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Melatonin

Melatonin is known by most people for helping jet lag, but the reality is that it has many functions in our body. It is the most powerful anti-oxidant found to date, is important in our sense of well-being, and is associated with longevity. Melatonin is the oldest of all the hormones, probably 3 billion years old. Melatonin is found in algae, and in every plant, and in every animal on the planet. Melatonin is produced by the pineal gland in our brain. Exposing the eyes to bright sunlight stimulates the production of serotonin during the day, and of melatonin during the night. Melatonin is produced best in total darkness, and is responsible for our sleep/wake cycle.

Some of the functions of this amazing hormone are the following: assists and enhances the immune system, involved in the production of growth hormone, improves mood, helps stress response, decreases and modulates cortisol, powerful ant-oxidant effects, stimulates the release of the sex hormones, stimulates the parathyroid for bone formation, and helps prevent cancer in several ways, i.e., it inhibits cell proliferation and helps facilitate cellular death  (apoptosis). All cells are programmed to die after 30, 120, etc. days depending on the type of cell.

Symptoms of melatonin deficiency are light, anxious, or agitated sleep, easily awakened, difficulty falling back to sleep, poor dreaming, hypersensitivity, and irritability.

Arnold Lerner, M.D. began researching melatonin in 1953. He was trying to find a way to lighten skin color. He did not find a way to lighten the skin with melatonin. He did find out many other things about melatonin, one of them being that there seemed to be no side effects or toxicity, other than mild sedation, even when he was injecting up to 200 mg into his subjects by 1960!

Melatonin supplementation has proven effective in sleep disorders in blind people, sleep disorders in autism and mental retardation, improving symptoms of jet lag, insomnia, improving the effectiveness of certain cancer medications, decreasing symptoms of tardine dyskinesia (TD), treatment of cluster headaches, and reducing anxiety.

Melatonin levels build from birth till about one year of age and then are fairly constant till puberty. A drop in melatonin signals estrogen which in turn stimulates estrogen receptors in the bone to close the epiphysis (growth plate). Children who have higher levels of melatonin reach an older age before puberty begins, and therefore have more height potential. Children who reach puberty at an early age have shown to have melatonin levels at 1/3 of average. Melatonin levels start to decline in middle age to older age.

Is it possible that the reason that women live longer than men is because women have higher melatonin levels than men do? Four studies done in France, Switzerland, and Germany in the 1980’s and 1990’s and after 2000 would suggest so. In each of the studies, women tested anywhere from 20% to 30% higher in melatonin compared with the men of comparable age. There have also been studies comparing elderly populations of healthy seniors vs. senile seniors of the same age and the healthy individuals had higher melatonin levels compared to the senile group. A 1993 Italian study showed a clear correlation between mental acuity in the elderly and melatonin levels. The healthy elderly had over 2X higher melatonin levels compared to individuals of the same age who had been diagnosed with Alzheimer‘s. In the United States, 50% of people over age 85 have been diagnosed with Alzheimer’s. How sad! Alzheimer’s patients have demonstrated high levels of free radicals in their brains. In 1954, Denham Harman M.D. proposed the free radical theory of disease and aging which most doctors embrace today. Most nutritionists will tell you that the three most powerful anti-oxidants are super oxide dismutase, catalase, and glutathione. Melatonin is 5x more powerful as an anti-oxidant than glutathione! Could it be that melatonin gives protection to the brain to those with higher levels, protecting them from the ravages of free radicals and Alzheimer’s?............... I think so.

In 1985,  Georges Maestroni found evidence of melatonin’s ability to extend life! His study was on two groups of mice. One group was given plain water and the other group was given water with melatonin added to it. The mice group with plain water lived for 752 days on average, and the group with the melatonin water lived for 931 days on average, 20% longer! Another study on rats was conducted in 1998. After 15 months, 87% of the rats given melatonin supplementation were alive, and only 43% of the rats without melatonin were alive. Of the seven rats left in the surviving control group without melatonin, 5 had pneumonia. All the rats in the group treated with melatonin showed no signs of illness. Well……. you are thinking ….. that is fine for mice and rats, what about us humans? A study on 23 centenarians (people over 100 years old) demonstrated that they had higher levels of melatonin than the other people in the control group that were 50-60 years of age!

At this point, if you are like me, you are thinking I would like to know how I can preserve and maximize my melatonin levels, right?  In 1993, there was an important study of 15 men and women, ages 20’s-30’s that were exposed to bright light 4 hours each day for two days vs. a similar group that was not exposed to any bright light during this time. After two days, the group that was exposed to the light scored significantly better cognitive functions, wakefulness, reaction times, and sense of well-being. We now know that at least an hour of bright sunlight will properly stimulate the hypothalamus and in turn the pineal gland to produce adequate amounts of melatonin. More is better. So you see, sunlight stimulates the production of vitamin D through our skin and melatonin through our eyes! Hmm…. Very interesting. However, melatonin needs total darkness to work optimumly. Close off your windows. Shut off your electronics with lights. Do not go to the bathroom or kitchen and turn on the light at midnight or two in the morning. You will just shut down your melatonin production. No bright lights at night. Melatonin is very sensitive to certain wavelength of light, especially from 460-480 Angstroms, which is blue light, or computer light. Turn it off at night. Ahhh… New York, New York, the city that never sleeps. WARNING! The International Agency for Cancer Research has classified light at night as a group 2b carcinogen. The cancer rates for large metropolitan populations are much higher than in rural areas. New York, London, Paris, Chicago, etc all have higher cancer rates than small town and rural areas. And, those cities that are further away from the equator have even higher cancer rates. Why? They are further from the angle of the sun more often, causing vitamin D levels to be lower. Well….. That is another story. The less sleep you get, the less melatonin you produce.  The more sleep you get, the more melatonin you produce. People who sleep 6 hours or less have an increased mortality rate of 70% compared to those who sleep 7-8 hours. How important is sleep? It is way important! In a study of 24 healthy men that agreed to be awakened at 3 a.m. and not allowed to return to sleep, demonstrated a reduction of 25% in their body’s own natural killer cells! Those people who work the night shift have higher cancer rates than the same employees doing the same job on a different, daytime shift. The others are asleep in the wee hours of the morning. Unfortunately both prescription and non-prescription sleep aides cause marked melatonin suppression. Drugs like halcion, valium, and xanex are also related to depression, anxiety, and amnesia. The simple and no side effect solution is to take melatonin if you need help to sleep. A 1993 M.I.T. study showed even very small amounts of melatonin allowed people to relax and get to sleep faster and stay asleep longer. Besides the sunlight in the eyes we talked about earlier, there are other ways to stimulate your melatonin production. One method is to increase your core temperature by a couple of degrees by getting into a sauna, hot tub, or just a hot bath. Tryptophan, St. John’s Wart, calcium, and magnesium at bed time, and meditation, all increase your melatonin as well.

There are a few other common medications that inhibit melatonin production such as aspirin, ibeprophen, less with Tylenol, pain medications, beta blockers, steroids, coffee at night, and tobacco. Another offender is EMF’s, electromagnetic frequencies. A study of women using a electric blanket at night caused a 75% suppression of melatonin production.

 As an interesting side note, there was a large study on depressed individuals vs. those in chronic pain. My interpretation of this would be two groups of depressed people, one group in physical pain and the other not. I have never met a person in chronic pain that was not somewhat depressed. The study was done because there were several similarities in the hormone patterns of these two groups. The interesting thing for me about this study is that 44% of the chronic pain patients noted marked improvement in their physical discomfort. Further studies on mice showed that melatonin’s benefit for pain was dose driven, but dose for dose melatonin was just as effective as morphine.

I want to explore this sense of well-being that melatonin produces. We do not know the full extent of involvement, but it is interesting to note that in manic depressant individuals, the melatonin levels are 2x higher than normal in the manic phase than in normal phase, and melatonin levels are below normal in the depressed phase. In 1992, a study of schizophrenic patients, sub-normal levels of melatonin were noted. When surgeons have had to remove the pineal gland due to brain trauma or cancer, these people suffer from depression, anxiety, excessive sleepiness, headaches, auditory and visual hallucinations very similar to a schizophrenic. Autism is a very complex neurological problem. One of the observations was that these children do not have a natural surge of melatonin at night. Most of these children have difficulty sleeping, and melatonin supplementation is effective for this.

Breast cancer is 5x more common in industrialized countries, but 50% of the reasons for this are unaccounted for. Women who work the night shifts have an increased breast cancer incidence. Physiological levels of melatonin inhibits breast cancer cell proliferation. Melatonin has specific effects to inhibit breast cancer cell growth. Studies using melatonin coupled with tomaxifen showed it to be 60% more effective than with tomaxifen alone, but only if melatonin was administered at night.

Each year 200,000 new cases of prostate cancer are diagnosed, with a 40,000 mortality rate. If the cancer is found when it is localized there is a 75% survival rate over 5 years. Melatonin has been very effective in reducing the toxic effects of chemotherapy. In animal studies it has shown to be effective in protecting the bone marrow from damage from the chemotherapy. Breast, prostate, lung, and liver cancers have shown to be inhibited from melatonin. Melatonin has been shown to protect against radiation.

In conclusion, melatonin seems to be necessary for a good sense of well-being. It is essential to our natural bio-circadian cycles, our sleep/wake cycle, is the most powerful anti-oxidant known to man attacking free radicals, has amazing characteristics for cancer protection, gives protection to our brain, and seems to be related to our longevity.

As an anti-aging physician, I am so very excited about what melatonin can do for me and my patients. I personally take 2 grams of melatonin, applied transdermally every night before going to bed for all the reasons I mentioned above. If you are experiencing any of the health challenges I have discussed in this article, call and make an appointment. It is extremely rare that only one hormone is involved. A thorough history and exam will reveal the deficiencies and/or imbalances. It is our purpose to help you return to your inherent harmony of health and well-being.

Kelly Miller DC NMD FASA FBAARM CFDMP*, physician for Hoffman Clinic for Optimal Health.

*There is currently no licensure for Naturopathic Physicians in the state of Florida and the Bard of Chiropractic Medicine does not currently recognize the Fellowship in Aging and Regenerative Medicine (FBAARM) from the Brazil-American Board of Aging and Regenerative Medicine or Certification in Functional Diagnostic Medicine (CFDMP) from Functional Medicine University.

PREGNENOLONE

Pregnenolone is the oldest of all the hormones, and is known as the “mother” of all hormones. Pregnenolone is converted from cholesterol in the adrenal cortex(part of the adrenal gland). Since cholesterol is the source of all sex hormone production, it is known as the “grandmother” of all hormones. It is of great concern to me of the indiscriminate use of stain drugs in an attempt to bring cholesterol levels. Pregnenolone converts to DHEA in one pathway or to Progesterone in the other pathway.

The functions of pregnenolone are the following: 1. Improves excitation and inhibition of the nervous system. 2. Increases resistance to stress. 3. Improves physical and mental energy. 4. Increases nerve transmissions and memory. 5. Reduces pain and inflammation.

In 1943, Dr. Hans Seyle, who is responsible for our modern day awareness of “stress”, found that pregnenolone negated the damaging effects of excess cortisol(a hormone produced by the adrenal gland that deals with stress and inflammation). Pregnenolone supplementation was able to neutralize the symptoms of excess cortisol such as depression, water retention, insomnia, over-eating, weakened immunities, and destabilized liver functions.

Pregnenolone is vital to the function of memory. Numerous studies through the years have shown that with optimum levels of pregnenolone one is able to think more clearly and with less delay in recalling information. Pregnenolone levels are optimum at age 35. Restoration and maintainence of the pregnenolone levels to where they were at in the top quartile  of the 35 year old population will greatly reduce the risk for dementia, Alzheimer’s, and senility.

Pregnenolone has demonstrated very positive effects directly correlated with arthritis. It has been shown to reduce swelling, inflammation, joint and muscle pain associated with arthritis. Pregnenolone supplementation has been shown to be helpful with auto-immune diseases such as lupus and psoriasis.

 Pregnenolone administration has shown promise in the areas of spinal cord injury and multiple sclerosis. It is helpful in neuropathies involving the myelin sheath.

Symptoms of pregnenolone deficiency are the following: 1. Loss of short term memory. 2. Forgetfulness 3.Fuzzy thinking. 4. Depression. 5. Reduction in the perceived brightness of colors 6. Pessimism.

There are two areas for certain that pregnenolone supplementation can be helpful; helping you think, and helping you cope with stress. The absolute best way to supplement pregnenolone is through transdermal application utilizing liposome technology. Liposome technology is certainly the nutritional breakthrough of the decade, if not the century. Liposome technology involves the encapsulation of a nutrient/hormone with phosphatidylserine. Phosphotidylserine is a naturally occurring lipid(fat) in all our cellular membranes. Because the nutrient is made of material that is part of the cell membrane, it is more readily accepted and transported through the cell membrane. Therefore, it a superior delivery system to get the nutrient/hormone into the cell.

DHEA

DHEA is known as the “father” of all hormones. It is converted from cholesterol in the adrenals. The adrenals are two small triangular shaped organs that sit on top of our kidneys. Cholesterol is the source, “grandmother”, to all hormones. Cholesterol is first converted to pregnenolone, the “mother” of all hormones which in turn converts to DHEA or Progesterone. From DHEA comes testosterone which can convert to estrogen. At age 25, our DHEA levels are at their peak. Each year afterwards, we lose about 2% of our DHEA, depending on our lifestyle and stress levels. At about age 50, on average we are only producing 50% of the amount we did at age 25. By age 75, most of us are out of luck if we don’t replenish. DHEA affects almost every organ in the body. It is an anabolic (Building) hormone that possesses the ability to heal and construct tissue. DHEA represents the largest pool of all our hormones, and is thought by some to represent our longevity potential.

Some of the functions of DHEA are the following: decrease blood cholesterol, decrease fatty deposits in the blood vessels, decrease incidence of blood clots, improve bone growth, weight loss, improve brain function, improve sense of well being, better stress management, support of immune system, improves cell repair, decrease allergic reactions, improves sleep, increases production of testosterone. The brain has 5-10 times more DHEA than the plasma.

Symptoms of low levels of DHEA are depression, difficulty handling stress, lack of stamina, moody, dry eyes, osteoporosis, memory loss, bone, joint, and muscle pain. Low levels of DHEA are found in obesity, type II diabetes, immune dysfunction, auto-immune disease, cancer, hypertension, cardiovascular disease, depression, a loss of sense of well-being, cognitive dysfunction, loss of libido, erectile dysfunction, and osteoporosis.

Some of the benefits of optimal levels of DHEA are increased muscle strength and lean mass, improved immune function, improved quality of life, improved sleep, feeling of wellness, decreased joint pain, improved sensitivity to insulin, lower fatty triglycerides, and stopping the damages of stress. DHEA has positive effects for men suffering from declining muscle mass, increased body fat around the waist and the middle of the body, libido reduction, fatigue, dry skin, energy loss, strength loss. DHEA has positive effects on women as an anti-depressant and anti-anxiety. It improves libido and boosts skin thickness. Topical DHEA is anti-aging, anti-obesity, anti-diabetes, and anti-heart attack.

Optimal levels of DHEA have been found to reduce risks for breast, lung, colon, liver, skin, and lymphatic cancers. Topical supplementation has shown positive effects in slowing the progression of cardiovascular disease. DHEA concentration in the body is independently and inversely related to death from any cause and death from cardiovascular disease in men over 50. In one study of 1700 men aging from 40-70, the men in the lowest quartile (25%) of DHEA levels had the most ischemic heart disease.

As with all hormones, optimal function occurs in the upper quartile (25%).  Optimum function occurs when all the hormones are balanced. If one hormone is down, then other hormones are down. What are your levels? Get them checked today.

PROGESTERONE

Progesterone is the antagonist or balancing counterpart to estrogen, specifically estradiol or E2. Progesterone gives protection to the breast, uterus, and ovaries from cancer, helps bone health, reduces heart disease, and gives peace of mind.

Progesterone is converted from Pregnenolone, the “mother” of the hormones, which comes directly from the source, cholesterol, the grandmother”, and can convert to Cortisol or Aldosterone in one pathway or Testosterone in another. It is the hormone that supports conception, carries, and sustains the pregnancy. Progesterone levels rapidly increase on day 14 following the mense and ovulation. The levels peak at day 21, and rapidly drop on day 28. The progesterone is made by the ovary after the ovulation.

Don’t be confused. Natural progesterone and prescription, progestin, are not the same! Natural progesterone is 100% active, while the prescription, progestin, is only 8% active. Progestin is an extraterrestrial molecule, not designed for your receptor sites, and plays havoc in the body, and creates many problems and challenges in dealing with its elimination from the body.

Some of the functions of progesterone are the following: pro-gestation, natural diuretic-blocks aldosterone, a hormone that helps us retain sodium (salt), uses fat for energy, natural anti-depressant and anti-anxiety, may increase libido, promotes cell differentiation, promotes normal cell death, decreases estrogen receptor synthesis, improves estrogen receptor sensitivity, decreases estrogen induced mitosis (the process where a cell splits/duplicates into two daughter cells), and prevents blood clots. Again, it is a major protector to the heart, uterus, ovaries, cysts, fibroids, and endometriosis.

Generally speaking, if a woman is having a lot of problems in her first 14 days, it is related to estrogen, and in the last 14 days, progesterone. The incidence of breast cancer is 40% greater in women with progesterone deficiency. Transdermal progesterone decreases the breast cell growth by 400%. There is 20X more progesterone in the brain than in serum blood, which explains its profound effect on mood-calming, relaxing.

Some of the primary symptoms of progesterone deficiency are the following: anxiety, depression, irritability, mood swings, insomnia, pain and inflammation, osteoporosis, amenorrhea, PMS, cystic breasts, painful breasts, water retention, craving for chocolate and sweets, post-partum depression, infertility, swelling of bely, hands and feet, headaches before mense, and excessive menstruation.

Some of the more common causes of progesterone deficiency are the following: stress, anti-depressant medications, excessive arginine consumption, sugar, saturated fat, deficiencies in vitamin A. B6, C, zinc, and decreased thyroid function. Women have their first mild drop in progesterone from age 30-35, followed by first mild drop in estrogen at age 40-45. These levels hit the floor at the onset of menopause, and continue to decline.  90% of women suffer with PMS, and 90% respond from transdermal progesterone therapy.

The best way to assess your hormone levels are through the saliva. See drkellymiller.com under the section, How We Help, for saliva hormone testing. I recommend every woman with PMS or any menopausal woman to her progesterone levels checked, as well as DHEA, estrogen, testosterone, and cortisol levels. Call 813-774-3744 today for an appointment.

Testosterone

Testosterone is not just for men. It is vital for both men and women. Testosterone comes from DHEA, which comes from Pregnenolone, which comes from Cholesterol. The cycle of production of Testosterone begins with the hypothalamus producing gonadotrophic hormones which cause the anterior pituitary to produce luteinizing hormone and follicular stimulating hormone. These hormones have a direct effect on the gonads, causing the production of testosterone and sperm respectively in the testicles of men, and in women effects the ovaries and initiates the menstrual cycle.  As Testosterone is produced, it is released into the bloodstream, creating the beginning of a negative feedback system involving the hypothalamus and anterior pituitary. Receptor sites in the hypothalamus and anterior pituitary monitor the need for more testosterone production. If testosterone levels drop in the blood, then the hypothalamus produces more gonadotrophic hormones and the anterior pituitary produces more luteinizing and follicular stimulating hormones. Conversely, if Testosterone levels are too high, the hypothalamus produces less gonadotrophic  hormones and anterior pituitary produce less luteinizing and follicular stimulating hormones.

Only about 2 % of Testosterone is free and bio-available, and is what is found in the saliva. The 98 % found in the blood is bound and not bio-available. The Testosterone in the blood is bound by albumin (38%) and by SHGB (Sex Hormone Binding Globulin) (60%). The molecules of SHGB are too large to go through the glands that produce saliva. That is why the Testosterone in the saliva is free, not bound. SHGB is produced  by the liver. SHBG not only binds with excess testosterone, but all other hormones. Therefore, free Testosterone levels in the saliva are much more useful than bound blood serum levels. Free testosterone in the saliva for men should be 145-155 pg/ml. Salivary free Testosterone in women should be 45-50 pg/ml. There is a difference of opinion on what is considered low Total Testosterone in the blood serum. The level of 300 ng/dl has been set by the Endocrine Society and the level of 340 ng/dl has been set by the International Society for the Study of Aging Males. At either level, you are in deep trouble in my opinion.  Reference levels in most labs for serum Total Testosterone in men fall between 350-1130 ng/dl, and in women between 10-55 ng/dl. These are very broad ranges, and do not reflect healthy, optimal levels. Healthier, more optimal levels would be 750-1100 ng/dl for men and 50-80 ng/dl for women.

Testosterone affects the brain, social interactions, libido, and gives confidence. Testosterone affects muscle strength, size, and endurance. Testosterone affects the glucose utilization in the mitochondria of the cells. Thyroid also influences the  energy utilization within the mitochondria. A deficiency of either will cause a lack of energy utilization in the muscles. Testosterone affects bone growth, development, and strength. Estrogen closes the epiphysis of bones to end the growth cycle in puberty.

Testosterone’s affect is greatest in those tissues that contain the greatest amount of testosterone receptors. Without proper working receptors, there cannot be normal activity even with high levels of Testosterone. It is the optimum level of hormone coupled with proper functioning receptors that creates optimum health. Testosterone, DHEA, Androstenedione, and DHT are all considered androgenic hormones. Their relative values as androgens are 100, 5, 10, and 300 respectively. The free Testosterone goes to the receptor site, and then is taken inside the cell and Is converted to DHT, which is 3x more powerful than Testosterone and is transported inside the nucleus of the cell.

Besides the testicles, the organ that has the most Testosterone receptor sites is the heart. Optimum Testosterone levels increase vasodilatation, improves exercise tolerance, and improves angina threshold. Optimum Testosterone levels reduce visceral and body fat, maintain muscle mass, bone mass, memory, intelligence, and libido.

Testosterone levels start dropping in men at age 25 at a rate of approximately 20 %/decade. This is one of the reasons it is so difficult for an athlete in their mid/late thirties to compete with an athlete in their lower/mid-twenties. There usually has been a significant loss in strength, endurance, and most importantly recovery by this time. When a man reaches age 50, he has, on average, lost 50% of his Testosterone, and is now in Andropause, the male version of Menopause. The physiological and bio-chemical changes that are occurring in men at this age are literally life threatening! Andropause is associated with the following symptoms: Increased belly fat, decreased muscle size and tone, decreased memory, decreased decision-making, moodiness, irritability, fatigue, increased stiffness in joints and muscles, loss of libido, decreased morning erections, decreased fullness of erection, decreased intensity of orgasms, and increased recovery time between orgasms.

The following chart reveals just how life threatening these changes can be with men at least 45 years of age with low Testosterone/Hypogonadism. Hypogonadism in men is a  classical syndrome that results from the failure of the testes to produce physiological levels of testosterone(androgen deficiency) and the normal amount of spermatozoa due to disruption of one or more levels of the hypothalamus (HPG) axis.

The HIM Study      Percentage of Incidence         Odds Ratio

Obesity                                 52.4 %                              2.38

Diabetes                               50 %                                  2.09

Hypertension                        42.4 %                               1.84

Rheumatoid Arthritis             47.3 %                                1.59

Hyperlipidemia                      40.4 %                                1.47

Osteoporosis                        44.4 %                                1.41

Asthma/COPD                      43.5 %                                1.40

Prostatic Disease/Disorder   41.3 %                                1.29

Chronic Pain                         38.8 %                                 1.13

Headaches(within 2 weeks)  32.1 %                                 0.81

What is very disconcerting is that there has been a very large epidemiological study of American men called The Massachusetts Male Aging Study spanning over the last thirty years, and the results demonstrate that the average Testosterone levels in men have been dropping steadily each of the last three decades! Why aren’t we men more aware of the signs and symptoms of low Testosterone and the associated increased health risks, and why are we not being screened for this? A recent Harris Interactive Male Survey of 522 men showed 91 % of the men polled were not aware of what the symptoms were associated with low Testosterone. I believe that every man should get a saliva hormone test at age 40.

Testosterone is needed for women to have a “sense of well being”. Testosterone is important in women to maintain muscular strength, especially in the upper body. Testosterone is responsible in part for a woman’s libido, and a woman’s nipple and clitoral sensitivity. Testosterone is essential for body composition and bone density. Testosterone is usually decreased in peri-menopusal and menopausal women. The aging woman often will suffer from a “Relative Androgen Deficiency” with normal reference levels.

The prevalence of lower levels of Testosterone in the lowest quartile (lowest 25% of reference range) or below is seen in many conditions such as Decreased  Cardiac Output, Obesity, Type II Diabetes and Metabolic Syndrome (Laskowen. Diabetic Care 2004), AIDS, Hypertension, Hyperlipidemia(Jones et al 2005), Erectile Dysfunction, Coronary Artery Disease (Jones et al 2005), Inflammation ( Muller. Circulation 2005), Fractures from Osteoporosis (Coutinho 2011), Prostate Cancer (Bhasin, Am. J. Physiol.-Endocrinol. Metab.2001), Dementia (Tan and PU 2003),  Alzheimer’s (Zang et al 2004, Rosario and Pike 2008, Moffet et al 2004),  and Increased Mortality in men from ages 50-91. Testosterone levels were inversely related to central obesity, systolic blood pressure and Hg A1C(Swartberg. J. Epedimiology 2006, July 20). In one study it was shown that men who had levels of Testosterone in their blood over 564 had a 41% less chance of dying than those with levels at 350. For every increase of 173, the chance of dying went down by 14%. Extrapolating , a man with a Testosterone level of  910 would have a  69% decreased risk of dying compared to the man with a Testosterone level of 350. This particular study was done evaluating endogenous Testosterone vs. men with supplemented Testosterone. In another study of 800 men over the age of 50 that were followed for 18 years, there was a 33% increase in all deaths of those men in the bottom 1/3 of the reference range vs. men in the upper 1/3 of Testosterone levels. (Laughlin, GA. JClinEndocrinolMet. 2007, Oct.2)

There are a number of natural products that will help elevate Testosterone levels including, but not limited to, Calcium Fructoborate, Tribulus Terrestris (Adimoelja A 2000), Eurycoma, Panax Ginseng.

 Testosterone Replacement Therapy has been shown to decrease body, visceral fat, increase muscle mass, strength, endurance (Midtkin), increase bone density (Herbst), improve cognitive function (Kenny et al 2010), decrease insulin resistance, reduce depression(Morley 2003, Carnham and Perry 2004), increase feelings of “well-being” (Orengo et al 2004) improved lipid blood profiles(Jones et al 2005).

Testosterone Replacement Therapy has not been shown to increase prostate cancer risk or elevate PSA levels, and did not increase risk of Prostate Cancer from returning if no  Testosterone suppressing medications were never administered (Roddam et al 2008).  However, If a man has received Testosterone suppressing medications for Prostate Cancer, he should not ever take supplemental Testosterone (Morgentaler 2006, 2009). In reviewing all the literature, it appears to be a myth that there Prostate Cancer is perpetuated or caused by Testosterone (Roddam et al 2008, Morgentaler 2006, 2009). In fact, the literature confirms that men with the lowest levels of Testosterone appear to be at the greatest risk for developing Prostate Cancer (Pechersky et al 2002). It would also appear that men become at higher risk when their Testosterone levels drop and Estrogen levels elevate due to aromitization ( conversion of Testosterone to Estrogen) after the age of 50(Shibata Y et al 2000, Gann PH et al 1995, Krieg M et al 1993). What most men don’t realize is that the average 50 year old male is producing more Estrogen than a menstruating woman, and that this excess Estrogen is what is causing the inflammation, hypertrophy, and Cancer(Severiel 2006) as the Estrogen receptor sites in the prostate are being overstimulated.

There are two prestigious organizations that have endorsed Bio-Identical Testosterone supplementation for men, Life Extension and Harvard School of Medicine. In Testosterone For Life,Dr. Abraham Morgentaler, Associate Professor at Harvard School of Medicine, explains his favorable position regarding Testosterone supplementation in the aging male to reduce the risks we have been discussing. The fallacy of Testosterone Supplementation as a cause of Prostate cancer is discussed in great detail. The book gives in depth review of the scientific literature that indicates an 88% increased mortality rate in men with Low Testosterone levels. Life Extension recommends even higher levels of Testosterone should be achieved than the 6 Harvard doctors do.

There are three weighs to test your Testosterone levels; through the blood, through the urine, or through the saliva. Testosterone goes up and down in 2-3 hour cycles during a 24 hour period, fluctuating as much as 800%! It is normally highest in the morning. However, when getting a blood draw, you will not know of at the time of the draw if your levels were on the mountain or the valley of a cycle. You should never have ablood draw in the afternoon for Testosterone as it will surely be low. The other problem with testing Testosterone I the blood is that it is all bound to either Albumin(38%) or SHGB(60%), and therefore, is inactive. In other words, your body cannot use this hormone to activate the cell receptor sites. A 24 hour urine sample can be used to accurately evaluate Testosterone as well as all the sex hormones, but it is somewhat cumbersome to have to collect all your urine during a 24 hour period refrigerated, and then get it back to the lab. On the other hand, saliva testing is very accurate, especially when collected five times during the day in three hour increments, and testing is very  easily achieved by simply depositing a small amount of your saliva through a straw into a small plastic tube. Saliva is stable for days at room temperature. Saliva tests only the Free Testosterone, the 2% that is unbound and can be utilized to activate the receptor site. I prefer saliva testing for my patients for all these reasons.

Once Testosterone levels have been evaluated and found below optimum levels, there are a number of different ways to administer Testosterone. The first option is a synthetic form over Testosterone, which I would never recommend. What the so-called experts don’t tell you is that a FDA approved Synthetic Testosterone costs about $220)/month vs. a compounded bio-Identical Testosterone will cost you about $50/month. Synthetic Testosterone is an extraterrestrial molecule not designed for your body. Hormones work in a specific lock(receptor)/key(hormone) mechanism, and this synthetic key is not ideally suited for your lock. It may open the door , but it also can break the lock. Synthetic hormones have to be altered in order to patent them. We are already seeing the class action from the synthetic Testosterone because of increased heart attacks, strokes, and blood clots just like women’s synthetic Estrogen was shown to do in 2002. I warned of this in my newsletter on bio-identical hormones vs. Synthetic hormones last year. The administration of the Bio-Identical Testosterone can be in oral (pill) form, injection form, surgically inserted pellets, or transdermal patches or transdermal creams. The administration of oral Testosterone can sometimes alter taste buds or irritate the gums. Also, absorption can vary among individuals, and may result in too much getting absorbed into the bloodstream, and a negative feedback can be initiated by the Hypothalamus causing the Liver to produce more SHGB(Sex Hormone Binding Globulin) and dramatically reducing all your sex hormones. This can be stressful to the Liver. Intramuscular injections can cause fluctuation in mood and libido as supra-physiological doses are given weekly, bi-monthly, or monthly, depending on the recommendations of the doctor.  These supra-physiological can cause the activation of SHGB and the injections can be painful.. Also, there is increased risk for excessive erythrocytosis, a problem involving the red blood cells, especially in older men. Pellet implants are inserted every 3-6 months, but involve minor surgery, and the possibility of infection exists, and sometimes the pellets are expelled by the body. Transdermal patches are effective but can sometimes cause a skin reaction at the application site. Transdermal creams/gels are used 70% of the time. I prefer this methodology utilizing liposome technology, as this ensures the best passage to the receptor site. Transdermal cream with liposome technology is also known as a “first pass technology”, because the lymphatic system takes the hormone to the receptor site in the cell where it is absorbed and used up, before it gets to the bloodstream, and therefore, very little, if any, production of SHGB occurs.

I want to emphasize that I believe no man should take bio-identical Testosterone without keeping his Estradiol/Estrone in check. As men age, they will convert more Testosterone to Estrogen through the aromatase enzyme. High or low levels of Estrogen is detrimental to both Men’s and Women’s Health. As men and women age, there will be a tendency to have higher Estrone levels. Some of the metabolites from Estrone are carcinogenic. The average 50 year old man has more Estrogen than a menstruating woman! This not only increases the risk for prostate hypertrophy and prostate cancer (Severi et al 2006), but cardiovascular complications. A study published in theJournal of the American Medical Association (JAMA) measured blood estradiol levels in 501 men with chronic heart failure. Men in the highest Estradiol quintile were 133% more likely to die than the men in the healthy quintile. Men in the lowest quintile were 317% more likely to die compared to the healthy quintile group. The men in the healthiest group had serum Estradiol levels between 21.80 and 30.11 pg/mL. The deficiency of Testosterone and excess Estradiol/Estrone is epidemic in the Aging Male.

There are a number of natural aromatase inhibitors and/or  protectors to the prostate in men,  and breast, uterus, ovaries in women, including but not limited to Quercitin (Eng et al 2002), Nettles (Anon 2007, Chreubasik 2007)), Indole-3 Carbinol (Sepkovic et al 2001, Bradlow 2008, Muti et al 2002), I-3-CDiindolylmethane (DIM), Reversatrol, Chrysin, (Walle et al 2001), and Piperine Extract (Srinivasin et al 2007).

It should be borne in mind that a single hormone deficiency never exists. This is true for Testosterone as well. If there is a Testosterone deficiency there is a concomitant deficiency in Pregnenolone and DHEA(Martina et al 2006) as well, as these hormones are the pathway to Testosterone.

All hormones have to be hydroxylated, methylated, or sulfated  to be taken through the feces or urine for disposal from the body. These three processes are the ways the body makes our hormones water soluble to eliminate them. Some of these metabolites are carcinogenic in the hydroxylated form, i.e. C-4 hydroxyestrone and especially C-16 hydroxyestrone. Both men and women are at risk from this process. This is why the ability to methylate is so very important. Methylation changes the hydroxy form to a methylated form that is not carcinogenic! Adequate folate, B6, and B12 are essential, as they are our primary source of methylation!  Without adequate levels of Folate, B6, and B12, we are at increased risk of prostate cancer in men, and breast, uterus, and ovary cancer in women, because of our inability to methylate the hydroxy forms. About 22% of the population has a gene variant related to B vitamin absorption/utilization. See Genetic Testing for Nutritional Needs! We will discuss these problems in a greater detail in our chapter on Estrogen.

Kelly Miller, DC NMD FASA FBAARM CFDMP*, physician for Hoffman Clinic for Optimal Health.

*There is currently no licensure for Naturopathic Physicians in the state of Florida and the Bard of Chiropractic Medicine does not currently recognize the Fellowship in Aging and Regenerative Medicine (FBAARM) from the Brazil-American Board of Aging and Regenerative Medicine or Certification in Functional Diagnostic Medicine (CFDMP) from Functional Medicine University.


                                                                    Estrogen

Estrogen is a group of compounds including Estrone(E1), Estradiol(E2), and Estriol(E3) .It is found in both men and women, but in much larger amounts in younger women than younger men. However, after age 50, men have more Estrogen in their bodies than a young 20 year old menstruating woman!

The manufacture of Estrogen occurs mostly in the corpus luteum of the ovaries by the developing egg follicles. It is also produced by the placenta during pregnancy, and in lesser mounts, the liver, adrenal glands, and breasts.

Estrone(E1) is secreted by the ovaries as well as the body fat. Estrone levels are very relevant to health and disease states. Estrone is converted to Estrone Sulfate which is a water soluble reservoir which can be converted back to Estrone as needed.m

Estradiol(E2)- 17B Estradiol is the predominant sex hormone in women. It is in a large pool with Estrone(E1). Estradiol is also produced by males as an active metabolic product of Testosterone. Estradiol represents the major form of estrogen in humans. It has a major impact on reproduction, sexual functioning, and on many organs, including the bones. Estradiol synthesis is derived from Cholesterol via the delta-5-pathway or the delta-6-pathway. Adrostenedione is the key intermediary. Part of Androstenedione is converted to Testosterone. In turn, Testosterone undergoes conversion to estradiol by an enzyme called aromatase.

The third and probably least understood form of estrogen is Estriol (E3). It is important in maintaining pregnancy as levels increase 1000% as does Progesterone during pregnancy. It is a protective form of estrogen and benign, meaning it does not have carcinogenic metabolites. Estriol is the end of the line for the cascade of all the hormones. The largest Estriol(E3) production occurs during pregnancy and it does not change much after menopause. It is the smallest pool of Estrogen in women., and is protective of the breast, uterus, and ovary tissue. Pgu, U, Bradlow, HL, Lvitz, M (1990) “ Estriol-3-sulfate in human breast cyst fluid concentration, possible pregnancy, and physiological implications” Ann N Y Acad Sci 586. 83-87. It is only found in minute amounts in men , and is not currently thought to be important in men’s health.

Some of the more important functions or roles of Estrogen are that it increases metabolic rate, blood flow, reasoning and new ideas, water content of the skin, HDL by 10-15 %, concentration, and sexual interest. Estrogen decreases the plaquing in the arteries, blood pressure, LDL and prevents oxidation, Lipoprotein A, wrinkle, and risk of colon cancer. Estrogen helps to prevent muscle damage, maintain muscles, deep sleep, maintain memory, fine motor skills, prevent tot loss, and maintain bone mass. Estrogen contributes to the development of secondary sex characteristics, defining the difference between men and women which include the breasts, the widened pelvis, increased amounts of body fat in the buttocks.

The three compounds, Estrone, Estradiol, Estriol are seen at work during the reproductive or follicular phase begins with the first menstruation and ends with menopause. During this time, Estradiol is the dominant estrogen. Estradiol is produced from androgens and Testosterone. Estrone is made from the intermediary Androstenedione.

A significant reduction in Estrogen occurs after Menopause. This reduction in Estrogen can lead to vaginal dryness and shrinkage, memory problems, hot flashes, night sweats, irritability, and decrease in bone density. These negative symptoms can be negated with Estradiol/Estriol bio-Identical supplementation.

The properties of Estrogen are many and varied and some are the following: creates the endometrium, sexual development at puberty, regulates menstrual cycle, moistens vaginal tissue, slows bone loss, anti-aging factor, increases sensitivity of progesterone receptors, affects more than 300 tissue systems, in the body, can reduce the incidence of heart attacks, uplifts the mood, lowers LDL, increase HDL, decreases Lipoprotein A and homocysteine, affects every neurotransmitter in the brain; including Serotonin, Dopamine, and GABA, adds moisture to the skin, affects brain function for memory and motivation, needed for verbal memory, needed to learn new concepts and reasoning, and fine motor skills.

Estradiol is essential to our bone growth. Without Estradiol, there is no epiphysial closure. Generally, tall and eunuchoid women have a later onset of puberty. Estradiol is what creates the protein matrix in the bone and its loss can cause early osteopenia and osteoporosis.

Canani C. Qin K. Simoni M, Fausinith, Serpente S, Boyd J, Korach KS, Simpson ER. “Testostereone and Estradiol in a man with aromatase deficiency.” New England Journal of Medicine Volume 337.91-95 July 10, 1997.

Estradiol has complex function and effects on the liver. Excess can lead to cholestasis(where the liver does not produce bile to digest fats). Estradiol affects the production of protein in the liver including lipoprotein A, binding proteins, and the protein responsible for blood clotting.

Canani C, Qin K, Simoni M, Fausinith, Serpente S, Boyd J, Korach KS, Simpson ER. “ Effect of Testosterone and Estradiol in a man with aromatase deficiency.” New England journal of Medicine Volume 337.91-95 July 10, 1997.

Estradiol affects many functions in the brain. It protects the neurons from free radicals acting as a powerful anti-oxidant. Via Estradiol, the Ovaries are linked to the Hypothalamus-Pituitary through positive and negative feedback system that Gonadatrophin regulates. Estradiol regulates Serotonin, Dopamine, and GABA. Without adequate levels, depression can occur. When Estradiol levels are not stable, it can lead to post-partum depression, perimenopause, and menopause depression.

Behl C, Wickman M, Trapp T, Holdsboer F. (November 1995) “17-Beta Estradiolprotects neurons from oxidative stress-induced cell death in vitro.” Biochem. Biophys. Res. Commun. 216(2):473-82.

Docima SI, Husband C, O'Donnel ME, Barwin RN, Woodend AK. (2005) “ Estrogen-related mood disorders reproductive life cycle factors.” Ans. Adv. Nurs. Sci. 28(4)3:364-75.

Lasiuk GC, Hegidiren KM. (October 2007). “ The effects of Estradiol on central seritonergic system and its relationship to mood in women.” Biol. Res. Nurs. 9(2):147-60.

In Menopause, Estriol controls hot flashes, insomnia, and vaginal dryness, and can be used as replacement therapy for these symptoms.

Head K, “Estriol, safety and efficacy.” Alter. Med. Rev. 1998;3(2):101-3.

Tzay-Shing, et al. “Efficacy and safety of Estriol replacement therapy for climacteric women.’ ’Chin. Med. J. (Tarpei)195.35.386-91.

Tzinjouris V., et al. :Estriol in the management of Menopause.”JAMA 1978.239.1638-1641.

Estriol helps maintain your GI tract for the growth of good bacteria and reduces pathogenic bacteria. Estriol helps restore the normal PH of the vagina which prevents UTI’s. It increases HDL, and thickens and moisturizes the vaginal lining.

Stam W, et al. “A controlled trial of intravaginal Estriol in post Menopausal women with urinary tract infections..” NEJM 1993; 329(1):753-756.

Collins, J. “ What’s your Menopause type/’ Roseville, CA. Prima Health 2000

Vander Linden, M et al. “The effect of Estriol on the etiology of urethra and vagina in post Menopausal women with genito-urinary symptoms. Eur. J. Obstet. Gynecol. Reproduct. Biol. 1993;51(1).29-33

Estrogen Self-Assessment                                  

Estrogen Deficiency                                         Estrogen Excess

Sagging breasts                                                 Water retention

Lack of libido                                                      Cervical dysphasia/fibroids

Vaginal dryness                                                  Cancer

Urinary incontinence/infection                            Hypothyroidism

Hot flashes                                                         Fatigue 

Night sweats                                                      Poor sleep

Memory  problems                                             Bloating

Fuzzy Thinking                                                   Anxiety/Fear

Irregular menstrual cycle                                    Breast swollen/tender

Lack of menstruation                                          Severe headaches

Thinner Skin                                                       Excess menstrual bleeding

More wrinkles/skin aging                                     Weight gain   

Increased Insulin resistance                            Increased Breast Cancer  

Diabetes                                                              In Men

Osteoporosis                                                      Enlarged breasts

Increase Cholesterol/Heart problems                 Prostate enlargement

                                                                            Difficulty urinating

                                                                            Increased emotionability

                                                                             Frequent forgetfulness  

The roles of Estrogen in men will be discussed next. Testosterone is produced in the Leydig cells of the testicles. The Testosterone is then carried tissues having Estrogen receptor cells, where the aromatization of the Testosterone to Estradiol occurs, within the receptor cell itself. This local cellular aromatization was not discovered until the work of Dr. Sharpe in 1998. This local transference of Testosterone into Estradiol at the cellular level changes the way we think of Estrogen related cancer of the breast, uterus, and ovaries.

Sharpe, RM. “The role of Estrogen in the male.” TEM Vol 9N091998.

Estrogen can also come from the body fat in men. Estrogen in men has has been active in every tissue studies. The Hypothalamus has a high concentration of both alpha and beta Estrogen receptors. These high levels of Estrogen and Aromatase receptors control the man’s sexuality, his libido, and his erectile function. The Brain is the largest sexual organ in the body. How does Estrogen help with erectile dysfunction? Estrogen produces the eNOS, i.e. nitric oxide production in the pelvic and penile arteries that causes vasodilatation, and increasing the nitric oxide in the sexuality centers in the brain. It is Estradiol that is necessary to activate the eNOS activation or nitric oxide production. Estradiol is also necessary for the pro-inflammatory activity involved in vascular plaquing, i.e., iNOS, MMP’s, IL-6, Cox2. This is why men’s cardiovascular risk increases if Estradiol levels are either too low (not enough nitric oxide), or too high (too much inflammation). Interestingly enough, too low of Estradiol levels in men increases cardiovascular risk more than excess Estradiol.

Estrogen receptor alpha and Estrogen beta receptors are what actually provide the brain function of sexuality, the modulation of hormone secretion from the pituitary, the bone growth, mineralization, epiphyseal closures, inhibition of bone absorption, the cardioprotective changes that increase HDL, lower LDL, increase vasodilation, the fat depositions and fat utilization for energy, and the widespread effect on all genital tissues and testicular function. There is aromatase activity in all these tissues. This means these tissues are not dependent upon the circulating hormone in the blood.

In Aromatization Deficiency Syndrome, the male phenotype features are preserved, but because of the lack of estradiol feedback, the testes enlarge. Testosterone levels are 2-3 x normal with very low Estrogen levels. Erectile function is preserved, but the libido is low or absent. Reduced ossification occurs. Osteopenia or osteoporosis can occur like in a post-Menopausal woman. It can cause a lack of epiphyseal closure, causing a taller status. There is increased atherosclerosis and calcification in the arteries, because of the absence of Estradiol protection.

J. Clinic. Endocrinol. Metab. “Too little or too much Estradiol increases cardiovascular risk.”

Syndrome X is known for the characteristics of dense LDL, increased triglycerides, low HDL2, hyperinsulinism, insulin resistance, early onset diabetes, obesity, and hypertension risk. All these changes move toward normal with Estradiol treatment, including the regression of carotid atheromas.

J. Clinic. Endocrinol. Metab.

Evaluating hormone levels in the blood or saliva only gives the doctor half of the information he or she needs. The other half of the information is in the receptor cells that need the hormone.

Estrogen receptor Alpha polymorphisms or gene variants can occur. This causes high Estrogen levels. The phenotype appears normal. However, this causes the same pathologies as Aromatase Deficiency Syndrome causing increased atherogenesis and Syndrome X changes. Estradiol treatment improves the patient with the Estrogen Receptor Alpha Polymorphism. Without treatment, the patient will have increased cardiovascular risks and early onset of disease.

Circulation 96.3774-3777. JAMA 290.2263-2270.

There are two patterns of Testosterone deficiency in men. The first is non-specific reduction in Testosterone production. There is normal or slightly elevated FSH/LH and there are low Estrogens. These are normal aging changes in some men. The other pattern of low Testosterone is accompanied with high Estrogen, normal or slightly low FSH/LH, Syndrome X, NIDDM (non-insulin dependent Diabetes Mellitus) and Obesity.

What are some of the other Estrogen problems in men? There are some men who have an increase in aromatase because of their genetics. These individuals will demonstrate gynecomastia, decrease in libido, erectile dysfunction, and infertility at a young age. There are also acquired Estrogen dominance brought on by mid-life Obesity and Syndrome X. These men will exhibit poor Testosterone treatment response as their levels of Estrogen rise from aromatization. These men will benefit from aromatase inhibitors. As men get older, they will produce more Estrone from the Adrenals and body fat.

Levels of Estrogen are important in the function of Insulin production., just as they are in cardiovascular risk. Too much or not enough Estradiol increases insulin resistance. Everything in nature is about balance. The more Estradiol and the less Testosterone, the more obese, and the higher the B. M.I. index.

J. Clinic. Endocrinol; Dobs, AS, et al.

In Obesity in men, lower serum Testosterone levels are seen with low SHGB (Sex Hormone Binding Globulin), normal free Testosterone, higher Estradiol and Estrone levels, with normal FSH/LH. Estradiol and Estrone are proportionate to body fat. The more body fat, the higher the Estrogen levels. Other markers of Estrogen excess will be evident as signs of feminization such as roundness of the belly and hips and thighs, and gynecomastia. In conclusion, if defective Estrogen receptors are present, decreased Testosterone is present as there is increased clearance of Testosterone, and elevated production of Estrogen occurs.

Schneider, GJ. Clinic. Endocrinol. Metab. Vol. 48.633-638. 1979

There are two other genetic variances of Estrogen involving the 17BetaHSD enzyme. If there is an increase in the enzyme, there will be increased aromatase activity causing the conversion of Estrone to Estradiol. If there is a decrease of this enzyme, instead of Androstenedione being converted to Estrone, it is converted to Testosterone.

J. Androl. 1990 Nov-Dec.:11(6).485-90.

Some types of Coronary Artery disease pathophysiology are influenced by Estrogen. There are two types of plaquing, one with calcification and one with soft plaquing. Coronary calcification is a highly significant factor in Coronary Artery Disease plaque, CV events, and mortality. There is a poor association between this type of plaque, and Cholesterol and Triglycerides, and traditional risk factors. This type of plaquing has a high correlation with the steroid hormones such as Parathyroid Hormone, Vitamin D, Estrogen, and Testosterone.

Fitzpatrick, et al. Endocrinology. 144(6) 2003.

Conversely, it is the soft plaque that is associated with VLDL’s and sudden death from the eruption of the soft plaque and foam cells. See “Heart Health” newsletter.

The next section focuses on Estrogen in the aging male and female, how Estrogen is excreted from the body, and some of the difficulties that can occur in this process, and how genetic variances in Estrogen can express itself in body functions, i.e., the epigenetics. Mainstream Western Medicine is based on a concept that we should look at ‘normal” people to determine the different needs for vitamin, mineral, and anti-oxidants intake. This concept was originated from Roger Williams in 1956. We now have confirmation from genetic testing that there are many genetic variances among individuals that affect the way we absorb, use, or react to certain nutrients or drugs. Moreover, this concept of variances among individuals is not new as the differences between individuals was discussed in Indian Ayurvedic Medicine, Chinese Traditional Medicine, and Ancient Greek Medicine. These differences and their influences were taken into consideration in the diagnosis and the treatment of individuals for thousands of years. We now know that individuals have varying amounts of receptors in their bodies which influences the dosing of a nutrient or drug. Likewise, dosing can vary for different sized individuals, different types of metabolisms, different builds, acute vs. chronic conditions  severe vs. mild conditions, etc. this is true for hormone therapy as well. Dosing must be individualized based on the needs of the patient.

Original synthetic hormones were called Triests, because it combined all three Estrogens; Estrone, Estradiol, and Estriol. Because the Estrone metabolites can be very carcinogenic, i.e. C16-alpha-hyodroxyestrone, physicians stopped using Estrone in formulations. Physicians opted for biest formulations containing only Estradiol and Estriol.  Estrone is closely related to our body mass index, and overall insulin levels, and insulin receptors. Estradiol is the most potent form of Estrogen, being 12x more powerful than Estrone and 80x more powerful than Estriol. High levels of Estradiol are associated with pre-menstrual syndrome, ovarian cysts, uterine fibroids, endometrial fibroplasia, and increased risk for Breast Cancer. Estriol is the smallest fraction of Estrogen, is not carcinogenic, and in fact, demonstrates anti-cancer properties.

Estriol can be used in bio-identical formulations. We recommend 4x more Estriol than Estradiol because it occupies the receptor site and keeps the more potentially carcinogenic Estrone and Estradiol from causing much of a problem. Estrone and Estradiol share a common pool together, and depending on the needs of the individual can enzymatically change from one to the other. This pool helps balance the amount of Estrogen available for the individual. To get rid of excess Estrogen, Estradiol will convert to Estrone. To begin the detoxification of Estrone from the body, it goes through a process called hydroxylation.  Hydroxylation (adding an OH group) makes the hormone more water soluble, so we can get rid of it through our sweat, urine, or stool. This hydroxylation process forms the metabolites 2-hydroxyestrone, 4-hydroxyestrone, or 16-alpha-hydroxyestrone. In a normal metabolism, 50 % is converted to 2-hydoxyestrone, 10% to 4-hydroxyestrone, and 40% to 16-alpha-hydroxyestrone. However this ration can change due to genetic variances. The 16-alpha-hydroxyestrone is very carcinogenic. The 4-hydroxyestrone is mildy carcinogenic. The 2-hydroxyestrone is benign. The second phase of Estrogen detoxification is called methylation. This is when a methyl group (CH3) is added to the metabolite. When the methyl group is added and displaces the hydroxyl group, the metabolite becomes benign. The genes play an important role in Estrogen metabolism. If the 2-hydroxyestrone is safe and, in fact protective, why would we produce the 4-hydroxyestrone or the 16-alpha-hydroxyestrone? This is where the genetic variants come into play. These variants are also called polymorphisms. 22% of the population has a gene variant or polymorphism involving Estrogen. When the 2, 4, 16 hydoxyestrones are out of balance, and fail to methylate, there is an increased risk for Breast Cancer or Osteoporosis. 2–hydroxyestrone is a weak binding Estrogen. High levels decrease the risk for Breast cancer, but increase the levels for Osteoporosis. 16-alpha-hydroxyestrone is a stronger binding Estrogen to the receptor. High levels increase Breast Cancer risks. 2-hydroxyestrone/16-alpha-hydroxyestrone ratios are a very important health risks.  A low ratio increases Breast Cancer risk. Too high a ration increases Osteoporosis risk. Like many things in nature, it is optimum to be balanced.  The ratio is important in the survivability and risk of Breast Cancer recurrence. The survival rate for women who have low levels of 2-hydroxyestrone is only half that compared to those with normal ratios. What is a normal ratio? We want as much of 2–hydroxyestrone compared to 16-alpha-hydroxyestrone or more, a 1:1 ratio or 1+:1 ratio. When 2-hydroxyestrone ratio is less than one, there is a 30% increased risk for Breast cancer. It is easier to raise 2-hydroxyestrone than to lower 16-alpha-hydroxyestrone. How can we raise the 2-hydroxyestrone? We can supplement with flaxseed, omeg-3-fatty acids, soy isoflavones, rosemary, turmeric, kadzu, strenuous exercise, weight loss, chrysin, indole-3-carbinol (I3C), or Diindolymethane (DIM). Research has shown that 400 mg of I3C increase the 2:16 ratio by 66%

Some polymorphisms make Estrogen metabolism incapable. Others will make the second phase more difficult. This causes a build up of toxic intermediate metabolites which will impact health and longevity. Specific kinds of nutrients such as B vitamins make tremendous difference in these genetic predispositions.

In normal metabolism, 50% of the time, the hydroxyl group is placed in the 2 position, 40% of the time in the 16 position, and 10% in the 4 position. Genetic predisposition drives Estrogen to the 4-position or 16-psition. 28% of the population has a genetic predisposition to place the hydroxyl in the 4 –position.

The most common form of polymorphism is called a (SNP), Single Nucleotide Polymorphisms. The good news is that 80-90% of these (SNP) are unimportant. The bad news is that 10-20% of these are clinically important. The changes always occur in the enzymes, rendering it non-functional. These variants can have a tremendous impact on our ability to utilize folate, riboflavin, B12, anti-oxidants, CoQ10, or I3C, etc. 20% have a variant called CYPIAI, the carrier that causes reduced amounts of 2-hydroxyestrone, decreased ability to metabolize acetaminophen, and decreased effective detoxification with Sulforaphanes like broccoli and brussel sprouts. 2 % of the population has a CYPIBI variant which causes increased formation of 4-hydroxyestrone which increases breast, ovarian, uterine, head, and neck cancers. Many people that have this variant never express the epigenetics because they take more of specific nutrients such as B vitamins, DIM, and Glutathione. Smoking increases the expression of the CYPIBI gene, and without adequate extra nutritional support, the gene variant increase the risk of Breast Cancer by 13-fold. Cruciferous vegetables such as broccoli and brussel sprouts, and or supplementation of I3C and DIM directs Estrogen to the 2 position and improves 2:16 ratio, and inhibits the expression of the CYPIAI gene variant. Supplementation of Reversatrol from red wine and DHEA inhibits the induced expression of the CYPIBI gene. Reducing the amount of Xenoestrogens from plastics and pesticides is important.  COMT polymorphism is critical as it reduces the phase II detoxification, which is the methylation process. This is the process that turns the 2,4, 16 hydroxyestrone into a 2, 4, or 16 methoxyestrone which is less carcinogenic. The COMT polymorphism reduces the phase II detoxification process by 400-700 %, increasing the risk for Breast Cancer. Most importantly, Estrogen detoxification pathways require adequate B vitamins. This is significant because it is estimated that 80 % of the American population is deficient in one or more B vitamins. An indirect way to measure methylation is through homocysteine. A better measure of methylation capacity is through urinary methylmalonic acid. Treatment of COMT polymorphisms are Cruciferous vegetables (broccoli, cauliflower, brussel sprouts, kale), garlic, onions, magnesium, NAC, vitamin E, Glutathione, glutamine, and glycine.

Glutathione-S-Transferase is an important Phase II enzyme which acts as a powerful ant-oxidant, makes the molecule more water soluble by adding Sulfur, and metabolizes carcinogenic Genomes. This is an extremely significant polymorphism or gene variant affecting 40% of the Caucasian, 22 % of the African-American, and 8% of the Asian populations. This is why Glutathione supplementation with sublingual liposome technology is so important to negate this gene expression.

Copyright 9/3/2014

Kelly Miller DC NMD FASA FBAARM