Postmenopausal Hormone Therapy

There is little question that women who suffer from vasomotor symptoms (VMS) or vaginal atrophy can be relieved by use of estrogen. However, over recent decades, the focus of menopausal hormone therapy (MHT) has shifted significantly. In the 1980s and 1990s, based upon observational cohort data that implied that women who used MHT had fewer cases of cardiovascular disease, dementia, and cancer, enthusiasm built for a long-term, preventive strategy, as opposed to a short-term, symptom-based strategy for MHT use. Since the primary findings from the Women’s Health Initiative (WHI) hormone trial^{1, 2} failed to demonstrate any cardiovascular benefit from estrogen, either given alone or in combination with a progestin (to women with a uterus), the early millennium was marked by a movement away from MHT entirely,³ as the absence of this benefit became a perception of excessive or unacceptable risk. However, over the past 5–6 years, we have been able to observe long-term outcomes of the WHI women (which have chiefly shown a cessation of risk when therapy was stopped)⁴ and a series of clinical trials demonstrating a relative lack of effectiveness of many alternatives to MHT.⁵ Thus, MHT is repositioned as an effective treatment for menopausal symptoms, appropriate for short term for most women who feel a need for symptom control. MHT remains an option for women whose menopausal symptoms do not abate over time, especially when the symptoms are severe and alternative methods have not been helpful.⁶ This chapter discusses the available hormonal preparations for treatment and their practical clinical use, along with the medical evidence supporting them, and the principal risks and benefits to be gained, and ends with a series of questions that remain to be answered about the role of MHT.

The dose of estrogen that is effective in maintaining the axial and peripheral bone mass in most women is equivalent to 0.625 mg of daily, oral conjugated estrogens.^{7, 8} However, there is potential for antiresorptive therapy even at very low doses of estrogen. In a randomized trial of 167 women who were aged 65 or older, Prestwood et al. showed that as little as 0.25 mg oral micronized estradiol daily increased bone mineral density at the hip, spine and whole body.⁹ Transdermal doses as low as 0.14 µg have also been shown to be effective as an antiresorptive.¹⁰ This dose equivalent is frequently effective for relief of VMS and is a useful clinical starting point for treatment. The relative potencies of commercially available estrogens are important to keep in mind when prescribing estrogen. Clinicians should be familiar with these relative potencies, which are based on antiresorptive activity in bone, ability to suppress follicle stimulating hormone (FSH) secretion, or to cause induction of liver proteins. These are not precise, but form reasonable guidelines for flexible dosing. Relative potencies are listed in Table 1.

Table 1 Relative effective estrogen doses^{11, 12, 13}

FSH, follicle stimulating hormone.

Esterified estrogens are synthetically prepared from plant precursors and are composed mostly of sodium estrone sulfate with a 6–15% component of sodium equilin sulfate. Estradiol valerate is rapidly hydrolyzed to estradiol, and the pharmacology and effects therefore are comparable at similar dosages.¹⁴

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,¹⁵ although there was no suppression of FSH observed with oral estriol, presumably because its undergoes conjugation through its first-pass effect on the liver.¹⁶

Transdermal administration of estrogens

Estradiol may be administered via an adherent skin patch, changed weekly or twice weekly, a gel applied directly to the skin of the upper arm, or a spray (‘mist’) applied to the inner forearm. The current generation of patches has the hormone dissolved and distributed throughout the adhesive matrix. Patch estrogen is available in doses ranging from 14 µg to 100 µg.

The effect of steroids on the liver is determined by the type of steroid, the dose, and the route of administration. A theoretical obstacle to the use of transdermal hormone therapy has been concern about the lack of benefit on the lipoprotein profile. However, a theoretical benefit of transdermal estradiol administration is its potential to be less effective at inducing liver production of clotting factors. The concentration of estrogen in the portal system after oral administration is four to five times higher than that in the periphery.¹⁷ Furthermore, the estradiol:estrone ratio differs in the portal system, with an unphysiologic, relative excess of estrone to estradiol.

Key differences between oral and non-oral estrogen administration

Short-term studies (6 weeks) document increased catabolism of low-density lipoprotein (LDL) and increased production of apoprotein A-I with oral estrogen, but no effect with transdermal estrogen.^{18, 19} Furthermore, a 2-year study in Los Angeles with a transdermal dose (100 µg) detected no significant change in high-density lipoprotein (HDL) cholesterol levels.²⁰ On the other hand, data from the UK indicate that the transdermal administration 50 µg of estradiol twice a week is equivalent to 0.625 mg of oral conjugated estrogens, on bone density and lipids over a duration of 3 years.²¹ It may be that transdermal estradiol causes similar changes in lipoproteins over time and with higher doses, but the bulk of the evidence suggests that it is less effective than oral estrogen in inducing favorable lipoprotein changes (increased HDL and decreased LDL). A potential advantage of transdermal estradiol is its null effect on triglycerides. However, the biological significance of the lipid and lipoprotein changes induced by MHT is unclear. MHT-induced lipoproteins are not strong predictors of subsequent cardiovascular disease and thus the salutary changes in HDL (increased) and LDL (decreased) cholesterol associated with oral estrogen use may not be of great clinical import.

There is suggestive evidence that non-oral administration of estrogen is associated with reduced risk of venous thromboembolism (VTE) and deep venous thrombosis (DVT). A recent meta-analysis of observational cohorts indicates an approximate doubling of the risk of VTE with oral estrogen, but no increased risk when transdermal estradiol is used.²² Interestingly, this doubling of VTE risk is seen only in settings where estrogen is given with progestin. In the WHI, women without a uterus taking estrogen (E) alone did not have a statistically significantly increased risk of pulmonary embolism (HR 1.34, 95% CI 0.87–2.06), whereas women taking estrogen plus progestin (E+P) experienced a doubling of risk compared to women randomized to placebo (HR 2.13, 95% CI 1.39–3.25).^{1, 2}

Non-FDA-approved regimens

Estradiol pellets are available in doses of 25, 50, and 75 mg for subcutaneous administration twice yearly. These formulations are not FDA-approved. The 25 mg pellet provides blood levels in the range of 40–60 pg/ml (150–220 pmol/l), levels which are comparable with those obtained with the standard oral dose.²³ However, the dosing can be cumulative, and after several years blood levels can rise to two to three times higher. Significant blood levels of estradiol may 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. Estradiol pellets confer no advantages over currently available, FDA-approved treatment regimens, have large potential variations in dosing, and a very long half life. Women receiving pellets should be monitored with periodic blood estradiol levels; levels greater than 200 pg/ml (and, preferably, 100 pg/ml) should be avoided and may well exacerbate harms associated with MHT.

Estrogen creams exist as non-FDA-approved, pharmacy compounded estradiol preparations, many admixed with estrone (Bi-Est) and estriol (Tri-Est). These are often advertised to the lay public as safer alternatives to FDA-approved MHT formulations. The American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine have recently published a Committee Opinion that evaluates these treatments.²⁴ There are insufficient data to recommend that compounded hormones are safe and effective. Individual pharmacokinetics of these compounds are not known. Thus practitioners are encouraged to avail themselves of the large number of FDA approved formulations of MHT that are demonstrated to be safe and effective and to recommend against the use of pharmacy compounded MHT.

Monitoring the estradiol blood level in postmenopausal women receiving MHT is not straightforward. 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, this process is not consistent within and between individuals. For example, a highly specific and sensitive assay for estradiol might detect very low levels of estradiol in women receiving 0.625 mg of conjugated equine estrogens (<10 pg/ml); however, most clinical assays would be expected to report a level of 40–100 pg/ml (150–370 pmol/l) in the same women. Blood estradiol levels may be useful in selected patients, such as a patient who requests ever-increasing doses of estradiol for the treatment of symptoms. If estradiol is to be measured, the patient should be taking estradiol only containing MHT, and not a multi-estrogen regimen, such as conjugated equine estrogens. The blood level should be drawn at a time that is consistent with the pharmacokinetics of the compound. For example, a women using a weekly estradiol patch at a dose of 100 µg who fails to note improvement in her symptoms can have her estradiol level measured at mid-week, 3.5 days after patch application (or on the second day after application of a twice-weekly patch). An estradiol level below 50 pg/ml is suggestive of inadequate transdermal absorption of the hormone, and higher doses or alternative methods of hormone delivery should be considered. In one study, 50% of women obtained relief from hot flashes with a mean serum estradiol level of 61 pg/ml.²⁵ This study utilized radioimmunoassay to determine circulating estradiol concentration; current methods based on mass spectrometry or equilibrium dialysis might indicate relief at even lower hormone levels.

Remember that because FSH is regulated by factors other than estrogen (i.e., inhibin), FSH levels cannot be used to reliably monitor estrogen dosage. Menopausal hormone therapy produces only a 10–20% decrease in FSH and luteinizing hormone, and there is great individual variability in the responses.²⁶

Continuous combined MHT

The continuous/combined method of treatment evolved to improve patient satisfaction with hormones and avoid bleeding and other adverse cyclic symptoms. The continuous activity of progestin allows the use of lower doses that, by virtue of daily availability, inhibit endometrial growth. There is evidence that continuous progestin administration is highly protective against the development of endometrial hyperplasia and cancer.²⁷ This approach involves the continuous daily use of the estrogen–progestin combinations listed in Table 2.

Table 2 Systemic MHT regimens

The most common sequential method in the US involves estrogen administration with 0.625 mg of conjugated estrogens or 1.0 mg of micronized estradiol daily. A daily dose of 5–10 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.³⁰ Oral estrogen may also be given with micronized progesterone, 200 mg nightly, for 12 days per month. This regimen has demonstrated satisfactory endometrial safety by biopsy criteria in 114 women followed for 3 years.³¹ Micronized progesterone has been administered vaginally as well, and appears effective in limited numbers of women.³²

Progestin withdrawal bleeding can be expected in 80–90% of women on a sequential regimen.³³ The sequential regimen also can cause adverse symptoms related to the relatively higher dose of progestin such as breast tenderness, bloating, fluid retention, and depression. Switching from MPA to norethindrone may relieve these complaints. However, for many women, the preferred regimen is continuous because it is likely to result in amenorrhea.

In the sequential regimen (Table 2), the amount of norethindrone equivalent to 10 mg of MPA is 1.0 mg.³⁴ Norethindrone is currently available in a dose of 0.35 mg in the progestin-only minipill oral contraceptive; thus three of these pills can be taken daily for 10–12 days per month. The lowest effective dose of micronized progesterone and the proper dose for continuous daily administration has not been well established; however, a short-term (6-month) study indicates that 100 mg/day was effective.³⁵ Micronized progesterone can be absorbed somewhat irregularly and metabolized rapidly. Peaks in blood levels of progesterone, and active metabolites are associated with sedation, and for some, a decrease in anxiety or insomnia. Rarely, women will report dysphoric mood or excessive sedation from micronized progesterone. Because of its potential to cause sedation, micronized progesterone is best taken at bedtime. Alternative dosing regimens for progesterone described include vaginal capsule placement and the use of vaginal progesterone gel (Crinone 4–8%). These latter regimens are far less well tested than MPA or micronized progesterone and endometrial surveillance should be conducted to avoid long-term complications of therapy. 

For optimal bone protection, MHT should be combined with adequate calcium intake (best achieved without supplementation, see www.nof.org) and vitamin D (600–4000 IU/day of vitamin D3 is sufficient for most women).³⁶

MHT adherence is generally low.³⁷ One of the best predictors of adherence is the presence of significant menopausal symptoms, and thus a clear perception of benefit from therapy.³⁸ The two most common reasons why women discontinue or do not start hormone treatment are fear of cancer and vaginal bleeding.³⁹ The addition of a progestational agent effectively prevents endometrial cancer. However, persistent vaginal bleeding with the traditional sequential regimen is a disadvantage. To go from 80–90% monthly withdrawal bleeding to no bleeding represents a major accomplishment, and thus, the continuous approach has a significant advantage for most women.

Approximately 25–30% of women report vaginal dryness or dyspareunia at menopause. These symptoms do not improve without treatment. Currently, only estrogen is FDA approved as a treatment for symptoms of vaginal atrophy. Dehydroepiandrosterone (DHEA; Prasterone) is currently under investigation, as is a systemic selective estrogen receptor modulator (SERM),⁴⁰ osfemipine, for this indication.^{41, 42}

Vaginal estradiol can be given as a cream, tablet or silastic ring. Conjugated estrogens can also be administered as a cream. Available regimens are indicated in Table 3. Current dosing of vaginal estrogen is believed to be low enough that progestin is not required for endometrial protection; however, endometrial surveillance with ultrasound should be considered periodically and any unscheduled vaginal bleeding should be investigated diligently.

Table 3 Vaginal estrogen preparations

What is a normal bleeding pattern on MHT? 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 to determine whether further endometrial surveillance is needed. 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 more likely to be associated with proliferative endometrium. Bleeding beginning on day 11 or later was associated with secretory endometrium, presumably indicating less need for biopsy.⁴³ Although this concept was felt to constitute a practical test to select women who were more likely to benefit from an endometrial biopsy, subsequent study of a relatively large sample of 413 postmenopausal women demonstrated that the day of bleeding does not predict endometrial safety.⁴⁴ Late, regular withdrawal bleeding on a sequential program does not give 100% assurance that there is no hyperplasia and perhaps endometrial cancer.

With sequential therapy, approximately 80–90% of women can be expected to have monthly withdrawal bleeding. With continuous, combined estrogen–progestin therapy, 40–60% of patients can be expected to experience breakthrough bleeding during the first 6 months of treatment; however, this percentage decreases to 10–20% after 1 year.^{31, 33} Although amenorrhea with continuous, combined therapy is a gratifying accomplishment, breakthrough bleeding is relatively frequent, and can become a difficult management problem, as it often causes alarm.

Why call it breakthrough bleeding? The bleeding experienced by women on continuous, combined therapy is similar to that seen with oral contraceptives. It originates from an endometrium dominated by progestational influence; hence, the endometrium usually is atrophic and yields little, if anything, to an 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. For most patients, the incidence of breakthrough bleeding with oral contraceptives is greatest in the first few months of treatment and usually disappears thereafter. 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. 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.

It is believed that 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 it is that she will experience breakthrough bleeding if switched to a continuous combined regimen. Some clinicians, therefore, recommend starting with a sequential progestin regimen and converting to a continuous progestin method years later. However, it is just as reasonable to start with a continuous method because women who achieve amenorrhea are highly appreciative. For those who develop bothersome breakthrough bleeding, it is always possible to return to the sequential program.

Options to control intractable breakthrough bleeding for a woman who wishes to remain on hormone therapy include endometrial ablation and progestin intrauterine device (IUD) use. With ablation, concern exists regarding the potential for isolated, residual endometrium to progress to carcinoma without recognition. The progestin IUD releases local progestin (levonorgestrel) in doses sufficient to be effective in suppressing endometrial response and often bleeding. Its chief limitations are the relatively large size of the insertion device, which can be problematic for women who are long past menopause, and the long-term potential for persistent spotting.^{45, 46} Patients also need to be notified that the levonorgestrel IUD is not FDA approved for this use. Finally, in cases where there are no other options, vaginal hysterectomy provides a definitive alternative.

It is not essential to routinely perform endometrial biopsies before initiating hormone therapy. Endometrial abnormalities in asymptomatic postmenopausal women are rare.^{47, 48} A reasonable economic moderation would be to limit pretreatment biopsies (using the plastic endometrial suction device in the office) to patients at highest 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 reasonable, and routine, periodic biopsies are not necessary when well-tested regimens are used. However, women who elect to be treated with unopposed estrogen, as well as those who are using ‘nonstandard’ progestin regimens (such as quarterly progestin, or preparations such as Crinone, which have not been extensively studied) require endometrial surveillance at least once a year.

Endometrial surveillance can be accomplished by aspiration biopsy (pipelle or its equivalent) or using transvaginal ultrasound with or without fluid contrast. For most situations, a transvaginal ultrasound with a sagittal endometrial thickness measurement less than 5 mm is reassuring.^{49, 50, 51} In one study of 85 women who underwent both ultrasound and biopsy, it was estimated that 75% of biopsies could be avoided by appropriate interpretation of ultrasound.^{52, 53} It is important that the ultrasonographer be experienced and provide a clear picture of the midplane of the uterine cavity. If there is uncertainty about the quality of the image, an endometrial biopsy should be performed. Common reasons for an unsatisfactory ultrasound image include the presence of fibroids, and an axial uterus that is in the same plane as the ultrasound probe. If bleeding persists despite a normal ultrasound or negative biopsy, office hysteroscopy or fluid contrast ultrasound can be performed to rule out polyps or submucous myomas. Since curettage and aspiration biopsy alone can miss focal endometrial disease,⁵⁴ hysteroscopy should be performed in concert with curettage procedures. The lack of a thin endometrium in women on MHT should not be a cause for alarm—just an indication for a biopsy or further evaluation.^{50, 55, 56} 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.⁵⁷ Doppler velocimetry does not improve the accuracy of discriminating between normal and abnormal endometrium.⁵⁸ Most importantly, a clinician should not be satisfied with “normal” findings on ultrasonography if a patient has persistent bleeding. Biopsies and ultrasound are imperfect monitoring tools and have false negative findings.⁵⁹ Regimens that do not involve at least 12 days of progestin a month, or in which progestin non-adherence occurs, carry a higher risk of endometrial abnormalities and cancers.^{60, 61} Continuous use of daily progestin carries a risk lower than that of no hormone use.²⁷ Vigilance on the part of the clinician is needed to detect endometrial cancer at the earliest possible stage, when it is amenable to curative treatment.

Many women do not tolerate treatment with progestational hormones. Typical side-effects include breast tenderness, bloating, and even depression. These reactions are significant reasons for discontinuation of MHT. While these reactions are likely rare, and do not appear to be major limitations to the conduct of randomized, clinical trials,^{62, 63} such women are overrepresented in clinical practice, as they present a clinical challenge. Oral, micronized progesterone given in 200 mg nightly as a sequential agent or 100 mg nightly in a continuous, combined regimen has been shown to result in the most favorable lipid profile of any of the progestins, effectively prevented endometrial hyperplasia over 3 years, and was associated with improved mood and few side-effects in the Postmenopausal Estrogens/Progestins Interventions (PEPI) trial^{31, 64} and other short-term studies.⁶⁵ Nonetheless, some patients are sensitive to micronized progesterone or to MPA.

Several clinical strategies can be employed to help patients maintain endometrial protection without incurring bothersome side-effects. The first is to reduce the frequency with which progestin is administered. While it is well documented that monthly or continuous exposure to progestin effectively prevents endometrial hyperplasia, experience with other regimens is limited. In one clinical trial, the administration of MPA every 3 months was associated with longer, heavier menses, more unscheduled bleeding and a 1.5% incidence of hyperplasia at 1 year, whereas in another, overall bleeding was less but the incidence of hyperplasia was approximately 4%.^{66, 67} 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 very high dosage, 20 mg of MPA daily for 14 days.⁶⁸ The Scandinavian LongCycle Study, a clinical trial scheduled to last 5 years, was cancelled after 3 years because of a 12% incidence of endometrial hyperplasia and four cases of endometrial cancer.⁶⁹ In this trial, the relatively short duration of progestin administration (10 days) may have been related to its ineffectiveness in preventing hyperplasia; however, norethindrone at a dose of 1 mg was used, which is a relatively potent progestin. Therefore, if a patient chooses this regimen as a means of managing progestin intolerance, more intensive endometrial monitoring is required on an ongoing basis. While ultrasound can be used to monitor in these cases, an annual endometrial biopsy should be strongly considered. Indeed, any program that differs from the standard regimen and is untested by clinical studies of sufficient length and subject numbers, requires periodic surveillance of the endometrium.

Alternative progestins can be tried. In a sequential regimen, the dose of norethindrone is 0.7–1 mg (available in the progestin-only minipill oral contraceptive; each pill contains 0.35 mg of norethindrone and thus two pills must be taken daily for 12–14 days each month). In the continuous, combined regimen, the dose of norethindrone is 0.35 mg daily. Vaginal administration of the micronized progesterone capsule may avoid some of these sedative or other untoward side-effects³².

Progesterone can also 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.⁷⁰ The administration of 90 mg every 2 days produces secretory changes in the endometrium.⁷¹ However, no long-term studies of sufficient size are available documenting endometrial safety and metabolic effects. Thus, women using this regimen should undergo periodic endometrial monitoring. It should also be noted that the use of vaginal progesterone gel is substantially more expensive than other, oral progestin preparations. Finally, the contraceptive levonorgestrel-releasing IUD can be considered. It is not FDA-approved for this use, but has the advantage of up to a 10-year duration of effectiveness.

After menopause, the circulating level of androstenedione is about half that seen before menopause.⁷² Most of this postmenopausal androstenedione is derived from the adrenal gland. Testosterone levels do not fall appreciably, however, and in most women, the free androgen index is the same as or greater postmenopause than it was premenopausally.⁷³ Adrenal androgen production, which declines steadily with age from young adulthood, is markedly reduced postmenopause⁷⁴ and thus there is a supposition that postmenopausal women may be relatively androgen deficient. 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 and to correlate with circulating estradiol in one study, while two other studies appeared to show a small incremental benefit of estrogen plus androgen.^{75, 76, 77}

Putative benefits of androgen treatment include improvement in psychological well-being and an increase in sexually motivated behavior. The therapeutic role of androgens for female sexual dysfunction remains unclear. To date, testosterone therapy for menopausal women has focused on the common complaint of low desire. Testosterone may influence multiple aspects of the female sexual response, as evidenced by improvements in desire,⁷⁸ subjective and objective measures of arousal,^{78, 79, 80} and increased frequency of orgasm.^{81, 82, 83} These effects, however, follow the administration of relatively large doses of androgen, and cannot be considered physiologic.⁸⁴ In a well-designed, placebo-controlled study of 40 naturally menopausal women, 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.⁸⁵

Benefits of androgen therapy must be balanced against known and unknown risks, as well as 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.⁸⁶ 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.⁷⁶ 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.⁸⁷ Transdermal testosterone treatment of women appears to avoid an adverse impact on the lipoprotein profile and does not appear to result in excess hirsutism.^{77, 82, 83, 88} Long-term safety data are lacking. Patients require a careful benefit to risk assessment and discussion before undertaking the non-FDA-approved use of androgens.

Androgens do not necessarily protect the endometrium. Addition of a progestin 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.

Research in estrogen receptor biology has led to the discovery of mixed estrogen agonists. These pharmaceuticals provide promise for selective actions on specific target tissues. It is now theoretically possible to isolate desired actions from unwanted side-effects. The ideal SERM would have antiresorptive properties on the skeleton, would reduce vasomotor symptoms, treat vaginal dryness/dyspareunia, and have no stimulatory effects on the endometrium, breast or liver. Such a compound is not yet clinically available, but a variety of SERMs are in clinical trials or are FDA approved for use in menopausal women.

Raloxifene is an oral SERM that exerts no proliferative effect on the endometrium but produces favorable responses in bone and lipids.^{89, 90, 91} Raloxifene’s mixed agonist properties make it an estrogen receptor antagonist at the breast. The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) indicated that both tamoxifen and raloxifene were similarly effective in preventing invasive breast cancer, with raloxifene being less effective in the prevention of noninvasive disease.⁹² In an updated analysis with a median 81-month follow-up, tamoxifen was significantly superior for preventing invasive cancer, and both tamoxifen and raloxifene were equally protective against the development of noninvasive disease.⁹³ Compared to tamoxifen, raloxifene caused far less endometrial cancer and hyperplasia, 25% fewer thromboembolic events, and fewer cataracts.

SERMs are currently under development for use in combination with estrogen, and as specific treatment for vulvovaginal atrophy accompanying menopause.

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 increased in one study of 50 perimenopausal women being treated with an intramuscular depot form of estrogen–progestin therapy.⁹⁴ However, this study contained women receiving relatively high-dose hormones in depot form every 6–10 weeks, which may have led to increased levels of hormones. Fibroid size increased a mean of 3–3.5 cm over the 1-year study period. No fibroid growth was observed after 1 year in women with small asymptomatic fibroids administered a daily combination of 0.625 mg of conjugated estrogens and 2.5 mg of MPA in another study; in this same cohort, women treated with transdermal estradiol (50 μg) and 5 mg of MPA daily did have an increase in the size of their fibroids (a response that may reflect the effect of a higher progestin dose).⁹⁵

In a follow-up study of 14 women taking standard doses of hormone therapy, ultrasonography detected no changes in uterine or myoma volume over a mean follow-up of 19.7 months.⁹⁶

Although the findings to date are reassuring, it is possible that some women will experience growth of pre-existing uterine fibroids after taking hormone therapy. On the other hand, there is no evidence to suggest that malignant disease of the myometrium is associated with menopausal hormone therapy, as suggested by a case–control study.⁹⁷

Exogenous estrogen, either oral contraceptives or postmenopausal therapy, has demonstrated protection,⁹⁸ a lack of association,^{99, 100} and a positive association with rheumatoid arthritis in a variety of observational studies. In one randomized clinical trial of 200 women with rheumatoid arthritis, the use of transdermal estrogen had no net effect on disease, although women with higher circulating estradiol seemed to improve the most, implying benefit of menopausal hormone therapy for rheumatoid arthritis.¹⁰¹

In the Nurses' Health Study (NHS), the use of postmenopausal estrogen was associated with an approximately two-fold increase in systemic lupus erythematosus, an observation based on 30 cases in past and current users of estrogen.¹⁰² In a 12-month follow-up study of 60 postmenopausal women with stable systemic lupus erythematosus, 30 of whom were taking menopausal hormone therapy, no adverse effects were demonstrated.¹⁰³

The approach of using the ‘lowest possible dose for the shortest possible time’ for menopausal hormone therapy is a reasonable path to pursue for symptomatic women with rheumatic diseases. Insufficient data exist to guide the clinician about preferred routes of administration in these settings. The course of the disease should be monitored in relation to the initiation of hormone therapy.

Osteoarthritis is the most common form of arthritis in older people, and its prevalence increases rapidly in women after menopause. The impact of estrogen therapy on osteoarthritis is therefore a logical concern. Increasing severity of osteoarthritis of the knee has been associated with increased bone density as well as increased estrogen levels in middle aged women.¹⁰⁴ Women with hip arthritis have been shown to have higher hip bone density in a manner that correlates with severity of disease—suggesting that increased bone density may play a pathogenetic role in the disease.¹⁰⁵ On the other hand, hormone use was associated with a halving of the risk of hip osteoarthritis and a lesser severity of the disease by these same investigators.¹⁰⁶ Thus, for this common condition, menopausal hormone use seems to have a salutary or neutral effect on the course of the disease.

Oral complaints are common among postmenopausal women. The administration of estrogen provides significant relief from oral discomfort, burning, bad taste, and dryness.¹⁰⁷ 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.^{108, 109}

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.¹¹⁰ An approximately 25% reduced risk of tooth loss in current users of estrogen has been observed in the Nurses' Health Study.¹¹¹

Professional singers have used hormone therapy to prevent what they view as unwanted voice changes associated with the menopause. 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.¹¹²

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.¹¹³ 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.¹¹⁴ However, one small study of women with and without dry eye who initiated hormone therapy indicated that symptoms were not alleviated in the 20 women who had dry eye at the outset of the study, and 11 of 20 developed dry eye after hormone therapy initiation.¹¹⁵ There is further evidence that postmenopausal estrogen therapy has an effect that protects against lens opacities.^{116, 117, 118} Estrogen–progestin treatment also lowers intraocular pressure.¹¹⁹

In general, the risks of MHT outweigh its benefits for long-term use. There is therefore little rationale for initiating MHT in women who are more than 10 years postmenopause. However, a positive impact of estradiol on bone clearly takes place in women over 65. Ultra-low doses of 0.25 mg of micronized estradiol daily were found to result in significant increases in bone mineral density confer osteoprotection. Given the panoply of agents available to treat postmenopausal osteoporosis, there are likely only few women appropriate for this treatment.

Based on the WHI findings^{1, 2} indicating a lack of cardiovascular benefit for MHT, MHT is currently prescribed for the treatment of menopausal symptoms. Symptoms considered to have a well established evidence base to be attributable to menopause and likely to be treatable with MHT, include:¹²⁰

o       Hot flushes and night sweats

o       Vaginal dryness and dyspareunia

o       Poor sleep

o       Adverse mood (depressive symptoms or major depression)

Symptoms for which evidence was found to be fair include:

o       Sexual dysfunction

o       Cognitive impairment

o       Urinary incontinence

Symptoms for which evidence was found to be poor include:

o       Body composition

o       Joint aches and pains

It should be noted that the relationships described above apply to women undergoing natural menopause, and not surgical menopause or antiestrogenic therapy (such as aromatase inhibition for breast cancer treatment or prophylaxis).

For women who wish to avoid pharmacologic therapy, behavioral methods may be employed. These are usually effective for women with mild to moderate symptoms. Paced respiration has been shown to be effective in one small randomized trial. Other complementary and alternative treatments have been suggested, but none have demonstrated consistent efficacy.^{5, 121, 122} At best, these treatments have not demonstrated harm in most of the clinical trials performed to date.

Several non-hormonal treatments are accumulating medical evidence for efficacy that is less than estrogen, but acceptable for many patients. These are gabapentin, venlafaxine and escitalopram (as well as other selective serotonin/norepinephrine reuptake inhibitors). None of these medications are FDA approved for this use. A brief summary is provided in the Table 4.

Table 4 Non-hormonal medication options for vasomotor symptoms

Concerns have been raised about the use of certain selective serotonin reuptake inhibitor (SSRI) class drugs in women who are being treated with tamoxifen for breast cancer. These agents can interfere with the metabolism of tamoxifen into more active antiestrogens and may thus reduce the effectiveness of tamoxifen. Paroxetine is the most active in this regard, followed by fluoxetine and venlafaxine. Although the data are inconsistent,¹²³ a recent study cited increased mortality in women taking tamoxifen concurrent with paroxetine.¹²⁴ Paroxetine should probably be avoided in women with breast cancer who are being treated with tamoxifen, and other SSRI drugs should be used with caution based on these findings.

For women who cannot tolerate these alternatives, there are other medications that have demonstrated mixed efficacy in small trials. Transdermal clonidine, at a 100 μg dose once weekly, has been shown to have efficacy.^{125, 126} Side-effects include postural hypotension. It may be prudent to begin with a lower dosage or even apply a half-sized patch at first. A modest impact can be expected.

Bellergal (a combination of belladonna alkaloids, ergotamine tartrate, and phenobarbital) treatment is slightly better than a placebo, but it also is a potent sedative.¹²⁷ Veralipride, a dopamine antagonist that is active in the hypothalamus, is relatively effective in inhibiting flushing at a dose of 100 mg daily.^{128, 129} Mastodynia and galactorrhea are the major side-effects. MPA (10–20 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.^{130, 131} Methyldopa, in doses of 500–1000 mg/day, is approximately twice as effective as a placebo, suggesting a role for adrenoreceptors in the hot flush mechanism.¹³² 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.¹³³ It has the additional advantages of lacking any endometrial stimulation, improving bone mineral density and reducing vaginal dryness. It is not available in the US due to concerns about breast cancer risk.

“Natural” therapies

The use of “natural” remedies for menopausal symptoms is widely promoted to women.^{134, 135} Patients should be asked about their use of “natural” therapies. Botanicals and non-oral, compounded hormones are exempted the same oversight applied by the FDA to pharmaceuticals. Such remedies need not provide proof of efficacy, and FDA is only authorized to intervene if safety is an issue. Due to overall underreporting of adverse events in postmarketed drugs, it is difficult to demonstrate that “natural” compounds are unsafe. Several botanicals are purported to contain estrogen-like compounds, including ginseng, agnus castus, red sage, and black cohosh. The dosage and purity of herbal and compounded preparations are not well controlled. In one FDA survey of 29 compounded hormone preparations, seven failed testing of purity and accuracy of the labelled dose.¹³⁶ Given the wide array of estrogen and progestin preparations, including many that contain pure 17-beta estradiol and natural progesterone, there is little need to deviate from FDA approved drugs to provide patients with “bioidentical” hormones. The use of non-FDA-approved products without rigorous scientific study should be discouraged.

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.¹³⁷ In the monkey, soybean phytoestrogens do not maintain bone density but do have favorable effects on atherosclerosis, vasomotor responses, lipids and lipoproteins, carbohydrate metabolism and fat deposition.^{138, 139} In the monkey, phytoestrogens did not stimulate proliferation of breast and endometrial cells after 6 months of exposure.¹⁴⁰

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.¹⁴¹ In normally cycling women, soy consumption increases menstrual cycle length and produces a reduction in the circulating levels of estradiol.¹⁴² The replacement of potent estradiol with target-specific phytoestrogens may be beneficial. However, in postmenopausal women, phytoestrogens may act as weak estrogen agonists, and promote some of the problems associated with estrogen use. Appropriate clinical trials are required to determine how phytoestrogens compare with estrogens, and the efficacy, safety, timing of administration, and dosage. In the meantime, clinicians should use phytoestrogens cautiously or avoid them entirely in women with estrogen-dependent cancers.

Dehydroepiandrosterone

The impressive decline (75–85%) in circulating levels of DHEA that occurs with aging (greater in men than in women)⁷⁴ has stimulated a search for a beneficial impact of DHEA supplementation. Several well performed, randomized clinical trials provide no support for a benefit of DHEA on cognition, mood, physical performance, and sexual function.^{143, 144, 145} One study demonstrated a detrimental effect of DHEA supplementation on cognition.¹⁴⁶

Metabolic

Patients with high-risk factors need special attention when estrogen therapy is being considered. Metabolic contraindications to estrogen therapy include 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.¹⁴⁷ 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 2–4 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 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.

Physiologic and epidemiologic evidence indicates that estrogen use increases the risk of gallbladder disease. In the WHI, both E+P and E alone groups had a higher incidence of overall gall bladder events (for E alone: HR 1.67, 95% CI 1.35–2.06; for E + P: HR 1.59, 95% CI 1.28–1.97).¹⁴⁸ Cholecystitis, cholelithiasis and cholecystectomy were all more prevalent in women randomized to active hormone compared to placebo; other biliary disease was not more prevalent. The NHS and other observational cohort studies indicate that oral estrogen therapy may carry a 1.5- to 2.0-fold increased risk of gallbladder disease.^{149, 150} The risk of cholecystectomy increased with dose and duration of use and was seen to persist for 5 or more years after stopping treatment.

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 appear to increase biliary cholesterol saturation (a lithogenic response) in contrast to oral treatment.¹⁵¹

Weight gain

The gain in weight that many middle-aged individuals experience is largely the result of lifestyle, specifically the balance of dietary intake and exercise. Weight gain in women at menopause is not necessarily caused by the hormonal changes associated with the menopause.¹⁵² The large Rancho Bernardo prospective cohort study and the randomized PEPI clinical trial indicate that hormone therapy with or without progestin is not associated with increased body weight.^{153, 154} In the PEPI trial, the hormone-treated groups gained less weight than the placebo group. In the multiethnic cohort of the Study of Women’s Health Across the Nation (SWAN), longitudinal evaluation of weight gain indicated that initiating hormones prior to the final menstrual period was associated with a higher likelihood of weight gain (OR 2.94, 95% CI 1.14–7.58), as was surgical menopause (OR 5.07, 95% CI 2.29–11.02).¹⁵⁵ Low sex hormone binding globulin (SHBG) and high testosterone or free androgen index have been associated with metabolic syndrome¹⁵⁶ and risk of obesity; however, a more recent analysis of SWAN data indicates that the adiposity precedes the hormone changes.¹⁵⁷

It has been proposed that estrogen (with or without progestin) prevents the tendency to increase central body fat with aging. There is limited evidence that this is the case. Studies using newer techniques of body fat compartment measurement may help resolve this issue.

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 with and without progestin appears to depend on the dose, the exact hormonal preparation given, and the route of administration. Given its relative rarity, attributing venous thromboembolism (VTE) to hormone use can only be done reliably in the context of a large, randomized, controlled trial. In the WHI, the use of estrogen plus progestin resulted in a hazard ratio of 2.13 (95% CI 1.39–3.25) for pulmonary embolism.¹ The WHI findings are in overall agreement with the Heart and Estrogen/Progestin Replacement Study (HERS) trial¹⁵⁸ and with the NHS), in which the risk of pulmonary embolism was increased twofold in the current hormone users.¹⁵⁹ The risk drops to a nonsignificant level within a year of hormone discontinuation.⁴

In the estrogen only arm of the WHI, the risk of pulmonary embolism was not significantly increased.² This finding implies that the progestin may be playing a role in pulmonary embolism risk. On the other hand, overall VTEs remained high in the women who took estrogen alone, suggesting that women who have had prior hysterectomies share characteristics that put them at higher VTE risk regardless of whether they are treated with estrogen. In settings where estrogen can be given alone, therefore, concern of a drug-related VTE is minimized, but surveillance should always be encouraged for this potentially life-threatening complication. In a large meta-analysis of postmenopausal hormone users, transdermal estradiol did not increase VTE risk, as opposed to oral estrogen which was associated with an approximate doubling of risk.²²

What is the final message for clinicians and patients? The personal VTE risk is low because of the low frequency of this event (about 1/10,000 to 1/15,000). If the relative risk is doubled, this would increase the incidence of venous thromboembolism to about one case per 5000 women per year of hormone use. VTE carries with it a 1% risk of mortality, and the background risk of VTE increases with age. It is prudent to stick to the recommendation of ‘lowest possible dose for the shortest possible time’ to minimize a patient’s exposure to this rare but potentially lethal complication of hormone therapy. On the other hand, clinicians can mitigate risk by favoring the prescription of non-oral estradiol when hormone therapy is needed.

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:

 Factor V Leiden mutation
 Antithrombin III
 Protein C
 Protein S
 Activated protein C resistance ratio
 Activated partial thromboplastin time
 Anticardiolipin antibodies
 Prothrombin gene
 Homocysteine
 Complete blood count

Varicose veins are not a risk factor unless they are extensive, and unlike arterial thrombosis, smoking is not a risk factor for VTE.

If a patient has a congenital predisposition for VTE or if she is otherwise considered to be high risk, alternative methods for symptom control should be considered. In cases in which hormones are the only viable option, the clinician and patient can consider the combination of hormone therapy and chronic anticoagulation, in consultation with a hematologist.

There are no studies of VTE 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. If possible, patients should discontinue hormone treatment several weeks before surgery.

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.³⁰ 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.³¹ About 10% of women with complex hyperplasia progress to frank cancer, and complex hyperplasia is observed to antedate adenocarcinoma in 25–30% of cases. If atypia is present, 20–25% of cases will progress to carcinoma within a year.¹⁶⁰

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 2–10 times the normal incidence of 1 per 1000 postmenopausal women per year.^{161, 162} The risk increases with the dose of estrogen and with the duration of exposure (reaching a 10-fold increase with 10–15 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. 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).¹⁶³

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.¹⁶⁴ 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.¹⁶⁵ 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. Possible exceptions include the low dose vaginal estradiol ring (2 mg given over 90 days; Estring), and twice weekly 10 µg vaginal tablets (Vagifem).

Risks of unopposed estrogen can be reduced or eliminated by the addition of a progestational agent to the regimen. Whereas estrogen promotes the growth of endometrium, progestins inhibit mitosis and promote differentiation of the endometrial glands. This counter effect is accomplished via a number of cellular signaling pathways activated by progestin. These include reduction in cellular receptors for estrogen and induction of target cell enzymes that convert estradiol to an excreted metabolite, estrone sulfate.

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.^{166, 167, 168, 169, 170} The protective action of progestational agents 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 10 days a month, most have argued in favor of 12 or 14 days. The minimal requirement is a monthly exposure of at least 10 days’ duration.^{171, 172} About 2–3% of women per year develop endometrial hyperplasia when the progestin is administered for less than 10 days monthly. Continuous daily progestin is associated with the lowest risk of endometrial hyperplasia.¹⁷³ Alternative regimens of progestin that have not been adequately studied include vaginal gel (Crinone), vaginal use of micronized progesterone capsules, and less-than-monthly courses of progestin. All alternative regimens should include endometrial surveillance because of the uncertainty of their long-term endometrial safety.

The lowest daily dose of progestin that protects the endometrium has not been established. Currently, the sequential program uses 200 mg of micronized progesterone or 5 or 10 mg of MPA, and the combined daily method uses 100 mg micronized progesterone or 2.5 mg MPA. The dose of norethindrone that is comparable with 100 mg micronized progesterone or 2.5 mg of MPA is 0.25 mg.³⁴ 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 clinical importance, because combined E+P treatment seems to carry additional risks for women that are not seen with E alone regimens.^{1, 2} Moreover, since the need for progestin is solely to protect the endometrium, minimizing systemic progestin exposure is desirable.

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 the patient’s clinical presentation are prudent and necessary. For women with no prior exposure to hormone therapy, irregular bleeding or spotting within the first 6 months of treatment is common. Thereafter, the vast majority of women on continuous progestin therapy become amenorrheic and most women on sequential progestin have predictable, monthly bleeding. Changes in an established bleeding pattern are cause for concern and should trigger a clinical response, such as ultrasound evaluation or endometrial sampling.

Ovarian cancer

In the WHI, estrogen alone hormone therapy, but not E+P therapy, was associated with an increased risk of ovarian cancer.¹⁷⁴ Other epidemiological data support a duration-dependent association, with a relative risk that ranges from approximately 1.5 to 2.0.^{175, 176, 177} Other case–control studies have not observed an association,¹⁷⁸ and a retrospective analysis of prognosis after surgery indicated no detrimental impact for ovarian cancer in patients who received postmenopausal hormone therapy after diagnosis.¹⁷⁹

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.^{180, 181} 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.¹⁸²

Colorectal cancer

Many cohort and case–control studies report a significantly reduced risk of colorectal cancer in past and current users of MHT,^{183, 184, 185, 186, 187} however, it is possible that women prescribed MHT may be healthier at baseline. Randomized controlled trials evaluating the effect of MHT on colorectal cancer have not shown as impressive a benefit.

The WHI initially found a significantly lower incidence of colorectal cancer among women in the E+P arm (RR 0.62, 95% CI 0.43–0.89), however, this difference was no longer statistically significant at a mean follow-up of 2.4 years after trial completion (RR 0.75, 95% CI 0.57–1.00).⁴ Of note, women on E+P who developed colorectal cancer had a greater number of positive lymph nodes (mean ±SD, 3.2 ± 4.1 vs. 0.8 ± 1.7; p = 0.002) and were more likely to have regional or metastatic disease (76.2% vs. 48.5%; p = 0.004) than those on placebo.¹⁸⁸

Data from the Heart and Estrogen/Progestin Replacement Study follow-up (HERS II) also did not support a significant benefit of E+P with regards to colorectal cancer incidence after a mean follow-up of 6.8 years (relative HR 0.81, 95% CI 0.46–1.45).¹⁸⁹ Five additional double blinded, randomized controlled trials did not find a significant risk reduction in colon cancer with at least 1 year of MHT use.¹⁹⁰

Given that the largest randomized trial to address this issue found a risk reduction, it is reasonable to assume that combined E+P hormone therapy reduces new cases of colon cancer; however, the effects are short lived and do not persist after hormones are discontinued. The use of MHT to reduce the risk of colorectal cancer is not recommended.¹⁹¹

Malignant melanoma

The possibility of a relationship between exogenous hormones and cutaneous malignant melanoma has been the subject of many observational studies. Only a few studies have found a statistically significant association between MHT and malignant melanoma.^{180, 192, 193} Others report slight increases in the risk of malignant melanoma associated with the use of exogenous estrogen, but none demonstrated statistical significance.^{194, 195, 196} Combining data from 36 observational studies published between 1977 and 2009 and including 5626 cases of melanoma, Gandini et al. did not find an increased risk of melanoma with the use of oral contraceptives (RR 1.04, 95% CI 0.92–1.18) or MHT (RR 1.16, 95% CI 0.93–1.44).¹⁹⁷ Post hoc analysis of the WHI randomized placebo controlled trial further supports the lack of an association between MHT and melanoma (HR 0.92, 95% CI 0.61–1.37)¹⁹⁸ and a study evaluating recurrence of melanoma with MHT suggests that exogenous hormones are safe even in women with a history of melanoma.¹⁹⁹

Breast cancer

Breast cancer is the second most common malignancy affecting women and the second most common cause of cancer death among women in the US. Over 230,000 new invasive cancer cases and 39,500 deaths were estimated to occur in 2011.²⁰⁰ Breast cancer is known to be hormonally influenced, and a large number of studies have been performed to evaluate the effects of exogenous hormones on the incidence of breast cancer. Several of the larger studies evaluating the relationship between postmenopausal hormone use and breast cancer are discussed here.

The British Million Women Study (MWS), California Teachers Study (CTS), Nurses’ Health Study (NHS) and WHI, have all reported an association between breast cancer and MHT in current, but not prior users of MHT. In addition to differences in risk related to current vs. prior use, differences in estrogen-only and E+P preparations have been consistently reported in these studies, with E+P conferring risk and estrogen alone treatments having less or no risk. As such, these regimens are discussed separately.

ESTROGEN ONLY

Several cohort studies have shown an association between estrogen only preparations of MHT and breast cancer. In the NHS, a prospective cohort study of 28,835 postmenopausal women who had undergone a hysterectomy, the risk of breast cancer was increased among current users with duration of use of 20 years or more (RR 1.42, 95% CI 1.13–1.77). Risk increased with increasing duration of use; however, the increase in relative risk did not become statistically significant until 20 years or more duration. Among women with estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer, the risk of breast cancer with MHT increased earlier at 15–15.9 years duration of use (RR 1.48, 95% CI 1.05–2.07).²⁰¹

Among 56,867 perimenopausal and postmenopausal women in California in the prospective cohort CTS, the risk of breast cancer was significantly increased among current users of estrogen only MHT after a mean follow-up of 9.8 years (adjusted RR 1.33, 95% CI 1.17–1.51). This significantly increased risk was seen even in current users with less than 5 years duration of use (RR 1.23, 95% CI 1.02–1.49) compared to never users. Of women diagnosed with breast cancer, those with current E-only MHT use had an increased risk of ER and PR positive breast cancer.²⁰²

The MWS, a prospective cohort study involving 1,084,110 British women, found an increase in breast cancer among current users of estrogen-only MHT (RR 1.30, 95% CI 1.21–1.40). When evaluated by duration of use, this increased risk became statistically significant at 1–4 years of use and increased progressively with longer duration. There was no variation in risk related to type of estrogen used (equine estrogen or estradiol).²⁰³

In contrast to these cohort studies, the WHI randomized, placebo-controlled trial found a non-significant reduction in breast cancer among the women on estrogen-only MHT.²⁰⁴ This reduction in risk became statistically significant after a mean follow-up of 10.7 years with HR 0.77 (95% CI 0.62–0.95).²⁰⁵ One possible reason for the discrepancy between the WHI and cohort studies may be the timing of initiation of estrogen therapy in relation to menopausal onset. However, when evaluated by age group, the women in the WHI did not differ in the risk reduction seen with estrogen-only therapy. Although apparently counterintuitive, the WHI findings imply that there is an enduring benefit of estrogen alone on breast cancer risk. It is important to recognize that breast cancer cases were higher overall in the women randomized to the E alone arm of the trial—all of whom had had a prior hysterectomy. It is therefore not appropriate to extrapolate these results to women with a uterus.

Although the WHI did not find an increased risk of breast cancer among women on estrogen-only MHT, the findings of the NHS, CTS and MWS should not be utterly disregarded at this time.

ESTROGEN AND PROGESTIN

The WHI E+P arm was stopped prior to completion in part because of an increased risk of breast cancer among women receiving E+P MHT. This trial enrolled 16,608 postmenopausal women who were monitored with yearly mammograms and clinical breast examinations. After a mean follow-up of 5.6 years (maximum 8.6 years), total breast cancer and invasive breast cancer was increased with E+P use compared to placebo (HR 1.24, 95% CI 1.02–1.50 and HR 1.24, 95% CI 1.01–1.54, respectively). The increase in risk was apparent after 4 years of MHT in women with no prior MHT use prior to enrolment, and after 3 years in women with prior MHT use,206 suggesting a possible cumulative effect of MHT on breast cancer risk. Follow-up of 15,730 women in the E+P arm of the WHI showed that the increase in breast cancer was no longer statistically significant after the intervention phase was stopped, suggesting that risk can be reduced to baseline after cessation of MHT.⁴ An analysis of both the WHI randomized clinical trial E+P arm and the WHI observational cohort further substantiated the risk reduction after cessation of MHT with the risk decreasing to non-significant levels in less than 2 years.²⁰⁶

The MWS also found an increased incidence of breast cancer among current users of E+P MHT with a RR of 2.00 (95% CI 1.88–2.12). This risk increased with increasing duration of hormone use and did not vary significantly by continuous or sequential use of progestin.²⁰³

The risk of breast cancer among current users of E+P MHT was increased with a RR of 1.69 (95% CI 1.50–1.90) among women in the CTS. This increase was persistent regardless of sequential or continuous administration of progestin and increased with increasing duration of use. The greatest breast cancer risk was seen among current users of E+P MHT who took continuous progestin for 15 years or more duration (RR 1.92, 95% CI 1.29–2.86). Current users of E+P MHT also had an increased risk of ER/PR positive breast cancer.²⁰² Of note, past users of E or E+P MHT did not have a significantly increased risk of breast cancer, further supporting the WHI findings of reduction of risk after cessation of MHT.  

Taken together, these studies support an increased risk of breast cancer with current E+P MHT use, with further increased risk with duration of use, and a relatively rapid reduction in risk following completion of MHT.

Timing of therapy in relation to menopause

One critique of the WHI randomized controlled trial is that 90% of women in the estrogen-only arm and 83% of women in the E+P arm were more than 5 years removed from their final menstrual period at the time of randomization for MHT. Various authors have explored the variation in risk related to time of initiation of MHT with respect to onset of menopause. An analysis of the WHI interventional and observational trial data for women who initiated MHT within 5 years of menopause found more incident invasive breast cancer among women who started MHT less than 5 years from onset of menopause in both the estrogen-only and E+P arms. The increase in breast cancer compared to placebo was significant in the E+P arm but only among those with MHT initiation within less than 5 years of menopause regardless of history of MHT use prior to randomization (HR 1.77, 95% CI 1.07–2.93 for women with no prior MHT use and HR 2.06, 95% CI 1.30–3.27 for those with prior MHT use).²⁰⁷

An analysis of the MWS evaluating time from menopause to MHT initiation and risk of breast cancer found similar results. Among current users of estrogen-only MHT, there was no significant increase in breast cancer risk if use began 5 years or more after menopause (RR 1.05, 95% CI 0.89–1.24), however, if use began less than 5 years from menopause, risk was increased compared to non-users (RR 1.43, 95% CI 1.35–1.70). Among current users of E+P formulations, risk was also increased with RR 1.53 (95% CI 1.38–1.70) for onset 5 or more years from menopause and 2.04 (95% CI 1.95–2.14) for onset less than 5 years from menopause.²⁰⁸

In the E3N study, a prospective cohort of 98,995 French women, recent users of E+P MHT who had initiated MHT within 3 years of menopause had a 1.61 relative risk of breast cancer (95% CI 1.43–1.81), while those who initiated more than 3 years from menopause had a 1.35 relative risk (95% CI 1.13–1.63) above never users.²⁰⁹

All of these studies suggest that early initiation of MHT may be detrimental with regards to breast cancer risk. Estrogen is a known stimulus for breast cancer growth and anti-estrogenic therapies are now standard of care for ER positive tumors. However, the relationship between estrogen and breast cancer is complex. In addition to its growth-promoting effects, estrogen is an apoptotic trigger for breast cancer cells exhibiting antihormone resistance.²¹⁰ It is theorized that the response of breast cancer cells to estrogen changes in response to the hormonal environment in which they are growing. In a low-estrogen environment (i.e. postmenopausal or antihormone treated), tumor cells become susceptible to estrogen-induced apoptosis. This and other properties of estrogen may explain the reduction in breast cancer seen in postmenopausal women on estrogen-only MHT in the WHI interventional trial.

Tumor characteristics/prognosis of women who develop breast cancer while taking MHT

A few observational studies have found more favorable breast cancer histology (lobular and tubular tumors)^{211, 212, 213} among MHT users, while others have observed that MHT-associated breast cancers are smaller and have fewer positive lymph nodes²¹⁴ suggesting more favorable prognosis. However, this is not consistent with the WHI findings.

A secondary analysis of the E+P arm of the WHI found no difference in type of breast cancer, histology or grade between the MHT and placebo groups. However, in women randomized to MHT, the invasive breast cancers were larger, more likely to be node positive, and of a more advanced stage among than those in women on placebo. There was no difference in the number of ER/PR positive or ER/PR negative breast cancers between the E+P and placebo groups. There was also a higher percentage of women with an abnormal ultrasound requiring medical evaluation among women randomized to E+P compared to those receiving placebo after only 1 year of MHT use.²¹⁵ These findings do not support the oft-touted notion that breast cancer contracted while taking MHT is a less aggressive disease. E+P use may also impair the ability of mammographic detection of malignancy, resulting in later cancer stage at diagnosis.

MHT use in women with a history of breast cancer

Several observational studies have not identified an increased risk of breast cancer recurrence among current MHT users with a history of prior breast cancer.^{216, 217} However, given the results discussed above, concern regarding the safety of MHT in breast cancer survivors should be maintained. Only two randomized studies have been published regarding the risk of breast cancer recurrence with MHT: the Hormonal Replacement Therapy after Breast Cancer-Is It Safe? (HABITS) trial and the Stockholm randomized trial.

Both the HABITS trial and the Stockholm trial are Swedish studies that started recruitment in 1997. Because of slow recruitment for both studies, a joint Data Monitoring and Safety Committee (DMSC) was formed in 2002 with plans for joint interim safety analyses and final data analysis. An interim safety analysis of the pooled data in October of 2003 found the combined hazard ratio (HR) for recurrence of breast cancer with MHT to be unacceptably high at 1.8 (95% CI 1.03–3.1). There was significant heterogeneity between the studies, however, with the HABITS study indicating an HR 3.3 (95% CI 1.5–7.4) and the Stockholm trial a non-significant HR of 0.82 (95% CI 0.35–1.9).²¹⁸ Subsequently, both studies were terminated prior to completion. Because of the conflicting findings of the two studies, they are more closely discussed here.

The HABITS trial was a prospective, randomized, open-label non-inferiority trial in which 447 women with a history of early stage breast cancer were randomized to either MHT or to best symptomatic treatment without hormone. All women had stage 0–2 disease with less than four positive axillary lymph nodes. The MHT regimen was at the discretion of their provider, but most women with an intact uterus received a sequential or continuous combined regimen of estradiol hemihydrate and norethisterone acetate; those who had undergone hysterectomy received estradiol alone. Therapy was to be continued for 2 years; women were followed by a breast cancer specialist for recurrence of disease twice yearly for 3 years then annually for a total of at least 5 years. Mammograms were done with a target interval of 18–24 months.

Baseline characteristics for women in the HT arm and non-HT arm were similar, with the exception being that there were more women with receptor-positive breast cancer in the HT arm (62.3% vs. 54.5%). Women in the HT arm had an increased rate of a new breast cancer event even after adjusting for use of HT prior to diagnosis of the original breast cancer, tamoxifen use, and hormone receptor status (HR 2.2, 95% CI 1.0–5.1). All of the women in HT arm who experienced a recurrence had been exposed to HT; five women in the non-HT arm with recurrence had also been exposed to HT after random assignment. There was no difference in distant metastasis-free survival or overall mortality between the two arms.²¹⁹

The Stockholm trial randomized 378 postmenopausal women with a history of treated breast cancer to HT or no HT for 5 years. Randomization was stratified by tamoxifen use, type of HT and time since primary diagnosis (less than 2 years vs. more than 2 years). For those randomized to HT, women under age 55 received cyclic combined therapy with estradiol for 21 days with medroxyprogesterone acetate added the last 10 days followed by 7 hormone free days, while those 55 years or older received a “long cycle” regimen composed of estradiol for 84 days with medroxyprogesterone acetate for the last 14 days followed by 7 days with no treatment. Women without a uterus received estradiol valerate continuously. Women were followed twice yearly for the first 5 years after the primary diagnosis and annually for the next 5 years. Mammograms were performed annually.

Baseline characteristics for the two groups were similar. Of women in the control group, 10% took some form of HT after randomization. At a median follow up of 10.8 years, the HR for breast cancer recurrence or death in the HR group compared to the non-HR group was non-significantly increased at 1.3 (95% CI 0.9–1.9). However, when analysed specifically for contralateral breast cancer, a significantly increased risk was observed with HT with 14 (of 23 total recurrences) reported among HT users compared to four (of 27 total recurrences) among non-users (HR 3.6, 95% CI 1.2–10.9);²²⁰ a hazard ratio that comes very close to that of the HABITS trial. Of the 18 total contralateral breast cancer cases, 11 were diagnosed in women on concomitant tamoxifen and eight (seven in the HT group) were of different histology than the primary tumor. In comparison, five of the 26 recurrent breast cancers in the HT arm of the HABITS trial were found in the contralateral breast.²¹⁸ Also of note, in the Stockholm trial, women who were diagnosed with breast cancer less than 2 years before randomization had an increased risk of contralateral breast cancer (HR 4.8, 95% CI 1.0–22).²²⁰ The occurrence of contralateral breast cancer is notable and may represent a new primary breast cancer occurrence or growth of non-excised multifocal primary disease. Similar to the HABITS trial, no difference in mortality was seen between the HT and non-HT groups in the Stockholm trial.²²⁰

The apparently contradictory findings between the HABITS trial and Stockholm trial may be due to chance, however several authors have suggested that differences in the patient populations, primary and secondary end points and interventions may explain their different outcomes. The Stockholm trial focused on minimizing progestin exposure. This reduction in progestin exposure in the Stockholm trial may explain the lack of an association between HT and breast cancer recurrence. In addition, the HABITS trial contained a higher proportion of women with positive lymph nodes (26% vs. 16%) and fewer women treated with concurrent tamoxifen (21% vs. 52%).²²¹  

A recent systematic review of 20 studies, including the HABITS and Stockholm trials, concluded that the available data are insufficient to exclude a harmful effect of HT on breast cancer recurrence.²²² The possibility that regimens minimizing progestin exposure may reduce risk of recurrence with MHT and the effect of length of time between cancer diagnosis and initiation of MHT on breast cancer recurrence are two areas in particular that warrant further evaluation.

Review of the data regarding breast cancer and MHT as discussed in the sections above can lead to a few general conclusions. E+P MHT increases the risk of breast cancer in current users, with increased risk seen with increasing duration of use and reduction of risk to baseline relatively quickly after cessation. Observational data suggests E-only MHT may increase risk in current users, however, the largest randomized controlled trial found a risk reduction among current users. Women who start MHT shortly after menopausal onset are at increased risk for breast cancer compared to those who start years after menopause which may explain the conflicting data seen in the WHI E-only arm compared to observational studies. Although observational studies have found more favorable features of breast cancer in MHT users, the WHI showed a worse prognosis for those women on MHT who developed breast cancer. The use of MHT in women with a history of breast cancer is still controversial, but regimens that minimize progestin exposure may confer less risk of recurrence than others.

Endometrial cancer, endometrioid tumors, and endometriosis

The question of safety of MHT in women with a history of endometrial cancer is still not adequately answered. Retrospective studies looking at MHT after treatment for early stage endometrial adenocarcinoma have not shown an increase in recurrence or cancer related mortality.^{223, 224, 225} However, the concern that MHT may stimulate residual cancer cells remains. The Gynecologic Oncology Group (GOG) attempted to answer this question more definitively with a prospective randomized placebo-controlled trial, however, patient recruitment decreased significantly after the initial WHI findings were released and the trial was terminated prematurely. Women with stage I or II endometrial cancer who had undergone surgical treatment with indications for MHT were randomized to receive either estrogen-only or placebo for 3 years. A total of 618 women were randomized to each arm and had a median follow up of 35.7 months. In all 1.3% of women in the placebo arm and 1.5% of women in the estrogen arm experienced disease recurrence (RR 1.27, 80% CI 0.92–1.77), while 0.6% and 0.8%, respectively, died from their endometrial cancer.²²⁶ Although this study did not find a statistically significant difference in disease recurrence with MHT, sample size was significantly short of their goal of 2108 patients.

Although lacking a well powered randomized, controlled trial, existing data suggest that MHT in women with early stage endometrial cancer may not increase recurrence risk. Little 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 if symptoms are severe and cannot be controlled with non-hormonal alternatives. Because the latent period of 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. 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 on unopposed estrogen, a combined estrogen–progestin program is also advised in patients with a history of endometriosis who require MHT.^{227, 228}

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).²²⁹ 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 hormone fluctuations 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.