Female Hormone and Receptor Pharmacology PDF

Female Hormone and Receptor Pharmacology M. Beazely Last Updated: Aug 7 2023 1 Outline/Learning Objectives ▪ Understand the actions of endogenous female sex hormones and their receptors ▪ Describe the mechanism of action of oral contraceptives ▪ Describe the mechanis...

Female Hormone and Receptor Pharmacology M. Beazely Last Updated: Aug 7 2023 1 Outline/Learning Objectives ▪ Understand the actions of endogenous female sex hormones and their receptors ▪ Describe the mechanism of action of oral contraceptives ▪ Describe the mechanism of action of agents used in fertility treatment ▪ Review vitamins and drugs used in pregnancy including treatments for nausea 2 Estrogen and Progesterone 3 Estrogen and progesterone Cholesterol is precursor hormone for steroid hormones Naturally occurring estrogens include: Estradiol (most potent) Estrone Estriol 4 Estrogen and progesterone Estrogens are formed from androstenedione or testosterone through aromatization of the A ring by aromatase enzymes Pre-menopause,the main source of estrogen is from ovary (estradiol) Post-menopause, the main source of estrogen is from adipose tissue (estrone) 5 Estrogen and progesterone Progesterone is synthesized in the ovaries, testes, adrenal, and placenta from cholesterol Also synthesized from the corpeus luteum in the ovary in the second half of the menstrual cycle 6 Estrogen and progesterone 7 Estrogen and progesterone “VI DE O #1” The ovarian production of estrogen and progesterone is controlled by a classic neuroendocrine cascade: Hypothalamus Pituitary Ovaries 8 Estrogen and progesterone “VI DE O #1” to Neurons in the hypothalamus fire at regular intervals, leading bursts of gonadotrapin releasing hormone (GnRH) GnRH causes pituitary release of gonadotropins (lutenizing hormone and follicle-stimulating hormone, LH and FSH) The frequency of GnRH pulses controls relative amount of synthesis of LH and FSH changes over the phases of the menstrual cycle LH and FSH affect maturation of follicles and ovarian production of estrogen/progesterone Like other endocrine systems, estrogen and progesterone provide negative feedback to the pituitary and hypothalamus 9 Estrogen and progesterone “VI DE O #1” 10 Menstrual Cycle “VI DE O #1” Follicular phase At the beginning of the cycle, FSH promotes follicular enlargement Day 5/6, one (sometimes 2+) follicle begins to develop rapidly and starts to produce estrogen Estrogen inhibits further FSH release (so the other follicles regress) Estrogen promotes endometrial growth 11 Menstrual Cycle “VI DE O #1” Ovulation Estrogen levels peak mid-cycle and triggers a mid-cycle LH surge LH surge stimulates ovulation (follicular rupture, releasing oocyte) 12 Menstrual Cycle “VI DE O #1” Luteal phase Ruptured follicle become corpus luteum, which synthesizes androgens, estrogen, and progesterone If fertilization/implantation does not occur, corpus luteum degenerates, and progesterone production drops off The decrease in progesterone leads to endometrial shedding (menstruation) 13 Menstrual Cycle “VI DE O #1” 14 Estrogen Receptors Estrogen receptors are nuclear receptors There are 2 “classic” estrogen receptors: ERα and ERβ 15 Estrogen Receptors ER α is most abundant in: the female reproductive tract mammary gland hypothalamus endothelial cells vascular smooth muscle ER β is present in: ovaries (and in lower levels in lung, brain, bones, vasculature) Each receptor subtype has different effects on transcription of several target genes 16 Estrogen Receptors An estrogen receptor agonist (e.g. estradiol) enters the cell and binds to ER ER dissociates from heat shock proteins and forms a homodimer (ERα/ERα or ERβ/ERβ) or a heterodimer (ERα/ERβ) The ER dimer binds to estrogen response elements (EREs) on target genes This leads to recruitment of co-activators, facilitating gene transcription 17 Estrogen Receptors 18 GPCRs? In addition to the “classic” estrogen receptors, estrogen can also bind GPCRs E.g. GPER (G protein-coupled estrogen receptor) These receptors facilitate faster, non- genomic, estrogenic activity 19 Progesterone Receptors There are 2 progesterone receptors, both derived from the same gene PR-A and PR-B Both have identical ligand-binding domain PR-A is missing the first 165 N-terminal amino acids found in PR-B PR-B – stimulation of progesterone activity by recruitment of co- activators PR-A – inhibits actions of PR-B by recruitment of co-repressors; can also inhibit transcriptional activity of other steroid receptors 20 Progesterone Receptors PR is present in the nucleus in an inactive state, bound to heat shock proteins Progesterone receptor agonists enter the nucleus and bind to PR, leading to dissociation of heat shock proteins Receptor dimers form and bind to protesterone response elements (PREs) on target genes Homodimers (PR-A/PR-A or PR-B/PR-B) or heterodimers (PR-A/PR-B) 21 Physiological effects: Estrogen: Causes endometrial proliferation Increases amount and water content in cervical mucous Increases differentiation of osteoblasts, reduces activity of osteoclasts in bone Changes in lipid levels Changes blood clotting factor levels 22 Physiological effects: Progesterone: Causes endometrial differentiation, inhibition of proliferation caused by estrogen Opposes the effects of estrogen on cervical mucus Involved in the “maintenance” of pregnancy Decline in progesterone at the end of the menstrual cycle results in onset of menstruation 23 Other ovarian hormones Androgens Small amounts of testosterone and other androgens are produced Inhibin Alpha-Beta dimer peptide that inhibits FSH production and release Also has local effects in the ovaries Activin Beta-Beta dimer version that promotes FSH release Relaxin Found throughout the female reproductive system, released in response to LH, has multiple effects 24  “VI DE O #2 ” Agonists, Antagonists, Both, Neither 25 Estrogen/Progesterone Receptor Agonists “VI DE #2 O Endogenous estrogens and exogenous” estrogens can bind and activate estrogen receptors Endogenous progesterone and exogenous progestins can bind and activate progesterone receptors 26 Progesterone Receptor Antagonists “VI DE O #2 Progesterone receptor antagonists ” (AKA antiprogestins) bind and block progesterone receptors E.g. mifepristone (AKA RU-486) is used to terminate pregnancy E.g. ulipristal acetate is a partial agonist 27 Estrogen Receptor Antagonists “VI DE O Estrogen receptor antagonists bind to estrogen receptors#and2” promote dimerization and binding to DNA (like estrogen receptor agonists) However, this leads to a different conformational change Co-repressors are recruited (instead of co-activators) Gene transcription is inhibited Examples: Clomiphene Fulvestrant 28  “ Estrogen Receptor Agonists vs. Antagonists VID EO #2 vs. How can ligand binding to estrogen receptors lead to activation inhibition? ” ER receptor agonists (relatively) recruit co-activators: Proteins with histone acetyltransferase activity are recruited Histone acetylation relaxes chromatin structure, allowing transcription machinery to initiate transcription ER receptor antagonists (relatively) recruit co-repressors: Proteins with histone deacetylase activity are recruited Histone deacetylation leads to tight chromatin structure, such that transcription machinery cannot bind and initiate transcription 29 Selective Estrogen Response Modulators “VI DE O #2 Selective estrogen response modulators ” (SERMs) are ligands at estrogen receptors Alter the conformation of ERα and/or ERβ Conformational change is distinct from that caused by either agonists or antagonists May lead to interaction with different co- activators and/or co-repressors in a cell- specific and promoter-specific manner 30 Selective Estrogen Response Modulators “VI DE O #2 ” 31 Selective Estrogen Response Modulators “VI DE O #2 ” 32 Selective Estrogen Response Modulators “VI DE O # SERMs are usually partially estrogenic in some2” tissues, and either have no activity or anti- estrogenic activity in other tissues Examples include: tamoxifen (used for breast cancer) raloxifene (Evista; used for osteoporosis) has anti-estrogenic activity in breast tissue (reduce proliferation), estrogenic activity in bone (anti-resorptive activity) 33 Indirect-Acting Agents Aromatase inhibitors block production of estrogens, used for the treatment of breast cancer Examples: Exemestane (Aromasin) – irreversible inhibitor Anastrozole (Arimidex) and Letrozole (Femara) – reversible inhibitors Do not have positive effect on bone (like tamoxifen) Often used as an add-on/second line to tamoxifen treatment 34 Compounds with Estrogenic Activity Plant-derived compounds (phytoestrogens): Isoflavones (e.g. found in soy, red clover), coumestan derivatives (e.g. found in alfalfa), lignans (found in flax) Soy isoflavones are used to manage menopausal symptoms Major isoflavones include genistein and daidzein, structurally related to estrogen, genistein is also a non- selective tyrosine kinase inhibitor Synthetic agents: e.g. bisphenol A 35  “VI DE O #3 ” Contraception 36 Hormonal Contraceptives “VI DE O #3 Estrogen/progestin combinations ” Progestin-only formulations Oral, vaginal, IM, transdermal, implantation formulations 37  ! ! ! Hormonal Contraceptives ! “VI DE ! ! Contraceptive!Pill!Activity!! Adapted!from:!Dickey!RP.Managing&Contraceptive&Pill&Patients!10th!ed! O #3 ” ! ! Estrogenic! Progestational! Androgenic! ! Activity:!μg! Activity:!mg! !Activity:!mg! Drug! EE!equivalents! Norithindrone! Methyltestosteron per!day! equivalents!per! e! day! per!28!days! Fixed!Dose! ! ! ! Minestrin!1/20! 13! 1.2! 0.53! Loestrin!1.5/30! 14! 1.7! 0.8! Demulen!30! 16! 2.8! 0.3! Alesse!|!Aviane! 17! 0.5! 0.31! Yaz! 20! 3! 0! MinMOvral!|!Portia!|!Seasonale!|! 25! 0.8! 0.46! Seasonique! Apri!|!Marvelon!|!OrthoMCept! 30! 1.5! 0.17! Yasmin! 30! 3! 0! Cyclen! 35! 0.3! 0.18! Brevicon!1/35!|!Ortho!1/35!|!Select!1/35! 38! 1! 0.34! Brevicon!0.5/35!|!Ortho!0.5/35! 42! 0.5! 0.17! Phasic! ! ! ! TriMCyclen!LO! 25! 0.3! 0.15! Linessa! 25! 1.3! 0.14! Triquilar! 28! 0.5! 0.29! TriMCyclen! 35! 0.3! 0.15! Synphasic! 40! 0.8! 0.25! Ortho!7/7/7! 48! 0.8! 0.25! Progestin!Only! ! ! ! 38 Micronor! 1! 0.12! 0.13! Combined oral contraceptives “VI DE O #3 Typically consists of: ” an estrogen (e.g. ethinyl estradiol) a progestin (usually a 17α-alkyl nortestosterone derivative) Some contain progestins with less androgenic activity (e.g. desogestrel) or that antagonizes the mineralocorticoid receptor (e.g. drospirenone) 39 Combined oral contraceptives “VI DE O # 3” Administered for the first 21 days of a 28-day cycle Extended cycle contraceptives also used (up to 84 days) Available in monophasic, biphasic, or triphasic formulations Designed to reduce the exposure to hormones, but to retain enough activity to maximize anti- ovulation effects and reduce breakthrough bleeding 40 Combined oral contraceptives “VI DE O # Primary mechanisms of action: 3” Estrogen inhibits FSH secretion via negative feedback early in the cycle to inhibit follicular development Progestins inhibit LH secretion, including the LH surge that stimulates ovulation Secondary mechanisms of action: Progestins alter cervical mucous and impede sperm passage Estrogens and progestins alter the endometrium and decrease the likelihood of implantation of fertilized eggs 41 Combined oral contraceptives Effects of oral contraceptives include: Cervical hypertrophy Breast enlargement Increased hormone-binding protein levels including corticosteroid-binding protein and thyroxine-binding globulin Increase in plasma renin activity Increased pigmentation of the skin Decreased acne Decreased hair growth Increases in clotting and other factors including VII, VIII, IX, X, and antithrombinIII Reduced bile flow and secretion Increased triglyceride levels Increased basal insulin levels, reduced GI carbohydrate absorption Increased cardiac output, blood pressure, heart rate 42 Progestin-only Contraceptives Inhibition of progesterone-dependent aspects of ovulation: Changes in cervical mucous to inhibit fertilization Changes in endometrial lining to inhibit implantation Examples/dosage forms include: Minipill (oral) depot medroxyprogesterone (IM) subdermal implants intrauterine device (releases levonorgesterel, localizes the progestin levels) 43 Fertility Clomiphene Citrate Gonadotropins 44 Clomiphene Citrate Estrogen receptor antagonist used to treat anovulation Inhibits the negative feedback of estrogen at the hypothalamus and pituitary Results in an increase in FSH levels that enhances follicular maturation Typically used between day 2 and day 5 45 Clomiphene Citrate Clomiphene increases ovulation but inhibits estrogen’s action at the endometrium, which makes it non-optimal for fertilization and implantation Can cause ovarian hyperstimulation syndrome, multifetal gestations ADRs include: ovarian cysts hot flashes headache blurred vision 46 Gonadotropins Gonadotropins are used to induce ovulation Daily injections of FSH, given until 1-2 mature follicles have developed This is followed by injection of hCG to complete follicular maturation and induce ovulation Fertilization is then attempted (by intercourse or intrauterine insemination) 47 Gonadotropins 48 Drugs often used during Pregnancy Folic acid, antihistamines, antipsychotics, promotility agents, 5-HT3 antagonists, cannabinoids 49 Folic Acid AKA vitamin B9 Several forms of folate found in diet; supplementation is with folic acid Food sources include leafy vegetables, legumes, liver, yeast, sunflower seeds (all high in folate), most other fruits and vegetables contain some folate Many foods fortified with folic acid (e.g. pasta, bread) 50 Folic Acid Deficiencies may result from: Chronic malnutrition Chronic alcohol use Vitamin C deficiency Chronic liver disease Malabsorption due to any cause 51 Folic Acid Average diet contains 500-700 μg, 50-200 μg absorbed Free folic acid and monoglutamate folic acid are completely absorbed in the proximal jejunum Dietary folates are usually in the polyglutamate form, and all but one of the glutamates need to be removed by α-L-glutamyl transferase in the brush border of the epithelium 5-20 mg of folates generally stored in the liver, about 1-2 months worth 52 Folic Acid Folic acid is required for purine biosynthesis, thymidine biosynthesis, DNA methylation, and other metabolic reactions Folic acid acts as a cofactor for 1-carbon transfer reactions (for carbons 2 and 8 of the purine ring, 5-position of uracil/thymidine) In the purine reaction, folic acid is regenerated, however in the thymidine reaction it is not 53 Nausea and Vomiting in Pregnancy 54 Antihistamines Doxylamine is an H1 antagonist with anti-emetic effects in general and specifically against vestibular disturbance-induced nausea, others: dimenhydrinate, diphenhydramine A first-generation anti-histamine also causes sedation and may be used as a sleep-aid in pregnancy Pyridoxine, vitamin B6 may also have anti-nausea effects and is combined with doxylamine (Diclectin) Promethazine is a phenothiazine antihistamine used as an anti- emetic to treat morning sickness (and, in combination with metoclopramide, to treat nausea associated with opioid administration during labour) 55 Antipsychotics Mechanism of action is D2 receptor antagonism at the CTZ Some possess antihistaminic and anticholinergic activities Chlorpromazine was the first antipsychotic widely used Used to treat morning sickness and during labour to promote analgesia and amnesia Most studies have demonstrated safety and efficacy if used occasionally at low doses although adverse effects (e.g. extra- pyramidal syndrome) have been observed in newborns born to mothers using chronically Use during near-term may be problematic due to an increase risk of maternal hypotension 56 Promotility Agents E.g. metoclopramide, domperidone Mechanism of action: Dopamine D2 receptor blockade In the GI tract, activation of dopamine receptors inhibits cholinergic smooth muscle stimulation Blocking this effect is responsible for prokinetic mechanism This leads to enhanced gastric emptying, with no effect on intestinal motility These drugs also block dopamine D2 receptors centrally, in the chemoreceptor trigger zone/area postrema 57 Promotility Agents Adverse effects: Both metoclopramide and domperidone: Increased prolactin levels (galactorrhea, gynecomastia, impotence, menstrual disturbances) Metoclopramide only: Extrapyramidal effects (restlessness, dystonia, Parkinsonian symptoms), drowsniness, insomnia, anxiety, agitation, tardive dyskinesias Domperidone: Does not cross blood brain barrier, therefore rare neuropsychiatric and extrapyramidal side effects 58 5-HT3 Receptor Antagonists Mechanism of action: Primary mechanism is blockade of 5-HT3 receptors on vagal and spinal afferent nerves from the GI tract Secondary mechanism is blockade of central 5-HT3 receptors in the vomiting center and chemoreceptor trigger zone No effect on dopamine or muscarinic receptors or on gastric motility 59 Cannabinoids Cannabinoids have demonstrated efficacy to treat chemotherapy-induced nausea and vomiting ONLY There is no evidence for efficacy in treating other types of nausea and vomiting, including in pregnancy Smoking cannabis during pregnancy is clearly linked to lower birth weights (similar to smoking tobacco) Cannabinoid exposure in animal models results in adverse effects to offspring There is emerging evidence that cannabinoid exposure in utero is associated with adverse effects in human newborns 60 Emergency Contraception, Abortifacients, and Drugs that regulate uterine smooth muscle Levonorgestrel, Yuzpe Regimens, Mifepristone, Prostaglandins, Oxytocin, Methotrexate, Tocolytics 61 Emergency Contraception Levonorgestrel is progestin used in combination oral contraceptives, used in implant birth control, or used alone at high doses in emergency contraceptives Primary mechanisms of action are to prevent ovulation and to impede sperm by increasing cervical mucous viscosity Yuzpe Regimens include both progestins and estrogens, typically ethinyl estradiol and levonorgestrel In addition to the progestin effects, the estrogen may also interfere with implantation of a fertilized egg 62 Mifepristone AKA RU-486 Binds to and blocks progesterone (and glucocorticoid) receptors Causes thinning of the endometrium, cervical ripening and dilation Used in combination with PGE1 or misoprostol, which induces uterine smooth muscle contraction 63 Prostaglandins Misoprostol is a synthetic, PGE1-like prostaglandin PGE1, PGE2, PGF2alpha, and misoprostol all cause cervical ripening and dilation Misoprostol vs. PGE2: actions are very similar, misoprostol binds prostaglandin receptors EP2, EP3, and EP4, PGE2 binds those too, plus EP1 Prostaglandins have multiple uses including inducing labour, medical abortion, or as a treatment post-miscarriage 64 Oxytocin Oxytocin is naturally-produced (posterior pituitary) to increase uterine contractions during labour Exogenous oxytocin also promotes uterine contraction when administered parenterally Adverse effects include uterine hyper-contraction (too frequent, intense) and water conservation (antidiuretic) that can increase the risk of hyponatermia during labour 65 Methotrexate An ecotopic pregnancy is when the pregnancy occurs anywhere other than the uterus In addition to surgery, methotrexate may be used Analogous to its use in cancer or autoimmune disease, the primary mechanism of action of methotrexate is to inhibit rapidly dividing tissue Methotrexate disrupts folic acid production by inhibiting dihydrofolate reductase, resulting in nucleic acid deficiencies and a slowing of cell division In a typical pregnancy, methotrexate would be contraindicated as it would have similar effects on an embryo or fetus developing in the uterus 66 Tocolytics A tocolytic drug delays or prevents labour Several classes of drugs have tocolytic effects, they typically cause uterine smooth muscle relaxation or prevent pro-contraction signaling 67 Tocolytics Figure 44-7 Sites of action of tocolytic drugs in the uterine myometrium. The elevation of cellular Ca2 promotes contraction via the Ca2 /calmodulin-dependent activation of MLCK. Relaxation is promoted by the elevation of cyclic nucleotides (cAMP and cGMP) and their activation of protein kinases, which cause phosphorylation/inactivation of MLCK. Pharmacological manipulations to reduce myometrial contraction include the following: (1) inhibiting Ca2 entry (Ca2 channel blockers, Mg2SO4); (2) reducing mobilization of intracellular Ca2 by antagonizing GPCR-mediated activation of the Gq-PLC-IP3- Ca2 pathway (with antagonists of the FP and OXT receptors) or reducing production of the FP agonist, PGF2α (with COX inhibitors); (3) enhancing relaxation by elevating cellular cAMP (with β2 adrenergic agonists that activate Gs-AC) and cellular cGMP (with NO donors that stimulate sGC). Note that pharmacological activators of sGC (e.g., riociguat) are contraindicated in pregnancy (see Chapter 31). AC, adenylyl cyclase; COX, cyclooxygenase; FP, the PGF2 receptor; OXT, the oxytocin receptor; PLC, phospholipase C; sGC, soluble guanylyl cyclase. 68