Estrogen Actions
Brain:
- Regulates areas that prepare body for reproduction,
- Helps to maintain stable temperature and avoid hot flashes
- May help protect memory
Breast:
- Programs glands to produce milk
- Promotes breast cancer
Liver and Heart:
- Helps to regulate production of cholesterol by the liver and thus to avoid artherosclerosis and heart attack
Uterus:
- Programs uterus to nourish a fetus
- Promotes cancer of the uterine lining
Bone
- Maintains density
Pre-Menopause
- Before menopause, ovaries produce estrogen and progesterone
- During year of ovarian estrogen production, women benefit from estrogenic activities:
- Protection against CV disease
- Estrogen prevents artherosclerotic lesion formation
- Prevention or reversal of bone loss (osteoporosis)
- Protection against CV disease
- With these protective effects, surely anyone would wish to continue benefits by taking replacement hormones
Menopause
- After menopause ovaries no longer produce estrogen and progesterone
- Average age of menopause in US is 51 years
- Preceded by perimenopausal transition of varying duration
- Common symptoms associated with estrogen deficiency
- Hot flushes
- Vaginal atrophy
- Sleep disturbances
Conjugated Equine Estrogen (CEE)
Premarin is commercial name for compound drug consisting primarily of conjugated estrogens used for hormone therapy
- Estrone (>50%), equilin (15-25%) and equilenin
- Estrogen molecules are conjugated (generally present with hydrophilic side-groups attached such as sulfate)
- Estrone sulfate is easily absorbed and converted to estradiol by body
Premarin is isolated from mare’s urine (PREgnant MARe’s urINe)
Prempro is Premarin (CCE) plus medroxyprogesterone acetate (MPA), a synthetic progesterone
Women’s Health Initiative Study
- 16,808 healthy postmenopausal women enrolled between 1993-1998 (planned duration 8 years)
- Treated daily with; 1) placebo, 2) estrogen alone (CEE; Premarin), or 3) estrogen and synthetic progesterone (CEE + MPA; Prempro)
- Women in estrogen alone study had prior hysterectomy
- Progestin reduced risk of endometrial (uterine) cancer by inducing or maintaining endometrial atrophy in women with uterus
- Women in estrogen alone study had prior hysterectomy
Women’s Health Initiative Study Stopped
- CEE + MPA study was stopped in July 2002 (average duration of 5.2 years) when researchers discovered that women taking CEE + MPA demonstrated health problems compared to women waking a placebo:
- Increased risk of stroke
- Increased risk of venous thromoembolic events
- Increased risk of invasive breast cancer
- Estrogen alone study was stopped in February 2004 (avaerage duration of 7.1 years) when researchers discovered that women taking CEE alone demonstrated health problems compared to women taking placebo:
Increased risk of stroke
Women’s Health Initiative Study Initial Results
- Study found that CEE + MPA conferred the following health benefits:
- Decreased risk of colorectal cancer
- Decreased risk of hip fractures
- However, because overall risk of adverse health conditions was 15% greater than benefit, United States Department of Health and Human Services made following recommendation in July 2002:
- “The USPTF recommends against the routine use of estrogen and progestin for the prevention of chronic conditions in post-menopausal women.”
Hazard Ratio
- In survival analysis hazard ratio is effect of explanatory variable (i.e., smoking) on the hazard (or risk) or an event (i.e., getting lung cancer)
- Hazard ratio is estimate of Relative Risk (RR)
- In statistics and mathematical epidemiology, relative risk is risk of event (or of developing a disease; i.e., lung cancer) relative to exposure (smoking)
- Relative risk is calculated as ratio of probability of the event occurring in exposed group (i.e., smokers) versus non-exposed group (i.e., non-smokers)
Calculating Hazard Ratio
In this example, a=20% b=80, and c=1, and d=99
How to interpret Relative Risk
- Smokers would be twenty times as likely as non-smokers to develop lung cancer
- Another term for relative risk is risk ratio because it is a ratio of risk in exposed group divided by the risk in unexposed group
RR=1: means there is no difference between the two groups
RR>1: means event is more likely to occur in experimental group than in control group
RR>1: means event is less likely to occur in experimental group than in control group
Cardiovascular disease (CHD) Hazard Ratio
Check the math: Hip Fracture hazard ratio=
Calculated hazard ration is presented with 95% confidence interval
Nominal 95% CI= 0.45 – 0.98
How do we know if the hazard ratio is statistically significant?
Associated CI excludes 1.00
How do we know if the hazard ratio is important medically?
In 10,000 women taking estrogen + progestin for 1 year, there will be 5 fewer hip fractures events than for women taking placebo (decreased)
Hip Fracture Hazard Ratio
Check the math: Hip Fracture hazard ratio=
Calculated hazard ration is presented with 95% confidence interval
Nominal 95% CI= 0.45 – 0.98
How do we know if the hazard ratio is statistically significant?
Associated CI excludes 1.00
How do we know if the hazard ratio is important medically?
In 10,000 women taking estrogen + progestin for 1 year, there will be 5 fewer hip fractures events than for women taking placebo (decreased)
Global Index Hazard Ratio
Represents first event for each participant among following:
- Cardiovascular disease
- Stroke
- Pulmonary embolism
- Breast cancer
- Endometrial cancer
- Colorectal cancer
- Hip fracture
- Death due to other causes
Global index is summary of overall balance of risks & benefits
- Result is highly dependent upon variables selected for inclusion
Global Index Hazard Ration Calculations
Check the math: Global Index Hazard ratio:
Calculated hazard ration is presented with 95% confidence interval
Nominal 95% CI= 1.03 – 1.28
How do we know if the hazard ratio is statistically significant?
Associated CI excludes 1.00
How do we know if the hazard ratio is important medically?
In 10,000 women taking estrogen + progestin for 1 year, there will be 19 more adverse reactions than for women taking placebo (170 per 10,000 versus 151 per 10,000; 170-159=19) risks outweigh benefits
Response to WHI Study
Annual prescriptions for hormone therapy in United States decreased dramatically after 2002 publication of WHI study
Initial Publication and “Final” Results
- After initial WHI publication, “final results” and mutiple additional analyses have been published
- Raw data have not been released
- “Final” results have modified interpretation of initial finding and revised early conclusions
- Less publicity was given to “final” results (e.g., where increased CHD risk was no longer statistically significant)
“Final” WHI results: The Swinging Pendulum of HRT
Criticism of WHI study
Study was designed to examine older post menopausal women based on assumption that hormone therapy would be beneficial regardless of when it was started
- Women ranged from 50-79 years
- Mean age of 63
- Two-thirds were over 60
“Therapeutic window of opportunity” hypothesis
- Estrogens have beneficial effects prior to menopause
- Estrogens have adverse affect when started well beyond the menopausal transition
Perhaps estrogens may have beneficial (i.e, cardioprotective) effects if initiated around entry to menopause (the “window”)
Atherosclerosis
Build up of plaque (fat, cholesterol, calcium and other molecules) in blood vessels
- Endogenous estrogens are thought to be protective against coronary artery atherosclerosis
- Atherosclerosis begins in youth and progresses with increasing age
- CHD is extremely rare in fertile age women compared to men of same age
- Women experiencing early menopause or surgically-induced menopause are more likely to develop CHD tan premenopausal women of same age
Thrombus and Thromboembolism
- Thrombus (blood clot) forms in blood vessel when plaque ruptures
- Rupture involves disruption of endothelium and fibrous cap covering plaque and release of constituents of plaque into lumen of blood vessel
- Thrombus can disrupt blood flow which can cause stroke or myocardial infarction (heart attack)
- Thromboembolism is clot that breaks loose and travels through bloodstream
Estrogen and Atherosclerosis
What is the basis for “therapeutic window of opportunity”?
- Endogenous estrogens are thought to be protective against coronary artery atherosclerosis
- Exogenous estrogens (ET/HT) administered well beyond menopausal transition can have deleterious (harmful) effects
Potentially harmful effects of exogenous estrogens administered post menopause
- Effects of exogenous estrogen on complicated plaque:
- Increases inflammatory response
- Promotes growth of atherosclerotic plaque
- Increases MMP expression
- Destabilizes & promotes rupture of atherosclerotic plaque
- Increases inflammatory response
- Fibrous cap separates necrotic core (potentially destructive components of plaque including thrombus) from blood
- MMPs (matrix metalloproteinases) are proteases that can digest fibrous cap resulting in release of thrombus into blood
Timing of initiation of treatment appears to make a difference for CHD
Current Recommendations
Hormone therapy should be initiated around onset of menopause:
- To treat menopause-related symptoms
- Hot flushes
- Vaginal atrophy
- Sleep disturbance
- To treat or reduce risk of disorders such as osteoporosis and/or fractures (and possibly CHD)
Benefit to risk ratio is favorable close to onset of symptoms but decreases with aging and with time since menopause in previously untreated women
Recommended duration of hormone therapy is still unresolved
