Dr. Kent Holtorf is a leading authority in the field of hormone replacement therapy, and is also a board examiner for the American Board of Anti-Aging Medicine (ABAAM).
Click here to read Dr. Holtorf’s article about the benefits of customized hormone therapy.
Menopausal Hormone Therapy and Mortality
Menopausal hormone therapy is the most effective treatment for symptoms related to the hormonal changes of menopause, such as hot flushes and sleep deprivation. Hormone therapy is also beneficial for bone health and may decrease mortality and cardiovascular disease. Risks associated with menopausal hormone therapy are acknowledged, but benefits derived will generally outweigh the risks for women under 60, or within 10 years of the menopause. Taking menopausal hormone therapy is a decision which needs to be individualized, according to a woman’s symptoms, and her individual health history. This decision should be made under the advisement of a qualified physician.
Climacteric. 2013 Apr;16(2):203-4.
After 10 years of treatment, women receiving hormone replacement therapy soon after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.
Based on the observed trends in the incidence of breast cancer following the decline in HRT use, the ecological evidence is too limited either to support or refute the possibility that HRT causes breast cancer.
J Fam Plann Reprod Health Care 2013;39:80-88 doi
The study examined the long-term effects of compounded natural transdermal hormones on cardiovascular biomarkers, hemostatic, inflammatory, immune signaling factors; quality of life measures; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care. This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in populations with high perceived stress and a history of stressful life events prior to, or during the menopausal transition.
Int J Pharm Compd. 2013 Jan-Feb;17(1):74-85.
Testosterone (T) therapy is being increasingly used to treat symptoms of hormone deficiency in pre and postmenopausal women. T is essential for physical and mental health in women. A source of confusion concerning the safety of T therapy in both men and women is the extrapolation of adverse events from high doses of oral and injectable anabolic-androgenic steroids to T therapy, despite a lack of evidence. Testosterone is not masculinizing and does not increase aggression or cause hoarseness. Testosterone increases scalp hair growth, is mood stabilizing, and is cardiac and breast protective. “Abandoning myths, misconceptions and unfounded concerns about T and T therapy in women will enable physicians to provide evidenced based recommendations and appropriate therapy.”
Maturitas. 2013 Feb 1. [Epub ahead of print]
Reviewers conclude that the choice of transdermal route of administration of estradiol and the use of natural progesterone might offer significant benefits and added safety.
Literature reviewers conclude that oral postmenopausal estrogen replacement is associated with an increased risk for venous thromboembolism. The review did not address transdermal estrogen therapy.
Ann Intern Med. 2002 May 7;136(9):680-90.
The use of oral estrogen plus progestin hormone therapy in postmenopausal women was associated with doubling the risk of development of venous thrombosis.
JAMA. 2004 Oct 6;292(13):1573-80.
According to this study's findings, oral postmenopausal estrogen/progesterone replacement may increase the risk of venous thromboembolism, but the risk of developing deep vein thrombosis (DVT) or pulmonary thromboembolism (TE) with transdermal estrogen therapy is negligible in comparison.
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):3071-8.
The PEPI trial demonstrated that micronized progesterone is as effective as the synthetic progestin medroxyprogesterone acetate (MPA) in preventing endometrial hyperplasia.
Mark E. Johnson et al of Massachusetts Institute of Technology finds that: “Steroids are an important class of pharmacologically active drugs which have been found to be well suited for transdermal delivery.” Steroid hormones, including estrogens, testosterone, pregnenolone, and progesterone, are low molecular weight, highly lipophyllic molecules, therefore, good candidates for absorption across the skin.
J Pharm Sci. 1995 Sep;84(9):1144-6.
Stanczyk et al. of Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, report: "antiproliferative effects on the endometrium have been demonstrated with progesterone creams when circulating levels of progesterone are low. Thus, effects of topical progesterone creams on the endometrium should not be based on serum progesterone levels, but on histologic examination of the endometrium. Despite the low serum progesterone levels achieved with the creams, salivary progesterone levels are very high, indicating that progesterone levels in serum do not necessarily reflect those in tissues"
Menopause. 2005 Mar;12(2):232-7.
“These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone.”
Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Epub 2007 Feb 27.
Ovarian androgens normally protect mammary epithelial cells and the addition of testosterone (not METHYLtestosterone) 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.
Chang et al. studied influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo and reported that progesterone decreases estrogen-induced breast cell proliferation by 400%.
Fertil Steril. 1995 Apr;63(4):785-91.
According to Fitzpatrick et al "A micronized progesterone-containing HRT regimen offers the potential for improved QOL as measured by improvement of menopause-associated symptoms."
While none of the hormone treatments used in this study had a detectable effect on mood, Cummings et al conclude "the lesser side effects of the micronized progesterone-containing regimen suggest that some women may prefer it to an MPA-containing regimen."
Menopause. 2002 Jul-Aug;9(4):253-63.
“This study demonstrates that the daily administration of a combination of micronized E2 and progesterone results in symptomatic improvement, minimal side effects, an improved lipid profile, and amenorrhea without endometrial proliferation or hyperplasia in menopausal women."
Obstet Gynecol. 1989 Apr;73(4):606-12.
This trial indicates that the use of natural progesterone does not increase the risk of breast cancer, as opposed to synthetic progestins.
Fertil Steril. 1998 May;69(5):963-9.
A growing body of medical literature suggests that various progestogens are not equivalent. Furthermore, trials indicate that the use of natural progesterone alone or combined with estradiol does not increase the risk of breast cancer while use of medroxyprogesterone acetate or norethisterone acetate stimulate proliferation of breast cancer cells.
Maturitas. 2003 Dec 10;46 Suppl 1:S55-8.
Estrogen deficiency during menopause contributes to the development of abdominal obesity and insulin resistance, and could represent a major step in the development of diabetes in women. In a 2006 meta-analysis of 107 trials, Salpeter et al. concluded that appropriate HRT reduces abdominal obesity, insulin resistance, new-onset diabetes, lipids, pro-inflammatory adhesion molecules and pro-coagulant factors in women without diabetes.
Diab Obes Metab 2006;8:538–54.
Glucose metabolism and insulin sensitivity can be improved by estrogen replacement therapy but the addition of an androgenic progestin, such as MPA or NETA, may reduce the beneficial effect of estrogens. While MPA is known to increase insulin resistance and impair glucose tolerance, natural progesterone does not.
Neuroprotective effects of progesterone include prevention and reversal of age-dependent changes and dysfunction. Some of these actions, particularly those mediated by conversion to neurosteroids such as allopregnanolone, may not be shared by synthetic progestins since progesterone behaves differently in the brain than synthetic progestins (particularly MPA), through direct effects, as well as indirectly through effects on the vascular endothelium. This may have important implications for the effective use of HRT in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases.
Endocr Rev. 2007 Jun;28(4):387-439. Epub 2007 Apr 12.
This study of the aftermath of the Women’s Health Initiative (WHI) found that 70% of women who were taking hormone therapy (conjugated equine estrogens and medroxyprogesterone acetate) discontinued it, and 26% of women lost confidence in medical recommendations in general. Many women have sought alternatives in the form of compounded hormones.
Women's Health Issues. 2005 Jul-Aug;15(4):187-95.
As women age and estrogen levels decline, cutaneous changes such as dryness, atrophy, fine wrinkling and poor healing occur. This article reviews the effects of declining estrogen levels on the skin and the effects of estrogen supplementation.
Ninety-seven percent of the 189 women participating in this study experienced varying degrees of symptom control, but complications described with traditional HRT did not develop in these patients using customized natural hormones. The findings of this study point out a need for larger controlled trials of customized natural hormones in the management of menopause.
Gynecol Endocrinol. 2009 Aug 19:1-5. [Epub ahead of print]
Click here to access the PubMed abstract of this article.
Transdermal estradiol was similarly effective as raloxifene in preventing bone loss at the lumbar spine, was well tolerated, and had no clinically significant effect on endometrium or breast density.
The objective of this analysis was to determine the effects of conjugated equine estrogens/medroxyprogesterone acetate on breast cancer mortality after a total mean follow-up of 11.0 years, through August 14, 2009. The analysis did not track or review patients taking natural estrogens or progesterone.
JAMA. 2010 Oct 20;304(15):1684-92.
Breast cancer incidence and mortality is increased in women using conjugated equine estrogens and medroxyprogesterone acetate (a synthetic progestin).
Lancet. 2003 Aug 9;362(9382):419-27.
In this 2005 review of clinical studies comparing synthetic progestins to natural progesterone, Campagnoli et al concluded: "The balance of the in vivo evidence is that progesterone does not have a cancer-promoting effect on breast tissue. ...We therefore suggest that when HRT is indicated, preparations containing progesterone and not a synthetic progestin should be used, according to a sequential or cyclic-combined regimen. In this way the risk of endometrial cancer is minimised without increasing the risk of BC [breast cancer]."
J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.
In this 2005 clinical trial, Fournier et al compared synthetic progestins to the natural progesterone and reported: "The risk was significantly greater… with HRT containing synthetic progestins than with HRT containing micronized progesterone, the relative risk being 1.4 and 0.9, respectively."
Int J Cancer. 2005 Apr 10;114(3):448-54.
This large French study raises the possibility that micronized progesterone, when combined with human estrogens, may have less impact on breast cancer mortality.
J Clin Oncol. 2008 Mar 10;26(8):1260-8.
Studies of women using HRT, including either micronized progesterone or synthetic medroxyprogesterone acetate (MPA), compared efficacy, patient satisfaction and quality of life. Women reported greater satisfaction, fewer side effects and improved quality of life when they were switched from synthetic progestins to micronized progesterone.
J Womens Health Gend Based Med. 2000 May;9(4):381-7.
Transdermal Progesterone and Estrogen Improve Blood Pressure in Menopausal Women with High Stress
Progesterone vs Synthetic Progestins: Clinical Options
James A. Simon, MD, Clinical Professor, George Washington University, Washington, DC, notes: “Clinicians have numerous options in selecting a progestogen for the individual patient. The specific properties of progesterone or synthetic progestins may result in differing side-effect profiles for individual patients. Route of administration also offers differing systemic or local effects that should be considered for some uses and specific patients.” Differences exist among the exogenous progestogens, which include both natural progesterone and synthetic and semi-synthetic progestins, drugs which are “structurally related - but are not identical - to either progesterone or testosterone... Progesterone and progestins differ not only in their structure, but also in their potency, as determined by standard bioassays... Additionally, studies often do not evaluate the effects of progestogens on specific organs or compare the side-effect profiles of individual agents. These characteristics constitute an important, although rarely discussed, aspect of the differences among progestogens.”
The Journal of Family Practice 2007 Feb; 2(7):S3-S5
Comparison of Different Routes of Progesterone Administration for Luteal Phase Support in Infertility Treatment
Uses of Progesterone in Clinical Practice
Pregnenolone – The Parent Hormone Affecting Memory, Sleep, Anxiety, and Mood
Please click on the links below for more information.
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. 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
The French E3N-EPIC cohort study assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women.
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.
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.
J Clin Endocrinol Metab. 2006 Jan;91(1):136-44.
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.
Absorption and Efficacy of Multiple Hormones Delivered in a Single Cream
Gynecol Obstet Invest. 2008 Apr 29;66(2):111-118.
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.
HRT Before Age 65 May Decrease Risk of Dementia and Alzheimer’s Disease
Progesterone Therapy for Catamenial Epilepsy
“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.” 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 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]
Adv Biomed Res. 2013 Mar 6;2:8.
Indian Journal of Pharmacology 2005;37(5):288-293
Seizure. 2008 Mar;17(2):176-80. - ADD
Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.
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.
The following finding that conjugated equine 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
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
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
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
Mayo Clinic researchers surveyed 176 women taking natural 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
Fertil Steril 1999 Sep;72(3):389-97
J Am Coll Cardiol 2000 Dec;36(7):2154-9
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.
The PEPI Trial, a 3-year multicenter, randomized, double-blind, placebo-controlled study of 875 healthy postmenopausal women, stated that synthetic progestins partially negate the beneficial effects on cholesterol levels that result from taking estrogen. Natural progesterone maintained the benefits of estrogen on cholesterol without side effects.
JAMA 1995 Jan 18;273(3):199-208
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
J Clin Endocrinol Metab 2002;87:1062-1067
J Neurosci. 2003 Dec 10;23(36):11420-6
Endocrinology 2001 Mar 1;142(3):969-973
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 estrogen, which is derived from pregnant mares' urine, 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
Chem Res Toxicol 1998 Sep;11(9):1105-11
The following study concluded that in non-human primates, medroxyprogesterone increases the risk of coronary vasospasm. Progesterone plus estradiol protected against vasospasm.
Nat Med 1997 Mar;3(3):324-7
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
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
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
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
In the following study, estrogen plus progestin increased the risk of ischemic stroke in generally healthy postmenopausal women.
JAMA 2003 May 28;289(20):2673-84
Click here to access the PubMed abstract of this article.
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