Menopause

Authors

Julie A. Elder, DO
Holly L. Thacker, MD

Published: October 2013
Last reviewed: February 2016

Definition

Menopause is defined as the absence of menses for 1 year. Women usually experience menopause between 40 and 55 years of age, with the median age being 51. Smokers and women with chronic illnesses tend to experience menopause at an earlier age.

Menopause transition consists of fluctuating ovarian function and occurs 2 to 8 years before menopause and up to 1 year after the final menses. It is a progressive process that eventually leads to persistent ovarian failure. The change in hormones during this period is often responsible for the clinical signs and symptoms that many women experience. Systems affected by the perimenopausal phase include skin and hair, genitourinary (GU), neuroendocrine, cardiovascular, and skeletal. The North American Menopause Society has published a comprehensive online study guide related to menopause and offers testing to credential menopause practitioners.

Premature ovarian insufficiency (POI) is the cessation of ovarian function before the age of 40. It occurs in less than 1% of all women. There are many reasons for secondary amenorrhea in addition to primary ovarian failure. Secondary causes of POI include chromosomal abnormalities (e.g., fragile X syndrome), autoimmune disorders, physical insults to the ovaries, isolated ovarian antibodies, and gonadotropic receptor defects. Pregnancy must always be considered in the differential diagnosis of secondary amenorrhea.

Pathophysiology

A female ovary has the greatest number of oocytes during the fifth month of gestation and has about 1 to 2 million oocytes at birth. As a woman ages, the process of atresia reduces the number of oocytes, so that at the time of menopause a woman may have only a few hundred to a few thousand oocytes left. The ovary primarily produces estrogen, progesterone, and androgens.

Estrogen

Estrone (E1), estradiol (E2), and estriol (E3) are three endogenously produced estrogens. Estradiol (E2) is produced by the dominant ovarian follicle during the monthly menstrual cycle and is the most potent natural estrogen. Estrone (E1) is the dominant form of estrogen during menopause. It is produced in small quantities by the ovary and the adrenal glands, and is principally derived by the peripheral conversion of androstenedione in adipose tissue.

Progesterone

Progesterone is produced by the corpus luteum and promotes thickening of the endometrium in preparation for a fertilized ovum. Progesterone also inhibits the actions of estrogen on certain tissues. In an anovulatory woman, no corpus luteum is formed. Therefore, estrogen often goes unopposed. This can lead to a buildup of the endometrium, causing irregular menstrual bleeding in the perimenopausal phase.

Menstruation

Menarche, or the first menses, usually begins around the age of 12 years. It is divided into three phases: follicular, ovulatory, and secretory. The follicular, or proliferative, phase is marked by the first day of menses. Estradiol (E2) is produced during this phase by a dominant ovarian follicle and causes proliferation of the endometrium. Through a negative feedback system, follicle-stimulating hormone (FSH) production is decreased. Luteinizing hormone (LH), however, increases and eventually triggers ovulation. When LH peaks, ovulation occurs. During this ovulatory phase, progesterone levels increase, whereas estrogen levels decrease.

Formation of a corpus luteum begins the secretory phase in which estrogen, progesterone, and androgens are secreted. Estrogen promotes cellular proliferation, whereas progesterone causes swelling and secretory development of the endometrium. If pregnancy does not occur, estrogen and progesterone levels fall and the endometrium is shed during menses.

Menopause

The menopausal ovary no longer produces estradiol (E2) or inhibin. Therefore, FSH and LH are no longer inhibited by estrogen's negative feedback mechanism. Fluctuations and deficiencies in estrogen levels cause many of the menopausal signs and symptoms.

Signs and Symptoms

Various tissues throughout the body are rich in estrogen receptors. When estrogen levels decrease or fluctuate, a number of systems can be directly affected.

Vasomotor and neuroendocrine hot flashes are common among women in the menopause transition. They are usually self limited but can continue for years. Hot flashes involve a sensation of warmth throughout the body, often accompanied by flushing. In addition, some women experience cephalalgia, nausea, or diaphoresis. Palpitations, dizziness, and "skin crawling" sensations are other vasomotor symptoms that women might encounter. Women with known depression or panic disorders might have exacerbations of their disease if they have associated menopausal symptoms.

Skin and hair estrogen deficiency leads to mucosal dryness, particularly in the eyes, nose, mouth, and vagina. Some women might also notice a loss of skin elasticity associated with decreased collagen and elastin production. Decreased estrogen levels are associated with a relative surplus of androgens. Androgen excess can cause male-pattern alopecia, hirsutism, and a deepening of the upper register of the voice.

Urogenital estrogen receptors are located on many tissues, including the urethra and bladder. During the estrogen deficiency state of menopause, urethral tissue can become thin, ultimately causing dysuria, urinary incontinence, and increased urinary frequency. In addition, changes in the vulva and vagina can occur, including vaginal atrophy, cervical atrophy, and vaginal dryness. Dyspareunia may result, as well as postcoital bleeding, pruritus vulvae, and discomfort during routine pelvic examinations. Women may also experience sexual dysfunction and a decreased libido.

Skeletal bone mass peaks at 30 years of age and starts to decline thereafter. This decline accelerates throughout the menopause transition and menopausal years. Genetics, estrogen status, exercise, and calcium and vitamin D intake all play significant roles in bone mass. Estrogen has a protective effect on bones by inhibiting overall bone loss. Postmenopausal women can lose up to 4% to 5% of their bone density annually due to the loss of estrogen. Bone loss is especially prominent in the trabecular spine.

Cardiovascular Disease

The incidence of cardiovascular disease (CVD) increases after menopause. Specifically, the risk of coronary heart disease is two to three times higher for postmenopausal women compared with premenopausal women of the same age. Alarmingly, after the age of 65, one out of every three women has some form of CVD. Hormone therapy (HT) is no longer used to prevent CVD based on the Heart and Estrogen-Progestin Replacement Study (HERS) trial and Women's Health Initiative (WHI) results; however the effects of the timing of HT initiation are being investigated.

Diagnosis

Women undergoing the menopause transition or menopausal changes seek medical counsel for a variety of reasons. Absent or irregular menses, insomnia, depression, cephalalgia, and vasomotor instability are just a few of the reasons women visit their physicians. Many women access information about menopause through a variety of sources including friends, family, Internet sources, television and other forms of media, which may not be accurate sources of information.

The initial evaluation by the health care provider should include a comprehensive history and physical examination accompanied by select laboratory studies and patient education. In addition, family, social, sexual, and medication histories are imperative. A complete physical examination might provide diagnostic clues to a woman's menopausal state. For example, a loss of height might suggest osteoporosis and a pelvic examination might reveal vaginal atrophy from lack of estrogen.

Baseline laboratory studies should also be performed including a screening thyroid stimulating hormone. During the menopause transition, FSH levels fluctuate, making a serum level unreliable for diagnostic purposes. In the face of prolonged amenorrhea with or without menopausal symptoms, an FSH level 40 mIU/mL is considered diagnostic of menopause. Although in this setting, a FSH evaluation is rarely needed to confirm the postmenopausal state. If a woman has taken oral contraceptives during the perimenopausal period, she must be taken off them for several months before an accurate FSH level can be determined. Serum estradiol levels fluctuate in perimenopausal women, making it a test that is seldom useful in diagnosing menopause. Testosterone and dehydroepiandrosterone levels are indicated only if a woman has symptoms of hyperandrogenism or if she is taking over-the-counter hormones that may contain these potent androgens.

Treatment

Various organizations provide recommendations regarding the treatment of menopause. The North American Menopause Society guidelines contain some of the most accurate and clinically relevant information. Women should be educated about the risks and benefits of HT and consider it based on personal risk assessment and quality of life issues. There are certain situations during which the use of HT is not recommended.

Contraindications to Hormone Therapy

Absolute contraindications to HT include pregnancy, an active venous thrombosis or embolism, undiagnosed vaginal bleeding, active liver disease, active breast or endometrial cancer, and active CVD.

Relative contraindications to HT include a history of previously treated breast or uterine cancer, previous thromboembolism, gall bladder disease, uncontrolled hypertension, migraine headaches, uterine fibroids, seizure disorders, hypertriglyceridemia, and a history of CVD. When considering the use of HT, risks and benefits must be individualized.

Risks of Hormone Therapy

Thromboembolism

There is an increased risk of developing thromboembolism associated with HT use. It is estimated that the incidence of deep venous thrombosis or pulmonary embolus occurs in 3 of 10,000 HRT users annually, especially during the first year of therapy. This risk is present regardless of the form of hormonal or transdermal estrogen used. Based on the conjugated equine estrogen/medroxyprogesterone (CEE/MPA) arm of the WHI, the risk of venous thromboembolism (VTE) persisted in subsequent years. A more recent randomized trial revealed a higher incidence of VTE in HT users, specifically in women who were older in age and overweight or obese, or both. In the estrogen-only arm of the WHI, conjugated equine estrogens had less risk for VTE than the combination estrogen- progestin regimen. The type of estrogen a woman takes may also influence her risk for VTE. However, the U.S. Food and Drug Administration (FDA) classifies all estrogen as having the same risks.

Gallbladder Disease

An increase in the incidence of gallbladder disease is noticed in women on HT. The HERS trial revealed that women with coronary artery disease had a 40% increased risk for developing symptomatic gallbladder disease while on HT.

Endometrial Cancer

The risk of developing endometrial adenomatous hyperplasia, a precursor for endometrial cancer, occurs in women with a uterus who are on estrogen therapy (ET) alone (unopposed estrogen). Current therapeutic regimens recommend that women on HT with intact uteri receive combinations of estrogen and progestin. This decreases the risk of endometrial cancer to baseline.

Breast Cancer

The increase in the relative risk of developing breast cancer associated with long-term use (⟨5 years) HT is a major reason that some women choose not to take it. The CEE/MPA arm of the WHI showed a hazard ratio of 1.26 (confidence interval [CI], 1.0-1.56). The degree of risk, however, is quite controversial. Various studies have shown that HT is associated with an increased risk of breast cancer, but others have not concurred. Short-term HT, used to treat menopausal symptoms, appears not to increase a woman's chance of developing breast cancer. However, women on HT for more than 5 to 10 years are calculated to have less than one extra occurrence of breast cancer per 1,000 women. There are no prospective, randomized controlled studies showing that women on HT are more likely to die of breast cancer. The estrogen only arm of the WHI showed no increased risk of breast cancer in women with a hysterectomy in taking estrogen alone. In fact, women adherent to conjugated estrogen showed a reduced risk of breast cancer.

The Boston Nurses Healthy Study showed no increase in breast cancer in women using ET for up to 15 years. After 15 years of use, however, ET was associated with an increased risk for breast cancer.

Benefits of Hormone Therapy

Vasomotor Symptoms

HT is effective in the treatment of hot flashes and is currently the only FDA-approved therapy. Many women only need vasomotor control for short periods of time (⟨5 years). HT has also been shown to improve symptoms of anxiety, irritability, and depression associated with menopause.

Osteoporosis

Hormone therapy is FDA-approved for the prevention and management of osteoporosis. A woman must continue HT indefinitely to sustain the bone protective benefits. In the WHI, impressive reductions in all types of fractures were seen. Most women take HT for less than 2 years; therefore, women with osteoporosis, low bone density, or both need alternative treatments. In addition to taking estrogen, it is recommended that women take 1,200 mg of calcium a day. If a woman is not on HT, or is older than 65 years, 1,500 mg of calcium daily is recommended. A clinical practice guideline for osteoporosis appears on the National Osteoporosis Foundation website. Vitamin D deficiency is widespread in North America and at least 400 to 800 IU of vitamin D are recommended daily.

Vaginal Atrophy

HT has been shown to improve the symptoms of vaginal atrophy in the intravaginal, oral, and transdermal forms.

Cognition

The effects of HT have been controversial in the literature. Observational studies have suggested a decreased risk of developing Alzheimer's dementia; however, HERS data found that older women with coronary artery disease on HT scored worse on verbal fluency tests and had worse cognition than women taking placebo. In addition, the WHI memory study revealed that HT did not prevent mild cognitive impairment and, in fact, doubled the relative risk of dementia, suggesting that, like CVD, timing is important.

Other Benefits

The WHI showed less risk of colon cancer with HT, hazard ratio 0.63 (CI, 0.43-0.92); however, ET did not show a reduction in colon cancer. HT and ET have no effect on ovarian cancer risk.

Types of Hormone Therapy

Estrogen

Estrogen is given orally, vaginally, or transdermally. Women with GU atrophy may benefit from intravaginal ET, used with or without standard HT (Table 1). Signs and symptoms of urogenital or vaginal atrophy can be assessed by visual inspection at the routine pelvic examination every 1 to 2 years.

Table 1: Vaginal Estrogens

© 2004 The Cleveland Clinic Foundation.

Women should be queried regarding complaints of sexual dysfunction, vaginal dryness, and dyspareunia. Intravaginal estrogen comes in various forms, including creams, tablets, and an intravaginal ring (Estring) that the woman herself can insert every 3 months. A health care provider can also insert and remove the ring, but generally the woman accomplishes this easily. The Estring vaginal ring has the added benefit of no significant systemic effects or endometrial stimulation, which is an advantage to women with uteri/endometria who are not using progestins and for women who are suffering from local GU symptoms. The Femring gives both local and systemic estrogen to women without uteri who have vasomotor symptoms.

The use of intravaginal estrogen creams and tablets may periodically necessitate evaluation of the endometrium with an outpatient endometrial pipelle biopsy because some of this estrogen is systemically absorbed and may stimulate endometrial growth. ET in a woman with an intact uterus must be accompanied by a progestin to prevent endometrial hyperplasia. Many oral forms of estrogen are available (Table 2). Transdermal estradiol in patch form may be beneficial for women who do not tolerate or cannot take oral forms because of nausea (Table 3). The patch may also be clinically beneficial to women with syndrome X, or insulin resistance accompanied by elevated triglycerides. Transdermal estradiol does not increase triglyceride levels, whereas oral estrogen does. Menostar is an ultra, ultra low-dose estrogen patch (0.014 mg/day) that has recently been approved for unopposed estrogen use in postmenopausal women. It is indicated for bone protection only and does not offer any vasomotor symptom relief. Estrasorb lotion (0.05 mg/day) has been approved for vasomotor symptom control, and Estrogel (0.06% topical gel) has been approved for vasomotor symptoms and vulvar/vaginal atrophy.

Table 2: Oral Estrogens

© 2004 The Cleveland Clinic Foundation.

Table 3: Transdermal Estrogens

© 2004 The Cleveland Clinic Foundation.

Oral estrogen doses vary. The standard starting dose of oral conjugated equine estrogen (CEE) or synthetic conjugated estrogen is no longer 0.625 mg daily, although lower doses (e.g., 0.45 mg or 0.3 mg) may suffice. The dose can be adjusted higher or lower according to the woman's symptoms after 1 month of therapy. Higher doses of estrogen are often required in younger women who have undergone hysterectomy Based on the women's HOPE trial results, ultra-low doses of HT, such as 0.3 or 0.45 mg of CEE combined with ultra-low doses of medroxyprogesterone acetate (MPA, 1.5 mg), are effective for symptom control.

Some women favor estrogens such as conjugated equine estrogen (Premarin) that have been used clinically for more than 60 years. Other women, however, prefer "synthetic" forms of conjugated estrogens (e.g., Enjuvia) that are not derived from animal products. Women who cannot tolerate conjugated estrogens may do better with other forms of estrogen, such as bioidentical estrone (E1), micronized estradiol (E2), or transdermal estradiol (E2). Other women prefer oral estradiol (E2) (the most potent form of estrogen) that is found in Femtrace (doses of 0.45 mg, 0.9 mg, and 1.8 mg).

It is important to note that although all postmenopausal estrogens have been FDA approved to treat vasomotor and local GU atrophy, only some estrogens have been FDA approved to prevent postmenopausal osteoporosis (PMOP). Examples of ET and HT products that are FDA approved to prevent PMOP include Premarin, Prempro, Estrace, Ogen, Vivelle, Climara, femhrt, and Activella. The newest low-dose HT is femhrtLo; it may afford symptom control, but it does not necessarily provide bone protection-so women on low doses of HT should have their bone density monitored periodically.

Progesterone

Progesterone is produced naturally in the body from the corpus luteum after ovulation and functions to down-regulate estrogen receptors. Progestagens include progesterone and progestins, which are synthetic formulations that are better absorbed than is progesterone. (Although oral absorption is improved with micronized progesterone in oil.) Oral progestins can be taken on the first 12 days of each month (cyclic) or taken continuously throughout the entire month (Box 3). For cyclic therapy, 5 to 10 mg of MPA or 200 mg of micronized progesterone (Prometrium) is taken orally with food, in the evenings of days 1 through 12. Younger and heavier women may require more progestins. Generally cyclic therapy is used for recently menopausal women because the goal is to switch to "continuous combined" (daily estrogen and progestin) therapy to promote amenorrhea, which is favored in older women and in women who do not want any monthly bleeding. For continuous estrogen-progestin therapy, 2.5 to 5 mg of MPA is taken orally every day. If ultra-low doses of estrogen are used, then lower doses of daily PA can be used, such as 1.5 mg of MPA or 100 mg of Prometrium or 4% Prochieve vaginal gel. The NIH and NAMS recommend using the lowest effective dose of HT for the shortest duration of time consistent with the reason the woman is using HT, with periodic reassessments recommended.

MPA, medroxyprogesterone acetate.

Cyclic regimens often cause withdrawal bleeding, whereas continuous use over 6 months induces amenorrhea in the majority of users. If amenorrhea is not induced after 6 months of continuous therapy, an endometrial biopsy or at the least a transvaginal ultrasound should be strongly considered to assess the endometrial thickness. Endometrial stripes of over 5 mm in postmenopausal women are suspect. Heavy bleeding persisting for more than 1 week per month also warrants an endometrial biopsy. Progestins are also combined with estrogen in a transdermal patch (CombiPatch) or weekly Climara-Pro or in an oral pill formulation (Table 4). Newer progestins, such as drospirenone, which have been used in the oral contraceptives Yasmin and Yaz, are now available in combination with estradiol for postmenopausal women (Angeliq 1 mg of estradiol and 0.5 mg DSP) for HT.

Table 4: Combined Regimens

© 2004 The Cleveland Clinic Foundation.

Other Treatment Options

In addition to standard HT, many women prefer alternative therapies such as herbal medicines and vitamin therapies.

Some of the more popular therapies for hot flashes include black cohosh, dong quai, and evening primrose oil. Black cohosh (Remifemin) is approved by the German Commission E for only 6 months of use. This agent may help with menopausal vasomotor symptoms; however, no studies on long-term benefits or risks are available. In general, "alternative" or "natural" therapies appeal to many women. However, they are not well studied, and their long-term outcomes are unknown and none has been shown to be salutary to the skeleton or GU tract. Their long-term use cannot be safely recommended. Women need to be informed that "natural" or bio-identical does not necessarily equate with "safe and free from problems." Therapeutic options are covered in The North American Menopause Society online study guide and their consensus panel on the treatment of menopausal vasomotor symptoms. Future options for vasomotor symptom control may include norepinephrine serotonin reuptake inhibitors and combinations of estrogen or selective estrogen receptor modulators.

Summary

• Menopause is a normal life cycle event that may or may not be accompanied by symptoms and medical consequences.
• The skeleton and the GU tract (vagina and base of the bladder) are the most likely organ systems to be affected by lowered estrogen levels.
• The severity of menopausal symptoms varies, and the need for hormone therapy (HT) needs to be individualized and periodically assessed for risks and benefits to the individual woman.
• There are a multitude of estrogen and progestagens with various doses and routes of administration.

Suggested Readings

• American Society for Reproductive Medicine. asrm.org Accessed August 21, 2013.
• Anderson GL, Limacher M, Assaf AR, et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701–1712.
• Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormonal therapy on cognitive function: the Heart and Estrogen/Progestin Replacement Study. Am J Med 2002; 113:543–548.
• Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health (Larchmt) 2006; 15:35–44.
• National Osteoporosis Foundation website. nof.org. Accessed August 21, 2013.
• North American Menopause Society website. menopause.org. Accessed August 21, 2013.
• Stefanick ML, Anderson GL, Margolis KL, et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006; 295:1647–1657.
• Women's Health Initiative. National Institutes of Health. National Heart, Lung, and Blood Institute website. www.nhlbi.nih.gov/whi. Accessed August 21, 2013.