Female Menopause/ Estrogen/ Progesterone/ Testosterone for Women - California Longevity & Vitality Medical Institute®

Female Menopause/ Estrogen/ Progesterone/ Testosterone for Women

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This information is under copyright by Harvey S. Bartnof, M.D. and California Longevity and Vitality Medical Institute®. It may be copied only for individual, personal use and is not for distribution or publication of any type without the explicit written permission of Dr. Bartnof.

What Is Menopause?
Why are Oral Estrogens Unhealthy and Why Are Topical Estrogens (on the Skin) Better?
How is Bio-Identical Progesterone Different from Synthetic Progesterone?
What Is “Individualized” Hormone Replacement Therapy?
What Is Estrone and Why Is It Beneficial?
What is Estriol and Is It Beneficial?
What Is the Relationship Between Menopause and Alzheimer’s Disease and Memory Loss?
What Is the Female Androgen Deficiency Syndrome?
What Are the Symptoms and Signs of Low Estrogen Levels in Menopause or Before Menopause?
What Are the Symptoms and Signs of Low Progesterone Levels in Menopause or Before Menopause?
References

What Is Menopause?

The menopause refers to a decline in female hormones in women, often with a significant drop when in their 40s or 50s—including estrogens, progesterone and testosterone. Menopause is defined as no menstrual cycle for 12 months; yet “perimenopausal” symptoms may begin up to 10-15 years before true menopause. Every day in the United States, approximately 3,500 women begin menopause. Due to longer lifespans, many women can expect to spend 3 decades or longer in menopause.

Why are Oral Estrogens Unhealthy and Why Are Topical Estrogens (on the Skin) Better?

Oral estrogens increase a protein called “CRP” (C-reactive protein), which is an independent risk factor for stroke, heart attacks, diabetes, blindness (due to macular degeneration) and certain cancers. Therefore it is not surprising that the “Premarin only” arm of the Women’s Health Initiative study published in April 2004 in the Journal of the American Medical Association revealed a significant increase in stroke risk. Bio-identical (same type that exists in women) estrogen (estradiol) cream applied on the skin does not increase CRP.

Oral horse estrogen (conjugated equine estrogen, Premarin) has estrogens that are natural to horses, but unnatural to humans, because they are not “bio-identical” to the estrogens found in women. Therefore it is not surprising that these foreign hormones (“equilin” “equilenin”) lead to unwanted symptoms and effects. PRE-MAR-IN is derived from the PREgnant MARe urINe. Bio-identical estrogen (estradiol) applied on the skin, in the correct dose, and when balanced with the correct dose of bio-identical progesterone avoids most, if not all, of unwanted side effects from Premarin.

Oral estrogens decrease blood levels of IGF-1, an active form of natural Growth Hormone that your own body makes. IGF-1 is involved in helping to maintain muscle and bone mass, while decreasing fat mass. Bio-identical estrogen (estradiol) cream applied on the skin does not decrease IGF-1 levels.

Oral estrogens decrease the level of free testosterone, due to an increase in a protein made by the liver called “sex hormone binding globulin.” Women normally have some testosterone (more abundant in men), which helps maintain libido (interest in sex), helps the intensity of orgasms, helps maintain muscle and bone mass, and has a number of beneficial mental benefits. Bio-identical estrogen (estradiol) cream applied on the skin does not affect levels of testosterone or sex hormone binding globulin.

Oral equine estrogen increases fat mass and decreases muscle mass. Bio-identical estrogen (estradiol) cream applied on the skin does not increase fat mass and does not decrease muscle mass.

Oral estrogens increase blood clotting factors, a risk for abnormal clotting and therefore increase the risk for heart attack, stroke and possibly dementia (decline in brain function) and Alzheimer’s disease. Bio-identical estrogen (estradiol) does not significantly increase these factors.

Oral estrogens increase blood pressure, the risk of gallstones and sometimes abnormally increase liver enzymes in the blood. Bio-identical estrogen (estradiol) does not have these effects.

Taking into account all these factors, it is no wonder that Premarin prescriptions in the US have plunged by almost half between 1999 and 2003!

How is Bio-Identical Progesterone Different from Synthetic Progesterone?

The common synthetic progesterone MPA (medroxyprogesterone acetate) is called Provera and is combined with Premarin to make a 2-drug pill called PremPro. MPA is associated with a number of bad health outcomes, as demonstrated by the results of the PremPro arm of the Women’s Health Initiative (WHI) Study. While the Premarin only arm had an increased risk of stroke and a mild increased risk (trend) of dementia (loss of brain function), the PremPro arm had a significant increased risk of stroke, heart attack, breast cancer, blood clots in the lungs, and (for those older than 65 years) dementia. Therefore, adding MPA (synthetic progesterone) to Premarin (horse estrogen) led to a number of bad health outcomes that did not occur with Premarin alone. No wonder PremPro prescription sales in the U.S. have plummeted by 75% from 1999 to 2003! (The drugs are not necessarily all bad, since both arms showed a significant decrease in colon cancer and hip and other bone fractures). Before the WHI study, MPA has been shown to have several adverse effects on body functions and measurements, including in the heart, other blood vessels and in the brain. On the other hand, natural, bio-identical progesterone is not associated with these same negative effects that MPA has. Bio-identical progesterone balances out some of the effects of estradiol, just as what happens to normal, healthy women in the 20s and 30s (who are not taking oral contraceptives). The benefits are in the brain, heart, breast and possibly other organs at risk of developing cancer. Note that MPA and bio-identical progesterone each have beneficial effects for balancing estrogen in the uterus (womb).

What Is “Individualized” Hormone Replacement Therapy?

Every woman’s body is unique and different. Therefore the specific dosing of hormones to be replaced is different for each and every woman during menopause and “perimenopause.” Part of this is due to genetic factors, body shape differences, nutrition (diet), lifestyle factors, other medical conditions, and other medications. In addition, over time, a woman’s hormonal needs may shift, necessitating a modulation in hormone dosing. Thus, monitoring of the hormone levels in body fluids regularly is important. Testing frequency may be decreased after a woman is completely stabilized. In summary, menopause is different for each woman and approaches to treating menopause must be individualized.

What Is Estrone and Why Is It Beneficial?

Estrone is one of three main types of estrogens in women. It is weaker than estradiol, and it comes in several forms. The beneficial “2-hydroxy” estrone is the good type, while the “16-hydroxy” and “4-hydroxy” are associated with cancer-inducing effects. Part of balanced hormone replacement therapy includes treatments and approaches to maximize the “2”, while minimizing the “16” and “4.” Estradiol is the strongest of the 3 major estrogen types. Interestingly, estradiol can be converted to estrone in the body and vice versa.

What is Estriol and Is It Beneficial?

Estriol is the weakest of the three major estrogen types. There is good evidence in the medical literature that it has some anti-cancer benefits, particularly in the breast. It is also very good in treating the “hot flashes,” other “vasomotor” symptoms of menopause, vaginal dryness, and recurrent urinary bladder infections that may occur.

What Is the Relationship Between Menopause and Alzheimer’s Disease and Memory Loss?

There are a number of studies that had shown that estrogen therapy was beneficial in delaying or avoiding Alzheimer’s Disease (decline in brain function), cognitive (ability to understand) decline, and possibly memory loss. This is not too surprising, since there are numerous estrogen receptors in the brain—they must be there for a reason. Also estrogen decreases the production of amyloid beta proteins (occur in Alzheimer’s) in brain nerve cells. In addition, estrogen increases the production of the enzyme “choline acetyltransferase” that makes the brain transmitter “acetylcholine.” A-C (for short) deficiency is a major abnormal characteristic in the brains of people with Alzheimer’s disease. (The first FDA-approved drugs to treat Alzheimer’s all increase A-C.)

Yet both arms of the Women’s Health Initiative Study have shown some evidence of dementia or cognitive. This is likely associated with an increase in CRP (see above), due to the oral route of administration, and possibly due to other risk factors for brain decline, including elevated homocysteine, insulin resistance (pre-diabetes), high blood pressure, and increased body weight. Since topical (on the skin) estrogens due not increase CRP, that risk factor for brain decline would no longer be present. Preventive Neurology incorporates several strategies to avoid brain decline and illness at California Longevity and Vitality Medical Institute®. However, the beneficial aspects of estrogen on the brain can be achieved with the transdermal route, specifically, increasing choline acetyltransferase and decreasing amyloid deposits in the brain.

What Is the Female Androgen Deficiency Syndrome?

Most women will have a decline in their normal blood levels of androgen hormones (male-like effects) before or during the menopause. Many people are not aware that women have androgens, although at levels only 5-10% of that in men. (Similarly, men have estrogens and even progesterone!) As defined in the April 2004 supplement of Mayo Clinic Proceedings, symptoms of the Androgen Deficiency Syndrome in women include (not all are necessarily required for the diagnosis):

Decreased libido (interest in sex), sexual receptivity and pleasure
Low energy and persistent, unexplained fatigue
Dysphoric (unhappy) mood
Diminished psychological well-being
Blunted motivation
Decrease in bone mineral density
Decreased muscle mass and strength
Fat tissue redistribution (away from hips towards abdomen, trunk)
Decreased pubic and armpit hair
Changes in cognition (ability to comprehend) or memory

Note that some of these are non-specific, meaning they might be due to other causes or some may have several underlying causes.

A blood test would usually reveal a low “bioavailable” (not tightly bound to protein) or free testosterone. Other androgens include DHEA (dehydroepiandrosterone, from the adrenal glands), DHT (dihydrotestosterone, converted from testosterone) and androstenedione.

What Are the Symptoms and Signs of Low Estrogen Levels in Menopause or Before Menopause?

Common symptoms of low estrogen include: fatigue, low energy, lack of stamina, lack of sexual drive, painful intercourse, depression, hot flushes, sweats, menstrual irregularities or lack (no or poor menstrual blood loss), headaches, lack of resistance to physical efforts, increase in urinary bladder infections, urinary loss with straining, coughing or laughing (stress incontinence), increase in vaginal infections, hair/skin changes, new hair on face, breast changes, possible weight change, and possible joint aches. Note that some of these are non-specific, meaning they might be due to other causes.

What Are the Symptoms and Signs of Low Progesterone Levels in Menopause or Before Menopause?

Common symptoms of low progesterone include: nervousness, superficial and restless sleep, anxiety, irritability, excessive emotions, painful or swollen breasts (often before menstrual flow), swelling in hands, feet and sometimes in abdomen area, excessive menstruation, headaches, and possible weight change. Note that some of these are non-specific, meaning they might be due to other causes.

Historical References of Interest

Wilson, Robert A. Feminine Forever; 1968, M. Evans & Co.

Contemporary therapy of the menopausal syndrome.
Kupperman HS, Wetchler BB, Blatt MH. Journal of the American Medical Association. 1959 [no typo: the year was 1959] Nov 21; 171:1627-37. [No Abstract available]

References of Interest-General

Smith, Pamela W. HRT [hormone replacement therapy]: The Answers; A Complete Guide for Solving the Hormone Replacement Therapy Puzzle (paperback, 116 pages); 2003 Healthy Living Books, Michigan. Available at Borders/Amazon or Medaus Pharmacy .

Lee, John R and Hopkins, Virginia. What Your Doctor May Not Tell You About Menopause (paperback, 372 pages); 1996 Warner Books, Inc., New York.

Rouzier, Neal and Constance, Cherie. Natural Hormone Replacement For Men and Women, How to Achieve Healthy Aging (paperback, 254 pages); 2001 WorldLink Medical Publishing, Utah.

Wright, Jonathan V and Morgenthaler J. Natural Hormone Replacement for Women Over 45 (paperback, 128 pages). 1997 Smart Publications, Petaluma, CA.

References of Interest-Horse Estrogens Used in Women (conjugated equine estrogen)

A metabolite of equine [horse] estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines.
Chen Y, Liu X and others. Chem Res Toxicol. 2000 May; 13(5): 342-50.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10813650

Evidence that a metabolite of equine [horse] estrogens, 4-hydroxyequilenin, induces cellular transformation [cancerous-like change] in vitro.
Pisha E, Lui X, Chem Res Toxicol. 2001 Jan; 14(1): 82-90.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11170511

References of Interest-Topical (Transdermal, Skin) Bio-Identical Estrogen versus Oral Estrogen, Body Composition, CRP (Inflammation Marker)

The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.
O'Sullivan AJ, Crampton LJ, and others. Journal of Clinical Investigation. 1998 Sep 1; 102(5): 1035-40.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9727072
{Results: 24 weeks of oral conjugated equine [horse] estrogen resulted in a significant increase in fat mass (2.6 pounds) and a decrease in lean [muscle, bone] mass (2.6 pounds) compared with transdermal [bio-identical] estrogen. Lean mass and fat mass did not change significantly with transdermal estrogen.}

Lacut K and others. Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein. Thromb Haemost. 2003 Jul; 90(1): 124-31.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12876635
{Results: transdermal estrogen has no significant effect on CRP levels at 6 months, but CRP concentrations increased significantly with oral estrogen.

Differential effects of [conjugated equine or horse] estrogen and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women.
Herrington DM, Brosnihan KB and others. Journal of Clinical Endocrinology and Metabolism. 2001 Sep; 86(9): 4216-22.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11549652
{Results: Oral equine estrogen significantly increased CRP and IL-6 [both inflammation markers].}

A cross-sectional study of the effects of hormone replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women [transdermal estradiol versus oral equine estrogen and CRP].
Prelevic GM, Kwong P and others. Fertility and Sterility. 2002 May; 77(5): 945-51.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12009348
{Postmenopausal women taking conjugated equine estrogens had a significant increase in CRP compared to those using transdermal estradiol or control women}

References of Interest-CRP (Inflammation Marker) Increases Risk of Stroke, Heart Disease and Diabetes

Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study.
Rost NS, Wolf PA and others. Stroke. 2001 Nov; 32(11): 2575-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11692019

High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular [heart] disease.
Ridker PM. Circulation. 2001 Apr 3; 103(13): 1813-8.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11282915

C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
Pradhan AD, Manson JE and others. Journal of the American Medical Association. 2001 Jul 18; 286(3): 327-34.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11466099

Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study.
Pradhan AD, Manson JE, and others. Journal of the American Medical Association. 2002 Aug 28; 288(8): 980-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12190368

References of Interest-Bio-Identical Progesterone versus synthetic MPA (medroxyprogesterone acetate)

Comparison of regimens containing oral micronized progesterone [bio-identical] or medroxyprogesterone acetate [MPA, synthetic] on quality of life in postmenopausal women: a cross-sectional survey.
Fitzpatrick LA, Pace C, Wiita B. Journal of Women’s Health Gender Based Medicine. 2000 May; 9(4): 381-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10868610
{Results: Women who switched to bio-identical progesterone plus estrogen for 1-6 months after having taken synthetic progesterone (MPA) plus estrogen experienced significant improvement in vasomotor (hot flash) symptoms, anxiety and depressive symptoms as well as improved perceptions of their patterns of vaginal bleeding.}

Natural progesterone, but not medroxyprogesterone acetate [synthetic], enhances the beneficial effect of estrogen on exercise-induced myocardial [heart] ischemia [decreased blood flow] in postmenopausal women.
Rosano GM, Webb CM and others. Journal of the American College of Cardiology. 2000 Dec; 36(7): 2154-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11127455

Breast cancer incidence in women with a history of progesterone deficiency.
Cowan LD, Gordis L and others. American Journal of Epidemiology. 1981 Aug; 114(2): 209-17.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7304556
{Results: 1,083 women with progesterone deficiency were followed for 13-33 years and had 5.4 times the risk of premenopausal breast cancer compared to women with non-hormonal causes; results persisted after accounting for other possible co-factors. Women with progesterone deficiency also experienced a 10-fold increase in deaths from all malignant cancers.}

Estradiol and progesterone [bio-identical] regulate the proliferation of human breast epithelial cells.
Foidart JM, Colin C and others. Fertility and Sterility. 1998 May; 69(5): 963-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9591509
{Results: Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast (epithelial) cells in vivo [living breast samples].}

Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53.
Formby B, Wiley TS. Ann Clin Lab Sci. 1998 Nov-Dec; 28(6): 360-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9846203

Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo.
Chang KJ, Lee TT, and others. Fertil Steril. 1995 Apr; 63(4): 785-91.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7890063

Effects of progestogens [progesterone types] on the postmenopausal breast.
de Lignieres B. Climacteric. 2002 Sep; 5(3): 229-35.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12419080
{Author’s quotation: “It is misleading to put all progestogens in the same bag irrespective of their chemical structure…”}

Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination [insulation around nerve tissue].
Baulieu EE, Schumacher M. Hum Reprod. 2000 Jun; 15 Suppl 1:1-13.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10928415

Progesterone as a bone-trophic hormone.
Prior JC. Endocrine Reviews. 1990 May; 11(2): 386-98.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2194787

References of Interest-Estriol

Estriol, the forgotten estrogen?
Follingstad AH. Journal of the American Medical Association. 1978 January 2; 239(1): 29-30.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12277809

Estriol in the management of the menopause.
Tzingounis VA, Aksu MF, Journal of the American Medical Association. 1978 Apr 21; 239(16): 1638-41.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=633576

Pathophysiologic considerations in the treatment of menopausal patients with estrogens; the role of estriol in the prevention of mammary carcinoma [breast cancer].
Lemon HM. Acta Endocrinol Suppl (Copenhagen). 1980;233:17-27.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=6996403

References of Interest-Hormone Replacement and Alzheimer’s Disease, Dementia [Brain Decline]

Estrogen replacement therapy may protect against intellectual decline in postmenopausal women.
Kimura D. Hormones and Behavior. 1995 Sep; 29(3): 312-21.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7490007

Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study.
Zandi PP, Carlson MC and others. Journal of the American Medical Association. 2002 Nov 6; 288(17): 2123-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12413371

Estrogen use and verbal memory in healthy postmenopausal women.
Kampen DL and Sherwin BB. Obstetrics and Gynecology. 1994 Jun; 83(6): 979-83.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8190445

References of Interest-Androgens (Including Testosterone) in Women

Use of androgens in postmenopausal women.
Davis SR, Burger HG. Current Opinion in Obstetrics and Gynecology. 1997 Jun; 9(3): 177-80.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9263701

Supplement on androgen therapy for women: the evidence.
(several authors). Mayo Clinic Proceedings 2004 Apr; 79(4): S1-S32
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15065635 and
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15065631

References of Interest- Selected Women’s Health Initiative Reports

Postmenopausal hormone replacement therapy: scientific review (Women’s Health Initiative).
Nelson HD, Humphrey LL and others. Journal of the American Medical Association 2002 Aug 21; 288(7): 872-81.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12186605

Effects of conjugated equine [horse] estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
Anderson GL, Limacher M and others. Journal of the American Medical Association 2004 Apr 14; 291(14): 1701-12.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15082697

The WHI estrogen-alone trial--do things look any better?
Hulley SB, Grady D. Journal of the American Medical Association. 2004 Apr 14; 291(14): 1769-71 (editorial, no abstract available on PubMed).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15082705

Other

Cardiovascular disease risk and hormone replacement therapy (HRT): a review based on randomized, controlled studies in postmenopausal women.
van Baal WM, Kooistra T, Stehouwer CD. Curr Med Chem. 2000 May; 7(5): 499-517.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10702621

Estrogen replacement therapy and protection from acute myocardial infarction [heart attack].
Henderson BE, Paganini-Hill A and others. American Journal of Obstetrics and Gynecology. 1988 Aug; 159(2): 312-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3251473

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