.35 mg Norethindrone, or
  100 mg Micronized progesterone

  and vitamin D (400 IU in winter and 800 IU for women older
  than 70 years of age).

Continuance with hormone therapy programs is notoriously poor.^24,25 The two most common reasons why women discontinue or do not start hormone treatment are fear of cancer and vaginal bleeding.²⁶ The current data on breast cancer are reassuring, and the addition of a progestational agent has effectively prevented endometrial cancer. But the persistence of bleeding with the traditional sequential regimen continues to be a barrier to good continuance. To go from 80% to 90% withdrawal bleeding to 80% no bleeding represents a major accomplishment, and thus, the continuous approach has a significant advantage.

With sequential therapy, approximately 80% to 90% of women experience monthly withdrawal bleeding. With continuous, combined estrogen-progestin therapy, 40% to 60% of patients can be expected to experience breakthrough bleeding during the first 6 months of treatment; however, this percentage decreases to 10% to 20% after 1 year.^20,21 Although this percentage of amenorrhea with continuous, combined therapy is a gratifying accomplishment, the number of women who experience breakthrough bleeding is considerable, and it is a difficult management problem. Indeed, the most aggravating and worrisome problem with daily, continuous therapy is this breakthrough bleeding.

Why call it breakthrough bleeding? The bleeding experienced by women on continuous, combined therapy is similar to that seen with oral contraceptives: breakthrough bleeding. It originates from an endometrium dominated by progestational influence; hence, the endometrium usually is atrophic and yields little, if anything, to the exploring biopsy instrument. It is helpful to explain to patients that this bleeding represents tissue breakdown as the endometrium adjusts to its new hormonal stimulation. From our experience with oral contraceptives, we have learned to be comfortable with this type of bleeding. For most patients, the incidence of breakthrough bleeding with oral contraceptives is greatest in the first few months of treatment and usually disappears in most women. Indeed, this is the same pattern exhibited by postmenopausal women on continuous, combined therapy, and, therefore, the most effective management strategy is patient education and support.

There is no effective method supported by clinical studies, or a large experience, of drug alteration or substitution to manage this breakthrough bleeding. The breakthrough bleeding rate is only slightly better with a higher dose of progestin (5.0 mg of MPA) compared with the lower dose (2.5 mg).²⁰ Therefore, there is not a strong reason to use the higher dose, thus minimizing side effects. The best approach is to gain time, since bleeding will cease in most patients. This means good educational preparation of the patient beforehand and frequent telephone contact to allay anxiety and encourage persistence.

A hard core of patients (10% to 20% at the end of 1 year) continue to bleed. The closer a patient is to having been bleeding (either to her premenopausal state or to having been on a sequential method with withdrawal bleeding), the more likely that patient will experience breakthrough bleeding. Some clinicians, therefore, prefer to start patients near the menopause on the sequential method and convert to the continuous method years later. We prefer to start with the continuous method because women who achieve amenorrhea are highly appreciative. For the patients who persist in having breakthrough bleeding, it is better to return to the sequential program to have expected and orderly withdrawal bleeding instead of the irregularity of breakthrough bleeding.

Some patients may choose to undergo endometrial ablation to overcome the problem of breakthrough bleeding. Remember, however, that concern still exists regarding the potential for isolated, residual endometrium to progress to carcinoma without recognition. Another option deserving consideration is the progestin intrauterine device (IUD). The local release of progestin is effective in suppressing endometrial response and preventing bleeding, but the progesterone-releasing IUD must be replaced every 18 months. The levonorgestrel-releasing IUD can be left in place for 10 years, a decided advantage.^27,28 Finally, for some patients, vaginal hysterectomy proves to be an acceptable alternative.

It is not essential to routinely perform endometrial biopsies before treatment. Endometrial abnormalities in asymptomatic postmenopausal women are rare.^29,30 A reasonable economic moderation would be to limit pretreatment biopsies (using the plastic endometrial suction device in the office) to patients at higher risk for endometrial changes: women with conditions associated with chronic estrogen exposure (obesity, dysfunctional uterine bleeding, anovulation and infertility, hirsutism, high alcohol intake, hepatic disease, and metabolic problems such as diabetes mellitus and hypothyroidism) and women in whom irregular bleeding occurs while on estrogen-progestin therapy. In the absence of abnormal bleeding, trusting in the protective effects of the progestin is justified, and routine, periodic biopsies are not necessary. However, women who elect to be treated with unopposed estrogen require endometrial surveillance at least once a year.

It is appropriate to perform an endometrial aspiration biopsy when the patient's anxiety over the possibility of disease requires this response. It is also appropriate to perform a biopsy when the clinician is concerned; with increasing experience with this method, it takes more and more to be concerned. If bleeding persists for 6 months, consider an office hysteroscopy: numerous polyps and intrauterine fibroids will be discovered.

Abnormal endometrium is more frequently encountered in patients on combination estrogen-progestin when the patients have previously been treated for a period of time with unopposed estrogen. Breakthrough bleeding or unscheduled bleeding in these patients requires endometrial surveillance because an increased risk for endometrial cancer persists beyond the period of exposure to unopposed estrogen, and the effectiveness of subsequent protective exposure to a progestin is unknown.^31,32,33 It is prudent to assess the endometrium in these patients before changing from unopposed to combined therapy. Clinicians should maintain a highly anxious state of mind with patients who have been treated previously with unopposed estrogen.

A combined estrogen-progestin program does not totally prevent endometrial cancer.³² Vigilance on the part of the clinician, however, will detect endometrial cancer at an early stage, a stage that can be treated with excellent results.

It is common for women on a sequential regimen to begin bleeding while in the midst of progestin administration. The timing of withdrawal bleeding in women on a sequential estrogen-progestin program has been suggested as a screening method for biopsy decision-making. In women taking a variety of progestins for 12 days each month, bleeding on or before day 10 after the addition of the progestin was associated with proliferative endometrium. Bleeding beginning on day 11 or later was associated with secretory endometrium, presumably indicating less need for biopsy.³⁴ But does this correlate with the risk of hyperplasia and cancer? According to a study of 413 postmenopausal women, the day of bleeding does not predict endometrial safety.³⁵ Late, regular withdrawal bleeding on a sequential program does not give 100% assurance that there is no hyperplasia and perhaps endometrial cancer. This uncertainty with the sequential program is another reason to turn to the daily, combined method, where irregular bleeding and sonographic measurement of increased endometrial thickness provide good indications for endometrial biopsy.

If a patient has recurrent bleeding despite repeated medical therapy, submucous myomas or endometrial polyps must be suspected. Thorough curettage can miss such disease, and further diagnostic study can be helpful. Either hysterosalpingography with slow instillation of dye and careful fluoroscopic examination or hysteroscopy may reveal a myoma or polyp; hysteroscopy also can direct a more accurate biopsy of the endometrium.

The thickness of the postmenopausal endometrium as measured by transvaginal ultrasonography in postmenopausal women correlates with the presence or absence of disease. However, the severity of pathologic change does not correlate with the measured thickness.³⁶ Endometrial thickness (the two layers of the anterior and posterior walls in the longitudinal axis) under 5 mm is reassuring and allows conservative management.^37,38 Endometrial thickness greater than 4 mm requires biopsy; it is estimated that 50% to 75% of patients on hormone therapy and evaluated by ultrasonography will require biopsy.^36,39 An endometrial thickness less than 5 mm in women receiving hormone therapy, either a sequential regimen or a daily combination of estrogen-progestin, also is reassuring.^38,40,41 Because endometrial thickness by ultrasonography in patients on a sequential regimen can be affected by day in the treatment cycle, ultrasonography assessment should be obtained toward the end of the progestin phase or at the beginning of the cycle.⁴² When a thick endometrium is associated with atrophic endometrium on biopsy, polyps often are present. Greater accuracy can be gained by the installation of saline into the uterine cavity during ultrasonography.⁴³ Doppler velocimetry does not improve the accuracy of discriminating between normal and abnormal endometrium.⁴⁴ A clinician should not be satisfied with “normal” findings on ultrasonography if a patient has persistent bleeding. The pursuit of abnormal bleeding despite “normal” findings should reduce missed cases of disease to nearly zero.⁴⁵

The administration of a progestational agent (e.g., 10 mg of MPA for 2 weeks) was developed by R. Don Gambrell as a means of detecting the presence of estrogen-dependent endometrium in postmenopausal women.⁴⁶ A withdrawal bleed indicates that an endometrial response has occurred to the progestin, a response that requires previous endometrial stimulation by estrogen, and indicates the need for endometrial assessment. In other words, the lack of a withdrawal bleed is reassuring for clinician and patient. Concern with this clinical maneuver has focused on whether there are false-negative and false-positive responses. Several studies support the efficacy and validity of this method.^47,48,49 The published data indicate that most women with endometrial proliferation, hyperplasia, and cancer will respond with a withdrawal bleed after a progestin challenge, and ultrasonography measurement of endometrial thickness will be greater than 4 mm. The problem is that the studies have insufficient numbers of subjects, and there is a lingering question as to whether a patient with abnormal endometrium will always bleed in response to progestin treatment and withdrawal.

Many women do not tolerate treatment with progestational hormones. Typical side effects include breast tenderness, bloating, and depression. These reactions are significant detrimental factors with continuance. However, appropriately designed, placebo-controlled studies fail to document adverse physical or psychological effects with short-term treatment using MPA.^50,51 This suggests that progestin's side effects are related to duration of treatment or that only studies with large numbers of subjects will detect the small percentage of women who have problems (and both explanations probably are true).

Can the progestational agent be administered less frequently? We are secure in our position, supported by clinical data, that a monthly estrogen-progestin sequential or a daily combination program effectively prevents endometrial hyperplasia. Experience with other regimens is limited. The administration of MPA every 3 months was associated in one study with longer, heavier menses and unscheduled bleeding and a 1.5% incidence of hyperplasia at 1 year, whereas in another study, overall bleeding was less but the incidence of hyperplasia was approximately 4%.^52,53 In a third study, there was no endometrial hyperplasia encountered by 143 women who completed 2 years of treatment; however, the progestin administered every 3 months was of high dosage, 20 mg of MPA daily for 14 days.⁵⁴ Impressively, the Scandinavian LongCycle Study, a clinical trial scheduled to last 5 years, was canceled after 3 years because of a 12% incidence of endometrial hyperplasia and four cases of endometrial cancer.⁵⁵ Therefore, if a patient chooses this regimen, more intensive endometrial monitoring is required. In our view, an annual endometrial biopsy is strongly recommended. Indeed, any program that differs from the standard regimen is untested by clinical studies of sufficient length and subject numbers, and, therefore, requires periodic surveillance of the endometrium.

Some patients are sensitive to MPA. These patients often are relieved of their symptoms by switching to norethindrone. In a sequential regimen, the dose of norethindrone is 0.7 mg (available in the progestin-only minipill oral contraceptive; each pill contains 0.35 mg of norethindrone). In the continuous, combined regimen, the dose of norethindrone is 0.35 mg daily.

Progesterone can be administered in a vaginal gel that allows the delivery of low doses that can effectively protect the endometrium with low systemic levels because of a first-pass effect on the uterus.⁵⁶ The administration of 90 mg every 2 days produces secretory changes in the endometrium.⁵⁷ No long-term studies are available documenting endometrial safety and metabolic effects.

The contraceptive levonorgestrel-releasing IUD has been reconfigured in a smaller model releasing as little as 5 μg of levonorgestrel per 24 hours.^28,58,59 The intrauterine presence of the progestin effectively protects the endometrium against hyperplasia and cancer. The local site of action provides endometrial protection and escapes systemic progestin side effects; for example, estrogen's favorable lipid effects are not attenuated.⁶⁰ As with the oral continuous, combined regimens, there is irregular breakthrough bleeding in the first 6 months, and after 1 year, approximately 60% to 70% of the women are amenorrheic. The levonorgestrel device has the advantage of a 10-year duration of use. The progesterone-releasing device is larger and must be replaced every 18 months, and there have been few studies in postmenopausal women.

Some special conditions warrant the use of a combined estrogen-progestin regimen in women after hysterectomy.

1. Patients who have had stage I or II adenocarcinoma of the endometrium can take estrogen without fear of recurrence,^61,62,63,64 but the combination of estrogen-progestin is recommended in view of the potential protective action of the progestational agent. Treatment can be initiated immediately postoperatively.
   
2. The combined estrogen-progestin approach makes sense for patients previously treated for endometrioid tumors of the ovary.
   
3. Because adenocarcinoma has been reported in patients with pelvic endometriosis being treated with unopposed estrogen,^65,66 the combined estrogen-progestin program is advised in patients with a history of endometriosis. In addition, we have encountered a case of hydronephrosis secondary to ureteral obstruction caused by endometriosis (with atypia) in a woman on unopposed estrogen for years after hysterectomy and bilateral salpingo-oophorectomy for endometriosis.
   
4. Responsive endometrium may be sequestered in patients who have undergone endometrial ablation. Combined estrogen-progestin treatment is recommended for these women.
   
5. Patients who have had procedures that have the potential to leave residual endometrium (e.g., a supracervical hysterectomy) should be treated with an estrogen-progestin combination.
   
6. There is evidence that the combination of estrogen and progestin has a greater positive impact on bone density than estrogen alone. Thus, in women after hysterectomy at high risk for osteoporosis, the combined estrogen-progestin program may offer an important potential advantage. However, this synergistic effect is influenced by the type of progestin, and a greater bone response may be limited to the 19-nortestosterone (norethindrone) family.
   
7. In women with elevated triglyceride levels, the addition of a progestin, especially a 19-nortestosterone progestin, may attenuate a further estrogen-induced increase in triglycerides.
   

After menopause, the circulating level of androstenedione is about one half that seen before menopause.⁶⁷ Most of this postmenopausal androstenedione is derived from the adrenal gland, with only a small amount secreted from the ovary. Testosterone levels do not fall appreciably, and in most women, the postmenopausal ovary, for a few years, secretes more testosterone than the premenopausal ovary. The remaining active stromal tissue in the ovary is stimulated by the elevated gonadotropins to this level of increased testosterone secretion. The total amount of testosterone produced, however, is slightly decreased because the primary source, the peripheral conversion of androstenedione, is reduced. Because of this decrease, some argue that androgen treatment is indicated in the postmenopausal period.

The potential benefits of androgen treatment include improvement in psychological well-being and an increase in sexually motivated behavior. These effects, however, follow the administration of relatively large doses of androgen.⁶⁸ In a well-designed, placebo-controlled study, lower doses of androgen (but still pharmacologic—5 mg of methyltestosterone) contributed little to actual sexual behavior, although an increase in sexual fantasies and masturbation could be documented.⁶⁹

Any benefit must be balanced by the unwanted effects, in particular, hirsutism and a negative impact on the cholesterol lipoprotein profile. In a short-term study comparing a product with estrogen and a relatively low oral dose of testosterone (1.25 mg of methyltestosterone) to estrogen alone, a negative impact on the lipid profile was apparent within 3 months.⁷⁰ Over a 2-year period, the administration of estrogen (1.25 mg) combined with 2.5 mg of methyltestosterone produced a significant overall adverse impact on the cholesterol lipoprotein profile.⁷¹ In addition, 30% of the patients experienced acne, and 36% developed facial hirsutism. A lower dose of this combination (0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone) also significantly lowers HDL cholesterol.⁷² The adverse impact on the lipid profile is less (and may even be avoided) by the parenteral administration of testosterone.⁷³

Also remember that androgens do not protect the endometrium, and the addition of a progestin still is necessary. It is uncertain (and unstudied) how much aromatization of the administered testosterone increases the estrogen impact and whether this might further increase the risk of endometrial or breast cancer. The addition of testosterone to an estrogen therapy program has been reported to provide no additional beneficial impact on bone or on relief from hot flushes.^71,74 On the other hand, others have demonstrated a greater increase in bone density with an estrogen-androgen combination compared with estrogen alone, although the blood levels achieved were higher than those associated with standard postmenopausal hormone therapy.⁷³

Pharmacologic amounts of androgen undoubtedly increase libido, but these same doses produce unwanted effects.⁷⁵ In addition, patients on high doses of androgens often become addicted to this therapy. Small amounts of androgen supplementation can be provided in situations where the patient and clinician are convinced a depressed libido cannot be explained by psychosocial circumstances. In these cases, the lipid profile should be carefully monitored. Any positive clinical response may be a placebo effect. After some months or a few years, conversion to a standard program without androgen is recommended.

A greater understanding of the estrogen receptor mechanism (discussed elsewhere in this volume) allows us to understand how mixed estrogen agonists-antagonists can have selective actions on specific target tissues. New agents are being developed to isolate desired actions from unwanted side effects. In relatively short-term studies, raloxifene exerts no proliferative effect on the endometrium but produces favorable responses in bone and lipids.^76,77 Raloxifene carries within its structure the inherent potential to protect against breast cancer. Short-term clinical trial data indicate that raloxifene has an impact on bone that is not as great as estrogen, the effect on lipids may not be sufficient to protect against cardiovascular disease, and raloxifene increases hot flushing.⁷⁸ Long-term clinical trial data will be necessary to determine the ultimate impact on clinical events, specifically fractures, coronary heart disease, stress incontinence, endometrial cancer, and cognition. In our view, raloxifene is an option for prevention of osteoporosis, especially for patients reluctant to use hormone therapy, but is not a substitute for estrogen.

Uterine leiomyomas are monoclonal tumors that retain sensitivity to both estrogen and progestin, and, therefore, it is appropriate to be concerned over whether leiomyomas will grow in response to postmenopausal hormone therapy. As assessed by vaginal ultrasonography, the number and size of uterine leiomyomas increase in women being treated with an intramuscular depot form of estrogen-progestin therapy.⁷⁹ However, the hormonal dose in this study was relatively high—higher than standard regimens. At the end of 1 year, women with small asymptomatic fibroids administered a daily combination of 0.625 mg of conjugated estrogens and 2.5 mg of MPA had no sonographic evidence of growth in contrast to an increase in size observed with transdermal estradiol (50 μg) and 5 mg of MPA daily (a response that may reflect the effect of a higher progestin dose).⁸⁰ In a follow-up study with standard doses of hormone therapy, ultrasonography detected no changes in uterine or myoma volumes.⁸¹ Clinical experience indicates that fibroid tumors of the uterus usually are not stimulated to grow by the usual postmenopausal doses of estrogen and progestin. Nevertheless, pelvic examination surveillance is a wise course. For example, a vulvar leiomyoma with growth stimulated by estrogen-progestin treatment has been reported.⁸² A case-control study could find no statistically significant increase in the risk of uterine sarcomas associated with estrogen therapy.⁸³

No clear conclusion is apparent from the studies of estrogen's effect on rheumatic diseases, especially rheumatoid arthritis. Studies indicate that exogenous estrogen, either oral contraceptives or postmenopausal therapy, protects against the onset of rheumatoid arthritis, whereas other studies find no effect.^84,85,86 These studies have been hampered by small numbers of subjects, a problem that will not be overcome unless postmenopausal hormone therapy becomes more widespread. In a randomized, placebo-controlled clinical trial, maintenance of standard serum estradiol levels was associated with improvements in some measurements of disease activity in patients with rheumatoid arthritis.⁸⁷ There has been no evidence that postmenopausal hormone therapy aggravates rheumatoid arthritis or causes a flare in disease activity.

In the Nurses' Health Study, the use of postmenopausal estrogen was associated with an approximately twofold increase in systemic lupus erythematosus, an observation based on 30 cases in past and current users of estrogen.⁸⁸ If this epidemiologic association is true, the absolute risk is small, and importantly, postmenopausal women with systemic lupus erythematosus may derive substantial benefit from the cardiovascular actions of estrogen. In a follow-up of 60 postmenopausal women with stable systemic lupus erythematosus, no adverse effects of hormone therapy could be detected.⁸⁹ Furthermore, patients with systemic lupus erythematosus treated with glucocorticoids are at greater risk for osteoporosis.⁹⁰

Bone loss associated with glucocorticoid therapy can be avoided with the usual postmenopausal hormone regimens.^91,92 These patients also are excellent candidates for bisphosphonate treatment, another effective option that prevents glucocorticoid-induced bone loss.⁹³ Calcium and vitamin D supplementation also has been demonstrated to prevent bone loss associated with low-dose glucocorticoid treatment.⁹⁴

Osteoarthritis is the most common form of arthritis in older people, and its prevalence increases rapidly in women after menopause. Osteoporosis protects against arthritis,⁹⁵ and, therefore, the impact of estrogen therapy on osteoarthritis is a logical concern. Increasing severity of osteoarthritis of the knee has been reported to be associated with increasing bone density and the current use of postmenopausal hormone therapy in middle-aged women.⁹⁶ However, a cross-sectional study concludes that current users of estrogen had a reduced prevalence of osteoarthritis of the hip, and there was protection against the severity of osteoarthritis, with a greater effect with longer duration of use.⁹⁷ Because there are no known treatments that modify the course of arthritis, this potential benefit of postmenopausal hormone therapy deserves study by a randomized clinical trial.

Oral complaints are common among postmenopausal women. The administration of estrogen provides significant relief from oral discomfort, burning, bad taste, and dryness.⁹⁸ Estrogen therapy also is associated with a reduction in gingival inflammation and bleeding. These changes may reflect epithelial responses to estrogen by the oral mucosa in a manner similar to that of the vaginal mucosa. Oral alveolar bone loss (which can lead to loss of teeth) is strongly correlated with osteoporosis, and the salutary effect of estrogen on skeletal bone mass also should be manifested on oral bone.^100,101 In the Leisure World Cohort, tooth loss and edentia were significantly reduced in estrogen users compared with nonusers (with a reduced need for dentures), and this beneficial effect was greater with increasing duration of estrogen use.¹⁰² An approximately 25% reduced risk of tooth loss in current users of estrogen has been observed in the Nurses' Health Study.¹⁰³

Professional singers have used hormone therapy to prevent what they view as unwanted voice changes associated with the menopause.¹⁰⁴ In a 1-year study, objective voice analyses documented a more androgenic change in voice in the early postmenopausal years with a lesser change associated with estrogen treatment, slightly attenuated by the addition of a progestin.

There is some evidence that estrogen therapy improves visual acuity (or lessens the decrease occurring during the early postmenopausal years), perhaps because of a beneficial effect on lacrimal fluid.¹⁰⁶ An increased prevalence of keratoconjunctivitis sicca (dry eyes) in menopausal and postmenopausal women is recognized by ophthalmologists, and estrogen therapy offers the potential for symptomatic relief.¹⁰⁷ There is further evidence that postmenopausal estrogen therapy has an effect that protects against lens opacities.^108,109,110 Estrogen-progestin treatment also lowers intraocular pressure.

The positive impact of hormone therapy on bone has been demonstrated to take place even in women older than 65 years of age.^111,112 This is a strong argument in favor of treating elderly women who have never been on estrogen. Estrogen treatment that is not begun until after 60 years of age can, with long-term use, achieve bone densities nearly comparable with those in women taking estrogen from menopause, and estrogen use between the ages of 65 and 74 years has been documented to protect against hip fractures.^113,114 Whether estrogen's cardiovascular protection has anything significant to contribute in the elderly has not been addressed. It makes clinical sense, however, that some positive contribution can be expected. Adding a pharmacologic regimen to an elderly woman's daily life is not a trivial consideration. This judgment requires the conclusion that a relatively youthful and vigorous elderly woman has something to gain from the treatment. Patients with osteoporosis or unfavorable lipoprotein profiles would qualify.

If postmenopausal hormone therapy is demonstrated to have a beneficial effect on the risk and severity of Alzheimer's disease, this would become a powerful reason to recommend treatment for elderly women.

Older women who have been deficient in estrogen for many years often experience side effects when standard doses of estrogen are initiated. Breast tenderness can be especially disturbing. It is usually better to start older women with lower doses. Oral products at half the usual doses (0.3 mg of conjugated estrogens or 0.5 mg of estradiol) or a transdermal product that delivers relatively low amounts of estrogen can be used. After 6 months, an increase to standard doses is recommended to maximize the bone, cardiovascular, and central nervous system benefits.

The answer to the question of how long to continue hormone therapy is relatively straightforward. A woman should continue her postmenopausal hormone regimen as long as she wants the benefits. Although some estrogen effects are long-lasting, the full impact is rapidly lost after discontinuation. For example, in the Nurses' Health Study, reduced risk of mortality (largely cardiovascular) was lost by the fifth year after discontinuing treatment.¹¹⁵

The best alternative option for treating hot flushes appears to be transdermal clonidine, applied with the 100-μg dose once weekly.^116,117 Side effects are minimal, and a modest impact can be expected.

Clonidine, bromocriptine, and naloxone given orally are only partially effective for the relief of hot flushes and require high doses with a high rate of side effects. Bellergal (a combination of belladonna alkaloids, ergotamine tartrate, and phenobarbital) treatment is slightly better than a placebo, but it also is a potent sedative.¹¹⁸ Veralipride, a dopamine antagonist that is active in the hypothalamus, is relatively effective in inhibiting flushing at a dose of 100 mg daily.^119,120 Mastodynia and galactorrhea are the major side effects. MPA (10 to 20 mg daily) and megestrol acetate (20 mg twice daily) also are effective, but concerns regarding exogenous steroids (especially in patients who have had breast cancer) would apply to progestins as well.^121,122 Methyldopa, in doses of 500 to 1000 mg/day, is approximately twice as effective as a placebo, suggesting a role for adrenoreceptors in the hot flush mechanism.¹²³ Propranolol and similar agents are ineffective, as is vitamin E.

Tibolone is a steroid, related to the 19-nortestosterone family, available in Europe for the treatment of hot flushes in a dose of 2.5 mg/day.¹²⁴ Because it is weakly estrogenic, androgenic, and progestogenic, it is free of endometrial response. However, a short-term reduction in HDL cholesterol is an undesirable consequence; the long-term impact has not been well studied.¹²⁵ In a 2-year study, the unfavorable effect on lipoproteins was accompanied by beneficial changes in coagulation factors, consistent with enhanced fibrinolysis and unchanged coagulation.¹²⁶

“Natural” Therapies

Patients should be questioned regarding the use of “natural” therapies. Some of the herbs that contain estrogen-like compounds include ginseng, agnus castus, red sage, black cohosh, and beth root. The dosage and purity of herbal preparations are unknown, and most importantly, there are no substantial studies documenting either harmful or beneficial effects. Herbs often are contaminated with heavy metals. In our view, the use of products without scientific study should be discouraged. A rigorous evaluation of one popular herb, dong quai, could detect no effects on vaginal maturation or menopausal symptoms, especially hot flushing.¹²⁷

Phytoestrogens

Phytoestrogens, also called isoflavones, are present in many plants, especially legumes, and bind to the estrogen receptor. Soybeans, a rich source of phytoestrogens, contain genistein, daidzein, and glycitein. These phytoestrogens are characterized by mixed estrogenic and antiestrogenic actions, depending on the target tissue. In addition, the soy phytoestrogens have a greater affinity for the estrogen receptor-beta compared with estrogen receptor-alpha.¹²⁸ In the monkey, soybean phytoestrogens do not maintain bone density but do have favorable effects on atherosclerosis and vasomotor responses.^{129,130,131,132} Estradiol and soy protein produce comparable metabolic changes in the monkey, including favorable lipid changes, improved carbohydrate metabolism, and a decrease in central, android abdominal fat.¹³³ Also in the monkey, these phytoestrogens do not stimulate proliferation of breast and endometrial cells.¹³⁴

The daily intake of dietary soy reduces the number of hot flushes in postmenopausal women, although there is significant variability in response, and efficacy appears to be less than that of estrogen.¹³⁵ In women, soya consumption produces a reduction in the circulating levels of estradiol, and the replacement of potent estradiol with target-specific phytoestrogens may be beneficial.¹³⁶ In the parts of the world where soy intake is high, there is a lower incidence of breast, endometrial, and prostate cancers.¹³⁷ For example, a case-control study concludes that there was a 54% reduced risk of endometrial cancer, and another case-control study indicates a reduction in the risk of breast cancer in women with a high consumption of soy and other legumes.^138,139 However, a direct effect of soy intake is uncertain.¹⁴⁰ Appropriate clinical trials are required to determine how phytoestrogens compare with estrogens, and the efficacy, safety, and correct dosage. In addition, the intake of sufficient soy to produce a clinical response is not easy, handicapped by gastrointestinal symptoms from a major alteration in diet or the use of an unpalatable supplement. A user-friendly preparation needs to be developed that minimizes individual variability in response.

Dehydroepiandrosterone

The impressive decline (75% to 85%) in circulating levels of dehydroepiandrosterone (DHEA) that occur with aging (greater in men than in women) has stimulated a search for a beneficial impact of DHEA supplementation. Animal studies (in animals that do not even synthesis DHEA) suggest that DHEA administration enhances the immune system and protects against many conditions associated with aging. Preliminary human studies indicate significant increases (even at the usual 50 mg/day dose) in testosterone and dihydrotestosterone levels in women (by peripheral conversion in a variety of tissues).¹⁴¹ What is the impact of a long-term increase in androgens? It is prudent to await the outcome of clinical trials before advocating DHEA supplementation.

Metabolic

Patients with high-risk factors need special attention when estrogen therapy is being considered. Metabolic contraindications to estrogen therapy include the following: chronically impaired liver function, acute vascular thrombosis (with or without emboli), and neurophthalmologic vascular disease. Estrogens may have adverse effects on some patients with seizure disorders, familial hyperlipidemias (high triglycerides), and migraine headaches.

Pancreatitis and severe hypertriglyceridemia can be precipitated by the administration of oral estrogen to women with elevated triglyceride levels.¹⁴² In women with triglyceride levels between 250 and 750 mg/dL, estrogen should be provided with great caution, and a non-oral route of administration is preferred. The triglyceride response is rapid, and a repeat level should be obtained in 2 to 4 weeks. If increased, hormone therapy must be discontinued. A level greater than 750 mg/dL represents an absolute contraindication to estrogen treatment. Although triglyceride levels in the normal range were not affected by progestins in the Postmenopausal Estrogens/Progestins Interventions (PEPI) trial, an exaggerated triglyceride response to estrogen might be attenuated by a progestin, especially a progestin of the 19-nortestosterone family, and, therefore, the daily combination method of treatment should be considered for women with elevated triglycerides.

Although physiologic and epidemiologic evidence indicates that estrogen use increases the risk of gallbladder disease, the overall impact is not great. The Nurses' Health Study indicates that oral estrogen therapy may carry a 1.5- to 2.0-fold increased risk of gallbladder disease.¹⁴³ The risk of cholecystectomy increased with dose and duration of use and to persist for 5 or more years after stopping treatment. Others also report increased risks of cholecystectomy in past and current users of estrogen.^144,145

However, at least two case-control studies conclude that estrogen use is not a risk factor for gallstone disease in postmenopausal women, although the statistical power was limited by small numbers of subjects.^146,147 A cross-sectional study of gallstone disease could detect no association with postmenopausal hormone treatment.¹⁴⁸ The routine, periodic use of blood chemistries is not cost-effective, and careful monitoring for the appearance of the symptoms and signs of biliary tract disease will suffice. This potential problem may be limited to oral therapy because non-oral routes of estrogen administration do not increase biliary cholesterol saturation (a lithogenic response) in contrast to oral treatment.¹⁴⁹

Weight Gain

The gain in weight that many middle-aged individuals experience is the result of lifestyle, specifically the balance of dietary intake and exercise. Weight gain in women at menopause is not caused by the hormonal changes associated with the menopause.¹⁵⁰ Likewise, postmenopausal hormone therapy cannot be blamed for weight gain. The large Rancho Bernardo prospective cohort study and the randomized PEPI clinical trial document that hormone therapy with or without progestin does not cause an increase in body weight.^151,152 In the PEPI trial, the hormone-treated groups gained less weight than the placebo group.

Estrogen (with or without progestin) prevents the tendency to increase central body fat with aging.^{153,154,155,156} This would inhibit the interaction among abdominal adiposity, hormones, insulin resistance, hyperinsulinemia, blood pressure, and an atherogenic lipid profile.

Venous Thrombosis

Pharmacologic doses of estrogen (oral contraceptives) are associated with an increased risk of venous thrombosis. The impact of the lower doses administered to postmenopausal women has been more difficult to ascertain. Older case-control studies failed to find a link between postmenopausal doses of estrogen and venous thrombosis.^157,158 However, these studies excluded cases with preexisting risk factors for thrombosis. A well-designed case-control study of older women unselected for other thrombotic risk factors indicates that postmenopausal doses of estrogen did not increase the risk of venous thrombosis.¹⁵⁹ Others also failed to find an increase in venous thromboembolism associated with postmenopausal hormone therapy.¹⁶⁰

The conventional wisdom that the low postmenopausal doses of estrogen do not increase the risk of venous thrombosis was challenged by three case-control studies and one cohort study. These studies were larger but still were limited to 20 to 40 cases on hormone therapy. In the Nurses' Health Study cohort, the risk of pulmonary embolism was increased twofold in the current hormone users.¹⁶¹ The case-control studies found a 2.1- to 3.6-fold increased risk of deep vein thrombosis in current but not past hormone users.^162,163,164 The numbers of subjects were too small to enable a reliable analysis of a dose-response effect or the effect of transdermal use. All of the studies indicate that the increased risk was confined to early use and that the risk drops to a nonsignificant level after a few years. The addition of a progestin did not change the risk.

The overall impact of postmenopausal hormone therapy on the clotting cascade is compatible with a favorable effect resulting from changes consistent with an increase in fibrinolysis.^{165,166,167,168} However, the favorable impact may be confined to arterial thrombosis. Furthermore, it is more prudent to make clinical judgments based on epidemiologic event data rather than laboratory tests. Epidemiologic study of venous thrombosis (deep vein thrombosis and pulmonary embolism) is difficult because of the low incidence of the complication and the problem of diagnostic bias (a clinician is more suspicious of the diagnosis because of the use of estrogen).

The clinching argument on this issue is the observation of an increased risk of venous thrombosis in both the Heart and Estrogen-Progestin Replacement study (HERS) secondary prevention study of daily estrogen-progestin therapy for women who already have coronary heart disease and the data obtained with raloxifene.¹⁶⁹ HERS has recorded an increased relative risk of venous thromboembolism comparable with that reported in the observational studies. The increased risk in these instances was observed in randomized clinical trials, and not accepting these results is difficult.

What is the final message for clinicians and patients? First, the risk applies only to new starters; women who have been on hormone therapy for a few years can be reassured that there is no evidence of an increased risk of venous thrombosis. The actual risk is low because of the low frequency of this event. If the relative risk is increased threefold, this would increase the incidence of venous thromboembolism by about one case per 5000 women per year of hormone use. Furthermore, venous thrombosis carries with it a low risk of mortality, around 1%, and most of the fatal cases have followed venous thrombosis associated with trauma such as surgery or an accident.

If a patient has a family history or a previous episode of idiopathic thromboembolism, an evaluation to search for an underlying abnormality in the coagulation system is warranted. The following measurements are recommended, and abnormal results require consultation with a hematologist regarding prognosis and prophylactic treatment:

  Antithrombin III
  Protein C
  Protein S
  Activated protein C resistance ratio
  Activated partial thromboplastin time
  Hexagonal activated partial thromboplastin time
  Anticardiolipin antibodies
  Fibrinogen
  Prothrombin G mutation (DNA test)
  Thrombin time
  Homocysteine level
  Complete blood count

A DNA-based test can be used to verify the presence of the factor V Leiden mutation. Other risk factors for thromboembolism that should be considered by clinicians include an acquired predisposition such as the presence of lupus anticoagulant or malignancy, and immobility or trauma. Varicose veins are not a risk factor unless they are extensive, and unlike arterial thrombosis, smoking is not a risk factor for venous thromboembolism.

If a patient has a congenital predisposition for venous thrombosis or if she is considered to be at high risk for venous thromboembolism, the clinician and patient can consider the combination of hormone therapy and chronic anticoagulation, in consultation with a hematologist.

There are no studies of venous thromboembolism after surgical procedures in postmenopausal hormone users. Recommending appropriate prophylactic treatment in hormone users having major surgery is sensible, especially if other risk factors are present. Some patients may elect to discontinue hormone treatment several weeks before surgery, but this is an empiric, individual decision.

Endometrial Neoplasia

Estrogen normally promotes mitotic growth of the endometrium. Abnormal progression of growth through simple hyperplasia, complex hyperplasia, atypia, and early carcinoma has been associated with unopposed estrogen activity, administered either continuously or in cyclic fashion. Only 1 year of treatment with unopposed estrogen (0.625 mg of conjugated estrogens or the equivalent) produces a 20% incidence of hyperplasia, largely simple hyperplasia; in the 3-year PEPI trial, 30% of the women on unopposed estrogen developed adenomatous or atypical hyperplasia.^18,21,170 About 10% of women with complex hyperplasia progress to frank cancer, and complex hyperplasia is observed to antedate adenocarcinoma in 25% to 30% of cases. If atypia is present, 20% to 25% of cases will progress to carcinoma within a year.¹⁷¹

Approximately 40 case-control and cohort studies estimate that the risk of endometrial cancer in women on estrogen therapy (unopposed by a progestational agent) is increased by a factor of about 2 to 10 times the normal incidence of 1 per 1000 postmenopausal women per year.^172,173 The risk increases with the dose of estrogen and with the duration of exposure (reaching a 10-fold increase with 10 to 15 years of use, and perhaps an incidence of 1 in 10 with long-term use) and lingers for up to 10 years after estrogen is discontinued, and the risk of cancer that already has spread beyond the uterus is increased threefold in women who have used estrogen 1 year or longer.^174,175 Although most endometrial cancer associated with estrogen use has a low grade and stage and is associated with better survival (probably because of earlier detection), the overall risk of invasive cancer and death is increased. The risk of endometrial hyperplasia and cancer is not reduced by the administration of unopposed estrogen in a cyclic fashion (a period of time each month without treatment).^172,176

A short-term study (2 years) indicates that one half the usual standard dose of estrogen (in this case, 0.3 mg of esterified estrogens) was not associated with an increased incidence of endometrial hyperplasia compared with a placebo group.¹⁷⁷ But we have learned that long-term exposure to low levels of estrogen can induce abnormal endometrial growth, and in our view, lower dose estrogen therapy requires either endometrial assessment annually or the addition of a progestin to the treatment regimen. This is supported by a case-control study from Washington that contained 18 cases and nine controls who had exclusively used only 0.3 mg/day of unopposed conjugated estrogens.¹⁷⁸ The use of this half-dose estrogen was associated with an overall fivefold increased risk of endometrial cancer, reaching a relative risk of 9.2 in current users for more than 8 years' duration. Although limited by small numbers of subjects, the conclusion is logical and consistent with our understanding of the importance of duration of exposure to any increased level of endometrial estrogen stimulation.

This risk can be reduced by the addition of a progestational agent to the program.¹⁷⁰ Whereas estrogen promotes the growth of endometrium, progestins inhibit that growth. This counter effect is accomplished by progestin reduction in cellular receptors for estrogen and by induction of target cell enzymes that convert estradiol to an excreted metabolite, estrone sulfate. As a result, the number of estrogen receptor complexes that are retained in the endometrial nuclei are decreased, as is the overall intracellular availability of the powerful estradiol. In addition, progestational agents suppress estrogen-mediated transcription of oncogenes.

Reports of the clinical impact of adding progestin in sequence with estrogen include both the reversal of hyperplasia and a diminished incidence of endometrial cancer.^{179,180,181,182,183} The protective action of progestational agents operates by a mechanism that requires time to reach its maximal effect. For this reason, the duration of exposure to the progestin each month is critical. Whereas one standard method incorporated the addition of a progestational agent for the last 10 days of estrogen exposure, most have argued in favor of 12 or 14 days. Studies indicate that the minimal requirement is a monthly exposure of at least 10 days' duration.^31,184,185 About 2% to 3% of women per year develop endometrial hyperplasia when the progestin is administered for less than 10 days monthly.

Important unanswered questions are “What will be the actual incidence of endometrial cancer in long-term users of postmenopausal hormone therapy?” and “Will there be differences among the various regimens and routes of administration?” A case-control study from Seattle reports that the use of combined estrogen-progestin (essentially all sequential and oral) for 5 or more years was associated with an increased relative risk of endometrial cancer, even with 10 to 21 days of added progestin per month.³³ However, the increased risk was confined to women who had been previously exposed to unopposed estrogen treatment; remember, after discontinuing unopposed estrogen treatment, the risk of endometrial cancer lingers for up to 10 years, even if a subsequent regimen includes a progestin. In the Swedish prospective cohort in Uppsala, a reduced risk of mortality from endometrial cancer was observed in women receiving an estrogen-progestin combination; however, there were only two deaths, precluding statistical significance.¹⁸⁶ A case-control study from Los Angeles found no increased risk of endometrial cancer with the continuous combined estrogen-progestin regimen or when at least 10 days of progestin was provided in a sequential regimen.^31,184,185

An attractive idea is that protection against endometrial cancer requires shedding of the endometrium. However, we know that at least one third and up to one half of the functioning endometrium is not lost during withdrawal bleeding, and it has not been established that endometrial shedding is essential to protect against cancer.¹⁸⁷ It is just as logical to believe that prevention of growth and development of atrophic endometrium are protective. There is good reason to believe that both the sequential regimens (with appropriate dose and duration of progestin administration) and the continuous combined regimens offer protection against endometrial cancer. The degree of protection and comparable performance ultimately will be determined by the long-term randomized clinical trials currently going on.

The lowest daily dose of progestin that protects the endometrium has not been established. Currently, the sequential program uses 5 or 10 mg of MPA, and the combined daily method uses 2.5 mg. The dose of norethindrone that is comparable with 2.5 mg of MPA is 0.25 mg.²² Although lower doses of progestational agents are effective in achieving target tissue responses (such as reducing the nuclear concentration of estrogen receptors), the long-term impact on endometrial histologic features has not been firmly established. The question of dose is an issue of major importance, especially in terms of the cardiovascular system and compliance because of progestin-induced side effects.

Whereas the protective effect of progestin is considerable and predictable, it is unwise to expect that no patients on estrogen-progestin therapy will develop endometrial cancer. Appropriate monitoring of patients cannot be disregarded. Although routine assessments are not cost-effective, interventions directed by clinical responses are prudent and necessary.

Ovarian Cancer

A prospective cohort study concludes that the risk of fatal ovarian cancer is increased with long-term estrogen use.¹⁸⁸ There was no significant increase in the relative risk of fatal ovarian cancer with ever using postmenopausal estrogen, and the link with long-term use achieved statistical significance only with the 18 cases using estrogen for 11 or more years. It is not certain if this association is real. There have been 12 case-control studies of ovarian cancer risk factors, and the pooled analysis of this literature could find no consistent evidence for an association between ovarian cancer and estrogen therapy.¹⁸⁹ Studies have been hampered by relatively small numbers of subjects, but the lack of a uniform and consistent association argues against a major impact of postmenopausal estrogen treatment on the risk of ovarian cancer. In a recent and relatively large case-control study, no indication could be found for an association between postmenopausal hormone therapy and the risk of epithelial ovarian cancer, even with long-term treatment.¹⁹⁰ Another case-control study reports a slightly increased risk, but it was not statistically significant.¹⁹¹ In a retrospective analysis, no detrimental impact could be detected on prognosis after surgery for ovarian cancer in patients who received postmenopausal hormone therapy after diagnosis.¹⁹²

Cervical Cancer

The association between postmenopausal hormone therapy and cancer of the uterine cervix has not been extensively studied. Evidence from one cohort study and one case-control study indicates that the postmenopausal use of estrogen does not increase the risk of cervical cancer.^193,194 Indeed, these studies observed protection against cervical cancer in the estrogen users, but this may reflect detection bias (more examinations and Pap smears in estrogen users). In a follow-up report of 120 women treated for stage I and II cervical cancer, no adverse effects of hormone therapy on survival or recurrence were observed.¹⁹⁵

Colorectal Cancer

Most cohort and case-control studies report a significantly reduced risk of colorectal cancer in past users of postmenopausal estrogen.^{196,197,198,199,200} The effect is greater in current users and increases with increasing duration of use, supporting a real beneficial impact. One can only speculate regarding the mechanism of this benefit. The estrogen-induced change in the bile (a decrease in bile acids with an increase in cholesterol saturation) favors gallstone formation but may reduce promotion (by bile acids) of colonic cancer.

Malignant Melanoma

The possibility of a relation between exogenous hormones and cutaneous malignant melanoma has been the subject of many observational studies. Accurate evaluation using the Royal College of General Practitioners and Oxford Family Planning Association prospective cohorts and accounting for exposure to sunlight did not indicate a significant difference in the risk of melanoma comparing users of oral contraceptives to nonusers.^201,202 Results with the use of postmenopausal estrogen therapy do not indicate a major impact. A slightly increased risk with long-term use of estrogen was noted in one case-control study (a conclusion based on 10 to 20 cases that did not achieve statistical significance), whereas another case-control study could find no association with postmenopausal estrogen treatment.^203,204 Others report slight increases in the risk of malignant melanoma associated with the use of exogenous estrogen, but all failed to reach statistical significance.^193,205,206 In an analysis of cancer incidence in a Swedish cohort of women prescribed postmenopausal hormone therapy, no increase in malignant melanoma was observed.²⁰⁷

Breast Cancer

The possibility that estrogen use increases the risk of breast cancer must be intensively scrutinized. The American epidemiologic data on the scope of human female breast cancer are astonishing: one of every eight women will develop breast cancer in her lifetime (assuming an 85-year life expectancy). In America, breast cancer is the leading type of cancer in women (30%) and now second to lung cancer as the leading cause of cancer death in women (16.5%), about 10 times the number of deaths from endometrial cancer.²⁰⁸

Sufficient evidence exists to indicate the possibility of a slightly increased risk of breast cancer associated with long duration (5 or more years) of postmenopausal estrogen use. However, the epidemiologic data on this relation are not consistent and uniform. A review of the epidemiologic studies on postmenopausal hormone therapy and the risk of breast cancer fails to provide definitive evidence regarding this issue. Nevertheless, we believe that patients must consider this possibility in their informed decision-making.

Early studies on estrogen use and breast cancer indicate higher risks in special subcategories, such as women with benign breast disease, long duration of use, or natural versus surgical menopause.^{209,210,211,212,213,214,215,216,217,218} All of these studies were limited by a lack of control groups or by relatively small numbers of subjects. The Cancer and Sex Hormone Study of the Centers for Disease Control and Prevention has not detected an overall increased risk of breast cancer with postmenopausal estrogen use and no relation with duration of use up to 20 years or longer.²¹⁹ An absence of an effect was evident in all of the following: parity, age at first pregnancy, early or late menopause, menopause by hysterectomy or oophorectomy, family history of breast cancer, presence of benign breast disease, use for many years (20 years or longer), and use of high doses.

A well-publicized study from Uppsala, Sweden concludes that estrogen use was associated with a slight increase in the risk of breast cancer (relative risk 1.1) and that there was a relation with duration of use, with the relative risk reaching 1.7 after 9 years (although this conclusion did not reach statistical significance).^220,221 Another conclusion of this study was the indication of increased risk with combined treatment with estrogen-progestin. This conclusion also was not statistically significant, based on only 10 women with breast cancer, and the confidence interval (CI) was impressively wide: 0.9 to 22.4. In a later report based on an additional 4 years of data, the overall risk of breast cancer associated with the use of the estrogen-progestin sequential product was 0.9 (CI 0.7 to 1.1); in women with 7 to 11 years of follow-up, the relative risk was increased to 1.6 (CI 1.1 to 2.1).²²² However, the statistical power of this study continues to be limited, and there is no control group; the relative risk was calculated by using the expected breast cancer incidence in the general population.

Another case-control study used questionnaires to obtain information from both the cases and controls and also indicates a slightly increased risk of breast cancer associated with postmenopausal hormone therapy.²²³ Interestingly, this report indicates an increased risk only with sequential estrogen and progestin and not with the daily administration of combined estrogen and progestin (however, these conclusions were limited by the small numbers of subjects involved). This study contains statistical problems similar to the Uppsala study (e.g., the relative risk associated with estrogen-progestin use was 1.41, but the CI included 1.0 and was not statistically significant).

The latest reports from the Nurses' Health Study represent 16 years of follow-up (1976 to 1992).^224,225 During that period, 1935 cases of breast cancer were identified among more than 69,000 postmenopausal women. The analysis reveals that women who had used estrogen in the past (even for 10 or more years) were not at increased risk of breast cancer. However, the relative risk for current users was 1.46 (CI 1.22 to 1.74) for 5 to 9 years of use, and 1.46 (CI 1.20 to 1.76) for 10 or more years of use.

Because of the large numbers of subjects in the Nurses' Health Study and the careful analyses by the investigators, reports from this study must be given great credibility. The 16-year follow-up report is disturbing with its finding of an increased risk in current users. Because estrogen users may be examined more frequently, detection bias is a major concern. Notice that current users had a 14% higher prevalence of mammography compared with never users. Current users were different when compared with never users (history of benign breast disease, birth only once or twice, menarche at 13 years of age or younger, body mass index of 21 to 23). Another important consideration is the need to adjust for alcohol consumption, an accepted risk factor for breast cancer. In the Iowa Women's Health Study, an increased risk of breast cancer was observed only in women who consumed one drink or more of alcohol daily.²²⁶ The concern is that alcohol consumption raises estrogen levels in hormone users to high concentrations.^227,228 Although each of these factors standing alone would not explain the observed outcome in the Nurses' Health Study, what is the additive effect of all factors? Thus, the finding of an increased relative risk in long-term current users is not definitive and not free of all confounding variables. The size of the statistical risk is not outside of the range of influence by biases.

Based on 359 deaths from breast cancer, the risk of dying of breast cancer in the Nurses' Health Study was 0.80 (CI 0.60 to 1.07) for past users, 0.99 (CI 0.66 to 1.48) for current users with less than 5 years of use, and 1.45 (CI 1.01 to 2.09) with 5 or more years of use. These mortality data raise a question of “prevalence bias,” also labeled by statisticians as interdependence between the probabilities of disease incidence in a population (an issue of competing risks).²²⁹ Is it possible that the protection against cardiovascular disease is so great with long durations of estrogen use that the long-term current users develop a problem that is prevalent with aging: breast cancer? The never users, deprived of the cardiovascular benefit of estrogen, may develop cardiovascular disease before living long enough to experience breast cancer.

A case-control study from Australia that controlled for secular trends in estrogen use, type of menopause, and duration of estrogen use concludes that there was no evidence for an association between estrogen use and the risk of breast cancer in postmenopausal women.²³⁰

One helpful study specifically addressed the relation between the use of estrogen and benign breast disease.²³¹ This study is impressive in that it is based on 10,366 consecutive breast biopsy specimens with follow-up information on 4227 biopsy specimens in 3303 women (a mean duration of follow-up of 17 years). Analysis indicates that the use of estrogen was associated with a reduced risk of developing breast cancer. Importantly, in patients whose biopsy specimens showed atypical hyperplasia, the use of estrogen did not increase and even lowered the risk of breast cancer. Whereas the protective effect probably indicates surveillance bias, this is strong evidence that estrogen use does not increase the risk of breast cancer in women with surgically proven benign breast disease, even with atypia.

In a study of 1686 cases and 2077 controls in the eastern United States, the relative risk for current users was 1.1 (CI 0.7 to 1.6); for a duration of use of 15 or more years, the relative risk was 0.9 (CI 0.4 to 1.9).²³² As in the eastern United States, a study from Toronto found no evidence of an increased risk in either current or recent users or in users for up to 15 years.²³³ A case-control study from Washington found no increased risk of breast cancer with past or long-term current use of estrogen alone or with estrogen-progestin.²³⁴ These large case-control studies fail to support the conclusion of the Nurses' Health Study that current users are associated with an increased risk, even with long duration of use. On the other hand, other studies (of smaller size and limited statistical power) have found an increased risk of breast cancer in current users and long-term users.^235,236 A prospective study from the National Cancer Institute documented only an increase in the risk of in situ breast cancer (not invasive disease), possibly reflecting surveillance bias in women taking either estrogen alone or a combination of estrogen and progestin.²³⁷

The Iowa Women's Health Study, like the Nurses' Health Study, is prospectively following a cohort of women (selected in 1985). After 6 years of follow-up, a statistically significant increase in the risk of breast cancer could not be detected in ever users or current users of hormone therapy.²³⁸ A report through 8 years of follow-up focused on whether postmenopausal hormone therapy increased the risks for breast cancer and mortality in women with a family history of breast cancer.²³⁹ Even in women with a positive family history of breast cancer who were current users of hormone therapy for more than 5 years, there was no significant increase in the rate of breast cancer. A large case-control study found no increased risk of breast cancer associated with the ever use of estrogen alone or estrogen and progestin combinations, and when long-term use for 15 years or more was examined, again no increase in risk was detected.²⁴⁰

META-ANALYSES.

Meta-analysis is an increasingly popular statistical method in which many studies are combined and undergo rigorous analysis. The term meta-analysis was coined in 1976 to indicate the reanalysis of data to answer new questions.²⁴¹ The method was first used in social science and then in the late 1980s in medicine. Simply put, the purpose of a meta-analysis is to gain the statistical power that is lacking in individual studies.

An Australian meta-analysis of 23 studies of estrogen use and breast cancer concludes “unequivocally” that estrogen use did not alter the risk of breast cancer.²⁴² In the meta-analysis by Dupont and Page (Nashville, Tennessee), the authors conclude that “considerable and consistent” evidence exists that a daily dose of 0.625 mg of conjugated estrogens taken for several years does not appreciably increase the risk of breast cancer.²⁴³ They found no evidence of an association between the duration of treatment and the risk of breast cancer at this dosage. On the other hand, the data suggest that a daily dose of 1.25 mg of conjugated estrogens and higher may increase the risk of breast cancer. This analysis fails to reveal an increased risk in patients with a history of benign breast disease.

A third meta-analysis was from the Centers for Disease control (CDC).²⁴⁴ This meta-analysis was conducted using what the authors called a “dose-response curve” for duration of use. The curve for each study analyzed was calculated by plotting breast cancer risk against duration of estrogen use. The combined dose-response slope represents the average change in risk associated with estrogen use over time. The analysis concludes that duration of estrogen use is associated with an increased risk of breast cancer, regardless of whether menopause is natural or surgical. No increase in risk was noted in the first 5 years of use, but after 15 years of use, the risk was increased by 30%. The effect was present irrespective of other risk factors such as family history, parity, or history of benign breast disease. The effect of estrogen therapy on risk of breast cancer was enhanced in women with a positive family history of breast cancer.

A fourth meta-analysis from Spain concludes that estrogen is associated with a small, but statistically significant, increased relative risk of breast cancer and that the increased risk is higher among current users.²⁴⁵ Confining their analysis to a dose of 0.625 mg of conjugated estrogens, however, the Spanish epidemiologists could not detect a statistically significant increased risk. Indeed, this meta-analysis concludes that an estrogen dose of 0.625 mg of conjugated estrogens is safe.

A fifth meta-analysis from the epidemiologists associated with the Nurses' Health Study concludes (based on 25 case-control and 6 cohort studies) that there is no increased risk of breast cancer in ever users of estrogen.²⁴⁶ Current use was associated with an increased risk (which was lost 2 years after using estrogen), and there was a slight increase with more than 10 years of use (but there was no linear trend with increasing duration of use). This observation in long-term users could be influenced by an increased proportion of current users in this group, and the increased risk in current users could be a consequence of detection bias. The statistical power of this meta-analysis was in the ever use category, giving strength to its negative conclusion. This meta-analysis could not detect a link between risk of breast cancer and dosage. Nevertheless, we continue to be concerned with a possible effect of higher doses. The Australia, Nashville, and Spain meta-analyses indicate an increased risk with a daily dose of conjugated estrogens greater than 0.625 mg (or its equivalent).

The Nashville, CDC, and Nurses' Health analyses do not find an enhanced risk in women with a history of benign breast disease. In contrast to the CDC report, the Australia and Nurses' Health analyses found no link between positive family history and estrogen use. The Nashville and Spain investigators did not consider family history.

In a major overview and assessment (yet another meta-analysis) of the world's literature on postmenopausal hormone therapy commissioned by the American College of Physicians, the authors conclude that long-term use of estrogen was associated with a relative risk of breast cancer of 1.25 (CI 1.04 to 1.51).²⁴⁷ This conclusion, in our view, was not appropriately critical and represents a judgment that extends beyond the statistical power available from the many heterogeneic studies. The heterogeneity of the many studies is an important issue: different drugs, different doses, different methods of diagnosis, and different comparison and control groups. The Spanish meta-analysis is the only one to raise the concern that perhaps the heterogeneity is too great to allow an accurate meta-analysis of this literature.

A REANALYSIS OF THE WORLD LITERATURE.

A team of epidemiologists invited all investigators who had previously studied the association of postmenopausal hormone use and the risk of breast cancer (51 studies) to submit their original data for a collaborative combined reanalysis, an undertaking more rigorous than a standard meta-analysis. This analysis reached the following conclusions²⁴⁸:

• Ever users of postmenopausal hormones had an overall increased relative risk of breast cancer of 1.14.
  
• Current users for 5 or more years had a relative risk of 1.35 (CI 1.21 to 1.49), and the risk increased with increasing duration of use.
  
• Current and recent users had evidence of having only localized disease (no metastatic disease), and ever users had less metastatic disease.
  
• There was no effect of a family history of breast cancer.
  
• There was no increase in relative risk in past users.
  
• The increase in relative risk in current and recent users was greatest in women with lower body weights.
  

The most compelling reason to believe that long-term use of postmenopausal estrogen increases the risk of breast cancer is the inherent biologic plausibility. Factors known to increase a woman's exposure to estrogen are known to increase the risk of breast cancer, that is, age of menarche and age of menopause. In this report, the authors make a point of demonstrating that the quantitative effect of their conclusion is similar to extending the age of menopause. According to their calculations, current and recent hormone use was associated with a 2.3% increase in breast cancer risk per year, and the effect of the age of menopause was equivalent to a 2.8% increase in risk per year of delay. Many clinicians are attracted by the logic in this comparison; however, the steady exposure to postmenopausal estrogen is not exactly the same as extended exposure to cyclic ovarian function.

A strong indication that the conclusion of the reanalysis is subject to bias is the finding that current and recent hormone users had evidence only of localized disease. This is consistent with surveillance bias and hormone acceleration of tumors already present and thus detection at an early, less-aggressive stage.

THE INFLUENCE OF DETECTION AND SURVEILLANCE BIAS: AN ANSWER TO THE PARADOX OF INCREASED INCIDENCE AND DECREASED MORTALITY.

Notice that all of the studies that examine the mortality rates of women who were taking estrogen at the time of breast cancer diagnosis document improved survival rates.²⁰⁷ This undoubtedly reflects earlier diagnosis in users because the greater survival rate in current users is associated with a lower frequency of late-stage disease.^{115,249,250,251} Evidence also suggests that estrogen users develop better differentiated tumors, and that surveillance/detection bias is not the only explanation for better survival.^251,252 This implies that hormone treatment accelerates the growth of a malignant locus already in place, and it presents clinically at a less virulent and aggressive stage.

Increased use of mammography by hormone users is a well-recognized phenomenon. When corrected for use of mammography, an apparent increase in breast cancer in long-term estrogen users in a retrospective cohort study lost its statistical significance.²⁵³

If the conclusion of the reanalysis of the world's literature were correct, it would mean that there would be a detectable increase in deaths from breast cancer from hormone use. However, studies indicate a decreased risk of breast cancer mortality in postmenopausal hormone users. For example, the American Cancer Society 9-year prospective follow-up documents a 16% reduced risk of fatal breast cancer.²⁵⁴ The mortality data support the contention that accelerated tumor growth and surveillance bias are influencing the results of observational studies.

WHY IS THERE NO DEFINITIVE ANSWER DESPITE APPROXIMATELY 40 OBSERVATIONAL STUDIES?

Misinterpretation of epidemiologic data should not be attributed to epidemiologic methods but to their interpreters. When the impact of an association is large, it is relatively easy to demonstrate uniformity and consistency of results with case-control and cohort studies (observational studies). This can be appreciated in the impressive data indicating protection against cardiovascular disease by the use of postmenopausal estrogen. In the case of postmenopausal hormone therapy and the risk of breast cancer, we have neither the comfortable position produced by uniformity and consistency among observational studies nor the results of a randomized clinical trial. The lack of a definitive answer can be attributed to the following:

1. Individual studies lack the statistical power to overcome recognized and unrecognized biases. A large effect yields uniformity and consistency of results with case-control and cohort studies (good examples are the benefits of a reduction in the risks of endometrial and ovarian cancer with the use of oral contraception). Therefore, any impact of postmenopausal hormone therapy on the risk of breast cancer is unlikely to be great, otherwise the observational studies would have achieved uniformity and consistency of results.
   
2. Most of the available data are derived from a time when hormone dosages and schedules (higher doses and shorter durations) were different compared with current methods—the problem of heterogeneity. In addition to different doses and durations of exposure, heterogeneity is the result of different study designs, different sources for controls, different geographic locations, different populations, and different drugs.
   
3. The method of meta-analysis was developed to combine the results of small, randomized trials.²⁴¹ Rapidly (perhaps too rapidly), the method has been extended to observational studies, especially when the results of the individual studies are contradictory. Combining the results of contradictory studies, rather than the results of small (randomized) studies, is precisely when meta-analysis is weakest. Statistical analysis is not an appropriate method to address contradictory results. And even when the technique of meta-analysis is restricted to small randomized trials, because of various subjective and objective problems, the outcomes of subsequent large randomized, controlled trials were not predicted accurately 35% of the time by the previous meta-analyses.²⁵⁵ The method of meta-analysis is not infallible and does not always yield the truth.
   

The method of meta-analysis has not overcome the problem of achieving sufficient statistical power. The conclusions of meta-analysis of observational studies are not free of selection bias, detection bias, and the problem of a positive result emerging just by chance when multiple subgroup analyses are performed. Meta-analysis is further limited, not only when the data base is subject to biases as is the case with observational studies, but also when there is heterogeneity among the studies (different drugs, doses, durations of exposures, and populations). A meta-analysis can make the problem of bias worse by magnifying the significance level of erroneous results; a meta-analysis does not correct for design flaws in individual studies.

Therefore, our uncertainty will not be resolved by more case-control studies, more cohort studies, or more meta-analyses. Only a properly performed, randomized clinical trial will provide definitive information.

WHERE DOES THIS LEAVE CLINICIANS AND PATIENTS?

The lack of agreement, uniformity, and consistency in approximately 50 case-control and cohort studies indicate that the use of postmenopausal hormone therapy cannot be associated with a major impact on the risk of breast cancer, otherwise there would be agreement among the studies. It is helpful to compare this situation with three other conditions: the protection against ovarian cancer by oral contraceptives, the protection against coronary heart disease by postmenopausal estrogen use, and the increase in lung cancer from cigarette smoking. Clinicians believe each of these three epidemiologic associations despite the lack of a single randomized clinical trial because all of the studies say the same thing—an impressive agreement and uniformity among observational studies. The results with postmenopausal hormone therapy and the risk of breast cancer indicate either a small impact of estrogen use or the effect of biases that can be eliminated only by a large, randomized trial such as the ongoing Women's Health Initiative.

If estrogen use were associated with an increased risk of breast cancer, would not an impact on mortality be expected? In the mortality report from the Leisure World follow-up study in California, the risk of breast cancer mortality was reduced by 19%, and a similar reduction in fatal breast cancer has been documented in the Nurses' Health Study and in the American Cancer Society cohort.^115,254,256 This lower relative risk probably is influenced by surveillance bias and by the presence of better differentiated tumors in estrogen users, but there is no evidence that women using estrogen for a long time are dying of breast cancer at a greater rate.

Doses of estrogen known to protect against osteoporosis and cardiovascular disease (0.625 mg of conjugated estrogens and 1.0 mg of estradiol) currently are not known to be associated with any clear-cut increased risk of breast cancer. However, because of the concern raised by some studies and reviews that there is a slightly increased risk of breast cancer associated with long-term use of postmenopausal estrogen, this issue requires discussion during the clinician-patient dialogue regarding postmenopausal hormone therapy.

The comfort found in large numbers of subjects with epidemiologic research is lost to us when we must make clinical decisions with individual patients. If we wish to minimize the uncertainty from imprecise measurements, an appropriate strategy must be adopted. If we wish to emphasize the possibility or probability of an outcome, we will adopt another. In our view, it is appropriate to emphasize the benefits of postmenopausal hormone therapy, point out the continuing concern regarding the relation between estrogen use and breast cancer (particularly long-term use), and emphasize the absence of definitive evidence linking such therapy to an increased risk of breast cancer.

THE RISK OF BREAST CANCER AND ESTROGEN-PROGESTIN THERAPY.

The addition of a progestational agent to postmenopausal estrogen therapy is accepted as a standard part of the treatment program. The reason for this combined estrogen-progestin approach is the need to prevent the increased risk of endometrial cancer associated with exposure to unopposed estrogen. Although endometrial cancer is not frequently encountered and survival rates are excellent with early disease, the fear of this cancer is a major force in patient continuance, and, therefore, the combined approach is warranted. Clinicians and patients have rapidly turned to the method of a daily combination of estrogen and a progestin to overcome bleeding, which is the second major continuance problem.

Only two reports claim that the addition of a progestational agent protects against breast cancer.^257,258 The first was limited by bias in treatment selection (the breast cancer risk factor profiles were not matched in the treated and untreated groups). The second (the Nachtigall study), although it is the only randomized, placebo-controlled trial, was hampered by small numbers of subjects.

The available epidemiologic evidence on the impact of combined estrogen-progestin treatment indicates neither a protective nor a detrimental effect has been convincingly demonstrated; studies find that the addition of a progestin does not change the findings with estrogen alone.^{225,234,235,236,237} Balancing the information available involving all of the health issues affected by hormone therapy, a combined estrogen-progestin program in appropriate doses continues to offer significant benefits for postmenopausal women. As time goes on, more studies and greater duration of use should provide better answers to many of our questions. Because of the magnitude of the postmenopausal female population, these questions deserve continuing biologic and epidemiologic research from both the public health and individual points of view.

SUMMARY: POSTMENOPAUSAL HORMONE THERAPY AND BREAST CANCER.

Some epidemiologic case-control and cohort studies conclude that long-term (5 or more years) of current use of postmenopausal hormone therapy is associated with a slight increase in the risk of breast cancer. This conclusion might result from confounding biases, particularly detection and surveillance bias.

• All epidemiologic studies fail to find an increased risk of breast cancer associated with short-term (less than 5 years) use or past use of postmenopausal hormone therapy.
  
• Epidemiologic data agree that the addition of a progestin to the treatment regimen neither increases nor decreases the risk observed in individual studies.
  
• Epidemiologic data indicate that a positive family history of breast cancer should not be a contraindication to the use of postmenopausal hormone therapy.
  
• Women who develop breast cancer while using postmenopausal hormone therapy have a reduced risk of dying from breast cancer. This is because of two factors: (1) increased surveillance and early detection; and (2) acceleration of tumor growth so that tumors appear at a less virulent and aggressive stage.
  

Endometrial Cancer, Endometrioid Tumors, and Endometriosis

Gynecologic oncologists report that patients who have had stage I and II adenocarcinoma of the endometrium can take estrogen without fear of an increased risk of recurrence or a decrease in disease-free interval.^61,62,63,64 Nothing is known about the risk in patients with more advanced disease. If a high-risk tumor is estrogen and progesterone receptor negative, it seems reasonable to allow immediate hormone therapy. Because the latent period with endometrial cancer is relatively short, a period of time (5 years) without evidence of recurrence would increase the likelihood of safety on an estrogen program. We recommend that hormone therapy be avoided in patients with high-risk tumors that are receptor positive until 5 years have elapsed. The combination of estrogen-progestin is recommended in view of the potential protective action of the progestational agent. A similar approach makes sense for patients previously treated for endometrioid tumors of the ovary. In view of the fact that adenocarcinoma has been reported in patients with pelvic endometriosis and on unopposed estrogen, the combined estrogen-progestin program is advised in patients with a history of endometriosis.^65,66

Should a Woman Who Has Had Breast Cancer Use Postmenopausal Hormones?

The increasing incidence of breast cancer, together with earlier detection and treatment, is producing a growing pool of patients for whom the question of estrogen treatment is important and at the same time difficult to answer. The problem is easy to articulate: there are no data. There are absolutely no published clinical trials of sufficient size and scope in which the impact of estrogen treatment has been documented when given to women with previously treated breast cancer.

Because there is good reason to believe that breast cancer is hormonally influenced, it is not hard to understand the breast surgeon or medical oncologist who believes that estrogen treatment is foolish and dangerous. Yet that position is just as unencumbered by data as the position of the gynecologist who believes that appropriate patients stand to benefit more from estrogen compared with the unknown risk of breast cancer recurrence.

The most useful prognostic information in women with operable breast cancer has been the histologic status of the axillary lymph nodes. At 10 years, only 25% of patients with positive nodes are free of disease compared with 75% of patients with negative nodes. If more than three nodes are involved, the 10-year survival rate drops to 13%. Because of this recognition for the importance of the axillary nodes, the traditional approach to breast cancer (the Halsted surgical approach) was based on the concept that breast cancer is a disease of stepwise progression. There has been an important change in concept. Breast cancer is now viewed as a systemic disease, with spread to local and distant sites at the same time. Breast cancer is best viewed as occultly metastatic (microscopically disseminated) at the time of presentation. Dissemination of tumor cells has occurred by the time of surgery in many patients, and it is concern over the possible response of these cells that fires the debate over this question: Should women who have had breast cancer take postmenopausal hormones? The argument that postmenopausal hormone therapy should not be given to women who have had breast cancer is a reasonable one. It is based on the recognition of a large body of evidence that indicates that breast cancer is a hormone-responsive tumor. The overriding fear of many clinicians (and patients) is that metastatic cells are present (perhaps being controlled by various host defense factors) that will be susceptible to stimulation by exogenous hormones.²⁵⁹ However, many women who have had breast cancer are aware of the benefits of postmenopausal hormone treatment (especially protection against cardiovascular disease and osteoporosis) and are asking clinicians to help make this risk-benefit decision. In addition, some women experience such severe hot flushing and vaginal dryness that they are willing to consider hormonal treatment.

Sitting on the other side of this debate is the clinician who has been impressed by the breast cancer studies with positive results reviewed in this chapter. Because of the current lack of epidemiologic data, both sides of this debate are strongly influenced by theoretical considerations and clinical experiences, which, unfortunately, often become an obstacle to the patient's own informed choice.

There is one small series in which a combination of 0.625 conjugated estrogens and 0.15 mg of norgestrel was given continuously for a short period of time (a maximum of 6 months) to women who had been previously treated for breast cancer.²⁶⁰ Over the next 2 years, no patients developed recurrence. Another small series (25 and then 77 women with breast cancer ranging from in situ to stage III disease) received estrogen-progestin therapy for 24 to 82 months; the recurrence rate was not greater than that expected.^261,262 From this group of patients, 41 breast cancer survivors receiving hormone therapy had the same outcomes when compared with 82 women selected from a cancer registry and not taking hormones.²⁶³ In a report from Australia, 90 women with a history of breast cancer who were given a combination of estrogen and progestin had lower mortality and recurrence rates; however, the dose of progestin was high (which in itself can be therapeutic), and treatment was not randomized.²⁶⁴ In a follow-up of 49 women treated with estrogen after treatment for localized breast cancer, only one patient developed recurrent disease.²⁶⁵ In another series of 114 women, hormone treatment of disease-free patients was associated with a low rate of recurrence.²⁶⁶ These patients have had both positive and negative nodes and estrogen receptor status. Whereas the results conform to an incidence of recurrent disease no greater than expected, the outcomes may reflect biases in clinician and patient decision-making that can only be overcome with a proper long-term, randomized clinical trial.

A clinical U.S. trial is currently under way, providing estrogen to randomized women who have been treated for stage I or II breast cancer, who have been disease free for at least 2 years from estrogen receptor-negative disease or 10 years if the estrogen receptor status is unknown.²⁶⁷

Because of better treatment and earlier diagnosis, 50% to 75% of women diagnosed with breast cancer are cured.²⁶⁸ Of 100 patients with breast cancer, about 60 will be cured by mastectomy or breast-conserving surgery with radiotherapy and would receive no benefit from adjuvant treatment. Is this group safe for hormone therapy? Of the remaining 40, some will live longer (average of 2 to 3 years) because of adjuvant treatment, but only a few. Is the unknown risk with exogenous hormone treatment worth it in this group? Although intuitively it seems that the risk-benefit ratio would be more favorable in the presence of negative nodes, negative receptors, and small tumors, are negative estrogen and progesterone receptor assessments sufficient to conclude that the cancer is not sensitive to hormones? And if the patient is in the high-cure category, does the receptor status make any difference? Receptor status is not absolute; it is always a relative measure. The answers to all of these questions are not known.

Patients and clinicians have to incorporate all of these considerations into this medical decision. But patients have to take an unknown risk if they want the benefits of estrogen treatment, and clinicians have to take an unknown medical-legal risk. Some patients will choose to take estrogen, judging the benefits to be worth the unknown risk. Physicians should support patients in this decision. Other patients will prefer to avoid any unknown risks. These patients, too, deserve support in their decision.

Women With Cardiovascular Disease

The woman with a previous history of a cardiovascular event, such as a myocardial infarction or stroke, is the woman who needs the protection of estrogen against cardiovascular disease. Evidence supports this contention. In the Leisure World study, estrogen users with previous myocardial infarctions, strokes, or hypertension had a 50% reduction in risk for death from a subsequent stroke or myocardial infarction.²⁵⁶ In the Lipids Research Clinics study, the cardiovascular mortality in women with previous cardiovascular disease was reduced 85%. And, most impressively, in women with severe coronary disease (documented by arteriography), estrogen users had a 97% survival rate at 5 years compared with a significantly different 81% rate in nonusers.²⁶⁹ In women with mild to moderate disease, there was no difference at 5 years, but at 10 years, estrogen users had a 96% survival rate compared with 85% in nonusers.

Estrogen therapy reduces the rate of restenosis in women who have undergone either coronary angioplasty or percutaneous atherectomy.²⁷⁰ In women who have undergone coronary artery bypass surgery, the 10-year survival rate in estrogen users was 81.4% compared with 65.1% in nonusers.²⁷¹ In women who have been treated with estrogen after coronary angioplasty, case-control analysis indicates that the treated women had a better survival rate and experienced fewer subsequent myocardial infarctions.²⁷² The number of patients on estrogen-progestin was too small in this study for analysis. A retrospective cohort study in Seattle determined prognosis in women surviving a myocardial infarction and detected a 36% reduced risk of reinfarction in current estrogen users, although small numbers prevented the achievement of statistical significance.²⁷³ All of these studies indicate reduced risks for adverse clinical events and support the use of postmenopausal hormone therapy in women with coronary heart disease. Furthermore, hormone therapy can improve the state of atherosclerosis, that is, produce a regression in disease.

Imaging studies document a reduction in intimal thickening in postmenopausal women who are estrogen users compared with nonusers, and this beneficial effect is not compromised by the addition of a progestational agent to the treatment regimen.^274,275 Thus, postmenopausal hormonal therapy can bring about a reduction in atherosclerosis, and this effect is comparable with that produced by a lipid-lowering drug.^274,276

In our opinion, estrogen treatment with the appropriate, standard dose is indicated and safe for patients with cardiovascular disease. The dose of estrogen is important because it is becoming increasingly apparent that the beneficial cardiovascular effects of estrogen are restricted to a relatively narrow therapeutic window; the benefits may be lost at does of estrogen equivalent to 1.25 mg of conjugated estrogens.

Women With Diabetes Mellitus

A strong argument can be made that postmenopausal women with diabetes mellitus can benefit from the cardioprotective actions of estrogen. In addition, estrogen may improve the metabolic changes associated with diabetes. In a double-blind, cross-over, placebo-controlled study of postmenopausal women with noninsulin-dependent diabetes mellitus, estrogen treatment improved all glucose metabolic parameters (including insulin resistance), the lipoprotein profile, and measurements of androgenicity.²⁷⁷ These changes should reduce the risk of cardiovascular disease; however, long-term studies are not available.

Women With Liver Disease

Osteoporosis is a major consequence of chronic liver disease. Although other bone-preserving agents can be used, none provides the multisystem benefits associated with estrogen therapy. In an evaluation of liver chemistries in a group of patients with primary biliary cirrhosis, standard hormone therapy doses produced no adverse changes over a period of 1 year.²⁷⁸ We recommend measurement of liver chemistries after 1 month of treatment, and every 6 months thereafter, with continuing hormone therapy in the absence of deterioration.

Many clinicians believe that estrogen administered intravaginally is not absorbed, and systemic effects can be avoided. However, estrogen is absorbed readily from a vagina with immature, atrophic mucosa.²⁷⁹ The initial absorption is rapid, and relatively high circulating levels of estrogen are easily reached. As the vaginal mucosa cornifies, absorption decreases.²⁸⁰ This decline takes approximately 3 to 4 months, after which lesser but still significant absorption takes place. European studies demonstrate that vaginal maturation can be achieved with a vaginal ring (that is left in place for 3 months) having incredibly small doses of estrogen, with a low-level absorption that is free of systemic effects.^281,282 This is an acceptable treatment to relieve atrophic vaginal symptoms in women with contraindications to estrogen treatment.

A nonoral route of administration should be considered for women at high risk of gallbladder disease because the nonoral route avoids the production of a more lithogenic bile (which is associated with oral treatment).¹⁴⁹ Close surveillance is indicated for some patients with seizure disorders, familial hyperlipidemias (elevated triglycerides), and migraine headaches. Patients with migraine headaches often improve if a daily, continuous method of treatment is used, eliminating a cyclic change in hormone levels that can trigger headaches.

Conditions that do not represent contraindications include controlled hypertension, diabetes mellitus, smoking, and varicose veins. The belief that estrogen is potentially harmful with each of these clinical situations is derived from old studies of high-dose oral contraceptives. Estrogen in appropriate doses is acceptable in the presence of these conditions.

No other cancers (besides those mentioned earlier) are known to be adversely affected by hormone therapy. Postmenopausal hormone therapy can be administered to all patients with cervical, ovarian, or vulvar malignancies.

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