Androgens increase in both males and females during puberty.[3] The major androgen in males is testosterone.[4]Dihydrotestosterone (DHT) and androstenedione are of equal importance in male development.[4] DHT in utero causes differentiation of the penis, scrotum and prostate. In adulthood, DHT contributes to balding, prostate growth, and sebaceous gland activity.
Although androgens are commonly thought of only as male sex hormones, females also have them, but at lower levels: they function in libido and sexual arousal. Androgens are the precursors to estrogens in both men and women.
Dehydroepiandrosterone (DHEA) is a steroid hormone produced in the adrenal cortex from cholesterol.[5] It is the primary precursor of both the androgen and estrogen sex hormones. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.
Androstenedione (A4) is an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenedione is converted metabolically to testosterone and other androgens, it is also the parent structure of estrone. Use of androstenedione as an athletic or bodybuilding supplement has been banned by the International Olympic Committee, as well as other sporting organizations.
Androsterone is a chemical byproduct created during the breakdown of androgens, or derived from progesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in the plasma and urine of both males and females.
Dihydrotestosterone (DHT) is a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. It is produced in the skin and reproductive tissue.
A4 and testosterone can also have an extra hydroxyl (-OH) or keton (=O) group bound on position 11. In this case you can have 11-hydroxyandrostenedione, 11-ketoandrostenedione, 11-hydroxytestosterone, and 11-ketotestosterone. The latter has the same biological activity as testosterone[6] and, therefore, these are also very important in healthy individuals and patients with diseases like, congenital adrenal hyperplasia, polycystic ovarian syndrome, or premature adrenarche.[6]
Determined by consideration of all biological assay methods (c. 1970):[7]
Female ovarian and adrenal androgens
The ovaries and adrenal glands also produce androgens, but at much lower levels than the testes. Regarding the relative contributions of ovaries and adrenal glands to female androgen levels, in a study with six menstruating women the following observations have been made:[8]
Adrenal contribution to peripheral T, DHT, A, DHEA and DHEA-S is relatively constant throughout the menstrual cycle.
Ovarian contribution of peripheral T, A and DHEA-S reaches maximum levels at mid-cycle, whereas ovarian contribution to peripheral DHT and DHEA does not seem to be influenced by the menstrual cycle.
Ovary and adrenal cortex contribute equally to peripheral T, DHT and A, with the exception that at mid-cycle ovarian contribution of peripheral A is twice that of the adrenal.
Peripheral DHEA and DHEA-S are produced mainly in the adrenal cortex which provides 80% of DHEA and over 90% of DHEA-S.
Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle[8]
Androgen
Ovarian (%) (F, M, L)
Adrenal (%)
DHEA
20
80
DHEA-S
4, 10, 4
90–96
Androstenedione
45, 70, 60
30–55
Testosterone
33, 60, 33
40–66
DHT
50
50
F = early follicular, M = midcycle, L = late luteal phase.
Biological function
Male prenatal development
Testes formation
During mammalian development, the gonads are at first capable of becoming either ovaries or testes.[9] 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 paracrinehormones required by the Sertoli cells to support sperm production. They are also required for the 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).
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.[10] 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.
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.[11] 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 in a coordinated manner by acting on several cell types in skeletal muscle tissue.[12] One cell type, called the myoblast, conveys androgen receptors for generating muscle. Fusion of myoblasts generates myotubes, in a process linked to androgen receptor levels.[13] Higher androgen levels lead to increased expression of androgen receptor.
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.[14] Although more recent studies showing the general mood of transgender men, who have undergone transgender hormone replacement therapy replacing estrogens with androgens, do not show any substantial long-term behavioral changes.[15][16][17]
Numerous reports have shown androgens alone are capable of altering the structure of the brain,[18] 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 androgen insensitivity syndrome, a genetic difference resulting in complete or partial insensitivity to androgens and a lack of external male genitalia.
Moreover, estrogens had no effect. This research demonstrates how androgens can increase AHN.[19]
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 increased via activation of the estrogen receptors.[20]
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 preadolescenthippocampalneurogenesis that may be linked with lower depression-like symptoms.[21]
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.
Miscellaneous
Yolk androgen levels in certain birds have been positively correlated to social dominance later in life. See American coot.
Determined by consideration of all biological assay methods (c. 1970):[7]
Androgen
Potency (%)
Testosterone
40
5α-Dihydrotestosterone (DHT)
100
Androstenediol
.0008
Androstenedione
.04
Dehydroepiandrosterone
.02
Androsterone
.06
5α-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.[24]
One of the 11-oxygenated androgens, namely 11-ketotestosterone, has the same potency as testosterone. [25]
Steroidogenesis, showing the relation between several androgens, is at bottom left. Estrone and estradiol, in contrast, are estrogens.
Biosynthesis
Androgens are synthesized from cholesterol and are produced primarily in the gonads (testicles and ovaries) and also in the adrenal glands. The testicles produce a much higher quantity than the ovaries. Conversion of testosterone to the more potent DHT occurs in prostate gland, liver, brain and skin.
Notes: "The concentration of a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. The secretion rate of a steroid refers to the total secretion of the compound from a gland per unit time. Secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. The metabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. The production rate of a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. At steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). If there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate." Sources: See template.
A low testosterone level (hypogonadism) in men may be treated with testosterone administration. Prostate cancer may be treated by removing the major source of testosterone: testicle removal (orchiectomy); or agents which block androgens from accessing their receptor: antiandrogens.
^Moini J (2015). Fundamental Pharmacology for Pharmacy Technicians. Cengage Learning. p. 338. ISBN978-1-30-568615-1. Androgen is the generic term for any natural or synthetic compound, usually a steroid hormone, which stimulates or controls the development of masculine characteristics by binding to androgen receptors.
^ abBriggs MH, Brotherton J (3 February 1970). Steroid Biochemistry and Pharmacology. London: Academic Press. ISBN978-0-12-134650-8.
^ abAbraham GE (August 1974). "Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle". The Journal of Clinical Endocrinology and Metabolism. 39 (2): 340–346. doi:10.1210/jcem-39-2-340. PMID4278727.
^Costantino A, Cerpolini S, Alvisi S, Morselli PG, Venturoli S, Meriggiola MC (14 February 2013). "A prospective study on sexual function and mood in female-to-male transsexuals during testosterone administration and after sex reassignment surgery". Journal of Sex & Marital Therapy. 39 (4): 321–335. doi:10.1080/0092623X.2012.736920. PMID23470169. S2CID34943756.
^Johnson JM, Nachtigall LB, Stern TA (1 November 2013). "The effect of testosterone levels on mood in men: a review". Psychosomatics. 54 (6): 509–514. doi:10.1016/j.psym.2013.06.018. PMID24016385.
