Bioidentical Hormone replacement for Men
By Michael A. Werner, M.D., FACS
Andropause describes an emotional and physical change that many men experience as they age. Although the symptoms: low sex drive, low energy level, and loss of strength and muscle are generally related to aging, they are also associated with significant hormonal alterations. We have known for a long time that the production of hormones by the testes slowly decreases as men age. Only recently has interest developed in the clinical implication of this condition. The condition has several names including male climacteric andropause, late onset hypogonadism, or androgen decline in the aging male (ADAM).
The process of andropause is not universal and occurs subtly over time rather than as an abrupt change with the end of the reproductive cycle that women experience.It is for this reason that the symptoms have a tendency to be ignored and are considered almost an unavoidable result of the aging process.Until recently, physicians had not targeted these symptoms or looked for a solution.
Andropause is a fairly common condition and the incidence of it increases with age.The incidence from ages 40 to 49 is estimated between 2% to 5%; from ages 50 to 59, it is estimated between 6% to 30%; from ages 60 to 69 it is estimated between 20% to 45%; and from ages 70 to 79, it is estimated between 34% to 70%.The incidence in men who are over 80 is estimated at 91%.The “spread” of normal ranges is fairly large because different specialists use different ways to measure androgens and use different levels to define andropause.
Andropause is identified as a drop in androgens.Androgens are the overall grouping of male hormones.They are made in the testes and in the adrenal gland (a small gland located above the kidney that produces a significant number of hormones).The main functions of androgens are:
* Initiation and maintenance of spermatogenesis.That is, they signal a man’s body to produce sperm.
* Determination, during pregnancy, that a fetus will be male.
* Sexual maturation at puberty, controlling sexual drive and potency.
Relative Androgenic Activity of Adrenal Androgens
DHEA, DHEA-S 5
In men, androgens are known to affect muscle, bone, the central nervous system, prostate, bone marrow, and sexual function.
We know that testosterone causes “the androgenic effects,” determining and shaping the male reproductive tract in an infant as well as the development of secondary sexual characteristics (body hair and male pattern baldness are examples).Androgens are also responsible for prenatal differentiation of the male fetus and for the development of the male reproductive tract.Androgens play an important role in stimulating and maintaining sexual function in men.Testosterone is necessary for normal libido, ejaculation, and spontaneous erections.
Anabolic effects are those that promote growth.They affect other tissues such as muscle mass and bone density.Androgens increase lean body mass and affect body weight as well.Androgens are required to maintain bone density in men.It is still not clear whether the androgens are needed themselves to affect the bone or whether it is important that they be present so that when they are converted to estrogens, the estrogens have an effect on the density of the bones.
Androgens can also affect red blood cell production and they appear to have an effect on blood fats and cholesterol.The most well-known effect of androgens is their effect on growth of the prostate.They affect both the non-cancerous and potentially cancerous cells in the prostate.
Androgens also play an activating role in cognitive function throughout life, keeping men sharp and alert.The relationship between androgens and mood is still unclear, but in-depth exploration has begun.
There may be many factors that contribute to andropause, but it is clear that one important reason for an aging man's decline in testosterone is that the testes begin to fail.As men get older, the Leydic cells, which produce most of the testosterone in the testes, do not secrete testosterone as frequently, and each secretion, on average, includes less testosterone.
Additionally, as men get older, there is a decrease in the hormones that prod the testes to make testosterone.Finally, there is an increase in the conversion of testosterone to other hormones, including estradiol and DHT.While testosterone levels decrease with age, DHT levels tend not to fall as significantly.
Specialized cells in the testis, called Leydic cells, make testosterone. An adult male produces approximately five grams of testosterone per day.Testosterone releases in pulses or bursts.There is a daily pattern to the secretion of testosterone, with a peak occurring early in the morning and a low point in the late evening.
Only certain cells have receptors for testosterone and some of these cells later convert the testosterone into Dihydro-testosterone (DHT). DHT is three times as potent as the testosterone itself. Interestingly, the testosterone can also be converted into estrogens (the main female hormone).This occurs particularly in fat cells.
Most testosterone in the body is bound or “attached” to proteins.Thirty percent is bound to a type of protein known as sex hormone-binding globulin (SHBG).The testosterone binds very tightly to SHBG, which has a tendency to increase as men age. The remaining testosterone is bound much less tightly to other proteins in the blood, the most prevalent being albumin.Two percent of the testosterone is unbound (not attached to any other protein) and is called free testosterone. Free and albumin-bound portions of testosterone make up the measure known as “bioavailable testosterone.” This is the testosterone that is seen in the tissue and that has the most effect on the body. Thus, any change will affect the total amount of available testosterone. The amount of SHBG, or blood proteins, also will affect the amount of available testosterone and will have an effect on the body.
As men get older, their SHBG increases, leaving less available testosterone. Other hormones can also affect SHBG. Elevated female hormones and thyroid hormones will increase SHBG, which will then, in turn, affect the bioavailable testosterone.
Since some of the symptoms associated with decreased androgens in the aging man may also be caused by similar decreases in other hormones, testosterone replacement may not completely resolve all of the symptoms. However, at this point, there appears to be good evidence that testosterone replacement can improve many of these symptoms.
Many of the active androgens in the body are not produced by the testes but by the adrenal glands. The major androgens created by the adrenal glands are DHEA, DHEA-S, and androstenedione. Although these androgens are not very strong, they are converted to the much stronger androgens: testosterone and DHT. However, they are a small percentage of the total androgens available in men. In men, the adrenal gland secretes approximately 3 to 4 mg of DHEA per day, 7 to 14 mg of DHEA-S per day, and 1 to 1.5 mg of androstenedione per day.
The adrenal steroid, DHEA-S, is the most plentiful steroid in circulation in the body.The amount of DHEA-S concentrated in the body is very dependent on age. Men have the most in their 20s and 30s. By his 70s, a man's DHEA-S level is down, on average, to twenty percentof its highest value.
Despite many years of intensive research, we don't know a great deal about the specific function of DHEA-S in the body. However, we think it has a "protective" role. It appears that the higher the DHEA/DHEA-S levels, the lower the incidence of cardiovascular disease and various forms of cancer, as well as many other aspects of cellular aging.
DHEA is considered the "mother" hormone. It is the hormone in the body that is later converted into other hormones, including testosterone. DHEA is first produced in children at the age of seven years. It reaches its peak production for men in their teens and twenties. From that point, it subtly decreases over a lifetime. Synthetic DHEA is widely available and widely used. It appears to be relatively safe. However, there is no evidence at this point as to whether or not it is effective in creating any changes in the aging male.
Growth hormone levels control the production of insulin-like Growth Factor 1 (IGF-1) that affects the body's composition, lean body mass, and bone density. As growth hormones decrease, so does IGF-1. Growth hormone production decreases after puberty at a rate of approximately 14% every 10 years. This decrease in growth hormone is called somatopause (similar to the decrease in androgens being called andropause). It appears that administration of growth hormone can help improve body composition with increases in lean body mass and bone density.
The pituitary hormone that stimulates the thyroid to make thyroid hormones is called TSH. As men get older, TSH decreases and the thyroid becomes less responsive to TSH. As a result, there is a decrease in the circulating amounts of thyroid hormones. Clinically, this may result in symptoms of hypothyroidism or decreased thyroid in the elderly. Decreased energy, metabolism and mental acuity are some of the symptoms. It is estimated that close to 20% of elderly men suffer from these symptoms.
Andropause is most commonly characterized by a subtle and insidious onset and very slow progression of symptoms. Often, these changes are attributed to the natural and unavoidable consequences of aging. However, not all men show these changes as they age and not all men show a significant decrease in androgens as they age. The andropause syndrome is characterized by:
* Diminished sexual desire and erectile quality. In particular, a decrease in nocturnal erections is a significant sign of decreased androgens. with a decrease in intellectual activity, fatigue, depression, anger, and poor spatial orientation.
* Mood changes. This can be also associated with a decrease in intellectual activity, fatigue, depression, anger, and poor spatial orientation.
* A decrease in lean body mass, along with decreases in muscle mass and strength.
* A decrease in body hair.
* A decrease in bone density, resulting in osteoporosis. Osteoporosis can often lead to increased incidence of bone fractures and breaks.
* An increase in fat surrounding the internal organs.
It is important to remember that not all of these symptoms need to be present to identify andropause. Also, it is important to remember thatsymptoms do not all appear to the same degree in all men. Some men may suffer from only one or two of these symptoms and at varying degrees.
Using a screening questionnaire can be helpful in diagnosing andropause. The most useful questionnaire is the ADAM Questionnaire. It is very simple and very effective at identifying those men who suffer from andropause. However, not all men who screen positively for these symptoms have andropause. The symptoms may be the result of other causes so a positive diagnosis can only be made with appropriate blood testing.
Generally, only a blood test can definitively diagnose andropause. After the age of 50, the average testosterone level decreases at a rate of approximately one percent per year. However, if only absolute testosterone levels are evaluated, many patients with andropause will be missed. There may be an increased level of sex hormone-binding globulin that binds the testosterone and makes less of it available to the tissues. Also, as men get older, the daily rhythm to the secretion of testosterone changes. Younger men have higher testosterone in the morning, which then decreases as the day wears on. In older men, this curve is flattened, leading to steady low levels of testosterone throughout a 24-hour period.
Here are some issues regarding testosterone that are important to remember:
* It is not yet known what level of serum testosterone defines a deficiency in older men. Generally, it is accepted that two standard deviations below the normal values for young men is considered abnormal.
* A man may have large variations in his serum testosterone levels over time. Since he may have normal testosterone levels one day and have decreased testosterone levels the next, it is important to look at hormone levels over a period of time.
* In older men, affected organs may respond differently to androgens.
Not all men will need the same level of testosterone to maintain proper function of their brain, bone, prostate, or muscle cells. Therefore, it would be incorrect to say that there is one standard level of testosterone that should be achieved by all men. Rather, the patient and the physician work together to find the level of testosterone that is most effective for the particular patient.
There remains significant controversy as to how best to measure testosterone levels and diagnose andropause. It is well accepted that if total testosterone is less than 200 ng/dl, a man will be considered as having a low testosterone level. If his total testosterone is greater than 600 ng/dl, low testosterone may be ruled out.
The analog-free testosterone method is the most commonly used test by most large commercial labs in the United States, but it is not considered a very accurate way of measuring testosterone. The best measurement of hormonal statusis either free testosterone or bioavailable testosterone. These measurements may only be available through specialty laboratories.
It is important to remember that there is significant variation in the recommendationsof what tests should be used in order to establish a biochemical diagnosis of andropause. However, it is widely accepted that the blood work should be done in the morning before ten o'clock to capture the potential peak values.
Testosterone Replacement Therapy
Therapy for andropause is often very effective. Treatment goals include restoration of sexual functioning, increased libido, increased sense of well-being, prevention of osteoporosis by optimizing bone density, restoration of muscle strength, and improved mental functioning. Biochemically, testosterone replacement should aim not only to reach normal levels of serum testosterone, but also to normalize levels of those secondary hormones that are affected by testosterone levels. These include DHT and estradiol.
Current treatment options include oral tablets or capsules, injections, plantable long-acting slow release pellets, and transdermal (through the skin) patches and gels. However, at this point, the vast majority of testosterone replacement is done through the skin. This method has a number of advantages:
* It is easy to apply.
* It is relatively safe with low incidence of side effects.
* It more closely mimics the natural daily rhythm, with higher levels of testosterone delivered in the morning and decreasing levels delivered as the day progresses.
There have been a number of studies involving hormone replacement therapy in men. Unfortunately, at this point, we are approximately 20 years behind the studies of hormone replacement therapy of postmenopausal women, so many of these studies are preliminary. However, they do point to a number of definite benefits of testosterone replacement:
- Improved sexual function: In general, testosterone has proved relatively effective for men who have low libidos (desire levels). Libido is believed to be significantly hormonally dependent.
- Improved erectile function: Erectile function is a more complicated phenomenon. There is a proven significant interaction between the hormonal level and sexual functioning, but many other factors are also involved. Newer studies seem to show that men and women will respond more effectively to traditional treatments for sexual dysfunction (including oral medications and injections) if they have adequate testosterone levels.
- Improved mood: In recent studies, older men on testosterone seem to report an improved sense of well-being and an overall improvement in mood when compared with similar men who have received a placebo. Energy levels often also improve.
- Improved body composition and strength: Studies evaluating body composition have consistently shown that with testosterone therapy, there is a decline in body fat, an increase in lean body mass (largely muscle mass), or an improvement in both. Several studies also indicate that muscle strength improves, affecting the upper and lower extremities such as hands, arms, and legs.
- Increased bone density: Low bone density or osteoporosis is an increasing problem in men. Men with osteoporosis have a relatively high incidence of bone fractures and, most significantly, hip fractures. Hip fractures in older men are closely associated with disability and death. Testosterone therapy has been shown to increase bone mineral density, especially in the spine. It has also been shown to decrease the rate at which bone is lost.
- Improved cardiovascular system: Men overall have a higher incidence of cardiovascular disease and cardiovascular-related deaths than women. It is not known whether this is due to the beneficial effects of female hormones (estrogens) or lifestyle patterns of women, or whether male hormones play a negative role in the cardiovascular system. However, it is believed that androgens may help lower the risk factors for cardiovascular disease, including serum lipoprotein profiles, vascular tone, platelet and red blood cell clotting parameters, and the process of atherosclerosis.
Early studies have shown that testosterone therapy may decrease platelet aggregation (clumping) and dilate blood vessels. This would have a positive effect on the cardiovascular system. Interestingly, and very importantly, testosterone therapy in older men has led to a decrease in total cholesterol levels. It has also led to a decrease in low-density lipoprotein cholesterol (bad cholesterol levels). These changes, however, have been modest. There has been no significant change in high-density lipoprotein cholesterol levels (HDL or good cholesterol levels) as a result of testosterone therapy. Basically, the effects of androgens on cardiovascular disease are unknown.
Men with a history of prostate cancer or breast cancer are absolutely not candidates for testosterone therapy. The testosterone can make both of these hormonally sensitive cancers grow more rapidly.
Other negative effects may include:
- Fluid Retention: It is possible, especially within the first few months of treatment, for a man to retain fluid. Studies of healthy older men have shown problems with fluid retention leading to ankle or leg swelling, worsening of high blood pressure, or congestive heart failure. It is unclear whether there would be an effect in men who are ill, for example, those with congestive heart failure.
- Liver Toxicity: There have been no reports of liver toxicity from transdermal testosterone replacement. However, oral testosterone replacement can cause significant liver problems. Interestingly, every manufacturer (even those producing transdermal testosterone) mentions the possibility of liver problems. This should be taken into account.
- Problems with Fertility: Spermatogenesis (the production of sperm) in all men is dependent on production of testosterone by the testes. If testosterone is given from outside the testes (exogenous testosterone), as in testosterone replacement therapy, the testes will then stop producingtheir own testosterone. This will actually shut down sperm production either significantly or completely in almost all men. This may be a temporary or permanent effect. It is very important that younger men who still plan to have a family take this into account. Some men have "banked" their sperm (for more information on this subject visit www.SpermBankDirectory.com). Other men have delayed testosterone replacement until they have finished having children. It is important that any man considering a family be very careful in starting testosterone treatment of any kind.
- Sleep Apnea: Sleep apnea is a condition in which an individual stops breathing for periods of time while sleeping. This can have significant medical effects. There have been reports that increased testosterone levels exacerbate pre-existing sleep apnea. However, a recent 36-month trial of testosterone therapy in older men reported no effect of treatment on apneic or hypoapneic episodes.
- Tender Breasts or Enlargement of Breasts: This may occur in some older men who are on testosterone therapy. This may be due to the conversion of testosterone to estrogen. Breast tissue in both men and women is very estrogen sensitive. Sometimes, this side effect can be overcome by decreasing the testosterone dose.
- Increased Red Blood Cell Concentration (Polycythemia): One of the most important side effects of testosterone replacement therapy can be an increase in the red blood cell mass and hemoglobin levels. This is particularly true of older men. Increased blood cell mass may increase thromboembolic events (heart attacks, strokes, or peripheral clotting in the veins). Men who develop increased hematocrit can decrease testosterone replacement or donate blood to decrease their blood cell mass.
- Prostate Growth: The growth of the prostate can have a negative effect on men in two ways. First, the prostate may increase in size (benign prostatic hyperplasia or BPH). This may cause problems with urination. Second, it may promote the growth of cancerous prostate cells. It is important to remember that prostate cancer is a common cancer for older men and is the second most common cause of cancer deaths in older men.
Decreasing testosterone levels has been a method used to treat diseases related to both the "benign" and the cancerous groups of cells, but it is still unclear whether testosterone therapy for the older man places him at increased risk of developing prostate disease (i.e., whether testosterone replacement therapy makes benign prostatic hyperplasia progress or makes previously unknown prostate cancer spread).
The vast majority of studies following PSA (prostate specific antigen made by both cancer cells at a higher rate and benign prostate cells) show that it does not increase significantly with testosterone therapy. All of the short-term studies have shown no negative effects on prostate size, maximum urination flow rates, and prostate symptom scores. It appears that testosterone replacement therapy has little short-term effect on the prostate. Long-term data, however, is not yet available.
Monitoring During Treatment
Hormone replacement may be started for a variety of reasons. Once started, it is usually maintained for life. Since patients must be monitored for the duration of time that they are on testosterone replacement, essentially, the monitoring is a lifetime commitment.
There is not yet ageneral consensus on how men with testosterone replacement should be monitored. It is clear that those patients who have begun testosterone replacement for a particular symptom should have that symptom carefully observed. For example, a patient using testosterone because of problems with osteoporosis should have regular serial bone density screens. Patients with mood or libido changes must also be carefully evaluated.
In general, dosage should begin low. Hormone levels and subjective impressions should then be checked 2 to3 months afterward. If adequate blood hormone levels have not been reached, the dosage should be increased, and, again, the patient should return in another 2 to 3 months for blood work.
The goal is to get the patient in the mid-range of the testosterone values. Once this has occurred, the patient must then be monitored at regular intervals both in terms of symptoms and blood work.
Our practice monitors blood fairly frequently. Once the patient has achieved the right dosage of hormone, we follow the patient's progress and draw blood every 3 months for at least a year. The following year, we evaluate the patientanddraw blood every 4 months. Thereafter, appointments and blood work are required every 6 months.
During the initial follow-up appointments, we evaluate the patient psychologically and physically. Blood work includes hormone levels, a complete chemistry profile including chemistries, lipids (fat profiles), and liver function tests. We also perform acomplete blood cell count to check the patient's hematocrit (an increased hematocrit is a common side effect of testosterone replacement therapy). It is important that the patient receive serial prostate exams at all of these visits as well as a PSA test. It is also important to discuss any sleep disorders with the patient and to assess his mood, libido, and emotional state.
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