Corticosteroids

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Corticosteroids

  1. 1. CORTICOSTEROIDS Prof. Dr. Shah Murad HOD, Pharmacology LM&DC, Lahore
  2. 2. <ul><li>Cholesterol </li></ul><ul><li>↓ </li></ul><ul><li>pregne-nolone ->17-hydroxy pregnenolone -> dehydro-epiandrosterone </li></ul><ul><li>↓ ↓ ↓ </li></ul><ul><li>progesterone -> 17 hydroxy-progesterone -> andro-stene-dione </li></ul><ul><li>↓ ↓ ↓ </li></ul><ul><li>deoxy-corticosterone ↓ estrone testosterone </li></ul><ul><li>11 deoxy-cortisol ↓ ∩ ↓ </li></ul><ul><li>↓ ↓ ESTRADIOL ESTRADIOL </li></ul><ul><li>Cortisol </li></ul><ul><li>corticosterone </li></ul><ul><li>↓ </li></ul><ul><li>Aldosterone </li></ul>
  3. 3.
  4. 4. Physiological control of steroids secretion
  5. 5. Adrenal Steroids <ul><li>The adrenal cortex is a factory for steroid hormones. </li></ul><ul><li>In total, at least two to three dozen different steroids are synthesized and secreted from this tissue, but two classes are of particular importance (1) glucocorticoids and (2) mineralocorticoids </li></ul>
  6. 6. <ul><li>Additionally, the adrenal cortex produces some sex steroids, particularly androgens, a talent of considerable importance in such diseases as congenital adrenal hyperplasia. </li></ul>
  7. 7. <ul><li>Like all steroids, adrenal &quot;corticosteroids&quot; are synthesized from >>>>>>> cholesterol through a series of enzyme-mediated transformations. </li></ul>
  8. 8. <ul><li>Each of the three major pathways involves sequential processing by a group of enzymes, >>>>>> some of which reside in endoplasmic reticulum and others inside mitochondria. </li></ul><ul><li>Hence, synthesis involves shuttling of the steroids between these two organelles </li></ul>
  9. 9. <ul><li>Synthesis of the different steroids is not uniformly distributed through the cortex. </li></ul><ul><li>For example, the outermost group of cells ( zona glomerulosa ) synthesizes aldosterone, but essentially no cortisol or androgens >>>>> because those cells do not express the enzyme 17-alpha-hydroxylase which is necessary for synthesis of 17-hydroxypregnenolone and 17-hydroxyprogesterone. </li></ul>
  10. 10. <ul><li>That enzyme is however present in cells of the inner zones of the cortex ( zonae fasiculata and reticularis ), which are the major sites of cortisol production </li></ul>
  11. 11. <ul><li>Like all steroid hormones, cortisol and aldosterone bind to their respective receptors, and the resulting hormone-receptor complexes bind to a >>>>>>hormone response element to modulate >>>> transcription of responsive genes. </li></ul>
  12. 12. <ul><li>Although the physiologic effects of these two steroid hormones are distinctly different, their receptors are quite similar and, most interestingly, they bind to the same consensus response element in DNA! </li></ul><ul><li>How then is it possible to get hormone-specific responses? </li></ul>
  13. 13. <ul><li>GLUCOCORTICOIDS </li></ul>
  14. 14. Short Acting (12 hrs) <ul><li>Hydrocortisone </li></ul><ul><li>Cortisone </li></ul>
  15. 15. Intermediate Acting (12-36 hrs) <ul><li>Prednisone </li></ul><ul><li>Prednisolone </li></ul><ul><li>Methylprednisolone </li></ul><ul><li>Triamcinolone </li></ul>
  16. 16. Long Acting (>48 hrs) <ul><li>Paramethasone </li></ul><ul><li>Betamethasone </li></ul><ul><li>Dexamethasone </li></ul>
  17. 17. Pharmacokinetics <ul><li>90% of glucocorticoid protein bound </li></ul><ul><ul><li>Receptors for CBG-steroid complex on cell surface. </li></ul></ul><ul><ul><li>Corticosteroid Binding Globulin &quot;delivers drug to cells&quot; </li></ul></ul><ul><ul><li>Albumin binding restricts volume of distribution </li></ul></ul>
  18. 18. <ul><li>Active transport of bound steroid into cell </li></ul><ul><li>Binding of glucocorticoid to receptor in cytoplasm (complex) </li></ul><ul><li>Active transport of complex to nucleus </li></ul>
  19. 19. Glucocorticoid Products (Esters and dose forms) <ul><li>Selection of a glucocorticoid ester is based on the route of administration and the desired duration and intensity of effect. </li></ul>
  20. 20. ORAL ROUTE <ul><li>The ester is irrelevant. </li></ul><ul><li>All are separated from the base in the GI tract. </li></ul><ul><li>The base drugs are well absorbed </li></ul>
  21. 21. IM, Subcutanous, Intralesional <ul><li>Rapidly absorbed products can be used as substitutes for oral preparations. </li></ul><ul><li>Their absorption and duration are roughly equivalent to the oral base products (and salts). </li></ul>
  22. 22. <ul><li>Slowly absorbed (Depot) products are designed to provide either low concentrations of glucocorticoids for extended periods of time or high concentrations in a local area (e.g., tumor injections). </li></ul>
  23. 23. Intravenous <ul><li>Water soluble salts. </li></ul><ul><li>These reach sites of action 1/2 - 1 hour faster than oral but are otherwise similar in potency. </li></ul>
  24. 24. IV <ul><li>This is the most appropriate route of administration for &quot;EXTREME-DOSE&quot; glucocorticoid therapy (e.g., CNS trauma, shock, etc.) </li></ul>
  25. 25. Pharmacodynamics <ul><li>After active transport of complex to nucleus >>>>>>>>> </li></ul><ul><li>Tight binding of complex to &quot;regulatable&quot; gene sequences. </li></ul><ul><ul><li>Cell type determines which sequences. </li></ul></ul><ul><li>Binding causes an increase in DNA transcription </li></ul><ul><li>A variety of proteins may be produced (depending on specific genes activated) </li></ul>
  26. 26. Uses <ul><li>Anti-inflammatory and Anti-immunologic Therapy </li></ul>
  27. 27. <ul><li>Steroids are potent drugs for interrupting events triggered at the cell membrane (prostaglandins, phospholipase, etc.), and cell mediated immunity (antigen recognition, cell migration, etc.) </li></ul><ul><li>Steroids are NOT effective inhibitors of antibody synthesis </li></ul>
  28. 28. inflammation <ul><li>DOSING </li></ul><ul><li>approximately 4 x replacement dose </li></ul><ul><li>usually 1 mg/kg prednisone or prednisolone </li></ul><ul><li>various &quot;protocols&quot; for dose are used </li></ul>
  29. 29. Discontinuation of glucocorticoids <ul><li>Taper off if Glucocorticoid therpy of greater than 2 weeks duration. </li></ul><ul><li>Rate of taper should be proportional to duration of prior therapy. </li></ul><ul><li>The longer the original therapy, the slower the rate of dose reduction </li></ul>
  30. 30. Inhibit immunologic responses <ul><li>DOSING </li></ul><ul><li>approximately 16x replacement dose (daily) </li></ul><ul><li>usually initiate with 4 mg/kg prednisone or prednisolone per day in two doses (2 mg/kg ) </li></ul><ul><ul><li>avoids relatively remote potential for acute adverse effects </li></ul></ul><ul><ul><li>possibly reduces initial efficacy (versus one single daily dose) </li></ul></ul><ul><li>Acute &quot;psychosis&quot; POSSIBLE with these doses (especially in one 4 mg/kg daily dose) </li></ul>
  31. 31. Reducing dose rates <ul><li>Goal is to &quot;acheive the lowest dose that will control the disease.&quot; </li></ul><ul><li>Disease break may require returning to original remission doses (or higher). </li></ul>
  32. 32. <ul><li>Dose characteristics of GLUCOCORTICOIDS are very essential to predict its EFFECTS/SEs </li></ul>
  33. 33. Alternate day therapy (Anti-inflammatory OR Anti-immunologic) <ul><li>Administration of a single dose of an >>>>>> intermediate-acting glucocorticoid >>>>>> on alternate days is a dose equivalent to >>>>>>>> that being employed over a 48 hour period. </li></ul>
  34. 34. <ul><li>200 mg given every other day has the same efficacy as 90 mg given every day. </li></ul>
  35. 35. <ul><li>200 mg given every other day produces the same adverse effects as 25 mg given every day. </li></ul>
  36. 36. <ul><li>Tapering the DOSE of GLUCOCORTICOIDS </li></ul>
  37. 37. When? <ul><li>any patient who is dosed with glucocorticoids for longer than 14 days </li></ul>
  38. 38. How? <ul><li>can be used as one step in &quot;tapering&quot; protocol but with greater risk of disease &quot;breakthrough&quot; 1 mg/kg SID (change to) 1 mg/kg EOD </li></ul><ul><li>can convert to EOD with SMALL loss of efficacy 1 mg/kg SID (change to) 2 mg/kg EOD </li></ul>
  39. 39. Which drugs? <ul><li>Prednisone, prednisolone, methylprednisolone . </li></ul><ul><li>Triamcinolone ???? </li></ul><ul><li>Dexamethasone, betamethasone inappropriate </li></ul>
  40. 40. Why? <ul><li>Greater reduction in side effects than can be acheived by dose reduction alone. </li></ul><ul><li>Does NOT eliminate side effects, merely minimizes them </li></ul>
  41. 41. IV use of Glucocorticoids <ul><li>Shock : (1) Methylprednisolone sodium succinate </li></ul><ul><li>(2) dexamethasone Na phosphate </li></ul><ul><li>Spinal cord trauma : Methylprednisolone sodium succinate </li></ul>
  42. 42. Mineralocorticoids <ul><li>Removal of the adrenal glands leads to death within just a few days. </li></ul><ul><li>Observation of such a unfortunate subject would reveal several key derangements: >>>>>>>>>>>>>>> </li></ul><ul><li>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> </li></ul><ul><li>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> </li></ul><ul><li>1. the concentration of potassium in extracelluar fluid becomes dramatically elevated </li></ul>
  43. 43. <ul><li>2. urinary excretion of sodium is high and the concentration of sodium in extracellular fluid decreases significantly </li></ul><ul><li>3. volume of extracellular fluid and blood decrease </li></ul><ul><li>4. the heart begins to function poorly, cardiac output declines and shock ensues </li></ul>
  44. 44. <ul><li>These phenomena are a direct result of loss of mineralocorticoid activity, and can largely be prevented by replacement of salts and mineralocorticoids. </li></ul><ul><li>Clearly mineralocorticoids are acutely critical for maintenance of life! </li></ul>
  45. 45. Aldosterone and Mineralocorticoid Receptors <ul><li>The principal steroid with mineralocorticoid activity is aldosterone . </li></ul>
  46. 46. <ul><li>Cortisol, the major glucocorticoid , is said to have &quot;weak mineralocorticoid activity&quot;, which is of some importance because cortisol is secreted very much more abundantly than aldosterone. </li></ul>
  47. 47. <ul><li>Another way to state this is that a small fraction of the mineralocorticoid response in the body is due to cortisol rather than aldosterone </li></ul>
  48. 48. <ul><li>The mineralocorticoid receptor binds both aldosterone and cortisol with equal affinity. </li></ul><ul><li>Moreover, the same DNA sequence serves as a hormone response element for the activated (steroid-bound) forms of both mineralocorticoid and glucocorticoid receptors. </li></ul><ul><li>An obvious question is: </li></ul>
  49. 49. <ul><li>How can aldosterone stimulate specific biological effects in this kind of system, particularly when blood concentrations of cortisol are something like 2000-fold higher than aldosterone? </li></ul>
  50. 50. <ul><li>A large part of the answer is that, in aldosterone-responsive cells, cortisol is effectively destroyed, allowing aldosterone to bind its receptor without competition. </li></ul><ul><li>Target cells for aldosterone express the enzyme 11-beta-hydroxysteroid dehydrogenase, which has no effect on aldosterone, but converts cortisol to cortisone, which has only a very weak affinity for the mineralocorticoid receptor. </li></ul>
  51. 51. <ul><li>In essence, this enzyme &quot;protects&quot; the cell from cortisol and allows aldosterone to act appropriately. </li></ul><ul><li>Some tissues (e.g. hippocampus) express abundant mineralocorticoid receptors but not 11-beta HSD - they therefore do not show responses to aldosterone because aldosterone is not present in quantities sufficient to compete with cortisol </li></ul>
  52. 52.
  53. 53. Physiologic Effects of Mineralocorticoids <ul><li>Mineralocorticoids play a critical role in regulating concentrations of minerals - particularly sodium and potassium - in extracellular fluids. </li></ul><ul><li>Loss of these hormones leads rapidly to life-threatening abnormalities in electrolyte and fluid balance </li></ul>
  54. 54. <ul><li>The major target of aldosterone is the distal tubule of the kidney, where it stimulates exchange of sodium and potassium. </li></ul><ul><li>Three primary physiologic effects of aldosterone result: </li></ul><ul><li>1. Increased resorption of sodium : sodium loss in urine is decreased under aldosterone stimulation. </li></ul>
  55. 55. <ul><li>2. Increased resorption of water , with consequent expansion of extracellular fluid volume. </li></ul><ul><li>(This is an osmotic effect directly related to increased resorption of sodium) </li></ul><ul><li>3. Increased renal excretion of potassium </li></ul>
  56. 56. <ul><li>Knowing these effects should quickly suggest the cellular mechanism of action of this hormone. </li></ul><ul><li>Aldosterone stimulates transcription of the gene encoding the sodium-potassium ATPase, leading to increased numbers of &quot; sodium pumps &quot; in the basolateral membranes of tubular epithelial cells. </li></ul><ul><li>Aldosterone also stimulates expression of a sodium channel which facilitates uptake of sodium from the tubular lumen </li></ul>
  57. 57. <ul><li>Aldosterone has effects on sweat glands, salivary glands and the colon which are essentially identical to those seen in the distal tubule of the kidney. </li></ul>
  58. 58. <ul><li>The major net effect is again to conserve body sodium by stimulating its resorption or, in the case of the colon, absorption from the intestinal lumen. </li></ul><ul><li>Conservation of water follows conservation of sodium </li></ul>
  59. 59. Control of Aldosterone Secretion <ul><li>Control over aldosterone secretion is truly multifactorial and tied into a spider web of other factors which regulate fluid and electrolyte composition and blood pressure. </li></ul>
  60. 60. <ul><li>If the major effects of aldosterone are considered, it is rather easy to predict factors which stimulate or suppress aldosterone secretion </li></ul>
  61. 61. The two most significant regulators of aldosterone secretion are: <ul><li>Concentration of potassium ions in extracellular fluid: Small increases in blood levels of potassium strongly stimulate aldosterone secretion. </li></ul><ul><li>Angiotensin II: Activation of the renin-angiotensin system as a result of decreased renal blood flow (usually due to decreased vascular volume) results in release of angiotensin II, which stimulates aldosterone secretion </li></ul>
  62. 62. <ul><li>Other factors which stimulate aldosterone secretion include adrenocorticotropic hormone (short-term stimulation only) and sodium deficiency. </li></ul><ul><li>Factors which suppress aldosterone secretion include atrial naturetic hormone, high sodium concentration and potassium deficiency </li></ul>
  63. 63. Disease States <ul><li>A deficiency in aldosterone can occur by itself or, more commonly, in conjunction with a glucocorticoid deficiency, and is known as hypoadrenocorticism or Addison's disease . </li></ul>
  64. 64. <ul><li>Without treatment by mineralocorticoid replacement therapy, a lack of aldosterone is lethal, due to electrolyte imbalances and resulting hypotension and cardiac failure </li></ul>
  65. 65. <ul><li>Anabolic Steroids </li></ul>
  66. 66. <ul><li>Anabolic steroids , officially known as anabolic-androgenic steroids ( AAS ), are drugs which mimic the effects of the male sex hormones testosterone and dihydrotestosterone. </li></ul>
  67. 67. <ul><li>They increase protein synthesis within cells, which results in the buildup of cellular tissue (anabolism), especially in muscles. </li></ul>
  68. 68. <ul><li>Anabolic steroids also have androgenic and virilizing properties, including the development and maintenance of masculine characteristics such as the growth of the vocal cords and body hair. </li></ul>
  69. 69. <ul><li>The word anabolic comes from the Greek ἀναβολή anabole , &quot;that which is thrown up, mound&quot;, and the word androgenic from the Greek ἀνδρός andros , &quot;of a man&quot; + -γενής -genes , &quot;born&quot;. </li></ul>
  70. 70. <ul><li>Anabolic steroids were first isolated, identified and synthesized in the 1930s, and are now used therapeutically in medicine to stimulate bone growth and appetite, induce male puberty, and treat chronic wasting conditions, such as cancer and AIDS. </li></ul>
  71. 71. <ul><li>The American College of Sports Medicine acknowledges that AAS, in the presence of adequate diet, can contribute to increases in body weight, often as lean mass increases, and that the gains in muscular strength achieved through high-intensity exercise and proper diet can be additionally increased by the use of AAS in some individuals </li></ul>
  72. 72. <ul><li>Some health risks can be produced by long-term use or excessive doses of anabolic steroids. </li></ul><ul><li>These effects include harmful changes in cholesterol levels (increased low-density lipoprotein and decreased high-density lipoprotein), acne, high blood pressure, liver damage (mainly with oral steroids) </li></ul>
  73. 73. <ul><li>Ergogenic uses for anabolic steroids in sports and bodybuilding are controversial because of their adverse effects and the potential to gain an advantage conventionally considered &quot;cheating.&quot; </li></ul><ul><li>Their use is referred to as doping and banned by all major sporting bodies </li></ul>
  74. 74. <ul><li>For many years AAS have been by far the most detected doping substances in IOC accredited laboratories. </li></ul><ul><li>In countries where AAS are controlled substances, there is often a black market in which smuggled or even counterfeit drugs are sold to users. </li></ul>
  75. 75. <ul><li>The traditional routes of administration do not have differential effects on the efficacy of the drug. </li></ul><ul><li>Studies indicate that the anabolic properties of anabolic steroids are relatively similar despite the differences in pharmacokinetic principles such as first-pass metabolism. </li></ul><ul><li>However, the orally available forms of AAS may cause liver damage in high doses </li></ul>
  76. 76. Mechanism of action <ul><li>The pharmacodynamics of anabolic steroids are unlike peptide hormones. </li></ul><ul><li>Water-soluble peptide hormones cannot penetrate the fatty cell membrane and only indirectly affect the nucleus of target cells through their interaction with the cell’s surface receptors. </li></ul>
  77. 77. <ul><li>Conversely, as fat-soluble hormones, anabolic steroids are membrane permeable and influence the nucleus of cells by direct action. </li></ul><ul><li>The pharmacodynamic action of anabolic steroids begin when the exogenous hormone penetrates the membrane of the target cell and binds to an androgen receptor located in the cytoplasm of that cell. </li></ul>
  78. 78. <ul><li>From there, the compound hormone-receptor diffuses into the nucleus, where it either alters the expression of genes or activates processes that send signals to other parts of the cell. </li></ul>
  79. 79. <ul><li>Some anabolic steroids such as methandrostenolone bind weakly to this receptor in vitro, but still exhibit androgenic effects in vivo. </li></ul><ul><li>The reason for this discrepancy is not known </li></ul>
  80. 80. <ul><li>The effect of anabolic steroids on muscle mass is caused in at least two ways: </li></ul><ul><li>1. first, they increase the production of proteins; </li></ul><ul><li>2. second, they reduce recovery time by blocking the effects of stress hormone cortisol on muscle tissue, so that catabolism of muscle is greatly reduced. </li></ul>
  81. 81. <ul><li>It has been hypothesized that this reduction in muscle breakdown may occur through anabolic steroids inhibiting the action of other steroid hormones called glucocorticoids that promote the breakdown of muscles. </li></ul>
  82. 82. <ul><li>Anabolic steroids also affect the number of cells that develop into fat-storage cells, by favouring cellular differentiation into muscle cells instead. </li></ul><ul><li>Anabolic steroids can also decrease fat by increasing basal metabolic rate (BMR), since an increase in muscle mass increases BMR </li></ul>
  83. 83. The androgenic effects of AAS <ul><li>Processes affected include pubertal growth, sebaceous gland oil production, and sexuality (especially in fetal development) </li></ul>
  84. 84. <ul><li>Some examples of virilizing effects are growth of the clitoris in females and the penis in male children (the adult penis does not grow even when exposed to high doses of androgens), increased growth of androgen-sensitive hair (pubic, beard, chest, and limb hair), increased vocal cord size, deepening the voice, increased libido, suppression of natural sex hormones, and impaired production of sperm </li></ul>
  85. 85. <ul><li>Compounds with a high ratio of androgenic to a anabolic effects are the drug of choice in androgen-replacement therapy (e.g. treating hypogonadism in males), >>>>>>> whereas compounds with a reduced androgenic:anabolic ratio are preferred for anemia, osteoporosis, and to reverse protein loss following trauma, surgery or prolonged immobilization . </li></ul>
  86. 86. <ul><li>Determination of androgenic:anabolic ratio is typically performed in animal studies, which has led to the marketing of some compounds claimed to have anabolic activity with weak androgenic effects. </li></ul><ul><li>This disassociation is less marked in humans, where all anabolic steroids have significant androgenic effects </li></ul>
  87. 87. Body composition and strength improvements <ul><li>A review spanning more than three decades of experimental studies in men found that body weight may increase by 2–5 kg as a result of short term (<10 weeks) AAS use, which may be attributed mainly to an increase of lean mass. </li></ul>
  88. 88. <ul><li>Animal studies also found that fat mass was reduced, but most studies in humans failed to elucidate significant fat mass decrements. </li></ul><ul><li>The effects on lean body mass have been shown to be dose dependent. </li></ul>
  89. 89. <ul><li>Both muscle hypertrophy and the formation of new muscle fibers have been observed. </li></ul><ul><li>The hydration of lean mass remains unaffected by AAS use, although small increments of blood volume cannot be ruled out </li></ul>
  90. 90. <ul><li>The upper region of the body (thorax, neck, shoulders and upper arm) seems to be more susceptible for AAS than other body regions because of predominance of androgen receptors in the upper body </li></ul>
  91. 91. <ul><li>The largest difference in muscle fibre size between AAS users and non-users was observed in type I muscle fibres of the vastus lateralis and the trapezius muscle as a result of long-term AAS self-administration. </li></ul>
  92. 92. <ul><li>After drug withdrawal the effects fade away slowly, but may persist for more than 6–12 weeks after cessation of AAS use </li></ul>
  93. 93. Side Effects <ul><li>Most of these side effects are dose-dependent, the most common being elevated blood pressure, especially in those with pre-existing hypertension, and harmful changes in cholesterol levels: some steroids cause an increase in LDL cholesterol and a decrease in HDL cholesterol. </li></ul>
  94. 94. <ul><li>Anabolic steroids have been shown to alter fasting blood sugar and glucose tolerance tests. </li></ul>
  95. 95. <ul><li>Anabolic steroids such as testosterone also increase the risk of cardiovascular disease or coronary artery disease. </li></ul>
  96. 96. <ul><li>Acne is fairly common among anabolic steroid users, mostly due to stimulation of the sebaceous glands by increased testosterone levels. </li></ul>
  97. 97. <ul><li>Conversion of testosterone to dihydrotestosterone (DHT) can accelerate the rate of premature baldness for males who are genetically predisposed, but testosterone itself can produce baldness in females </li></ul>
  98. 98. <ul><li>High doses of oral anabolic steroid compounds can cause liver damage, as the steroids are metabolized (17α-alkylated) in the digestive system to increase their bioavailability and stability </li></ul>
  99. 99. <ul><li>There are also sex-specific side effects of anabolic steroids. </li></ul><ul><li>Development of breast tissue in males, a condition called gynecomastia (which is usually caused by high levels of circulating estradiol), may arise because of increased conversion of testosterone to estradiol by the enzyme aromatase </li></ul>
  100. 100. <ul><li>Reduced sexual function and temporary infertility can also occur in males. </li></ul>
  101. 101. <ul><li>Another male-specific side effect which can occur is testicular atrophy, caused by the suppression of natural testosterone levels, which inhibits production of sperm (most of the mass of the testes is developing sperm) </li></ul>
  102. 102. <ul><li>This side effect is temporary: the size of the testicles usually returns to normal within a few weeks of discontinuing anabolic steroid use as normal production of sperm resumes. </li></ul>
  103. 103. <ul><li>Female-specific side effects include increases in body hair, deepening of the voice, enlarged clitoris, and temporary decreases in menstrual cycles. </li></ul>
  104. 104. <ul><li>When taken during pregnancy, anabolic steroids can affect fetal development by causing the development of male features in the female fetus and female features in the male fetus </li></ul>
  105. 105. <ul><li>A number of severe side effects can occur if adolescents use anabolic steroids. </li></ul><ul><li>For example, the steroids may prematurely stop the lengthening of bones (premature epiphyseal fusion through increased levels of estrogen metabolites), resulting in stunted growth. </li></ul>
  106. 106. <ul><li>Other effects include, but are not limited to, accelerated bone maturation, increased frequency and duration of penile erections, and premature sexual development. </li></ul>
  107. 107. Psychiatric effects <ul><li>&quot;significant psychiatric symptoms including aggression and violence, mania, and less frequently psychosis and suicide have been associated with steroid abuse” </li></ul>
  108. 108. <ul><li>Long-term steroid abusers may develop symptoms of dependence and withdrawal on discontinuation of AAS&quot;. </li></ul>
  109. 109. <ul><li>High concentrations of AAS, comparable to those likely sustained by many recreational AAS users, produce apoptotic effects on neurons, raising the specter of possibly irreversible neuropsychiatric toxicity </li></ul>

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