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					Reproduction Pharmacology   Estrogens, Progestins, and Drugs that Alter Uterine Motility
Estradiol                   Major Estrogens
                            o 17- estradiol-first part of the cycle it’s made in the theca and the granulosa cells of the ovarian follicle
                                     o After ovulation, it’s made by the lutenized theca and the granulosa cells
                                     o During pregnancy, the fetoplacental unit takes over in the second trimester where the
                                          aromatization of the androgen takes place in the placenta
                            o Estrogens bind to SHBG (steroid hormone binding hormone) in the blood
                            o It’s the free estrogen that’s biologically active. It can be converted into estrone and estriol
                            o It can be conjugated to glucuronic acid or sulfate. It is excreted in the bile, but the conjugates can be
                                hydrolyzed and reabsorbed. That’s enterohepatic cycling.

                            Mechanism of Action
                            o Estrogen is a lipid soluble hormone so it doesn’t have receptors in the plasma membrane
                            o It has receptors in the nucleus. Estrogen will get into the cell and into the nucleus
                            o It’ll find the estrogen receptor and then bind to it and cause a conformational change
                            o The bound estrogen and receptor (ER) will dimerize, another conformational change occurs, and attach
                               itself to the ERE (estrogen response element)
                            o Once on the ERE, there will be another conformational change that will cause it to recruit co
                               activators: SCR1 (steroid response complex 1)
                            o Once the co-activators bind to the demonized ER on the ERE, there will be yet another conformational
                               change that will cause to recruit a HAT (his tone acetyl transferees)
                            o The HAT will move the his tone out of the way to enable transcription
                            o GTA (general transcriptions activator) to be recruited and transcription ensues

                            Effects on Women
                            o Normal sexual maturation and growth. Development of the vagina, uterus, and fallopian tubes
                            o Secondary sex characteristics such as breast development (stoma and ducal growth)
                                      o Maxillary and pubic hair is formed and Body fat distribution
                            o Growth of long bones and the closure of the epiphyses
                            o Skin pigmentation
                            o Proliferative phase of the menstrual cycle (development of the endometrium)
                            o Metabolically estrogens…
                                      o Maintain the skin and blood vessels
                                      o Decrease the rate of bone resorption
                                      o Alter plasma lipids
                                                 Increase HDL’s
                                                 Decrease LDL’s
                                                 Increase in plasma triglycerides (minor effect)
                            o Blood coagulation
                                      o Increase the coagulability of blood by…
                                                 Increasing factors II, VII, IX, and X
                                                 Decreasing antithrombin III
                                      o But can also decrease coagulability by…
                                                 Increasing plasminogen
                                                 Decreasing platelet adhesiveness
                                                 Increasing protein S and C
                            o Synthesis of Pg receptor
                            o Female sexual behavior

                            Indications
                            o Estrogen deficient states: Oophrectomy. Menopause. Osteoporosis
                            o Cardiovascular and GI – there may be decrease in colon cancer risk with estrogen
                            o Alzheimer’s disease. Contraception. Hirsuitism –
                            o Prostate cancer
                            o Amenorrhea, Dysfunctional uterine bleeding, Dysmenorrheal

                            Toxicities: Carcinogenesis, Uterine bleeding. Increased coagulation. Gallbladder disease. HTN. Nausea
                            Exacerbation of migraine – the headaches are normally due to the withdrawal of the hormone, not the
                            administration. Teratogenesis – discussed with DES

                            Contraindications
                            o Patients with estrogen dependent tumor
                            o If you have undiagnosed genital bleeding – the bleeding can be estrogen dependent
                            o Liver disease – remember that estrogen is broken down by the liver
                            o History of thromboembolic disease
                            o Heavy smoker – this means 15 or more cigarettes a day
                            o Pregnancy – can’t rule out teratogenesis of estrogen

                                                          Page 1 of 8
Ethinyl Estradiol   - Estradiol with a Different R-2 Group (C---CH)
Progesterone        - Progesterone
                    - This is progesterone, the natural form of progestin
                    - It is the precursor to estrogen
                    - Mechanism-This is very similar to the estrogen mechanism because they are both steroid
                      hormones
                    - It’s the most important form of progestin in humans
                    - It’s produced in the ovary by the corpus luteum
Norethindrone       - Norethindrone is the 19 nortestosterone like progestin
                    - Dosing
                    - Physiologic
                            o Supports the luteal phase of the menstrual cycle
                            o Makes the secretory endometrium
                            o Feedback inhibits the production of LH
                            o When there is a withdrawal of Pg, menstruation ensues
                    - Pharmacologic
                            o Endometrial regression occurs – atrophic decidualized endometrium is unfavorable
                                for the implantation of the blastocoel
                            o Creates a thick cervical mucus that makes it difficult for sperm to travel through the
                                cervix

                    - Mechanism
                    o This is very similar to the estrogen mechanism because they are both steroid hormones
                    o Pg comes into the cell and binds to the nuclear progesterone receptor (PR) inside the nucleus
                    o The PR with the Pg dimerizes and binds to the PRE (progesterone response element) to
                       activate gene transcription
                    o This process can be an inhibitory or stimulatory event depending on the receptors

                    -Receptors
                    o There are two types of receptors: A form and B form
                    o You can have the hetero dimmers of AB or homo dimmers (AA, BB)
                    o Both of these receptors are isoforms of the same gene produced by alternative splicing
                    o The A form is inhibitory – it can inhibit estrogen’s effects as well
                    o The B form is stimulatory
                    o Note that the PR’s are different from the ER’s in two aspects:
                            o PR comes from the same gene, not two different genes like ER
                            o PR has two forms that adhere strictly to inhibition and stimulation, whereas the two
                               forms of ER are not strictly inhibitory or stimulatory

                    - Clinical Uses
                    o Hormone replacement therapy – this is to prevent unopposed estrogen
                    o Hormonal contraception – can be in a combo pill or by itself (examples to follow)
                    o Long term ovarian suppression – to create prolonged anovulation and amenorrhea
                              o Dysmenorrhea
                              o Endometriosis
                              o Bleeding disorders when estrogens are contraindicated
                    o Test of estrogen secretion – you can give a progesterone challenge to see if estrogen is being
                         secreted normally

                    Adverse Effects
                     Increase blood pressure
                     19-nor – reduces HDL. It has androgen effects.
                     Increased risk of breast cancer when used with estrogen for HRT compared to estrogen alone
                     Long term therapy can lead to delayed return of ovulatory function
                    -
Norgestrel          - 19 Nor 13 ethyl compounds
                    - Norgetrel – another progestin, but this one exhibits less androgenic effects than norethindrone



                                              Page 2 of 8
Tamoxifen      - Hormonal Antagonist Category
               - What: Partial Agonist actually
               - Partial agonist:
                                  o Agonist on bone, endometrium, coagulation, and lipids
                                  o Antagonist on breast
                                  o Can inhibit hot flushes and increase coagulation
               - Mechanism of action:
                                  o Causes a different conformational change than estrogen does on the ER
                                  o Instead of recruiting activation elements, it recruits repressor elements to
                                    stop transcription and deacetylates the recruiters to prevent transcription
               - Used for the treatment of advanced breast cancer and prophylaxis of breast cancer in high risk
                 women
               - Adverse Effects: Hot Flashes; Increased Risk for DVT, PE, Endometrial Cancer; Cataracts,
                 and Nausea.
Raloxifen      - SERM; Hormonal Antagonist
               - Estrogen agonist for bone and lipids, but not for breast or endometrial cells
                                 o So there is no effect on the breast and endometrium
               - To treat osteoporosis in postmenopausal women
               - It can reduce breast cancer by 76% in women taking Raloxifen
               - Can inhibit hot flushes and increase coagulation
Clomiphene     - Hormonal Antagonist
               - Weak estrogen, which makes it a great competitive inhibitor of estrogen
               - Used to treat anovulatory or oligoovulatory women with potentially functioning HPO axis
                 (hypothalamic pituitary ovarian axis)
               - Reduces estrogen’s inhibition of GnRH in the hypothalamus (arcuate nucleus) as a
                 competitive inhibitor
                                 o This can lead to and increase of GnRH secretion which will lead to
                                     increased LH and FSH which will lead to ovulation.
Mifepristone   - What: Anti-progestin
               - Binds to progestin receptor (PR) as a competitive antagonist
               - Binds to glucocorticoid receptor and androgen receptor -> multitude of uses
               - When it acts as a PR antagonist, it has a luteolytic effect. Used to terminate an early pregnancy
                 and as emergency contraception. Also used to treat endometriosis.
               - Because of glucocorticoid effect, can used to treat Cushing’s syndrome.
               - In terminating an early pregnancy, it interrupts progestin stimulation of the uterus, causing
                 breakdown of decidual membrane and detachment of blastocysts.
               - Can also prevent ovulation.
Letrozole      - What: Aromatase Inhibitors
               - Post-menopausal women will produce estrogen from the conversion of adrenal androgens in
                  the fat
               - So the more fat you have, the more estrogen you make, which is bad news if you have an
                  estrogen dependent breast cancer
               - Use an aromatase inhibitor and stop the peripheral production of estrogen (Letrozole)
                                o Used in advanced breast cancers when anti estrogen therapy has failed
                                o It has been shown to extend remissions longer than tamoxifen, which
                                    means that there must be something else going on than just the estrogen
                                    production inhibition
                                o Other –ozoles are aromatase inhibitors-anastrozole




                                         Page 3 of 8
Oxytocin                       - Structure: Nonapeptide what looks like vasopressin
                               - Mechanism: Alters the transmembrane ion currents to produce sustained contractions of the
                                 uterus as well as the myoepithelial cells surrounding the mammary alveoli
                                                  o These effects can be negated by 2 receptor agonists, MgSO4, and
                                                      inhalational anesthetics
                               - Administered IV for the stimulation of labor
                                                  o Augments labor and can control postpartum hemorrhage
                                                  o Very dose dependent
                               - Administered nasally for the induction of lactation postpartum
                               - Half life is short ~5min
                               - The sensitivity of oxytocin increases throughout gestation, mostly after week 20 due to the
                                 increase in oxytocin receptors
                               - Adverse effects:
                                                  o Very safe drug, low toxicities
                                                  o Death can occur with maternal hypertension
                                                  o Very rarely you can get uterine rupture, water intoxication, and fetal death
Ergonovine                     - Ergot alkaloid that has very little vasoconstriction and antiadrenergic effects, which is very
                                 different from the ergots we learned about in the migraine lecture
                               - Increases the force of contractions and frequency of contraction at low concentration
                               - At higher concentrations, it can produce prolonged contractions
                               - Like oxytocin in that there is an increase in sensitivity to the ergonovine as gestation
                                 progresses
                               - Used for the control of postpartum hemorrhage by inducing a firm active uterus
                               - Toxicities include a transient increase in blood pressure and nausea and vomiting
Ritodrine                      2 agonist
                               - Ritodrine - directly relaxes the uterine muscle, but any 2 receptor agonists can do this
                                                 o Increase in cAMP will relax the smooth muscles
                               - Given IV then orally to maintain
                               - Only prolongs delivery by 24-48 hours!
                                                 o This is just enough time to give the mother some glucocorticoids so the
                                                      fetus’s lungs will get a head start to mature
                               - There may be some reflexive tachycardia and possible 1 effects at higher doses
                                                 o These adverse effects do not seem to affect the neonate, but the mother is
                                                      at risk
Magnesium Sulfate              - What: magnesium sulfate substitutes for calcium and is used to relax the uterus.
                               - M.O.A: Decreases the frequency and strength of contractions. Uncouples the excitation-
                                 contraction process.
                               - Use: Drug of choice for preeclampsia and eclampsia.

Objectives Continued for Reproduction Pharmacology
    1. List the ovarian hormones and describe the mechanism by which they alter gene expression
        Ovary Hormones:
             A. Estrogen
                 Mechanism of action
                           Binds to cytosolic receptors ER-α and ER-β – undergo a conformational change
                                  o Similar but distinct receptors
                                  o Have different ligand binding domains
                                  o Are at different levels in different tissues
                                  o Are on 2 separate genes
                                  o Nuclear receptor family
                           Receptors undergo dimerization and move from the cytosol to the nucleus
                           Sit on the Estrogen Response Element (ERE) at the recognition sequence
                           Doesn’t alter gene expression by itself, instead it attracts other proteins called co-activators
                           Co-activators attract histone acetylase, which acetylates histones causing them to change shape and
                              allowing the DNA to open up. This allows the rest of the transcription machinery to sit down on
                              the DNA and change protein production

             B. Progesterone
                - Mechanism

                                                         Page 4 of 8
                          This is very similar to the estrogen mechanism because they are both steroid hormones
                          Pg comes into the cell and binds to the nuclear progesterone receptor (PR) inside the nucleus
                          The PR with the Pg dimerizes and binds to the PRE (progesterone response element) to activate
                           gene transcription
                          This process can be an inhibitory or stimulatory event depending on the receptors

             -Receptors
                          There are two types of receptors: A form and B form
                          You can have the hetero dimmers of AB or homo dimmers (AA, BB)
                          Both of these receptors are isoforms of the same gene produced by alternative splicing
                          The A form is inhibitory – it can inhibit estrogen’s effects as well
                          The B form is stimulatory
                          Note that the PR’s are different from the ER’s in two aspects:
                               o PR comes from the same gene, not two different genes like ER
                               o PR has two forms that adhere strictly to inhibition and stimulation, whereas the two forms
                                    of ER are not strictly inhibitory or stimulatory

2.   Describe the control of estrogen production and list the factors in its synthesis and distribution
     Control of Estrogen Production:
          The arcuate nucleus in the hypothalamus is the oscillator. It secretes pulsitile GnRH.
          The GnRH activates the anterior pituitary to produce LH and FSH
          LH goes to the ovaries to make androstenedione in the theca cell. This occurs via a cAMP messenger system.
          The androstenedione is converted into estrogen with the enzyme aromatase in the granulosa cell with the help of
              FSH. This also occurs via a cAMP system.
          But how is progesterone made? Well… First there has to be a large amount of LH, let’s say an LH surge. This
              occurs because there is a very small amount of Pg in the circulation and Pg normally inhibits LH in a negative
              feedback loop. This LH will go to the theca cells and produce a large amount of androstenedione. This
              androstenedione will go to the granulosa cells. Because there has been some estrogen made already, there is a
              relative decrease in the amount of FSH made. Estrogen is an inhibitor of FSH. With less FSH, there is less
              activation of the aromatase system and thus there will be less aromatase made. With less aromatase, the
              granulosa cells will take the androstenedione and convert it into progesterone.
          So that’s how you get the LH surge and the progesterone that comes after ovulation. Hopefully that helps you
              with the menstrual cycle.
          Also remember that there are some adrenal androgens made and they are normally made by the zona recticularis
              in the adrenal cortex.
          The zona recticularis is stimulated by ACTH made in the anterior pituitary which is stimulated by CRH in the
              hypothalamus.
          The androgens (DHEA) formed in the adrenal cortex is converted into testosterone or into estrogen in the
              adipose tissue.

3.   See Table

4.   Describe how estrogens and progesterone are linked
     Progestins




             Progesterone
             o This is progesterone, the natural form of progestin
             o It is the precursor to estrogen
             o Mechanism-This is very similar to the estrogen mechanism because they are both steroid hormones
             o It’s the most important form of progestin in humans
             o It’s produced in the ovary by the corpus luteum
                                                     Page 5 of 8
     Estrogen




     This is the chemical structure of estrogen, specifically estradiol.
     Note that the A ring is aromatized. And there are OH groups on the 3 rd and 17th carbons.
     The aromatization of the A ring is what separates this compound from all the other cholesterol products.

     How Estrogen and Progesterone are related:
         LH goes to the ovaries to make androstenedione in the theca cell. This occurs via a cAMP messenger system.
         The androstenedione is converted into estrogen with the enzyme aromatase in the granulosa cell with the help of
            FSH. This also occurs via a cAMP system.
         Progesterone is made? First, there has to be a large amount of LH, let’s say an LH surge.
         This occurs because there is a very small amount of Pg in the circulation and Pg normally inhibits LH in a
            negative feedback loop. This LH will go to the theca cells and produce a large amount of androstenedione. This
            androstenedione will go to the granulosa cells. Because there has been some estrogen made already, there is a
            relative decrease in the amount of FSH made. Estrogen is an inhibitor of FSH. With less FSH, there is less
            activation of the aromatase system and thus there will be less aromatase made. With less aromatase, the
            granulosa cells will take the androstenedione and convert it into progesterone.

5.   See Table

6.   List the indications and adverse effects of progestin therapy
     See Table

7.   Describe the mechanisms by which the combination “pill” and the progestin-alone pill can be used to produce
     contraception. List the indications, contraindications, benefits, drug interactions, and adverse effects for both methods

     Progestin-only preparations
         o Pills are designed to block ovulation, but are only 80% effect. High doses also cause thickening of cervical
              mucus and changes the endometrium so that it is unsuitable for implantation. Pill is taken continually.
         o Depot preparations produce plasma progestin levels that are high enough to block ovulation entirely. This
              includes progestin-releasing IUDs and subcutaneous needles (replaced only every 5 years)! Useful where
              compliance is an issue.
         o Alternative for women who can’t have estrogen!

     Adverse effects:
        o Most common: Menstrual irregularity (lots of spotting), but that decreases with time. After one year, the spotting
             usually has resolved at the patient is amenorrheic. Spotting is one of the reasons why women stop using
             progestin-only contraceptives
        o Headache (second most common)
        o Dizziness
        o Bloating (due to androgen-like effect)
        o Weight gain (due to androgen-like effect)
        o Glucose intolerance (reversible)

     Combination Pills
             Both estrogen and progestin are in pharmacologic doses
                      o Progestin – LH suppression, thickens cervical mucus, atrophies the endometrium
                      o Estrogen – FSH suppression, altered tubular transport
                             Estrogen can make the cilia disordered
                      o Those are the ancillary mechanism because the major mechanism behind inhibiting conception is
                        suppressing ovulation
                      o There is excess progestin compared to the levels of estrogen

                                                       Page 6 of 8
             The conventional combination is a steady dose for 3 weeks and 1 week of placebo to get your period
             The triphasic combination is a steady dose of estrogen for 3 weeks, but an increasing amount of progestin
              every week. It’s supposed to match the natural cycle better, but it may just be a marketing ploy.

Pill Ingredients
      Estrogen: ethinyl estradiol
      Progestins: noresthindrone and norgestrel

Dosing
             Estrogen is usually dosed low:
                  o Low - 20g
                  o Medium – 35g
                  o High – 50g
                  o Triphasics - 35g
             Progestins are dosed slightly higher:
                  o Norethindrone – 1mg for most preparations

Indications
             Contraception
             Endometriosis – suppress ovarian function and inhibits the growth and proliferation of the endometrium
             Hirsuitism – you can decrease the amount of hair
             Acne – this is how some contraceptive companies are advertising their pill now
             Emergency contraception

Minor toxicities
         Nausea and vomiting
         Breast enlargement
                 o You would think that this is a good effect of the pill, but it’s not. The breasts get enlarged and
                      tender to the touch. No one wants to be touched when they’re tender. Even me.
         Alterations in libido
         Breakthrough bleeding – which we learned in ICM is a misnomer. For the sake of understanding what this
             means, think of it as bleeding in the middle of the cycle, when you don’t expect it to happen.
         Melasma – which is skin discoloration
         Acne, oily skin, and hirsuitism – can actually be caused by the androgen effects of the progestins
         Hair loss

Major toxicities
         Thromboembolism and myocardial infarction
                 o This normally occurs with increased age (35+ y.o.) and with smoking
         Migraine headaches can occur – this was discussed earlier
         Gallbladder disease – also discussed earlier
         Carcinogenesis – breast cancer risk can be increased, perhaps…
                 o Note that the combination birth control is anticarcinogenic for the ovary and endometrium
                         Patients enjoy this decreased risk for 15 years after not being on birth control
                         The patients must have used birth control for at least 6 months to 2 years
         Lipid changes
                 o Decrease in HDL’s and increase in LDL’s if progestin is androgenic
         Benign liver tumors
         Mild hypertension
         Teratogenesis
         Delay in return to fertility

Drug Interactions
     If other drugs induce CYP, you can get a 50% decrease in the half-lives if both estrogen and progestin
     If that happens, you may become pregnant, especially with low estrogen pill combinations
     Antibiotics may decrease the enterohaptic cycling and decrease the amount of free hormone in the blood
             o Ketoconazole inhibits the P450 system and affects the combination pill
     ICM correlation: remember that St. John’s Wort is an inhibitor of the pill, so you have to ask your patients if
        they are taking any natural substances for depression or for anything for that matter.

                                                 Page 7 of 8
     Contraindications
          Thrombophlebitis
          Cardiovascular disorders, hypertension, heart failure
          Vaginal bleeding of an unknown cause
          Breast cancer – most early breast cancers are ER+
          Use with caution with patients with liver disease, asthma, migraine, and diabetes
                  o The combination pill can exacerbate these conditions
          Fibroids – remember that fibroids are estrogen dependent and giving your body more estrogen is a bad idea

8.   See Table
9.   See Table




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