Pharmacology of Repro Hormones Overview of HPG axis hormone PDF

Pharmacology of Repro Hormones Overview of HPG axis hormone agonists and antagonists Reproductive/GU DMDSYS-762 Spring 2024 Undral Munkhsaikhan MS, MD [email protected] Office: LMU Tower 324 Phone: (865) 370-2109 Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition,...

Pharmacology of Repro Hormones Overview of HPG axis hormone agonists and antagonists Reproductive/GU DMDSYS-762 Spring 2024 Undral Munkhsaikhan MS, MD [email protected] Office: LMU Tower 324 Phone: (865) 370-2109 Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition, chapter 37,40. Hypothalamic pituitary-gonadal (HPG) axis Hypothalamus produces -> GnRH-> stimulates anterior pituitary gland-> release gonadotropin hormones (LH & FSH) -> gonads (testis releases testosterone in males/ovary release estrogen in females) -> Secondary sex characteristics & spermatogenesis in males/folliculogenesis for females. HPG axis hormone agonists and antagonist drugs in this lecture GnRH analog – Leuprolide, goserelin, histrelin. GnRH antagonist – Degarelix, Ganirelix, cetrorelix Gonadotropin agonist – Menotropin - Mixed LH & FSH – Follitropin – FSH – Lutropin –LH Testosterone agonists – Methyltestosterone Testosterone antagonists – Spironolactone, Finasteride, Abiratone, Flutamide, Ketoconazole SERMs – Raloxifene, clomiphene, tamoxifen. Aromatase inhibitors – Exemestane, anastrazole, letrozole Estrogen agonists – Ethinyl estradiol Antiprogestins – Mifepristone, ulipristal Progestins – Levonorgestrel, medroxyprogesterone, etonogestrel, norethindrone, megestrol. General Uses of HPG axis drugs Inappropriate growth of hormonedependent tissues – Benign Prostatic Hyperplasia – Cancers – Endometriosis – estrogen drives growth of endometrium – Leiomyomas (also estrogen dependent) – Puberty suppression for precocious puberty and gender dysphoria Disruption of HPG axis – Polycystic ovarian syndrome – Prolactinomas Hormone replacement – Menopause (menopausal symptoms) – Prevention of osteoporosis post menopause – Low testosterone – Hypogonadism Control of ovulation – Ovulation stimulation (infertility treatment) – Contraception Gender-affirming hormone therapy GnRH agonist/antagonist GnRH (gonadotropin-releasing hormone) – When released or administered in a pulsatile fashion GnRH INCREASES LH and FSH. – When provided continuously as a drug, GnRH DECREASES LH and FSH (after a few days-weeks of initial “flare” or increase in release) FSH and LH increase production of estrogen and testosterone – Testosterone produces negative feedback on its own production – Estrogen can produce either negative or positive feedback on its own production. – Progesterone produces negative feedback. Golan D, ed (2012) Principles of Pharmacology p. 473 HPG axis GnRH analogs (agonists) GnRH analogs: leuprolide, goserelin, histrelin. – Initial Flare-Up (short-acting GnRH agonist) – a temporary increase in FSH and LH. – Sustained Release formulations (GnRH antagonist) – Inhibiting the release of GnRH from the hypothalamus suppresses the production of LH and FSH and leads to a decrease in the production of testosterone in males and estrogen in females. – Used for prostate carcinoma, advanced breast cancer, endometriosis, thinning of endometrium prior to ablation or surgical excision of leiomyoma, beginning puberty at an abnormally early age (temporarily suppressing the HPG axis), delay of puberty in gender dysphoric children. ADE: – Hypogonadism, hot flashes, erectile dysfunction, decreased libido, osteoporosis (long-term exposure). GnRH antagonists GnRH long-acting analogs first cause testosterone and/or estrogen to rise No start-up flare. Degarelix– prostate cancer Ganirelix, cetrorelix for ovulation induction to control timing for IVF (stop follicular rupture for harvest), off-label for endometriosis, uterine fibroids, menorrhagia, gynecomastia ADE: Hot flashes, liver toxicity. Eckstein, Niels & Haas, Bodo. (2014). Clinical pharmacology and regulatory consequences of GnRH analogues in prostate cancer. European Journal of Clinical Pharmacology. 70. 10.1007/s00228-014-1682-1. Glycopeptide hormones: LH FSH hCG The gonadotropins (and thyroid stimulating hormone) are glycopeptide hormones – Heterodimers that contain identical α subunits and β subunits that confer biological specificity – Gonadotropins Synthesized by gonadotropes in the anterior pituitary – luteinizing hormone (LH) – follicle stimulating hormone (FSH) Synthesized by syncytiotrophoblast of placenta – human chorionic gonadotropin (hCG) » Exogenous hCG is a LH receptor agonist – it can be used in infertility treatments – TSH or thyroid-stimulating hormone Gonadotropins - LH and FSH agonists LH and FSH agonists as part of ovulation induction LH and FSH agonists are used in ovulation induction: Stimulation of Follicle Development: endogenous LH and FSH, stimulating the growth and development of ovarian follicles. Controlled Ovarian Stimulation: increasing the chances of successful ovulation and pregnancy Triggering Ovulation: ovulation is triggered using human chorionic gonadotropin (hCG) or a GnRH agonist LH and FSH agonists use in vitro fertilization (IVF) or intrauterine insemination (IUI). LH and FSH agonists as part of ovulation induction Human chorionic gonadotropin (hCG) is an LH receptor agonist; Human menopausal gonadotropins (hMG) (Menotropin) –purified from the urine of menopausal women (high FSH and high LH) Follitropin – FSH from urine of menopausal women Lutropin (hCG) –recombinant LH The goal is complete control of the ovulatory cycle to harvest multiple oocytes GnRH agonist and antagonist suppress endogenous cycle, hMG stimulates follicular development, hCG or FSH stimulate ovulation Menotropin Uses fertility treatments Ovarian Stimulation – stimulate the ovaries to produce multiple follicles Hormone Replacement Therapy – stimulate the growth and development of ovarian follicles Regulating Hormone Levels ADE: ovarian hyperstimulation syndrome Ovarian Hyperstimulation syndrome Stimulation of ovaries for infertility treatment may cause ovarian hyperstimulation syndrome (OHSS). Excessive stimulation of the ovaries -> multiple ovarian follicles -> large amounts of ovarian hormones. Bloating, weight gain Ascites Dyspnea (pleural effusion), oligura/anuria Thromboembolism, sepsis, death ANDROGENS AND ANTIANDROGENS Clinical use of testosterone agonists and antagonists in HPG axis Agonists – – – – Male hypogonadism Low testosterone levels Anabolism Female-to-male gender affirmation Antagonists – Prostate cancer – 5-alpha reductase inhibitors BPH Male pattern baldness – Virilization in females/PCOS (polycystic ovarian syndrome = excess testosterone, insulin resistance) (spironolactone!) – Male to female gender afirmation Testosterone agonists Effects of testosterone Development of Primary and Secondary Sexual Characteristics Mood and Cognitive Function Libido (sex drive) and erectile function Integument – Sebum (acne), male hair pattern (beard, body hair, male pattern baldness), increased hematopoiesis Metabolism – fat distribution, insulin sensitivity, and glucose metabolism MSK – Anabolic, increased bone mineral density Regulation of Reproductive Function – Sperm production, male genitalia, prostate hyperplasia Excess testosterone decreases sperm production – why?? Adverse Effects of testosterone replacement Acne and oily skin Erythrocytosis Prostate cancer Impaired fertility Cholestatic jaundice, hepatic peliosis Roid rage, aggression Dependence Transdermal absorption of gel through physical contact Available testosterone Treat hypogonadism and promote the development of 2nd sex characteristics. Oral Buccal tablets Methyltestosterone – Anabolic effects – High risk of liver toxicity Injectable Enanthate (IM)  Cypionate (IM)  Undecanoate (IM)  Transdermal Scrotal patch (matrix) Nongenital transdermal Gel Pellets NOTE WELL: nongenital transdermals are applied over areas on the torso – large surface area increases absorption Close contact with others may lead to unintended exposure when gel form is used Testosterone Antagonists Antiandrogens Use: Benign and malignant prostate disease Precocious puberty Hair loss Hirsutism inhibition of testosterone synthesis Inhibition of DHT inhibition of androgen binding at its receptor Antiandrogens Adverse effects of anti-androgens Androgen deprivation – Loss of libido, impotence – Gynecomastia, mastodynia – Vasomotor flush (hot flash), fatigue, anemia, insulin resistance – Osteoporosis – Decreased muscle mass Antialdosterone effects of spironolactone – Hyperkalemia – Polyuria, orthostatic hypotension ESTROGEN AGONISTS AND ANTAGONISTS Effects of estrogen Development of secondary female sex characteristics – Growth of axillary/pubic hair – Breast development – Softening of skin – Fat accumulation in hips, thighs, buttocks – Reproductive tract development Feedback inhibition of GnRH release (at low levels) Positive feedback to increase LH/FSH midcycle (high levels) Endometrial proliferation Other Effects – Decreased LDL, increased HDL, increased TG – Increased leptin production – Hepatic: Increased thyroxinebinding globulin, increased corticosteroid-binding globulin – Hepatic: Prothrombotic – Decreased bile acid secretion and increased cholesterol secretion risk of gallstone and cholestasis, ↓risk of colon cancer – – – – Hepatic vascular changes Induction of osteoclast apoptosis Nausea Capillary leak = edema, compensatory Na+ (and H2O) retention; Clinical uses of estrogen agonists and antagonists Agonists – Female hypogonadism – Hormone replacement therapy (HRT) – Contraception component – Dysmenorrhea – Uterine Bleeding – Acne – Palliative care in prostate cancer – Gender affirmation transgender females Antagonists; partial agonists (aka SERMS) – – – – – Breast Cancer Infertility Ovarian cancer Prevention of osteoporosis Role in gender affirmation not well defined SERM = selective estrogen receptor modifier Adverse Effects of Pharmacologic Estrogen Nausea Gallstones, cholestasis Hepatotoxicity (cholestatic most common) GI Thrombus formation (MI, stroke, DVT, etc) Increased TG Na+ retention (think about risk to COPD, CHF) Cardiovasc Repro/GU CNS Breast tenderness, breast cancer Proliferation of endometrium: heavy menses, endometrial cancer Teratogenic (category X in pregnancy) Migraine Seizures (catamenial seizures) Boxed warnings estrogens should NOT be used to prevent CHD estrogens may increase risk of dementia Estrogen replacement without progestin replacement may increase risk of endometrial CA in women with intact uterus Hepatic Cardiovascular Neoplastic Contraindications to estrogen replacement therapy Hypersensitivity to any component of the product Undiagnosed vaginal bleeding Breast Cancer or endometrial cancer* Estrogen-dependent tumor Untreated hypertension Hx or current venous thrombus, recent (within 1 year) arterial thrombosis (MI, stroke) Hepatic dysfunction (consider PV and transdermal) Hypertriglyceridemia Porphyria cutanea tarda *stage I successfully treated endometrial cancer is not an absolute contraindication Estrogen Agonist Estrogen Agonist Ethinyl estradiol, DES, mestranol Binds estrogen receptors Clinical use: Hypogonadism or ovarian failure, menstrual abnormalities (combined OCPs), hormone replacement therapy in postmenopausal females. Adverse effects: Risk of endometrial cancer (when given without progesterone), bleeding in postmenopausal patients, clear cell adenocarcinoma, and thrombi. Contraindications—ER ⊕ breast cancer, history of DVTs, tobacco use in females > 35 years old. Ethinyl estradiol Ethinyl estradiol is commonly combined with progestins. Suppressing the release of gonadotropins (LH and FSH) from the pituitary gland, thereby inhibiting ovulation (the release of an egg from the ovary). Thickens cervical mucus (difficult for sperm to penetrate the cervix and reach the egg) Alters the endometrium to prevent implantation of a fertilized egg. Regulation of menstrual cycles Reduction of menstrual-related symptoms. ADE: nausea, breast tenderness, headache, breakthrough bleeding, blood clots, stroke, heart attack, and certain types of cancer (such as breast cancer). Antagonist of Estrogen SERM (selective estrogen receptor modulator) Selective estrogen receptor modulators (SERMs) are a class of medications that interact with estrogen receptors in various tissues throughout the body. Can act as either agonists (mimicking the effects of estrogen) or antagonists (blocking the effects of estrogen) depending on the specific tissue. SERMs act as estrogen receptor antagonists, used in the treatment and prevention of breast cancer. In bone tissue, SERMs act as estrogen receptor agonists. SERM: Raloxifene Antagonist at breast, uterus, bone, agonist in liver. Causes hot flashes, ↑ risk DVT (tobacco smoking) ↓ risk breast CA in high-risk women (but not used to TREAT breast CA), no risk endometrial neoplasia Former category X in pregnancy. Used primarily to treat osteoporosis. SERM: Clomiphene Antagonist at estrogen receptors in the hypothalamus. Prevents normal feedback inhibition and release of LH and FSH from the pituitary, which stimulates ovulation. Used to treat infertility due to anovulation ADE: Thickening of cervical mucus Thinned endometrium Multiparity Hot flashes, mood swings SERM: Tamoxifen Antagonist at the breast, a partial agonist at the uterus, bone. Hot flashes, thromboembolic events (smokers) Used to treat and prevent recurrence of ER/PR ⊕ breast cancer prevent gynecomastia in patients undergoing prostate cancer therapy. Aromatase Inhibitors Inhibit peripheral conversion of androgens to estrogen. ER ⊕ breast cancer in postmenopausal women – Anastrazole, letrozole Competitive inhibitors of aromatase – Exemestane Androstenedione analog = irreversible steroidal inhibitor of aromatase – No cross-resistance between agents with different mechanisms – Adverse effects Fatigue Arthralgia Increased risk of fracture Less vaginal bleeding than SERM Testosterone levels may increase No risk of uterine/endometrial cancer or venous thromboembolism, BUT INCREASED RISK OF BONE LOSS Comparison Drug(s) Class Effects FYI use Anastrazole letrozole Aromatase inhibitors Hot flash, headache Bone loss No risk DVT or endometrial cancer; may ↑ testosterone Vaginal atrophy Postmenopausal women with ER+ breast ca; off label RR for breast Ca post menopause, endometrial, uterine, ovarian Ca Clomiphene SERM Hot flash, headache not used continuously Infertility Exemestane Irreversible aromatase inhibitor Hot flash, headache Bone loss No risk DVT or endometrial Ca; Vaginal atrophy may ↑testosterone Postmenopausal ER+ breast cancer treatment; off-label risk reduction (RR) post menopause Raloxifene SERM Hot flash, headache, edema DVT risk, NO risk bone loss or endometrial cancer Post-menopause Prevent/tx osteoporosis, RR breast cancer Tamoxifen SERM Hot flash, headache No risk bone loss; risk endomet cancer; risk DVT Premenopausal ER+ adjuvant Ductal Ca in situ RR, RR preand post-menopause, others Progesterone agonists and antagonists Progesterone Progesterone is a hormone that plays a crucial role in the female reproductive system and pregnancy. Menstrual Cycle Regulation: promotes the growth and thickening of the uterine lining (endometrium) to prepare it for the implantation of a fertilized egg. Pregnancy Support Effects on Breast Tissue - lactation during pregnancy and breastfeeding Regulation of Ovulation:preventing multiple ovulations in a single cycle Treatment of Hormonal Disorders: irregular menstrual cycles, infertility, premenstrual syndrome (PMS), and menopausal symptoms Clinical use of progesterone agonists and antagonists in HPG axis Agonists – Contraception – HRT (prevention of uterine cancer in women with uterus) – 17-OH progesterone to support pregnancy at high risk of loss (not PO) Partial agonists – Ulipristal – emergency contraceptive Antagonists: mifepristone – Abortion – Investigational in certain malignancies – Antiglucocorticoid ADVERSE EFFECTS OF PROGESTOGENS PMS-like symptoms ↓HDL ↑LDL Sodium and water retention, hypertension Glucose intolerance Breakthrough bleeding Androgenic (depending on individual synthetic drug) – Hirsutism – Weight gain – Acne Former category X in pregnancy (synthetic progestins ONLY; 17α hydroxyprogesterone is sometimes used to maintain pregnancy) Antiprogestins Mifepristone, ulipristal. Competitive inhibitors of progestins at progesterone receptors. Preventing implantation of a fertilized egg in the uterine lining – Termination of pregnancy (mifepristone with misoprostol); – emergency contraception (ulipristal). ADE: nausea, vomiting, abdominal pain, headache, and menstrual irregularities. Progesterone antagonists Levonorgestrel, medroxyprogesterone, etonogestrel, norethindrone, megestrol. Bind progesterone receptors, decrease growth and increase vascularization of the endometrium, and thicken cervical mucus. Contraception (forms include pill, intrauterine device, implant, depot injection), endometrial cancer, abnormal uterine bleeding. Treatment of Menstrual Disorders Endometrial Disorders Breast Cancer Treatment and Prevention Acne, hirsutism, endometrial hyperplasia, and female infertility. Transgender hormone therapy for transgender men (assigned female at birth) to induce amenorrhea and suppress ovulation