Drugs used in gonads disorders II Dr.Hazar+oxy

Clinical use of oestrogens and antioestrogens Oestrogens Replacement therapy: Replacement therapy: primary ovarian failure (e.g. Turner's syndrome) primary ovarian failure (e.g. Turner's syndrome) secondary ovarian failure (menopause) for flushing, vaginal dryness and to preserve bone mass( secondary ovarian failure (menopause) for flushing, vaginal dryness and to preserve bone mass( osteoporosis associated with menopause) Contraception. Contraception. To treat oestrogen-sensitive breast cancer (tamoxifen). To treat oestrogen-sensitive breast cancer (tamoxifen). To induce ovulation (clomiphene) in treating infertility. To induce ovulation (clomiphene) in treating infertility.

Oestrogens The endogenous oestrogens are oestradiol (the most potent), oestrone and oestriol; there are numerous exogenous synthetic forms (e.g. ethinylestradiol). Mechanism of action involves interaction with nuclear receptors (termed ERα or ERβ) in target tissues, resulting in modification of gene transcription. Their pharmacological effects depend on the sexual maturity of the recipient: before puberty, they stimulate development of secondary sexual characteristics given cyclically in the female adult, they induce an artificial menstrual cycle and are used for contraception given at or after the menopause, they prevent menopausal symptoms and protect against osteoporosis, but increase thromboembolism.

Synthetic steroids Used in oral contraceptives Inactive prodrug metabolized in the liver (demethylated)

Adverse Effects Nausea Breast tenderness Weight gain Endometrial cancer (estrogen alone) Breast cancer (vs. protection from CVD, Alzheimer’s, and bone fractures)

Estrogens- Drug are competitive antagonists or partial agonists. Tamoxifen is used in oestrogen-dependent breast cancer. Clomiphene induces ovulation by inhibiting the negative feedback effects on the hypothalamus and anterior pituitary. Selective drugs that are oestrogen agonists in some tissues but antagonists in others are being developed. Raloxifene (SERMs (selective estrogen receptor modulators) is used to treat and prevent osteoporosis.

Breast cancer ↑Estrogen → ↑breast proliferation →↓ TGF- β Progression of malignancy is associated with ↓ level cytokines transforming growth factor β (TGF- β ). Tamoxifen → ↓ Estrogen → ↑↑ TGF- β side effects- side effects- 1.nausea, vomiting, hot flashes, menstrual irregularities, cataracts. 1.nausea, vomiting, hot flashes, menstrual irregularities, cataracts. 2.Increase in endometrial cancer (2-fold). 2.Increase in endometrial cancer (2-fold).

Ostrogen receptor antagonist 1-fulvestrant Monthly IM injection “for hormone receptor-positive metastatic breast cancer in postmenopausal women whose breast cancer has recurred or progressed following antiestrogen therapy.” Used to treat tamoxifen resistant breast cancer 1-Tormifene Used in estrogen –sensitive breast cancer. Used in estrogen –sensitive breast cancer.

Aromatase Inhibitors

1-Formastane As effective as tamoxifen, but don’t increase uterine cancer treatment for breast cancer 2 Letrozole Mainly used as adjuvant therapy for post-menopausal women with ER+ early stage breast cancer & for metastatic breast cancer Not for premenopausal women 3-Anastrozole Used for the treatment of postmenopausal breast cancer 4-Exemestane in treatment for breast cancer

Clomiphene Clomiphene citrate. Taken orally Acts as a competitive inhibitor to Estrogen Receptors cis- weak agonist trans- potent antagonist Prevents the feedback inhibition by estrogens on the anterior pituitary, increasing gonadotropin secretion and stimulating ovulation. M.O.A is induction of ovulation by inhibits-ve feedback effects of endogenous estrogen →↓ binding in the ant. Pit.→↑secretion of GnRH & LH,FSH→ ↑estrogen secretion.

Used to treat infertility. (oligomenorrhea, PCOD) sometimes used in combination with gonadotropins Major side effect is ovarian enlargement, also multiple births, nausea, vomiting, vision problems

Progesterone 1.Progesterone 1.Progesterone In the ovary, progesterone is produced by the corpus luteum,circulating levels are highest in luteal phase of cycle. Stimulates the development of the uterine endometrium and vagina Important in the maintenance of pregnancy. Suppresses menstration and uterine contractility & Stimulates lactation. Complement the action of estrogen on primary and secondary sex characteristics Complement the action of estrogen on primary and secondary sex characteristics

Progestins Drugs which mimic the action of progesterone Drugs which mimic the action of progesterone agonists of the progesterone receptor Longer acting and enhanced oral effectiveness compared with progesterone Receptors: one gene, two isoforms, PR-A and PR-B (longer) & both bind ligand the same nuclear transcription factors PR-B primarily mediates progesterone responses. A variety of progestational agents have been synthesized, ex. orally active, ex. Norgestrel, Desogestrel

Types of PROGESTERONE Many are used as oral contraceptives: Many are used as oral contraceptives: 1.Progesterone & analogues. 1.Progesterone & analogues. Dydrogesterone,Gestronol, Megestrol Medroxyprogesterone. Dydrogesterone,Gestronol, Megestrol Medroxyprogesterone. 2. Testosterone analogues 2. Testosterone analogues Norethindrone, Norgestrel, Ethynodiol. Norethindrone, Norgestrel, Ethynodiol. 3.Derivative of Norgestrel 3.Derivative of Norgestrel levonorgestrel,Desogestrel and Norgestimate levonorgestrel,Desogestrel and Norgestimate Gestadone. Gestadone. However,Desogestrel and Gestadone. However,Desogestrel and Gestadone are associated with higher risk ofvenus thromboembolism.

Adverse effects may reduce plasma HDL *venus thromboembolism weight gain( fluid retension ) Depression Acne menstrual irregularities

Therapeutic uses Contraception,IVF hormone replacement therapyHRT dysfunctional uterine bleeding Dysmenorrhea PMT

Anti-progestin Mifepristone Partial agonist at progesterone receptor in the uterus and sensitize the uterus to the action of PG Progesterone is required for the maintenance of early pregnancy High amounts induce prostaglandin F2, leading to abortion and is used with Gemeprost as a medical alternative to surgical termination of pregnancy

Drugs acting on the uterus

At parturition, oxytocin causes regular coordinated uterine contractions, each followed by relaxation; At parturition, oxytocin causes regular coordinated uterine contractions, each followed by relaxation; Ergometrine, an ergot alkaloid, causes uterine contractions with an increase in basal tone. Ergometrine, an ergot alkaloid, causes uterine contractions with an increase in basal tone. Atosiban, an antagonist of oxytocin, delays labour. Atosiban, an antagonist of oxytocin, delays labour.

Prostaglandin (PG) analogues, for example dinoprostone (PGE2) and dinoprost (PGF2α), contract the pregnant uterus but relax the cervix. Cyclo-oxygenase inhibitors inhibit PG synthesis and delay labour. They also alleviate symptoms of dysmenorrhoea and menorrhagia. Prostaglandin (PG) analogues, for example dinoprostone (PGE2) and dinoprost (PGF2α), contract the pregnant uterus but relax the cervix. Cyclo-oxygenase inhibitors inhibit PG synthesis and delay labour. They also alleviate symptoms of dysmenorrhoea and menorrhagia. The β2-adrenoceptor agonists (e.g. ritodrine) inhibit spontaneous and oxytocin- induced contractions of the pregnant uterus The β2-adrenoceptor agonists (e.g. ritodrine) inhibit spontaneous and oxytocin- induced contractions of the pregnant uterus

Clinical uses of drugs acting on the uterus

Myometrial stimulants (oxytocics)

Oxytocin Oxytocin Oxytocin is used to induce or augment labour when the uterine muscle is not functioning adequately. It can also be used to treat postpartum haemorrhage. Oxytocin is used to induce or augment labour when the uterine muscle is not functioning adequately. It can also be used to treat postpartum haemorrhage. Ergometrine can be used to treat postpartum haemorrhage. Carboprost can be used if patients do not respond to ergometrine. Ergometrine can be used to treat postpartum haemorrhage. Carboprost can be used if patients do not respond to ergometrine. A preparation containing both oxytocin and ergometrine is used for the management of the third stage of labour; the two agents together can also be used, prior to surgery, to control bleeding due to incomplete abortion. A preparation containing both oxytocin and ergometrine is used for the management of the third stage of labour; the two agents together can also be used, prior to surgery, to control bleeding due to incomplete abortion.

Dinoprostone given by the extra-amniotic route is used for late (second trimester) therapeutic abortion; given as vaginal gel, it is used for cervical ripening and induction of labour. Dinoprostone given by the extra-amniotic route is used for late (second trimester) therapeutic abortion; given as vaginal gel, it is used for cervical ripening and induction of labour. Gemeprost, given as vaginal pessary following mifepristone, is used as a medical alternative to surgical termination of pregnancy (up to 63 days of gestation). Gemeprost, given as vaginal pessary following mifepristone, is used as a medical alternative to surgical termination of pregnancy (up to 63 days of gestation).

Myometrial relaxants The β-adrenoceptor agonists (e.g. ritodrine) are used to delay preterm labour. The β-adrenoceptor agonists (e.g. ritodrine) are used to delay preterm labour. Atosiban (oxytocin antagonist) also delays preterm labour Atosiban (oxytocin antagonist) also delays preterm labour

HRT

Short term effects of the menopause - physical Vasomotor symptom ex.Hot flushes Palpitations, Night sweats Headaches Feeling dizzy Feeling tired Urinary symptoms Crawling sensation under the skin

Short term effects of the menopause - Mental Irritability Mood swings Anxiety Insomnia Loss of concentration Lack of confidence Memory disturbance Loss of libido Panic attacks

Medium term effects of menopause Vaginal dryness ( vaginitis ) Dyspareunia Urinary problems Bladder and vaginal infections Thinning hair Aches and pains Skin thinning

Long term effects of the menopause Osteoporosis Increased CHD,M.I

Patient Concerns Breast cancer Breast cancer Weight Gain Weight Gain Mensruations Mensruations Duration Duration

Partial agonists 1-Raloxifene Used to prevent fractures in postmenopausal at risk of Used to prevent fractures in postmenopausal at risk of Osteoporosis No effect on No effect on Vasomotor symptom Tibolone Combine activities of estrogenic +proges.+weak androgenic For & For Vasomotor symptom & Osteoporosis prophylaxis

Osteoporosis Bone mineral homostasis: Ca & Po 4, are major mineral constituents of bones. PTH & vit.D are primary regulators. 2ndry ( Cal., Glucocort., estrogens) Bones provide structural support & hematopoiesis.

Osteoporosis Natural Estrogens↓ bone resorption by: 1.Antagonizing the effect of PTH & interlukin-6 on bones but but it does not ↑bone formation. 2.Promoting apoptosis of oesteoclasts.

Antiresorptive 1.Bisphosphonates alendronate, risedronate, ibandronate, etidronate 2.SERMs (Selective estrogen receptor modulators)ex. Raloxifene 3.Estrogen. 4.Calcitonin

Pro’s and Con’s of Available Osteoporosis Therapies Agent Pro’s Con’s Calcium/Vit D Cheap, accessible Partial efficacy HRT Effective  breast ca,  DVT,  MI Raloxifene  vert Fx,  breast ca? Bisphosphonates  vert and nonvert Fx GI intolerance Teriparatide Effective Expensive, daily injections