A brief explanation of androgens, oestrogens and progesterone. an explanation of ER signalling pathway and their pharmacological aspects

1. SEX HARMONES
A.Hemanth Babu(Mpharm)
—RECQUIRED FOR SEXUAL FUNCTIONS

2. CONTENTS
• Introduction
• Formation of sex harmones
• Types of sex harmones
• Male sex harmones
• Female sex harmones
• Molecular and cellular
mechanism of action
• Harmone imbalances and
causes to human body
ESTROGEN
TESTOSTERONE PROGESTERONE
MALE SEX
HARMONE
FEMALE SEX HARMONES

3. The endogenous oestrogens are estradiol (the most potent), ostrone and ostriol; numerous exogenous
synthetic forms (e.g. ethinylestradiol) exist.
Estrogen is a group of steroid hormones that play a crucial role in the development and maintenance
of various physiological processes in the body. There are several types of estrogen, each with distinct
functions:
1. **Estradiol (E2)**: Estradiol is the most potent and abundant form of estrogen in reproductive-age
women. It is primarily produced by the ovaries and plays a central role in regulating the menstrual
cycle, promoting the development of secondary sexual characteristics, and maintaining bone health.
Estradiol also a
ff
ects the cardiovascular system, brain function, and skin health.
2. **Estriol (E3)**: Estriol is mainly produced during pregnancy, particularly by the placenta. It has
weaker estrogenic activity compared to estradiol and is often used as an indicator of fetal well-being.
Estriol levels rise signi
f
icantly during pregnancy and decline after childbirth.
Female sex hormones, primarily estrogen and progesterone, play crucial roles in the development and
regulation of female reproductive functions and secondary sexual characteristics. These hormones are
produced in the ovaries, although small amounts are also synthesized in the adrenal glands and other
tissues. Let's explore the molecular and cellular mechanisms of action of female sex hormones:
ESTROGEN

4. 3. **Estrone (E1)**: Estrone is less potent than estradiol and is primarily produced in adipose
tissue after menopause. It is the dominant estrogen during menopause and contributes to
maintaining certain estrogenic functions, such as bone density and skin health.
4. **Estetrol (E4)**: Estetrol is a less well-known estrogen that is produced only during
pregnancy. It is mainly synthesized by the fetal liver and has been explored for potential
therapeutic uses due to its unique properties and limited estrogenic e
ff
ects.
5. **17β-Hydroxysteroids**: This category includes various estrogenic compounds, such as 17β-
estradiol, 17α-estradiol, and others. These compounds have di
ff
erent a
ff
inities for estrogen
receptors and can have varying e
ff
ects on target tissues.
Estrogen receptors, mainly ERα and ERβ, mediate the e
ff
ects of these estrogen hormones. These
receptors are found in various tissues throughout the body, including the reproductive organs,
brain, bone, cardiovascular system, and skin. The binding of estrogen to its receptors triggers a
cascade of cellular events that regulate gene expression and lead to speci
f
ic physiological
responses.

5. Estrogen receptor (ER) signaling is a complex molecular process that involves the interaction of
estrogen hormones with their corresponding receptors in cells. Here's a brief overview of the
mechanism:
1. **Estrogen Binding**: Estrogen, a steroid hormone, can be produced by the ovaries, placenta, and
adipose tissue. When circulating estrogen reaches its target cells, it di
ff
uses across the cell membrane.
2. **Receptor Activation**: Inside the cell, estrogen binds to estrogen receptors (ER), which exist in two
main isoforms: ERα and ERβ. Once bound, the ER undergoes a conformational change, allowing it to
form a dimer (usually ERα-ERα or ERα-ERβ) and exposing its DNA-binding domain.
3. **DNA Binding**: The ER dimer with estrogen now binds to speci
f
ic DNA sequences known as
estrogen response elements (EREs) within the promoter regions of target genes. This interaction is
facilitated by coactivators and corepressors.
4. **Transcription Regulation**: The binding of ER to EREs initiates a series of events that lead to the
recruitment of various transcriptional coactivators. These coactivators interact with the ER to promote
the transcription of target genes, resulting in the synthesis of messenger RNA (mRNA).
ER SIGNALING PATHWAY

6. 5. **mRNA Translation**: The newly formed mRNA is then transported to the cytoplasm and
translated into speci
f
ic proteins, which can include growth factors, enzymes, and other
regulatory proteins.
6. **Cellular Response**: The newly synthesized proteins play a key role in mediating the diverse
e
ff
ects of estrogen signaling. These e
ff
ects can vary widely depending on the tissue and target
genes involved. ER signaling is involved in regulating various physiological processes, such as
development, reproduction, bone health, cardiovascular function, and more.
7. **Feedback Regulation**: To maintain balance, the estrogen signaling pathway includes
feedback mechanisms. The expression of certain genes, such as those encoding enzymes
involved in estrogen synthesis, can be regulated by ER-mediated signaling.
8. **Degradation and Recycling**: After its function is ful
f
illed, ER can be degraded by the
ubiquitin-proteasome system. The ER molecules can also be recycled for further rounds of
signaling.
Overall, estrogen receptor signaling is a dynamic and intricate process that orchestrates various
cellular responses essential for normal physiology. Dysregulation of this pathway can contribute
to a range of health issues, including hormone-dependent cancers and metabolic disorders.

7. • Estrogen is additionally produced by fat cells and
therefore the adrenal. At the onset of puberty,
estrogen plays a task within the development of so-
called female secondary sex characteristics, like
breasts, wider hips, and bush and armpit hair.
• Estrogen also helps regulate the cycle, controlling
the expansion of the uterine lining during the
primary part of the cycle. If the woman's egg isn't
fertilized, estrogen levels decrease sharply and
menstruation begins. When the egg is fertilized,
estrogen functions with progesterone, another
hormone, in order to prevent ovulation at the time
of pregnancy.
PHARMACOLOGICAL
ACTIONS

8. • During pregnancy, the placenta produces estrogen, speci
f
ically the hormone estriol. Estrogen
controls lactation and other changes within the breasts, including at adolescence and
through pregnancy.
• In bone formation, estrogen acts as instrumental in working with vitamin D, calcium, and
other hormones in order to e
ff
ectively break down and rebuild bones consistent with the
body's natural processes. As estrogen levels stop in a time of life, the process of rebuilding
bones slows, with postmenopausal women
f
inally breaking down more bone than they
produce. This is the reason why often postmenopausal women are fourfold more likely to
su
ff
er from osteoporosis than men, consistent with the Cleveland Clinic.
• Estrogen also plays a pivotal role in blood coagulation, maintaining the strength and thickness
of the vaginal wall and hence the urethral lining, vaginal lubrication, as well as many other
bodily functions.

10. Estrogen Side E
ff
ects
• While there are many bene
f
its to estrogen, there are side e
ff
ects as well in some cases. For instance,
elevated estrogen levels may cause an increased risk for injury. A 2016 study published within the
journal Medicine & Science in Sports & Exercise found that the danger of ligament injury could also
be mitigated by the utilization of oral contraceptives.
• The majority of breast cancers also are sensitive to estrogen, meaning that estrogen promotes tumor
growth. These cancers are hormone receptor-positive breast cancers. For people with these
cancers, treatments to lower estrogen levels or block estrogen production are often wont to help
prevent cancer recurrence after surgery or to slow cancer growth.
• According to carcinoma .org, alcohol can increase a woman's risk of hormone-receptor-positive
carcinoma. Alcohol also enhances the consequences of estrogen in driving the expansion of
carcinoma cells, consistent with 2016 research at the University of Houston.
• Endometriosis is another estrogen-dependent disease. For the treatment of endometriosis, reducing
estrogen levels and providing non-estrogen treatments have all been considered. The matter is that
reducing the amount of estrogen in women can cause infertility.

11. The natural progestational hormone (progestogen) is progesterone . This is secreted by the corpus
luteum in the second part of the menstrual cycle, and by the placenta during pregnancy. Small
amounts are also secreted by the testis and adrenal cortex.Progestogens act, as do other steroid
hormones, on nuclear receptors. The density of progesterone receptors is controlled byostrogens
Preparation
There are two main groups of progestogens:
1. The naturally occurring hormone and its derivatives (e.g. hydroxyprogesterone,
medroxyprogesterone, dydrogesterone). Progesterone itself is virtually inactive orally, because of
p re sy s t e m i c h e p a t i c m e t a b o l i s m . O t h e r d e r i v a t i ve s a re av a i l a b l e fo r o r a l
administration,intramuscular injection or administration via the vagina or rectum.
2. Testosterone derivatives (e.g. norethisterone, norgestrel and ethynodiol) can be given orally.
The
f
irst two have some androgenic activity and are metabolised to give ostrogenic products.
Newer progestogens used in contraception include desogestrel and gestodene; they may have
fewer adverse e
ff
ects on lipids than ethynodiol and may be considered for women who experience
side e
ff
ects such as acne, depression or breakthrough bleeding with the older drugs. However,
these newer drugs have been associated with higher risks of venous thromboembolic disease (see
later).
PROGESTERONE

12. Actions
The pharmacological actions of the progestogens are in essence the same as the physiological actions of
progesterone described previously. Speci
f
ic e
ff
ects relevant to contraception are detailed later.
CLINICAL USES
• Contraception:
• with ostrogen in combined oral contraceptive pill;
• as progesterone-only contraceptive pill;
• as injectable or implantable progesterone-only contraception;
• as part of an intrauterine contraceptive system.
• Combined with ostrogen for ostrogen replacement therapy in women with an intact uterus, to prevent
endometrial hyperplasia and carcinoma.
• For endometriosis.
• In endometrial carcinoma; use in breast and renal cancer has declined.
• Poorly validated uses have included various menstrual disorders.Contraception:

13. Pharmacokinetic aspects
Injected progesterone is bound to albumin, not to the sex steroid-binding globulin. Some is stored in
adipose tissue.
It is metabolised in the liver, and the products, pregnanolone
ANTIPROGESTOGENS
Mifepristone is a partial agonist at progesterone receptors.It sensitises the uterus to the action of
prostaglandins. It is given orally and has a plasma half-life of 21 h. Mifepristone is used, in combination
with a prostaglandin (e.g. gemeprost), as a medical alternative to surgical termination of pregnancyThe
antiprogestogen mifepristone, in combination with prostaglandin analogues, is an e
ff
ective medical
alternative to surgical termination of early pregnancy.
CLINICAL USES
Medical termination of pregnancy: mifepristone (partial agonist) combined with a prostaglandin (e.g.
gemeprost).

14. Testosterone is the main natural androgen. It is synthesised mainly by
the interstitial cells of the testis, and in smaller amounts by the ovaries
and adrenal cortex. Adrenal androgen production is in
f
luenced by
adrenocorticotrophic hormone (ACTH, corticotrophin). As for other
steroid hormones, cholesterol is the starting substance. Dehydroe-
piandrosterone and androstenedione are important intermediates. They
are released from the gonads and the adrenal cortex, and converted to
testosterone in the liverActions
In general, the e
ff
ects of exogenous androgens are the same as those of
testosterone, and depend on the age and sex of the recipient. If
prepubertal boys are given androgens, they do not reach their full
predicted height because of premature closure of the epiphyses of the
long bones. In boys at the age of puberty, there is rapid development of
secondary sexual characteristics (i.e. growth of facial, axillary and pubic
hair, deepening of the voice), maturation of the reproductive organs and
a marked increase in muscular strength.
ANDROGENS

15. Preparations
Testosterone itself can be given by subcutaneous implantation or by transdermal patches
(male replacement dose approximately 2.5 mg/ day). Various esters (e.g. enanthate and
propionate) are given by intramuscular depot injection.
Testosterone undecanoate and mesterolone can be given orally.
Pharmacokinetic aspects
If given orally, testosterone is rapidly metabolised in the liver. Virtually all testosterone in the
circulation is bound to plasma protein - mainly to the sex steroid-binding globulin.
Approximately 90% of endogenous testosterone is eliminated as metabolites. The elimination
half-life of the free hormone is short (10-20 min). It is converted in the liver to androstenedione
(see Fig. 36.3), which has weak androgenic activity. Synthetic androgens are less rapidly
metabolised, and some are excreted in the urine unchanged.

16. Unwanted e
ff
ects
• Unwanted e
ff
ects of androgens include decreased gonado-trophin release during continued use,
with resultant male infertility, and salt and water retention leading to edema.
• Adenocarcinoma of the liver has been reported. Androgens impair growth in children (via
premature fusion of epi-physes), cause acne and lead to masculinisation in girls.
• Adverse e
ff
ects of testosterone replacement and monitoring for these are reviewed by Rhoden
and Morgentaler (2004).
Clinical uses of androgens
Androgens (testosterone preparations) as hormone replacement in:
- male hypogonadism due to pituitary or testicular disease (e.g. 50-100 mg per day as gel applied to
the skin)

17. Androgens can be modi
f
ied chemically to alter the balance of anabolic and other e
ff
ects.
'Anabolic steroids' (e.g. nandrolone) increase protein synthesis and muscle development
disproportionately, but clinical use (e.g. in debilitating or muscle wasting disease) has been
disappointing.ANABOLIC STEROIDS
ANABOLIC STEROIDS

18. ANTI-ANDROGENS
Both estrogens and progestogens have anti-androgen activity, oestrogens mainly by inhibiting
gonadotrophin secretion and progestogens by competing at androgen receptors in target organs.
Cyproterone is a derivative of progesterone and has weak progestational activity. It is a partial
agonist at androgen receptors, competing with dihydrotestosterone for receptors in androgen-
sensitive target tissues. Through its e
ff
ect on the hypothalamus, it depresses the synthesis of
gonadotropins. It is used as an adjunct in the treatment of prostatic cancer during the initiation of
GnRH agonist treatment (see later). It is also used in the therapy of precocious puberty in males and
of masculinisation and acne in women. It also has a central nervous system e
ff
ect, decreasing
libido, and has been used to treat hyper-sexuality in male sexual o
ff
enders. Flutamide is a non-
steroidal anti-androgen used with GnRH agonists in the treatment of prostate cancer.

19. CLINICAL USES
Anti-androgens (e.g.
f
lutamide, cyproterone) are used as part of the treatment of prostatic cancer.
• 5a-Reductase inhibitors (e.g.
f
inasteride) are used in benign prostatic hyperplasia.
Drugs can have anti-androgen action by inhibiting synthetic enzymes. Finasteride inhibits the
enzyme (5o-reductase) that converts testosterone to dihydro-testosterone (see Fig. 36.3). This
active metabolite has greater a
ff
inity than testosterone for androgen receptors in the prostate
gland. Finasteride is well absorbed after oral administration, has a half-life of about 7 h, and is
excreted in the urine and faces. It is used to treat benign prostatic hyperplasia, although
-adrenoceptor antagonists, for example, terazosin or tamsulosin (Chs 15 and 30), are more e
ff
ective
(working by the entirely di
ff
erent mechanism of relaxing smooth muscle in the capsule of the
prostate gland and opposing ∞-adrenoceptor-mediated prostatic growth).Surgery is another
option.

20. Causes of androgen de
f
iciency
The most common cause of androgen de
f
iciency is a genetic condition called Klinefelter
syndrome, which goes undiagnosed in up to 75% of men who have it4.
Androgen de
f
iciency is caused by problems with testosterone production by the testicles. This
can be due to the testicles themselves not working properly (known as primary hypogonadism),
or because there’s a problem with the production of the hormones that control the testicles’
function(secondary hypogonadism).
Primary hypogonadism can be caused by genetic abnormalities, undescended testes, testicular
injury, some types of infections (e.g. mumps) or other diseases (e.g. haemochromatosis).
Secondary hypogonadism can be caused by some genetic syndromes (e.g. Kallmann’s
syndrome), disease, or injury to the pituitary gland at the base of the brain.

21. REFERENCES
• _KD - Tripathi-Essentials of medical pharmacology 7th edition
• RANG AND DALE’S - Pharmacology 9th edition
• WWW.COLLEGEDUNIA.COM