Introduction

A 1998 survey by the North American Menopause Society showed that 51% of postmenopausal women reported being happiest and most fulfilled between the ages of 50 and 65 compared with when they were in their 20s (10%), 30s (17%), or 40s (16%). They also reported an interest in healthy activities and in menopause information in order to make informed health decisions.[1]

Physicians have the opportunity to play a key role in the lives of midlife women by having up-to-date information, by being aware of women’s preferences, and by being open to discussion and change.

What are the main concerns of perimenopausal women?

During the perimenopauasal years (early 40s to 12 months after the last menses), women’s greatest concern is to find relief from distressing symptoms that affect their busy lives.[2-6] Those having the most severe symptoms are most likely to seek a physician’s help. Other women will try lifestyle changes and/or alternative treatments first. Knowledge about lifestyle modification, alternative remedies, and prescription treatments will help most women pass through these years gracefully.

While concern about perimenopausal symptoms is the foremost reason for a woman to consult her physician, fear of breast cancer is a pervasive concern for all perimenopausal women. The demographics of the baby boomers indicate that the total number of women aged 40 to 55 with breast cancer will increase. Heart disease and osteoporosis will remain remote concerns for most women during their 40s to mid-50s. Consequently, short-term symptomatic treatments that have no impact on breast cancer are easier to accept. Perimenopausal women are happy to re-evaluate treatment options on an annual basis, or earlier, if they have side effects or a lack of response.[3-6]

What are the symptoms of the perimenopause?

The menopause transition can begin as early as the mid-30s but most often begins in the early- to mid-40s. Women often feel “not quite right” as their internal hormonal milieu changes dramatically from month to month. During the early transition menses are often more frequent (every 15 to 21 days), heavier, with significant premenstrual syndrome (PMS) symptoms, mood swings, insomnia, aching muscles, increased migraines (in migrainous women), and intermittent vasomotor symptoms. The cyclic nature of these symptoms distinguish them from other causes. As time passes and menopause approaches, menses become less frequent (every 2 to 3 months) and symptoms such as hot flushes (also referred to as “hot flashes”), night sweats, vaginal dryness, fatigue, and muscle and joint aches become prominent. Once menses cease, symptoms stabilize, but may be quite disabling for 30% of menopausal women (Table 1). Symptoms of menopause may last from a few months to several years. They are usually worse during the first year after menopause and gradually decrease over time. About 20% of women will continue to have hot flushes for many years.

What treatment options are available?

When assisting midlife women, consider all options for relief of symptoms: lifestyle, alternative remedies, and prescription therapies.

Lifestyle changes, including exercise, diet, and vitamins

Many of the leading causes of death are influenced by modifiable factors including cigarette smoking, diet, and exercise. Lifestyle changes alone may improve symptoms, and this knowledge can help motivate women to abandon unhealthy behaviors.

Cigarette smoking is a strong independent risk factor for cardiovascular disease, stroke, peripheral vascular disease, osteoporosis, and certain cancers. The cardioprotective and anticarcinogenic effects of a diet low in saturated and trans-unsaturated fats and high in fibre cannot be over emphasized. Weight-bearing exercise enhances well-being, promotes balance and agility, and has cardioprotective and osteoprotective effects.[3,4,7,8] Both regular aerobic exercise[9] and periodic deep breathing exercises like yoga[10] may result in a 40% to 50% reduction in hot flushes. Alcohol and caffeine reduction may ease perimenopausal mood changes. Alcohol intake of greater than seven drinks per week is thought to increase breast cancer risk.[11]

Phytoestrogens are plant compounds that have estrogen-like biological activity and exhibit mixed estrogen-agonist and estrogen-antagonist actions on different target tissues.[8] Phytoestrogens are present in the highest concentrations in soybean and linseed (flaxseed) products. In addition to the commonly known soy foods (tofu, tempeh, miso, and soya milk), newer products have been introduced that are more palatable to a Western diet (see for the isoflavone content of various soy products). Epidemiological data and some clinical evidence suggests that the typical Asian diet, which contains 20 to 50 g of soy protein per day, will lower total cholesterol, LDL, and triglycerides.[8] Less robust evidence points to a lower incidence of breast and endometrial cancer, improved menopausal symptoms, and less postmenopausal bone loss.[8] Studies on linseed (flaxseed) are not extensive.

The effectiveness of vitamin B6 for treatment of perimenopausal PMS symptoms remains controversial. Some studies show a positive effect while others are ambiguous or negative. Care should be taken to limit the dose to 150 mg per day. Higher doses may be neurotoxic.[3,4] Although vitamin E capsules are often used orally to relieve hot flushes and intravaginally to relieve dryness, studies show minimal effectiveness.[3]

Alternative (herbal) remedies

The 1998 Society of Obstetricians and Gynaecologists (SOGC) Canadian Consensus Conference on Menopause and Osteoporosis evaluated useful herbal remedies for treating perimenopausal symptoms.[3] The recent Menopause Core Curriculum Study Guide 20004 from the North American Menopause Society updated this review. Interest in herbal therapy is growing rapidly in Canada and the US.[12] Consumers often consider herbs inherently safe, even though they contain biologically active ingredients. Several hundred herbal products have now undergone scrutiny by the Therapeutic Products Programme of Health Canada and have been issued drug identification numbers (DIN) or general public numbers (GP). These numbers indicate that there has been a review of their formulation, labeling, and instructions, but do not confirm bioactivity or clinical efficacy. Finding herbal medicines that have undergone clinical trials is time consuming and the trials are of poor quality. Women with minor perimenopausal symptoms or who are unable or unwilling to take HRT will appreciate reliable information about the most useful herbal remedies, dosage, side effects, and precautions (Table 3). The Canadian Medical Association, in conjunction with the Canadian Pharmacists’ Association, has recently published an excellent, evidence-based reference book: Herbs: Everyday Reference for Health Professionals (see Resources, below).

The two herbal remedies for menopause symptoms that have undergone placebo-controlled clinical trials are black cohosh and St. John’s wort.

Four controlled clinical trials have shown that black cohosh (specifically Remifemin, a German product) improves hot flushes and mood disturbances in perimenopausal women without altering hormone levels, endometrium (by transvaginal ultrasound), or breast tissue (by in vitro studies). Further studies are justified to scrutinize the effect of black cohosh on endometrium (by biopsy), breast tissue, bone, and lipids. Its mode of action has not been fully determined; it appears to exert estrogen-like actions in some tissue and anti-estrogen effects in others. Considering its slow onset of action (6 weeks), clinical trials are short (6 months). However, the toxicology studies in animals are reassuring and the clinical trials show few side effects.[3,4]

St. John’s wort has been evaluated in 23 randomized controlled trials (from 2 to 4 months in duration) involving patients with mild to moderate depression. It appears as effective as standard antidepressants, with fewer side effects.[3,4] Additional studies are needed to characterize the precise mechanism of action and long-term effects of the compound. It should not be used in conjunction with other antidepressants. It may alter the metabolism of other medications (warfarin, digoxin). St. John’s wort can be useful in managing the mild mood disturbances that often accompany perimenopause. A recent study of 900 patients (in Germany) found that a medication combining these two herbs (Remifemin Plus) improved global symptoms (flushes, mood, and insomnia) in 80% of users.[13]

Other herbs used by women are valerian, ginkgo, and kava. Valerian has been used for over 1000 years as a tranquilizer and sedative. Three placebo-controlled trials showed a mild dose-dependent hypnotic effect (Table 3). Valerian may be useful for short-term therapy of menopausal sleep disturbances.[3,4]

Ginkgo biloba has been evaluated in at least three randomized controlled trials that show it to be useful for some postmenopausal women experiencing difficulties with memory.[3,4] Caution should be used, however, as ginkgo may further reduce clotting time in women on anticoagulants.

Kava has been found useful in treating anxiety disorders in seven randomized, placebo-controlled trials.[3,4]

Prescription therapies

Prescription remedies are most helpful for women with severe symptoms or women who have exhausted alternative avenues, and have a positive attitude toward evidence-based therapy. During the premenopause transition, when menses are frequent and sometimes heavy, progesterone (Provera 5 mg or Prometrium 200 mg) taken daily for the last 2 weeks of the menstrual cycle may regulate anovulatory cycles and improve sleep (bedtime dosing, especially with Prometrium).[3-5] If this measure fails, the optimal control of symptoms and bleeding patterns may be achieved with the use of a low-dose combined oral contraceptive therapy (OCT).[3-5] A randomized controlled trial of healthy nonsmokers resulted in positive effects on bleeding patterns, cycle control, and overall quality of life.[14] Migraines with aura are a contraindication to this therapy. Oral contraceptive therapies can be used at any time during the perimenopause transition to mask the signs and symptoms of menopause. The question of when to discontinue OCT or switch to hormone replacement therapy (HRT) will arise. A brief period (1 month) off OCT followed by a serum follicle-stimulating hormone (high) and estradiol (low) and assessment of symptoms will help decide what is the next step. Standard HRT is usually commenced after a period of amenorrhea because it may be associated with irregular, heavy bleeding if used when estrogen levels are still fluctuating, giving women a negative attitude toward HRT.[4]

Prescription antidepressants are useful for severe clinical depression. In addition, low-dose intermittent premenstrual use can alleviate PMS in some women (Zoloft 25 mg, Paxil 10 mg, Prozac 10 mg, or Effexor 75 mg for 10 to14 days per cycle may alleviate hot flushes and are an excellent choice for women with breast cancer).[3-5]

Once menses have stopped, standard HRT provides the most effective symptomatic relief. There are many different estrogen products, both oral and transdermal, available in Canada (a table listing the various preparations and their doses and costs will appear in Dr Timothy Rowe’s article in the November 2001 issue of the BCMJ). All estrogens are equally effective for symptom relief and osteoporosis prevention. Familiarity with different products is useful since women respond differently to different products. Oral estrogen is associated with increases in HDL and triglycerides, whereas transdermal therapy lowers triglycerides, total cholesterol, and LDL cholesterol and has minimal effect on HDL. Other differences between oral and transdermal estrogen are listed in (Table 4). Transdermal estrogen is preferred when prescribing for diabetics, hypertriglyceridemics, and smokers.[15]

The addition of progesterone or progestin (medroxyprogesterone acetate, norethindrone) to estrogen therapy has been shown to reduce the estrogen-attributable risk of endometrial hyperplasia or cancer (an addition not necessary in hysterectomized women).[3,4] Maximum protective effects are obtained with 12 to 14 days of cyclic progesterone/progestin per month. Many regimens are being used in an effort to improve compliance (Table 5 [8]). Of the oral products available, only micronized progesterone does not attenuate the effects of estrogen on lipids.[3,4] A recent study found an association between long-term estrogen/medroxy progestin acetate use and breast cancer that was significantly greater than long-term use of estrogen alone.[16] This has led some physicians to avoid the progestin Provera in favor of the micronized progesterone product Prometrium. Still others are using lower continuous doses or intermittent doses of progestins/progesterone. Newer combination estrogen/progestin products recently introduced contain norethindrone (FemHRT, Estalis). Their effect on breast cancer is unknown. Progesterone creams are not recommended for endometrial protection.[17,18] These preparations contain variable amounts of progesterone or progesterone precursors (wild yam, discorea), and there is little consistency or quality control. The amount of progesterone absorbed from the various preparations is highly variable. A recent study[18] shows no endometrial protection when progesterone cream was added to transdermal estrogen. However, pharmaceutical-quality progesterone cream was found to be useful for controlling hot flushes.[17,18]

When using estrogen for symptom relief, titrate the dose, starting low and increasing it if flushing is not controlled and decreasing it if breast tenderness or heavy bleeding occurs. Remain flexible in trying different products. Frequent re-evaluation helps promote compliance, as does prompt attention to any side effects or concerns. Common complaints include breast tenderness, nausea, headache, and bloating.[3-5] These side effects are often dose-related and may resolve with a decrease in dose or a switch to a transdermal product. Side effects of progestins include alterations in mood, breast tenderness, and bloating. These may be less severe with a low-dose, continuous regimen.

Adding androgens to estrogen therapy

Consider adding androgens to estrogen in women on estrogen replacement with decreased libido following bilateral oophorectomy.[3,4] An 8-week to 12-week trial of androgen therapy may also be appropriate in spontaneously menopausal women on estrogen therapy with no other explanation for their loss of libido, particularly in the presence of other symptoms of androgen deficiency (loss of pubic hair or loss of energy and well-being). There is currently no role for testosterone therapy in premenopausal women.[3,4] Symptoms should be re-evaluated after the trial period, and if the degree of symptom relief warrants continued use, it is prudent to monitor the lipid profile and free testosterone level and watch for androgenic side effects. When managing libido issues, many nonhormonal factors can influence sexual health, including:

• Fatigue 
• Health concerns, chronic illness 
• Medication (antihypertensives, SSRI antidepressants) 
• Depression, insomnia 
• Relationship difficulties 
• Lack of a functioning partner 
• Previous attitude toward sex (positive or negative) 
• Age-related changes 
• Change in appearance (weight gain) 
• Incontinence

Symptomatic treatment of the urogenital area may be all that is required for some postmenopausal women. The choice of local therapies ranges from the nonhormonal (Replens, K-Y lubricating jelly, Astroglide) to the hormonal (estrogen creams, estradiol vaginal rings). Local estrogen therapy with a less than 1/8th applicator (Premarin Vaginal Cream, dienestrol cream) or an estradiol vaginal ring (Estring) does not elevate serum estradiol levels and may therefore be useful for women with breast cancer.

What is the bottom line?

Addressing symptom relief with a full range of options will help the majority of perimenopausal women improve their quality of life.[3-6,19] Their choices range from lifestyle modification or alternative therapies to HRT.

There are a few exceptions: Women with loss of ovarian function in their late 30s and early 40s as a result of premature ovarian failure, surgical menopause, or chemotherapy will need encouragement to take estrogen until at least age 50, at which time a re-evaluation of symptoms and osteoporosis risk factors should be undertaken.[5] Women at high risk for breast cancer will need to avoid hormones and use lifestyle modification and complementary and alternative therapies almost exclusively.

Resources

Web site 
 www.menopause-center.org [9]

Society 
North American Menopause Society (NAMS) 
PO Box 94527, Cleveland OH 44101 USA 
(440) 442-7550 
www.menopause.org  [10]
info@menopause.org [11]

Book 
Chandler F (ed). Herbs: Everyday Reference for Health Professionals Canadian Medical Association. Tel: 1 888 855-2555, fax (613) 236-8864, e-mail cmamsc@cma.ca [12].

*Not available in Canada

Suzanne Montemuro, MD, CCFP

Dr Montemuro is a family physician, a clinical instructor in the Department of Family Practice at the University of British Columbia, and the director of the North Shore Menopause Information Centre.