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Clinical Manifestations of Perimenopause

Scheduled nonsteroidal anti-inflammatory drugs (NSAIDs) effectively reduce menstrual blood flow in 40% to 60% in women with ovulatory cycles. NSAIDs block prostaglandin synthetase activity and should be initiated at the onset of menses and given on a regular schedule until past the risk of heavy flow. NSAIDs may be useful in the treatment of menstrual migraines.

A. Manifestations of estrogen excess

During perimenopause, some women present with evidence of estrogen excess rather than deficiency, due to a transient increase from increased FSH levels.

  • Abnormal uterine bleeding (AUB) is bleeding that is excessive in amount, duration, and frequency. It can occur due to prolonged exposure of the uterine lining to estrogen stimulation unopposed by progesterone. It may also be due to structural or systemic abnormalities. AUB without known structural or endocrine causes is called dysfunctional uterine bleeding (DUB).
    • Anovulatory cycles, common to the perimenopausal transition, lead to unopposed estrogen stimulation of the endometrial lining. This in turn can cause AUB, due to dyssynchronous shedding of the endometrium, which occurs with increased frequency in perimenopausal women. The type of AUB seen most commonly in the perimenopause transition is due to anovulatory cycles.
    • Increased endogenous estrogen can also be caused by increased peripheral conversion of androgen precursors to estrone and estradiol. This is most frequently seen in obese perimenopausal women.
    • Less commonly, pathologic conditions are associated with increased estrogen production (ovarian tumors) or decreased metabolic clearance of estrogen (hepatic or renal disease), leading to elevated circulating estrogen levels.
    • There are many other causes of AUB not related to sex hormone fluctuation. Examples are endometrial polyps, fibroids, pregnancy, infection, coagulopathy, disorders of thyroid or prolactin regulation, chronic illness, and exogenous medications.
    • Uterine leiomyoma, previously present, may grow during menopause transition due to estrogen excess. This may result in AUB and pelvic symptoms such as pain or pressure.
  • Endometrial neoplasia
    • Prolonged unopposed estrogen stimulation of the endometrial lining may lead to excessive endometrial proliferation and subsequent endometrial pathology.
    • Abnormal uterine bleeding that occurs either in a woman older than 40 years of age or in a younger woman with risk factors (history of chronic anovulation or unopposed estrogen, prolonged bleeding, obesity) must be evaluated with pelvic examination, pregnancy test, lab work as indicated by history, and endometrial sampling to rule out disease. Office endometrial biopsy, with or without pelvic ultrasonography, is usually sufficient. Dilation and curettage (D&C) with hysteroscopy and sonohysterography are alternatives for diagnostic testing.
    • Simple endometrial hyperplasia has low risk of progression to endometrial carcinoma and can be treated medically.
    • Complex endometrial hyperplasia without atypia is a more advanced type of hyperplasia, with a 3% risk of progressing to endometrial carcinoma. Complex hyperplasia may also be treated medically, followed up with posttreatment tissue sampling.
    • Complex endometrial hyperplasia with atypia is associated with an increased risk of an associated endometrial carcinoma. Because of an approximately 25% risk of progression to endometrial carcinoma, hysterectomy is the treatment of choice for this condition. However, if medical management is elected, hysteroscopy with D&C is necessary first to rule out the coexistence of endometrial cancer.
    • Endometrial cancer should be suspected in all perimenopausal women who present with abnormal bleeding. As much as 10% of postmenopausal bleeding is secondary to a carcinoma. Treatment is surgical.

B. Manifestations of hormonal fluctuation

  • Menstrual cycle changes. Some change in the character of established menstrual cycles is the most common manifestation of perimenopause. Ninety percent of women may experience menstrual changes in perimenopause.
    • Menorrhagia is defined as increased blood flow (more than 80 mL) during menses, or bleeding that lasts longer than 7 days. Cycles are regular and ovulatory. Increased flow may result from a relative reduction in progesterone levels. Increased bleeding at regular intervals is also called hypermenorrhea.
    • Metrorrhagia is bleeding at irregular intervals or between menses. Shortening of cycle length is a common change reported early in the menopausal transition. Cycle length remains longer than 21 days but is typically shorter than cycles experienced during the reproductive years. Cycles are ovulatory with a shortened follicular phase.
    • Oligomenorrhea is the decreased frequency of menstruation. As menopause approaches, missed periods are common, and cycle length increases until a permanent cessation of menses occurs.
    • Amenorrhea is the absence of menses.
  • Other symptoms. Many women who are still menstruating experience a variety of symptoms traditionally attributed to menopause.
    • Hot flashes are symptoms of vasomotor instability. This is the second most common perimenopausal symptom, reported by 75% of perimenopausal women. Hot flashes can come and go over time and are not consistent from cycle to cycle. They typically are present for up to 2 years after the FMP, but may persist for up to 10 years. When they occur with sleep and are associated with perspiration, they are called night sweats. Peripheral vasodilation is associated with a rise in skin temperature, resulting in a hot flash. There may also be a modest increase in heart rate at the same time. Although there is no objective link between alcohol, caffeine, and hot flashes, there are anecdotal reports supporting an association.
    • Headaches may worsen during perimenopause, and then improve again after menopause. There may be a hormonal link, but this has not been well studied.
    • Sleep disturbance. Interrupted sleep, with or without hot flashes, is reported by one-third to one-half of U.S. women in this age group.
    • Mood disturbance is reported by 10% of perimenopausal women. This includes symptoms of irritability, depression, insomnia, fatigue, and difficulty with memory or concentrating. Sleep deprivation and midlife stresses maybe strong contributing factors. There is no evidence that cognitive function actually deteriorates with perimenopause or menopause.
    • Sexual function such as libido, arousal, and vaginal lubrication and elasticity can be affected by the onset of perimenopause. These changes can be due to many causes, including hormonal fluctuation, medications, sleep disturbance, loss of partner, and life stresses.
    • Weight gain occurs for many women during the menopause transition, possibly due to aging and lifestyle. Obesity increases a woman’s risk for other health problems, such as cardiovascular disease and diabetes. A theory that weight gain during this time may also be due to a decrease in metabolically active tissue and less overall time spent in the secretory phase of the cycle as menses become farther apart needs further study.

C. Treatment

  • Progestogen (natural progesterone or synthetic progestin) supplementation. Periodic administration of a progestogen is used to treat conditions associated with estrogen excess.
    • DUB can be treated with intermittent progestogen in 12-to 14-day monthly cycles, which provides estrogen antagonism and allows for the orderly sloughing of the endometrium. Therapy may also be administered continuously, preventing withdrawal bleeding. These therapies decrease the incidence of anovulatory uterine bleeding and the development of endometrial neoplasia.
      • Medroxyprogesterone acetate (MPA) is the most commonly used progestogen for DUB. Therapy may be used for only one cycle, continued cyclically until there is absence of withdrawal bleeding, or used continuously to suppress bleeding altogether. Absence of withdrawal bleeding signifies a reduction of estrogen levels to the menopausal range.
      • Norethindrone acetate, also a progestin, can be used as an alternative to MPA.
      • Oral micronized progesterone, derived from plant sources, is also an alternative.
      • The progestin-containing intrauterine system delivers continuous low-dose progestin (levonorgestrel) directly to the endometrium. Ninety percent of women who use it have a reduction in blood flow and 20% have complete absence of any bleeding.
    • Simple and complex hyperplasia may be treated effectively with progestogen supplementation. Treatment with progestin or progesterone as described for DUB is prescribed. Follow-up biopsy is performed after 3 months of treatment to verify resolution of the hyperplasia.
    • Complex hyperplasia with atypia may be treated with high-dose progestogen if surgical therapy is not an option, once the presence of carcinoma has been excluded by such methods as ultrasonography, hysteroscopy, and D&C. Follow-up biopsy after 3 months of treatment is mandatory to verify resolution.
      • Progestogen is given daily for 3-6 months.
      • Megestrol (a strong progestin) is given daily for 3-6 months.
  • Combination (estrogen-progestin) hormonal contraceptives are useful for both contraception and treating symptoms in perimenopausal women who are normotensive nonsmokers without other risk factors. Choices include oral contraceptive pills, vaginal ring, and contraceptive patch.
    • Low-dose combination hormonal contraceptives (35 µg ethinyl estradiol or less) can be an effective treatment for abnormal bleeding and hot flashes associated with perimenopause.
    • These medications are obviously also an effective method of contraception for women in whom this is still a concern. There is no increased risk using combination hormonal contraceptives in perimenopausal-aged women without risk factors compared to younger women.
    • Because combination hormonal contraceptives contain five to seven times the estrogen equivalent of postmenopausal hormone therapy, it is desirable to change therapy with the onset of menopause. FSH levels fluctuate rapidly and are not consistent in perimenopause. Therefore, FSH is not a reliable test for evaluating or predicting menopause status and the need for contraception. One suggested option is to continue combination hormonal contraception in women who tolerate it and have no risk factors until the age of 50 to 55.
    • Other methods of contraception maybe considered as well, as long as pregnancy is an issue.
  • Hormone therapy (HT) refers to the combined use of estrogen and progestogen in subcontraceptive doses. Estrogen therapy (ET) refers to the use of estrogen without a progestogen, usually only given in women who have undergone hysterectomy.
    • HT and ET may be used to treat perimenopausal symptoms in women with oligomenorrhea before permanent cessation of menses. There are many variations in dose, drug types, and delivery systems for HT and ET.
    • Progestogen is added to estrogen in women who have their uterus. Otherwise, unopposed estrogen increases the risk of endometrial neoplasia in these women. The risk is related to duration of use and dose. The absolute risk of endometrial cancer is 1 per 1000 in postmenopausal women. In general, the risk increases to 1 per 100 in women on unopposed estrogen.
  • Scheduled nonsteroidal anti-inflammatory drugs (NSAIDs) effectively reduce menstrual blood flow in 40% to 60% in women with ovulatory cycles. NSAIDs block prostaglandin synthetase activity and should be initiated at the onset of menses and given on a regular schedule until past the risk of heavy flow. NSAIDs may be useful in the treatment of menstrual migraines.
  • Alternative therapies such as herbal remedies, acupuncture, and non-Food and Drug Administration (FDA)-approved hormones require further study.
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