I’ve written several newsletters about potential side effects of bisphosphonates medications used to treat osteopenia and osteoporosis (Fosomax, Boniva, and Actonel….just to remind you of some brand names). This time I want to share some potentially good news about this bone density enhancing class of medications. And I am especially happy to share the report because it comes from a study conducted in Israel. (As many of you know, I have taught and worked there and indeed will be in Tel Aviv when this article appears.)

The Israeli researchers conducted a study entitled The Molecular Epidemiology of Colorectal Cancer. It was supported by the National Cancer Institute and published in the February issue of the American Journal of Clinical Oncology. (I hope I haven’t lost most of my readers by this point…just bear with me. So many of you or your relatives take bisphosphonates so that your skeletons can successfully bear your weight without an osteoporetic fracture)

They found that postmenopausal women who had taken an oral bisphosphonates longer than one year had a 59% reduced risk of colorectal cancer. Like the Scandinavian countries, pharmaceutical records in Israel are extremely well documented. (All the citizens have health insurance and most of their prescription medications are covered…I wish I could say the same for us!) The researchers used computerized pharmacy records and identified almost 2000 women who had colorectal cancer.

They found that in these women, compared to controls who were matched for age, weight, and religion, the use of bisphosphonates longer than 1 year, but not less than 1 year, reduced the risk of colorectal cancer by half, even when they adjusted for other factors that could perhaps lower colorectal cancer risk. (Here is where I list these factors to remind you that they too count in our “war on colorectal cancer”…as does screening. They include vegetable consumption, physical activity, and weight control, use of low-dose aspirin, statins, vitamin D and postmenopausal hormones.)

Ongoing research indicates that oral bisphosphonates may exert a cancer-protective effect (including breast and prostate cancer.)  Clearly this study is not large enough to persuade the FDA to approve any official indication that this class of medication will diminish colorectal cancer. So I’ll end with the phrase that is used in the conclusions of most medical articles: “Further studies are needed”. I felt , however, that a bit of good news about the medications that can lower the huge toll of osteoporotic fractures in women (and men) is welcome.

Let’s discuss several hormonal scenarios: (1) You’ve been on hormones for several years and now think you may try to stop. (2) You have just started having hot flashes and you haven’t quite made up your mind as to whether you will want to take hormones during the menopausal transition. (3) You are not yet menopausal but worry about what you will experience when it inevitably develops.

The defining question for most women (at least in regards to quality of daily life) is: “How long will I experience hot flashes?” One would think that since menopause has been around before and since the written word that we could estimate the average duration of this pesky and sweaty symptom. (Well maybe not, 120 years ago the average life expectancy for women was 47 and most did not outlive their ovaries.)

Hot flashes generally begin when estrogen levels plummet in menopausal or during the premenopausal transitions. The ovaries run out of follicles that are capable of responding to pituitary messages to develop and hence produce estrogen. In the absence of said estrogen, the pituitary works harder (it’s trying to get those damn follicles to work), hence it puts out more and more FSH (follicle stimulating hormone). The pituitary gets its signals from the part of the brain called the hypothalamus which produces GnRH or gonadotropic releasing hormone, the master hormone that instigates FSH production. In the absence of “usual” estrogen production, GnRH and FSH levels soar and there is a veritable hypothalamic storm. This then causes a state of confusion in the central thermostat in the brain which begins to “think” that the body’s core temperature is too hot. In order to correct this, the hypothalamus sends out directives to dilate the small blood vessels in the skin (the flush) and causes water to evaporate from the skin’s surface (as sweat, facial and body perspiration) in order to cool the body down. All of this may lower the core body temperature by as much as half a degree. Often subsequent to a hot flash, a woman may shiver as small muscles contract to re-elevate the core body temperature.

Hot flashes are associated with poor sleep, decreased quality of life, may worsen depressive symptoms and even signal the onset of a major depressive disorder. The flashes may also be a clinical sign for underlying cardio vascular disease as well as a risk factor for poor bone heath. Although “natural”, hot flashes are not great to experience and ultimately may correlate with poor overall health.
What we do know is that the peak incidence of hot flashes occurs approximately 1 year after menopause in 80% of women in the US, but (and this is what is so surprising) the overall duration of hot flushes is unclear.

(Sorry that this intro is so long, but now I’ll get to a recent attempt to answer the “how long will this last” question…) A study published in the May issue of Obstetrics and Gynecology tried to assess the duration of menopausal hot flashes and associated risk factors.

The “flushing and flashing” women that were followed were part of The Penn (Pennsylvania) Ovarian Aging Study of 435 women (half white and half African American) that were monitored for 13 years. Hot flushes (they use this term instead of “flash”) were evaluated at 9 -month and 12-month intervals though in-person interviews. At enrollment, the participants’ ages were 35 to 47 (mean age 42.2) and 91% were still premenopausal. The most common age at onset of moderate-to-severe hot flushes was 45-49(35%); 30% were between 40-44years, 21% were older than age 50and 14% were younger than 40 years. Age at the onset was inversely associated with duration of hot flashes. In other words, the younger the women were, the longer they suffered. This totaled 11.57 years for those whose onset of hot flushes occurred before the age of 40; and decreased with onset at older ages: 11.25 years for those whose flushes started at 40 to 44 years; 8.1 years with onset ages 45-59 and 3.8 years duration with onset at 50 years of age or older.

Other independent predictors of the duration of the flushes were race (African Americans had a longer duration) and body mass (thin women also had a longer duration.) It’s thought that obese women convert hormones produced by their adrenals to estrogen-like hormones in their abundant fat and hence have production of estrogen that “saves them” from many years of flushes. It’s interesting that in this study smoking, alcohol use and number of children the women bore had no association with the duration of their hot flushes. (Although in general, the data has shown that smokers enter the menopause at an earlier age than non smokers, simply because the toxins in cigarettes kill off the follicles in the ovaries….my comment in this article against smoking!).

In the discussion portion of the article, the author’s state that “the median duration of moderate-to-severe hot flushes was 10.2 years, well beyond the duration considered in clinical guidelines. When women who reported mild hot flushes were included, the median duration increased to 11.6 years.”

Before all you women who begin to have menopausal symptoms in your early 50′s freak that these will continue unabated into your 60′s, I have to point out that the majority of the women in this study were younger than 50 when they reported moderate-to-sever hot flushes. (Most were 45 to 49.) Hot flush duration was approximately 8 years for this group compared to less than 4 years when onset occurred at ages 50 years or older.

Bottom line: The earlier you begin to have hot flashes (even if you are still getting your period) the longer you can expect them to continue during menopause. Now that you have this information, discuss therapies with your doctor.

In addition to my usual Friday website article, I felt it was necessary to address the recent JAMA article on estrogen-only therapy (in women who have had a hysterectomy.) The women were followed and results have just been published years after the Women’s Health Initiative (WHI) was stopped. The American Menopause Society (NAMS) said it best and hence I am simply forwarding the message that appeared on their website in response to this article. Once more, their conclusions reinforce the fact that estrogen (without a progestin) did not increase, but actually decreased breast cancer, in follow-up of over 10 years. Premarin (CEE) therapy was found to be beneficial vis a vis heart disease, colorectal cancer and overall, all-cause mortality for women under the age of 70 but appeared to lose its benefits and indeed worsen mortality rates after the age of 70. So here is the data and the NAMS conclusion:

Brief summary of the article: The final results of the Women’s Health Initiative Estrogen-Alone Trial, reflecting a median of 6 years of treatment and an average of 10.7 years of follow-up, are published in this article. The long-term follow-up and post-stopping findings for this trial have not been previously reported. The authors examined health outcomes in 10,739 women with prior hysterectomy, comparing those randomized to receive CEE treatment versus placebo. The median duration of adherence (taking >80% of study pills) to CEE was 3.5 years.

The main outcomes were CHD and invasive breast cancer. In addition, a global index of risks and benefits included CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, hip fracture, and death.

Results: For the overall study population, there was a significantly reduced risk of invasive breast cancer among women randomized to CEE versus placebo over the 10.7 years of follow-up (23% reduction; HR 0.77; 95% CI, 0.62-0.95). Risk reductions were similar in the treatment and post-stopping periods. In the overall study population, there was no significant effect of CEE on CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. However, younger women (ages 50-59 at enrollment) tended to have much more favorable outcomes on CEE than the older women for CHD, heart attack, colorectal cancer, all-cause mortality, and the global index. For heart disease endpoints, risks were 40% to 50% lower with CEE than placebo in women ages 50 to 59 but were higher with CEE than placebo in women ages 70 to 79. For example, for every 10,000 women per year taking CEE, there were 12 fewer heart attacks, 13 fewer deaths, and 18 fewer adverse events for women ages 50 to 59. In contrast, for every 10,000 women per year ages 70 to 79, there were 16 extra heart attacks, 19 extra deaths, and 48 extra adverse events for women taking CEE (P values for interaction by age were statistically significant).

Conclusions: In this randomized trial, conjugated equine estrogens (CEE) use was associated with a decreased risk of invasive breast cancer and much more favorable results for coronary heart disease (CHD), all-cause mortality, and several other outcomes in younger than in older women. Overall, the observed pattern provides more support for the “timing hypothesis.” The findings highlight the differences between estrogen alone and estrogen plus progestin in terms of breast cancer risk and other chronic disease outcomes, as well as important differences by age group. Whether the reduction in breast cancer risk with CEE alone will apply to all women at menopause and to estradiol or other formulations of estrogen, and whether it will persist with longer-term estrogen use, remains unknown.

Once upon a time most of us moved here, to LA, from other states or countries. And we love it!  As veteran Los Angelinos we live, work and of course, look at others in this, our youth and media oriented city. The inevitable follows: we would like to look like a celebrity worthy of an appearance on Oprah or at least appear younger than our chronologic age. So when we see ads politely inquiring whether we are developing a bulge above our jeans, flushing, flashing (from heat, not exhibitionism), sleeping poorly, loosing our libido or worse… wrinkling; we go on the alert. Who can resist that spiel? : Step right up and spit here; we’ll see what you’re missing and order you a very special, made- just- for- you therapy. Rub this cream on, swallow these capsules, put these drops under your tongue and don’t worry, these “bioidentical” hormones are chockfull of health, not like the ones made by those big, bad pharmaceutical companies.

Many of my tenured (note I refrain form using the adjective “old”) and new patients want to know if they should start these “bioidentical” hormones or switch to them.  To quote Shakespeare, who was hormonally clueless but recognized some distressing female symptoms:  Here’s the rub.

“Bioidentical” is a marketing term. It’s as ingenious as the word natural when it comes to selling a product; both appeal to consumers’ aversion to artificial ingredients. But remember, hemlock is natural.

When the term “bioidentical” is used by compounding pharmacies and celebrities who are often selling their products or touting their own books, it refers to formulations of various types of estrogens, progesterone, adrenal hormones, and androgens (male hormones) compounded within creams, gels, lotions, capsules, drops, capsules, and even suppositories.  The compounded estrogens are often a combination of weak forms of estrogen (estrone or estriol) as well as the stronger  estradiol. In order to get significant relief of menopausal symptoms, large doses of the estriol or estrone   have to be used and there is no evidence that this is safer than the lower dose of estradiol which, by the way, was produced by our ovaries and accepted by nearly every cell in our bodies during our reproductive years. Estradiol is the estrogen contained in many of the FDA approved hormone therapy medications, and/or the metabolite (the end result after processing in the body) of these medications.  Nearly all plant derived estrogen therapy, both individually compounded formulations and pharmaceutical products come from the same soy and yam precursors. They all undergo chemical conversion to become hormones. ( The concept of plant gathering followed by stomping created a great “I Love Lucy” sketch and will work for grape juice and ultimately wine, but will not result in a biologically active hormone product, no matter how skillful the stomping and crushing.) Compounding pharmacies may claim that the combination of their estrogens is either safer or more natural than any of the products that are commercially prepared by pharmaceutical companies. No clinical studies published in reputable peer review journals have shown this to be true. As for the claim that estriol may reduce the risk of breast cancer; this is pure speculation based on old studies that were usually carried out on animals. The FDA has unequivocally stated that it is not aware of any credible scientific evidence to support claims made regarding the safety and effectiveness of compounded “bioidentical” hormone replacement drugs. They have taken action against seven pharmacy operations that claim their compounded “bioidentical drugs” which contain hormones such as estrogen, progesterone and estriol are superior to FDA-approved menopausal hormone therapy medications. The American College of Obstetricians and Gynecologists (my professional entity) has the same concerns stating that “most compounded products have not undergone rigorous clinical tasting for safety or efficacy and issues regarding purity, potency and quality”.

Doctors who prescribe these “bioidentical” hormones often use salivary (spit) testing to tailor the amount of hormones they prescribe. But salivary hormone levels vary tremendously throughout the day and differ from woman to woman. Moreover we don’t have studies that demonstrate a correlation between the levels of spit hormones and a woman’s clinical state or her response to hormone preparations. The major mavens on menopause (we have a society for everything), The North American Menopause Society, does not recommend saliva testing to determine hormone levels, nor do they recommend custom compounded products over “well tested, government approved products for the majority of women”. All these institutions are concerned that patients do not see the black box warnings that are prominently displayed with FDA approved medications…the ones that state that hormones should not be used if you have had certain conditions that include estrogen related cancers and blood clots and the concerns about risks for long term use.

Finally who pays? Sometimes insurance companies do, but often the patient is stuck with a bill that is higher than the one she would pay (or co-pay) for commercially prepared hormones. Moreover if the practitioner who prescribes “bioidentical” hormones also sells them from her or his office, there is a potential conflict of interest.

Some hormones including testosterone and DHEA (used for low libido or specific deficiency disorders) may not be available in pharmaceutical products and will have to be compounded. As a matter of full disclosure, I do prescribe compounded hormones when the latter are needed or when a patient becomes allergic to standard therapy. But I advise all my patients that there are no free hormones, no matter how they are made. There is an indication and contraindication to every medication and it’s imperative that your physician use appropriate, up-to-date studies in order to inform you of both.

Unfortunately, no hormone will provide you with that lost fountain of youth. But when prescribed for significant symptoms in appropriate doses, hormone therapy will help you feel better. Exercise, proper nutrition, weight control, hair color, make-up, and the right lighting are the only proven (and risk free) ways to help you feel and look your best.

A quick reminder (or as I like to put it, a 101 course on menstrual cycles):

Two ovarian hormones are responsible for your menstrual cycles; estrogen and progesterone. Each has some amazing effects on your tissues and may instigate  good days and bad days. Estrogen  begins to be synthesized from cholesterol  within the ovary on day one of your cycle (when your period starts). It’s production in the primitive eggs your born with (called follicles) is “commanded”  by the pituitary release of FSH (follicular stimulating hormone), which in turn is produced in response to the low levels of estrogen that occur just before the onset of your period. Levels of estrogen begin to exponentially rise about a week before ovulation and peak just a day before. This estrogen peak then sensitizes the pituitary and it responds with a surge of LH (luteinizing hormone). LH then causes the follicle to release an egg (ovulation). The “shell” of the follicle now becomes a corpus luteum which now concentrates on producing increasing amounts of progesterone.  Circulating progesterone can rise 10 fold during the week following ovulation. Estrogen production also rises about 6 or 7 days after ovulation. Both these hormones cause the glands in the lining of the uterus to become thick and lush so, if an embryo were to be deposited, it could implant, be nourished and grow. If there is no pregnancy to keep the corpus luteum going it succumbs and there is a decline (so sad) of both estrogen and progesterone. These fallen levels can no longer support the lining of the uterus….it sloughs and hence bleeding occurs. The now low level of estrogen stimulates the pituitary to begin to produce FSH and the entire process begins once more. (Just think of it as waves of rising and falling hormones each month.) Androgens (male hormones) are also produced in the ovaries.

The combination birth control pill basically supplies amounts of synthetic estrogen and progestin which shuts off the pituitary signals to the ovary and hence cyclical hormone production (and ovulation) cease. After menopause, when the follicles in the ovary are “used up” the levels of both estrogen and progesterone will drastically fall.  In an abortive effort to get the ovary to produce these hormones, FSH levels rise and continue to remain high for the rest of our postmenopausal lives.

How do the rise and fall of these hormones effect our skin:

• The skin is the largest organ we “own”….There are hormone receptors in the skin and the blood vessels that supply it. Most of what we know regarding to the effects of estrogen on the skin come form studies of what happens to the skin in the absence of estrogen (during menopause).

Here is the estrogen good stuff: It increases skin thickness, decreases collagen breakdown, increases collagen production, increases water binding capacity, increases the ability of blood vessels to dilate, increases elasticity and improves wound healing. This hormone helps prevent sebum (lipid) production, which feeds bacteria and increases the development of pimples. Estrogen also effects fat accumulation under the skin (subcutaneous). Here’s an interesting stat: The thickness of subcutaneous fat has been measured during the menstrual cycle, using ultrasound and MRI. The maximum thickness of subcutaneous fat over the thighs and abdomen has been found to increase during the menstrual cycle (as much as 7.3% in the abdominal region and 4.1% in the thighs). This certainly appears to validate your frequently voiced concerns that you are “get fatter” during your period. Whether this is due to an increase in water retention or changes in the fat cells is not clear.
There is also estrogen bad stuff that can occur in the skin. It increases pigmentation (this is especially evident when combined with sun exposure and use of the estrogen containing birth control pills in sensitive women who then develop pigmentation on the cheeks (chloasma). It also has been associated with decreases cellular-immune response.
Here is what has been noted during the luteal (progesterone) phase of the cycle: There is more sebum production and an increase in skin microbial count….these 2 factors can make you more prone to acne a week before and during your period. The skin is also more sensitive to UVB rays between days 20 and 28 which mean an increase in sun sensitivity.
Effects on the Immune system:   This is complicated….estrogens suppress immune response in the cells as well as what we call natural killer activity. (There is a war going on between our bodies and the antigens to which we are exposed. )  Estrogen also increases certain immune proteins in the blood. Because of this increase in antibodies, estrogen may be the significant factor in our high ratio compared to men (20:1) of developing the autoimmune disorder systemic lupus erythematosis (SLE).  And if you remember that T cells help us fight infection….well progesterone seems to suppress their formation. (Note T cell numbers remain depressed throughout pregnancy when there is a huge amount of progesterone produced by the placenta….a possible reason for infection severity in pregnant women.)

Effects on Vaginal Discharge: Obviously in the beginning of the cycle there is menstrual blood flow. The average amount is 50 to 100 mL and lasts for 4 to 6 days. As estrogen levels rise the cervix produces more and more mucous and the discharge becomes clear and slippery …sort of like uncooked egg white. (Women as well as their doctors have been checking for this type of mucous to predict fertile days for decades….I even wrote a paper about it in medical school.) As progesterone levels rise after ovulation the mucous becomes stickier. There is a greater glycogen (a form of sugar) content and some women complain of an increase in yeast infections. On the other hand growth of bacteria that don’t like oxygen (bacterial vaginosis) is more likely to become worse during the first 2 week of the cycle.
Effects on overall health:  Disorders and distress seem to increase during the luteal phase of our cycles. The list is long: asthma, acne, epilepsy, migraines, myasthenia gravis (severe muscle weakness), certain tachycardias (fast heart beat), sleeping disorders, Reynaud syndrome (where hands and feet become blue from diminished circulation), schizophrenia, glaucoma, insulin resistance and viral diseases. Skin disorders that worsen include acne, rosacea, skin lupus, psoriasis, eczema, vulvar itching, lichen planus and uticaria.

When it comes to estrogen surges and cancer there seems to be an influence on melanoma, certain blood vessel cancers of the skin and of greatest impotence to so many of us, breast cancer. This is a subject for multiple entries and I still wouldn’t be able to give all the final conclusions….But estrogen does stimulate cell divisions in the breast. Many therapies for breast cancer are geared to stopping this estrogen stimulation….these include removal of the ovaries before menopause, inhibition of estrogen production with compounds termed LH agonists  and aromatase inhibitors as well as estrogen receptor blockers such as tamoxifen. But pregnancy with its high production of estrogen, especially in younger women is protective! And I have to add this….estrogen and progestin (now termed hormone therapy or HT) may not increase breast cancer for the first few years of use, moreover estrogen therapy given alone (in postmenopausal women who have had a hysterectomy) seems to have little impact on breast cancer risk.

This started out as a simple menstrual cycle primer….sorry that it (and the complexity if our hormonal responses) became more than that. I guess this is the reason that some of us intensely study the effects of female hormones during and after our reproductive years.