“THE EVOLVING USE OF ESTROGEN AND HORMONAL THERAPY: WHAT I DO IN 2012”

2. “THE EVOLVING USE OF ESTROGEN AND HORMONAL THERAPY: WHAT I DO IN 2012” T. Watson Jernigan, MD MA Chairman and Professor Department of Ob/Gyn Quillen College of Medicine

3. Disclosure Statement of Financial Interest DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

4. OBJECTIVES • “As a result of participating in this activity, the participant will be able to…” • …appreciate the impact of the W.H.I. on the treatment of Menopausal Symptoms • …demonstrate an understanding of subsequent studies reviewing the use of hormonal therapy

5. OBJECTIVES • …apply the principles of treatment based on current practice guidelines and position statements to current patients • …appreciate that the modality of therapy plays a marked role in the treatment of current menopausal patients

6. INTENT OF LECTURE • This lecture is designed to evaluate the evolving use of hormones in postmenopausal patients since the publishing of the W.H.I. Study. It will discuss the evidence based medicine that has led this physician in his prescribing of hormonal therapy. It is hoped that this journey will impact the prescribing habits of other providers.

8. LESSONS LEARNED PRIOR TO 2000 • Use of estrogens can improve menopausal symptoms such as hot flashes (1940s) • Use of estrogens can cause thromboembolic phenomenon (1950s) • Use of estrogen can improve subjectively feminine sense of well being (1960s) • Use of unopposed estrogen can lead to endometrial hyperplasia or endometrial cancer (1970s)

9. MENOPAUSE • According to records of prescriptions, there were 129 million prescriptions for Hormonal Therapy (HT) including estrogen in the year 2000 • In 2001, a Women’s Health Initiative (WHI) study was undertaken to evaluate the efficacy of Estrogen and Progestin as well as Estrogen alone in preventing heart disease in postmenopausal women

15. POST-WHI MENOPAUSE • After the 2002 WHI study was published approximately 65% of women on HT stopped therapy • In 2003, there were just over 76 million HT prescriptions dispensed • By 2008, this number had dropped to approximately 42 million prescriptions for HT in USA (29 million were for estrogen only RXs)

18. POST W.H.I. EFFECT • “Trends in hormone therapy use before and after publication of the Women’s Health Initiative trial: 10 years of follow-up” • Published 2009 but showed the impact of the W.H.I. on European prescribing of estrogen in Barcelona, Spain • By 2007, there was a peak reduction of 89% in percentage of overall prevalence • Barbaglia, Gabriela MD, et al, Menopause Vol. 16, No. 9, 2009; 1061-1064

19. POST W. H. I. EFFECT • This was a retrospective cohort study of 300,000 inhabitants in Barcelona, Spain from 1998-2007 • Women ages 50-69 years were evaluated • The age groups evaluated were: 50-54; 55-59; 60-64; and 65-69 • In addition to prevalence, the percentage of new users was also evaluated

22. LESSONS LEARNED AFTER W. H. I. • Use of estrogen in postmenopausal patients should not be used in prevention of chronic illnesses especially cardiovascular disease • Use of estrogen if started should be considered early in Menopause (ages 50-59) for benefit of specific symptoms • Use of estrogen in postmenopausal patients is not for everyone

27. YEAR 2007 • “Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause” • Rossouw et al reviewed the original data of the WHI and created a secondary analysis • The study reviewed both arms of the trials (E2 + P4 and E2 alone) Rossouw, J. E. et al JAMA 2007; 297: 1465-1477

28. YEAR 2007 • In the combined trials, there were 396 cases of CVD and 327 cases of stroke in the hormone treated group • In the combined trials, there were 379 cases of CVD and 239 cases of stroke in the placebo group • For women with less than 10 years since Menopause, the RR was 0.76 95% CI 0.50-1.16 Rossouw, J. E. et al JAMA 2007; 297: 1465-1477

29. YEAR 2007 • Rossouw et al stated, “These analyses, although not definitive, suggest that the health consequences of hormone therapy may vary by distance from menopause, with no apparent increase in CHD risk for women close to menopause, and particularly high risks in women who are distant from menopause and have vasomotor symptoms.” Rossouw, J. E. et al JAMA 2007; 297: 1465-1477

37. LESSONS LEARNED 2012 • Use of Alternative Therapies (e.g. black cohosh, soy, dong quai) have not been shown to have “statistically significant” improvement of VMS in postmenopausal women • Use of estrogen should be started at the lowest possible dosage • Use of estrogen by topical or non-oral route should be considered to avoid the First Pass Effect of the liver

38. IN 2012, WHAT DO I DO? • Reviewing the literature, I have made several decisions • Lack of estrogen causes hot flashes, night sweats, and VMS • These VMS can be substantial and in certain patients cause a change in quality of life • The treatment for VMS is estrogen

39. IN 2012, WHAT DO I DO? • In patients who have undergone hysterectomy, I discuss the use of estrogen for severe VMS and other quality of life issues • Given the difficulty with Alternative Therapies and the First Pass Effect of the Liver, I discuss extensively non-oral approach to treatment • Use of patch, cream, gel, lotion, and vaginal ring are legitimate treatments

40. IN 2012, WHAT DO I DO? • If the patient is agreeable, I start with the lowest dosage possible for four (4) weeks • After 4 weeks, I see the patient in follow-up to discuss the effectiveness of treatment • It will take upwards of two weeks to see improvement of the number or the intensity of the VMS for the patient • If there is excellent control of the VMS, the patient is seen in three months

41. IN 2012, WHAT DO I DO? • In patients who have severe atrophic vaginitis and have reservations about use of systemic estrogen, then I offer topical vaginal estrogen either by cream or tablet • In some patients who are already on systemic estrogen for VMS but continue to have problems with severe atrophic vaginitis, I will supplement with topical vaginal estrogen

42. IN 2012, WHAT DO I DO? • Once a patient is stabilized on the estrogen for VMS/Quality of Life issues, she is seen at 6 months and then 12 months • Every year she returns for her annual examination including pap smear and mammogram, a discussion regarding the use of estrogen is done • New information from the literature is given to the patient and discussion regarding continuation of therapy commences

43. IN 2012, WHAT DO I DO? • In patients who have not had a hysterectomy (have an intact uterus), the discussion regarding therapy is more extensive • The patient is specifically explained about the WHI and the risk of breast cancer • The severity of the VMS is weighed against the concerns generated for breast cancer • If patient wishes to proceed, she is started on estrogen alone first

44. IN 2012, WHAT DO I DO? • The same principles for starting estrogen (lowest dosage, non-oral) are followed • The patient is continued on increasing dosages of estrogen until her VMS are stabilized • Once the VMS are treated, then progestin/natural progesterone is added to prevent endometrial stimulation

45. IN 2012, WHAT DO I DO? • In neither scenario do I obtain Serum Estradiol Levels or for that matter LH/FSH unless patient is uncertain she is postmenopausal • I do not do pretreatment endometrial biopsy or transvaginal ultrasound • I do mandate a pretreatment mammogram for determining occult breast cancer/ breast calcifications

46. IN 2012, WHAT DO I DO? • After a patient has been on either estrogen alone or estrogen with progesterone for greater than one year, I talk seriously about decreasing the amount of medication or even stopping the medication • If VMS recur, then the patient will resume at her previous treatment dosages • Most patients use the hormonal therapy for an average of 3-4 years

47. CONCLUSIONS “OR WHAT DO I REALLY THINK IS GOING TO HAPPEN”

49. A FINAL THOUGHT • RELATIVE RISKCHARACTERISTIC • 14 2 FAMILY MEMBERS WITH BREAST CA • 2.2 1 FAMILY MEMBER WITH BREAST CA • 1.8 OBESITY • 1.6 YOUNG AGE AT MENARCHE • 1.3 >30 AT BIRTH OF FIRST CHILD • 0.7 MENOPAUSE <49 YEARS OF AGE • 1.3 HORMONE THERAPY (E+P)<5 YEARS Archer, David. “Postmenopausal HRT: What is fact, what is fiction” OBG MANAGEMENT; June 2006: 76-85.