Menopause

Etiology

As women grow older, their ovarian follicles diminish in number. There is a decline in granulosa cells of the ovary, which were the main producers of estradiol and inhibin. With the lack of inhibition from estrogen and inhibin on gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production increases. FSH levels are usually higher than LH levels because LH is cleared from the blood faster. The decline in estrogen levels disrupts the hypothalamic-pituitary-ovarian axis. As a result, a failure of endometrial development occurs, causing irregular menstrual cycles until they stop altogether.

Menopause may occur due to surgical procedures such as a hysterectomy with bilateral oophorectomy. Menopause can be caused by treatment for certain conditions, like endometriosis and breast cancer with antiestrogens and other cancers due to chemotherapy medications.

Epidemiology

In the United States, approximately 1.3 million women become menopausal each year. It typically begins between the ages of 51 and 52. However, about 5% of women experience early menopause between the ages of 40 and 45. Additionally, 1% of women experience premature menopause before the age of 40 due to permanent ovarian failure that may be associated with sex chromosome abnormalities.[4]

Pathophysiology

Menopause is a normal physiologic process in aging women in which the number of ovarian primary follicles quickly diminishes, such that there are inadequate amounts to respond to the effects of FSH. In turn, there is no LH surge, and ovulation does not take place, resulting in the decline of estrogen production and the cessation of menstruation. Moreover, LH and FSH go uninhibited and remain at high levels years after the onset of menopause. Small amounts of estrogen may still be produced via conversion from testosterone released by the adrenal glands, such that symptoms other than the discontinuation of periods may be negligible in some individuals.[5]

Histopathology

During menopause, histopathology is focused on the ovaries, urogenital, bones, and arteries.

Ovaries

In menopause, follicles age, and the 2 structures of the ovaries (cortex and medulla) change. The cortex becomes thinner, such that the distinction between the cortex and medulla is less evident.  The cortex also has fewer follicles, and there is a tendency toward the fragmentation of the corpora arenacea. Additionally, there are invaginations of the surface epithelium of the cortex, and epithelial inclusion cysts are present. The medulla develops stromal fibrosis and scars. The medulla also undergoes the hyalinization of vessel walls, with architectural changes of vessels.

Urogenital

There is also a significant change in the vagina during menopause. The vagina has several epithelial layers: mucosa (most superficial), muscularis, and the adventitia (deepest). The mucosa layer of the vagina begins to atrophy due to decreased estrogen, which causes this cell layer to become drier and thinner. As a result, the vaginal mucosa loses its elasticity and becomes fragile.

Bone

Healthy normal bone is constantly remodeling via a 5-step process, which involves resorption (via osteoclasts) and production (via osteoblasts). During menopause, estrogen deficiency increases osteoclastic activity, such that there is an imbalance of osteoclastic and osteoblastic activity. This results in more bone being reabsorbed and overall bone loss.  Estrogen deficiency leads to the release of cytokines, among them RANKK ligand (RANKL), which plays a critical role in the osteoclastogenesis cascade.

Arteries

An artery consists of 3 layers, the tunica intima (surrounding the lumen), tunica media, and tunica adventitia. Estrogen is believed to have a positive effect on the tunica intima of the artery wall, helping to keep blood vessels flexible. During menopause, estrogen deficiency causes vasoconstriction of the vessel wall and an accelerated increase of low-density lipoprotein (LDL). Thus, menopause is linked to the increased risk of cardiovascular disease, which can be denoted by increased intima-media thickness.

History and Physical

The history will include symptoms related to estrogen deficiency. The obvious symptom is the cessation of menses, typically heralded by changes in the menstrual cycle.

Vasomotor Symptoms

Approximately 75% of women experience vasomotor symptoms. These symptoms include hot flashes, night sweats, palpitations, and migraines. Hot flashes often last approximately three to four minutes at unpredictable intervals. They may be worsened by alcohol, eating, emotional stress, and exertion. Migraines may change in intensity and severity. Migraines without aura are more common than migraines with aura. Migraines with aura have an increased risk of stroke, especially if women smoke or use oral contraceptives. Other types of headaches, such as cluster and tension headaches, may also increase with a change in hormone levels.

Urogenital Symptoms

Approximately 60% of women experience urogenital symptoms. These symptoms include vaginal atrophy, urethral atrophy, and sexual dysfunction (i.e., a decline in libido).  Vaginal atrophy results in dryness, pruritus, and dyspareunia (painful intercourse). Urethral atrophy results in stress incontinence, frequency, urgency, and dysuria.  

Psychogenic Symptoms

Approximately 45% of women experience psychogenic symptoms. These symptoms include anger/irritability, anxiety/tension, depression, sleep disturbance, loss of concentration, and loss of self-esteem/confidence. 

Physical Examination

Should include measurement of blood pressure, weight, and height, breast palpation, vaginal examination, and Pap smear. 

• Blood Pressure: Elevated blood pressure may be noted resulting from arterial vasoconstriction.  
• Weight and Height: Weight gain may be noted, as many women report some degree of weight gain during menopause. The North American Menopause Society stated women gained an average of 5 pounds (2 kg) over the menopause transitional period. Additionally, a decrease in height may be noted, associated with osteoporosis and spine fractures. 
• Breast and vagina: Breast palpation usually notes decreased breast size. The vaginal examination notes dryness and urogenital atrophy. Abnormal uterine bleeding is an indication to perform a pap smear.

Evaluation

Generally, no laboratory tests are required for the diagnosis of menopause. The diagnosis is clinically based on the patient's age, symptoms, and ruling out other conditions for patients older than 45 years old. Furthermore, symptoms may precede changes in laboratory values. However, an elevated serum FSH (greater than 40 mIU/mL) can be indicative of menopause (via ovarian failure), although it is insensitive. Additionally, drugs like estrogens, androgens, and hormonal contraceptives may alter lab results.

The United States Preventive Services Tasks Force suggests starting screening for osteoporosis at age 65 if normal risk factors are present. If osteoporosis is a concern (i.e., falls, fractures, medications), a dual-energy x-ray absorptiometry (DEXA) scan can be done. A T-score on DEXA of 1.0 to 2.5 is indicative of osteopenia, while a T-score greater than 2.5 is indicative of osteoporosis.

Treatment / Management

Menopause treatment and management revolve around minimizing disruptive symptoms and preventing long-term complications.[5][6][7][8](A1)

Hormonal Treatment

Hormone therapy can treat vasomotor symptoms and prevent vaginal/urogenital atrophy, as well as preserve an advantageous lipoprotein profile and prevent bone loss. It can be given in various forms (i.e., tablets, creams, patches), in different modalities (i.e., continuous versus cyclic), and is available as systemic estrogen, estrogen-progestin, estrogen-bazedoxifene, progestin alone, or combined oral contraceptives. The use of unopposed estrogen may cause uterine hyperplasia and uterine cancer; therefore, should be avoided in women with a uterus. The cyclical administration of combination estrogen-progestin therapy is recommended for women with an intact uterus.  It significantly decreases the severity and frequency of hot flashes and improves urogenital atrophy and sleep disturbances. It is also useful in preventing osteoporosis and associated fractures. However, hormone therapy should only be used for the shortest duration of time and at its lowest effective dose, as it increases the relative risk of breast cancer, ovarian cancer, thromboembolism, stroke, and coronary heart disease. There is an increased breast cancer risk after 3 to 5 years with estrogen-progestin and 7 years with estrogen only. It is contraindicated in those with a history of breast cancer, endometrial cancer, deep vein thrombosis, pulmonary embolism, liver disease, unexplained vaginal bleeding, and coronary heart disease. For atrophic vaginitis, in particular, systemic or vaginal estrogen can be utilized; however, localized estrogen therapy at very low doses is preferable when there are no other systemic symptoms. The use of localized estrogen therapy (via vaginal rings, creams, or tablets) has been shown to enhance blood flow and reverse vaginal atrophy. However, this also carries a small risk of venous thromboembolism. 

Selective Estrogen Receptor Modulators (SERMs)

Selective estrogen receptor modulators, such as raloxifene, bazedoxifene, and ospemifene, have the ability to modulate estrogen action without stimulating endometrial growth or increasing the risk of cancer. SERMs have the same outcome as hormone therapy in preventing bone loss and promoting beneficial lipoprotein levels. Raloxifene acts as an estrogen agonist (pro-estrogen) on bone and lipids and like an estrogen antagonist (anti-estrogen) on the uterus and breast. Thus, it is effective in preventing/treating mild osteoporosis and decreasing serum LDL. Having a similar profile to raloxifene, bazedoxifene, when combined with estrogen, does not influence the endometrium (i.e., women with a uterus do not need to take progestin). Thus, when combined with estrogen, it is effective in treating vasomotor symptoms like hot flashes. Ospemifene is a newer SERM that is effective in treating urogenital symptoms, such as vaginal dryness.

Non-Hormonal Treatment

Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, and clonidine. These treatments can be used for short durations (a few months) for menopause symptoms. SSRIs and SNRIs, like paroxetine and venlafaxine, are antidepressants that treat vasomotor symptoms, such as hot flashes and result in one fewer hot flashes a day. Paroxetine, in particular, is the only FDA-approved drug for this indication, and symptoms diminish within a week of initiating treatment. While neither is FDA-approved for the treatment of vasomotor symptoms, both gabapentin and clonidine have been shown to reduce hot flashes in menopausal women. Gabapentin reduces hot flashes by up to 2 hot flashes per day, and clonidine is most effective in mild hot flashes, as it is less effective than SSRIs/SNRIs and gabapentin.

Osteoporosis-Specific

For menopausal women experiencing osteoporosis alone, bisphosphonates, denosumab, and supplementation with calcium and vitamin D can be utilized. Bisphosphonates inhibit osteoclast action and resorption of bone. They have been shown to be safe and efficacious in treating osteoporosis. However, at high doses and over a prolonged period, there may be a risk of developing adynamic bone. For this reason, periodic discontinuation of this drug is recommended, as bone density is retained for quite a few years. Denosumab is an antibody to RANKL. It inhibits the osteoclasts and their activity, such that bone resorption is decreased and bone density is increased. In turn, it is reducing the risk of fractures in menopausal women with osteoporosis (via biannual subcutaneous treatment).

Nonprescription Remedies

A proper diet can ease symptoms and prevent some complications. Complementary and alternative treatments include phytoestrogens, vitamin E, and omega-3 fatty acids. Vitamin E and omega-3 fatty acids have been used to treat the vasomotor symptoms of menopause. They are generally safe; however, studies have shown that they are no better than placebo. Phytoestrogens like soy, red clover, and black cohosh have also been safely used to treat menopause symptoms. Though studies on black cohosh have shown mixed results when treating hot flashes, soy and red clover have been shown to be effective in treating osteoporosis and high cholesterol.

Differential Diagnosis

If menopause occurs at 45 years of age or older, a diagnosis of menopausal can be made clinically with no testing. In younger women, it is necessary to exclude other diagnoses that cause secondary amenorrhea. The most common cause of amenorrhea is pregnancy, and it should be ruled out first.

• Anatomic defects: Other causes of amenorrhea can be from anatomic defects, such as Asherman’s syndrome, the scarring of the uterine cavity after a dilation and curettage (D and C) procedure. Obstruction of the uterine outflow tract is another anatomic defect. In addition, infections and scarring (i.e., tuberculosis) can cause anatomic defects.
• Hypothalamic-pituitary-gonadal axis: Amenorrhea can also result from a dysfunction in the hypothalamic-pituitary-gonadal axis. For this reason, hypothalamic dysfunction should be examined. Obesity, malignancy, and anorexia nervosa should be considered as they can cause hypothalamic deficiency. Pituitary dysfunctions, such as hyperprolactinemia, Sheehan syndrome (necrosis of the anterior pituitary), and pituitary adenoma should be worked up. Ovarian dysfunctions like ovarian tumors, polycystic ovarian disease, and premature ovarian failure.
• Endocrine gland disorders: Amenorrhea can also result from other endocrine gland disorders, such as thyroid dysfunction, which is the most common endocrine gland disorder. Also, consider adrenal gland disorders such as congenital adrenal hyperplasia and Cushing disease/syndrome.

Staging

During the Stages of Reproductive Aging Workshop (STRAW) in 2011, the STRAW+10 staging system was established. Since then, this system has become the gold standard in the staging of menopause. Its principal criteria rely on the menstrual cycle (with supportive criteria being lab work) and divide the female reproductive cycle into 3 categories: reproductive, menopause transition, and post-menopause.

Reproductive

During the reproductive stage, the menstrual cycle is regular. There may be variability earlier on following menarche, as well as slight changes to flow (lighter or heavier) and duration (shorter or longer) before entering the next stage. Supportive lab work may be done during the late reproductive stage and typically conveys low to variable levels of FSH when blood is drawn between days 2 and 5 of the cycle.

Menopausal Transition

The menopausal transition stage is where perimenopause primarily occurs. Earlier on in this stage, the menstrual cycle undergoes variability in its duration, such that the length of time between menstruations differs by 7 or more days each cycle. As this stage progresses, women typically experience amenorrhea for a period of 60 or more days. Once this occurs, women are in the late menopausal transition, which takes place for 1 to 3 years. Supportive lab work may show a variable elevated FSH level earlier on in the menopausal transition stage and an elevated FSH greater than 25 IU/L later on. The FSH greater than 25 IU/L is due to the decline of estrogen. At this stage, women may likely experience vasomotor symptoms.

Post-Menopause

During the post-menopause state, menstruation has ceased. Perimenopause continues until there has been no menstruation for 1 year. Then early post-menopause continues for another year. Supportive lab work conveys that this interval of time is characterized by an elevated FSH level greater than 40 IU/L, in which women are more likely to experience vasomotor symptoms. As the post-menopause stage progresses, lab work indicates that FSH levels stabilize and antral follicle count is very low. After 3 to 6 years, women enter into late post-menopause, in which they may experience more symptoms of urogenital atrophy.

Prognosis

If untreated, vasomotor symptoms will eventually dissipate after approximately 7.4 years on average. Additionally, women may develop complications, as discussed below.

Complications

Long-term complications related to menopause are associated with decreased estrogen.

Cardiovascular Disease

During menopause, the decline in estrogen not only causes vasoconstriction but also changes in a woman’s lipid profile. As a result, women who have gone through menopause are at a greater risk of cardiovascular disease (i.e., coronary artery disease and stroke). In fact, coronary heart disease rates are 2 to 3 times higher in those that have reached menopause than those of the same age who have not. Cardiovascular risk factors can optimize by starting hormone therapy within 10 years of the final menstrual period, younger patients less than 60 years old, nonsmokers, and better lipid panel LDL less than 130. For this reason, menopausal and postmenopausal women are encouraged to maintain a healthy diet and exercise to mitigate some of the risk factors.

Osteoporosis

More than 250,000 menopausal and postmenopausal women are affected by osteoporosis. The characteristic bone loss or decreased bone density in osteoporosis is due to estrogen deficiency in these women. At the age of 40, women begin to lose bone at a rate of 0.3% to 0.5% per year. During menopause, women experience an increased rate of bone loss of 3% to 5% per year for 5 to 7 years.  In the Women’s Health Institute trial, hormone replacement was chosen to decrease osteoporotic fractures. This and various other studies have shown that hormone therapy is protective against bone loss. However, there are risks associated with the long-term use of hormone therapy, such as endometrial and breast cancer and deep vein thrombosis/pulmonary embolism. For this reason, several other approaches to decreasing the risk of osteoporosis and related injuries are encouraged. Among these approaches are smoking cessation, physical activity, calcium supplementation, and non-hormonal treatments such as bisphosphonates and denosumab.