"We wanted to find out why women and men are affected differently at times by Asthma. We found out that women with severe asthma but not men had an increase proportion of type of white blood cell called T-helper 2 cell.
T-helper 2 cells are a specialized population of T cells. They are important for immune responses against pathogens that do not directly infect cells, such as helminth parasites. They also promote tissue repair, but contribute to allergic disorders and diseases such as asthma. (1)
How many types of T helper cells are there? Helper T cells can be classified into at least two classes, referred to as Th1 and Th2 cells.
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In the lab, it turned out that it may boil down to hormones. When cell are treated with estrogen and then given steroids, it increases their capacity to be inflammatory, so we think that if these white blood cells are more capable of causing inflammation which means even if women are given an increased dose of steroids it may actually do more harm than good. Steroids in some cases were being knocked down or reduced when you also add estrogen."
Lauren Solomon, postdoctoral Associate
Lauren Solomon, postdoctoral Associate
Estrogen Medications and Products
Image: https://www.shecares.com/hormones/estrogen/medications-products
Steroids
Steroids (also known as cortisone or corticosteroids) are chemicals (hormones) that occur naturally in the body. Steroid medicines are man-made but are similar to these natural hormones. (1) |
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Steroids occur naturally in the body
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Steroids occur naturally in plants
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Which medicines contain steroids?
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Types of Steroids
1. Adrenocorticoids (at least 21 carbons) 2. Estrogens (18 carbons) 3. Progestins (at least 21 carbons) 4. Androgens (19 carbons) - Mostly synthesized from cholesterol - Catabolized in liver |
This group includes steroids such as:
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Adrenocorticoids
- Synthesized in adrenal glands - Have at least 21 carbons |
Two classes of Adrenocorticoids
1. Glucocorticoids: regulate carbo, lipid and protein metabolism (primary GC=hydrocortisone) 2. Mineralocorticoids: influence salt balance and water retention (primary MC=aldosterone) |
Adrenocorticoids are used for treatment of:
1. Adrenal insufficiency 2. Rheumatoid diseases 3. Symptom relief from asthma, allergies 4. Topical application for dermatologic conditions 5. Cancer therapy |
Toxicity of GCs when used for longer than brief periods
- GC-induced adrenocortical insufficiency - GC-induced osteoporosis - Generalized protein depletion |
Addison disease
- 1:100,000 - Caused by decreased secretion of adrenocorticoids - Weakness, anorexia, anemia, N/V, low BP |
Cushing disease
1:500,000 - Caused by pituitary tumors that release excessive ACTH -> increased GC synth - Adrenal glands produce elevated levels of cortisol -> weight gain, fat pads along trunk and face, sweating, polyuria |
Conn syndrome
1:1,000,000 - Caused by inability to carry out 17α-hydroxylation -> high aldosterone levels (not hydroxylated) - Hypernatremia (high blood Na+), polyuria, alkalosis, HTN |
What is the most common cause of Addison disease?
Tuberculosis (TB) is the most common cause of Addison's disease worldwide, but it's rare in the UK. TB is a bacterial infection that mostly affects the lungs but can also spread to other parts of your body. It can cause Addison's disease if it damages your adrenal glands. (1)
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How do you get Addison's disease?
Addison's disease is caused by an autoimmune response, which occurs when the body's immune system (which protects it from infection) assaults its own organs and tissues. With Addison's disease, the immune system attacks the outer portion of the adrenal glands (the cortex), where cortisol and aldosterone are made. (2)
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GC Effects
- Muscle breakdown and weakness
- Steroid-induced osteoporosis
- Hyperglycemia
- Redistribution of fat; expansion of fat pads
- Immune deficiency
- Mood changes (depression/mania, hallucinations)
MC Effects
- HTN
- Alkalosis
--- NA, water retention
--- Loss of K+ ions
Hydrocortisone and cortisone
- interconverted enzymatically
- Equal MC and GC activity (1:1)
- Serves as reference compound
- Cortisone is inactive form
- Interconverts cortisone to HC by 11β steroid dehydrogenase (type 1) in liver
- 11β steroid dehydrogenase (type 2) at MC receptors; unidirectional to produce cortisone
--- Present in kidney and colon; protects MC receptors from being overwhelmed by HC
Hydrocortisone SAR
- 11β hydroxyl required for GC activity
- Not necessary for MC activity
- 4,5 double bond and 3-ketone essential for activity
- 17α hydroxyl is not required, but promotes optimal GC activity
Prednisone SAR
- 1,2 double bond favors GC activity (4 GC:0.6 MC)
- More potent anti-rheumatic, anti-allergic activity
- Decreased inactivation; increased half-life
- Prednisone needs to be reduced to prednisolone for activity
- Patients w/ liver impairment should use prednisolone
Fludrocortisone SAR
- 9α-fluoro increases GC (10X) and MC (125X) activity
--- Fluoro group has EW effect on 11-OH
--- Decreased rate of metabolism
- In contrast, 9α-bromo had less GC activity
--- GC activity inversely proportional to size of halogen
Triamcinolone, Dexamethasone, Betamethasone SAR
- Combining 9α-fluoro with 1,2 double bond
increases activity
- Substitutions at 16 eliminate MC activity
--- Methyl better than OH
- 16-substitutions: β>α 35:30x
AC SAR: 6α substitutions
- have variable effects
- On hydrocortisone, 6α-methyl enhances GC and MC activity
- On prednisolone, methyl enhances GC but has no MC activity
- 6α-F increases potency over methyl
--- Fluoro group has EW effect on 3-ketone
Paramethasone SAR
- slightly more potent than fluprednisolone
--- Methyl substitution at 16
- Analog with additional 9α-fluoro has increased potency
--- Used topically only
AC SAR: 21-hydroxyl
- Present in all natural adrenocorticoids
- Present in most synthetic analogs
- 21-OH required for MC but not GC activity
- Introducing halogen increases lipophilicity
- All of these compounds used topically
AC SAR: Increasing lipophilicity
- Increases topical and systemic potency
- The more lipophilic the ester or ketone, the more potent the compound (topically)
- Types of modifications:
1. Ketal formations with 16-OH and 17-OH
2. Esters at 17 only
3. Esters at 17 and 21
AC SAR: Fluticasone
- Designed to be metabolically susceptible to hydrolysis and to have low bioavailability
--- Once absorbed, it is rapidly inactivated in liver
- Aimed to design safer drug with increased therapeutic index
AC SAR: Aldosterone
- Although aldosterone is main physiological MC, not available for therapy
- DOCA was previously used (Addison's disease)
--- DOCA lacks 11-OH and 17-OH
- Fludrocortisone now used to treat Addison's due to its high potency
AC SAR Summary
1. 6-substitution has a variable effect on potency and gluco vs. mineralo activity, not easily predicted ( i.e. can not ask a question about this)
2. 9-Fluoro substitution increases potency overall, increases mineralo more than gluco because it makes the 11-OH harder to oxidize to the ketone (remember HC is equal G vs. M), it's 11 dehydrogenase that protects the receptor)
3. 16-substitution give gluco only, eliminates mineralo activity
- Muscle breakdown and weakness
- Steroid-induced osteoporosis
- Hyperglycemia
- Redistribution of fat; expansion of fat pads
- Immune deficiency
- Mood changes (depression/mania, hallucinations)
MC Effects
- HTN
- Alkalosis
--- NA, water retention
--- Loss of K+ ions
Hydrocortisone and cortisone
- interconverted enzymatically
- Equal MC and GC activity (1:1)
- Serves as reference compound
- Cortisone is inactive form
- Interconverts cortisone to HC by 11β steroid dehydrogenase (type 1) in liver
- 11β steroid dehydrogenase (type 2) at MC receptors; unidirectional to produce cortisone
--- Present in kidney and colon; protects MC receptors from being overwhelmed by HC
Hydrocortisone SAR
- 11β hydroxyl required for GC activity
- Not necessary for MC activity
- 4,5 double bond and 3-ketone essential for activity
- 17α hydroxyl is not required, but promotes optimal GC activity
Prednisone SAR
- 1,2 double bond favors GC activity (4 GC:0.6 MC)
- More potent anti-rheumatic, anti-allergic activity
- Decreased inactivation; increased half-life
- Prednisone needs to be reduced to prednisolone for activity
- Patients w/ liver impairment should use prednisolone
Fludrocortisone SAR
- 9α-fluoro increases GC (10X) and MC (125X) activity
--- Fluoro group has EW effect on 11-OH
--- Decreased rate of metabolism
- In contrast, 9α-bromo had less GC activity
--- GC activity inversely proportional to size of halogen
Triamcinolone, Dexamethasone, Betamethasone SAR
- Combining 9α-fluoro with 1,2 double bond
increases activity
- Substitutions at 16 eliminate MC activity
--- Methyl better than OH
- 16-substitutions: β>α 35:30x
AC SAR: 6α substitutions
- have variable effects
- On hydrocortisone, 6α-methyl enhances GC and MC activity
- On prednisolone, methyl enhances GC but has no MC activity
- 6α-F increases potency over methyl
--- Fluoro group has EW effect on 3-ketone
Paramethasone SAR
- slightly more potent than fluprednisolone
--- Methyl substitution at 16
- Analog with additional 9α-fluoro has increased potency
--- Used topically only
AC SAR: 21-hydroxyl
- Present in all natural adrenocorticoids
- Present in most synthetic analogs
- 21-OH required for MC but not GC activity
- Introducing halogen increases lipophilicity
- All of these compounds used topically
AC SAR: Increasing lipophilicity
- Increases topical and systemic potency
- The more lipophilic the ester or ketone, the more potent the compound (topically)
- Types of modifications:
1. Ketal formations with 16-OH and 17-OH
2. Esters at 17 only
3. Esters at 17 and 21
AC SAR: Fluticasone
- Designed to be metabolically susceptible to hydrolysis and to have low bioavailability
--- Once absorbed, it is rapidly inactivated in liver
- Aimed to design safer drug with increased therapeutic index
AC SAR: Aldosterone
- Although aldosterone is main physiological MC, not available for therapy
- DOCA was previously used (Addison's disease)
--- DOCA lacks 11-OH and 17-OH
- Fludrocortisone now used to treat Addison's due to its high potency
AC SAR Summary
1. 6-substitution has a variable effect on potency and gluco vs. mineralo activity, not easily predicted ( i.e. can not ask a question about this)
2. 9-Fluoro substitution increases potency overall, increases mineralo more than gluco because it makes the 11-OH harder to oxidize to the ketone (remember HC is equal G vs. M), it's 11 dehydrogenase that protects the receptor)
3. 16-substitution give gluco only, eliminates mineralo activity
Estrogens
Three primary Estrogens
1. Estradiol: most active endogenous estrogen
2. Estrone
3. Estriol
- Produced primarily in ovaries and placenta and excreted into circulation
Estrogen Metabolism
- Estradiol quickly metabolized to estrone by 17β steroid dehydrogenase (17β SDH); this is reversible
- Estradiol and estrone can be converted to estriol
Estrogens: Therapeutic Use
- Menopausal symptoms
- Amenorrhea, dysmenorrhea, oligomenorrhea
- Ovarian development failure
- Hypoestrogenism
- Suppression of lactation
Antiestrogens: Therapeutic Use
ER-dependent breast cancer
Estrogens: Conjugations
- for transport and metabolism
- Majority of estrogens in plasma and tissues are conjugated
- occurs in liver
- form sodium salts and increase water solubility
- Primary conjugates: glucuronides and sulfates
Estrogens: Benefit of Conjugation
- Allows for excretion in liver
- Also excreted in bile in the intestinal tract
- Gut bacteria can de-conjugate primary sulfates, thereby allowing reabsorption
Estrogens: Half-life
generally have a very long half-life
(~1 day)
Estradiol
- poor oral bioavailability due to 1st pass metab
- Rapidly converted to estrone and estriol
- Also undergoes conjugation reactions
Ways to increase Bioavailability of Estradiol
- Oral formulation of micronized estradiol (Estrace®) allows for more rapid absorption
- Transdermal preparations (Evamist®) avoid 1st pass metab
Natural Conjugated estrogens
1. Premarin
Premarin
- Mixture of sulfate salts of estrone, equilin, and equilenin
- Originally obtained from pregnant mares' urine
- A true generic can't be made since the amount of the two main estrogens varies and can't be duplicated
Synthetic Conjugated estrogens
1. Cenestin (A)
2. Enjuvia (B)
- All future synthetic conjugated estrogens will continue with same lettering system (C, D, ...)
Cenestin
- Synthetic Conjugated Estrogens A
- Mixture of 9 estrogenic hormone sodium salts
- Hormones synthesized from soy- and yam-derived sterols; named "synthetic" to distinguish it from mare-derived urine
- Considered a substitute for Premarin
Enjuvia
- Synthetic Conjugated Estrogens B
-Enjuvia has the same 9 estrogenic sulfates as Cenestin, plus one more (Δ8,9-dehydroestrone sulfate)
- Also considered a substitute for Premarin
Esterified Estrogens
1. Menest
Menest
- Contains some of the same sulfate conjugates of estrogens, but ratios and minor composition components differ
- Sodium estrone sulfate added to urine extract
- Not considered an equivalent to Premarin
Ethinyl Estradiol
- Synthetic estrogen
- Greatest advantage: orally active; Equal to estradiol in potency by injection, but is 15-20x more orally active
- Substitution at C-17 prevents oxidation (3° alcohol)
- Undergoes sulfate conjugation and is recirculated
- Primary use: oral contraceptives
- 3-methyl ether derivatives also used as OCs
- Must be dealkylated for activity
Non-steroid estrogens
- Steroid nucleus isn't required for estrogenic activity
- Stilbene derivatives also active, but less potent
--- Aromatic ring A and 3-OH are essential for estrogenic activity
--- Distance between C-3 and C-17 hydroxyl important
--- Planar hydrophobic scaffolding important
Chlorotrianisene
- Non-steroid estrogens
- Third ring stabilizes orientation on receptor
- Ethers must be metabolized for activity
- Note distance between 3- and 17-hydroxyls
Genistein
- Non-steroid estrogens
- Isoflavone found in soybeans and other plants
- Can interact with ERs and cause effects similar to estrogen
- Neutraceutical preparations have estrogenic properties (i.e. Estroven)
Selective Estrogen Receptor Modulators (SERMs)
1. Clomiphene (Clomid)
2. Tamoxifen
3. Raloxifene
Clomiphene (Clomid)
- Used as ovulation stimulant for women desiring pregnancy
-- Blocks negative feedback by inhibiting ERs in hypothalamus -> increase in GnRH-> enhanced release of LH and FSH
- Mixure of two geometric isomers; Isomers found to have different estrogenic actions on different tissues
1. Enclomiphene has antagonist actions on uterine tissue
2. Zuclomiphene has weak agonist activity on all tissues
Tamoxifen
- Structurally related to clomiphene
- SERM used to treat early and advanced stage ER+ breast cancer; also approved for prevention of breast cancer in women who are at high risk
- Prodrug; metabolized in liver to form active metabolites
- Has antagonist activity on breast tissue
- Has agonist activity on endometrium, liver, CV tissues, bone (prevents osteoporosis; initiated field of SERMs)
- Major ADR: uterine cancer
Raloxifene
- Structurally different than triphenylethylene SERMS (contains benzothiophene)
--- Has carbonyl hinge; hinge is key element that causes its differing actions
Raloxifene Action
- Has antagonist activity on breast and endometrium tissue
- Acts as agonist on bone and CV tissues
- Primary use: prevention and treatment of osteoporosis in post-menopausal women
- Was also compared side-by-side with tamoxifen in recurring breast cancer
-- Similar effectiveness to tamoxifen, but Raloxifene has better side effect profile
Anti-estrogens
1. Fulvestrant (Faslodex®)
Fulvestrant (Faslodex®)
- Based on scaffold of estradiol
- Has long substituted alkyl chain
--- When bound to ER, alkyl chain induces a distinct conformational change in receptor -> Conformational change blocks agonist action
- Estrogen receptor antagonist; Has NO agonist effects
--- Blocks activity, also stimulates degradation of ER
- Used for women who have rapid disease progression after prior antiestrogen activity (usually tamoxifen)
1. Estradiol: most active endogenous estrogen
2. Estrone
3. Estriol
- Produced primarily in ovaries and placenta and excreted into circulation
Estrogen Metabolism
- Estradiol quickly metabolized to estrone by 17β steroid dehydrogenase (17β SDH); this is reversible
- Estradiol and estrone can be converted to estriol
Estrogens: Therapeutic Use
- Menopausal symptoms
- Amenorrhea, dysmenorrhea, oligomenorrhea
- Ovarian development failure
- Hypoestrogenism
- Suppression of lactation
Antiestrogens: Therapeutic Use
ER-dependent breast cancer
Estrogens: Conjugations
- for transport and metabolism
- Majority of estrogens in plasma and tissues are conjugated
- occurs in liver
- form sodium salts and increase water solubility
- Primary conjugates: glucuronides and sulfates
Estrogens: Benefit of Conjugation
- Allows for excretion in liver
- Also excreted in bile in the intestinal tract
- Gut bacteria can de-conjugate primary sulfates, thereby allowing reabsorption
Estrogens: Half-life
generally have a very long half-life
(~1 day)
Estradiol
- poor oral bioavailability due to 1st pass metab
- Rapidly converted to estrone and estriol
- Also undergoes conjugation reactions
Ways to increase Bioavailability of Estradiol
- Oral formulation of micronized estradiol (Estrace®) allows for more rapid absorption
- Transdermal preparations (Evamist®) avoid 1st pass metab
Natural Conjugated estrogens
1. Premarin
Premarin
- Mixture of sulfate salts of estrone, equilin, and equilenin
- Originally obtained from pregnant mares' urine
- A true generic can't be made since the amount of the two main estrogens varies and can't be duplicated
Synthetic Conjugated estrogens
1. Cenestin (A)
2. Enjuvia (B)
- All future synthetic conjugated estrogens will continue with same lettering system (C, D, ...)
Cenestin
- Synthetic Conjugated Estrogens A
- Mixture of 9 estrogenic hormone sodium salts
- Hormones synthesized from soy- and yam-derived sterols; named "synthetic" to distinguish it from mare-derived urine
- Considered a substitute for Premarin
Enjuvia
- Synthetic Conjugated Estrogens B
-Enjuvia has the same 9 estrogenic sulfates as Cenestin, plus one more (Δ8,9-dehydroestrone sulfate)
- Also considered a substitute for Premarin
Esterified Estrogens
1. Menest
Menest
- Contains some of the same sulfate conjugates of estrogens, but ratios and minor composition components differ
- Sodium estrone sulfate added to urine extract
- Not considered an equivalent to Premarin
Ethinyl Estradiol
- Synthetic estrogen
- Greatest advantage: orally active; Equal to estradiol in potency by injection, but is 15-20x more orally active
- Substitution at C-17 prevents oxidation (3° alcohol)
- Undergoes sulfate conjugation and is recirculated
- Primary use: oral contraceptives
- 3-methyl ether derivatives also used as OCs
- Must be dealkylated for activity
Non-steroid estrogens
- Steroid nucleus isn't required for estrogenic activity
- Stilbene derivatives also active, but less potent
--- Aromatic ring A and 3-OH are essential for estrogenic activity
--- Distance between C-3 and C-17 hydroxyl important
--- Planar hydrophobic scaffolding important
Chlorotrianisene
- Non-steroid estrogens
- Third ring stabilizes orientation on receptor
- Ethers must be metabolized for activity
- Note distance between 3- and 17-hydroxyls
Genistein
- Non-steroid estrogens
- Isoflavone found in soybeans and other plants
- Can interact with ERs and cause effects similar to estrogen
- Neutraceutical preparations have estrogenic properties (i.e. Estroven)
Selective Estrogen Receptor Modulators (SERMs)
1. Clomiphene (Clomid)
2. Tamoxifen
3. Raloxifene
Clomiphene (Clomid)
- Used as ovulation stimulant for women desiring pregnancy
-- Blocks negative feedback by inhibiting ERs in hypothalamus -> increase in GnRH-> enhanced release of LH and FSH
- Mixure of two geometric isomers; Isomers found to have different estrogenic actions on different tissues
1. Enclomiphene has antagonist actions on uterine tissue
2. Zuclomiphene has weak agonist activity on all tissues
Tamoxifen
- Structurally related to clomiphene
- SERM used to treat early and advanced stage ER+ breast cancer; also approved for prevention of breast cancer in women who are at high risk
- Prodrug; metabolized in liver to form active metabolites
- Has antagonist activity on breast tissue
- Has agonist activity on endometrium, liver, CV tissues, bone (prevents osteoporosis; initiated field of SERMs)
- Major ADR: uterine cancer
Raloxifene
- Structurally different than triphenylethylene SERMS (contains benzothiophene)
--- Has carbonyl hinge; hinge is key element that causes its differing actions
Raloxifene Action
- Has antagonist activity on breast and endometrium tissue
- Acts as agonist on bone and CV tissues
- Primary use: prevention and treatment of osteoporosis in post-menopausal women
- Was also compared side-by-side with tamoxifen in recurring breast cancer
-- Similar effectiveness to tamoxifen, but Raloxifene has better side effect profile
Anti-estrogens
1. Fulvestrant (Faslodex®)
Fulvestrant (Faslodex®)
- Based on scaffold of estradiol
- Has long substituted alkyl chain
--- When bound to ER, alkyl chain induces a distinct conformational change in receptor -> Conformational change blocks agonist action
- Estrogen receptor antagonist; Has NO agonist effects
--- Blocks activity, also stimulates degradation of ER
- Used for women who have rapid disease progression after prior antiestrogen activity (usually tamoxifen)
Progestins
- Key endogenous hormone that binds progestin receptors: progesterone
- Structurally similar to glucocorticoids
Progesterone Production
- produced in ovaries, testes, adrenal glands
- Produced by corpus luteum in women; adrenal and testicular tissue in men
- Involved in fertility for women:
1. Progesterone produced by hCG by fertilized egg; eventually produced by placenta
2. Also maintains endometrium throughout pregnancy
Progestins: Therapeutic Uses
- Birth control (inhibits ovulation)
- Preventative for endometrial cancer in women taking postmenopausal estrogens
- Treatment of amenorrhea (functional uterine bleeding)
- Pallative Tx of advanced breast or endometrium cancer
Progesterone
- Low oral bioavailability
--- Poor absorption and rapidly, completely metabolized after 1st pass (T1/2=5 min)
- Oral formulation designed to micronize progesterone (Prometrium)
Progestins: SAR 1
- 17α-OH progesterones are inactive
- 17α-esters are active via IM or SQ
- Limitation: no oral activity due to 1st pass
Progestins: SAR 2
- Activity enhanced by halogen or methyl substitutions at C6
- Also makes compounds orally active
--- Prevents metabolic oxidation at C6
- Compounds have relatively selective progestin activity
Progestins: SAR 3
activity is also enhanced by unsaturation at C6 and C7
SAR: Ethisterone
First synthetic progestin to be used
therapeutically
- Found to be effective oral progestins
--- Ethynyl group protects alcohol oxidation
SAR: 19-norsteroids
- Found that C19 methyl was not necessary for progestin activity
- Analogs without C19 (19-norsteroids) have activity that is equal to or greater than progesterone
- Less selective and show gluco, mineralo, and androgenic activity
- Ethynyl group on C17 protects alcohol from oxidation
--- Modification allows for orally active compounds
19-norsteroids Activity
- 19-norsteroids with ethyl derivatives have increased potency
- Norgestrel has some androgenic activity, but no gluco or mineralo activity
--- Desogestrel, Norelgestromin (Ortho-Evra), Norgestimate (Cyclen, Tri-Cyclen) all have less androgenic activity
Drospirenone
(in Yasmin, Angeliq)
- Has 2 cyclopropyl groups and C17 lactone
- Only progestin with antimineralo activity
- Has progestin activity but is antagonist of aldosterone
--- Causes K-sparing diuretic effect
- Causes increased risk of developing thromboembolism, hyperalkalemia
- Structurally similar to glucocorticoids
Progesterone Production
- produced in ovaries, testes, adrenal glands
- Produced by corpus luteum in women; adrenal and testicular tissue in men
- Involved in fertility for women:
1. Progesterone produced by hCG by fertilized egg; eventually produced by placenta
2. Also maintains endometrium throughout pregnancy
Progestins: Therapeutic Uses
- Birth control (inhibits ovulation)
- Preventative for endometrial cancer in women taking postmenopausal estrogens
- Treatment of amenorrhea (functional uterine bleeding)
- Pallative Tx of advanced breast or endometrium cancer
Progesterone
- Low oral bioavailability
--- Poor absorption and rapidly, completely metabolized after 1st pass (T1/2=5 min)
- Oral formulation designed to micronize progesterone (Prometrium)
Progestins: SAR 1
- 17α-OH progesterones are inactive
- 17α-esters are active via IM or SQ
- Limitation: no oral activity due to 1st pass
Progestins: SAR 2
- Activity enhanced by halogen or methyl substitutions at C6
- Also makes compounds orally active
--- Prevents metabolic oxidation at C6
- Compounds have relatively selective progestin activity
Progestins: SAR 3
activity is also enhanced by unsaturation at C6 and C7
SAR: Ethisterone
First synthetic progestin to be used
therapeutically
- Found to be effective oral progestins
--- Ethynyl group protects alcohol oxidation
SAR: 19-norsteroids
- Found that C19 methyl was not necessary for progestin activity
- Analogs without C19 (19-norsteroids) have activity that is equal to or greater than progesterone
- Less selective and show gluco, mineralo, and androgenic activity
- Ethynyl group on C17 protects alcohol from oxidation
--- Modification allows for orally active compounds
19-norsteroids Activity
- 19-norsteroids with ethyl derivatives have increased potency
- Norgestrel has some androgenic activity, but no gluco or mineralo activity
--- Desogestrel, Norelgestromin (Ortho-Evra), Norgestimate (Cyclen, Tri-Cyclen) all have less androgenic activity
Drospirenone
(in Yasmin, Angeliq)
- Has 2 cyclopropyl groups and C17 lactone
- Only progestin with antimineralo activity
- Has progestin activity but is antagonist of aldosterone
--- Causes K-sparing diuretic effect
- Causes increased risk of developing thromboembolism, hyperalkalemia
Androgens
Androgens
- synthesized in testes
- Precursor for estrogens
Androgens: Target receptor and tissues
- target the androgen receptor (AR)
--- Two major endogenous forms: testosterone, 5α-dihydrotestosterone (DHT)
--- DHT is more potent
- mainly expressed in androgen target tissues
--- Skeletal muscle, adrenal gland, prostate, liver, CNS
Testosterone
- Anabolic effects (muscle bulk)
- Gonadotropin regulation
- Spermatogenesis
DHT
- Male pattern baldness
- Prostate enlargement and cancer
- Sexual differentiation
- Sexual maturity
Androgens Metabolism
Androgens: Therapeutic Use
- Male hypogonadism
- Andropause
- Testosterone replacement therapy
Testosterone Routes
- Oral dosing is ineffective due to 1st-pass metab
- IM injections bypass 1st-pass, but absorption is slow
- Available as implant (Testopel)
--- Not as flexible for dose adjustment; faster absorption in first month -> decreases
- Transdermal- most common route
--- Peak response within 3-6 months
Testosterone SAR 1: Ester derivatives
- increase absorption after IM admin
- Esters make it more lipophilic
- Still can't be used orally (1st-pass effect)
Testosterone: SAR 2, Methylation
- Methylation of C17 allows increased oral bioavailability
--- Prevents oxidation of alcohol
- Why not 17α-ethynyl group? Compound acts like a progestin
- Not as active as testosterone (~1/2 activity)
- Seldom used due to potential hepatotoxicity
Testosterone: SAR 3
- Adding 9α-fluoro and 11-hydroxy group to 17α-methyltestosterone increases activity
- 10x more active than 17α-methyltestosterone
- 20x more anabolic effects than 17α- methyltestosterone
- Also has potential hepatotoxicity
Testosterone: SAR 4, Alkylated Anabolic Steroids
- Common 17α-alkylated anabolic steroids in clinical use
--- Used for osteoporosis, anemia
- Cannot completely dissociate anabolic and androgenic effects
Testosterone: SAR 5, 19-norandrogens
Removal of 19-methyl reduces androgenic properties but retains anabolic properties
5α-Reductase Inhibitors
1. Finasteride (Proscar, Propecia)
2. Dutasteride (Avodart)
Finasteride (Proscar, Propecia)
- Selectively inhibits Type II 5α-reductase
- Rapidly reduces plasma DHT levels
- Used to treat BPH (5 mg daily), male pattern baldness (1 mg daily)
Dutasteride (Avodart)
- Competitive inhibitor of both type I and type II 5α-reductase
- Dual suppression results in more extensive and more consistent reduction of DHT in plasma
Anti-Androgens
1. Bicalutamide (Casodex, Kalumid)
2. Enzalutamide (Xtandi)
Bicalutamide (Casodex, Kalumid)
- Blocks binding of DHT at AR -> diminishes effects of androgens on androgen-sensitive tissues
- Non-steroidal; pure anti-androgen activity
- Used for prostate cancer, but most advanced prostate cancer patients develop resistance
Enzalutamide (Xtandi)
- for castration-resistance prostate cancer
- Also in preclinical studies for breast cancer
- Has 5x higher affinity for AR than bicalutamide
--- Prevents nuclear translocation, DNA binding by AR
- synthesized in testes
- Precursor for estrogens
Androgens: Target receptor and tissues
- target the androgen receptor (AR)
--- Two major endogenous forms: testosterone, 5α-dihydrotestosterone (DHT)
--- DHT is more potent
- mainly expressed in androgen target tissues
--- Skeletal muscle, adrenal gland, prostate, liver, CNS
Testosterone
- Anabolic effects (muscle bulk)
- Gonadotropin regulation
- Spermatogenesis
DHT
- Male pattern baldness
- Prostate enlargement and cancer
- Sexual differentiation
- Sexual maturity
Androgens Metabolism
Androgens: Therapeutic Use
- Male hypogonadism
- Andropause
- Testosterone replacement therapy
Testosterone Routes
- Oral dosing is ineffective due to 1st-pass metab
- IM injections bypass 1st-pass, but absorption is slow
- Available as implant (Testopel)
--- Not as flexible for dose adjustment; faster absorption in first month -> decreases
- Transdermal- most common route
--- Peak response within 3-6 months
Testosterone SAR 1: Ester derivatives
- increase absorption after IM admin
- Esters make it more lipophilic
- Still can't be used orally (1st-pass effect)
Testosterone: SAR 2, Methylation
- Methylation of C17 allows increased oral bioavailability
--- Prevents oxidation of alcohol
- Why not 17α-ethynyl group? Compound acts like a progestin
- Not as active as testosterone (~1/2 activity)
- Seldom used due to potential hepatotoxicity
Testosterone: SAR 3
- Adding 9α-fluoro and 11-hydroxy group to 17α-methyltestosterone increases activity
- 10x more active than 17α-methyltestosterone
- 20x more anabolic effects than 17α- methyltestosterone
- Also has potential hepatotoxicity
Testosterone: SAR 4, Alkylated Anabolic Steroids
- Common 17α-alkylated anabolic steroids in clinical use
--- Used for osteoporosis, anemia
- Cannot completely dissociate anabolic and androgenic effects
Testosterone: SAR 5, 19-norandrogens
Removal of 19-methyl reduces androgenic properties but retains anabolic properties
5α-Reductase Inhibitors
1. Finasteride (Proscar, Propecia)
2. Dutasteride (Avodart)
Finasteride (Proscar, Propecia)
- Selectively inhibits Type II 5α-reductase
- Rapidly reduces plasma DHT levels
- Used to treat BPH (5 mg daily), male pattern baldness (1 mg daily)
Dutasteride (Avodart)
- Competitive inhibitor of both type I and type II 5α-reductase
- Dual suppression results in more extensive and more consistent reduction of DHT in plasma
Anti-Androgens
1. Bicalutamide (Casodex, Kalumid)
2. Enzalutamide (Xtandi)
Bicalutamide (Casodex, Kalumid)
- Blocks binding of DHT at AR -> diminishes effects of androgens on androgen-sensitive tissues
- Non-steroidal; pure anti-androgen activity
- Used for prostate cancer, but most advanced prostate cancer patients develop resistance
Enzalutamide (Xtandi)
- for castration-resistance prostate cancer
- Also in preclinical studies for breast cancer
- Has 5x higher affinity for AR than bicalutamide
--- Prevents nuclear translocation, DNA binding by AR
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Naturally Occurring Elements in the Human Body
Atomic #
1
|
.
H
Boron B Boron 5 Carbon C Carbon 6 Nitrogen N Nitrogen 7 Oxygen O Oxygen 8 Fluorine F Atomic Number for Fluorine 9 Sodium Na Atomic Number for Sodium 11 Magnesium Mg Atomic Number for Magnesium 12 Silicon Si Atomic Number for Silicon 14 Phosphorus P Atomic Number for Phosphorus 15 Sulfur S Atomic Number for Sulfur 16 Chlorine Cl Atomic Number for Chlorine 17 Potassium K Atomic Number for Potassium 19 Calcium Ca Atomic Number for Calcium 20 Vanadium V Atomic Number for Vanadium 23 Chromium Cr Atomic Number for Chromium 24 Magnese Mn Atomic Number for Magnese 25 Cobalt Co Atomic Number for Cobalt 27 Copper Cu Atomic Number for Copper 29 Zinc Zn Atomic Number for Zinc 30 Selenium Se Atomic Number for Selenium 34 Molybdenum Mo Atomic Number for Molybdenum 42 Tin Sn Atomic Number for Tin 50 Iodine I Atomic Number for Iodine 53 |
Elemnt
Hydrogen
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