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Testosterone is the primary androgen produced by the Leydig cells of the testes and is responsible for sexual differentiation and male secondary sex characteristics. Young men exhibit a diurnal pattern of testosterone secretion, with a peak at about 08:00 and a nadir at about 20:00. Levels increase after exercise. In women, levels are 5 to 10% of male levels.
Testosterone is a systemic hormone that affects many organs. Target organs include male sexual organs, muscle, fat, bone, skin, liver, kidney, brain and bone marrow. Testosterone can have a direct effect or be converted to dihydrotestosterone (DHT) by the 5-alpha-reductase enzyme, which is present mainly in liver, skin, prostate, and external genitalia.
Testosterone secretion is regulated by luteinizing hormone (LH), which acts on the Leydig cells of the testes to stimulate synthesis and secretion of testosterone. LH is secreted by the pituitary gland under the control of hypothalamic peptide gonadotropic releasing hormone (GnRH). Testosterone, DHT and estradiol exert negative feedback on GnRH secretion. Lowering testosterone levels results in increasing LH secretion in an attempt to correct the testosterone deficit. Conversely, raising testosterone levels inhibits LH secretion and reduces endogenous production of testosterone.
Testosterone circulates in the blood 98% bound to protein. In men, approximately 40% is bound with high affinity to sex hormone binding globulin (SHBG) and approximately 60% is bound weakly to albumin. The testosterone fraction that is bound to albumin dissociates freely in the capillary bed, becoming available for tissue uptake. Only 2 to 3% of testosterone exists in the free state. All non-SHBG bound testosterone is considered to be bioavailable.
Measurement of serum testosterone concentration is useful in the evaluation of hypogonadism, infertility, impotence and replacement therapy monitoring in males and hirsutism and virilization in females. Testosterone levels may also be helpful in the evaluation of ambiguous genitalia and precocious puberty in children.
Testosterone dependent changes of puberty can begin from age 10 to 14. In early puberty, testosterone levels initially increase during the night and return to prepubertal levels by morning. As puberty progresses, testosterone levels eventually remain elevated throughout the day. Measurement of an early morning testosterone level is indicated as part of the work-up for precocious puberty, which is defined as the onset of pubertal changes before age 9, and in the work-up of delayed puberty, which is the lack of pubertal changes by age 14. Testosterone is usually increased in precocious puberty.
In adult men, serum testosterone is decreased in both testicular and pituitary failure. The manifestations of hypogonadism are loss of libido and reduced volume of ejaculate. Often hypogonadal men may not offer specific complaints, but may present with scant facial, axillary and pubic hair; pale, fine wrinkled skin; eunuchoid body habitus; small or atrophic testes or prostate; and mild normocytic anemia. They may complain of decreased vitality and energy and mood changes including depression. More advanced cases may have decreased muscle mass, increased body fat, decreased bone mineral density and anemia. The diagnosis is confirmed by a low serum testosterone concentration. If LH and FSH are elevated, the problem is primary testicular failure. Testosterone levels may also be decreased in hepatic cirrhosis and severe obesity.
Two conditions are associated with male sexual dysfunction and elevated total testosterone level: hyperthyroidism and the syndromes of androgen resistance. Hyperthyroidism causes an increase in SHBG, which elevates total but not free testosterone. Androgen resistance is associated with a defective androgen receptor or 5-alpha reductase deficiency. Exogenous testosterone or testosterone precursor overtreatment or abuse can also result in elevated serum testosterone levels.
Female hirsutism is caused by excess androgen secretion by either the adrenal glands or ovary. Virilization or rapidly progressive hirsutism suggests a tumor is present and requires prompt investigation. Testosterone is a good indicator of ovarian function, while dehydroepiandrosterone sulfate (DHEA-S) is a good indicator of adrenal function. A serum total testosterone level above 200 ng/dL is indicative of ovarian stromal hyperthecosis (a benign condition) or an adrenal or ovarian tumor. If the total testosterone is less than150 ng/dL then a tumor is unlikely.
The polycystic ovary syndrome is the most common hormonal cause of anovulation and hirsutism. Most women will have slightly elevated testosterone, elevated LH, and normal FSH. The differential diagnosis of polycystic ovary syndrome includes hyperprolactinemia, acromegaly and congenital adrenal hyperplasia.
Testosterone and Aging As men age, their serum total testosterone concentrations fall, mostly due to a diminution of the early morning peak. The major cause of decreased testosterone production appears to be diminished testicular response to luteinizing hormone (LH). Alterations in pituitary function may also be partly responsible, because LH concentrations do not increase appropriately in response to falling testosterone concentration.
After the age of 40 years, men’s total testosterone levels begin to decline about 0.4% per year. The result is that 60 to 80 year old men have total serum testosterone concentrations that are about 70% of those of 20 to 40 year old men. By the 8th decade, 30% of men have testosterone levels below the reference range. Men with chronic illnesses have testosterone levels that are 10–15% below that of healthy age-matched men.
Measurement of total testosterone concentrations in 255 male outpatients at Saint Luke’s Hospital revealed the following data.
Age
(years)
Mean Testosterone
(ng/mL)
20-29
410
30-39
422
40-49
378
50-59
379
60-69
303
70-79
260
80-85
188
Serum concentrations of sex hormone binding globulin (SHBG) rise gradually with increasing age, so that serum free testosterone concentrations decrease even more dramatically than total testosterone. In 60 to 80 year old men, serum free testosterone concentrations are only 33 to 50% of those of 20 to 40 year old men. Conditions that alter SHBG levels are summarized in the following table.
Young men have a circadian rhythm of testosterone, with the zenith occurring in the morning between 0600 and 0800 h and the nadir in the late afternoon between 1700 and 1800 h. This circadian rhythm disappears in elderly men. The difference in testosterone levels between young and elderly men is most pronounced when measurements are made in the morning.
Decreased serum testosterone is associated with:
decreased energy and libido
decreased muscle mass & strength
increased upper and central body fat
decreased bone mineral density
decreased hemoglobin concentration
Some experts have likened this syndrome to menopause and named it andropause. However, several major differences exist. Testosterone levels in men decline much more gradually than estrogen levels in women and there does not appear to be a definitive testosterone level at which all men exhibit symptoms of hypogonadism. The efficacy of testosterone replacement therapy in reversing these age-related changes has not been established. Testosterone treatment has been associated with numerous adverse effects including polycythemia, gynecomastia, edema, prostate cancer, benign prostatic hyperplasia and coronary artery disease.
Some men with prominent symptoms of androgen deficiency may benefit from testosterone supplementation. A total testosterone level below 300 ng/dL is often used as the cutoff point for considering replacement therapy in symptomatic men. Testosterone can be administered by intramuscular injection and transdermal gel or patches. Using intramuscular injections, the dose and frequency of injections should be adjusted to keep the peak level, obtained 1 to 2 days after injection, at the upper end of the normal range. The nadir level, measured just prior to the next injection, should be at the lower end of the normal range. With transdermal patches, testosterone levels do not fluctuate significantly day to day and the dose should be adjusted to stay in within the normal range.
Total testosterone is the most appropriate test to determine whether an older man is hypogonadal or not. If the total testosterone level is below 200 ng/mL, the individual should be considered hypogonadal, regardless of age. The question that cannot be answered today is whether men with total testosterone levels between 200 and 300 ng/mL are hypogonadal and whether they would benefit from androgen replacement.
A symposium on “Issues in Testosterone Replacement in Older Men”, concluded that no well designed clinical trials have indicated that one testosterone assay is better than any other at determining whether an older man is androgen deficient (J CE & M 1998;83:3436-38). Total testosterone is as good a measurement, and less expensive, than the more complex and labor intensive measurement of free or bioavailable testosterone. Measurements of free or bioavailable testosterone should be considered experimental, until they are clearly shown to be a better marker of hypogonadism in elderly men than total testosterone levels.
According to Mayo Medical Laboratories, total testosterone should be measured to monitor testosterone replacement therapy. During treatment with depot-testosterone preparations, trough levels of serum testosterone should remain within the normal range, while peak levels should not be significantly above the normal young adult range.
Measurement of free testosterone is indicated in the following situations.
Assessment of androgen status in men with suspected SHBG binding abnormalities.
Assessment of bioavailable testosterone in early pubertal boys and elderly men.
Assessment of women with signs and symptoms of hyperandrogenism but normal total testosterone levels
Monitoring of testosterone or antiandrogen therapy in older men and in females.
Reference ranges are based on morning samples in a healthy young male population. Afternoon or evening samples may appear to be low even though they are normal for the time of sampling. Samples should preferably be drawn in the morning between 07:00 and 10:00. Beginning in middle age, the differences between morning and evening values lessen.
Total
Male 241 - 827ng/mL
Female 14 – 76 ng/mL
Free
Male 8.70 – 54.70 pg/mL
Female 0.30 – 3.20 pg/mL
It is important to repeat testing in a patient with a borderline low morning serum testosterone level before starting replacement therapy. One third of men with an initial low result will have a normal repeat value.
Specimen requirement is one plain red top tube of blood.
