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Menopause Presentation
- 1. MENOPAUSE Presented by: Megan Handley Pharm.D.Candidate Class of 2015 University of Arizona College of Pharmacy
- 2. OBJECTIVES Background Staging of menopause Hormonetherapy Over the counter options Non-pharmacological treatment options Conclusions
- 3. BACKGROUND Mean age:51 years 95% of women become menopausal between 45 & 55 years of age Permanent cessation of menstrual periods (12 months of amenorrhea) Perimenopause (transition phase) begins on average 4 years before the final menstrual period Diagnosis of menopausal transition is made in women: >45 years old Irregular menstrual cycles Menopausal symptoms Serum follicle-stimulating hormone is often measured, however the result offers no additional information
- 4. SYMPTOMS hot flashes vaginal dryness sleep disturbances new-onset depression cognitive changes (memory loss) changesin sexual function joint pain menstrual migraines breast pain
- 5. STAGES OF MENOPAUSE Late Reproductive Years -seruminhibin B -FSH may slightly -luteal phase progesterone Perimenopause –change in intermenstrual interval –bleeding pattern changes –dramatic FSH & estradiol fluctuations (FSH >25 IU/L) –serum inhibin B –ovarian antral follicle count -vasomotor symptoms Menopause –permanent cessation of menses –FSH over several years after the final period. -vasomotor symptoms
- 8. HORMONE THERAPY Goal:to relieve menopausal symptoms & treat vulvovaginal atrophy during perimenopause & early menopause Indications: moderate to severe vasomotor symptoms moderate to severe symptoms of vulvar & vaginal atrophy prevention of postmenopausal osteoporosis Disease prevention: Osteoporosis Dementia Cardiovascular disease Risks are plentiful, but short-term use (≤5 years) does not seem to be associated with significant risk
- 9. RISKS OF HORMONETHERAPY Endometrial cancer Venous thromboembolic disease: Increased risk within 1-2 years after initiation of hormone therapy Smoking cessation Breast cancer Increased breast density with progestogens via proliferation of estrogen-dependent mammary tissue, making it more difficult to detect breast cancer early with a mammogram Family history Duration of exposure Ovarian cancer >10 years estrogen therapy Cerebrovascular accidents
- 10. CONTRAINDICATIONS OF HORMONE THERAPY Breastcancer Estrogen- sensitive malignant conditions Undiagnosed genital bleeding Untreated endometrial hyperplasia Previous idiopathic or current venous thromboembolism Active or recent arterial thromboembolic disease Untreated hypertension Active liver disease Porphyria cutanea tarda
- 11. ESTROGEN Oral, transdermal,topical, intravaginal creams & tablets, vaginal rings, injections Dose-related effects on hot flashes. Use lowest dose necessary to provide relief of symptoms or bone protection Oral Favorable effects on lipid profiles in serum triglycerides & C-reactive protein in testosterone concentrations Dose (17β-estradiol): 0.5-1mg /day Dose (ethinyl estradiol): 0.01-0.02mg /day Conjugated equine estrogens: 0.3-0.625mg /day Transdermal Risk of venous thromboembolism, hypertriglyceridemia & stroke are lower than oral therapy Contain 17β-estradiol (14-100μg/day) Starting dose: 0.025mg patch monthly. If hot flashes still present in 1month, to 0.0375mg & reassess 1month later
- 12. ESTROGEN: LOCAL/VAGINAL Indications:atrophy, sexual function, dyspareunia, atrophic vaginitis Wash hands before use, insert with vaginal applicator, clean applicator in warm, soapy water & rinse Conjugated estrogens (Premarin cream): Start with 0.5g vaginally twice weekly (usually 3weeks on /1week off). Do not exceed 2g/day. Estradiol Estrace cream: 2-4g daily for 1-2weeks, gradually reduce to half initial dose for 1- 2weeks Maintenance dose:1g 1-3 times weekly may be used after restoration of vaginal mucosa Vagifem tablets: insert one10mcg tablet daily for 2weeks then one tablet twice weekly Estragyn (estrone) cream: 2-4g intravaginally daily Continuously or 25days on/5days off. Attempts to discontinue or taper should be made at 3-6month intervals
- 13. PROGESTINS Intact uterus:need progestin+estrogen to prevent endometrial hyperplasia Oral, transdermal, transvaginal, intrauterine Adverse effects: mood swings, bloating, fluid retention, sleep disturbance Cyclic: 10-14days/month (produces monthly menstrual periods) Continuous: progestogen+estrogen daily (amenorrhea, breakthrough bleeding) Micronized progesterone: 100mg PO daily or 200mg PO for 10-12days/month Norethindrone: 0.35mg PO daily or 5mg PO for 10-12 days/month Levonorgestrel (Mirena): intrauterine device releasing 20mcg/day Medroxyprogesterone acetate: 2.5mg PO daily or 5-10mg PO for 10-12days/month Abnormal bleeding necessitates careful monitoring of the endometrium with ultrasonography & biopsy
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- 15. OTC/HERBAL TREATMENTS Phytoestrogens:sterol molecules produced by plants, weak estrogenic activity Soy Inconsistent trial results, no long-term safety & efficacy trials completed Food sources preferred (tofu, soy sauce, soybean oil, soy milk) Avoid over dosage with supplements Women with personal or strong family history of hormone-dependent cancers, thromboembolic or cardiovascular events should not use soy products Black cohosh (Remifemin) Trials yielded inconsistent results Rare case reports of hepatitis associated with preparations containing black cohosh No safety trials have been conducted for longer than 6months ProFema: vitamins, minerals, black cohosh, spirulina, kelp, digestive plant enzymes, etc. ($40/month) Estroven: vitamins, minerals, natural extracts, isoflavones (soybeans), black cohosh ($15/month)
- 17. NON-PHARMACOLOGICAL TREATMENTS Avoid spicyfoods Avoid stress triggers Cool environment (fans, air conditioning, light/layered clothing) Relaxation therapy Cognitive behavioral therapy Placebo effect Weight loss Exercise Hypnosis
- 18. ANDROGEN DEFICIENCY Symptoms:low libido, decreased sexual response, depression, insomnia, headache, poor concentration, decreased lean body mass, fatigue Adverse effects: acne, hirsutism, voice, deepening, ↓ in high-density lipoprotein levels Variation in normal ranges of serum testosterone levels, DHEA, DHEAS, & androstenedione. Makes diagnosis of androgen deficiency difficult. Patients who continue to have symptoms on estrogen replacement alone Use of androgens other than testosterone (DHEA, DHEAS, androstenedione) cannot be recommended due to uncontrolled amounts of medication in OTC preparations. Methyltestosterone dose not to exceed 2.5mg daily Estratest:1.25mg esterified estrogens & 2.5mg methyltestosterone, 0.625mg esterified estrogens & 1.25mg methyltestosterone
- 19. CONCLUSIONS Hormone therapyis prescribed during perimenopause & early menopause for relief of symptoms & treatment of vaginal atrophy Progestational agent should be used in women with an intact uterus & can be administered with estrogen Hormone therapy dose may be reduced with increasing age Hormone therapy results in benefits on bone protection & possibly dementia Risks of endometrial cancer, breast cancer, ovarian cancer, vascular & thromboembolic disease with hormone therapy Clonidine, antidepressants, & anticonvulsants may have benefit OTC preparations have inconsistent trial results & often interact with other medications Androgen deficiency symptoms despite estrogen therapy may warrant addition of methyltestosterone to estrogen treatment
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- 21. REFERENCES National Institutesof Health. The 2012 hormone therapy position statement of the North American Menopause Society. Menopause 2012; 19:257. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocrine Practice 2006; 12:315-30. Martin KA, Barbieri RL. Treatment of menopausal symptoms with hormone therapy. UpToDate. 2014. Accessed February 2015. Beral V, Million Women Study Collaborators. Ovarian cancer and hormone- replacement therapy in the Million Women Study. Lancet. 2007;369:1703- 1710. Menopausal hormone therapy and cancer risk. American Cancer Society. 2014.http://www.cancer.org/cancer/cancercauses/othercarcinogens/medicaltr eatments/menopausal-hormone-replacement-therapy-and-cancer-risk. Accessed February 2015. Sattar N, Forouhi NG, Wild RA. C-rective protein and hormone replacement therapy. Circulation. 2000; 102:e96-7. US Food and Drug Administration. Questions and Answers for Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm135339.ht m5. (Accessed February 2015). Anderson GL, Clebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012 Mar 6
Editor's Notes
- #4 Normal women have menopause at a mean age of 51.4 years. 95% of woman experience menopause between 45 and 55 years of age. The definition of menopause is_____. Without any other obvious physiological causes. Permanent cessation of menstrual periods, determined retrospectively after 12 months of amenorrhea Hot flashes are the most common symptom in of menopause transition. They often resut in sleep disturbances
- #5 -Hot flashes are the most common and most bothersome symptom associated with menopause and its transition. Often times, this is why people seek treatment. -HOT FLASHES HAVE BEEN REPORTED IN UP TO 70% OF WOMEN UNDERGOING NATURAL MENOPAUSE AND ALMOST ALL WOMEN UNDERGOING SURGICAL MENOPAUSE. ABOUT 31% EXPERIENCED HOT FLASHES DURING PERIMENOPAUSE IN ONE TRIAL.
- #6 -Inhibin B is a hormone produced by the granulosa cells in the overy that suppresses synthesis and secretion of the FSH, thereby regulating the menstrual cycle. -FSH follicle stimulating hormone: does exactly what its name implies, stimulates the growth and recruitment of immature ovarian follicles in the ovary. In women in the reproductive years, this is highest at about the 3rd day of a period. (As a woman nears perimenopause, the number of small antral follicles recruited in each cycle diminishes and consequently insufficient Inhibin B is produced to fully lower FSH and the serum level of FSH begins to rise. Eventually the FSH level becomes so high that downregulation of FSH receptors occurs and by menopause any remaining small secondary follicles no longer have FSH receptors. -Luteal phase progesterone: the luteal phase is the latter phase of the menstrual cycle in humans, lasts between 10-16 days. Progesterone is the main hormone associated with this phase, and it is highest during this phase. Progesterone is vital in implantation and support of early pregnancy. -Ovarian antral follicle count: Antral follicles are ovarin follicles that are present during a latter stage of foliculogenesis. These follicules contain receptors for leutinizing hormone, resulting in estrogen production. When the count of these follicles decreases, less estrogens are being made, and the chances of fertilization becomes slim. This level is often used in in vitro fertilization to determine fertility and levels of viable follicles remaining. -In the early transition phase, there begins to be a persistent difference in length of consecutive cycles (greater than or equal to 7 day difference). The antral follicle count is low and FSH may or may not be increased. -in late transition, the interval of amenorrhea will be greater than or equal to 60 days. FSH will be greater than 25 international units per liter -VASOMOTOR SYMPTOMS: HOT FLASHES
- #7 -this picture depicts the stages of reproductive aging workshop(STRAW) developed based on multiple studies. Considered the gold standard for characterizing reproductive aging. -As you can see in the supportive criteria row, Follicle stimulating hormone increases beginning in perimenopause (possibly earlier), it reaches its highest levels prior to the final menstrual period FMP=final menstrual period, and stabilizes eventually in postmenopause. -AMH stands for antimullerian hormone, it is a hormone expressed by overy cells during the reproductive years and limits the formation of primary follicles by inhibiting excessive follicular recruitment by FSH. This level is often used to determine fertility and predict the age a woman will go through menopause. As would be expected, it decreases during the menopause transition. -women during the menopausal transition appear to have a higher rate of mood symptoms than pre or post menopausal women
- #8 -LH: as we know this hormone triggers ovulation and regulates the menstrual cycle. High luteinizing hormone levels mean that ovaries are not inducing ovulation, so the LH levels are rising trying to stimulate ovary function. Therefore, it increases during menopause. -Progesterone decreases drastically during perimenopause, which makes sense seeing as its function is in implantation. -As you can see, dramatic hormone changes are occurring during this period, resulting in the symptoms of menopause experienced by most women at this phase in their life. So be nice.
- #9 -Dementia: recently, a study conducted by Standford University Medicine found that hormone therapy, initiated soon after menopause, prevented degredation in key brain regions of women at heightened risk for dementia (hx major depression, first degree relative with the condition, or Apo4 allele gene). This effect was mostly seen in the estradiol treated patients. Not proven. -Heart disease is common in the aging population. Postmenopausal women should always be encouraged to make lifestyle, diet, and other health changes that will decrease their risk. Some studies have come out saying early treatment with estrogen or estrogen+progestin therapy may result in cardiovascular protection. Hormone therapy should not be used for the primary or secondary prevention of coronary heart disease at the time since long-term safety and efficacy trials need to be conducted.
- #10 -physicians responsible for the care of postmenopausal women must manage and attempt to prevent health consequences associated with aging and monitor for the risks of hormone therapy -the risks of endometrial cancer and VTE with hormone therapy are clearly established. Irregular bleeding should prompt frequent follow-ups with a physician to test for endometrial cancer. -VTE: increasing age and obesity is also a major factor, healthy lifestyle changes should be enforced, smoking cessation should ALWAYS be enforced with women on HT. Patients on hormone therapy should ALWAYS be counseled on this risk -breast cancer: estrogen and progesterone can stimulate the growth of some breast cancer. The increased breast density often results in tumors being found when they are bigger and have spread to other organ systems. The longer HT is used, the higher the risk. If 10.000 women took EPT for a year, about 8 more cases would arise than if they had not taken HT. -ovarian cancer: possible risk, harder to draw conclusions since this cancer is less common. A recent analysis combined the results of more than 50 studies and found women who took estrogen and progestin after menopause did have an increased risk of acquiring OCA. This risk was highest in women taking hormones and decreased over time after treatment was stopped. If 1000 women who were 50years old took HT for menopause for 5 years, one extra ovarian cancer would be expected to develop. -after menopause the risk of stroke almost doubles in women. This is attributed to the estrogen concentrations declining leading to androgen excess, which could result in CV risk factors. The risks are thought to be small in the short-term. -Short duration of therapy is always a wise option to avoid these risks. About 5 years.
- #11 -Breast cancer (current, past, or suspected) -Active or recent arterial thromboembolic disease (MI, angina) -porphyria cutanea tarda is a genetic, enzyme deficiency that affects the heme pathway in the body. Porphyria (a heme precursor) reaches toxic levels resulting in photosensitivity, blisters, and necrosis of the skin.
- #12 -GOLD STANDARD FOR RELIEF OF MENOPAUSAL SYMPTOMS, ESPECIALLY HOT FLASHES -decreases the quantity and severity of hot flashes -ORAL: studies have found serum LDL is decreased while HDL is increased on estrogen therapy. Triglycerides levels may increase due to estrogen therapy, and these should be monitored regularly. C reactive protein. It is suggested that not all HRTs are alike in their effect on CRP concentrations. The route of delivery of the estrogen, the relative androgenicity of the progestogen, and the chronicity of use might be important in this respect. More trials need to be done. Be cauteous for possible cardiovascular effects. -17-beta estradiol is the main estrogen the ovary secretes prior to menopause -ethinyl estradiol is a derivative of 17B -conjugated equine estrogens (aka Premarin or Prempro) consist of estrogen isolated from a mare’s urine (horse)
- #13 -local/vaginal therapies are usually used for vaginal symptoms, where as systemic therapies are more for vasomotor symptoms such as hot flashes.
- #14 -adverse effects: switching among various progestational agents may decrease these symptoms
- #15 -the SSRIs are the most effective nonestrogen therapy for vasomotor symptoms, with venlefaxine being the most studied. Clinical response of SSRIs is days, rather than a couple weeks like it is for depression. Good choice for women with breast cancer. -venlafaxine has more acute toxicity and significant withdrawal symptoms. Must taper up and down. Pristiq does not require tapering schedule, but it is pricey -paroxetine (SSRI/SNRI) modestly effective. Avoid in women taking tamoxifen. -Fluoxetine effect is not clinically important. Can not use on tamoxifen. -If antidepressants are not tolerated, clonidine may be considered, but it is associated with a high incidence of adverse effects (dizziness, dry mouth, constipation, sedation) If used, the transdermal preparation is superior due to stable blood levels. Begin with 0.1mg per day. -gabapentin long term efficacy and safety have yet to be established. Can be a good option in nocturnal hot flashes. Begin with 100mg QHS and increase by 100mg Q3nights until relief of hot flashes, side effects, or max 900mg
- #16 -Soy: estrogenic activity of soy facilitates the risk of these conditions, and women with a personal or strong family history of these should avoid soy-based therapies until long term trials are completed. -Black cohosh: Package labeling recommends use for no more than 6 months. -These are a couple of examples of the stuff I see patients buying in retail. Based off the lack of evidece, they could be wasting their money. However, the placebo effect is significant in treating menopause symptoms.
- #18 placebo effect, which can reduce hot flashes by approximately 20 to 50 percent. even statistically significantly effective agents may act at least partially through a placebo-mediated mechanism
- #19 -symptoms look similar to estrogen deficiency -DHEA: Dehydroepiandrosterone, dehydroepiandrosterone sulfate, Androstenedione :natural steroids in the body. -add androgen if symptoms persist -estratest aka methyltestos
- #20 -cyclic dosing may result in menstruation, amenorrhea is achieved with continuous dosing -Clonidine, antidepressants, & anticonvulsants may have benefit for example patients experiencing depression may consider antidepressant therapy for hot flashes and depression treatment