Reproductive System Pharmacology including contraceptives.pptx

Reproductive System Pharmacology
*Female sex hormones
*Male sex hormones

1. Reproductive System Pharmacology Haftom G. ( BPharm ., MSc.) Email: [email protected]

2. Reproductive System Pharmacology Presentation outline Sex Hormones ( E strogens and Androgens) Agonists (both natural and synthetic) and Antagonists Drugs used in fertility enhancement and regulation

3. Sex hormones- E strogens and Androgens The gonadal hormones are used therapeutically Hormone replacement therapy Contraception Management of menopausal symptoms Several antagonists are effective in cancer chemotherapy

4. Cholesterol Pregnenolone Estradiol OH OH OH A B C D 1 2 3 4 5 6 7 8 9 10 CH 3 11 19 12 13 14 15 16 17 18 CH 3 CH 2 CH 3 CH CH 2 CH 2 CH 2 CH 3 CH 3 20 21 23 22 24 25 27 28 Testosterone DHEA Androstenedione Progesterone Androstenedione aromatase Synthesis of sex hormones

5. Fig: Estrogen and Progesterone production and negative feedback

6. Figure: The menstrual cycle, showing plasma levels of pituitary and ovarian hormones.

7. I. Estrogens

8. I. Estrogens Estrogenic activity : shared by both steroidal & non-steroidal estrogens Natural Estrogens: major estrogens produced by women are estradiol (estradiol-17β), estrone , and estriol . Estradiol : most potent estrogen Estrone : one-third as biologically active as estradiol and is the 1 estrogen after menopause Estriol : the weakest Estriol is synthesized by the placenta and is excreted at high levels in the urine of pregnant women .

9. Natural Estrogens cont’d…. Readily absorbed through the GIT, skin, and mucous membranes. Estradiol : rapidly metabolized (and partially inactivated) by the microsomal enzymes of the liver. Micronized estradiol is available and has better bioavailability. Although there is some first-pass metabolism , it is not sufficient to lessen the effectiveness when taken orally.

10. Synthetic estrogen analogs Include : ethinyl estradiol , mestranol , and estradiol valerate well absorbed after oral administration. Fat soluble : stored in adipose tissue, from which they are slowly released → have a prolonged action and a higher potency than natural estrogens . Nonsteroidal compounds with estrogenic activity have been synthesized and used clinically . Include : diethylstilbestrol , methallenestril , and chlorotrianisene .

11. 11 Estrogen and synthetic analogs

12. Mechanism of action of estrogen’s α and β nuclear receptors Activated estrogen–receptor complex interacts with nuclear chromatin to initiate hormone-specific RNA synthesis which results in the synthesis of specific proteins that mediate a number of physiologic functions . Rapid estrogen-induced effects such as granulosa cell Ca 2+ uptake and increased uterine blood flow do not require gene activation. These appear to be mediated by non-genomic effects of the classic estrogen receptor-estrogen complex, influencing several intracellular signaling pathways.

13. Fig: Transcriptional regulation by intracellular steroid hormone receptors. ERE = estrogen response element; ER = estrogen receptor.

14. Mechanism of action estrogen’s …. The activated estrogen receptor binds to specific DNA sequences, or estrogen-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects Location of Estrogen receptors: tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women

15. Physiologic and pharmacologic effects of estrogen’s Female Maturation : Development of the breast, vagina , uterus, uterine tubes and secondary sex characteristics Pigmentation of the genital region Growth and closure of the epiphyses of long bones (puberty) Endometrial Effects: Stimulation of endometrial growth Chronic exposure : hyperplasia of the endometrium which is usually associated with abnormal bleeding patterns

16. Physiologic and pharmacologic effects cont’d… Metabolic and Cardiovascular Effects: Maintenance of blood vessels and skin  production of proctacyclin  endothelin-1  angiotensin II receptors  superoxide free radicals  nitric oxide synthase expression and activity ( nitric oxide) R eduction of bone resorption and increase of bone formation

17. Metabolic and Cardiovascular Effects cont’d… Increase high-density lipoproteins (HDL), a slight reduction in the low-density lipoproteins (LDL) Increase saturation of bile with cholesterol  HDL ,  LDL ,  total cholesterol Alters liver metabolism Affects clotting and fibrinolysis  synthesis of clotting factors (VII, IX, X, XIII) Decrease the anticoagulation factors: protein C, protein S, and antithrombin III

18. Therapeutic uses Primary Hypogonadism Replacement therapy in estrogen-deficient females starting at puberty, but not before Estrogen deficiency may be due to Primary failure of development of the ovaries Premature menopause Surgical menopause Contraception : combination estrogen and progestogen provides effective contraception via oral , transdermal, or vaginal route

19. Therapeutic uses cont’d… Postmenopausal Hormone Replacement Therapy Controversial benefit: may ↑ risk of breast and endometrial cancer & thromboembolic disorders Cessation of normal ovarian function is associated with Loss of menstrual periods Vasomotor symptoms (e.g., “hot flashes”) Sleep disturbances Genital atrophy Acceleration of bone loss: vertebral , hip, and wrist fractures Lipid changes: atherosclerotic cardiovascular disease

20. Postmenopausal Hormonal Therapy cont’d …. Intact uterus : progestogen is always included to reduce risk of endometrial hyperplasia and cancer Hysterectomy : estrogen only therapy is recommended as progestins may unfavorably alter the beneficial effects of estrogen on lipid parameters. Hormone therapy : should use lowest effective dose for the shortest possible time If estrogen is contraindicated : Medroxyprogesterone acetate or clonidine are considered to treat vasomotor symptoms.

21. Therapeutic uses cont’d… Osteoporosis An appropriate diet with adequate intake of Ca 2+ and vitamin D and weight-bearing exercise enhance the effects of estrogen treatment. Intractable dysmenorrhea: (given along w/ progesterone for severe pain accompanying ovulation ) Endometriosis : Estrogen & progesterone are used to suppress ovulation for a long time, resulting in endometrial atrophy.

22. Therapeutic uses cont’d… Vaginal Dryness and Urogenital Atrophy: Loss of tissue lining the vagina or bladder leads to a variety of symptoms in many postmenopausal women. These include dryness and itching of the vagina, dyspareunia, swelling of tissues in the genital region, pain during urination, a need to urinate urgently or often, and sudden or unexpected urinary incontinence. Estrogens are administered locally as a vaginal cream, ring device, or tablets may be considered.

23. Therapeutic uses cont’d… Carcinoma of the prostrate - DES is used Morning after pill (DES or ethinyl estradiol)

24. Adverse Effects Vaginal Bleeding Breast cancer ( w / or w/o a progestin ) Endometrial cancer ( if estrogen is taken w/o a progestin) Breast tenderness Edema Hypertension Dizziness Nausea / Vomiting & Anorexia Change in libido ↑ risk of thromboembolic disorders Gallbladder disease Hyperpigmentation Breast tenderness & enlargement Headache, Migraine Headache

25. Contraindications Pregnancy (known or suspected ) Undiagnosed abnormal genital bleeding Estrogen-dependent neoplasia (known or suspected ) Smoking (especially if heavy smoking) Patients with history of thromboembolic disorder

26. Major drug interactions Drugs that increase the metabolism of estrogens: phenytoin, barbiturates & rifampin. Decrease the effectiveness of oral contraceptives . Antimicrobial drugs can reduce the bioavailability of estrogens due to their effect on GI flora & alterations in enterohepatic cycling of estrogens

27. Selective estrogen receptor modulators (SERMS) and anti-estrogens Compounds that bind to estrogen receptors and exert either estrogenic or anti-estrogenic effects depending on tissue type Includes : tamoxifen , toremifene , raloxifene , clomiphene and Fulvestrant

28. Tamoxifen Exhibits anti-estrogenic, estrogenic, or mixed activity Inhibits the proliferation of breast cancer cells and reduces tumor size and number Stimulates proliferation of endometrial cells and causes endometrial thickening Has an antiresorptive effect on bone ↓ es total cholesterol and LDL, but does not increase HDL and triglycerides

29. Tamoxifen Therapeutic Use: orally active Breast cancer in women with ER-positive tumors To reduce risk of developing contralateral breast cancer in women at high risk Adjuvant therapy following mastectomy or radiation for breast cancer

30. Tamoxifen cont’d…. Adverse effects Increase in the relative risk of deep vein thrombosis and pulmonary embolism Increase in endometrial carcinoma Produces hot flashes Menstrual irregularities Vaginal bleeding Note: tamoxifen is metabolized by various CYP450 isoenzymes , which makes it subject to many drug interactions. it also an inhibitor of CYP3A4 and P-glycoprotein. Toremifene : has therapeutic actions similar to tamoxifen .

31. Raloxifene Decrease bone resorption and overall bone turnover. Bone density is increased, and vertebral fractures are decreased Lowers total cholesterol and LDL But has no effect on high-density lipoprotein (HDL) or triacylglycerol levels. It does not cause proliferation or thickening of the endometrium Does not alleviate the vasomotor symptoms associated with menopause 31

32. Raloxifene cont’d…. Therapeutic uses: orally active Prevention and treatment of osteoporosis in postmenopausal women. Prevention of breast cancer in high-risk postmenopausal women. Adverse effects Hot flashes and leg cramps Increased risk of deep-vein thrombosis and pulmonary embolism 32

33. Clomiphene A competitive inhibitor at estrogen nuclear receptors (a drug with antagonist/partial agonist properties) It interfere with the negative feedback of estrogens on the hypothalamus ↑ secretion of gonadotropin-releasing hormone and gonadotropins → release of FSH and LH → stimulation of ovulation. 33

34. Clomiphene Therapeutic use: infertility associated with anovulatory cycles (orally active ) It is an ovulation-inducing agent Adverse effects: Can lead to ovarian hyper-stimulation , with formation of multiple cysts and multiple births H eadache, nausea, vomiting, vasomotor flushes, and ovarian enlargement (estrogenic effects) Prolonged use may increase risk of ovarian cancer 34

35. Fulvestrant Purely anti-estrogenic Efficacious in treating tamoxifen -resistant breast cancers Adverse effects include hot flashes, GI symptoms, headache, back pain, and pharyngitis. 35

36. Estrogen-Synthesis Inhibitors Continual administration of GnRH agonists prevents ovarian synthesis of estrogens but not their peripheral synthesis from adrenal androgens. Inhibits aromatase activity Exemestane , letrozole , and anastrozole are currently approved in the United States for the treatment of breast cancer. 36

37. Nonsteroidal Estrogens Diethylstilbesterol The trans form is the active one As active as Estradiol Longer duration of action Orally active Cheap Adverse effect : Increase the risk of uterine cancer. Uses: Treatment of prostate cancer.

38. Relationship between Estrogen and progesterone   38 1. Estrogen exerts positive feedback on its own activity . Estrogen stimulates the expression of estrogen receptors . 2. Estrogen must precede progesterone to elicit full progesterone sensitivity . Estrogen stimulates the expression of progesterone receptors.   3. Progesterone has anti-estrogenic activity - which helps to terminate estrogenic activity Progesterone suppresses expression of estrogen receptors. Progesterone facilitates the metabolism of estradiol to weaker metabolites. Progesterone may act as a partial agonist at the estrogen receptor.

39. II. The Progestins 39

40. II. The P rogestins Compounds with biological activities similar to those of progesterone Also referred as progestins , progestational agents, progestagens , progestogens , gestagens , or gestogens Natural Progestins : Progesterone ( low oral bioavailability ) Have important hormonal effects Serves as a precursor to the estrogens, androgens, and adrenocortical steroids

41. Synthetic Progestins Progesterone derivatives : Hydroxyprogesterone , medroxyprogesterone ( PROVERA® ) , megestrol 17-Ethinyl testosterone derivatives : Dimethisterone 19-Nortestosterone derivatives : Desogestrel , Norethynodrel , Lynestrenol , Norethindrone , Norethindrone acetate, Ethynodiol diacetate , L- Norgestrel Note: Norgestrel is a racemic mixture of an inactive dextrorotatory isomer and the active levorotatory isomer, levonorgestrel .

42. 42 Progesterone and synthetic analogs

43. Synthesis and Secretion Progesterone is secreted by the ovary , mainly from the corpus luteum , during the second half of the menstrual cycle in response to LH After fertilization, the trophoblast secretes hCG into the maternal circulation to sustain the corpus luteum . During the second or third month of pregnancy, the developing placenta begins to secrete progesterone in collaboration with the fetal adrenal glands

44. Physiological and Pharmacological Actions Neuroendocrine Actions : decrease frequency of GnRH pulses, which is the major mechanism of action of progestin-containing contraceptives .

45. A ctions on the Reproductive Tract : ↓ es estrogen-driven endometrial proliferation and leads to the development of a secretory endometrium Abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation. Under normal circumstances, estrogen antecedes and accompanies progesterone in its action upon the endometrium and is essential to the development of the normal menstrual pattern.

46. Progesterone cont’d…. Progesterone also influences the endocervical glands , and the abundant watery secretion of the estrogen-stimulated structures is changed to a scant, viscid material → decrease penetration of the cervix by sperm Important for the maintenance of pregnancy → suppresses menstruation and uterine contractility Progestins are used to prevent threatened abortion and maintain pregnancy

47. Mammary Gland Development of the mammary gland requires both estrogen and progesterone. Progesterone , acting with estrogen, brings about a proliferation of the acini of the mammary gland. During the normal menstrual cycle, progesterone triggers transient mitotic activity in breast epithelium . So progesterone may be responsible for the increased risk of breast cancer associated with estrogen-progestin use in postmenopausal women.

48. CNS Effects During a normal menstrual cycle, an increase in basal body temperature of about 0.6°C (1°F) at mid-cycle is due to progesterone (this correlates with ovulation). The exact mechanism of this effect is unknown Depressant and hypnotic actions in the CNS (giving at bedtime may help some patients to sleep )

49. Metabolic Effects Long-term administration of potent progestins (e.g., norgestrel ) decrease glucose tolerance . Stimulate lipoprotein lipase activity and enhance fat deposition. Progesterone and its analogs increase LDL and cause either no effects or modest reductions in serum HDL levels. Diminish the effects of aldosterone in the renal tubule and cause a decrease in sodium reabsorption that may increase mineralocorticoid secretion from the adrenal cortex .

50. Mechanism of action Two isoforms of the progesterone receptor (PR): PR-A and PR-B PRs are expressed in the female reproductive tract, the mammary gland, the CNS (including the pulse generator in the hypothalamus), and the pituitary Expression of PRs is induced by estrogens; its presence is a common marker for E action Similar to that of other steroid hormones. Progestins enter the cell and bind to progesterone receptors that are distributed between the nucleus and the cytoplasm. The ligand-receptor complex activate gene transcription.

51. Therapeutic Uses Two most frequent uses of progestins are for Contraception (either alone or with an estrogen) and HRT to limit estrogen’s effects on the endometrium Uterine Bleeding disorders: in patients without underlying organic pathology ( e.g., fibroids or cancer ) Luteal-phase support to treat infertility Premature labor (decrease uterine contractions) Diagnostically to test for estrogen secretion and for responsiveness of the endometrium Stimulate Appetite in AIDS or cancer patients ( off label )

52. Pharmacokinetics : Progesterone itself is rapidly metabolized, which limits its use as a therapeutic agent Synthetic progestins are not rapidly inactivated by first pass metabolism, and can be administered orally

53. Side Effects Weight gain Edema Depression Thrombophlebitis Pulmonary embolism Chronic use of progestins :↓HDL levels → atherosclerosis .

54. Medroxyprogesterone Depo-Provera Indications : Contraception Side Effects : Menstrual irregularities (bleeding or amenorrhea, or both ) Weight changes Headache , nervousness, dizziness Abdominal pain or discomfort Weakness or fatigue

55. Medroxyprogesterone Return of Fertility : Depo-Provera contraceptive injection has a prolonged contraceptive effect Clinical trials indicate that following the last injection, only 68% of women who do eventually become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection (2018).

56. Medroxyprogesterone Pharmacokinetics : IM or SC injections are effective for 3 months Therapy can be initiated at any time, but is typically initiated within 1 week after the onset of menses or before discontinuing another method of contraception. The dose is repeated every 3 months, with a 2 week grace period . IM Formulation : It is recommended that the IM formulation be injected into the gluteal or deltoid muscle, and that the SC formulation be administered into the anterior thigh or abdomen (rotating locations with each dose ).

57. Medroxyprogesterone SC Formulation : provides slower and more sustained absorption of the progestin compared to the i.m . formulation . Slower sustained absorption enables the use of a 30% lower dose of progestin (104 versus 150 mg) that also reduces peak blood levels by half, but with the same duration of effect as the conventional i.m . formulation . Administration via the SC route is less painful than i.m . injection and may potentially allow patient self-administration; self-administration is currently considered an “off-label” use ( Kaunitz , 2016).

58. Anti- progestins Mifepristone Progesterone and glucocorticoid receptor antagonist Used in first trimester to terminate pregnancy (combined with the prostaglandin analog, misoprostol) Post-coital contraceptive (prevent implantation) Adverse Effects : vaginal bleeding, abdominal pain and cramp Contraindicated: patients with vaginal bleeding, adrenal dysfunction or asthma (due to anti-glucocorticoid actions ) Interactions: Decreases efficacy of anticoagulants. Inhibits hepatic metabolism by CYP3A4 ( eg . anti-retroviral protease inhibitors, calcium-channel blockers, carbamazepine )

59. Hormonal contraceptives

60. Hormonal contraceptives History ???? Oral, parenteral & implanted contraceptives Types of preparations include: Combinations of estrogens and progestins Monophasic forms (constant dosage of both components during the cycle) and Biphasic or triphasic forms (dosage of one or both components is changed once or twice during the cycle). Progestin only Postcoital or Emergency Contraceptives

61. Combined Oral Contraceptives Combinations of estrogens and progestins : e.g., Norgestrel-ethinyl estradiol Medroxyprogesterone -estradiol Ethinyl estradiol- norelgestromin Ethinyl estradiol- etonogestrel

62. Combined Oral Contraceptives Monophasic pills (e.g., choice, microgynon , yasmin ) Contain the same dose for the first 3 weeks, and a placebo, hormone-free pill sometimes containing an iron supplement, for the last seven days. OR 24 days of hormone, and 4 days of placebo ( Newly designed) Biphasic COCs : one dose for 10 days, and then an increased dose for the next 11 days . Triphasic COCs (e.g., style): have altered doses every 7 days, and a hormone-free cycle.

63. Combined Oral Contraceptives Monophasic pills (e.g., choice, microgynon , yasmin ) Contain the same dose for the first 3 weeks, and a placebo, hormone-free pill sometimes containing an iron supplement, for the last seven days. OR 24 days of hormone, and 4 days of placebo ( Newly designed) Biphasic COCs : one dose for 10 days, and then an increased dose for the next 11 days . Triphasic COCs (e.g., style): have altered doses every 7 days, and a hormone-free cycle.

64. Combined Oral Contraceptives The pill must be taken at the same time every day. Women must wait to take the pill until the first day of their menstrual period, or the first Sunday following the start of their period. With perfect (method) use, less than one out of every 100 women gets pregnant. With typical, or user-effectiveness, 2 to 8 out of 100 women will become pregnant????

65. Combined Oral Contraceptives The placebo pills : The last seven pills of 28-day package . Mainly taken as a reminder or comfort factor to increase overall compliance . Some contain iron supplements due to increased iron requirements during menstruation.

66. Combined Oral Contraceptives Mechanism of combination oral contraceptives Estrogens: Inhibits the release of FSH from the anterior pituitary, which blocks selection of the dominant follicle. Stabilizes the endometrium . Decreases breakthrough bleeding . By itself, thins the cervical mucus. Increases the number of progestin receptors, allowing the use of smaller dosages The progestin component of the pill : Makes the cervical mucus thicker, making it harder for the sperm to penetrate . Decreases the likelihood of implantation . May inhibit an estrogen-induced LH surge at mid cycle from the anterior pituitary.

67. Adverse Effects Combined Oral Contraceptives Chronic use depresses ovarian function After stopping administration of the COC, approximately 97% of women will return to normal ovulation patterns after their third post-treatment cycle. However, approximately 2% of women will not ovulate for up to several years after discontinuing treatment . Prolonged use can lead to uterine hypertrophy and polyp formation in the cervix . Breast stimulation and enlargement due to estrogen. Lactation is also generally suppressed.

68. Adverse Effects Combined Oral Contraceptives Cardiovascular effects : hypertension, MI, hemorrhagic or ischemic stroke, and venous thrombosis and embolism. Miscellaneous Effects Nausea, edema, and mild headache occur in some individuals, and more severe migraine headaches may be precipitated by oral contraceptive use in a smaller fraction of women. Acne and hirsutism are thought to be mediated by the androgenic activity of progestins

69. Advantages and Disadvantages  Combined Oral Contraceptives

70. Contraindications of COC Thrombolic phenomena, thrombophlebitis, cerebrovascular disorders Any estrogen-dependent neoplasm. Efficacy of the Pill is reduced with P450 modulating drugs.

71. Cautions: COC The majority of women taking the pill report few or no side effects, but serious risks include blood clots (may lead to deep vein thrombosis), heart attacks, and strokes. Hypercoagulability is associated with estrogen , but the lower dose pills appear to have less coagulation effects.

72. Cautions: COC Women are advised to discontinue pill use one month prior to surgery and possibly switch to a progestin only pill to prevent coagulation. Women taking the pill should not smoke, as smoking causes a 3-to-6 fold increases the risk of blood clots. Women who are pregnant, nursing or think they may be pregnant should not take COCs.

73. Progestin-Only Contraceptives Slightly less efficacious than combination oral contraceptives Most commonly used in select patient subgroups, most commonly in women who cannot take estrogen Breast feeding Have migraines Experience heavy and painful menstruation periods resulting in anemia, or for women who smoke

74. Progestin-Only Contraceptives Drugs include: Norgestrel (taken daily without interruption), Subdermal implants norgestrel (for slow release and resultant long-term contraceptive action ( e.g., up to 5 years), and Crystalline suspensions of medroxyprogesterone acetate (DEPO-PROVERA) for intramuscular injection, which provides effective contraception for 3 months.

75. Adverse Effects Progestin-Only Contraceptives Menstrual cycle disruption Headache , breast tenderness, nausea, acne, dizziness, weight gain, mood changes and depression. ↑ ed risk of osteoporosis: ↓ ed endogenous estrogens caused by lowered gonadotropins ↓ HDL levels and ↑ in LDL levels If progestin-only users do become pregnant, an average of 6-10% of pregnancies are ectopic—which is higher than in women not using contraception.

76. Contraindications of POP Contraindicated in the presence of undiagnosed vaginal bleeding, benign or malignant liver disease, and breast cancer . While package labeling for Depo-Provera and levonorgestrel indicate that they are contraindicated in women with a history of thromboembolic disorders , the American College of Obstetricians & Gynecologists and the CDC consider these progestin only medications an acceptable contraceptive option for women with an uncomplicated history of venous thromboembolism, in whom estrogen-progestin contraceptives is contraindicated ( Kaunitz , 2016 ). POPs should not be taken with P450 modulating drugs.

77. Advantages of POP Fewer side effects compared to combination pills due to the lack of estrogen: No evidence that minipill preparations increase thromboembolic events or blood pressure. WHO recommends POP for women with a history of venous thrombosis, pulmonary embolism, diabetes, obesity, or hypertension . Safe during lactation: it may increase the flow of milk. Safe for women with sickle cell disease (S/S or S/C ). POPs are easily reversible since ovulation is quickly re-established upon discontinuation of the drug.

78. Disadvantages of POP Ovulation may not be consistently suppressed . POPs will not prevent ovarian cysts as well as a combination contraceptive . If a pill is taken more than 3 hours late, a back-up method of contraception should be used for the next 48 hours

79. Postcoital or Emergency Contraceptives Three main types of emergency contraceptives are available : Hormonal Emergency Contraceptive pills (Combined Oral Contraceptives???? or Progestin-only Pills ) Copper Bearing IUDs (Intrauterine Device ) Mifeprestone

80. Postcoital or Emergency Contraceptives ECs are not always effective: COC formulations : prevent about 75 %? of expected pregnancies, Progestin-only ( levonorgestrel ) : prevent pregnancy in 85 %? of cases. Studies show that these formulations are more effective the sooner they are taken after intercourse. Copper intrauterine device ( IUD): failure rates of less than 1%.

81. Postcoital or Emergency Contraceptives Two doses of the " minipill " (0.75 mg levonorgestrel per pill) separated by 12 hours. PREVEN® : ( 0.25 mg of levonorgestrel and 0.05 mg of ethinyl estradiol per pill) separated by 12 hours. The first dose of such preparations should be taken anytime within 72 hours after intercourse, and this should be followed 12 hours later by a second dose.

82. Patients should be advised that ECs are less likely to work if : 2 nd dose of pills is not taken Patient vomits within 2 hours of taking either of the doses Patient experiences severe diarrhea within 2 hours of taking either dose

83. Mechanism of EC The mechanism of EC is unknown but has been shown to involve such things as the inhibition or delay of ovulation, alteration in endometrial receptivity for implantation, interference with the ability of the corpus luteum to maintain pregnancy, production of cervical mucus that prevents sperm penetration, and changes in tubular transport of sperm, egg, or embryo. These pills do not, however, interrupt pregnancy after implantation.

84. Contraindications for oral ECs : Pregnancy , breast cancer, endometrial cancer, clinical history of thrombophlebitis and liver disease . Adverse effects of oral ECs: Nausea and vomiting. Abdominal pain, fatigue, headache, dizziness, and breast tenderness . Delayed or early menstrual bleeding or heavier bleeding.

85. III. ANDROGENS

86. Testosterone and other Androgens Testosterone Synthesised by Leydig cells (95%) and adrenal cortex (men ) corpus luteum and the adrenal cortex (women) Androstenedione and dehydroepiandrosterone ( testosterone precursors) are weak androgens that can be converted peripherally to testosterone.

87. Androgens : Synthesis

88. Androgens : Regulation

89. Androgens : Regulation

90. Fig : Metabolism of testosterone to its major active and inactive metabolites ( Copyright © 2006 by The McGraw-Hill Companies, Inc .)

91. Physiological and Pharmacological Effects of Androgens The biological effects of testosterone might be due to Testosterone Dihydrotestosterone (DHT) Estradiol

92. Androgens : Physiology

93. Physiologic and pharmacologic effects Puberty : T estosterone or DHT Secondary sexual characteristics Penile and scrotal growth Changes in the skin include Appearance of pubic, axillary, and beard hair. Sebaceous glands become more active, and the skin tends to become thicker and oilier larynx grows and the vocal cords become thicker

94. Physiologic and pharmacologic effects cont’d…. Puberty…….. Skeletal growth is stimulated, epiphysial closure accelerated and subcutaneous fat decreases Bones also become thicker : increase in the mass of muscle and bone results in a pronounced increase in body weight. Erythropoiesis increases, resulting in higher hematocrit and hemoglobin concentrations in men than boys or women. Libido develops Growth of the prostate and seminal vesicles

95. Physiologic and pharmacologic effects cont’d… Adulthood Gradual development of male pattern baldness , beginning with recession of hair at the temples and the vertex . Changes in prostate gland Gradual development of benign prostatic hyperplasia , which obstructs urine outflow by compressing the urethra as it passes through the prostate. This development is mediated by the conversion of testosterone to DHT by 5 α - reductase II within prostatic cells. Development of cancer : although no direct evidence suggests that testosterone causes the disease , prostate cancer is dependent on testosterone, at least to some degree and at some time in its course.

96. Transport & MOA of androgens: 5 α - reductase Testosterone 5 α - dihydrotestosterone (sex organs ) ( skeletal muscles) cytosloic ; nuclear receptors increase transcription of a specific protein androgen effects DHT is 10 times more potent than testosterone and mediates effects of testosterone on skin and sexual apparatus (prostate; seminal vesicle, epididymis…)

97. The androgens are required for Normal maturation in the male Sperm production Increased synthesis of muscle proteins and hemoglobin, and Decreased bone resorption Synthetic modifications of the androgen structure modify solubility and susceptibility to enzymatic breakdown (thus prolonging the half-life of the hormone) and separate anabolic and androgenic effects.

98. Consequences of Androgen Deficiency Before Completion of Puberty ??? After Completion of Puberty libido and energy decrease within a week decrease in hematocrit and hemoglobin decrease in muscle mass decrease in bone mineral density probably loss of sexual hair Erectile dysfunction Infertility Fatigue, weakness Depression, loss of motivation, irritability Small prostate and testes Gynecomastia Osteoporosis Anemia

99. In Women: Loss of androgen secretion in women results in a decrease in sexual hair, but not for many years.

100. Therapeutic Uses of Androgens Male Hypogonadism : transdermal testosterone preparations or testosterone esters are used to treat testosterone deficiency. Gynecologic Disorders To reduce breast engorgement during the postpartum period, usually in conjunction with estrogens. The weak androgen danazol is used in the treatment of endometriosis Osteoporosis: Androgens and anabolic agents are used in the Rx of osteoporosis , either alone or in conjunction with estrogens . Muscle wasting associated with acquired immunodeficiency syndrome (AIDS )

101. Therapeutic Uses of Androgens cont’d…. Use as Protein Anabolic Agents To reverse protein loss after trauma, surgery, or prolonged immobilization Anemia: aplastic anemia, sickle cell anemia and hemolytic anemia's Use as Growth Stimulators Anabolic Steroid and Androgen Abuse in Sports: to enhance performance Aging Androgen replacement in aging males with low androgen levels show an increase in lean body mass and hematocrit and a decrease in bone turnover

102. Side Effects Men: acne , sleep apnea, erythrocytosis , gynecomastia , and azoospermia , decrease in testicular size. 17a-alkylated androgens ( Methyltestosterone , Oxandrolone , Stanozolo , Fluoxymesterone and Danazol ) cause hepatotoxicity. high doses: ↓ HDL and ↑ LDL women and children: Both experience virilization , including facial and body hirsutism , temporal hair recession in a male pattern, clitoral enlargement, deepening of the voice and acne. Boys and girls whose epiphyses have not yet closed experience premature closure and stunting of linear growth.

103. Contraindications & Cautions Pregnant women or women who may become pregnant during the course of therapy Male patients with carcinoma of the prostate or breast. Infants and young children

104. Androgen suppression & antiandrogens Inhibitors of Testosterone Secretion Inhibitors of Androgen Action Androgen Receptor Antagonists 5α- Reductase Inhibitors

105. Antiandrogens Inhibitors of Testosterone Secretion Both agonists and antagonists of the GnRH receptor Analogs of GnRH effectively inhibit testosterone secretion by inhibiting LH secretion. GnRH " superactive " analogs, given repeatedly, down-regulate the GnRH receptor and are available for treatment of prostate cancer . Extended-release form of the GnRH antagonist abarelix is approved for treating prostate cancer.

106. Inhibitors of Testosterone Secretion cont’d…. Some antifungal drugs of the imidazole family, such as ketoconazole , inhibit CYPs and thereby block the synthesis of steroid hormones, including testosterone and cortisol. Because they may induce adrenal insufficiency and are associated with hepatotoxicity, these drugs generally are not used to inhibit androgen synthesis, but sometimes are employed in cases of glucocorticoid excess .

107. Inhibitors of androgen action Androgen Receptor Antagonists Flutamide , Bicalutamide and Nilutamide Have limited efficacy when used alone because the increased LH secretion stimulates higher serum testosterone concentrations. Used primarily in conjunction with a GnRH analog in the treatment of metastatic prostate cancer → they block the action of adrenal androgens, which are not inhibited by GnRH analogs. Flutamide : also used to treat hirsutism in women (hepatotoxicity)

108. Spironolactone aldosterone antagonist Weak inhibitor of the androgen receptor and a weak inhibitor of testosterone synthesis When the agent is used to treat fluid retention or hypertension in men, gynecomastia is a common side effect. In part because of this adverse effect, the selective mineralocorticoid receptor antagonist eplerenone was developed. Used in women to treat hirsutism ; moderately effective but may cause irregular menses.