This document discusses sex hormones, including androgens (male sex hormones like testosterone), estrogens (female sex hormones), and progesterone (the corpus luteum hormone). It covers the classification, sources, mechanisms of action, structure-activity relationships, and uses of these steroidal hormones. The hormones are produced in the gonads and act on secondary sex characteristics and reproductive functions through binding intracellular receptors and regulating gene expression.

1. Sex Hormones
By: Vinayak M.Gaware
Department of Pharmaceutical Chemistry

2. Introduction
 Hormones are substances which are secreted by the
ductless glands (Endocrine Glands) in very minute
amounts and exert important functional effects upon
other tissues.
 They do not relate to each other chemically.
 Physiological activity of these hormones serve as a basis
for their classification.
 The steroidal hormones possess a steroidal nucleus and
are produced in the gonads (i.e. testes in the male and
ovaries in the female).
 Their activity appears to be controlled by the following
three gonadotropic hormones.

3.  Follical Stimulating Hormones of FSH
 Lutenizing Hormone or LH or interstitial cell
stimulating hormone (ICSH) and
 Luteotropin or prolactin.

5.  Although estrogens and progesterone are usually
called female sex hormones and testosterone is
called a male sex hormone, all of these steroids are
biosynthesized in both males and females.
 Progesterone serves as a biosynthetic precursor to
hydrocortisone and aldosterone and, to a lesser
extent, to testosterone and estrogens.
 Testosterone is one of the precursors of estrogens.
Estrogens and progesterone are produced in much
larger amounts in females, however, as is
testosterone in males. These hormones play
profound roles in reproduction, in the menstrual
cycle, and in giving women and men their
characteristic physical differences.

8. Classification
 The Sex Hormones are of three types:
 Androgens (Male Sex Hormones)
 Estrogens (Female Sex Hormones)
 The Corpus Luteum Hormone

9. Androgens (Male Sex Hormones)
 Androgens originate in the adrenal cortex and
gonads and primarily affect maturation and function
of secondary sex organs (male sexual
determination).
 Testosterone (C-19): an androgen, male sex
hormone synthesized in the testes, responsible for
secondary male sex characteristics, produced from
progesterone; most potent androgen in blood.
Testosterone

11.  The term androgens includes a number of natural
and synthetic compounds that exhibit the
masculinizing and anabolic action of testosterone.
 The main physiological, endogenic, and androgenic
hormones. Androgen, commonly referred to as male
sex hormones or anabolic steroids, in particular,
testosterone, are produced by male sex glands in
the male body.

12. Common Anabolic Androgenic Agents

13.  Testosterone is the natural androgen secreted by the
interstitial cells of the testis; it is necessary for
normal spermatogenesis, for the development of the
male secondary sex characteristics, and for the
growth, at puberty, of the sexual apparatus. It is
converted by hydroxylation to the active
dihydrotestosterone.
 Protein anabolism especially in skeletal muscles is
increased by androgens. Growth of bone is
promoted, but the rate of closure of the epiphyses is
also hastened, causing short stature in cases of
precocious puberty or of androgen overdose in the
course of treating hypo gonadal children.

15.  Metabolism of
Testosterone
to its major
active and
Inactive
Metabolites

16. SAR of Androgen Agents
 For a substance to have activity, it must contain the
androstane skeleton.
 Oxygen at C-3 and C-17 are not essential for the
androgenic activity.
 The basic nucleus having 5β-androstane which having
androgenic activity, whereas 5α-androstane having no
activity.
 There should not be chain constriction or extension
because it leads to finished the activity.

17.  Introduction of 3-hydroxy group and 3-keto group
enhance the activity.
 Hydroxy group at C-17 position has no androgenic or
anabolic activity.
 Halogen substitution produces compounds with
decreased activity except when placed at C-4 or C-9
position. For example, 9-fluoro derivatives produces
an anabolic effect 20 times that of 17α-methyl
testosterone

18.  Halogen introduction will decrease the activity except
the C-4 and C-9.
 Introduction of double bond at C-1 position increases
the anabolic activity for example –
methandrostenolone is more active than
methyltestosterone.
 Replacement of carbon atom at C-2 position by
oxygen (e.g. Oxandrolone) gives the oral anabolic
activity.

19.  Removal of –CH₃ group in testosterone gives 19-nor
testosterone with more anabolic activity and less
androgenic activity when compared with testosterone.
 The introduction of heterocyclic system into the steroid
nucleus in ring A improve the anabolic activity. For
example, stanozolol are found to possess more anabolic
activity, possessing pyrazole.

20. Mechanism of Effects
 Effects of testosterone in humans and other
vertebrates occurs by way of two main mechanisms:
 by activation of the androgen receptor (directly or as
DHT), and
 by conversion to estradiol and activation of
certain estrogen receptors.

21. Figure: Mechanism of Action of Androgen Receptor

22.  Free testosterone (T) is transported into the
cytoplasm of target tissue cells, where it can bind to
the androgen receptor, or can be reduced to 5 ±-
dihydrotestosterone (DHT) by the cytoplasmic
enzyme 5 ±-reductase.
 DHT binds to the same androgen receptor even
more strongly than T, so that its androgenic potency
is about 2.5 times that of T.
 The T-receptor or DHT-receptor complex undergoes
a structural change that allows it to move into the
nucleus and bind directly to specific nucleotide
sequences of the chromosomal DNA.
 The areas of binding are called hormone response
elements (HREs), and influence transcriptional
activity of certain genes, producing the androgen
effects.

23.  Effect of Testosterone
when converted into
estradiol

24. Estrogens (Female Sex Hormones)
 Estrogen are a group of steroid compounds that
function as the primary female sex hormones.
 Three naturally occurring estrogen are estradiol,
estriol and estrone, In the body these are all
produced from androgens through enzyme action.
 SOURCE
 Estrogen are produced by developing follicles in the
ovaries, the corpus luteum and the placenta, some
estrogens are also produced in smaller amounts by
other tissues such as liver, adrenal glands and the
breasts .
 These secondary source of estrogen are especially
important in post menopausal women.

27. Classification
 Chemically estrogenic substances are divided into
three classes:
 Human Estrogens and derivatives
 Stallion Estrogens
 Synthetic or Non-steroidal Estrogens

28. Human Estrogens
These compounds
are naturally
occurring
estrogens in
human and are
regarded as
derivatives of
Estranes.

29. Stallion Estrogens
 Human urine of pregnancy is an abundant source of
natural estrogens but stallion excretes more
estrogen than any other living form.
Equilin Equilenin

30. Synthetic or Non-Steroidal Estrogens
 As the name indicates, these are the synthetic
compounds having a considerable estrogenic
activity.
Diethylstilbestrol
Chlorotrianisene

31. SAR of Estrogens
 Presence of steroid nucleus
(cyclopentanoperhydrophenanthrene ring) is essential
for pharmacological activity of oestrogen.

32.  Modification of ring A
 Ring A is aromatic in nature in all estrogens, which is
essential for estrogenic activity.
 -OH group at C-3 is also essential for estrogenic
activity. Removal of this –OH group leads to loss of
activity.
 Substitution at C-1 reduces the activity.
 Smaller groups can be substituted at positions C-2
and C-3. Ex. 2- hydroxyl ethinyl estradiol.

33.  Modification of Ring B
 Presence of unsaturation at positions C-6 and C-7
increase the potency of drug. Similarly additional
double bond between C-8 and C-9 positions further
increase the activity. Ex. Equilin, equilenin.
 7α-substituents show increased activity.

34.  Modification of Ring C
 Substitution of –OH groups at C-6, C-7 and C-11
position reduces the activity.
 Substitution at C-11 β-position with alkyl group or
alkoxy groups which has 17-ethinyl group greatly
increase affinity for the estrogenic receptor
compared to estradiol. Ex. 11β-methoxy or 11β-ethyl
estradiol.
 –CH2Cl group at C-11 with β-configuration shows
more potent activity.
 Larger substituents, ex. N,N-dialkyl undecylamides,
shows antagonistic activity.

35.  Modification of Ring D
 17 β-OH is essential for estrogenic activity.
 Epimerization of 17 β-OH to a α-configuration
formation of less active analogues.
 17 α-Ethinyl or 17 α-vinyl groups provide greatest
activity due to increase in polarity. Ex. Ethinyl
estradiol.
 Reversal of configuration of C-2 or replacement of H
for ethynyl in D ring leads to loss of estrogenic
activity or increase in androgenic activity.
 The distance between C-3 and C-17 –OH groups
should be 11-12 Aᵒ, presence of this hydrophobic
scaffolding helps to optimize estrogenic activity. Ex.
All estrogens and diethylstilbestrol.

36. Mechanism of Action
 The actions of estrogen are mediated by the estrogen
receptor (ER), a dimeric nuclear protein that binds to
DNA and controls gene expression. Like other steroid
hormones, estrogen enters passively into the cell where it
binds to and activates the estrogen receptor.
 The estrogen: ER complex binds to specific DNA
sequences called a hormone response element to
activate the transcription of target genes.
 Since estrogen enters all cells, its actions are dependent
on the presence of the ER in the cell.
 The ER is expressed in specific tissues including the
ovary, uterus and breast.
 The metabolic effects of estrogen in postmenopausal
women have been linked to the genetic polymorphism of
the ER.

37.  While estrogens are present in
both men and women, they are usually present at
significantly higher levels in women of reproductive
age. They promote the development of
female secondary sexual characteristics, such
as breasts, and are also involved in the thickening of
the endometrium and other aspects of regulating the
menstrual cycle. In males, estrogen regulates certain
functions of the reproductive system important to the
maturation of sperm and may be necessary for a
healthy libido.

39. The Corpus Luteum Hormone (Progestin)
 They also called luteum hormones, mostly secreted by the
corpus luteum portion of the ovary and the metabolised to
various inactive products, e.g. pregnanediol. The
metabolites are essentially excreted through urine.
 The natural progestational hormone is progesterone , which
is secreted by the corpus luteum in the second part of the
menstrual cycle.
 Small amounts are also secreted by the testis in the male
and the adrenal cortex in both sex and large amounts are
secreted by the placenta.

40. Uses
 Prevent habitual abortion.
 For treatment of functional uterine bleeding resulting due
to the lack of oestrogens and progesterone
 For treatment of dysmenorrhoea or painful menstruation
 Pregnancy diagnosis,
 Oral contraceptives,
 For treatment of an advanced carcinoma of breasts.
 To treat premature discomfort in the breasts
 Progesterone can be used to treat catamenial epilepsy.
 Progesterone also has a role in skin elasticity and bone
strength, in respiration, in nerve tissue and in female
sexuality, and the presence of progesterone receptors in
certain muscle and fat tissue.

41. Classifications
 Derivatives of progesterone
Progesterone
Medroxyprogesterone Acetate

43.  Synthetic Progestins-Testosterone and
Nortestosterone Derivatives

44.  Miscellaneous Synthetic Progestins

45. SAR of Progesterone
 Presence of steroid nucleus
(cyclopentanoperhydrophenanthrene ring) is
compulsory for pharmacological activity of progestins

46.  Ketone group at C-3 is not essential for the activity of
progesterone, because removal of it retains the
progesterone. Ex. Desogestrel.
 Presence of ethyl or ethinyl or diethyl group at C-17
in α configuration increase bioavailability through
oral route, but decreases by subcutaneous route.
 The l-enantiomer of the compound resulting from
substitution of ethyl group at C-ring junctures found
to be active.
 Derivatives of the progestins like 3-oxime-17-ester
decreases androgenic side effect, while retaining
progestin activity.

47.  Introduction of halogen or –CH₃ at C-6 configuration
increases hormonal activity or C-7 atoms in α of
progestins. Ex. Medroxyprogesterone acetate.
 Presence of methyl at C-19 is not essential for
activity because its removal leads to formation of
compound with increased activity.
 Addition of Cl or F at C-21 prevents metabolic
hydroxylation, which also enhances oral
effectiveness.
 Unsaturation at ring A and B enhances activity of 19-
norethindrone. Ex. Trimegestone.
 Addition of methyl at 18th position increases the
activity.
 In ring D at C-17, acetylation of 17α-hydroxyl group
increases the duration of action.

49. Mechanism of Action of Steroid Hormones
 Steroid hormones are soluble in the plasma
membrane and readily enter the cytosol.
 Steroids bind to intracellular receptor either in the
cytosol or in the nucleus.
 The hormone-receptor complex acts as a
transcription factor which turns on / turns off the
genes.