Hormones & Contraceptives PDF

Pharmacology 3 Dr. Omaima Aly Ahmedy  Sex hormones produced by the gonads are necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty. Hypothalamus secretes gonadotropin releasing hormone (GnRH = gonador...

Pharmacology 3 Dr. Omaima Aly Ahmedy  Sex hormones produced by the gonads are necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty. Hypothalamus secretes gonadotropin releasing hormone (GnRH = gonadorelin) which stimulates the release of both gonadotropins [follicle stimulating hormone (FSH) & luteinizing hormone (LH)] from the anterior pituitary. These hormones stimulate the normal functioning of the gonads & the secretion of sex hormones in both men & women. 3 Pharmacology 3  = Conception At puberty, the ovary begins a 30 to 40 yrs period of cyclic function called the menstrual cycle bec. of the regular episodes of bleeding. Then It fails to respond to Proliferative Secretory gonadotropins secreted by the anterior pituitary gland → the cessation of Cycle bleeding ∴ called the menopause 21days 35days ⚫ Cycle begins with menstruation, which lasts for 3-6 days during which the superficial layer of uterine endometrium is shed. ⚫ Under the influence of FSH, a Gp of follicles each contains an ovum begin to enlarge. One follicle develops faster than the others &forms Graafianfolliclewhile rest degenerate, the ripening Graafian follicle produces estrogen, this phase of the cycle is thefollicularphase. Oestrogens are responsible for the proliferative phase of endometrial regeneration which occurs from day 5 or 6 until midcycle. ⚫ During this phase: The endometrium increases in thickness & vascularity. ⚫ At the peak of oestrogen secretion, there is cervical secretion of mucus rich in protein &CHO which facilitates entry of sperms. 6 ⚫ Oestrogen has a -ve feedback effect on the anterior pituitary decreasing GnRH → degeneration of non-dominant follicles &marked ↑in oestrogen secretion just before midcycle, sensitizes LH secretion from the anterior pituitary. ⚫ LH secretion causes rapid swelling &rupture of graafian follicle, →ovulation. ⚫ Ovulatory phase is constant, occurs 14 days before menses e.g if cycle 35 days ∴ ovulation occurs at 21th. ⚫ Ruptured follicle proliferates &develops into the corpus luteum which secretes progesterone → Secretory phase. progesterone stimulates secretory phase of the cycle, which renders endometrium suitable for the implantation of fertilized ovum i.e. stimulates glands secretion &glycogen deposition asnutrition for zygote + relax myometrium ⚫ During this phase, cervical mucus becomes more viscous &in general less welcoming for sperms. progesterone exerts -ve feedback on hypothalamus &pituitary gland decreasing the release of L.H. If implantation of the ovum does not occur, progesterone secretion stops, uterine contraction occurs that trigger menstruation → new cycle. ⚫ If implantation occurs, the corpus luteum continues to secrete progesterone, which by -ve effect on the hypothalamus &anterior pituitary prevents further ovulation. 7 1-Development of female sex organs: Development of 1ry & 2ry female sex characteristics. Endometrial proliferation & watery cervical secretions. 2-Effect on bones: Growth spurt & stimulates epiphyseal closure at puberty. ↓ rate of bone resorption by antagonizing PTH “estrogen not stimulate bone ∴formation” ∴ At Menopause, osteoporosis occurs - Bone loss occurs in 1st 5 years after menopause estrogen Should be started after menopause but ↑risk of endometrial &breast cancer !! 3-Metabolic effects: Impaired glucose tol erance = risk of diabetes Na+/H2O retention = risk of Hypertension ↓LDL & ↑HDL ∴ ↓in plasma cholesterol levels →↓the risk of coronary artery dis. 4-Effect on blood: ↑blood coagulation (↑synthesis of clotting factors II, VII, IX, X) = risk of Stroke 5-Effect on pituitary gland: -ve feedback on FSH secretion = Contraception 6-Carcinogenic effect = Adverse effect Continuous exposure for prolonged periods >> endometrial hyperplasia & risk of breast cancer 8 1. Postmenopausal hormone therapy (HT): ⚫ Amount of HT used is less than that required in contraceptives →  estrogen- related adverse effects than contraceptives. ⚫ Women who only have urogenital symptoms, such as vaginal atrophy, should be treated with vaginal topical rather than systemic estrogen. *Postmenopausal symptoms: Hot flushes, sweating, fatigue, irritability, osteoporosis, nervousness & insomnia. *Treatment of Osteoporosis: 1. Ca2+ supplement 2. Vitamin D, Calcitriol, Alfa-calcidiol " 1- hydroxycholecalciferol" 3. Bisphosphonates 4. Calcitonin 5. Estrogen (HRT) 9  2. Component in Contraceptive: Synthetic estrogen analogue will be discussed later 3. Stimulation of development of secondary sex characteristics in young women (11 to 13 years of age) with primary hypogonadism. Continued treatment is required after growth is completed. 4. Used for women who have premature menopause or premature ovarian failure. Replacement therapy is usually continued until about age 50, the average age of normal menopause. 5. Treatment of prostatic carcinoma as it decreases androgens 10  Jaundice Migraine Breast and Endometrial cancer is increased with use of estrogen therapy. [The increased risk of endometrial cancer can be offset by including a progestogen along with the estrogen therapy]. 11  SERMs are a class of estrogen-related compounds that display selective agonism or antagonism for estrogen receptors depending on the tissue type. This category includes Tamoxifen, Raloxifene, and Clomiphene. 12  Clomiphene Tamoxifen Blocks central E receptors Blocks peripheral E receptors (in (in anterior pituitary & hypothalamus) breast) TTT of anovulatory infertility TTT of estrogen-dependent breast in males & females (5 days) cancer 13 Clomiphene ⚫ Hot flashes – nausea - visual disturbances. ⚫ Ovarian enlargement. The risk of multiple births (twins or triplets) with clomiphene is 3 to 5 percent. Tamoxifen ⚫ Hot flashes – nausea - menstrual irregularities and vaginal bleeding. ⚫ Due to its estrogenic agonistic activity in the endometrium → hyperplasia and malignancies have been reported. 14 It has estrogenic effects in bone, CVS & HDL activity and antiestrogenic effects in the breasts and uterus. Raloxifene is also approved for the prevention and treatment of osteoporosis in postmenopausal women with less risk of endometrial & breast cancer. -Tamoxifen or Raloxifen ??? Adverse Effect 1. Hot flashes and leg cramps are common adverse effects with Raloxifene. 2. Increased risk of deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. 15 ⚫ It is produced by corpus luteum, placenta & in smaller amount by adrenal cortex and testes. ⚫ Pharmacological Actions: ⚫ proliferates the endometrium which is stimulated by oestrogen & ↑secretory activity of glands of the uterus &breast. ⚫ prepares endometrium for implantation of the fertilized ovum & maintains pregnancy. ⚫ relaxation of the myometrium &inhibits contraction of the uterus → prevent abortion in pregnancy (Preserve conception). ⚫ ↑ the viscosity of cervical secretion which impairs the passage of sperms to the uterus ⚫ inhibits LH release from the pituitary ∴ inhibits ovulation (Contraception) ⚫ Progesterone prevents oestrogen withdrawal bleeding but oestrogen cannot prevent progesterone withdrawal bleeding as A) Estrogen makes weak thickening but Progesterone makes strong thickening of endometrium B) Estrogen → ↑Progesterone receptor but not vice versa. ⚫ It has a thermogenic effect ∴ responsible for the slight rise in 16 temperature after ovulation. ⚫ Preparations:Progesterone itself is inactive orally because it is metabolized in the liver. ⚫ There are 2maingroups of progestogens: 1.Naturally occurring hormone &its derivatives (hydroxyprogesterone, medroxyprogesterone) given Injections 2.Testosterone derivatives, (norethisterone, norgestrel) can be given orally. -Newer progestogens used in contraception include desogestrol & gestodene, drosperione. Most synthetic progestins possess some androgenic activity because of their structural similarity to testosterone. 17 1. For contraception: Alone or in combination with syn estrogen ⚫ Synthetic progestogens (progestins) used in contraception are more stable to first-pass metabolism (norethindrone, levonorgestrel, desogestrel, and drospirenone). ⚫ Medroxyprogesterone acetate is an injectable contraceptive (3 months duration). 2. Progestins are also used for the control of dysfunctional uterine bleeding (perimenopause), treatment of dysmenorrhea (painful menstruation), and management of endometriosis-associated pain. Contraindications: 1. Pregnancy (teratogenic) 2. Hepatic disease 3.Thromboembolism 4.undiagnosed vaginal bleeding. 18 1. Headache, depression, irreversible weight gain (Anabolic), and changes in libido. 2. Some androgenic activity because of their structural similarity to testosterone and can cause acne and hirsutism 3. Blockers of androgenic receptors, such as norgestimate and drospirenone, may be preferred in women with acne. 4. Drospirenone may raise serum potassium as analog to spironolactone, and concurrent use with other drugs that increase potassium (for example, ACEIs) may increase the risk of hyperkalemia 19 ⚫ Blocks progesterone receptors &inhibits Progesterone relaxant effect on uterus → It sensitizes the uterus to the action of prostaglandins. ⚫ Administration to females early in pregnancy → interference with the progesterone needed to maintain pregnancy → abortion of the fetus. ⚫ Mifepristone is often combined with the prostaglandin analog misoprostol (administered orally or intravaginally) to induce uterine contractions → successful termination of pregnancy. ⚫ Mifepristone has also been investigated as an oral contraceptive and an emergency contraceptive agent. ⚫ Adverse effects: uterine bleeding - possibility of an incomplete abortion. 20 ⚫ Estrogen: Provides a negative feedback on the release of LH & FSH by the pituitary gland →  ovulation. ⚫ Progestin: 1. Inhibits LH release. 2. Thickens the cervical mucus →  transport of sperm. 1. ↓ fallopian tube contractility. 2. Endometrial atrophy >> not suitable for implantation. ⚫ Withdrawal of the progestin stimulates menstrual bleeding during the placebo week. 21 ⚫ Synthetic estrogen analogues have a prolonged action and higher potency than of natural estrogens → because synthetic ones are metabolized more slowly in liver and they are stored in adipose tissue from which they are slowly released. ⚫ Natural estrogen has  oral bioavailability due to 1st-pass metabolism in the liver. ⚫ To reduce 1st-pass metabolism: administer via the transdermal route (patch, topical gel, topical emulsion, or spray), intravaginally (tablet, cream, or ring), or by injection. ⚫ The parent drugs and their metabolites undergo excretion into bile and are then reabsorbed through the enterohepatic circulation. 22 1. Oral (Combined - Minipills) 2.Transdermal patch 3. Injectables 4. Vaginal ring 5. Implants 6. IUD  1. Oral pill is taken for 21 consecutive days followed by 7 pill free days, with causes a withdrawal bleeding. A. Combined oral contraceptives (COCs): decrease FSHandLH ⚫ A combination of an estrogen (ethinyl estradiol) and a progestin (norethindrone, levonorgestrel). ⚫ Monophasic pills: contain a constant dose of E & P (21 days). ⚫ Triphasic pills: constant dose of E + increasing doses of P (21 days). ⚫ Efficacy: high. Triphasic has the advantage of low thromboembolism. B. Progestin-only pills (POPs) [Minipills]: Taken daily on a continuous schedule. Efficacy: less than COCs. May produce irregular menstrual cycles more frequently than COCs. POPs may be used for patients who are breastfeeding (unlikeestrogen, progestinsdo not have an effect on milk production), areintolerant to estrogen, are smokers, or have C.I. to estrogen-containing products. *Clinical uses of POPs: 1.Oral contraception 2. Dysfunctional uterine bleeding 3. Postpone menstruation. 4.Treatment of endometriosis & endometrial fibrosis “relief pain only” 5. Dysmenorrhoea “pain & cramps during menses but subsides as menses taper 23 off” 2. Transdermal patch: ⚫ Contains (ethinyl estradiol + norelgestromin). ⚫ Patch is applied each week for 3 weeks to the abdomen, or buttock. ⚫ Week 4 is patch free, and withdrawal bleeding occurs. ⚫ Efficacy: as oral contraceptives (less effective in women weighing > 90 kg). 3. Vaginal ring: ⚫ Contains (ethinyl estradiol + etonogestrel) or etonogestrel only. ⚫ Inserted into the vagina and is left in place for 3 weeks. Week 4 is ring free, and withdrawal bleeding occurs. ⚫ Efficacy: high ⚫ Disadvantage: ring may occasionally slip or be expelled accidentally. 24 4. Injectable progestin (Medroxyprogesterone acetate): ⚫ Administered every 3 months (SC or IM). ⚫ Adverse effects: weight gain - amenorrhea – return to fertility may be delayed for several months after discontinuing use of this agent. ⚫ Injectable medroxyprogesterone acetate → risk of osteoporosis → recommendations for limiting the duration of use to 2 years 5. Progestin implants: A subdermal implant is placed subdermally in the upper arm and provides contraception for approximately 3-5 years. Very low failure rate for this method (no patient role). Adverse effects: irregular menstrual bleeding & 25 headaches. 6. Progestin intrauterine device (IUD): ⚫ IUDs may be medicated or non-medicated, the most widely used contains copper &the medicated type contains progesterone. *M.O.A. ⚫ Cu metal (non-specific foreign body)→inflammation of endometrium → preventing implantation (non-medicated IUD) for up to 10 years. ⚫ low dose of progesterone released by the medicated type alter the endometrium in awaythat ↓the possibility of implantation of the fertilized ovum (in medicated IUD) for up to 5 yearsit is ⚫ It is a suitable method of contraception for women who already have at least one child and do not have a history of pelvic inflammatory disease or ectopic pregnancies. 27  7. Postcoital contraception: ⚫ The overall risk of pregnancy after an episode of coitus is shown in the figure. ⚫ Emergency contraception uses high doses of progestin (for example, 0.75 mg of levonorgestrel) or high doses of estrogen (100 μg of ethinyl estradiol) plus progestin (0.5 mg of levonorgestrel) administered within 72 hours of unprotected intercourse (the “morning-after pill”). ⚫ A second dose of emergency contraception should be taken 12 hours after the first dose. ⚫ A newer progestin-only regimen consists of a one- time dose of 1.5 mg levonorgestrel.The progestin-only emergency contraceptive regimens are generally better tolerated than the estrogen-progestin combination regimens. ⚫ progesterone agonist/antagonist ulipristal: It is indicated for emergency contraception within 5 days of unprotected intercourse. 28 ⚫ Major: Breast tenderness, depression, fluid retention, headache, N&V. ⚫ CVS: 1. Thromboembolism, hypertension, and cerebral and coronary thrombosis. 2. High risk groups: smokers – age>35 years. ⚫ Metabolic: Abnormal glucose tolerance - weight gain (less with drospirenone). ⚫ Serum lipids: 1. Estrogen → HDL +  LDL 2. Progestins may cancel some of the beneficial effects of estrogen. Therefore, estrogen-dominant preparations are best for individuals with elevated serum cholesterol. ⚫ Contraindications: 1. Cerebrovascular and thromboembolic disease 2. Estrogen-dependent neoplasms, liver disease, and pregnancy. 28 Pharmacology 3 33 Actions: 1. Development of 1ry & 2ry male sex characteristics 2. Sperm production (together with FSH) 3. ↑ synthesis of muscle proteins and erythropoiesis. 4. Growth spurt & epiphyseal closure at puberty. 5. Decreased bone resorption. Mechanism: 1. Like the estrogens and progestins, androgens bind to a specific nuclear receptor in a target cell. 2. Testosterone itself is the active ligand in muscle and liver 3. In other tissues it must be metabolized to DHT (dihydrotestosterone) by 5α-reductase 34 ⚫ Replacement therapy in hypogonadism,delayed puberty, infertility, testicular failure. ⚫ Treats refractory anemiasuch as aplastic anemia [bone marrow not produce RBCs]. ⚫ Anabolic agent e.g. nandrolone +dietary measures + exercises to reverse protein loss in patients with debilitating condition. ⚫ Treats senile osteoporosisdue to anabolic effect. ⚫ Treats breast tumor in postmenopausal women by changing environment around estrogen Derivative of Testosterone : Anabolic steroids e.g. Nandrolone, Stanozolol These are steroids with ↑anabolic effects + ↓ androgenic effects. 35 1) Liver damage or hepatic dysfunction. 2) Masculinization action in women (acne, hirsutism). 3) In older males, prostatic hyperplasia may develop. 4) Na+ &H2O retention →oedema. 5)Infertility as↑doses of testosterone suppress gonadotropins secretion→ atrophy of interstitial tissue. 36 1. Finasteride - Dutasteride: ⚫ 5--reductase inhibitors → DHT →USE:  prostate size in BPH 2. Flutamide-Bicalutamide: ⚫ Competitive blocker on T receptors →ttt of prostatic cancer 37 Androgen antagonist with weak progestational activity. *M.O.A. ✓ competes with DHT for its receptors on target tissues. ✓Through its effect on hypothalamus, it depresses the synthesis of gonadotrophins. ⚫ Androcur t t t androgen-dependent conditions such as acne, excessive hair growth, early puberty, and prostate cancer ⚫ Diane and Diane-35 is a combination of ethinylestradiol (EE), an estrogen, and cyproterone acetate (CPA), a progestin and antiandrogen, which is used as a birth control pill to prevent pregnancy in women, with same uses of androcur 38 Gonadotropin HMG HCG Gn Used in female & male infertility due to deficiency in FSH &/or LH Human menopausal Humanchorionic gonadotrophin gonadotropins (HCG) = Choriomon (HMG) Menotropins= Fostimon Contains FSH & LH activities in equal With LH activity. units (FSH: 75 I.U. + LH: 75 I.U./amp). Obtained from postmenopausal women’s urine. Produced by trophoplastic cells of ! placenta of pregnant females & obtained from their urine.  Used primarily for its FSH activity →  Measure its endogenous level to diagnose given to promote maturation of pregnancy. ovarian follicles in anovulatory  Used after HMG to induce ovulation in infertility. infertile female.  Used in some types of male infertility  Used in males with cryptorchidism (= to promote spermatogenesis. undescended testes)