US Pharm. 2018;43(1):13-16.

Menopause is the cessation of menstruation in a woman, typically occurring between the ages of 45 and 55 years. Smokers and women with chronic diseases may experience earlier menopause.¹ This is a natural biological process, not a disease.

Menopause and perimenopause—the period of transition beginning 2 to 8 years before and lasting up to 1 year after a woman’s final menstrual period—occur because as women get older, the ovaries begin to shut down.¹ Eventually, ovaries stop producing estrogen and other hormones. Since the body has depended on these hormones for years, when hormone levels decrease, the changes are noticeable and may result in emotional reactions and bodily changes.² These may include physical symptoms, such as hot flashes, decreased energy levels, and sleep disruption, as well as mood-related symptoms, such as anxiety and depression. Over time, these symptoms gradually disappear.¹ Although menopause ends fertility, women can stay healthy, vital, and sexual. This article will briefly review the physiology and types of menopause, signs and symptoms, and symptomatic treatment.

PHYSIOLOGY

A human ovary has the largest number of gametocytes during the fifth month of gestation and has approximately 1 million gametocytes at birth. As a woman ages, normal openings or follicular tubes in the body are closed (atresia), which reduces the number of gametocytes. As a result, at the time of menopause a woman may have only a few hundred to a few thousand gametocytes left.¹ The ovary produces three hormones: estrogen, progesterone, and androgens. Among the estrogens, estrone (E1), estradiol (E2), and estriol (E3) are the three endogenously produced estrogens. Estradiol is the most potent natural estrogen and is produced during the monthly menstrual cycle. Although estrone is the dominant form of estrogen during menopause, it is produced in small quantities by the ovary and adrenal glands.²

Progesterone promotes thickening of the endometrium in preparation for a fertilized ovum, but in an anovulatory women, this hormone is not produced. This can lead to a buildup of the endometrium induced by estrogen, causing irregular menstrual bleeding in premenopausal women. Fluctuations and deficiencies in estrogen levels cause many of the menopausal signs and symptoms.³

Types of Menopause

There are several types of menopause and each depends on the cause and/or timing of the end of menstruation.⁴

Natural Menopause: This occurs when a woman's ovaries slowly stop functioning and, as a result, menstruation finally stops. For most women, this happens between the ages of 45 and 55 years. As the ovaries stop producing hormones like estrogen, progesterone, and testosterone, the body responds and adapts.

Premature or Early Menopause:  Premature menopause occurs when a woman stops menstruating before the age of 40. Early menopause is one that occurs before the age of 45. Besides surgery, there are many reasons a woman might go through menopause early, including smoking, heavy drinking, endocrine disorders, chemotherapy, chromosomal defects, autoimmune disease, and thyroid disease.

Surgical or Induced Menopause: Sometimes menopause is brought on by a deliberate action, such as surgery or medication that affects the ovaries. A hysterectomy or other surgery that removes or damages the ovaries will cause an abrupt menopause. Usually, women can anticipate this type of menopause and plan ahead for treating the sudden symptoms that result. A hysterectomy that removes only the uterus may not damage the ovaries and, therefore, will not cause menopause; surgical menopause results when the ovaries are also removed. Chemotherapy or radiation during cancer treatment will make the ovaries shut down and can cause temporary menopause.

Signs and Symptoms

Many tissues in the female body are rich in estrogen receptors. When estrogen levels decrease, a number of organs can be directly affected. Menopause signs and symptoms may be of early, intermediate, or late onset.^3-5

Changes in Menstrual Cycle: Monthly periods may not be as regular and may be shorter or longer in duration. Women may experience heavier- or lighter-than-usual bleeding, and there may be occasional spotting. If a period is missed, pregnancy must be ruled out. If there is no pregnancy, a missed period could indicate the onset of menopause. In addition, if spotting is seen after not having a monthly period for 12 consecutive months, a woman should talk to her doctor to rule out any serious conditions, such as cancer.^3-5

Hot Flashes: Many women complain of hot flashes as a primary menopausal symptom. Hot flashes can be a sudden feeling of heat, either in the upper portion of the body or all over. The face and neck might turn red, and a woman may feel sweaty or flushed. The intensity of a hot flash can range from mild to very strong, and may occasionally wake some women up at night. A hot flash generally lasts between 30 seconds and 10 minutes. Most women experience hot flashes for a year or two after their final menstrual period. Hot flashes may continue after menopause, but usually decrease in intensity over time.^3-5

Vaginal Dryness: The decreased production of estrogen and progesterone can affect the thin layer of moisture that coats the vaginal walls. Women can experience vaginal dryness at any age, but it can be a particular problem for women going through menopause. It is also common to feel less interested in sex during menopause. This is caused by physical changes brought on by reduced estrogen. Sexual activity can increase blood flow to the vaginal area, which in turn keeps the vagina more lubricated and may help prevent vaginal atrophy.^3-5

Vulvar Itching: Signs can include itching around the vulva and stinging or burning. Vaginal dryness can make intercourse painful and may cause women to feel like they need to urinate frequently. To combat dryness, a water-based lubricant or a vaginal moisturizer can help.^3-5

Sleep Disturbances: During menopause, some women may find it hard to fall asleep or stay asleep. A woman may wake up earlier than she wishes and have trouble going to back to sleep. Relaxation and breathing techniques may promote better sleep. Bathing, reading, or listening to soft music before bed may help with relaxation. It is also important to exercise during the day. Going to bed at the same time every night, taking steps to stay cool while sleeping, and avoiding foods and drinks like chocolate, caffeine, or alcohol may help improve sleep.^3-5

Urinary Tract Infections: During menopause, some women may experience more urinary tract infections. Lowered levels of estrogen and changes in the urinary tract make women more susceptible to infection. The persistent urge to urinate, urinating more frequently, or feeling a burning sensation are signs of infection; antibiotics may be needed.^3-5

Vaginal Atrophy: Vaginal atrophy is a condition caused by the decline in estrogen production and characterized by the thinning and inflammation of the vaginal walls. The condition can make sexual intercourse painful for some women, which can ultimately decrease interest in sex. OTC lubricants or prescription treatments that include localized estrogen therapy, such as an estrogen cream or a vaginal ring, can treat the condition.^3-5

Mood Symptoms: Declining estrogen levels associated with menopause can cause more than hot flashes. Some of the mood changes experienced by women undergoing menopause may include irritability, feelings of sadness, lack of motivation, anxiety, aggressiveness, difficulty concentrating, fatigue, changeable moods, and tension. Although there are other conditions that can cause women to feel sad or irritable, these feelings are common emotional symptoms of menopause. Often, they can be managed through lifestyle changes such as relaxation training and stress reduction with yoga and breathing techniques.^3-5

Osteoporosis: There is a direct relationship between the lack of estrogen after menopause and the development of osteoporosis. After menopause, bone resorption (breakdown) overtakes the building of new bone. Early menopause (before age 45 years) and any long phases in which a woman has low hormone levels and no, or infrequent, menstrual periods can cause loss of bone mass. A women may not know she has osteoporosis until her bones become so weak that a sudden strain, bump, or fall causes a fracture or a vertebra to collapse. A collapsed vertebra after menopause may first be noticed when a woman suffers back pain, loss of height, or spinal deformities. In addition to menopause, other risk factors for osteoporosis are age, gender, race, bone structure, body weight, and family history.^3-5

Menopausal hormone therapy is believed to be useful in preventing or decreasing the increased rate of bone loss, especially in early menopause; however, it is associated with some risk factors such as breast cancer, blood clots, and high blood pressure in some women.^3-5

Cardiovascular Symptoms: The incidence of cardiovascular disease 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. A decline in estrogen may be a factor in heart disease increase among postmenopausal women. Estrogen is believed to have a positive effect on the inner layer of the artery wall, helping to keep blood vessels flexible. That means they can relax and expand to accommodate blood flow. Despite the benefits of estrogen, the American Heart Association recommends against using postmenopausal hormone therapy to reduce the risk of coronary heart disease or stroke, because some studies have shown that it might not reduce the risk.⁶ It is important to note that estrogen decline is not the only reason women face a higher cardiovascular disease risk after reaching menopause.^3-6

Skin and Hair: Loss of fatty tissue and collagen will make the skin drier and thinner, and will affect the elasticity and lubrication of the skin near their vagina and urinary tract. Reduced estrogen may contribute to hair loss or cause hair to feel brittle and dry. Harsh chemical hair treatments may cause further damage.^3-5

TREATMENT

Menopause treatments focus on relieving the signs and symptoms and preventing or managing chronic conditions that may occur with aging. Treatments may include those listed below.^7-10

Menopausal Hormone Therapy

There are two basic types of hormone therapy:

Estrogen-only Therapy: Estrogen is the hormone that provides the most relief for menopausal symptoms. Estrogen is prescribed for women without a uterus owing to a hysterectomy.^7-10

Combined Estrogen-plus-Progestogen Therapy: Progestogen is added to protect women with a uterus against uterine (endometrial) cancer from estrogen alone. Combined estrogen/progestogen therapy, but not estrogen alone, increases the risk of breast cancer when used for more than 3 to 5 years. Therefore, in women with a uterus, it is currently recommended that physicians prescribe combination therapy only to treat menopausal symptoms such as vasomotor symptoms (hot flashes) and vaginal atrophy, using the smallest effective dosage for the shortest possible duration. All types and routes of estrogen are effective for relieving menopausal symptoms, particularly hot flashes. Conjugated estrogen 0.625 mg/day and 17-beta estradiol (oral 1 mg/day or transdermal 0.05 mg/day) have been reported to be equally effective for the treatment of hot flashes.¹¹ These doses completely eliminate hot flashes in about 80% of women and reduce the frequency and severity in the remainder.^7-10

Depending on the personal and family medical history, physicians may recommend estrogen in the lowest dosage and the shortest time frame needed to provide symptom relief. Estrogen also helps prevent bone loss. Long-term use of hormone therapy may have some cardiovascular and breast cancer risks, but starting hormones around the time of menopause has shown benefits for some women. To relieve vaginal dryness, estrogen can be administered directly to the vagina using a vaginal cream. This treatment releases just a small amount of estrogen, which is absorbed by the vaginal tissues.^7-10

Other Treatments

Low-dose Antidepressants: Selective serotonin reuptake inhibitors are effective for perimenopausal depression, and some provide modest benefit for hot flashes as well. Data also suggest that adding estrogen to antidepressant therapy may result in additional benefit for perimenopausal women with depression.¹¹ A low-dose antidepressant such as fluoxetine or sertraline for management of hot flashes may be useful for women who cannot take estrogen for health reasons or for women who need an antidepressant for a mood disorder. In June 2013, the FDA approved paroxetine mesylate (Brisdelle) as the first nonhormonal therapy for vasomotor symptoms (hot flashes) associated with menopause.^7-10

Gabapentin (Neurontin): Gabapentin is approved to treat seizures, but it has also been shown to help reduce hot flashes. This drug is useful in women who cannot use estrogen therapy and in those who also have nighttime hot flashes. Gabapentin 300 mg three times daily is prescribed for menopausal hot flashes as well as mood disturbances.^7-10

Ospemifene (Osphena): This medicine is similar to estrogen, but it is not an estrogen (it is an estrogen agonist/antagonist with tissue-selective effects). It is available in pill form and is taken once a day. It helps relieve vaginal dryness caused by menopause, but it can also cause hot flashes. It is for women who have trouble using vaginal estrogen or prefer to not use vaginal medicine.^7-10

Osteoporosis Medications: Depending on individual needs, doctors may recommend medication to prevent or treat osteoporosis. Several medications, such as bisphosphonates, (e.g., alendronate) are available that help reduce bone loss and risk of fractures. Physicians may prescribe vitamin D supplements to help strengthen bones.^7-10

Plant Estrogens (Phytoestrogens): These estrogens occur naturally in certain foods. There are two main types of phytoestrogens—isoflavones and lignans. Isoflavones are found in soybeans, lentils, chickpeas, and other legumes. Lignans occur in flaxseed, whole grains, and some fruits and vegetables. Although they are used in many people to relieve hot flashes, most studies have found them ineffective.¹² Isoflavones have some weak estrogen-like effects, so women who have had breast cancer should consult with their physicians before using them.

CONCLUSION

Although estrogen is the most effective treatment for hot flashes, nonhormonal alternatives such as low-dose paroxetine, venlafaxine, and gabapentin are effective alternatives. Women with a uterus who are using estrogen should also take a progestogen to reduce the risk of endometrial cancer. Many reports suggest modest improvement in hot flashes and vaginal dryness with soy products. Patients with genitourinary syndrome of menopause may benefit from vaginal estrogen or nonhormonal vaginal moisturizers. The decision to use hormone therapy depends on clinical presentation and a thorough evaluation of the risks and benefits with patient.

REFERENCES

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2. The North American Menopause Society (NAMS). Clinical evaluation and counseling. In: Bilancini AM, ed. Menopause Practice: A Clinicians Guide. 4th ed. Mayfield Heights, OH: The North American Menopause Society. 2010:170-194.
3. Grady D, Barrett-Connor E. Menopause. In L Goldman, A Shafer, eds., Goldman’s Cecil Medicine, 24th ed. Philadelphia, PA: Saunders. 2012;1565-1571.
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6. American Heart Association. Menopause and heart disease. Updated June 23, 2017. www.heart.org/Conditions/More/MyHeartandStrokeNews/Menopause-and-Heart-Disease_UCM_448432_Article.jsp#.WkQFgmQ-eqQ. Accessed December 27, 2017.
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8. Hill AD, Crider M. Hormone therapy and other treatments for symptoms of menopause. Am Fam Physician. 2016;94(11):884-889.
9. Guttuso T, Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101:337-345.
10. Canonico M. Hormone therapy and hemostasis among postmenopausal women: a review. Menopause. 2014;21(7):753-762.
11. Martin KA, Barbieri RL.  Treatment of menopausal symptoms with hormone therapy. UpToDate. Updated November 21, 2017. www.uptodate.com/contents/treatment-of-menopausal-symptoms-with- hormone-therapy. Accessed December 27, 2017.
12. Physicians Committee for Responsible Medicine. Food for life cancer project. Ask the expert: soy. www.pcrm.org/health/cancer-resources/ask/as-the-expert-soy. Accessed December 27, 2017.

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