Bio-Equivalent Hormone Replacement Therapy Strategies for 2003

By Phyllis Jordan,2014-05-15 10:51
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Bio-Equivalent Hormone Replacement Therapy Strategies for 2003

    Bio-Equivalent Hormone Replacement

    Therapy Strategies for 2003

    Presented by David L. Greene, M.D.

    Medical director at the Eastern Sierra Women’s Clinic

    Positive Aspects to

    Hormonal Replacement Therapy

     Reduction in the rate of osteoporosis and osteoporotic fractures

     Reduction in the incidence of heart disease

     Reduction in the incidence of Alzheimer's

     Reduction in the incidence of fatal Colon Cancer

     Reversal of Post Menopausal symptoms

     Stabilization of Peri menopausal symptoms

     Improvement in skin tone

     Improvement in breast tone

     Reduction in risk of developing macular degeneration

     Slows tooth decay

     Improvement in overall feeling of well being

     Estrogens are an anti-aging therapy

     Negative Aspects to

    Hormonal Replacement Therapy

     Increased risk of endometrial cancer

     unopposed ERT increases 2-10x the risk of uterine cancer (1/1,000 to 4-8/1,000)

     The addition of progesterone reduces this risk back to baseline

     Possible increased risk of breast cancer (1.3-1.5 RR)

     Increased risk of DVT

     Breast tenderness

     Water retention at some doses

     Resumption of menses in some cases

     Irregular bleeding

     Need for medical surveillance

     Prescription costs

Why use Bio-Identical replacement rather than Conjugated estrogen or

    Mono estrogen therapy?

    Catechol Estrogens: Theories on the Origins of Breast Cancer and Detoxification


     17beta Estradiol Estrone Estriol


     2, 4,16 Catechol Estrogen

1970 &1980’s research identified two important metabolic pathways in which the liver may

    hydroxylate estradiol.

     16 alpha hydroxyestrone or 2-hydroxyestrone are produced

     In the mouse model and human studies high levels of 16 alpha hydroxyestrone relative to the

    2-hydroxyestrone are associated with the increased incidence of breast cancer

     1997 Cavalieri and associates identified what appears to be the most dangerous of the

    estrogen metabolites -4-hydroxyquinone estrogens

     Cavalieri’s research found much higher amounts of 4- hydroxyestrogens as compared to 2-

    hydroxy or 16 alpha hydroxy estrogens in breast cancer tissue

catecol ortho-methyltransferase (COMT) peroxidase Methylated Catechol 99% 1% estrogen-quinones (safely excreted) 2,4,16-Catechol Estrogen DNA Binding Mutation

     Cancer Methylation is the mechanism by which unhealthy compounds including estrogens are excreted from the body. After performing its normal activity, estradiol which is not methylated and excreted may be oxidized to compounds now identified as being associated with tumor production- 4 and 16 hydroxyestrone Methylation pathways in the liver may be overwhelmed under certain conditions: A genetic flaw in the production of COMT Nutritional deficiencies that result in limited availability of methyl groups for the enzyme Excess production of estrogens

     Research suggests that Indole 3-carbinol (400mg) found in cruciferous vegetables will favor the 2-hydroxyestrone pathway reducing the production of 16 alpha hydroxyestrone

    Catechol Estrogens: Theories on the Origins of Breast Cancer and Detoxification


    Bio-Identical vs. CEE and Mono Estrogen Therapies

     Triple estrogen a bio-identical balanced combination of estriol, estradiol,

    estrone mirroring normal human endocrinology

     CEE contains high levels of equine estrone sulfate, estradiol, with

    indeterminate amounts of equine estriol Mono estrogen therapies commercially available contain no estriol and rely

    on the bodies ability to convert to other estrogens in an effort to achieve


     As we age our bodies lack both glandular secretion and enzyme activity

    necessary to maintain the balance found in young healthy individuals (The Hormone Solution-Thierry Hertoghe, M.D.)

    Estriol The Forgotten Estrogen Estriol is the major circulating estrogen in the body. (80-90%) Estriol has been shown to reduce bone loss, reverse vaginal atrophy, reduce chronic urinary tract infections due to atrophy (Raz-N Eng J Med 329 (11) 1993:753-756) Estriol improves cholesterol profiles Estriol has a greater propensity for inducing ganglion nerve cell proliferation in brain tissue than either estradiol or estrone Swedish data suggests that estriol has a very weak ability to induce endometrial hyperplasia (Utian, Acta Endocrinologica 235 (1980):51-46) Estriol replacement therapy as a mono therapy has been reported to reduce the incidence of breast cancer (Lauritzen, Acta Endocrinologica 38 (1961):73-87) Nature provides for a pregnant mother and her fetus to be bathed in estriol levels hundreds of times higher than non pregnant levels as are the levels of progesterone suggesting that these hormones may provide some type of protective mechanism against DNA mutation Estriol ameliorates autoimmune demyelinating disease (Neurology 1999 Apr 12;52(6):1230-8) Estriol used in the treatment of MS (Ann Neurol 2002 Oct;52 (4) 421-8) Estriol binds weakly to SHBG unlike estradiol, allowing it to bind more readily with cell receptors In Western Europe Estriol in 2mg 5mg daily has been used successfully for reversal of p.m. syndrome

    The Neurotrophic effect of Premarin and its estrogenic steroids

    R. Brinton, PhD. U.S.C. Pharmaceutical Sciences Center

    The Neurotrophic effect of Premarin and its estrogenic steroids

    R. Brinton, PhD. USC Pharmaceutical Sciences Center

    Henry Lemon, M.D.-Professor, University of Nebraska

     1966-JAMA,-high levels of estriol excretion in women was associated with reduced incidence of breast cancer.

     In animal models he demonstrated that rats pretreated with estriol prior to exposure to cancer causing agents such as radiation or chemicals demonstrated a protective effect against mammary tumor production, estradiol and estrone treated rats did not

    demonstrate this same effect.

     Lemon could not demonstrate a proliferative effect on breast or uterine tissue in the rats treated with estriol.

     1975 Dr. Lemon published reported his finding of estriol inducing remission or arrest of metastatic breast tumors in 37% of his population treated. Cancer Res 35 (1975) 1341:1353)

     Estriol may just be the perfect SERM we have been searching for.

    First Results from the International Breast Cancer Intervention Study (IBIS-I): A Randomized Prevention

    Trial (Lancet. 2002;360:817-824) Tamoxifen for the chemoprevention of breast cancer in women deemed to be at high risk

     7152 women randomized and 25% completed a full 5 years of treatment

     Patients ranged from 35-70 years in age, the preponderance between ages 45-54

     For those treated with Tamoxifen the odds ratio was 0.31 for ductal carcinoma insitu ( 5-tamoxifen vs. 16 placebo CI 0.12-0.82) 0.75 for invasive breast cancer (64-tamoxifen vs. 85 placebo-CI 0.54-1.04)

     0.69 with ER positive breast cancer (16-tamoxifen vs. 23 placebo-CI 0.47-1.02)

     1.00 with ER negative breast cancer ( 19 cases in each group)

    Risks of Tamoxifen Therapy

     Rate of venous thromobembolism was 2.5 times higher in the tamoxifen group (43 vs. 17 cases P=0.001) Rate of DVT was 4.8 time higher in the tamoxifen group ( 24 vs. 5 cases P=0.0005)

     Gynecologic and vasomotor symptoms were higher in the tamoxifen group

     2 fold increase in endometrial cancer in the tamoxifen group (11 vs. 5 P=0.2)

     Rate of pelvic ultrasound, D&C, hysteroscopy were significantly higher and there were more women with endometrial polyps in the tamoxifen group.

     Rates of hysterectomy were also higher in tamoxifen users 4.2% vs. 2.7% P=0.002

     Rates of monilial vaginitis were substantially higher in both pre and post menopausal women taking tamoxifen.

     A new finding was an increase report in brittle nails in the tamoxifen group

     Inexplicably, the death rate from all causes was significantly higher in the tamoxifen group (25 vs. 11, P=0.03)

    What does the data reflect?

     The data in this study are not reassuring. They suggest that chemoprophylaxis with tamoxifen might prevent the kind of breast cancer that are associated with a low chance of mortality while subjecting the users to a number of untoward health risks.

     Remember no agent has been promoted as preventing aggressive breast cancers, the types that

    metastasize rapidly and kill

     There are multiple studies including the most recent by O’Meara J Natl Cancer Inst. 2001;93: 754-762)

    that suggest women with breast cancer who take estrogen preparations after the diagnosis of breast cancer survive longer ( total mortality 0.48-CI 0.29-0.78) and have fewer recurrences (mortality 0.50-CI 0.3-0.85) and fewer contra lateral breast cancers

     Since we know that tamoxifen has a partial estrogen agonist effect, the agonist properties accounting for its main side effects of thromboembolic disease and endometrial cancer; Could it be acting agonistically on the breast?

     If tamoxifen was acting as an agonistic fashion on the alpha receptors in ER positive tumors it would suggest a role for ER alpha agents including traditional estrogens. (Sarah Berga, M.D.-Professor and Director of Reproductive Endocrinology, University of Pittsburgh)

    How safe are bio-identical hormones?

     No one knows for sure

Experience with other bio-identical hormones support the hypothesis that they are safer and more

    efficacious than non bio-identical formulations

     Clinical experience demonstrates they are as effective in managing symptoms and disease states as

    CEE or mono estrogen therapy

     Ntx data from ESWC-shows effectiveness in slowing bone loss, J. Wright large patient pool

    demonstrates efficacy in controlling symptoms, PEPI study demonstrates safety and efficacy in

    preventing uterine hyperplasia

    How safe are you without your hormones? Neuroendocrine theory of aging suggests you are placing yourself in serious jeopardy by

    allowing your hormone levels to dwindle

     Data on post menopausal women is startling regarding the rapid advancing diseases and

    deterioration that sets in without hormonal therapy

     Reversal of p.m.symptoms improve physical, psychological and spiritual well being of treated


    The Why’s of Therapy

     Carefully explore why you are initiating therapy with your patient

     Is it strictly for relief of symptoms?

     Are the symptoms local or systemic?

     Is it for anti-aging principles such as “wellness” and disease


     Is this patient a cancer survivor?

     What are your patients long range goals?

     Assess risk factors and carefully weigh them against benefits

    Compounded Bio-Identical Hormones

    HRT-Optimal Route of Delivery To mimic the human endocrine system would be optimal

     The ovary releases the hormones estradiol and estrone along with progesterone directly into

    the blood stream via theca and granulosa cell production

     Use of transdermal or intramuscular injection would more closely mimic this system, vs. an

    oral preparation subjecting steroids to stomach acids and delivering a large load to the liver via

    the portal circulation (first pass phenomena)

     Increased liver stimulation may produce increased binding proteins such as SHBG which will

    reduce the amount of available hormone to the tissues

     Higher levels of HDL cholesterol have been reported using the oral route as a result of the first

    pass phenomena

     Ultimately compliance will play a role in choosing the optimal route of delivery for your patient

    Common Hormonal Regiments

     Tri-Est 2.5 or 5.0mg days 1-25 / Progesterone 100- 200 mg days 12-25 in creams or


     Tri-Est 2.5 or 5.0mg + Progesterone 100mg daily as a transdermal cream or oral capsule

     Testosterone in a transdermal preparation varying from 1%-5% applied to the lower

    abdomen and inner thigh nightly oral preparations appear to be less effective

    Cycling the Estrogens and Progesterone

    Daily Combination of Estrogens and Progesterone

    The How’s of Therapy

     How do we initiate therapy in a new patient? How do we convert over to bio-identical therapy from CEE or other estrogen therapy?

     How do we treat peri-menopause vs. post menopause? How do we manage PMS?

     How do we manage irregular bleeding or amenorrhea? What monitoring tools may we use to help determine the effectiveness of our therapy?

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