Hrmne Replacement Therapy Therapeutics III December 8, 2003 Alicia Frinash, Pharm.D. Required Readings Kalantaridu S, Davis S, Calis K. Hrmne replacement therapy. In: DiPir J, Talbert R, Yee G et al. Pharmactherapy: a pathphysilgic apprach, 5 th ed. New Yrk: McGraw-Hill, 2002:1491-1510. Supplemental Readings Hulley S, Grady D, Bush T et al. Randmized trial f estrgen plus prgestin fr secndary preventin f crnary heart disease in pstmenpausal wmen. Heart and estrgen/prgestin replacement study (HERS) research grup. JAMA 1998;280:605-13. Grady D, Herringtn D, Bittner V et al. Cardivascular Disease Outcmes During 6.8 Years f Hrmne Therapy Heart and Estrgen/Prgestin Replacement Study Fllw-up (HERS II). JAMA 2002;288:49-57. Writing grup fr the wmen s health initiative investigatrs. Risks and benefits f estrgen plus prgestin in healthy pstmenpausal wmen principle results frm the wmen s health initiative randmized cntrlled trial. JAMA 2002:288;321-33. (WHI trial) Mrelli V, Naquin C. Alternative therapies fr traditinal disease states: menpause. Am Fam Physician 2002;66:129-34. Cntent Questins: 1. Describe the changes in the hypthalamus-pituitary-vary (HPO) axis in menpause 2. List symptms present with menpause 3. List nnpharmaclgic treatments fr menpausal symptms 4. List the gals fr menpause treatment 5. Describe the difference between estrgen replacement therapy (ERT) and hrmne replacement therapy (HRT) 6. Name the predminant frm f estrgen in premenpausal and pstmenpausal females 7. List cmmn adverse effects frm HRT. Describe ADRs that are less cmmn in transdermal estrgen cmpared t ral 8. Define rle fr prgestins in HRT 9. List the benefit f teststerne therapy in menpausal females. Explain why estrgen must be administered when giving teststerne therapy. 10. Explain the mechanism f actin, benefits, and ADRs fr selective estrgen receptr mdulatrs (SERMs) 11. List the cntraindicatins t HRT 12. List and explain the benefits and risk f HRT therapy 13. List imprtant cunseling pints fr HRT/ERT 14. List alternative treatments fr vasmtr symptms 1
1. Intrductin Menpause: lss f varian functin leading t a state f permanent amenrrhea Occurs after 12 cnsecutive mnths f amenrrhea Climacteric r Perimenpausal At menarche, 380,000 cytes are present within varian fllicles After age 35, the varies begin t decrease in weight and size and cntain fewer cytes and fllicles; als a gradual decline in estrgen prductin Series f irregular menstrual cycles with increased menstrual cycle length and variable intermenstrual intervals Average age f menpause is 51 years ld, usually between 49-53 Average life expectancy fr a female is 79.7 years, s 1/3 f life is pstmenpausal Surgical menpause Wmen wh smke typically underg menpause apprximately 2 years earlier likely due t alteratins in sterid metablism and gamettxic effects f cigarette smke 2. Hrmnal Changes Changes in the Hypthalamus-Pituitary-Ovarian (HPO) axis Hypthalamus GnRH Anterir Pituitary FSH, LH Ovaries Estrgen Prgesterne Andrgens FSH levels increase 10-15x and LH increases 4-5x nrmal premenpausal levels; pstmenpausal levels are >40mIU/mL Lab tests TSH Urine HCG 3. Menpausal symptms and changes Vasmtr Osteprsis Urgential atrphy 2
Athersclersis Dry Skin 4. Estrgen Metablism and Effects andrstenedine armatizatin Estrne (E1) teststerne armatizatin 17β Estradil (E2) is the predminant estrgen premenpausal females and is derived frm develping fllicles predminant estrgen in pstmenpausal females and is derived frm adipse tissue. Adrenal glands and varian strma cells prduce the andrgen andrstenedine which is cnverted t estrne peripherally in the adipse and ther tissues. This cnversin is enhanced in bese wmen. Is steprsis mre cmmn in bese r thin wmen? Is breast cancer Oral estrgens mre cmmn are largely in cnverted bese r t estrne thin wmen? Transdermal r intravaginal estrgen des nt have first pass metablism, s the effects f hepatic metablism are less likely t ccur. Sme (minimal) effects n lipids may still be seen. Effects f Hepatic Metablism Estrgens Prgestins HDL and LDL* HDL and LDL ** TG and VLDL N effect n cltting factrs factrs VII and X antithrmbin III activity Renin substrate* PAI-1 * May nt be true fr nn-ral rutes that avid first-pass effect ** May nt be as significant fr micrnized prgesterne Prgesterne levels decrease. PEPI trial invlved 875 wmen t cnjugated equine estrgens (CEE) 0.625mg/d, CEE 0.625mg + medrxyprgesterne (MPA) 2.5mg, CEE 0.625mg + MPA 10mg 12 days/m, CEE 0.625mg + micrnized prgesterne (MP) 200mg/d fr 12 days/m, r placeb CEE alne have the mst beneficial effects n the lipid panel fr increasing HDL. Hwever, estrgen plus prgestins still have beneficial effects n HDL Patients with a uterus n CEE alne had significantly higher rates f endmetrial hyperplasia All treatment grups decreased LDL and increased TG withut significant difference 5. Histrical Perspectives in HRT 3
CAD Number ne cause f death fr females (nt breast cancer) Observatinal trials suggest 35-50% lwer risk f crnary artery disease in wmen taking estrgen cmpared t nnusers. Effect is prpsed t be frm lipid effects Hwever, randmized trials have NOT supprted bservatinal trials Primary Preventin Wmen s Health Initiative randmized trial 16,608 pstmenpausal wmen Results In 10,000 wmen 50-79 years ld that use HRT >1 year, HRT resulted in - 7 mre CHD events + 6 fewer cases f cln cancer - 8 mre PE + 5 fewer hip fractures - 8 mre cases f breast cancer **Still has an arm f Estrgen alne versus placeb nging t evaluate 8 years f therapy. Expected cnclusin in 2004. Secndary Preventin HERS first randmized, duble blind, cntrlled trial Cnjugated equine estrgens 0.625mg + medrxyprgesterne 2.5mg (Prempr) vs. placeb fr fur years with ne year fllw-up Primary utcme was nnfatal MI and cardivascular deaths Results Significantly increased risk during year ne fr the HRT grup N significant difference during years 2-4 but the data starting t trend in HRT s favr American Cllege f Cardilgists Recmmendatin:...des nt supprt the initiatin f cnjugated equine estrgens cmbined with medrxyprgesterne acetate in lder pstmenpausal wmen with cnfirmed crnary disease. Fr wmen with CHD already n ERT fr at least ne year, it may be reasnable t cntinue therapy while awaiting the results f a HERS fllw-up study HERS II 2.7 years fllw-up (ttal 6.8 years) t the HERS, N significant difference in CAD events between HRT and placeb grups at years 5,6,7,8 r fr, cmbined 6.8 years * Prfessinal Cnclusins n HRT fr CAD: United States Preventative Services Task Frce (USPSTF) harmful effects f estrgen and prgestin are likely t exceed the chrnic disease preventin benefits in mst wmen. The balance f benefits and harms fr an individual wman will be influenced by her persnal preferences, individual risks fr specific chrnic diseases, and the presence f menpausal symptms. Insufficient evidence t recmmend fr r against the use f unppsed estrgen fr the preventin f chrnic diseases in pstmenpausal wmen with a hysterectmy. did nt evaluate HRT fr the management f menpausal symptms. Nrth American Menpause Sciety (NAMS) Treatment f menpause symptms are the primary indicatin fr ERT and HRT. N HRT regimen shuld be used fr CHD. the effects f ERT n CHD is still unknwn. Use HRT/ERT shuld be limited t the shrtest duratin cnsistent with treatment gals, benefits, and risks fr the individual wman 4
Wmen shuld be infrmed f knwn risks Questins still t be answered Will ERT prduce the same results? D different frmulatins f HRT (i.e. Activella, FemHRT) prduce different effects? D different delivery rutes (i.e. transdermal) have different results? Shuld different prgestins be used? Dsed cyclically instead f QD? Many, many mre 6. Benefits f HRT Vasmtr Symptms Mst effective therapy fr treatment Higher dses ften required t cntrl vasmtr symptms Therapy cntinued fr 1-2 years t cntrl symptms Oral and transdermal preparatins effective in treatment Bne turnver increases with decrease in estrgen levels Only fr preventin, nt treatment f steprsis WHI fund significant decrease f 34% f hip and vertebral fractures but HERS fund n significant difference in vertebral and hip fractures Oral and transdermal estrgens are effective Is it wrth the risk? Urgential Symptms Treatment f vaginal atrphy, dysparunea, vaginitis is successful with ral, transdermal, and vaginal preparatin Questinable Benefit CVA Preventin Epidemilgic data prpsed that HRT wuld decrease risk f CVA. Recent randmized, duble-blind, secndary preventin trial nted n significant differences in CVA mrtality r recurrence WHI fund significant increased risk f 41% and HERS fund n significant difference Cgnitive Functin and Alzheimer s Disease Early bservatinal trials suggested prtectin frm cgnitive decline. Hwever, randmized, cntrlled trials have failed t supprt this. Prpsed mechanism invlves estrgen prmte grwth f chlinergic neurns, pssess antixidant effects, decrease aplipprtein E levels, increase metablism f amylid precursr prteins, prmte neurite grwth, and increase cerebral bld flw Cln Cancer Observatinal studies reprt a decreased risk f 8-33% WHI fund a significantly lwer rate f 37%, the HERS II trial fund n difference Miscellaneus Preventin in tth lss Decreased risk f peripheral arterial disease 7. Risks f HRT Thrmbemblism can decrease with estrgen,, and can increase with estrgen Increases risk f DVT by 2-3.5, but the abslute risk if relatively small (20 per 100,000 cases) 5
Endmetrial Cancer Estrgen stimulates endmetrial cell mitsis and prliferatin Unppsed estrgen (>1 year) increases the risk f endmetrial cancer 8-10 times Endmetrial hyperplasia is precursr Prgestin therapy added t ERT decreases the risk Risk Factrs: besity, nulliparity, infertility, liver disease, and estrgen-secreting varian tumrs NF is a 46yAAF wh presents t yur clinic with cmplaints f ht flashes, irregular menses fr 8 mnths and amenrrhea fr the past 3 mnths, vaginitis, and insmnia. She wants t start replacement therapy fr these symptms. PMH: HTN and GERD, PSH: s/p TAH/BSO (10/02) Shuld NF receive HRT r ERT? Why? Breast Cancer lifetime risk fr wmen in general with a greater incidence in thse >60 years ld N significant increase in the incidence f breast cancer fr wmen wh take HRT fr LESS than 5 years. Reanalysis f data frm 51 trials shws that breast cancer risk increases with lng-term use f estrgen. 5 years after HRT has been discntinued, there is n lnger an increased risk fr breast cancer WHI was stpped early because f the higher rate f breast cancer in the HRT grup. 15% higher rate fr the first five years (nnsignificant) and 54% higher rate fr greater than 5 years f use (significant) Gallbladder dysfunctin Observatinal trials reprt an increased risk f 2-3x. HERS trial had a 38% higher rate f gallbladder disease in thse taking HRT Cnsider transdermal estrgen in high risk patients 8. Adverse Reactins Nausea (less likely with transdermal) GI discmfrt Blating, fluid retentin Breast tenderness Headaches/Migraines (less likely with transdermal) Weight gain (cyclic) (frm fluid retentin) Decreased libid PMS-like symptms frm prgestin Depressin Sptting/breakthrugh bleeding (BTB) 9. Cntraindicatins Abslute * * * * * Relative Uterine leimyma Histry f migraines Histry f chlelithiasis Histry f thrmbsis related t pregnancy r ral cntraceptives Seizure disrder HTN Hypertriglyceridemia CAD 6
10. HRT Regimens and Prducts - Nt effective as cntraceptives because regimens cntain ~1/5 estrgen dse Rutes f Administratin ORAL Advantages: Greater increase in effect n hepatic lipprteins, ease f administratin Disadvantages: Liver effects Cntinuus Estrgen and cyclic Prgestin Estrgen is given every day at a set dse Prgestin is added fr 10-12 days/mnth Advantages: n return f menpausal symptms because estrgen is given each day Disadvantages: bleeding each mnth (usually begins 1-2 days after last prgestin dse) Cntinuus Estrgen and Prgestin Thught t create an atrphic endmetrium and induce amenrrhea Decreasing the estrgen dse r increasing the prgestin dse can help induce amenrrhea Advantages: 75% f wmen have amenrrhea at ne year Disadvantages: unpredictable sptting r BTB when beginning therapy Unppsed Estrgen ONLY fr wmen WITHOUT a uterus N prgesterne given, s n bleeding TRANSDERMAL Applied ne (Climara) r tw (Estraderm, Vivelle) times per week Advantages: Decreased r n liver effects, useful in patients with GI absrptin prblems, stable cncentratins f estrgen Disadvantages: Skin irritatin, less significant effects n lipids, still need t give prgestins fr wmen with an intact uterus COMBIPATCH is a cmbinatin patch f estradil and nrethindrne 9cm 2 patch cntains 0.62mg E2 and 2.7mg NETA (0.05/0.14mg/d) 16cm 2 patch cntains 0.51mg E2 and 4.8mg NETA (0.05/0.25mg/d) Apply the patch t the abdmen twice a week VAGINAL Cream Dsing QD x1 week, QOD x1 week, then 1-2x/wk thereafter Vaginal rings (Estring, Femring) prvides a sustained release f estrgen t treat vaginal atrphy Advantages: Useful fr symptms f vaginal atrphy Disadvantages: Erratic absrptin, lng-term use may cause endmetrial hyperplasia PARENTERAL Little infrmatin n hepatic effects Des nt underg hepatic first pass metablism, s thught t nt have much effect n lipids SUBCUTANEOUS PELLETS Implanted int the anterir abdminal wall r buttck and cntain crystalline 17β estradil Pellets are difficult t remve and may cntinue t release estrgen fr a lng time after insertin; implanted every 6 mnths fr steprsis prtectin Nt ppular in the U.S. PRODUCTS Start mderate dses and titrate therapy based upn ADRs. Gal is t keep patient symptm-free n lwest pssible dses. 7
There is n evidence t suggest that ne prduct is mre effective than anther. Prduct Premarin (cnjugated estrgens) Ogen (estrpipate [piperazine estrne sulfate]) Estrace (micrnized 17β estradil) Estinyl (ethinyl estradil) Estratab, Menest (esterified estrgen) Estraderm, Vivelle (17β estradil transdermal) Equivalent Dse 0.625 mg 0.625 mg 1 mg 0.02 mg 0.625 mg 0.05 mg/d Cnjugated equine estrgen: 10 different estrgen cmpnents Mst studied estrgen prduct Varius cmpnents are being investigated fr specific effects f lipids, breast tissue, antixidant capabilities, and direct cardivascular effects Synthetic estrgen (ethinyl estradil, quinestrl, DES) Mst ptent hepatic effects and extended half-life DES nt cmmnly used fr HRT Micrnized estradil Rapid cnversin t estrne when given rally Estrne sulfate, estradil valerate, equine estrgens: Mre ptent hepatic effects than micrnized estradil when given at dses that reach similar serum estrail levels Estrgen/teststerne cmbinatins Prescribed fr wmen with decreased libid r sexual difficulties n estrgen May be mst useful in surgically induced menpause because f severe symptms after rapid declines in estrgen and teststerne levels Methylteststerne available alne, but shuld nt administer withut estrgen Administer cautiusly and use lwest dse fr shrt perids f time ADRs: hirsutism, acne, ptential hepattxicity, adverse lipid effects( TC, LDL, TG, HDL), ptential insulin resistance, fluid retentin ptential increased risk f breast cancer, ptential fr thrmbemblic effects Teststerne Cntraindicatins: pregnancy, lactatin, knwn r suspected andrgen-dependent tumr. Relative cntraindicatins: mderate t severe acne, clinical hirsutism, and andrgenic alpecia PROGESTINS Medrxyprgesterne (MPA) Prgestin added t prducts fr endmetrial prtectin but must be taken fr a minimum f 12-14 days per mnth t prtect against endmetrial hyperplasia Mst used and studied prgestin Synthetic prgestins (nrethindrne, nrgestimate, desgestrel) Newer prducts use these prgestins in an effrt t induce amenrrhea quicker and t ease the transitin frm OC t HRT Higher incidence f amenrrhea at ne year which may be due t the higher binding affinity t the endmetrium than MPA 11. Discntinuing HRT/ERT Abrupt discntinuatin may result in vasmtr symptms Tapering days reduce the number f days/week the patient 8
Tapering dses reduce the dse f expsure 12. Mnitring Befre initiatin f therapy Cmplete H&P (including medical and family histry, BP, weight, breast and pelvic exams, PAP smear) Baseline mammgram Fasting lipid prfile Fllw-Up Mammgram yearly Breast and pelvic exam yearly Fasting lipid prfile 13. Nnpharmaclgic treatments Vasmtr Reduce r avid the intake f ht beverages and caffeine Exercise Cl shwers befre bedtime Avid turtlenecks Avid spicy fds Relaxatin/stress reductin (massage, meditatin, yga) Avid wl r synthetic clthing Cl envirnment Cl beverages r ice chips Other Calcium intake Vaginal lubricating gels, if needed Cunseling fr depressin, if needed Vaccinatins 14. Educatin Purpse(s) Prper use Administratin Imprtance f cmpliance Imprtance f cmmunicatin Ptential ADRs Cmmn ADRs Ptentially serius ADRs Decide tgether with the patient whether r nt HRT is fr her 15. Selective Estrgen Receptr Mdulatrs (SERM) MOA: activates sme estrgen receptrs while blcking ther estrgen receptrs in the bdy Advantages: steprsis preventin, breast cancer preventin, lipid effects Disadvantages: ht flushes, leg cramps, thrmbemblism risk Ralxifene (Evista) 60mg p QD Tamxifen (Nlvadex) 10mg p QD 16. Alternative Treatments fr Vasmtr Symptms Many wmen cannt r d nt want t take HRT fr vasmtr symptms fr varius reasns including CAD, breast cancer, ADRs, cst, etc. Pr r limited date n therapies; hwever, many patients will ask abut r take these prducts Antidepressants venlafaxine 75mg/d, fluxetine 20mg/d, parxetine 10-30mg/d, sertraline 25-50 mg/d 9
In small studies, 50-87% reductins in ht flushes Antihypertensive Agents Clnidine has been studied as tablets and patches fr reducing vasmtr symptms. Adverse events limit its effectiveness β-blckers have als been shwn effective in reducing ht flushing Bellergal-S Cntains belladnna 0.2 mg, phenbarbital 40 mg, ergtamine 0.6 mg) Has peripheral adrenergic and chlinergic antagnizing effects Duble-blind, placeb cntrlled trial demnstrated 60% reductin in symptms Others Megesterl Gabapentin Mirtazapine Herbal Prducts Herbal (Prducts) Black Chsh (Remifemin) Red Clver (Prmensil) Evening Primrse Dn quai Sy, phytestrgens (Healthy wman 55mg/tab, Natrl fr wmen 10mg/tab, etc) F.Y.I. -MOA: unknwn -Uncntrlled, pen-label trials demnstrated benefit ver placeb -Limited t a maximum f 6 mnths f therapy in Germany -Usually takes >1mnth f therapy t relieve symptms -May cause intlerable GI effects. Nt effective fr steprsis -FDA statement -Phytestrgen with mild effects n vasmtr symptms -N steprsis r lipid benefit -Shuld nt use if patient has histry f breast cancer -MOA: unknwn -One small study fund benefit ver placeb but ther studies d nt supprt any benefit -Pssess vasmtr and antispasmdic effects -N significant difference cmpared t placeb in a RCT -Chinese herbalists cmment that dn quai must be used in cmbinatin with ther herbals t effectively relieve vasmtr symptms -Be sure t avid fr patients n warfarin because f in the INR -Metablized in the GI tract t frm structures that are similar t estrgens and can bind t the estrgen receptr and prduce antixidant effects -Active ingredients are Isflavnes, lignans, and cumestans -37-100 mg/d f sy isflavne r 20-60 mg/d sy prtein given fr effects - Has been shwn t increase tumr grwth in wmen with estrgen-receptr psitive breast cancer and may interfere with tamxifen - Small studies have demnstrated psitive results in cntrlling ht flashes - Als prpsed t prevent steprsis * Other prducts tried include flaxseed il, fish il, mega-3 fatty acids, red clver, ginseng, rice bran il, wild yam, calcium, gtu kla, licrice rt, sage, sarsaparilla, passin flwer, chaste berry, ginkg bilba, valerian rt; hwever, n gd evidence exists in the literature t supprt these prducts. ***D nt recmmend these prducts because f little primary literature t supprt use. Be aware f drug interactins, adverse drug reactins. Als, FDA des nt regulate cntents f herbals because they are cnsidered dietary supplements. 10