Hormone Replacement Therapy for Women : Supporting
Literature
Researchers at The University of Texas at Tyler, led by Kenna Stephenson, M.D., showed that use of progesterone in a topical cream (20 mg per day) relieved menopausal symptoms, and did not produce the adverse effects associated with progestins (synthetic MPA). In sharp contrast to earlier studies with conventional hormone replacement therapy (progestins), topical progesterone did not increase thrombotic and inflammatory factors. Total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFá and IL-6 levels were all unchanged. In addition, in a subpopulation of hypercortisolemic women, nocturnal cortisol levels were reduced to normal range while they were using the progesterone cream as compared to placebo. Stress activates cortisol, and an abnormal cortisol pattern has been associated with an increased risk of heart attacks, cancer, obesity and other diseases.
Blood 2004 Nov; 104(11):16
Progesterone Relieves Menopausal Symptoms and Normalizes Nocturnal Cortisol Levels
The French E3N-EPIC cohort study assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women and found the risk was significantly greater with HRT containing synthetic progestins than with HRT containing micronized progesterone.
Breast Cancer Res Treat. 2008 Jan;107(1):103-11
Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.
Fournier A, Berrino F, Clavel-Chapelon F.
Institut National de la Santé et de la Recherche Médicale ERI 20, Institut Gustave Roussy, 94805, Villejuif, France
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The neuroprotective and promyelinating effects of progesterone are promising not only for preventing, but also for reversing, age-dependent changes and dysfunctions.
Endocr Rev. 2007 Jun;28(4):387-439.
Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system.
Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, El-Etr M, Akwa Y, Rajkowski K, Baulieu EE.
INSERM UMR 788, 80, rue du Général Leclerc, 94276 Kremlin-Bicêtre, France.
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Clinical evidence shows that, during menopause, estrogen withdrawal gives rise to modifications in mood, behavior and cognition and that estrogen administration is able to improve mood and cognitive efficiency in post-menopause. There may be a critical period of time for HRT-related neuroprotection, and early initiation of estrogen therapy may be necessary for cognitive benefit.
Hum Reprod Update. 2007 Mar-Apr;13(2):175-87
Estrogen, cognition and female ageing.
Genazzani AR, Pluchino N, Luisi S, Luisi M.
Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy.
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Pharmacokinetics of Testosterone Gel in Healthy Postmenopausal Women
J Clin Endocrinol Metab. 2006 Jan;91(1):136-44.
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Absorption and Efficacy of Multiple Hormones Delivered in a Single Cream
This study is the first documenting systemic absorption of multiple hormones by both saliva and blood as well as improvement of health-related quality of life.
Gynecol Obstet Invest. 2008 Apr 29;66(2):111-118.
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New research from the Women's Health Initiative Memory Study (WHIMS) links the use of hormone replacement therapy (HRT) before the age of 65 years to a reduced risk of all-cause dementia and Alzheimer's disease (AD) in women. At the American Academy of Neurology’s 59th Annual Meeting, researchers presented an analysis that showed early HRT use was associated with a 46% overall reduction in dementia risk and a 64% reduction in AD. WHIMS also included 2 studies that looked at cognitive outcomes and HRT in women over 65 years old. At an average 5-year follow-up, both the conjugated equine estrogens plus medroxyprogesterone acetate (CEE + MPA) and the CEE-alone trials showed conjugated estrogens, with or without MPA, increased dementia risk when therapy was initiated after age 65 years. In the CEE + MPA trial the risk doubled, while in the CEE-alone trial there was about a 50% increased risk. There is evidence from animal models suggesting estrogen at an earlier age may be beneficial, and these results are intriguing because they seem to support that evidence.
While studies describe the therapies used in the WHI as “estrogen with or without progesterone”, the WHI actually used only synthetic CEE and MPA (which is significantly different than progesterone).
HRT Before Age 65 May Decrease Risk of Dementia and Alzheimer’s Disease
American Academy of Neurology 59th Annual Meeting: Abstract S31.004. April 28 – May 5, 2007
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Progesterone Therapy for Catamenial Epilepsy
Catamenial epilepsy refers to seizures that occur or worsen around menstruation. Researchers at North Carolina State University evaluated the hypothesis that neurosteroid "replacement" is an effective and a rational therapy for catamenial epilepsy. It is well known that progesterone possesses anticonvulsant properties. The clustering of seizures around the beginning of menstruation corresponds with a significant drop in the levels of progesterone circulating in the body and an increase in the estrogen:progesterone ratio. Recent studies have shown that progesterone is metabolized to the neurosteroid allopregnanolone which plays a crucial role in seizure protection. Declining levels of allopregnanolone, which occur during the menstrual cycle, can provoke seizures.
“Cyclic natural progesterone use has been demonstrated as an effective treatment for catamenial and non-catamenial seizures in women. Progesterone is efficiently absorbed after oral administration as lozenges, and rectal administration as suppositories.”4 Progesterone was given at 100 to 200 mg, t.i.d. on days 15 to 28 of the menstrual cycle. In a 3 month investigation of cyclic natural progesterone therapy, 23 of 25 (92%) women with intractable seizures completed the trial. Average monthly seizure frequency was reportedly reduced by 54% to 68% during the 3 month treatment period. A 3 year follow-up report found that 15 of the women continued on the same AED and progesterone protocol and continued to have a very substantial (62% to 74%) reduction in seizure frequency.
Epilepsy Behav. 2008 Mar 16 [Epub ahead of print]
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Seizure. 2008 Mar;17(2):176-80.
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Indian Journal of Pharmacology 2005; 37(5):288-293
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Neurology 1995;45:1660-2
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Neurology 1999;52:1917-8
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The Women's Health Initiative Memory Study (WHIMS) links the use of hormone replacement therapy (HRT) before the age of 65 years to a reduced risk of all-cause dementia and Alzheimer's disease (AD) in women.
American Academy of Neurology 59th Annual Meeting: Abstract S31.004.
April 28 - May 5, 2007
Click here to read a Medscape article on this topic.
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
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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.
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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
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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.
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Fertil 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.
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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.
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An extensive federally sponsored double-blind study was conducted at 19 academic medical centers that comprise the Maternal-Fetal Medicine Units Network under the National Institutes of Health and found that 17-alpha-hydroxyprogesterone caproate (17P) provides substantial benefit for decreasing the risk of pre-term birth at less than 37 weeks gestation.
N Engl J Med 2003;348:2379-85
Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
Department of Obstetrics and Gynecology, Wake Forest University, Winston-Salem, NC
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Am J Obstet Gynecol 2007;196:224.e1-224.e4.
Increased recurrence of preterm delivery with early cessation of 17-alpha-hydroxyprogesterone caproate.
Department of Maternal Fetal Medicine, Mount Sinai School of Medicine, New York, NY
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Vaginal progesterone suppositories have also been shown to decrease the rate of preterm birth in patients at increased risk. Da Fonseca et al noted that among 142 women who had one prior preterm birth, prophylactic cerclage, or uterine malformation, daily use of a 100-mg vaginal progesterone suppository compared with placebo significantly decreased the likelihood of delivery prior to 37 weeks.
Am J Obstet Gynecol. 2003; 188(2):419-424.
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
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Other related articles:
Obstet Gynecol 2005 May;105(5 Pt 1):1128-35
Am J Obstet Gynecol. 2007 May;196(5):453.e1-4
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.
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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
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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.
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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.
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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.
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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
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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.
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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.
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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
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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.
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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.
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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.
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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.
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