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16
Jan

Male sex hormones

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   Introduction

Definition:

Male sex hormones are group of steroid hormones called androgens. Androgens are hormones responsible for the male features and reproduction. Some are naturally produced in the body, and if the body doesn’t make them properly, they can be obtained through prescription medication. Androgens are responsible for sexual development in males and are produced by the testes. Women have smaller amounts of androgens too, and the ovaries produce them. The most well-known is probably testosterone.

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Hormones, like androgens, facilitate communication between cells around the entire body. Some cells have androgen receptors. Think of each hormone as a key and receptors as a lock—together they make your body systems work. Hormones created from cholesterol, like androgens, are known as steroid hormones.
Androgens are produced in the adrenal gland and the ovaries through the conversion of cholesterol. Muscle and fat tissue can also synthesize testosterone.
Importance:
Androgens don’t just impact sexual health; they also play a role in metabolism, insulin sensitivity, and possibly body composition (the amount and distribution of body fat and muscle).
Androgens may also impact bone density and cardiovascular health in cis-gender women, and some research suggests that they may have an impact on brain function and mood, but more research is needed.
Testosterone is not only important for males, androgens generally and testosterone specifically have serious role in females:
The most important progesterone, estradiol, is actually synthesized from testosterone by an enzyme called aromatase. Androgens also appear to impact the function of the endometrium (the lining of the uterus), and may play a role in helping prepare it to
support a potential pregnancy.

    Types & Sources

v Androgens are classified into natural or synthetic 

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Ø 
Natural androgens:
These are the androgens naturally occurring in male or female body which are:

  • Testosterone
  • Dehydrotestosteron(DHT) {more active derivative of testosterone by 5α-reductase)
  • Weaker androgens
    • Dehydroepiandrosteron(DHEA)
    • Androstenedione
  • Androsterone (execratory form)
    • Testes of adult male produce 5–12 mg of testosterone daily, a part of which is converted in extra glandular tissues to the more active dihydrotestosterone (DHT); by the enzyme steroid 5 α-reductase; cholesterol is the starting material and the same pathway is utilized.
    • 
Adrenal cortex produces small quantities of dehydroepiandrosterone(DHEA) and androstenedione which are called ‘weak androgens’ (potency 1/20 to 1/30), but are in fact inactive as such and derive their weak activity from partial conversion to testosterone in peripheral tissues. Adrenals themselves do not 
produce significant quantity of testosterone.
    • In women ovary produces small quantity of testosterone; this together with that derived indirectly from adrenals amounts to 0.25–0.5 mg/day.
    • Androsterone It is a metabolite of testosterone which is excreted in urine. It has 1/10 the activity of testosterone. 

    Ø Synthetic androgens:
    This group include the androgens that have been developed outside the body to be used as androgen replacement therapy.
    Synthetic androgens include both steroidal and nonsteroidal androgens. Synthetic steroidal androgens, most developed by 1970, comprise categories of:
  • 17α-alkylated androgens, (methyltestosterone, fluoxymesterone, oxymetholone, oxandrolone, ethylestrenol, stanozolol, danazol, methandrostenolone, norethandrolone)
  • 1-methyl androgen

– Nandrolone and its derivatives.

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v Source of male sex hormones:
a) Testosterone
Like other steroid hormones, testosterone is derived from cholesterol.
The largest amounts of testosterone (>95%) are produced by the testes in men, while the adrenal glands account for most of the remainder. Testosterone is also synthesized in far smaller total quantities in women by the adrenal glands, thecal cells of
the ovaries, and, during pregnancy, by the placenta. In the testes, testosterone is produced by the Leydig cells.] The male generative glands also contain Sertoli cells, which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone-binding globulin (SHBG).
b) Androgens
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), androstenedione (A4), and androstenediol (A5).
Besides testosterone, other androgens include:

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1- Dehydroepiandrosterone (DHEA): is a steroid hormone produced in the adrenal cortex from cholesterole t is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.
2-Androstenedione:is an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically
to testosterone and other androgens, they are 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.
3-Androstenediol: is the steroid metabolite thought to act as the main regulator of gonadotropin secretion
4-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.
5-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.

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Preparations
Androgens are synthetically modified to make drugs used for both men and women which is called Androgen replacement therapy (ART), often referred to as testosterone replacement therapy (TRT), is a form of hormone therapy in which androgens, often testosterone, are replaced. ART is often prescribed to counter the effects of male hypogonadism. It typically involves the administration of testosterone through:
Injections
skin creams patches
gels
subcutaneous pellets

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Modifications
injectable testosterone, an “ester” functional group is usually added to the
testosterone molecule (see Figure 3, below). There are many different ester
groups that can be added to testosterone: (cypionate, enanthate, acetate,
propionate, phenylpropionate, isocaproate, caproate, decanoate, and
undecanoate.)
Ester groups are added to improve the solubility of testosterone in oil, which in turn
slows the release of the testosterone from its injection site into the blood stream.
Without an added ester group, injectable testosterone would enter the blood
stream very quickly, and would have to be administered in small doses daily (or
several times a day) in order to maintain acceptable levels of the hormone in the
body. Thus, adding an ester group to an injectable allows for a relatively easy

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dosing regimen, far fewer shots, and a slow release of hormone into the system.
“esterase enzymes” in a process known as “hydrolization.” Once the ester group
has been removed by these enzymes, the testosterone is returned to its
As a testosterone ester enters the blood stream, the ester group is cleaved off by

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“bioidentical” form, thus making it bioavailable and ready to perform its various
actions and effects.
e to do its work in the body.
The use of methylated testosterone did have the result of making oral testosterone more readily bioavailable, but it also was found to be very hard on the liver, and thus caused health problems. Because of this, methyltestosterone is rarely used for hormone therapy today, as safer forms of delivery have become available.
A more recent development in oral testosterone delivery is the use of a capsule form of testosterone (undecanoate), a testosterone ester dissolved in oleic acid. Because it is designed to be absorbed through the small intestine into the lymphatic system (thus circumventing the “first pass” through the liver), it poses less burden on the liver than methyltestosterone. Therefore, it is considered a safer oral form of testosterone.
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orally, modifications have been made to the testosterone molecule to try to combat
problems caused by the “first pass effect.” Drugs that are taken orally (i.e.,
swallowed) are absorbed from the gastrointestinal tract and pass via the portal
vein into the liver. If bioidentical testosterone is given orally, a very large portion is
metabolized during this “first pass” through the liver, and therefore it cannot

become bioavailabl

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Ø Transdermal (i.e., medication is absorbed through the skin)
bioidentical testosterone becomes active quickly once absorbed through the skin,
it must be applied daily to maintain appropriate levels of testosterone in the body. Depending on the formulation, transdermal preparations might also include additional ingredients to accelerate the absorption of the testosterone through the skin. Some of these ingredients can cause side effects, such as rashes and skin irritation. Transdermal testosterone is available in both brand-name and compounded preparations; a prescription for compounded transdermal testosterone can be tailored by your doctor for your specific dosage requirement
Ø Sublingual/buccal
Sublingual and buccal testosterone treatments, which are dissolved in the mouth rather than swallowed, are generally made with bioidentical testosterone. Sublingual preparations are dissolved under the tongue; these can be prepared by compounding pharmacies. Buccal testosterone delivery works placing a tablet against the surface of the gums. Buccal testosterone systems are available as name-brand or compounded preparations. Sublingual/buccal delivery is different

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from oral delivery in that very little of the substance is swallowed, avoiding potential “first pass effect” problems with the liver. Because bioidentical testosterone is absorbed quickly through sublingual/buccal routes, it must be applied more than once a day to maintain appropriate levels of testosterone in the body.
Ø Subcutaneous pellet
Subcutaneous testosterone pellets are made of bioidentical, crystalline testosterone that is implanted beneath the skin. The pellets are about the size of a grain of rice, and are typically placed in the buttocks or abdomen by a doctor. Because of their crystalline form, the testosterone in subcutaneous pellets is released slowly over a period of weeks or months.

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Pharmacokinetics
Testosterone
The pharmacokinetics of testosterone, including
its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration. Likewise, the potency of testosterone, and its local effects in certain tissues, for instance the liver, differ by route of administration as well. In particular, the oral route is subject to a high first- pass effect, which results in high levels of testosterone in the liver and consequent hepatic androgenic effects, as well as low potency due to first- pass metabolism in the intestines and liver
into metabolites like dihydrotestosterone and androgen
conjugates. Conversely, this is not the case for non-oral routes, which bypass the first pass.
Different testosterone routes and dosages can achieve widely varying circulating testosterone levels.
• routes of administrations
Testosterone can be taken by a variety of different routes of administration. These include:

  • oral
  • buccal
  • sublingual
    intranasal
  • transdermal (gels, creams, patches, solutions)
  • vaginal (creams, gels, suppositories)
  • rectal (suppositories)
  • injections: intramuscular or subcutaneous (in oil solutions or aqueous suspensions)
  • subcutaneous implant
    1- Absorption: –
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  • The oral bioavailability of testosterone is very low. The bioavailability of oral testosterone undecanoate is 3 to 7%.
  • Topical testosterone gels have a bioavailability of about 8 to 14% when administered to recommended skin sites including the abdomen, arms, shoulders, and thighs.
  • The bioavailability of testosterone by subcutaneous implant is virtually 100%.The bioavailability of drugs that are administered intramuscularly is generally almost 95%
    Oral administration:
    Testosterone is well-absorbed but extensively metabolized with oral
    administration due to the first pass through the intestines and liver. It is
    rapidly and completely inactivated in men at doses of less than 200 mg. In
    large doses, such as 200 mg however, significant increases in circulating
    testosterone levels become apparent. In addition, while a 60 mg dose has
    no effect on testosterone levels in men, this dose does measurably increase
    testosterone levels in prepubertal boys and women.
    The oral bioavailability of testosterone in young women after a single 25 mg
    dose was found to be 3.6 ± 2.5%. but Instead of in its free unesterified form,
    testosterone is used by oral administration in the form of testosterone
    undecanoate. this testosterone ester
    bypass a portion of first-pass
    metabolism in the liver and producing measurable increases in testosterone
    levels at much lower doses than free testosterone.
    Buccal administration:
    Mucoadhesive tablets are applied to the gums of the mouth and provide
    controlled and sustained release of testosterone as the buccal system
    hydrates. This system delivers testosterone directly into the systemic
    circulation and bypasses the liver, avoiding first pass metabolism and –
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    increasing bioavailability. Each tablet contains 30 mg of testosterone and
    one tablet is applied every 12 hours, alternating sides of the mouth above
    the incisor teeth
    Transdermal administration:
    Testosterone is available for transdermal administration in the form
    of gels, creams, scrotal and non-scrotal patches, and axillary solutions.
    Transdermal testosterone gel has a bioavailability of about 8 to 14% when administered to recommended skin sites including
    the abdomen, arms, shoulders, and thighs. Scrotal skin is the thinnest skin of the body and has enhanced absorption characteristics relative to other skin areas. Application of testosterone gels and creams to the scrotum has been studied and achieves much higher levels of testosterone than conventional skin sites. Scrotal application of testosterone requires approximately 5-fold lower doses relative to non-scrotal application.
    Subcutaneous implant:
    Testosterone can be administered in the form of a subcutaneous pellet
    implant. The bioavailability of testosterone when administered as a
    subcutaneous pellet implant is virtually 100%.
    Levels of testosterone vary considerably between individuals, but are fairly
    constant within individuals.The absorption half-life of subdermal
    testosterone implants is 2.5 months.The replacement interval is once every
    four to six months.
    Intramuscular injection:
    Testosterone can be administered by intramuscular injection either as
    an aqueous suspension of testosterone or as an oil solution or aqueous
    suspension of testosterone esters such as testosterone
    propionate, testosterone enanthate, testosterone cypionate, testosterone
    undecanoate, and testosterone isobutyrate. These preparations are prodrugs of progesterone that have a long-lasting depot
    effect when injected
    into muscle or fat, ranging from days to months in duration. The bioavailability of drugs that are administered intramuscularly is generally almost 95% –
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    2- Distribution:
    In the circulation, 97.0 to 99.5% of testosterone is bound to plasma proteins, with 0.5 to 3.0% unbound.It is tightly bound to SHBG and weakly
    to albumin.Of circulating testosterone, 30 to 44% is bound to SHBG while 54 to 68% is bound to albumin. Unlike testosterone that is bound to SHBG, bioavailable testosterone is bound to plasma proteins weakly enough such that, similarly to free testosterone,and it may be biologically active.
    3- Metabolism:
    Testosterone is metabolized primarily in the liver mainly (90%) by reduction via 5α- and 5β-
    reductase and conjugation via glucuronidation and sulfation.The
    major urinary metabolites of testosterone
    are androsterone
    glucuronide and etiocholanolone glucuronide.
    The elimination half-life of testosterone varies depending on the route of administration and formulation and on whether or not it is esterified.The elimination half-life of testosterone in the blood or by intravenous injection is only about 10 minutes.Conversely, testosterone and testosterone esters in oil solution or crystalline aqueous
    suspension administered by intramuscular or subcutaneous injection have much longer half-lives, in the range of days to months, due to slow release from the injection sites .
    (less than 0.01%) is found unchanged in the urine.
    4- Elimination:
    Testosterone and its metabolites are eliminated in urine. It
    is excreted mainly as androsterone glucuronoide and etiocholanolone glucuronide. It is also excreted to a small extent as other conjugates such as testosterone glucuronide (1%), testosterone sulfate (0.03%), and androstanediol glucuronides. Only a very small amount of testosterone
    Student name:
    Elsayed Naser Abd-Elrahman Yousef Anas Abd-Elbaset Abd-Elmohsen –
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    Pharmacodynamics
    a) Mechanism of action:
    1-pre-receptor activation
    Androgen action involves pre-receptor, receptor and post-receptor mechanisms that are centered on the binding of testosterone (or an analog) to the androgen receptor. Testosterone undergoes pre-receptor activation by conversion to potent bioactive metabolites, DHT and estradiol. The steroidogenic enzyme 5a-reductase has two isozymes, types 1 and 2, which form a local androgen amplification mechanism converting testosterone to the most potent natural androgen, DHT. The two isozymes have different chromosomal location and distinct biochemical features but are homologous genes . They are structurally and functionally unrelated to a third 5a- reductase (SRD5A3) which may have physiological role in fatty acid rather than steroidal biochemistry . This local androgen amplification mechanism is exemplified in urogenital sinus derived tissues, notably external and internal genitalia and the prostate, which characteristically express high levels of 5a-reductase type 2. Other tissues such as non-genital skin and liver express 5a-reductase type 1. The other form of pre-receptor androgen activation is conversion of testosterone to estradiol by the enzyme aromatase, which diversifies androgen action by facilitating effects mediated via Estrogen Receptors(ER). Consequently, while DHT may be considered a pure androgen because its bioactivity is solely mediated via Androgen Receptors(AR), testosterone has a wider spectrum of action which includes diversification by aromatization and ER mediated effects. These pre-receptor mechanisms provide testosterone with a versatile and subtle range of regulatory mechanisms prior to receptor mediated effects, depending on the balance between direct AR mediated vs indirect actiational and/or ER mediated mechanisms. In addition, tissues vary in their androgenic thresholds and dose-response characteristics to testosterone and its bioactive metabolites

2-action on receptors

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The biological effects of testosterone can be considered by the receptor it activates and by the tissues in which effects occur at various stages of life. Testosterone can act as:

  • an androgen, either directly, by binding to the androgen receptor, or indirectly by conversion to dihydrotestosterone, which binds to the androgen receptor even more avidly than testosterone.
  • an estrogen, by conversion to estradiol, which binds to the estrogen receptor
    • Direct effects of testosterone and effects mediated indirectly via dihydrotestosterone or estradiol
    testosterone, after conversion into DHT, is also metabolized into 3α-androstanediol,
    a neurosteroid and potent positive allosteric modulator of the GABAA receptor, and 3β- androstanediol, a potent and preferential agonist of the ERβ. These metabolites, along with estradiol, may be involved in a number of the effects of testosterone in the brain, including its antidepressant, anxiolytic, stress-relieving, rewarding, and pro-
    sexual effects
    Effects That Occur Via the Androgen Receptor:
    Testosterone and dihydrotestosterone act as androgens via a single androgen receptor
    The androgen receptor officially designated NR3A is a member of the nuclear receptor superfamily (steroid hormone receptors, thyroid hormone receptors, and orphan receptors). The androgen receptor is comprised of an amino-terminal domain, a DNA-binding domain, and a ligand-binding domain. Testosterone and dihydrotestosterone bind to the ligand-binding domain, causing a conformational change in the receptor that allows the ligand-receptor complex to translocate to the nucleus and bind via the DNA-binding domain to androgen response elements on certain responsive genes. The ligand-receptor complex acts as a transcription factor complex and stimulates expression of those genes
    The mechanisms by which androgens have different actions in diverse tissues have become clearer in recent years. –
    • Effects That Occur Via the Estrogen Receptor:
    The effects of testosterone on at least one tissue are mediated by its conversion to
    estradiol, catalyzed by the CYP19 enzyme complex , In the rare cases in which a male does not express CYP19 or the estrogen receptorthe epiphyses do not fuse and long- bone growth continues indefinitely. In addition, the patients are osteoporotic. Administration of estradiol corrects the bone abnormalities in patients with CYP19 deficiency but not in those with an estrogen-receptor defect. Because men have larger bones than women, and bone cells express the androgen receptor testosterone also may have an effect on bone via the androgen receptor. Administration of estradiol to a man with CYP19 deficiency increased his libido suggesting that the effect of testosterone on male libido may be mediated by conversion to estradiol
    b) Effects:
    Effects in the body and brain:
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  • One mechanism is the higher affinity with which dihydrotestosterone binds to and activates the androgen receptor compared to testosterone.
  • Another mechanism involves transcription co-factors, both co-activators and co- repressors, which are tissue-specific. At this time, the roles of co-factors are better described for other nuclear receptors than for the androgen receptor
    o Promotes growth, function, and maintenance of the prostate gland, seminal vesicles, and penis during puberty and thereafter
    o Promotes growth and maintenance of muscles, particularly of the upper body
    o Causes subcutaneous fat to be deposited in a masculine pattern and decreases
    overall body fat –
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    o Suppresses breast development induced by estrogens, but can also still produce gynecomastia via excessive conversion into estradiol if levels are too high
    o Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin, but can also cause oily skin, acne, and seborrhea
    o Promotes the growth of facial and body hair, but can also cause scalp hair loss and hirsutism
    o Contributes to bone growth and causes broadening of the shoulders at puberty
    o Modulates liver protein synthesis, such as the production of sex hormone-binding
    globulin and many other proteins
    o Increases production of erythropoietin in the kidneys and thereby stimulates red
    blood cell production in bone marrow and elevates hematocrit
    o Exerts negative feedback on the hypothalamic–pituitary–gonadal axis by
    suppressing the secretion of the gonadotropins follicle-stimulating
    hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, thereby inhibiting gonadal sex hormone production as well
    as spermatogenesis and fertility
    o Regulates the vasomotor system and body temperature via the hypothalamus, thereby preventing hot flashes
    o Modulates brain function, with effects on mood, emotionality, aggression, and sexuality, as well as cognition and memory
    o Increases sex drive and erectile capacity and causes spontaneous erections and nocturnal emissions
    o Increases the risk of benign prostatic hyperplasia and prostate cancer and accelerates the progression of prostate cancer
    o Decreases breast proliferation and the risk of breast cancer

Androgens are used for several reasons, such as:

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• To replace the hormone when the body is unable to produce enough on its own.
• To stimulate the beginning of puberty in certain boys who are late starting puberty naturally.
• To treat certain types of breast cancer in females.
In addition, some of these medicines may be used for other conditions as determined by the doctor.
In Men
Androgen replacement is the classic treatment of hypogonadism. It is also used in men who have lost the ability to produce androgens due to disease or its treatment
Androgen replacement therapy formulations and dosages used in men show
In Diabetes
The risks of diabetes and of testosterone deficiency in men over 45 (i.e., hypogonadism, specifically hypoandrogenism) are strongly correlated. Testosterone replacement therapies have been shown to improve blood glucose management. Still, “it is prudent not to start testosterone therapy in men with diabetes solely for the purpose of improving metabolic control if they show no signs and symptoms of hypogonadism.”
In Women
Androgen replacement is used in postmenopausal women: the indications are to increase sexual desire; and to prevent or treat osteoporosis. The androgens used for androgen replacement in women include testosterone (and esters), prasterone (dehydroepiandrosterone; DHEA) (and the ester prasterone enanthate), methyltestosterone, nandrolone decanoate, and tibolone, among others.
Androgen therapy for men :
Androgen therapy can be classified as physiologic replacement or pharmacologic therapy according to the dose, type of androgen and objectives of treatment.

  • Androgen replacement therapy aims to restore tissue androgen

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exposure in androgen-deficient men due to pathological hypogonadism (disorders of the reproductive system) to levels comparable with those of eugonadal men. Using the natural androgen testosterone and a dose limited to one that maintains blood testosterone levels within the eugonadal range, androgen replacement therapy aims to restore the full spectrum of androgen effects while replicating the efficacy and safety experience of eugonadal men of similar age. Androgen replacement therapy is unlikely to prolong life because androgen deficiency, whether due to castration or biological disorder, has minimal effect in shortening life expectancy .
As an alternative, pharmacologic androgen therapy uses androgens without restriction on androgen type or dose but aims to produce androgen effects on muscle, bone, brain, or other tissues. In such pharmacological treatment, regardless of androgen status, an androgen is used therapeutically to exploit the anabolic or other effects of androgens on muscle, bone, and other tissues as hormonal drugs in various non-reproductive disorders. Such pharmacological androgen therapy is neither constrained to using the natural androgen, testosterone, nor it is limited to physiological replacement doses or their equivalent. Rather, it is judged on its efficacy, safety, and relative cost- effectiveness for that specific indication just as any other hormonal or xenobiotic non-hormonal therapeutic drug.
Many older uses of pharmacologic androgen therapy are now considered second-line therapies as more specific treatments are developed. For example, erythropoietin has largely supplanted androgen therapy for anemia due to marrow or renal failure and improved first-line drug treatments for endometriosis, osteoporosis and advanced breast cancer have similarly relegated androgen therapy to a last resort while newer mechanism-based agents in development for hereditary angioedema may displace 17a-alkylated androgens. Nevertheless, in many clinical situations, pharmacological androgen therapy remains a cost-effective option with a long-established efficacy and safety profile.
Androgen Replacement Therapy
The sole unequivocal clinical indication for testosterone treatment is in replacement therapy for androgen deficient men suffering from pathological
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disorders of their reproductive system (hypothalamus, pituitary, testis) that prevent the testes producing sufficient testosterone supply to meet the body’s usual needs. These disorders can, and often do, lead to persistent testosterone deficiency either due to disorders of the testis, where damaged Leydig cells cannot produce sufficient testosterone, or disorders of the hypothalamus and/or pituitary, where impaired pituitary luteinizing hormone (LH) secretion reduces the sole driving force to testosterone production by Leydig cells.
This treatment uses only the natural androgen, testosterone, aimed at restoring a physiologic pattern of androgen exposure using a dose limited to that which maintains blood testosterone levels within the eugonadal range.. This requires restricting replacement therapy to the major natural androgen, testosterone, which aims to not only replicate physiological circulating testosterone levels but also to provide testosterone’s two bioactive metabolites, DHT and estradiol, so that all 3 bioactive sex steroids are available to androgen target tissues.
Taking in considerations that Synthetic androgens are unsuitable because they are incapable of metabolism to the more potent 5α reduced metabolites or aromatized to estrogens.
Although life expectancy is not reduced by castration as an adult or only minimally (~2 years) shortened by life-long androgen deficiency, the hormonal deficit causes preventable morbidity and a suboptimal quality of life . Due to its variable and often subtle clinical features, androgen deficiency remains significantly underdiagnosed, thus denying sufferers simple and effective medical treatment 

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Side effects

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Ø When androgens are used in women, especially in high doses, male-like changes may occur, such as :
-hoarseness or deepening of the voice
-unnatural hair growth or unusual hair loss
Most of these changes will go away if the medicine is stopped as soon as the changes are noticed. However, some changes, such as voice changes or enlarged clitoris, may not go away.
Ø When androgens are used in high doses in males, they interfere with the
production of sperm. This effect is usually temporary and only happens
during the time you are taking the medicine.
Ø Although not all of these side effects may occur
a medicine may cause some unwanted effects such as :
More common
FOR FEMALES ONLY
• Acne or oily skin
• decreased breast size
• irregular menstrual cycles
FOR MALES ONLY
• hoarseness or deepening of voice
• increase in size of female genitals
• increase in unnatural hair growth or male
pattern baldness
• Blistering of skin under patch
• breast soreness or enlargement
• frequent or continuing erection of penis lasting up to 4 hours or painful penile
erections lasting longer than 4 hours

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FOR FEMALES WITH BREAST CANCER OR BEDRIDDEN MALES OR FEMALES— IN ADDITION TO THE SIDE EFFECTS LISTED ABOVE
• Confusion or mental depression
• constipation
• increased thirst
• increased urge to urinate or polyuria
FOR MALES ONLY
• frequent urge to urinate
• itching or redness of skin under patch
FOR PREPUBERTAL BOYS ONLY
• Acne
• early growth of pubic hair
Less common
FOR MALES OR FEMALES
• Dizziness
• frequent or continuing headache
• lack or loss of strength
• nausea
• overall body flushing, redness, or itching of skin
• rapidly changing moods,
• yellow skin or eyes (occurring with fluoxymesterone or methyltestosterone)
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• enlargement of penis
• frequent or continuing erections
• • • •
• • • •
burning sensation or hardening or thickening of skin under patch
continuing pain at site of implants
itching, skin redness, or rash under patch, severe (less likely with nonscrotal patch) vomiting of blood or material that looks like coffee grounds
chills
difficulty in urinating
Black, tarry stools pain in scrotum or
groin
• swelling of feet or lower legs • unusual bleeding
• unusual tiredness

Contraindications

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Ø Allergies
Some patients may develop unusual or allergic reaction to medicines in this group or
any other medicines.
Ø Pediatric
Androgens may cause children to stop growing. In addition, androgens may make male children develop too fast sexually and may cause male-like changes in female children
Ø Geriatric
When older male patients are treated with androgens, they may have an increased risk of enlarged prostate (a male gland) or their existing prostate cancer may get worse. For these reasons, a prostate examination and a blood test to check for prostate cancer is often done before androgens are prescribed for men over 50 years of age. These examinations may be repeated during treatment.
Ø Pregnancy
Androgens are not recommended during pregnancy. When given to pregnant women, the medicine has caused male features to develop in female babies.
Ø Breastfeeding
Use is not recommended in nursing mothers, since androgens may pass into the breast milk and may cause unwanted effects in the nursing baby, such as premature (too early) sexual development in males and development of male features in female babies.
Ø Drug Interactions
Using medicines in this class with any of the following medicines is not recommended. the doctor may decide not to treat patient with a medication in this class or change some of the other medicines that
• Phenprocoumon Simvastatin
• Acenocoumarol
• Anisindione
Ø Other Interactions
Certain medicines should not be used at or around the time of eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur.
• Atorvastatin he takes. • Bupropion
• Dicumarol
Ø Other Medical Problems

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The presence of other medical problems may affect the use of medicines in this class, especially:
• Breast cancer (in males) or Prostate cancer
Androgens can cause growth of these tumors.
• Breast cancer (in females)
Androgens may cause high calcium levels in the blood to become worse.
• Diabetes mellitus (sugar diabetes)
Androgens can increase or decrease blood sugar levels. Careful monitoring of blood glucose should be done.
• Edema (swelling of face, hands, feet, or lower legs) or Kidney disease or Liver disease
These conditions can be worsened by the fluid retention, that can be caused by androgens. Also, liver disease can prevent the body from removing the medicine from the bloodstream as fast as it normally would. This could increase the chance of side effects occurring
• Enlarged prostate
Androgens can cause further enlargement of the prostate.
• Heart or blood vessel disease
Androgens can make these conditions worse because androgens may increase blood cholesterol levels. Also, androgens can cause fluid retention , which also can worsen heart or blood vessel disease.
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  Anabolic steroids

Anabolic steroids are synthetic, or human- made, variations of the male sex hormone testosterone. The proper term for these compounds is anabolic-androgenic steroids. “Anabolic” refers to muscle building, and “androgenic” refers to increased male sex characteristics. Some common names for anabolic steroids are Gear, Juice, Roids, and Stackers.

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Health care providers can prescribe steroids to treat hormonal issues, such as delayed puberty. Steroids can also treat diseases that cause muscle loss, such as cancer and AIDS. But some athletes and bodybuilders misuse these drugs in an attempt to boost performance or improve their physical appearance.
The majority of people who misuse steroids are male weightlifters in their 20s or 30s. Anabolic steroid misuse is much less common in women. It is difficult to measure steroid misuse in the United States because many national surveys do not measure it. However, use among teens is generally minimal. The 2016 NIDA-funded Monitoring the Future study has shown that past-year misuse of steroids has declined among 8th and 10th graders in recent years, while holding steady for 12th graders.
Ø anabolic steroids misuse
People who misuse anabolic steroids usually take them orally, inject them into muscles, or apply them to the skin as a gel or cream. These doses may be 10 to 100 times higher than doses prescribed to treat medical conditions. Commons patterns for misusing steroids include:
• cycling—taking multiple doses for a period of time, stopping for a time, and
then restarting
• stacking—combining two or more different steroids and mixing oral and/or
injectable types
• pyramiding—slowly increasing the dose or frequency of steroid misuse,
reaching a peak amount, and then gradually tapering off to zero
• plateauing—alternating, overlapping, or substituting with another steroid to

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avoid developing a tolerance
There is no scientific evidence that any of these practices reduce the harmful medical consequences of these drugs.
Ø Effect of anabolic steroids on the brain
Anabolic steroids work differently from other drugs of abuse; they do not have the same short-term effects on the brain. The most important difference is that steroids do not directly activate the reward system to cause a “high”; they also do not trigger rapid increases in the brain chemical dopamine, which reinforces most other types of drug taking behavior. Misuse of anabolic steroids might lead to negative mental effects, such as:
• paranoid (extreme, unreasonable) jealousy
• extreme irritability and aggression (“roid rage”) • delusions—false beliefs or ideas
• impaired judgment
• mania
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  • Aside from mental effects, steroid use commonly causes severe acne.
  • It also causes the body to swell, especially in the hands and feet. Long-Term Effects
    Anabolic steroid misuse might lead to serious, even permanent, health problems such as:
    • kidney problems or failure
    • liver damage and tumors
    • enlarged heart, high blood pressure, and changes in blood cholesterol, all
    of which increase the risk of stroke and heart attack, even in young
    people
    • increased risk of blood clots
    Several other effects are gender- and age-specific: • In men:
    shrinking testicles
    decreased sperm count
    baldness
    development of breasts increased risk for prostate cancer
    • In women:
    growth of facial hair or excess body hair decreased breast size
    male-pattern baldness
    changes in or stop in the menstrual cycle enlarged clitoris
    deepened voice
    • In teens:
    stunted growth (when high hormone levels from steroids signal to the
    body to stop bone growth too early)
    stunted height (if teens use steroids before their growth spurt)
    Some of these physical changes, such as shrinking sex organs in men, can add to mental side effects such as mood disorders.
    Ø Other health effects of anabolic steroids
    Anabolic Steroids and Infectious Diseases
  • People who inject steroids increase their risk of contracting or transmitting HIV/AIDS or hepatitis.
    Ø Anabolic steroids and addiction
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    Even though anabolic steroids do not cause the same high as other drugs, they can lead to a substance use disorder. A substance use disorder occurs when a person continues to misuse steroids, even though there are serious consequences for doing so. The most severe form of a substance use disorder is addiction. People might continue to misuse steroids despite physical problems, high costs to buy the drugs, and negative effects on their relationships. These behaviors reflect steroids’ addictive potential. Research has further found that some steroid users turn to other drugs, such as opioids, to reduce sleep problems and irritability caused by steroids.
    People who misuse steroids might experience withdrawal symptoms when they stop use, including:
    • fatigue
    • restlessness
    • loss of appetite • sleep problems
    • decreased sex drive
    • steroid cravings
    • depression: One of the more serious withdrawal symptoms, which can
    sometimes lead to suicide attempts
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    Student name:
    Antonuoes Gamal Abdo Astaphanos Elsayed Eid Elsayed Omar Anti-androgens
    Ø The chemistry:

»

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Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen
receptor (AR) and/or inhibiting or suppressing androgen production.
Antiandrogens can be divided into several different types based on chemical structure,
including:

  • Steroidal (
    ) Peptides (
    Ø Mechanism of action:
    • Inhibitors of Androgen Biosynthesis:
    Ketoconazole (Nizoral) is a broad-spectrum antifungal agent that in very high doses inhibits several steps in the biosynthesis of both adrenal and gonadal steroids. While the normal antifungal dose is 200 mg/day, testosterone biosynthesis in both the adrenal and testis is completely abolished by doses of 800 to 1,600 mg/day. This drug
    like cyproterone acetate, spironolactone, estradiol, abiraterone acetate,
    and finasteride
    Non-steroidal (like bicalutamide, elagolix, diethylstilbestrol, aminoglutethimide,
    and ketoconazole)

GnRH analogues like leuprorelin and cetrorelix.)

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is used most commonly for large virilizing adrenal tumors that cannot be surgically removed.
• Androgen Receptor Antagonists
Spironolactone (Aldactone) is a compound originally developed as a mineralocorticoid antagonist and is used as a diuretic and antihypertensive agent .However, at high doses spironolactone binds to the androgen receptor. In clinical practice it is a weak androgen antagonist used to treat hirsutism in women by blocking testosterone binding to androgen receptors in hair follicles. Use of spironolactone in women for the treatment of hirsutism or male pattern baldness can result in elevated serum potassium levels; these levels should be checked within 1 month of starting the medication.
Flutamide (Eulexin) is a nonsteroidal androgen receptor antagonist that inhibits androgen binding to its nuclear receptor. It is effective in inducing prostatic regression and is approved for the treatment of prostatic carcinoma. For maximum clinical effectiveness it has to be used in combination with a GnRH antagonist (e.g., leuprolide acetate) that inhibits androgen production. Flutamide may eventually be used for the treatment of hirsutism and male pattern baldness in women if a topical preparation is developed.
Cyproterone acetate is a progestational antiandrogen that blocks androgen receptor binding and suppresses androgen-sensitive tissues. It is available in a topical form in Europe for the treatment of hirsutism.
• 5-Reductase Inhibitors
Finasteride (Proscar) is a 5-reductase inhibitor that blocks the conversion of testosterone to DHT in target tissues. Since DHT is the major intracellular androgen in the prostate, finasteride is effective in suppressing DHT stimulation of prostatic growth and secretory function without markedly affecting libido. It is approved for the treatment of benign prostatic hyperplasia.Although there is usually some regression in the size of the prostate gland following administration of finasteride, clinical response may take 6 to 12 months. If the obstructive symptoms are severe, there is often not enough time to allow this compound to work. The principal adverse effects of finasteride are impotence, decreased libido, and decreased volume of ejaculate. The compound is generally well tolerated in men
• Gonadotropin-Releasing Hormone
Analogues GnRH analogues can induce chemical castration by suppressing the pulsatile release of LH and FSH, hence inhibiting testicular steroidogenesis. Administration of these compounds reduces circulating testosterone levels. These compounds are inhaled, injected subcutaneously, or implanted subcutaneously. They are used in males in the treatment of precocious puberty and carcinoma of the prostate.
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  Ø Medical uses:

For men:

• Prostate cancer:

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Androgens like testosterone and particularly DHT are importantly involved in the development and progression of prostate cancer They act as growth factors in
the prostate gland, stimulating cell division and tissue growth In accordance, therapeutic modalities that reduce androgen signaling in the prostate gland, referred to collectively as androgen deprivation therapy, are able to significantly slow the course of prostate cancer and extend life in men with the disease.
The most common methods of androgen deprivation therapy currently employed to treat prostate cancer are castration (with a GnRH modulator or orchiectomy), nonsteroidal antiandrogens, and the androgen synthesis inhibitor abiraterone acetate. Castration may be used alone or in combination with one of the other two treatments. When castration is combined with a nonsteroidal antiandrogen
like bicalutamide, this strategy is referred to as combined androgen blockade (also known as complete or maximal androgen blockade). Enzalutamide, apalutamide, and abiraterone acetate are specifically approved for use in combination with castration to treat castration-resistant prostate cancer.
In addition to active treatment of prostate cancer, antiandrogens are effective
as prophylaxis (preventatives) in reducing the risk of ever developing prostate cancer.
• Enlarged prostate
The 5α-reductase inhibitors finasteride and dutasteride are used to treat benign prostatic hyperplasia, a condition in which the prostate becomes enlarged and this results in urinary obstruction and discomfort. They are effective because androgens act as growth factors in the prostate gland. The antiandrogens chlormadinone
acetate and oxendolone and the functional
antiandrogens allylestrenol and gestonorone caproate are also approved in some countries for the treatment of benign prostatic hyperplasia
• Scalp hair loss
5α-Reductase inhibitors like finasteride, dutasteride, and alfatradiol and
the topical nonsteroidal AR antagonist topilutamide (fluridil) are approved for the treatment of pattern hair loss, also known as scalp hair loss or baldness This condition is generally caused by androgens, so antiandrogens can slow or halt its
progression Systemic antiandrogens besides 5α-reductase inhibitors are not generally used to treat scalp hair loss in males due to risks like feminization (e.g., gynecomastia) and sexual dysfunction However, they have been assessed and reported to be effective for this indication

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• Acne
Antiandrogens are generally not used to treat acne in males due to their high risk of feminization (e.g., gynecomastia) and sexual dysfunction. However, they have been studied for acne in males and found to be effective. Clascoterone, a topical antiandrogen, is effective for acne in males and may become approved for this indication in the future.
• Sexual deviance
Androgens increase sex drive, and for this reason, antiandrogens are able to reduce sex drive in men In accordance, antiandrogens are used in the treatment of conditions of sexual deviance such as hypersexuality (excessively high sex drive)
and paraphilias (atypical and sometimes societally unacceptable sexual interests)
like pedophilia (sexual attraction to children). They have been used to decrease sex drive in sex offenders so as to reduce the likelihood of recidivism (repeat offenses). Antiandrogens used for these indications include cyproterone
acetate, medroxyprogesterone acetate, and GnRH modulators
• Early puberty
Antiandrogens are used to treat precocious puberty in boys They work by opposing the effects of androgens and delaying the development of secondary sexual characteristics and onset of changes in sex drive and function until a more appropriate age. Antiandrogens that have been used for this purpose include cyproterone
acetate, medroxyprogesterone acetate, GnRH
modulators, spironolactone, bicalutamide, and ketoconazole. Spironolactone and bicalutamide require combination with an aromatase inhibitor to prevent the effects of unopposed estrogens, while the others can be used alone
For Women and girls:
Skin and hair conditions
Antiandrogens are used in the treatment of androgen-dependent skin and hair conditions including acne, seborrhea, hidradenitis suppurativa, hirsutism, and pattern hair loss in women. All of these conditions are dependent on androgens, and for this reason, antiandrogens are effective in treating them. The most commonly used antiandrogens for these indications are cyproterone acetate and spironolactone. Flutamide has also been studied extensively for such uses, but has fallen out of favor due to its association with hepatotoxicity. Bicalutamide, which has a relatively minimal risk of hepatotoxicity, has been evaluated for the treatment of hirsutism and found effective similarly to flutamide and may be used instead of it. In addition to AR antagonists, oral contraceptives containing ethinylestradiol are effective in treating these conditions, and may be combined with AR antagonists.
High androgen levels
Hyperandrogenism is a condition in women in which androgen levels are excessively and abnormally high. It is commonly seen in women with PCOS, and also occurs in

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women with intersex conditions like congenital adrenal hyperplasia. Hyperandrogenism is associated with virilization – that is, the development of masculine secondary sexual characteristics like male-pattern facial and body hair growth (or hirsutism), voice deepening, increased muscle mass and strength, and broadening of the shoulders, among others. Androgen-dependent skin and hair conditions like acne and pattern hair loss may also occur in hyperandrogenism, and menstrual disturbances, like amenorrhea, are commonly seen. Although antiandrogens do not treat the underlying cause of hyperandrogenism (e.g., PCOS), they are able to prevent and reverse its manifestation and effects. As with androgen-dependent skin and hair conditions, the most commonly used antiandrogens in the treatment of hyperandrogenism in women are cyproterone acetate and spironolactone. Other antiandrogens, like bicalutamide, may be used alternatively.
Transgender hormone therapy
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Antiandrogens are used to prevent or reverse masculinization and to facilitate feminization in transgender women who are undergoing hormone therapy and who have not undergone sex reassignment surgery or orchiectomy. Besides estrogens, the main antiandrogens that have been used for this purpose are cyproterone acetate, spironolactone, and GnRH modulators.Nonsteroidal antiandrogens like bicalutamide are also used for this indication.In addition to use in transgender women, antiandrogens, mainly GnRH modulators, are used as puberty blockers to prevent puberty in transgender girls until they are older and ready to begin hormone therapy.

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