快樂小藥師 Im pharmacist nichts glücklich

Release Date:  September 1, 2009

Menopause is the point in time when a woman has not had a spontaneous menstrual period for one year. Perimenopause is the period leading up to this cessation of ovulation and menstrual cycling and includes the first year after the last menstrual bleed. Most symptoms attributed to menopause are also experienced during perimenopause.

Population Definition

Women can begin experiencing loss of menses as early as their 30s and into their 50s.¹ Although anytime after age 40 is considered normal for the onset of menopause, the average age is 51 years. Nonsurgical menopause occurring before 40 years is considered early and may warrant a referral for medical endocrine evaluation due to the increased incidence of autoimmune disorders.² Women who smoke often begin perimenopause earlier than nonsmokers. Women who have never given birth (i.e., nulliparity) tend to reach menopause earlier than those who have had children. Other factors that may cause an earlier age of menopause include a diet high in vegetables, fibers, and cereals, autoimmune disorders (i.e., type 1 diabetes mellitus), and low body mass index (BMI). There may also be a genetic link between mothers and daughters and the age of transition.³

Physiology of Menopause

The physiology of menopause is complex and involves numerous hormones and feedback loops. Over a woman’s reproductive lifespan, the number of ovarian follicles decreases and hormonal changes lead to irregular maturation of estrogen-producing follicles. Menstrual irregularity includes changes in cycle length and menstrual flow. One of the early hormonal changes to occur is a decrease in inhibin B, which leads to higher follicle-stimulating hormone (FSH) levels in the early part of a woman’s cycle. This stimulates the ovarian follicles to release estradiol. An elevated FSH level is the first measurable sign of reproductive aging. Once there is a complete depletion of ovarian follicles, the ovary will no longer respond to the high FSH levels, and estradiol levels will decrease. During this time of transition, FSH and estradiol levels fluctuate significantly; therefore, they cannot be used as diagnostic criteria for perimenopause. The FSH and estradiol levels should be measured over more than one cycle to account for natural fluctuations. It is the fluctuations in estrogen levels that are thought to account for many of the symptoms of perimenopause.⁴ After menopause, the amplitude of the FSH and luteinizing hormone (LH) release is increased.⁵

Clinically, the menopausal transition is divided into early and late stages.⁶ Healthy individuals may progress from one stage to another or may go back and forth between stages or may skip a stage. During the early stage, cycle length varies in some women to greater than 7 days from baseline cycle length. The late menopausal transition occurs when a woman experiences at least two skipped cycles or amenorrhea lasting 60 or more days. Vasomotor symptoms are increased during this late stage. Physiologic changes in late perimenopause include reduced ovarian activity, reduced stamina, and changes in skin, the vagina, and hair. Sleep difficulties, forgetfulness, irritability, night sweats, and hot flashes are the most prevalent symptoms. Women may experience varying intensities and combinations of these symptoms (TABLE 1); however, not all women exhibit symptoms during the menopausal transition. Since the measurement of symptoms and history can be subjective, there is difficulty in qualifying the data available.⁷

Women who smoke, are at the extremes of body weight (BMI <18 kg/m² or >30 kg/m²), do heavy aerobic exercise (>10 h/wk), have chronic menstrual cycle irregularity, or have had a hysterectomy, uterine fibroids, or ovarian endometrioma should be individually assessed for stage of reproductive life.⁶

Why Is It Important to Treat?

Many women see the symptoms of menopause as a reduction in quality of life. Since “50 is the new 30,” many women entering midlife expect more out of life and want to function at peak performance capacity. Women may have delayed child rearing and still have children at home. They may also have elderly parents to care for in addition to work responsibilities. These women cannot slow down, so it is important to their quality of life that the symptoms of perimenopause be treated.

For women who do not experience a reduced quality of life during the menopausal transition period, treatment is not necessary. For women who experience moderate to severe symptoms, there should be education about the potential benefits and hazards of treatment options to improve quality of life and prevent or manage disease. These women should be given alternatives and choices that individually address the goals and desires of the person while minimizing the risks of those choices.

Pregnancy and Contraception

The CDC has reported that a woman’s fertility decreases from her mid 40s into her 50s. The average fertility rate for women 20 to 34 years of age was 108 births per 1,000 women in 2007. The preliminary birth rate to mothers between 35 and 39 years of age was 47.5 births per 1,000 women. This further decreases to 9.5 births per 1,000 women from 40 and 44 years, which is higher than the 0.6 births per 1,000 women aged 45 to 54 years.⁸

After age 35, there is an increased risk of health problems during pregnancy. The risk of first trimester miscarriage increases to 20% after 35 years and increases again to 50% after 40 years. This may be due to increased chromosomal abnormalities, such as Down syndrome (1 in 400 chance at age 35, 1 in 100 at age 40, 1 in 30 at age 45, and 1 in 10 at age 49). Women over age 35 are twice as likely to have gestational diabetes as younger women. The risk of developing hypertension during pregnancy increases at maternal age above 40 years.^9,10

Some women may assume they no longer need to use contraceptive measures during perimenopause due to reduced frequency of coitus, irregular menstrual cycles, or the belief that they cannot get pregnant. However, a slight chance of pregnancy in the perimenopausal age group, even without fertility treatments, is still a concern. Due to the increased risk that pregnancy places on the mother and the increased risk of birth concerns for the infant, health care providers should educate women about the risks of becoming pregnant during perimenopause. Contraception to prevent unintentional pregnancies continues to be necessary until ovulation ceases.

One option for effective contraception in older women who are nonsmokers and otherwise healthy is combination estrogen/progestin contraceptives. Agents containing low estrogen doses would be preferred. In addition to providing contraception, combined oral contraceptives may also improve vasomotor symptoms and restore regular cyclicity during perimenopause. They also provide protection against ovarian and endometrial cancer, and long-term use may help preserve bone mineral density.¹¹ Combined hormonal contraceptives would not be appropriate in perimenopausal women who smoke, have uncontrolled hypertension, hyperlipidemia, diabetes mellitus, migraines, breast cancer, liver disease, undiagnosed vaginal bleeding, or a history of venous thromboembolism. Perimenopausal women on combined hormonal contraception should be closely monitored for any factors that may increase the risk of arterial or venous disease and the method be discontinued if necessary.¹²

Although all combined oral contraceptives may increase the risk of venous thromboembolism, there is a heightened concern reported for women using those containing desogestrel or gestodene and the transdermal patch containing norelgestromin.^12,13 Perez Gutthann et al reported a positive association of thromboembolism risk in women with BMIs over 25.¹⁴ In the Women’s Health Initiative (WHI) study, BMI greater than 30 was associated with a much greater thromboembolism risk than BMI of less than 25 (hazard ratio 5.61 vs. 1.78).¹⁵

How long combined oral contraceptives should be continued is a difficult decision. Because it is not possible to assess the natural menstrual pattern while a woman is taking hormonal contraceptives, it is very difficult to determine when she has become menopausal. The average age of final menses among female relatives and the patient’s own symptoms can serve as a guide for when to initiate the process of assessing menopausal status. One option to assess whether a woman is still potentially fertile would be to transition to nonhormonal contraceptive methods, monitor for spontaneous menses, and check serial FSH levels. The woman who does not want to discontinue hormonal contraception and does not have contraindications for use may continue until the age of 55, at which time the probability of menopause is high.¹¹

Women who are not candidates for combined hormonal contraception may be candidates for progestin only methods, intrauterine devices, surgical sterilization, or other nonpharmacologic methods. Nonsurgical methods do not have any impact on hormonal fluctuations and therefore will not lessen perimenopausal vasomotor symptoms or regulate cycle control. Spermicides containing nonoxynol-9 used alone or within a contraceptive sponge may be a consideration for those who have infrequent intercourse. There is an increased risk of sexually transmitted disease with long-term use of nonoxynol-9 products due to disruption of the vaginal epithelium.¹²

Efficacy of contraceptive methods depends on consistent and correct use regardless of the method chosen. Adherence to methods that are longer acting, such as patches, implants, and intrauterine devices, may have a higher rate of prevention of unintended pregnancy than daily-use methods.

Vasomotor Symptoms

Vasomotor symptoms include hot flashes and night sweats. Although most women begin experiencing hot flashes around the time of the first menstrual irregularity, approximately 20% of perimenopausal women report significant hot flashes. Even though the prevalence and intensity of hot flashes tend to peak in the perimenopausal and early postmenopausal years, hot flashes can last for several years in some women.³

Low levels of estrogen during perimenopause and menopause are thought to be related to hot flashes. One hypothesis suggests that decreasing estrogen levels may affect the norepinephrine and serotonin systems in the hypothalamus, which is responsible for thermoregulation. As a hot flash develops, skin temperature, cutaneous blood flow, and heart rate all increase. Many women complain of a sensation of heat across the head and upper body, often with a reddening of the skin, followed by sweating.¹⁶ When hot flashes occur at night, they are known as night sweats. Night sweats often result in sleep disturbances, which are then thought to contribute to fatigue, irritability, anxiety, and other common menopausal complaints.

It is estimated that 85% of women transitioning to menopause experience more than one vasomotor symptom, and 10% of these women seek medical attention. Many women do not require treatment for mild symptoms and often find improvement over time without intervention.¹⁶ Most pharmacologic options have been studied in postmenopausal women or those with breast cancer and therefore evidence is limited in perimenopausal women.

Pharmacologic Treatment: 

 Perimenopausal women desiring both contraception and treatment for hot flashes may benefit from oral contraceptives. Studies in perimenopausal women have shown that low-dose combined oral contraceptives may reduce both the frequency and intensity of hot flashes.¹⁷ Hot flashes should improve within 2 to 3 months. Once the woman has ceased ovulation and no longer needs contraception, she should be transitioned to hormone therapy if she is still experiencing disruptive vasomotor symptoms.¹⁷

Hormone replacement therapy (HRT), consisting of either estrogen alone or estrogen plus progestin, is the most effective pharmacologic treatment option for reducing the frequency and severity of vasomotor symptoms.¹⁸ A review conducted by the Cochrane Group found that treatment with estrogen significantly reduced the frequency of hot flashes by 75% compared to placebo in perimenopausal and postmenopausal women.¹⁹ Quality of life has also been improved with the use of HRT.¹⁶

While HRT is effective for vasomotor symptoms, it is not without risks. The WHI studied over 16,000 postmenopausal women on combined estrogen and progestin or placebo to prevent coronary heart disease. After the first year of therapy, women in the estrogen and progestin arm had a significantly higher risk of coronary heart disease events. The study was stopped early after a mean follow-up of 5.2 years due to an increased risk of invasive breast cancer, coronary heart disease, stroke, and pulmonary embolism.²⁰

HRT for vasomotor symptoms is available as oral, transdermal, or vaginal formulations. No evidence indicates one route is more effective than another. However, transdermal therapy may be preferred due to reduced frequency of dosing, lack of first-pass metabolism, and steady levels of circulating estrogen.¹⁶ Transdermal therapy should be considered for patients with elevated triglycerides to avoid oral estrogen-induced increases in serum concentrations.¹⁶ Vaginal estrogen products at doses used to treat atrophic vaginitis are not effective at reducing hot flashes.¹⁷

A variety of estrogen formulations, such as estradiol, estriol, esterified estrogens, and conjugated equine estrogens, are available. All formulations have been shown to be effective for the treatment of vasomotor symptoms. The North American Menopause Society recommends starting with lower-than-standard doses because the lower doses may be better tolerated while still providing relief from hot flashes (TABLE 2). The effect of lower doses on endometrial safety has not been tested.¹⁷ Combination estrogen plus progestin is recommended in women with an intact uterus to avoid the increased risk of endometrial cancer seen with unopposed estrogen. Abrupt discontinuation of HRT may cause hot flashes to return; therefore, therapy should be gradually reduced.¹⁷

Common side effects of HRT include uterine bleeding, breast tenderness, nausea and vomiting, edema, and headache. The long-term risks (breast cancer, coronary heart disease, thromboembolism, stroke, dementia) associated with HRT should be considered and discussed with patients prior to initiation of therapy.^20,21 If HRT is used for the treatment of vasomotor symptoms, it should be used at the lowest effective dose and limited to the shortest duration necessary.

Although data are limited regarding the use of HRT in perimenopausal women, a recent Cochrane review evaluated the effects of long-term hormonal therapy for perimenopausal and postmenopausal women. The authors reported that based on a subgroup analysis from the Women’s Health Initiative study, relatively healthy women between the ages of 50 and 59 years taking HRT had an increased risk of venous thromboembolism, although the absolute risk remained low. Other adverse outcomes were not statistically increased over placebo in this age-group.²²

Some women are not candidates for HRT for vasomotor symptoms because of anticipated risks. Many non-HRT therapies do not have FDA approval for the treatment of vasomotor symptoms; however, there have been studies to support their use. Antidepressants may be a treatment option in symptomatic women unable to take HRT. The serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine has been studied in women who had at least 14 hot flashes a week and either a history of breast cancer or concerns about the risks of breast cancer with HRT. After 4 weeks of treatment, median hot flash scores were reduced up to 61% from baseline in women taking 150 mg/day of venlafaxine compared to a 27% reduction in patients receiving placebo. The full effect of venlafaxine was noted within the first 1 to 2 weeks of treatment.²³

Venlafaxine is generally well tolerated. Common adverse effects seen in this study included dry mouth, decreased appetite, nausea, and constipation.²³Other side effects include somnolence, dizziness, and sexual dysfunction. Increases in blood pressure may also be seen, especially with higher doses. Venlafaxine should not be used by women also taking a monoamine oxidase (MAO) inhibitor.

The selective serotonin reuptake inhibitors (SSRIs) paroxetine and fluoxetine have both been studied in postmenopausal women with hot flashes. Controlled release paroxetine at doses of 12.5 or 25 mg/day for 6 weeks decreased hot flash composite scores by approximately 62% compared to a decrease of 38% in patients treated with placebo.²⁴ Common adverse effects of paroxetine and fluoxetine include headache, dizziness, nausea, diarrhea, insomnia, and drowsiness. Like venlafaxine, these agents are contraindicated in women also using an MAO inhibitor.

Gabapentin, an anticonvulsant, may be another option for the treatment of vasomotor symptoms in women who are not candidates for HRT. A small trial in postmenopausal women with moderate to severe hot flashes found that gabapentin 900 mg/day for 12 weeks reduced both hot flash frequency and the hot flash composite score significantly more than placebo.²⁵ More recently, the use of gabapentin was studied in women with breast cancer. After 4 weeks of treatment, women receiving 900 mg/day of gabapentin had a 41% reduction in hot flash frequency and a 49% reduction in hot flash severity, compared to 18% and 21% reductions, respectively, in patients receiving placebo.²⁶ Use of gabapentin is well tolerated by most patients. The most common reasons for discontinuation of gabapentin when used for the treatment of vasomotor symptoms include somnolence, dizziness, rash, and peripheral edema.

The alpha-adrenergic agonist clonidine is thought to reduce hot flash frequency by reducing central noradrenergic activation and may be a good choice in symptomatic perimenopausal women with hypertension.¹⁷ Clonidine, administered at 0.1 mg/day, has been shown to modestly reduce hot flash frequency in small studies of postmenopausal women and in women being treated with tamoxifen.¹⁶ Transdermal clonidine may be better tolerated than the oral formulation. Common adverse effects include dry mouth, drowsiness, constipation, insomnia, and itchiness under the patch. Clonidine can also lower blood pressure and heart rate, although no adverse hemodynamic effects were seen in one study of 0.1 mg/day oral clonidine used in women with tamoxifen associated hot flashes.¹⁶

Other Treatments: Lifestyle modifications, including wearing layered clothing, using personal fans, and consuming cool drinks, can modify core body temperature and give the woman some relief from hot flashes. Relaxation training may also reduce hot flash symptoms; however, studies were done with small groups and may be biased. Paced respiration utilizing slow, deep abdominal breathing at symptom onset has been shown to reduce hot flash symptom duration and frequency.¹⁷

Phytoestrogens are plant constituents with a phenolic structure similar to estrogen. Isoflavones from soy protein have had mixed results in studies. Small decreases in hot flash severity or reduced frequency have been found in a few studies in the 40 to 150 mg/day range. Differences in study results may be due to variability in products studied and participant age. Soy isoflavones can be obtained in a protein powder or through soy consumption (e.g., tofu, soy milk).²⁷ Red clover has isoflavone content similar to that of soy products, although there is no evidence to support its use for hot flashes. Currently, there are no reported adverse effects.²⁸

Black cohosh 20 mg twice daily may be of benefit to some women for the reduction of hot flashes and night sweats. Evidence is not strong, with conflicting data and small study samples. Symptom relief is not immediate; therefore, a 6- to 12-week trial should be attempted for best results. Hepatotoxicity, a rare side effect, has been reported with black cohosh use. Due to lack of extended studies, use of black cohosh should be limited to 6 to 12 months.²⁹

Evening primrose oil has no evidence to support any benefit for hot flashes. Gamma-linolenic acid, an essential omega-6 fatty acid, is the major component of the oil. Evening primrose oil may cause an increase in bleeding risk.²⁹

Vitamin E 800 IU daily may induce a slight decrease in hot flash frequency. A known side effect, especially with higher doses, is an increased risk of bleeding.²⁹

Bioidentical hormone replacement products are a synthetic mix of estrogens (estradiol, estriol, estrone) that are produced from plant derived material, often wild yam. The formulations can be compounded to meet an individual woman’s needs. Large, well-designed trials are lacking. Safety considerations should be the same as for any hormonal therapy.³⁰

Vaginal Atrophy

Estrogen deficiency associated with late perimenopause and progressing into menopause may have a negative impact on sexual function for the woman. during perimenopause, vaginal dryness is common, with an estimated prevalence of 7% to 39%.⁷ After menopause, dyspareunia (painful sexual intercourse), vaginal mucosal changes with loss of rugae, thinning of the vaginal tissue and subcutaneous fat, and loss of labial sensation can decrease sexual satisfaction for women. Other factors such as medications, lack of sleep, anxiety, or external life issues can also impact sexual function.⁵

Although data are limited in perimenopausal women, vaginal lubricants and moisturizers may help alleviate the vaginal dryness experienced by many women. Water based lubricants would be preferred if latex condoms are also being used. A small study in postmenopausal women showed that one nonhormonal treatment had similar efficacy to vaginal estrogen cream with regard to vaginal dryness.³¹

For moderate to severe vulvar and vaginal atrophy, estrogen therapy is effective. Due to the risks associated with systemic HRT, local administration is recommended for women with only urogenital complaints.¹⁸ In these situations, low-dose vaginal estrogen available as a cream, tablet, or ring may be considered. Endometrial stimulation and systemic symptoms may be higher with cream formulations than with vaginal tablets or the ring.³² Since some systemic absorption is possible with vaginal administration of HRT, women should be warned of the risks associated with HRT as previously discussed.

Urinary Incontinence

Urinary incontinence (UI) is a serious lifestyle concern for perimenopausal women. Common forms of UI include stress incontinence, overactive bladder (OAB), and mixed incontinence. An involuntary loss of urine while coughing, exercising, or doing another activity that increases intra-abdominal pressure is known as stress incontinence. It is due to poor bladder neck support that may be attributed to tissue and nerve injury during vaginal delivery. Inadequate estrogen levels and advancing age may further diminish urethral sphincter function. The hallmark of OAB is a strong urge to void, with or without a full bladder, and involuntary loss of urine during or after the urge is presented. Detrusor overactivity or involuntary detrusor contractions are linked to this disorder. Common symptoms of OAB include urgency, frequency, dysuria, and nocturia. Mixed incontinence is a combination of stress incontinence and OAB.³³

Prevalence of UI increases with age. Stress incontinence (40%) and mixed incontinence (50%) are most prevalent in the perimenopausal age-groups of 40 through 59. The incidence of UI increases with a high BMI, medical comorbidities, major depression, and the number of vaginal deliveries.³⁴

Medications that are associated with incontinence symptoms, such as diuretics and caffeine, should be assessed and changed if possible. Discontinuing or replacing medications that are contributing to UI increases the chance of success in diminishing symptoms.³⁵

Nonpharmacologic Options: 

 One nonpharmacologic option to improve bladder control is to give a bladder diary to the patient. The diary, which includes a 24 hour calendar, asks about fluid intake and urine output. A practitioner may see a pattern of incontinence when reviewing a patient’s bladder diary and suggest a schedule for timed voiding, usually every 2 to 3 hours. As the patient gains additional control, she can extend the time between scheduled trips to void.³⁶

Pelvic floor muscle exercises (Kegel exercises) are used to strengthen the muscles that help hold in urine. In a review of randomized trials of women with stress, urge, or mixed urinary incontinence, Dumoulin and Hay Smith report that women with a previous history of urinary incontinence showed improvement with pelvic floor muscle exercises. The authors also concluded that the greatest positive effects were seen in women in their 40s and 50s with stress incontinence who participated in these exercises for 3 months or more.³⁷

Pharmacologic Options: 

 Unfortunately, there are not many pharmacologic treatment options for stress incontinence. Duloxetine, a selective SNRI, has been studied in women with stress incontinence, although it does not have an FDA-approved indication for UI. Stimulation of the urethral sphincter by serotonin and norepinephrine is thought to be the mechanism by which duloxetine may work for stress UI.³⁸ A systematic review of the literature found that duloxetine administered for 3 to 12 weeks did not have better curative effects than placebo, but it did show improvement in UI and quality of life.³⁹There was not a dose response effect noted between 20 mg and 80 mg of duloxetine. Common adverse effects included nausea, dry mouth, fatigue, insomnia, constipation, headache, and dizziness, with about one-fifth of women discontinuing duloxetine due to side effects.³⁹

Duloxetine is not recommended for women with a creatinine clearance <30 mL/min or on dialysis or for those with hepatic insufficiency. Duloxetine is contraindicated in women also taking MAO inhibitors or with uncontrolled narrow angle glaucoma. Although not specific to this population, due to its classification as a selective SNRI, duloxetine carries the same black box warning that other antidepressants do regarding the increased risk of suicidal thinking and behavior in children, adolescents, and young adults when used for depression and other psychiatric disorders.⁴⁰

Hendrix et al assessed the effects of HRT on the incidence and severity of symptoms of stress, urge, and mixed UI in healthy postmenopausal women who received 0.625 mg conjugated equine estrogen with or without medroxyprogesterone or placebo. Menopausal hormonal therapy increased the incidence of all types of UI at 1 year among women who were continent at baseline.⁴¹

Antimuscarinics are the mainstay of pharmacologic therapy for OAB. Use of antimuscarinics results in a decreased frequency and intensity of detrusor smooth muscle contractions.⁴² While all of the currently available antimuscarinic agents (i.e., darifenacin, tolterodine, oxybutynin) are effective for the treatment of OAB, they differ in many other areas, including their administration and dosing, adverse-effect profile, drug interactions, and selectivity for muscarinic receptors. All of the antimuscarinics are available as oral formulations, and oxybutynin is also available as a transdermal patch. The most common side effects include dry mouth, constipation, headache, and blurred vision. These side effects tend to be better tolerated in patients using extended release formulations or agents that are more selective for muscarinic receptors in the bladder. Head-to-head comparisons of agents are limited, as most agents were compared to either placebo or oxybutynin.⁴³ Due to their anticholinergic properties, these agents should be avoided in women with uncontrolled narrow-angle glaucoma or urinary retention. Depending on the agent used, the dose may need to be adjusted for renal or hepatic impairment.

Treatment options for perimenopausal symptoms are summarized in TABLE 3.

Conclusion

Perimenopause is a change in reproductive health for women. Pharmacists and other health care providers should be ready to discuss with their patients the complex health concerns and common treatment options during perimenopause. Education about lifestyle changes, health maintenance, and the risks and benefits of pharmacologic interventions through the menopausal transition will benefit the patient.

Women’s symptomatology should be acknowledged and treated in an appropriate and individualized manner to improve quality of life. Pharmacists should remain aware of any changes that occur in the recommendations from organizations and government agencies that would affect perimenopausal women. In addition, the pharmacist who can show empathy and communicate with the perimenopausal patient will find a loyal patient base.

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