Menopause is defined as the absence of menses for one year. During this time, estrogen, progesterone and ovarian androgens are diminished due to adult-onset ovarian failure.¹ Women usually experience menopause between 40 and 55 years old, with the median age being 51 for non-smokers.^2,3 (Figure 1) Smokers and women with chronic illnesses tend to experience menopause at an earlier age (Table 1).

Perimenopause is comprised of fluctuating ovarian function and occurs 2 to 8 years prior to menopause and up to 1 year after the final menses.² It is a progressive process that eventually leads to persistent ovarian failure.¹ 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, neuroendocrine, cardiovascular and skeletal. The term "menopause transition" is often used interchangeably with perimenopause.

Premature ovarian insufficiency (POI) is the cessation of ovarian function prior to the age of 40. It occurs in less than 1% of all women.³ There are many reasons for amenorrhea in addition to primary ovarian failure.

Secondary causes of POI include chromosomal abnormalities (eg, Fragile X Syndrome), autoimmune disorders, physical insults to the ovaries, isolated ovarian antibodies and gonadotropic receptor defects.³ Pregnancy must always be considered in the differential diagnosis of secondary amenorrhea.

The North American Menopause Society has published an online study guide related to menopause. Section A covers definitions and epidemiology.

Women not only live long enough to experience the menopause transition, they live approximately 30 years beyond it. Presently in the U.S., there are approximately 35 million postmenopausal women.¹ These staggering numbers have prompted a great deal of interest and concern in the area of menopause from the medical community and the lay public.

Physicians are often expected to be well-versed in the physiology of menopause, its associated conditions and symptoms, and its diagnosis and treatment.

A female ovary has the greatest number of oocytes during the fifth month of gestation and has about 1-2 million 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 only have 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 3 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 build-up of the endometrium, causing irregular menstrual bleeding in the perimenopausal phase.

Menstruation
Menarche, or the first menses, usually begins around the age of 12. It is divided into 3 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, while estrogen levels decrease.

Formation of a corpus luteum begins the secretory phase, in which estrogen, progesterone and androgens are secreted. Estrogen promotes cellular proliferation, while 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). 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.

Various tissues throughout the body are rich in estrogen receptors. When estrogen levels decrease or fluctuate, a number of systems can be directly affected: (Table 2)

Vasomotor and Neuroendocrine
Hot flashes are common among perimenopausal women. 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.² 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. The World Health Organization describes menopausal symptoms and their treatment in its Progress in Human Reproduction newsletter.

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 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 may postcoital bleeding, pruritus vulvae and discomfort during routine pelvic exams.³ Women may also experience sexual dysfunction and a decreased libido.

An 8-year study by Australian researchers explored the relationship between female aging and sexual function. A summary of the study findings is published on the American Society for Reproductive Medicine web site.⁴

Skeletal
Bone mass peaks at the age of 30 and starts to decline thereafter. This decline accelerates throughout the perimenopausal and menopausal years. Genetics, estrogen status, exercise, calcium and vitamin D intake all play a significant role 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
The incidence of cardiovascular disease increases after menopause. Specifically, the risk of coronary heart disease is 2-3 times higher for postmenopausal women compared to premenopausal women of the same age.5 Alarmingly, after the age of 65, 1 out of every 3 women has some form of cardiovascular disease (CVD).6 Hormone therapy (HT) is no longer used to prevent CVD.^7,8

Women undergoing perimenopausal 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 may access information about menopause through a variety of sources including friends, family, the Internet, television and other forms of media.

The initial evaluation by the health care provider should include a comprehensive history and physical exam accompanied by select laboratory studies and patient education. In addition, family, social, sexual and medication histories are imperative. A complete physical exam might provide diagnostic clues to a woman's menopausal state. For example, a loss of height might suggest osteoporosis and a pelvic exam might reveal vaginal atrophy from lack of estrogen. Baseline labs should also be performed including a screening thyroid stimulating hormone (TSH). During perimenopause, 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.^1,3 Although in this setting, an FSH is rarely needed to confirm the post-menopausal state. If a woman has taken oral contraceptives during the perimenopausal period, she must be taken off of 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.¹ Testosterone and dihydroepiandrosterone (DHEA) levels are only indicated if a woman has symptoms of hyperandrogenism or if she is taking over-the-counter hormones that may contain these potent androgens.

THERAPY

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.⁹ 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 in which the use of HT is not recommended.

Contraindications to HT:

Absolute contraindications to HT include pregnancy, an active venous thrombosis or embolism, undiagnosed vaginal bleeding, active liver disease, and active breast or endometrial cancer and active cardiovascular disease.²

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.^1,2,10 When considering the use of HT, risks and benefits must be weighed.

Risks of HT:

Thromboembolism
There is an increased risk of developing thromboembolism associated with HT use. It is estimated that the incidence of deep vein thrombosis (DVT) or pulmonary embolus (PE) occurs in 3/10,000 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.^1,3,7 In the WHI, the risk of venous thromboembolism (VTE) persisted in subsequent years.⁷ A more recent randomized trial revealed a higher incidence of VTE in HT users, specifically in women who were older in age and overweight/obese.¹¹ The type of estrogen a woman takes may also influence her risk for VTE. For example, a recent study revealed that conjugated equine estrogen (CEE) was associated with a risk for VTE; however, esterified estrogen was not.¹²

Gall Bladder Disease
A slight increase in the incidence of gall bladder disease is noticed in women on HT. The Heart and Estrogen-Progestin Replacement Study (HERS) trial revealed that women with coronary artery disease had a 40% increased risk for developing symptomatic gall bladder disease while on HT.^1,3,10

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 alone ("unopposed estrogen"). Current therapeutic regimens recommend that women on HT with intact uteri receive combinations of estrogen and progestin. This will decrease the risk of endometrial cancer to slightly less than the spontaneous occurrence rate in non-HT users.¹

Breast Cancer
The increase in the relative risk of developing breast cancer associated with long-term (over 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 (CI 1.0-1.56).⁷ 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.¹ 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 years may have a 30% increased risk of a breast cancer diagnosis.^1-3,7,10 There is no prospective randomized controlled studies showing that women on HT are more likely to die of breast cancer. Additional information about the study is available on the National Heart, Lung, and Blood Institute's web site.¹³ The estrogen only arm of the WHI showed NO increased risk of breast cancer in women with a hysterectomy in taking estrogen alone.⁵

Systemic Lupus Erythematosis
The risk of developing lupus is also increased with HT use. The Nurse's Health Study suggested that the relative risk was doubled in women using HT.^2,3

Benefits of HT:

Vasomotor Symptoms
HT is very effective in the treatment of hot flashes. 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.^1,3,10

Osteoporosis
HT 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.⁷ Most women take HT for less than two years; therefore, women with osteoporosis/low bone mass need alternative treatments. In addition to taking estrogen, it is recommended that women take 1200 mg of calcium a day. If a woman is not on HT, or is greater than 65 years old, 1500 mg of calcium daily is recommended.¹ A clinical practice guideline for osteoporosis appears on the National Osteoporosis Foundation web site.¹⁴

Vaginal Atrophy
HT has been shown to improve the symptoms of vaginal atrophy in the intravaginal, oral and transdermal forms. Often, the intravaginal route is most effective, as higher doses of estrogen are directly delivered to the vaginal mucosa.³

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 pills.¹⁵ In addition, the WHI memory study revealed that HT did not prevent mild cognitive impairment and in fact, doubled the relative risk of dementia.¹⁶

Others
The WHI showed less risk of colon cancer with HT, hazard ratio 0.63 (CI 0.43-0.92)⁷ but a more advanced stage when diagnosed. HT appears to have no effect in ovarian cancer risk.

Hormone Therapy:

Estrogen
Estrogen is given orally, vaginally or transdermally. Women with genitourinary atrophy may benefit from intravaginal estrogen therapy, used with or without standard HT (Table 3). Signs and symptoms of urogenital or vaginal atrophy can be assessed by visual inspection at the routine pelvic exam every 1-2 years.

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 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 genitourinary symptoms. The Femring is now available and gives both local and systemic estrogen to hysterectomized women.

The use of intravaginal estrogen creams and tablets may periodically necessitate evaluation of the endometrium with an outpatient endometrial pipelle biopsy, as some of this estrogen is systemically absorbed and may stimulate endometrial growth. Estrogen therapy in a woman with an intact uterus must be accompanied by a progestin to prevent endometrial hyperplasia.² Many oral forms of estrogen are available (Table 4). Transdermal estradiol in patch form may be beneficial for women who do not tolerate or cannot take oral forms due to nausea (Table 5). 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.¹⁷ Estrasorb lotion (0.05 mg/day) has been approved for vasomotor symptom control and Estrogel (0.06%) has been approved for vasomotor symptoms and vulvar/vaginal atrophy.^18,19

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 rather lower doses like 0.45 mg or 0.3 mg may suffice. The dose can be adjusted higher or lower according to the woman's symptoms after one month of therapy. Higher doses of estrogen are often required in younger women who have been surgically castrated. 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 medroxy-progesterone acetate (MPA), are used more frequently for symptom control.^1-3

Some women favor more "natural" estrogens like conjugated equine estrogen (Premarin) that has been used clinically for over 6 decades. Other women, however, prefer "synthetic forms" of conjugated estrogens (Cenestin) that are not derived from animal products. Women who cannot tolerate conjugated estrogens may do better with other forms of estrogen, such as estrone E3, micronized estradiol E2, esterified estrogens, or transdermal E2. It is important to note that while 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 products approved to prevent PMOP include Premarin, Prempro, Estrace, Ogen, Vivelle, Climara, FemHRT, Activella and Prefest.

Progesterone
Progesterone is produced naturally in the body and functions to down-regulate estrogen receptors. Progestins are synthetic formulations that are better absorbed than "natural," micronized progesterone. Oral progestins can be taken on the first 12 days of each month ("cyclic") or continuously throughout the entire month (Table 6). For cyclic therapy, 5-10 mg of medroxyprogesterone acetate (MPA) or 200 mg of micronized progesterone (Prometrium) is taken orally with food, in the evenings of days 1-12. Younger and heavier women may require more progestins. Generally cyclic therapy is used for recently menopausal women, as 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 MPA 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 hormone therapy for the shortest duration of time consistent with the reason the woman is using hormone therapy.

Cyclic regimens often cause withdrawal bleeding, while continuous use over 6 months induces amenorrhea in the majority of users.² If amenorrhea is not induced after 6 months of continuous therapy, an endometrial biopsy or at 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 7).

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 so-called "natural" therapies appeal to many women. However, they are not well studied, and their long-term outcomes are unknown and none have been shown to be salutary in the skeleton. Therefore, their long-term use cannot be safely recommended. Women need to be informed that "natural" does not necessarily equate with "safe and free from problems." Therapeutic options are covered in The North American Menopause Society online study guide⁹ and their consensus panel on the treatment of menopausal vasomotor symptoms.²⁰

1. American Association of Clinical Endocrinologists. AACE medical guidelines for clinical practice for management of menopause. Endocrine Practice. 1999;5:355-366.
   
   
2. Greendale GA, Lee NP, Arriola ER. The menopause. Lancet. 1999;353:571-580.
   
   
3. Johnson SR. Menopause and hormone replacement therapy. Med Clin North Am. 1998;82:297-320.
   
   
4. www.asrm.org. The web site of the American Society for Reproductive Medicine. Includes information regarding reproductive medicine and biology.
   
   
5. American Heart Association. Heart Disease and Stroke Statistics-2003 Update. Dallas, TX: American Heart Association; 2002.
   
   
6. Eaker ED, Chesebro JH, Sacks FM, Wenger NK, Whisnant JP, Winston M. Cardiovascular disease in women. Circulation. 1993;88:1999-2009.
   
   
7. Writing group for the WHI Investigators. Risks and benefits of estrogen plus progestin in healthy, postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
   
   
8. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-12.
   
   
9. www.menopause.org. The web site of The North American Menopause Society. Includes comprehensive information about menopause.
   
   
10. McNagny S. Prescribing hormone replacement therapy for menopause symptoms. Ann Intern Med. 1999;131:605-613.
    
    
11. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-80.
    
    
12. Smith NL, Heckbert SR, Lemaitre RN, et al. Esterified estrogens and conjugated equine estrogens and the risk for venous thrombosis. JAMA. 2004;292:1581-7.
    
    
13. www.nhlbi.nih.gov. The web site of the National Institutes of Health, the National Heart, Lung, and Blood Institute and the Women's Health Initiative. Provides comprehensive information regarding the Women's Health Initiative, one of the largest preventive health studies in the US.
    
    
14. www.nof.org. The web site of the National Osteoporosis Foundation. Includes comprehensive information about osteoporosis evaluation, diagnosis and treatment.
    
    
15. Grady D. Effect of postmenopausal hormonal therapy on cognitive function: the hormone therapy and estrogen/progesterone replacement study. Amer J Med. 2002;113:543-8.
    
    
16. Shumaker SA, Legault C, Rapp SR, et. al. Estrogen plus progestin and the incidence and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2651-62.
    
    
17. Menostar: a low-dose estrogen patch for osteoporosis. Obstetrics and Gynecology. 2005;105:432-3.
    
    
18. Estradiol-topical--Novavax: Estrasorb. Drugs in R & D. 2003;4:49-51.
    
    
19. Archer DF, EstroGel Study Group. Percutaneous 17 beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003;10:516-21.
    
    
20. NAMS position paper on menopausal symptoms. Menopause. 2004.