Estrogen and Progesterone Receptors Overview

Estrogen Receptors

• Estrogen enters the cell and binds to estrogen receptors (ER)
• ER dissociates from heat shock proteins and forms homodimers or heterodimers
• The ER dimer binds to estrogen response elements (EREs) on target genes
• This leads to the recruitment of co-activators, facilitating gene transcription

G-Protein Coupled Estrogen Receptors

• In addition to ERs, estrogen can also bind to G-protein coupled receptors (GPCRs)
• For example, GPER (G protein-coupled estrogen receptor) facilitates faster, non-genomic, estrogenic activity

Progesterone Receptors

• There are two progesterone receptors (PR), both derived from the same gene: PR-A and PR-B
• Both have identical ligand-binding domains, but PR-A is missing the first 165 N-terminal amino acids found in PR-B
• PR-B stimulates progesterone activity by recruitment of co-activators
• PR-A inhibits the actions of PR-B by recruitment of co-repressors and can also inhibit transcriptional activity of other steroid receptors

Progesterone Receptor Mechanism

• 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 the dissociation of heat shock proteins
• Receptor dimers form and bind to progesterone response elements (PREs) on target genes
• These dimers can be homodimers (PR-A/PR-A or PR-B/PR-B) or heterodimers (PR-A/PR-B)

Physiological Effects of Estrogen

• Causes endometrial proliferation
• Increases the amount and water content in cervical mucus
• Increases differentiation of osteoblasts and reduces the activity of osteoclasts in bone
• Changes in lipid levels
• Changes blood clotting factor levels

Physiological Effects of Progesterone

• Causes endometrial differentiation and 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 the onset of menstruation

Other Ovarian Hormones

• Androgens - small amounts of testosterone and other androgens are produced by the ovaries
• Inhibin - an alpha-beta dimer peptide that inhibits FSH production and release
• Activin - a beta-beta dimer version that promotes FSH release
• Relaxin - found throughout the female reproductive system, released in response to LH, has multiple effects

Agonists, Antagonists, Both, Neither

Estrogen/Progesterone Receptor Agonists

• Endogenous and exogenous estrogens can bind and activate estrogen receptors
• Endogenous progesterone and exogenous progestins can bind and activate progesterone receptors

Progesterone Receptor Antagonists

• Progesterone receptor antagonists (AKA antiprogestins) bind and block progesterone receptors
• These drugs are used to terminate pregnancy

Estrogen Receptor Antagonists

• Estrogen receptor antagonists bind to estrogen receptors and promote dimerization and binding to DNA
• These drugs lead to different conformational changes that recruit co-repressors, inhibiting gene transcription

ER Agonists vs. Antagonists

• ER agonists recruit co-activators - proteins with histone acetyltransferase activity that relax chromatin structure, allowing transcription machinery to initiate transcription
• ER antagonists recruit co-repressors - proteins with histone deacetylase activity that tighten chromatin structure, preventing transcription machinery from binding and initiating transcription

Selective Estrogen Response Modulators (SERMs)

• SERMs are ligands at estrogen receptors
• They alter the conformation of ERα and/or ERβ
• This conformational change is distinct from both agonists and antagonists
• May lead to interaction with different co-activators and/or co-repressors in a cell-specific and promoter-specific manner

SERM Activity

• These are usually partially estrogenic in some tissues and either have no activity or anti-estrogenic activity in other tissues

Indirect-Acting Agents

• Aromatase inhibitors block the production of estrogens
• These drugs are used for the treatment of breast cancer
• Examples include: exemestane, anastrozole, and letrozole

Compounds with Estrogenic Activity

• Plant-derived compounds (phytoestrogens)
• Some contain progestins with less androgenic activity or that antagonizes the mineralocorticoid receptor

Combined Oral Contraceptives (COCs)

• Administered for the first 21 days of a 28-day cycle
• Extended cycle contraceptives (up to 84 days) are also used
• Available in monophasic, biphasic, or triphasic formulations
• Designed to reduce hormone exposure while maximizing anti-ovulation effects and minimizing breakthrough bleeding

COC Mechanisms of Action

• Primary Mechanisms:
• Estrogen inhibits FSH secretion to inhibit follicular development
• Progestins inhibit LH secretion to prevent ovulation.
• Secondary Mechanisms:
• Progestins alter cervical mucus to impede sperm passage
• Estrogens and progestins alter the endometrium to decrease implantation of fertilized eggs

COC Effects

• Cervical Hypertrophy
• Breast enlargement
• Increased hormone-binding protein levels
• Increase in plasma renin activity
• Increased pigmentation of the skin
• Decreased acne
• Decreased hair growth
• Increases in clotting and other factors
• Reduced bile flow and secretion
• Increased triglyceride levels
• Increased basal insulin levels, reduced GI carbohydrate absorption
• Increased cardiac output, blood pressure, and heart rate

Progestin-Only Contraceptives

• Inhibit progesterone-dependent aspects of ovulation
• Examples/dosage forms include: minipill, depot medroxyprogesterone, subdermal implants, intrauterine device
• These contraceptives localize progestin levels.

Fertility

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 enhance follicular maturation

Clomiphene Citrate Effects

• Increases ovulation but inhibits estrogen's action at the endometrium
• Can cause ovarian hyperstimulation syndrome and multifetal gestations
• ADRs include: ovarian cysts, hot flashes, headache, blurred vision

Gonadotropins

• Gonadotropins are used to induce ovulation
• Daily injections of FSH are given until 1-2 mature follicles have developed
• This is followed by an injection of hCG to complete follicular maturation and induce ovulation

Drugs During Pregnancy

• Folic acid, antihistamines, antipsychotics, promotility agents, 5-HT3 antagonists, cannabinoids

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
• Many foods are fortified with folic acid (e.g., pasta, bread)

Folic Acid Deficiencies

• Chronic malnutrition
• Chronic alcohol use
• Vitamin C deficiency
• Chronic liver disease
• Malabsorption due to any cause

Folic Acid Metabolism

• Average diet contains 500-700 mcg, 50-200 mcg absorbed
• Free folic acid and monoglutamate folic acid are completely absorbed in the proximal jejunum
• 5-20 mg of folates generally stored in the liver, about 1-2 months worth

Folic Acid Function

• Required for purine biosynthesis, thymidine biosynthesis, DNA methylation, and other metabolic reactions
• Acts as a cofactor for 1-carbon transfer reactions

Nausea and Vomiting in Pregnancy

Antihistamines

• Doxylamine, dimenhydrinate, diphenhydramine
• Pyridoxine (vitamin B6) may also have anti-nausea effects
• Promethazine is a phenothiazine antihistamine used to treat morning sickness

Antipsychotics

• Mechanism of action is D2 receptor antagonism at the CTZ
• Some possess antihistaminic and anticholinergic activities

Promotility Agents

• Metoclopramide
• Domperidone
• These drugs stimulate upper GI motility without affecting the lower GI

5-HT3 Antagonists

• Ondansetron
• Granisetron
• These agents block serotonin receptors to reduce nausea and vomiting

Cannabinoids

• THC (tetrahydrocannabinol)
• Several studies have indicated safety and efficacy for use in nausea and vomiting in pregnancy

Prostaglandins

• Misoprostol
• Actions are very similar to PGE2
• Used for inducing labor, medical abortion, or as a treatment post-miscarriage

Oxytocin

• Naturally produced to increase uterine contractions during labor
• Exogenous oxytocin also promotes uterine contraction
• Adverse effects include uterine hyper-contraction and water conservation

Methotrexate

• Used to treat ectopic pregnancy, inhibiting rapidly dividing tissue
• Inhibits dihydrofolate reductase, resulting in nucleic acid deficiencies

Tocolytics

• Tocolytics delay or prevent labor
• They typically cause uterine smooth muscle relaxation or prevent pro-contraction signaling.