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Steroid Hormones
S.SEETARAM SWAMY, M.Pharm.,
Asst. professor,
Dept. of Pharmaceutical Chemistry,
E-mail:seetaram.443@gmail...
STEROID HORMONES
Steroid hormones and related products represents one of the most widely
used classes of therapeutic agent...
Steroid hormone receptors
Steroid hormones are lipid soluble molecules(Hydrophobic) that bind
to hormone receptors in the ...
A general scheme for steroid hormone receptor interactions:
1. Steroid crosses cell
membrane into
cytoplasm
2. Steroid bin...
Estrogen receptor(ER)
There are two distinct estrogen receptors(ERs).
estrogen receptor α(ERα)
estrogen receptor β(ERβ)
ER...
Progesterone receptor(PR)
The PR can also be found in two forms, but these are derived from a
single gene.
Progesterone re...
Steroid hormones are classified in to two types.
Adrenal cortical hormones.
 Sex hormones.
The adrenal cortex secrets st...
S. A. R OF ADRENAL CORTICAL HORMONES
 Cortisone and hydrocortisone have too much salt-retaining activity in the
doses nee...
9
sitaram
10
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SEX HORMONES
ANDROGENS (OR) MALE SEX HORMONES
Androgens are synthesized from cholesterol in the testes and adrenal
cortex....
12
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Testosterone exerts its physiological activity after its conversion to
Dihydrotestosterone.
A steroidal skeleton is minimu...
Reduction of the A ring e.g., DHT may increase potency.
Introduction of 17α methyl group confers oral activity on testoste...
Esterification of testosterone at C-17 with a number of acids have long
duration of action when used parenterally.
-OH gro...
19-norandrogens were synthesized, some of which were found to be
effective anabolic agents. E.g. 19-nortestosterone.
The 3...
In men, effects:
Bone
Spermatogenesis
Behavior
Estrogens and progestin's are hormones that produce many physiological
acti...
Estrogens
A group of steroid hormones that readily diffuse across the cell membrane
Inside the cell, they interact with ...
23
sitaram
24
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 The most potent naturally occurring estrogen in humans for both the
Estrogen Receptor alpha and beta mediated actions is...
Activity depends on mode of action
Subcutaneous= Estradiol > Estrone > Estriol
Oral = Estriol > Estradiol > Estrone
 Eth...
Progesterone
Progesterone is secreted mainly by the corpus luteum of the ovary. It is
also Formed in the placenta, adrenal...
28
sitaram
Steroidal nucleus is essential for activity.
Substitution at 17 α with ethynyl, methyl, ethyl reduce activity.
Ethindro...
Hormonal Contraceptives
Ethinyl estradiol (a synthetic estrogen) and mestranol are the estrogens
most frequently used .
Le...
31
sitaram
32
sitaram
Steroids Formation from Cholesterol
33
sitaram
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Steroid Hormones

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Steroid hormones can be grouped into 2 classes, corticosteroids (typically made in the adrenal cortex, hence cortico-) and sex steroids (typically made in the gonads or placenta).

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Steroid Hormones

  1. 1. Steroid Hormones S.SEETARAM SWAMY, M.Pharm., Asst. professor, Dept. of Pharmaceutical Chemistry, E-mail:seetaram.443@gmail.com
  2. 2. STEROID HORMONES Steroid hormones and related products represents one of the most widely used classes of therapeutic agents.  Birth control  Hormone-replacement therapy(HRT)  Inflammatory conditions  Cancer treatment Most of these agents are chemically based on a common structural backbone, the steroid backbone. Steroid hormones in mammals are biosynthesized from cholesterol, which in turn is made in vivo from acetyl-coenzyme A(acetyl-CoA) via the mevalonate pathway. These drugs are primarily in: Cholesterol synthesis occurs in smooth ER and enzymatic conversion occur in mitochondria. 2 sitaram
  3. 3. Steroid hormone receptors Steroid hormones are lipid soluble molecules(Hydrophobic) that bind to hormone receptors in the cytoplasm of the target cell. Greatest progress in steroid research in recent years has been in the area of steroid receptors, Considering the many diverse actions at even a single class of steroid hormones. The receptor-hormone complex binds to the regulatory region of the gene and changes the expression of that gene. Cytosolic and nuclear receptors - in the cytoplasm or nucleus (“genomic”) Activated receptor binds to DNA and initiates/alters gene transcription Hormone must enter cell first 3 sitaram
  4. 4. A general scheme for steroid hormone receptor interactions: 1. Steroid crosses cell membrane into cytoplasm 2. Steroid binds cytosolic receptor which is kept inactive by heat-shock proteins (HSPs) 3. Binding alters receptor confirmation, releasing HSPs 4. Active receptors bind directly to DNA and initiate transcription 5. mRNA enters cytoplasm and a new protein is synthesized. 4 sitaram
  5. 5. Estrogen receptor(ER) There are two distinct estrogen receptors(ERs). estrogen receptor α(ERα) estrogen receptor β(ERβ) ERα can be found in high abundance in the uterus, vagina, and ovaries, as well as in the breast, hypothalamus. ERβ is found in the ovaries and prostate, and low amount in the lungs, brain, and vasculature. Which are encoded by different genes. Estrogens exert their effects by interaction with receptors that are members of the super family of nuclear receptors. After entering the cell by passive diffusion through the plasma membrane, the hormone binds to an ER in the nucleus In the nucleus, the ER is present as an inactive monomer bound to heat-shock proteins, and upon binding estrogen, a change in ER confirmation dissociates the heat-shock proteins and causes receptor dimerization, which increases the affinity and the rate of receptor binding to DNA 5 sitaram
  6. 6. Progesterone receptor(PR) The PR can also be found in two forms, but these are derived from a single gene. Progesterone receptor A(PRA) Progesterone receptor B(PRB) Progesterone receptor B mainly mediates the stimulatory actions of progesterone. PRA acts as a transcriptional inhibitor of ER, AR, GR, MR, and PRB. Androgen, Glucocorticoids, and Mineralocorticoid receptors The AR, GR, and MR are present in only a single form . Only one gene and one protein are known for each receptor. 6 sitaram
  7. 7. Steroid hormones are classified in to two types. Adrenal cortical hormones.  Sex hormones. The adrenal cortex secrets steroidal hormones which have  Mineralocorticoids -Aldosterone.  Glucocorticoids - Hydrocortisone Sex hormones - Androgens & Estrogens Uses: Mineralocorticoid effects on Na+, K+ and fluid balance. Glucocorticoids effects on carbohydrate, protein, and fat metabolism. Androgens effects on muscle development and maturity and coordination. 7 sitaram
  8. 8. S. A. R OF ADRENAL CORTICAL HORMONES  Cortisone and hydrocortisone have too much salt-retaining activity in the doses needed for some therapeutic purpose.  Substituents which significantly increase anti inflammatory and glucocorticoid activity. E.g. 1-dehydro,6α-fluro.  Substituents which significantly decrease mineralocorticoid activity and glucocorticoid activity. E.g. 16α-hydroxy, 16α and 16β-methyl.  Substituents which significantly increase both mineralocorticoid and glucocorticoid activity. E.g. 9α-fluro, 21-hydroxy, 2α-methyl, 9α-chloro. 8 sitaram
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  11. 11. SEX HORMONES ANDROGENS (OR) MALE SEX HORMONES Androgens are synthesized from cholesterol in the testes and adrenal cortex. It also been isolated from adrenal cortex and ovaries. There are 4 naturally occurring androgens in man i. Testosterone ii. Androsterone iii. Epiandrosterone (or) androstenedione iv. Dehydroepiandrosterone (or) DTH Adrenal cortex produces small quantities of Dehydroepiandrosterone and androstenedione, which are called WEAK ANDROGENS. Progestins are precursors to all androgens. 11 sitaram Sex hormones are usually classified as follows i. Androgens (Male sex hormones) ii. Oestrogens (Female or Follicular hormones) iii. Gestogens (Corpus luteum hormones)
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  17. 17. Testosterone exerts its physiological activity after its conversion to Dihydrotestosterone. A steroidal skeleton is minimum structural requirement to have androgenic activity. 17β hydroxyl function to be essential for androgenic and anabolic activity. 1-Dehydro isomer of testosterone is a potent compound. S .A.R OF ANDROGENS 17 sitaram
  18. 18. Reduction of the A ring e.g., DHT may increase potency. Introduction of 17α methyl group confers oral activity on testosterone. Testosterone not effective orally, because metabolic changes at 17-β oxygen, which is used to attach the receptor site. 17-α alkyl groups prevent these metabolic changes so that compounds are orally active. E.g.17α methyl testosterone. Increasing the length of alkyl side chain at 17α position results reduced activity. 18 sitaram
  19. 19. Esterification of testosterone at C-17 with a number of acids have long duration of action when used parenterally. -OH group in 17α position decreases androgenic or anabolic activity. Heterocyclic rings are also incorporated yield good anabolic agents. E.g. Stanozolol 19 sitaram
  20. 20. 19-norandrogens were synthesized, some of which were found to be effective anabolic agents. E.g. 19-nortestosterone. The 3-deoxy analogs have been found to be potent androgen . Several heterocyclic rings were then fused to ring A. the pyrazole and isoxazole were much more active then 17α-methyl testosterone. 20 sitaram
  21. 21. In men, effects: Bone Spermatogenesis Behavior Estrogens and progestin's are hormones that produce many physiological actions. Female sex hormones In women: Developmental effects (estrogens are largely responsible for pubertal changes in girls and secondary sexual characteristics). Neuroendocrine actions involved in: Control of ovulation and the preparation of the reproductive tract for fertilization and implantation. Major Actions on: Minerals, Carbohydrates, Proteins, and Lipid Metabolism Estrogens and Progestin's 21 sitaram
  22. 22. Estrogens A group of steroid hormones that readily diffuse across the cell membrane Inside the cell, they interact with estrogen receptors Synthesis of estrogen begins from the synthesis of androstenedione from cholesterol. Androstenedione crosses the basal membrane into surrounding granulosa cells, where its converted to estrone or estradiol wither immediately or through testosterone. The conversion is catalyzed by aromatase. Therapeutic uses: Development of secondary sex characteristics. Growth of uterus during puberty. Initial growth of endometrium during menstrual cycle. 22 sitaram
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  25. 25.  The most potent naturally occurring estrogen in humans for both the Estrogen Receptor alpha and beta mediated actions is 17beta-estradiol, followed by estrone and estriol.  Each estrogen contains a phenolic A ring with a hydroxyl group at carbon 3 and a beta-OH or ketone in position 17 of ring D.  The phenolic A ring is the principal structural feature responsible for selective, high-affinity binding to both receptors.  Ring A and 3-OH, 17β-OH groups is necessary for activity. S .A.R OF ESTROGEN 25 sitaram
  26. 26. Activity depends on mode of action Subcutaneous= Estradiol > Estrone > Estriol Oral = Estriol > Estradiol > Estrone  Ethinyl estradiol having greatest activity, because of resistant to metabolism in liver and degradation by enzymes in GIT.  Removal of 3-OH group, epimerization of 17β-OH group, introduction of unsaturation in ’B’ ring, expansion of ‘D’ ring drastically decrease the activity.  Compound without steroid nucleus also shows activity. 26 sitaram
  27. 27. Progesterone Progesterone is secreted mainly by the corpus luteum of the ovary. It is also Formed in the placenta, adrenal cortex& testis. Progestin's include the naturally occurring hormone progesterone, 17- acetoxyprogesterone derivatives in the pregnane series, 19-nortestosterone derivatives (estranges), and norgestrel and related compounds in the gonane series. Progesterone 17-acetoxyprogesterone 19-nortestosterone pregnenolone, which is a progestin and is the precursor to all other steroid hormones. Pregnenolone is a prohormone. Progesterone is important in maintaining pregnancy. 27 sitaram
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  29. 29. Steroidal nucleus is essential for activity. Substitution at 17 α with ethynyl, methyl, ethyl reduce activity. Ethindrone more active orally than progesterone. Removal of CH3 at C19 is more active. E.g. (Norethindrone) Unsaturation of B or C ring of 19-Androstane derivatives increase activity. Acetyalation of the 17β –OH of norethindrone long duration of action. S .A.R OF PROGESTERONE 29 sitaram
  30. 30. Hormonal Contraceptives Ethinyl estradiol (a synthetic estrogen) and mestranol are the estrogens most frequently used . Levonorgestrel is the most common progestin used worldwide. This type is the most frequently used in the United States, which contain both an estrogen and a progestin. Levonorgestrel 30 sitaram
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  32. 32. 32 sitaram Steroids Formation from Cholesterol
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