Dr. Clarke's Website
A Laughing Matter
As I stated in my Home Page, the purpose of this website has been to evaluate articles in the media about “medical science”. I just couldn’t pass up the recent press release by the FDA regarding Estriol. On all the news shows, bioidentical hormones were denounced vehemently and the public was warned not to use them. Even as I’m writing this I’m trying to suppress my amusement. The FDA has “reached an agreement” with Wyeth Pharmaceutical Company’s “Citizen Complaint” about the use of Estriol by menopausal women to alleviate their climacteric symptoms. The FDA has stated that Estriol is an “unapproved drug”. Now, I found that humorous because aspirin is also a drug that has not been approved by the FDA. Here’s the truth of the matter.
Estriol is the predominant estrogen produced by the female ovary and is widely and successfully used and accepted as HRT in Japan, Europe and Scandinavia. As you can see from the abstracts that I have attached to this writing, much of the research comes from respected labs and academic institutions in those countries as well as American researchers. The studies are published only after review by expert scientific reviewers, usually other doctors and researchers in the same field. Normally, I would read and analyze the entire paper, but, in the interest of a quick upload, I only reviewed the abstracts in this case.
The FDA is encouraging the public to use only FDA approved drugs….like Zetia and Vioxx, and Avandia and ……. I don’t need to go on, do I? Doesn’t it seem like the epitome of arrogance that a branch of government does not approve of a hormone that was designed by God? Sadly, that also made me laugh. If we’re going to ban estriol from America, the women will have to find another place to live. Maybe “hair” and “fingernails” also need FDA approval. Do we need government approval for everything? How about Fords and Chevys? This is becoming no laughing matter. Here’s why. If doctors are not allowed to try treatments that are “out of the box”, we will never discover new treatments. Are you getting that? If we are not allowed to evaluate the current science literature and implement it for our patients, we will never discover the new penicillin or the new treatment for strokes or spinal injury….because remember, penicillin is a nasty fungus and could make the public sick. We don’t need the government to make us doctors be careful. We took an oath to do that. And we care deeply for our patients, certainly more that the FDA does in their Washington offices. And we want to help our patients.
The FDA has also objected to the use of the term “bio-identical” when referring to these hormones that are chemically identical to those produced by the human body. They have stated that this word has no meaning and is not to be found in any medical dictionary. However, over the past 20 years this term has been coined to describe synthetically manufactured molecules that are identical to those that occur in nature. Perhaps we should use “synthetic, but chemically and allosterically identical molecules or hormones.” I suppose that would be more accurate. However, the coining of new terms has precedence. “Nauseous”, “ain’t”, “dove” as in “I dove into the pool” were all words that I was taught were not to be used because they were not in the dictionary. They are now. It is thought that Warren G. Harding coined the word “normalcy”. It’s in the dictionary now.
What is NOT humorous is that the FDA has been entrusted with protecting the health of 250 million people. After you peruse the attached abstracts, you can decide if they have abrogated that responsibility in this instance.
Autoimmune Neurodegenerative Disease: In the Neurology 2004 abstract written by researchers at Brown University in the Department of Clinical Neurosciences, they are reviewing some of the current regimens for treatment of Multiple Sclerosis. In the second sentence they state, “However, drugs that are not FDA-approved are routinely used to treat M.S.” Interesting isn’t it? These M.S. studies show that estriol has been found to put multiple sclerosis into remission in a UCLA study published in Annals of Neurology 2002, and I understand that it is in Phase II/III trial pending FDA approval for this use (which may take several years). Two studies, published in Neurology 1999 and in Journal of Neuroimmunology 2004, demonstrated similar results in autoimmune encephalomyelitis treated with estriol. These doctors found that estriol decreased proinflammatory cytokine production in both males and female patients while increasing antibodies to the autoantigen responsible for the demyelination or destruction of the nerves. Another possible protective mechanism in this M.S. story may be the inhibition of an enzyme nitric oxide synthetase by estriol which is produced by microglial cells activated by these inflammatory cytokines. See the abstract by Drew and Chavis from University of Arkansas Medical School in Journal of Neuroimmunology 2000. And it may be that some of this protective effect in M.S. may be the result estriol decreasing the T cell production of matrix metalloproteinase-9 ( see my section on Alzheimer’s and scroll down to the section on Minocycline to learn about how these substances promote inflammatory responses and destroy tissue.) as discussed by Baylor researchers in Journal of Neuroimmunology 2002. So estriol is probably a “potent regulator of T cell functions through its interaction with NF-Kappa B signaling pathway”. This same mechanism may explain the estriol effect noted in macaques where vaginally applied estriol strongly protected against HIV vaginal transmission, a study from New Jersey Medical School researchers published in the journal AIDS 2004. So if your daughter had MS or autoimmune encephalomyelitis or was at high risk for contracting vaginal HIV (God forbid) wouldn’t you want ESTRIOL to be available?
Reversal of Vaginal and Urethral Atrophy: You will note that several European and Japanese studies show that estriol will treat both the climacteric hot flashes in menopausal women and improve urinary urgency and leakage and frequency of infections and improve the vaginal atrophy of menopause without endometrial side effects. In addition, no adverse effects were noted in the bone, lipids, liver, or blood pressure in the treatment groups in these studies. No mammogram changes in breast tissue was noted in any of these studies evaluating the use of estriol. As an added benefit estriol appears to promote a restoration of normal vaginal flora as well.
Breast Cancer: These breast study results mentioned above are supported by the epidemiologic studies from Finland in Obstetrics and Gynecology 2006 that demonstrate that estriol, unlike estradiol and conjugated estrogens (an FDA approved drug), was NOT associated with a risk of breast cancer. In another study in Gynecologic Endocrinology 2006 there is evidence that estriol binds to a different estrogen receptor (estrogen receptor-beta) that actually inhibits some of the undesirable effects of estradiol. Takahashi, et.al. (Hum Reprod,2000) used histologic evaluation of the uterine endometrium and ultrasound of the breasts to evaluate the effects of a year of low dose estriol HRT and found no abnormalities. And to reiterate, there have been no mammogram changes in breast tissue noted in any of these studies evaluating the use of estriol.
Cardioprotective? You will remember that the concerns raised by the Women’s Health Initiative study included strokes and heart attacks. The FDA is chiding the pharmacies for stating that compounded HRT containing estriol is safer than the FDA approved drugs, by which I assume the FDA means the conjugated estrogens. As you can see from the study abstracts, it does appear that the preponderance of the studies show a potent antioxidant effect of estriol on LDL, and so does “bio-identical” estradiol in the Spanish study by Arteaga, et.al. The Takahashi study demonstrated that systolic and diastolic blood pressures were significantly decreased after 3 months of estriol HRT in menopausal patients. Hayashi showed an increase in “endothelium-dependent flow-mediated dilatation” with estriol treatment, which I assume must mean that estriol HRT dilates the arteries. That may explain why Takahashi saw a decrease in blood pressures with estriol.
NOW, Itoh, et.al. (Maturitas, 2000) interestingly, comparing the FDA approved conjugated estrogens to estriol found that after 4 years, total cholesterol did not change in the conjugated estrogen group, but significantly decreased in the estriol treated group. AND triglycerides increased in the conjugated estrogen group but decreased in the estriol group. Perhaps this is one of the bases for the claims made by the compounding pharmacies with which the FDA takes issue.
Houser et.al. (Cardiovasc Pathol, 2000) at Harvard also showed that estriol treatment decreased aortic plaque formation in the hypercholesterolemic rabbits. Tsuda et.al. (Hypertes Res 2001) found an increased red blood cell membrane fluidity in estriol treated patients suggesting that this might be an effective mechanism to decrease the viscosity and increase capillary microcirculation. This was proposed to be an effect of estriol to increase nitric oxide activity and it is supported by other Japanese authors in the Life Sciences 2002 abstract that observed a decrease in the atherosclerotic plaque area in the thoracic aorta of rabbits with both estriol and “bio-identical” estradiol.
Take a look at the study by Yamanaka, et.al. Gynecology and Obstetric Investigations 2005. With estriol HRT treated women, it was found that the atherosclerotic wall thickness of the carotid artery evaluated by ultrasound was significantly decreased when estriol was used together with pravastatin. However, pravastatin alone did not result in any decrease in atherosclerotic thickness of the carotid artery. Perhaps this is where the compounding pharmacies found a basis for the cardiovascular protective claims for estriol.
Bone Density: The bone mineral density abstracts clearly demonstrate an increase in bone density with estriol. This mechanism in one study was postulated to be via inhibition of bone resorption. It is supported by Wang’s rat study in which he shows that estriol not only inhibited bone resorption, but did so without the estrogenic side effects on the uterus and weight gain, making it a good candidate for HRT. In another study it was demonstrated that estriol increases the Vitamin D3 receptor mRNA expression in cultured osteoblasts thereby supposedly stimulating bone formation. There’s really not much more to add to this.
Alzheimer’s: The two abstracts dealing with Alzheimer’s are quite intriguing. In Morinaga et.al.’s in vitro study using immunoflourescence and electron microscopy, they demonstrated not only an inhibition of the formation of new beta-amyloid, but a destabilization of existing beta-amyloid, and this anti-amyloidogenic activity was greatest for estriol when compared with estradiol and estrone. In Yonker et.al’s study there was a correlation with levels of “bio-identical” estradiol and episodic memory and verbal fluency.
Summary: I hope that after this quick overview of the last 4 years of research on estriol, it is clear to the reader that the claims of the compounding pharmacies actually have some scientific basis. Here are some basic points.
1. Estriol is a hormone which is made in the human ovary. Because it occurs in nature, it cannot be patented by any company. Because it belongs in the human body to begin with, replacing it at physiologic levels is reasonable and logical and should not be harmful since it has not harmed the body for the 40 years puberty to menopause. It is used in this country in the form of Biest (a combination of estriol and estradiol) which is compounded by specialty pharmacies. Without estriol, there would be very little compounding of HRT. Wyeth is obviously counting on this as a strategy to regain the market.
2. Since estriol is used in Japan, Europe, and Scandinavia as an accepted regimen for HRT and has been shown to be safe and effective in these populations, there exists a plethora of data regarding its use. Even if the attached abstracts are not perfectly designed studies, it is reasonable to conclude from them that estriol has a significantly low risk-to-benefit ratio.
3. These studies also suggest that, in fact, estriol may cause fewer unwanted side effects than the FDA alternative of conjugated equine estrogens, because it is a weak estrogen and has different estrogen receptor kinetics. It does not overstimulate either breast or endometrium. It may well be cardioprotective and may protect cognition, and it indeed is osteogenic. So not only is estriol less risky, but may provide benefits that FDA approved drugs do not.
4. To date, there are disease entities for which there is no other treatment that has been shown to be effective such as the neurodegenerative diseases discussed above and the potential protection from vaginal transmission of HIV. With such therapeutic potential as this, the FDA’s vitriolic denouncement and banning of estriol is not only unwarranted, but frightening. It suggests an agenda that is not in the interest of the public. And as much as I would like to think otherwise, I can see no other motivation that the FDA could have except to appease Wyeth who stand to financially benefit from the FDA decision. This is certainly a victory for Wyeth, but sadly, not for the health of Americans.
5. Physicians need the freedom to treat needs of the patients based on reasonable medical and scientific judgment. I’ll give an example.
Recently, a 15 year old girl came to me with complaints of nocturnal enuresis. Despite trials of conventional nasally-applied DDAVP, a pituitary hormone that decreases production of urine by the kidney, she still wet her bed. After reviewing the basic scientific literature, not the medical literature, I was impressed that the amino acid taurine sensitized the receptor for DDAVP. Since these receptors are present in the kidney, it was a logical assumption that I could increase her response to the pituitary hormone by giving her taurine, even though there is no clinical study demonstrating this, nor any FDA approval of the use of taurine for this purpose. With some minor adjustments of the dose of this oral, over-the-counter amino acid, she has had no further problem with nocturnal enuresis. This has dramatically improved the quality of her teenage life as well as her future. I am NOT anti-FDA, but am certainly PRO doctor-patient. Doctors need this freedom to heal and help.
"If people let the government decide what foods they eat and what medicines they take, their bodies will soon be in as sorry a state as are the souls who live under tyranny"
Thomas Jefferson (1743 - 1826)
The Use of Estriol in Cancer, Degenerative Neurologic Disease, Atherosclerotic Disease, Hyperlipidemia, Bone Density, Renal Disease
Neurology 1999 Apr 12;52(6):1230-8
Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis.
Kim S, Liva SM, Dalal MA, Verity MA, Voskuhl RR.
Department of Neurology, University of California Los Angeles School of Medicine, USA.
OBJECTIVE: To evaluate the use of estriol in the treatment of experimental autoimmune encephalomyelitis (EAE) and other cell mediated autoimmune diseases. BACKGROUND: Experimental autoimmune encephalomyelitis is a T helper 1 (Th1)-mediated autoimmune demyelinating disease that is a useful model for the study of immune responses in MS. Interestingly, both EAE and MS have been shown to be ameliorated during late pregnancy. METHODS: Estriol, progesterone, and placebo pellets were implanted in mice during the effector phase of adoptive EAE. Disease scores were compared between treatment groups, and autoantigen-specific humoral and cellular responses were examined. RESULTS: Estriol treatment reduced the severity of EAE significantly compared with placebo treatment whereas progesterone treatment had no effect. Estriol doses that induced serum estriol levels that approximated estriol levels during late pregnancy were capable of ameliorating disease. Estriol-treated EAE mice had significantly higher levels of serum antibodies of the immunoglobulin (Ig) G1 isotype specific for the autoantigen myelin basic protein (MBP). Further, MBP-specific T-lymphocyte responses from estriol-treated EAE mice were characterized by significantly increased production of the Th2 cytokine interleukin 10 (IL-10). T lymphocytes were shown to be the primary source of IL-10 within antigen-stimulated splenocyte populations. CONCLUSIONS: Estriol as a hormone involved in immune changes during pregnancy may provide a basis for the novel therapeutic use of estriol for MS and other putative Th1-mediated autoimmune diseases that improve during late pregnancy.
Pregnancy Hormone May Treat MS
Sept. 24, 2002 -- Melissa Sherak Resnick has had multiple sclerosis for 15 years and is now seven months pregnant with her second child. Like most women with MS, the 30-year-old Californian says her disease symptoms virtually disappear during pregnancy and she often has energy to spare.
"This morning I woke up at 6:30, had my daughter in preschool by 9:00, and was at my Tae-bo class by 9:30," she tells WebMD. "I know I should relax, but it's hard because I feel so good right now."
Spurred by the observation that women with certain autoimmune diseases have fewer symptoms during pregnancy, UCLA researchers may have identified a new treatment for multiple sclerosis. Estriol, a hormone produced during pregnancy, was found to reduce symptoms in a small group of women with early-stage MS when given in pill form. The preliminary findings must be confirmed in larger studies, but researchers hope they will lead to better, cheaper, and more easily administered treatments for MS.
"At present, the only approved treatments for MS are anti-inflammatory drugs administered by injection," lead researcher Rhonda Voskuhl, MD, says. "Our findings also hold promise for [the discovery of] new treatments for a host of other autoimmune disorders that improve during pregnancy, such as rheumatoid arthritis." Voskuhl is an associate professor of neurology at UCLA.
As many as 400,000 Americans have multiple sclerosis, a progressive neurological disorder that occurs two to three times more often in women than in men. Symptoms develop when the body's immune system attacks the insulation of nerve fibers, and they can range from sensations of tingling, dizziness, and numbness to blindness and paralysis.
In earlier studies, Voskuhl and colleagues tested estriol in mice with MS and found that symptoms improved in treated mice. In their latest study, published in the September issue of the Annals of Neurology, a dozen female MS patients were treated with 8 mg of estriol daily for six months. The dosage was selected to mimic estriol levels occurring naturally in a woman's sixth month of pregnancy. Six of the women in the study had a common, early version of MS in which symptoms come and go, and the other six had more advanced disease.
After six months of treatment, the women with the earlier form of the disease were found to have less inflammation within their brains, as measured by magnetic resonance imaging, and their symptoms improved. Improvements disappeared when the women were taken off the hormone, but the women improved again when put back on it. Patients with more advanced disease did not show improvement during estriol therapy. The researchers believe that Estriol increased an immune response in the body, which halted the disease.
"This is the first time there has ever been a trial of hormone therapy specifically targeted to MS," says Stephen Reingold, PhD, vice president for research at the National Multiple Sclerosis Society, which funded the UCLA study. "The concept is based on a well-known, well-described phenomenon, which is the retrenchment of the disease during the second part of pregnancy."
Reingold says these early data are encouraging enough to merit more research but warns that the long-term safety of estriol could not be established in this six-month study. Estriol is widely prescribed in Europe but not in the United States.
Estriol is a weaker form of estrogen. During a pregnancy, doctors use it to measure development of the fetus.
"It is very easy to overlook the potential long-term consequences of hormone therapy, but I think the world has had a bit of a wake-up call about that recently with the new revelations about hormone replacement therapy," he says.
© 2002 WebMD Inc. All rights reserved.
Neurology. 2004 Dec 28;63(12 Suppl 6):S47-54.
Department of Clinical Neurosciences, Brown University School of Medicine, 2 Dudley Street, Suite 555, Providence, Rhode Island 02905, USA. email@example.com
Research into therapy for multiple sclerosis (MS) is occurring at a rapid pace, and current treatment options approved by the FDA specifically target the inflammatory phase of MS. However, drugs that are not FDA-approved are routinely used to treat MS. One example is corticosteroids, which are commonly used to treat acute relapses. Other drugs that are commonly used to treat patients who do not respond to the FDA-approved agents include the following: methotrexate, azathioprine, cyclophosphamide, and pulse steroids. Drugs being studied as possible therapeutic agents include the statins, mycophenolate mofetil, various monoclonal antibodies (e.g., alemtuzumab, daclzumab, natalizumab, and rituximab), antibiotics and antivirals, and the pregnancy hormone estriol. Disease modifying agents (DMAs) that promote remyelination would be beneficial for preventing long-term disability, and such agents are also under active investigation (e.g., IV immunoglobulin G and stem cell transplantation). Combination therapy with DMAs with different mechanisms of action may be advantageous in the future for providing optimal treatment that both delays the progression of disability and promotes repair and remyelination.
J Neuroimmunol 2002 Mar;124(1-2):106-14
Regulatory effects of estriol on T cell migration and cytokine profile: inhibition of transcription factor NF-kappa B.
Zang YC, Halder JB, Hong J, Rivera VM, Zhang JZ.
Multiple Sclerosis Research Unit, Baylor-Methodist Multiple Sclerosis Center and Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
The protective role of pregnancy in autoimmune conditions, such as multiple sclerosis (MS), is potentially associated with immune regulation by sex hormones produced during pregnancy. This study was undertaken to examine the regulatory effects of estriol on the T cell functions, including transmigration and the cytokine production. The results revealed for the first time that estriol significantly inhibited T cell transmigration at a concentration range typical of pregnancy, which correlated with decreased T cell expression of matrix metalloproteinase-9. Estriol was also found to alter the cytokine profile of T cells toward Th2 phenotype by up-regulating the production of IL-10 and inhibiting TNFalpha secretion of T cells. However, the inhibitory effects of estriol on T cells were not antigen-dependent. Further characterization indicated that estriol inhibited nuclear transcription factor kappa B (NF-kappa B), which controls a variety of immune-related genes. This study provides new evidence that estriol is a potent regulator for the T cell functions potentially through its interaction with the NF-kappa B signaling pathway.
J Neuroimmunol 2000 Nov 1;111(1-2):77-85
Female sex steroids: effects upon microglial cell activation.
Drew PD, Chavis JA.
University of Arkansas for Medical Sciences, Department of Anatomy, Slot 510, Shorey Bldg., Rm. 922, 4301 W. Markham St., 72205, Little Rock, AR, USA. firstname.lastname@example.org
Multiple sclerosis occurs more commonly in females than males. However, the mechanisms resulting in gender differences in multiple sclerosis are unknown. Activated microglia are believed to contribute to multiple sclerosis pathology, perhaps in part due to production of nitric oxide (NO) and TNF-alpha, molecules which can be toxic to cells including oligodendrocytes. The current study demonstrates that the female sex steroids estriol, beta-estradiol and progesterone inhibit lipopolysaccharide (LPS) induction of nitric oxide (NO) production by primary rat microglia and by the mouse N9 microglial cell line. These hormones act by inhibiting the production of inducible nitric oxide synthase (iNOS) which catalyses the synthesis of NO. Estriol likely inhibits iNOS gene expression since the hormone blocks LPS induction of iNOS RNA levels. The pro-inflammatory cytokines IFN-gamma and TNF-alpha are believed to be important modulators of multiple sclerosis. Here, we demonstrate that estrogens and progesterone also inhibit NO production by microglial cells activated in response to these cytokines. Activated microglia elicit TNF-alpha in addition to NO and we further demonstrate that estrogens and progesterone repress TNF-alpha production by these cells. Finally, estriol and progesterone, at concentrations consistent with late pregnancy, inhibit NO and TNF-alpha production by activated microglia, suggesting that hormone inhibition of microglial cell activation may contribute to the decreased severity of multiple sclerosis symptoms commonly associated with pregnancy.
J Neuroimmunol. 2004 Apr;149(1-2):84-9.
Department of Neurology, Reed Neurological Research Center, University of California School of Medicine, 750 Westwood Plaza, Los Angeles, CA 90095, USA.
Estrogen treatment has been found to be protective in experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS). We investigated whether the effect of estrogen treatment is gender-specific. Estrogen receptor (ER) expressions, ERalpha and ERbeta, were found to be equivalent in both genders. EAE disease severity in both females and males was decreased with estriol treatment as compared to placebo. Finally, proinflammatory cytokine production during autoantigen-specific immune responses was decreased with estriol treatment in both females and males. These data support a potential role for estriol treatment for men in addition to women with MS.
AIDS. 2004 Aug 20;18(12):1637-43.
Saint Michael's Medical Center and the New Jersey Medical School, Newark, New Jersey 07102, USA.
BACKGROUND: Accumulating data suggest that the state of the vaginal epithelium affects a woman's risk of HIV vaginal transmission and several human and non-human primate studies have shown that the rate of HIV or SIV vaginal transmission is decreased when estrogen is dominant. Systemic estrogen can protect against SIV vaginal transmission. OBJECTIVE: To determine the safety and efficacy of topical estrogen in preventing SIV vaginal transmission. DESIGN: The non-human primate model of HIV vaginal transmission was used to assess vaginal estriol cream in ovariectomized macaques. METHODS: Twelve macaques were treated intravaginally with estriol and eight with placebo cream twice a week. The vaginal and systemic effects of estriol were determined by colposcopy and serum luteinizing hormone, levels of which would decline in the presence of systemic estrogen. After 5 weeks of therapy, the animals were challenged vaginally with pathogenic SIVmac251. RESULTS: Vaginal estriol resulted in minimal serum estriol levels and had no effect on serum luteinizing hormone levels. Vaginal epithelia cornified and thickened significantly in response to estriol therapy. One of the estriol-treated animals became infected after this single challenge, while six of the control animals became infected (P = 0.0044). CONCLUSIONS: These data demonstrate that topical vaginal estriol can strongly protect against SIV vaginal transmission, while having no detectable systemic effect. These results support the study of topical vaginal estriol in preventing HIV vaginal transmission in at-risk women.
Urogenital Atrophy Abstracts
Int J Antimicrob Agents 2001 Apr;17(4):269-71
Postmenopausal women with recurrent UTI.
Infectious Diseases Unit, Haemek Medical Center, Afula 18101, Israel. email@example.com
Urinary tract infection is a frequent disease in elderly women. The lack of estrogen, which characterizes the postmenopause, plays an important role in the pathogenesis of this infective disease. Exogenous estrogen replacement, however, is very effective in the prevention of bacteriuria in these women. The safety of oral and vaginal estriol and their efficacy in comparison to antimicrobial prophylaxis should be confirmed in the future.
J Reprod Med 2001 Mar;46(3):213-20
Hormone replacement therapy plus pelvic floor muscle exercise for postmenopausal stress incontinence. A randomized, controlled trial.
Ishiko O, Hirai K, Sumi T, Tatsuta I, Ogita S.
Department of Obstetrics and Gynecology, Osaka City University Medical School, and Hanwa Sumiyoshi General Hospital, Osaka, Japan. firstname.lastname@example.org
OBJECTIVE: To investigate the effects of the combination of pelvic floor muscle exercise (PFME) and estriol on postmenopausal stress incontinence (SI). STUDY DESIGN: Sixty-six patients with postmenopausal SI were randomized to a group treated with a combination of estriol (1 mg/d) and PFME (group A, n = 32) and a group treated with PFME alone (group B, n = 34). Efficacy was evaluated every three months based on stress scores obtained from a urinary incontinence (UI) questionnaire. RESULTS: A significant decrease in stress score was observed in mild and moderate UI patients in both groups three months after the commencement of therapy (A and B, P < .0001). The therapeutic effect in group A was more prominent for up to 18 months in mild UI and for up to 12 months in moderate UI (A vs. B, P < .05). Kaplan-Meier analysis showed that the cumulative morbidity rate in mild SI patients was significantly lower in group A (0%) than in group B (12%, P < .005). CONCLUSION: Combination therapy with estriol plus PFME was effective and is capable of serving as first-line treatment for mild SI.
Ceska Gynekol 1999 Jan;64(1):6-9
[Ultrasound imaging of the lower urinary tract in post-menopausal women with urinary stress or combined type of incontinence before and after intravaginal administration of estriol].
[Article in Czech]
Martan A, Masata J, Halaska M, Voigt R.
I. gynek.-porod. klinika 1. LF UK a VFN, Praha.
The finding that climacteric symptoms are caused mainly by a decline of the oestrogen level and that their development can practically always be prevented by long-term local or general oestrogen treatment was a great asset to the treatment of this problem. Oestriol, a less effective natural oestrogen, has a favourable effect on urogenital tissues without stimulating the endometrium . The objective of the present investigation was to analyze ultrasonographic parameters of the lower urinary tract in women after the menopause with the stress or mixed type of urinary incontinence before and after two-month local oestriol treatment (Ovestin). The trial comprised 40 women with confirmed stress (GSI) or the mixed type of urinary incontinence. The group with GSI comprised 124 patients and the group suffering from the mixed type of incontinence comprised 26 women. The type of incontinence was assessed by urogynaecological examination. This was followed by transperineal and introital ultrasound examination of patients in a supine position by means of an Acuson 128 XP10 apparatus using a convex probe with a frequency of 5 MHz and a vaginal probe with a frequency of 7.0 MHz. Assessment of the position and mobility of the urethrovesical junction was implemented by the transperineal route using a convex probe and filling the bladder with 300 ml. After urination followed assessment of the urethral sphincter by the introital route in a vertical plane whereby the authors followed the anterior and posterior surface of the rhabdosphincter, and in a horizontal plane its left and right surface (10). The authors assessed also in both planes the maximal thickness of the sphincter. In the vertical plane and in a proximal position in relation to the urethra they evaluated the vascular supply qunatitatively (minimal-1 to very abundant-4) and also the arterial flow-the pulsatile index PI was investigated as well as the resistance index RI. In the vertical plane 1 cm from the urethrovesical junction the authors assessed the thickness of the urethral mucosa; at the same level they evaluated the thickness of the urinary bladder wall; the anterior wall, the vertex and the area of the trigone. They assessed also the thickness of pelvic floor muscles. The assessments were made before and after two-month intravaginal oestriol administration (Ovestin crm)-two weeks 0.5 mg/day and then 0.5 mg twice a week. After treatment no statistically significant differences in thickness and areas of the urethral sphincter were found nor in the thickness of the pelvic floor muscles before and after oestriol administration. Statistically significant differences were recorded in the mobility of the urethrovesical junction and there was a significant increase in the thickness of the urethral mucosa and a more abundant vascularization was recorded during the quantitative evaluation and evaluation of PI. In women with the mixed type of incontinence after oestrogen treatment a decline in the thickness of the urinary bladder was found. Ultrasound examination of the lower urinary tract before and after oestriol treatment (Ovestin crm) is a useful supplement of common examination methods and it confirms its favourable therapeutic effect when administered by the intravaginal route.
Effect of oral estriol on urogenital symptoms, vaginal cytology, and plasma hormone level in postmenopausal women.
Manonai J, Theppisai U.
Department of Obstetrics and Gynaecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
OBJECTIVE: To evaluate the effects of oral estriol on urogenital symptoms, vaginal cytology, and plasma follicle stimulating hormone (FSH) and estradiol level in postmenopausal women with urogenital symptoms. METHOD: Twenty-eight postmenopausal women with urogenital symptoms who volunteered to participate in this study received 2 mg of oral estriol daily for 12 weeks. The urogenital symptoms, vaginal cytology, and plasma hormone level before and after treatment were analysed using paired t-test. RESULTS: The genital and urological symptoms improved (P < 0.05) after treatment in all subjects. The vaginal cytology showed estrogenic effect on the karyopyknotic index and maturation value. There was a significantly (P < 0.05) higher level of plasma estradiol after 12 weeks of treatment. However, the difference of plasma FSH level before and after treatment was not statistically significant. CONCLUSION: The daily oral estriol had a positive effect on the urogenital symptoms and vaginal cytology. The plasma estradiol increased after 12 weeks of treatment but the plasma FSH did not change.
Vet Rec 2001 Dec 22-29;149(25):764-7
Treatment of bitches with acquired urinary incontinence with oestriol.
Mandigers RJ, Nell T.
Referral Clinic De Wagenrenk, Wageningen, The Netherlands.
Oestriol, a naturally occurring short-acting oestrogen, was used to treat acquired urinary incontinence in 129 bitches selected by 48 veterinary practitioners in the Netherlands, Belgium, France and Germany. The dogs were treated daily for 42 days with oestriol tablets, using a self-controlled study design. The dogs were examined and blood sampled at the beginning and end of the trial. According to the veterinary practitioners 83 per cent of the dogs either became continent or improved, but the others showed no change or became worse. The owners reported similar results: 82 per cent of the dogs responded to treatment and the others did not. The dose and treatment schedule for each dog were established on the basis of clinical efficacy. Mild and transient oestrogenic effects such as swelling of the vulva and attractiveness to male dogs were observed soon after the treatment began and at the higher dose schedule used in 12 of the dogs. A haematological examination of 114 of the dogs revealed no abnormalities.
Maturitas 2001 Sep 28;39(3):253-7
Short term oral estriol treatment restores normal premenopausal vaginal flora to elderly women.
Yoshimura T, Okamura H.
Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Honjo 1-1-1, 860-8556, Kumamoto, Japan. email@example.com
OBJECTIVE: Estriol is an estrogen with considerably weaker stimulatory effects on endometrial proliferation than estradiol. A study was conducted to determine the effects of oral estriol on vaginal flora and endometrial thickness. METHODS: Fifty-nine postmenopausal women (50-75 years of age), complaining of pruritus or vaginal discharge, participated in the study. Vaginal flora and endometrial thickness were evaluated before treatment and after receiving oral estriol (2 mg/day) for 14 days. RESULTS: Prior to treatment, lactobacilli were found in vaginal cultures from only six of the 59 study participants, whereas after treatment, the vaginal flora of 27 women showed a presence of lactobacilli (P<0.0001). Endometrial thickness exceeded 5 mm in only five cases. No side effects were reported. CONCLUSION: Estriol, which has little effect on the endometrium, has the potential to be highly useful for the treatment of atrophic vaginitis.
Am J Vet Res. 2006 May;67(5):901-8.
Department of Clinical Sciences, College of Veterinary Medicine, University of Liège, 4000 Liège, Belgium.
OBJECTIVE: To compare the urodynamic and morphologic effects of the administration of estriol alone and in combination with phenylpropanolamine on the lower portion of the urogenital tract in female dogs. ANIMALS: 3 sexually intact and 3 spayed female Beagles without urinary incontinence. PROCEDURE: Dogs received estriol (2 mg, PO) once daily for 7 days followed by estriol (2 mg, PO) and phenylpropanolamine (1.5 mg/kg, PO) once daily for 7 days. Urethral pressure profilometry, diuresis cystometry, and vaginourethrography were performed before treatment (day 0) and at days 7 and 14. The maximum urethral pressure (MUP) and closure pressure (MUCP), urethral functional and anatomic profile lengths, integrated pressure (IP), plateau, distance before MUP, maximum meatus pressure, threshold pressure, threshold volume, compliance, urethral length, and vaginal length and width were measured. RESULTS: Before treatment, no urodynamic differences were observed between the 2 groups; however, vaginal length and width were significantly shorter in spayed dogs. Compared with day 0 values, estriol treatment significantly increased MUP, MUCP, and IP values at day 7, but at day 14, this effect decreased despite phenylpropanolamine administration. No morphologic changes from baseline were detected after either treatment in any dog. CONCLUSIONS AND CLINICAL RELEVANCE: Data suggest that estriol mainly acts on the urethral sphincter mechanism by increasing urethral resistance in sexually intact and spayed female dogs without urinary incontinence. Administration of estriol and phenylpropanolamine did not increase the urethral resistance more than estriol alone. The urodynamic effects of estriol in female dogs with urinary incontinence remain to be elucidated.
Eukaryot Cell. 2006 Jan;5(1):180-91.
Department of Pathobiology, 2522 VMBSB, 2001 S. Lincoln Avenue, Urbana, Illinois 61802, USA.
Candida albicans is the most common etiological agent of vaginal candidiasis. Elevated host estrogen levels and the incidence of vaginal candidiasis are positively associated. Elevated estrogen levels may affect host and/or fungal cells. This study investigates the effect of 17-beta-estradiol, 17-alpha-estradiol, ethynyl estradiol, and estriol on several C. albicans strains at concentrations ranging from 10(-5) to 10(-10) M. The addition of 17-beta-estradiol or ethynyl estradiol to C. albicans cells caused an increase in the number of cells forming germ tubes and an increase in germ tube length in a dose- and strain-dependent manner. The addition of 17-alpha-estradiol or estriol did not have a significant effect on germ tube formation by the cultured cells. Exposure to exogenous estrogens did not significantly change the biomass of any C. albicans culture tested. The transcriptional profile of estrogen-treated C. albicans cells showed increased expression of CDR1 and CDR2 across several strain-estrogen concentration-time point combinations, suggesting that these genes are the most responsive to estrogen exposure. Analysis of strain DSY654, which lacks the CDR1 and CDR2 coding sequences, showed a significantly decreased number of germ tube-forming cells in the presence of 17-beta-estradiol. PDR16 was the most highly up-regulated gene in strain DSY654 under these growth conditions. The cell biology and gene expression data from this study led to a model that proposes how components of the phospholipid and sterol metabolic pathways may interact to affect C. albicans germ tube formation and length.
Menopause. 2005 Jul-Aug;12(4):421-7. Epub 2005 Jul 21.
Department of Obstetrics and Gynecology, Campus Bio-Medico University of Rome, Rome, Italy. firstname.lastname@example.org
OBJECTIVE: To evaluate whether the frequency of overactive bladder (OAB) symptoms increases in menopause patients after a tension-free vaginal tape (TVT) procedure, and to determine if topical estrogen therapy can help prevent these symptoms. DESIGN: After undergoing a preoperative assessment, enrolled patients were randomly allocated to receive TVT plus postoperative vaginal estrogen therapy (ET group) or TVT without adjunctive medical treatment (No ET group). The pre- and postoperative assessments included: acquisition of a urogynecologic history with standardized questions regarding urinary function (including a 10-grade visual analogue scale score), urogynecologic clinical examination, and urodynamic assessment. Follow-up assessments were performed at 1, 3, and 6 months after surgery. RESULTS: Fifty-six of 59 patients were evaluable; 28 received topic vaginal estrogen after surgery (ET group) and 28 did not receive adjunctive medical treatment (No ET group). The overall OAB syndrome rate in menopause patients (No ET group) was 7% (2 of 28 patients) at baseline and 32% (9 of 28 patients) 6 months after surgery (P = 0.04). At the 6-month follow-up assessment, the incidence of urinary urgency was 4% (1 of 28 patients) and 29% (8 of 28 patients) in the ET and No ET groups, respectively (P = 0.01). Differences in frequency and nocturia were not statistically significant. Analysis of the visual analogue scale scores revealed that at the 6-month follow-up assessment, urgency significantly improved in the ET group compared with the No ET group (0.23 +/- 1.0 vs 2.30 +/- 3.7, respectively; P = 0.02). CONCLUSIONS: The TVT procedure seems to increase the frequency of OAB syndrome in menopause patients. Vaginal estriol therapy significantly reduces symptoms of urinary urgency, has a high rate of patient satisfaction, and can be used to treat postmenopausal women for at least 6 months after a TVT procedure.
BJOG. 2005 Feb;112(2):234-40.
Department of Obstetrics and Gynecology, Ege University Faculty of Medicine, Izmir 35100, Turkey.
OBJECTIVE: To evaluate the effectiveness of live lactobacilli in combination with low dose oestriol for restoration of the vaginal flora after anti-infective treatment. DESIGN: The study was designed as a single centre, randomised, placebo-controlled, double-blind clinical trial. SETTING: University Hospital. SAMPLE: Three hundred and sixty women out of 1750 were randomised. METHODS: Three hundred and sixty women with the complaints of vaginal infections (bacterial vaginosis, candidiasis, trichomoniasis or fluor vaginalis) were randomly assigned two to seven days after the end of the anti-infective therapy, to therapy with live lactobacilli in combination with low dose oestriol (study group, n= 240) or placebo (n= 120). The follow up visits occurred three to seven days and four to six weeks after the end of the restoration therapy. MAIN OUTCOME MEASURES: The Normal Flora Index (NFI), which consists of numbers of lactobacilli, pathogenic microorganisms, leucocytes and vaginal pH, was used as the primary outcome of the study. Secondary outcomes included the total symptoms score, the degree of purity of the vaginal flora and the global assessment of the treatment by the investigator and the women. RESULTS: During restoration therapy, the NFI increased significantly more in the study group than in the control group in both first and second control visits (P= 0.002 and P= 0.006, respectively). The degree of purity of the vaginal flora also increased significantly more in the study group compared with the control group (P < 0.0001 and P= 0.001, respectively). No serious adverse event was reported during restoration therapy. CONCLUSION: Restoration of the vaginal flora can be significantly enhanced by the administration of live lactobacilli in combination with low dose oestriol.
Eur Urol. 2005 Feb;47(2):243-9.
Department of Urology, University of Innsbruck, 6020 Innsbruck, Austria. email@example.com
BACKGROUND: Previous studies have demonstrated the efficacy of local application of estrogen in treating postmenopausal women with recurrent urinary tract infections (RUTI) and urinary incontinence. Younger women under oral contraceptives (OC) can suffer from similar symptoms. The aim of this pilot study was to evaluate the effectiveness of local estrogens on RUTI and the impact of local hormonal supplementation on bladder neck vascularization. METHODS: 30 women (mean age 22.7 years) with a longstanding history of RUTI were included. Pre-treatment investigation included complete clinical history, urinalysis, urine culture and cystoscopy. All subjects completed a questionnaire about onset and duration of disease and quality of life before and after treatment. Local (vaginal) estrogen therapy consisted of 1mg estriol (E3) 7 times a week for two weeks and twice a week for two additional weeks. Sonographic examination of bladder vascularization was performed before and after treatment using transperineal color Doppler ultrasound (6 MHz, Acuson Sequoia 512, Mountain View, CA, USA) with a filled bladder. After angle correction, peak systolic blood flow velocity (PSBFV) and end diastolic blood flow velocity (EDBFV) were measured in 2 bladder arteries; and the Resistive Index (RI) was calculated. Flow velocity in each vessel was measured at least four times and the mean value determined. RESULTS: All patients completed the therapy course without severe side effects. Patients had a mean history of RUTI over 2.3 years; the mean period under OC was 3.2 years. In the follow-up period of 11 months after treatment, 24/30 patients reported no symptoms of cystitis and used no additional medication. Normal bladder epithelium in control cystoscopy after E3 therapy was seen in all patients with trigonal metaplasia and vulnerable, highly vascularized urothelium at the initial investigation. RI decreased from 0.945 to 0.705 after treatment (p<0.001), concomitantly the mean EDBFV increased highly significantly from 0.82 cm/sec to 4.45 cm/sec after estrogen treatment (p<0.001). INTERPRETATION: In a majority of young patients under OC and a longstanding history of RUTI, a considerable infection-free period was achieved after local application of estrogen. Decreased RI and increased EDBFV indicate vasodilatation and less peripheral vascular resistance. Responsiveness to local E3 may correspond to improved cystoscopic findings as a consequence of increased bladder perfusion.
Ceska Gynekol. 2004 Jul;69(4):329-35.
[Article in Czech]
Gynekologicko-porodnická klinika VFN a 1. LF UK, Praha.
OBJECTIVE: The objective of this work was to evaluate the efficacy, acceptability and safety of the vaginal estriol on symptoms in postmenopausal women with urogenital atrophy. DESIGN: Prospective clinical study. SETTING: Department of Obstetrics and Gynecology of the 1st Medical Faculty and General Faculty Hospital, Prague. METHODS: We included in our study 68 postmenopausal women with proved urogenital symptoms of the atrophic genitourinary tract. We administration them two years vaginal estriol 0.5 mg daily, later 1-2 times a week and then detected subjective and objective changes in their low urinary tract and vagina. These women had a normal biochemistry, uterus, mammary and bone density. These parameters were evaluated before starting the treatment and after 3 and 6 month. The statistical significance of the phenomen was evaluated by exact t-test. RESULTS: Statistically significant positive differences and remission were observed in all symptoms and recurrent infection of the atrophical urogenital tissues. The first satisfaction was after 3rd month and the best after 6th month of this therapy, and in the end of this study (24 month) it was the same. We recorded no difference in other monitored parameters (endometrium, biochemistry, mammography, densitometry, blood pressure, weight) and compliance was satisfactory (85% after 6 months). In the 6 month profile of estriol we found a significant decrease of the Kupperman index and the Menopause rating scale. CONCLUSION: Administration of vaginal estriol is an advisable choice for every postmenopausal woman with the genitourinary problems (urgency, pollakisuria, dysuria, nycturia, recurrent infection of the low urinary tract). It has very good clinical effects and minimum side effects.
J Br Menopause Soc. 2004 Mar;10(1):30-2.
Obstetrics and Gynaecology, Milton Keynes General Hospital, Milton Keynes MK6 5LD, UK.
Lower urinary tract symptoms are a common, distressing and embarrassing problem for women of all ages, but become increasingly more common with advancing age. Oestrogen preparations have been used for many years to manage urinary symptoms, but there is still controversy over the efficacy of these preparations. The purpose of this review is to provide a critical overview of the epidemiological evidence when considering hormone replacement therapy for treatment of urinary symptoms in women. Various studies have demonstrated that oestrogen replacement can improve, or even cure, urinary stress and urge incontinence. High dose oestrogen can reduce the total number of voids in 24 hours, including nocturnal voids. Vaginal oestriol significantly reduces the risk of recurrent infections in postmenopausal women with a history of recurrent urinary tract infections. Data on combining oestrogen with a progestogen are limited, but suggest it may negate the benefit and more research is still required in this area to clarify their role.
Lancet 1999 May 29;353(9167):1824-8
Low-potency oestrogen and risk of endometrial cancer: a case-control study.
Weiderpass E, Baron JA, Adami HO, Magnusson C, Lindgren A, Bergstrom R, Correia N, Persson I.
Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden. Elisabete.Weiderpass@mep.ki.se
BACKGROUND: Urogenital symptoms are common among postmenopausal women. Such symptoms may be alleviated by low-potency oestrogen formulations administered orally or vaginally. Although low-potency oestrogen formulations are assumed to have few, if any, adverse effects on the endometrium, risk of endometrial neoplasia has not been quantified. METHODS: In a nationwide population-based case-control study in Sweden of endometrial cancer among postmenopausal women, we obtained detailed information on hormone replacement from 789 cases of endometrial cancer and 3368 population controls. In a histopathological review, 80 cases were reclassified as having endometrial atypical hyperplasia. Odds ratios and 95% CI were calculated with unconditional logistic regression. FINDINGS: After multivariate adjustment, oral use of oestriol 1-2 mg daily increased the relative risk of endometrial cancer and endometrial atypical hyperplasia: the odds ratios for at least 5 years of use compared with never use were 3.0 (95% CI 2.0-4.4) and 8.3 (4.0-17.4), respectively. The association was stronger for well-differentiated cancers and those with limited invasion. The excess relative risk was lost rapidly after cessation of treatment. Only weak associations were observed between vaginal application of low-potency oestrogen formulations and relative risk of endometrial neoplasia. INTERPRETATION: Oral, but not vaginal, treatment with low-potency oestrogen formulations increases the relative risk of endometrial neoplasia. Thus close surveillance of patients is needed, and addition of a progestagen should be considered.
Climacteric 2001 Mar;4(1):42-8
Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens.
Lundstrom E, Wilczek B, von Palffy Z, Soderqvist G, von Schoultz B.
Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden.
OBJECTIVE: The aim of this study was to evaluate the impact of different hormone replacement therapy (HRT) regimens on mammographic breast density. STUDY DESIGN: Mammographic density was recorded in women participating in a population-based screening program. At first mammogram, all women were non-users of HRT, and thereafter reported continuous use of the same HRT regimen. The study population comprised 158 women: a total of 52 women were using continuous combined HRT (conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 5 mg); 51 women were using low-dose oral estrogen alone (estriol 2 mg daily); and 55 women were using unopposed transdermal estrogen given as a patch (estradiol 50 micrograms/24 h). Films were coded and analyzed for mammographic density by an independent radiologist blinded to treatments. Mammographic density was classified according to Wolfe. RESULTS: An increase in mammographic density was much more common among women taking continuous combined HRT (40%) than for those using oral low-dose estrogen (6%) and transdermal (2%) treatment. The increase in density was already apparent at the first visit after starting HRT. During long-term follow-up, there was very little change in mammographic status. CONCLUSION: HRT regimens were shown to have different effects on the normal breast. There is an urgent need to clarify the biological nature and significance of a change in mammographic density during treatment and, in particular, its relation to symptoms and breast cancer risk.
Gynecol Endocrinol. 2006 Oct;22(10):564-77.
Southwest College Research Institute, Southwest College of Naturopathic Medicine, Tempe, Arizona, USA. firstname.lastname@example.org
Oral administration of conjugated equine estrogens (CEE) with and without the synthetic progestin medroxyprogesterone acetate (MPA) in postmenopausal women is associated with side-effects that include increased risk of stroke and breast cancer. The current evidence that transdermal administration of estradiol may provide a safer alternative to orally administered CEE is reviewed. Transdermally administered estradiol has been shown to be an efficacious treatment for hot flushes possibly without the increase in blood clotting that is associated with administration of oral CEE. Further, natural progesterone may have a more beneficial spectrum of physiological effects than synthetic progestins. The substantial differences between CEE compared with estradiol and estriol, as well as the differences between synthetic MPA and natural progesterone, are detailed. Estriol is an increasingly popular alternative hormone therapy used for menopausal symptoms. There is evidence that estriol, by binding preferentially to estrogen receptor-beta, may inhibit some of the unwanted effects of estradiol. New clinical trials are needed to evaluate the safety and efficacy of topically or transdermally administered combinations of estradiol, estriol and progesterone. Future studies should focus on relatively young women who begin estrogen supplement use near the start of menopause.
Obstet Gynecol. 2006 Dec;108(6):1354-60.
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
OBJECTIVE: To evaluate whether the risk of estrogen-only therapy on breast cancer varies by dose, constituent, and route of administration. METHODS: All Finnish women older than age 50 years using oral or transdermal estradiol (n=84,729), oral estriol (n=7,941), or vaginal estrogens (n=18,314) for at least 6 months during 1994-2001 were identified from the national medical reimbursement register. They were followed for breast cancer with the aid of the Finnish Cancer Registry to the end of 2002. RESULTS: Altogether, 2,171 women with breast cancer were identified. The standardized incidence ratio of breast cancer with systemic estradiol for less than 5 years was 0.93 (95% confidence interval 0.80-1.04), and for estradiol use for 5 years or more, 1.44 (1.29-1.59). Oral and transdermal estradiol was accompanied by a similar risk of breast cancer. The risk was most prominent with the dose greater than 1.9 mg/d orally; whereas the risk associated with transdermal route was not dose-dependent. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26-1.66) and cancer spread to regional nodes (1.35; 1.09-1.65). The incidence of carcinoma in situ (n=32) was increased (2.43; 1.66-3.42) among estradiol users. CONCLUSION: Estradiol for 5 years or more, either orally or transdermally, means 2-3 extra cases of breast cancer per 1,000 women who are followed for 10 years. Oral estradiol use for less than 5 years, oral estriol, or vaginal estrogens were not associated with a risk of breast cancer. LEVEL OF EVIDENCE: II-2.
Breast Cancer Res. 2006;8(1):R11. Epub 2006 Feb 17.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, S-171 77 Stockholm, Sweden. email@example.com
INTRODUCTION: Breast cancers of different histology have different clinical and prognostic features. There are also indications of differences in aetiology. We therefore evaluated the risk of the three most common histological subtypes in relation to menopausal hormone therapy and other breast cancer risk factors. METHODS: We used a population-based case-control study of breast cancer to evaluate menopausal hormone therapy and other breast cancer risk factors for risk by histological subtype. Women aged 50 to 74 years, diagnosed with invasive ductal (n = 1,888), lobular (n = 308) or tubular (n = 93) breast cancer in Sweden in 1993 to 1995 were compared with 3,065 age-frequency matched controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for ductal, lobular, and tubular cancer. RESULTS: Women who had used medium potency estrogen alone were at increased risks of both ductal and lobular cancer. Medium potency estrogen-progestin was associated with increased risks for all subtypes, but the estimates for lobular and tubular cancer were higher compared with ductal cancer. We found OR 5.6 (95% CI 3.2-9.7) for lobular cancer, OR 6.5 (95% CI 2.8-14.9) for tubular cancer and OR 2.3 (95% CI 1.6-3.3) for ductal cancer with > or =5 years use of medium potency estrogen-progestin therapy. Low potency oral estrogen (mainly estriol) appeared to be associated with an increased risk for lobular cancer, but the association was strongest for short-term use. Reproductive and anthropometric factors, smoking, and past use of oral contraceptives were mostly similarly related to the risks of the three breast cancer subtypes. Recent alcohol consumption of > 10 g alcohol/day was associated with increased risk only for tubular cancer (OR 3.1, 95% CI 1.4-6.8). CONCLUSION: Menopausal hormone therapy was associated with increased risks for breast cancer of both ductal and lobular subtype, and medium potency estrogen-progestin therapy was more strongly associated with lobular compared with ductal cancer. We also found medium potency estrogen-progestin therapy and alcohol to be strongly associated with tubular cancer. With some exceptions, most other risk factors seemed to be similarly associated with the three subtypes of breast cancer.
Maturitas 2000 Oct 31;36(3):217-22
Comparison of the long-term effects of oral estriol with the effects of conjugated estrogen on serum lipid profile in early menopausal women.
Itoi H, Minakami H, Iwasaki R, Sato I.
Department of Obstetrics and Gynecology, Jichi Medical School, Minamikawachi-machi, 329-04, Tochigi, Japan.
OBJECTIVE: We investigated the long-term effects of oral estriol (E(3)) on serum levels of total cholesterol (t-Cho), high-density lipoprotein cholesterol (HDL-Cho), low-density lipoprotein cholesterol (LDL-Cho), and triglycerides in early menopausal women. METHODS: We studied 67 healthy early menopausal women who were treated for 48 months with 2.0 mg of E(3) plus 2.5 mg of medroxyprogesterone acetate daily (E(3) group, n=21), 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily (CE group, n=19), or 1.0 &mgr;g of 1alpha-hydroxyvitamin D(3) daily or 1.8 g of calcium lactate containing 250 mg of elemental calcium daily (control group, n=27). The serum levels of t-Cho, HDL-Cho, LDL-Cho, and triglycerides were evaluated at baseline and every 6 months. RESULTS: After 48 months of treatment, the t-Cho decreased significantly by 4.3+/-2.1% (mean+/-SE) from baseline in the E(3) group, did not change in the CE group (-1.9+/-2.1%), and significantly increased (5.4+/-3.4%) in the control group. The HDL-Cho significantly increased in the CE group (10.7+/-2.4%), but not in the E(3) group (3.8+/-3.3%) or in the control group (-3.6+/-3. 0%). The LDL-Cho significantly decreased in the CE group (-11.4+/-4. 0%), did not change in the E(3) group (-5.2+/-3.6%), and significantly increased in the control group (11.8+/-6.3%). The triglyceride level decreased significantly in the E(3) group (-6. 7+/-4.9%), whereas it significantly increased in the CE group (17. 6+/-11.4%), and did not change in the control group (6.1+/-6.4%). CONCLUSIONS: Oral E(3) prevented a postmenopausal rise in the t-Cho. Oral estriol did not induce the hypertriglyceridemia that was seen after treatment with conjugated estrogen. Oral E(3) may be a useful alternative therapy in women with hypertriglyceridemia and in women who are reluctant to continue conventional hormone replacement therapy because of uterine bleeding.
Hum Reprod 2000 May;15(5):1028-36
Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause.
Takahashi K, Okada M, Ozaki T, Kurioka H, Manabe A, Kanasaki H, Miyazaki K.
Department of Obstetrics and Gynecology, Shimane Medical University, 89-1, Enya-cho, Izumo 693-8501, Japan.
To assess the safety and efficacy of oestriol in relieving post-menopausal symptoms 53 post-menopausal Japanese women with climacteric symptoms, 27 with natural menopause (group I) and 26 with surgically induced menopause (group II), received oral oestriol, 2 mg daily for 12 months. Clinical parameters including Kupperman index (KI) and the degree of satisfaction with symptomatic relief; serum concentrations of oestradiol, FSH and LH; serum lipids; blood pressure; bone mineral density, serum calcium (Ca), alkaline phosphatase (ALP), and urinary Ca were compared between the two groups. Oestriol improved KI in groups I and II by 49 and 80% respectively. Satisfaction with treatment was 85% in group I and 93% in group II. For both parameters, values were significantly different between groups I and II (P < 0.05 for both). Serum concentrations of oestradiol, FSH and LH changed in group I versus group II 6 months after initiation. A significant decrease in serum ALP and Ca/Cr was observed in group I at 6 months. Except for serum triglycerides, oestriol had no significant effect on lipids. Systolic and diastolic blood pressures were significantly decreased in group I at 3 months versus baseline. Slight vaginal bleeding occurred in 14.3% of group I. Histological evaluation of the endometrium in all women of group I and ultrasound assessment of the breasts following 12 months of oestriol treatment found normal results in all women. Therefore, oestriol appeared to be safe and effective in relieving symptoms of menopausal women. The beneficial biochemical effects of oestriol were marked in the natural menopause. Overall, oestriol may serve as a good choice for hormone replacement therapy to protect against other climacteric symptoms in post-menopausal women who do not need medication for osteoporosis or coronary artery disease.
Rev Med Chil 1998 May;126(5):481-7
[Comparison of the antioxidant effect of estriol and estradiol on low density lipoproteins in post-menopausal women].
[Article in Spanish]
Arteaga E, Villaseca P, Rojas A, Arteaga A, Bianchi M.
Departamento de Endocrinologia, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile.
BACKGROUND: Estradiol (E2) has a potent antioxidant effect on low density lipoproteins (LDL) in vitro and in vivo, which could be important in explaining the cardioprotective effect of hormone replacement therapy (HRT) in post menopausal women. Estriol (E3), on the other hand, is a weak estrogen with low metabolic effects on different tissues, and at present no cardioprotective effect has been attributed to this steroid. AIM: To study the antioxidant effect of E3 on LDL and to compare it with the potent antioxidant action exhibited by E2. SUBJECTS AND METHODS: After LDL was isolated by ultra centrifugation from plasma of 12 healthy untreated post menopausal women, it was divided into aliquots containing 0.5 mg of LDL protein. Estriol and E2 in doses of 0, 1, 5, 15 and 50 microM were incubated with different aliquots of LDL. CuSO4 15 microM was added to each aliquot to induce an oxidative stress. The aliquots were then incubated during 4 hours at 37 degrees C. Malonaldehyde (MDA) was measured as a marker of LDL oxidation, and expressed as nM/mg protein. RESULTS: (mean +/- SD): Estriol induced a dose-dependent decrease in MDA concentration (baseline 62.8 +/- 21.7; 1 microM: 61.5 +/- 23.0; 5 microM: 52.9 +/- 20.3; 15 microM 43.5 +/- 20.1 and 50 microM: 31.0 +/- 17.6 nM/mg protein; F = 92.4; p < 0.0001), reaching a mean decrease of 50.7% at the highest dose tested. Estradiol has a similar dose-dependent decrease in MDA concentration (F = 60.2; p < 0.0001), revealing a more potent effect than E3 (p < 0.05), with a mean decrease of 67.4% at the highest dose tested. CONCLUSIONS: Our results demonstrate that estriol shows an important antioxidant action of LDL in vitro, although its effect is less potent than estradiol. These results raise the possibility that estriol could have a cardioprotective effect in post menopausal women, possibility that has not been yet demonstrated.
Cardiovasc Pathol 2000 Nov-Dec;9(6):317-22
Serum lipids and arterial plaque load are altered independently with high-dose progesterone in hypercholesterolemic male rabbits.
Houser SL, Aretz HT, Quist WC, Chang Y, Schreiber AD.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. firstname.lastname@example.org
Antiatherogenic effects of sex steroids in premenopausal women are not well defined. Therefore, we employed an established rabbit model for atherosclerosis to study the effects of exogenous estrogen and a progesterone analogue (P) on serum lipids and aortic plaque load. Serum cholesterol (C) and triglyceride (T) levels and atherosclerotic plaque loads were compared in 5 groups of male New Zealand White rabbits fed a 12-week, C-rich diet: 1 control group (CG) and 4 groups treated with estriol (E), haloperidol (H), low-dose 17-hydroxyprogesterone (LDP), or high-dose 17-hydroxyprogesterone (HDP). Serum P was measured in the LDP and HDP groups. Serial histologic sections (15 each of 27 ascending aortas) were studied by light microscopy and computerized morphometric analysis. Plaque load is defined as the ratio of intimal area to medial area (I/M). Exogenous E (p<0.001), H (P = 0. 02), LDP and HDP (P<0.001, each) were found to be significantly associated with less aortic plaque load than controls. In a multivariate analysis, after controlling for the differences in serum C and T levels, HDP (p = 0.014) was found to be associated with less aortic plaque load than controls, and this association approached statistical significance in the E (p = 0.052) and H (p = 0.069) groups. These data suggest that the mechanism(s) involved with the antiatherogenic effect of HDP in this animal model is, or are, independent of an alteration in serum lipids.
Hypertens Res 2001 May;24(3):263-9
Estriol improves membrane fluidity of erythrocytes by the nitric oxide-dependent mechanism: an electron paramagnetic resonance study.
Tsuda K, Shimamoto Y, Kimura K, Nishio I, Masuyama Y.
Department of Medicine, Wakayama Medical University, Japan. email@example.com
The present in vitro study was performed to investigate the effects of estriol (E3) on membrane fluidity of erythrocytes by means of an electron paramagnetic resonance (EPR) and spin-labeling method. E3 was shown to significantly decrease the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-NS obtained from EPR spectra of erythrocyte membranes. This finding indicated that E3 might increase the membrane fluidity of erythrocytes. The effect of E3 was significantly potentiated by the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP), and a cyclic guanosine 3',5'-monophosphate (cGMP) analog, 8-bromo-cGMP. In contrast, the change in the membrane fluidity induced by E3 was antagonized by the NO synthase inhibitor, L-NG-nitroarginine-methyl-ester (L-NAME), and asymmetric dimethyl-L-arginine (ADMA). The results of the present study showed that E3 significantly increased the membrane fluidity and improved the microviscosity of erythrocyte membranes, partially mediated by an NO- and cGMP-dependent pathway. Furthermore, the data might be consistent with the hypothesis that E3 could have a beneficial effect on the rheological behavior of erythrocytes and may play a crucial role in the regulation of microcirculation.
Life Sci 2002 May 24;71(1):31-42
Estriol retards and stabilizes atherosclerosis through an NO-mediated system.
Kano H, Hayashi T, Sumi D, Matusi-Hirai H, Tsunekawa T, Endo H, Iguchi A.
Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Estriol (E3) has little effect on the female genitals. E3 is used in hormone replacement therapy, particularly in Europe and Japan, since it obviates the need for progestin administration. However, the effect of E3 on atherosclerosis has not been elucidated. In this study, we evaluated the effect of E3 on the progression of atherosclerosis in a rabbit model. Thirty-six rabbits total were used. Twenty-eight were bilaterally oophorectomized, and 8 were not. The rabbits were divided into 5 groups and treated for 12 weeks as follows. Gp I (n = 8) was fed a high cholesterol diet (HCD; standard diet plus 0.5% cholesterol); Gp II (n = 8) was fed a HCD with E3 (0.3 mg/kg/day); Gp III (n = 8) was fed a HCD with 17beta estradiol (E2) (0.1 mg/kg/day); Gp IV (n = 8), the non oophorectomized group, was fed a HCD; and Gp NC was oophorectomized (n = 4), and fed a regular diet. E3 treatment increased the plasma E2 and E3 levels in Gp II. The plasma lipid levels were not altered by the E2 or E3 treatment. A HCD diminished the acetylcholine-induced NO mediated relaxation in the thoracic aorta. The E2 treatment (Gp III) and E3 treatment (Gp II) restored the aortic basal NO release and the aortic cyclic GMP levels, particularly effectively in the E3 group. E3 treatment also decreased the atherosclerotic area, and its effect was comparable with E2 (surface involvement: 41.2 +/- 5.1% in Gp I; 10.1 +/- 2.7% in Gp II; and 6.5 +/- 1.3% in Gp III). All four hyperlipidemic groups showed an increase of eNOS mRNA in the aortae, and this was especially pronounced in Gps II and III. The level of peroxynitrite, as determined by immunohistochemical nitrotyrosine staining, was lower in Gps II and III than in Gp I. E3 strongly activates NO-mediated systems, and could play a role in retarding the progression of atherosclerosis and in stabilizing atheroma.
Obstet Gynecol 2000 Oct;96(4):521-8
Eicosapentaenoic acid effect on hyperlipidemia in menopausal Japanese women. The Niigata Epadel Study Group.
Kurabayashi T, Okada M, Tanaka K.
Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Japan.
OBJECTIVE: To assess the efficacy and safety of eicosapentaenoic acid for the treatment of hyperlipidemia in symptomatic menopausal Japanese women. METHODS: We performed a prospective observational 48-week study in hyperlipidemic menopausal women. We randomly assigned 141 women, whose levels of serum total cholesterol were 220 to 280 mg/dL or whose serum triglycerides were 150 to 400 mg/dL at baseline to groups treated with estriol (E3) 2 mg daily (control group, n = 72) or ethyl icosapentate 1800 mg daily and E3 2 mg (eicosapentaenoic acid group, n = 69). RESULTS: Serum levels of total cholesterol decreased significantly from 249.4 to 238.6 mg/dL (-4.3%, P =.003) in the control group and from 252.3 to 234.0 mg/dL (-7.3%, P =.001) in the study group at week 48 in the women whose total cholesterol was not less than 220 mg/dL at baseline. Serum levels of triglycerides decreased significantly from 194.5 to 141.5 mg/dL (-27. 2%, P =.001) in the study group but increased slightly from 192.9 to 207.4 mg/dL (+7.5%) in the control group at week 48 in the women whose level of triglycerides was not less than 150 mg/dL. There were significant differences between these two groups at weeks 12, 24, and 48. Serum levels of total cholesterol and triglycerides were significantly decreased at week 48 in the study group regardless of whether the women were obese. There were no severe adverse effects. CONCLUSION: Combination therapy with eicosapentaenoic acid and E3 was effective and safe for menopausal women with hypertriglyceridemia.
Atheroprotective effect of estriol and estrone sulfate on human vascular smooth muscle cells.
Kikuchi N, Urabe M, Iwasa K, Okubo T, Tsuchiya H, Hosoda T, Tatsumi H, Honjo H.
Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan. firstname.lastname@example.org
In patients with atherosclerosis, fibrosclerotic focuses are induced by multiplication of vascular smooth muscle cells (VSMC), and they are regulated by cytokines and regulators. There have been few reports about the atheroprotective effect of estriol (E(3)). Estrone sulfate (E(1)-S) is the predominant estrogen of conjugated equiline estrogens, which is commonly used in hormone replacement therapy, but it should be hydrolyzed by steroid sulfatase (STS) to enter the cells of target tissues. The purpose of this study was to detect STS in VSMC and to investigate whether E(3) and E(1)-S have atheroprotective effects like E(2). First, we detected the presence of STS mRNA in VSMC by in situ hybridization. We then examined the changes in the expression of mRNAs of cytokines, namely, PDGF-A chain, IL-1, IL-6 and TGF-beta, in VSMC, in the presence and absence of E(3) and estrogens. As a result, the expression of PDGF-A chain, IL-1 and IL-6 mRNAs was suppressed by E(3) (P<0.05 vs control) significantly like E(1)-S and E(2), but that of TGF-beta mRNA was not significantly affected by any estrogen. These results indicate that E(1)-S can be hydrolyzed by STS in VSMC, and that E(3) may regulate the cytokines by suppressing the production of mRNAs. It is suggested that there is a possibility of E(1)-S and E(3) having a direct effect on vessels in atherogenesis.
Gynecol Endocrinol. 2007 Jul 2;:1-4 [Epub ahead of print]
Second Department of Medicine, Semmelweis University, Budapest, Hungary.
The present study aimed to test whether, beyond the known antioxidant effect of estradiol, such a property is also possessed by estrone and estriol. For this purpose, an in vitro investigation of the effect of estrone and estriol on superoxide anion production by human neutrophil granulocytes was carried out. Blood samples were obtained from healthy volunteers and neutrophil granulocytes were separated for measurement of superoxide anion generation after incubation with estrone, estriol (10(-7), 10(-6) and 10(-5) M) and 17beta-estradiol (10(-7) M). Superoxide anion production of isolated neutrophil granulocytes was quantified by photometry and using the reduction of ferricytochrome-C. When adding estrone and estriol to neutrophil granulocyte suspensions, the production of superoxide anion fell (10(-5) M: 84.17 +/- 3.14% and 88.77 +/- 1.98% of control production, p < 0.01 and p < 0.05, respectively). Estradiol produced an antioxidant effect at lower concentration (10(-7) M: 72.91 +/- 7.94% of control production, p < 0.001). The weak estrogens estrone and estriol, similarly to estradiol, are also able to reduce the superoxide anion release in our experimental model. This may have importance in the antioxidant defense of biological systems.
Bull Exp Biol Med. 2006 Mar;141(3):337-8.
Department of Molecular Pharmacology and Radiobiology, Medical and Biological Faculty, Russian State Medical University, Moscow.
Estrone, estriol, and estradiol valerate exhibited antiarrhythmic activity in rats with aconitine-induced arrhythmia. Estrone was most effective in this respect.
Gynecol Obstet Invest. 2005;59(2):67-9. Epub 2004 Nov 9.
Department of Obstetrics and Gynecology, Faculty of Health Sciences, Kobe University Graduate School of Medicine, Kobe, Japan. email@example.com
BACKGROUND: Several studies show that 17beta-estradiol (E2) has protective effects on atherosclerosis in the arterial wall in postmenopausal women. Little information is, however, available regarding the effect of estriol (E3) on atherosclerosis. This study was conducted to investigate the effects of E3 alone and combined E3/pravastatin therapy on intima-media thickness (IMT) of common carotid artery in postmenopausal women. METHODS: Thirty-three postmenopausal women were allocated to four groups: daily treatment with E3 (2 mg) alone (E3 group, n = 10), pravastatin (10 mg) alone (pravastatin group, n = 6), combined treatment with E3 (2 mg) and pravastatin (10 mg; E3/pravastatin group, n = 7) and untreated control group (n = 10). All women attended the Kobe University Hospital once a year for routine gynecological and ultrasonographic examinations for the evaluation of atherosclerosis. RESULTS: A significant decrease in IMT was noted in the E3/pravastatin group compared with that in the untreated control group (p < 0.05), whereas there was no significant difference in the reduction rate of IMT in the pravastatin group, E3 group and untreated control group. CONCLUSIONS: The combined E3/pravastatin therapy appeared to retard the progression of atherosclerosis in postmenopausal women. Copyright 2005 S. Karger AG, Basel
J Am Soc Nephrol. 2004 Feb;15(2):348-58.
Departments of Pathology and Internal Medicine, University of Heidelberg, Heidelberg, Germany. Marie-Luise_Gross@med.uni-heidelberg.de
Renal diseases tend to be less severe among premenopausal female patients, compared with male patients. Experimental data on the effects of estrogens on renal damage are controversial, and potential underlying mechanisms have not been fully clarified. Three-month-old, female, uninephrectomized (UNX), sham-operated or ovariectomized (OVX) SHRsp rats were left untreated or received either 17beta-estradiol 3-benzoate (25 micro g/d) or estriol (0.02 mg/d) daily. After 3 mo, indices of renal damage (glomerulosclerosis index and tubulointerstitial damage index) and glomerular geometric parameters were investigated. The expression of desmin, TGF-beta, endothelin-1, collagen IV, endothelial nitric oxide synthase, and estrogen receptors alpha and beta in the glomeruli and tubulointerstitium was immunohistochemically evaluated. Estradiol and estriol did not significantly affect kidney weights or BP. Estradiol and estriol caused significant reductions in albuminuria (vehicle-treated UNX/OVX animals, 25.4 +/- 8.52 mg/24 h; estradiol-treated UNX/OVX animals, 15.37 +/- 6.12 mg/24 h; estriol-treated UNX/OVX animals, 6.54 +/- 2.24 mg/24 h). The glomerulosclerosis index was significantly lower in estriol- and estradiol-treated animals (estradiol-treated UNX/OVX animals, 0.69 +/- 0.16; estriol-treated UNX/OVX animals, 0.21 +/- 0.12; P < 0.05), compared with vehicle-treated animals (1.46 +/- 0.09); the tubulointerstitial damage index exhibited a similar pattern. The mean glomerular volume was significantly less in estrogen-treated animals. UNX/OVX animals demonstrated significantly greater expression of TGF-beta and endothelin-1 in immunohistochemical, in situ hybridization, and reverse transcription-PCR assays. This increase was abrogated by estriol but not estradiol. Similarly, significantly higher glomerular and tubulointerstitial expression of proliferating cell nuclear antigen and collagen IV was observed in UNX/OVX animals, and expression was decreased by estriol but not estradiol. It was concluded that, in the UNX model of spontaneous renal damage, glomerular lesions and glomerular hypertrophy were reduced by estriol but less consistently by estradiol. In parallel, loss of podocytes, evidence of podocyte injury (i.e., desmin expression), and expression of mediator systems of glomerular damage were decreased, pointing to a major renoprotective action of estriol.
Kidney Int. 2005 Mar;67(3):849-57.
Department of Pathology, University of Heidelberg, Heidelberg, Germany. Marie-Luise_Gross@med.uni-heidelberg.de
BACKGROUND: The risk of cardiovascular disease in uremic patients is greater in male than in female patients. Estrogens seem to play a cardioprotective role until menopause. Experimental data on the effect of estrogens on cardiovascular damage are controversial and potential underlying mechanisms especially in renal failure have not been fully clarified. METHODS: Three-month-old female uninephrectomized stroke-prone spontaneously hypertensive (SHRsp) rats were sham-operated or ovariectomized. Subsequently, they received either vehicle (sesame oil) or 17-beta-3 benzoate estradiol (E2) (25 microg/day) or estriol (E3) (0.02 mg/day), respectively. After 3 months the animals were sacrified and the organs were harvested using pressure-controlled perfusion fixation. Stereologic parameters such as capillary length density (L(V)), mean intercapillary distance (MID), and volume density of the interstitial tissue (Vv) were quantitated. Additionally, expression of transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF), flt-1, endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), endothelin A receptor (ETA) receptor, and alpha estrogen receptor was assessed using immunohistochemistry. Intramyocardial capillaries and the aorta were investigated by morphometric methods. RESULTS: L(V) (mm/mm(3)) was significantly lower (2421 +/- 500) and MID (microm) significantly higher (22.2 +/- 2.33) in vehicle-treated uninephrectomized/ovariectomized compared to uninephrectomized/sham-ovariectomized controls (L(V) 3629 +/- 960, MID 12.7 +/- 2.7) as well as estradiol (L(V) 3340 +/- 739, MID 12.1 +/- 4.96) and estriol (L(V) 4655 +/- 618, MID 14.2 +/- 2.89) treated uninephrectomized/ovariectomized animals. The volume density of the cardiac interstitium was higher in vehicle-treated uninephrectomized/ovariectomized animals compared to uninephrectomized/sham-ovariectomized, estradiol and estriol treated uninephrectomized/ovariectomized rats. The protein level expression of TGF-beta was higher in vehicle treated uninephrectomized/ovariectomized compared to uninephrectomized/sham and all treatment groups. CONCLUSION: In ovariectomized SHRsp rats with moderate renal failure cardiac lesions were strikingly less after estradiol or estriol treatment. The results document a beneficial role of estrogens on cardiac abnormalities in a model of moderate renal dysfunction.
: Altern Med Rev 1999 Aug;4(4):266-70
Comparative measurements of serum estriol, estradiol, and estrone in non-pregnant, premenopausal women; a preliminary investigation.
Wright JV, Schliesman B, Robinson L.
Tahoma Clinic, 515 W. Harrison, Ste. 200, Kent, WA 98031, USA.
Little to no data exists in the literature for serum estriol values in non-pregnant, premenopausal women. The current medical community opinion holds that estriol has no significant role in non-pregnant women relative to the other estrogens. It is a possibility that estriol's primary function has yet to be discovered. Accordingly, the first step is to understand cycle-dependent serum estriol concentrations. We have made a preliminary investigation for serum estriol concentration of 26 women during the known cycle peaks of estrone and estradiol. Five of the women were also tested for serum estriol on various days throughout the cycle in order to develop a cycle-dependent concentration profile. The result of these experiments show that serum estriol was always significantly higher than the sum of estrone and estradiol and less fluctuating. We conclude that estriol is probably a significant estrogen component.
Maturitas 2000 Feb 15;34(2):169-77
Efficacy and safety of oral estriol for managing postmenopausal symptoms.
Takahashi K, Manabe A, Okada M, Kurioka H, Kanasaki H, Miyazaki K.
Department of Obstetrics and Gynecology, Shimane Medical University, Izumo, Japan. firstname.lastname@example.org
OBJECTIVE: to assess the therapeutic efficacy and safety of oral estriol for the treatment of climacteric symptoms in postmenopausal women. METHODS: 68 postmenopausal women with climacteric symptoms received oral estriol, 2 mg/day, daily for 12 months. We evaluated the degree of climacteric complaints with estriol therapy; serum levels of gonadotropins, estradiol (E2) and lipids; biochemical markers of bone metabolism; blood pressure; and side effects both at baseline and during treatment. Climacteric symptoms were assessed according to the menopausal index (MI), a version of the Kupperman index that had been modified for Japanese women. RESULTS: oral estriol therapy significantly reduced total MI scores. The greatest relief was noted for hot flushes, night sweats, and insomnia. Estriol treatment significantly lowered serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations but did not affect any of the other parameters (lipids, bone, liver and blood pressure) during the study period. Slightly vaginal bleeding occurred in 14.3% of those who underwent natural menopausal women. Histologic evaluation of the endometrium and ultrasound assessment of the breasts following 12 months of estriol treatment found normal results in all women. CONCLUSION: Estriol is a safe and effective alternative for relieving climacteric symptoms in postmenopausal Japanese women.
Maturitas 1999 Jan 4;31(2):111-6
Effect of long-term local or systemic hormone replacement therapy on post-menopausal mood disturbances. Influences of socio-economic and personality factors.
Cagnacci A, Neri I, Tarabusi M, Volpe A, Facchinetti F.
Institute of Obstetrics and Gynecology, University of Modena, Italy. email@example.com
OBJECTIVES: To clarify the effect exerted by hormone replacement therapy (HRT) versus socio-economic and personality factors in improving postmenopausal mood disorders. STUDY DESIGN: The effect of the 1-year administration of systemic hormone replacement therapy (HRT; n = 22) or a vaginal cream of estriol (n = 14) versus no treatment (n = 26) was evaluated on mood states of anxiety, depression, somatization and inadequacy, as evaluated by the symptom rating test (SRT) scale. Results were correlated with the woman socio-economic status, and her capability to cope with daytime distresses, as evaluated by the Coping Style questionnaire. RESULTS: A spontaneous decline of all SRT scores, except that of inadequacy, was observed in the group with no treatment. In comparison HRT induced a greater improvement of only the SRT score of inadequacy (P < 0.01) and to a lesser extent of anxiety (P < 0.06). Similarly, vaginal estriol induced a greater decline of the SRT score of inadequacy (P < 0.01). Multiple regression analysis showed that modifications of the total SRT score and the SRT score of anxiety were related mainly to socio-economic factors, while those of the SRT score of depression were related only to the coping style of the woman. The decline of somatization was related only to time since the menopause while, the reduction of the SRT score of inadequacy was only the consequence of therapy, either systemic or local. CONCLUSIONS: In a 1-year period improvement of post-menopausal psychological discomfort, is spontaneous and independent of therapy. Only symptoms of inadequacy are improved by the hormonal therapy. Likely, the perceived menopausal 'losses' make the woman to feel inadequate and the use of sex-related hormones is capable to improve this feeling.
Ann Plast Surg 2001 Jun;46(6):617-20
Facilitated tissue expansion with topical estriol.
Tercan M, Cokkeser Y, Ozyazgan I, Bekerecioglu M, Sari I.
Department of Plastic and Reconstructive Surgery, Gaziantep University, Turkey.
Tissue expansion is a helpful technique in reconstructive plastic surgery. Unfortunately, tissue expansion still needs to be improved. Twenty-four male Wistar rats were used to evaluate the effect of estriol on tissue expansion. The agents hyaluronidase, estriol, and base cream (as a control) were applied topically to separate animal groups for 5 weeks, and their effects were studied on tissue expansion. Both hyaluronidase (p < 0.05) and estriol (p < 0.001) enhanced the rate of expansion when compared with control animals. Estriol was more effective than hyaluronidase (p < 0.05). Breaking strengths were measured in the estriol and the control groups. Breaking strength was not evaluated in the hyaluronidase group because of the necrotic changes seen at the end of the fifth week. The breaking strength was higher in the control group than in the estriol group (p < 0.05). The authors suggest that topical estriol be used as an adjunctive agent to facilitate tissue expansion.
Toxicology 2002 Jul 15;176(3):229-43
Estradiol enhances and estriol inhibits the expression of CYP1A1 induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in a mouse ovarian cancer cell line.
Son DS, Roby KF, Rozman KK, Terranova PF.
Center for Reproductive Sciences, University of Kansas Medical Center, 3901 Rainbow Boulevard, 66160, Kansas City, KS, USA
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous pollutant and promoter of carcinogenesis. This study investigated the interaction between TCDD and different estrogens in a cancer cell line (ID8) derived from mouse ovarian epithelium. TCDD-induced ethoxyresorufin-O-deethylase (EROD) activity and cytochrome P4501A1 (CYP1A1) expression in a dose- and time-dependent manner. Estrogen receptor (ER) alpha mRNAs were constitutively expressed, but ERbeta and progesterone receptor (PR) mRNAs were not expressed. Induction of EROD by TCDD was completely inhibited by a alpha-naphthoflavone and phenanthroline, two aryl hydrocarbon receptor (AhR) antagonists. Progesterone and gonadotropins (FSH and LH) had no effect on the induction of EROD by TCDD. Congeners of 17beta-estradiol (E2) increased the induction of EROD activity by TCDD dose-dependently in the relative potency order: estrone (El)>E2>/=4-hydroxyestradiol (4OHE2)>/=2-hydroxyestradiol (2OHE2). In contrast, estriol (E3) decreased EROD activity induced by TCDD. E2 increased TCDD-induced CYP1A1 protein and mRNA whereas E3 decreased both the protein and mRNA. E2 did not alter luciferase activity induced by TCDD in cells transfected with a luciferase reporter containing dioxin response elements (DRE) or a CYP1A1 promoter. In contrast, E3 dose-dependently decreased the luciferase activity. A pure anti-estrogen (ICI 182780) inhibited the interaction between E2 and TCDD but did not block E3's effect on EROD activity. These results indicate that E2 may affect TCDD-induced CYP1A1 expression by a mechanism different from E3 in ID8 cells. It appears that the potentiation of E2 in the induction of CYP1A1 by TCDD occurs by a mechanism involving ERalpha since a specific ER antagonist blocked the potentiation. The inhibitory effect of E3 may be due to a rapid direct effect on EROD and a later suppression of CYP1A1 expression.
Gynecol Endocrinol 2001 Feb;15(1):74-80
Estrogen replacement therapy in postmenopausal women: a study of the efficacy of estriol and changes in plasma gonadotropin levels.
Ushiroyama T, Sakai M, Higashiyama T, Ikeda A, Ueki M.
Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Japan.
The purpose of this study was to clarify the efficacy of estriol for estrogen replacement therapy in postmenopausal women with undefined symptoms and to evaluate endocrinological changes during therapy in relation to clinical outcome. Administration of 2 mg estriol in 168 postmenopausal patients was markedly effective in 22.6% of cases, effective in 45.2%, fairly effective in 14.3%, and ineffective in 17.9% of cases. The plasma concentration of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) after administration of estriol decreased significantly (p < 0.001), by 52.2% and 32.9%, respectively for markedly effective cases, and by 39.1% and 48.0% for effective cases. In contrast, the plasma estradiol concentration remained unchanged. On the other hand, decreases in FSH and LH concentration were 13.9% and 5.9% for the fairly effective and 8.2% and 1.9% for ineffective cases, demonstrating a significantly lower decrease in plasma FSH and LH levels than in the markedly effective and effective cases (p < 0.001). For cases showing side-effects, the plasma FSH and LH levels decreased by 52.0% and 64.3%, respectively, whereas the plasma estradiol level remained unchanged. In conclusion, the efficacy of estriol was significantly correlated to the degree of decrease in plasma FSH and LH levels in patients with undefined symptoms. In addition, efficacy appeared to be correlated to the incidence of side-effects. The degree of reduction of FSH (39.1-52.2%) and LH (48.0-64.3%) from the baseline may possibly be used as a guide to the therapeutic hormone levels during HRT. The present results suggest that plasma gonadotropin levels could be a useful indicator in the management of patients undergoing estrogen replacement therapy.
BONE DENSITY ABSTRACTS
J Gerontol A Biol Sci Med Sci 2000 Apr;55(4):B183-90; discussion B191-3
Estriol (E3) replacement improves endothelial function and bone mineral density in very elderly women.
Hayashi T, Ito I, Kano H, Endo H, Iguchi A.
Department of Geriatrics, Nagoya University School of Medicine, Japan. firstname.lastname@example.org
We investigated the effects of estriol (E3) on endothelial function and bone mineral density (BMD) in very elderly women. Twenty-four very elderly women (80 +/- 3.5 years old) were administered CaCl2 with or without estriol treatment (2 mg/day) for 30 weeks (hormone replacement treatment [HRT] group vs control group). Endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation by nitroglycerin of the brachial artery, and BMD were assessed. Levels of plasma lipids and apoproteins were not changed; however, both plasma E3 and E2 were substantially increased (E2, 4.6 to 31.3 +/- 8.1; E3, <5 to 45.3 +/- 7.9 pg/mL) by HRT. The FMD value was also increased by HRT, as were the plasma nitrite/nitrate and cGMP values. The response to nitroglycerin was not changed. The BMD was increased by HRT, but decreased in the control group. There were significant differences between the HRT group and control group after 30 weeks' treatment in the levels of osteocalcin, P1CP, and urinary deoxypiridinoridine. E3 significantly improved BMD by inhibiting bone resorption. Endothelial function was improved in line with the antiatherosclerotic effects. E3 might be effective for use in HRT in elderly patients.
: J Bone Miner Res 2000 Dec;15(12):2513-20
The oxidative metabolism of estradiol conditions postmenopausal bone density and bone loss.
Leelawattana R, Ziambaras K, Roodman-Weiss J, Lyss C, Wagner D, Klug T, Armamento-Villareal R, Civitelli R.
Department of Medicine, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri, USA.
Because lifelong exposure to estrogen is a strong determinant of bone mass, we asked whether metabolic conversion of estrogen to either inactive or active metabolites would reflect postmenopausal bone mineral density (BMD) and rate of bone loss. Biochemical markers of inactive estrogen metabolites, urinary 2-hydroxyestrogen (2OHE1) and 2-methoxyestrogen (2MeOE1), and active metabolites, urinary 16alpha-hydroxyestrone (16alphaOHE1), estradiol (E2), and estriol (E3), were determined in 71 untreated, healthy postmenopausal women (age, 47-59 years) followed prospectively for 1 year. Urinary 2MeOE1 was correlated negatively with baseline vertebral (anteroposterior [AP] projection, r = -0.23 andp < 0.05; lateral view, r = -0.27 and p < 0.05) and proximal femur bone density measured by dual-energy X-ray absorptiometry (DXA; total, r = -0.38 and p < 0.01; neck, r = -0.28 and p = 0.02; trochanter, r = -0.44 and p < 0.01). BMDs of women in the lowest quartile of urinary 2MeOE1 (< 15 ng/g) were significantly higher than those in the highest quartile at all skeletal sites (p < 0.05). Likewise, women in the lowest quartile of urinary 2OHE1/16alphaOHE1 ratio (< 1.6) did not experience bone loss after 1 year, in contrast to women in the higher quartiles. We propose that the rate of inactivation of estrogens through 2-hydroxylation may contribute to postmenopausal osteoporosis.
in Calcium. 2002 Aug;12(8):1165-9.
[Article in Japanese]
Department of Health Sciences, Kobe University School of Medicine.
In cultured human osteoblast-like cells (HOS), combined treatment with estriol (E(3)) and vitamin D(3) (VD(3)) increases the cell viability relative to treatment with E(3) alone and that E(3) treatment remarkably increases VD(3) receptor mRNA expression in the cells. Our findings in the present study with osteoblast cells may explain at least in a part the molecular basis of the clinical efficacy of combined treatment with E(3) and VD(3) in osteoporotic women.
J Endocrinol 2000 May;165(2):467-73
Comparison of the effects of add-back therapy with various natural oestrogens on bone metabolism in rats administered a long-acting gonadotrophin-releasing hormone agonist.
Wang Y, Yano T, Kikuchi A, Yano N, Matsumi H, Ando K, Kasai Y, Watanabe M, Okagaki R, Osuga Y, Taketani Y.
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
The hypoestrogenic state induced by gonadotrophin-releasing hormone agonist (GnRHa) has been shown to be effective in the treatment of oestrogen-dependent disorders but to induce bone loss. Adding back low doses of oestrogen in GnRHa therapy has been proposed to prevent bone loss. The purpose of this study is to assess the efficacy of add-back therapy with different natural oestrogens such as oestrone (OE(1)), oestradiol (OE(2)) and oestriol (OE(3)). Three-month-old female rats (250 g) were subcutaneously administered microcapsules of leuprorelin acetate in doses of 1 mg/kg of body weight every 4 weeks. GnRHa therapy lasted 16 weeks, and pellets of OE(1), OE(2) or OE(3) (0.5 mg/pellet, 60 day release), as an add-back agent, were implanted at 8 weeks of treatment. At the end of treatment, GnRHa alone decreased bone mineral density of the femur and lumbar vertebrae, and increased serum levels of bone metabolic markers such as alkaline phosphatase and osteocalcin levels. As for cancellous bone histomorphometry, GnRHa decreased bone volume while it increased osteoid volume, osteoid surface, eroded surface, mineral apposition rate and bone formation rate. All the oestrogens tested prevented these changes caused by GnRHa therapy. GnRHa induced a significant increase in body weight and a marked reduction in uterine weight, which was not observed in OE(1) or OE(2) add-back group. Body weight and uterine weight of the OE(3) add-back group were the same as those of the GnRHa group. These findings indicate that GnRHa induces high turnover bone loss which can be prevented by concomitant administration of natural oestrogens such as OE(1), OE(2) and OE(3) to the same extent. In addition, OE(3) is unique in that it is much less effective than OE(1) and OE(2) in blocking body weight gain and in promoting growth of uterine tissues. Because of its tissue-selective actions, OE(3) could be considered as one of the most appropriate oestrogens used for GnRHa add-back therapy.
Bone. 2004 Sep;35(3):682-8..
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA. email@example.com
We have previously demonstrated that estrogen metabolism is one of the determinants of bone density after menopause. Increased hydroxylation to relatively nonestrogenic metabolites 2-hydroxyestrone (2OHE1) and 2-methoxyestrone (2MeOE1) was associated with low bone mineral density (BMD), while increased hydroxylation to the potent 16alpha-hydroxyestrone (16alphaOHE1) and weakly estrogenic estriol (E3) was associated with higher BMD. In this study, we tested the hypothesis that response to estrogen-hormone replacement therapy (ERT/HRT) is also related to individual differences in estrogen metabolism. Urinary estrogen metabolites were measured in 310 postmenopausal women using ESTRAMET enzyme immunoassay kit. Of these, 163 were on HRT with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA, Premarin and Provera) or ERT with conjugated equine estrogen alone (Premarin), and 147 women not on ERT/HRT acted as comparison. Annual rates of BMD changes were calculated on a subset of 81 women on ERT/HRT who had more than one previous BMD measured by dual-energy X-ray absorptiometry (DEXA). Controlling for age, years since menopause (YSM), body mass index (BMI), waist to hip ratio, and smoking, we found that urinary estrogen metabolite levels were significantly higher in ERT/HRT-treated women compared to those not on ERT/HRT. Furthermore, women in the higher 2 tertiles of 2OHE1 and 2OHE1/16áOHE1 ratio had positive increments in BMD compared to those in the lowest tertile who lost bone while on ERT/HRT. Thus, women with estrogen metabolism favoring the 2-hydroxylation pathway respond favorably to ERT/HRT.
Gynecol Endocrinol. 2003 Dec;17(6):455-61.
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
It is clinically evident that administration of estriol (E3) increases the bone mass density of the lumbar vertebrae in postmenopausal women, and that combined treatment with estrogen and 1,25-dihydroxyvitamin D3 (VD3) increases femoral neck bone mass density compared with treatment with estrogen alone in postmenopausal osteoporotic women. However, the molecular mechanism whereby treatment with E3 affects osteoblast cell function is still unknown. This study was conducted first to examine the comparative effects of E3 and VD3 on the cell viability of cultured human osteoblast-like cells (HOS) and second to determine whether E3 affects VD3 receptor mRNA expression in HOS. The cell viability and VD3 receptor mRNA expression of cultured HOS were assessed by MTT assay and semi-quantitative reverse transcriptase-polymerase chain reaction with Southern blot analysis, respectively. The treatment with E3 increased the cell viability of cultured HOS compared with untreated control cultures. The increase in cell viability caused by the treatment with E3 was further augmented by the combined treatment with VD3. The addition of either E3 (3.52 x 10(-8) mol/l) or E3 (3.52 x 10(-7) mol/l) to cultured HOS for 24 h resulted in a fourfold and eightfold increase, respectively, in VD3 receptor mRNA expression in HOS, compared with that in untreated control cultures. These results suggest that E3 may up-regulate the cell viability of osteoblast cells, and that the concomitant treatment with E3 and VD3 further augments the cell viability being associated with an E3-induced increase in VD3 receptor mRNA expression in those cells.
Biochem Biophys Res Commun. 2007 Aug 3;359(3):697-702. Epub 2007 Jun 4.
Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.
Inhibition of the assembly of amyloid beta-peptide (Abeta) as well as the destabilization of preformed beta-amyloid fibrils (fAbeta) in the central nervous system could be valuable therapeutics of patients with Alzheimer's disease (AD). Epidemiological studies have indicated that estrogen therapy reduced the risk of developing AD in women. Here, we examined the effects of estrogen (estrone (E1), estradiol (E2), and estriol (E3)) and related sexual steroids (androstenedione (AND) and testosterone (TES)) on the polymerization, extension and destabilization of fAbeta(1-42) and fAbeta(1-40) at pH 7.5 at 37 degrees C in vitro, using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies. E1, E2, and E3 dose-dependently inhibited the formation, as well as destabilization of fAbetas. The overall anti-amyloidogenic activity of these molecules was in the order of: E3>E2=E1>>AND=TES. Estrogen could be a potential therapeutic agent to prevent or delay AD progression.
Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2006 Sep-Dec;13(3-4):291-307.
Department of Psychology, Stockholm University, Sweden. Julie.Yonker@uc.edu
Studies of hormone therapy (HT) and cognition have yielded conflicting results. The aim of this observational study was to examine the effect of estradiol, via serum verified HT (estradiol, estriol, progesterone) and endogenous estradiol, on 108 healthy postmenopausal women's cognitive performance. The results demonstrated that the 43 HT-users performed at a significantly higher level than non-users on episodic memory tasks and on a verbal fluency task, whereas HT-users and non-users did not differ on tasks assessing semantic memory and spatial visualization. In addition, there was a positive relationship between serum estradiol level and episodic memory performance, indicating that postmenopausal HT is associated with enhanced episodic memory and verbal fluency, independent of age and education. These observational results suggest that HT use may be sufficient to exert small, yet positive effects on female sensitive cognitive tasks. Hormone therapy compliance and formulation is discussed as confounding factors in previous research.