Controversies in HRT

C.R.Kannan, M.D.Professor of MedicineUNSOM, Las Vegas

In several cross sectional studies…..

Women taking HRT aftermenopause appeared to have

Less CAD

Less Fractures

Premarin became the best selling drug inU.S.History with FDA approval despite little or no data onrandomized trials

Women’s Health Initiative (WHI)

1992

2007

HRTERTversusPlacebo27,500

What are the protectiveeffects of HRT inhealthy women with no obvious disease?

First randomised trial

Summary Use of Estrogen Plus Progesterone in healthywomen for prevention…….

CAD 29%Stroke 41%VTE 111%

Breast ca 26%

Colo-Rectal ca 37%Hip Fracture 34%Vert fracture 34%

WHI data: the bone protection is NOT worth the risks. Study was terminated before completion

Summary Use of Estrogen alone in healthywomen for prevention…….

Stroke VTE BUT NOT Breast ca

Hip Fracture Vert fracture

WHI data: the bone protection is NOTworth the other risks

SummaryUseof HRT ( PremPro) in healthywomen for prevention…….

CAD 29%Stroke 41%VTE 111%

Breast ca 26

Colo-Rectal ca 37%

Hip Fracture 34%Vert fracture 34%

Results

WHI data: the bone protection is NOTworth the other risks

Criticismsof theWHI trial

Is this truly a primary prevention trial?

Would the same CV risk be applicable if started earlier?What about other routes of administration?Can these data be applied to

patients taking Estrogen only?

Can these data be applied to patients taking Estrogen (CEE) only? Anderson et al JAMA 2004

CHD CVA VTEBreastCA

HipFract

SlightincreaseNSS

39% 33% 23%

SlightdecreaseNSS

39%

In 2001 WHI stopped the E+P trialIn 2004 WHI stopped then Estrogen only trial

Many women came off ERT

WHI changed practice

ERT prescriptions fell by 70% in 07

Short term use for vasomotor Sx

Transdermal HT doubled vs PO

Long awaited KEEPS trial

Healthy women 42-58 years old within 3 years of final menses at time of randomisation

Double blind RCT

727 women

Low dose oral Estrogen

Trans Dermal Estrogen

Cyclic monthly Progesterone

Placebo O-CEE Premarin0.45 mg

Trans Dermal EstrogenClimara 50 mcg day

Cyclic monthly Prometrium 200 mg/d x 12 days

KEEPS trial Results

Presented in the North American Menopause Society in October 2012

Relieved vasomotorsymptoms Neutral effects on BP

Lowered LDL, Increased HDL and TG

O-CEE Premarin0.45 mg

Trans Dermal EstrogenClimara 50 mcg dayNeutral effect on LDL HDL, TG

Increased Insulin sensitivity

Improved Sexual functionLibido, ArousalLubricationAnd Orgasm

Long awaited KEEPS trial Results

Presented in the North American Menopause Society in October 2012

No significant RISKS or BENEFITS regarding Breast cancer Uterine cancer MI or Stroke VTE Atherosclerosis progression

O-CEE Premarin0.45 mg

Trans Dermal EstrogenClimera 50 mcg day

Study not sufficiently powered to determine risks or benefits on clinical events

Summary

Short term Rx with lowest dose estrogen is safe , relieves vasomotor sxand improves QOL

Remains to be seen if long term HRT is harmful when started early.As it stands, long term HRT is not indicated forprevention of disease(USPSTF Oct 12, 2012)

ERT is contraindicated in….

Hx of Breast CancerEndometrial CancerStrong Family Hx of aboveEstablished Heart diseaseVTE?Gall bladder diseaseNicotine abuse

“I want naturalhormones!”

“Prescription estrogens are not identical to what my body makes!”

“Bioidentical hormones are safer than those made by the industry! ”“I want my estrogens customized to my body’s needs!”“ Test my saliva and customize my hormone replacement!“ I do not want to take a pill made from horse’s urine!!

What are Bioidentical Hormones?

Definition of terms

BioidenticalHormones

Hormones identical inhormone structure to endogenous hormones

Synthetic Synthetic hormonese.g. premarin

Customized Compounded Formulations

Tailor made, customizedTo the individual.

Myth 1

“Bioidentical hormones and Synthetic hormones are polar opposites.”

Bioidentical hormones are also syntheticSynthetic hormones are also bioidentical.

Tri estBi-est

Chemically Extracting diosgenin fromPlants (yams and soy)

17 β- estradiol

The prototypical estrogen most identical to endogenouslyproduced hormone is synthesized And available as brand e.g Estrace

Bioidentical hormones are also syntheticSynththetic hormones are also bioidentical.

Tri estBi-est

Chemically Extracting diosgenin fromPlants (yams and soy

17 β- estradiol

In fact, the most bioidenticalestrogen is branded, prescription-regulated and FDA approved

Origin of this concept of Bioidentical hormones?

Womens’ Health Initiative 2001

Use of Estrogen Plus Progesterone in healthy women carries a risk.

CAD 29%Stroke 41%VTE 111%

Breast ca 26%

Women came off estrogen.

Other “safer” and “natural”alternatives were sought .

celebrities got into the actSpawning a whole new industry.

Prescription Regulated Bioidentical

CustomizedCompounded Bioidenticals

Chemical IdentityTo human hormones

Yes Yes

FDA oversight Yes No Published

ResearchYes minimal to none

Dose Reproducibilty

Exact Inexact , inconsistent

Proven efficacy Yes No RCT

Myth 2 “I want natural hormones”

Nature

E2 17 β Estradiol Most bioactive estrogenProduced by dominant follicle

E1 Estrone Second Most bioactive estrogen.Derived from E2 and Androgens

E3 Estriol Least bioactive, derived from E2

How natural are bioidenticals?

Tri est

Bi-est

Compounded hormone80 % Estriol10% Estrone10% Estradiol

Compounded hormoneEstriol: Estradiol 8:1 or 9:1

How natural can it be when it has very little of Estradiol, the most bioactive estrogen?

Myth 2 “I want natural hormones”

Truth So called BioidenticalsContain very little bioactive Estrogen!

Myth 3 “Prescription estrogens are not Bio identical”

Truth There are at least 23 products that are FDA tested and approved with hormones identical to Endogenous estrogen

Oral Estrace 0.5, 1 and 2 mg

Dermal Climara 0.025 to 0.1 mg Vivelle 0.025 to 0.1 mg Alora

Dermal Estraderm 0.05 to 0.1 mg gel Estragel 0.035

Local Vaginal cream and ring

17 β Estradiol

Progesterone Prometrium 100 to 200 mg

Myth 4

“Bioidentical hormones are safer than those made by the industry ”

Truth There are no RCT that have proven that the compounded bioidenticals are safer.

Myth 5

“Customized bioidentcal hormone therapy provides better results because it is individualized”

Truth There are only half a dozen variations available. This is hardly sufficient for ‘individualization’

Myth 6

“Customized bioidentcal hormone therapy can be provided by testing saliva for hormones ”

Truth Salivary testing is not a relaible means of assessing the hormonal status.

Bioidentical hormone therapyRepresents unchartered waters.

There are alternatives that have been Tested and provide the best replacement with the most bioactiveIngredients.