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https://pmc.ncbi.nlm.nih.gov/articles/PMC1332036/pdf/brjsmed00014-0009.pdf

In testosterone therapy , testosterone (often called "T" for short) can be administered into the body in a number of ways. The most common method is intramuscular (IM) injection with a syringe. Other delivery methods include transdermal application through gel, cream, or patch applied to the skin; orally by swallowing tablets (this method is uncommon as it has been shown to have negative effects on the liver); sublingually/buccally by dissolving a tablet under the tongue or against the gums; or by a pellet inserted under the skin. The T-delivery method used will depend on the type of medication available in the country of treatment, the health risks/benefits for the patient of the delivery method in question, personal preference, and cost.

Testosterone is not stored by the body for future use, so in order to maintain healthy levels, it must be administered in timed intervals, and in appropriate dosages. Injectable and subcutaneous T pellets remain active in the body the longest. Injectable T is typically administered between once a week to once every three weeks, and subcutaneous T pellets are replaced every 3-4 months. Transdermal T (patch, gel, or cream) is typically applied to the skin in smaller daily doses; oral and sublingual/buccal T are also typically taken daily.

"Normal" testosterone Levels

An individual's testosterone levels are usually confirmed through a blood test called a "serum total testosterone test ." Testosterone exists in your bloodstream in two forms-- "bound" testosterone and "free" testosterone . The majority of bound testosterone in the body is chemically bound to a protein called "sex hormone binding globulin" (SHBG). The remaining bound testosterone in the system is mostly bound to albumin, another protein . Free testosterone is considered the "active" form of testosterone , as it is not chemically attached to any proteins; thus, it is readily available to bind to androgen receptor sites on cells.

A serum total testosterone test measures the total of these two forms of T. What are considered normal test levels of combined bound and free testosterone in male bodies can range anywhere from 300-1100 ng/dl (nanograms per deciliter). Levels will vary with age and individual factors.

It is useful to also measure the level of free testosterone in the system, as this may be more indicative of how hormone therapy is progressing. Levels of free testosterone can range between 0.3%-5% of the total testosterone count, with about 2% considered an optimal level. Ask your doctor to check for both total and free levels of testosterone in your system.

A note of caution about greatly increasing your T dosage

During the first months of T therapy, many men feel impatient waiting for changes to happen. Some may consider doubling or tripling their dose, thinking that the more they put in, the faster the changes will come. However, dramatically increasing your dose might have the effect of slowing your changes. This is because excess testosterone in your body can be converted into estrogen by an enzyme called "aromatase." This conversion is part of the body's natural feedback system-- if there is an abundance of testosterone in the body, it is converted ("aromatized") to estrogen in order to maintain a "normal" hormonal balance. Therefore, taking very large doses of testosterone might not be a great idea. Be patient; if you are not seeing results in a reasonable period of time, and/or your T levels are low, discuss modifying your dosage with your doctor.

Testosterone esters: what they are and how they work

Much of the testosterone that is prescribed for the purposes of hormone therapy is in the form of testosterone "esters." An ester is simply a name for a chemical compound that is formed from reaction between a carboxylic acid and an alcohol. A simple chemical diagram of this reaction is shown below in Figure A. Figure B shows the chemical structure of free testosterone (chemical formula C19H28O2) as well as two different esters of testosterone (testosterone cypionate and testosterone enanthate ).

There are a number of different esters of testosterone , including the commonly prescribed injectables of testosterone enanthate and testosterone cypionate , as well other esters such as acetate, propionate , phenylpropionate, isocaproate, caproate, decanoate, and undecanoate. Each of these different esters is a molecular chain composed of carbon, hydrogen and oxygen atoms. The main difference between the different esters is how many carbon and hydrogen atoms make up the chain. For example, the propionate ester is composed of 3 carbons, 6 hydrogens, and 2 oxygens, whereas the cypionate ester is composed of 8 carbons, 14 hydrogens, and 2 oxygens.

Esterification of testosterone is done in order to improve the solubility of testosterone in oil, which in turn slows the release of the testosterone from the site at which it enters the body.

Testosterone , in its free, non-esterified form, has poor solubility in either oil or water-- though it can be suspended in water. Non-esterified testosterone is available in an aqueous injectable form with the drug name "Aquaviron." However, this form of testosterone stays active in the body for only a very short period of time (only a matter of hours, which is explained further below). Because of this, it must be injected on a daily basis in order to maintain a continuous level of testosterone in the blood. Therefore it is rarely used for testosterone repla***ent therapy as an injectable.

Once you have added an ester group to testosterone , it becomes even less soluble in water and more soluble in oil. Additionally, as a general rule, the more carbon atoms there are in an ester, the more soluble the ester is in oil. For example, testosterone propionate (with 3 carbon atoms in the ester group) is less soluble in oil than testosterone cypionate (with 8 carbon atoms in the ester group). Remember, this is general, simplified rule for our purposes herein; the solubility of a molecule depends on structural factors that are beyond the scope of this section.

So, generally, the more carbons the ester group has, the more soluble in oil it becomes, and the less soluble in water. The term for this ratio between oil and water solubility is called the "partition coefficient"-- the higher the solubility in oil, the higher the partition coefficient.

The partition coefficient of the ester in question is important because is effects how long the drug itself stays in the system. If the testosterone transfers too quickly from the oil to the blood, the result is a sudden spike in testosterone which then rapidly drops once the dose has been used up. In the example of free testosterone injected into the muscle from a water suspension (as in Aquiviron, mentioned above), the testosterone is essentially immediately available to the bloodstream due to its low partition coefficient, and thus there is an immediate spike of testosterone which is used up quickly in the body.

Testosterone cypionate , on the other hand, has a high partition coefficient. When injected into the muscle, the drug remains in its esterified form in a deposit in the muscle tissue. From there, it will slowly enter the circulation as it is picked up in small quantities by the blood. Once the esterified testosterone is brought into the blood stream, "esterase enzymes" cleave off the ester chain in a process known as "hydrolization," thus leaving the testosterone in its free form to perform its various actions and effects.

When people speak of whether a particular testosterone ester is "fast acting" or "slow acting," they are usually referring to the partition coefficient/solubility in oil. As described above, esters with more carbon atoms will generally be more soluble in oil-- they are often referred to as "slow-acting" esters (they stay active in the system longer). Esters that are less soluble in oil are often referred to as "fast-acting" forms of testosterone , referring to the fact that they are more quickly available and used up in the blood stream.

For men who are using injectable testosterone , slow-acting esters tend to be preferred, as fewer injections are needed over time to keep the blood levels of T reasonably constant. Testosterone enanthate (7 carbons) and testosterone cypionate (8 carbons) both take about 8-10 days to be fully released in the system, and so they are typically injected once every 7-14 days. Testosterone propionate (3 carbons) takes about 3-4 days to be fully released in the system, and must be injected in smaller doses at least weekly if not twice weekly. For this reason it is not often prescribed for men in transition.

Testosterone delivery methods

Injectable testosterone

The dosage amount and timing for injectable testosterone will depend largely upon which ester is being used, as well as the individual's own response to the hormone . In general, dosages will vary between 50 mg and 300 mg per injection , depending on the ester and the dosing regimen. An average injectable dose is about 200-250 mg every two weeks, though many trans men inject 100 mg every week or every 10 days, or other variations depending on their own bodies' needs and sensitivities. Again, the exact dosage required will vary from person to person, and health and well-being should be carefully monitored while determining an individual's ideal dose.

Some doctors recommend decreasing the dosage of injectables to 100-150 mg every two weeks for those trans men whose ovaries are inactive, or who have had their ovaries removed. Again, this will vary from person to person.

There are a number of different types of injectable testosterone ; those available may differ depending on the country in which you reside. The drug names for the same ester of testosterone may also differ depending on the company who produces it. This is not an exhaustive list, though it does cover the main injectable forms of T which are used by trans men for testosterone therapy .

Finally, testosterone esters are typically suspended in either cottonseed oil or sesame seed oil. Some people find that they may have an allergic reaction to one of the oils, or they might find that their acne increases or decreases depending on the type of oil they use. Certain brand-name testosterone esters are mass produced using one oil or the other (as noted below), but by using a compounding pharmacy, you can have any testosterone ester suspended in your choice of oil (with a proper prescription).

Injectable esters commonly used for testosterone therapy:

Testosterone enanthate: Chemical formula C26H40O3
Testosterone enanthate is one of the main forms of testosterone prescribed to men in the United States. It is a slow-acting ester with a release time between 8-10 days. The name-brand of T-enanthate available in the United States is called "Delatestryl," which is suspended in sesame oil. Testosterone enanthate is typically injected anywhere between once every week to once every three weeks. Generic testosterone enanthate can also be obtained through a compounding pharmacy; such pharmacies can mix the enanthate in either sesame or cotton seed oil.

Testosterone cypionate: Chemical formula C27H40O3
Testosterone cypionate is the other main injectable form of testosterone prescribed tomen in the United States. It is a slow-acting ester with a release time between 8-10 days, similar to that of enanthate . The name-brand of T-cypionate available in the United States is called "Depo-Testosterone ," which is suspended in cottonseed oil. Testosterone cypionate is typically injected anywhere between once every week to once every three weeks. Generic testosterone cypionate can also be obtained through a compounding pharmacy; such pharmacies can mix the cypionate in either sesame or cotton seed oil.

Sustanon 100 or 250
"Sustanon " is the brand name for two formulas of injectable testosterone that contain a blend of esters. "Sustanon 100" contains three testosterone esters: testosterone propionate (C22H32O3), testosterone phenylpropionate (C28H36O3), and testosterone isocaproate (C25H3803). "Sustanon 250" contains four testosterone esters: testosterone propionate (C22H32O3), testosterone phenylpropionate (C28H36O3), testosterone isocaproate (C25H3803), and testosterone decanoate (C29H4603). Both formulas feature both fast-acting and slow-acting esters, and can be injected anywhere from once every week to once every four weeks. Sustanon is prescribed outside of the United States.

Other injectable esters of testosterone:

Testosterone propionate: Chemical formula C22H32O3
Testosterone propionate is a fast-acting ester with a release time of 3-4 days. To keep blood levels from fluctuating greatly, propionate is usually injected between one to three times a week. It is for this reason that it is not usually prescribed hormone therapy . Some users also report that propionate is a more painful injection , with swelling and noticeable pain around the injection site. Brand names of testosterone propionate include "Testovis" and "Virormone."

Testosterone phenylpropionate: Chemical formula C28H36O3
Testosterone phenylpropionate is a slow-acting ester, with a release time of 1-3 weeks. A popular name brand for T-phenylpropionate is "Testolent ." Testosterone phenylpropionate is also one of the components of Sustanon and Omnadren .

Omnadren

"Omnadren " is the brand name for a blend of four testosterone esters: testosterone propionate (C22H32O3), testosterone phenylpropionate (C28H36O3), testosterone isocaproate (C25H3803), and testosterone decanoate (C29H4603). In the past, Omnadren consisted of a blend of different esters, but now is essentially the same formula as Sustanon , mentioned above. It features both fast-acting and slow-acting esters, and can be injected anywhere from once every week to once every four weeks. It is sometimes prescribed in parts of Europe.

Aqueous testosterone suspension

In the United States, injectable aqueous (non-esterified) testosterone is available, but it is very short-acting (it is completely released in the system within a matter of hours). Therefore, it is not typically used for men in transition, as it would require constant re-injection to maintain regular blood levels. The brand name for aqueous testosterone suspension is "Aquaviron."

Transdermal testosterone

The term "transdermal" refers to topical testosterone delivery through the skin, by the use of a patch, gel, or cream.

Transdermal testosterone is usually applied to the skin daily in small doses in an effort to keep a steady level of testosterone in the system at all times. This approach avoids the "peaks and valleys" in T-levels sometimes associated with injectable testosterone . With injectables, T levels can reach a low-point a few days before the next shot is due, which can cause irritability, hot flashes, and low energy in some users. Daily transdermal application can help alleviate such problems. Indeed, some men who regularly use injectable testosterone sometimes supplement with a gel or patch during the last few days of their dosing cycle to maintain their T levels.

Transdermal application is also attractive to those individuals who are not comfortable with needles and injections .

However, there are some disadvantages to transdermal delivery. Some forms of daily transdermal testosterone application, particularly the patch, are substantially more expensive than injectable testosterone . Testosterone patches often cause skin irritation and/or allergic reactions to users. They can fall off with excessive sweating, and they must be fully protected with plastic when swimming. Testosterone cream and gel can be transferred by direct skin contact with a partner; special care must be taken with female partners who wish to avoid potential virilization.

Testosterone patches

There are currently two brand-name testosterone patches available in the United States: "Androderm" and "Testoderm." (Note that there are two forms of Testoderm available: a scrotal patch and a non-scrotal patch. The non-scrotal patch, "Testoderm TTS," is described herein). Generic testosterone patches are not yet available. Both Androderm and Testoderm TTS are very fast-acting once they have permeated the skin. The testosterone in the patches is suspended in an alcohol-based gel.

In order to deliver the testosterone efficiently into the body, chemical enhancers are added to the patch to increase permeability of the skin. It is these enhancers that are often the cause of skin irritation in many users. Some individuals find Testoderm TTS to be less irritating to the skin than Androderm, but this will vary from person to person.

Androderm

Androderm patches come in two doses: 2.5 mg/patch and 5.0 mg/patch. The actual amount of testosterone in the 2.5 mg patch is 12.2 mg, and the actual amount in the 5.0 mg patch is 24.3 mg. The reason is that much of the testosterone in the patch will not manage to get into the system. So, for example, the aim of the 2.5 mg patch is to get about 2.5 mg successfully into the bloodstream per day. Therefore, it is possible to absorb slightly more or slightly less than the 2.5 mg of the patch's ideal dosage (the same reasoning, of course, applies to the 5.0 mg patch as well).

Androderm patches are usually applied on the back, abdomen, thighs, or upper arms. Because the active area of the patch is covered, the wearer does not have to worry about skin contact with a partner. Dosages will vary between 2.5 mg - 10 mg daily, by applying a single patch or combination of patches. As with any form of testosterone , dosage should be determined by your overall health, your testosterone levels as checked by your doctor, and your progress in masculinization.

Testoderm TTS

There are two types of Testoderm patches: one is intended for scrotal application, and one for application on other areas of the body. Testoderm TTS refers to the non-scrotal version of the patch-- this is the patch that should be used by men.

Testoderm TTS patches come in two doses: 4.0 mg/patch and 6.0 mg/patch. As with Androderm, the actual amount of testosterone in these patches is greater than the listed dose. The reason is the same as explained above in the Androderm section.

Testoderm TTS patches are usually applied on the back, abdomen, thighs, or upper arms. Because the active area of the patch is covered, the wearer does not have to worry about skin contact with a partner. Dosages will vary between 4.0 mg - 10 mg daily, by applying a single patch or combination of patches. As with any form of testosterone , dosage should be determined by your overall health, your testosterone levels as checked by your doctor.

Testosterone gel and cream

There are currently two brand-name versions of testosterone gel available in the United States: Androgel and Testim. There are no brand-name testosterone creams at this time. Both cream and gel formulations of testosterone can be made by compounding pharmacies. (For more information about compounding pharmacies, click here.) Gel formulations of testosterone are typically alcohol-based, whereas creams are typically safflower oil-based. The testosterone in creams and gels is typically very fast-acting once absorbed through the skin. Thus, it must be applied once or twice daily to maintain T levels.

Creams and gels are applied directly onto the skin. Care must be taken to avoid skin-to-skin contact with a partner on the site of application. Transfer of the testosterone from the site can be prevented by keeping the area covered.

Androgel

Androgel is a clear, alcohol-based gel that contains 1% non-esterified testosterone . It is very fast-acting once it has been absorbed by the skin, and so must be applied 1-2 times daily to maintain T levels. It is available in either unit-dose packets or multiple-dose pumps. The unit dose packets contain either 25 mg or 50 mg of testosterone . Approximately 10% of the applied testosterone from the packets is absorbed into the system, resulting in an effective dose of 2.5 mg or 5.0 mg, respectively.

Androgel should be applied to clean, dry skin and should not be applied to the genital area. Application sites should be allowed to dry for a few minutes prior to dressing. Hands should be washed thoroughly with soap and water after application.

In order to prevent transfer to another person, clothing should be worn to cover the application sites. If direct skin-to-skin contact with another person is anticipated, the application sites should be washed thoroughly with soap and water. Users should wait at least 2 hours after applying before showering or swimming; for optimal absorption, it may be best to wait 5-6 hours.

Testim

Testim, like Androgel , is a clear, alcohol-based gel that contains 1% non-esterified testosterone . It is very fast-acting once it has been absorbed by the skin, and so must be applied 1-2 times daily to maintain T levels. It is available in 5.0g unit-dose tubes. A 5.0g unit dose tube contains 50 mg of testosterone . Approximately 10% of the applied testosterone from the tube is absorbed into the system, resulting in an effective dose of 5.0 mg.

Testim should be applied to clean, dry skin-- preferably to the shoulders and/or upper arms. It should not be applied to the genitals or to the abdomen. Application sites should be allowed to dry for a few minutes prior to dressing. Hands should be washed thoroughly with soap and water after application.

In order to prevent transfer to another person, clothing should be worn to cover the application sites. If direct skin-to-skin contact with another person is anticipated, the application sites should be washed thoroughly with soap and water. Users should wait at least 2 hours after applying before showering or swimming; for optimal absorption, it may be best to wait 5-6 hours.

Compounded creams and gels

Compounded creams and gels can be mixed by compounding pharmacies, and are similar in dosing, application, and precautions to what is described above for Androgel and Testim.

There are two advantages of using compounding pharmacies for testosterone gel or cream. The first is cost: until a generic version of the gel is available, compounded gel will usually be the cheaper alternative. The second is customization: your doctor can write a prescription of varying concentration for gels or creams.

Oral testosterone

Methyltestosterone (C-17 alpha methylated testosterone )
Methyltestosterone is one of the earliest available oral testosterones. Its chemical structure is the hormone testosterone with an added methyl group at the c-17 alpha position of the molecule. The use of oral c-17 alpha methylated testosterone for masculinization is obsolete due to its toxicity to the liver. As such, methyltestosterone is not recommended for FTM hormone therapy . Brand names include "Metesto," "Methitest," "Testred," "Oreton Methyl," and "Android."

Testosterone undecanoate

Testosterone undecanoate is not a c-17 alpha alkylated hormone . Therefore, it is considered a safer oral form of testosterone . It is designed to be absorbed through the small intestine into the lymphatic system, posing less burden on the liver. Brand names for testosterone undecanoate include "Andriol ," "Androxon," "Understor," "Restandol," and "Restinsol." It is not available in the United States.

One disadvantage of orally administered undecanoate is that it is eliminated from the body very quickly, usually in 3-4 hours. Thus, frequent administration is necessary-- usually between 3-6 capsules a day. This can prove to be expensive when compared to injectable testosterone .

Sublingual/buccal testosterone

Sublingual and buccal testosterone delivery works by either placing a dissolving tablet under your tongue (sublingual) or by placing a tablet against the surface of the gums (buccal). It is different from oral delivery in that very little of the substance is swallowed, avoiding potential liver toxicity.

Sublingual
Sublingual testosterone can be obtained through compounding pharmacies. (For more information about compounding pharmacies, click here.)

Buccal

In 2003, the FDA approved a sustained-release buccal testosterone tablet called "Striant." It acts by adhering to the buccal mucosa (the small depression in the mouth where the gum meets the upper lip above the incisor teeth). Once applied, the tablet softens and delivers testosterone through the buccal mucosa, where it is then absorbed directly into the bloodstream, bypassing the gastrointestinal system and liver.

The recommended dosage for Striant is to replace the tablet about every 12 hours, though a different dosing schedule or number of tablets might be required depending on the needs of the patient.

Subcutaneous testosterone pellet

Another relatively new form of testosterone delivery is via a pellet of pure, crystalline testosterone implanted beneath the skin. The pellets are about the size of a grain of rice, and are typically placed in the buttocks or abdomen. The insertion of the pellets is a quick procedure, usually done under local anesthesia. Pellets are typically replaced after 3-4 months. "Testopel" is a brand name for testosterone pellets in the United States.

A 200 mg testosterone pellet releases testosterone at a steady rate of 1-3 mg per day. Several pellets can be inserted at the same time to increase dosage.

Some users have reported problems with the pellets working their way out from under the skin.

As men age past year 40, hormonal changes occur that perceptibly inhibit physical, sexual, and cognitive function. The outward appearance of a typical middle-age male shows increased abdominal fat and shrinkage of muscle mass, a hallmark effect of hormone imbalance. A loss of feeling of well being, sometimes manifesting as depression, is a common psychological complication of hormone imbalance.

Until recently, these changes were attributed to "growing old," and men were expected to accept the fact that their body was entering into a long degenerative process that would someday result in death.

A remarkable amount of data has been compiled that indicates that many of the diseases that middle-aged men begin experiencing, including depression, abdominal weight gain, prostate and heart disease are directly related to hormone imbalances that are correctable with currently available drug and nutrient therapies. To the patient's detriment, conventional doctors are increasingly prescribing drugs to treat depression, elevated cholesterol, angina and a host of other diseases that may be caused by an underlying hormone imbalance.

If doctors checked their male patient's blood levels of estrogen, testosterone, thyroid, and DHEA (instead of prescribing drugs to treat symptoms), they might be surprised to learn that many problems could be eliminated by adjusting hormone levels to fit the profile of a healthy 21-year- old.

Few physicians know what hormone blood tests to order for men, nor do they have the experience to properly adjust hormones to reverse the degenerative changes that begin in mid-life. This protocol will provide the patient and physician with the information necessary to safely modulate hormone levels for the purpose of preventing and treating many of the common diseases associated with growing older.

Too Much Estrogen

The most significant hormone imbalance in aging men is a decrease in free testosterone while estrogen levels remain the same or precipitously increase. Through a variety of mechanisms, as men grow older, they suffer from the dual effects of having too little testosterone and excess estrogen. The result is a testosterone/estrogen imbalance that directly causes many of the debilitating health problems associated with normal aging.

One cause of hormone imbalance in men is that their testosterone is increasingly converted to estrogen. One report showed that estrogen levels of the average 54-year-old man is higher than those of the average 59-year-old women.

The reason that testosterone replacement therapy by itself does not work for many men is that exogenously administered testosterone may convert (aromatize) into even more estrogen, thus potentially worsening the hormone imbalance problem in aging males, i.e., too much estrogen and not enough free testosterone. While there are studies showing that testosterone replacement therapy does not increase estrogen beyond normal reference ranges, we are going to show later how the standard laboratory reference ranges do not adequately address the issue of estrogen overload.

Estrogen is a necessary hormone for men, but too much causes a wide range of health problems. The most dangerous acute effect of excess estrogen and too little testosterone is an increased risk of heart attack or stroke. High levels of estrogen have been implicated as a cause of benign prostatic hypertrophy (BPH) and one mechanism by which nettle extract works is to block the binding of growth-stimulating estrogen to prostate cells .

When there is too little testosterone present, estrogen attaches to testosterone cell receptor sites throughout the body and creates many problems in aging men. In youth, low amounts of estrogen are used to turn off the powerful cell-stimulating effects of testosterone. As estrogen levels increase with age, testosterone cell stimulation may be locked in the "off " position, thus reducing sexual arousal and sensation and causing the common loss of libido so common in aging men.

High serum levels of estrogen also trick the brain into thinking that enough testosterone is being produced, thereby slowing down the natural production of testosterone. This happens when estrogen saturates testosterone receptors in the hypothalamus region of the brain. The saturated hypothalamus then stops sending out a hormone to the pituitary gland to stimulate secretion of luteinizing hormone, which the gonads require to produce testosterone. High estrogen can thus shut down the normal testicular production of testosterone.

One further complication of excess estrogen is that it increases the body's production of sex hormone-binding globulin (SHBG). (280) SHBG binds free testosterone in the blood and makes it unavailable to cell receptor sites.

Based on the multiple deleterious effects of excess estrogen in men, aggressive actions should be taken to reduce estrogen to a safe range if a blood test reveals elevated levels. We will discuss the appropriate blood tests and steps that can be taken to lower estrogen levels later in this protocol.

The Critical Importance of Free Testosterone

Testosterone is much more than a sex hormone. There are testosterone receptor sites in cells throughout the body, most notably in the brain and heart. Youthful protein synthesis for maintaining muscle mass and bone formation requires testosterone. Testosterone improves oxygen uptake throughout the body, helps control blood sugar, regulate cholesterol, and maintain immune surveillance. The body requires testosterone to maintain youthful cardiac output and neurological function. Testosterone is a critical hormone in the maintenance of healthy bone density, muscle mass, and red blood cell production.

Of critical concern to psychiatrists are studies showing that men suffering from depression have lower levels of testosterone than control subjects. For some men, elevating free testosterone levels could prove to be an effective anti-depressant therapy. There is a basis for free testosterone levels being measured in men suffering from depression and replacement therapy initiated if free testosterone levels are low normal or below normal.

One of the most misunderstood hormones is testosterone. Body builders tarnished the reputation of testosterone by putting large amounts of synthetic testosterone drugs into their young bodies. Synthetic testosterone abuse can produce detrimental effects, but this has nothing to do with the benefits a man over age 40 can enjoy by properly restoring his natural testosterone to a youthful level.

Conventional doctors have not recommended testosterone replacement therapy because of an erroneous concern that testosterone causes prostate cancer. As we will later show, fear of prostate cancer is not a scientific reason to avoid testosterone modulation therapy.

Another concern skeptical doctors have about prescribing testosterone replacement therapy is that some poorly conducted studies showed it to be ineffective in the long-term treatment of aging. These studies indicate anti-aging benefits when testosterone is given, but the effects often wear off. What doctors fail to appreciate is that exogenously administered testosterone can convert to estrogen in the body. The higher estrogen levels may negate the benefits of the exogenously administered testosterone. The solution to the estrogen-overload problem is to block the conversion of testosterone to estrogen in the body. Numerous studies show that maintaining youthful levels of free testosterone can enable the aging man to restore strength, stamina, cognition, heart function, sexuality and their outlook on life, i.e., alleviate depression.

Why Testosterone Levels Decline

Testosterone production begins in the brain. When the hypothalamus detects a deficiency of testosterone in the blood, it secretes a hormone called gonadotrophin-releasing hormone to the pituitary gland. This prompts the pituitary to secrete luteinizing hormone (LH) which then prompts the Leydig cells in the testes to produce testosterone.

In some men, the testes lose their ability to produce testosterone, no matter how much LH is being produced. This type of testosterone deficiency is diagnosed when blood tests show high levels of LH and low levels of testosterone. In other words, the pituitary gland is telling the testes (by secreting LH ) to produce testosterone, but the testes have lost their functional ability, so the pituitary gland vainly continues to secrete LH because there is not enough testosterone in the blood to provide a feedback mechanism that would tell the pituitary to shut down. In other cases, the hypothalamus or pituitary gland fail to produce sufficient amounts of LH, thus preventing a healthy pair of testes from secreting testosterone. Blood testing can determine if sufficient amounts of LH are being secreted by the pituitary gland and help determine the proper therapeutic approach.

If serum (blood) testosterone levels are very low, it is important to diagnose the cause, but no matter what the underlying problem, therapies exist today to safely restore testosterone to youthful levels in any man (who does not already have prostate cancer).

As indicated earlier in this article, a major problem aging men face is not low production of testosterone, but excessive conversion of testosterone to estrogen. Again, specific therapies will be discussed later about how to suppress excess estrogen and boost free testosterone back to youthful physiologic levels.

The Effects of Testosterone on Libido

Sexual stimulation and erection begin in the brain when neuronal testosterone-receptor sites are prompted to ignite a cascade of biochemical events that involve testosterone-receptor sites in the nerves, blood vessels, and muscles. Free testosterone promotes sexual desire and then facilitates performance, sensation, and the ultimate degree of fulfillment.

Without adequate levels of free testosterone, the quality of a man's sex life is impacted and the genitals atrophy. When free testosterone is restored, positive changes in structure and function of the sex organs can be expected. (It should be noted that sexual dysfunction can be caused by other factors unrelated to hormone balance such as arteriosclerotic blockage of the penile arteries.)

The genital/pelvic region is packed with testosterone receptors that are ultra-sensitive to free testosterone-induced sexual stimulation. Clinical studies using testosterone injections, creams, or patches have often failed to provide a long-lasting libido enhancing effect in aging men. We now know why. The testosterone can be converted to estrogen. The estrogen is then taken up by testosterone receptor sites in cells throughout the body. When an estrogen molecule occupies a testosterone receptor site on a cell membrane, this blocks the ability of serum testosterone to induce a healthy hormonal signal. It does not matter how much serum free testosterone is available if excess estrogen is competing for the same cellular receptor sites.

Estrogen can also increase the production of sex hormone-binding globulin (SHBG), which binds the active free testosterone into a non-active "bound testosterone". Bound testosterone is not able to be picked up by testosterone receptors on cell membranes. For testosterone to produce long-lasting libido enhancing effects, it must be kept in the "free" form (not bound to SHBG) in the bloodstream. It is also necessary to suppress excess estrogen as this hormone can compete for testosterone receptor sites in the sex-centers of the brain and the genitals.

Restoring youthful hormone balance can have a significant impact on male sexuality.

Testosterone and the Heart

Normal aging results in the gradual weakening of the heart, even in the absence of significant coronary artery disease. If nothing else kills the elderly, at some point their heart just stops beating.

Testosterone is a muscle-building hormone and there are many testosterone-receptor sites in the heart. The weakening of the heart muscle can sometimes be attributed to testosterone deficiency. Testosterone is not only responsible for maintaining heart muscle protein synthesis, but it is a promoter of coronary artery dilation and helps to maintain healthy cholesterol levels.

There is an ever-increasing number of studies indicating an association between high testosterone and low cardiovascular disease rates in men. In the majority of patients, symptoms and EKG measurements improve when low testosterone levels are corrected. One study showed that blood flow to the heart improved 68.8% in those receiving testosterone therapy. In China, doctors are successfully treating angina with testosterone therapy.

The following list represents the effects of low testosterone on cardiovascular disease:

• Cholesterol, fibrinogen, triglycerides, and insulin levels increase
• Coronary artery elasticity diminishes
• Blood pressure rises
• Human growth hormone (HGH) declines (weakening heart muscle)
• Abdominal fat increases (increasing heart attack risk)
• Those with cardiovascular disease should have their blood tested for free testosterone and estrogen. Some men (with full cooperation from their physician) may be able to stop taking expensive drugs to stimulate cardiac output, lower cholesterol, and keep blood pressure under control if they correct a testosterone deficit and/or a testosterone/estrogen imbalance.

Despite numerous studies substantiating the beneficial effects of testosterone therapy in treating heart disease, conventional cardiologists continue to overlook the important role this hormone plays in keeping their cardiac patients alive.

Testosterone and the Prostate Gland

Many doctors will tell you that testosterone causes prostate disease. The published scientific literature indicates otherwise.

As readers of Life Extension Magazine learned in late 1997, estrogen has been identified as a primary culprit in the development of BPH. Estrogen has been shown to bind to SHBG in the prostate gland and cause the proliferation of epithelial cells in the prostate. This is corroborated by the fact that as men develop benign prostate enlargement, their levels of free testosterone are plummeting while their estrogen levels remain the same or are rising. As previously discussed, aging men tend to convert their testosterone into estrogen. The published evidence shows that serum levels of testosterone are not a risk factor for developing benign prostate disease.

The major concern that has kept men from restoring their testosterone to youthful levels is fear of prostate cancer. The theory is that since most prostate cancer cell lines need testosterone to proliferate, it is better to not replace the testosterone that is lost with aging. The problem with this theory is that most men who contract prostate cancer have low levels of testosterone and the majority of published studies show that serum testosterone levels do not affect one's risk for contracting prostate cancer.

Since the perception is so strong that any augmentation of testosterone can increase the risk of prostate cancer, we did a MEDLINE search on all the published studies relating to serum testosterone and prostate cancer. The appendix at the end of this article provides quotations from the published literature as it relates to the issue of whether testosterone causes prostate disease. Out of 27 MEDLINE studies we found, five indicated that men with higher testosterone levels had a greater incidence of prostate cancer, whereas 21 studies showed that testosterone was not a risk factor. One study was considered neutral. The score was therefore:

21 studies indicating testosterone does not cause prostate cancer

versus

5 studies indicating testosterone causes prostate cancer

(and one study that did not produce significant results)

Before anyone starts a testosterone replacement program, they should have a serum PSA test and a digital rectal exam to rule out prostate cancer. Nothing is risk free. A small minority of men with low testosterone and prostate cancer will not have an elevated PSA or palpable lesion detectable by digital rectal exam. If these men use supplemental testosterone, they risk an acute flare up in their disease state. That is why PSA monitoring is so important every 30-45 days during the first 6 months of any type of testosterone augmentation therapy. If an underlying prostate cancer is detected because of testosterone therapy, it is usually treatable with non-surgical means.

Please remember that testosterone does not cause acute prostate cancer, but if you have existing prostate cancer and don't know it, testosterone administration will likely sharply boost PSA and provide your doctor with a quick diagnosis of prostate cancer (and an opportunity for very early treatment). We acknowledge that some aging men will not want to take this risk.

As stated above, the MEDLINE score was 21 to 5 against the theory that testosterone plays a role in the development of prostate cancer. None of these studies took into account the prostate cancer prevention effects of men who take lycopene, selenium, and vitamins A and E. Nor did they factor in possible prostate disease preventives such as saw palmetto, nettle, soy, and pygeum.

In Dr. Jonathan Wright's book, Maximize Your Vitality and Potency, a persuasive case is made that testosterone and DHEA actually protect against the development of both benign and malignant prostate disease. Dr. Wright also points out that natural therapies such as saw palmetto, nettle, and pygeum provide a considerable degree of protection against the alleged negative effects that higher levels of testosterone might have on the prostate gland.

We eagerly await the results of more studies, but the fear of developing prostate cancer in the future should not be a reason to deprive your body today of the life-saving and life-enhancing benefits of restoring a youthful balance.

Once a man has prostate cancer, testosterone therapy cannot be recommended because most prostate cancer cells use testosterone as a growth promoter. This regrettably denies prostate cancer patients the wonderful benefits of testosterone therapy. Men with severe BPH should cautiously approach testosterone replacement. It would be prudent for those with BPH who are taking testosterone replacement therapy to also use the drug Proscar (finasteride) to inhibit 5- alpha-reductase levels, thereby suppressing the formation of dihydrotestosterone (DHT). DHT is ten times more potent than testosterone in promoting prostate growth, and suppressing DHT is a proven therapy in treating benign prostate enlargement. Saw palmetto extract suppresses some DHT in the prostate gland, but its effectiveness in alleviating symptoms of BPH probably has more to do with:

• Its blocking of alpha-adrenergic receptor sites on the sphincter muscle surrounding the urethra. (This is how the drug Hytrin works.)
• Its inhibition of estrogen binding to prostate cells (like nettle).
• Its inhibition the enzyme 3-ketosteroid (that causes the binding of DHT to prostate cells).
• Its anti-inflammatory effect on the prostate.
• It is unfortunate that many people still think that restoring testosterone to youthful levels will increase the risk of prostate disease. This misconception has kept many men from availing themselves to this life-enhancing and life-saving hormone.

While it is clear that excess estrogen causes benign prostate enlargement, the evidence for excess estrogen's role in the development of prostate cancer is uncertain. Some studies show elevated estrogen is associated with increased prostate cancer risk while other studies contradict this. For more information on testosterone, estrogen and the prostate gland, refer to the February 1999 issue of Life Extension Magazine.

Testosterone and Depression

A consistent finding in the scientific literature is that testosterone replacement therapy produces an increased feeling of well being. As stated earlier, newly published studies show that low testosterone correlates with symptoms of depression and other psychological disorders.

A common side-effect of prescription anti-depressant drugs is the suppression of libido. Those suffering with depression either accept this drug-induced reduction in quality of life, or get off the anti-depressant drugs so they can at least have a somewhat normal sex life. If more psychiatrists tested their patients blood for free testosterone and prescribed natural testosterone therapies to those with low free testosterone, the need for libido-suppressing anti-depressant drugs could be reduced or eliminated. As previously described, testosterone replacement often enhances libido which has the opposite effect of most prescription anti-depressants.

One study showed that patients with major depression experienced improvement that was equal to that achieved with standard antidepressant drugs.

Androderm is one of several natural testosterone replacement therapies that can be prescribed by doctors. A 12- month clinical trial on this FDA-approved drug resulted in a statistically significant reduction in the depression score (6.9 before vs 3.9 after). Also noted were highly significant decreases in fatigue from 79% before the patch to only 10% after 12 months.

According to Jonathan Wright, M.D., author of the book Maximize Your Vitality & Potency, the following effects have been reported in response to low testosterone levels:

• Loss of ability to concentrate
• Moodiness/emotionality
• Touchiness/irritability
• Great timidity
• Feeling weak
• Inner unrest
• Loss of ability to concentrate
• Memory failure
• Reduced intellectual agility
• Passive attitudes
• General tiredness
• Reduced interest in surroundings
• Hypochondria

The above feelings can all be clinical symptoms of depression, and testosterone replacement therapy has been shown to alleviate these conditions. Testosterone thus has exciting therapeutic potential in the treatment of depression in men.

Testosterone and Aging

We know that many of the degenerative diseases of aging in men such as Type II diabetes, osteoporosis, and cardiovascular disease are related to a testosterone deficiency. We also know that common characteristics of middle-age and older age such as depression, abdominal fat deposition, muscle atrophy, low energy, and cognitive decline are also associated with less than optimal levels of free testosterone.

A consistent pattern that deals with fundamental aging shows that low testosterone causes excess production of a dangerous hormone called cortisol. Some anti-aging experts call cortisol a "death hormone" because of the multiple degenerative effects it produces such as immune dysfunction, brain cell injury, arterial wall damage, etc.

A group of scientists conducted two double-blind studies where they administered supplemental testosterone to groups of aging men and observed the typical responses of lower levels of cholesterol, glucose and triglycerides, reductions in blood pressure, and decreased abdominal fat mass. These scientists then showed that excess cortisol suppressed testosterone and growth hormone production and that the administration of testosterone acted as a "shield" against the over-production of cortisol in the adrenal gland.

It is important to point out that testosterone is an anabolic (or protein building) hormone while cortisol is a catabolic hormone that breaks down proteins in the body. Normal aging consists of a progressive decrease in free testosterone with a marked increase in cortisol. As men age past 40, cortisol begins to dominate, and the catabolic effects associated with growing older begin to dominate.

These findings have significant implications in the battle to maintain youthful hormone balance for the purpose of staving off normal aging and its associated degenerative diseases.

The Testosterone Doctor

Eugene Shippen, M.D., authored a book in 1998 called The Testosterone Syndrome. He was a speaker at the American Academy of Anti-Aging Medicine Conference held in December 1998 where he provided extensive evidence documenting the pathology of the testosterone deficiency syndrome in men. Here are some excerpts from Dr. Shippen's presentation that appeared in the March 1999 issue of Life Extension Magazine:

First, Testosterone is not just a "sex hormone." It should be seen as a "total body hormone," affecting every cell in the body. The changes seen in aging, such as the loss of lean body mass, the decline in energy, strength, and stamina, unexplained depression, and decrease in sexual sensation and performance, are all directly related to testosterone deficiency. Degenerative diseases such as heart disease, stroke, diabetes, arthritis, osteoporosis, and hypertension are all directly or indirectly linked to testosterone decline. Secondly, testosterone functions also as a prohormone. Local tissue conversion to estrogens, dihydrotestosterone (DHT), or other active metabolites plays an important part in cellular physiology.

Excess estrogen seems to be the culprit in prostate enlargement. Low testosterone levels are in fact associated with more aggressive prostate cancer. While fear of prostate cancer keeps many men from testosterone replacement, it is in fact testosterone deficiency that leads to the pathology that favors the development of prostate cancer.

Testosterone improves cellular bioenergetics. It acts as a cellular energizer. Since testosterone increases the metabolic rate and aerobic metabolism, it also dramatically improves glucose metabolism and lowers insulin resistance.

Another myth is that testosterone is bad for the heart. Actually, low testosterone correlates with heart disease more reliably than high cholesterol. Testosterone is the most powerful cardiovascular protector for men. Testosterone strengthens the heart muscle; there are more testosterone receptors in the heart than in any other muscle. Testosterone lowers LDL cholesterol and total cholesterol, and improves every cardiac risk factor. It has been shown to improve or eliminate arrhythmia and angina. A Testosterone replacement is the most underutilized important treatment for heart disease.

Testosterone shines as a blood thinner, preventing blood clots. Testosterone also helps prevent colon cancer.

Previous research on testosterone used the wrong form of replacement. Injections result in initial excess of testosterone, with excess conversion to estrogens. Likewise, total testosterone is often measured instead of free testosterone, the bioavailable form. Some studies do not last long enough to show improvement. For instance, it may take six months to a year before the genital tissue fully recovers from atrophy caused by testosterone deficiency, and potency is restored.

Physicians urgently need to be educated about the benefits of testosterone and the delicate balance between androgens (testosterone) and estrogens. Each individual has his or her own pattern of hormone balance; this indicates that hormone replacement should be individualized and carefully monitored.