The Menopausal Transition

1. The Menopausal Transition Dr. J. Mladic Ob/Gyn Associate Physicians Jan 28, 2010

2. Menopause is the time when permanent cessation of menstruation has occurred for 12 months following the final menses. The decrease in the amount of ovarian follicular estrogen synthesis occurs gradually over several years.

3. Unlike the age of menarche, which is affected by nutritional status and general health, the age of menopause occurs secondary to a genetically programmed loss of ovarian follicles. • The age of menopause is reduced by about two years in women who smoke. • There is also a tendency for women who have never had children and for those with more regular cycles to have an earlier age of menopause.

4. Other factors that may be important in determining the age of menopause include: • A family history of early menopause • A history of type 1 diabetes mellitus • galactose consumption • The presence of a variant of form galactose-1-phosphate uridyl transferase • Shorter cycle length during adolescence

5. Clinical Manifestations • Abnormal Bleeding • Chronic anovulation and progesterone deficiency in this transition period may lead to long periods of unopposed estrogen exposure and therefore anovulatory bleeding and endometrial hyperplasia. • Oligomenorrhea for six or more months, or an episode of heavy dysfunctional bleeding is an indication for endometrial surveillance. • Endometrial biopsy is the standard to rule out the occurrence of endometrial hyperplasia, but many clinicians are comfortable screening with transvaginal ultrasound. • Irregular or heavy bleeding during the menopausal transition may be treated with low-dose oral contraceptives or intermittent progestin therapy.

6. Endometrial Ablation Endometrial ablation techniques are FDA approved to treat some causes of abnormal uterine bleeding. Endometrial ablation provides a minimally invasive, outpatient treatment option for patients who require surgical intervention.

7. Clinical Manifestations • Hot Flashes • Hot flashes occur in about 75 percent of menopausal women in the United States. • The flashes most often begin in the perimenopausal period when relative estrogen deficiency occurs together with cycle irregularity secondary to anovulation, although in some women they do not begin until after menopause. • Hot flashes are almost always due to the onset of menopause; other possible causes are rare.

8. Clinical Manifestations • Hot flashes typically begin as a sudden sensation of heat centered on the face and upper chest that rapidly becomes generalized. The sensation of heat lasts between two and four minutes, is often associated with profuse perspiration and occasionally palpitations, and is often followed by chills and shivering. • Hot flashes usually occur several times per day, although the range may be from only one or two each day to as many as one per hour during the day and night. • Hot flashes can cause arousal from sleep, leading to sleep disturbances. In addition, many women have profuse perspiration which can be embarrassing in social situations.

9. Prevalence • A systematic review of menopausal symptoms estimated that vasomotor symptoms occur in 14 to 51 percent of women before the perimenopausal transition, 35 to 50 percent in perimenopause, and 30 to 80 percent after menopause. • It is generally believed that hot flashes do not occur in premenopausal women because serum estrogen concentrations are never very low, even during the menstrual period. However, a large observational Swan study found that 20 percent of premenopausal women reported hot flashes.

10. More than 80 percent of women who have hot flashes will continue to have them for more than one year. • Untreated, hot flashes stop spontaneously within a few years of onset in most women. • However, it is estimated that nine percent of women continue to experience hot flashes beyond the age of 70 years.

11. Genitourinary Symptoms • Vaginal dryness • The mucosal lining of the vagina and urethra are very sensitive to estrogen, and estrogen deficiency leads to thinning of the vaginal epithelium. This results in vaginal atrophy, causing symptoms of vaginal dryness, itching and often, dyspareunia. • The prevalence of vaginal dryness in one longitudinal study was 3, 4, 21, and 47 percent of women in the reproductive, early menopausal transition, late menopausal transition, and three years postmenopausal stages, respectively. • In a large prospective cohort study of women ages 40 to 55 years, the overall prevalence of vaginal dryness was 13.1 percent, but the prevalence was lower in the early menopausal transition, and increased across the transition.

12. On exam, the vagina typically appears pale, with lack of the normal rugae and often has visible blood vessels or petechial hemorrhages. • Vaginal pH, which is usually <4.5 in the reproductive years, increases to the 6.0 to 7.5 range in postmenopausal women not taking estrogen. • The increase in pH and vaginal atrophy may lead to impaired protection against vaginal and urinary tract infection.

13. Sexual dysfunction • Estrogen deficiency leads to a decrease in blood flow to the vagina and vulva. This decrease is a major cause of decreased vaginal lubrication and sexual dysfunction in menopausal women. • Vaginal dryness and dyspareunia may also contribute to reduced sexual function. • Symptoms related to genitourinary atrophy are quickly responsive to estrogen therapy, in particular, vaginal estrogen therapy.

14. Breast pain — Breast pain and tenderness are common in the early menopausal transition, but begin to diminish in the late menopausal transition. • Menstrual migraines — Menstrual migraines are migraine headaches that cluster around the onset of each menstrual period. In many women, these headaches worsen in frequency and intensity during the menopausal transition. • Skin changes — The collagen content of the skin and bones is reduced by estrogen deficiency. Decreased cutaneous collagen may lead to increased aging and wrinkling of the skin.

15. Pharmacologic Treatment for Menopausal Symptoms Estrogen therapy — Postmenopausal hormone therapy is currently recommended short-term for the management of moderate-to-severe vasomotor flushes. • Long-term use for prevention of disease is no longer recommended. • Women with mild hot flashes do not usually require any pharmacologic intervention. • For women with moderate-to-severe hot flashes, the most effective therapy is estrogen.

16. In women who have not had a hysterectomy, estrogen should always be given in combination with a progestin, to prevent the occurrence of endometrial hyperplasia. • Estrogen therapy is recommended for as short a duration possible for relief of moderate-to-severe hot flashes. • Short-term therapy is considered to be two to three years, and generally not more than five years. • Other factors to consider include the patient's age, sleep, sexual function, medical history and quality of life.

17. Estrogen Products Oral Estrogens* Estradiol Estrace (Warner Chillcott) 0.5, 1, 2 mg Gynodiol (Novavax) 0.5, 1, 1.5, 2 mg Esterified estrogens Menest (Monarch) 0.3, 0.625, 1.25, 2.5 mg Estropipate Ogen (Pharmacia) 0.75, 1.5, 3 mg Ortho-est (Women First Healthcare) 0.78, 1.5 mg Conjugated equine estrogens (CEE) Premarin (Wyeth-Ayerst) 0.3, 0.45, 0.625, 0.9, 1.25 mg Conjugated synthetic estrogens Cenestin (Elan) 0.3, 0.45, 0.625, 0.9, 1.25 mg Enjuvia (Elan) 0.625, 1.25 mg Estrogen-progestin combinations Prempro (Wyeth-Ayerst) 0.3 mg CEE/1.5 mgmedroxyprogesterone, 0.45/1.5 mg, 0.625/2.5 mg, 0.625/5 mg Ortho-Pretest (Monarch) 1 mg estradiol/0.9 mg norgestimate Activella (Pharmacia) 1 mg estradiol/0.5 mg norethindrone acetate FemHRT (Warner Chilcott) 5 mcg ethinyl estradiol/1 mg norethindrone acetate Angeliq (Berlex) 1 mg estradiol/0.5 mg drosperinone Transdermal estrogens* Estradiol patches Alora (Watson) 0.025, 0.05, 0.075, 0.1 mg/d Climara (Beriax) 0.025, 0.05, 0.06, 0.075, 0.1 mg/d Esclim (Women First) 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d Estraderm (Novartis) 0.05, 0.1 mg/d Vivelle (Novartis) 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d Estrogen-progestin patches Combi-Patch (Novartis) 0.05 mg estradiol/0.14 mg norethindrone, 0.05 mg/0.25 mg Climara Pro (Berlex) 0.045 mg estradiol/0.015 mg levonorgestrel Gel EstroGel (Solvay) 1.25 g (0.75 mg estradiol) Emulsion Estrasorb (Novavox) 0.025 mg estradiol/pouch Intravaginal rings* Femring (Warner-Chilcott) 0.05 mg estradiol/day over 3 months

18. Alternative treatments for the Treatment Menopausal Symptoms • Black cohosh: Phytoestrogens of black cohosh rhizome have mild estrogenic binding effects. • Standardized extracts have been demonstrated to improve menopausal and premenopausal symptoms in clinical studies. • Contraindicated in individuals with a history of estrogen-dependent tumors or endometrial cancer. Black cohosh may cause nausea, vomiting, headache, and hypotension at higher dosages.

19. Osteoporosis • Osteoporosis or osteopenia occurs in about 44 million American men and women, accounting for 55 percent of the population age 50 and over. • Osteoporosis is defined as "a skeletal disease characterized by compromised bone strength predisposing a person to an increased risk of fracture".

20. Diagnosis of Osteoporosis • Bone strength primarily reflects the integration of bone density and "quality". In the absence of a fragility fracture, bone mineral density by dual-energy X-ray absorptiometry is the clinical tool used to diagnose osteoporosis according to the classification of the World Health Organization. • BMD that is 2.5 standard deviations or more below the mean BMD of a young-adult reference population, which is a T-score of -2.5 or less, qualifies for a diagnosis of osteoporosis, provided that other causes of low BMD have been ruled out. • As BMD decreases, fracture risk increases as a continuum, with no "fracture threshold." In one analysis, for every one SD decrease in BMD at the hip, there is a 2.6-fold increase in the risk of hip fracture.

21. Maximizing Peak Bone Mass • PBM is the maximum bone mass achieved in life. The time of PBM is not known with certainty, but probably occurs in the third decade of life in most individuals, with variability according to ethnicity, sex, skeletal site, and method of BMD measurement. • Nutrition — Good nutrition from infancy through adolescence, with particular attention to adequate daily intake of calcium and vitamin D, is a key component in the attainment of maximum PBM. • Physical activity — Observational, retrospective, and prospective randomized trails have demonstrated beneficial effects of exercise on bone accumulation during growth, with particular benefit from high impact exercise.

22. Minimizing Bone Loss • Bone loss may begin soon after PBM is attained: • A longitudinal study of 620 men and women age 20 to 89 showed a small bone loss (<0.4 percent per year) at the hip and spine in premenopausal women, with a tripling of the bone loss rate in the early postmenopausal years.

23. Stabilizing BMD or reducing the rate of bone loss is the primary objective in the prevention of osteoporosis once PBM has been attained. • A typical rate of bone loss in early postmenopausal estrogen deficient women is probably about 1.0 to 1.5 percent per year, with a small percentage of women being "rapid bone losers" who may lose as much as 3 to 5 percent of bone mass per year.

24. Adequate calcium and vitamin D intake can result in positive calcium balance and a reduction in the rate of loss of bone. • In postmenopausal women with osteoporosis, intake of at least 1200 to 1500 mg of elemental calcium (total diet plus supplement) and 800 IU of vitamin D daily is suggested. • Calcium supplementation in excess of 500 mg/day should be given in divided doses.

25. Pharmacological therapy • Bisphosphonates — Medications in this class of potent antiresorptive agents have been shown to increase BMD and reduce fracture risk. • Those currently available for the prevention of postmenopausal osteoporosis are: • alendronate (5 mg/day or 35 mg/week), • risedronate (5 mg/day or 35 mg/day), and • ibandronate (150 mg/month).

26. Discontinuation of Estrogen Many women have no trouble stopping estrogen, and are able to stop without assistance. • In women whose vasomotor symptoms at the start of therapy were only mild-to-moderate, we suggest having the patient attempt abrupt discontinuation. This may be followed by a second attempt using a taper if the patient experiences bothersome symptoms. • In patients with a history of severe vasomotor symptoms at baseline, a very gradual taper (typically over six months to one year) is suggested. • The North American Menopause Society suggests that after a failed attempt at stopping therapy, extended use of hormone therapy may be reasonable in women who feel that the benefits of symptom relief outweigh risks. In this setting, additional attempts should be made at a later date to stop the hormone therapy.

28. Droegemeuller Comprehensive Gynecology: Menopause 1127-1258 • Precis Reproductive Endocrinology ACOG • Up to Date Menopause: Clinical Manifestations