Perimenopause Case File
Eugene C. Toy, MD, Patti Jayne Ross, MD, Benton Baker III, MD, John C. Jennings, MD
CASE 30
A 49-year-old woman complains of irregular menses over the past 6 months, feelings of inadequacy, vaginal dryness, difficulty sleeping, and episodes of warmth and sweating at night. On examination, her blood pressure is 120/68 mm Hg, heart rate is 90 beats per minute, and temperature is 99°F (37.2°C). Her thyroid gland is normal to palpation. The cardiac and lung examinations are unremarkable. The breasts are symmetric, without masses or discharge. Pelvic examination is without any masses or other abnormalities.
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ANSWER TO CASE 30:
Perimenopause
Summary: A 49-year-old woman complains of irregular menses, feelings of inadequacy, sleeplessness, and episodes of warmth and sweating.
- Most likely diagnosis: Climacteric (perimenopausal state).
- Next diagnostic step: Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) levels.
ANALYSIS
Objectives
- Understand the normal clinical presentation of women in the perimenopausal state.
- Understand that the diagnosis of perimenopause is a clinical diagnosis and may include elevated serum FSH and LH levels. It is a diagnosis of exclusion and requires an awareness of disease processes that could also cause her symptoms.
- Know that estrogen-replacement therapy is usually effective in treating the hot flushes.
- Know the risks of continuous estrogen– progestin therapy.
Considerations
This 49-year-old woman complains of irregular menses, feelings of inadequacy, and intermittent sensations of warmth and sweating. This constellation of symptoms is consistent with the perimenopause, or climacteric state. The average age of menopause in the United States is 51 years old but can be anywhere from age 40 to 58 age range. The majority of women begin to experience the perimenopause for several years before and after the actual menopause. The predominant symptom of hypoestrogenemia is the hot flush. Hot flushes are a vasomotor reaction associated with skin temperature elevation and sweating lasting for 3 to 4 minutes. The low estrogen concentration also has an effect on the vagina by decreasing the epithelial thickness, leading to atrophy and dryness, but she will complain of symptoms long before actual signs are evident on pelvic examination of decreased vaginal rugation and moisture. With these changing levels of estrogen and progestin during the perimenopausal years leading up to the actual menopause, the woman will usually experience altered menstrual cycles, with sometimes a skipped menses, a lighter one, or a prolonged one. Elevated serum FSH and LH levels may be helpful. However, these levels will fluctuate in the perimenopause leading up to actual menopause and cannot be relied upon until persistently elevated. The value is determined by the particular reference lab being used but in general is 30 mIU/mL or greater. Saliva testing of estrogen or other levels is not reliable and is expensive. Treatment for hot flushes may include clonidine, gabapentin, selective serotonin reuptake inhibitors (SSRIs) medications, or estrogen-replacement therapy with progestin, which is the most effective of the choices. When a woman still has her uterus, the addition of progestin to estrogen replacement is important in preventing endometrial cancer. When estrogen and progestin are used in combination, this is referred to as hormone-replacement therapy (HRT). For a woman who has had a hysterectomy, the estrogen alone is adequate, and is referred to as estrogen-replacement therapy. Until a woman reaches the menopause, treatment for the irregular menstrual cycle may include a progestin or a low-dose oral contraceptive (dependent on her risk factors). This also has the added benefit of providing a back-up method for contraception. The choice of therapy depends on a careful review of the patient’s medical conditions and risk factors for thrombosis, cardiovascular disease, and breast cancer weighed against the severity of the hot flushes. Bioidentical hormones or pharmacy-compounded hormones are not recommended as they are not as closely regulated as FDA-approved medications, and there are no studies that prove their safety or efficacy above standard therapies.
Note: The selective estrogen receptor modulator (SERM), raloxifene, does not treat hot flushes.
APPROACH TO:
Menopause
DEFINITIONS
MENOPAUSE: The point in time in a woman’s life when there is cessation of menses for 12 months due to follicular atresia occurring after age 40 years (mean age 51 years). It describes the final menstrual cycle, but is commonly used to describe the time in a woman’s life after that point.
PERIMENOPAUSE (CLIMACTERIC): The transitional few, sometimes several years, spanning from before to 1 year after the menopause. It is characterized in the years leading up to the menopause by irregular menstrual cycles. If hot flushes occur, they usually increase in frequency as menopause is reached. The hot flushing may continue for several years after menopause.
HOT FLUSHES (FLASHES): Irregular unpredictable episodes of increased skin temperature and sweating lasting about 3 to 4 minutes caused by vasomotor changes. Women often complain of night sweats, another form of hot flushes, which must be differentiated from a disease process or other causes.
PREMATURE OVARIAN FAILURE: The cessation of ovarian function due to atresia of follicles prior to age 40 years. At ages younger than 30 years, autoimmune diseases or karyotypic abnormalities should be considered.
CLINICAL APPROACH
At about 47 years of age, most women experience perimenopausal symptoms due to the ovaries’ impending failure. This is a clinical diagnosis, although lab tests can help somewhat. Symptoms include irregular menses due to anovulatory cycles, vasomotor symptoms such as hot flushes, and decreased estrogen and androgen levels. Because ovarian inhibin levels are decreased, FSH and LH levels rise even before estradiol levels fall. The decreased estradiol concentrations lead to vaginal atrophy, bone loss, and vasomotor symptoms. While most clinicians agree that hormone replacement therapy is currently the best treatment for the vasomotor symptoms and to prevent osteoporosis, scientific data raises concerns about the risks of this therapy. The Women’s Health Initiative Study of continuous estrogen– progestin treatment reported a small but significant increased risk of breast cancer, heart disease, pulmonary embolism, and stroke. The cardiovascular risk was not seen in the women who were in the 50 to 59 age group—those women who were most likely to benefit from beginning HRT in the early menopause years. Women on hormone replacement therapy had fewer fractures and a lower incidence of colon cancer.
Short-term hormone-replacement therapy (5 years or less) is indicated for vasomotor symptoms, and should be used for as short a duration as possible in the smallest dose. It is the most effective therapy for relief of symptoms. For women who cannot or choose not to take estrogen, clonidine, or gabapentin may help with the vasomotor symptoms. Another class of pharmaceuticals that may be helpful to relieve the hot flushes is the selective serotonin reuptake inhibitors. A selective estrogen receptor modulator, such as raloxifene, is helpful in preventing bone loss, but does not alter the hot flushes. Weight-bearing exercise, calcium and vitamin D supplementation, and estrogen replacement are important cornerstones in maintaining bone mass. Because FSH responds to feedback by inhibin, the FSH level cannot be used to titrate the estrogen-replacement dose. In other words, the FSH concentration will still be elevated even though the estrogen replacement may be sufficient.
Other diseases that are important to consider in the perimenopausal woman include hypothyroidism, diabetes mellitus, hypertension, and breast cancer. Women in this stage of life may also experience depression, whether spontaneous in its onset or situational due to grief or midlife adjustments. The practitioner should advocate aerobic exercise at least three times a week, again, with weight-bearing exercise being advantageous for the prevention of osteoporosis. Bone mineral density (BMD) testing, such as by dual-energy X-ray absorptiometry (DEXA), is useful in the early identification of osteoporosis and osteopenia. BMD testing is indicated for all postmenopausal women aged 65 years or older and postmenopausal women at risk for osteoporosis and presenting with a bone fracture. Alcohol abuse may be seen in up to 10% of postmenopausal women, and requires clinical suspicion to establish the diagnosis.
EMERGING CONCEPTS
The Stages of Reproductive Aging Workshop (STRAW) research group published a system in 2012 that attempted to predict when women would go into menopause and also characterized the clinical and laboratory changes in the various reproductive stages from adolescence through menopausal transition and into menopause. The next step is to individualize patients based on stage and risk factors into the treatment of these women (Table 30– 1). Anti-Mullerian hormone (AMH) is the earliest marker to indicate decreased ovarian reserve. Inhibin B is the next serum marker to decrease. Finally, estradiol falls.
Data rom STRAW+10 Workgroup; 2012.
Data rom Fritz MA, Sperof L. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2011:673-748.
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CASE CORRELATION
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COMPREHENSION QUESTIONS
Which of the following single best direct mechanisms for amenorrhea (A-H) best matches the clinical situations described (30.1-30.6)?
A. Gonadotropin receptor insensitivityB. Pituitary dysfunctionC. Ovarian failureD. Ovarian cortical atrophy syndromeE. Peritoneal interference with ovulationF. Hypothalamic dysfunctionG. Estrogen excessH. Immune downregulation of ovary
30.1 A 51-year-old woman with oligomenorrhea and hot flushes.
30.2 A 22-year-old nonpregnant woman with hyperprolactinemia due to psychotropic medication use.
30.3 A 25-year-old woman slightly obese, slightly hirsute, and with a long history of irregular menses.
30.4 An 18-year-old adolescent female with infantile breast development who has not started her menses. She has some webbing of the neck region.
30.5 A 19-year-old nonpregnant woman marathon runner with amenorrhea.
30.6 A 33-year-old woman who has not started her menses since a vaginal delivery 1 year previously complicated by postpartum hemorrhage. She was unable to breast-feed her baby.
30.7 A 25-year-old woman has a history of 1 year of amenorrhea due to hyperprolactinemia. She has bilateral galactorrhea due to a prolactin-secreting adenoma. Which of the following tests is also likely to reveal an abnormal finding?
A. DEXA scan of the spineB. Endometrial biopsyC. Mammography of the breastsD. Thyroid-stimulating hormone level
ANSWERS
30.1 C. Ovarian failure due to follicular atresia is the reason for oligo-ovulation in the perimenopausal years. During perimenopause (or climacteric), follicular atresia occurs from hypoestrogenemia, as do the vasomotor changes that lead to hot flushes. There is nothing dysfunctional occurring in this scenario, as it is a common occurrence in a perimenopausal patient.
30.2 F. Both hypothyroidism and hyperprolactinemia may cause hypothalamic dysfunction, which inhibits gonadotropin-releasing hormone (GnRH) pulsations, which in turn inhibit pituitary FSH and LH release. The lack of gonadotropins, FSH and LH, leads to hypoestrogenic amenorrhea. A common cause of hyperprolactinemia in a girl of this age is a prolactinoma. This is not a pituitary problem, nor a receptor insensitivity issue. There is no pathology related to the ovaries; however, this patient will most likely be amenorrheic due to the lack of stimulation to the ovaries by the gonadotropins.
30.3 G. This patient most likely has polycystic ovarian syndrome (PCOS). Women with PCOS often are obese and hirsute, have anovulation and insulin resistance, but an estrogen excess. Because of this, they are often prescribed progesterone alone or combination oral contraceptive pills to induce vaginal bleeding and to prevent endometrial hyperplasia.
30.4 C. Ovarian failure is the most likely etiology in this woman with probable Turner syndrome (45,X). It would be reflected by elevated gonadotropin levels and streaked ovaries. She most likely has decreased estrogen levels as well, which predisposes her to complications such as osteoporosis later in life. This patient’s symptoms result from a chromosomal abnormality and not a hypothalamic or pituitary dysfunction.
30.5 F. Excessive exercise may lead to hypothalamic dysfunction, but many times simple weight gain will lead to its restoration of function. This patient has amenorrhea, and therefore is in a hypoestrogenic state. This puts this patient at an increased risk of bone fractures. The “female athlete triad” of eating disorder, amenorrhea, and osteoporosis is associated with hypothalamic dysfunction and hypoestrogenemia. Many times these individuals are placed on oral contraceptive pills (OCPs) in order to maintain normal hypothalamic function. There is no pathology related to the ovaries or pituitary in this scenario.
30.6 B. Sheehan syndrome is when the anterior pituitary suffers from hemorrhagic necrosis associated with postpartum hemorrhage. She is unable to breast-feed due to her inability to release prolactin from the anterior pituitary. This patient’s symptoms are unrelated to the ovaries and hypothalamus. This patient would be in a hypoestrogenic state due to the lack of gonadotropin stimulation. Treatment for this would be supplemental hormonal replacement.
30.7 A. Amenorrhea due to hyperprolactinemia causes a hypoestrogenic state due to decreased GnRH release, and decreased FSH and LH secretion. Ovarian estrogen levels are decreased, leading to decreased bone mineral density. Hence, the DEXA scan is most likely to be abnormal. The endometrial biopsy is likely to be normal, or perhaps show atrophic changes due to the hypoestrogenic state, and certainly not likely to show hyperplasia or cancer. The mammogram would not be affected. The thyroid gland is not affected by hyperprolactinemia; rather, hypothyroidism can lead to hyperprolactinemia, not vice versa.
CLINICAL PEARLS
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» Hot flushes and irregular menses after the age of 45 years are most likely due to the climacteric state (or perimenopause). These symptoms usually respond to estrogen recommended to be given as a combination of estrogen and progestin (HRT). » Significant vasomotor symptoms are the current indication for hormone replacement therapy in the menopausal woman, and the lowest dose should be used or the shortest duration feasible. » The most common location of an osteoporosis-associated fracture is the thoracic spine as a compression fracture. » Weight-bearing exercise, calcium and vitamin D supplementation, and estrogen-replacement therapy are the important cornerstones in the prevention of osteoporosis. » Progestin should be added to estrogen-replacement therapy when a woman has her uterus, to prevent endometrial cancer. » Continuous estrogen–progestin therapy may be associated with a small but significant risk of cardiovascular disease and breast cancer. » The sequence of biochemical markers in the life o the ovary is as follows: AMH falls first, inhibin B next, and then finally estradiol. » Pregnancy should be ruled out in any patient who presents with amenorrhea. |
REFERENCES
American College of Obstetricians and Gynecologists. Hormone therapy and heart disease. ACOG Committee Opinion 420. Washington, DC; 2008.
American College of Obstetricians and Gynecologists. Low bone mass (osteopenia) and fracture risk. ACOG Committee Opinion 407. Washington, DC; 2008.
Harlow SD, Glass M, Hall JE, et al. Executive summary of the stages of reproductive aging workshop + 10: addressing the unfinished agenda of staging reproductive aging. Fert Steril. 2012;87(4): 843-851.
Laufer LR, Gambone JC. Climacteric: menopause and peri and post-menopause. In: Hacker NF, Gambone JC, Hobel CJ, eds. Essentials of Obstetrics and Gynecology. 5th ed. Philadelphia, PA: Saunders; 2009:379-385. Lobo RA. Menopause. In: Katz VL, Lentz GM,
Lobo RA, Gersenson DM, eds. Comprehensive Gynecology. 5th ed. St. Louis, MO: Mosby-Year Book; 2007:1039-1072.
Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321-333.
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