Androgens:
For men with a low level of free testosterone in the blood, testosterone or other hormone replacement therapy (HRT) can be considered. HRT can help men with low testosterone levels increase their libido and sexual arousal. Testosterone replacement also can improve muscle strength and bone mineral density in men and women with low levels of the hormone.

Androgens such as testosterone, also promote an overall decrease in fat and an increase in muscle strength and lean body mass. Testosterone replacement therapy has been shown to lift mood and decrease anxiety. It may enhance orientation and memory and it may also have antidepressant effects.

How is testosterone produced:
The testes produce testosterone regulated by a complex chain of signals that begins in the brain. This chain is called the hypothalamic-pituitary-gonadal axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) to the pituitary gland in carefully timed pulses (bursts), which triggers the secretion of leutenizing hormone (LH) from the pituitary gland. Leutenizing hormones thus stimulate the Leydig cells of the testes to produce testosterone. Normally, the testes produce 4–7 milligrams (mg) of testosterone daily.

Testosterone production increases rapidly at the onset of puberty and starts to decrease there after. It decreases rapidly after age 40 (to 20% to 70% of peak level by age 70). Approximately 8 million men in the United States experience testosterone deficiency; approximately 700,000 receive treatment.

Signs and Symptoms
Men are generally reluctant or unwilling to acknowledge that the syndrome has crept up on them.  The symptoms are not as overwhelming as the dramatic changes women experience and it may not affect all men; however, about 40% of men in the 40s, 50s, and 60s will experience some of the symptoms, including lethargy, depression, irritability, mood swings, and erectile dysfunction.

Testosterone levels begin to decrease for a number of reasons, including (1) the Leydig cells begin to decrease in number and function, (2) a sex hormone binding globulin (SHBG) increase with age, resulting in greater binding of testosterone with less free testosterone.  There is a higher relative amount of estradiol with less testosterone being produced.

As men pass 50, they tend to develop an enlarged prostate.  As the gland increases in size, it squeezes the urethra, often causing increased urinary frequency, a weaker flow and difficulty beginning urination.  The current treatments include finasteride (Proscar) and Saw Palmetto (made from the berries of a plant native to the American Southeast) which reduces the size of the prostate in only four to six weeks and is relatively effective.  Zinc is also used to maintain a healthy prostate. In addition to enlarged prostate, other prostate problems include prostatitis, and prostate cancer.  It has been stated that men have odds of 100% of experiencing one of these three disorders.

Visceral fat increase has been associated with an increased vascular risk. Body fat in men increases from 18% to 36% between 18 and 85 years of age, with the largest increases in intraabdominal fat. Also, by age 70, an average man has about 26 pounds less lean body mass than at age 25.

Low testosterone can lead to osteoporosis in elderly men. This tends to happen later in men than in women because of the general tendency for men's bones to be thicker and denser than women's. In hypogonadal men, bone mineral density tends to increase with testosterone treatment. In men, there may be an increase in circulating estrogen levels; common causes of estrogen increase during mid-life include age-related increases in aromatase activity, alteration in liver function, zinc deficiency, obesity, overuse of alcohol, drug-induced estrogen imbalance and ingestion of estrogen-enhancing food or environmental substances.  Also, fatty tissue contains more aromatase activity as compared with lean tissue resulting in more testosterone being converted to estradiol. Vitamin C deficiency is associated with high levels of aromatase activity whereas zinc inhibits aromatase activity.

Low testosterone levels may tend towards depression; the decrease in sexual function may also lead to depression, irritability, and mood swings...this depression further leading to decreased sexual function.

Complications
Testosterone deficiency has been linked to muscle weakness and osteoporosis. In one study, proximal and distal muscle weakness was detected in 68% of men with primary or secondary hypogonadism. Spinal, trabecular, and radial cortical bone density may also be significantly reduced in testosterone-deficient men. Thirty percent of men with spinal osteoporosis have long-standing testosterone deficiency, and one-third of men have subnormal bone density that puts them at risk for fracture.

Diagnosis
Serum and blood testing is done to determine the availability of testosterone and levels of leutenizing and gonadotropin-releasing hormones in the body. Men with low testosterone in whom normal or high gonadotropin levels are found typically have primary hypogonadism, which stems from a problem in the testicles. Secondary and tertiary types, caused by problems of the hypothalamus or pituitary gland, often result in low testosterone and low gonadotropin level.

Laboratory Evaluation
Laboratory evaluation for andropausal men can include

Treatment
The therapeutic goal is enable the adult man to maintain or improve strength to function better and more consistently.  Many physicians hesitate to use testosterone supplementation as it is new, they have heard stories (sometimes related to synthetic androgen supplementation), and they are unsure of the results as it takes quite some time for them to become evident.  There is no evidence that exogenous testosterone stimulates the development of prostate carcinoma; there has been no relationship established between endogenous testosterone and BPH.  However, a contraindication to androgen replacement therapy is the presence of prostate cancer.

Who qualifies for testosterone therapy programs.
The decision to use HRT is an individual one, based on the individual's particular risks. The goals of natural HRT are to:

Natural testosterone replacement is central to the treatment of all aspects of "male menopause". Testosterone supplementation has resulted in decreasing body fat mass from 6.4% to 1.4% and increases in lean mass from 3.2% to 5%.  Increases in strength (grip strength) also are reported.

Total cholesterol and low density lipoproteins tend to significantly decrease with testosterone administration. Three steroids of importance in the male reproductive function are testosterone, dihydrotestosterone and estradiol.  By far the greatest percentage of testosterone (over 95%) is secreted by the testicular Leydig cells.  The dihydrotestosterone and estradiol are derived from both the direct secretion from the testes (20%) and also from conversion in peripheral tissues on androgen and estrogen precursors secreted by both the testes and adrenal glands (80%).

Hormone preparations that have been used include testosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, fluoxymestrone, methyltestosterone (methyltestosterone is toxic to the liver and heart and may have clouded the benefits of testosterone replacement therapy), oxandrolone, progesterone, and estradiol.  Commercial testosterone products have been administered either by injection, implants/pellets, orally or as transdermal patches.

Injections: One disadvantage to testosterone enanthate and testosterone cypionate injections is that they are injected at 2 to 3 week intervals.   The blood profiles are high after the injection, follow by a slow decline over the time interval until the next injection.  This clearly does not follow the normal adult physiological pattern.

Implants/Pellets: Subdermal testosterone implants produce a similar pattern to the injections. Testosterone undecanoate administered orally gives a rapid onset of action but a short duration of action, consequently it may be administered several times daily.

Transdermal: In transdermal testosterone, the hormone is released slowly through the skin to deliver a constant level in the blood, again not a routine pattern, but convenient.

Our compounding pharmacists can offer many options to provide for different blood level profiles and convenience of administration. Topical testosterone can be applied using different vehicles to more closely mimic the normal adult physiological pattern, i.e., apply early in the morning where it should be absorbed over a period of a few hours.

Testosterone, the most common agent used in male hormone replacement therapy, occurs as white or slightly creamy white crystals or crystalline powder that is odorless and stable in air.  It is practically insoluble in water, soluble 1 g in 5 mL of ethanol, 2 mL of chloroform and 100 mL of ether and is soluble in vegetable oils, melts between 153 and 157ºC., and is subject to photodegradation in the presence of light. Testosterone is not very bioavailable when given as an oral-swallow preparation, but is absorbed when administered bucally and sublingually.  The different esters of testosterone are hydrolyzed to free testosterone and, subsequently, are metabolized in the same way as testosterone itself .

Possible side effects
The goal of testosterone replacement therapy is to achieve normal to optimal levels of testosterone. For most patients, testosterone replacement therapy is safe. Possible side effects, however, include water retention, male pattern baldness, gynecomastia (enlarged breasts). The oral forms are also associated with liver problems. The use of large doses of testosterone (in bodybuilding, for example) increases the risks of side effects.

Decreased normal testosterone production, prolonged or excessive testosterone therapy prompts the pituitary gland to stop producing the hormone gonadotropin. This in turn, surpresses normal testosterone and sperm production, accompanied by shrinkage of the testicles and frequent or continuing (and sometimes painful) erections. Because of this, testosterone replacement therapy is usually prescribed in cycles. After a 2- or 3-month period, the patient takes a different drug (such as HCG) that stimulates the testicles to begin production of natural testosterone again.