Testosterone is a steroid-based hormone made by special cells in the testes called Leidig cells. It is an anabolic hormone, which basically means that it mostly up-regulates its targets, stimulating them. Testosterone helps to define gender during early development. It stimulates growth before puberty and helps to develop male sexual characteristics during puberty. As an adult, testosterone helps to regulate libido, sperm development, development and maintenance of muscle mass and strength, bone density, production of red blood cells, energy usage, and sense of wellbeing and drive.
There are three primary organs involved in the regulation of testosterone. These include an area of the brain called the hypothalamus, a small gland sitting just below the brain called the pituitary gland, and the testicles. The hypothalamus is like a thermostat. It senses the concentration of testosterone in the blood and make adjustments throughout the day. As a part of the circadian rhythm, it adjusts the stimulation of the rest of the control axis such that the highest testosterone level is seen in the morning and falls throughout the rest of the day. When the hypothalamus wants more testosterone, it releases a special hormone called Gonatotrophin Releasing Hormone (GnRH), which travels through special veins to the pituitary gland. The pituitary gland is a small, pea-sized gland that is encased in its own protective bony pocket just below the brain. It makes and releases various stimulating hormones based on the orders it receives from the hypothalamus. When it receives increasing amounts of GnRH, it makes and releases the sex hormones. These are Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). The FSH goes to the testes through the blood stream where it stimulates the production of sperm from the Sertoli cells in the testes. This is important to fertility and will be discussed later. The LH goes to the testes and stimulates the Leidig cells to make and release testosterone into the blood. The blood then circulates to the brain where the hypothalamus detects the new level and adjusts its secretion of GnRH accordingly. This results in a balanced control circuit where, if the testosterone levels are in your hypothalamus’s normal range, then the stimulation from the hypothalamus to the pituitary should be in its normal range, and the LH level in the blood should be normal.
When you look online and through medical journals, you can find numerous charts and graphs showing varying normal ranges for men depending on how tightly they group the population by age. Most of the time, the range is for men between the ages of 25 and 85 and the levels defined as normal will go from about 250-950 ng/dl. This is because normal ranges have to include about 97% of the targeted population. Conventional wisdom would say that the testosterone levels reach a peak in young adulthood and then decline by about 1-1.5% yearly as we age, and that we should accept this until the testosterone levels drop so low that it affects our general health and we develop symptoms that interfere with our full enjoyment of life. Your own individual normal range is likely to be much narrower than this “normal” population range. As an example, let’s say that your testosterone level comes back at 500 ng/dl. If your own personal range was 400-600 ng/dl, then you would feel normal. If, however, your normal range was 600-800 ng/dl, then you would likely feel at least some of the signs and symptoms of low testosterone. In some men, their testosterone levels fall faster through time than is common. This could lead to a much quicker fall to levels that interfere with health and well-being. If, as an example, 0.5% of men lose testosterone at a rate of 4% per year, then there may be millions of young and middle-aged men in this country with low testosterone levels, and many of them will have significant signs and symptoms. There are many reasons why the testosterone levels may fall prematurely and they should be diagnosed accurately so that they may be treated effectively.
Testosterone deficiency is the condition of having abnormally low testosterone levels as measured between 8:00 and 10:00 in the morning. It is also known as hypogonadism or Low-T, but it is not treated unless it has become symptomatic, meaning that there are significant signs and symptoms that interfere with your health, productivity, fertility, or sense of enjoyment in life.
There are signs and symptoms that are specific to low testosterone and others that are more generalized in nature. Those that are fairly specific to testosterone deficiency include a loss of libido (sex drive), erectile dysfunction, testicular shrinkage, loss of male characteristics such as body or beard hair, reduction of fluid in the ejaculate, fatigue or loss of stamina, weight gain (especially around the waist), loss of muscle mass or inability to put muscle on with exercise, and gynecomastia (development of breast tissue or man-boobs). Signs and symptoms that are less specific to testosterone deficiency but often occur with it include scalp hair loss, difficulty sleeping, depression, irritability, anxiety, loss of focus or mental clarity, difficulty with memory, reduction in sports or work performance, loss of overall sense of drive or ambition, aching joints, hot flashes, and weakening of the bones by loss of the calcium-containing hydroxyapatite crystal matrix (osteopenia or osteoporosis).
Testosterone has wide ranging effects on the body in that low testosterone levels can increase the risk for anemia (too few red blood cells in the blood), reduced muscle mass, strength, and endurance, increased levels of cholesterol (an independent cardiovascular risk factor), reduced glycemic control leading to pre-diabetes and type 2 diabetes, obesity, reduced fertility, metabolic syndrome (a complex of metabolic disorders and an independent risk factor for cardiovascular disease), and medical issues such as problems with concentration and memory, and spatial abilities (and possible links with dementia).
There are two general classifications of testosterone deficiency defined by whether the low testosterone levels are due to failure of the testes or due to some other factor. Primary hypogonadism occurs when the testes cannot make enough testosterone to keep you in your normal range despite having adequate LH stimulation. It is called secondary hypogonadism when the testosterone level is low, but the testes are not the cause and the fault usually lies with the hypothalamus or pituitary gland. There can also be a mixed form with primary and secondary issues.
There are two inherited syndromes that can cause hypogonadism, however, they are beyond the scope of this discussion. Structural issues include things like undescended testes (where the testicles did not migrate down into the scrotum) and trauma (including surgery) to the testes, both of which can reduce testosterone and sperm production. Infectious diseases such as childhood or adult mumps, HIV/AIDS, or infections of the testes themselves are also causes. Hemochromatosis is the condition of having too much iron in the blood and this can cause primary or secondary hypogonadism. Chemotherapy and radiation therapy can affect the testes reducing both testosterone and sperm count.
The most common cause is aging and likely resides in the hypothalamus. Another uncommon but worrisome cause is a pituitary adenoma. This is a usually benign tumor that grows inside the bony pocket that the pituitary gland sits in. As it grows it puts pressure on the rest of the pituitary gland leading to its dysfunction. This may result in abnormal testosterone and other hormone levels. It may also produce a hormone called prolactin. If the adenoma gets very large, it can cause headaches and visual changes. This is one of the things that must be considered whenever testosterone deficiency is being evaluated. The most common genetic cause of secondary hypogonadism is Kallmann’s syndrome and is usually diagnosed in childhood. Head trauma and strokes can injure the hypothalamus or the pituitary gland. Tumors of the brain or tumors near the pituitary gland can also cause secondary hypogonadism. Infections such as HIV/AIDS or histiocytosis, or inflammatory diseases like sarcoidosis can also be causes. Hormonal issues such as hypothyroidism and medical issues such as obstructive sleep apnea, cirrhosis of the liver, chronic kidney failure, uncontrolled diabetes mellitus, and administration of some medicines can also cause secondary hypogonadism. There is also evidence that lack of exercise, exposure to blue light, abuse of alcohol and “recreational” drugs, or non-medical use of anabolic steroids can cause failure or suppression of the hypothalamus or pituitary gland. Multiple nutritional issues, likely through their effect on the hypothalamus or pituitary gland, can cause low-T. Finally, modern man lives in a chemical soup containing hormones, herbicides, pesticides, and other pollutants in our air, water, and food. Many of these are being shown to affect our physiologic processes, including control of our hormone levels.
How is testosterone deficiency diagnosed? The first step is getting a complete physical exam. Once other issues have been eliminated and testosterone deficiency is considered likely, you may be referred to a clinician with expertise in the condition. He/she will likely ask you to fill out a variety of questionnaires, forms for personal and family medical history, insurance coverage, your prior medical records, and consent for treatment. The questionnaires will ask about the various signs and symptoms of testosterone deficiency, signs and symptoms of problems with the prostate gland, and possibly even questions about mental health. A clinician will then review those questionnaires with you and ask additional history questions followed by a focused physical exam. If the clinician believes there is a significant likelihood that you may have testosterone deficiency, then certain blood tests will be ordered. In follow-up, based on the results of those tests, a treatment plan will be discussed with you and implemented with your permission. These blood tests may include levels of total testosterone, free testosterone, sex hormone binding globulin, albumin, luteinizing hormone, estradiol, FSH, prolactin, hemoglobin A1C, thyroid hormone, and hemoglobin or hematocrit. Based on these results, the clinician can diagnose primary, secondary, or mixed hypogonadism. Rarely, further testing may be needed in the form of an MRI scan of the pituitary gland or a bone density study.
Most people refer to estradiol as estrogen, which is fine for this discussion. It is a major sex hormone in women, however, it is important in men as well. In men, it acts to moderate some of the effects of testosterone, and is detected in the hypothalamus resulting in reduction of its stimulation of the pituitary gland. It is created in men from testosterone by an enzyme in the fat cells called aromatase. Having too many fat cells can mean that there is too much of the aromatase enzyme leading to the production of too much estradiol and the removal of too much testosterone. Other issues that can raise estradiol levels in men include stress, certain medications like antibiotics, and some herbs like ginseng and gingko biloba. It is also important to remember that as one is treated for testosterone deficiency and their testosterone levels go up, there is more testosterone available to the fat cells to be converted into estradiol. Symptoms of elevated estradiol include moodiness, tearfulness, loss of concentration, hot flashes, acne, hair loss, erectile dysfunction, gynecomastia (development of breast tissue), swelling in the hands and feet, and weight gain. Elevated estradiol levels can be treated with prescription medications, like Anastrozole, which interfere with the action of the aromatase enzyme. There are herbal supplements including fenugreek, chrysin, maca root, stinging nettle, and DIM (diindolylmethane) which also suppress the aromatase enzyme. Other dietary remedies may include green tea, eating cruciferous vegetables, flax seed or nuts, or taking supplements like fish oil or vitamin B complex. Eating organic foods may help avoid some of the environmental chemicals which may affect the estradiol levels as well. It may also be moderated by weight loss, stress reduction, avoidance of alcohol, avoidance of plastic fluid containers, and the avoidance of over usage of cell phones and other sources of electromagnetic radiation.
SHBG is a protein produced mainly by the liver. It grabs testosterone in the blood and holds onto it very tightly making it unavailable to be used elsewhere in the body. It is the biggest reason why the free testosterone and bioavailable testosterone levels are a lot lower than the total testosterone level in the blood. If there is too much SHBG in the blood, even a man with a normal total testosterone level may have an abnormally low free testosterone level and symptoms of testosterone deficiency. If this is the case, then treating the high SHBG in the blood may be all that is needed to improve a man’s symptoms. High SHBG can be a sign of liver disease, hyperthyroidism, or pituitary issues. It can occur de novo or be caused by certain medications or binge drinking alcohol. There is no medical treatment available to reduce the SHBG in the blood, however there are things that you can do. Exercising, eating cruciferous vegetables such as broccoli, cauliflower, cabbage, brussel sprouts, radishes, and bok choy, or taking supplements such as zinc, boron, iron, and vitamins A, D, and K have been shown to reduce the SHBG levels in the blood. You should also avoid drinking large amounts of alcohol or caffeine.
This is another question that is best answered in two parts; secondary and primary hypogonadism, and these will be discussed below. Remember that it took years to see your testosterone drop to its current levels and it may take months for various treatments to improve the situation. Please be patient as it is usually rewarded with a better result with the fewest long-term effects. Also, testosterone deficiency may be a combination of primary and secondary hypogonadism and it might take some time to get the treatment regimen right.
If the LH is low along with the low testosterone levels, then we can give a trial of treatment for secondary hypogonadism. This may be preferable in many ways as it results in stimulating the hypothalamus-pituitary-testes axis rather than suppressing it, as occurs with testosterone replacement therapy. This regimen maintains the normal circadian rhythm and avoids the complications of testosterone replacement therapy. Many of the same herbal supplements and lifestyle changes also improve secondary hypogonadism. Ashwagandha, vitamin D, ginger, zinc, D-aspartic acid, and maca extract can improve hypothalamic or pituitary function. Reducing estradiol levels by weight loss or supplements like fenugreek can reduce the estradiol suppression of the hypothalamus. Clomid (clomiphene) is an estrogen receptor blocker that also reduces the hypothalamic and pituitary suppression resulting in up-regulation of the hypothalamus and can result in an increase in total testosterone between 250-350 ng/dl (higher in some studies) without the short and long term complications or inconvenience of testosterone replacement therapy. Clomid is usually started at 25 mg/day and takes 2-3 months to up-regulate the axis. It can be increased to 50 mg/d if needed to get to a therapeutic testosterone level. It is usually well tolerated, but may cause initial nausea, bloating, flushing, headaches or visual changes. Make sure you tell your doctor if you have liver disease, other hormonal issues, or neurological issues. It is frequently used as the first line therapy, even in primary hypogonadism, especially in men who want to have kids in the future, as it is stimulatory of the testes, rather than suppressive.
When I think of treating primary testosterone deficiency, I break it into two classes: physiological and non-physiological therapies. In physiological therapies, we give a daily dose of testosterone in the mornings to get a high level which gradually falls through the day, just like the body would see in healthy men. This therapeutic class would include transdermal creams, gels, or patches that are placed on the skin, as well as sublingual troches or buccal patches that are placed in the mouth where the testosterone is absorbed into the bloodstream. The transdermal therapies must be applied in the morning and allowed to dry before dressing. They must stay on for at least a couple of hours before being washed off, and must be completely washed off before coming into skin-to-skin contact with women or children to prevent them from absorbing some of the testosterone from your skin. The troches/buccal patches are applied in the mornings and allowed to dissolve, but they cannot be swallowed or the liver may see too large of a testosterone dose. While these methods work for many men, about 60% consider them inconvenient and eventually elect to go a different route.
The non-physiological class includes testosterone injections and testosterone pellet insertion. In both cases, the doses last for days to weeks interrupting the circadian-like rhythm maintained by the physiological therapy. Injections can be Intramuscular (IM) or subcutaneous (SQ). The SQ route is more common in Europe than in the US, but both are valid and effective therapies. The half-life in the blood is about 10-11 days with each dose. In either case, dosage schedules vary between weekly and tri-weekly in frequency. Personally, I prefer the weekly schedule as it results in peaks and valleys that remain in the therapeutic range rather than going supratherapeutic for the first week and subtherapeutic before the next dose. Because the next dose is given before the prior one is gone, the overall levels will taper up over 4-5 doses and the testosterone levels can be measured and dosages adjusted based on the trough levels just prior to the 5th or 6th dose. Testosterone powder can be compressed into pellets that are about the size of a grain of rice. They can be inserted into the fat just below the skin with the dose adjusted by varying the number of pellets inserted. This is usually based on the intramuscularly injected dosage required to get a good therapeutic effect as the basis to calculate the pellet dosage. The pellets usually take between 3-6 months to dissolve, so repeat pellet insertions can be done at 3-6 month intervals. This is a great therapy for those who will be away from medical care for long periods of time or those who just want to have one-and-done treatments every few months. There are some, however who dissolve them faster than expected resulting in high levels for the first month and low levels in the last month. There are also those who dissolve slower and may never reach a therapeutic level with the first insertion and then high levels with the following one. For those, the injection route may be more appropriate.
The first thing to remember is that testosterone replacement therapy is a permanent, life-long therapy. There are guidelines that recommend treating for six months and then stopping to see if this short-term therapy readjusted the “normal” level desired by the hypothalamus. If that occurs, great, but I am not convinced that this is all that common. Most men who start on testosterone replacement therapy should expect to be on it for the rest of their lives. This is one of the reasons to try the Clomid therapy as the first line, even in primary hypogonadism. While major complications are very rare, testosterone replacement therapy is not completely benign. It is metabolized in the liver so liver function tests are done to follow the liver enzymes in the blood. It stimulates prostate tissue and may result in the prostate gland growing at a faster rate, causing urinary problems that may require treatment with medications or surgery. It has not been shown to cause prostate cancer, but could stimulate a cancer that does develop to grow faster or metastasize earlier. That is why the prostate specific antigen (PSA) and digital rectal exams are followed. You will likely be asked to fill out a questionnaire asking about prostate/urinary symptoms during your work-up. Testosterone stimulates the bone marrow to produce red blood cells. If it produces too many, the blood becomes viscous and flows through small blood vessels too slowly. This increases the risk for forming blood clots, which can go to the lungs as pulmonary emboli. It can also increase the risk for slow-flow strokes, something we earnestly want to avoid. You will have your blood count measured on a regular basis. If the count goes too high, you may have to reduce the testosterone dosage or donate blood to get the count down. When we give exogenous testosterone, the hypothalamus sees more than it is used to, so it stops stimulating the pituitary, which stops releasing normal amounts of LH and FSH. This results in reduced testosterone production by the testes and possible reduction in sperm production. It may result in shrinkage of the testes, which may be aesthetically displeasing to the man. The sperm count may drop below levels usually required for fertility, but this should not be considered adequate birth control. Some of the shrinkage and reduction in sperm count may be offset by administration of human chorionic gonadotropin (HCG) a hormone made by the placenta in pregnant women. In men, this simulates LH and FSH to some extent and may preserve testicular size and fertility. If not, men on testosterone replacement therapy who want kids may have to consult with a male infertility specialist. There are occasional allergic reactions to the testosterone carriers or adhesives in the patches. Injections and pellets can also cause bruises.
First, take one of the self-assessment questionnaires like the ADAM questionnaire available on this website. The qADAM is another valid questionnaire you can find on the web. If it says you are likely to have low testosterone, get a complete physical exam including a prostate exam if you are over 50. Tell your doctor that you are worried about your testosterone levels to help guide the diagnostic investigation. Expect blood testing to look at hormone levels, other organ function, and general metabolic parameters, but remember that the testosterone levels should be taken before 10:00 AM. I have tremendous respect for primary care clinicians. Their breadth of knowledge is amazing, but there is only so much time that they can devote to their continuing education and they have to keep up with advances in all aspects of their fields. They may justifiably elect to choose to concentrate their continuing education on such things as diabetes, hypertension, heart disease, and other killers, and spend less time on less life-threatening things like male hypogonadism. That is where I and my colleagues in men’s health come in. Our practices are more limited, allowing us to be at the cutting edge of this therapeutic niche. If you are happy with your primary care physician and getting good results, great. If not, schedule a virtual appointment with me. Have the medical records and test results available so that you can save some time and inconvenience.
