S.SEETARAM SWAMY, M.Pharm.,
Dept. of Pharmaceutical Chemistry,
Steroid hormones and related products represents one of the most widely
used classes of therapeutic agents.
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
These drugs are primarily in:
Cholesterol synthesis occurs in smooth ER and enzymatic conversion
occur in mitochondria.
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
Activated receptor binds to DNA and initiates/alters gene transcription
Hormone must enter cell first
A general scheme for steroid hormone receptor interactions:
1. Steroid crosses cell
2. Steroid binds cytosolic
receptor which is kept
inactive by heat-shock
3. Binding alters receptor
4. Active receptors bind
directly to DNA and
5. mRNA enters
cytoplasm and a new
protein is synthesized.
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,
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
The PR can also be found in two forms, but these are derived from a
Progesterone receptor A(PRA)
Progesterone receptor B(PRB)
Progesterone receptor B mainly mediates the stimulatory actions of
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.
Steroid hormones are classified in to two types.
Adrenal cortical hormones.
The adrenal cortex secrets steroidal hormones which have
Glucocorticoids - Hydrocortisone
Sex hormones - Androgens & Estrogens
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.
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.
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
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.
Sex hormones are usually classified as follows
i. Androgens (Male sex hormones)
ii. Oestrogens (Female or Follicular hormones)
iii. Gestogens (Corpus luteum hormones)
Testosterone exerts its physiological activity after its conversion to
A steroidal skeleton is minimum structural requirement to have
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
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
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.
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.
In men, effects:
Estrogens and progestin's are hormones that produce many physiological
Female sex hormones
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
Estrogens and Progestin's
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
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.
Development of secondary sex characteristics.
Growth of uterus during puberty.
Initial growth of endometrium during menstrual cycle.
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
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
Compound without steroid nucleus also shows activity.
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
pregnenolone, which is a progestin and is the precursor to all other steroid
Pregnenolone is a prohormone.
Progesterone is important in maintaining pregnancy.
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
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.