Ronald Barentsen, MD, PhD

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During a gynecologic consultation my patient, Mrs. Andersen age 48 years was distraught and asked me for advice. She was worried about her mother, but also about herself. She was very concerned and proceeded to explain in detail the current situation.

She believes her mother is probably suffering from osteoporosis

. Mother had experienced a forearm fracture more than 10 years ago, at the age of 63, and recently she suffered a hip fracture. She had been operated on for the fracture and was recovering very well. Her mother’s physician had told her that at her age (75), there is no way to prevent more fractures other than take measures to diminish the risk of falling. My patient, Mrs. Andersen has heard from her friends that osteoporosis has strong genetic influences and she is also worried that she will have fractures in the future too. Her question is, "What can I do to prevent what happened to Mother from happening to me?"

Questions like this are not uncommon in daily practice. With Ms. Andersen a generally accepted risk factor was involved (the genetic factor), but sometimes the same question arises just because a woman is concerned about her health. For a proper answer, you need more information about her fracture risk, so an inventory of risk factors is the first step.

Mrs. Andersen. is a Caucasian woman and her mother has had multiple fractures. She has a dietary intake of calcium with 2 portions of milk each day. She is non-smoking with average exercise. Her menarche was at 14 years, she has 3 children, and she was usually regular menstruating until recently. During the last year, her periods became more irregular and her last menstrual period

Weight 148 lbs. (67 kg). Height 5’5" (1.68 m). No disease, no drug therapy.

The history reveals no risk factors other than the genetic one and perhaps a smaller intake of calcium than advised.

What to advise her? Two important measures serve general health and can always be advised to women: to increase the daily intake of calcium to at least 4 portions of dairy products (eventually as calcium supplements) and somewhat more exercise. You can advise women who are at very high risk to start hormone replacement therapy or bisphosphonates, but when available, measurement of bone mass is the best next step.

Complaints/symptoms of possible osteoporosis

Impression of osteopenia at a X-ray investigation

Bone mass measurement was subsequently done on Mrs. Andersen both at the lumbar spine and at the proximal femur with DXA.

Result: Bone mass - L1-L4: 0,83 g/cm2: T: -1.7

As it turns out Mrs. Andersen has osteopenia. This is a clinical definition. But her personal concern is what can she expect in terms of fractures? There is a strong relationship between bone mass and fracture rate. It has been calculated that the fracture risk doubles with every standard deviation below the mean. So a woman with a bone mass of T=-1 has twice the risk of a woman with a bone mass T=0. And the lifetime risk of a woman at the age 50 for one or more fractures is nearly 40%. With a T-score of -1.7, her risk will be increased substantially.

Mrs. Andersen is still premenopausal, perhaps perimenopausal. After menopause one can expect that her bone mass will decrease within 3-5 years by about 15%. This amount is about 1 standard deviation. Her bone mass will decrease within a few years to a level of T –2.7 in the lumbar spine and a level of -2.4 in the proximal femur. After that first few years the decrease in bone mass will continue at the rate of 0.5% each year. Mrs. Andersen will certainly suffer from osteoporosis in about 5-10 years unless action is taken.

There are several options available nowadays.

Prevention of bone loss is achieved with adequate hormone supplementation from the moment that the ovaries cease their activity, so during perimenopause or shortly after menopause. With an adequate amount of estrogen, bone mass will remain unchanged and consequently fracture risk remains the same. For optimal results, one has to continue the hormone supplementation for at least 5-7 years. It is proven that with such therapy the number of fractures decreases significantly.

Recently bisphosphonates have been introduced in the prevention of osteoporosis. Before, these substances were used only in established osteoporosis after the occurrence of fractures. With the bisphosphonates, bone mass can be maintained for many years and we can expect that the number of fractures will decrease subsequently, but this outcome (less fractures) has yet to be proven.

In some countries the new "selective estrogen receptor modulator", raloxifene has been introduced recently for the prevention of osteoporosis. The experience is limited, but the expectation is that the effect on bone mass will be the same as that of estrogen.

First of all, we have to counsel Mrs. Andersen about the natural course of her bone mass and the risk of fractures. It is always difficult to speak in terms of risk. With severe osteoporosis, it is possible that no fracture will occur and with normal bone mass, a fracture is not impossible, but Mrs. Andersen has a substantial risk to suffer from one or more fractures in the future. She can diminish her risk. First of all, with some general measures: a change of her lifestyle with more physical exercise, preferably in the open air (vitamin D!) and increased intake of calcium to 4-5 portions of dairy products every day (or calcium supplements of about 1000 mg).

Secondly, medication has to be offered: estrogen/progestagen supplementation or bisphosphonates. For the definite choice, one has to consider the other benefits of hormone supplementation, such as the decrease of cardiovascular disease and the effect on dementia, but also the possible increase in risk of breast cancer, especially in long-term users. In addition, side effects such as withdrawal bleeding should be discussed. The most important point in this decision process has to be the proven effect of HRT on the number of fractures. On the other hand, with bisphosphonates, the side effects are rarely seen. But the ultimate proof of benefit after many years has yet to be found.

After counseling, Mrs. Andersen decided to start with HRT at least during the first few years. Her opinion was that she could always change to bisphosphonates if the treatment with HRT becomes problematic and she has no risk factors for breast cancer.

She will start therapy soon because we considered her already perimenopausal. A simple urine test that measures bone breakdown (resorption) can be done as soon as three months after the commencement of her treatment to make sure it is working. Then, after 2-3 years of treatment, bone mass measurement will be repeated to monitor the treatment.

Mrs. Anderson is satisfied with this course of action but still concerned for her mother’s prognosis. She comments on the fact that the type of information and treatment options offered to her were not available 30 years ago to her mother. "If they had been", she muses, "Perhaps Mother would be out enjoying herself instead of recovering from hip surgery." She is more than likely correct. 

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Like Mother, Like Daughter

The relationship of sex hormones and breast cancer is a matter of concern of many women. Breast cancer is the most common form of cancer in women in industrialized countries. Approximately one in every 10-12 women develops this disease during her course of life, sometimes before menopause (25%), but mostly after menopause. Many studies with conflicting results have investigated the relation between hormone replacement therapy (HRT) and breast cancer. The overall opinion was very confusing and publications in lay press underlined more often the studies that published an increase in risk than studies with less spectacular results. During 1997 a excellent paper was published that combined all earlier studies, but the paper contains an enormous amount of data and is very difficult to read even for doctors. This contribution to 

 describes what really is known about the risk of breast cancer

 by the use of HRT based on the publication by: "The Collaborative Group on Hormonal Factors in Breast Cancer" in: Lancet 1997, volume 350, pages 1047-1059.

The authors have carefully searched the literature for all studies concerning the relation between risk of breast cancer and HRT. They included all studies with at least 100 women with breast cancer and clear information on the use of HRT and on other factors related to reproduction and the menopause. They were rather successful and they give details on 63 eligible studies. Thereafter, the authors have retrieved all original data of those 63 studies. Unfortunately, for ten studies original data were not available anymore and one group with 2 studies declined collaboration. Ultimately, detailed information was available from 51 studies of 52705 women with breast cancer and 108411 women without breast cancer.

This enormous amount of data is described in the paper in The Lancet, but only experts with a thorough knowledge of epidemiology and statistics can read it easily. So is the cumulative incidence of breast cancer increasing with age, but at the same time the relative risk decreases with time since menopause. Furthermore, many variables are interdependent.

To calculate the risk of HRT, the authors have constructed a model with all other factors constant. In this model age at menopause is set on 50 years and the cumulative incidence of breast cancer is calculated for women never using HRT and for women using 5 or 10 or 15 years of HRT.

The results are demonstrated in the figure.

On age 45 already 10 of 1000 women have acquired breast cancer and at the estimated age of menopause (=50 years) this number increased to 18. Without use of HRT 77 of every 1000 women will have diagnosed with breast cancer on age 75 and probably more of them when they become older. This number of breast cancers is represented in the figure with the blue line: the incidence without any exogenous hormonal influence.

With the use of HRT during 5 years, from 50 to 55 years, there is a very small increase in the calculated incidence of 2 extra breast cancers in 1000 women using HRT during this 5 years: 40 women with breast cancer on the age of 60 years instead of 38 (red line in the figure). But this difference is statistically not significant: this means that there is no real difference in the number of diagnosed breast cancers in 1000 women never using HRT and in 1000 women using HRT during 5 years. So, short term use has no breast cancer risk.

With longer duration of HRT also the number of breast cancers increases. Ten years of HRT (from 50-60 years) result in the extra diagnosis of breast cancer in 6 out of 1000 women in this group (green line in the figure). Without HRT 77 cases of breast cancer will be diagnosed in 1000 women, and with 10 years of HRT this number will be 83.

With 15 years duration of HRT the yellow line in the figure has to be followed. And this ends with an excess of 12 women more with breast cancer at age 75 than without HRT: 89 per 1000 women instead of 77 per 1000. 

Do these data prove that HRT causes breast cancer? No, because this kind of research can only demonstrate that a relation exists, but not if this relation is causal. The possibility of better surveillance, more frequent palpation of the breasts, more mammographies in HRT-users as consumers more concerned with their health than never-users still exists. An argument for this so called healthier user effect is the observation that breast cancer diagnosed in HRT users is often more localised and has a better prognosis. This problem will only be solved by randomised trials. Such research is on-going: the Women’s Health Initiative. But the first results are not available before the year 2006. In the meantime, it is prudent to consider the small increase in number of breast cancers in HRT-users as a unwanted side-effect. On this moment most medical professionals have the opinion that breast cancer is not caused by oestrogens. In fact, the lesion starts as early as the second or third decade of life. But oestrogens can definitely promote the growth of an existing small breast cancer.

There are several other conclusions to drawn from the paper in the Lancet.

The central hypothesis of the model described above is an age at menopause of 50 years. But the authors have also calculated the number of women with breast cancer with a menopause at age 55. These women have endogenous production of oestrogens during 5 years more than women with menopause at age 50. Comparing both models, one can conclude that one has to calculate not only the duration of use of HRT, but the total number of years with endogenous and exogenous oestrogens together. So, women with menopause at age 55 have the same number of breast cancer with 10 years of HRT use as women with menopause at age 50 and 15 years of use of HRT. This is good news for women with an early menopause. The length of use of HRT in terms of breast cancer has to be calculated from age 50 and not from their earlier start: only the total number of years of endogenous and exogenous oestrogens count.

The small increase in the incidence of breast cancer in long-term users of HRT should be considered in the context of the benefits of HRT. Long-term use is indicated for the prevention of serious disorders as osteoporosis and cardiovascular disease (and perhaps also useful in the prevention of dementia). Only in women without any risk factor for these diseases and especially for cardiovascular disease, the excess of breast cancer is of real importance in terms of cost-benfit calculations. But for some women a small increase in the incidence of breast cancer is so terrifying, that they accept the probability of an earlier (premature) cardiovascular death.

The relationship of sex hormones and breast cancer is a matter of concern of many women. Breast cancer is the most common form of cancer in women in industrialized countries.

Breast Cancer and Hormone Replacement Therapy

 I am an Ob/Gyn and patients are asking me for "Natural Estrogens" and natural progesterones for HRT.  They understand the studies are not as complete as other HRT medications but desire to stay away from Premarin.  Could you please discuss these medications and their use in HRT?
 
    

The         request for "natural hormones" is nearly universal. But there         is a lot of misunderstanding regarding this idea. What is natural?         Compounds derived from nature? Or compounds from pharmaceutical         companies that are structurally similar to hormones produced by the         ovaries?

Premarin is a mixture of many compounds,         estrogens progestagens and even androgens. It is derived from the urine         of pregnant mares and contains mainly oestronsulphate but also equilines         that are natural for horses but not for women. The estrogen activity of         equilines is about the same as estradiol. So no difference in activity         but difference in source.

Natural estrogens (in women) are estradiol and         estron. Micronized estradiol is a very popular prescription in Europe.         With oral ingestion of estradiol, the estradiol is converted in the         intestine to estron and absorbed as such and during the passage through         intestine and liver most of it is converted to estronsulphate.         Estronsulphate is the pool for the active compound estradiol. So, no         difference in the end result with estronsulphate tablets and micronized         estradiol. Is estronsulphate now a natural estrogen or not?

In premenopausal women the estron:estradiol         ratio is about 1. With oral estrogen medication there are much higher         levels of estron than estradiol. Is this natural? With transdermal         estrogens, estradiol is absorbed through the skin and partly converted         to estron. The ratio estron:estradiol is about 1, just as before         menopause. This looks much more natural than all other ways of         administration. 

 The same is true with progesterone. The only natural compound is progesterone. But         this is absorbed very poorly both in the intestine and through the skin.         Nowadays we have special products with micronized progesterone with a         reasonable absorption pattern (Prometrium). This product is expensive         and high doses are needed, and can cause sedative or  hypnotic side effects. Because         of the rather bad properties of progesterone in the early days,         progestagens were developed with the same activity as progesterone, and         several other activities. These are not natural progestins. 

         Progesterone is also developed in a vaginal cream with good absorption         pattern (Crinone). The natural progesterone creams (very popular among         women) give no measurable progesterone levels in serum and are not         protective for the endometrium.

Herbal remedies for perimenopausal symptoms is         something for believers. The use of herbal remedies can be compared with         religion. No proof, but many know for certain that it works. As an obgyn         specialist in gynecology, I limit my comment to proven remedies. Only         with red clover (and only with one brand, Promensil) a proof of benefit         for hot flushes exists. When you wish an overview of non-western         medicine you have to consult an alternative practitioner.

Alternatives         to Menopause Management

reprinted with the kind permission from         Andrew         Dott, MD, MPH 

What         are the sources of widely used estrogen?

Menopause         & Perimenopause Ask the Expert Archives

The request for "natural hormones" is nearly universal. But there is a lot of misunderstanding regarding this idea. What is natural? Compounds derived from nature? Or compounds from pharmaceutical companies that are structurally similar to hormones produced by the ovaries?

A Discussion of Natural Hormones

An excerpt from the Menopause & Perimenopause

An excerpt from the Menopause & Perimenopause Ask the Expert column

Author | Ronald Barentsen, MD, PhD

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