1. Reproductive Hormonal Pharmacology Douglas Danforth, Ph.D. The Ohio State University

2. Objectives 1.Describe the feedback mechanisms related to stimulation and inhibition of the hypothalamic, pituitary, and gonadal hormones involved in male and female reproduction 2.Describe the effects, medical uses, and consequences of abuse and androgens 3.Describe the effects and consequences of testosterone insufficiency or suppression 4.Describe the medical uses of antiandrogens and their mechanism of action Explain the endocrinology of the male reproductive system and the physiological processes of testosterone production and spermatogenesis 1.Describe the difference types of estrogens and progestins, their effects, and their medical uses 2.Describe the medical uses of SERM’s and antiprogestins, as well as possible problems associated with their use 3.Describe the mechanism of action of aromatase inhibitors and their use in cancer patients Describe the interplay of feedback mechanisms that affect the menstrual cycle.

6. leuprolide (GnRH Agonist) NH 2 pGluHisTrpSerTyrGlyLeuArgProGly NHE t pGluHisTrpSerTyrLeuArgPro D-Leu NH 2 NAcD 2 NalD4CIPhe D3Pal SerTyr ) DhArg(Et2) hArg (Et2) ProD-Ala Leu Antagon (GnRH Antagonist) 12345678910 Amino Acid Number GnRH

7. Agonist U U Short Term LH FSH Effects of GnRH Agonist U U U U U U U U U Long Term U U U U U U U U U U U U

8. Days T, E 2, P 4 LH, FSH 0 10 20 30 0 10 20 30 Hours E 2, P 4 LH, FSH Start Administration GnRH Agonist GnRH Antagonist

9. X Short Term X X X X X X X X U U U U U U U U U U U X X X X X X X X Long Term X X X X X X X X X U U U U U U U U U U X X X X X X X X GnRH Antagonist U LH FSH Effects of GnRH Antagonist

10. Days T, E 2, P 4 LH, FSH 0 10 20 30 0 10 20 30 Hours T, E 2, P 4 LH, FSH Start Administration GnRH Agonist GnRH Antagonist

11. Stimulation – Pulsatile GnRH or GnRH agonist Delayed puberty Ovulation induction in hypogonadotropic hypogonadism Suppression – Continuous GnRH agonist – side effect of bone loss due to hypoestrogenism caused by ↓ FSH/LH. Prostate/Breast Cancer Endometriosis Precocious puberty GnRH analogs – clinical uses GnRH Agonist GnRH Antagonist Suppression – Daily GnRH Antagonist Assisted Reproduction Technologies – IVF – prevent LH surge Prostate Cancer – suppress testicular androgen production

12. Gonadotropins– clinical uses Stimulation of spermatogenesis rFSH vs hMG vs hCG Assisted Reproduction Technologies FSH for gonadal stimulation hCG vs LH for ovulation induction

13. Progestin (Progesterone) Estrogen (Estradiol) Testosterone Dihydrotestosterone 5-α reductase Type 1 Type 2 Skin, liver 1/3 circulating DHT Reproductive tissues (prostate, penis, scrotum), skin 2/3 circulating DHT

14. Androgen effects

15. Male Hypogonadism – Low T Low libido Decreased erection Alopecia Bone loss Gynecomastia Decreased testicular size Side effects Infertility – feedback suppression of LH/FSH Gynecomastia – T is precursor for E

16. Androgens – abuses Performance enhancement Androstenedione Precursor for T Dietary supplement Dihydrotestosterone Much more potent than T Side effects Infertility liver damage hypertension heart disease prostatic hypertrophy testicular atrophy

17. Antiandrogens 5 α-reductase inhibitors Finasteride/Dutasteride BPH, alopecia Androgen antagonists Flutamide/bicalutamide/nilutamide Prostate Cancer Spironolactone Androgen and aldosterone antagonist Also inhibits 17 α hydroxylase ↓ T and androstenedione, ↑ Na Hirsutism and hypertension

19. Estroge n Oral contraceptives – usually include progestin to block proliferation Hormone Replacement Therapy – need progestin if intact uterus Hot flashes Vaginal dryness Osteoporosis Infertility Treatment – followed by progestin to prepare uterus for implantation in frozen embryo transfer cycles Estrogen – clinical uses Estrogen – abuses?

20. Clinical Profile of Ideal Selective Estrogen Receptor Modulator (SERM) Site of actionEffectClinical outcome BoneER agonistPrevent osteoporosis Reduce fracture risk CNSER agonistReduce hot flushes and other menopausal symptoms Cardiovascular/lipidsER agonistLower cardiovascular risk BreastER neutral or antagonist Prevent or no increase in breast cancer (and limit proliferation) UterusER neutral or antagonist Prevent or no increase in endometrial cancer (and limit proliferation) Menopause. 16(3): 609–615, 2009

21. Raloxifene (Evista) Tamoxifen (Nolvadex) Clomiphene (Clomid) Tissue Selective Estrogen Complex (TESC) Bone + Breast - Uterus - Breast - Uterus + CNS - Bazedoxifene Breast – Uterus – Estrogen Bone + Selective Estrogen Receptor Modulator (SERMS) bazedoxifene +

22. Aromatase Inhibitors Competitive (reversible) inhibitors Anastrazole Letrozole Irreversible (covalent) inhibitors Exemestane Formestane

23. Progesterone Effects Gonadotropin Secretion Cervical mucus production Uterus Mammary Gland Basal Body Temperature Progesterone Progesterone antagonist Mifepristone (RU486) Blocks P receptor in endometrium Causes endometrium to slough Combined with prostaglandin for pregnancy termination Progesterone Clinical Uses Gonadotropin Secretion Combined with E for OC P only mini-pill – thicken cervical mucus Long acting Injectable P – inhibit ovulation Uterus HRT to stop endometrial proliferation

24. GnRH Testosterone GnRH agonist – short term flare, long term suppression GnRH antagonist – immediate suppression LH/hCG – induce ovulation FSH – follicle simulation for IVF/ART FSH/hMG – stimulate spermatogenesis Estrogen Aromatase inhibitors Gene transcription SERMs Progesterone Gene transcription Testosterone Dihydro- testosterone Gene transcription Mifepristone 5 α reductase inhibitors Androgen Receptor Antagonists Pituitary

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