Estrogens & Progestins

Introduction to the players:

• Estrogens: estradiol, conjugated estrogens (Premarin), ethinyl estradiol, mestranol

• SERMS:          clomiphene, tamoxifen, raloxifene
• Functional       Anastrozole, exemestane (inhibit production from androgens).  Block
• estrogens:    enzyme.
• Progestins:      progesterone, medroxyprogesterone acetate, norethindrone, norgestrel
• progest.:       mifeprostone or mifeprix (ru 486)

Sex Steroids:

1.     widely used

2.     efficacious

3.     several potenetial SE – spp for pt.

Analyze risk/benefit ratio.

OVERVIEW

Estrogen and Progesterin almost always produce the desired effect.  The clinical choice over which variety to use is based on the side effect profile.

SE depend on agent used, dose and duration.

1.     most estrogens are specific (only e axn)

2.     p & drugs derived from it spp too.

3.     MANY 19-NOR progestins in OC have progestational, androgenic, estrogenic, and/or antiestrogenic activity.

Estrogen Replacement Therapy (ERT)

Low dose [high potency], selective progestins, long duration of use.  Endometrial carcinoma risk increases with unopposed esterogen use.  Progestin added to alleviate this risk.  Progestins may increase breast CA risk.  Overall, ERT reduces the risk of cardiovascular disease and osteoporosis. It’s not recommended for more than 4-6 years and unfortunately doesn’t reliable relieve menopausal symptoms.

OC

Higher dose [lower potency], less selective progestins (androgenic activity),

limited duration.  SE = thromboembolism, esp in women over 35 that smoke. Protective against uterine and ovarian CA.  May increase breast CA risk, esp in thin women.

Endometrial CA ERT inc incidence HRT doesn’t inc incidence. OC protects

Ovarian CA OC protects

Breast CA “increases for population at large” current view – some increase risk net health benefits of HRT outweigh BC risk Progestins (Used in HRT)

Estrogens & progestins affect ovulation by regulating gonadotropin levels.

Both have major axns on endometrium and mammary gland, and axns on

smoth muscle of myometrium, fallopian tubes, and oviduct.  These may

contribute to contraceptive axns, esp of porgestin only and post coital

contraceptive.

Estradiol – supresses LH at beginning of cycle, then switches to be + stimulus on pituitary to release LH.

Progesterone – works on hypothalamus changing GNRF to keep LH and FSH low.  (decrease frequency of LH pulses)

Review a good graph of the menstrual cycle to complete your knowledge base.

Estrogen – primary stimulus for endometrial growth.

Progesterone – converts endometrium to secretory type.  WD –shedding.

E&P – both involved in stimulating mammary epithelium growth.  Mitotic activity of mammary epithelium correlates with increased progesterone in luteal phase.  (estrogen may work by increasing progesterone receptor levels).

LIPID METABOLISM:

Estrogen increase TG& HDL, decrease LDL.

Progesterone decreases HDL, increases LDL. (Synthetics with androgenic activity worst).

BONES:

Estrogen mainly prevents bone loss.

LIVER:

Estrogen affects synthesis of serum proteins involved in clotting and fibrinolytic cascades, and regulation of blood pressure.

VASCULAR WALL:

Estrogens prevent vasospasm, relax smooth muscle, prevent sm proliferation after injury, prevent LDL oxidation (decrease plaques).

CARB METABOLISM:

Progestins (esp 19-nor variety) elevate glucose and increase insulin resistance.  Estradiol reduces insulin resistance.

RECEPTOR MECHANISMS:

E&P mediated by nuclear receptors that stumulate tx of target genes.  Receptors interact with short DNA sequences.  There exist 2 specific receptor genes: alpha and beta.  These code for receptors with different tissue distributions and binding selectivities.  A & B forms of progesterone receptor exist.

E increases # of P receptors

P decreases axn of E, # E receptors, increases E metabolism, and blocks ER gene activation.

E receptors present in most tissues, levels vary.  Different tissues express different patterns of nuclear transcription factors, the basis of selective effects of SERMS.

Estradiol – micronized po with large first pass effect, IM long acting esters, transdermal patch which attenuates greatly the first pass effect.

Conjugated Estrogens – Premarin given PO.  Esp used in ERT.  SE may be due to the extra ingredients.

Ethinyl estradiol (mestranol) – part of OC.  Substitution that prevents 1^st pass metabolism.

SERMS – selective estrogen receptor modulators.

-    Raloxifene – selective axns on bones

-        tamoxifen – antagonist axn on breast and agonist on endometrium, et al. Antagonist on hypothalamus therefore SE = hot flash.

Plant Estrogens – phytoestrogens.  Weak estrogenic/anti-estrogenic activity.  OTC and prescription.

Environmental chemicals may have estrogenic effects.

PROGESTINS

Progesterone: micronized for PO use and suspentions for IM injection.

Progesterone derivitives: mederoxyprogesterone acetate (provera), megestrol acetate.  PO and depot forms.  Relatively “clean” drugs–only progestin activity.

19-Nor steroids: – norethindrone, noethynodrel, norgestrel, norethindrone acetate, ethyndoliol diacetate.  Widely used in OCs  Similar to testosterone, various degrees of progestin, androgenic, and estrogen activity.  Newer ones have less androgen activity.

Androgens & Anabolic Steroids

Intoduction to the players:

• Testosterone & Testosterone Esters – cypionate, enanthate, proprionate.
• Methyltestosterone
• Anabolic Steroids – oxyandrolone, oxymetholone, methandrosternolone, nandrolone ecanoate.
• Inhibitors of production of endogenous androgens – GnRH, Leuprolide, Finasteride, cyproterone cetate, flutamide.

Overview & Perspective

Androgenic steroids are associated with the devolopment of primary and secondary sexual characteristics in males.

Anabolic – promotion of growth (increase in muscle & bone mass, altered fat distribution, + nitrogen balance)

Androgen replacement – used in men with hypothalamic or pituitary disease, insensitivity of gonads, or testicular damage.  Hypogonadism primary (testes unresponsive to LH/FSH) or secondary (low levels of LH/FSH due to hypothalamic or pituitary ds).  Puberty until death.

Infertility in males due to hypgonadotropic hypogonadism – give hCG and human menotropins to mimic LH/FSH.  Stimulates spermatogenesis and increases testosterone.  Androgens given after kid’s born b/c easier to use and less money.

Old men – androgen levels decline after middle age –> osteoporosis, decrease in lean muscle mass and strength, loss of libido & function, et al.  Benefits of therapy include the opposite effects and possibly decreasing anxiety, depression, irritability, maintaining cognition and preventing dementia.

***ALL anabolic steroids developed to date have substantial androgenic activity ***

Vide Infra – wasting condition in which efficacy is not established, but they are sometimes used.

Physiology/Endocrinology

Pdn (95%) is the testis.  Minor amounts produced by adrenals.  LH stimulates T pdn.  T exerts (-) feedback through GnRH decrease and decrease in pituitary stimulation by GnRH.  T also converted to estrogen by aromatase.  E also has (-) feedback at Hypothalamus/Pituitary.

LH & FSH required for spermatogenesis.  Used to Rx infertility in men with secondary hypogonadism due to low gonadotropin levels.

T àDHT in target tissues.  T & DHT both bind to androgen receptors, but DHT has higher affinity.  DHT–prostate proliferation.  T–other androgenic axns.

T bound to serum proteins, low T1/2.  Elimination afer oxidations and conjugations, esp in liver.  Peripheral metabolism to E occurs.

Chemistry & Drug Types

Testosterone & 17-substituted Esters – depot injections (IM) or patch.  T –high 1^st pass.

17-substituted Alkyl derivatives – PO b/c 17-alkyl substitution decreases 1^st pass.

Substituted compounds increase ratio of anabolic to androgenic activity:  “anabolic steroids”.  Ie nandrolone, oxandrolone, oxymetholone.  Substantial androgenic activity.  Many contain 17-alkyl substitutions.  PO.

MOA:  mediated by steroid receptor system in muscle.  T & DHT act thru same receptor, different effects.  Androgen receptor is nuclear receptor.  Occupied receptor binds to DNA sequences.  Receptor mutations cause testicular feminization.

Therapeutic Uses:  mostly for hypogonadism & androgen deficiency.  Some ds and drugs affect testis (mumps, chemotx) .

Anemia, inoperable breast carcinoma, decreased libido, growth & devo in childhood conditions, and for post menopausal women with E are also possible and rare indications.

Occasionally used for debilitating ds/wasting conditions to enhance muscle and bone mass and prevent debilitation.

Athletic Training:  Supraphysiological doses increase muscle mass/size and strength in normal men, esp when combined with strength training.

SE/Toxicities:  Acne, gynecomastia (due to TàE by aromatase in fat cells), increase crit.  Old men – may exacerbate latent prostate cancer, cause edema (bad for CHF).   Women / kids may have virilizin/masculinizing effects.  DON’T use with PREGOS. May reduce HDL with anabolic steroids used in sports.  T does not do this as much, because some of it’s changed to E which has good effects.

Jaundice & hepatotoxicity – ass’d with 17-alpha substituted alkylk compounds.  Ie methyltestosterone, et al anabolic agents with this substitution.  T not as likely to cause this.

Decreased spermatogenesis with anabolics due to (-) feedback of LH/FSH. Anabolics may also cause roid rage.

Increased risk of prostate cancer (cause prostate proliferation). In fact benign prostatic hypertrophy increases with age because of the long-term influence of testosterone on the gland.

Danazol – weak/impeded androgen used for endometriosis, not much any more.  MOA = receptor blockage to reduce gonadotropins and pdn of ovarian steroids that stimulate growth of ectopic endometrial tissue.

Androgen Antagonists – treatment of androgen dependent neoplasia such as prostate cancer.

a)     Cyproterone acetate & flutamide – direct androgen receptor antagonists.

b)     Finasteride – 5 alpha-reductase inhibitor that blocks pdn of DHT (most important androgen for prostate growth).

c)     Leuprolide – physiological antagonist (GnRH analog).  Endogenous GnRH secreted in a pulsatile fashion.  Continous admin inhibis pituitary and decreases gonadotropin pdn, decreasing endogenous androgens pdn in men.

Complete Androgen Blockade (CAB) – leuprolide + receptor antagonist (flutamide/cyproterone) to block axns of androgens.

Tags: Anastrozole, Androgen replacement, conjugated estrogens, E receptors, estradiol, Estrogen Replacement Therapy, Estrogens, exemestane, gonadotropin levels, hepatotoxicity, Jaundice, lipid metabolism, Medroxyprogesterone acetate, mifeprostone, norethindrone, norgestrel, P receptors, progesterone, Progestins, selective estrogen receptor modulators, Testosterone Esters, vasospasm

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