Controversies in HRT C.R.Kannan, M.D. Professor of Medicine UNSOM, Las Vegas

In several cross sectional studies….. Women taking HRT after menopause appeared to have Less CAD Less Fractures Premarin became the best selling drug in U.S.History with FDA approval despite little or no data on randomized trials

Women’s Health Initiative (WHI) HRT ERT versus Placebo 27,500 What are the protective effects of HRT in healthy women with no obvious disease? First randomised trial

Use of Estrogen Plus Progesterone in healthy women for prevention……. CAD 29% Stroke 41% VTE 111% Breast ca 2 6 % 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

Use of Estrogen alone in healthy women for prevention……. Stroke VTE BUT NOT Breast ca Hip Fracture Vert fracture WHI data: the bone protection is NOT worth the other risks

Criticisms of the WHI 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 CHDCVAVTE Breast CA Hip Fract Slight increase NSS 39%33% 23% Slight decrease NSS 39%

Even though ERT provides Bone Protection This Rx is not worth the risk Many women are coming off ERT

Even though ERT provides Bone Protection This Rx is not worth the risk Many women came off ERT

In 2001 WHI stopped the E+P trial In 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 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 Premarin 0.45 mg Trans Dermal Estrogen Climara 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 vasomotor symptoms Neutral effects on BP Lowered LDL, Increased HDL and TG O-CEE Premarin 0.45 mg Trans Dermal Estrogen Climara 50 mcg day Neutral effect on LDL HDL, TG Increased Insulin sensitivity Improved Sexual function Libido, Arousal Lubrication And 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 Premarin 0.45 mg Trans Dermal Estrogen Climera 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 sx and improves QOL Remains to be seen if long term HRT is harmful when started early. As it stands, long term HRT is not indicated for prevention of disease (USPSTF Oct 12, 2012) ERT is contraindicated in…. Hx of Breast Cancer Endometrial Cancer Strong Family Hx of above Established Heart disease VTE ?Gall bladder disease Nicotine abuse

“I want natural hormones!” “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 Bioidentical Hormones Hormones identical in hormone structure to endogenous hormones Synthetic Synthetic hormones e.g. premarin Customized Compounded Formulations Tailor made, customized To the individual.

Myth 1 “Bioidentical hormones and Synthetic hormones are polar opposites.”

Bioidentical hormones are also synthetic Synthetic hormones are also bioidentical. Tri est Bi-est Chemically Extracting diosgenin from Plants (yams and soy) 17 β- estradiol The prototypical estrogen most identical to endogenously produced hormone is synthesized And available as brand e.g Estrace

Bioidentical hormones are also synthetic Synththetic hormones are also bioidentical. Tri est Bi-est Chemically Extracting diosgenin from Plants (yams and soy 17 β- estradiol In fact, the most bioidentical estrogen is branded, prescription- regulated and FDA approved Origin of this concept of Bioidentical hormones?

Use of Estrogen Plus Progesterone in healthy women carries a risk. CAD 29% Stroke 41% VTE 111% Breast ca 2 6 % Women came off estrogen. Other “safer” and “natural” alternatives were sought. celebrities got into the act Spawning a whole new industry.

Prescription Regulated Bioidentical Customized Compounded Bioidenticals Chemical Identity To human hormones Yes FDA oversight Yes No Published Research Yes 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 estrogen Produced 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 hormone 80 % Estriol 10% Estrone 10% Estradiol Compounded hormone Estriol: 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” TruthSo called Bioidenticals Contain 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 to 0.1 mg Vivelle to 0.1 mg Alora Dermal Estraderm 0.05 to 0.1 mg gel Estragel 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 therapy Represents unchartered waters. There are alternatives that have been Tested and provide the best replacement with the most bioactive Ingredients.