Pharmacology 10 بسم هللا الرحمن ارحيم. Androgens and antiandrogens

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1 بسم هللا الرحمن ارحيم Androgens and antiandrogens The androgens are a group of steroids that have anabolic and/or masculinizing effects in both males and females. Testosterone, the most important androgen in humans, is synthesized by ledydig cells in the testis and,in smaller amounts, by cells in the ovary of the females and by the adrenal gland. *The testis has two major functions : Spermatogenesis production of sperms occurring within the seminiferous tubules. Production of androgenic hormones. Naturally occurring androgenic hormones are : Testosterone, the principal naturally secreted hormone produced by the leydig cells of testis. Dehydroepiandrosterone ( DHEA) (major androgen secreted by the adrenal cortex) Androstenedione The testis produce other hormones like 1-Small quantities of estradiol 1 P a g e

2 2-Inhibin and activin : these are proteins involved in the regulation of FSH release,inhibin inhibits FSH release and it s the major hormone or protein produced by the testicles and responsible for the negative feedback effect on FSH, activin has many roles not only in stimulating FSH release,it has a role in the regulation of the menstrual cycle in females and in homeostasis. NOTE : the adrenal gland usually synthesize some sort of andrognes and any defect in the adrenal gland affecting the inner zone of the cortex which make androgens and sex hormones in general in both males and females could lead to sexual abnormalities in both sexes. Testosterone synthesis: It s initially synthesized from cholesterol the same enzymes involved in steroidogenesis in general are involved in androgenic production. -Initial step from cholesterol to pregnolone catalyzed by debranching enzyme or side chain cleavage enzyme -Pregnolone is oxidized and isomerized to progesterone -Further steps involve different hydroxylases ending up with testosterone in the testicles or androgens in the adrenal (the same enzymes are involved in both pathways ) 2 P a g e

3 In sex organs and in the skin there s is another step related to synthesis of androgens where testosterone is converted to 5 alphadihydrotestosterone which is 10 times more potent than testosterone,and it mediates the effects of testosterone in sexual organs and skin, WHILE in bone,liver,skeletal muscles testosterone itself interacts with cytosolic and nuclear receptors, this has a clinical significance from pharmacological point of view ( differences in effects mediated by andrognes mainly testosterone and 5 alpha-dihydrotestosterone) Not to forget that 5 alpha-dihydrotestosterone in the skin is responsible for: -baldness in males -enlargement of the prostate : it s a normal aging process, all males usually develop some sort of enlargement in prostate, this condition is known as benign hyperplasia of the prostate, and could be managed well by antiandrognes or you can hit the synthetic machinery of androgens by drugs that control excess production of androgens : 1-aminoglutethimide 2-selective desmolase inhibitor but unfortunately it s a very toxic drug 3-trilostane which acts by inhibiting dehydrogenase enzyme 4-ketoconazole : antifungal,it inhibits different hydroxylases that could be of value in the management of cushing syndrome and cancer of the prostate. NOTE : -* what inhibit hydroxylase inhibit it on both testicles and adrenals *more andrognes are produced by the testicles in males while androgens in females are produced in the adrenal there is no other source 3 P a g e

4 *ovaries are the major source of estrogen and progesterone but a little andrognes can be produced by the ovaries *testicles produce a little estradiol and estrogen **according to the mentioned points if I give estrogen to a male he will develop a female sexual characteristics and vise versa if I give a female an androgen she will develop a male sexual characteristics (mustache, deepening of the voice,,, etc). *regulation of synthesis and release of testosterone : - GnRH has two effects androgen and antiandrogen - GnRH is a unique hypothalamic hormone, made of one polypeptide of 10 amino acids very simple structure secreted by the specific nuclei present in the hypothalamus, reaches the anterior pituitary,interacts with specific surface membrane receptors and its believed that such binding increases the intracellular calcium which mediates the effects of GnRH leading to an increase in the production of two different hormones LH and FSH. - one hormone, small polypeptide gives large glycoproteins (LH and FSH) which have alpha and beta subunits,each is encoded by a specific gene, there is a glycosylation step in combination between them, all these steps could be regulated by GnRH and eventually LH and FSH will be secreted in blood reaching gonads ( testicles) interact with specific membrane receptors on the testicles and activating adnylate cyclase and consequently producing camp. 4 P a g e

5 -LH is the main hormone that stimulate the production of the androgens (testosterone) while FSH is involved mainly in the process of spermatogenesis. -After producing the desired effect by testosterone, it exerts a negative feedback effect on LH, GnRH whereas inhibin regulates FSH release by the anterior pituitary. -Testoserone is converted to estrogen in the hypothalamus by aromatase enzyme which is responsible for the negative feedback on GnRH Now how GnRH is released from the hypothalamus? GnRH is synthesized in the hypothalamus and released into the portal system network of capillaries of the anterior pituitary in a PULSATILE manner, it pulses every 30 mins, and this pulses lead to an increase in FSH and LH synthesis and release. Later on they found that if GnRH is given from outside continuously not mimic the physiological normal pattern of its release in large doses or if you give whats known as a superagonist to GnRH this will lead to inhibition of LH and FSH and hence androgenic production by the testicles. **** Clinical uses of GnRH are classified into two major categories : a)those conditions where we need GnRH given in pulses or in small amonts deficiency states 5 P a g e

6 b)those conditions where you want to suppress this axis ( GnRH>>>LH,FSH>>>androgens) OPPOSITE CINICAL USES So GnRH could have an androgenic or an antiandrogenic effect as mentioned before Can I use GnRH in the management of precious puberty? YES This condition is associated with increased amounts of the pituitary gonadotropin-luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Increased LH levels stimulate production of sex steroids by testicular Leydig cells or ovarian granulosa cells (form the internet) Its also associated with GnRH deficiency but with excess androgens Precious puberty in females may lead to menses in a 6 years old female child. This condition is treated by giving GnRH to suppress LH and FSH. DELAYED PUBERTY can be treated also with GnRH but its given in a pulsatile manner. You will be asked in the exam about this Structure of GnRH -10 amino acids,the first 3 amino acids are essential for agonistic activity (releasing estrogen and progesterone form the ovaries, synthesizing LH,FSH and testosterone) 6 P a g e

7 - amino acids form 4 to 10 are important for binding characteristics of the hormone If I changed any of the first 3 amino acids(e.g changing proline to glycine) I will end up with an antagonist but if I changed any of the rest it will remain an agonist but I will end up with a superagonist. The superagonist down regulates GnRH pituitary receptors ( this is how a superagonist produces inhibition on cells that produce TSH,LH) Conclusion: pulsatile( agonistic acticity,small doses) GnRH bind to receptor,increases intracellular calcium and consequently increases LH and FSH. 1- Less frequent administration of GnRH is used in cases of GnRH deficiency like kallmann syndrome (genetic condition which results in the failure to commence on the non-completion of puberty) 2- It can be also used in hypogonadism or deficiency of testosterone (tertiary hypogonadism) in cases where FSH and LH can be produced by the pituitary otherwise GnRH will be ineffective.(theres is no defect in the pituitary gland function) While large doses of GnRH (superagonist) down regulate the receptors inhibiting FSH,LH release and consequently testosterone : 1- GnRH can be used as a treatment in Precious puberty.. any GnRH agonists, may be used. Non-continuous usage of GnRH agonists stimulates the pituitary gland to release Follicle Stimulating Hormone (FSH) and Luteinizing 7 P a g e

8 Hormone (LH). However, when used regularly, GnRH agonists cause a decreased release of FSH and LH. 2-Another use of GnRH as a treatment is in cases where I don t need testosterone in males like in the case of cancer of the prostate, the major problem of this cancer that its discovered very late. Transport and MOA of androgens : GnRH interacs with LH,FSH and increases the production and release of testosterone in the testicles,testosterone produced reach the blood stream,bound to specific globulin and reach the target cells where it s responsible for the primary and secondary sexual characteristics of the males,,at time of puberty there will be a surge in testosterone release and production to produce these charactarestics ( penis,mustache, muscles, deep voice ) whereas in females an increase in GnRH and LH,FSH will increase estrogen and progesterone and this will lead to beginning of the menstrual cycle. In the sexual organs as we said before testosterone is converted to 5 alphahydrotestosterone by 5 alpha reductase and then interacts with cytosolic and nuclear receptors increasing transcription of specific protein that will mediate the effect of this particular steroid or androgen. In skeletal muscle,bone testosterone itself acts on cytosolic and nuclear receptors increasing transcription and production of specific protein which will mediate the ANABOLIC effects of androgen (opposite to glucocorticoids which have a catabolic effects on protein), this anabolic effect build up bones and 8 P a g e

9 make the muscles bulkier in response to androgens, therefore androgens will be of value in the management if osteoporosis, while antiandrogens lead to osteoporosis. **DHT is 10 times more potent than testosterone and mediates the effects of testosterone on skin and sexual apparatus ( prostate, seminal vesicle, epididymis) Testosterone physiological and pharmacological effects: 1- Virilizing = masculinizing effect Primary and secondary characteristics *primary characteristics : sexual organs like prostate, seminiferous tubules, vas deference, epididymis), without testosterone there will be no growth of such organs in the male. * its also important in the development of the testicles (they become larger at puberty) * enlargement of the breast in females, softness of skin, straightening of the hair are mediated by the actions of estrogen and progesterone. 2- Increase production of sperms, not only FSH do that but it s the major one,therefore if we have some sort of infertility we have to think of other hormones like estrogen. (could be from estrogen deficiency or testosterone deficiency ). 3- Increase production of RBCs. erythropoisis 4- Anabolic or growth promoting effect (bone,skeletal muscles) 9 P a g e

10 Testosterone metabolism : its metabolized in the liver to 17- ketosteroids (main metabolite for testosterone) like androsterone and etiocholanolone. CIinical uses of testosterone : 1-Testosterone deficiency 2-Hypogonadism, impotency, decrease libido, aging Infertility : if I have a case of infertility I have to assist this, is it only testosterone deficiency or testosterone deficiency with FSH deficiency,,,, if there is a deficiency in FSH release from the pituitary I have to give the patient FSH because testosterone alone doesn t work in this case, so I have to know what the defect is to give the appropriate treatment. 3-Anemia,leukemia,lymphoma.. testosterone increases RBCs content in blood 4-Endometriosis : ectopic growth of endometriam like in the parietal cavity, ovaries, fallopian tubes and associated with severe pelvic pain, abdominal pain and menstrual disorders a condition affect ladies especially young ladies that could be managed easily by weak androgens, clinical studies proved that danazol is the best androgen in the management of endometriosis NOTE : we give weak androgens because strong ones may help in the development of secondary male characteristics (mustache,muscles etc) 5- breast cancer,, cancer is managed by anticancerous drugs,hormones radiotherapy,sugery (best treatment if detected in early stages) 10 P a g e

11 usually we take a biopsy from the cancer and measure the density of estrogens receptors and we classify breast cancer into estrogen receptor rich and estrogen receptor poor, now if the breast cancer is estrogen receptor rich type the response will be good to hormonal therapy, WHAT sort of hormonal therapy it depends,it can be estrogen dependent and in this case we use -antiestrogens (not related to androgens) -testosterone ( antagonist for estrogen) -aromatase inhibitors 6- anabolic effect.. osteoporosis (major clinical use of androgens) NOTE : athletes use androgens to build up muscles but they become sexually dead because of the negative feedback on GnRH,LH,FSH and consequently androgens. Testosterone preparations primary use for androgen replacement (hormonal replacement therapy for testosterone deficiency ): Testosterone IM ;DC Testosterone propionate IM;SL Testosterone cypionate IM;depo;IM Methyltestosterone O;SL Fluoxymestrone O 11 P a g e

12 primary use for breast cancer testolactone (progesterone derivative and aromatase inhibitor),orally used in certain types of breast cancer that respond to androgen therapy primary use for osteoporosis Androgen : anabolic ratio= 1:2 or 1:3 ( these preparations are used in osteoporosis due to its good anabolic effect with little effect on sexual organs ) Ethylesternol O Stanozolol O Oxandrolone O Nandrolone decanoate IM Methandienone O Testosterone side effects : 1-virilization (masculinization ).. appearance of male characteristics in females hirsutism,acne,menstrual disorders in females 2-precious puberty and hirsutism in children 12 P a g e

13 3-salt and water retention..universal side effect to all steroids (androgen,aldosterone, testosterone, estrogen, progesterone) all of them lead to this sort of side effects because of their aldosterone like effect. 4-jaundice, gall bladder stones (methyltestosterone) 5-enlargement of prostate 6-liver cancer antiandrogens there are different antiandrogens based on their MOA 1-estrogens we have different preparations.. they have antiandrogenic effect by negative feedback mechanism.diethylsilbesterol, mestranol 2-progestins.. they work also by negative feedback on GnRH,FSH,LH, testosterone,e.g cyproterone actate (oral preparation, synthetic progesterone, most widely used ), progestins also interfere with binding of testosterone to its cytosolic receptors more than nuclear receptors. 3-GnRH antagonist or superagonist Antagonist : we can make a huge number of antagonists by changing the aminoacids,previously mentioned point, the antagonist don t interact with the receptor while the superagonist interacts and down regulates these receptors. 13 P a g e

14 -Antagonists act very quickly (advantage)blocking the effect of histamine, ganirelix is specific GnRH antagonist associated with the least release of histamines as compared to others. -Leuprolide acetate is a superagonist of GnRH(different glycine residues from 6 to 10 amino acids),excellent antiandrogen, but it has a problem that it may cause osteoporosis..its used in IVF to suppress the axis of GnRH and used in conditions where we don t need androgens. 4-Flutamide, bicalutamide and nilutamide..used to interfere with the binding of testosterone to its receptor particularly nuclear receptor. 5-5 alpha reductase inhibitors, finasteride,,inhibit the conversion of testosterone to 5 alpha hydrotestosterone. 6-Ketoconazol.. antiandrogen through inhibition of different hydroxylases 7-Spironolactone.. it works by two mechanisms - Decrease the production of androgens - Interference with testosterone binding to nuclear receptors * It s a potassium sparing diuretic drug via aldosterone blockade 8- Gossypol : it s a natural ketone,phenolic compound derived from the cotton plant There is a great research on using gossypol as an anticancerous agent and it will be reused in markets as an anticancerous agent rather than an antiandrogen. 14 P a g e

15 A short story about gossypol : in china they extracted gossypol as an oil from the cotton seeds and used it in their food, later on they found that most of the men are infertile, they studied this phenomena and found that gossypol is an antiandrogen and they started to use it frequently, but we stopped using gossypol 15 years ago because of its severe toxicity and side effects ( e.g irreversibility in infertility,severe azoospermia and oligospermia) Now gossypol is used in replacing surgical castarion instead of removing the testicles but its no more used as a contraceptive method. Exactly like Viagra (sildenafil citrate ),first was used as antihypertensive and antiarrhythmic but this resulted in many cases of death, because of using Viagra with nitrates which leads to severe drop in blood pressure and death later a man came to the pharmacy and requested Viagra to use it for sexual dysfunction,therefore studies of viagra using in male impotency started from this point,,now Viagra is the main drug used in males impotency but it has one precaution,don t use it with nitrates. Antiandrogenic clinical uses: 1 cancer of the prostate, its discovered very late and its highly dependent in its growth,metastases, and the pain which originates from it on testosterone or androgen level, if you decrease androgens you decrease the size of the cancer, you decrease the metastases and improve the pain. Cancer of the prostate treatment :if discovered early surgery (removing the prostate) is the best treatment but unfortunately this rarely happens usually they discover it in its 4 th stage or even more so this surgery doesn t work and they then remove the testicles and sometimes the adrenal also (both adrenals)to remove the source of androgens,, this is in the past,now we use 15 P a g e

16 antiandrogens, all of them can be used (e.g diethylstilbesterol, cyproterone acetate) but the best treatment is leuprolide acetate, this drug replaces the castration (even better than castration). Major cause of this late discovery that the manifestation usually appear after 10 years of the onset of this cancer Sometimes they use prostate specific antigen (psa) test but its not conclusive because they didn t find a difference in this antigen between normal people and people that have cancer of the prostate. 2-Benign hyperplasia of the prostate finastride ( 5 alpha reductase inhibitor),highly effective along with alpha one blockers, its as mentioned before a normal aging process and this hyperplasia could press on urethra and lead to some difficulty in urination (urinary retention sometimes) 3-Severe acne and hirsutism in females (spironolactone, cyproterone acetate) 4-Precious puberty 5-Male antifertility agents (male contraceptive) gossypol (not used anyomore) 6-Baldness (cytocol=topical antiandrogen,finasteride) Antiandrogens side effects : Decrease libido, impotency, decrease spermatogenesis, decrease ejaculation Done by : Deema Al Souri 16 P a g e

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