chemistry of all sex hormones androgens female sex hormones

1. Chemistry of steroidal hormones and
contraceptive agents
Shree dhanvantary pharmacy college
Prepared by: arzoo dharasandia
Guided by: Stephen sir
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2. Adrenocortical Hormones
Adrenal gland:
 Medulla:
 produces Epinephrine
(stimulated by sympathetic
impulse)
 Cortex:
 Zona glomerulosa – produces
Aldosterone
(stimulated by Angiotensin II and
ACTH)
 Zona fasciculata – produces
Glucocorticoids
(stimulated by ACTH =
Corticotropin)
 Zona reticularis – produces
Androgens
2

3. Adrenocortical Hormones
Glucocorticoids (GC):
 Inhibit all phases of inflammatory reaction
 Promote fetal development (lungs)
 Unregulate lipocortin => inhibits PLA2 => no PG and LT synthesis
 Undesirable effects of increased GC:
 Immune suppression
 Increased glucose release (=> “steroid diabetes”)
 Glucose coverted to fat => adiposity
 Increased protein catabolism => muscle atrophy
 Salt and water retention (increased GC lead to reduction in ACTH =>
decreases levels of aldosterone) => hypertension
 Osteoporosis
3

4. Adrenocortical Hormones
Glucocorticoids (GC):
 Hydrocortison (= Cortisol)
 Main glucocortocoid in humans
 Also binds mineralocorticoid receptor
(Cortison does NOT)
 Used for replacement therapy (Addison’s Disease)
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5. Topical Hydrocortisone
 Hydrocortisone is a topical steroid. It reduces the
actions of chemicals in the body that cause
inflammation, redness, and swelling.
 Hydrocortisone topical is used to treat inflammation of
the skin caused by a number of conditions such as
allergic reactions, eczema, or psoriasis.
 Hydrocortisone topical may also be used for other
purposes .it do not give any antibacterial activity.
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6. Hydrocortisone oral
 Hydrocortisone is also used
to treat low hydrocortisone
levels caused by diseases of
the adrenal gland (such as
Addison's disease,
adrenocortical
insufficiency).
 Corticosteroids are needed
in many ways for the body
to function well. They are
important for salt and water
balance and keeping
blood pressure normal.
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7. Female sex hormone and
hormonal drugs
7

8. Hormones involved in ovulation process
 Gonadotropin Releasing Hormone
(GnRH) = Gonadoliberin
stimulates release of
 Follicle stimulating hormone
(FSH) = Follitropin
and
 Luteinising Hormone
(LH) = Lutropin
which trigger production of
 Estrogens (E) and Gestagens (G)
which in turn negatively regulate
 Pituitary (E+G) and Hypothalamus (G)
hormone production
8

9. How estrogen and progesterone are produced and
involved in female reproductive cycle
 Cycle length varies from 21-35 days
 Menstruation 3-6 days
 First (= Proliferative) phase:
 Variable (7-21 days)
 FSH and LH promote follicle development
 One follicle becomes the Graafian follicle
(the rest degenerate)
 Graaffian Follicle:
 Consists of thecal and granulosa cells
which surround the ovum
 FSH-stimulated granulosa cells produce
estrogens from androgen precursors
generated by LH-stimulated thecal cells
 Estrogens are responsible for the
proliferative phase: increase in thickness
and vascularity of endometrium; secretion
of protein+ carbo-rich mucus
 Constant low estrogen inhibits LH/FSH production BUT high estrogen cause surge
of LH production => swelling and rupture of Graafian follicle = Ovulation
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10. Sex Steroids
 Female reproductive cycle
 Second (= Secretory) phase:
 Secretory phase constant (~ 14 days)
 LH-stimulated ruptured follicle develops
into Corpus luteum which secrets
Progesterone
 Progesterone (Pg) is responsible for the
secretory phase: endometrium becomes
suitable for implantation; mucus thickens
 Thermogenic effects of Pg =>
body temperature increase 0.5º C
 Without implantation: Pg secretion stops
=> menstruation is triggered
 With implantation: continued Pg
production
which (via inhibition of LH and FSH prod.)
blocks further ovulation
 Chorion (“precursor” of placenta)
secretes
human chorionic gonadotropin (HCG)
which
maintains endometrium lining throughout
pregnancy (HCG -> see pregnancy test)
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11. Sex Steroids 11

12. ESTROGENS
All produced from androgen precursors
Three main endogenous estrogens:
 Estradiol
 Primary estrogen in humans
 Breast development
 Improving bone density
 Growth of the uterus
 Accelerating bone maturation
 Development of the endometrium to support pregnancy
 Promoting vaginal mucosal thickness and secretions
 Increase HDL
 Estrone
 1/3 active than estradiol
 Estriol
 only during pregnancy (made by fetus)
12

13. NATURAL ESTROGENS 13
HO
OH
OH
HO
O
HO
OH
17β-estradiol Estrone Estriol

14. Sar of estrogens 14
 Aromatic ring with C-3-OH is essential for activity.
 Steroidal structures is not essential for activity.
 The intensity of activity changesif route of administration
changes, e.g.,for oral route: Estriol > estradiol > estrone.
 For subcutaneous route: estradiol > estrone > estriol.
 Alkylation of the aromatic ring decrease the activity.
 The 17β-hydroxyl with constant distance from 3-OH is
essential for activity.
 The group between the two hydroxyl must be
hydrophobic.
 Unsaturation of ring B decreases the activity.
 17α- and 16 position when modified enhance the activity.
Example: mestranol.

15. 15
O
OH
OH
HO
O
Genisten
O
OH
O
O
Coumesterol
mestranol

16.  Estradiol:
 Estradiol is rapidaly oxidized in the liver to form estrone,
which is ineffective.
 Ethinyl estradiol:
 15- 20 more potent than estradiol orally.
 Adding a 17β-ethiny to estradiol blocks this oxidation and
makes the compound orally active.
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17. Synthetic or non-steroidal estrogens
 Diethylstilbesterol:
 The trans form is the active
one.
 Advantages:
 As active as Estradiol.
 Longer duration of action.
 Orally active
 Cheap.
 Disadvantages:
 Increase the risk of uterine
cancer.
 Uses:
 Treatment of prostate cancer.
17
OH
HO

18. ESTROGEN ANTAGONISTS
 Tamoxifen
 Antiestrogenic effects on mammary
tissue
 Weak estrogenic effects on bone and
lipid metabolism
 Clomiphene
 Inhibits estrogen binding in the pituitary
=> prevention of negative feedback=>
ovulation
Clinical uses of anti-estrogens:
 Breast cancer therapy (Tamoxifen)
 Infertility (Clomiphen)
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19. progesterone
 Progesterone
 Inhibits rhythmic contractions of the myometrium
 Not suitable for oral administration
(rapid hepatic elimination) => stable derivatives:
 Hydroxyprogesterone
 Medroxyprogesterone
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20. Sar of progesterone
 Steroidal nucleus essential for activity.
 Have some androgenic activity.
 Removal of the 19 CH3 increase activity.
 Unsaturation of ring B or C increase the activity.e.g., megestrole
acetate.
 Removal of the keto function remove androgenic activity.
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21. progesterone
Semisynthetic progestine with pure progesterone activity
 Norethindrone
 Norgestrel
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O
O
Progesterone
(Natural)
OH
Lynesrenol
(Synthetic)
C CH

22. Progestine antagonist
mifepristone
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23. Male sex hormones
 Gonadotropin Releasing Hormone
(GnRH) = Gonadoliberin
stimulates release of
 Follicle stimulating hormone (FSH)
(Stimulates Sertoli cells =>
promotes gametogenesis)
and
 Luteinising Hormone (LH) =
Interstitial Cell Stimulating Hormone
(ICSH)
which triggers production of
 Testosterone (T) (by Leydig cells)
which in turn negatively regulates
 Pituitary and Hypothalamus hormone
production
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24. SAR 24

25. SAR CONTI……... 25

26. androgens
 Testosterone
 Primary androgen in humans
 Possesses androgenic and anabolic effects:
Androgenic effects:
 Growth and development of male sex organs
 Important for (male) sex drive and performance
 Development of secondary sexual characteristics
 Important role in spermatogenesis
Anabolic effects:
 Development of muscle mass
 Reverse catabolic or tissue-depleting processes
 Dihydro-Testosterone
 Active metabolite
 Mediates most of testosterone actions
CH3
OH
O
CH3
CH3
OH
O
CH3
H
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27. androgens
 Testosterone
 Hepatic elimination after oral administration
 Also short half-life after injection => ester derivatives:
Proprionate, enanthate, cypionate…
 Fluoxymesterone
 Hepatic elimination after oral administration
CH3
OH
O
CH3
OH
F
CH3
CH3
OH
O
CH3
R
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28. Anabolic androgens
Testosterone derivatives: anabolic effects dominant
 Nandrolone
 Injection
 Stanozolol
 oral administration
CH3
OH
O
CH3
H
OH
O
CH3
CH3
OH
N
CH3
CH3
NH
H
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29. Anti androgens
 Flutamide
 Non-steroidal receptor antagonist
 Used in prostate cancer treatment
 Finasteride
 Inhibits 5α-reductase => prevent conversion of
testosterone into the more potent dihydrotestosterone (DHT)
 Used to treat prostate gland enlargement and hair loss
(bald man have higher average levels of DHT)
NH
CF3
O
CH3
NO2
CH3
CH3
CH3
N
H
O
O
N
H
CH3
CH3
CH3
H
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