1. Drugs used in gonads disorders I Dr.Hazar

2. Objectives After studying this unit, you should be able to: 1.Describe the physiological actions of estrogen as they relate to the adverse affects of estrogen replacement therapy HRT 2. Discuss the most current data relating to estrogen and progestin replacement therapy 3. List the drugs and mechanisms used to attenuate the actions of sex hormones 4. Understand the mechanisms of action of the hormonal contraceptive drugs

3. Outline Hormone physiology Ovulation Hormone regulation and cycling Estrogen and progesterone / receptors SERMs (selective estrogen receptor modulators) Hormones as drugs Contraceptives Infertility

4. Female Reproductive Anatomy and Physiology: Overview Ovary Fallopian tube Uterus – Cervix – Endometrium Vagina –Clitoris –Labia

6. Ovary: Details of Histology & Physiology FollicleOocytes Thecal cells Granulosa cells –Estrogen –  Corpus luteum Corpus luteum –Progesterone –Inhibin

8. Menstrual Cycle: Egg Maturation, and Endometrial Growth Follicular phase –Egg matures Ovulation –Egg released Luteal phase –Corpus luteum –Endometrium –Prep for blastocyst No Pregnancy –Menses

9. Neuroendocrine Control of Menstrual Cycle: Follicular Phase FSH stimulates follicular development Estrogen: + feedback, limits more follicles

13. Gonadotrophines & Analogues 1. Follitropin α -Recombinant human FSH. 2. Follitropin β -Recombinant human FSH. 3. Lutropin α -Recombinant human LH. 4. Choriog -Recombinant HCG. 4. Choriogonadotropin α -Recombinant HCG. 5. 5. Follitropin -FSH 6. 6. HumanMenopausalgonadotrophin -LH&FSH No 5&6 are made from purified extract of human Menopausal urine.

14. Clinical uses LH &FSH are used in Infertility..Female Infertility 1.caused by lack of ovulation as a result of Hypopituitarism or failure of treatment with Clomiphene. 2.Induction of ovulation IVF InVitro fertilisation(Infertility is caused by mechanical obstruction of the fallopian tubes). Monitor to avoid ovarian hyperstimulation →multiple pregnancy

15. Male infertility Oligospermia (associated with Oligospermia (associated with hypopituitarism + Anosmia). HCG In boys with Delayed puberty (Testosterone is preferred ).

16. Androgens and the hormonal control of the male reproductive system LHRH from the hypothalamus acts on the anterior pituitary to release both follicle-stimulating hormone, which stimulates gametogenesis, and LH (also called interstitial cell-stimulating hormone), which stimulates androgen secretion. The endogenous hormone is testosterone; intramuscular depot injections of testosterone esters are used for replacement therapy. Mechanism of action is via intracellular receptors. Effects depend on age/sex, and include development of male secondary sexual characteristics in prepubertal boys and masculinisation in women.

17. Clinical use of androgens and antiandrogens Androgens (testosterone preparations) as hormone replacement in: –male hypogonadism due to pituitary or testicular disease (e.g. 2.5 mg/day patches) –hyposexuality following ovariectomy (e.g. 300μg/day patches). Antiandrogens (e.g. flutamide, cyproterone,bicalutamide) are used as part of the treatment of prostatic cancer. 5α-Reductase inhibitors (e.g. finasteride) are used in benign prostatic hypertrophy.

18. Aromatase Inhibitors

19. ERECTILE DYSFUNCTION Erectile function depends on complex interactions between physiological and psychological factors. Erection is caused by vasorelaxation in the arteries and arterioles supplying the erectile tissue. Innervations of the penis includes autonomic and somatic nerves. Nitric oxide is probably the main mediator of erection and is released both from nitrergic nerves and from endothelium. Erectile function is adversely affected by several therapeutic drugs (including many antipsychotic, antidepressant and antihypertensive agents),. There are several organic causes, including hypogonadism,hyperprolactinaemia, arterial disease and various causes of neuropathy (most commonly diabetes).

20. PHOSPHODIESTERASE TYPE V INHIBITORS Sildenafil, the first selective phosphodiesterase type V inhibitor, was found incidentally to influence erectile function. Tadalafil and vardenafil are also phosphodiesterase type V inhibitors licensed to treat erectile dysfunction. Tadalafil is longer acting than sildenafil.

21. Mechanism of action Phosphodiesterase V is the isoform that inactivates cGMP. Nitrergic nerves release nitric oxide (or a related nitrosothiol), which diffuses into smooth muscle cells, where it activates guanylate cyclase. The resulting increase in cytoplasmic cGMP mediates vasodilation via activation of protein kinase G. Consequently, inhibition of phosphodiesterase V potentiates the effect on penile vascular smooth muscle of endothelium-derived nitric oxide and of nitrergic nerves that are activated by sexual stimulation.

22. Unwanted effects Many of the unwanted effects of phosphodiesterase type V inhibitors are caused by vasodilation in other vascular beds; these effects include hypotension, flushing and headache. Visual disturbances have occasionally been reported and are of concern because sildenafil has some action on phosphodiesterase VI, which is present in retina and important in vision. The manufacturers advise that sildenafil should not be used in patients with hereditary retinal degenerative diseases (such as retinitis pigmentosa) because of the theoretical risk posed by this. Vardenafil is more selective for the type V isozyme than is sildenafil, but is also C.I in patients with hereditary retinal disorders

23. Prolactin Prolactin is secreted from antr.pit. Under the inhibitory effect of PRIF(dopamine). Its main function is to control milk production. Pit. Deficiency ↓PRL Pit. Deficiency → ↓PRL → failure to lactate Hyp. Destruction ↑ PRL Hyp. Destruction → ↑ PRL →Hyperprolactinemia. In Men Hyperprolactinemia -Impotance &Gynecomastia. In women Galactorrhea & Hypogonadism

25. Bromocriptine & Analogues Bromocriptine is a dopamine agonist (D2-R) ↓PRL used in : ↓PRL used in : 1. Parkinsons. 2. Acromegaly. 3. Prolactinomas. 4. Galactorrhea.(hyperprolactinemia) 5. Benign breast diseases. 6. Suppression of lactation

26. Analogues 1. 1. Cabergoline M.O.A ditto brom.but longer duration of action,better tolerated than brom.used to inhibit lactation. 2.Quinagolide M.O.A ditto brom.but S.E. Hypotension used only in hyperprolactinemia

27. PROTOTYPE DRUGS: Estrogen - ethinyl estradiol Progestin - levonorgestrel (L- norgestrel) SERM - tamoxifen, raloxifene Aromatase inhibitor - letrozole

28. Estrogens Physiological &pharmacological effects ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy uterus: endometrial growth vagina: cornification of epithelial cells with thickening and stratification of epithelium cervix: increase of cervical mucous with a lowered viscosity (favoring sperm access)

29. Estrogens Development and maintenance of internal (fallopian tubes, uterus, vagina), and external genitalia skin: increase in vascularization, development of soft, textured and smooth skin bone: inhibits osteoclastic activity. electrolytes: retention of Na+, Cl- and water by the kidney cholesterol: hypocholesterolemic effect