Dr. Jennifer Pearlman 51st Annual Scientific Assembly Grants/Research Support: none Speakers Bureau/Honoraria: none Consulting Fees: none Other Payments or Relationships with commercial interests: none This program has received NO financial support from any commercial or for-profit entity This program has received NO in-kind support from any commercial or for-profit entity Potential conflict of interest: none • Dr. Jennifer Pearlman has received NO support from related organizations and/or organizations whose product(s) are being discussed in this program No potential sources of bias identified Case Introduction Defining BioHT Historical Perspective Why Consider BioHT Safety of BioHT Prescribing BioHT Conclusion 52 yr, FMP 18m ago Corporate executive Wife, mother, daughter, friend Hot flashes, night sweats Poor sleep Irritable, labile mood Impaired recall and concentration Loss of libido Agents of change Produced by endocrine cells in specialized organs Travel via blood/lymph Exert effect at distant site Bioidentical HT: Molecularly equivalent with same lock-and-key fit with in vivo receptor Source: Natural v. Synthetic • Form: Pharmaceutical v. Custom Compounded • Route: Oral v. Transdermal v. Transvaginal • Traditional HT: Synthetic Hormone Analogues or Non-human equivalent Outcomes: Cognitive, Bone, Heart Side Effects: Bleeding, Mood, Sleep, Weight Risks: Cardiovascular, Clotting, Breast Cancer Nomenclature confusion Perceived paucity of evidence No patents No sponsor No drug reps/patient leaflet Political/regulator intervention (i.e. estriol) Perceived as alternative treatment Stigma “Suzanne Effect” 1930’s -Collip & McKenna (Ayerst) produce EMMENIM (urine of pregnant Canadian women) Reformulated w Stallions, Pregnant mares (T2-3), potency 2-3x human 1942 -FDA approves Premarin (PREgnant MARes urINe), depsite known risk EC 1966 -Robert Wilson “Feminine Forever” (Ayerst $50k research grant) Sodium Estrogen Sulfate Mg/tablet Estrone 0.37 Equilin 0.168 17a-Dihydroequilin 0.102 17a-Estradiol 0.027 17b-Dihydroequilin 0.011 l7a-Dihydroequilenin 0.011 17b-Dihydroequilenin 0.021 Equilenin 0.015 l7b-Estradiol 0.005 D8,9-dehydroestrone 0.026 http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm168836.htm E1 -Estrone: • E2 -Estradiol: • made in fat cells from Testosterone by aromatase most active, abundant, ovarian, stimulates breast/uterus (ER alpha) E3 -Estriol: • weak estrogen, made by placenta/liver, breast protective, neuroprotective, specific to vaginal mucosa Widely approved/used 1st line for urogenital atrophy (outside NA) • Ovestin 0.5mg E3 supp, 1mg cream • New ultra low dose 50mcg E3 gel Currently unavailable in NA: • Politicized in US (blocked by FDA), no HC approved Rx Under Investigation: • Clinical trial P3 5mg oral dose in MS Clin Exp Obstet Gynecol. 2011;38(2):143-5. Chuery AC, Speck NM, de Moura KF, Belfort PN, Sakano C, Ribalta JC. OBJECTIVE: This study evaluates the effect of intravaginal estriol on urogenital atrophy, Pap smear parameters, colposcopy parameters and discomfort during gynecological examination. METHODS: 31 postmenopausal women who had not used hormone therapy in the previous six months were studied. All women used intravaginal estriol, 1 mg/day for 21 days. The following variables were analyzed before and after treatment: complaints of urogenital atrophy; cytological parameters, colposcopic parameters, and subjective evaluation of discomfort during gynecologic examination. RESULTS: All urogenital atrophy complaints improved after treatment. At the first visit, 45.2% of women presented a predominance of profound cells, 51.6% with predominance of intermediate cells, and 3.2% with predominance of superficial cells. At the second visit, these rates were 35.5%, 64.5%, and 0%, respectively. Evaluation of the maturation index showed that 83.9% of women had atrophic Pap smears, and 16.1% showed good estrogenic level before treatment. At the second visit, atrophic smears occurred in 12.9%, and 87.1% of women exhibited good estrogenic level (chi2 = 20.045; p = 0.000). Colposcopy showed that 71% of women had atrophic colpitis and/or petequiae before treatment, while atrophy after therapy was present in only 6.4%. The evaluation of other colposcopic parameters also improved after treatment. Great discomfort was reported by 19.4% before and by 0% after treatment. CONCLUSION: Intravaginal estriol 1 mg/day for a period of 21 days was efficient in improving urogenital atrophy, Pap smear parameters and colposcopic evaluation in postmenopausal women. Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Biglia N, et al. Gynecol Endocrinol. 2010 Jun;26(6):404-12. OBJETIVES: The study aim is to evaluate the efficacy and safety of two low-dose vaginal estrogen treatments (ETs) and of a nonhormonal vaginal moisturizer in postmenopausal breast cancer survivors with urogenital atrophy. METHODS: Eighteen patients receiving estriol cream 0.25 mg (n = 10) or estradiol tablets 12.5 microg (n = 8) twice/week for 12 weeks were evaluated and compared with eight patients treated with polycarbophil-based moisturizer 2.5 g twice/week. Severity of vaginal atrophy was assessed using subjective [Vaginal Symptoms Score (VSS), Profile of Female Sexual Function (PFSF)] and objective [Vaginal Health Index (VHI), Karyopycnotic Index (KI)] evaluations, while safety by measuring endometrial thickness and serum sex hormones levels. RESULTS: After 4 weeks, VSS and VHI were significantly improved by both vaginal ETs, with further improvement after 12 weeks. PFSF improved significantly only in estriol group (p = 0.02). Safety measurements did not significantly change. Vaginal moisturizer improved VSS at week 4 (p = 0.01), but score returned to pre-treatment values at week 12; no significant modification of VHI, KI, PFSF was recorded. CONCLUSIONS: Both low-dose vaginal ET are effective for relieving urogenital atrophy, while nonhormonal moisturizer only provides transient benefit. The increase of serum estrogens levels during treatment with vaginal estrogen at these dosages is minimal. Progesterone Precursor to all steroid sex hormones Made by CL at ovulation Progestational Anti-proliferative (breast, uterus) Crosses BBB (GABA agonist) Bone Stimulating (osteoblast activation) Progestins (synthetic analogue) Androgenic (NETA) Non-androgenic (MPA= Provera) • • Medroxy Progesterone Acetate (MPA) RR Breast cancer: MPA 1.48 v. Progesterone 1.0 (no risk) RR VTE: MPA 1.8 v. Progesterone 0.9 (10% decrease) French E3n Cohort Study ,Fournier, Br Ca Res. Treat 2008;107:103-111 18 1940’s –Marker Process discovered 1950’s –MPA developed to be more potent, orally bioavailable than progesterone 1956 -MPA (Provera) patented, approved • Approval based on –ve EB data only (3y, n=596) 1980 -Oral MP (Prometrium) approved in France 1990’s -Upjohn provides MPA & MP for PEPI 1994 -NHI funded WHI begins, using CEE+ MPA 1999 –FDA approves Prometrium in US Progesterone’s improved cardiovascular safety profile established prior to WHI enrollment Estrogen “with cyclic MP has the most favorable effect on HDL-c and no excess risk of endometrial hyperplasia” The Writing Group for the PEPI trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA. 1995; 273(3)1:199-208. “The contrasting effects of progesterone and MPA seem clinically important, inasmuch as MPA is a widely used progestin in the regimen of HRT”. Otsuki M, et al. Progesterone, but not MPA, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2001; 21(2): 243-8. Santen, RJ. Risk of breast cancer with progestins: critical assessment of current data. Steroids 2003; 68:953-64. Stahlberg C. Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe. Int J Cancer 2004; 109: 721-7. Fournier, A. Unequal risks for breast cancer associated with different hormone replacement therapies; results from the E3N cohort study. Breast Cancer Res Treat 2008; 107 (1): 103-11 “the choice of the progestagen in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone” • E3N French epidemiologic cohort study • Self-administered questionnaires 1990-2002 • 80,377 postmenpoausal women w. up to 12 yrs f/u Compared with HT Never-Use Relative Risk (CI) Estrogen alone RR 1.29 ( 1.02-1.65)* Estrogen + progesterone RR 1.0 (0.83-1.22) Estrogen + dydrogesterone RR 1.16 (0.94-1.43) Estrogen + other progestins RR 1.69 (1.50-1.91)* Fournier A et al. Breast Cancer Res Treat 2008: 107:103 Study Author(s) Sample (n) Duration Findings KEEPS Multi-centre, Harman (2005) 720 36m/5yrs Compared 0.45mg CEE, 50mcg estradiol in combinations with cyclic oral MP 200mg 12d monthly v placebo PEPI 1995, 2002 Writing Group 875, age 4564yr 3 yrs Lipoprotein: MP greatest inc HDL-c (p0.004) Bleeding: MP fewer days, amount and episodes of VB BP: CEE + MP dec in SBP and DBP v. MPA Endometrial: MP spares ET and preserves favorable effects HERS JAMA 1998 *funded by Wyeth 2,763, avg age 67yr 4.1y; HERS, 6.8y; HERS2 CEE+ MP superior results. CEE+MPA did not reduce rate CHD. E3N Cohort (2005, 2008) Fournier, A 80,377, age 4065yr 12yrs Estrogen only group had 1.32x inc risk BC (p=0.93); use of MP+E eliminated risk (p0.001), v sig inc risk with MPA RR1.48. E3N-EPIC: Progestins inc risk BC (RR= 1.4), reduced with MP (RR=0.9) ESTHER, JACC (2007) Canonico, M 271, age 4570yr Oral but not transdermal E inc VTE risk. Progestins may be thrombogenic, MP safer. No first pass effect (limited effect on lipids, clotting factors, SHBG and free testosterone, thyroid) Safety: lower risk VTE, CVA, cholecystitis decrease in risk BC) Higher bioavailability (nearly 10-fold) Choice of formulation (patch, gel) Convenience (2 patch/week) Consistent blood levels (no Current Estrogen Therapy VTE Cases (DVT & PE), (n=259) Controls (n=603) Risk VTE compared to nonusers (OR 95% CI) Oral Estrogen 45 39 4.2 (1.5-11.6) Transdermal Estrogen 67 180 0.9 (0.4-2.1) Canonico M, et al. Circulation 2007; 115:840. Estrogen* Oral: • Estrace 1mg oral tablet Transdermal/Topical: Estradot 25-100mcg patch • Divigel 0.1% ( 0.25-1mg), Estragel 0.75mg/pump (gel) • Progesterone Prometrium 100mg capsule po/pv • Micronized progesterone in peanut oil *Combined EPT: Progestagen required if systemic ET and intact uterus Vaginal low-dose Estradiol: *Systemic ET not adequate or indicated for VVA • Tablets: Vagifem (10mcg HS PVx2w then 2/w) • Ring: Estring (5-10mcg daily over 12w) Vaginal Progesterone • • Crinone (4% cream, 45mg 2x/wk) ENDOMETRIN® 100mg vag insert (ART) Luteal phase defect Menorragia/AUB Fertility- luteal support in ART and RPL Obx- Preterm Labour prevention Endometrial Hyperplasia Menopausal EPT Ann N Y Acad Sci. 1997 Sep 26;828:291-9. The endometrial effects of vaginal progesterone have been found to be unexpectedly reliable. This has led us to suspect that a local direct vagina-to-uterus transport or first uterine pass effect was the basis of the uterine targeting of vaginal progesterone. After vaginal administration of progesterone, uterine tissue concentration has been found to exceed by more than 10-fold the levels achieved by systemic administration, despite plasma levels in the latter case that were more than seven times higher. Similar differences in systemic-to-uterine tissue level ratios have been observed between oral and vaginal administration of danazol. Originally seen as a pharmacological advantage permitting the uterine targeting of vaginally administered substances, it is possible that the first uterine pass effect plays a physiological role in the control of uterine contractile activity through the prostaglandins contained in the semen. Pharma BioHT Drug Industry Manufactured Health Canada regulated API* (authorized) Fixed dose/formulation Patented Drug insert, monograph, ads *API=active pharmaceutical ingredient Compounded BioHT Customized Solution Small batches Provincially regulated** API* (authorized) No drug insert, monograph, etc. **Federal Policy; POL-0051 http://www.hcsc.gc.ca/dhp-mps/compli-conform/gmpbpf/docs/pol_0051-eng.php#a51 Biest: E3 estriol: E2 estradiol • • • • • Ratio: 50:50, 80:20 Dose (0.05-1mg) Volume (0.1cc-0.5cc) Base (versabase) Route: transdermal, transvaginal Progesterone Dose: 10-200mg • Schedule: cyclical, sequential • Route: Vaginal, Oral • Format: capsule (SR), supp, cream • Labs: FSH, estradiol, progesterone, FAI Screen: MGM, TVUS (if AUB) Rx: Pharmaceutical BioHT Estradot 25mcg patch x2/wk Prometrium 100mg cap HS 5d/wk Vagifem 10mcg tab, HS PV 2wk then 2x/wk Bioidentical hormones are chemically and biologically equivalent to nature’s Substantial evidence favours their safety The hormone, the dose and the route matter Pharmaceutical BioHT can be safely prescribed Transdermal estrogens may be preferred to oral Compounding may be an appropriate option Nomenclature matters…educate patients! Questions?