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Postmenopausal Hormone Replacement Therapy Controversy at the Biochemical Level

Postmenopausal Hormone Replacement Therapy Controversy at the Biochemical Level. Sam Ekstein GRECC, VA Hospital Craig S. Atwood, Ph.D., Department of Medicine. Indications for Hormone Replacement Therapy (HRT) in Postmenopausal Women. Symptoms of menopause Vasomotor Symptoms Sweating

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Postmenopausal Hormone Replacement Therapy Controversy at the Biochemical Level

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  1. Postmenopausal Hormone Replacement Therapy Controversy at the Biochemical Level Sam Ekstein GRECC, VA Hospital Craig S. Atwood, Ph.D., Department of Medicine

  2. Indications for Hormone Replacement Therapy (HRT) in Postmenopausal Women • Symptoms of menopause • Vasomotor Symptoms • Sweating • Hot flashes • Night sweats • Palpitations • Urogenital Symptoms • Osteoporosis prevention • Considered an important component of postmenopausal healthcare prior to 2002

  3. Women’s Health Initiative (WHI) Study • Initiated in 1991 by the National Institutes of Health • 161,808 postmenopausal women • HRT trials examined the 2 major forms of HRT in the U.S. • Estrogen-alone study • Premarin®(conjugated equine estrogens; CEE) • Estrogen + Progestin study • Prempro® (CEE+ medroxyprogesterone acetate; MPA)

  4. WHI Disastrous Findings • First HRT trial halted early in 2002 • HRT trials using Premarin® (CEE)and Prempro® (CEE + MPA) • Increased risk of breast cancer • Increased risk of coronary heart disease • Increased risk of stroke and blood clots  Usage rates dropped 40-80%!

  5. Average composition of two 0.625-mg Premarin® (CEE) tablets 10 different estrogens have been identified

  6. Only 3 out of the10estrogens in Premarin® (CEE) are naturally found in humans

  7. Nearly identical chemical structures = identical biologic effects???

  8. Nearly identical chemical structures = identical biologic effects???

  9. Nearly identical chemical structures do NOT induce identical biologic effects Progesterone Testosterone

  10. Two Broad Categories of HRT • Bioidentical HRT • Hormones that are identical to those produced by the human body • Includes 17β-estradiol and progesterone for women • Non-bioidentical HRT • Hormones that are not identical to those produced by the human body • Includes CEE (used to replace estrogen) • Estrogens derived from horses • Premarin® (contraction of pregnant mare urine) • Includes MPA (used to replace progesterone) • Prempro® (composed of CEE + MPA)

  11. Chemical Structures of Major Sex Steroids Used for HRT Bioidentical HRT Non-bioidentical HRT Progesterone Medroxyprogesterone acetate (MPA)

  12. Chemical Structures of Major Sex Steroids Used for HRT Bioidentical HRT Non-bioidentical HRT (CEEs) 17b-estradiol Estrone sulfate Equilin 17α-Dihydroequilin

  13. Specific Aim • Thoroughly examine the biochemical and physiological differences between the major bioidentical (17β-estradiol; progesterone) and non-bioidentical hormones (CEE; MPA) used in HRT

  14. Methods • Comprehensive literature review • Key selection criteria: comparison of a bioidentical hormone to a non-bioidentical hormone within the same study • Reduce variability of results • In vitro (cell culture) and pre-clinical in vivo (animal) studies • Inclusion of all comparative biochemical and physiological effects • Brain biochemistry, cognitive function, vasculature, reproductive tissues, bone, etc. • > 100 studies fit criteria above

  15. Selected Findings • CEE is not equivalent to 17b-estradiol • 17b-estradiol is beneficial • Vascular tissues • 17b-estradiol is more potent than CEE at increasing coronary blood flow in sheep • CEE increases platelet reactivity and aggregation, while 17b-estradiol has no effect in mice • Nitric oxide production • 17b-estradiol upregulates nitric oxide production to a significantly greater extent than CEE in vitro

  16. Selected Findings • MPA is not equivalent to Progesterone • Progesterone is beneficial • Brain • Unlike P4, MPA prevents neuronal proliferation and does not enhance cognitive recovery following traumatic brain injury in rats • MPA inhibits allopregnanolone production, while P4 induces allopregnanolone levels in the hippocampus of rats • Vasomotor response of coronary arteries • Unlike P4, MPA inhibits the vasomotor response of coronary arteries by 50% in monkeys • Breast tissue • Progesterone is generally more inhibitory of breast cancer cell proliferation and migration compared to MPA

  17. Significance • Crucial to health outcomes in women • Premarin® and Prempro® indeed help with menopausal symptoms • Long-term use can result in detrimental health outcomes given the differences in physiological function • May influence success of HRT formulations • Future clinical trials of postmenopausal HRT should focus on bioidentical hormones

  18. Acknowledgements • Principal Investigator: Craig Atwood, Ph.D. THANK YOU!

  19. Questions?

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