Symptoms

The decline of endogenous estrogen leads to multiple tissue and organ changes and problems. In addition to the reproductive and urinary tracts, estrogen-sensitive tissues are skin, bone, vascular lining, teeth and gums, eyes, the brain, and the central nervous system.

Some 50% to 80% of women in the United States report menopause-related hot flashes, night sweats, vaginal dryness, insomnia, mood swings, and depression. During the first 5 to 10 years of menopause, vulvovaginal symptoms begin to appear. Later, as the other mucous membranes of the urogenital tract become affected, rates of incontinence and infection rise.

There is strong evidence and data from randomized clinical trials that estrogen therapy is very effective in controlling vasomotor and genitourinary symptoms. Vaginal estrogen is as efficacious as oral or transdermal estrogen for genitourinary symptoms and may be an advantageous method because of the local delivery and effect.

Sex steroids also affect sleep, libido, cognitive function, motor coordination, and pain sensitivity. Data are mixed regarding the role of menopause in depression and mood swings; however, depression and mood disorders appear to be more common or at least exacerbated in perimenopause or early menopause compared with the reproductive period, and HT benefits many women.

The North American Menopause Society and its advisory panel published a post-WHI report and recommendations on postmenopausal HT. One of its basic recommendations is that the treatment of menopausal symptoms (especially vasomotor and urogenital) remains the primary indication for HT or estrogen replacement therapy (ERT).

Osteoporosis

Estrogen is known to inhibit the age-related bone loss that occurs in most menopausal women. Observational studies have indicated that the use of estrogen reduces the risk of vertebral fracture by approximately 50% and the risk of hip fracture by 25% to 30%.³ Estrogen has been considered the therapeutic agent of choice for both the prevention and treatment of postmenopausal osteoporosis in women for many years—until the WHI results. It has been the most studied agent for prevention and has been shown to decrease bone resorption, prevent osteoporosis, and reduce fractures. Nevertheless, the U.S. Food and Drug Administration (FDA) has removed estrogen from the list of agents approved as effective in treating women who already have osteoporosis. This decision has nothing to do with any new discovery of a decrease in effectiveness for this indication; rather, it arose as an issue of fairness in new standards that have been applied to approving other drugs for osteoporosis treatment, such as the bisphosphonates (risedronate and alendronate). These agents have involved prospective fracture reduction studies on women with low bone mass and/or fracture. The data on estrogen treatment for existing osteoporosis are largely observational and retrospective in nature. These studies do demonstrate the efficacy of estrogen in treating patients with osteoporosis, but randomized clinical trials will be required before the FDA reinstates its indication.⁴

That being said, the WHI was a large clinical trial in which 16,608 postmenopausal women 50 to 79 years of age were studied at 40 U.S. clinical centers.⁵ The regimen used, was continuous combined estrogen-progestogen therapy (CCEPT) (e.g., PremPro). Women in the CCEPT group experienced lower rates of hip fracture (10 per 10,000 person-years vs 15 per 10,000 person-years in the placebo group, a 34% lower relative risk) and vertebral fracture (9 events per 10,000 women annually vs 15 events per 10,000 women annually for placebo, also a 34% lower relative risk). Statistically significant fracture reductions were also seen in other osteoporotic fractures (23%) and total fractures (24%).

The different estrogen agents approved for the prevention of osteoporosis and their antiresorptive effects are as follows:

It is important to keep in mind that some women derive benefits from these doses, some will need higher doses, and others will have adequate bone protection with lower doses. Dual-energy x-ray absorptiometry (DEXA) scans provide the most reliable objective information on the status of bone mineral density.

Colorectal Cancer

Accumulated observational studies now suggest that the use of ERT reduces the risk for colorectal cancer as well as the risk of dying from colon cancer.⁶ Although not all study findings are consistent, some studies have shown that the risk of developing fatal colon cancer was reduced by 33%⁷; others show as little as an 8% reduction in risk.⁸

Endometrial Cancer

Unopposed estrogen administration is associated with an increase in the risk of endometrial cancer by a factor of 8 to 10. This results in an excess of 46 cases per 10,000 women for women who use unopposed estrogen for at least 10 years.⁹ The risk decreases after discontinuation of the ERT, but it is still elevated after more than 10 years. Adding a proved dose and delivery method of a progestogen (progestins or progesterone), which opposes the effects of estrogen on the endometrium, reduces the risk to a minimum and is essential to preventing endometrial hyperplasia and endometrial cancer.

A boon to the use of natural hormones, particularly oral micronized progesterone (OMP), came in the form of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial and its study of the effects of HT on endometrial histology in postmenopausal women.¹⁰ This trial confirmed that daily CEE, 0.625 mg, enhanced the development of endometrial hyperplasia, and that combining CEE with cyclic or continuous medroxyprogesterone acetate (MPA) protected the endometrium from hyperplastic changes. What was new was that the trial also concluded that cyclic OMP (200 mg daily for 12 days per month) also protected the endometrium from the hyperplastic changes associated with estrogen-only therapy. Thus, the PEPI was the first clinical trial proving that OMP was as appropriate as MPA for use in the protection of the endometrium. Compounded OMP was already available, but the product Prometrium came on to the market as a result of that study.

Venous Thromboembolism

Venous thromboembolism (VTE) is an almost expected complication of the postmenopausal use of exogenous hormones. Observational studies have demonstrated that in postmenopausal women who use ERT, the risk of VTE is increased by a factor of 2 to 3.5. These observations are consistent with the data found in HERS I (discussed later). The investigators reported that the risk of thromboembolic events was increased by a factor of 2.7 in the women receiving the estrogen-progestin therapy.⁷ HERS II showed that the relative risk (RR) of VTE increased 108% (RR 2.08) and the absolute risk was 0.59% in the HT group compared with 0.29% in the placebo group (59 events vs. 28 events annually per 10,000 women, respectively).¹¹

The WHI reported similar results. The relative risk was 2.11 in the HT group, a 111% increased risk. The absolute risk was 34 events in the HT group compared with 16 events in the placebo group per 10,000 women.⁷ Owing to the uncommon presence of idiopathic venous thromboembolism in women above 50 years of age, the absolute risk associated with postmenopausal HT is pretty small. For women who are already at risk for thromboembolism or who are older, the absolute risks of HT will be higher.

Coronary Heart Disease

For the past 30 years, practitioners have been advising menopausal women that HT reduces the risk of CHD. More than 40 observational studies in these past three decades have suggested that this risk is 35% to 50% lower among women who take estrogen than in women who do not.^12,13 These observational data have been reinforced by additional research demonstrating some of the impact of estrogen on individual factors known to be associated with CHD, thereby also establishing a biologically plausible mechanism for the association of HT and reduced CHD. Randomized trials have shown that estrogen therapy reduces plasma levels of low-density-lipoprotein cholesterol (LDL-C) by 10% to 14% and raises plasma levels of high-density-lipoprotein cholesterol (HDL-C) by 7% to 8%.^7,14 Estrogen has also been shown to reduce Lp(a) lipoprotein, inhibit oxidation of LDL-C, improve the endothelial vascular function, reduce fibrinogen, and reduce thickening in the arterial walls.

However, estrogen may have detrimental effects on cardiovascular risk markers, as by raising triglyceride levels, increasing clotting, and raising levels of C-reactive protein. These detrimental effects of estrogen may override the beneficial effects of estrogen on cardiovascular function and may explain the surprising results of randomized, placebo-controlled trials indicating that HT did not reduce the overall rate of CHD. In HERS II and the WHI, it actually increased the rate of CHD. These new data from randomized trials, compared with the 30 years of observational data and the biologically plausible mechanisms, have rendered recommendations to postmenopausal women about HT more complex and challenging. Both patients and practitioners have questions with no clear-cut answers, and concerns about the benefits and risks of HT are more difficult to sort out.

Heart disease is the leading cause of morbidity and mortality in women, and an understanding of the current state of the evidence and the potential for the cardioprotective effects of HT, as well as the cardiovascular negative effects of HT, is of vital importance to women’s health. In this discussion, however, one must not forget the potential cardioprotective effects of nutrition, exercise, stress management, and select nutrients such as niacin, magnesium, and fish oils.

The basic problem with HT and CHD is that the later randomized trials of estrogen among women with preexisting CHD have not confirmed the 40 observational studies of the last 30 years. The first large-scale randomized double-blind placebo-controlled trial of HT (a combination of CEEs [Premarin] and CEEs with medroxyprogesterone acetate [Provera]) for the secondary prevention of CHD was the Heart and Estrogen/Progestin Replacement Study (HERS I).⁷ In a total of 2763 women with established CHD studied at 20 clinical centers throughout the United States, the death rates from coronary causes and nonfatal myocardial infarctions in the hormone group and the placebo group were similar. Perhaps more worrisome was the 50% increase in the risk of CHD events (thromboembolism) during the first year in the women receiving HT. The HERS I data prompted a barrage of questions, as follows:

A brief attempt at some answers was made after HERS I: The early risk for increased CHD events in the hormone-treated group has been a pattern seen in subsequent studies—the Puget Sound Group Health Cooperative of Seattle,¹⁵ the Nurses’ Health Study,¹⁶ and the early data from WHI.¹⁷ An early risk for blood clots in the legs and lungs, heart attack, and stroke appears to be a real phenomenon in postmenopausal women who begin HT. Two hypotheses to explain this finding are that estrogen has a prothrombotic effect and a proinflammatory effect on the vascular endothelium.

There indeed may be some subgroup of women with a predisposition for the prothrombotic and/or proinflammatory effects of estrogen—for example, women with hyperinsulinemia, hypertension, elevated homocysteine levels, increased C-reactive protein and Lp(a) lipoprotein levels, obesity, and/or elevated LDL-C. Interestingly, in the HERS I trial, differences were observed between hormone-treated women who also took lipid-lowering therapy (statins) and hormone-treated women who did not. The rate of CHD events after 1 year was much lower in the HT-plus-statin group than in those who did not use statins. The same was true for risk of venous thromboembolic events.

Another controlled trial attempted to address the question of whether estrogen inhibits atherosclerosis. In the placebo-controlled Estrogen Replacement and Atherosclerosis (ERA) trial, neither estrogen alone nor estrogen plus the progestin¹⁸ affected the progression of coronary atherosclerosis. Plasma levels of LDL-C were reduced by 9.4% in the unopposed estrogen group and by 16.5% in the estrogen-plus-MPA group. Both groups had significant increases in HDL-C (18.8% and 14.2%, respectively) compared with the placebo group. The two estrogen groups had rises in triglyceride levels (6.1% and 10.1%, respectively), but these changes were not significantly different from the levels in the placebo group. The ERA trial provided the first anatomic endpoint (angiographically determined effects on coronary arteries) in women who had known CAD. The ERA trial supported the overall null effect found by the HERS I trial and also showed that the MPA did not cancel out the beneficial effects of estrogen, as was suspected in the HERS I trial. These data and other study results indicate that HT does not have a significant impact on the progression of atherosclerosis in women with established heart disease.

Preliminary data from the Papworth Hormone-Replacement Therapy Atherosclerosis Study (PHASE), a small clinical trial in 225 postmenopausal women with angiographically proved CAD, showed no cardiovascular benefits of HT and also possibly a slight increase in the rates of cardiovascular events during the first 2 years of HT.¹⁹ This trial evaluated transdermal natural estradiol alone or with norethindrone, a different progestin.

An interim analysis of the WHI data also suggested that there had been a slight increase in the number of heart attacks, strokes, and thromboembolic events during the first 1 or 2 years in postmenopausal women undergoing HT.²⁰

One clinical trial looked at estrogen use in postmenopausal women without clinical coronary disease. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was designed to determine whether unopposed natural estradiol reduces the progression of subclinical atherosclerosis.²¹ Postmenopausal women with high cholesterol levels but no preexisting cardiovascular disease, diabetes, or smoking history received either oral micronized natural estradiol or placebo and also lipid-lowering medication if serum LDL-C exceeded 160 mg/dL. The women were monitored for 2 years. The investigators evaluated the rate of change in carotid artery intimal-medial thickness. Women in the placebo group had an expected progression in the thickening of the carotid arteries over the 2 years. The women taking estradiol had a small amount of regression of the thickness of the carotid arteries. In women not receiving lipid-lowering therapy, the placebo group had a greater progression and the estradiol group had no progression of intimal-medial thickness—a dramatic difference. Curiously, in the women who received lipid-lowering drugs, there was no difference in the rate of progression between the women receiving estrogen and those receiving placebo.

On the basis of data from these randomized clinical trials conducted before HERS II and WHI, HT did not appear to reduce the risk of cardiovascular events in postmenopausal women who already had CHD. Then along came the world-shifting news in July 2002, when the results of HERS II and the WHI were published less than a week apart.

HERS II investigated the effects of 0.625 mg of CEE plus 2.5 mg of MPA on the prevention of CHD in older U.S. women (average age 71 years) with preexisting CHD.¹¹ This study, a continuation of HERS I, was intended to determine whether a trend toward prevention of heart disease would appear if the study were continued longer. Once again, though, the results were not positive for women with heart disease. In HERS II there were no significant decreases in rates of primary CHD events (or strokes or clots) among women assigned to the HT treatment group who had already had CHD before starting the HT regimen (RR, 1% decreased risk and absolute risk of 3.66% for HT vs. 3.68% for placebo). The investigators concluded that “postmenopausal hormone replacement therapy should not be used to reduce the risk of CHD events in women who already have CHD.”¹¹

A few days later, results of the landmark WHI study were published.⁵ The WHI investigated the effect of the most common HT regimen in the United States (0.625 mg Premarin plus 2.5 mg Provera, or PremPro) on the incidence of heart disease, breast and colorectal cancers, and fractures in postmenopausal women. The cardiovascular research was intended to investigate the effect of this HT regimen on the prevention of CHD in healthy postmenopausal U.S. women (aged 50 to 79 years) who do not have CHD. After a mean of 5.2 years of follow-up, the trial was stopped earlier than planned for the women using combined HT (mostly owing to harm from breast cancer incidence). In the WHI, there was a significantly higher risk of CHD annually per 10,000 women: a 29% increase in the relative risk and 37 more events in the HT group compared with 30 events in the placebo group. These findings, showing that estrogen plus progestin does not confer benefit in preventing CHD among women with a uterus, concurs with the HERS findings among women with clinical CHD as well as those of the ERA trial and others. The WHI results extend the findings of the earlier trials to include a wider range of women.

Stroke

In the WHI, there was no excess risk of stroke in the estrogen-plus-progestin group in the first year, but such a risk did appear in the second year, and it persisted.²² The mechanism does not seem to be related to an increase in blood pressure. The WHI findings were consistent but more dramatic than those of the HERS, which reported a nonsignificant 23% increase in the treatment group.¹¹ WHI results were also more extreme than those of the Women’s Estrogen for Stroke Trial (WEST) of estradiol (without progestin) in women with a history of a prior stroke. Overall, the WEST trial found no effect of estrogen on recurrent strokes but some rise in rates in the first 6 months.²³ Some might criticize the WHI statistics because they include older women. However, there was no indication that excess strokes were more likely to occur in older women, in women with prior stroke, through differences in race/ethnicity, or in women with high blood pressure. It is apparent that estrogen plus a progestin increases the risk of stroke in women who have been judged to be healthy. The estrogen-only arm of the WHI showed a slight increase in stroke for women in the youngest age group at study entry.²⁴ The ERT arm was quite different from the HT arm.

One of the most recent studies on estrogen leads us to the most provocative question: Do different kinds of estrogens have different effects? In this study, the risk of VTE was compared among those who used esterified estrogen, conjugated equine estrogen, and no estrogen at all.²⁵ The findings concluded that CEE but not esterified estrogen was associated with venous thrombotic risk.

Gallstones

The risk of gallstones or cholecystectomy appears to be raised by a factor of 2 to 3 in postmenopausal women who are taking ERT. This finding has been reported by several large observational studies. In HERS I, the women taking estrogen plus progestin were at a 38% higher risk of gallbladder disease than women who were taking placebo.⁷ HERS II found similar results, reporting a higher incidence of biliary tract surgery, with a 48% increased relative risk for those in the HT group and an absolute risk of 191 versus 129 events annually per 10,000 women.²⁶

Areas of Uncertainty

Focus on Estrogen Only

The WHI originally had three components: HT, a low-fat dietary modification, and supplementation with calcium and vitamin D. In addition, many of the women who did not qualify for the active treatments of the WHI became part of an observational group that was studied. Both arms of the placebo-controlled HT component (estrogen plus progestin [HT] and estrogen only [ERT]) were terminated before the planned ending date. The ERT arm of the WHI was halted on March 1, 2004, after 6.8 years of follow-up and less than a year before the planned closing date.²⁴ The ERT arm was quite different from the HT arm in that the risks in the ERT arm did not exceed the benefits. The study showed a slightly increased risk of stroke, a decreased risk of hip fracture, a lack of increase in the risk of breast cancer and a possible reduction in breast cancer risk, and no effect on the incidence of CHD.

The key clinically relevant issues from the WHI ERT study are as follows:

The middle age group had about the same death rate in both the ERT and placebo groups, and there was a slightly higher death rate in the oldest age group.

What the WHI ERT study basically showed is that ERT, using CEE, is safe for most menopausal women who do not have a uterus. ERT reduced the risk of CHD in those women who started ERT near the age of menopause, it decreased the risk of fractures, it did not increase the risk of breast cancer, the risk of colorectal cancer was increased in women who started therapy at age 70 or older, and ERT was associated with a slight increase in the risk of stroke and VTE but there was no increase in death rates.

It would appear that use of ERT alone by women without a uterus is safer than using estrogen plus a progestin.

Natural Hormones

It is important to understand that most of the research on hormone regimens is on CEEs and MPA. However, that is not exclusively the case, and certainly some of the cardiovascular research has equally implicated 17-beta-estradiol (bioidentical estradiol). Nonetheless, in the most damaging data to date, from HERS I and II and the WHI, the hormones used were the equine estrogens and progestin. So, what we definitely know to be negative effects are associated with those regimens, and we do not in fact know whether the data can be applied to other regimens. It would be naive to dismiss the data and not to admit the possibility that the results would be the same. When hormones are determined to be appropriate or even necessary, however, it would at the very least seem logical to use the hormones we know not to be those with adverse effects.

Natural compounded estrogens and natural compounded progesterone, as well as natural testosterone and dehydroepiandrosterone (DHEA), such as those used by compounding natural pharmacies and the natural progesterone creams sold over the counter, are distinct and different in several critical ways from CEEs, conjugated plant estrogens, synthetic estrogens, and synthetic progestins. Natural hormones are made from either beta-sitosterol extracted from the soybean or from diosgenin extracted from Mexican wild yam root. Those compounds are then made into the desired hormone and are biochemically identical to the hormone the body produces. By definition, a natural hormone is plant-derived and bioidentical. The natural compounded estrogens are either estriol, estrone, or estradiol. Estriol is particularly unique because it has approximately one-fourth the potency of estradiol and estrone. Natural compounded estrogens are generally used in lower doses owing to the combined effect of the weaker estriol along with the estradiol and/or estrone. These natural estrogens are thought to be metabolized significantly differently by the body, have shorter half-lives, can be used in customized dosing regimens and potencies to fit each individual woman and clinical situation, and can be adjusted to be stronger or weaker in small units to taper someone off or onto hormones.

CEEs, those that were used in the WHI study, are quite different. In the 1970s it was believed that Premarin consisted only of 10 estrogens: 17-β-estradiol, 17-β-dihydroequilin, 17-β-dihydroequilenin, 17-α-dihydroequilin, 17-α-estradiol, estrone, equilin, 17-α-dihydroequilenin, Δ-8-9-dehydroestrone sulfate, and equilenin. Since then, advancements in technology have shown that the original 10 estrogens make up less than 40% of the hormonal content of Premarin. Through the use of modern analytic techniques, more than 200 individual components have been identified, including androgens and progestins.⁴⁷ The composition of Premarin is complex, and different estrogens have various effects in different tissues. Herein may lie an explanation for problems with conjugated equine estrogens versus natural bioidentical estradiol, estrone, and estriol.

The steroid hormones, including the sex steroids produced by the ovaries, represent a subclass of lipids that share a four-ring steroid structure. The native compound from which all the sex steroids are derived is cholestane, the parent of cholesterol. When nutritional states of the individual and cell are normal, the principal precursor of steroid production is cholesterol in the plasma. The cholesterol enters the cells through a lipoprotein receptor system. The activity of the enzymes within the cells of that tissue determine the particular classes of steroids produced. Steroids, either endogenous or exogenous, enter the cells via passive diffusion. The tissues responsive to steroids have very specific intracellular receptors, each with a high affinity for its particular steroid. The primary action of the steroids is the binding of a steroid hormone to a receptor and the interactions of this receptor-hormone complex with the components of the cell. When the steroid binds, the steroid-receptor complex becomes activated and binds with very specific regions within the steroid-responsive regions of the genes. Most of the effects of steroids on responsive cells are mediated through the activation of very specific genes. The hypothesis is that a nonbioidentical hormone may act like a constant and indiscriminant environmental toxin to the genetic material within the cell because, even though it can bind to the receptor-hormone complex, it is a foreign substance.

Consider CEEs, which consist of more than 200 substances mostly foreign to a human. These substances, once ingested, are a part of that complex and therefore are activating those genes within the cell. Thus, there is a profound distinction between a hormone that is bioidentical to human hormones and one that is not. Beside the effect on the genes themselves, bioidentical hormones and nonbioidentical hormones may very well leave different metabolic footprints on the rest of the body, with different metabolic consequences. They may be directly cytotoxic to estrogen-sensitive tissues, alter binding of other hormones to those receptors, or change the liver’s metabolism of carcinogens. It is because of this distinction and the potential difference in metabolic consequences—as well as the shorter half-life of natural hormones—that naturopathic physicians prefer bioidentical natural hormones almost exclusively for the treatment of symptomatic menopause when hormones are required.

The distinctions between synthetic progestins and progesterone are even clearer. Natural progesterone has been studied and shown to have less adverse effects on the cardiovascular system than synthetic progestins such as MPA. Specifically, natural progesterone lowers HDL-C significantly less than MPA, is less atherogenic, and does not cause coronary artery spasm, whereas MPA does.

Natural estradiol may not be without concerns about its effects on the cardiovascular system and breast. However, it is typically used in a half-strength dose (0.5 mg total daily) because it is combined with the significantly weaker estriol. Estriol has been shown to have some ability to act as an antiestrogen in the breast and no significant effect on the cardiovascular system.

Further consideration of a natural hormone approach and a more holistic approach to menopause would lead one to use the hormones in combination with other strategies known to reduce the risk of breast cancer and heart disease. For examples, soy, flax seeds, cabbage family foods, and supplements can promote the metabolism of estrogens to their anticarcinogenic breakdown products. Diets designed to help prevent breast cancer and heart disease can also be emphasized, along with nutritional and botanical supplements to be considered, such as vitamins E and C, the carotenes, soy, coenzyme Q₁₀, green tea, and garlic.

Women who are using CEE and MPA should consider other natural estrogen and natural progesterone regimens or nonhormonal menopause management. Women who are using natural estrogens and natural progesterone, should consider a reevaluation of the hormone regimen to establish the lowest dose for achieving the benefits and minimizing the risks. Regular, at least annual, consideration should be given to duration of use on an individual basis. Women who do not have a uterus and are being treated with any hormone regimen should take estrogen alone. Neither synthetic MPA nor natural progesterone is needed.

Additional herbal and nutritional supplements may be considered as well. Studies on black cohosh, red clover, soy, maca, bioflavonoids, and kava have all shown proved scientific efficacy in the treatment of menopausal symptoms. The majority of women require only these nonhormonal supplements for symptom relief and never need any kind of HT. Other women may be able to lower their dose of cHT or natural hormones by using them in combination with the herbal and nutritional supplements.

Guidelines on the use of the different forms of HT are given following the discussion of nonhormonal approaches.

Nutrition

Nutrition plays a fundamental role in integrative medicine. Although dietary advice should be individualized, common themes include a diet rich in whole “natural” and unprocessed foods, with an emphasis on vegetables, whole grains, beans, seeds, nuts, fruits, lean low-fat proteins, and healthy fats; to be minimized are saturated fats and fried foods, simple carbohydrates, alcohol, sugar, and salt. Some foods, such as soy and flax, have been studied for their beneficial effects on menopause-related symptoms.

Exercise

The benefits of exercise for peri- and postmenopausal women are numerous (Box 188-1). Women can achieve substantial reductions in cardiovascular disease⁵⁴ and breast cancer risk,⁵⁵ increases in bone density,⁵⁶ and reductions in body fat and body mass index while also experiencing an improved sense of well-being.⁵⁷

However, whether exercise can reduce hot flashes during menopause is not clear. Moderate exercise may be beneficial for hot flashes; more vigorous exercise may actually exacerbate them.

Stress Management

Perimenopause/menopause can be a stressful time in a woman’s life. Surprisingly, studies of women in midlife suggest that depression, as defined by the current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), is no more common during menopause than at any other time of life.^58,59 Most studies indicate that the perimenopausal transition is associated with depressive symptoms and that women experience mood changes but fail to meet the DSM-IV criteria for the diagnosis of depression.^60–62

A woman’s ability to manage stress can be enhanced with self-care tools that may include meditation, yoga, breathing exercises, being out in nature, and getting regular exercise.

Hesperidin, Vitamin C, and Procyanidolic Oligomers

Combined with vitamin C, hesperidin and other citrus flavonoids may be effective in relieving hot flashes. In one clinical study, 94 women suffering from hot flashes were given a formula containing 900 mg of hesperidin, 300 mg of hesperidin methyl chalcone (another citrus flavonoid), and 1200 mg of vitamin C daily.⁶⁴ At the end of 1 month, symptoms of hot flashes were relieved in 53% of the patients and reduced in 34%. Improvements in nocturnal leg cramps, nosebleeds, and easy bruising were also noted. The only side effect was a slightly offensive body odor with a tendency for the perspiration to discolor the clothing.

Perhaps more useful than hesperidin are preparations containing procyanidolic oligomers (PCOs); see Chapter 117. In a double-blind study, a group of perimenopausal Taiwanese women 45 to 55 years of age were given either placebo or 100 mg of PCOs (as Pycnogenol) twice daily for 6 months.⁶⁵ Of the total, 155 women received the Pycnogenol and 75 women the placebo. The 36-item Women’s Health Questionnaire was used to evaluate the climacteric symptoms at baseline and at 1, 3, and 6 months. Blood pressure decreased similarly in both groups. HDL-C increased and LDL-C decreased significantly from baseline with Pycnogenol, but no significant differences were seen in HDL-C between the two groups. However, LDL-C was more significantly reduced in the Pycnogenol group. Perimenopausal symptoms of depression, vasomotor symptoms, memory, anxiety, sexual function, and sleep all improved significantly (P <0.001) in both severity and frequency with Pycnogenol as soon as 1 month after starting the treatment. Most symptoms also improved with placebo, but not significantly.

Gamma-Oryzanol

Gamma-oryzanol (ferulic acid) is a growth-promoting substance found in grains and isolated from rice bran oil. In the treatment of hot flashes, its primary action is to enhance pituitary function and promote endorphin release by the hypothalamus. Gamma-oryzanol was first shown to be effective in the treatment of menopausal symptoms, including hot flashes, in the early 1960s.⁶⁶ Subsequent studies have further documented its effectiveness.⁶⁷

In one of the earlier studies, 8 menopausal women and 13 women whose ovaries had been surgically removed were given 300 mg/day of gamma-oryzanol. At the end of the 38-day trial, more than 67% of the women had a 50% or greater reduction in menopausal symptoms.⁶⁶ In a later study, the benefit of a 300-mg/day dose of gamma-oryzanol was even more effective in that 85% of the subjects reported improvement in their menopausal symptoms.⁶⁷

Gamma-oryzanol is an extremely safe natural substance. No significant side effects have been produced in experimental and clinical studies. In addition to being helpful in improving the symptoms of menopause, gamma-oryzanol has also been shown to be quite effective in lowering blood cholesterol and triglyceride levels.⁶⁸

Fish Oils

A study on fish oil supplementation and hot flashes has afforded clinicians with another option in treating hot flashes and night sweats. Women in this study were between 40 and 55 years of age and had moderate to severe psychological distress, defined as a score of 72 or greater on the Psychological General Well-being Schedule. Only women with hot flashes were included in the current analysis.⁶⁹ A total of 120 women were randomly assigned to an ethyl-eicosapentaenoic acid (E-EPA) plus omega-3 fatty acid supplementation or placebo for 8 weeks. The E-EPA supplementation was a 500-mg capsule taken three times daily, with each capsule containing 350 mg of EPA and 50 mg of DHA. The baseline level of hot flashes was an average of 2.8 per day. After 8 weeks, the frequency of hot flashes decreased by a mean of 1.58 per day in the E-EPA group and by only 0.50 per day in the placebo group. There was a significant reduction of 55% in frequency of hot flashes in the E-EPA group compared with only a 25% decrease in the placebo group. There was also a greater responder rate in the E-EPA group of 58.5%, versus 34.4% in the placebo group. However, there were no differences in the severity of hot flashes or in quality-of-life scores between the two groups.

In another fish oil–hot flash study, 20 perimenopausal or postmenopausal women received 8 weeks of fish oil (840 mg EPA and 375 mg DHA). Hot flashes were monitored using diaries and the hot flash related daily interference scale. The response rate was 70% (a MADRS score decrease of 50% or more; the remission rate was 45%). Responders had significantly lower pretreatment DHA levels than nonresponders did with a pre-treatment score of 4.3 and post-treatment score of 1.8 for daytime hot flashes and a pretreatment score of 4.6 and posttreatment score of 0.7 for night time hot flashes.⁷⁰

Vitamin E

In the late 1940s, several clinical studies found vitamin E to be effective compared with a placebo in relieving hot flashes and menopausal vaginal complaints.^71,72 Unfortunately there have been no further clinical investigations. In one study, vitamin E supplementation was shown to improve not only the symptoms but also the blood supply to the vaginal wall when taken for at least 4 weeks.⁷¹ A follow-up study published in 1949 demonstrated that vitamin E (400 IU/day) was effective in about 50% of postmenopausal women with atrophic vaginitis.⁷²

Vitamin E oil, creams, ointments, or suppositories can be used topically to provide symptomatic relief of atrophic vaginitis. Vitamin E may be effective in relieving the dryness and irritation of atrophic vaginitis as well as other forms of vaginitis.⁶⁴

Black Cohosh (Cimicifuga racemosa)

In the last 30 years, black cohosh has emerged as the most studied of the herbal alternatives to hormone replacement therapy for menopause symptoms (see Chapter 77 for a complete description). Despite some studies demonstrating no benefit of black cohosh, the collective findings in black cohosh studies and long-term clinical anecdotal evidence on black cohosh indicate that it is most effective for menopause symptoms of daytime or nighttime hot flashes, mood swings, sleep disorders, and body aches.⁷⁷

In one of the largest studies, 629 women with menopausal complaints were seen by 131 general practitioners.⁷⁸ In this study, as early as 4 weeks after beginning the therapy, a clear improvement in the menopausal ailments was seen in approximately 80% of the women. After 6 weeks, complete disappearance of symptoms occurred in approximately 50%.

Some recent studies have used black cohosh in combination with other botanical extracts. For example, in a trial of black cohosh combined with St. John’s wort, healthy perimenopausal women with typical climacteric symptoms and not on HT for at least the previous 3 months were given a 264-mg tablet containing 0.364 mL of extract from black cohosh, equivalent to 1 mg terpene glycosides, and 84 mg of St. John’s wort extract with 0.25 mg hypericin.⁷⁹ Forty-two women in the treatment group and 35 women in the placebo group completed the study. Mean Kupperman Index scores at 4 and 12 weeks were significantly lower in the treatment group (P ≤0.002). At the end of the study, the average decrease in the Kupperman Index was 20 points in the treatment group and only 8.2 points in the placebo group (P <0.001). Vaginal dryness and low libido were two symptoms that did not improve, but the average hot flash score was significantly lower in the black cohosh/St. John’s wort group.

In 2007, a clinical trial of a combination of black cohosh, red clover, soy, chaste tree, valerian and vitamin E resulted in a significant lowering of the mean score value of the Kupperman Index after 4 and 6 months, yet it was found equal to placebo after 2 months.⁸⁰ This multicenter randomized double-blind placebo-controlled trial included 125 symptomatic postmenopausal women 45 to 65 years of age. The supplement tested contained 72 mg of total isoflavones with 60 mg of soy isoflavones and 12 mg of red cover isoflavones in combination with the following: 40 mg of black cohosh extract, 30 mg of chaste-tree extract, 250 mg of valerian extract, and 121 mg of vitamin E. After 2 months, the reduction in mean score value of the Kupperman Index was the same in the placebo and treatment groups. At months 4 and 6, the Kupperman Index was significantly lower in the treatment group (4 months: 13.6 score for placebo and 11.1 for treatment; 6 months: 12.2 for placebo and 9.6 for treatment) Secondarily, lipids were evaluated. No difference was seen on total cholesterol or HDL-C, but there was a nonsignificant decrease (P = 0.0608) in LDL-C and a statistically significant reduction in triglycerides (P = 0.0151) in the herbal treatment group. The study investigators and patient’s clinical global impression on the treatment group were superior compared with placebo. Both herbal and placebo groups tolerated the treatment well, while a few individual had mild and temporary side effects.

Also in 2007, black cohosh was studied for its effects on lipids, fibrinogen, glucose, and insulin. A total of 351 perimenopausal or postmenopausal women aged 45 to 55 were randomized to a 3-month double-blind trial of either (1) black cohosh extract at 160 mg/day; (2) a multibotanical formula containing black cohosh, alfalfa, chaste-tree berry, dong quai, false unicorn, licorice root, oats, pomegranate, Siberian ginseng, and boron; (3) a multibotanical formula administered with boron and a soy diet with dietary counseling; (4) 0.625 mg of conjugated equine estrogen with or without 2.5 mg of medroxyprogesterone acetate (women with a uterus received both medications while women without a uterus received the estrogen only); or (5) a placebo.⁸¹ Whereas the primary objective of the study was to determine the effects on hot flashes, the secondary measures included the effects on lipids, fibrinogen, glucose, and insulin. Study participants were women who were experiencing hot flashes, mostly white and with college degrees. The average total and LDL-C levels were borderline high (219 and 146 mg/dL); HDL-C was medium at 53 mg/dL, triglycerides were normal at 107 mg/dL. At the 3-month mark, there were no statistically significant treatment effects on total cholesterol, LDL-C, HDL-C, triglycerides, fibrinogen, glucose or insulin among women who had any of the three herbal regimens (all three of which contained black cohosh). The evidence from this randomized controlled trial of perimenopausal and postmenopausal women does not support any short-term benefit or adverse effects of black cohosh on lipids, fibrinogen, glucose, or insulin when used alone, in combination with other botanicals, or in conjunction with soy consumption. This is reassuring in that black cohosh does not appear to affect any thrombotic biomarkers, as does oral estrogen therapy (OET), nor does it increase triglycerides, as seen with OET.

Hops (Humulus lupulus)

Hops have shown positive effects for mood issues, such as anxiety and restlessness, and for sleep disruptions in menopausal women. In one randomized double-blind placebo-controlled study, 67 menopausal women were given either a placebo or a 120-mg or 300-mg of standardized hop extract (providing 100 mcg and 250 mcg of 8-prenylnaringenin, respectively) for 12 weeks.⁸² At 6 weeks, the 120-mg dose was significantly superior to placebo, but not at 12 weeks. Even so, there was a more rapid decrease in menopausal symptoms scored for both doses of hop extract, especially the hot flash score. The higher dose was not any better than the lower one.

A second double-blind study in 36 menopausal women indicated significant reductions in the Kupperman Index and the visual analog scale (VAS) for the hops group and a marginal reduction in symptoms for the menopause rating scale (MRS) after 16 weeks.⁸³

Maca (Maca peruvianum)

Research on perimenopausal and menopausal women using a proprietary maca product (Maca-GO) found that, unlike hormone replacement therapy (HT) and phytoestrogenic botanicals, maca can increase the body’s production of estrogen—versus simply adding estrogen replacement to the body—and lower levels of cortisol and adrenocorticotropic hormone.⁸⁴ What makes this especially interesting is that, from other research conducted on the composition of various powdered preparations of maca root, it appears that the herb does not contain plant estrogen or hormones.^85–88 It has been suggested that maca’s therapeutic actions rely on plant sterols stimulating the hypothalamus, pituitary, adrenal, and ovarian glands and therefore also affecting the thyroid and pineal glands. Thus, it has effects in improving sleep, mood, fertility, energy, and hot flashes. As such, maca tends to treat menopausal symptoms as a whole rather than only one specific symptom of menopause (such as hot flashes).

In one double-blind randomized 4-month study of early postmenopausal 20 women, patients were given either placebo or two 500-mg capsules of Maca-GO twice daily for a total of 2 g/day.⁸⁴ Menopausal symptoms were assessed according to Greene’s Score and Kupperman Index. After 2 months, this maca product stimulated estradiol production and suppressed follicle-stimulating hormone, T3, aderenocorticotropic hormone, and cortisol. It also had a small effect on increasing bone density and alleviated numerous menopausal symptoms including hot flashes, insomnia, depression, nervousness, and diminished concentration.⁶

A small randomized double-blind placebo-controlled crossover trial comprising 14 postmenopausal women was completed using 3.5 g of powdered maca (Lepidium meyenii) for 6 weeks and matching placebo for 6 weeks.⁸⁹ Measurements of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone–binding globulin (SHBG) were taken at baseline, and then at weeks 6 and 12. The Greene Climacteric Scale was used to assess the severity of menopause symptoms. Serum concentrations of estradiol, FSH, LH, and SHBG were similar in both groups. The Greene Climacteric Scale revealed a significant reduction in psychological symptoms including anxiety, depression, and sexual dysfunction after maca consumption compared with baseline and placebo. These findings were independent of androgenic or alpha-estrogenic activity present in the maca using assays to measure hormone-dependent activity.

Red Clover (Trifolium praetense)

Red clover, a member of the legume family, has been used worldwide as a source of hay for cattle, horses, and sheep and used by humans in the past as a source of protein in the leaves and young sprouts. Historically it has also been recognized as a medicinal plant for humans and, more recently, as a menopausal herb. The principal substances of red clover are the flavonoid glycosides, coumestans, volatile oils, L-dopa, caffeic acid conjugates, polysaccharides, and some miscellaneous resins, fatty acids, hydrocarbons, alcohols, chlorophylls, minerals, and vitamins.

At least six clinical trials have been conducted on the effect of red clover isoflavones on vasomotor symptoms; three showed benefit and and three did not. The first two published studies on red clover and vasomotor symptoms showed no statistically significant difference between the red clover standardized extract and placebo during a 3-month period, although both groups did improve.^90,91 It was suggested that the negative results of these studies were due to inadequate controls and that women in the control group were in fact obtaining meaningful amounts of phytoestrogens in their diets. Two other studies using 40 mg of standardized red clover extract produced a 75% reduction in hot flashes after 16 weeks in 30 women. The difference between placebo and red clover isoflavones was statistically significant (P <0.001).⁹² A similar study evaluating 40 mg of red clover standardized isoflavones for 2 months in 23 postmenopausal women found that the red clover users had a 54% reduction in hot flashes versus 30% in the placebo group.⁹³ Two more recent studies continue the contradictions. In 2002, the use of 80 mg of isoflavones daily resulted in a significant reduction in hot flashes as compared with baseline.⁹⁴ Another study, called the ICE study, compared two different doses of red clover isoflavones—82 mg and 57 mg per day—with placebo for 12 weeks. The reductions in the mean daily hot flash count at 12 weeks were similar for both treated groups as well as the placebo group.⁹⁵

Other intriguing effects of red clover reported by these studies are as follows: no endometrial thickening and an increase in HDL-C as well as and no abnormalities in liver function parameters, complete blood count, or estradiol determination. Last, a published study showed that red clover isoflavones may reduce the risk of coronary vascular disease by increasing arterial elasticity by 23%.^96,97

Siberian Rhubarb (Rheum rhaponticum)

A special extract, ERr 731, from the roots of rhapontic rhubarb has been in wide use in Germany since 1993, specifically for the treatment of menopausal symptoms. This medicinal species of rhubarb is not the same species as the garden rhubarb used for food. Other rhubarb species included R. officinale, R palmatum, R polygonatum; these have been traditionally used as laxatives owing to their content of anthraquinone glycosides such as emodin and aloe-emodin. The R. rhaponticum used in clinical studies and in the extract form of Err 731 does not contain any emodin or aloe-emodin and thus has no laxative effects.

A standardized extract, ERr 731, from the roots of Rheum rhaponticum, also known as Siberian rhubarb, was studied in a 12-week randomized double-blind placebo-controlled clinical trial in 109 perimenopausal women with climacteric complaints. One tablet (250 mg) containing 4 mg of dry extract was used in the treatment group (n = 54) while the control group (n = 55) received placebo. The primary outcome was the change in the Menopause Rating Scale II (MRS II). After 12 weeks, the MRS II total score and each MRS II symptom significantly decreased in the rhubarb extract group compared with the placebo group (P <0.0001). The overall menopause quality-of-life score was also significantly better in the treatment group compared with placebo. No adverse events were observed.⁹⁸

Another randomized double-blind placebo-controlled clinical trial of the standardized extract of Rheum rhaponticum was conducted in 109 perimenopausal women with menopausal symptoms, including anxiety. One tablet containing either 250 mg of ERr 731, (containing 4 mg of Rheum rhaponticum dry extract) or placebo, was given for 12 weeks. After only 4 weeks of treatment, the Hamilton Anxiety Scale total score and anxiety score for ERr 731 group decreased significantly. This was maintained after the 4 weeks and was even more significant after 12 weeks of treatment. Anxiety decreased from moderate or severe to slight in 33 of 39 ERr 731 women. Quality-of-life issues also increased in the ERr 731 group far more significantly than in the placebo group, by 22.4 points versus 7.6 points.⁹⁹

In an observational study, 363 menopausal women with menopausal symptoms were given one 4-mg tablet of ERr 731 for 6 months. The MRS was used to evaluate symptoms, and a change in the MRS was the primary outcome. After 6 months of treatment, 252 women completed the study. At that point, there was a significant decrease in the total MRS score from an average of 14.7 points at baseline to 6.9 points (P <0.0001)—a decrease of 7.8 points. The most pronounced improvement occurred within the first 3 months of treatment in those women who were the most symptomatic at baseline, with a score equal to or greater than 18 points. The most significant improvement was for symptoms of hot flashes, irritability, sleep problems, depressive mood, and physical/mental exhaustion.¹⁰⁰

St. John’s Wort (Hypericum perforatum)

Research on St. John’s wort extract has focused mainly on mild to moderate depression (see Chapter 99) and several studies have also considered menopausal symptoms. In the most recent trial, a total of 100 women with an average age of 50 participated in a randomized double-blind placebo-controlled clinical trial comparing St. John’s wort with placebo in women with perimenopausal/menopausal hot flashes.¹⁰¹ Fifty women received 20 drops three times daily of St. John’s wort extract (Hypiran) containing hypericin 0.2 mg/mL and 50 women received a placebo of distilled water. The study duration was 2 months. Clinical examinations and interviews were performed at baseline, 4 weeks, and 8 weeks. Treatment effectiveness was measured by the Blagg-Kupperman Index. Evaluation of frequency, duration and severity of hot flashes was the main objective of the study. Forty-five women in the treatment group and 43 in the control group completed the study.

In women taking St. John’s wort, the frequency of hot flashes began to decline during the first and second months, but more improvement was shown during the second month. There was no statistical change in hot flash frequency during the first month of placebo but some improvement during the second month. Women who used St. John’s wort showed more improvement in frequency than did those on placebo. The decline in duration of hot flashes was statistically significant at week 8, and the decline was much more evident in the St. John’s wort arm. The severity of hot flashes was relieved by St. John’s wort during the 2 months of treatment and was more significant in the second month. Women in the placebo group did not show any significant decrease in the severity of hot flashes during the first month. They did have some improvement during the second month, but not as much as those in the St. John’s wort group.

Another double-blind randomized clinical trial studied the effect of St. John’s wort extract compared with placebo on symptoms and quality of life of 47 symptomatic perimenopausal women aged 40 to 65 with three or more hot flashes per day.¹⁰² Women were randomly assigned to receive a St. John’s wort extract (900 mg three times daily) or placebo. After 12 weeks of treatment, a nonsignificant difference in favor of the St. John’s wort group was observed on the daily hot flash frequency and the hot flash severity scores. After 3 months of treatment, women in the St. John’s wort group reported significantly better quality-of-life scores and significantly fewer sleep problems compared with those on placebo.

A drug monitoring study conducted in women with menopausal symptoms using 900 mg of St. John’s wort for 12 weeks found that about three quarters of the women experienced improvement in both the self-rating scale and the physician rating; they also improved significantly in psychological and psychosomatic symptoms as well as a feeling of sexual well-being.¹⁰³

Several double-blind studies have used a combination of St. John’s wort and black cohosh extract. These studies have been described previously.

Although it appears to be common for practitioners to use chaste tree (Vitex agnus castus) in perimenopause and menopausal women for symptom relief, there have been no mono-ingredient studies on this plant for these symptoms. Vitex has been shown to be helpful when combined with black cohosh. The most recent menopause related study using Vitex was in combination with St. Johns wort. In this double-blind, randomized, placebo-controlled 16 week trial of late perimenopausal or postmenopausal women who reported hot flushes and other menopause symptoms, the herbal combination showed no significant difference from that of placebo.¹³⁵

Kava (Piper methysticum)

Kava has most often been associated with analgesic, sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. It is not typically thought of as an herb for menopause; however, anxiety, irritability, tension, nervousness, and sleep disruption are common perimenopausal and menopausal symptoms for which kava can offer some help. Several controlled trials have investigated the value of kava for menopausal symptoms.^104–106 The main results noted were a significant reduction in anxiety and depression. For more information on the pharmacology of kava, see Chapter 114.

Ginseng (Panax ginseng)

Panax ginseng, also known as Korean or Chinese ginseng, contains at least 13 different triterpenoid saponins, collectively known as ginsenosides. Whether it involves reducing mental or physical fatigue,^107–110 enhancing the ability to cope with various physical and mental stressors by supporting the adrenal glands,¹¹¹ or treating the atrophic vaginal changes due to lack of estrogen,¹¹² ginseng is a valuable tool for many menopausal women. In one trial, a standardized extract of P. ginseng was studied in 384 postmenopausal women.¹¹³

Depression and well-being showed a statistically significant improvement with ginseng. In another randomized controlled trial, 1 month of P. ginseng increased energy and decreased insomnia and depression.¹¹⁴ These results indicate that P. ginseng can significantly improve the general sense of well-being of women going through menopause.

Kudzu (Pueraria mirifica)

Pueraria mirifica was examined for its effect on vaginal symptoms, vaginal health index, vaginal pH, and vaginal cytology in postmenopausal women.¹¹⁵ In this randomized double-blind placebo-controlled study, 51 women were given either 20, 30, or 50 mg of Pueraria mirifica or placebo daily for 24 weeks. After 12 weeks of treatment, significant improvements in vaginal symptoms were seen, and they were maintained over the study period. The mean vaginal dryness symptoms decreased at all the herbal doses, but the results were not significantly different from those seen in the placebo group. The frequency of dyspareunia decreased from 56.9% to 39.2% in the study group, whereas it did not change in the placebo group. The changes in the vaginal health index (scoring vaginal appearance with regard to moisture, fluid volume, elasticity, epithelial integrity, and pH on a scale of 1, poorest, to 5, best) were significantly improved in the herbal group, as noted in weeks 12 and 24. Before treatment, the mean vaginal pH was 8.41 in the treated group; after 12 and 24 weeks, the mean pH was 5.52 and 5.83 respectively. After 12 weeks of treatment, most measures of vaginal health in the treated group were significantly higher than in the placebo group.

After 12 and 24 weeks of treatment, the maturation value and maturation index were also significantly higher in the study group than in the placebo group. In essence, Pueraria mirifica improved the parabasal:intermediate:superficial cells, which is what occurs when vaginal estrogen is used. There were no statistically significant changes in endometrial thickness and no significant difference in adverse effects between the treatment and placebo groups.

Dong Quai (Angelica sinensis)

By far the most popular use of Angelica species has been the use of A. sinensis in the treatment of menopausal complaints. Although a double-blind placebo-controlled study showed no significant benefit, the preparation used (a dried aqueous extract) was clearly lacking some of the important volatile compounds, although it was standardized for ferulic acid content.¹¹⁶ In addition, the traditional use of Angelica has been in combination with other plants. A study conducted in China showed that a combination of A. sinensis, Paeonia lactiflora, Ligusticum monnieri, Atractylodes chinensis, Sclerotium poriae, and Alisma orientalis was effective in roughly 70% of women experiencing menopausal symptoms.¹¹⁷ Although not double-blind, this study shows promise for using Angelica in the management of menopausal symptoms in combination with other compounds. Also, in a double-blind study, the combination of 100 mg Angelica, 60 mg soy isoflavones, and 50 mg of black cohosh extract significantly reduced menstrual migraines.¹¹⁸

Interestingly, in an in vitro study with human bone, the aqueous extract of A. sinensis was found to directly stimulate proliferation, alkaline phosphatase activity, protein secretion, and type I collagen synthesis in a dose-dependent manner.¹¹⁹ These results indicate the A. sinensis may have an effect on preventing age-related bone loss.

Valerian

A double-blind study on the impact of valerian for sleep quality in postmenopausal women who were experiencing insomnia concluded that valerian may be helpful. The postmenopausal women studied were generally healthy women 50 to 60 years of age who were menopausal for at least 1 year, who were not using a hormone therapy, and were experiencing insomnia as evaluated by the Pittsburgh Sleep Quality Index (PSQI). One group of women was given capsules containing 530 mg of concentrated valerian extract twice per day and the other group was given a placebo twice per day, for 4 weeks. A statistically significant change was reported in the quality of the sleep in the valerian group when compared to the placebo group. The average score on the sleep scale before valerian was 9.8 and after valerian it was 6.02. The placebo group had an initial average sleep scale score of 11.1 and after placebo 9.4. Overall, 30% of the women taking valerian and 4% taking placebo reported an improvement in their sleep quality. ¹³⁶

Bioidentical Estrogens

Some would argue that the advantage of conventional pharmaceutical company HT is that it has undergone years of scientific study. Although this is true, there has been little effort to make distinctions between different kinds of estrogens in particular. To a lesser degree but still true, there has not been much effort to distinguish between the various progestins (synthetic) and bioidentical progesterone. Whereas many alternative practitioners point to the superior safety profile of bioidentical estrogens over nonbioidentical estrogens, it cannot be stated with science-based facts that an equivalent dose of bioidentical estradiol is innately safer or better than the synthetic form or CEE. Whereas logic and common sense might lead us to assert that a bioidentical estrogen is more akin to the body’s enzymatic pathways, bowel flora, and general physiology, thus leading to enhanced safety, we have yet to adequately prove this. For now it remains in the realm of hypotheticals and philosophical issues. There are however, some better safety profiles with bioidentical progesterone versus the progestins, to be discussed further.

The ability to individualize prescriptions with compounded bioidentical hormones can provide endless customized options with the ability to be flexible in dosing and delivery according to the needs of each woman. If for no other reason, this is compelling enough reason to prescribe compounded bioidentical hormones. The combination of estriol with estradiol and the use of bioidentical progesterone and testosterone with the estrogens provides the potential maximum benefit and a more individualized approach for each patient. The hope is that there is less risk that nonbio-identical hormones in the case of combining the weaker estriol with estradiol/estrone. In the case of progestogens there is more than hope, there is some actual evidence of reduced risk.

Estriol seems to be helpful in treating many of the symptoms of menopause, such as hot flashes. Vaginal estriol for vaginal dryness is considered a potentially preferred form of vaginal estrogen owing to the dominance of estriol receptors in the vagina and vulva.

Alternative practitioners often use estriol to treat menopausal symptoms, as it is thought to have a better safety profile than estradiol and estrone. Estriol is about one fourth as potent as estradiol.¹²⁰

Estriol can be taken orally in capsules or tablets and intravaginally as a cream. Vaginal estriol creams and suppositories have been shown to restore normal vaginal cytology¹²¹ and to decrease the incidence of bladder infections.¹²²

These creams most likely work by restoring the vaginal flora, improving vaginal and bladder health, and increasing lubrication, elasticity, and thickness of the vaginal epithelium. A common prescription is 1 mg of estriol per gram of cream inserted vaginally daily for 2 weeks and then twice a week for maintenance.

A popular practice for prescribing compounded bioidentical estrogens is to combine the lower dose and perhaps potentially safer effects of estriol with small doses of estradiol and estrone. Currently, those who prescribe a triple-estrogen compound typically use a formula composed of 80% estriol, 10% estradiol and 10% estrone. Progesterone is added to the formula at a minimum of 100 mg/day to protect the uterus from the potential effects of the estrogen in thickening the lining of the endometrium. Use of estrogen only, without the proper dose of progesterone, in women with a uterus might put them at risk for endometrial hyperplasia or even endometrial (uterine) cancer.

A biestrogen formulation, with estriol and estradiol, is increasingly popular because of concerns that estrone may be associated with more carcinogenic estrogen metabolites, which are associated with an increase in the risk of breast cancer. (Recommended dose ratios for both triestrogen and biestrogen formulations are discussed later.)

Progesterone

Progesterone is available with a prescription as oral capsules, sublingual drops, sublingual pellets, lozenges, transvaginal or rectal suppositories, and by injection. Progesterone is also available over the counter as a cream. Progesterone is added to a compounded biestrogen or triestrogen formulas at a minimum of 100 mg/day to protect the uterus.

For women with a uterus, a progestogen must be added to any estrogen preparation to prevent endometrial hyperplasia and uterine cancer. Progesterone is a natural hormone made by the ovaries and its main function is to support pregnancy. Progestin is the term applied to the synthetic derivatives, which differ in biochemical structure from progesterone. Progestins used in conventional HT and birth control pills often account for the side effects that patients experience, such as irritability, depression, bloating, and mood swings. Progestins tend to cause water retention, can effect brain chemistry, and alter other steroid pathways. Progestogen is the term applied to any substance possessing progesterone qualities. It can refer to progesterone or progestin.

The advantages of bioidentical progesterone over progestins are better validated than are the advantages of estrogens.

Bioidentical progesterone minimizes the side effects associated with progestogens and has a more favorable effect on lipid profiles and cardiovascular function.¹²³

In some women, insomnia, fatigue, anxiety, and mood swings may be more responsive to progesterone than estrogen.

Progesterone Cream

Bioidentical progesterone by itself can also be used very effectively in perimenopause. Problems that can be addressed include regulation of the menstrual cycle, hot flashes, night sweats, mood swings, sleep disruption, and premenstrual symptoms.

A transdermal progesterone cream was studied for its ability to control vasomotor symptoms (hot flashes) and in order to evaluate its ability to prevent bone loss. In this study, 102 healthy women within 5 years of menopause were randomly assigned to receive either transdermal progesterone cream or a placebo.¹²⁴ Subjects were instructed to apply a 1/4 tsp of cream (this amount contained 20 mg progesterone or placebo) to the skin daily. Each also received a multivitamin and 1200 mg of calcium. Measurements included medical history, physical examination, DEXA scanning of the hip and spine, measurements of TSH and FSH, a lipids profile (cholesterol, etc.), and a regular blood chemistry profile. The women kept weekly symptom diaries and were seen every 4 months for 1 year. Bone density scanning and blood chemistry profiles were obtained again at the end of 1 year.

Before the initiation of the study, 30 of the 43 (69%) in the treatment group and 26 of the 47 (55%) in the placebo group had hot flashes. Twenty five of 30 (83%) women in the treatment group experienced improvement or resolution of the hot flashes, and 5 of 26 (19%) placebo subjects showed improvement or resolution. The numbers of women who showed a gain in bone mineral density did not differ in the two groups.

The latest randomized clinical trial compared the effect of a transdermal natural progesterone cream (32 mg/day) with a placebo cream. Eighty postmenopausal women in Australia were randomly assigned to each group. They were evaluated using the Greene Climacteric Scale and the Menopause Quality of Life Questionnaire; serum lipid levels and bone markers were also monitored over 12 weeks. No detectable change was seen in vasomotor symptoms, moods, libido, serum lipid levels, or metabolic markers of bone turnover. There was a slight elevation of blood levels of progesterone. The researchers concluded that the 32 mg of transdermal progesterone was not sufficiently absorbed into the bloodstream to achieve biological effects.¹²⁵

Testosterone

The majority of women treated with estrogen replacement have resolution of their menopausal symptoms. For those who do not, and especially for those complaining of a loss of libido, estrogen with testosterone may be beneficial.

One study of early postmenopausal women (both natural and surgical) who were switched from estrogen alone to estrogen/testosterone therapy found that overall symptom relief was superior to estrogen-only therapy. Sex drive and satisfaction both increased.¹²⁶ A double-blind study of women dissatisfied with their HT regimens showed that sexual desire, satisfaction, and frequency of sexual activity were increased when they used the estrogen/testosterone combination.¹²⁷

Other studies have shown that the combination of 1.25 mg of esterified estrogen and 2.5 mg of methyltestosterone given daily for 2 years after surgical menopause significantly reduced the intensity of hot flashes and vaginal dryness in 81% and 73% of women, respectively.¹²⁸

A trial comprising 814 postmenopausal women with hypoactive sexual desire revealed that a 300-g testosterone patch improved the frequency of satisfying sexual episodes and decreased their distress.¹²⁹

In this study, the women were not treated with estrogen or progesterone. Three excess cases of breast cancer were detected but were not statistically significant. Formulations of CEE and methyltestosterone combined either 0.625 or 1.25 mg of CEE with 5 mg of methyltestosterone. Other preparations come as either 1.25 or 0.625 esterified estrogens combined with 2.5 or 1.25 mg of methyltestosterone respectively. At present, bioidentical testosterone can be obtained only from a compounding pharmacy, where 4 to 6 mg of bioidentical testosterone is generally formulated alone or together with the biestrogen or triestrogen formulation. Testosterone cream applied to the genital region can be used as an alternative delivery method. Common prescriptions are anywhere from 1 to 10 mg/g of cream. The cream is applied to the external genitalia just before sexual activity to enhance sensitivity to touch and orgasm. Such use should not occur more than twice a week to avert local testosterone side effects, such as clitoral enlargement. The NAMS concluded that “Postmenopausal women with decreased sexual desire who have no cause other than being postmenopausal, may be candidates for testosterone treatment.” Other causes of low libido should be ruled out and laboratory testing of testosterone levels should be used to monitor for supraphysiologic levels before and during therapy. Testosterone therapy is contraindicated in women with breast or uterine cancer and in those with cardiovascular or liver disease. Testosterone should be given at the lowest dose for the shortest time that meets treatment objectives.

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a bioidentical hormone and another of the androgens. It is the most abundant circulating steroid in humans. DHEA is called a precursor hormone because it is produced in large amounts in the body and because other steroid hormones are made from DHEA, including estrogen and testosterone.

Many claims have been made about DHEA’s effect on the immune system, and its antiaging properties are said to include better memory, less fatigue, more energy, relaxation, and increased ability to handle stress. It is also touted as having positive effects on bone density and helping to prevent cancer and cardiovascular disease. However, the exact effect DHEA has on the body’s cells is unclear. Observationally, DHEA may increase energy, improve stress response, improve muscle mass, and occasionally increase libido. However, in the DAWN trial, DHEA supplementation of 50 mg/day did not improve well-being or cognitive performance in healthy older adults.¹³⁰ In a 1-year study with 10 mg/day of DHEA alone or in combination with HT in postmenopausal women, DHEA was able to restore the androgenic milieu and had a positive effect on estrognic tone in postmenopausal women.¹³¹ (There also appears to be an insulin-sensitizing effect of DHEA, reducing abdominal visceral fat, lowering insulin level, and producing a significant increase in insulin sensitivity.)¹³²

Perhaps the most intriguing use of DHEA in menopausal women is for vaginal atrophy and/or sexual dysfunction. One study used three doses of DHEA ovules (0.25%, or 3.25 mg DHEA; 0.5%, or 6.5 mg DHEA; and 1.0%, or 13 mg DHEA) in 54 women; this was applied daily intravaginally for 12 weeks.¹³³ All three doses induced a significant beneficial change in vaginal epithelial cells, pH, and bothersome symptoms at 2 weeks. These benefits were accomplished with no effect on endometrial histology, and no or minimal effects on serum estrogens and androgens and their metabolites. Another intravaginal DHEA study was a prospective randomized double-blind placebo-controlled trial that evaluated the effect of daily local intravaginal DHEA ovules for 12 weeks in postmenopausal women.¹³⁴ The main assessment criteria were sexual dysfunction parameters of libido, arousal, orgasm, and dyspareunia in postmenopausal women who had vaginal atrophy. In this study, 218 postmenopausal women were randomized to receive a daily ovule of either no DHEA, 3.25 mg DHEA, 6.5 mg DHEA or 13 mg of DHEA. At 12 weeks, compared with placebo, the 13-mg ovule showed 68% improvement in the abbreviated sexual function arousal/sensation domain, in the arousal/lubrication domain by 39%, in orgasm by 75%, and in dryness during intercourse by 57%. DHEA also fared better than placebo in the desire domain of menopause-specific quality of life by 49% to 23%.

Nonbioidentical Hormones

Nonbioidentical conventional HT includes estrogens manufactured by a pharmaceutical company that are not identical in chemical structure to an endogenous hormone. As examples, conjugated equine estrogens are derived from the urine of pregnant mares. Esterified estrogens are in part estrone sulfate and in part equilin sulfates. Progestins are synthetic substances.

Oral capsules containing 1 mg of bioidentical hormones are equivalent to 0.625 mg of conjugated equine estrogens (CEE). Estrogen patches that contain 0.05 mg of bioidentical estradiol are considered to be equivalent to 0.625 mg CEE (Premarin) or 0.625 mg of esterified estrogens and equivalent to 1 mg of oral bioidentical estradiol. Current available products are available through the NAMS.

Recommended dose ratios for triestrogen and biestrogen formulations with progesterone:

Additional Medications

Nonhormonal options for hot flashes include clonidine, usually 0.1 to 0.2 mg daily at bedtime. The neuroleptic neurontin is administered at 300 mg three times daily. Venlafaxine and paroxetine have shown a reduction in hot flashes in studies using 37.5 to 75 mg and 10 to 20 mg daily respectively. However, selective serotonin reuptake inhibitors and selective norepiniphrine reuptake inhibitors have occasionally been shown to cause vasomotor symptoms in both men and women. Bellergal, an ergot and belladonna combination, was used for many years for vasomotor symptoms but is now available only from compounding pharmacies. There are no studies, and empirical reports show mixed results.

Perimenopause–Menopause Evaluation

The onset of perimenopause–menopause is an important time for a comprehensive health and lifestyle evaluation. A comprehensive medical history and complete physical examination are essential prior to initiating menopausal HT of any kind. Assessment of risk factors for stroke, CHD, venous thrombolic embolism, osteoporosis, diabetes and breast/ovarian/uterine cancer is highly recommended. DEXA testing, lipid profiles, fasting glucose, and mammography should be performed according to national guidelines, age, and medical judgment. Other selected tests depend on age, symptoms, and other medical problems.

There is no one test for menopause. Tests to determine ovarian function are not routinely done because the diagnosis of perimenopause or menopause cans largely be made based on the medical history. Practitioners can use hormone testing on an individual basis, mostly to differentiate menopause from thyroid problems, abnormal causes of a lack of menses such as elevated prolactin levels, or premature ovarian failure (premature menopause). The follicle-stimulating hormone (FSH) test is not as accurate as one would like in a perimenopausal woman. The difficulty with FSH tests is that they can fluctuate immensely during perimenopause. What a woman’s FSH is on any given day is not meaningful in diagnosing her symptoms as being due to menopausal changes or not. In a woman who is still having menses, especially irregular/random cycles, as is often the case in perimenopause, the FSH fluctuates unpredictably; it can easily be within normal range on one day and elevated on another. In fact, FSH tests are frequently normal in perimenopausal women and a physician with lack of experience in menopausal/midlife patients may mistakenly attribute symptoms to depression, anxiety, or unknowns rather than to perimenopause. There are two regular scenarios to consider for ordering an FSH: (1) If a woman is suspected to be perimenopausal or menopausal and is using contraception, the FSH can be useful in determining if she still needs contraception. A FSH above 30 mIU/mL that, when repeated 1 month later, is also above 30 mIU/mL would justify a diagnosis of menopause. It is important to continue the contraception during that 1-month period until this is determined. (2) If a woman is reporting irregular menses, irritability, fatigue, insomnia, and so on, an FSH and a thyroid-stimulating hormone (TSH) test will be helpful in sorting out her problems.

There is a popular notion, especially among alternative health care providers, that saliva or serum testing or urinary hormone testing can be done to determine hormone management. One major problem with this thinking is that there is little or no value in these tests in a perimenopausal woman for the purpose of diagnosing her hormone levels. What her levels are on the hour/day/days of the test is the only information that is gleaned, but this is not diagnostic of perimenopause and, as mentioned, it is highly variable. There is no scientific evidence to support claims of increased efficacy, enhanced safety, or need for testing in order to determine the dosing of the hormonal prescriptions. In particular, there are numerous problems with saliva testing of estrogen and progesterone: (1) there is only a very small amount of these hormones in the saliva, (2) there are high false-positive elevations in those already taking a sublingual hormone, (3) there may be contamination of the saliva collection tube if a patient is already using topical hormone creams/gels, (4) there is little proficiency testing, (5) varying technologies yield broad differences in results, (6) technical challenges are not adequately addressed by all laboratories conducting these tests, (7) there is a lack of scientifically proved accuracy, and (8) there are interfering components such as food, beverages, medications, and chewing gums.

Salivary testing of cortisol and DHEA levels holds more promise, as these do not fluctuate so much from day to day, we have a known daily rhythm of cortisol production, and there are naturally higher amounts of these in the saliva than of the hormones estrogen and progesterone.

Serum testing of estrogen, progesterone and testosterone has proven to be more accurate with standardized methods of measuring. However, it is not often that even these are necessary tests in perimenopausal and menopausal women. For one, the reference ranges are often wide, and with testosterone in particular we are not even sure what the normal reference range of testosterone is for women. Again, in a perimenopausal woman, estrogen levels in particular fluctuate from day to day and therefore are not valuable in diagnosis or management. In a postmenopausal woman, estrogen and progesterone levels are predictably low, as they are supposed to be.

Although saliva estrogen/progesterone testing has yet to prove its accuracy or efficacy, even if it were accurate, neither salivary nor serum hormone testing is necessary or even helpful for the perimenopausal woman, because it is difficult to draw conclusions from test results when the hormones are in such a fluctuating state. There are so many peaks and valleys and erratic hormone activity that testing offers little value in most situations. For the women taking HT, it is tempting to think that the blood or saliva could be tested to determine dose. This is a popular recommendation in some consumer menopause books. However, there is no mathematical grid or equation comparing values of estrogen or progesterone or testosterone levels in the blood or saliva and how that would equate with a certain dose of the comparable hormone. There are reference ranges for these hormones, but we do not know exactly what dose to give in order to keep a patient within the reference range. Women absorb and metabolize hormones differently. The form of the hormones and the delivery method—oral, transdermal, sublingual, injection—are also different from woman to woman. In very occasional and selective cases, serum testing may be a helpful guide, but these are generally cases in which a woman is on HT and not doing well and, despite our best efforts with a good medical history and adjusting the dose, she still does not feel well. The majority of the time, it requires the practitioner’s experience and menopause expertise and time to listen to the patient, to know what dose to prescribe and what dosing adjustments and forms and deliveries of hormones may work best. Even if testing is done, it basically comes down to good clinical judgment and the willingness of the woman and her practitioner to try something else.

Urinary testing of estrogen metabolites can be considered in evaluating a woman’s risk of health problems that may be associated with higher or lower levels of certain estrogen metabolites. Although such data are limited, the use of estrogen metabolism testing to try to gain some insight as to a patient’s risk of cervical and breast cancer in particular or how to decrease the recurrence of these diseases is a preventive medicine practice that is hard to argue with. A complete discussion of the metabolites of the various forms of estrogen, progesterones, DHEA, and testosterone is beyond the scope of this chapter. As an example, the metabolites of one estrogen, estrone, are known to play both oncogenic and antioncogenic roles. Estrone’s oncogenic metabolites, 4-hydroxyestrone (4-OH estrone), considered the most carcinogenic estrogen metabolite) and 16α-OH estrone (needed in small amounts because of its bone-building actions), are produced by phase I metabolism. Estrone’s protective metabolites (2-hydroxyestrone [2-OH estrone], 2-methoxyestrone [2-CH3O-estrone], and estriol [E3]) are produced in phase II metabolism. The primary value of these tests is that they help the clinician to use nutrients, botanicals, and lifestyle modification to facilitate the optimal metabolism of these hormones through the pathways that lead to the potential for the reduction of breast and cervical cancers.

Practitioners should be encouraged to rethink the use of salivary and serum estrogen/progesterone testing in the diagnosis and management of perimenopausal/menopausal symptoms. In the perimenopausal woman, these hormones fluctuate within a day and from day to day. In the postmenopausal woman not on hormones, I would also assert that this is a poor use of a woman’s funds. Her estrogen and progesterone levels are low. She is a postmenopausal woman, and mother nature had this in mind. It is rarely necessary to test the estrogen levels of a postmenopausal woman on HT for prescription management; however, there are times when testing may help to determine absorption/delivery and dosing issues when there is a lack of response or an adverse response to customary prescriptions. For select and very difficult cases, it is likely more useful to use the testing of neurotransmitters, amino acids, and nutrients while ensuring that due diligence has been done with regard to the basics of history, physical examination, and conventional testing.