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hormone replacement therapy new advance.ppt
- 1. Hormone Replacement Therapy AndMenopause Mikael D. Jones, Pharm.D, BCPS College of Pharmacy College of Nursing University of Kentucky
- 2. Objectives Discuss thecurrent recommendations for the use of hormone replacement therapy Compare and contrast the various dosage forms available for hormone replacement therapy
- 3. Facts and Figures 35 million women are >50 years of age 50-85% of menopausal women will experience symptoms of estrogen deficiency 25% of these women will have significant distress from these symptoms Endocrine Practice Vol 12 No. 3 May/June 2006 Fertility and Sterility Vol. 86, Suppl 4, November 2006
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- 5. Clinical Presentation VasomotorSymptoms Vaginal Dryness Sleep Disturbances Mood Symptoms Cognitive Disturbances Uterine Bleeding Sexual Dysfunction Quality of Life Increasing Evidence Symptoms Attributable to Menopause NIH Consensus State Sci Statements. 2005. Mar 21-23; 22(1) 1–38.
- 6. Vasomotor Symptoms Hotflash (or flush) Few minutes or several minutes Occur every hour to several per week Narrowing of threshold between sweating and shivering Risk Factors Cigarette smoking BMI 30 kg/m2 Menopause <52 years Abrupt Menopause Endocrine Practice Vol 12 No. 3 May/June 2006
- 7. Vaginal Atrophy Vaginaldryness Vaginal itching Dyspareunia Persists and may worsen with age Urologic symptom may not always be menopause
- 8. Reproductive Menopausal TransitionPost Menopause Early Peak Late Early Late* Early* Late Perimenopause Prevalence of Hot Flashes 10% 40% 65% 65% 10-15% Prevalence of Vaginal Symptoms 30% 47% N Engl J Med 2006;355:2338-47.
- 9. Treatment of Menopause Goals of Therapy Reduce symptoms resulting from estrogen imbalance Treat urogenital atrophy and vaginal dryness Minimize risk of disorders that may be more frequent during hormone replacement therapy Fertility and Sterility Vol. 86, Suppl 4, November 2006
- 10. Therapeutic Options Non-pharmacologic Maintain cool environment Cotton Clothing Exercise/ stretching Vaginal lubricants/moisturizers (vaginal sxs) Pharmacologic Hormone Replacement Therapy (HRT) Antidepressants Clonidine Gabapentin
- 11. Hormone Replacement Therapy Contraindications Current, past, or suspected breast cancer Known or suspected estrogen-sensitive malignant conditions Undiagnosed genital bleeding Untreated endometrial hyperplasia Previous idiopathic or current venous thromboembolism Active or recent arterial thromboembolic disease (angina, MI) Untreated hypertension Active liver disease
- 12. Estrogen Therapy Conjugatedequine estrogen Synthetic conjugated estrogen Estradiol & Ethinyl Estradiol Esterified estrogen Estropipate Estrone
- 13. Progestogen Therapy Medroxyprogesteroneacetate Progesterone Norethindrone acetate Norgestimate
- 14. Hormone Replacement Therapy Systemic Dosing strategies Estrogen Only Progestogens 10-14 days Sequential Therapy Estrogen Daily + Continuous Therapy Estrogen + Progestogens Daily Local Estroge n
- 15. Risk Associated withERT/HRT Use Effect on Risk ERT HRT Venous Thromboembolism Endometrial Cancer Unopposed with uterus Breast Cancer ? ? Stroke
- 16. Use of HRT/ERTto Prevent Disease Effect on Risk ERT HRT Fracture Dementia Cardiovascular Disease ? ? Colon Cancer Stroke
- 17. Current Recommendations FDAIndications for HRT Treatment of moderate to severe vasomotor symptoms associated with menopause Treatment of moderate to severe symptoms of vulvar and vaginal atrophy Prevention of postmenopausal osteoporosis
- 18. Current Recommendations Decisionto use HRT should be based on patient specific risk vs benefit Use the lowest dose to control symptoms for the shortest duration Reevaluate dose as patient ages Use progestogen with estrogen in women with a uterus HRT should not be used to prevent chronic diseases Ann Intern Med. 2005;142:855-860. Endocrine Practice Vol 12 No. 3 May/June 2006
- 19. Treatment Modalities Transdermal/Topical Oral Therapy Focus on Low Dose Vaginal Rings Creams Bioidentical
- 20. Focus on NewHRT Dosage Forms
- 21. Transdermal Advantages Avoidsfirst-past effect Avoids induction of triglyceride production Does not increase production of angiotensinogen May reduce thromboembolic risk associated with oral estrogen
- 22. Transdermal Transdermal Patches 17-estradiol (e.g. Menostar , Vivelle Dot , Estraderm ) Doses 0.014 mcg to 0.1 mcg 17-estradiol + Norethindrone acetate (CombiPatch ) 17-estradiol + levonorgestrel acetate (Climara Pro ) Once or twice weekly application
- 23. Transdermal Transdermal Gel All 17-estradiol products EstroGel 0.06% Metered pump (0.035mg/day) Elestrin 0.06% Metered pump (0.0125mg/day) Divigel 0.1% Gel Packets (0.25-1 mg/day) Transdermal Emulsion Estrasorb Emulsion packets (0.05 mg/day) Transdermal Spray Evamist 1.7% solution
- 24. Transdermal Gels Allproducts are once a day Apply at the same time each day Apply after bath, shower, sauna use Wash hands after application No currently available products with a progestogen Women with a uterus still require a progestogen All Gels and spray are not approved for osteoporosis prevention or treatment
- 25. Reduction in DailyHot Flash Frequency (12 weeks) -12 -10 -8 -6 -4 -2 0 Mean Change from Baseline Estrogel Elestrin Divigel Estrasorb Evamist Placebo Product *<0.01 * * * * * Prescribing Information for respective product
- 26. Transdermal Gel Application ProductApplication Procedures EstroGel 1 pump of gel applied to 1 arm (wrist to shoulder); Dries in 2-5 mins Elestrin Pump gel onto upper arm; Spread on upper arm and shoulder with 2 fingers Divigel Cut open packet; Apply to right or left upper thigh (alternate daily); Spread gel over 5-7 inches Estrasorb 2 packet = dose; Apply one packet per leg; Start at upper thigh and massage into thigh and calf area Prescribing Information for respective product
- 27. Transdermal Spray Application EvamistPrescribing Information 8/2007 •Remove Cover •Hold upright and rest cone flat against the skin •Depress pump fully once •If a second or third dose has been prescribed, apply in area next to original dose
- 28. Low Dose OralRegimens What is considered low dose? 0.3mg of oral conjugated estrogens 0.25-0.5 mg oral micronized 17 -estradiol 0.025mg transdermal 17 -estradiol patch Effectiveness Hot flash reduction similar Dose-related effects on bone Fracture risk reduction not clear Maturitas 57 (2007) 81–84
- 29. Reduction in HotFlash Frequency 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Reduction in Frequency CEE Oral 17b estradiol Transdermal 17b estradiol Placebo Traditional Dose Low Dose N Engl J Med 2006;355:2338-47.
- 30. Low Dose OralRegimens Safety Potential decrease in adverse effects Stroke Risk VTE Risk More studies needed! Progestogen Dose reduction 0.625mg dose of CEE 2.5mg of medroxyprogesterone acetate 0.3mg dose of CEE 1.5 mg of medroxyprogesterone acetate Maturitas 57 (2007) 81–84
- 31. 17 -Estradiol + Drospirenone Angeliq 17 -Estradiol (1mg) + Drospirenone (0.5mg) Indicated for treatment of moderate to severe vasomotor symptoms/ vulvar and vaginal atrophy May cause hyperkalemia Only available in 1mg/0.5mg Cannot provide low dose estrogen with this product Angeliq Package Insert Bayer 2007
- 32. 17 -Estradiol + Drospirenone Drospirenone Spironolactone analog Antimineralocorticoid and antiandrogenic effects Prevents endometrial hyperplasia Reduce Sodium/water retention May reduce blood pressure CLIMACTERIC 2007;10(Suppl 1):3–10
- 33. Vaginal Products Localtherapy is effective in treating vaginal therapy Cochrane Review suggests all vaginal estrogen products are equally effective Progestogen therapy is not needed for local therapy However systemic absorption does occur Conjugated estrogens creams may have higher incidence of adverse effect compared to the ring or vaginal tablet delivery Suckling J, Lethaby A, Kennedy R. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD001500.
- 34. Vaginal Products Creams 17-estradiol Conjugated Equine Estrogens Vaginal Tablet Estradiol hemihydrate Rings 17-estradiol (local therapy) Estradiol acetate (systemic therapy)
- 35. Avoid Ring Confusion 17-estradiol (local therapy) Estring Silicone Ring 7.5g/24H over 90 days Patient can insert Estradiol acetate (systemic therapy) Femring Silicone Ring 0.05mg or 0.1mg/ day over 90 days Patent can insert Patient’s with uterus will require progestogen therapy Estring Package Insert Pfizer Femring package Insert Warner Chilcott
- 36. Androgens In 2003FDA question the effectiveness of conjugated estrogen/ methyltestosterone products Products never have been approved by FDA Controversial when androgens should be utilized Difficult to determine true androgen deficiency Endocrine Practice Vol 12 No. 3 May/June 2006 Federal Register: April 14, 2003 (Volume 68, Number 71)
- 37. Androgens Androgen insufficiency Loss of Libido Decreased sexual motivation, enjoyment Insomnia, depression, poor concentration Adequate estrogen status Very low free-testosterone levels Testosterone typically does not decline in menopause Produced by ovaries Endocrine Practice Vol 12 No. 3 May/June 2006
- 38. Androgens Possible applications(more studies needed) Post-menopausal women with androgen insufficiency despite adequate estrogen replacement Women who have undergone bilateral oophorectomy and are on estrogen therapy Generally not recommended Endocrine Practice Vol 12 No. 3 May/June 2006
- 39.
- 40. Women’s Health Initiative JAMA2002;288:321–33. N Engl J Med 2003;349:523–34. JAMA 2003;289:3243–53 JAMA 2004;291:1701–12. Estrogen and progestin Estrogen Only Outcome Relative Hazard 95% CI Relative Hazard 95% CI CHD 1.2 0.97-1.6 0.95 0.79-1.16 Stroke 1.4 0.86-2.31 1.39 0.97-1.99 VTE 2.1 1.26-3.55 1.333 0.86-2.08 Breast Cancer 1.2 0.97-1.59 0.77 0.57-1.06 Colon Cancer 0.6 0.32-1.24 1.08 0.63-1.86 Hip Fracture 0.6 0.33-1.33 0.61 0.33-1.11
Editor's Notes
- #4 The average age of menopausal transition is 47 years and takes about 4 years to progress to menopause In early menopausal transition the menstrual menstrual cycles remain regular, but the duration changes by seven days or more. The late menopausal transition (stage 1) is characterized by two or more skipped menstrual periods and at least one intermenstrual interval of 60 days or more. Menopause is determined in retrospect, after a woman has had a year of amenorrhea. Women with three to 11 months of amenorrhea will likely become menopausal within four years. Women over the age of 45 who have a year of amenorrhea have a nine in 10 chance of not having another spontaneous menstrual period. Environmental influences also may alter the ovarian aging process. For example, smoking advances the age of menopause by about two years (6).
- #5 It is difficult to determine which symptoms are actually associated with ovarian aging or general aging. The decline in estrogen function is highly correlated with vasomotor symptoms and vaginal dryness
- #6 hot flash occurs is thought to be a result of elevated body temperature leading to cutaneous vasodilatation, which results in flushing and sweating in association with a subsequent decrease in temperature, chills, and potentially relief. One belief is that within the hypothalamic thermoregulatory zone there is an interthreshold zone, defined as the threshold between sweating and shivering. Available evidence indicates that, after menopause, this interthreshold zone becomes narrowed. Proposed triggers for this change in interthreshold zone include serotonin (5-hydroxytryptamine), norepinephrine, and estrogen deprivation.
- #7 Vaginal atrophy occurs b/c of the decline of estrogen in the vaginal tissue and leads to a thinning a drying of the vaginal walls. Women also lose a host defense b/c the acidic pH of vaginal found in premenopausal women changes to a more alkaline pH and thus can become colonozid or infected easier with pathogens
- #8 The prevelance of hot flashes increases through the menopausal transition and declines in late menopause with about 10-15% that will continue to have vasomotor symptoms. Vaginal symptoms occur after the menopausal transition and increases with time
- #14 Estrogen alone therapy is reserved for patients that have undergone a hysterectomy because unopposed estrogen will cause endometrial hyperplasia and endometrial cancer In women with an intact uterus a progestogen should be added. Sequential or cyclica therapy refers to progestogens being taken for 10-14 days each month usually causing monthly menstrual periods Continuous is when the estrogen and lower progestogen dose is given daily. This causes ammenorrhea which may be more acceptable to the patient. However many women will experience break through bleeding. Lastly local estrogen therapy can be used to treat local vaginal symptoms this may be advantageous because it minimizes systemic exposure
- #15 VTE risk has been clearly established by both randomized clinical trials and epidemiological trials. Endometrial cancer risk increase in women using unoppposed estrogen therapy with a uterus. The addition of a progestogen is to reduce endometrial hyperplasia Breast Cancer is a complex issue. Breast cancer risk seems to influenced by the duration of exposure to estrogens and progestogens. ERT may not have a significant risk based on WHI ERT arm. Progestogens may make it more difficult to detect breast cancer by increasing the density of breast tissue. Risk seems to be increased in older women with longer estrogen exposures. The risk may disappear after be off estrogen for >5 years. Being obese or smoking has a higher attributable risk than HRT. Both arms of the WHI had an increased risk of stroke compared to placebo (significant in the nominal rather than adjust pool). May be dose related
- #16 Decrease Hip fracture CV diesease Risk of heart attack from hormones may not be increased in women who start the hormones less than 10 years after menopause, but there is increasing risk in women who are more distant from menopause Risk of stroke from hormones does not depend on when a woman starts hormone therapy; strokes are increased regardless of years since menopause Risk of death from any cause appeared to be reduced in women who were 50-59 years at the time they started hormones in the two WHI trials \\ dementia Stroke: Both ERT and HRT increase stroke
- #21 The oral route is characterized by first-pass enterohepatic removal of a substantial fraction of the estrogen, followed by hepatic metabolism and conjugation to sulfates and glucuronides, which are then excreted through the bile back into the digestive tract. At this site, the sulfates are deconjugated to some extent and reabsorbed. All drugs subject to the firstpass effect show greater interindividual variability in the blood levels attained. This finding is true of the estrogens—a fact that may be of considerable clinical relevance. Furthermore, the high concentrations of estrogen delivered to the liver by the oral route (in comparison with transdermal absorption directly into the peripheral circulation) induce increased synthesis of triglycerides and certain proteins such as cortisol-binding globulin (transcortin), sex hormone-binding globulin, and angiotensinogen. Therefore, transdermal administration of estrogen is preferred in certain clinical situations, such as in women with hypertension, hypertriglyceridemia, and increased risk for cholelithiasis Ester trial multicentre hospital-based case-control study of postmenopausal women Overall, 32 (21%) cases and 27 (7%) controls were current users of oral ERT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal ERT. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users was 3·5 (95% CI 1·8–6·8) and 0·9 (0·5–1·6), respectively. Estimated risk for VTE in current users of oral ERT compared with transdermal ERT users was 4·0 (1·9–8·3). Interpretation- Oral but not transdermal ERT is associated with risk of VTE in postmenopausal women.
- #25 Evamist 12 week change from baseline