The findings of numerous studies on hormone replacement therapy (HRT) conflict and, as a result, have raised serious questions regarding the appropriateness of HRT. Hormone replacement is an approved therapy for relief from moderate to severe hot flashes and symptoms of vulvar and vaginal atrophy. Numerous studies have confirmed that estrogen replacement decreases the risk of colon cancer, estrogen and progesterone decrease fracture risk, and various hormones increase energy levels and enhance libido. Reputable sources offer conflicting reports regarding issues such as memory, Alzheimer's disease, and stroke.

With the exception of the Postmenopausal Estrogen/Progestin Intervention (PEPI) study, major studies have either failed to distinguish among types and dosages of HRT used in the study, or examined only the use of synthetic HRT preparations (as in the case of the Women's Health Initiative). The Women's Health Initiative (WHI) study was designed to identify the potential risks and benefits of HRT. The estrogen-progestin portion of the clinical trial was stopped in 2002 after results showed that a synthetic hormone combination containing conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) increased the women's risks of developing invasive breast cancer, heart disease, stroke, and pulmonary embolism. The data and safety monitoring board concluded that the risks outweighed the evidence of benefit for fractures and colon cancer. Utilizing data from the WHI, researchers later concluded that synthetic CEE plus MPA does not improve mental functioning and may increase the risk of dementia in women over age 65. They suggest these hormones increase the risk of stroke, which is known to increase the risk of dementia. With regard to the risk of dementia, typical HRT users are in their 50s and the WHI study focused on women aged 65 and over, who have a higher risk for dementia. The "estrogen-only" portion of the WHI study was halted in March 2004 after analysis of data suggested that synthetic CEE alone had no impact either way on heart disease (the main focus of the study), but may increase the risk of stroke.

Many patients and medical professionals are unaware of the availability of bio-identical alternatives. In reality, women's experiences and clinical outcomes of HRT differ vastly depending on the dose, dosage form, and route of administration, and most importantly, whether the hormones are synthetic or bio-identical. As a result of concerns and doubts generated by studies that use synthetic hormones, many women who could substantially benefit from bio-identical hormone replacement may never have the opportunity.

Published research delineating the differences between natural bio-identical and synthetic HRT is now more abundant, but studies of bio-identical HRT will probably never be as plentiful as those dealing with patented synthetic hormones. Our pharmacy welcomes your questions.

Estrogens actually refers to a group of related hormones, each with a unique profile of activity. Under normal circumstances, a woman's circulating estrogen levels fluctuate based on her menstrual cycle. For Hormone Replacement Therapy, these hormones are often prescribed in combination to re-establish a normal physiologic balance. The two main estrogens produced in female humans are:

• Estrone -E1- (10-20% of circulating estrogens) is the primary estrogen produced after menopause.

• Estradiol -E2- (10-30% of circulating estrogens) is the most potent and major secretory product of the ovary, and the predominant estrogen produced before menopause.

Progesterone is a term that is incorrectly used interchangeably to describe both natural bio-identical progesterone and synthetic non- bio-identical derivatives. Synthetic progestins (also called progestogens or progestational agents) are analogues of bio-identical progesterone, and have been developed because they are patentable, more potent, and have a longer duration. Medroxyprogesterone acetate, the most commonly used synthetic progestin, was shown in a large study to cause significant lowering of HDL "good" cholesterol, thereby decreasing the cardioprotective benefit of estrogen therapy. Bio-identical progesterone has not been reported to produce any serious side effects when administered in physiologic doses. However, progestins can have significant and serious side effects at typical doses, including migraine headache, weight gain, mood swings, depression, irritability, acne, menstrual irregularities, and fluid retention. These side effects are a frequent cause for discontinuation of HRT.  Only about 20% of women who start synthetic HRT remain on it two years later.

Progesterone:

• is commonly prescribed for perimenopausal women to counteract "estrogen dominance" which occurs when a woman produces smaller amounts of progesterone than normal relative to estrogen levels.

• alone, or combined with estrogen, may improve Bone Mineral Density.

• minimizes the risk of endometrial cancer in women who are receiving estrogen.

• is preferred by women who had previously taken synthetic progestins.

• may enhance the beneficial effect of estrogen on lipid and cholesterol profiles and exercise-induced myocardial ischemia in postmenopausal women (in contrast to medroxyprogesterone acetate).

The benefits of progesterone are not limited to prevention of endometrial cancer in women who are receiving estrogen replacement. Progesterone therapy is not only needed by women who have an "intact uterus",  but is also valuable for women who have had a hysterectomy. Vasomotor flushing is the most bothersome complaint of menopause, and is the most common reason women seek HRT and remain compliant. For over 40 years, estrogens have been the mainstay of treatment of hot flashes, but transdermal progesterone cream may be effective as well. Women who have had postpartum depression once have about a 68% chance of having it again after another pregnancy, but trials using prophylactic progesterone have shown that it is possible to reduce the recurrence rate to 7%. Other benefits include improved bone density and enhanced glucose utilization.

Estrogen replacement restores atrophic mucosa, lowers vaginal pH, and may prevent urinary tract infections in postmenopausal women.

N Engl J Med. 1993 Sep 9;329(11):753-6
A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections.

In order to access the PubMed abstract of this article, visit this website link.

Low dose vaginally administered estradiol and estriol are equally efficacious in alleviating lower urinary tract symptoms which appear after menopause.

BJOG. 2000 Aug;107(8):1029-34
Oestradiol-releasing vaginal ring versus oestriol vaginal pessaries in the treatment of bothersome lower urinary tract symptoms.

In order to access the PubMed abstract of this article, visit this website link.

Intravaginal administration of estriol may represent a satisfactory therapeutic choice for those postmenopausal women with urogenital tract disturbances who have contraindications or refuse to undergo standard hormone therapy.

Menopause. 2004 Jan-Feb;11(1):49-56.
Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women.

In order to access the PubMed abstract of this article, visit this website link.

The following finding that conjugated equine estrogen but not esterified estrogen was associated with venous thrombotic risk may have implications for the choice of hormones in perimenopausal and postmenopausal women.

JAMA. 2004 Oct 6;292(13):1581-7

Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis.

Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM.
Department of Epidemiology, University of Washington, Seattle, USA. nlsmith@u.washington.edu
In order to access the PubMed abstract of this article, visit this website link.

These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.

Menopause. 2004 Sep-Oct;11(5):531-5

Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy.

Dimitrakakis C, Jones RA, Liu A, Bondy CA.
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
In order to access the PubMed abstract of this article, visit this website link.

The pharmacodynamic differences of testosterone and methyltestosterone are briefly reviewed in the context of choice for individualized clinical use.

Mayo Clin Proc. 2004 Apr;79(4 Suppl):S8-13

Hot flashes and androgens: a biological rationale for clinical practice.

Notelovitz M.
Adult Women's Health & Medicine, Boca Raton, Fla, USA. mnotelo@aol.com
In order to access the PubMed abstract of this article, visit this website link.

The results of this study suggest a significant reduction in the incidence of type 2 diabetes in our population of non-obese, healthy postmenopausal women who used transdermal 17-beta-estradiol. This could suggest that, in some women, the estrogen deficiency that occurs after menopause could represent a fundamental step in the process of diabetogenesis.

Diabetes Care. 2004 Mar;27(3):645-9

Transdermal 17-beta-estradiol and risk of developing type 2 diabetes in a population of healthy, nonobese postmenopausal women.

Rossi R, Origliani G, Modena MG.
Institute of Cardiology, University of Modena and Reggio Emilia, Modena, Italy. rossi.r@policlinico.mo.it

The full text article is available FREE online:  http://care.diabetesjournals.org/cgi/content/full/27/3/645

Mayo Clinic researchers surveyed 176 women taking natural bio-identical micronized progesterone who had previously taken synthetic progestins. After one to six months, the women reported an overall 34% increase in satisfaction on micronized progesterone compared to their previous HRT, reporting these improvements: 50% in hot flashes, 42% in depression, and 47% in anxiety. Micronized progesterone was also more effective in controlling breakthrough bleeding.

J Womens Health Gend Based Med 2000 May;9(4):381-7

Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey.

Fitzpatrick LA, Pace C, Wiita B.

Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
In order to access the PubMed abstract of this article, visit this website link.

ertil Steril 1999 Sep;72(3):389-97

Micronized progesterone: clinical indications and comparison with current treatments.

Fitzpatrick LA, Good A.
Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
In order to access the PubMed abstract of this article, visit this website link.

J Am Coll Cardiol 2000 Dec;36(7):2154-9

Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women.

Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P.
Department of Cardiology, Ospedale San Raffaele, Rome, Italy.
Click here to access the PubMed abstract of this article.

The PEPI Trial, a 3-year multicenter, randomized, double-blind, placebo-controlled study of 875 healthy postmenopausal women, confirmed that synthetic progestins partially negate the beneficial effects on cholesterol levels that result from taking estrogen. Natural bio-identical progesterone, on the other hand, maintains all the benefits of estrogen on cholesterol without any of the side effects associated with synthetic progestins, such as medroxyprogesterone acetate.

JAMA 1995 Jan 18;273(3):199-208

Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.

The Writing Group for the PEPI Trial.
In order to access the PubMed abstract of this article, visit this website link.

Certain progestogens, such as micronized progesterone, can be administered concurrently with estrogen replacement therapy, providing protection against endometrial hyperplasia without significantly affecting the beneficial effects of estrogen on lipid profiles, atherosclerosis and vascular reactivity.

J Reprod Med 2000 Mar;45(3 Suppl):245-58

Rationale for hormone replacement therapy in atherosclerosis prevention.

Wagner JD
Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC
In order to access the PubMed abstract of this article, visit this website link.

J Clin Endocrinol Metab 2002;87:1062-1067

Estrogen status correlates with the calcium content of coronary atherosclerotic plaques in women.

Christian RC, Harrington S, Edwards WD, Oberg AL, Fitzpatrick LA.
Division of Endocrinology, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
In order to access the PubMed abstract of this article, visit this website link.

J Neurosci. 2003 Dec 10;23(36):11420-6

Estradiol attenuates programmed cell death after stroke-like injury.

Rau SW, Dubal DB, Bottner M, Gerhold LM, Wise PM.
Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
In order to access the PubMed abstract of this article, visit this website link.

Endocrinology 2001 Mar 1;142(3):969-973

Minireview: Neuroprotective Effects of Estrogen-New Insights into Mechanisms of Action.

Wise PM, Dubal DB, Wilson ME, Rau SW, Bottner M
Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536.
In order to access the PubMed abstract of this article, visit this website link.

The use of conjugated equine estrogen plus medroxyprogesterone acetate in a double-blind, randomized, controlled trial of 16,608 postmenopausal women between the ages of 50 and 79 years doubled the risk of venous thrombosis. This horse estrogen plus synthetic progestin therapy increased the risks associated with age, overweight or obesity, and factor V Leiden.

JAMA. 2004 Oct 6;292(13):1573-80

Estrogen plus progestin and risk of venous thrombosis.

Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR; Women's Health Initiative Investigators.
Department of Medicine, University of Vermont, Burlington 05446, USA. mary.cushman@uvm.edu
In order to access the PubMed abstract of this article, visit this website link.

Chem Res Toxicol 1998 Sep;11(9):1105-11

The equine estrogen metabolite 4-hydroxyequilenin causes DNA single-strand breaks and oxidation of DNA bases in vitro.

Chen Y, Shen L, Zhang F, Lau SS, van Breemen RB, Nikolic D, Bolton JL
Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, The University of Illinois at Chicago, IL, USA.
In order to access the PubMed abstract of this article, visit this website link.

The following study concluded that in non-human primates, medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm. Progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm.

Nat Med 1997 Mar;3(3):324-7

Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm.

Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K.
Oregon Regional Primate Research Center, Oregon 97006, USA.
In order to access the PubMed abstract of this article, visit this website link.

MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, accelerates low-density lipoprotein uptake in plaque, increases the thrombogenic potential of atherosclerotic plaques and promotes insulin resistance and its consequent hyperglycemia. These effects may be largely limited to MPA and not shared with other progestogens.

J Reprod Med  1999 Feb;44(2 Suppl):180-4

Progestogens and cardiovascular disease. A critical review.

Clarkson TB.
Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC
In order to access the PubMed abstract of this article, visit this website link.

Significant bone loss occurs during the 10 to 15 years before menopause when estrogen levels are still normal. Progesterone can stimulate new bone formation in women with osteoporosis.  Dr. Prior measured estrogen and progesterone levels in female marathon runners who had osteoporosis. Although their estrogen levels were still high, they had stopped ovulating (common in female athletes) and progesterone levels had fallen, triggering the onset of osteoporosis. This can indicate a role for progesterone use, alone or combined with estrogen which reduces bone loss, in improving Bone Mineral Density.

Endocr Rev 1990 May;11(2):386-98

Progesterone as a bone-trophic hormone.

Prior JC.
Division of Endocrinology and Metabolism, University of British Columbia, Vancouver, Canada.
In order to access the PubMed abstract of this article, visit this website link.

The WHI assessed the major health benefits and risks of the most commonly used combined hormone preparation in the United States, the synthetic combination of conjugated equine estrogens and medroxyprogesterone acetate. Absolute excess risks per 10,000 person-years attributable to this synthetic hormone combination were 7 more CHD events, 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

JAMA. 2002 Jul 17;288(3):321-33

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators.
Division of Women's Health Initiative, National Heart, Lung, and Blood Institute, 6705 Rockledge Dr, One Rockledge Ctr, Suite 300, Bethesda, MD 20817, USA.
In order to access the PubMed abstract of this article, visit this website link.

Among postmenopausal women aged 65 years or older, synthetic estrogen plus progestin did not improve cognitive function when compared with placebo. However, typical HRT users are in their 50s and this study focused on women aged 65 and over, who have a higher risk for dementia.

JAMA  2003 May 28;289(20):2663-72

Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial.

Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D; WHIMS Investigators.
Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
In order to access the PubMed abstract of this article, visit this website link.

Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. This finding is consistent with the differences noted earlier between synthetic medroxyprogesterone acetate and bio-identical progesterone.

JAMA 2003 May 28;289(20):2673-84

Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.

Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ; WHI Investigators.
Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.