​For many physicians of my era (started practice in 1991) the story of hormone replacement therapy reflects the bandwagon nature of medicine.  In the mid-nineties as I opened my practice, we actively recommended that almost all menopausal women should take hormone replacement (HRT) or estrogen replacement therapy (if they had a hysterectomy).  As physicians we measured ourselves by our HRT percentage - feeling that if we were doing our jobs this should approach 100%.

​The reasons for our enthusiasm for estrogen replacement seemed clear.

In menopause, estrogen levels plummet to 1% of pre-menopausal levels.

Using estrogen to replace this loss, appeared to have significant benefits:

• Decreased menopausal symptoms (night sweats, hot flushes, joint/muscle pain, memory loss, etc.)
• Reduction in osteoporotic bone fractures - especially hip fractures
• Decreased heart disease
• Decreased dementia
• Decreased colon CA

...and while these benefits were offset by a small but real increased risk in venous blood clots - the benefits seemed overwhelming.

Then on July 17, 2002 the world of estrogen replacement came crashing down.  

The Woman's Health Initiative - the largest and most expensive trial ($1B)  ever done at that time was stopped because HRT increased the risk of breast cancer by 26%.

Overnight, physicians jumped off the bandwagon and rates of HRT fell dramatically.

Unfortunately most of us did not read the details of the study (once it was eventually released).

In the new book, "Estrogen Matters" by Dr. Avrum Bluming and Carol Tavris, the data from WHI is examined in the broader context.

Starting with the conclusion that HRT increases breast cancer by 26% - the first and most stunningly underappreciated fact was that this increase did not meet statistical significance, meaning that it did not clear the commonly accepted threshold that there has to be less than a 5% chance that this result could be random.

Next, even if you accepted that the result was real and not random, then it is important to understand the result.  There are two ways that the study could have shown an increased rate of breast CA, either the rate of breast CA actually increased in the treatment group OR the rate of breast CA went down in the control group.  Of course if the latter explanation is correct then the study is flawed.

Closer analysis of the WHI data has clearly shown that the reported increase rate of breast CA did not come from higher breast cancer rates than expected in the treatment group but resulted from the fact that the control group had a lower incidence of breast cancer than expected.  

Even more confusing was the fact that this reduction of breast cancer in the control group occurred because there was a significant number of woman who had been on HRT previously and in this group there was less breast cancer.

So the WHI concluded that HRT increases breast CA because previous HRT experience decreased the rate of breast CA in the control group - incredible!

The third thing to consider when reviewing the WHI findings is the absolute rate of the increase in breast cancer.

So even if you accept that the effect is real and not the result of randomness or a decreased rate in the control group the absolute increase in was 8 more breast cancer diagnoses per 10,000 patient years.

Taken together, this review significantly decreases, if not removes altogether, the concern that I have about estrogen causing an increase in breast cancer.

Bluming and Tavris then revisit the benefits and risks of HRT - providing links to the best available current evidence and in doing so provide perhaps the best single source of HRT information for anyone considering HRT.

Summary of the Risks and Benefits of Estrogen Replacement:

Benefits

• Effective treatment of menopausal symptoms - night sweats, hot flushes, joint/muscle pain, memory loss, etc.
  • especially vasomotor symptoms
• Reduction in fractures:  33-50% reduction of fractures (including hip fractures)
  • As we posted last week - nothing really works as well as estrogen replacement
  • It must be noted that a woman will need to take HRT for at least 10 years - and probably forever
  • ...and that fracture risk returns to normal within 6 years of stopping HRT.
  • Hip fractures are incredibly significant cause of suffering - approximately 21% of women who fracture their hip will die within a year of the hip fracture
    • In the US that number is approximately 40,000, which is similar to the number of women who die in this country of breast cancer every year
• Decrease in mortality from cardiovascular disease when started close to menopause - addition of 3-4 years of healthspan
  • This study by Nananda Col showed that if every woman in the United States do hormone replacement therapy (HRT) it would increase the median survival of women by 3.3 years in this country
  • Again it must be noted that there is a possible increased risk for women who begin HRT in their 60's with established atherosclerosis (at least in the first year) so HRT should be started at menopause.
  • When viewed from a numbers perspective the number of woman dying from heart disease is significantly greater than from breast cancer - so even if you accept that increased risk from the WHI study - the cardiovascular benefits will far outweigh that small absolute risk.
• Decreased risk of dementia from 24% to 65% if started at the onset of menopause - data is mixed with starting after menopause and may result in worsening of dementia
  • "If neurons are healthy at the time of estrogen exposure, their response to estrogren is beneficial for both neurological function and survival.  But if those neurons are not healthy when a woman starts estrogen or begins taking HRT ten or more years after menopause, estrogen may, over time make her condition worse" - Roberta Diaz Brinton.
  • Currently there is no treatment for Alzheimer’s
  • The one potential preventive medication is estrogen which can reduce the incidence of Alzheimer’s disease by between 20 and 50% depending upon the study you look at
  • Here’s one study
• Decreased colon CA - (oral HRT only)
  • Colon cancer mortality was reduced in the WHI and other studies
  • Interestingly while not as lethal as pancreatic or lung cancer, colon cancer is more lethal than breast cancer
• Decreased Ovarian CA
  • oral contraceptives decrease the rate of ovarian CA by up to 80% and the reduced risk persists with HRT

Risks

• Increased rates of breast CA - this is not supported by current evidence
  • The WHI which led to the conclusion that HRT increased breast cancer:
    • did not meet statistical significance
  • What about in women with pre-existing breast CA
    • neither increases (pregnancy) or decreases (oophorectomy) in physiological estrogen show changes in breast CA recurrence. 
    • Studies of HRT show no increased risk and may actually reduce the recurrence rate and prolong survival.
• Stroke
  • WHI showed higher rates of strokes, however when re-analyzed this looks to be an effect of starting HRT long after menopause in woman who were not healthy.
  • Further, the estrogen only arm was stopped because of a very small increased rate of 12 per 10,000 woman years - and these were using a very broad definition of stroke including TIA's
• Venous blood clots (pulmonary embolism and deep venous thrombosis
  • This risk is real but overall this is small and comparable to the accepted risk of oral contraceptives
• Gallstones
  • again - small but real risk.

Bottom Line:
For every woman going through menopause, HRT should be given personalized and individualized consideration.

I highly recommend this book to anyone who wants to review the data for themselves and make a fully informed decision.

As for my physician colleagues, I have already been recommending "Estrogen Matters"

For a great listen - check out Peter Attia's podcast. with Bluming and Tavris

You may be interested:
Osteoporosis Considering the Role of Estrogen Therapy
Osteoporosis
The Science of Bone Health - 3 Principles to Develop and Maintain Bone

Our bones are remarkable examples of evolution's ingenuity. 

From a functional perspective, bones serve multiple roles - structure, mobility, support, protection as well as serving as a reservoir for essential minerals. 

​These roles became important, when our distant predecessors left the calcium-rich ocean to live in calcium-poor fresh water, and then further evolved to live on land where gravitational forces (without the buoyancy effect of water) put greater stress on the skeleton.

Our skeletons store two key minerals, calcium and phosphorus, both essential for the healthy functioning of cells and bodily organs, and our bones are called, in times of stress, to maintain blood levels of both. 

A complex system of hormones regulates calcium and phosphorus in our bodies acting on bone, intestine and kidneys to maintain adequate supply for proper cellular function in all cells but particularly in nerves and muscle.

These hormones include:
Calcium Regulating Hormones

1. Parathyroid Hormone (PTH) - the parathyroid gland monitors calcium levels and releases PTH when levels drop.  PTH increase osteoclast numbers and activity and result in bone resorption - freeing calcium for other purposes.
2. Vitamin D - acts on the intestines to absorb calcium and on the osteoclasts to resorb bone and maintain blood calcium levels thereby keeping PTH in check.
3. Calcitonin - released by the thyroid, calcitonin decreases osteoclast activity and decreases resorption of Calcium and phosphate from the kidneys

Sex Hormones

1. Estrogen -  In both males and females, estrogens play a key role in bone maturation and maintenance of bone density.  The drop in estrogen in menopause leads to dramatic bone loss in women. (more on this to come)
2. Testosterone -  can influence bone health by binding to androgen receptors directly or to estrogen receptors (ERs) indirectly via aromatization to estrogen

Other Hormones

1. Thyroid hormone - elevated levels of thyroid hormones lead to bone loss through increase osteoclast activity as well as decreased resorption of Calcium in the kidneys
2. Cortisol - elevated cortisol likewise increases bone loss through increased osteoclast activity
3. Growth Hormone & Insulin-Like Growth Factor (IGF-1) - most of the effect of growth hormone is through the GH dependant secretion of IGF-1 from the liver.  IGF-1 acts on osteoblasts to increase bone formation.

Of these, Vitamin D stands out, as we are dependent on our environment, specifically sunlight to synthesize adequate Vitamin D to maintain adequate dietary calcium absorption from our intestines.

The dual roles of bone, to act as structure and at the same time represent a reservoir for calcium and phosphorus, are in direct conflict with each other. 

Bones must be strong and flexible to respond to the weight bearing and mechanical forces of our activities.  When our activities increase in intensity, our bones get stronger in order to sustain the load. 

However if calcium or phosphorus are in short supply, our regulatory hormones will draw them out of bone to serve vital functions in other cells in the body, and in the process potentially weaken bone.

Bone is an incredible material providing both strength and flexibility in order to be resilient to the mechanical forces imposed by daily activities, not to mention sports. To accomplish this bone is a composite material made of minerals bound to protein, predominantly collagen. 

If bone was made only from mineral crystals it would be brittle and fracture easily; if made solely from protein it would be too flexible and would not provide adequate structure and flexibility. 

The mineral components of bone are crystals of calcium and phosphate called hydroxyapatite.  They are bound in a matrix to a triplet of three long, thin, intertwined collagen rods with are strengthened by chemical bonds between proteins. 

Other proteins further strengthen the collagen matrix and regulate mineral binding.  Small changes in shape of the bones, from mechanical forces, act on the cells inside the bone to send signals that allow bone to respond to these loads by remodelling and strengthening.

In this way, our bones are always changing and growing, responding to mechanical loads, resorbing and laying down new bone.

Bone health depends on the balanced effects of two kinds of bone cells:

• Osteoblasts - the cells that make bone and
• Osteoclasts - the cells that dissolve and remove old bone

During our childhood, as our bones are growing both cell types are constantly working, osteoclasts reshaping and osteoblasts rebuilding bone with osteoblast activity predominating so that bone length, thickness and overall mass increase as our bodies grow in stature. 

Once growth is finished and we are adults, osteoblasts spend less time creating new bone and more time regulating bone repair - osteoblasts signal osteoclast to hollow out bone in a specific location and then fill in that area with new & healthy bone.

Bone also has another remarkable feature - it is anti-fragile:  if stressed it gets stronger. 
This phenomena, called Wolff's Law was originally recognized in late 19th century, but is probably most dramatically visualized in tennis players who show far greater bone mass in their racket arm as compared to their non-dominant arm.

This remarkable gift, that our bones grow stronger through stress and usage has a dark, flip side:  our bones grow weaker through disuse.

Only in modern times has this become a downside.  For most of human history, our lives were simply too active.  Our predecessors had very strong bones from all the physical work and stress placed on their bones throughout their lives.  From the industrial revolution on onward, labor saving technologies have decreased the degree to which we need to use our bodies to the point that many of us are no longer building enough bone.  This is another example of evolutionary mismatch that I have previously written about.

Compounding this fundamental mismatch, modern diets and lifestyles also lead to deficiencies in dietary calcium, protein and Vitamin D necessary for bone health.

To develop and maintain bone mass three key principles emerge:

1. Use your bones to increase their strength
   • "use it or lose it" applies to your bones
2. Supply your body with the key ingredients to develop bone
   • Osteoblasts use calcium to build new bone, calcium comes from the food we eat and requires adequate Vitamin D for absorption. (for more on Vitamin D - see these previous blog posts: Should I Take Vitamin D? How much? and A Better Way to Get Vitamin D in the Winter
   • Bone formation is also dependent on adequate protein intake to build the collagen-hydroxyapatite bone matrix.
   • Finally Vitamin K2 is necessary to for activating proteins released by the osteoblasts that draws calcium into the bone matrix.  (Vitamin K2 is generally produced by bacteria in our GI tract - so another reason to maintain gut health.)
3. Avoid substances that decrease bone strength:
   • tobacco - smokers lose bone density sooner than non-smokers
   • alcohol - 3 or more drinks per day can increase bone loss
   • colas - the phosphoric acid in colas leaches calcium from bones.  (our partner BodyComp have numerous case studies of young people with decreased bone density due to excessive cola consumption).
   • some medications
     • excess thyroid replacement
     • corticosteroids

Next week, we will look at osteoporosis and what you can do to prevent or reverse it.