Testosterone
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Testosterone is a steroid hormone from the androgen group. Testosterone is primarily secreted in the testes of males and the ovaries of females although small amounts are secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid. In both males and females, it plays key roles in health and well-being. Examples include enhanced libido, energy, immune function, and protection against osteoporosis. On average, the adult male body produces about twenty times the amount of testosterone an adult female's body does [Williams textbook of endocrinology. Jean D. Wilson pp 535, 887].
Sources of testosterone
Like other steroid hormones, testosterone is derived from cholesterol. The largest amounts of testosterone are produced by the testes in men, but it is also synthesized in smaller quantities in women by the theca cells of the ovaries, by the placenta, as well as by the zona reticularis of the adrenal cortex in both sexes.
In the testes, testosterone is produced by the Leydig cells. The male generative glands also contain Sertoli cells which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone binding globulin (SHBG).
Mechanism of effects
The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors.
Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5α-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.
Androgen receptors occur in many different vertebrate body system tissues, and both males and females respond similarly to similar levels. Greatly differing amounts of testosterone prenatally, at puberty, and throughout life account for a large share of biological differences between males and females.
The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of aromatization to estradiol. In the bones, estradiol accelerates maturation of cartilage into bone, leading to closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatized to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion). In many mammals, prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived from testosterone programs later male sexual behavior.
Effects of testosterone on humans
In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizing and anabolic effects, although the distinction is somewhat artificial, as many of the effects can be considered both. Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation. Virilizing effects include maturation of the sex organs, particularly the penis and the formation of the scrotum in fetuses, and after birth (usually at puberty) a deepening of the voice, growth of the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics.
Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone.
Most of the prenatal androgen effects occur between 7 and 12 weeks of gestation.
- Genital virilization (midline fusion, phallic urethra, scrotal thinning and rugation, phallic enlargement)
- Development of prostate and seminal vesicles
Early postnatal effects are the first visible effects of rising androgen levels in childhood, and occur in both boys and girls in puberty.
- Adult-type body odour
- Increased oiliness of skin and hair, acne
- Pubarche (appearance of pubic hair)
- Axillary hair
- Growth spurt, accelerated bone maturation
- Fine upper lip and sideburn hair
- Phallic enlargement (including clitoromegaly)
- Increased libido and erection frequency
- Pubic hair extends to thighs and up toward umbilicus
- Facial hair (sideburns, beard, moustache)
- Chest hair, periareolar hair, perianal hair
- Increased tendency for violence or aggressive behavior directly correlated with testosterone amounts.
- Subcutaneous fat in face decreases
- Increased muscle strength and mass
- Deepening of voice
- Growth of the adam's apple
- Growth of spermatogenic tissue in testes, male fertility
- Growth of jaw, brow, chin, nose, and remodeling of facial bone contours
- Shoulders widen and rib cage expands
- Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.
- Maintenance of muscle mass and strength
- Maintenance of bone density and strength
- Libido and erection frequency
- Mental and physical energy
Therapeutic use of testosterone
Testosterone was first isolated from a bull in 1935. There have been many pharmaceutical forms over the years. Forms of testosterone for human administration currently available in North America include injectable (such as testosterone cypionate or testosterone enanthate in oil), oral ([Andriol]), buccal ([Striant]), transdermal skin patches, and transdermal creams or gels ([Androgel] and [Testim]). In the pipeline are a "roll on" delivery method and a nasal spray.
The original and primary use of testosterone is for the treatment of males who have too little or no natural endogenous testosterone production; males with hypogonadism. Appropriate use for this purpose is legitimate hormone replacement therapy, which maintains serum testosterone levels in the normal range.
However, over the years, as with every hormone, testosterone or other anabolic steroids has also been given for many other conditions and purposes besides replacement, with variable success but higher rates of side effects or problems. Examples include infertility, lack of libido or erectile dysfunction, osteoporosis, penile enlargement, height growth, bone marrow stimulation and reversal of anemia, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug (e.g., see Paul de Kruif's The Male Hormone) in exactly the same way that growth hormone is being described today.
Anabolic steroids have also been taken to enhance muscle development, strength, or endurance. After a series of scandals and publicity in the 1980s (such as Ben Johnson's improved performance at the 1988 Summer Olympics), prohibitions of anabolic steroid use were renewed or strengthened by many sports organizations, and it was made a "controlled substance" by the United States Congress.
To take advantage of its virilizing effects, testosterone is often administered to transmen (female-to-male transsexual and transgender people) as part of the hormone replacement therapy, with a "target level" of the normal male testosterone level. And like-wise, transwomen are sometimes prescribed drugs [anti-androgens] to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.
There is a myth that exogenous testosterone can more or less definitively be used for male birth control. However, the vast majority of physicians will agree that to prescribe exogenous testosterone for this purpose is inappropriate. But perhaps more importantly, many men of first hand found this myth to be untrue or at least, unreliable. This is especially true when exogenous testosterone is used in conjunction with hCG.
The \"testosterone deficiency\" of aging and the andropause controversy
Testosterone levels decline gradually with age in men. The clinical significance of this decrease is debated (see andropause), and there is no general agreement if and when to treat aging men with testosterone replacement therapy. The position of the American Society of Andrology is that testosterone therapy "is indicated when both clinical symptoms and signs suggestive of androgen deficiency and decreased testosterone levels are present". Unfortunately, there is no general agreement on the threshold of testosterone value below which a man would be considered hypogonadal. In the United States, levels below 200 to 300 pmol/l from a morning sample are generally considered low. Similarly, the signs and symptoms are non-specific, and are generally associated with aging such as loss of muscle mass and bone density, decreased physical endurance, decreased memory ability and loss of libido.
Replacement therapy can take the form of injectable depots, transdermal patches and gels, subcutaneous pellets and oral therapy. Adverse effects of testosterone supplementation include minor side effects such as acne and oily skin, and more significant complications such as increased hematocrit, exacerbation of sleep apnea and acceleration of pre-existing prostate cancer growth. Testosterone also causes suppression of spermatogenesis and can lead to infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and PSA (prostate specific antigen) level prior to initiating therapy, and monitor hematocrit and PSA levels closely during therapy.
Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking. Many caution against embracing testosterone replacement therapy because of lessons from the female hormone replacement therapy trials, where initially promising results were later refuted by larger studies.
Testosterone replacement therapy is also indicated for transsexual men who were born female and thus cannot biologically produce testosterone. Testosterone therapy is usually begins before the onset of gender reassignment surgery. The changes are similar to an adolescent boy in puberty. This allows transsexual men to gradually adapt to living in the male role. Hormone therapy for transsexual persons is standard practice for physicians practicing under the guidelines of the Harry Benjamin Association of Gender Dyshphoria.
Synthesis
Testosterone is synthesized from pregnenolone, which is the precursor of all steroid hormones and a derivative of cholesterol. two pathways are possible, In the delta-5 pathway, pregnenolone is converted to DHEA to androstenedione.
In the delta-4 pathway there is hydroxylation of C-17 of progesterone, to yield 17α-hydroxyprogesterone. The side chain is then cleaved to form androstenedione. Androstenedione is the immediate precursor to testosterone.
The keto group on C-17 is reduced to an alcohol to yield testosterone. Testosterone is a potential precursor of estradiol.
Zinc supplementation is known to result in increased levels of testosterone synthesis, especially in those who are zinc deficient. Zinc is critical to the proper function of steroid receptors (see zinc finger) and plays a vital role as a cofactor to many enzymes which is the likely mechanim for its effect on testosterone synthesis.
References
External links
- [NIST entry for Testosterone]
- [NIST results of search for Testosterone (Shows androstenone.)]
- [NIST Standard Reference Database]
| Hormones and endocrine glands - [edit] |
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Hypothalamus: GnRH - TRH - CRH - GHRH - somatostatin - dopamine | Posterior pituitary: vasopressin - oxytocin | Anterior pituitary: GH - ACTH - TSH - LH - FSH - prolactin - MSH - endorphins - lipotropin Thyroid: T3 and T4 - calcitonin | Parathyroid: PTH | Adrenal medulla: epinephrine - norepinephrine | Adrenal cortex: aldosterone - cortisol - DHEA | Pancreas: glucagon- insulin - somatostatin | Ovary: estradiol - progesterone - inhibin - activin | Testis: testosterone - AMH - inhibin | Pineal gland: melatonin | Kidney: renin - EPO - calcitriol - prostaglandin | Heart atrium: ANP Stomach: gastrin | Duodenum: CCK - GIP - secretin - motilin - VIP | Ileum: enteroglucagon | Liver: IGF-1 Placenta: hCG - HPL - estrogen - progesterone
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