Hormonal Optimization

WHI is the largest clinical trial in the US.
The multi-million dollar, 20+ year project sponsored by NIH, originally enrolled around 162,000 women 50-79 y/o between 1993-1998. Trial components: Hormonal therapy (HT), diabetes mellitus (DM), Calcium and Vitamin D (CaD)
Follow ups in 2005-2010, 2010-2015, continue through 2020
During the WHI project, women were divided into 4 groups, two mains branched on either CEE or combination of CEE and MPA as study groups along with two placebo groups for each branch. We do not use CEE or MPA due to numerous side effects, we use bio- identical Hormones: Estradiol and Progesterone.
The result of this study cannot be generalized into our practices at this point.
The term ” Bio-Identical Hormonal Replacement Therapy (BHRT) is what I, myself and other like- minded physicians use to differentiate this type of hormonal management from the conventional medicine and WHI study.
CEE (conjugated Equine Estrogen) from the horse’s urine, contains conjugated estrogen which has to become activated by converting to Estrone (E1) by the action of sulfatase enzyme. E1 is the form of Estrogen with the highest risk for breast cancer. We do not want to use this form in HRT.
Sample of brochure for oral contraceptive from the pharmaceutical company:
“Distribution Etonogestrel: Etonogestrel is approximately 32% bound to sex hormone- binding globulin (SHBG) and approximately 66% bound to albumin in blood.
Ethinyl estradiol: Ethinyl estradiol is highly but not specifically bound to serum albumin (98.5%) and induces an increase in the serum concentrations of SHBG. Metabolism In vitro data shows that both etonogestrel and ethinyl estradiol are metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. Ethinyl estradiol is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulfate and glucuronide conjugates. The hydroxylated ethinyl estradiol metabolites have weak estrogenic activity.
The biological activity of etonogestrel metabolites is unknown.

Excretion

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces”. So, let’s see: FDA approves a medicine that its harmful effect is proven, on every brochure listed and it clearly says: the biological activity … is unknown! And why should we take it and prefer it over bio-identical hormones that is shown less harm and more benefit?! Something is wrong with this picture, don’t you agree?
And, on this website which is supposed to be a credible source of information for women, it says: www.womenshealth.org January 2019 “ Oral contraceptives for perimenopausal women: Many women experience irregular periods, intensified PMS, and irritability before they meet the clinical requirement for starting hormone replacement therapy. For these women, the newest treatment is birth control pills. These pills can alleviate annoying symptoms while offering protection from unwanted pregnancy”.

What is in oral contraceptives?

Ethinyl Estradiol as Estrogen and progestin: Drospirenone, Levonorgestrel or Norethinrone acetate, cyproterone, Ethynodiol diacetate…
I encourage you to watch my videos regarding this topic. If you need to dig into it and read the reference articles, here they are:
References for women hormonal optimization:
1. Andréen L, Bixo M, Nyberg S, Sundström-Poromaa I, Bäckström T. Progesterone effects during sequential hormone replacement therapy. Eur J Endocrinol. 2003;148(5):571-577.
2. Asthana S, Baker LD, Craft S, et al. High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology. 2001;57(4):605-612.
3. Asthana S, Craft S, Baker LD, et al. Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer’s disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology. 1999;24(6):657-677.
4. Bhavnani BR. Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer’s. J Steroid Biochem Mol Biol. 2003;85(2-5):473-482.
5. Davis SR, Braunstein GD. Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. J Sex Med. 2012;9(4):1134-1148. doi:10.1111/j.1743- 6109.2011.02634.x.
6. Dessole S, Rubattu G, Ambrosini G, et al. Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women. Menopause. 2004;11(1):49-56. doi:10.1097/01.GME. 0000077620.13164.62.
7. Gao S, Hendrie HC, Hall KS, Hui S. The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-
analysis. Arch Gen Psychiatry. 1998;55(9):809-815.
8. Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testosterone therapy improves well- being, mood, and sexual function in premenopausal women. Menopause. 2003;10(5):390-398. doi: 10.1097/01.GME.0000060256.03945.20.
9. Gołebiewska J, Rozwadowski P, Spodnik JH, Knap N, Wakabayashi T, Woźniak M. Dual effect of 2- methoxyestradiol on cell cycle events in human osteosarcoma 143B cells. Acta Biochim Pol. 2002;49(1):59-65.
10. Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and actions of estrogens. N Engl J Med. 2002;346(5):340-352. doi:10.1056/ NEJMra000471.
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and estrogen receptors alpha and beta. J Biol Chem. 2005;280(20): 19704-19710. doi:10.1074/jbc.M501244200.
12. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis.Neuroscience. 2000;101(3):485-512.
13. Horsburgh K, Macrae IM, Carswell H. Estrogen is neuroprotective via an apolipoprotein E-dependent mechanism in a mouse model of global ischemia. J Cereb Blood Flow Metab. 2002;22(10):1189-1195. doi: 10.1097/01.wcb.0000037991.07114.4e.
14. Irwin RW, Yao J, Ahmed SS, Hamilton RT, Cadenas E, Brinton RD. Medroxyprogesterone acetate antagonizes estrogen up-regulation of brain mitochondrial function. Endocrinology. 2011;152(2):556- 567. doi: 10.1210/en.2010-1061.
15. Jacobs EG, Kroenke C, Lin J, et al. Accelerated cell aging in female APOE-ε4 carriers: implications forhormone therapy use. PLoS One. 2013;8(2):e54713. doi:10.1371/journal.pone.0054713.
16. Jodhka PK, Kaur P, Underwood W, Lydon JP, Singh M. The differences in neuroprotective efficacy of progesterone and medroxyprogesterone acetate correlate with their effects on brain-derived neurotrophic factor expression. Endocrinology. 2009;150(7):3162-3168. doi:10.1210/en. 2008-1247.
17. Kantarci K, Lowe VJ, Lesnick TG, et al. Early postmenopausal transdermal 17β-estradiol therapy and amyloid-β deposition. J Alzheimers Dis. 2016;53(2):547-556. doi:10.3233/JAD-160258.
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19. Li C, Brake WG, Romeo RD, et al. Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice. Proc Natl Acad Sci USA. 2004;101(7):2185-2190. doi:10.1073/pnas.0307313101.
20. Li R, Shen Y, Yang LB, Lue LF, Finch C, Rogers J. Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex. J Neurochem. 2000;75(4):1447-1454.
21. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative randomized trials. JAMA. 2017;318(10):927- 938. doi:10.1001/jama.2017.11217.
22. McCullough LD, Hurn PD. Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab. 2003;14(5):228-235.
23. McEwen BS, Woolley CS. Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing
brain. Exp Gerontol. 1994;29(3-4):431-436.
24. NAMS 3rd Utian Translational Science Symposium, October 2016, Orlando, Florida. A conversation about hormone therapy: is there an appropriate dose, route, and duration of use? Menopause. 2017;24(11): 1221-1235. doi:10.1097/GME.0000000000000986.
25. Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD. Estrogen protects neuronal cells from amyloid beta- induced apoptosis via regulation of mitochondrial proteins and function. BMC Neurosci. 2006;7:74. doi: 10.1186/1471-2202-7-74.
26. Nilsen J, Irwin RW, Gallaher TK, Brinton RD. Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci. 2007;27(51): 14069-14077. doi:10.1523/JNEUROSCI.4391-07.2007.
27. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol. 1994;140(3):256-261.
28. Pribluda VS, Gubish ER, Lavallee TM, Treston A, Swartz GM, Green SJ. 2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate. Cancer Metastasis Rev. 2000;19(1- 2):173-179.
29. Rasgon NL, Geist CL, Kenna HA, Wroolie TE, Williams KE, Silverman DHS. Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia. PLoS One. 2014;9(3):e89095. doi:10.1371/journal.pone. 0089095.
30. Rifici VA, Khachadurian AK. The inhibition of low-density lipoprotein oxidation by 17-beta estradiol. Metab Clin Exp. 1992;41(10):1110-1114.
31. Sack MN, Rader DJ, Cannon RO. Oestrogen and inhibition of oxidation of low-density lipoproteins in postmenopausal women. Lancet. 1994;343(8892):269-270.
32. Scharfman HE, MacLusky NJ. Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS. Front Neuroendocrinol. 2006;27(4): 415-435. doi:10.1016/j.yfrne.2006.09.004.
33. Shufelt CL, Braunstein GD. Testosterone and the breast. Menopause Int. 2008;14(3):117-122. doi:10.1258/mi.2008.008015.
34. Shughrue PJ, Merchenthaler I. Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J Comp Neurol. 2001;436(1):64-81.
35. Shughrue PJ, Merchenthaler I. Estrogen is more than just a “sex hormone”: novel sites for estrogen action in the hippocampus and cerebral cortex. Front Neuroendocrinol. 2000;21(1):95-101. doi:10.1006/ frne.1999.0190.
36. Shughrue PJ, Merchenthaler I. Evidence for novel estrogen binding sites in the rat hippocampus.Neuroscience. 2000;99(4):605-612.
37. Shughrue PJ, Scrimo PJ, Merchenthaler I. Estrogen binding and estrogen receptor characterization (ERalpha and ERbeta) in the cholinergic neurons of the rat basal forebrain. Neuroscience. 2000;96(1):41-49.
38. Shwaery GT, Vita JA, Keaney JF. Antioxidant protection of LDL by physiologic concentrations of estrogens is specific for 17-beta- estradiol. Atherosclerosis. 1998;138(2):255-262.
39. Singh S, Chakravarti D, Edney JA, et al. Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma. Oncol Rep. 2005;14(4):1091-1096. doi: 10.3892/or.14.4.1091.
40. Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev. 2008;57(2):386-397. doi:10.1016/j.brainresrev. 2007.06.012.
41. Tang M, Abplanalp W, Ayres S, Subbiah MT. Superior and distinct antioxidant effects of selected estrogen metabolites on lipid peroxidation. Metab Clin Exp. 1996;45(4):411-414.
42. Tannen RL, Weiner MG, Xie D, Barnhart K. Perspectives on hormone replacement therapy: the Women’s Health Initiative and new observational studies sampling the overall population. Fertil Steril. 2008;90(2):258-264. doi:10.1016/j.fertnstert.2008.05.031.
43. Tinley TL, Leal RM, Randall-Hlubek DA, et al. Novel 2- methoxyestradiol analogues with antitumor activity. Cancer Res. 2003;63(7):1538-1549.
44. Toran-Allerand CD, Miranda RC, Bentham WD, et al. Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc Natl Acad Sci USA. 1992;89(10): 4668-4672.
45. van Amelsvoort T, Compton J, Murphy D. In vivo assessment of the effects of estrogen on human brain. Trends Endocrinol Metab. 2001;12(6):273-276.
46. Wharton W, Gleason CE, Lorenze KR, et al. Potential role of estrogen in the pathobiology and prevention of Alzheimer’s disease. Am J Transl Res. 2009;1(2):131-147.
47. Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Cline JM. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007;101(2):125-134. doi:10.1007/ s10549-006-9276-y.
48. Woolley CS, McEwen BS. Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci. 1992;12(7):2549-2554.
49. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998;4(4): 447-451.
50. Yue X, Lu M, Lancaster T, et al. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci USA. 2005;102(52):19198-19203. doi:10.1073/pnas. 0505203102.
51. Zegura B, Keber I, Sebestjen M, Koenig W. Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis. Atherosclerosis. 2003;168(1):123- 129.
52. Menopause, Vol. 24, No. 7, 2017: Position statement of the North American Menopause Society
53. International Menopause Society April 25, 2016 : 2016 Recommendations on women’s midlife health and menopause hormone therapy

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Dr.Izadi is a quadruple board certified Medical Doctor (MD) with over 25 years of experience in a variety of settings that range from prestigious medical centers, where she has gained experience with cutting edge medical technology and techniques, to war zones intensive care facilities where her stethoscope was her only tool.

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