Dr. Leon Speroff M.D. author of med school textbook: “Clinical Gynecologic Endocrinology and Infertility”

• “By definition, a hormone can only be called a hormone if naturally occurring in the body,”
• Furthermore, “If the structure of a hormone is altered, it is no longer a hormone, it becomes a DRUG,

possessing different effects and side effects.”

• “A woman can only feel optimal when all of her different hormones reflect a balance of actions

in the body.”

• WHI 2002- Wyeth sales of Premarin and Prem-Pro dropped from 2 billion to 800 mil

Bioidentical Hormones. Position Statement. Endocrine Society. October 2006- “Bio-identical hormones are defined as compounds that have exactly the same chemical and molecular structure as hormones that are produced in the human body.”

The Bioidentical Hormone Debate: Are Bioidentical Hormones (Estradiol, Estriol, and Progesterone) Safer or More Efficacious than Commonly Used Synthetic Versions in Hormone Replacement Therapy. Review Article. Postgrad Med 2009;121(1):1-13. Holtorf K.

https://pubmed.ncbi.nlm.nih.gov/19179815/

Preponderance of Evidence

(RR- Relative Risk or risk ratio. 1.0= no increased risk, RR 1.5= 50% increased risk)

Breast Health

• E2 and E3 cancer risks- Hormone replacement therapy and incidence of hormone‐dependent cancers in the Norwegian Women and Cancer study, Bakken, cohort study 67,000 women. RR 1.0 for Estradiol >5yrs and 1.0 for Estriol users
• Receptor sites- Quantitative structure activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: insights into the structural determinants favoring a differential subtype binding. Endocrinology. 2006; 147(9): 4132-4150.. ERa- Estradiol, Estrone, ERb-Estriol
• Metabolites of Estrogen and Cancer risks- Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women, Fuhrman, case controlled study 277 w/breast cancer and 433 controls, 2 Hydroxylation safer than 4-hydroxy or 16aHydroxyestrone. Methylation of 4-OH E1 reduced risk
• Metabolite risk- Muti P et al. Estrogen metabolism and risk of breast cancer: a prospective study of the 2hydroxyestrone:16ahydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 2000;11(6):635-40. case controlled 10,800 women. Odds Ratio 0.58 Premenopausal and 1.29 Postmenopausal 40% less likely to develop breast cancer

➢ Progestin vs Progesterone- Fournier A. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N Cohort Study. Breast Cancer Res Treat. 2007 Feb. 80,377 women. E-alone RR 1.2, E+Progesterone RR 1.0 (no risk), E+progestogen RR 1.69

https://pubmed.ncbi.nlm.nih.gov/17333341/

• Estrogen replacement therapy after breast cancer: a 12-year follow-up. Ann Surg Oncol. 2001 Dec 8. Cohort study 600 women- 28 on ERT –No increased recurrence found
• Can Breast Cancer Survivors Safely Take Estrogen or Hormone Replacement Therapy? Hall 09/04/2018 Science Based Medicine.org )
• Postmenopausal Estrogen and Risk of Breast Cancer: What Is the Real Story? by AVRUM BLUMING, MD, responding to article Jan 25, 2020, issue of The ASCO Post on conclusion of the 19-year follow- up on the Women’s Health Initiative (WHI) Chlebowski, MD, PhD, 2019 San Antonio Breast Cancer Symposium
• Endogenous Progesterone levels and breast cancer risks
• Endogenous sex hormones and subsequent breast cancer in premenopausal women.

Micheli et al, Int J Ca 2004. Prospective study 5,953 cycling females- Higher Progesterone 40%

less likely to develop breast cancer

• Breast cancer incidence in women with a history of progesterone deficiency. Cowan, case

controlled 1083 women with progesterone defic- 5.4x more likely to develop breast cancer

• Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk, Schairer et al. cohort 46,355 women CEE/MPA >15 years / RR 1.36, 8X increased risk in CEE/MPA combo than CEE Alone. JAMA Jan 2000 283:485-491

• Swedish record review study 30,000 women 1990’s 3X increase CEE/MPA RR 4.6 (2.39-8.84)/ CEE RR

1.9 (NS .8-5.56) Cancer. 2003;97:1387-92

Million Women Study 2X increase with Progestin CEE/MPA RR 2.1 /CEE RR 1.2 (1.1-1.4) Beral et al, Lancet 2003; 362:419-424

• Chang et al: double-blind, placebo-controlled study of estrogen and progesterone on women prior to breast surgery given placebo, estrogen, transdermal progesterone, or estrogen + transdermal progesterone for 10-13 days prior to surgery
• Progesterone given with estradiol inhibited estrogen induced breast cell proliferation Chang KJ, Lee TY, Linarez-Cruz G, Fournier S, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 1995;63(4):785-791
• Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998;69(5):963-969, Foidart JM, Colin C, Denoo X, et al.
• Endogenous Hormone Levels, Mammographic Density, and Subsequent Risk of Breast Cancer in Postmenopausal Women. Rulla M. Tamimi, Celia Byrne, Graham A. Colditz, Susan E. J Natl Cancer Inst 2007;99:1178–87.

o Mammographic density is a well-confirmed predictor of breast cancer risk.

• Progesterone receptor modulates estrogen receptor-α action in breast cancer, Mohammed et al, Progesterone works at ERa and PR receptor to upregulate breast cancer cell apoptosis and down-

regulate ERa-stimulated tumor growth

• Reduced Estriol Excretion in Patients With Breast Cancer Prior to Endocrine Therapy JAMA.

1966;196(13):1128-1136. Henry M. Lemon, MD; Herbert H. Wotiz, PhD; Langdon Parsons, MD; Peter J. Mozden, MD

o The urinary quotient of estriol/(estrone + estradiol) (“Eq”) was measured in women with and without breast cancer… The median Eq was 1.3 in healthy women and 0.5 in women with breast cancer.

• Differential Regulation of Estrogen Receptor (ERα) and ERβ in Primate Mammary Gland Guojun Cheng, et. al. The Journal of Clinical Endocrinology & Metabolism 90(1):435–444. 2005 by The Endocrine Society

o Expressions of ERα, ERβ… were detected by immunohistochemistry. ERα [was] mainly expressed in epithelial cells of both lobules and ducts, whereas ERβ [was] expressed not only in epithelial cells but also in myoepithelial and stromal cells.

o The level of ERα expression in epithelial cells was high at early follicular phase (EFP) and low at late follicular phase (LFP) and luteal phase (LP) during the menstrual cycle, whereas it was low during pregnancy and absent in lactation. ERβ expression level was very low at early follicular phase, but its level increased sharply at late follicular and luteal phases during the menstrual cycle.

• Estrogen Receptor β Binds to and Regulates Three Distinct Classes of Target Genes. J Biol Chem.2010 Jul 16;285(29):22059-66 Omar I. Viva, et. al.

o Estrogen receptor β (ERβ) has potent antiproliferative and anti-inflammatory properties, suggesting that ERβ-selective agonists might be a new class of therapeutic and chemopreventative agents.

• Loss of ERβ expression as a common step in estrogen-dependent tumor progression. Bardin, et. al., Endocrine related Cancer. Review article. 2004 Sep; 11(3). 537 – 551.

o The characterization of estrogen receptor beta (ERβ) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues and the mitogenic effects of estrogen in these tissues (e.g. breast, endometrium and ovary) are well documented both in vitro and in vivo.

o In all of these tissues, most studies have shown decreased ERβ expression in cancer as compared to benign tumors or normal tissues, whereas ERα expression persists.

o The loss of ERβ expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression.

o ERβ may exert a protective effect and thus constitute a new target for hormone therapy, e.g. via ligand specific activation.

o The potential distinct roles of ERα and ERβ expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

• Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential Ilaria Paterni, et al, Steroids. 2014 Nov 15;

o The beta subtype seems to have a more profound effect on the central nervous and immune systems, and it generally counteracts the ERα-promoted cell hyperproliferation in tissues such as breast and uterus [2–3].

o In many breast cancers ERα activation by estrogens is generally considered responsible for enhanced proliferation, whereas this is counteracted by the presence of ERβ, which exerts an antiproliferative effect.

• The role of estrogen receptor beta (ERbeta) in malignant diseases–a new potential target for antiproliferative drugs in prevention and treatment of cancer. Warner M, Gustafsson JA. Biochem Biophys Res Commun. Review article. 2010 May 21;396(1):63-6.

o In this review, focus is on the role of ERbeta in malignant diseases where the anti proliferative activity of ERbeta gives hope of new therapeutic approaches.

• Estrogen receptor β: an overview and update

o o

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254331/

”Consensus regarding a protective role of ERβ against breast cancer development seems to

have been reached during the recent few years. ERβ is lost in a majority of breast tumors apparently by ERβ promoter methylation in breast cancer cells. Since promoter methylation is frequently observed in cancer, these data suggest that ERβ is a possible tumor suppressor gene.”

• Quantitative Structure-Activity Relationship of Various Endogenous Estrogen Metabolites for Human Estrogen Receptor α and β Subtypes: Insights into the Structural Determinants Favoring a Differential Subtype Binding. Endocrinology Zhu et al. September 2006 147 (9): 4132.

o …Several of the D-ring metabolites, such as…estriol (E3) ,… had distinct preferential binding affinity for human ERβ over ERα (difference up to 18-fold).

o Notably, although E2 has nearly the highest and equal binding affinity for ERα and ERβ, E1 and 2-hydroxyestrone [a metabolite of estrone] (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ERα over ERβ,

o E3 … had a markedly decreased binding affinity for ERα compared with E2 (RBA 11% of E2), but it retained a rather high binding affinity for ERβ (RBA 35% of E2)

o E3 has a more than 5-fold preference for the activation of human ERβ over ERα, and it is a quantitatively predominant estrogen metabolite produced during pregnancy. It is of interest to suggest that the very high levels of E3 present during pregnancy may produce a differential activation of the ERβ signaling system in the pregnant woman and fetus for fulfilling various unique physiological functions.

• Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis. Noriko Itoh, Rhonda R. Voskuhl, M.D. et. al. Journal of Neuroimmunology Accepted 28 September 2016

o Protective effects of pregnancy during MS have led to clinical trials of estriol, the pregnancy estrogen, in MS. Since estriol binds to estrogen receptor (ER) beta, ER beta ligand could represent a “next generation estriol” treatment. Here, ER beta ligand treatment was protective in EAE [Experimental autoimmune encephalitis] in both sexes and across genetic backgrounds.

o A major clinical observation in MS is that pregnancy is protective (Confavreux et al., 1998). Relapses are decreased by over 70% in the last trimester.

o Two trials have been completed, and one is ongoing (www. clinicaltrials.gov), with oral estriol treatment of 8 mg per day in women with MS to induce an estriol level in blood that recapitulates pregnancy. The first pilot clinical trial used the biomarker of enhancing lesions on monthly MRIs as the primary outcome measure. There was an over 70% reduction in enhancing lesions with estriol treat- ment compared to pretreatment in a single arm crossover design (Sicotte et al., 2002).

o Estriol has been considered the safest of the estrogens for decades, likely due to its preferential binding to ER beta over ER alpha, since toxicities related to breast and uterus are mediated by ER alpha, not ER beta (Head, 1998; Lauritzen, 1987; Takahashi et al., 2000)

o Other Recommendations:

• Estrogen Matters Avrum Bluming M.D and Carol Tavris PhD. Little, Brown Spark. September 2018.

Debunking the long-term implications of HRT and Women’s health Initiative Study • Estriol Emerging Clinical Benefits (2017)

o https://journals.lww.com/menopausejournal/Abstract/2017/09000/Estriol__emerging_clinic al _benefits.15.aspx

o Emerging evidence indicates that estriol has potential immunomodulatory benefits for: o -Autoimmune, inflammatory, and neurodegenerative conditions

o -Menopausal symptoms

o -Osteoporosis

o -Hyperlipidemia

o -Vascular disease o -Multiple sclerosis

• Pharmacotherapy for the Treatment of Vaginal Atrophy (2019)

o https://pubmed.ncbi.nlm.nih.gov/30897020/ 6) Estriol (E3) Replacement Improves

Endothelial

• http://mj-med-u-tokai.com/pdf/340308.pdf
• Function and Bone Mineral Density in Very Elderly Women
• https://academic.oup.com/biomedgerontology/article/55/4/B183/2948084 . Some info on the benefit of estriol in colon cancer

Estrogen Receptor Beta as Target for Colorectal Cancer Prevention

o https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744541/

• Estrogen Receptors and Their Implications in Colorectal Carcinogenesis

o https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313613/

Clotting, DVT, Coronary Heart Disease

• Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115(7):840- 845. +Maturitas. 2015 Nov;82(3), case controlled 881 cases- 271 w/VTE and 610 controls. Canonico et al, Odds Ratio (OR) 3.9 (4 fold) with progestins and 0.7 with micronized Progesterone. Also, Oral E increased risk (4.2) but only for first year of treatment-then no increased risk. Transdermal E, no increased risk (0.9)
• The longer the duration of menopausal hormone treatment, the more favorable the effects on coronary heart disease risk. CVD risk reduced 18-54%, Stroke 18-39%, All-cause mortality 12-38%

o AmJMed 2011 March; 124(3):199-205,doi:10.1016/jamjmed2010.09.021 

Beneficial Aspect of Oral Estriol as Hormone Replacement Therapy: Consideration on Bone

  and Lipid Metabolism

2. Menopause. 2015 Sep;22(9):976-83. doi: 10.1097/GME.0000000000000450. Mikkola, Tuomikoski et al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality.

• The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years, Yale study, Katz et al Sept 2013 American Journal of Public Health, 90,000 preventable deaths in 10 yrs post WHI
• Oral micronized progesterone for vasomotor symptoms–a placebo-controlled randomized trial in healthy postmenopausal women.,Hitchcock CL Women experienced significant relief from VMS (60% improved over placebo)
• Transdermal Matters: Update on Menopausal Hormone Replacement
• The Female Patient. 2010:35(9):24-27. John E. Buster, MD. Professor of Obstetrics and Gynecology,

reproductive endocrinologist at the Warren Alpert Medical School of Brown University.

o Transdermalestradiolisreplacingoralestrogensastheprincipalhormonaltherapyfor

treatment of vasomotor symptoms (VMS) in postmenopausal women.

o Estradiol is dosed into the microvascular circulation directly through the skin so there is no

first-pass hepatic transformation or deactivation of the dosed native steroid.

o First-pass metabolism of oral estradiol is associated with adverse events traditionally

attributed to menopausal hormone therapy.

o First pass significantly impairs bioavailability of oral estradiol. Large doses required to

overcome first pass induce supraphysiologic release of hepatic proteins,

o Coagulation factors: Oral estrogens increase hepatic production of coagulation factors and

affect activity of platelets. Transdermals have little or no effect on coagulation factors.3,13 o Transdermal matters because effective doses are closer approximations of endogenous

estradiol secretion and are therefore much lower than oral doses. Supraphysiologic

production of hepatoproteins and steroid metabolites are minimized, if not eliminated.

• Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Teede

HJ, et. al., Arterioscler Thromb Vasc Biol. 2000 May;20(5):1404-9

o Hormone replacement therapy (HRT) appears to be cardioprotective in postmenopausal

women; however, concerns exist over its thrombogenic effects.

o Forty-two healthy postmenopausal women aged 50 to 75 years received continuous

combined HRT with 2 mg estradiol+1 mg norethisterone

o HRT increased the markers of coagulation

o Coagulationactivationmaypartlyexplaintheincreasesinvenousthrombosisand

cardiovascular events reported with the use of combined HRT. • 1)Sex hormones, aging and cardiometabolic syndrome (2019)

o o o o

Testosterone

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604485/

“ … sex hormone changes in menopause and their consequences to increase visceral adipose accumulation may involve other hormones,(other than estrogen) such as progesterone or testosterone.”

• Low salivary testosterone levels in patients with breast cancer, Dimitrakakis et al. 
• Testosterone effects on the breast: implications for testosterone therapy for women. Somboonporn et al. National Health and Medical Research Council.
• Testosterone Androgens and the breast Bondy, Breast Cancer Res. 2009; 11(5): 212.2009 Oct 30. doi: 10.1186/bcr2413 Androgens reduce mammary breast cancer cell proliferation

Brain, Cognitive

• HRT and Brain- Cognitive Impairment risks reduced by 50-64%

o Bushra Imtiaz, MD, et al Postmenopausal hormone therapy and Alzheimer disease, A

prospective cohort study, Neurology® 2017;88:1–7

o Bagger YZ et al.; PERF Study Group. Early postmenopausal hormone therapy may prevent

cognitive impairment later in life. Menopause. 2005 Jan-Feb;12(1):12-7. • BHRT- Neuroactive Steroids

o Kilts et al. Neurosteroids and Self-Reported pain in veterans who served in the military after September 11, 2001. Pain Med 2010:10;1469-1476

o Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone induced suppression. Eur J Neurosci 2002;16:445-453 | Zhang

o role for pregnenolone in combination therapy that promotes recovery after spinal cord injury. Proc Natl Acad Sci. 1994;91:12308-12312.

• Dimentia, Neurodegenerative Disease Prevention:

o Looked at 400K women’s cases- women using menopausal hormone therapy for six years or

greater were 79% less likely to develop Alzheimer’s and 77% less likely to develop any neurodegenerative disease. Natural steroids estradiol or progesterone resulted in greater risk reduction than the use of synthetic hormones. Oral hormone therapies resulted in a reduced risk for combined neurodegenerative diseases, while hormone therapies administered through the skin reduced the risk of developing dementia. Yu Jin Kim et al, Association between menopausal hormone therapy and risk of neurodegenerative diseases: Implications for precision hormone therapy, Alzheimer’s & Dementia: Translational Research & Clinical Interventions (2021). DOI: 10.1002/trc2.12174

Men’s BHRT

• Primary Hypogonadism- testicular failure
• Secondary Hypogonadism- H/P axis dysregulation
• Physical/Emotional stress, Aging, Insulin Resistance/Weight/SHBG, Anabolic Steroid Abuse, TBI, Meds

(statins, beta-blockers, Corticosteroids, Opiates)

Dr Abraham Morgantaler MD- Harvard Urologist. Gould DC, et al, Testosterone replacement therapy for late onset hypogonadism: what is the risk of

inducing prostate cancer? 16 Studies. Prost Canc Prostatic Dis 2006;9(1):14-8

https://www.researchgate.net/publication/7502453_Testosterone_replacement_therapy_for_late_onset_hypogonadism_What_is_the_risk_of_inducing_prostate_cancer

• Haider A, Zitzmann M, Doros G, Isbarn H, Hammerer P, Yassin A. “Incidence of Prostate Cancer in

Hypogonadal Men Receiving Testosterone Therapy: Observations from 5-Year Median Follow-up of 3 Registries.” J Urol. 2014 Jun 26. pii: S0022-5347(14)03885-3.

• Roddam AW et al, Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Nat Cancer Inst 2008 100:170-183
• Agwaral PK et al, Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 2005 Feb;173(2):533-6
• Heart Disease

Baillargeon J et al, Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy

July,2014 Annals of Pharmacotherapy 25,000 men

https://pubmed.ncbi.nlm.nih.gov/24989174/

Sharma, Oni, Chen et al, “Normalization of testosterone level is associated with reduced

incidence of myocardial infarction and mortality in men” Eur HeartJ 2015 Aug 6,pii:ehv 346

83,000 men

https://pubmed.ncbi.nlm.nih.gov/26248567/

Muller M et al, Endogenous sex hormones and progression of carotid atherosclerosis in elderly

men. Circulation 2004 May 4;109(17):2074-9 (higher T, less risk atherosclerosis)

https://pubmed.ncbi.nlm.nih.gov/15096452/

Turhan S et al, The association between androgen levels and premature coronary artery disease

in men. Cor Arter Dis 2007 May;18(3)159-162 (low T = 3x increase risk of premature CVD)

https://pubmed.ncbi.nlm.nih.gov/17429287/

Khaw,KT et al, Endogenous testosterone and mortality due to all causes, cardiovascular disease, and

cancer in men Circulation 2007;116:2694-2701 (higher T, less mortality- CVD/cancer)

https://pubmed.ncbi.nlm.nih.gov/18040028/

Risks of testosterone replacement therapy in men. E. Charles Osterberg, Aaron M. Bernie, and Ranjith

Ramasamy, Department of Urology, New York Presbyterian Hospital, Weill Cornell Medical College, Indian Journal of Urol 2014 Jan-Mar’ 30(1): 2-7

The majority of reports of liver toxicity and jaundice are limited to orally-administered alkylated forms of testosterone.Svartberg J. Epidemiology: testosterone and the metabolic syndrome Int J Impot Res 2006 July

https://pubmed.ncbi.nlm.nih.gov/24497673/

Svartberg J. Epidemiology: testosterone and the metabolic syndrome Int J Impot Res 2006 July

https://pubmed.ncbi.nlm.nih.gov/16858366/

 Boyanov MA et al, Testosterone supplementation in men with type 2 diabetes, visceral obesity and

partial androgen deficiency. Aging Male 2003/6(1)/1-7. 17% reduction in A1c and Insulin resisitance

https://pubmed.ncbi.nlm.nih.gov/12809074/

Moffat SD et al, Long-term measures of free testosterone predict regional cerebral blood flow patterns

in elderly men Neurobiol Aging 2006 May 11 (less cognitive decline)

https://pubmed.ncbi.nlm.nih.gov/16698125/

• Mood and depression

▪ Am J of Psychiatry 2003; Jan:160(1)103-111, & 157;1884, Nov 2000

▪ J Geriat Psychiat Neurology 2000 Summer;12(2) 93-101

▪ Cooper MA, Testosterone Replacement Therapy For Anxiety Am J Phychiatry 157:1884,

November 2000

Brain Protection from Progesterone

Horm Behav. 2013;63(2):284-290.

Acta Pharmacologica Sinica. 2013; 34:1485-1490.

KEEP (Kronos Early Estrogen Prevention) Trial   po CEE + po prometrium vs. transdermal E2 + po progesterone in recently menopausal women, 662 women entered into the cognitive and mood portion of KEEPS, CEE but not patch increased HDL levels, CEE increased TG, Transdermal had no effect on HDL or TG, Significant improvement in depression, anxiety, tension

BHOT (Bio-identical Hormones On Trial)   Univ. of Texas   Comparison of patterns of administration and dosing of compounded bio-identical hormone therapy Women (n = 296) receiving BHRT at texas. Mean age of 52 (9) years. The BHRT dosage forms utilized were topical (71%) and oral (43%). Compounded BHRT regimens were generally initiated at low doses (<0.5mg E, <50mg Prog) regardless of route. Women experienced a 25% decrease in emotional lability, 25% decrease in irritability, and a 22% reduction in anxiety within 3 to 6 months. These women also experienced a 14% reduction in night sweats and a 6% reduction in hot flashes.

Nurses Study 67% increased risk for CEE + MPA, 23% increased risk for E alone

Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003;289(24):3243-3253

https://pubmed.ncbi.nlm.nih.gov/12824205/

Lyytinen H, Pukkala E, Ylikorkala O, et al. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy.

https://pubmed.ncbi.nlm.nih.gov/19104361/

Obstetrics & Gynecology 2009;113(1):65-73

Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332(24):1589-1593

https://pubmed.ncbi.nlm.nih.gov/7753136/

Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus

Estrogen plus progestin. J Natl Cancer Inst 2000;92(4):328-332

https://pubmed.ncbi.nlm.nih.gov/10675382/

Fournier A, Berrino F, Riboli E, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3NEPIC cohort. Int J Cancer 2005;114:448-545

https://pubmed.ncbi.nlm.nih.gov/15551359/

Wood CE, Register TC, Lees CJ, et al. 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

https://pubmed.ncbi.nlm.nih.gov/16841178/

Peck JD, Hulka BS, Poole C, et al. Steroid hormone levels during pregnancy and incidence of maternal breast cancer. Cancer Epidemiol Biomarkers

https://pubmed.ncbi.nlm.nih.gov/11927496/