MENOPAUSE

1. MENOPAUSE 40 million menopausal women in the U. S. presently

2. DEFINITION • Spontaneous or Natural Menopause – 12 months of amenorrhea with no obvious pathological cause. Age range of onset is 40-58 years with the average age of 51.4 years. • Induced Menopause– due to surgery, chemotherapy or radiation therapy which can happen at any age. • Premature Menopause or Ovarian Failure –defined as less than age 40. • Transient – due to eating disorders or stress. • Permanent – due to autoimmune disorders or genetic abnormalities (may be confirmed by karyotyping), usually 2/3 of the causes are idiopathic.

3. DIAGNOSIS • A woman’s medical and menstrual hx and symptoms are sufficient to confirm the diagnosis of menopause. • Serum FSH can potentially allow an earlier diagnosis of menopause but must be consistently elevated > 30 mlU/ml. • Hormonal contraceptives may lower FSH levels making it difficult to diagnose menopause – measuring FSH on the 7th pill free day was not a sensitive test. You may need to measure FSH:LH ratio looking for > than 1 or estradiol < than 20 pg/ml on the 7th pill free day. • Always remember thyroid disease can mimic menopause, a TSH measurement may be necessary.

4. Menopausal Symptoms • Vasomotor Symptoms – Hot flashes and night sweats. In the U.S., about 75% of women experience vasomotor symptoms during the transition from perimenopause to postmenopause which last a median of 3.8 yrs. 25% of women have symptoms that continue for longer than 5 yrs. 90% of women experience vasomotor symptoms with surgical menopause and their symptomatology may be worse than for women experiencing spontaneous menopause.

5. Menopausal Symptoms • Vulvar and Vaginal Atrophy with vaginal dryness and painful intercourse. Lack of estrogen also causes the urethra to become thinner and less efficient with detrusor pressure at the urethral opening decreasing, both during and after voiding. These changes increase a women’s risk of vaginal and urinary tract infections, and also urinary incontinence.

6. Menopausal Symptoms • Sexual Dysfunction - ? Related to all of the changes of the genitourinary tract can result in dyspareunia, leading to a decreased interest in sexual intercourse. Fatigue and depression brought on by the vasomotor symptoms and sleep disturbances of menopause can exacerbate this lack of interest in coitus. • Also possible decrease levels of endogenous testosterone especially in women who have undergone sugical menopause may cause decreased libido.

7. Do You Treat with Hormonal Therapy??? • The Women’s Health Initiative Study was terminated in 1998 due to harmful outcomes associated with hormonal replacement therapy such as an increase in invasive breast cancer, coronary heart disease, pulmonary embolism and stroke. Although it was the largest and best controlled, blinded study it had several shortcomings.

8. Women’s Health Initiative Study • Average age of women in the trail was 63.2. This mean does not reflect the customary hormonal therapy user who is 10 to 30 years younger. • Only one regime of hormonal replacement, 0.625mg of estrogen with 2.5mg of progesterone was used. • The women used in the study had an overall higher risk for heart disease than the general population. • Breast Cancer was associated with those women who had been previous on hormonal replacement therapy suggesting that exposure to hormones required at least 5 years before an effect was noted and also those women diagnosed in the first year of the trial suggest that the cancer was preexisting. The increase risk is small in the WHI study, being 4 to 6 additional invasive cancers per 10,000 women who use it for 5 or more years. • The WHIMS, a supplementary study to the WHI, found an increase in Alzheimer. The findings of increase dementia was for those women over the age of 65. These findings have little relevance to hormonal replacement therapy given to women during the menopausal transition who are 10 to 15 years younger.

9. The HERS study (mean age of 66.7 years and established CHD) showed a increase in cardiovascular events in the first year and a decrease over time, suggesting that an at-risk group of women were affected particularly in the first year. The WHI study also observed an increase in heart attacks during the early stages of treatment. The two studies did reinforce that older women with CVD who have not taken hormonal replacement therapy should not begin treatment.

10. So what about lower doses of hormonal therapy??? • The HOPE study examined the use of lower doses in healthy women age 40-65 and found that similar benefits were achieved regarding reduction in hot flashes, and prevention of bone loss. The Nurses Health Study has suggested that lower doses may protect against stroke, with the study demonstrating absolute risk of stroke almost tripled for women on at least 0.625mg of estrogen as compared with those taking a 0.3 mg dose. With respect to breast CA, studies, though controversial, contend that there is direct evidence to suggest that lover doses are correlated with a lower risk of breast cancer.

11. Today the general indications for hormonal therapy are the treatment of moderate to severe menopausal related vasomotor symptoms and the prevention and possible treatment of osteoporosis. Women at high risk for serious medical outcomes with the use of estrogen include those with a history of breast cancer, those with an elevated risk for both ovarian and breast CA due to genetic factors, family hx or both; and those at high risk for CVD. Other risk factors include hx of PE, DVT, CVA or liver disease.

12. When the benefit outweighs the risk consider using hormonal therapy in lower doses for shorter periods of time. If lower doses not effective than consider standard dose therapy or twice daily therapy with half doses or even consider transdermal administration (bypasses the liver so no increase in TG or HDL.) which delivers more consistent blood levels of estrogen. Remember if the woman has a uterus, you must also treat with both estrogen & progesterone. Using Hormonal Preparations

13. Oral Estrogen Products • Conjugated Equine Estrogen – Premarin, doses are 1.25, 0.9,0.625, 0.45, 0.3mg/d • Synthetic Conjugated Estrogen – Cenestin, 0.3, 0.45, 0.625, 0.9, 1.25 • Estradiol – Estrace, 0.5,1.0, 2.0 – transdermal patches are made of this. • Very few head to head trials comparing different estrogens

14. Continuous combined has decrease rate of breakthrough bleeding and fewer endometrial bx than cyclic regimen. Continuous combined – Prempro Continuous Cyclic – Premphase Intermittent Combined – Prefest Transdermal Continuous Combined - Combipatch Estrogen/Progesterone Preparations for Postmenopausal Use

15. If perimenopausal and still having menses, consider low dose OCPs Progesterone alone can be used to tx vasomotor S/S but like estrogen has been linked to increase risk of breast cancer. Hormonal Treatments

16. Effexor 37.5-75mg Paxil 12.5-25mg/day Prozac 20mg/day Neurontin 300mg Qd-TID Clonidine 0.05-0.1mg BID – consider transdermal for consistant blood levels SSRI’s being the most effective When Hormone Therapy isn't an Option

17. Soy foods or isoflavone supplements - ? use in women with hx of breast cancer because of their estrogen effect. The most popular OTC tx presently. Black Cohosh – Clinical evidence mixed but trials ongoing. At this time the suggestive use of Remifemin 20mg – 2 tabs everyday Vitamin E – clinical evidence show mixed results. 800 IU/day OTC topical progesterone cream – not recommended due to content and concentrations differ widely in a variety of preparations and ? systemic effects. Also not recommended at this time is dong quai, evening primrose oil, ginseng, licorice, chinese herb mixtures, acupuncture or magnet therapy Alternative Therapies

18. Vulvovaginal Changes with Menopause • Vaginal Dryness/Atrophic Vagnitis – Systemic hormonal therapy not recommended unless treating also moderate to severe vasomotor S/S or for osteoporosis prevention. • First line treatment is vaginal lubricants that are water soluble and advise if possible regular sexual stimulation. • Hormonal preparations: • Vaginal Estrogen Rings – Estring & Femring are available with concerns with Femring for systemic effects. It is possilbe to use Femring for both vaginal therapy and systemic therapy. Ring last 90 days. • Vaginal Estrogen Tablets –Vagifem, usual dose is 1x/day x 2 wks then 2x/wk. • Vaginal Estrogen creams – (Estrace or Premarin) 1x/day x 2 wks than 1-3x/wk. • If using unopposed estrogen locally for long periods of time, yearly vaginal Ultrasound may be needed to assess the endometrium.

19. Urinary Symptoms During Menopause • Estrogen Therapy is not recommended with Stress or Urge incontinence. Clinical trials have shown no benefit. • Assess for UTI, diabetes, drug interaction or cognition related phenomena if urinary symptoms present. • Frequent UTIs can be due to lack of estrogen – only vaginal estrogen preparations have been proven to work with decreasing the frequency of UTIs in menopausal women. • The HERS study showed no benefit with using systemic estrogens to treat reoccurring UTIs.

20. North American Menopause Society www.menopause.org