ESTROGENS, PROGESTINES, DRUGS IN CONTRACEPTION AND ANTI-INFERTILITY DRUGS Flashcards
What is ESTROGEN?
What are the natural estrogens?
Which is the most potent natural?
Which is the least active?
It is a female sex hormone produced in males too where it is important for the normal physiology.
•Steroid hormone which can be natural or synthetic.
•Natural are estradiol, estrone and estriol.
•Estradiol is the most potent and is synthesised in the graffian follicles, the placenta, the corpus luteum, the testes by aromatization and also in other parts of the body.
Types of estrogens
- Natural
- Synthetic
The synthetic estrogens can be steroidal or non-steroidal.
•Steroidal include ethinylestradiol, mestranol, tibolone, estradiol valerate, estrone sulphate.
•The non-steroidal estrogens include diethylstilbesterol, hexestrol, dienestrol, benzestrol, methestrol, methallenestril, chlorotrianesene.
- Phytoestrogens are naturally occuring estrogen-like compounds found in plants
Phytoestrogens and their classes
•Estrogen-like compounds derived from plants and structurally similar to 17β-estradiol.
•Classes
-Isoflavones: genistein, daidzein, glycitein, formononetin, biochanin A. They are found in soybeans, red clover, other legumes
-stilbene: resveratrol. Found in grapes and peanuts
-Lignans: found in flaxseed, wheat flour, peanuts, fruits, berries, vegetables, tea, coffee. Example is matairesinol
-Coumestan: from nuts, broccoli, cabbage, spinach
Discuss the Regulation of estrogen secretion
•“clock” or hypothalamic GnRH pulse generator in the arcuate nucleus of the hypothalamus determine pulsatile release of FSH and LH.
•FSH and LH regulate growth and maturation of graffian follicles which secrete estrogen.
•Estrogen exerts a negative feedback on the pituitary.
•Inhibin and to a lesser extent activin and follistatin selectively inhibits FSH secretion
•Estradiol level rises above threshold at midcycle exerting a brief positive feedback on pituitary.
LH surge triggers ovulation.
Corpus luteum produce estrogen and progesterone.
Absence of pregnancy leads to waning of the corpus luteum with drop in estrogen levels.
Menstruation occurs and cycle recommences
What is are actions of Estrogen?
Reproductive organs:
•Growth and development of vagina, uterus and fallopian tubes.
•Appearance of axillary and pubic hair.
•Enlargement of breasts, proliferation of ducts and stroma.
•Pigmentation of the genital area and of the nipples and areola.
•Feminine body contours and behaviour.
Anabolic
•Pubertal growth spurt in both sexes, closure of the epiphyses of the long bones.
Metabolic:
•Inhibition of bone resorption.
•Slight Elevation of serum triglycerides and slight reduction in total serum cholesterol levels.
•Increase HDL and decrease LDL levels.
•Decreased bile acid secretion.
•Decrease FBS and insulin levels.
•Increase levels of SHBG (sex hormone binding globulin), TBG (thyroxine binding globulin) cortisol binding globulin.
•Small increase in coagulation factors II, VII, IX, X and XII.
•Decrease anticoagulation factors protein C, protein S, and antithrombin III.
•Others.
What is the Mechanism of action of estrogen?
•ER are nuclear receptors existing in two isoforms as Erα and Erβ.
•Both exist as inactive monomers.
•Binding of estrogen triggers dimerization of the receptors and the dimers bind to EREs in the promoter region of target genes.
•ER/DNA complex recruit co-activator and other proteins with initiation of transcription.
Pharmacokinetics of estrogen
Does it undergo enterohepatic circulation?
•Available as oral, transdermal, topical or parenteral preparations.
•Absorption is good but oral preparations are subject to first pass effect.
•Metabolism is in the liver and estradiol is converted by 17β-hydroxysteroid dehydrogenase to estrone.
•Estrone is converted to estriol which is eliminated in the urine.
•They undergo enterohepatic circulation.
•Ethinyl estradiol has a longer half life than estradiol.
•Mestranol is converted to ethinyl estradiol.
Pcokinetics
•Strong binding to SHBG and with less affinity to albumin in the plasma.
•Estradiol is Metabolized to estrone and estriol and their conjugated metabolites by the liver.
•Excretion in bile, breast milk (small quantities).
•Conjugates are subject to enterohepatic circulation.
Uses of estrogen
•HRT
•Contraception
•Dysmenorrhea
•Treatment of acne
•Delayed puberty in failure of ovarian development.
Side effects of estrogen
•Nausea.
•Irregular vaginal bleeding and increased risk of endometrial Ca in patients on HRT.
•Vagina and cervical Ca in female offsprings of women who used diethylstilbesterol in pregnancy.
•Early epiphyseal closure in children.
•Worsening of migraine.
•Increased incidence of gallstones, cholestasis and HT.
What are the Estrogen inhibitors and antagonists?
•SERMs
•Antiestrogens
SERMs
(Selective estrogen, receptor modulators)
Acts as an agonist in the absence of estrogen, acts as an antagonist in the presence of estrogen
•Have tissue selective actions being agonist in some tissues and antagonist in others.
•They are tamoxifen, raloxifene and toremifene, bazedoxifene, lasofoxifene, ormeloxifene, ospemifine.
Tamoxifen
•It is administered orally and has a long half life.
•It decreases total cholesterol, LDL and lipoprotein (a).
•Metabolised by CYP to a more potent metabolites, 4-hyroxytamoxifen and N-desmethyltamoxifen.
•Excreted in faeces.
•It is used for treatment of Ca breast and also for primary prevention of Ca breast in high risk women.
•Side effects include increased risk of endometrial Ca and of thromboembolic disease, hot flashes, cataract, nausea.
Raloxifene
Where does it act as an agonist and where does it act as an antagonist?
•It is an agonist in bone (antiresorptive effect) and CVS.
•Antagonist in breast and endometrium.
•It significantly reduces the risk of ER-positive breast cancer.
•It reduces total cholesterol and LDL
•Used for prevention and treatment of osteoporosis in postmenopausal women.
•Side effects include leg cramps, hot flashes, deep vein thrombosis, pulmonary embolism.
Antiestrogens and types and examples
Types:
1. Competitive ER blockers
2. Aromatase Inhibitors
Competitive ER blockers include:
*Clomiphene and fulvestrant.
Clomiphene and it’s side effects
*It exist in a trans and cis isomers.
*Binds to both types of ER.
*It has a weak agonist and strong antagonist action.
*Administration is oral and absorption is good.
*Half life is 5-7 days.
*Eliminated in feces and urine
*Used for ovulation induction.
*Side effects include ovarian hyperstimulation, multiple pregnancies, ovarian cysts, hot flashes, blurred vision, increased risk of ovarian Ca.
Fulvestrant
What is it used for and when can it be used?
•Administration i/m as monthly depot.
•It is a selective estrogen receptor downregulator.
•It accelerates the proteolytic degradation of Erα.
•Eliminated mainly in the feces.
•Used for treatment of breast cancer in women who become resistant to tamoxifen.
Aromatase inhibitors
Classification
Action
Main side effects
Use
Examples
Aromatase is an enzyme that converts testosterone to 17 B-estradiol.
Therefore Aromatase inhibitors will decrease estrogen synthesis
•Classified as steroidal (formestane, exemestane), and nonsteroidal
(aminoglutethime, fadrozole, rogletimide, anastrozole, letrozole, vorozole).
•A second classification is based on when the agents were made.
•Steroidal irreversibly inactivate aromatase.
•Non-steroidal reversibly interact with heme groups of CYPs.
•They are used for treatment of Ca breast.
•Main side effect is hot flashes.
Anastrozole and exemestane
•Triazole.
•Binds to the heme of CYP19.
•Reduces total body aromatization by 96-98%.
•Well absorbed orally.
•Metabolised in the liver to several inactive metabolites.
•Used in the treatment of HR positive breast cancer.
•Side effects include hot flashes, nausea, arthralgia( joint pain), myalgia (muscle pain)
Exemestane
Synthetic analogue of androstenedione.
Suicide substrate of aromatase.
It inhibits aromatization by about 98%.
Good oral absorption.
High protein binding.
T1/2 0f 24 hours.
Metabolised by the liver to inactive metabolites.
Used in treatment of HR-positive breast cancer.
Side effects include nausea, hot flushes, fatigue, increased sweating, peripheral oedema, increased apetite.
What are Progestins and types?
Types:
•Natural (progesterone).
• Synthetic:
Progesterone derivatives (MPA, megesterol acetate, dydrogesterone, hydroxyprrogesterone caproate, nomegestrol acetate).
•19-nortesterone derivatives (norethindrone, lynestrenol, levonorgesterel, desogestrel, norgestimate, gestodene).
•19-nor-progestin derivatives (nomegestrol, nestorone, trimegestone)-less androgenic.
•Spironolactone derivative (drospirenone).
What is Progesterone is secreted by?
•Ovary (Corpus luteum)
•Placenta (at the later stages of pregnancy)
Actions of progesterone
•Reproductive tract: formation of secretory endometrium, reduction in quantity and thickening of cervical secretion.
•Maintaneance of pregnancy by supressing menstruation and uterine contractility.
• Breast development.
•Thermogenic action.
•CNS depressant and hypnotic effects.
•Increased basal insulin levels.
•Enhanced fat deposition.
•Increased LDL.
Mechanism of action of progesterone
•Two isoforms of PR (PR-A AND PR-B).
•Mechanism of action similar to that of estrogen as I will explain now.
Pharmacokinetics of progesterone
•Administration orally, parenterally, topically, implants, intrauterine devices.
•Rapid first pass metabolism therefore low oral bioavailability.
•High plasma protein binding to albumin and corticosteroid binding globulin.
•Half-life of 5 minutes but the synthetic progestins have much longer half lives.
•The 19-nor steroids, MPA and megesterol acetate are more resistant to hepatic metabolism.
The 19-nor compounds bind to SHBG and albumin.
•Esters such as MPA bind primarily to albumin.
•All the synthetic compounds are extensively protein bound.
•Progesterone is metabolised primarily in the liver to hydroxylated metabolites and their sulfate and conjugated glucuronides.
•A major metabolite of progesterone is pregnane-3α,20α-diol.
•Metabolism mainly in liver.
•Elimination in urine.
Uses of progesterone
•Contraception (alone or in
combination with estrogen): in combination increases risk of breast cancer, alone it forms a mucus plug preventing sperm entry and reduced FSH and LH
•HRT (in association with estrogen)
•Secondary amenorrhoea
•DUB (dysfunctional uterine bleeding): due to irregular breakdown of an overgrown endometrium
•Luteal phase support to treat infertility
•Palliation of metastatic endometrial Ca
•Megesterol acetate is used as second line treatment for Ca breast and also for AIDS-related wasting.
