Low AMH hormone levels predict faster bone loss

The antimullerian hormone is a simple blood test that measures ovary function. This discovery shows the connection of hormone deprivation at menopause and major bone loss in women. I have posted extensively elsewhere on this site about post-menopausal deprivation being associated with a major bone loss between menopause and age 60. There is increasing evidence for hormone replacement hormone therapy to increase this bone loss.” Bill Chesnut, MD.

(Return to New Health News, https://billchesnutmd.com/new-health-news/)

Low AMH hormone levels predict faster bone loss.    AMA News 5.12.16

Lower levels of a hormone produced by the ovaries is associated with a woman’s risk for bone loss during menopause, according to a recent study. Researchers at the University of California Los Angeles found testing levels of anti-mullerian hormone in women who are pre- or early-menopausal shows their likely rate for bone loss, suggesting early intervention may be possible to slow or prevent the condition. Anti-mullerian hormone is produced by cells in the ovarian follicles and is a marker for ovarian health, which the new study linked to decline in bone density of the spine and femur, researchers said in a press release. Bone strength in older ages and the ability to avoid devastating hip and spine fractures depend equally on peak bone mass achieved in young adulthood and the amount of bone lost during and after the menopause transition, Dr. Arun Karlamangla, a professor at UCLA, said in a press release in April, when the study was presented at the Endocrine Society’s 2016 annual conference. For the study, which was published on the society’s website ahead of the conference, researchers analyzed data for 474 women in the Study of Women’s Health Across The Nation who were between 42 and 52 years old, in pre- or early-perimenopause, had an intact uterus with at least one ovary and were not taking supplemental hormones. The researchers found that each fourfold decrease in anti-mullerian hormone was linked to a 0.15 percent faster decline in bone density of the spine and a 0.13 percent per year faster decline in density of the top of the femur, the femoral neck. The same decrease in the hormone was also linked to an 18 percent increase in odds of faster-than-average decline in bone density of the spine and 17 percent increase in odds for decline of the femoral neck. The researchers suggest early intervention — with treatments including increasing exercise or calcium and vitamin D intake — could help stave off bone loss for women at higher risk during menopause. This study’s findings open up the possibility of identifying the women who are going to lose the most bone mass during the transition and targeting them before they have lost a substantial amount of bone mass, Karlamangla said. .

Hormone replacement therapy, HRT, in early menopause may slow progression of cardiovascular disease.

“Hormone Replacement therapy in early menopause is important to decrease the bone loss following menopause. I have posted several articles on this website related to osteoporosis. Post-menopausal women not taking hormone replacement lose 60% of their total bone mass between menopause and 60 years of age.

Now another benefit is reported. The study below shows slowing of atherosclerosis by taking hormone replacement.

It is important to know what replacement is most safe. Also know the safety advantages of vaginal or topical HRT versus oral hormone placement. The metabolism is different when taking a medical orally than transcutaneous. Vaginal HRT with estriol elevates estriol a little and transiently if it elevates blood levels at all.

Testosterone is another hormone loss in menopause. Its involvement in bone loss and atherosclerosis has not been as extensively tested. The research available that I found does not report a significant risk of  testosterone replacement to keep the normal pre-menopausal blood level.

This finding is so important in my view that I posted the abstract of the original article just below the announcement in the popular press.

If you know women in the age group to be peri-menopausal please tell them the news.” Bill Chesnut, MD

To go back to New Health News: https://billchesnutmd.com/new-health-news

Starting HRT in early menopause may slow progression of cardiovascular disease, study indicates

The Wall Street Journal (3/30, Beck, Subscription Publication) reports the findings of a 643-patient study published in the New England Journal of Medicine study add to the evidence that beginning hormone replacement therapy (HRT) in early menopause may be protective against cardiovascular disease.

The NPR (3/30, Bichell) “Shots” blog reports that in the study, investigators “directly tested the effect of starting hormone therapy within the first six years after menopause, versus the effect of starting 10 years or more after menopause.” After five years, researchers found that “women who started hormones within six years of menopause had artery walls that thickened a little more slowly than the women on the placebo, whereas the extra estrogen did not seem to slow thickening in the group that started the hormone therapy later.”



Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

Howard N. Hodis, M.D., Wendy J. Mack, Ph.D., Victor W. Henderson, M.D., Donna Shoupe, M.D., Matthew J. Budoff, M.D., Juliana Hwang-Levine, Pharm.D., Yanjie Li, M.D., Mei Feng, M.D., Laurie Dustin, M.S., Naoko Kono, M.P.H., Frank Z. Stanczyk, Ph.D., Robert H. Selzer, M.S., and Stanley P. Azen, Ph.D., for the ELITE Research Group*

N Engl J Med 2016; 374:1221-1231March 31, 2016DOI: 10.1056/NEJMoa1505241



Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.


A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima–media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.


After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.


Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.)



Postmenopausal bone loss is a major concern for orthopedic surgeons.

“Postmenopausal bone loss is a major concern for orthopedic surgeons. We know that 25% of a woman’s total bone mass before menopause is lost by age 65. There are a high emphasis and research trying to deliver methods to restore that bone loss or stop further loss. Some women have striking amounts of bone loss and pathological fractures. Fractures occurring from a standing height are called a “fragility fractures” whether it is the wrist, kneecap, hip or spine. A fragility fracture is an alarm to begin studies of bone mass and metabolism. The odds are high of another fragility fracture occurring without medical intervention.

 Developing methods to restore bone loss years after menopause is the late side of this problem. The early smart approach in medicine is to prevent the bone loss by methods in peri-menopausal women. Many studies were done relating to the safety of using some form of estrogen early in menopause. There are increased risks starting estrogen five years after menopause. These may be lessened by using Estriol, the weakest form of estrogen and avoiding giving the medication orally. By avoiding the oral administration, you avoid the “first pass” metabolism that affects the hormone.  Using estriol intravaginally has increasing research experience to show it does not cause hyperplasia of the endometrium. The data is increasing that it decreases urinary incontinence by its effect on the urethra and vaginal tissue. There have not been extensive studies of estriol vaginally yet. There is a reason to combine testosterone with the estriol vaginally for muscle strength and the bone strengthening result of getting more physical activity.

 Many practitioners are not aware of the most recent developments in my experience. My bigger concern is that so many people I have seen as patients were not aware they need to research safe hormone replacement early in menopause. I posted 14 articles related to postmenopausal hormone deprivation as a “category of posts” on the homepage.” Bill Chesnut, MD.  

To go back to New Health News: https://billchesnutmd.com/new-health-news

 Anti-Mullerian Hormone and Prediction of Trans-Menopausal Bone Loss                              The Endocrine Society 1016 meeting _ a presentation.  Friday, April 1, 2016          

Arun S Karlamangla*1, Albert Shieh1, Sherri-Ann M Burnett-Bowie2, Elaine W. Yu2, Gail A Greendale1, Patrick M. Sluss2, Deborah Martin3and Joel S Finkelstein2
1University of California, Los Angeles, CA, 2Massachusetts General Hospital, Boston, MA, 3University of Pittsburgh, Pittsburgh, PA

The menopause transition (MT) in women is a period of bone loss, with the most rapid declines occurring in a 3-year period bracketing the final menstrual period (FMP). This period of rapid bone loss has been called the trans-menopause, and the rate of BMD decline over this period varies substantially between women (1).  Circulating levels of Anti-Mullerian Hormone (AMH) made by ovarian granulosa cells also decline as women progress through the MT (2). We hypothesized that serum levels of AMH in women early in the MT will predict the rate of bone loss over the trans-menopause. We tested this hypothesis using data from The Study of Women’s Health Across the Nation, a 7-site, multi-ethnic study of the MT. At baseline, participants had to be 42 to 52 years old, pre- or early peri-menopausal, have an intact uterus with 1 or 2 ovaries, and not be taking exogenous sex steroid hormones. Enrollment began in 1996 and women were asked to return annually.  At each visit, blood was collected between 8:00 and 10:00 AM after a 12-hour fast, during the early follicular phase (cycle days 2–5) whenever possible, and serum was stored at -80F.  In all women who had a natural (non-surgical) MT and a dateable FMP, serum level of AMH was measured from frozen blood samples using a new high-sensitivity monoclonal ELISA with a detection limit of 2 pg/mL (Pico AMH, Ansh Labs, Webster, TX). BMD [bone mass density] in the lumbar spine and femoral neck was measured annually in 5 of the 7 study sites.  In 474 women who had AMH and BMD measurements between 2 and 4 years before the FMP, had a 2nd BMD measurement 3-4 years later, and had not taken any medications that affect bone prior to the 2nd BMD measurement, we examined the ability of AMH level to predict the annualized rate of BMD decline between the two visits (% decline per year). AMH inter-quartile range was [11,146] pg/mL. Median rate of BMD decline was 1.3% per year in the spine and 1.0% per year in the femoral neck. Adjusted for age, BMI, smoking, race/ethnicity, and study site, in multivariable linear regression, each 75% (or four-fold) decrement in AMH level was associated with 0.15% per year faster decline in spine BMD (p<0.001) and 0.13% per year faster decline in femoral neck BMD (p=0.005).  These associations persisted even after additional adjustment for time from FMP and serum levels of estradiol and FSH. In multivariable logistic regression, adjusted for age, BMI, smoking, race/ethnicity, and study site, each four-fold decrement in AMH level was also associated with 18% increase in the odds of faster-than-median decline in spine BMD (p=0.02) and 17% increase in the odds of faster-than-median decline in femoral neck BMD (p=0.02). These findings suggest that serum levels of AMH in women going through the MT can indeed predict the rate of trans-menopausal bone loss, and help identify the women at risk of most loss.  AMH levels appear to provide information about the rate of bone loss beyond that provided by serum levels of estradiol and FSH.

(1) Greendale GA et al., JBMR 2012; 27: 111-8. (2) Sowers MFR et al., JCEM 2008; 93: 3478-83.


Menopausal hot flashes decrease with evercise.

“Exercise during menopause to stay cool is a good idea for many reasons. Without hormone replacement, menopausal women lose 25% of their total bone mass by age 60. That is a strong reason for exercise, calcium, checking your Vit D level to be sure you are around 50 ng/dl and staying current on available safe hormone replacement. Talk to a medical provider who has interest and is current in hormone replacement therapy. “ Bill Chesnut, MD.
Keep your cool during menopause — with exercise!____Cleveland Clinic Wellness newsletter March 2, 2016.
Call it a paradox, but getting sweaty can help you stay cool as a cucumber — in more ways than one! Not only can regular exercise help you manage stress, but in addition, if you’re going through menopause, it can help keep you cool literally. In a large population study, physically active women experienced fewer hot flashes and other uncomfortable symptoms than their more sedentary counterparts. And because “the change” is sometimes accompanied by weight gain, menopausal women may be especially responsive to the effects of exercise. One study showed that light exercise, such as casual walking and yard work, improved the body composition of menopausal women more than that of premenopausal women. (Take that, twentysomethings!) If you’re planning to start an exercise routine from scratch, clear it with your doctor, and choose your inspirational slogans carefully. To avoid injury or burnout, think “slow and steady” rather than “just do it.” Start with a 10-minute walk once a day, and increase by a couple of minutes every few weeks, with a goal of 30 minutes daily. And remember to include moves for balance, flexibility, and resistance, all valuable aspects of your health and fitness.
Cleveland Clinic Wellness Newsletter_ March 2, 2016

Effects of Testosterone Treatment in Older Men

“Hormone replacement has many benefits. As an orthopedic surgery specialty hormone deprivation is a concern for commonly causing a loss of bone mass and density. In women, it is established that 25% of the total bone mass is lost from menopause to age 60 years. The same occurs in men with hyperandrogenism, low testosterone; I do not have the frequency (incidence rate) nor the average amount of bone loss in men. There are many other benefits besides increased sexual function. The effects of the various methods of replacing testosterone are not addressed here. In addition to testosterone gels, there is injectable testosterone cypionate and an implantable deposit of testosterone showing promising early results. My point with this post is there are more medical reasons to consider hormone replacement in addition to changing sexual activity. A simple Internet search can lead you to the right data; especially look for statements from a specialty society such as the American Academy of Orthopaedic Surgeons.” Bill Chesnut, MD.

Effects of Testosterone Treatment in Older Men

Peter J. Snyder, M.D., Shalender Bhasin, M.D., Glenn R. Cunningham, M.D., Alvin M. Matsumoto, M.D., Alisa J. Stephens-Shields, Ph.D., Jane A. Cauley, Dr.P.H., Thomas M. Gill, M.D., Elizabeth Barrett-Connor, M.D., Ronald S. Swerdloff, M.D., Christina Wang, M.D., Kristine E. Ensrud, M.D., M.P.H., Cora E. Lewis, M.D., M.S.P.H., John T. Farrar, M.D., Ph.D., David Cella, Ph.D., Raymond C. Rosen, Ph.D., Marco Pahor, M.D., Jill P. Crandall, M.D., Mark E. Molitch, M.D., Denise Cifelli, M.S., Darlene Dougar, M.P.H., Laura Fluharty, M.P.H., Susan M. Resnick, Ph.D., Thomas W. Storer, Ph.D., Stephen Anton, Ph.D., Shehzad Basaria, M.D., Susan J. Diem, M.D., M.P.H., Xiaoling Hou, M.S., Emile R. Mohler, III, M.D., J. Kellogg Parsons, M.D., M.H.S., Nanette K. Wenger, M.D., Bret Zeldow, M.S., J. Richard Landis, Ph.D., and Susan S. Ellenberg, Ph.D. for the Testosterone Trials Investigators

N Engl J Med 2016; 374:611-624February 18, 2016DOI: 10.1056/NEJMoa1506119


Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established.


We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials — the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants.


Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy–Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.


In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.)


How are Bioidentical Estradiol and Progesterone Produced? What about Compounding Pharmacies?

“Dr. Lindner has a lot of helpful information he posted at his website HormoneRstoration.com. He has a depth of experience with menopause hormone deprivation symptoms and their treatment. This is about bioidentical hormone replacement as an example of the information he has. He writes a good explanation of the term bioidentical medications. ” Bill Chesnut, MD

Henry Lindner, MD

How are Bioidentical Estradiol and Progesterone Produced? What about Compounding Pharmacies?
“Bioidentical” is the term that signifies that the molecule is exactly the same as the one in our bodies. Yams,
soy, and other plants contain a molecule called diosgenin that has no hormonal effects, but it is similar to cholesterol and is
easily converted by chemical processes into bioidentical estradiol, progesterone, testosterone, cortisol, and DHEA.
However, all the alien steroid substitutes are also made from diosgenin. The issue is not whether the molecule is natural or
synthetic–the source does not matter–it’s the chemical structure that makes a hormone right or not. Also, the route of
delivery is very important as bioidentical estradiol can cause problems if swallowed. The body accepts and metabolizes
bioidentical hormones as if it made them. There are FDA-approved bioidentical estradiol and progesterone products, but
they are often expensive and hard to individualize. They are often not in the best form for delivery. There isn’t any FDA-
approved testosterone for women (The drug companies are trying to fix that!) Therefore many physicians prefer to
prescribe compounded estradiol, progesterone, and testosterone. A compounding pharmacy uses USP-certified
bioidentical hormones (the same raw products used in FDA-approved products). They simply combine carefully measured
amounts of the hormone powder into a delivery vehicle–a cream, gel, tablet, or capsule. Nothing could be simpler.
Pharmacists are certified experts. They take their responsibilities seriously. Any slight batch to-batch differences in
concentration or delivery that may occur are insignificant to hormone replacement. Compounded hormones work
perfectly well, are very convenient, and are less expensive in most cases. 
The scare-mongering lies about
compounded hormones that you are hearing are just drug-company propaganda passed on through drug company-
funded professional organizations
 like ACOG and NAMS straight to your local OB/GYN. (ACOG=American College of
Obstetrics and Gynecology, NAMS=North American Menopause Society)

Sleep quality improvement with hormone replacement therapy

Sleep disturbance symptoms are common in post menopause hormone deprivation. This paragraph is a brief post of research being done showing improvement of sleep function with hormone replacement. I am referring to this as an area you may wish to investigate further. Bill Chesnut, MD

 Journal of Sleep Research

Volume 12Issue 3pages 239–254September 2003

In the open-label phase, subjective sleep quality improved further, significantly in the former regimen A group. Awakening quality, somatic complaints and morning thymopsyche did not yield any significant findings. Concerning morning noopsychic performance, memory improved significantly after regimen A compared with baseline, fine motor activity after regimen EV. Reaction time performance increased with all three compounds. In conclusion, Climodien [estradiol and progesterone] significantly improved subjective sleep quality, the apnea and apnea–hypopnea indices of insomniac postmenopausal syndrome patients, while it only marginally improved variables concerning objective sleep and awakening quality.

The Truth About Menopausal Hormone deprivation with hormone therapy

The Truth About Hormone Therapy

Two menopause experts set the record straight on bioidenticals, breast cancer risk, and more. By Alan Altman, MD. and Susan Wysocki

Read more: http://www.oprah.com/health/Hormone-Therapy#ixzz3zYGASeaM

Ever felt like the only thing that fluctuates more than a menopausal woman’s hormone levels is expert opinion on hormone therapy? You’re not alone. When the National Association of Nurse Practitioners in Women’s Health (NPWH) recently surveyed its members, nearly 80 percent said their patients were in the dark about hormonal treatment options for menopause. Susan Wysocki, a nurse practitioner and president of the NPWH, and Alan Altman, MD, a gynecologist specializing in perimenopausal and postmenopausal care, sort out the facts. 

Hormone therapy will seriously imperil your health.  “Compared with women who don’t take hormones, those who start oral hormone therapy [HT] after age 60 have a greater risk of heart attacks and dementia,” says Altman. “However, the latest research shows that beginning HT before age 60 can have theopposite effect: Women who do so have a 32 percent decreased risk of heart attack and a 65 percent decreased risk of Alzheimer’s.” Taking estrogen combined with progestin can increase your chances of developing breast cancer, but going off HT within five years seems to minimize any additional risk.

A blood test can determine the amount of hormones you need.
“Perimenopausal women’s hormones fluctuate so much that blood tests are all but meaningless,” Altman says. “These tests are also based on the false idea that there’s a standard, ideal amount of estrogen for everyone.” A woman with a low blood-hormone level may have no menopausal symptoms, while a woman with a higher blood level could be sweating through the dead of winter. “The best way to determine how much estrogen you need is simply to see how your symptoms respond to treatment,” says Altman. “Your doctor should start you off with a very low dose. After a month, if you’re still suffering, you may need to recalibrate upward.”

Compounded bioidenticals are totally different from FDA-approved bioidenticals

“Advertisers have led women to believe that compounded hormones are safer than FDA-approved products,” Wysocki says. But don’t let the marketing fool you. “Many contain estradiol, the same hormone found in standard prescription patches, creams, and gels that’s 100 percent identical to what your body produces,” says Altman. However, there is one important difference between FDA-approved bioidenticals and compounded formulas, which are hand-mixed by a pharmacist. “With FDA-approved HT, you get the same amount of hormones in every dose,” says Altman. “And even small fluctuations can make a big difference in how you feel.”

The safest way to get estrogen is through your skin, with a patch, cream, or gel.
Like every oral medication, estrogen taken in pill form travels through the digestive system and liver before it’s absorbed into the bloodstream. “That’s not a problem for many prescription drugs, but when estrogen hits the liver, it triggers the production of proteins that raise the risk of blood clots,” Altman says. “When you use a skin patch or vaginal cream, on the other hand, the estrogen is absorbed straight into the bloodstream—with no increased risk of clots.”

Read more: http://www.oprah.com/health/Hormone-Therapy#ixzz3zYGF0RlJ

Systemic effects and endometrial safety of local estrogen therapy


Systemic effects and endometrial safety of local estrogen therapy

November 2010 · Vol. 22, No. 11

Steven R. Goldstein, MD
Professor, Department of Obstetrics and Gynecology, New York University School of Medicine, Director, Gynecologic Ultrasound, Co-Director, Bone Densitometry, New York University Medical Center, New York, NY


  • Vaginal administration of estrogen is effective and well tolerated for treatment of symptoms of vulvovaginal atrophy
  • Estradiol tablets, estrogen creams, and estrogen rings are the three local estrogen formulations available in the United States
  • Relief of symptoms is achieved with low dosages of estrogen and limited systemic exposure
  • Vaginal administration is not associated with clinically important increases in serum estrogen levels or changes in endometrial proliferation

Vaginal atrophy is a prevalent condition resulting from estrogen deficiency that can occur at any time in a woman’s life but is more common after menopause.1 The precise prevalence of vaginal atrophy is difficult to ascertain. A recent review of vaginal atrophy found reports ranging from 4% of women in early perimenopause to 47% of postmenopausal women. Fortunately, in most women, local or systemic estrogen preparations relieve vaginal atrophy symptoms.2

Interest in the potential for lower systemic hormonal exposure with use of local vaginal estrogen therapy has grown since the results of the Women’s Health Initiative (WHI) were made public almost 10 years ago.3 Vaginal administration of low-dose estrogen provides sufficient estrogen to relieve symptoms and reverse the atrophic changes associated with menopause, with the added benefit of limited systemic absorption.4 Therefore, local vaginal treatment is typically recommended for women seeking estrogen therapy solely for the treatment of vaginal atrophy.5

Estradiol tablets, estrogen creams, and estrogen rings are the three local estrogen formulations available in the United States. This review presents the clinical evidence about the safety of these formulations.

SYSTEMIC ABSORPTION OF VAGINAL ESTROGEN THERAPY.  Absorption of estradiol and other steroid hormones is rapid, particularly through the thin vaginal epithelium characteristic of postmenopausal women.6 All three available formulations—the 17β-estradiol-releasing ring, 17β-estradiol tablets, and conjugated equine estrogen (CEE) and estradiol creams—are water-soluble and easily absorbed through the vaginal epithelium.7 Absorption with the ring or tablets may be slower than with creams.8 The concentration gradient across the epithelium determines the absorption rate; therefore, dosage may affect the extent of systemic exposure. Moreover, the distribution of absorbed estrogen within the pelvic region may differ depending on the anatomic position of administration. Some evidence suggests that delivery of estrogens to the lower one third of the vagina may limit distribution to the uterus, thereby lowering the risk of hyperplasia, and may be preferable for the treatment of vaginal atrophy.8,9

An important diference between local vaginal and oral administration of estrogen is that vaginal administration circumvents metabolic and physiologic barriers to estrogen absorption.6 Consequently, substantially lower dosages of estrogen are required when applying estrogen directly to the vagina, compared with oral administration.10 Although circulating levels of estrogen do increase with local administration, serum estrogen levels typically remain relatively low.


ESTROGEN CREAM. Several small studies have examined elevations in plasma estrogen concentrations with administration of low-dose vaginal creams containing either CEEs or estradiol across a range of doses.11,12 After 24 weeks of treatment at the highest dose of CEE cream used (1.25 mg/d), 21 of 59 (47%) women had a serum estradiol level outside the postmenopausal range (>49 pg/mL), although the magnitude of the elevation was not reported.12 In an other study,11 of 20 women treated for 6 months, CEE cream (0.3 g/d) produced only a minimal increase in estradiol and estrone levels.

Circulating levels of estradiol were measured in seven postmenopausal women treated with estradiol 10 µg vaginal cream for relief of symptoms of vaginal atrophy.13 After 3 weeks of daily administration, followed by an additional 9 weeks of twice-weekly treatment, circulating estradiol levels remained within the postmenopausal range.

No change in circulating mean estradiol (E2) levels have been reported with estriol cream, a vaginal estrogen therapy not available in the United States14,15; according to a Cochrane Review, this is the only cream not associated with systemic absorption.16

ENDOMETRIAL EFFECTS.   The primary concern regarding use of any estrogen therapy in women who have an intact uterus is the risk of endometrial hyperplasia and carcinoma associated with unopposed estrogen.

The endometrial safety of the 10-µg estradiol vaginal tablet was most recently evaluated for the treatment of vaginal atrophy in 336 non hysterectomized postmenopausal women.24 As shown in FIGURE 2,24 baseline endometrial thick ness was 2.04 mm as determined by transvaginal ultrasonography (double layer) compared with 1.94 mm after 52 weeks of treatment. At study’s end, there was no evidence of increased endometrial proliferation or hyperplasia.

A preliminary study35 on the use of local estrogen therapy in breast cancer survivors has been conducted. In this study, both low-dose vaginal estradiol tablet and estriol cream relieved vaginal atrophy, whereas a nonhormonal moisturizer provided only transient relief. Safety was evaluated by measuring serum estradiol levels and changes in endome-trial thickness, both of which were found to be minimal and clinically insignificant, although an evaluation of a longer duration of treatment is warranted. Because of the impact of moderate or severe vaginal atrophy on quality of life, women who do not respond to nonhormonal therapies may consider discussing the risks and benefits of local estrogen therapy.

SUMMARY AND CLINICAL IMPLICATIONS. Vaginal estrogen therapy is safe and well tolerated in postmenopausal women with vaginal atrophy, although these conclusions are based on experience in small trials, largely of short duration.

  • As with all forms of estrogen therapy, the Food and Drug Administration and NAMS have recommended the use of the lowest possible effective dose of vaginal estrogen for treating vaginal atrophy.5,39
  • Local estrogen treatments are associated with minimal systemic absorption.
  • Endometrial hyperplasia with local vaginal therapy is rare. Use of progestin therapy is generally not needed in patients using low-dose local vaginal estrogen therapy.4
  • In the absence of more rigorous studies suggesting otherwise, vaginal estrogens are not indicated for women receiving adjuvant AI therapy for breast cancer, and the potential for recurrence should be discussed with patients with a history of any hormone-sensitive cancer.
  • Because efficacy and safety of the local estrogen formulations appear to be similar, the preparation preferred by the patient and the provider should be used. Therapy should be continued as long as the troublesome symptoms remain.


Testosterone therapy in women: Myths and misconceptions

Testosterone therapy in women: Myths and misconceptions

The European Menopause Journal, vol. 895, March 2016.

Rebecca Glaser  and  Constantine Dimitrakakis

URL: http://dx.doi.org/10.1016/j.maturitas.2013.01.003

Abstract.   Although testosterone therapy is being increasingly prescribed for men, there remain many questions and concerns about testosterone (T) and in particular, T therapy in women. A literature search was performed to elucidate the origin of, and scientific basis behind many of the concerns and assumptions about T and T therapy in women.

This paper refutes 10 common myths and misconceptions, and provides evidence to support what is physiologically plausible and scientifically evident: T is the most abundant biologically active female hormone, T is essential for physical and mental health in women, T is not masculinizing, T does not cause hoarseness, T increases scalp hair growth, T is cardiac protective, parenteral T does not adversely affect the liver or increase clotting factors, T is mood stabilizing and does not increase aggression, T is breast protective, and the safety of T therapy in women is under research and being established.

Abandoning myths, misconceptions and unfounded concerns about T and T therapy in women will enable physicians to provide evidenced based recommendations and appropriate therapy.



Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor®) for vaginal atrophy in postmenopausal breast cancer patients

“This publication in a research publication is of a clinical trial using transvaginal estriol in menopausal women with vaginal atrophy. Bill Chesnut, MD

 Clinical Trial.  Breast Cancer Research and Treatment.  June 2014, Volume 145, Issue 2, pp 371-379.  First online: 10 April 2014.  Open Access

Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor®) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study

  • Phase I pharmacokinetic (PK) study assessed circulating estrogens in breast cancer (BC) patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacilluscombination vaginal tablets (Gynoflor®). 16 women on NSAI with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor® for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks. Primary outcomes were serum concentrations and PK of E3, estradiol (E2), and estrone (E1) using highly sensitive gas chromatography–mass spectrometry. Secondary outcomes were clinical measures for efficacy and side effects; microscopic changes in vaginal epithelium and microflora; and changes in serum FSH, LH, and sex hormone-binding globulin. Compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2–3 h post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed. The low-dose 0.03 mg E3 and Lactobacillus acidophilus vaginal tablets application in postmenopausal BC patients during AI treatment suffering from vaginal atrophy lead to small and transient increases in serum E3, but not E1 or E2, and therefore can be considered as safe and efficacious for treatment of atrophic vaginitis in BC patients taking NSAIs.


Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol

“This article summarized research about the effect of the hormone estriol in multiple sclerosis. For more information search the full article available online.” Bill Chesnut, MD

 Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol 1

The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy. The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis. In addition, estrogens induce cytokine changes consistent with a Th1 to Th2 shift when administered in vitro to human immune cells and in vivo to mice. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging. Here, the immunomodulatory effects of oral estriol therapy were assessed. PBMCs collected longitudinally during the trial were stimulated with mitogens, recall Ags, and glatiramer acetate. Cytokine profiles of stimulated PBMCs were determined by intracellular cytokine staining (IL-5, IL-10, IL-12 p40, TNF-α, and IFN-γ) and cytometric bead array (IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ). Significantly increased levels of IL-5 and IL-10 and decreased TNF-α were observed in stimulated PBMC isolated during estriol treatment. These changes in cytokines correlated with reductions of enhancing lesions on magnetic resonance imaging in relapsing remitting multiple sclerosis. The increase in IL-5 was primarily due to an increase in CD4+ and CD8+ T cells, the increase in IL-10 was primarily due to an increase in CD64+ monocytes/macrophages with some effect in T cells, while the decrease in TNF-α was primarily due to a decrease in CD8+ T cells. Further study of oral estriol therapy is warranted in Th1-mediated autoimmune diseases with known improvement during pregnancy.


Estriol: Its Weakness is Its Strength. A listing of research article references.

“The summary article I included because it lists relevant research of estriol vaginal hormone replacement. The URL for further research is: http://www.lifeextension.com/magazine/2008/8/estriol-its-weakness-is-its-strength/page-01 “Bill Chesnut, MD


Estriol: Its Weakness is Its Strength

August 2008 By Olivia A.M. Franks, ND and Jonathan V. Wright, MD

Estriol, an estrogen that has virtually been ignored by the mainstream medical community, is one of the three principal estrogens produced by the body. Estriol was originally thought to have little significance due to its weak estrogenic activity when compared with estrone and estradiol. Nonetheless, research has found that its weakness may very well be its strength.

Studies suggest that when the lower-potency estrogen, estriol, is administered topically, it does not increase the risk of hormone-dependent cancers of the breast or endometrium (uterine lining).1-3 However, having weaker estrogenic effects does not mean that estriol has none of the benefits that come with more potent estrogens. Studies suggest that estriol reduces symptoms of menopause, such as hot flashes and vaginal dryness, but with a better safety profile compared with more potent estrogens.1,4,5 This makes estriol a better choice for bioidentical hormone-replacement treatment regimes.

That is not all this ‘weak’ hormone is good for! Research suggests that estriol has benefits for bone density, heart health, multiple sclerosis, and postmenopausal urinary tract health.6-12 In this article, we will review the attributes of this ‘weaker’ estrogen, and why this estrogen is currently in the news


Most of the research cited in this article used oral estrogen as the route of administration. However, for enhanced safety, topical estriol would be a better choice. Several studies have shown that transdermal estrogen confers less health risk as a route of administration than oral estrogen.3,21-25 Clinical experience of many doctors over the past 20-30 years suggests that transdermal estrogen is also more effective for some women. This is largely thought to be due to the ‘first-pass effect’—meaning that orally ingested drugs are often first metabolized in the liver, before having any activity in the body. Orally ingested estrogen hormones are among these drugs that are first metabolized in the liver before exerting their effects in the body. Physicians experienced in hormone replacement often observe that women treated with oral estrogens show high levels of estrogen metabolites in 24-hour urine specimens, suggesting that most of the orally ingested hormones are being excreted.

In addition, several studies suggest that bioidentical estrogen has less health risk when given with low doses of bioidentical progesterone.26,27


Estriol Reduces Markers of Cardiovascular Risk

Growing evidence suggests that estriol may offer protective benefits for the cardiovascular system. For instance, Takahashi et al. found that some women with natural menopause given 2 mg/day oral estriol for 12 months had a significant decrease in both systolic and diastolic blood pressure.1

Another study compared the use of oral estriol at a dose of 2 mg/day for 10 months in 20 postmenopausal and 29 elderly women. Some of the elderly women had decreases in total cholesterol and triglycerides and an increase in beneficial high-density lipoprotein (HDL).7

Estriol Improves Bone Mineral Status in Women With Osteoporosis

A Japanese study involving 75 postmenopausal women found that after 50 weeks of treatment with 2 mg/day of oral estriol cyclically and 800 mg/day of calcium lactate, women had an increase in bone mineral density, a decrease in menopausal symptoms, and no increased risk of endometrial hyperplasia (tissue overgrowth that may precede cancer).6

Similarly, Nishibe et al. investigated treatment of postmenopausal and elderly women with 2 mg/day of oral estriol and 1,000 mg/day of calcium lactate versus 1,000 mg/day calcium lactate alone. The bone mineral density significantly increased in women who received estriol, whereas the women who did not take estriol experienced a decrease in bone mineral density.7

Estriol Reduces Brain Lesions of Multiple Sclerosis

The high levels of estriol during pregnancy have been known to alleviate some autoimmune conditions due to its ability to shift immune response.9 For instance, Sicotte et al. at the Reed Neurological Research Center in Los Angeles investigated the effects of pregnancy-level doses of estriol (8 mg/day) in non-pregnant women with multiple sclerosis (MS). Cerebral MRI images showed a significant reduction of gadolinium-enhancing cerebral lesions from multiple sclerosis. These lesions increased when treatment stopped and decreased when treatment was restarted.28 Gadolinium is a contrast agent used in certain MRI studies; gadolinium-enhancing lesions are associated with an increased inflammatory response marking disease progression in patients with MS. Lowered amount of these lesions seen on MRI with gadolinium contrast would equate to a decrease in disease progression.

This effect may also apply to men with autoimmune conditions. Another team of researchers from the Reed Neurological Research Center in Los Angeles found that estriol treatment ameliorates experimental autoimmune encephalomyelitis (EAE) in males, compared with placebo treatment.29 EAE is an experimental demyelinating inflammatory disease that shares numerous characteristics with MS. Estriol treatment also resulted in a decrease of proinflammatory immune markers. This is very promising news for patients and their doctors who are struggling to treat challenging neurological conditions associated with inflammation.

Estriol Protects Urinary Health in Postmenopausal Women

Postmenopausal women who suffer from incontinence or recurrent urinary tract infections will be pleased to know that estriol offers benefit in the context of these troublesome conditions. In a prospective, randomized, placebo-controlled study, 88 women were given 2 mg intravaginal estriol suppositories (once daily for two weeks, then twice weekly for six months) or placebo. Of the women in the estriol group, 68% reported improvement in symptoms of incontinence. In addition, measurements of mean maximal urethral pressure and mean urethral closure pressure were significantly improved.10

In another randomized, double-blind, placebo-controlled trial, women with recurrent urinary tract infections (UTI) were given either intravaginal estriol cream (containing 0.5 mg estriol, once daily for two weeks, then twice weekly for eight months) or placebo. The incidence of urinary tract infection was dramatically reduced in the estriol group compared with placebo (0.5 versus 5.9 episodes per year).11


Estriol menopause hormone deprivate treatment, the Women’s health Initiative and estriol topical hormone replacement.

“The article is obtained from the US National Library of Medicine, a division of the National Institutes of Health. It is from German studies. For anyone wanted detailed information about the women’s Health Initiative and hormone replacement therapy, I included this article.  It gives the history of the initial conclusions and subsequent conclusions about the data derived from the WHI.

The article discusses in detail the question of hormone replacement therapy in women who have had breast cancer. I emphasized the segments of this extensive text. It is from the European experience that the early understanding of the safety of estriol alone used topically in the vagina emerged. I will post later articles about estriol alone vaginal hormone replacement for menopause showing increased experience in women who do not have breast cancer.” Bill Chesnut, MD

Vaginal Estrogen Therapy for Patients with Breast Cancer

  1. MoegeleS. BuchholzS. SeitzC. Lattrich, and O. Ortmann

Introduction.  The advances in the diagnosis of and therapy for breast cancer in the past few years have led to a declining mortality of breast cancer 1. On account of the good prognosis for the disease, many patients suffer from long-term side effects that may be caused by operations, radiotherapy, chemotherapy, or endocrine therapy. Thus, improvement or, respectively, maintenance of quality of life is becoming increasingly important in the aftercare of breast cancer patients. The increasing wish for treatment of climacteric complaints is shown in Fig. 1.

Increasing wish for treatment of climacteric complaints.

About 75 % of climacteric patients experience menopausal complaints such as hot flushes, sleeping disorders, decline in libido and vaginal atrophy. The average age of onset of breast cancer is about 62 years, thus most patients are in the postmenopause at the first diagnosis of breast cancer. The majority of these patients suffer from hormone receptor-positive breast cancer and thus receive an adjuvant endocrine therapy with tamoxifen or aromatase inhibitors (AI). In many of the cases these therapeutic options lead to an increasing rate of estrogen deficiency symptoms 2. And just the increasing usage of AIs in postmenopausal breast cancer patients leads to an increase of vaginal atrophy with symptoms such as vaginal dryness, petechial bleeding, dyspareunia and recurrent cystitis 3. In a retrospective evaluation of the Swedish cancer register, a significant number of severe vaginal atrophies were found among users of AIs as compared with patients under tamoxifen therapy (33.3 vs. 5.95 %) 4. These results can also be reconstructed in older study evaluations 5, 6. After an appropriate check for contraindications and oncological safety, a switch from endocrine therapy to tamoxifen may be discussed with the respective patients 7.

The symptoms of vaginal atrophy have a severe detrimental effect on the quality of life of breast cancer patients and it is estimated that up to 20 % of all patients do actually terminate or consider terminating their adjuvant endocrine therapy for this reason 8. The most effective treatment for vaginal atrophy comprises the use of a topically applied estrogen therapy 9. However, the use of not only systemic but also topical hormone therapy (HT) is contraindicated for breast cancer patients 10, 11.

In the following paragraphs the current data situation on the use of hormone-containing, topically applied formulations by breast cancer patients is presented and possible alternatives are discussed.

Diagnosis of Vaginal Atrophy. When serum estradiol level decreases below 73 pmol/l postmenopausal patients can develop a clinically relevant vaginal atrophy. An exact knowledge of the symptoms of vaginal atrophy is necessary in order to make a rapid and targeted diagnosis. The diagnosis of vaginal atrophy is generally made in the course of a gynaecological examination. Here, attention should be paid first of all to dry vaginal mucous membranes and possible petechial haemorrhages or, respectively, bleeding on contact. Patients often report on accompanying dyspareunia, itching and burning sensations. Furthermore, breakage of collagenous reinforcement fibres in the vaginal epithelium can lead to a loss of vaginal membranous folds, the so-called rugae of the vagina.

An increase of the vaginal pH value to a basic value > 5 can be an indication for a vaginal infection caused by reduced colonisation of the vagina by lactobacilli. A summary of the clinical symptoms of vaginal atrophy is given inTable 1.

Table 1 Symptoms of a vaginal atrophy (adapted after 47).

Due to the close embryological relationship of the female urinary bladder and urethra with the vaginal system, they all have a high density of estrogen receptors. This can lead to recurrent cystitis and prolapse complaints due to a postmenopausal or therapy-induced decline of the serum estradiol level.

As supplement to clinical diagnostics, the vaginal maturation index (VMI) has proved its value as a standard score in the cytological diagnosis of vaginal atrophy. The VMI describes the relative ratio of parabasal and intermediate cells to superficial cells in the vaginal epithelium. A proportion of > 15 % superficial cells is defined as a physiological finding. In postmenopausal patients values of less than 5 % can be found.

Many patients are not aware of the relationship between postmenopausal estrogen deficiency and vaginal atrophy. Only few patients seek consultations with their gynaecologist about treatment options. Upon diagnosis of vaginal atrophy in the course of gynaecological examinations, the patients should be informed about the symptoms and their treatment options by their gynaecologist. The initiation of a local HT depends on the degree of distress of the individual patient.


Breast Cancer Risk due to HT. The usage of HT increases the risk of developing breast cancer. The increased risk becomes apparent after duration of use of 5 years or more. In the past few years the relationship between HT and breast cancer has been mostly investigated in observational trials. These have come to differing assessments of the risks of a purely estrogen therapy (ET) or, respectively, of a combination therapy with estrogens and progesterone (EPT). These studies showed that EPT increases the risk more than ET does. Furthermore, the relatively low risk increase due to ET is apparent only after a markedly longer period of use (> 7–10 years).

In this context, special mention must be made of the results of the Womenʼs Health Initiative (WHI) study. Altogether 16 608 women aged from 50 to 79 years participated in the trial. After 5.2 years the study was prematurely terminated since the combined HT had increased the risk of coronary heart diseases, thromboembolic events and breast cancer. For EPT use of 5 or more years duration, the absolute risk in the WHI trial amounted to 8 additional breast cancers per 10 000 women/year 12. Subsequent investigations of the WHI post intervention phase additionally revealed an increased mortality due to breast cancer. In the follow-up observation group of 12 788 patients there were 25 deaths due to breast cancer per year in comparison to 12 deaths in the control group treated with placebo 13. More recent evaluations of the WHI data show that use of EPT for less than 5 years can also lead to an increase of the breast cancer risk 14. The breast cancer risk under and after ET with an average duration of use of 5.9 years is lower 15. This effect is significant and differs from data collected in observational trials. Several further meta-analyses, cohort studies and randomised trials have demonstrated an increased risk of breast cancer after EPT

HT after Breast Cancer. The relative risk (RR) for a breast cancer recurrence due to the use of HT was examined in a systematic review by Col et al. 20. Altogether 11 trials with 669 breast cancer patients who had received HT were analysed. Merely 4 of the 11 trials included a control group and in these no significantly increased recurrence rate could be detected. The yearly recurrence rate amounted to 4.2 % after an observation period of 30 months. A recurrence of breast cancer was diagnosed in 17 patients (8 %) under HT in comparison to 66 patients (11 %) without HT (RR 0.64). Taken together, in a total of 11 analysed studies (7 uncontrolled trials) on 669 breast cancer patients with HT there was no significant increase in the recurrence of breast cancer with an RR of 0.82 20. The case numbers in these studies were, however, too small to enable an unambiguous conclusion to be drawn about the safety of HT in this patient collective.

The effects of systemic HT after breast cancer disease were examined in 2 independent, prospective randomised trials.

In the HABITS trial (Hormonal Replacement Therapy after Breast Cancer – Is it Safe?) 434 patients aged from 40 to 75 years were enrolled. The study had to be terminated in 2003 due to an increased risk of breast cancer recurrence with a hazard ratio (HR) of 3.3 (95 % confidence interval [CI]: 1.5–7.4) 21. Altogether in 26 of 219 patients in the HT group and in 8 of 215 patients in the control group there was a recurrence of the known breast cancer. In contrast to this, in the Stockholm study no significantly increased recurrence risk among 378 postmenopausal breast cancer patients could be detected (HR: 0.82; 95 % CI: 0.35–19) 22. Despite the higher proportion of lymph node-positive breast cancer patients in the HABITS trial, HT is contraindicated for patients after breast cancer.

On the other hand, the use of HT in patients with hormone receptor-negative breast cancer seems to be quite safe. In an unplanned subgroup analysis of the HABITS trial no increase in the recurrence rate could be detected 21. Also in the WHI trial no increase in the recurrence rate for hormone receptor-negative breast cancers could be detected 12. Even so, patients with hormone receptor-negative breast cancers should be treated analogously to those with hormone receptor-positive breast cancers on account of the inadequate data situation for an evaluation of the oncological safety 10.

Up to publication of the LIBERATE trial (Livial intervention following breast cancer: efficacy, recurrence and tolerability endpoints), tibolone, a synthetically produced steroid possessing estrogen, gestagen and androgen activities, was considered to be a potential low-risk therapeutic option for vasomotoric complaints in relation to HT. Although in the LIBERATE trial it could be shown that the use of tibolone (2.5 mg) led to a significant improvement in vasomotoric complaints and bone density, 237 of 1556 patients on the other hand suffered from a recurrence of the previously known breast cancer, in comparison to 165 cases of recurrence among 1542 patients in the placebo group (HR 1.40; 95 % CI: 1.14–1.70) 23. Thus, as a consequence of the consumption of tibolone the recurrence rate was increased by 40 % and the incidence of metastases by 38 %. These data correspond with the results of subgroup analyses of the One Million Women Study and the HABITS trial in which similar data were gathered. The use of tibolone thus cannot be recommended for patients with breast cancer.

Topical Oestrogen Therapy for Vaginal Atrophy. Topical ET is a widespread and common routine treatment option for patients with vaginal atrophy.

Several meta-analyses have shown that, independently of its application form, topical ET can improve the signs of vaginal atrophy and its symptoms 24, 25. The use of topical ET, however, also makes possible the administration of lower estrogen dosages in comparison to systemic HT. It has been shown that a low-dose topical ET has the same efficacy as a systemic administration 25. Thus, in cases with a sole indication for the treatment of vaginal atrophy, a topical vaginal ET should be preferred to a systemic therapy. This is also reflected in the current recommendations of the German S3 guidelines as well as in a position paper of the North American Menopause Society.

Estradiol-, estriol- and estrone-containing formulations are available in Germany for topical ET. With regard to systemic estradiol absorption, upon application of a vaginal tablet with 25 µg estradiol a merely minor systemic absorption at a still low serum estradiol level of < 14 pg/mL could be detected 27. On comparison of an estradiol liberating vaginal ring with estradiol-containing vaginal tablets also only a minimal increase of the serum estradiol level could be recorded. On comparison of the two forms of administration no significant differences can be found. In addition, it has been shown that no endometrial proliferation is to be expected on use of topical ET 28. An additional administration of gestagens cannot be recommended on the basis of the currently available data.

Estriol is a short-working estrogen with low potency that is irreversibly transformed into estradiol or estrone. The safety of estriol with regard to endometrial hyperplasia as well as its therapeutic efficacy for vaginal atrophy is well known 29, 30. In a prospective monocentric trial with 19 postmenopausal patients suffering from vaginal atrophy, the bioavailability of low-dose estriol (0.03 mg) was recently examined. The patients received a once daily vaginal application of the trial medication for 21 days. Blood samples taken on days 1, 2, 6, 11, 16 and 22 were able to show an increase in the serum estriol concentration up to 42.1 pg/mL only during the first hour after application. Already after 12 hours the estriol concentration in all patients had fallen under the detection level of 5 pg/mL 31.

The efficacy of a fractionated estriol administration was already demonstrated in 48 postmenopausal patients in 2005. Through the fractionated application of an estriol-containing vaginal cream there was a rapid and significant improvement of the atrophic vaginitis with a reduction of the pH value and an increase of the VMI. The fractionated administration consisted in the 1st week of 2 applications at intervals of 28 hours. In the weeks 2–4 the application interval amounted to 3 or, respectively, 4 days (application 2 times per week) 32. In the daily routine the use of topical estriol in the form of a once daily application for the first 3–4 treatment weeks followed by a maintenance therapy of 2–3 applications per week has become established.

Quality of Life. Due to the markedly better therapeutic options and a decreased mortality of breast cancer, an exact sexual case history is becoming more and more important in the aftercare period in order to detect therapy-related symptoms of vaginal atrophy and the thus accompanying decrease in quality of life. It is estimated that about 25 % of the afflicted patients do not inform their responsible physician about the symptoms of urogenital atrophy. In addition, about 70 % of the afflicted patients report that they had not been questioned about the symptoms of vaginal atrophy such as pruritus, burning sensation and dyspareunia 33. Estrogens play a decisive role in modulating the haemodynamic processes of the sexual reaction. An estrogen deficit leads to, beside a reduction in size of the labia majora and minora, a decline in the clitoral tumescence and inadequate vaginal lubrication. In up to 20 % of the afflicted women this leads to a deterioration of clitoral sensitivity and in up to 50 % of them to dyspareunia 34. Sexually active, postmenopausal breast cancer patients thus often complain about a severe impairment of their quality of life and their partnership relations.

Vaginal ET after Breast Cancer. Because of the possible systemic absorption and an eventually increased probability of recurrences the use of topical HT in breast cancer patients has been a subject of controversial discussion for some years.

The increased use of AIs in endocrine therapy for breast cancer has led to a markedly increased rate of vaginal atrophy and decline in quality of life. In contrast to endocrine therapy with tamoxifen, the production of estriol is inhibited by the use of AIs. In the serum of these patients you can find estriol levels that have dropped to as little as 3 pmol/L.

The use of topical HT in breast cancer patients has been investigated in only a few clinical trials.

In a small, prospective randomised study of 6 postmenopausal breast cancer patients under endocrine therapy with AL, Kendall et al. found a significant increase in the serum estradiol level from ≤ 5 pmol/L to 72 pmol/L upon use of low-dosed estradiol-containing vaginal tablets (25 µg) for 2 weeks 35. However, after use for 4 weeks the serum estradiol levels in most of the thus treated patients dropped again to levels of < 35 pmol/L. This result was confirmed by Wills et al. in a recently published study with a similar design. In this study 24 breast cancer patients with symptomatic vaginal atrophy under AI or, respectively, tamoxifen therapy received a topical HT with estradiol-containing vaginal tables (25 µg) or, respectively, an estradiol-containing vaginal ring. Significant increases in the serum estradiol levels were observed in both groups 36. These trial results clearly illustrate that a systemic absorption by the still highly vulnerable vaginal mucous membranes is possible just in the first weeks of use of topical HT. The thus resulting increase in the serum estrogen levels can lead to an increased risk of recurrence. In contrast, Dew et al. in a retrospective cohort study on the use of low-dose estradiol-containing vaginal tablets or an estriol cream with an average follow-up of 5.5 years did not find an increased risk of recurrence. In the study group comprising a collective of 1472 breast cancer patients, 69 (4.7 %) were mainly afflicted with a clinically symptomatic vaginal atrophy. In these patients vaginal ET in the form of an estriol cream (0.5 mg) or estradiol vaginal tablets (25 µg) were used. In the group of patients using vaginal ET a significant difference in the risk of recurrence compared with the control group could not be demonstrated 37.

With estriol a hormone-containing, short-acting topical therapy for vaginal atrophy is available which cannot be metabolised into more potent estrogens such as estradiol or estrone. The rapid alleviation of complaints due to estrogen deficiency by use of topical estriol therapy is well known 38. Just recently it was shown in 436 patients that the same efficacy and safety could be achieved with very low-dose estriol formulations (0.03 mg) 39. In a prospective, randomised study of 10 postmenopausal breast cancer patients under endocrine therapy with AI it was found that the daily use of 0.5 mg estriol for 2 weeks did not result in elevated serum levels of estriol or estradiol 40. The efficacy of a lower dosed estriol cream (0.25 mg) in comparison to estradiol-containing vaginal tablets and non-hormonal lubricants was examined in a small study with 18 breast cancer patients. An equally significant improvement of the clinical symptoms was achieved with the low-dose estriol therapy in comparison to estradiol therapy. The use of a non-hormonal preparation led merely to a short-term improvement of the symptoms. However, serum estrogen levels were not determined.

In some earlier studies on postmenopausal patients, however, increases of the serum estriol concentrations to values between 100 and 150 pg/mL were observed within 2 hours after use of 0.5 mg of estriol. An elevation of the serum estradiol level could not be detected 42. We recently presented the data from a bicentric phase I study on the efficacy and safety of an ultralow vaginal estriol administration (0.03 mg) in breast cancer patients with symptomatic vaginal atrophy under AI therapy. In all, 16 breast cancer patients were treated daily for 28 days with topical applications of estriol. This was followed by a maintenance therapy with 3 tablets per week for further 8 weeks. After the first application of estriol no elevations of the estrone or estradiol serum levels were detected. The serum estriol levels in 15 patients underwent a short-term elevation to a maximum value of 168 pg/mL. At the latest after 6 hours elevated estriol levels were no longer detectable in any of the patients. Over a period of 12 weeks 15 of the patients did not exhibit any changes of their serum estriol levels. In one of the patients after 4 weeks an increase to 14.4 pg/mL was measured. The estrone and estradiol values were not elevated at any time. The detailed results of this study will be published in the near future 43.

Thus, large, prospective randomised studies for a final concluding assessment of the safety vaginal ET in breast cancer patients is still lacking. With the currently available data not only the use of a systemic but also that of a topical HT in breast cancer patients is contraindicated. Even so, on the basis of the above-mentioned results from studies with ultralow dosed estriol, it can be assumed that this therapy is safe in spite of the lack of studies with the endpoint recurrence-free, or, respectively, total survival. However, it should only be used in cases with relevant impairments of quality of life due to vaginal atrophy and after appropriate informed consent discussions with the individual patient.

Androgens for Vaginal Atrophy. Beside the described estrogen receptors, vulva and vagina also possess androgen receptors. On the basis of recent data it can be assumed that estrogen receptors are important in the regulation of the number of androgen receptors in vaginal epithelium. The receptor density correlates well with the VMI and is lower in cases of vaginal atrophy 44.

However, only very few data are available on vaginal testosterone treatment after breast cancer. In a small phase I/II trial, 21 postmenopausal breast cancer patients under AI therapy with symptomatic vaginal atrophy were treated with a topical testosterone ointment in various doses for 28 days. A significant improvement of the atrophy complaints in the absence of elevated estradiol or estrone serum levels was observed 45. Further results of prospective randomised trials on larger patient numbers are still lacking.

Alternative Non-Hormonal Treatment Options. Alternative treatment forms such as glide agents, lubricants, humectants or also topical anaesthetics are also available. Bygdeman and Swahn demonstrated significant improvements in vaginal dryness, pruritus and dyspareunia through the use of a non-hormonal vaginal ointment 46. However, any improvement of symptoms achieved by these alternative methods is generally only of short duration. These treatment options can only be recommended for the short-term relief of symptoms but are not suitable to eliminate vaginal atrophy.

Conclusions. Topical HT is the means of choice for the treatment of clinically symptomatic vaginal atrophy. An elevation of the serum estrogen levels cannot be excluded with certainty on the basis of the currently available data. Thus, an unambiguous assessment of topical HT after breast cancer has been diagnosed cannot be made at present. As a result, the use of topical HT after the diagnosis of breast cancer has been made should only be initiated in cases where the patient experiences a high degree of distress with corresponding impairments in quality of life and after comprehensive consultations with the patient about the current state of knowledge and the fact that the possibility of an increased risk of recurrence cannot be excluded. cccccc



The common symptoms of hormone deprivation following menopause.

“Menopause includes the loss of several hormones as their production ceases. This hormone deprivation results in a variety of symptoms in most menopausal women. http://menopausehealthmatters.com/symptoms-of-menopause/ has a complete description of the most common 34 symptoms. This source is in December 2015, and I recommend it for further information.” Bill Chesnut, MD

  • Common Symptoms
  • Hot Flashes. Hot flashes, also known as hot flushes, are a sudden, transient sensation of warmth or heat that spreads over the body, creating a flushing, or redness, that is particularly noticeable on the face and upper body.
  • Night Sweats. Night sweats are classified as severe hot flashes that occur during sleep accompanied by intense bouts of sweating. Also known as “sleep hyperhidrosis”, night sweats aren’t actually a sleep disorder, but a common perspiration disorder that occurs during sleep in menopausal women.
  • Irregular Periods
  • Loss of Libido. Everyone experiences peaks and valleys in sexual desire, an ebb and flow in libido that could be caused by any of a variety of factors. However, for women going through menopause, this sudden drop in desire for sexual activity or intimacy can be troubling. In menopausal women, the main cause of low sex drive is hormonal imbalance, predominantly androgen deficiency.
  • Vaginal Dryness. Vaginal dryness occurs when the usually moist and soft feeling of the lining of the vagina disappears, bringing about symptoms such as itchiness and irritation. When estrogen levels drop during perimenopause, the vaginal tissue becomes drier, thinner, and less elastic. Lack of lubrication leads to sex becoming uncomfortable, and the vagina is frequently itchy, easily irritated, and more prone to infections.
  • Mood Swings. Menopausal mood swings are surprisingly common, but can be hard to cope with. A woman experiencing mood swings may feel like she is on a rollercoaster of emotions: one minute she’s up, the next minute she’s down. Mood swings can be sudden and intense, although the experience of them may differ from woman to woman.
  • Changes
  • Fatigue. Fatigue, one of the most common menopause symptoms, is defined as an ongoing and persistent feeling of weakness, tiredness, and lowered energy levels, rather than just sleepiness or drowsiness. Other characteristics of fatigue may include apathy, irritability, and decreased attention span. Crashing fatigue is a phenomenon which comes on suddenly, leaving a woman devoid of energy and unable to continue her activity.
  • Hair Loss. Hair loss, one of the most physically noticeable menopause symptoms, is caused by estrogen deficiency, because hair follicles need estrogen to sustain hair growth.
  • Sleep Disorders. Waking many times during the night, tossing and turning, and insomnia, are all sleep disorders connected with menopause. Women going through menopause may find that their sleep is less restful and that getting to sleep becomes increasingly difficult.
  • Difficult Concentrating. In the lead-up to menopause, many women are concerned to find they have trouble remembering things, experience mental blocks, or have difficulty concentrating. This can be confusing or worrying for women, and can have a big impact on all aspects of daily life. The main reason why these symptoms occur during menopause is hormonal imbalance, specifically estrogen deficiency.
  1. Memory Lapses. Women approaching menopause often complain of memory loss, memory lapses, and an inability to concentrate. Misplaced car keys, skipped appointments, forgotten birthdays, and missed trains of thought might seem like trivial occurrences, but these can be extremely distressing for women who have never missed a beat before. However, thesememory lapsesare a normal symptom of menopause, associated with low levels of estrogen and with high stress levels.
  • Dizziness. Dizziness is a transient spinning sensation, which may be accompanied by a feeling of lightheadedness or unsteadiness, as well as the inability to maintain balance upon standing or while walking.
  • Weight Gain. Weight gain, specifically a thickening around the waist, is another sign of changing hormones levels during menopause. While some sources claim that menopause has nothing to do with weight gain, hormonal changes during menopause actually influence weight gain and redistribution of fat.
  • Incontinence. Incontinence in menopausal women can be divided into three types. Stress incontinence is the accidental release of urine while laughing, coughing, sneezing, or due to over-exertion. This usually happens when the internal muscles fail to work effectively, because of age, surgery, or childbirth. With urge incontinence, the bladder develops a “mind of its own,” contracting and emptying whenever full despite an individual’s conscious efforts to resist. Overflow incontinence is the absence of the sensation of a full bladder, whereby accidental urination occurs because the individual doesn’t realize the bladder is full.
  • Bloating. Bloating occurs in most women throughout their lives, due to digestive issues or as a part of PMS. This symptom is characterized by a swollen belly, a feeling of tightness, and discomfort or pain in the stomach area.
  • Allergies. Hormones and the immune system are inextricably linked, so hormonal changes during menopause can lead to an increase in allergies among menopausal women.
  • Brittle Nails. Nail appearance can tell a lot about a person’s general health and habits. There are a variety of nail changes that occur during menopause that could indicate an underlying problem, but the most common is brittle nails, or nails that are softer, or that crack, split, or break horizontally across the top of the nail.
    • Changes in Odor. Changes in body odor can make the menopausal women experiencing them very self-conscious. Menopausal hormonal changes cause an increase in sweat production, in response to physical menopause symptoms such as hot flashes and night sweats, or psychological symptoms such as anxiety and panic disorder.
    • Irregular Heartbeat. Irregular heartbeat is one of the more concerning menopause symptoms. Bouts of pounding, rapid heartbeat scare many women because of their sudden onset and the difficulty in calming them. One of the causes of these symptoms during menopause is hormonal imbalance.
    • Depression. Feelings of sadness can be normal, appropriate, and even necessary during life’s setbacks or losses. Feeling blue or unhappy for short periods of time without reason or warning is also normal and ordinary. But if such feelings persist or impair daily life, it could signal a depressive disorder.
    • Anxiety. Anxiety is a vague or intense feeling caused by physical or psychological conditions, typified by feelings of agitation and loss of emotional control.
    • Irritability. Irritability is a pervading “bad mood” characterized by feelings of stress, reduced patience and tolerance, and lashing out in anger or frustration over matters that may seem trivial to others. Irritability during menopause is most often caused by hormonal changes, whereby low levels of circulating estrogen have an adverse effect on the neurotransmitters in the brain that are responsible for regulating mood.
    • Panic Disorder. Irritability is a pervading “bad mood” characterized by feelings of stress, reduced patience and tolerance, and lashing out in anger or frustration over matters that may seem trivial to others. Irritability during menopause is most often caused by hormonal changes, whereby low levels of circulating estrogen have an adverse effect on the neurotransmitters in the brain that are responsible for regulating mood.
    • Pains
    • Breast Pain. Typically, breast pain is characterized as a generalized discomfort or pain associated with touching or applying pressure to the breasts. Breast pain, soreness, or breast tenderness in one or both breasts is symptomatic of hormonal changes.
    • Headaches. Headaches can be caused by a variety of factors such as muscle tension, drinking too much alcohol, or as a side effect of common illnesses such as the flu. However, headaches are also linked with the effects of hormonal imbalance.
    • Joint Pain. Joint pain is one of the most common symptoms of menopause. It is thought that more than half of all postmenopausal women experience varying degrees of joint pain. Joint pain is an unexplained soreness in muscles and joints, which is unrelated to trauma or exercise, but may be related to the effects of fluctuating hormone levels on the immune system. Estrogen helps prevent inflammation in the joints, so low levels of estrogen during menopause can lead to increased instances of inflammation, and therefore increased joint pain.
    • Burning Tongue. Burning mouth syndrome is a complex, vexing condition in which a burning pain occurs on the tongue or lips, or throughout the whole mouth, without visible signs of irritation, but accompanied with other symptoms such as bad breath or a bad taste in the mouth.
    • Electric Shocks. This symptom presents a peculiar “electric” sensation, like the feeling of a rubber band snapping in the layer of tissue between skin and muscle, or, when it appears as a precursor to a hot flash, it is often felt across the head. Electric shocks usually only occur for a brief moment, but it can still be quite an unpleasant sensation. The cause of electric shock sensation in menopause is thought to be related to the effect of fluctuating estrogen levels on the cardiovascular and nervous systems.
    • Digestive Problems. Digestive problems are defined as changes in gastrointestinal function, with symptoms such as excessive gas production, gastrointestinal cramping, and nausea.
    • Gum Problems. Gum problems are common among menopausal women; although these could be due to poor dental hygiene, they are also caused by menopausal hormonal changes, mainly estrogen deficiency.
    • Muscle Tension. Muscle tension is when muscles, especially the ones in the neck, shoulders, and back, feel tight or strained, or when there is a general increase in aches, pains, soreness, and stiffness throughout the body. Muscle
    • Itchy Skin. When estrogen levels drop during perimenopause, collagen production also slows down. Collagen is responsible for keeping skin toned, fresh-looking, and resilient. So when the body starts running low on collagen, it shows in the skin, as the skin gets thinner, drier, flakier, and less youthful-looking.
    • Tingling Extremities. Tingling extremities is where menopausal women experience the feeling of “creepy-crawlies” walking all over their skin, a burning sensation like an insect sting, or super-sensitivity in their hands, arms, legs, and feet.
    • Others
    • Osteoporosis. Osteoporosis is a degenerative bone disorder, characterized by thinning and weakening of the bone and a general decrease in bone mass and density. Menopause negatively affects bone growth. Normally, bones go through a process whereby old bone is replaced with new bone cells, but the body’s ability to handle this process changes with age.


The long term health risks of menopause.

“CLEVELAND CLINIC Wellness newsletter about the LONG TERM RISKS OF MENOPAUSE.” Bill Chesnut,MD

Osteoporosis.  Osteoporosis, a “brittle-bone” disease, occurs when the inside of bones become less dense, making them more fragile and likely to fracture. Estrogen plays an important role in preserving bone mass. Estrogen signals cells in the bones to stop breaking down.

Women lose an average of 25 percent of their bone mass from the time of menopause to age 60, due in large part to the loss of estrogen. Over time, this loss of bone can lead to bone fractures. There are many options, including estrogen therapy, to treat brittle bones.

Coronary artery disease.  Coronary artery disease is the narrowing or blockage of arteries that surround the heart muscle. It results when fatty plaque builds up in the artery walls (known as atherosclerosis). This buildup is associated with high levels of cholesterol in the blood. After menopause, a woman’s risk for coronary artery disease increases.

A healthy diet, not smoking, and getting regular exercise are your best options to prevent heart disease. Treating elevated blood pressure and diabetes as well as maintaining cholesterol levels with “statin” medications and aspirin therapy for selected at-risk persons are the standards of care. The benefits and risks of hormone therapy vary depending on a woman’s age and her individual history. In general, younger women in their 50s tend to get more benefits from hormone therapy as compared to postmenopausal women in their 60s. Women who undergo premature menopause are often treated with hormone therapy until age 50 to avoid the increased risk that comes from the extra years of estrogen loss.

What are the symptoms of menopause?

You may be transitioning into menopause if you begin experiencing some or all of the following symptoms:

  • Hot flashes (a sudden feeling of warmth that spreads over the upper body)
  • Night sweats and/or cold flashes
  • Vaginal dryness; discomfort during sex
  • Urinary urgency (a pressing need to urinate more frequently)
  • Difficulty sleeping (insomnia)
  • Emotional changes (irritability, mood swings, mild depression)
  • Dry skin, eyes or mouth

Women who are still in the menopause transition (perimenopause) may experience the above as well as:

  • Breast tenderness
  • Worsening of premenstrual syndrome (PMS)
  • Irregular periods or skipping periods
  • Periods that are heavier or lighter than usual

Some women might also experience:

  • Racing heart
  • Headaches
  • Joint and muscle aches and pains
  • Changes in libido (sex drive)
  • Difficulty concentrating, memory lapses (often temporary)
  • Weight gain
  • Hair loss or thinning


A new remedy for hot flashes

“_ A new hot flash aid from the Cleveland Clinic.” Bill Chesnut, MD.

Menopause Hot flashes. ” Chill out! A new remedy for hot flashes is right under your nose.”

Feeling like a human inferno these days? For a hot-flash remedy that’s supremely safe, readily accessible, and free, take a deep breath. And another one. Practicing what’s called paced breathing — slow, deliberate, deep breathing — for 15 minutes twice a day may reduce both the intensity and frequency of hot flashes. To practice paced breathing, set a timer for 15 minutes. Lie on your back and make yourself comfortable. Slowly start to relax the muscles in your legs, hips, belly, chest, arms and neck. Start to bring attention to your breath, feeling yourself relax from the inside out. As you relax, inhale and allow your belly to rise; then slowly exhale and allow your belly to fall. Notice the pace of your breath slowing as you relax. Continue until the timer rings. Other natural strategies that may squelch the flames of hot flashes include: acupuncture, caffeine reduction, and mindfulness meditation.