5α-dihydrotestosterone
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Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an
endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
and
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
primarily involved in the growth and repair of the
prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
and the
penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...
, as well as the production of
sebum A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur ...
and
body hair Body hair or androgenic hair is terminal hair that develops on the human body during and after puberty. It is different from head hair and also from less visible vellus hair, which is much finer and lighter in color. Growth of androgenic hai ...
composition. The
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
5α-reductase catalyzes the formation of DHT from
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
in certain tissues including the
prostate gland The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
,
seminal vesicles The seminal vesicles (also called vesicular glands or seminal glands) are a pair of convoluted tubular accessory glands that lie behind the urinary bladder of male mammals. They secrete fluid that largely composes the semen. The vesicles are 5 ...
,
epididymides The epididymis (; : epididymides or ) is an elongated tubular genital organ attached to the posterior side of each one of the two male reproductive glands, the testicles. It is a single, narrow, tightly coiled tube in adult humans, in length; ...
,
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...
,
hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction betwee ...
s,
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, and
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
. This enzyme mediates reduction of the C4-5
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
of testosterone. DHT may also be synthesized from
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
and 17α-hydroxyprogesterone via the
androgen backdoor pathway The androgen backdoor pathway (the backdoor pathway of androgen biosynthesis) is a metabolic route in which androgens are produced from 21-carbon () steroids bypassing testosterone and androstenedione as intermediates. This process starts wi ...
in the absence of testosterone. Relative to testosterone, DHT is considerably more potent as an
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...
(AR). In addition to its role as a natural hormone, DHT has been used as a
medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
, for instance in the treatment of low testosterone levels in men; for information on DHT as a medication, see the
androstanolone Androstanolone, or stanolone, also known as dihydrotestosterone (DHT) and sold under the brand name Andractim among others, is an androgen and anabolic steroid (AAS) medication and hormone which is used mainly in the treatment of low testoste ...
article.


Biological function

DHT is biologically important for
sexual differentiation Sexual differentiation is the process of development of the sex differences between males and females from an undifferentiated zygote. Sex differentiation is usually distinct from sex determination; sex determination is the designation of the de ...
of the
male genitalia Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilisation. A male organism cannot reproduce sexually without access to a ...
during
embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
, maturation of the penis and scrotum at
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
, growth of
facial A facial is a family of skin care treatments for the face, including steam, exfoliation (physical and chemical), extraction, creams, lotions, facial masks, peels, and massage. They are normally performed in beauty salons, but are also a c ...
,
body Body may refer to: In science * Physical body, an object in physics that represents a large amount, has mass or takes up space * Body (biology), the physical material of an organism * Body plan, the physical features shared by a group of anim ...
, and
pubic hair Pubic hair (or pubes , ) is terminal hair, terminal body hair that is found in the sex organ, genital area and pubic region of adolescent and adult humans. The hair is located on and around the sex organs, and sometimes at the top of the inside ...
, and development and maintenance of the
prostate gland The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
and
seminal vesicles The seminal vesicles (also called vesicular glands or seminal glands) are a pair of convoluted tubular accessory glands that lie behind the urinary bladder of male mammals. They secrete fluid that largely composes the semen. The vesicles are 5 ...
. It is produced from the less potent
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
by the
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
5α-reductase in select tissues, and is the primary androgen in the genitals,
prostate gland The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
,
seminal vesicles The seminal vesicles (also called vesicular glands or seminal glands) are a pair of convoluted tubular accessory glands that lie behind the urinary bladder of male mammals. They secrete fluid that largely composes the semen. The vesicles are 5 ...
,
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...
, and
hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction betwee ...
s. DHT signals act mainly in an
intracrine Intracrine signaling is a mode of hormone and growth factor action in which signaling molecules exert their effects within the same cell that produces them, without being secreted into the extracellular environment. The term intracrine was origin ...
and
paracrine In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication (biology), cellular communication in which a Cell (biology), cell produces a signal to induce changes in nearby cells, altering the behaviour of ...
manner in the tissues in which it is produced, playing only a minor role, if any, as a circulating
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
hormone. Circulating levels of DHT are one-tenth and one-twentieth those of testosterone in terms of total and free concentrations, respectively, whereas local DHT levels may be up to 10 times those of testosterone in tissues with high 5α-reductase expression such as the prostate gland. In addition, unlike testosterone, DHT is inactivated by 3α-hydroxysteroid dehydrogenase (3α-HSD) into the very weak androgen 3α-androstanediol in various tissues such as
muscle Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
,
adipose Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...
, and
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
among others, and in relation to this, DHT has been reported to be a very poor
anabolic Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catab ...
agent when administered exogenously as a medication. In addition to normal biological functions, DHT also plays an important causative role in a number of
androgen-dependent condition An androgen-dependent condition, disease, disorder, or syndrome, is a medical condition that is, in part or full, dependent on, or is sensitive to, the presence of androgenic activity in the body. Known androgen-dependent conditions include acne ...
s including hair conditions like
hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a male pattern of hair growth in a female that ma ...
(excessive facial/body hair growth) and
pattern hair loss Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front h ...
(androgenic alopecia or pattern baldness) and prostate diseases such as
benign prostatic hyperplasia Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, urinary retention, inability t ...
(BPH) and
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
. 5α-Reductase inhibitors, which prevent DHT synthesis, are effective in the prevention and treatment of these conditions. Androgen deprivation is a therapeutic approach to prostate cancer that can be implemented by castration to eliminate gonadal testosterone as a precursor to DHT, but metastatic tumors may then develop into castration-resistant prostate cancer (CRPC). Although castration results in 90-95% decrease of serum testosterone, DHT in the prostate is only decreased by 50%, supporting the notion that the prostate expresses necessary enzymes (including 5α-reductase) to produce DHT without testicular testosterone, that outline the importance of 5α-reductase inhibitors. DHT may play a function in skeletal muscle amino acid transporter recruitment and function.
Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s of DHT have been found to act as
neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...
s with their own AR-independent biological activity. 3α-Androstanediol is a potent
positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...
of the GABAA receptor, while 3β-androstanediol is a potent and selective agonist of the
estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...
(ER) subtype
ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by t ...
. These metabolites may play important roles in the central effects of DHT and by extension testosterone, including their
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
,
anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
, rewarding/
hedonic Hedonism is a family of philosophical views that prioritize pleasure. Psychological hedonism is the theory that all human behavior is motivated by the desire to maximize pleasure and minimize pain. As a form of egoism, it suggests that people ...
, anti-stress, and pro-cognitive effects.


5α-Reductase 2 deficiency

Much of the biological role of DHT has been elucidated in studies of individuals with
congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
5α-reductase type 2 deficiency, an
intersex condition Intersex people are those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...
caused by a
loss-of-function mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
in the
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
encoding 5α-reductase type 2, the major enzyme responsible for the production of DHT in the body. It is characterized by a defective and non-functional 5α-reductase type 2 enzyme and a partial but majority loss of DHT production in the body. In the condition, circulating testosterone levels are within or slightly above the normal male range, but DHT levels are low (around 30% of normal), and the ratio of circulating testosterone to DHT is greatly elevated (at about 3.5 to 5 times higher than normal). Genetic males (46,XY) with 5α-reductase type 2 deficiency are born with undervirilization including
pseudohermaphroditism Pseudohermaphroditism is an outdated term for when an individual's gonads were mismatched with their internal reproductive system and/or external genitalia. The term was contrasted with "true hermaphroditism" (now known as ovotesticular syndrome), ...
(ambiguous genitalia), pseudovaginal perineoscrotal hypospadias, and usually undescended testes. Their external genitalia are female-like, with
micropenis A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...
(a small,
clitoris In amniotes, the clitoris ( or ; : clitorises or clitorides) is a female sex organ. In humans, it is the vulva's most erogenous zone, erogenous area and generally the primary anatomical source of female Human sexuality, sexual pleasure. Th ...
-like
phallus A phallus (: phalli or phalluses) is a penis (especially when erect), an object that resembles a penis, or a mimetic image of an erect penis. In art history, a figure with an erect penis is described as ''ithyphallic''. Any object that symbo ...
), a partially unfused,
labia The labia are the major externally visible structures of the vulva. In humans and other primates, there are two pairs of labia: the ''labia majora'' (outer lips) are large and thick folds of skin that cover the vulva's other parts, while the ''la ...
-like
scrotum In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" or "skin") or scrotal sac is a part of the external male genitalia located at the base of the penis. It consists of a sac of skin ...
, and a blind-ending, shallow vaginal pouch. Due to their lack of conspicuous
male genitalia Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilisation. A male organism cannot reproduce sexually without access to a ...
, genetic males with the condition are typically raised as girls. At the time of
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
however, they develop striking phenotypically masculine
secondary sexual characteristic A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...
s including partial virilization of the genitals (enlargement of the phallus into a near-functional penis and descent of the testes),
voice deepening A voice change or voice mutation, sometimes referred to as a voice break or voice crack, commonly refers to the deepening of the voice of men as they reach puberty. Before puberty both sexes have roughly similar vocal pitches, but during puberty ...
, typical male
musculoskeletal The human musculoskeletal system (also known as the human locomotor system, and previously the activity system) is an organ system that gives humans the ability to move using their muscular and skeletal systems. The musculoskeletal system provid ...
development, and no
menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...
,
breast development Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life. It occurs across several phases, including prenatal development, puberty, and pregnancy. At menopause, breas ...
, or other signs of feminization that occur during female puberty. In addition, normal
libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...
and spontaneous erections develop, they usually show a sexual preference for females, and almost all develop a male
gender identity Gender identity is the personal sense of one's own gender. Gender identity can correlate with a person's assigned sex or can differ from it. In most individuals, the various biological determinants of sex are congruent and consistent with the in ...
. Nonetheless, males with 5α-reductase type 2 deficiency exhibit signs of continued undervirilization in a number of domains.
Facial hair Facial hair is hair grown on the face, usually on the chin, cheeks, bottom lip and upper lip region. It is typically a secondary sex characteristic of human males. Men typically start developing facial hair in the later stages of puberty or adol ...
was absent or sparse in a relatively large group of Dominican males with the condition, known as the Güevedoces. However, more facial hair has been observed in patients with the disorder from other parts of the world, although facial hair was still reduced relative to that of other men in the same communities. The divergent findings may reflect racial differences in androgen-dependent hair growth. A female pattern of
androgenic hair Body hair or androgenic hair is terminal hair that develops on the human body during and after puberty. It is different from head hair and also from less visible vellus hair, which is much finer and lighter in color. Growth of androgenic hai ...
growth, with
terminal hair In humans, terminal hair is a variant of hair that is thick and long such as that growing on the scalp, as compared with vellus hair, colloquially known as peach fuzz, growing elsewhere.Marks, James G; Miller, Jeffery (2006)''Lookingbill and ...
largely restricted to the
axilla The axilla (: axillae or axillas; also known as the armpit, underarm or oxter) is the area on the human body directly under the shoulder joint. It includes the axillary space, an anatomical space within the shoulder girdle between the arm a ...
e and lower
pubic triangle Pubic hair (or pubes , ) is terminal body hair that is found in the genital area and pubic region of adolescent and adult humans. The hair is located on and around the sex organs, and sometimes at the top of the inside of the thighs, even ex ...
, is observed in males with the condition. No temporal recession of the hairline or
androgenic alopecia Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ...
(pattern hair loss or baldness) has been observed in any of the cases of 5α-reductase type 2 deficiency that have been reported, whereas this is normally seen to some degree in almost all Caucasian males in their teenage years. Individuals with 5α-reductase type 2 deficiency were initially reported to have no incidence of
acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...
, but subsequent research indicated normal
sebum A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur ...
secretion Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mec ...
and acne incidence. In genetic males with 5α-reductase type 2 deficiency, the
prostate gland The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
is rudimentary or absent, and if present, remains small, underdeveloped, and unpalpable throughout life. In addition, neither BPH nor prostate cancer have been reported in these individuals. Genetic males with the condition generally show
oligozoospermia Terms oligospermia, oligozoospermia, and low sperm count refer to semen with a low concentration of sperm and is a common finding in male infertility. Often, semen with a decreased sperm concentration may also show significant abnormalities in sper ...
due to undescended testes, but
spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the Mitosis, mitotic division of the stem cells located close to the basement membrane of ...
is reported to be normal in those with testes that have descended, and there are case instances of men with the condition successfully fathering children. Unlike males, genetic females with 5α-reductase type 2 deficiency are phenotypically normal. However, similarly to genetic males with the condition, they show reduced body hair growth, including an absence of hair on the arms and legs, slightly decreased axillary hair, and moderately decreased pubic hair. On the other hand,
sebum A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur ...
production is normal. This is in accordance with the fact that sebum secretion appears to be entirely under the control of 5α-reductase type 1.


5α-Reductase inhibitors

5α-Reductase inhibitors like
finasteride Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat pattern hair loss and benign prostatic hyperplasia (BPH) in men. It can also be used to treat hirsutism, excessive hair growth in women. It ...
and
dutasteride Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before bene ...
inhibit 5α-reductase type 2 and/or other isoforms and are able to decrease circulating DHT levels by 65 to 98% depending on the 5α-reductase inhibitor in question. As such, similarly to the case of 5α-reductase type 2 deficiency, they provide useful insights in the elucidation of the biological functions of DHT. 5α-Reductase inhibitors were developed and are used primarily for the treatment of BPH. The drugs are able to significantly reduce the size of the prostate gland and to alleviate symptoms of the condition. Long-term treatment with 5α-reductase inhibitors is also able to significantly reduce the overall risk of prostate cancer, although a simultaneous small increase in the risk of certain high-grade tumors has been observed. In addition to prostate diseases, 5α-reductase inhibitors have subsequently been developed and introduced for the treatment of
pattern hair loss Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front h ...
in men. They are able to prevent further progression of hair loss in most men with the condition and to produce some recovery of hair in about two-thirds of men. 5α-Reductase inhibitors seem to be less effective for pattern hair loss in women on the other hand, although they do still show some effectiveness. Aside from pattern hair loss, the drugs are also useful in the treatment of hirsutism and can greatly reduce facial and body hair growth in women with the condition. 5α-Reductase inhibitors are overall well tolerated and show a low incidence of
adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
s.
Sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...
, including
erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...
, loss of libido, and reduced ejaculate volume, may occur in 3.4 to 15.8% of men treated with finasteride or dutasteride. A small increase in the risk of affective symptoms including depression,
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
, and
self-harm Self-harm refers to intentional behaviors that cause harm to oneself. This is most commonly regarded as direct injury of one's own skin tissues, usually without suicidal intention. Other terms such as cutting, self-abuse, self-injury, and s ...
may be seen. However risk within the affected group can vary very strongly with some patients vividly reporting very strong persistent effects. Both the sexual dysfunction and affective symptoms may be due partially or fully to prevention of the synthesis of
neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...
s like
allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...
rather necessarily than due to inhibition of DHT production. A small risk of
gynecomastia Gynecomastia (also spelled gynaecomastia) is the non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...
has been associated with 5α-reductase inhibitors (1.2–3.5%). Based on reports of 5α-reductase type 2 deficiency in males and the effectiveness of 5α-reductase inhibitors for hirsutism in women, reduced body and/or facial hair growth is a likely potential side effect of these drugs in men. There are far fewer studies evaluating the side effects of 5α-reductase inhibitors in women. However, due to the known role of DHT in male sexual differentiation, 5α-reductase inhibitors may cause
birth defect A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
s such as ambiguous genitalia in the male
fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...
es of
pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
women. As such, they are not used in women during pregnancy. MK-386 is a selective 5α-reductase type 1 inhibitor which was never marketed. Whereas 5α-reductase type 2 inhibitors achieve much higher reductions in circulating DHT production, MK-386 decreases circulating DHT levels by 20 to 30%. Conversely, it was found to decrease sebum DHT levels by 55% in men versus a modest reduction of only 15% for finasteride. However, MK-386 failed to show significant effectiveness in a subsequent clinical study for the treatment of acne.


Biological activity

DHT is a potent
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the AR, and is in fact the most potent known
endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
of the receptor. It has an
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
(Kd) of 0.25 to 0.5 nM for the human AR, which is about 2- to 3-fold higher than that of
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
(Kd = 0.4 to 1.0 nM) and 15–30 times higher than that of
adrenal androgen Adrenal steroids are steroids that are derived from the adrenal glands. They include corticosteroids, which consist of glucocorticoids like cortisol and mineralocorticoids like aldosterone, adrenal androgens like dehydroepiandrosterone (DHEA), DHE ...
s. In addition, the dissociation rate of DHT from the AR is 5-fold slower than that of testosterone. The EC50 of DHT for activation of the AR is 0.13 nM, which is about 5-fold stronger than that of testosterone (EC50 = 0.66 nM). In
bioassay A bioassay is an analytical method to determine the potency or effect of a substance by its effect on animal testing, living animals or plants (''in vivo''), or on living cells or tissues (''in vitro''). A bioassay can be either quantal or quantit ...
s, DHT has been found to be 2.5- to 10-fold more potent than testosterone. The
elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
of DHT in the body (53 minutes) is longer than that of testosterone (34 minutes), and this may account for some of the difference in their potency. A study of transdermal (patches) DHT and testosterone treatment reported terminal half-lives of 2.83 hours and 1.29 hours, respectively. Unlike other androgens such as testosterone, DHT cannot be converted by the enzyme
aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze man ...
into an
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
like
estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...
. Therefore, it is frequently used in research settings to distinguish between the effects of testosterone caused by binding to the AR and those caused by testosterone's conversion to estradiol and subsequent binding to and activation of ERs. Although DHT cannot be aromatized, it is still transformed into metabolites with significant ER affinity and activity. These are 3α-androstanediol and 3β-androstanediol, which are predominant agonists of the ERβ.


Biochemistry


Biosynthesis

DHT is synthesized irreversibly from
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
by the enzyme 5α-reductase. This occurs in various tissues including the
genital A sex organ, also known as a reproductive organ, is a part of an organism that is involved in sexual reproduction. Sex organs constitute the primary sex characteristics of an organism. Sex organs are responsible for producing and transporting ...
s (
penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...
,
scrotum In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" or "skin") or scrotal sac is a part of the external male genitalia located at the base of the penis. It consists of a sac of skin ...
,
clitoris In amniotes, the clitoris ( or ; : clitorises or clitorides) is a female sex organ. In humans, it is the vulva's most erogenous zone, erogenous area and generally the primary anatomical source of female Human sexuality, sexual pleasure. Th ...
,
labia majora In primates, and specifically in humans, the labia majora (: labium majus), also known as the outer lips or outer labia, are two prominent Anatomical terms of location, longitudinal skin folds that extend downward and backward from the mons pubis ...
),
prostate gland The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
,
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...
,
hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction betwee ...
s,
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, and
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
. Around 5 to 7% of testosterone undergoes 5α-reduction into DHT, and approximately 200 to 300 μg of DHT is synthesized in the body per day. Most DHT is produced in peripheral tissues like the skin and liver, whereas most ''circulating'' DHT originates specifically from the liver. The testes and prostate gland contribute relatively little to concentrations of DHT in circulation. There are two major
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s of 5α-reductase, SRD5A1 (type 1) and
SRD5A2 The human gene ''SRD5A2'' encodes the 3-oxo-5α-steroid 4-dehydrogenase 2 enzyme, also known as 5α-reductase type 2 (5αR2), one of three isozymes of 5α-reductase. 5αR2 catalyzes the conversion of the male sex hormone testosterone into the m ...
(type 2), with the latter being the most biologically important isoenzyme. There is also third 5α-reductase: SRD5A3. SRD5A2 is most highly expressed in the genitals,
prostate gland The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
,
epididymides The epididymis (; : epididymides or ) is an elongated tubular genital organ attached to the posterior side of each one of the two male reproductive glands, the testicles. It is a single, narrow, tightly coiled tube in adult humans, in length; ...
,
seminal vesicle The seminal vesicles (also called vesicular glands or seminal glands) are a pair of convoluted tubular accessory glands that lie behind the urinary bladder of male mammals. They secrete fluid that largely composes the semen. The vesicles are 5 ...
s, genital skin,
facial A facial is a family of skin care treatments for the face, including steam, exfoliation (physical and chemical), extraction, creams, lotions, facial masks, peels, and massage. They are normally performed in beauty salons, but are also a c ...
and
chest The thorax (: thoraces or thoraxes) or chest is a part of the anatomy of mammals and other tetrapod animals located between the neck and the abdomen. In insects, crustaceans, and the extinct trilobites, the thorax is one of the three main di ...
hair follicles, and
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, while lower expression is observed in certain
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
areas, non-genital skin/hair follicles,
testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...
, and
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s. SRD5A1 is most highly expressed in non-genital skin/hair follicles, the liver, and certain brain areas, while lower levels are present in the prostate, epididymides, seminal vesicles, genital skin, testes,
adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...
s, and kidneys. In the skin, 5α-reductase is expressed in
sebaceous gland A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in ...
s,
sweat gland Sweat glands, also known as sudoriferous or sudoriparous glands, , are small tubular structures of the skin that produce sweat. Sweat glands are a type of exocrine gland, which are glands that produce and secrete substances onto an epithelial s ...
s,
epidermal cell The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermal layer provides a barrier to infection from environmental pathogens and regulates the amount of water relea ...
s, and hair follicles. Both isoenzymes are expressed in scalp hair follicles, although SRD5A2 predominates in these cells. The SRD5A2 subtype is the almost exclusive isoform expressed in the prostate gland.


Backdoor pathway

DHT under certain normal and pathological conditions can additionally be produced via a route that does not involve testosterone as an intermediate but instead goes through other intermediates. This route is called the "backdoor pathway". The pathway can start from 17α-hydroxyprogesterone or from
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
and can be outlined as follows (depending on the initial substrate): * 17α-hydroxyprogesterone5α-pregnan-17α-ol-3,20-dione5α-pregnane-3α,17α-diol-20-one
androsterone Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone. It is a weak androgen with a potency that is approximately 1/7 that of testosterone. Androsterone is a metabolite of te ...
5α-androstane-3α,17β-diol → DHT. *
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
5α-dihydroprogesterone
allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...
5α-pregnane-3α,17α-diol-20-one
androsterone Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone. It is a weak androgen with a potency that is approximately 1/7 that of testosterone. Androsterone is a metabolite of te ...
5α-androstane-3α,17β-diol → DHT. This pathway is not always considered in the clinical evaluation of patients with
hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infre ...
, for instance due to rare
disorders of sex development Disorders of sex development (DSDs), also known as differences in sex development, variations in sex characteristics (VSC), sexual anomalies, or sexual abnormalities, are congenital conditions affecting the reproductive system, in which developme ...
like 21α-hydroxylase deficiency. Ignoring this pathway in such instances may lead to diagnostic pitfalls and confusion, when the conventional androgen biosynthetic pathway cannot fully explain the observed consequences. As with the conventional pathway of DHT synthesis, the backdoor pathway similarly requires 5α-reductase. Whereas 5α-reduction is the last transformation in the classical androgen pathway, it is the first step in the backdoor pathway.


Distribution

The
plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...
of DHT is more than 99%. In men, approximately 0.88% of DHT is unbound and hence free, while in premenopausal women, about 0.47–0.48% is unbound. In men, DHT is bound 49.7% to
sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...
(SHBG), 39.2% to
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...
, and 0.22% to
corticosteroid-binding globulin Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein produced in the liver in animals. In humans it is encoded by the SERPINA6 gene. It is an alpha-globulin. Function This gene encodes an alpha-globulin ...
(CBG), while in premenopausal women, DHT is bound 78.1–78.4% to SHBG, 21.0–21.3% to albumin, and 0.12% to CBG. In late pregnancy, only 0.07% of DHT is unbound in women; 97.8% is bound to SHBG while 2.15% is bound to albumin and 0.04% is bound to CBG. DHT has higher
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
for SHBG than does testosterone, estradiol, or any other steroid hormone.


Metabolism

DHT is inactivated in the liver and extrahepatic tissues like the skin into 3α-androstanediol and 3β-androstanediol by the enzymes 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase, respectively. These
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s are in turn converted, respectively, into
androsterone Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone. It is a weak androgen with a potency that is approximately 1/7 that of testosterone. Androsterone is a metabolite of te ...
and
epiandrosterone Epiandrosterone, or isoandrosterone, also known as 3β-androsterone, 3β-hydroxy-5α-androstan-17-one, or 5α-androstan-3β-ol-17-one, is a steroid hormone with weak androgenic activity. It is a metabolite of testosterone and dihydrotestosterone ...
, then conjugated (via
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...
and/or
sulfation Sulfation (sometimes spelled sulphation in British English) is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected ...
), released into circulation, and excreted in
urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
. Unlike testosterone, DHT cannot be aromatized into an
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
like estradiol, and for this reason, has no propensity for estrogenic effects.


Excretion

DHT is excreted in the
urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
as
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s, such as conjugates of 3α-androstanediol and
androsterone Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone. It is a weak androgen with a potency that is approximately 1/7 that of testosterone. Androsterone is a metabolite of te ...
.


Levels

Ranges for circulating total DHT levels tested with HPLC–MS/MS and reported by LabCorp are as follows: * Men: 30–85ng/dL * Women: 4–22ng/dL * Prepubertal children: <3ng/dL * Pubertal boys: 3–65ng/dL (mean at Tanner stage 5: 43ng/dL) * Pubertal girls: 3–19ng/dL (mean at Tanner stage 5: 9ng/dL) Ranges for circulating free DHT levels tested with HPLC–MS/MS and equilibrium dialysis and reported by LabCorp are as follows: * <18 years of age: not established * Adult males: 2.30–11.60pg/mL (0.54–2.58% free) * Adult females: 0.09–1.02pg/mL (<1.27% free) Other studies and labs assessing circulating total DHT levels with LC–MS/MS have reported ranges of 11–95ng/dL (0.38–3.27nmol/L) in adult men, 14–77ng/dL (0.47–2.65nmol/L) for healthy adult men (age 18–59years), 23–102 ng/dL (0.8–3.5 nmol/L) for community-dwelling adult men (age <65years), and 14–92ng/dL (0.49–3.2nmol/L) for healthy older men (age 71–87years). In the case of women, mean circulating DHT levels have been found to be about 9ng/dL (0.3nmol/L) in
premenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
women and 3ng/dL (0.1nmol/L) in
postmenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
women. There was no variation in DHT levels across the
menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...
in premenopausal women, which is in contrast to testosterone (which shows a peak at mid-cycle). With
immunoassay An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...
-based techniques, testosterone levels in premenopausal women have been found to be about 40ng/dL (1.4nmol/L) and DHT levels about 10ng/dL (0.34nmol/L). With
radioimmunoassay A radioimmunoassay (RIA) is an immunoassay that uses radioactive tracer, radiolabeled molecules in a stepwise formation of immune complexes. A RIA is a very sensitive in vitro assay technique used to measure concentrations of substances, usually m ...
s, the ranges for testosterone and DHT levels in women have been found to be 20 to 70ng/dL and 5 to 30ng/dL, respectively. Levels of total testosterone, free testosterone, and free DHT, but not total DHT, all measured with LC–MS/MS, are higher in women with
polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...
(PCOS) than in women without this condition. Circulating DHT levels in eugonadal men are about 7- to 10-fold lower than those of testosterone, and plasma levels of testosterone and DHT are highly correlated (
correlation coefficient A correlation coefficient is a numerical measure of some type of linear correlation, meaning a statistical relationship between two variables. The variables may be two columns of a given data set of observations, often called a sample, or two c ...
of 0.7). In contrast to the circulation however, levels of DHT in the prostate gland are approximately 5- to 10-fold higher than those of testosterone. This is due to a more than 90% conversion of testosterone into DHT in the prostate via locally expressed 5α-reductase. Because of this, and because DHT is much more potent as an androgen receptor agonist than testosterone, DHT is the major androgen in the prostate gland.


Medical use

DHT is available in
pharmaceutical Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...
formulation Formulation is a term used in various senses in various applications, both the material and the abstract or formal. Its fundamental meaning is the putting together of components in appropriate relationships or structures, according to a formula ...
s for
medical use Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...
as an
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
or
anabolic–androgenic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...
(AAS). It is used mainly in the treatment of male
hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...
. When used as a medication, dihydrotestosterone is referred to as ''androstanolone'' () or as ''stanolone'' (), and is sold under brand names such as ''Andractim'' among others. The availability of pharmaceutical DHT is limited; it is not available in the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
or
Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...
, but is available in certain
Europe Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...
an countries. The available formulations of DHT include buccal or
sublingual Sublingual (List of abbreviations used in medical prescriptions, abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through Tissue (biology), t ...
tablets,
topical gels Topical gels are a Topical medication, topical drug delivery dosage form commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. They are formed from a mixture of Thickening agent, gelator, so ...
, and, as
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
s in
oil An oil is any nonpolar chemical substance that is composed primarily of hydrocarbons and is hydrophobic (does not mix with water) and lipophilic (mixes with other oils). Oils are usually flammable and surface active. Most oils are unsaturate ...
, injectables like androstanolone propionate and androstanolone valerate.


Performance enhancement

DHT has been used as a
performance enhancing drug A performance is an act or process of staging or presenting a play, concert, or other form of entertainment. It is also defined as the action or process of carrying out or accomplishing an action, task, or function. Performance has evolved glo ...
, specifically as an alternative to
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
, as it was once known to be capable of falsifying drug tests.


Chemistry

DHT, also known as 5α-androstan-17β-ol-3-one, is a
naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...
androstane Androstane is a C19 steroidal hydrocarbon with a gonane core. Androstane can exist as either of two isomers, known as 5α-androstane and 5β-androstane. File:androstane.png, 5α-Androstane File:androstane 5beta.png, 5β-Androstane Pharmacolog ...
steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...
with a ketone group at the C3 position and a
hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
at the C17β position. It is the
derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...
of testosterone in which the
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
between the C4 and C5 positions has been reduced or
hydrogenated Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organi ...
.


History

DHT was first synthesized by
Adolf Butenandt Adolf Friedrich Johann Butenandt (; 24 March 1903 – 18 January 1995) was a German biochemist. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government pol ...
and his colleagues in 1935. It was prepared via
hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or Saturated ...
of testosterone, which had been discovered earlier that year. DHT was introduced for medical use as an AAS in 1953, and was noted to be more potent than testosterone but with reduced androgenicity. It was not elucidated to be an endogenous substance until 1956, when it was shown to be formed from testosterone in rat liver homogenates. In addition, the biological importance of DHT was not realized until the early 1960s, when it was found to be produced by 5α-reductase from circulating testosterone in target tissues like the prostate gland and seminal vesicles and was found to be more potent than testosterone in bioassays. The biological functions of DHT in humans became much more clearly defined upon the discovery and characterization of 5α-reductase type 2 deficiency in 1974. DHT was the last major sex hormone, the others being testosterone,
estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...
, and
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
, to be discovered, and is unique in that it is the only major sex hormone that functions principally as an intracrine and paracrine hormone rather than as an endocrine hormone. DHT was one of the original "underground" methods used to falsify drug testing in sport, as DHT does not alter the ratio of testosterone to epistestosterone in an athlete's urinary steroid profile, a measurement that was once the basis of drug tests used to detect steroid use. However, DHT use can still be detected by other means which are now universal in athletic drug tests, such as metabolite analysis. In 2004, Richard Auchus, in a review published in Trends in Endocrinology and Metabolism coined the term "backdoor pathway" as a metabolic route to DHT that: 1) bypasses conventional intermediates
androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...
and testosterone; 2) involves 5α-reduction of 21-carbon (C21)
pregnanes Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally all ...
to 19-carbon (C19)
androstanes An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This include ...
; and 3) involves the 3α-oxidation of 5α-androstane-3α,17β-diol to DHT. This newly discovered pathway explained how DHT is produced under certain normal and pathological conditions in humans when the classical androgen pathway (via testosterone) cannot fully explain the observed consequences. This review was based on earlier works (published in 2000–2004) by Shaw et al., Wilson et al., and Mahendroo et al., who studied DHT biosynthesis in tammar wallaby pouch young and mice. In 2011, Chang et al. demonstrated that yet another metabolic pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC). This pathway can be outlined as
androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...
5α-androstane-3,17-dione → DHT. While this pathway was described as the "5α-dione pathway" in a 2012 review, the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.


References

* {{Navboxes , title =
Biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
, titlestyle = background:#ccccff , list1 = {{Androgen receptor modulators {{Estrogen receptor modulators {{GABAA receptor positive modulators 5α-Reduced steroid metabolites Anabolic–androgenic steroids Androstanes Animal reproductive system Cyclopentanols GABAA receptor positive allosteric modulators Hormones of the hypothalamus-pituitary-gonad axis Hormones of the testis Human hormones Ketones Selective ERβ agonists Sex hormones Testosterone