9/27/2017. Disclosure. Selecting Progestogens: Breast, Cardiovascular, and Cognitive Outcomes. James H Liu, MD. Overview

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1 Disclosure Selecting Progestogens: Breast, Cardiovascular, and Cognitive utcomes James H Liu, MD Arthur H Bill Professor and Chair Departments of Reproductive Biology and bstetrics and Gynecology UH Cleveland Medical Center Advisory Consulting Allergan Therapeutics MD Pfizer Bayer Clinical Trials for the University Hospitals Allergan AbbVie NIH Contraceptive Trials Network Palatin 9/7/017 verview Progesterone Signaling 1. Focus on progestins in clinical use Steroid Progesterone (P4) Medroxyprogesterone acetate (MPA) Norethindrone (Norethisterone, NET). Biology, metabolism, structure functional relationships. Caveat: All studies discussed will reflect the effects of combination of estrogen (E, CEE) with different progestin exposures. Steroid Hormone Receptor Ulipristal Gi LH Surge Drowsy Coregulators Secretory Endo Effector genes genes 1

2 Structural Differences Among Progestins ral Progesterone Intake and the First Pass Effect Progestins: Related But Distinct Agents CH C= CCH C=CH CH C= CCH Progesterone Norethindrone acetate Deletion of the methyl group between rings A and B Addition of an ethinyl group at position 17 CH Medroxyprogesterone acetate ral progesterone metabolites i.e. 0- DHP4 results in drowsiness Bailey D G, Dresser G K CMAJ 004;170: ral Progesterone Metabolism: ff Target Effects Medroxyprogesterone acetate Metabolism H HP 5 -reductase H Progesterone H 5 P Breast 0 DHP Brain Sedation MPA template structure is not broken by CYPA4 during metabolism and binds as MP-acetate to progesterone receptors Zhang Drug Metabolism and Dispostion 008;9

3 Minimal Dose of MPA Required for Endometrial Protection n Target Effects 00 ENDMETRIUM n Target Effects D Cytosolic Estrogen Receptor Femtamoles/mg protein ±SEM 100 y=0.99 FM/mgP ±SEM B CEE only * +.5 MPA 0.65 mg CEE +5 MPA +10 MPA 0. mg 0.65 mg CEE CEE 1.5 mg CEE CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate. Gibbons WE et al. Am J bstet Gynecol. 1986;154: Suggested Progestin Doses Required For Secretory Changes in E-Primed Endometrium for 10-1 days How Much Progestin is Sufficient? ral Progestin Medroxyprogesterone acetate Micronized progesterone Vaginal progesterone gel Drospirenone Norethindrone Norgestrel Dydrogesterone Dose Required 5-10 mg/d mg/d 45 mg/d* mg/d* mg/d g/d 10-0 mg/d A Simple Method for Determining the ptimal Dosage of Progestin in Post menopausal Women Receiving Estrogens Padwick ML, Pryse Davies J, Whitehead MI. NEJM 1986;15:90 4 Regardless of the preparation and dosage of the (cyclic) estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue was associated with bleeding on day 11 or later. King et al. Fertil Steril 1986;46(6):106; Whitehead et al. bstet Gynecol 1990;75(4):59S; * ther data

4 Biology: Progesterone Effects on Gland Mitoses in Human Breast and Endometrium Are Different Mitoses n Target Effects Endometrium Breast BREAST ff Target Effects Cycle Days ff Target Effects T.A. Longacre et al. Am J. Surg Path, Vol.10 No. 6, WHI CEE+MPA Trial: Mammography Results Increased Breast Density, Cysts WHI CEE+MPA: During Study and Follow-up Breast Cancer Year 1 % Abnormal* E+MPA Proportion verall *Abnormal mammograms included those that were associated with recommendations for short-term follow-up, showed a suspicious abnormality, or were highly suggestive of malignancy P <.001 vs E+P. Chlebowski RT, et al. JAMA. 00;89:4-5. Modified from Heiss et al. JAMA 008;99: /7/

5 No Increased Risk of Invasive Breast Cancer in the WHI CEE-Alone Trial Cumulative Proportion Kaplan-Meier Estimate HR = % nci = CEE Time (years) Women s Health Initiative Steering Committee. JAMA. 004;91: WHI CEE+MPA Trial: Characteristics of Invasive Breast Cancers E+P (n = 199) (n = 150) P-Value Tumor size, mean ± SD (cm) 1.7 ± ± Positive lymph nodes, % SEER stage, % Localized Regional Metastatic Morphology, grade, % Well differentiated Moderately differentiated Poorly differentiated/anaplastic SEER = Surveillance, Epidemiology, and End Results. Chlebowski RT, et al. JAMA. 00;89:4-5. Summary: WHI Breast Cancer Results CEE alone used for an average of 7 yrs did not increase breast cancer risk in women with prior hysterectomy 1 CEE+MPA used for an average of 5 yrs was associated with a small increased risk of breast cancer in women without prior hysterectomy Increased risk was limited to those women with prior HT use Absolute risk of breast cancer was low in both WHI trials, regardless of treatment assignment 1, 1 Women's Health Initiative Steering Committee. JAMA. 004;91: Chlebowski RT, et al. JAMA. 00;89:4-5. Summary: WHI Breast Cancer Results Breast cancers among women assigned to CEE+MPA were somewhat larger and more likely to involve regional lymph nodes Higher rate of abnormal mammograms observed in women assigned to CEE+MPA Cannot make direct comparisons between the CEEalone and CEE+MPA results Study populations had important differences in baseline risk Chlebowski RT, et al. JAMA. 00;89:4-5. 5

6 Breast Cancer Risk Among CEE+MPA Users in Randomized Controlled Trials WHI HERS HERS II Chlebowski RT, et al. JAMA. 00;89:4-5. Hulley S, et al. JAMA. 00;88: Relative Hazard (95% CI) Million Women Study Investigators recruited 1,084,110 women in the UK, aged years, between 1996 and 001 Questionnaire about lifestyle, SES, medical history, and HT use sent in conjunction with invitation from NHSBSP for screening mammography Mean age, 56 years; 964 cases of invasive breast cancer and 67 breast cancer deaths identified during follow-up Analysis of HT and breast cancer risk restricted to postmenopausal women (n = 88,9) 50% were ever-users of HT; % were current users; mean duration of use was 5.8 years SES = socioeconomic status; NHSBSP = National Health Service Breast Screening Programme. Million Women Study Collaborators. Lancet. 00;6: Incident Invasive Breast Cancer in Relation to Recency and Type of HT Used Relative Risk HT Use at Baseline (95% FCI)* All never-users 1.00 ( ) All past users 1.01 ( ) Current users E-only 1.0 (1. 1.8) E+P.00 ( ) Tibolone 1.45 ( ) ther/unknown types 1.44 ( ) FCI = floated CI *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, body mass index, region, and deprivation index. Million Women Study Collaborators. Lancet. 00;6: Incident Invasive Breast Cancer in Current Users of E-only Preparations Type of Estrogen? Relative Risk E-only Formulation (95% CI)* All E-only formulations 1.0 ( ) By constituent and dose All equine estrogen 1.9 ( ) 0.65 mg 1.5 ( ) >0.65 mg 1.6 ( ) All 17 -estradiol 1.4 ( ) 1 mg 1.5 ( ) >1 mg 1.19 ( ) By formulation ral 1. ( ) Transdermal 1.4 ( ) Implanted 1.65 (1.6.16) Dotted line represents overall relative risk for current users of estrogen-only preparations compared with never-users at baseline *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 00;6:

7 Incident Invasive Breast Cancer in Relation to Recency and Type of HT Used Total Duration of HT Use by Type of HT Used at Baseline Relative Risk (95% FCI)* Never-users of HT Past users of HT <1 year 0.94 ( ) 1 4 years 1.01 ( ) 5 9 years 1.14 ( ) 10 years 1.05 ( ) Current users of E alone <1 year 0.81 ( ) 1 4 years 1.5 ( ) 5 9 years 1. ( ) 10 years 1.7 ( ) Current users of E+P <1 year 1.45 ( ) 1 4 years 1.74 ( ) 5 9 years.17 (.0.) 10 years.1 (.08.56) FCI = floated CI. *Relative to never-users, stratified by age, age at first birth, family history of breast time 0.0 since 1.0 menopause,.0 parity.0 and cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 00;6: Incident Invasive Breast Cancer in Current Users of E+P Preparations Type of Progestin Duration of Use, <5 Years Relative Risk E+P Formulation (95% CI)* All E+P formulations 1.70 ( ) By progestin constituent Medroxyprogesterone acetate 1.60 (1. 1.9) Norethisterone 1.5 ( ) Norgestrel/levonorgestrel 1.97 (1.74.) By type of regimen Sequential 1.77 ( ) Continuous 1.57 ( ) Dotted line represents overall relative risk for current users of estrogen-progestin preparations compared with never-users at baseline *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 00;6: Incident Invasive Breast Cancer in Current Users of E+P Preparations Duration of Use, 5 Years Relative Risk E+P Formulation (95% CI)* All E+P formulations.1 (.06.6) By progestin constituent Medroxyprogesterone acetate.4 (.10.80) Norethisterone.10 (1.89.4) Norgestrel/levonorgestrel. (.04.44) By type of regimen Sequential.1 (1.95.0) Continuous.40 (.15.67) CGNITIN ff Target Effects Dotted line represents overall relative risk for current users of estrogen-progestin preparations compared with never-users at baseline *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 00;6:

8 Defining Cognition Domains Cognition comprises multiple mental processes Attention Perception Working memory Executive function Spatial ability Language Learning Memory Figural Verbal Adapted from Loring DW, ed. INS Dictionary of Neuropsychology. New York, NY: xford University Press; 1999:9. Normal Cognitive Aging Preserved vocabulary Memory Motor/psychomotor speed Attention Visuospatial performance Visuomotor skills Ashman TA, et al. In: Hazzard WR, et al, eds. Principles of Geriatric Medicine and Gerontology. New York, NY: McGraw-Hill; 1999; Normal Cognitive Aging Versus Dementia Everyone with dementia has cognitive impairment, but not everyone with cognitive impairment has dementia Dementia represents a decline in memory and at least one other cognitive domain 1 With dementia, the decline interferes with occupational or social functioning 1 1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; Fitted Mean MSE Score WHIMS: Mean Modified Mini-Mental State Exam (MSE) Scores ver Time CEE/MPA Trial P =.055 CEE-Alone Trial P =.04 Active Drug Years Since Randomization Adapted from Espeland MA, et al. JAMA. 004;91:

9 WHIMS: Probable Dementia Shumaker SA, et al. JAMA. 00;89: Shumaker SA, et al. JAMA. 004;91: CEE+MPA (n = 9) (n = 0) HR (95% CI) Cases of probable dementia* (1.1.48) Rate per 10,000 person-years 45 CEE Alone (n = 1464) (n = 148) HR (95% CI) Cases of probable dementia (0.8.66) Rate per 10,000 person-years 7 5 *Mean follow-up in CEE+MPA vs placebo arms: 4.05 ± 1.19 years. Mean follow-up in CEE alone vs placebo arms: 5.1 ± 1.7 years. WHIMS: Mild Cognitive Impairment Cases of mild cognitive impairment* E+P (n = 9) Rate per 10,000 person-years 6 59 (n = 0) HR (95% CI) ( ) E Alone (n = 1464) (n = 148) HR (95% CI) Cases of mild cognitive ( ) impairment Rate per 10,000 person-years *Mean follow-up in CEE+MPA vs placebo arms: 4.05 ± 1.19 years. Mean follow-up in CEE alone vs placebo arms: 5.1 ± 1.7 years. Calculated from published data. Shumaker SA, et al. JAMA. 00;89: Shumaker SA, et al. JAMA. 004;91: WHIMS CEE+MPA: Cumulative HR for a Diagnosis of Probable Dementia Cumulative Hazard CEE/MPA HR,.05 95% CI, WHIMS CEE Alone Study: Cumulative HR for a Diagnosis of Probable Dementia Cumulative Hazard CEE Alone HR = % CI = Number of Events CEE/MPA 5 Years Since 7 Randomization Shumaker SA, et al. JAMA. 00;89: Years Since Randomization No. of Events CEE Alone Shumaker SA, et al. JAMA. 004;91:

10 WHIMS: Effect of CEE+MPA on Mild Cognitive Impairment and Probable Dementia WHIMS Summary Number of Events Mild Cognitive Impairment Years of Follow-Up Shumaker SA, et al. JAMA. 00;89: CEE/MPA Number of Events Probable Dementia CEE/MPA Years of Follow-Up Significant increase in risk of all cause dementia in the CEE+MPA arm, but not significant in the CEE alone arm No significant increase in mild cognitive impairment AD was not evaluated as a separate outcome Shumaker SA, et al. JAMA. 00;89: Shumaker SA, et al. JAMA. 004;91: WHI CEE+MPA: During Study and Follow-up Stroke WHI Results: Effect of CEE Alone on Risk of Stroke Kaplan-Meier Estimate Proportion Cumulative Hazard HR = % nci = % aci = CEE Modified from Heiss et al. JAMA 008;99: Time (years) Women's Health Initiative Steering Committee. JAMA. 004;91: /7/017 University Hospitals Case Medical Center / Case Western Reserve University School of Medicine 9 10

11 PSTMENPAUSAL ESTRGEN/PRGESTIN INTERVENTINS PEPI TRIAL ( ) Post Rx Lipoproteins HDL-C (mg/dl) LDL-C (mg/dl) Total Chol (mg/dl) Trigly (mg/dl) 0 CARDIVASCULAR ff Target Effects CEE CEE + MPA (cyc) CEE + MPA (con) CEE + P4 (cyc) JAMA 7:199-08, KEEPS Study: Impact of Micronized Progesterone All E subjects took 00 mg P4 x 1d/m Carotid Intimal Thickness Coronary Artery Calcium Elite Trial:Timing Hypothesis and Progesterone Use oe 1 mg/d with Vaginal Progesterone Gel 45 mg X 10d/m ocee- n=0 te- n=11 n=6 Early Menopause < 6 yrs Late Menopause >10 yrs PLoS Medicine 015; 1(6): e10018 Hodis et al N Engl J Med 016; 74:

12 Elite Trial: Timing Hypothesis and Progesterone Use WHI CEE+MPA: Study and Follow up Coronary Heart Disease Hodis et al. N Eng J Med 016;74:11-1 Early Menopause < 6 yrs Late Menopause >10 yrs Modified from Heiss et al. JAMA 008;99: /7/ WHI E+P: During Study and Follow-up Pulmonary Embolism Total Mortality in WHI and HERS CEE/MPA WHI 1, HERS CEE Alone CEE/MPA utcomes (n = 8506) (n = 810) (n = 510) (n = 549) (n = 180) (n = 18) CHD death Cancer death ther deaths Unadjudicated deaths Modified from Heiss et al. JAMA 008;99: Total deaths Writing Group for the Women's Health Initiative Investigators. JAMA. 00;88:1-; Women's Health Initiative Steering Committee. JAMA. 004;91:1701-1; Hulley S, et al. JAMA. 1998;80: /7/017 University Hospitals Case Medical Center / Case Western Reserve University School of Medicine 47 1

13 Summary of Randomized Controlled Trials: CHD and verall Mortality Length CHD Total Mortality Trial Treatment (yrs) RR (95% CI) RR (95% CI) HERS 1* ral CEE + MPA ( ) 1.08 ( ) PHASE Transdermal E ( ) Not reported alone or with NE ESPIRIT ral E valerate ( ) 0.79 ( ) WHI E+P 4* ral CEE + MPA ( ) 0.98 ( ) WHI-E 5 ral CEE ( ) 1.04 ( ) NE = norethisterone. * Early CHD events; No early CHD events. 1 Hulley S, et al. JAMA. 1998;80:605-1; Clarke SC, et al. Br J bstet Gynecol. 00;109:1056-6; Cherry N, et al. Lancet. 00;60:001-8; 4 Writing Group for the Women s Health Initiative Investigators. JAMA 00;88:1-; 5 The Women's Health Initiative Steering Committee. JAMA 004;91: Summary of Serial Arterial Imaging Controlled Trials Coronary Artery Stenosis Trial ERA 1 Treatment ral CEE + MPA ral CEE alone Length (yrs) utcome P. : 0.09 mm CEE: 0.09 mm CEE + MPA: 0.1 mm WAVE ral CEE + MPA.8 : 0.04 mm/y CEE + MPA: mm/y WELL- HART ral 17β-E + MPA ral 17β-E alone. : 1.89% S 17β-E + MPA: 1.4% S 17β-E:.18% S EPAT 4 ral 17β-E.0 : mm/y 17β-E: mm/y S = stenosis. 1 Herrington DM, et al. N Engl J Med. 000;4:5-9; Waters DD, et al. JAMA. 00;88:4-40; Hodis HN, et al. N Engl J Med. 00;49:55-45; 4 Hodis HN, et al. Ann Intern Med. 001;15: