Reproduction v0.1

7/31/2019 Reproduction v0.1

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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?

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What are the hormones controlling the menstrual cycle?

GnRH

FSH

LH

Estrogen

Progesterone

GnRH release will cause FSH and LH release from the anterior pituitary

Causes endometrial regeneration (gets endometrium ready for

implantation)

Causes the cells responsible for LH secretion to become more

sensitive to GnRH, causing a massive spike in LH release

The follicles will produce estrogen which is important for two processes

The spike in LH and estrogen causes ovulation

FSH will stimulate follicles to grow, especially the Graafian follicle, which is the'main' follicle. Normally 10 or so eggs are stimulated per cycle, but only one

develops to maturity.

Progesterone causes endometrial build-up to prepare for implantationIt also triggers negative feedback to reduce the release of GnRH, FSH and

LH.

LH will stimulate the corpus luteum to develop, which then produces estrogens

and progesterone

Menstration (shedding of endometrium)

Secretion of FSH and estrogen to develop endometrium and follicles

Follicular phase (variable, days 1-14)

Growth of the endometrium

Development of the corpus luteum

Luteal phase (fixed, days 14-28)

The cycle is split into two phases:

Hormonal contraceptives

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How does the combination pill work?

Contains an estrogen and a progesterone analogue

Inhibit FSH secretion due to feedback loop

No FSH= no follicle production

Stops the endometrium from breaking down as well, stops bleeding

Estrogen will:

Inhibit LH secretion due to feedback loop

Prevents ovulation, as there is no LH spike

Also thickens up the mucus in the cervix, which makes it hard for the

sperm to get through

Progesterone will:

Both will work together to make the endometrium unsuitable for implantation

Remember: both progesterone and estrogen are released by the corpus luteum

and placenta during pregnancy. Therefore, the body thinks it is pregnant

How has the combination pill changed over the years?

Not suitable for use as the high doses of estrogen were linked to

thrombosis formation

Initially used high doses of estrogen and estrane progestins

One of the progestins is levonorgestrel, which is still used by itself in the

emergency pill

Problem is, the gonanes just have too much androgenic activity (women

growing beards)

The second generation used less estrogen and gonanes as the progestins

Not available in NZ, had too much DVT risk

But had a reduced androgenic effect due to other gonanes being used

The third generation used even less estrogen but still used gonanes

They have anti-mineralocorticoid and anti-androgenic effects, so they have

Fourth generation pills haven't dropped the estrogen levels, but have switched

to non-testosterone derived progestins

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a low side effect profile

Monophasic pills had the same amount of hormones in each pill

Biphasic pills has two types of pills in the pack with differing amounts of

hormone

Triphasic pills had three types of pills, each with a different amount of

hormones, making them more complicated

They thought having multiphasic pills would lead to better control

But it's not true

Another change we saw was to do with the amounts of hormones in the pills:

Useful due to a continuous release of hormones (making hormone

levels flat) while having a better adherence due to the long duration

of action per patch.

Otherwise same as the oral form

Not available in NZ

Patches

Can also be used long term (3 weeks), which leads to good

compliance

Beware of rings being displaced

Otherwise the same as the oral form

Not available in NZ

Vaginal rings

There are other routes of administration to consider:

Side effects of contraceptives

Breast tenerness

Mood

Weight gain

Estrogen

AcneProgestins

Nausea

Spotting/breakthrough periods

Longer, heavier bleeds or more severe cramps

Etc

Generally mild symptoms are common

Estrogen causes hypercoaguability (makes the blood more prone to

clotting)

Therefore, it is contraindicated for women suffering from

hypercoaguability; and treated as a caution for smokers

Note: although it increases the chance of DVT, pregnancy has a

greater chance for DVT

MI (myocardial infarction) , DVT (Deep Vein Thrombosis) and stroke

Remember: increased exposure to estrogen is a risk factor for breast

cancer

Increased chance of breast cancer

All reduced in chance

Endometrial cancer, colon cancer and ovarian cancer

But there are rarer (more severe) ones available

Contraindications and cautions

Might make it worseUndiagnosed endometrial bleeding

Estrogen causes hypercoaguability

Past or present circulatory disease

Thrombophillia

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Estrogen causes hypercoaguability

Would increase hypertension

Estrogen-induced hypertension

Migranes suggests reduced blood flow to the brain, estrogen increases the

chance of stroke

Migrane with aura

Metabolised by the liver

Liver disease

Lupus

Daughters have an increased chance of cancer of the uterus

Pregnancy

Smokers

Hypertension

Diabetes

Not contraindicated, but cautioned

Interactions

Therefore, need to be very careful with CYP3A4 inducers, as they can cause

failure (observe 7 day rule)

Phenytoin

Carbamazepines

Rifampacin

Anti-retrovirals

Metabolised by CYP3A4

Use barrier contraceptives during the unsafe period PLUS another 7 days

after treatment is finished

See workshop for more details

7 day rule is:

Normally, estrogen is conserved due to enterohepatic recycling

Only in combined oral contraceptives only, because estrogen is

important

Progesterone only pills have no estrogen, so they are not affected

If broad-spectrum antibiotics are used, the bacteria responsible for the

recycling may be killed off, leading to therapeutic failure

This has shown to be not true

Broad-spectrum antibiotics?

Diarrhoea.

It causes the loss of the pill, leading to treatment failure of both the

combined oral contraceptive and progesterone only pill

Observe 7 day rule

Then why do antibiotics cause therapeutic failure?

Progesterone only Pill (POP)

Given continuously

Compared to the COC which has 7 days of placebo pills

Also called the mini-pill

Only contains progesterone analogues (progestins)

Women with contraindications or cautions (see above)

Estrogen causes negative feedback inhibition of prolactin, caused

reduced milk production

Breastfeeding females

Used for:

May also be given as a long acting implant in case of poor compliance

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Only has a 3 hour window, compared to 12 hours for the COCs

Instead, the progesterone will cause the mucus around the cervix to

thicken, which prevents sperm from entering

Although it has a chance to prevent ovulation, its main mechanism of action

differs from COCs

But in reality, poor compliance leads to higher failure rates

Theoretically, it's just as effective as COC

Male pills

Females just don't trust males

Not a popular idea

Plus it's much easier to make a pill for females, as there are easy and safe

methods to prevent pregnancy

Continuous treatment with testosterone

Causes negative feedback inhibition as well

Problem is we don't know its long term health effects, and it takes 3

months to work and a 3 month washout

How would we pharmacologically use male contraception?



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Female hormones

Estrogen metabolism

High extraction, or first pass metabolism

Natural estrogens are rapidly metabolised by the body

Rapidly converted into estrone

And to estriol (least potent)

The most potent is 17-beta-estradiol

The metabolism of 17-beta-estrdiol is rapid, especially in the liver, which is why it

has high first pass metabolism, and has very little oral activity

Glucuronides can be formed. These can undergo hepatic recirculation

Sulfates can be formed, they may be converted back into the original

estrogen in tissues

In addition to this oxidation, natural estrogens will undergo conjugation:

Modified estrogens: orally active estrogens

Because 17-beta estradiol is the most active form, we want to keep it that way

without having it being rapidly converted to the weaker compounds

Because the 17 beta alcohol is oxidised, we can protect this from happening by

attaching something else at the 17 position:

Still widely used today

The above compound is ethinylestradiol, the first orally active estrogen

Modified estrogens: IM injection estrogens

For IM depot injections, we want something long lasting

Which is why these are prodrugs

The esters must be hydrolysed into free alcohols for the drug to become active

All about medchem



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Conjugated estrogens

Also known as equine estrogens

Works for hormone replacement therapy

These are structurally similar to human estrogens

Which is why they are water soluble (easy to inject)

Called conjugated estrogens as they are conjugated to sulfates

Progesterone

Ketones are reduced to alcohols OR

OH added at the 6 position

Also orally inactive due to first pass metabolism

Basic skeleton plus:

Two carbon chain sprouting from the 17 position

Two methyl groups

They are 21 carbon steroids

Semi-synthetic progestins: esterified

Again, these esterified hormones are good for a depot injection

Notice how an ester exists

The ester is hydrolysed to form the active 17-alphahydroxyprogesterone

(bottom right)

Medroxyprogesterone acetateis in depo-Provera (bottom left)

Semi-synthetic progestins: 19-nortestosterone derivatives

Fun fact: orally active progestins may be 19-nortestosterone derivatives

Notice how there is a bulky substituent at the 17 position. This is for oral

activity

Norethindrone (top) is one of them

If it is compared to testosterone (bottom), we can see the only chance between



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Because it's only a minor change, the older generations of progestins have

androgenic activity

Which means women can grow beards, get acne etc.

them (ignoring the 17 substituent) is the lack of the methyl group on the 19

position

But they give a higher risk of CVD, a second generation one is

recommended

New generations have reduced androgenic effects

Produced from spironolactone instead of a testosterone backbone

Gives antimineralocorticoid activity (like spirinolactone)

Causes reduced breast tenderness and blood pressure

Drospirenone is quite interesting

If added to COCs, it inhibits 5-alpha-reductase (normally responsible for

converting androgens to the more active form)

Therefore, it stops androgenic effects, which is important for women with

acne (remember: androgenic effects cause acne)

Cytoproterone goes further

Pharmacokinetics

Along with enterohepatic recycling

Again, first pass metabolism is something we need to keep in the back of our

minds

May be induced by ethinyl estradiol

Note: personally, I'm going to guess here and say that means more

progestins bind to SHBG, so they are less available. I don't think that has

any clinical effects though, which is why both are put into the same pills inCOCs

Sex hormones are bound to Sex Hormome Binding Globulin (SHBG)

10 (plasma):2 (milk) for levonogestrel and 10:1 for norethindrone

Little distribution into the milk occurs



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Misc. hormones

Odd because it has no phenol ring (but it still has effects)

Has several metabolites which have their effects around the body

The hydroxy metabolites have estrogenic effects on bone (prevent

osteoporosis) and vagina (prevent dryness and itching)

The delta metabolites have progesteronic effects on the endometrium,

and androgenic effects on the brain

Tibolone is a pro drug used in hormone replacement therapy

Actually causes more estrogen to be released, because it inhibits the

negative feedback loop

i.e. makes the brain think there isn't enough estrogen, because it's

sensor (estrogen receptors) have been blocked

The E isomer is anti-estrogenic (antagonist)

The Z isomer is estrogenic (agonist)

Clomiphene is very interesting due to its isomerism

We've met this drug in GI, where it can be used to reduce gastric acid

production to protect against the harmful effects of NSAIDs

Uncouples the placenta, pushes it out

It is also able to cause uterine contractions

Good for either abortions, or helping induce contractions during childbirth

Misoprostol is a synthetic form of prostaglandin E1

Male hormones

5-alpha reductase

Testosterone can have its double bond reduced to a single bond to make it into

dihydrotestosterone

It is 3 times more potent compared to testosterone

Remember this when it comes to SAR

Structure Activity Relationship



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At least in androgens, this causes a drop in activity, but at least it's orally

active

Alkylation at the 17 position in pretty much all steroids allows a orally active

form to be made

Along with the 17 beta esterification for IM depot injection

And the 9 alpha fluro which improves activity

As stated above, 5a reduction increases the activity

Note: the androgens will have anabolic effects and vice versa

Therefore, when making an anabolic steroid, it will always have androgenic

effects (keep this in mind as a side effect)

Different modifications can improve this anabolic:androgenic ratio (like

removing the 19 carbon)

We will talk more about this in the MS module instead

Although it is not shown on the diagram below, removing the 19 carbon (themethyl group above the double bond) will improve the anabolic effects

And finally, the 3 ketone is essential for activity

Erectile dysfunction

Alpha 1 stimulates phospholipase C to produce IP3 to increase calcium

levels to maintain contraction (prevents the blood leaking into the

lacunae)

Alpha 2 inhibits adenylate cyclase to reduce cAMP levels to stop the

calcium levels from dropping, maintaining contraction

Treat pripratism (painful, long lasting erections)

PHENTOLAMINE is a potent antagonist which can be injected

Alpha antagonists can work here to prevent erections

Erection is prevented by a continuous stimulation by the sympathetic system

acting on alpha 1 and 2 adrenoceptors of the smooth vascular muscle to prevent

blood flowing into the lacunae of the corpus cavenosum of the penis

Alloprostadil (synthetic E1) works here

Activation by prostaglandin E1 stimulates adenylate cyclase to produce more

cAMP to reduce intracellular calcium levels, causing relaxation, which allows

blood to flow into the lacunae

Although it is not shown here, nitric oxide (NO) will stimulate cGMP production,

which has the same effect as increasing cAMP

Also not shown below

The penis has mostly PDE-5 and some PDE-2

There are 11 types in the body, so PDE-5 blockers are partially specific to

the penis

Lastly, cGMP is broken down by phosphodiesterase (PDE)



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Phosphodisesterase (PDE) inhibitors

Notice the far right ring (two heterocyclic rings, called a pyrimidinone)

Again, they break down cGMP. Remember: keeping cGMP allows the male to

have an erection by keeping the vascular smooth muscle relaxed

See how the two heterocyclic rings are similar to caffeine

So it's not surprising to see caffeine is a weak inhibitor of this enzyme

Weak PDE inhibitor

Long term use can cause fibrosis of the penis

Papaverine is a antispasmodic

Tertiary nitrogen is basic enough to allow the citrate salt to beproduced for greater solubility

Notice the heterocyclic ring to the left of the molecule, it is there to mimic

the cyclic phosphate on cGMP to allow for better binding

Vardenafil uses a electronically rich ring compared to sildenafil, gives

greater selectivity against PDE-5

It's ironic because Viagra comes as blue pills

Because sildenafil isn't perfectly selective for PDE-5, it can also

inhibit PDE-6 in the retina to cause blue vision (only has 10 times

selectivity of PDE-5 over PDE-6)

The ring on the right copies the pyrimidinone in cGMP, and it gives

selectivity against PDE-5

Has a half-life of around 4 hours for both

High solubility and permeability

However, they are extensively cleared by first pass metabolism

Metabolites are active

CYP3A4 is the major metaboliser of both drugs

Class I BCS drug

Sildenafil is a popular PDE-5 inhibitor



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Avoid grapefruit juice

Beware of CYP3A4 inhibitors and inducers

Taking a dose after a fatty meal reduces absorption AND delays

absorption (as tmax) as well

Sildenafil (but not vardenafil) is affected by the food effect

Looks nothing like sildenafil

Salt formation is not possible

No blue vision

Potent and selective for PDE-5

Low solubility/high permeability

Remember: no salt formation, may lead to this low solubility

Classified as Class II BCS drug

One for the weekend, keeps it up

Half-life is at least 4 times longer (17 hours) than the other two

Inactive catchecol metabolite

May be glucouridated (enterohepatic recirculation?)

Avoid grapefruit juice

Is also metabolised by CYP3A4

Very long half-life

Has a larger volume of distribution and lower clearance compared to the

other two drugs

Taladafil is another popular PDE-5 inhibitor

Different selectivities against PDE-5 (leads to reduced side effects)

Different pharmacokinetics (especially the food effect)

Longer half-life in the case of vardenafil

Why does sildenafil sell better? Probably good marketing...

It appears both tadalafil and vardenafil have advantages over sildenafil:

Must NOT be used with nitrates (taken for people who have heart disease)

Remember: nitrates release nitric oxide to cause an increase in cGMP

Since cGMP breakdown is inhibited by these drugs, cGMP builds up in the

muscle

It might be alright if this effect was locallised to the penis, but it happens

systemically (remember: none of these are perfectly selective)

Therefore, since a lot of the blood vessels dilate around the body, it causes

massive hypotension, and the person could die due to it

All PDE-5 inhibitors have a very important contraindication

Other side effects include



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Headache

GI disturbances

Nasal congestion

Postural hypotension (if you stand up, due to the minor systemic

vasodilation caused by the blockers, your brain can lose quite a bit of

blood, responsible for headaches and lightheadedness)

And again, blue vision is possible for sildenafil

Less side effects (including cardiac vasodilation)

No food effects

Fast acting

Best choice if they are taking nitrates (although it might still be a bad idea)

Avanafil is a pyrimidine derivative which is very selective for PDE-5

Apomorphine

Is a D1 and D2 dopamine agonist

Although there are some D1 and D2 receptors in the penis, they don't do very

much

The main activity is in the brain

Will actually cause erection

Give sublingually to reduce this effect somehow

However, the problem is, because it's a dopamine agonist, it also hits the

vomiting centers in the brain

Because of the side effects, it's generally not used much

Benign prostatic hypertrophy (BPH)

The prostate will actually grow over time

It can grow so large that it can block the urethra to prevent normal urination

Very common at old age

They don't have much life left anyway, why put them through quality of

life reducing treatments

The most common treatment is to monitor the growth to prevent it from causing

too much trouble

Microwaving to destroy tissue

Surgically removing the prostate

Non-pharmacological treatment includes

Relaxes muscles at the urethra to let urine pass through more easily

Alpha-1 receptor antagonists

Prevents conversion of testosterone into the more active DHT

Finasteride is the drug most commonly used

Because the prostate relies on androgenic activation for growth,

reducing androgen potency will reverse growth and may delay

surgery

Note: finasteride may also be used to treat male balding as DHT is

also responsible for balding as well

5-alpha reductase inhibitors

Pharmacological options include:



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Pre-eclampsia

Need to have both, no protein in urine is just pregnancy-induced

hypertension

High blood pressure AND protein in the urine during pregnancy

Note: this means there's a good chance they are taking an ACE inhibitor

(renoprotective effect + reduced blood pressure)

They MUST come off the ACE inhibitor/AT2 antagonist during pregnancy,

and replaced with another drug

Women with pre-existing diabetes or hypertension are more likely to have it

For diabetic patients who are normotensive (normal blood pressure), they

can temporarily come off the ACE inhibitor during pregnancy

Regardless of what type of diabetes they might have, they need keep a

tight control of blood glucose with insulin only (not the other drugs)

Without proper blood glucose control, the developing baby will convert allthe extra glucose into fat, which makes the baby much larger, and harder

to give birth to.

Notes about diabetics and pregnancy:

140/90 can be cut-offs

Hypertension

300mg/day

Proteinurea

May be caused by a protein imbalance in the blood

Peripheral odema

Hb levels decreased, free Hb causes kidney damage

Hemolysis

Elevated Liver enzymes

Low Platelets

HELLP syndrome

Headaches

Even more severe odema

Higher blood pressure

Spots in vision (due to micro-haemorrhages in the blood vessels of the

eyes)

Severe pre-eclampsia also has:

Tonic-clonic seizures (affects the whole brain, bad news for the baby as

well)

The disease progresses to eclampsia where seizures and organ failure occur ifuntreated

Signs and symptoms

Orally, 500mg tid

Alpha 2 antagonist

This leads to a decrease in blood pressure

Works at the brain, presynaptically to trigger a negative feedback

mechanism to slow down sympathetic activity

Caution: renal failure patients need a smaller dose (renally secreted)

Contraindicated with hepatic disease and depression

Side effects:

Alpha-methyldopa

Treatments

Therapeutics



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Haemolytic anaemia (watch for headaches, tiredness, paleness,

darker urine etc. discontinue)

Liver damage (watch for fever or jaundice. discontinue)

Headaches are common (continue medicine obviously)

Given IV as an emergency measure for severe pre-eclampsia

Prevents seizures from occuring

Magnesium sulfate

Beta-1 antagonist

Can be given IV during severe pre-eclampsia to counter high blood pressure

Safe for pregnancy

Labetalol

Used as a last-ditch attempt to prevent eclampsia if the symptoms can't be

controlled by the IV drugs

Only needed in premature babies

Betamethasone is given IV to encourage surfactant production in the foetal

lungs (make them a bit more mature) so the baby can breath properly

Caesarean section (C-section)

Oral contraceptives

Combined Oral Contraceptives (COC)

Progestin only pill (POP)

There are two general types of oral contraceptives available:

COCs have a 12 hour window, while POPs have a 3 hour window (Cerazette

doesn't count)

Theoretically, both the COC and POP have the same efficacy (around 99%).

However, the COC tends to be more effective as the POP has a much narrower

safety margin when it comes to compliance

Migranes with aura

History of heart or cardiovascular disease (includes hypercoagulability)

Smokers over 40

Suspected breast cancer

Liver damage/dysfunction

Obese and/or hyperlipidemia

COCs are given as a first line treatment, unless there's an absolute

contraindication present:

Smoking

Taking CYP3A4 inducers

Being overweight

And we have to be cautious in certain cases:

So if there is a contraindication present, the POP is given

Increased exposure to estrogen

Breast cancer

Hypercoagulability of the blood

Note: risk of DVT is higher in pregnancy anyways...

Deep Vein thrombosis and other CVD

Advise women the COC will increase chances of:

COC (and POP) timing

Timing is very important for contraceptives

But should be started within 5 days of menstruation

If it is started within 5 days, then no additional contraception is needed

This is because within those 5 days, another ovum can't be in the uterus,

because it just got flushed out during menstruation

Start pills on the same day as menstruation



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If you miss pills:

Vomiting and diarrhoea:

Circumstance When to take pill Other recommendations

Missed one on days

8-21 in COC

Take pill soon as you remember

(within 12 hours) or take two

the next day

Extra precautions not

needed

Missed one on days 1-7

in COC

Same as above Consider ECP if

unprotected intercourse

Missed 2 COC pills

within 7 days (during

days 1-14)

As above

7 day rule (->)

Extra precautions for 7

days (until 7 active pills

taken)

Consider ECP if

unprotected intercourse

Missed 2 COC pills

during 15-21 (last week)

Start next pack immediately

(pills during 22-28 are inactive

anyway, we're skipping it)

Missed POP by 3

hours/12 hours withCerazette

Take as soon as possible, can

combine 2 pills, carry on asnormal

Varies, check on pack

(generally extraprotection)

COC + vomiting/diarrhoea

for >24h

As

above

Addition contraceptive method + 7 day

rule

POP + vomiting/diarrhoea ? Varies, check info on pack

Originally thought to cause failure due to reduced enterohepatic

recycling of the estrogen

Normal antibiotics will not cause failure of the medicine

Rifampicin is the common one

St John's Wort is not an antibiotic, but it induces CYP3A4 as well

Practice 7 day rule, where you should use additional contraception

during the antibiotic course AND for 7 days (7 complete pills) after

treatment

NOTE: CYP3A4 inducers cause failure, not inhibitors (so grapefruit is

fine because it's an inhibitor, not an inducer)

But antibiotics which will cause CYP3A4 induction can cause failure of the

COC

In addition, antibiotics can cause vomiting and diarrhoea, follow

instructions as above

What about antibiotics?

Generally are made with copper

Copper prevents sperm motility and irritates the endometrium, preventing

implantation of the embryo

Sits inside the uterus, needs replacing every few years

Intrauterine devices

Tie the fallopian tubes

Surgery

Non-pharmacological treatments

Erectile dysfunction



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Tends to be experienced by older males

The body is fine, brain is not

Stress, anxiety and reduced libido etc.

Psychogenic

The body isn't fine, there's something stopping it from going up

Metoprolol and other beta blockers can cause it

Excessive alcohol

Smoking

Decreased physical activity

Surgery on or around the prostate

Neuropathy near the region (poor, poor diabetics)

Organic

But can also be a mix of the two

Has two causes:

Pharmacological treatments

Tadalafil, sildenafil

Prevents the breakdown of cAMP, which causes extended relaxation of

smooth muscles, allowing blood to flow into the lacunae of the penis

Taken orally

Which is a shame, people who are on nitrates tend to need it

If nitrates are taken, it causes systemic vasodilation and death

WARNING: contraindicated with nitrates

Postural hypotension (because of vasodilation)

Nausea and headaches

Vomiting

Sildenafil: Warning: can cause blue vision

Can cause vascular, GI or psychiatric disorders

Fatty foods should be avoided

Avoid grapefruit juice and its products

PDE-5 (phosphodiesterase-5) inhibitors

Synthatic prostaglandins (E1)

Stimulates adenylate cyclase to produce more cAMP for muscle relaxation

Given intraurethrally or injected

Works for people with CVD or nitrates

Can form nodules on the penis or cause pripatism (painful, long erections)

Alprostadil

Works at brain and penis

Mostly the brain, not so much at the penis

Dopamine agonist at D1 and D2

Given sublingually or injected into the penis

Remember: these receptors exist in the CTZ of the brain

Strong emetic ability

Also contraindicated in CVD and nitrate use

Apomorphine (not really used)

Reduce smoking and drinking

Increase exercise

Lifestyle modification

Good for psychogenic causes

Psychotherapy/ couples counselling

Penis pump

Non-pharmacological treatments



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Most effective non-pharmacological treatment for organic causes

Potentially painful

Insertion of things into the penis

Last line measure

Surgery



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Patient Assessment

Documents

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