Demystifying Bioidentical Hormones

Dr. Jennifer Pearlman,MD CCFP NCMP FAARM ABAARM

ASA51 November 2013

Dr. Jennifer Pearlman Disclosure

Dr. Jennifer Pearlman51st Annual Scientific Assembly Grants/Research Support: none Speakers Bureau/Honoraria: none Consulting Fees: none Other Payments or Relationships with

commercial interests: none

Disclosure of Commercial Support

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

Mitigating Potential Bias

No potential sources of bias identified

Today’s Discussion

Case Introduction Defining BioHT Historical Perspective Why Consider BioHT Safety of BioHT Prescribing BioHT Conclusion

Case Study: Ms. Flash

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

Defining Bioidentical Hormones:What are hormones?

Agents of change

Produced by endocrine cells in specialized organs

Travel via blood/lymph

Exert effect at distant site

Bioidentical Nomenclature

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

BioHT v. Traditional HT: Different Actions in Vivo

Outcomes: Cognitive, Bone, Heart

Side Effects: Bleeding, Mood, Sleep, Weight

Risks: Cardiovascular, Clotting, Breast

Cancer

Barriers to BioHT

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”

History of Premarin 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)

Possible Components of CEE (Premarin)

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 0.026http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm168836.htm

Human Estrogens

E1 -Estrone: • made in fat cells from Testosterone by

aromatase

E2 -Estradiol: • most active, abundant, ovarian, stimulates

breast/uterus (ER alpha)

E3 -Estriol: • weak estrogen, made by placenta/liver, breast

protective, neuroprotective, specific to vaginal mucosa

Estriol- the forgotten estrogen

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

Efficacy of vaginal use of topical estriol in postmenopausal women with urogenital

atrophy.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.

Safety of Estriol in BCLow-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 non-

hormonal 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 non-hormonal moisturizer only provides transient benefit. The increase of serum estrogens levels during treatment with vaginal estrogen at these dosages is minimal.

Differentiating Progestagens

Progesterone v. Progestin

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)

• RR Breast cancer: MPA 1.48 v. Progesterone 1.0 (no risk)

• RR VTE: MPA 1.8 v. Progesterone 0.9 (10% decrease)

18

Medroxy Progesterone Acetate (MPA)

French E3n Cohort Study ,Fournier, Br Ca Res. Treat 2008;107:103-111

History of MPA

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

MP Preserves Estrogen Increase of HDL-c and Decrease of Fn

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.

Progesterone v. Progestin in Cardiovascular Risk

“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.

Progesterone v. Progestin in Breast Cancer Risk

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”

Breast Cancer Risk according to Different Hormone Regimens

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)*

• E3N French epidemiologic cohort study• Self-administered questionnaires 1990-2002• 80,377 postmenpoausal women w. up to 12 yrs f/u

Fournier A et al. Breast Cancer Res Treat 2008: 107:103

Comparative BHT StudiesStudy 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 45-64yr

3 yrs Lipoprotein: MP greatest inc HDL-c (p0.004)Bleeding: MP fewer days, amount and episodes of VBBP: CEE + MP dec in SBP and DBP v. MPAEndometrial: 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 40-65yr

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 45-70yr

Oral but not transdermal E inc VTE risk. Progestins may be thrombogenic, MP safer.

Benefits of Transdermal v. Oral Estrogen

No first pass effect (limited effect on lipids, clotting factors, SHBG and free testosterone, thyroid)

Safety: lower risk VTE, CVA, cholecystitis (no decrease in risk BC)

Higher bioavailability (nearly 10-fold) Choice of formulation (patch, gel) Convenience (2 patch/week) Consistent blood levels

Hormone Therapy and VTE Among Postmenopausal WomenCurrent Estrogen Therapy

VTE Cases (DVT & PE), (n=259)

Controls (n=603)

Risk VTE compared to non-users (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.

Pharmaceutical BioHT

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 BioHT

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)

Vaginal Progesterone

Luteal phase defect Menorragia/AUB Fertility- luteal support in ART and

RPL Obx- Preterm Labour prevention Endometrial Hyperplasia Menopausal EPT

The first uterine pass effect

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.

Pharmaceutical v. Compounded BioHT

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.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/pol_0051-eng.php#a51

Compounded BioHT

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

Case Study: Ms. Flash

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

Conclusions

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!

Bioidentical Hormones Demystified

Questions?