Androgen

Types

The main subset of androgens, known as adrenal androgens, is composed of 19-carbon steroids synthesized in the zona reticularis, the innermost layer of the adrenal cortex. Adrenal androgens function as weak steroids (though some are precursors), and the subset includes dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione.

Besides testosterone, other androgens include:

Testes formation

During mammalian development, the gonads are at first capable of becoming either ovaries or testes. In humans, starting at about week 4, the gonadal rudiments are present within the intermediate mesoderm adjacent to the developing kidneys. At about week 6, epithelial sex cords develop within the forming testes and incorporate the germ cells as they migrate into the gonads. In males, certain Y chromosome genes, particularly SRY, control development of the male phenotype, including conversion of the early bipotential gonad into testes. In males, the sex cords fully invade the developing gonads.

Androgen production

The mesoderm-derived epithelial cells of the sex cords in developing testes become the Sertoli cells, which will function to support sperm cell formation. A minor population of nonepithelial cells appear between the tubules by week 8 of human fetal development. These are Leydig cells. Soon after they differentiate, Leydig cells begin to produce androgens.

Androgen effects

The androgens function as paracrine hormones required by the Sertoli cells to support sperm production. They are also required for masculinization of the developing male fetus (including penis and scrotum formation). Under the influence of androgens, remnants of the mesonephron, the Wolffian ducts, develop into the epididymis, vas deferens and seminal vesicles. This action of androgens is supported by a hormone from Sertoli cells, Müllerian inhibitory hormone (MIH), which prevents the embryonic Müllerian ducts from developing into fallopian tubes and other female reproductive tract tissues in male embryos. MIH and androgens cooperate to allow for movement of testes into the scrotum.

Early regulation

Before the production of the pituitary hormone luteinizing hormone (LH) by the embryo starting at about weeks 11–12, human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of androgens at week 8. Androgen action in target tissues often involves conversion of testosterone to 5α-dihydrotestosterone (DHT).

Spermatogenesis

During puberty, androgen, LH and follicle stimulating hormone (FSH) production increase and the sex cords hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout adulthood, androgens and FSH cooperatively act on Sertoli cells in the testes to support sperm production. Exogenous androgen supplements can be used as a male contraceptive. Elevated androgen levels caused by use of androgen supplements can inhibit production of LH and block production of endogenous androgens by Leydig cells. Without the locally high levels of androgens in testes due to androgen production by Leydig cells, the seminiferous tubules can degenerate, resulting in infertility. For this reason, many transdermal androgen patches are applied to the scrotum.

Inhibition of fat deposition

Males typically have less body fat than females. Recent results indicate androgens inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function. Also, androgens, but not estrogens, increase beta adrenergic receptors while decreasing alpha adrenergic receptors- which results in increased levels of epinephrine/ norepinephrine due to lack of alpha-2 receptor negative feedback and decreased fat accumulation due to epinephrine/ norepinephrine then acting on lipolysis-inducing beta receptors.

Muscle mass

Males typically have more skeletal muscle mass than females. Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to function by acting on several cell types in skeletal muscle tissue. One cell type conveys hormone signals to generating muscle, the myoblast. Higher androgen levels lead to increased expression of androgen receptor. Fusion of myoblasts generates myotubes, in a process linked to androgen receptor levels.

Brain

Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of human aggression and libido. Indeed, androgens are capable of altering the structure of the brain in several species, including mice, rats, and primates, producing sex differences.

Numerous reports have shown androgens alone are capable of altering the structure of the brain, but identification of which alterations in neuroanatomy stem from androgens or estrogens is difficult, because of their potential for conversion.

Evidence from neurogenesis (formation of new neurons) studies on male rats has shown that the hippocampus is a useful brain region to examine when determining the effects of androgens on behavior. To examine neurogenesis, wild-type male rats were compared with male rats that had testicular feminization mutation (TMF), a genetic disorder resulting in complete or partial insensitivity to androgens and a lack of external male genitalia.

Neural injections of Bromodeoxyuridine (BrdU) were applied to males of both groups to test for neurogenesis. Analysis showed that testosterone and dihydrotestosterone regulated adult hippocampal neurogenesis (AHN). Adult hippocampal neurogenesis was regulated through the androgen receptor in the wild-type male rats, but not in the TMF male rats. To further test the role of activated androgen receptors on AHN, flutamide, an antiandrogen drug that competes with testosterone and dihydrotestosterone for androgen receptors, and dihydrotestosterone were administered to normal male rats. Dihydrotestosterone increased the number of BrdU cells, while flutamide inhibited these cells.

Moreover, estrogens had no effect. This research demonstrates how androgens can increase AHN.

Researchers also examined how mild exercise affected androgen synthesis which in turn causes AHN activation of N-methyl-D-aspartate (NMDA) receptors.

NMDA induces a calcium flux that allows for synaptic plasticity which is crucial for AHN.

Researchers injected both orchidectomized (ORX) (castrated) and sham castrated male rats with BrdU to determine if the number of new cells was increased. They found that AHN in male rats is increased with mild exercise by boosting synthesis of dihydrotestosterone in the hippocampus.

Again it was noted that AHN was not increase via activation of the estrogen receptors.

Androgen regulation decreases the likelihood of depression in males. In preadolescent male rats, neonatal rats treated with flutamide developed more depression-like symptoms compared to control rats.

Again BrdU was injected into both groups of rats in order to see if cells were multiplying in the living tissue. These results demonstrate how the organization of androgens has a positive effect on preadolescent hippocampal neurogenesis that may be linked with lower depression-like symptoms.

Social isolation has a hindering effect in AHN whereas normal regulation of androgens increases AHN. A study using male rats showed that testosterone may block social isolation, which results in hippocampal neurogenesis reaching homeostasis—regulation that keeps internal conditions stable. A Brdu analysis showed that excess testosterone did not increase this blocking effect against social isolation; that is, the natural circulating levels of androgens cancel out the negative effects of social isolation on AHN.

Effects specific to females

Androgens have potential roles in relaxation of the myometrium via non-genomic, androgen receptor-independent pathways, preventing premature uterine contractions in pregnancy.

Insensitivity to androgen in humans

Reduced ability of an XY-karyotype fetus to respond to androgens can result in one of several conditions, including infertility and several forms of intersex conditions.

Relative potency of natural androgens (%)

Determined by consideration of all biological assay methods (circa 1970). Data from Steroid Biochemistry and Pharmacology by Briggs and Brotherton, Academic Press.

5-alpha-dihydrotestosterone (DHT) was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass (this is a measure of epithelial cell function stimulation). Whereas DHT was equally potent as testosterone at preventing prostate cell death after castration.

Androgenic impact of exercise

In cross-sectional analyses, aerobic exercisers have lower basal total and free testosterone compared to the sedentary. Anaerobic exercisers also have lower testosterone compared to the sedentary but a slight increase in basal testosterone with resistance training over time. There is some correlation between testosterone and physical activity in the middle aged and elderly. Acutely, testosterone briefly increases when comparing aerobic, anaerobic and mixed forms of exercise. A study assessed men who were resistance trained, endurance trained, or sedentary in which they either rested, ran or did a resistance session. Androgens increased in response to exercise, particularly resistance, while cortisol only increased with resistance. DHEA increased with resistance exercise and remained elevated during recovery in resistance-trained subjects. After initial post-exercise increase, there was decline in free and total testosterone during resistance recovery, particularly in resistance-trained subjects. Endurance-trained subjects showed less change in hormone levels in response to exercise than resistance-trained subjects. Another study found relative short term effects of aerobic, anaerobic and combined anaerobic-aerobic exercise protocols on hormone levels did not change. The study noted increases in testosterone and cortisol immediately after exercise, which in 2 hours returned to baseline levels.

Aerobic

In trained long term aerobic exercisers, basal levels are unchanged, or decreased. Acutely, endurance based aerobic efforts cause testosterone to rise.

A year long, moderate-intensity aerobic exercise program increased DHT and SHBG in sedentary men age 40–75, but had no effect on other androgens. Both DHT and SHBG increased 14% in exercisers at 3 months, and at 12 months they remained 9% above baseline. SHBG is protective against DHT as it binds free androgen. In acute assessment of hormone levels in soccer players before, during and after a game, DHT and testosterone increased during the match, but returned to baseline after 45 minutes rest. Aerobic exercise in Japanese rats done on a rodent treadmill doubled local concentrations of DHT in calf muscles as assessed by protein assay. After intense aerobic effort, high endurance athletes were also found to have lower free testosterone the next day. In prolonged endurance exercise, such as a marathon, levels ultimately decrease. Similarly, DHT drops, while adrenal androgen and cortisol will increase with the stress response.

Anaerobic

It is unknown if anaerobic training changes individual hormone profiles, or if conditioned athletes in studies self-selected because of physiologic predisposition to athletic conditioning. There is variation of response to anaerobic stress depending on exercise intensity, age, gender, length of time studied, and time at which serum indices were drawn. Most studies report that testosterone increases or is unchanged acutely, though some even report it to decrease. Anaerobic exercisers have testosterone levels below sedentary controls in cross sectional analysis. Over months to years, levels are stable to slightly increased.

The ratio of testosterone to cortisol can both increase and decrease during resistance training, depending on intensity of exercise. A study comparing young and old subjects showed acute increases in GH and testosterone for both, although the latter increased less in older men. Testosterone rises in late hours of sleep after anaerobic exercise. Androgen receptor expression increases with acute exercise in correlation to free testosterone. When comparing men and women in the 30, 50 and 70 year age groups, young and middle aged men showed increased testosterone after exercise, with the latter also having increased cortisol. Elderly men showed no change. Other studies have also shown with age there is a downtrend of testosterone and attenuated growth hormone response. Young men have shown no acute change in testosterone with resistance training, with increase in cortisol and growth hormone depending on intensity. One study in young men showed testosterone acutely stable, with increase in GH and IGF-1. Similarly, a study showed testosterone did not increase in young men, women, and pubescent boys unaccustomed to weight training when corrected for plasma volume. Extreme intensity of strength training may trigger the stress response, resulting in lower testosterone levels, an effect accentuated by energy deprivation. A separate study comparing different ages, however, found no difference in acute testosterone and cortisol levels between groups, but attenuated growth hormone response in the elderly. Acutely, other studies have shown testosterone to increase. In a small group of anaerobically trained athletes, stressful training acutely even decreased serum testosterone and its ratio to cortisol and SHBG, with an increase in LH. With subsequent decompensation, testosterone was stable, but cortisol and SHBG decreased. Another case control showed with intense training followed by rest, testosterone dropped and LH increased initially.

Interval and quality of exercise also affect hormonal response. Sessions of moderate to high intensity with multiple sets and short time intervals, during which energy is derived from glycolytic lactate metabolism, appear to be the greatest stimulus for steroid hormone response. Hormonal response in young men varies with the number of sets in the exercise session. However, when the number increased from 4 to 6, anabolic levels stabilized and cortisol continued to rise, suggesting that alterations in anaerobic volume could alter anabolic and catabolic hormonal balance. When sets are performed at maximum repetitions, interval has no influence at a certain intensity range, with no acute hormone response difference between protocols at 10 maximum reps with 2- and 5-minute intervals. There is a higher total testosterone response in hypertrophy protocols compared to those for strength and power, despite equalization of total work load (defined as load x sets x repetitions). There is a 27% greater testosterone response using protocols with simultaneous use of all four limbs. Androgenic response was also noted in protocols using upper and lower limbs separately to a lesser degree.

A number of studies have looked at effects of anaerobic exercise over months to years, showing it to be constant or slightly increased. A small case-control of anaerobic training in young untrained males over six weeks found decline in free testosterone of 17 percent. With men in their 60s, resistive training over 16 weeks did not affect baseline anabolic hormone levels, although GH increased acutely with exercise. A study over 21 weeks in male strength athletes showed basal hormone levels to be constant, despite strength increase. A follow up study looked at a larger group of weight trainers over 24 weeks, with 12 week decompensation. Training caused no change in total testosterone, but there were decreases in free testosterone, progesterone, androstendione, DHEA, cortisol, transcortin, and in the cortisol:CBG ratio, suggesting androgen turnover increased with training intensity, without change in total testosterone. A study looking at young men and resistance training over 48 weeks found increases in baseline serum testosterone from 20 ± 5 to 25 ± 5 nmol/l, and an increase in testosterone:SHBG ratio, LH and FSH.

Combined training

One study showed GH increase with anaerobic effort to be blunted in those who performed aerobic training for 60 minutes prior to strength training. Testosterone levels remained high only at the end of the training session with aerobic training followed by strength training, a phenomenon not seen with weight training done before aerobics. In an 11-week soccer training program focusing on combined vertical jumps, short sprints, and submaximal endurance running, total testosterone increased, but SHBG rose in parallel, maintaining a constant free androgen index.

Miscellaneous

Non-genomic actions

Androgens have also been found to signal through membrane androgen receptors, which are distinct from the classical nuclear androgen receptor.