Pharmacology of Sex Hormones

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Introduction

Growth and development of sex structures

Behaviour

Sex hormones are produced in the body, which are required for several

important processes

Therefore, if we try to change something, the body will resist our changes

Generally, we want to modify sex hormone release to treat a disease

The production of these hormones are under feedback control

In early pregnancy, progeterone, estrogen and hCG (Human chorionic

gonadotropin) are produced

Hormonal release tends to be tied to circadian rhythms, so hormone release

tends to be pulsatile (released with visible peaks)

Control and secretion of hormones

Factors stimulate the hypothalamus to release gonadotropin releasing

hormone (GnRH) to the anterior pituitary

GnRH stimulates the anterior pituitary to secrete Follicular Stimulating

Hormone (FSH) and Luteinizing Hormone (LH)

Testosterone from the testes

Oestrogen and Progesterone from the ovaries

They stimulate the release of either

Finally, the whole system is under negative feedback control, where these

sex hormones will prevent the production of more sex hormone

The secretion of sex hormones ultimately depends on control by the brain

Gonadotropin releasing hormone

Pharmacology of sex hormones

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Responsible for stimulating the anterior pituitary to secrete LH and FSH

Also released in pulses

Give GnRH continuously

But this is accompanied by a flare of sex hormone release due

to the initial agonist action by GnRH

This causes the receptors in the anterior pituitary to become

desensitised, and stop releasing FH and LSH to reduce sex hormonerelease

Remember back to oncology, groselin injections is an injection

of GnRH. This comes with tumour flare as well.

Used to treat testicular cancers and endometriosis (extra

endometrium growing where it shouldn't be)

Decreasing sex hormones

Needs to be given in pulses (otherwise the receptors in the pituitary

will become desensitised, leading to a decrease of hormones as seen

above)

Increasing sex hormones

Has two clinical uses:

Removes the negative feedback, makes the body think it doesn't have

enough sex hormone so it makes more

Another way to increase sex hormone production is to block the action of the sex

hormone against the receptors in the hypothalamus and anterior pituitary

The action of estrogen

17 beta-estradiol

17 beta-estrone

17 beta-estriol

Actually a group of three steroids (in order of potency):

Estrogen receptor (ER) alpha

ER beta

They bind to estrogen receptors, which there are two types of

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Intracellular

Exist in dimers

The dimers are able to be made up of either just alpha, beta or a mix of the

two types

The receptors are

Binds to a specific response element in the DNA, called the estrogen

response element (ERE)

OR it can bind to and activate kinases in the cytosol

Once an estrogen binds to the receptor dimer:

Either way, gene transcription is activated

Because there are two types of receptors, and at least three combinations

available, different tissues will be affected differently by estrogens.

Functions of estrogens

Produce sex structures

During development

Breasts and uterus developed

Prepares body for producing babies

Deposition of fat around the abdomen

This is called bone arrest

Stop bones from growing longer, stops vertical growth

At puberty

Increases HDL

Decreases bone resorption (prevents osteroporosis)

Retention of salt and water as it has mineralcorticoid activity

Increased coagulability (especially deep vein thrombosis , DVT)

During menstral cycles

Increase uterine blood flow to keep the baby alive

Growth of the breast duct system to prepare for milk production

During pregnancy

Neuroprotective

Causes mood swings

Develops structures in the brain for women

Effects on the CNS

Estrogen as a drug

Contraception

As shown above, estrogen is used for different reasons in the body depending on

age

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Protect against osteoporosis

Menstrual disorders

Some cancers

Ethinyl estradiol is orally active as it is resistant against first pass

metabolism (natural estrogens have low bioavailability due to extensive

first pass)

Synthetic estrogens also have a longer half-life (hours, instead of minutes)

Synthetic estrogens are much more potent compared to their natural

counterparts

Although natural estrogens can be used, synthetic estrogens (especially ethinyl

oestradiol) are much better as a drug:

Progesterone

Produced mainly by the corpus luteum and the placenta

Developing the breast duct system (in conjunction with estrogen) to

prepare for milk production

Allows the smooth muscle in the uterus to relax, to allow the uterus to

grow in size to accomadate for the growing foetus.

Involved in two things during pregnancy:

The synthetic forms are orally active, while progesterone itself will be

orally inactive due to extensive first pass metabolism

Again, synthetic forms of progesterone are available

Androgenic activity, women may grow beards

Acne (therefore, progesterone is not recommended for people with acne)

Fluid retention (due to mineralcorticoid activity)

Three common side effects are:

Oxytocin

Causing contractions in the uterus

Milk production in the breasts

Maternal behaviours in the CNS

Oxytocin is responsible for three things:

It is secreted by the posterior pituitary (GnRH is released from the anterior

pituitary)

Prolactin

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Hormone responsible for triggering milk release from the breasts

Causes the release of Prolactin Releasing Factor (PRF) to the anterior

pituitary

PRF causes the anterior pituitary to release prolactin

Prolactin then acts on breast tissue to trigger milk release

Triggered by suckling action

Therefore, a dopamine agonist may be used to prevent excess

prolactin/milk production

Dopamine will prevent the release of prolactin from the anterior pituitary

Menopause

Usually occurs around 50 years of age

Menopause is accompanied by some unpleasant symptoms due to

hormonal changes

Menopause is when a female stops ovulating for the rest of her life

First stage

Estrogen is reduced while FSH is increased (this is due to the

feedback loop kicking in, trying to get estrogen back up)

Periods get close and less frequent

Peri-menopause

Last stage

This is where the classic symptoms present themselves

Post-menopause

Split into two stages:

Hot flushes due to reduced estrogen release

This can lead to dryness, which can either be painful or itchy

Vaginal atrophy

Chance of osteoporosis, as estrogen normally prevents bone reabsorption

Mood disorders (as if they were having a period)

Symptoms of menopause are:

Hormone replacement therapy and menopause

Hormone replacement therapy (HRT) may be used to relieve the symptoms of

menopause

Estrogen-only replacement is for people who don't have uteruses,

because they don't have an endometrial layer anymore

Otherwise, HRT involves estrogen and progesterone to prevent

endometrial cancers

Use of estrogen alone will lead to an increase in endometrial cancer

However, there are some limitations

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Associated with greater chances of stroke (hypercoagulation due to

estrogen) and breast cancer (estrogen exposure is linked to breast cancer)

Associated with reduced hip fractures (estrogen prevents bone

breakdown)

Protection against colorectal cancers

Reduced symptoms

Then what's the point of HRT?

The recommendation now is to use it for healthy people under 60 for no longer

than 5 years

Testosterone

A bit produced in adrenal cortex and ovaries

Produced mostly in the testes of males

Growth of hair (and loss of hair later!)

Spermatogenesis

Muscle growth

Erythropoiesis (production of red blood cells)

Prevent bone reabsorption

Responsible for several different functions:

Again controlled by pulsatile release

98% bound to proteins, 2% free (active form)

40% of testosterone is tightly bound to sex hormone binding globulins,

while the rest is loosely bound to others, including albumin

Is affected by protein binding

Used as a replacement if testosterone can't be secreted normally due to

pituitary or gonad damage.

Only problem is it can lead to a long-term suppression of secretion of GnRH

(because the exogenous testosterone will cause the hypothalamus to

reduce secretion as a part of a negative feedback mechanism)

Testosterone is used clinically

Cyproterone is a partial agonist at androgen receptors. It works by

reducing GnRH production by negative feedback

Low doses are useful to prevent acne and as a contraceptive

High doses are used against testosterone dependent cancers

It may also be used in psychiatry to blunt the sex drive in aggressive males

Anti-testosterone activity also has some uses:

Decreased libido, osteoporosis, decreased body hair etc. suggests

reduction in testosterone

This may not be attributed to reduced production of testosterone, but

rather may be due to increased binding with sex hormone binding globulin,which leads to less free testosterone

However, this field is not well researched (i.e. ignore it)

Does male menopause exist?

Pharmacology of Sex Hormones

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