Hormones, Estrogen, and Menopause (Alternative Medicine Book 12)

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Black cohosh was the main ingredient in Lydia Pinkham's Vegetable Compound, and an ethanol extract is sold over the counter as Remifemin in the United States and Europe. The company that manufacturers Remifemin publishes a monograph containing a series of clinical trials. Closer scrutiny reveals that some studies are of very short duration and some are done in women with one or both ovaries in situ , and that in some, the women treated with estrogen have little or no improvement in symptoms. Black cohosh, as well as a number of other plants, are reputed to have estrogenic activity, and therefore are listed in herbal text books as contraindications for women with estrogen-sensitive disease processes.

Table 4 lists botanicals claiming to have estrogenic effects in humans or animals. Reassuringly, these studies show no estrogen-like effects on target tissues traditionally used as in vivo measures of estrogen effect. Black cohosh shows not effect on endometrial thickness and vaginal maturation index, and no change in serum luteinizing hormone LH , follicle-stimulating hormone FSH , estradiol , and prolactin.

The literature recommends use for no more than 6 months. There is no reason cited for this proscription, except for a lack of long-term studies. Black cohosh should not be confused with blue cohosh, Caulophyllum thalictroides , which has weak nicotine activity and is thought to have toxic potential.

Studies have shown that vitex contains hormone-like substances that bind competitively to sex hormone receptors, producing antiandrogenic effects, hence its use as an anaphrodisiac said to reduce libido in males. Antithetically, vitex is recommended to boost libido in postmenopausal women. Studies suggest that vitex can be used to treat the inadequate luteal phase, and that it restore LH-releasing activity. It is also recommended for vaginal dryness and depression at menopause. Vitex's purported antihormonal activity explains its proposed role in treating mastalgia.

In a double-blind randomized trial using vitex versus pyridoxine, Wuttke and colleagues 24 demonstrated no difference in self-assessed scoring in women with premenstrual tension syndrome. Very little quality evidence exists to support the claims about vitex. Dong quai is a type of angelica. The root stock is advised for virtually every gynecologic ailment.

Moreover, critics state that dong quai is never used alone, but always in combination with other herbs to produce the synergy needed for clinical efficacy. We await studies of such a product. More importantly, dong quai contains numerous coumarin-like substances, acts as an anticoagulant, and is photosensitizing. Given the lack of data supporting efficacy, and anticoagulant and other potential side effects, dong quai should not be used for menopausal management.

Evening primrose produces seeds rich in oils containinggamolenic acid. Available commercial preparations contain both the gamma and cis forms of linolenic acid, typically 45 mg gamolenic acid plus mg cis-linolenic acid. Patients are told to use 1 to 12 capsules a day at a cost of per capsule. Consequently, primrose oil is expensive. Well-controlled clinical trials show that evening primrose oil is ineffective in treating premenstrual syndrome and vasomotor symptoms during menopause.

Ginseng is reputed to be an adaptogen, helping people deal with internal and environmental stressors. It is supposedly estrogenic, easing menopausal symptoms. Ginseng is promoted to boost athletic performance and stamina. The great hook, as it is for many herbal products, is the promise of weight loss without dieting or exercise. The side effects reported with ginseng have not been well studied. They are said to include irritability, tachycardia, insomnia, and restlessness.

Because many ginseng products are highly adulterated, often with large quantities of caffeine , the side effect profile might be the result of the additives. Most claims reside with research done in rats; a very limited body of information is available from clinical trials. Lindgren and associates 28 , 29 presented two abstracts on the effects of ginseng on quality of life in postmenopausal women at the North American Menopause Society meeting in Toronto in The first study included women undergoing active treatment and placebo cases studied for using measures of estrogenicity, including vaginal maturation index, FSH, and estradiol.

No differences were seen in controls versus estrogen users. A separate study of women undergoing active treatment and placebo controls demonstrated no improvement in vasomotor symptoms. The improvements were seen in scales measuring depression, general health, and well-being. There is no evidence that ginseng improves athletic performance, despite claims made in radio and television ads. More importantly, the American Botanical Council tested 54 ginseng products. As a specific remedy for menopausal complaints, ginseng has scant documentation of efficacy.

Patients in the United States are being cheated more often than not when purchasing ginseng preparations. If this fact were known, it might cause consumers to be more cautious about their expenditures for ginseng products. Licorice is one of a number of botanicals, including ginseng, fenugreek, sarsaparilla, gotu kola, dong quai, and wild yam, claiming estrogen-like activity.

Commercial uses include as a sweetening agent, happily in beers and unhappily in cigarettes. Licorice candies sold in the United States generally are flavored with anise oil. Before the synthesis of mineralocorticoids, licorice was used to treat Addison's disease. The resultant hypertension often persists for months after consumption ceases. As little as 0. Many multiple botanicals for menopause list licorice on their boxes, although the amounts are usually small.

However, this is undocumented by any regulatory process. Physicians should ask all patients with unexplained hypertension about herbal use, particularly herbs supposedly containing licorice. Its use for menopause cannot be confirmed.

Recent reports state that licorice ingestion can lower testosterone in men. Phytoestrogens are naturally occurring plant sterols capable of exerting effects similar to estrogen. Phytoestrogens are broken into three groups:. Studies of populations in which large amounts of soy-based phytoestrogens are consumed report lower rates of a wide variety of cancers, including breast, endometrium, prostate, intestine, and pancreas. In countries such as China and Japan, where the local diet is high in soy foods, women appear to have few menopausal ailments, and, coincidentally, the incidence of breast, endometrial, and prostate cancers are also markedly reduced when compared with Westernized countries.

Although American and European diets tend to elevate plasma levels of sex hormones and decrease sex hormone-binding globulin concentrations, thus increasing the exposure of peripheral tissues to the effects of circulating estrogens, 34 high soy diets act through several mechanisms to lower effective circulating and tissue levels of steroids. High isoflavone intake decreases LH levels and secondarily decreases estrogen production.

Bean products are rich sources of diphenols, which are thought to lower cancer risk by modifying hormone metabolism and production and limiting cancer cell growth.

Bean foods also provide large amounts of fiber, and fiber modifies the level of sex hormones by increasing gastrointestinal motility. Fiber alters bile acid metabolism and partially interrupts the enterohepatic circulation, 35 causing increased estrogen excretion by decreasing the rate of estrogen reuptake in the enterohepatic system. A recently published study by Lu 36 helps to elucidate the magnitude of altered steroid metabolism induced by high isoflavone intake.

Women were fed 36 oz of soy milk a day for one menstrual cycle. The calculated intake of isoflavone in this amount of soy milk is approximately mg of daidzein mostly as daidzin and mg of genistein mostly as genistin.

Endotext [Internet].

Steroid levels remained lower for an additional two or three menstrual cycles. Menstrual cycle length increased from This study offers two profound pieces of information. First, when isoflavone intake is increased, endogenous endocrine function modifies very rapidly thereafter. Second, the effects of such dietary modification are long lived, disappearing slowly over time. These findings suggest that although a lifetime of exposure to isoflavones clearly modifies risks, initiation of dietary changes later in life might substantially modify risk in a very short interval thereafter.

Like quitting smoking or starting exercise, it may never be too late to start enjoying the benefits of soy-based foods. Interventional trials examining the effects of soy-based foods and isoflavone supplements are presently underway. Very few interventional trials have been done assessing the impact of isoflavones on menopausal symptoms such as hot flashes, dyspareunia, and vaginal dryness.

Several trials are currently in progress, 37 and oral abstracts were reported in at the Second International Symposium on the Role of Soy in Preventing and Treating Chronic Disease. Albertazzi and colleagues 38 recently published a double-blind, parallel, randomized placebo-controlled trial in women. For women with severe and frequent hot flashes, soy may not offer effective symptom relief.

There are no studies on the concomitant use of soy and estrogen for symptom control. Table 6 lists prepared soy foods that are becoming increasingly available. Most foods contain 1. Relying on one food source for such a large portion of calories will lead to nutritional deficits. The easy solution to getting lots of isoflavones is to use isoflavone-rich foods such as tempeh, or isoflavone-rich supplements such as soy shake mixes and soy bars.

Soy products are excellent sources of plant proteins, and using them as a substitute for animal protein holds the promise of lowered rates of malignancy and vascular disease. Studies are underway to assess whether supplementation with isoflavones can lower that rates of primary breast cancer or alter the rates of recurrent in women with antecedent breast cancer. It remains to be seen whether whole soy-based foods, soy isolates, or isoflavones are effective in modifying patterns of disease. No interventional trials have been done assessing the impact of additional dietary soy or isolated isoflavone supplements on bone mass losses.

A genistein-derived synthetic isoflavone, ipriflavone, slows bone reabsorption and stimulates bone collagen synthesis. Several commercial isoflavone preparations are currently being promoted in the United States. Promensil is produced from red clover. According to the technical information provided by the manufacturer, each mg tablet contains approximately to mg of dried aqueous alcoholic extracted Trifolium pratense red clover , and contains four isoflavones: Most of the biochanin and formononetin are rapidly demethylated after absorption to genistein and daidzein, respectively.

Conversion is incomplete, so that some residual detectable amounts of these two isoflavones remain in the circulation and exert some biological activity. Promotional literature from the manufacturer cites general studies on isoflavones and cancer.

Estroven is a supplement derived from soybean and pureria root, containing 50 mg isoflavones with black cohosh, kava kava, calcium, boron, vitamin E, B 12 , folic acid , thiamine B 1 , riboflavin B 2 , niacin B 3 , and selenium. This type of study has little scientific validity. In Australia, sheep grazed on large amounts of subterranean red clover were rendered sterile because of disruption of estrus cycles. No studies in humans can be found about extracts or concentrates of red clover affecting female endocrine functions.

As noted previously in the section on phytoestrogens, Promensil, a red clover derivative, exerts its effects through concentrated levels of isoflavones synthesized from the plant, not from coumestans. In Europe, a fat-solubilized form of saw palmetto is used to treat benign prostatic hypertrophy. Saw palmetto is also touted to have antiandrogenic activity, but the mechanism is unknown. Its use in menopause to stimulate flagging libido seems inconsistent with other claims made and is not supported by any source material. Extracts of this flower have been used for centuries to treat mild to moderate depression.

The constituents include hypericin, pseudohypericin, hyperforin, and flavonoids. Several mechanisms of action for the psychotropic effects of St. John's Wort SJW have been proposed but not confirmed, including 1 inhibiting monoamine oxidase MAO and catechol methyl-transferase COMT ; 2 decreasing corticotropin-releasing hormone and then decreasing levels of cortisol or affecting GABA receptors in the brain; and 3 blocking serotonin receptors. Hypericin does not appear to be an MAO inhibitor and is no longer thought to be the substance responsible for the effects of SJW. Preparations previously standardized to the hypericin content now are being prepared to a standardized level of hyperforin, usually 0.

Although products sold in Germany are manufactured to strict guidelines, regulation and standardization are virtually nonexistent in the United States, and patients are not necessarily getting what they pay for. The Los Angeles Times had the potency of 10 SJW products tested and found that 3 contained less than half the amount on the label.

Only three had the doses listed. Reports that Hypericum perforatum compares favorably to antidepressant drugs like amitriptyline, imipramine, and, more recently, fluoxetine , are exaggerated. The doses of antidepressant used in most studies were marginal and subtherapeutic, whereas the amounts of SJW are generally high. Side effect profiles in studies seem to document that SJW is safer and better tolerated. Most studies have looked at mild to moderate depression, seasonal affective disorder, and depression in the elderly.

Studies in severe depression are lacking. Fifteen controlled trials have been reported and assessed by meta-analysis by Linde and colleagues. An emerging body of literature documents profound drug-herb interactions with SJW. In particular, SJW decreases serum concentrations of cyclosporine , decreases international normalized ratio INR resulting from use of warfarin, and lowers serum levels of the protease inhibitor indinivar. SJW has also been found to lower levels of theophylline , amitriptyline, and the steroids in oral contraceptives.

Therefore, patients who are using or who have recently discontinued the use of MAO inhibitors or SSRIs are cautioned not to use SJW for several weeks, if not months, after stopping these drugs, and visa versa. Fugh-Berman 45 summarized drug-herb interactions in a recent article and cited evidence of drug-herb interactions attributable to SJW, including mild serotonin syndrome in patients who mix SJW Hypericum perforatum with SSRI and decreased bioavailability of digoxin , theophylline , cyclosporine , and phenprocoumon when these drugs are combined with SJW.

The effects appear to be due to potent stimulation of metabolism in the cytochrome P system by SJW. Sporadic reports of interaction with analgesics such as meperidine and tramadol, anesthetics, sedatives, sex steroids, lithium, reserpine, and even dextromethorphan-containing cough medicines should cause unease.

Moreover, given these problems and the anticoagulant activity of many herbals, anesthesiologists are asking for a 2- to 3-week washout of all botanicals before elective surgeries. Because emergency surgeries and traumas cannot be anticipated, it would be prudent for practitioners to advise against the use of SJW in general. Uva ursi, also commonly known as bearberry and mountain box, is widely recommended as a urinary aseptic and bladder sedative.

It contains the phenolic glycoside arbutin, which produces hydroquinone, a mild urinary septic, but this conversion only takes place when urine is alkalinized. Uva ursi should not be regarded as a substitute for antibiotics in active urinary infection. Hydroquinone, the active ingredient, is potentially toxic. One gram equal to 6 to 20 g of plant material may induce tinnitus, nausea, vomiting, shortness of breath, seizures, and loss of consciousness, and 5 g is clearly lethal.

Valerian root, the common valerian or garden heliotrope, has been used for ages as a tranquilizer and soporific. Note that a similar GABA-like compound has been found in chamomile, which also is proffered as a herbal sleep aid. Little is known about its actions, effects or potential drug-drug interactions. Before the common use of benzodiazepines and barbiturates, many psychiatric disorders were treated with valerian.

There are few reports of valerian toxicity, but dystonic reactions and visual disturbances have been mentioned in the literature, perhaps because of other drugs used concomitantly or contamination or adulteration. Recently, a case of seizures was reported when a man taking high doses of valerian abruptly stopped taking it.

‘The Wisdom of Menopause’

When L-tryptophan was taken off the market, valerian enjoyed a mild upswing in popularity. Despite its lack of toxicity, many botanical practitioners recommend against its use during pregnancy and lactation. In , the US Pharmacopoeia began publishing a series of updated monographs on botanical medicines and has stated that data on the use of valerian are not good enough to prove that it is effective.

Yam creams containing extract from Diascorea villosa , the Mexican yam, claim to provide effects similar to natural progesterone. This process can only be done in the laboratory. Practitioners should be aware, however, that yam creams are often adulterated with progesterone ; progesterone creams adulterated with estrogens, and pharmaceutical grade estrogen creams are also being sold in health food stores.

Any uterine bleeding in a woman using these creams or gels deserves thorough evaluation, including appropriate studies to rule out endometrial hyperplasia or neoplasia. Patients have come to believe that sincere and empathic treatment of menopause resides in the world of alternative medical practices. Women are suspicious and critical of what they see as profiteering and commercialism in mainstream medicine, a system seemingly dominated by managed-care corporations, insurance companies, and pharmaceutical giants.

Given the recent outpouring of negative reports contradicting the presumed benefits of conventional hormone therapies, women and even some researchers in the field say believe that there are simply not enough data about hormones. Many providers and patients are then seduced by the words botanical , herbal , and natural , suspending all disbelief, and are using these products with unquestioning abandon.

The term natural has lost all semblance of meaning and integrity. It has become an amorphous catch-all suggesting purity, simplicity, and reliability, when it actually may suggest that a product is untested, unregulated, and unstudied. By being well versed and well acquainted in alternative therapies, allopathic physicians may be able to maintain open lines of communications with women reluctant to use conventional hormone therapy.

When scientific studies support the claims made for complementary care, practitioners may seek to incorporate such practices in the treatment of symptoms unresponsive to or poorly controlled by conventional medical interventions—for example, using acupuncture for chronic pain syndromes. By having ready and reliable information on CAM, we can assist women in making intelligent choices.

We also can greatly improve our ability to create treatment plans that harmonize with the physical, emotional, and philosophical aspects of women's lives, thereby providing more supportive care. Excellent information is available from several sources listed in the Suggested Readings and Resources. Vessey MP, Doll R: Investigation of relation between use of oral contraceptives and thromboembolic disease.

Br Med J 2: However, while women with a first-degree relative mother, sister, or daughter who has or had premenopausal breast cancer are at increased risk by virtue of their family history alone, their risk of breast cancer is not thought to be increased further by HT use. Eighty percent of women who develop breast cancer do not have a family history. This is supported by the findings of Rebbeck et al. HT use did not negate the observed reduction in cancer risk. Interestingly, studies of breast cancer survivors showed that women using HT had a lower risk of recurrence compared to survivors not using HT , Breast cancer incidence is thought to increase after hormone use and since WHI there has been much interest on the role of the progestin in combination with estrogen in contrast to the use of estrogen alone 13, 14, In general most studies that have shown a small increase have shown more of an effect with the combination 26 and nurse health and collaborative study.

This has led to speculation as to the role of progestin, and to the minimization of progestin use despite the well-recognized and significant risk of endometrial cancer with the use of unopposed estrogen. Some recent studies suggest the progesterone and dydrogesterone may be safer than other progestins but no randomized studies examine this question In general, some effect is seen with treatment duration and some studies show an effect although small. WHI reported an increase in breast cancer risk in the combined therapy arm in subjects who had used hormones prior to enrollment but only after 5 years A later paper from the WHI study however suggested that the risk was higher in women who initiated therapy soon after menopause within 3 to 5 years However, in this study, a much larger group of women who were recently menopausal had been on HT and the effect was more pronounced in the less rigorous observational arm.

In general the effect takes several years to appear and is small. When hormones are discontinued the effect starts to decline within one year All of this confusing and contradictory data suggests that the combined HT may be acting as a promoter in susceptible women with undiagnosed subclinical cancer and the promoter effect may disappear with discontinuation of therapy. This may also explain the overall drop in breast cancer seen with the Seer Surveillance, Epidemiology and End Result cancer registries database report.

This report showed a drop in breast cancer rates after when women stopped hormone therapy after the WHI publications This effect has not been seen universally and the trend was actually seen prior to the reports. In fact there has been a drop in many different cancer rates, possibly due to earlier detection and earlier treatment However this effect was not seen in WHI.

Both combined hormone use and estrogen alone lead to denser breasts and more abnormal mammograms , This effect is rapidly reversible and stopping hormones 10 to 30 days before a mammography may decrease abnormalities requiring follow up One group of women who benefit from hormone therapy is the women with BRAC 1 and 2 mutations who undergo oophorectomy as prophylaxis.

Use of HT does not appear to place them at risk for the genetically determined breast cancer and will improve quality of life It will also prevent the effects of estrogen deprivation at a young age. The effects of stopping hormones are contradictory depending on the study. Breast cancer prognosis does not appear to be influenced by the high hormone levels during pregnancy, nor has oral contraceptive use been shown to increase breast cancer risk. These observations may allay some of the fear regarding the use of exogenous hormones after menopause.

Data on ovarian cancer has not shown a consistent risk with use of hormone therapy. There is possible weak association with long term at least 10 years of therapy but data are inconclusive for recommendations Its use does not adversely affect the risk of cancer in BRCA mutations Other studies too, including HERS and a meta-analysis of 15 case-controlled studies found no significant association In , 38, cases of endometrial cancer were diagnosed, and 6, women died of the disease.

The mean age at diagnosis is 61 years, with most cases occurring in women 50 to 59 years old. Estrogen alone causes endometrial hyperplasia and a two to three-fold increase in the risk of endometrial cancer. However, the addition of progestogen reduces this risk to lower levels than those seen in women not on HT , Thus, the addition of a progestational agent to postmenopausal estrogen therapy is now standard for women with an intact uterus.

While there have been some reports that the risk of endometrial cancer may be slightly increased even with the combined therapy, most studies have not confirmed this. Women in the WHI study on combined therapy showed no difference in endometrial cancer rates compared to women on placebo Recent research has focused on the use of lower doses of estrogen and a progestogen in HT to reduce the risk of endometrial cancer The dose of progestogen given depends on several factors, including the number of days given each month, the amount of estrogen given, the individual needs of the patient, and her ability to tolerate the medication.

Side effects of progestogen can include anxiety, irritability, depressed mood, acne, bloating, fluid retention, headaches, breast tenderness, and bleeding problems. The inability to tolerate these effects is the main reason for poor compliance or discontinuation of HT. Despite being one of the major causes of cancer-related mortality in women, colon cancer is often overlooked by patients in their risk assessment of HT. In addition, reports from the WHI study showed that the combined estrogen plus progestin therapy was associated with a decrease in the incidence of colon cancer compared to women on placebo 6 fewer cases per 10, women on HT This was not found with estrogen alone At present; however, although the evidence that HT may be beneficial in reducing the risk of colon cancer should be considered, there is insufficient evidence to warrant recommending long-term HT solely for this purpose.

The existence of estrogen receptors in the hippocampus, a part of the brain essential to learning and memory, has been known for some time.

Several mechanisms may account for the effects of estrogen on the brain. Firstly, estrogen increases levels of choline O-acetyl-transferase, the enzyme needed to synthesize acetylcholine, a neurotransmitter thought to be critical for memory Studies on healthy middle-aged and elderly postmenopausal women have supported the theory that estrogen may help to maintain aspects of cognitive function , Data also suggest that estrogen therapy may enhance short- and long-term memory , Additional effects of estrogen on neural function include: A recent review of clinical trials of hormone therapy suggest that there is a clear difference between the effects of estrogen therapy and estrogen plus progestin There is modest support for the beneficial effect of estrogen alone on verbal memory in women under 65, and possibly surgically menopausal, while a harmful effect is seen with estrogen plus progestin in women over Conjugated estrogen with medroxyprogesterone acetate may also have some detrimental effect on younger women.

Estrogen alone appears to be neutral in women over Thus the age of initiation of therapy and the use of progestins are important when evaluating possible effects on verbal memory At present there is no combination which appears to be neutral to verbal memory and there is suggestion of some harm even with micronized progesterone Hot flashes appear to relate to memory dysfunction, and some of the cognitive improvement on hormone therapy may relate to the treatment of the hot flashes For every five years after the age of 65, the prevalence of Alzheimer's disease doubles in the population.

As the population ages over the next 20 years, these numbers are expected to increase. According to epidemiologic evidence, there is reason to believe that estrogen deficiency may contribute to Alzheimer's disease. Low body weight is associated with low levels of circulating estrogens in postmenopausal women. Women who suffer from Alzheimer's disease tend to have lower body weights than women without the disorder Incidences of Alzheimer's disease are low or its expression is delayed in postmenopausal women with high levels of endogenous estrogenic steroids or those receiving long-term HT.

One explanation for estrogen's apparent protective effect may involve neurotransmission. Estrogen acts as a trophic factor for cholinergic neurons in vitro. Cholinergic depletion is the most prominent neurotransmitter deficit in Alzheimer's disease. However, while HT does show promise in preventing or delaying the onset of the disease, a recent study showed no benefit of either 0.

Most likely, estrogen may merely delay the deterioration seen in Alzheimer's patients. The effect of HT on different subtypes of dementia could not be determined because the number of cases was too small. It must be noted, however, that because the WHIMS participants were all 65 or older, these results may not apply to women who initiate HT at a younger age. The results of the Cache County Study serve to further confuse the issue. In this prospective study of incident dementia in older women mean age For current users with more than 10 years of therapy the HR was 0.

Interestingly, in past users, reductions were present in all age groups and showed a duration effect HR 0. The Nurses' Health Study showed a twofold increase in the risk of pulmonary embolism among postmenopausal women who were current estrogen users. The recent findings of the WHI study confirmed these findings for women on combined estrogen plus progestin therapy. Women on this treatment suffered 8 more pulmonary emboli per 10, than women on placebo Although estrogen use has been associated with an increase in the relative risk of venous thromboembolism VTE , the absolute risk remains low, as VTE occurs infrequently in this setting.

Women on combined estrogen-progestin therapy in the WHI study suffered 18 cases of more venous thromboembolism than women on placebo. It does, however, show that patients should be screened for a history of idiopathic thrombosis as this has been a consistent finding Some epidemiologic studies have found an increased risk of gallstones among women who use HT. Estrogen has been shown to increase cholesterol saturation of bile, alter bile acid composition, and decrease bile flow.

Each of these effects can enhance gallstone formation. Data from the Nurses' Health Study 54, postmenopausal women monitored for eight years showed that current HT users were more likely to have undergone cholecystectomy than nonusers relative risk, 2. This risk tends to increase with long-term therapy and with high doses of estrogen Because many women gain weight as they age, a common fear is that HT will exacerbate this problem.

However, this is unconfirmed by prospective studies. Attention to diet with reduced fat intake and regular aerobic exercise for weight maintenance should be recommended to all postmenopausal women. Data from WHI also showed an attenuation of increases in weight seen with age in the combined hormone treated arm This suggests there may be some beneficial effect to HT on the normal increases that are seen in postmenopausal women and that the effect may protect against the increase in central obesity seen in hypoestrogenic menopausal women.

A decrease in the incidence of diabetes, and lower insulin levels suggestive of better insulin sensitivity may be related to this attenuated weight gain. Some studies have shown a small reduction in the incidence of this eye disorder among users of HT , It is thought that skin may be an important target organ for reproductive hormones.

In postmenopausal women, dermal collagen decreases, and skin becomes thinner. Applying estrogen cream to the skin after menopause improves the external appearance of facial skin. In addition, systemic HT increases dermal collagen and limits age-related skin extensibility. To date, of the eleven clinical trials that examined the effect of HT on collagen levels, only one failed to demonstrate efficacy Furthermore, results from a recent study indicates that estrogen also increases skin thickness HT has also been shown to accelerate cutaneous wound healing, both microscopically and macroscopically, in postmenopausal women This study also showed delayed repair of acute incisional wounds in ovariectomized young female rodents; the delay was reversed by the topical application of estrogen.

The risk of tooth loss increases after menopause. Osteoporosis, as well as estrogen deficiency, could both be contributing to this effect. Data from the Nurses' Health Study indicate that the risk of tooth loss may be decreased in women with a history of estrogen therapy Several treatments have recently become available and have FDA approval for relief of vasomotor symptoms.

A progestin is not necessary as this combination offers endometrial safety , Another SERM ospemifene has been approved for the treatment of postmenopausal vulvovaginal atrophy Another treatment consists of a Swedish pollen extract femal, which has been shown to be effective in a small study for a composite of menopausal symptoms including vasomotor symptoms, fatigue and quality of life Over the years, doses of estrogen in hormone therapy have been decreasing: Today, a CE dose of 0.

The goal of hormone therapy is to reduce menopausal symptoms e. Use of the lowest clinically effective dose of HT for relief of menopause-related symptoms and for prevention of osteoporosis is now recommended. The benefit-risk ratio of hormone therapy for each woman is influenced by the severity of her menopausal symptoms and their impact on quality of life, her current age, age at menopause, time since menopause, cause of menopause, and baseline disease risks.

Generally appropriate indications include also treatment or prevention of osteoporosis in women who are not candidates for or cannot tolerate other osteoporosis therapies including bisphosphonates or teriparatide. Absolute contraindications for systemic HT include hormone-related cancer, active liver disease, history of hormone-induced venous thromboembolism, history of pulmonary embolism not caused by trauma, vaginal bleeding of unknown etiology, and pregnancy.

Relative contraindications include chronic liver disease, severe hypertriglyceridemia, endometriosis, history of endometrial cancer, history of breast cancer, coronary artery disease. Guidelines for hormone use are reviewed in the statement of the North American Menopause Society and recently by the Endocrine Society Considerable confusion has developed as a result of the numerous transdermal preparations which have appeared on the market. The effective dose depends on the delivery rate and the surface area applied so that there is much variation in terms of estradiol delivered to the blood stream.

The following charts attempt to present equivalent doses. Lower doses take longer weeks for effective relief, and it is important to individualize therapy. Most preparations take a full 12 weeks for maximum effect although standard therapy provides relief sooner weeks. There is also much debate as to the safety of oral vs. One study suggests that venous thromboembolism may be lower with transdermal products, but the doses compared were not equivalent Another study shows a decreased risk of stroke in women on transdermal preparations with higher doses of both oral and transdermal estrogen showing significant effect One study suggests progesterone may be associated with a lower risk of breast cancer than progestins but this again awaits further study These preparations offer no advantage over regulated and tested preparations approved by the FDA, and their risk is equivalent to commercial compounds.

Claims that they are safer are misleading particularly since they have not been studied and one of the estrogens used, estriol, has no safety or efficacy data. In general initiation of treatment of the symptomatic newly menopausal women will provide benefit which greatly outweighs risk and provides protection from bone loss.

Older women who continue to be symptomatic may.

‘Mayo Clinic: The Menopause Solution’

Although the decision to treat menopausal women rests on individualized risk vs. In general, hormone treatment is being used for symptoms. These include vasomotor symptoms and vulvovaginal atrophy. There are, however, a variety of symptoms which make up the menopausal syndrome and are not strictly classified as vasomotor or vulvovaginal symptoms and are distressing to the patient and may also be a consideration for treatment Some patients can endure two hot flashes a day while others who are in stressful or public jobs cannot.

Patients are usually uncomfortable and distressed by more than two hot flashes per day. In particular the patient who wakes at night two or more times and suffers from sleep deprivation is usually in need of treatment. Patients suffering from five to seven hot flashes a day are experiencing moderate to severe symptoms and should be offered treatment. The physician should help the patient make a quality of life decision and advise these patients on the low risks associated with treatment particularly for a few years.

Some patients may be experiencing bone loss and hormone therapy is ideal for this type of patient. Some of the estrogens on the market are also approved for prevention of osteoporosis and data shows they are very effective and prevent fractures. A patient on hormone therapy does not need a second drug for prevention of bone loss.

If bone loss is occurring on hormone therapy a secondary cause should be searched for such as vitamin D deficiency, over treatment with thyroid hormone or hyperparathyroidism. Patients with mood issue may have problems with progestins and micronized progesterone or a vaginal delivery system may be better tolerated. Estrogens should be started first and a progestin added after a few weeks. Patients with migraines also have special tolerability issues and fluctuations of hormone levels which may be triggering the headaches may persist or be aggravated initially by hormone treatment.

A transdermal patch may be the best option and a progestin should be started after a trial of treatment with estrogen. The issue of duration of hormone treatment will arise. Two to five years is usual. The small risk of breast cancer is also important to review with the patient. This risk surfaces after 5 years of use and did not surface at all with estrogen alone therapy after 7 seven years.

This interval does not apply to patients with premature menopause who have been shown to be at risk for osteoporosis and premature heart disease if they are not replaced. All patients need a yearly mammogram and the increase in density can be avoided by stopping hormones for two weeks prior to the mammogram if she can tolerate it. Some patients stay on hormone therapy long term because of mood or other issues or they are in the unfortunate 10 percent who continue to suffer form vasomotor symptoms or cannot tolerate other drugs for osteoporosis.

Patients with severe mood issues may require antidepressants. Recent data has shown the efficacy of low doses for vasomotor symptoms and many are available. However the patient with severe symptoms may prefer a standard dose which may be lowered after 6 months when symptoms are well controlled. Lastly, vaginal estrogens are an excellent option for patients with symptoms of vaginal atrophy and do not have the risks associated with systemic use. In particular, recurrent urinary tract infections and or vulvovaginitis are a hallmark of genitourinary estrogen deficiency which can be easily relieved or prevented with the use of vaginal estrogen.

Treatment with hormone therapy is very individualized and quality of like may be greatly improved its use. When therapy is discontinued, a return of symptoms is common although generally in a milder form. Unfortunately there is little data to guide the physician but many clinicians slowly taper doses over several months. When assessing risk vs. The normal menopause transition. Clinical observations on the use of an ovarian hormone: Am J Med Sci. Overview of estrogen replacement therapy: Proc Soc Exp Biol Med. Postmenopausal estrogen for treatment of hot flashes: Steroid and gonadotropin levels in women during the peri-menopausal years.

Factors associated with age at natural menopause in a multiethnic sample of midlife women. Vasomotor flushes in menopausal women. Am J Obstet Gynecol. Options for hormone therapy in women who have had a hysterectomy. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. Global consensus statement on menopausal hormone therapy. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.

Hormone replacement therapy and risk of breast cancer: Postmenopausal hormone therapy and mortality. Postmenopausal hormone use and secondary prevention of coronary events in the nurses' health study. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J Clin Endocrinol Metab. The impact of hormone therapy on health-related quality of life: Breast cancer and hormone-replacement therapy in the Million Women Study.

Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Risk for new onset of depression during the menopausal transition: Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: Freeman EW, Sherif K.

Prevalence of hot flushes and night sweats around the world: Management of menopausal symptoms. Ann N Y Acad Sci. Commonly used types of postmenopausal estrogen for treatment of hot flashes: Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Comparison of Alora estradiol matrix transdermal delivery system with oral conjugated equine estrogen therapy in relieving menopausal symptoms.

Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: Health Qual Life Outcomes. Symptoms during the perimenopause: Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance. Effects of estrogens on sleep and psychological state of hypogonadal women. Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: Psychologic distress and natural menopause: Am J Public Health.

Depressive symptoms during the menopausal transition: Hormones and menopausal status as predictors of depression in women in transition to menopause. Predictors of first lifetime episodes of major depression in midlife women. A longitudinal analysis of the association between menopause and depression.

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Results from the Massachusetts Women's Health Study. A population-based study of depressed mood in middle-aged, Australian-born women. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Sex hormones and mood in the perimenopause. Female psychopathologic profile during menopausal transition: Vasomotor symptoms are associated with depression in perimenopausal women seeking primary care.

Depressed mood during the menopausal transition and early postmenopause: A cross-sectional evaluation of perimenopausal depression. Factors associated with early menopause. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: Lack of efficacy of estradiol for depression in postmenopausal women: Panay N, Studd J.

Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Sex steroids and affect in the surgical menopause: Affective changes with estrogen and androgen replacement therapy in surgically menopausal women. A study of European womens' experience of the problems of urogenital ageing and its management. Vulvar transepidermal water loss TEWL decay curves.

Effect of occlusion, delipidation, and age. Advances in the treatment of menopausal symptoms. Womens Health Lond Engl. Treatment of atrophic vaginitis with topical conjugated equine estrogens in postmenopausal Asian women. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: Treatment of urogenital atrophy with low-dose estradiol: Management of symptomatic vulvovaginal atrophy: The role of androgen in the maintenance of sexual functioning in oophorectomized women.

Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women. Hormonal determinants and disorders of peak bone mass in children. Rates of bone loss in the appendicular and axial skeletons of women. Evidence of substantial vertebral bone loss before menopause. Characterization of perimenopausal bone loss: J Bone Miner Res.

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Questions and answers for estrogen and estrogen with progestin therapies for postmenopausal women updated http: A practical guide to prescribing estrogen replacement therapy. Int J Fertil Menopausal Stud. The report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. Menopause and risk factors for coronary heart disease.

Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy. Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up. J Am Coll Cardiol. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.

Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Estrogen therapy and coronary-artery calcification. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Banks E, Canfell K. Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: Ann Intern Med; 4: Coronary heart disease and menopause management: Latest Data from the Elite Trial.

Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes. J Clin Endocrinol Metab;95 3: Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition? Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. The effects of estradiol on blood lipids and lipoproteins in postmenopausal women.

Angina and normal coronary arteries in women: Beneficial effect of oestrogen on exercise-induced myocardial ischaemia in women with coronary artery disease. Pulsatility index in internal carotid artery in relation to transdermal oestradiol and time since menopause.

A clinical trial of estrogen-replacement therapy after ischemic stroke. The lifetime risk of developing breast cancer. J Natl Cancer Inst. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin.

Effects of menopausal hormonal therapy on occult breast tumors. J Steroid Biochem Mol Biol. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: Breast cancer and hormone replacement therapy: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer.

Hormone replacement therapy and risk of breast cancer with a favorable histology: Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Mammographic densities and breast cancer risk. Effects of estrogen and estrogen-progestin on mammographic parenchymal density.

Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapy. Effect of hormone replacement therapy on breast cancer risk: Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. Hormone replacement therapy after a diagnosis of breast cancer: Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality.

Estrogen-progestagen menopausal hormone therapy and breast cancer: The decrease in breast-cancer incidence in in the United States. CA Cancer J Clin. Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas. Cancer Epidemiol Biomarkers Prev. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. Short-term cessation of hormone replacement therapy and improvement of mammographic specificity.

Oral contraceptives, salpingo-oophorectomy and hormone replacement therapy in BRCA mutation carriers. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. Hormone therapy for the prevention of chronic conditions in postmenopausal women: Preventive Services Task Force. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: Noncardiovascular disease outcomes during 6. A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer.

Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy--long-term follow-up of a Swedish cohort. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: The cholinergic hypothesis of geriatric memory dysfunction. Estrogen improves psychological function in asymptomatic postmenopausal women. Estrogen use and verbal memory in healthy postmenopausal women. Estrogen effects on cognition in menopausal women. Estrogen replacement therapy and longitudinal decline in visual memory.

A possible protective effect? Neuroprotection against oxidative stress by estrogens: The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. Maki PM, Sundermann E. Hormone therapy and cognitive function. The effect of 3-year treatment with 0.

J Am Geriatr Soc. Objective hot flashes are negatively related to verbal memory performance in midlife women. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. Low Body Mass Index in demented outpatients. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: Alzheimer's Disease Cooperative Study. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: Hormone replacement therapy and incidence of Alzheimer disease in older women: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: Postmenopausal hormone use and cholecystectomy in a large prospective study.

Postmenopausal hormone therapy and body composition--a substudy of the estrogen plus progestin trial of the Women's Health Initiative. Am J Clin Nutr. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: Macular degeneration and early menopause:

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