Menopause Part 2


The diagnosis of menopausal transition may be suspected on the basis of symptoms (e.g., menstrual irregularity and vasomo-tor symptoms) in a woman older than 40 years [see Figure 4] well before it can be proven by FSH testing [see Laboratory Tests, below]. The clinical diagnosis of natural menopause is made if a woman is of an appropriate age and has had 12 months of amenorrhea accompanied by symptoms suggestive of ovarian failure, at which point the FSH serum concentration is so certainly elevated that testing is usually not useful.

Clinical Manifestations

Reproductive system changes The most common changes in the bleeding pattern in the menopausal transition are shortened cycle length, heavier flow (menorrhagia), and irregular cycle length (metrorrhagia). Intermenstrual bleeding may also occur, but it warrants specific attention because of its association with endometrial neoplasia in women older than 40 years [see Laboratory Tests, Biopsy, below]. A woman with vasomotor symptoms who has completely missed a menses is likely to experience her final menstrual period within the next 1 to 2 years.14 Menopause usually occurs several years after the onset of menstrual changes; however, about 10% of women experience abrupt onset of amenorrhea.3,4 Infertility and the cessation of menses are the only universal manifestations of menopause.

Genitourinary atrophy Genitourinary atrophy is typically mild and asymptomatic during the menopausal transition, but it is progressive and can become quite severe in the post-menopausal years.3,31 Atrophic vulvovaginitis can present as vaginal dryness, vulvovaginal pruritus, vaginal dyspareunia, or postcoital spotting. Atrophic urethritis and recurrent cystitis can manifest as dysuria, frequency, and incontinence.

Vasomotor symptoms Vasomotor symptoms (i.e., hot flushes and night sweats) are common manifestations of the meno-pausal transition; for example, 80% of white women experience vasomotor symptoms.56 Women typically describe hot flushes as a strong sensation of warmth accompanied by flushing, a prickling sensation of the skin, and perspiration that seems to move from the trunk toward the head before it dissipates. These flushes are spontaneous, uncomfortable, and unpredictable, and they can occur any time of the day or night. Each episode is self-limited and typically lasts several minutes. A number of women describe feeling excessively warm in a more continuous pattern. The frequency of vasomotor symptoms may be represented by a bell-shaped curve that peaks around the time of the final menses.3,37 The occurrence of vasomotor symptoms usually ceases within 4 to 5 years from first onset, although 10% of women may suffer symptoms for much longer (up to 10 years).

Changes in libido, sleep, mood, and cognition Changes in mood, libido, and sleep may also occur but are variable in sever-ity37 and have a wider differential diagnosis. Snoring and daytime sleepiness suggest the possibility of obstructive sleep ap-nea. Women may complain of mildly diminished cognitive capacity, particularly during the menopausal transition; however, this has not been well studied.

Physical Examination

There are no pathognomonic physical findings in the meno-pausal transition. However, the physical examination may provide information that suggests the presenting symptoms are the result of an underlying pathologic condition and are not related to normal menopausal transition. Palpation of the thyroid gland and examination for physical signs of hypothyroidism or hyper-thyroidism are warranted, particularly if menstrual irregularity, excessive diaphoresis, or neurocognitive changes are present. When intermenstrual bleeding is reported, speculum examination should be performed to rule out cervical or vaginal lesions, such as endocervical polyps. Bimanual pelvic examination is indicated when bleeding is heavy or frequent, to rule out the presence of adnexal masses and evaluate the uterus for fibroids; it is also indicated when pregnancy is possible. When the clinical presentation of oligomenorrhea or amenorrhea is not classic for the menopausal transition, prolactinoma may be suspected, in which case visual-field testing for bitemporal hemianopsia and breast examination for galactorrhea are appropriate. In addition,inspection of the skin for needle tracks from possible injection use of heroin and evaluation for low body weight or significant weight loss may be useful, because these findings suggest a hy-pothalamic cause for oligomenorrhea or amenorrhea.

After menopause, vulvovaginal atrophy typically occurs. The vulvovaginal skin may appear pale, thin, and friable and may exhibit a loss of rugae and possible fissuring and erythema. The uterus is smaller, measuring 5 to 6 cm in length, and the ovaries are usually nonpalpable. The cervix may become stenotic and flush with the vagina.

Laboratory Tests

Urine or serum fi-human chorionic gonadotropin (fi-hCG) testing is crucial in the evaluation of any woman suspected to be in menopausal transition but who has the potential for pregnancy and who presents with a missed period, oligomenorrhea, or irregular vaginal bleeding with or without pain. In addition, testing for high-sensitivity thyroid-stimulating hormone (TSH) should be considered when menorrhagia, excessive diaphoresis, or neurocognitive changes—all potentially associated with the menopausal transition—suggest thyroid dysfunction. If the clinical picture suggests hemorrhagic diathesis, it may be helpful to obtain a platelet count, prothrombin time, and partial thrombo-plastin time. Additional evaluation for coagulopathies, such as von Willebrand factor, should follow, if appropriate.

With the onset of menstrual irregularity, there are wide variations in the production of FSH, estradiol, and LH.23 Because of these wide variations, measurement of serum concentrations of these hormones is generally not useful during the menopausal transition and is not indicated unless the clinical situation is atypical and suggests an underlying condition. An elevated fol-licular-stage FSH level demonstrates that ovarian function is declining, but the FSH level cannot predict when the final menstrual period will occur.19,21,23 Once a woman has had 12 months without a menses, the FSH is reliably elevated at 25 IU/L, and the estradiol level is less than 50 pg/ml.

Oral contraceptive use during the menopausal transition will treat menopausal symptoms and mask menopause. Oral contraceptives suppress FSH; therefore, the FSH should be drawn on the seventh day of placebo pills or the seventh day of the pill-free week. If menopause has occurred, the serum FSH level will be greater than 25 IU/L when drawn on two separate occasions.

Measurement of FSH serum concentration can assist in the diagnosis of menopause in a woman with vasomotor symptoms who has had a hysterectomy without oophorectomy. FSH testing may also be appropriate in the evaluation of atypical clinical situations; for example, in a case of abrupt-onset amenorrhea in a 40-year-old woman with negative fi-hCG testing, measurement of FSH, prolactin, and TSH concentrations should be performed to evaluate for premature ovarian failure, prolactinoma, or thyroid dysfunction [see Differential Diagnosis, below].

Tests of other body fluids Vaginal fluid pH is elevated after menopause, and vaginal cytology shows a decreased maturation index (increase in parabasal cells).30 These tests are not typically performed, nor are they necessary, to establish the diagnosis of menopause. In evaluation of vaginal dyspareunia or vulvovaginal pruritus, vaginal fluid pH testing and microscopic examination of vaginal fluid (saline and 10% potassium hydroxide preparations) should be performed to rule out common vaginal infections such as candidiasis, trichomoniasis, or bacterial vaginosis. It should be noted that with genitourinary atrophy, the shift toward a more basic pH can precipitate bacterial overgrowth and concomitant infection.

Imaging Studies

No imaging study is useful in establishing the diagnosis of the menopausal transition or menopause, although pelvic ultrasound may be indicated in the diagnostic evaluation of women with abnormal vaginal bleeding before or after menopause. In women who present with metrorrhagia or menorrhagia during the menopausal transition, pelvic ultrasound can confirm a diagnosis of leiomyomas or endometrial polyps and can suggest a diagnosis of adenomyosis; however, ultrasound cannot rule out endometrial neoplasia in premenopausal women [see Biopsy, below]. In contrast, ultrasound can serve as a screening test for en-dometrial neoplasia in postmenopausal women who experience bleeding or spotting spontaneously or in conjunction with hormone therapy (HT). In a postmenopausal woman, a homogeneous endometrial thickness of 4 mm or less confers assurance that endometrial hyperplasia or cancer is not present in more than 96% of cases.

Biopsy In the menopausal transition, endometrial biopsy should be performed in women who experience intermenstrual bleeding (i.e., bleeding at intervals of fewer than 21 days) or in obese women who present with menometrorrhagia. If the biopsy results are normal or if examination suggests leiomyoma or adenomyosis, ultrasonography should follow. Endometrial biopsy is also indicated in postmenopausal women at heightened risk for endometrial neoplasia (e.g., women with diabetes or obesity) who experience any bleeding after 12 months of amen-orrhea or who have an ultrasound result that demonstrates an endometrium at least 4 mm in thickness.

Differential diagnosis

Menstrual Changes

For women 45 to 55 years of age who are experiencing progressive oligomennorhea, the most likely diagnosis is the meno-pausal transition, especially if there are associated vasomotor symptoms. In this setting, a wider differential diagnosis rarely needs to be considered. In younger women who have no vaso-motor symptoms or whose menstrual changes are abrupt, a wider differential should be considered [see Premature Ovarian Failure, below]. The differential diagnosis for oligomenorrhea and secondary amenorrhea should always include pregnancy, prolactinoma, thyroid dysfunction, and medication or supplement use.

For women with excessive or intermenstrual bleeding, the differential diagnosis includes hypothyroidism, hyperthyroid-ism, blood dyscrasias, leiomyoma, adenomyosis, endometrial polyps, endometriosis, endometrial or cervical neoplasia, and hormone-secreting neoplasms such as granulosa cell ovarian cancer. Increased menstrual bleeding induced by medication or supplement use should also be considered.

Genitourinary Atrophy

Multiple conditions can cause genitourinary symptoms similar to those associated with hypoestrogenism occurring in the menopausal transition and menopause. Vulvovaginal symptoms (e.g., vaginal dryness, pruritus, dyspareunia, and postcoital spotting) may be caused by trichomonas vaginitis, yeast vulvo-vaginitis, bacterial vaginosis, desquamative inflammatory vaginitis, vestibulitis, allergic vulvovaginitis, and vulvar dysplasia or cancer. Urinary symptoms (e.g., dysuria, urinary frequency, and incontinence) may be caused by dietary bladder irritants, detru-sor instability, urinary tract infection, and interstitial cystitis. The presence of isolated microscopic hematuria on urinalysis should prompt evaluation for neoplasia of the urinary tract.

Hot Flushes and Night Sweats

Hot flushes and night sweats may be symptoms of a number of disease processes, including hyperthyroidism, pheochromo-cytoma, carcinoid, and occult infection or neoplasm (e.g., tuberculosis, HIV), and lymphoma with B symptoms. Nonvolitional weight loss or documented fevers suggest a possible underlying disease. On the other hand, weight gain or existing obesity, which provides insulation against loss of body heat, may explain easy perspiration and a sensation of excess warmth in some women.

Changes in Libido, Sleep, Mood, and Cognition

The changes in libido, sleep patterns, mood, and cognition associated with the menopausal transition and menopause may also be induced by mood or anxiety disorders, thyroid dysfunction, and stress. Medications or other substances may cause insomnia, anxiety, mood abnormalities, cognitive changes, and sexual dysfunction. Other symptoms, such as fatigue, may be the result of an unrecognized sleep disorder (e.g., obstructive sleep apnea and restless legs syndrome), an inflammatory or neoplastic process, or multiple sclerosis. New cognitive dysfunction may be the first manifestation of dementia.

Menopausal transition and postmenopausal symptom management

Management of women experiencing menopausal symptoms is best approached by (1) defining the reproductive phase2 of the patient [see Figure 1]; (2) identifying the menopausal symptoms for which treatment is desired [see Figure 4]; and (3) identifying the medical conditions that might influence management options [see Sidebar Internet Resources for Information on Menopause].

The menopausal transition and menopause do not warrant management in and of themselves. However, women who experience bothersome symptoms may want to consider treatment. HT is effective in controlling symptoms of the meno-pausal transition and menopause, but it carries risks [see Hormone Therapy Risks and Benefits, below].

The Food and Drug Administration has recommended that HT be used only for women with symptoms severe enough to warrant its use and at the lowest dose and for the shortest duration required to ease the menopausal transition. The FDA further recommends that tissue-targeted therapies be used whenever possible.60

Because of the potential risks associated with HT, it is recommended that all women taking HT be evaluated on an annual basis. The woman who is taking HT should be instructed to refrain from taking HT 1 week before the annual assessment to allow the physician and patient to evaluate the current severity of symptoms. Women who choose to stop HT may require a slow taper, ranging from 3 to 6 months, for successful cessation. Women on HT are encouraged to attempt cessation after 5 years of use.

Uterine Bleeding

Vaginal bleeding during the menopausal transition is best managed (after appropriate evaluation) with low-dose, combination oral contraceptives (containing 20 |ig ethinyl estradiol) or a progestin intrauterine device; both protect against pregnancy and reduce menstrual blood loss. The overall effect of ethinyl estradiol at 20 |ig/day is estimated to be three to four times that of 0.625 mg/day of conjugated estrogen; head-to-head trials comparing the clinical effects of the two estrogens do not exist. Although the chance of pregnancy is low (< 1% after age 50),61 pregnancy may occur during the menopausal transition. Women 40 to 49 years of age have a rate of unintended pregnancy that is now higher than that of any other age group, even teenagers62; thus, it is important to address the issue of contraception with every potentially fertile woman until she has experienced 12 months of amenorrhea. Oral contraceptives can be discontinued and symptoms reassessed at approximately age 50 [see Laboratory Testing, above]. Those with persistent and severe vasomotor symptoms and amenorrhea may be transitioned to postmenopausal HT.

Genitourinary Atrophy

Symptoms of genitourinary atrophy may be present during the menopausal transition but typically become more prominent after menopause. Symptoms of genitourinary atrophy usually improve within 2 weeks after initiation of estrogen therapy and should be controlled after 1 to 3 months of use.63 Estrogen can be administered topically with excellent local effect. Vaginal estrogen creams result in little or no systemic absorption when used at extremely low doses of less than one-eighth applicator (< 0.15 mg conjugated estrogen cream) and one-sixteenth applicator (< 0.025 mg estradiol cream); a full applicator of vaginal estrogen cream can deliver a dose equivalent to that of an oral formulation, although the rate of absorption varies considerably. Initial therapy constitutes nightly application for 2 to 6 weeks; thereafter, maintenance doses can be applied one to three times a week, depending on the severity of symptoms. Use of low-dose vaginal creams does not necessitate the use of a progestin; however, cessation of therapy results in the return of genitourinary atrophy. Low-dose vaginal estrogen rings effectively treat genitourinary atrophy with little or no systemic absorption and no significant endometrial stimulation.

Nonhormonal alternatives include lubricants for use during intercourse and vaginal moisturizers.

Vasomotor Symptoms

Estrogen is highly effective for the treatment of vasomotor symptoms. For women in the menopausal transition who are at risk for pregnancy and who have heavy or frequent menses, treatment with low-dose oral contraceptives provides amelioration of vasomotor symptoms, control of bleeding, and contraception. Cyclical HT is preferable for women in the menopausal transition who are predominantly anovulatory and who do not need contraception, because it provides lower doses of hormones than oral contraceptives. Continuous HT, which is commonly used in women who are approximately 12 months from the final menstrual period, is often associated with bothersome bleeding patterns in women in earlier stages of the menopausal transition.

Low-dose oral contraceptives and HT result in prompt resolution of symptoms within 1 to 2 weeks in 80% of women; they should be titrated to the lowest dose possible to achieve acceptable symptom relief. Systemic administration of estrogen can be achieved orally, transdermally (in the form of a gel or patch), or transmucosally (at a higher dose via the use of a vaginal ring).

Internet Resources for Information on Menopause

General Information about Menopause for Clinicians and Patients

North American Menopause Society

Women’s Health Initiative

Alternative Therapies for Management of Menopausal Symptoms

University of Washington School of Medicine, Department of Family Medicine, on Complementary and Alternative Medicine

The Longwood Herbal Task Force

Natural Medicines Comprehensive Database

Some formulations include progestins. Implants and intramuscular injections are less preferable forms of delivery because they release extremely high levels of HT at the time of administration or placement. The lowest doses of estrogens found to be effective for vasomotor symptoms include oral conjugated estrogen 0.03 mg, oral estradiol 0.5 mg, and transdermal estradiol 0.025 mg.

Several nonhormonal alternatives for treatment of vasomotor symptoms may have some efficacy. These include venlafax-ine,64,65 selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine and paroxetine),66-68 and gabapentin.69 Less evidence supports the use of clonidine70,71 and vitamin E72 as being effective in the control of vasomotor symptoms. Results from controlled clinical trials evaluating the effectiveness of phytoestrogens (including dietary soy) for vasomotor symptoms vary, but most studies indicate that the use of phytoestrogens offers no significant improvement over placebo in reducing the frequency of hot flushes.73 Black cohosh, a possible phytoestrogen, may be effective, but no large controlled trials have been conducted.74 Pro-gestin alone is effective75,76 but is not recommended because of a potential increased risk of breast cancer.77 Behavioral modifica-tion78,79 and increased exercise78,80 may diminish the severity of hot flushes. Red clover extract, dong quai, evening primrose oil, and Siberian ginseng have not been found to be effective in small randomized, controlled trials. Other botanicals purported to be effective, including valerian, motherwort, and chasteberry, have not been studied in clinical trials.81

Libido, Sleep, Mood, and Cognition

Treatment of sexual dysfunction depends on the underlying etiology. If the cause of decreased libido is not predominantly psychosocial, testosterone therapies have been shown, in some circumstances, to improve sexual function, interest and frequency of desire, and psychological well-being.82,83 There are no FDA-approved products for diminished libido in women; however, esterified estrogen combined with methyltestosterone is commonly used. Vaginal estrogen therapy, if indicated, can play an important role in the treatment of diminished sexual function resulting from urogenital atrophy.63

Vasomotor instability may contribute to disruption of sleep;thus, estrogen is effective for some women who begin to experience insomnia during the menopausal transition. Alternative therapies include short-term zolpidem and low-dose trazodone.

Estrogen may be beneficial in the treatment of depression in the menopausal transition.84 Estrogen alone, without an antide-pressant, does not appear to be sufficient to treat significant clinical depression in postmenopausal women.85 However, some investigators support the use of estrogen as an adjunct to other therapies, such as SSRIs, particularly in older women.

Management considerations

Risks and Benefits of Hormone Therapy

Although the risks and benefits of using HT for the relief or prevention of symptoms in women in the menopausal transition have not been evaluated in clinical trials, information has been established on the risk-to-benefit profile of short-term and long-term use of HT for postmenopausal women 50 to 79 years of age. Historically, it was believed that the estrogen deprivation that accompanies menopause increases the risk of some chronic diseases—specifically, heart disease, osteoporosis, and dementia. On the basis of observational data, long-term postmeno-pausal HT was recommended during the 1980s and 1990s not only for symptom relief but also to reduce the risk of chronic disease and to prolong life. However, two large randomized, controlled trials (i.e., Heart and Estrogen/Progestin Replacement Study [HERS]87 and the Women’s Health Initiative [WHI])88,89 called this practice into question. HT is no longer recommended for primary or secondary prevention of these conditions in women older than 50 years.

HERS demonstrated no evidence to support the use of HT for the secondary prevention of heart disease87; more important, WHI found that HT use conferred an increased risk of cardiovascular disease,90 stroke,91 dementia,92 thromboembolism,88 and breast cancer93 in women 50 to 79 years of age. Striking discrepancies in the findings of the randomized trials and the earlier nonrandomized (observational) studies can be explained by selection biases in participants in the observational studies. In the observational studies, women opting for HT therapy tended to be healthier and of higher socioeconomic status than non-HT users. In addition, these women were more likely to be carefully screened for chronic disease before starting HT and, therefore, had a lower risk of developing chronic disease than nonusers of HT.94 The selection biases inherent in the observational studies were virtually eliminated in the randomized trials.

Counseling about the risks of postmenopausal HT use should now be based on the evidence provided by WHI.88,89,91-100 The WHI postmenopausal estrogen and progestin therapy (EPT) and estrogen therapy (ET) trials are discussed in greater detail below.

Estrogen and progestin therapy The WHI prematurely halted its clinical trial of EPT in 2002; participants had been followed for an average of 5.2 years. The trial randomized over 16,000 postmenopausal women who were 50 to 79 years of age to take either conjugated equine estrogen (0.625 mg/day) plus medroxyprogesterone acetate (2.5 mg/day) or placebo. The study was halted because the rates of adverse events (i.e., cardiovascular events, stroke, thromboembolism, and breast cancer) were 1% higher in the intervention group and overshadowed the reduced risk of osteoporotic fractures and colon can-cer.88 There was no difference in overall or disease-specific mortality between the HT and placebo groups. The study reported the following risks: (1) thromboembolic events were highest in the first year and remained elevated over 5 years (absolute risk difference, 21/10,000/yr); (2) ischemic cardiac events were highest in the first year and remained elevated and statistically unchanged thereafter (absolute risk difference, 7/10,000/yr); (3) stroke risk was not elevated in the first year, rose slightly in the second year, and remained elevated through year 5 (absolute risk difference, 8/10,000/yr); and (4) breast cancer risk was not appreciably higher in years 1 to 3 but became elevated in year 4 (absolute risk difference, 8/10,000/yr), with the increased breast cancer risk being strongest in the approximately 25% of women who had taken HT before enrolling in the study [see Table 1]. The EPT portion of the WHI study showed a reduction in the risk of hip fractures (absolute risk difference, 6/10,000/yr)96 and colorectal cancer (absolute risk difference, 6/10,000/yr).100

Table 1 WHI Findings: Outcomes Associated with Use of Combined Estrogen and Progestin and Estrogen Alone in Healthy Postmenopausal Women

Combined Estrogen and Progestin*

Estrogen Aloneh


Relative Risk (95% CI)

Absolute Risk Dijferencet

Relative Risk 95% (CI)

Absolute Risk Dijferencet


Deep vein thrombosis8889

2.07 (1.49-2.87)


1.47 (1.04-2.08)


Pulmonary embolism8889

2.13 (1.39-3.25)


1.34 (0.87-2.06)


Coronary artery disease89,90

1.24 (1.00-1.54)


0.91 (0.75-1.12)


Ischemic stroke8991

1.44 (1.09-1.90)


1.39 (1.10-1.77)


Breast cancer89-93

1.24 (1.01-1.54)


0.77 (0.59-1.01)


Probable dementia§9598

2.05 (1.21-3.48)


1.49 (0.83-2.66)



Colorectal cancer88,89,100

0.56 (0.38-0.81)


1.08 (0.75-1.55)


All fractures88,89,96

0.76 (0.69-0.85)


0.70 (0.63-0.79)



0.98 (0.82-1.18)


1.04 (0.88-1.22)


*Patients received 0.625 mg/day of conjugated estrogen and 2.5 mg/day of medroxyprogesterone acetate. ^Hysterectomized patients received 0.625 mg/day of conjugated estrogen.

 tmp25337_thumb[2]Annual per 10,000 women.

 tmp25338_thumb[2]Ages: 65-79 yr. CI—confidence interval

The Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI continuous combined HT intervention trial, observed the effect of HT on memory and cognition in women 65 to 79 years of age (average age, 73 years).92,95 A reduction in memory and thinking abilities (as measured by the Modified Mini-Mental State Examination)95 and an increase in dementia of all types (absolute risk increase, 2/1,000/yr) were observed in women who took HT.92

Estrogen therapy The estrogen-only arm of WHI was halted prematurely in early 2004 because of increased risk of stroke; participants had been followed for an average of 6.8 years.89 Over 10,000 women 50 to 79 years of age were randomized to receive 0.625 mg/day of conjugated equine estrogen or placebo. As in the EPT portion of WHI and HERS, the ET portion of the WHI trial found that estrogen use conveyed an increased risk of deep vein thrombosis (1.47 relative risk; 95% confidence interval [CI], 1.04 to 2.08) and stroke (1.39 relative risk; 95% CI, 1.10 to 1.77) [see Table 1]. Women taking ET had 12 more strokes and six more events of deep vein thrombosis a year than the women taking placebo. The study showed a reduction in the incidence of hip fractures (0.61 relative risk; 95% CI, 0.41 to 0.91) and an unanticipated, though not statistically significant, reduction in breast cancer incidence, a finding that requires further investigation. Observational studies support an increased risk of throm-boembolism,101-103 cholecystitis,104 and breast cancer77 in women taking ET.

In contrast to the EPT portion of the WHIMS study, women taking estrogen alone did not have a statistically increased risk of dementia.98 For women taking ET, as compared with placebo, the risk of having a 10-unit decrease in the Modified Mini-Mental State examination scores (greater than two standard deviations) was 1.47 (95% CI, 1.04 to 2.07). The risk was greater in women with lower cognitive function at initiation of ET.99

Type, route of administration, and dose of HT Two observational studies77,105 and a population-based study from Southern California106 have increased current understanding of the type, route of administration, and dose of HT with associated breast cancer risk. The findings are as follows: (1) use of estrogen therapy confers greater risk than nonuse77,107; (2) use of estrogen plus progestin confers greater risk than use of estrogen alone77,105,106; (3) risk increases with duration of estrogen use77,105,106;

(4) risk with estrogen use is increased in women with low or normal body mass index but not in overweight and obese women105; (5) increased risk of breast cancer is associated with any dose and type of commonly used estrogen (i.e., conjugated estrogen and estradiol) and progestin (i.e., medroxyprogesterone acetate, norethisterone, and levonorgestrel/norgestrel); and (6) transdermal formulations of estrogen also confer increased risk.77 Surprisingly, the use of tibolone, a synthetic steroid with estrogenic, progestogenic, and androgenic properties that is marketed in Europe for its favorable effect on breast symptoms (e.g., tenderness and mastalgia), was also associated with a greater risk of breast cancer than nonuse of steroid hor-mones.77 Current evidence indicates that all forms of HT are associated with an increased risk of breast cancer.

Transdermal delivery of estrogen may not be safer if administration is long term; however, transdermal patches and trans-mucosal delivery systems (including estrogen vaginal rings that provide systemic levels of estrogen for treatment of vasomotor symptoms) avoid the first-pass effect through the liver and may carry a lower risk of thromboembolism,48,102,108,109 elevation of bile acids,110 and hypertriglyceridemia111 than oral estrogen. Studies of moderate- to high-dose regimens suggest that transdermal systems may have a more favorable effect on the coagulation pathway112 and C-reactive protein113 than oral products. Trans-dermal and transmucosal products have been shown to be effective as treatment for vasomotor symptoms114 and maintenance of bone mineral density.115

Given the newly appreciated risks of oral progestins,77,88 alternative approaches to progestin therapy are gaining popularity. There is a widely held belief that natural progesterone is better than synthetic progestins, but this hypothesis has never been studied. Lower-dose oral micronized progesterone formulations have been widely used in Canada and Europe and were evaluated in the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial.116 The PEPI study of 596 postmenopausal women found that micronized progesterone combined with estrogen sufficiently diminished the hyperplastic endometrial changes associated with estrogen-only therapy.116 No other randomized clinical trials exist to better inform us about risks and safety of micronized progesterone, particularly with respect to breast cancer. Likewise, over-the-counter transdermal progesterone creams have not been studied in this regard.

In addition, attention has been directed at nonsystemic therapies. Off-label use of a progestin intrauterine system (IUS) (20 |ig/day of levonorgestrel) in postmenopausal women taking estrogen provides low systemic levels of progestin and attenuation of endometrial stimulation by estrogen.117 Intrauterine levonorgestrel at doses of 10 |ig and 14 |ig/day have been studied in Europe.117,118 No increased risk of endometrial hyperplasia or cancer has been observed in women taking estrogen with a progestin IUS in place.117 Vaginal application of progesterone creams result in local uterine and systemic effects.

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