Pharmacology of sex hormones

Introduction Sex hormones are produced in the body, which are required for several important processes Growth and development of sex structures Behaviour The production of these hormones are under feedback control 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 Hormonal release tends to be tied to circadian rhythms, so hormone release tends to be pulsatile (released with visible peaks) In early pregnancy, progeterone, estrogen and hCG (Human chorionic gonadotropin) are produced

Control and secretion of hormones

The secretion of sex hormones ultimately depends on control by the brain 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) They stimulate the release of either Testosterone from the testes Oestrogen and Progesterone from the ovaries Finally, the whole system is under negative feedback control, where these sex hormones will prevent the production of more sex hormone Gonadotropin releasing hormone

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 Responsible for stimulating the anterior pituitary to secrete LH and FSH Also released in pulses Has two clinical uses: Decreasing sex hormones Give GnRH continuously This causes the receptors in the anterior pituitary to become desensitised, and stop releasing FH and LSH to reduce sex hormone release But this is accompanied by a flare of sex hormone release due to the initial agonist action by GnRH Used to treat testicular cancers and endometriosis (extra endometrium growing where it shouldn't be) Remember back to oncology, groselin injections is an injection of GnRH. This comes with tumour flare as well. Increasing 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) 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 Removes the negative feedback, makes the body think it doesn't have enough sex hormone so it makes more The action of estrogen Actually a group of three steroids (in order of potency): 17 beta-estradiol 17 beta-estrone 17 beta-estriol They bind to estrogen receptors, which there are two types of Estrogen receptor (ER) alpha ER beta

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The receptors are Intracellular Exist in dimers The dimers are able to be made up of either just alpha, beta or a mix of the two types Once an estrogen binds to the receptor dimer: 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 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 During development Produce sex structures At puberty Prepares body for producing babies Breasts and uterus developed Deposition of fat around the abdomen Stop bones from growing longer, stops vertical growth This is called bone arrest During menstral cycles 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 pregnancy Increase uterine blood flow to keep the baby alive Growth of the breast duct system to prepare for milk production Effects on the CNS Neuroprotective Causes mood swings Develops structures in the brain for women Estrogen as a drug As shown above, estrogen is used for different reasons in the body depending on age Contraception Protect against osteoporosis
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 Protect against osteoporosis Menstrual disorders Some cancers Although natural estrogens can be used, synthetic estrogens (especially ethinyl oestradiol) are much better as a drug: 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 Progesterone Produced mainly by the corpus luteum and the placenta Involved in two things during pregnancy: 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. Again, synthetic forms of progesterone are available The synthetic forms are orally active, while progesterone itself will be orally inactive due to extensive first pass metabolism Three common side effects are: Androgenic activity, women may grow beards Acne (therefore, progesterone is not recommended for people with acne) Fluid retention (due to mineralcorticoid activity) Oxytocin Oxytocin is responsible for three things: Causing contractions in the uterus Milk production in the breasts Maternal behaviours in the CNS 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 Triggered by suckling action 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 Dopamine will prevent the release of prolactin from the anterior pituitary Therefore, a dopamine agonist may be used to prevent excess prolactin/milk production Menopause Menopause is when a female stops ovulating for the rest of her life Usually occurs around 50 years of age Menopause is accompanied by some unpleasant symptoms due to hormonal changes Split into two stages: Peri-menopause 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 Post-menopause Last stage This is where the classic symptoms present themselves Symptoms of menopause are: Hot flushes due to reduced estrogen release Vaginal atrophy This can lead to dryness, which can either be painful or itchy Chance of osteoporosis, as estrogen normally prevents bone reabsorption Mood disorders (as if they were having a period) Hormone replacement therapy and menopause Hormone replacement therapy (HRT) may be used to relieve the symptoms of menopause However, there are some limitations Use of estrogen alone will lead to an increase in endometrial cancer 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 Associated with greater chances of stroke (hypercoagulation due to
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 Associated with greater chances of stroke (hypercoagulation due to estrogen) and breast cancer (estrogen exposure is linked to breast cancer) Then what's the point of HRT? Associated with reduced hip fractures (estrogen prevents bone breakdown) Protection against colorectal cancers Reduced symptoms The recommendation now is to use it for healthy people under 60 for no longer than 5 years Testosterone Produced mostly in the testes of males A bit produced in adrenal cortex and ovaries Responsible for several different functions: Growth of hair (and loss of hair later!) Spermatogenesis Muscle growth Erythropoiesis (production of red blood cells) Prevent bone reabsorption Again controlled by pulsatile release Is affected by protein binding 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 Testosterone is used clinically 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) Anti-testosterone activity also has some uses: 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 Does male menopause exist? 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)

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Hormonal contraceptives
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 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. The follicles will produce estrogen which is important for two processes 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 spike in LH and estrogen causes ovulation LH will stimulate the corpus luteum to develop, which then produces estrogens and progesterone Progesterone causes endometrial build-up to prepare for implantation It also triggers negative feedback to reduce the release of GnRH, FSH and LH. The cycle is split into two phases: Follicular phase (variable, days 1-14) Menstration (shedding of endometrium) Secretion of FSH and estrogen to develop endometrium and follicles Luteal phase (fixed, days 14-28) Growth of the endometrium Development of the corpus luteum

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How does the combination pill work? Contains an estrogen and a progesterone analogue Estrogen will: Inhibit FSH secretion due to feedback loop No FSH= no follicle production Stops the endometrium from breaking down as well, stops bleeding Progesterone 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 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? Initially used high doses of estrogen and estrane progestins Not suitable for use as the high doses of estrogen were linked to thrombosis formation The second generation used less estrogen and gonanes as the 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 third generation used even less estrogen but still used gonanes Not available in NZ, had too much DVT risk But had a reduced androgenic effect due to other gonanes being used Fourth generation pills haven't dropped the estrogen levels, but have switched to non-testosterone derived progestins They have anti-mineralocorticoid and anti-androgenic effects, so they have a low side effect profile
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a low side effect profile Another change we saw was to do with the amounts of hormones in the pills: 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 There are other routes of administration to consider: Patches 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 Vaginal rings 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 Side effects of contraceptives Generally mild symptoms are common Estrogen Breast tenerness Mood Weight gain Progestins Acne Etc Nausea Spotting/breakthrough periods Longer, heavier bleeds or more severe cramps But there are rarer (more severe) ones available MI (myocardial infarction) , DVT (Deep Vein Thrombosis) and stroke 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 Increased chance of breast cancer Remember: increased exposure to estrogen is a risk factor for breast cancer Endometrial cancer, colon cancer and ovarian cancer All reduced in chance Contraindications and cautions Undiagnosed endometrial bleeding Might make it worse Past or present circulatory disease Estrogen causes hypercoaguability Thrombophillia Estrogen causes hypercoaguability
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 Estrogen causes hypercoaguability Estrogen-induced hypertension Would increase hypertension Migrane with aura Migranes suggests reduced blood flow to the brain, estrogen increases the chance of stroke Liver disease Metabolised by the liver Lupus Pregnancy Daughters have an increased chance of cancer of the uterus Obesity (BMI greater than 30) Due to CVD risks Smoking over a certain age Due to CVD risks

Not contraindicated, but cautioned Smokers Hypertension Diabetes Overweight

Interactions Metabolised by CYP3A4 Therefore, need to be very careful with CYP3A4 inducers, as they can cause failure (observe 7 day rule) Phenytoin Carbamazepines Rifampacin Anti-retrovirals 7 day rule is: Use barrier contraceptives during the unsafe period PLUS another 7 days after treatment is finished See workshop for more details Broad-spectrum antibiotics? Normally, estrogen is conserved due to enterohepatic recycling If broad-spectrum antibiotics are used, the bacteria responsible for the recycling may be killed off, leading to therapeutic failure Only in combined oral contraceptives only, because estrogen is important Progesterone only pills have no estrogen, so they are not affected This has shown to be not true Then why do antibiotics cause therapeutic failure? 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 Progesterone only Pill (POP) Also called the mini-pill Given continuously Compared to the COC which has 7 days of placebo pills Only contains progesterone analogues (progestins) Used for: Women with contraindications or cautions (see above)
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 Women with contraindications or cautions (see above) Breastfeeding females Estrogen causes negative feedback inhibition of prolactin, caused reduced milk production May also be given as a long acting implant in case of poor compliance Only has a 3 hour window, compared to 12 hours for the COCs Although it has a chance to prevent ovulation, its main mechanism of action differs from COCs Instead, the progesterone will cause the mucus around the cervix to thicken, which prevents sperm from entering Theoretically, it's just as effective as COC But in reality, poor compliance leads to higher failure rates Male pills

Not a popular idea Females just don't trust males Plus it's much easier to make a pill for females, as there are easy and safe methods to prevent pregnancy How would we pharmacologically use male contraception? 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

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All about medchem

Female hormones
Estrogen metabolism Natural estrogens are rapidly metabolised by the body High extraction, or first pass metabolism The most potent is 17-beta-estradiol Rapidly converted into estrone And to estriol (least potent) 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 In addition to this oxidation, natural estrogens will undergo conjugation: Glucuronides can be formed. These can undergo hepatic recirculation Sulfates can be formed, they may be converted back into the original estrogen in tissues

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:

The above compound is ethinylestradiol, the first orally active estrogen Still widely used today 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

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

Conjugated estrogens Also known as equine estrogens These are structurally similar to human estrogens Works for hormone replacement therapy Called conjugated estrogens as they are conjugated to sulfates Which is why they are water soluble (easy to inject) Progesterone Also orally inactive due to first pass metabolism Ketones are reduced to alcohols OR OH added at the 6 position They are 21 carbon steroids Basic skeleton plus: Two carbon chain sprouting from the 17 position Two methyl groups

Semi-synthetic progestins: esterified Again, these esterified hormones are good for a depot injection Medroxyprogesterone acetateis in depo-Provera (bottom left) Notice how an ester exists The ester is hydrolysed to form the active 17-alphahydroxyprogesterone (bottom right)

Semi-synthetic progestins: 19-nortestosterone derivatives Fun fact: orally active progestins may be 19-nortestosterone derivatives Norethindrone (top) is one of them Notice how there is a bulky substituent at the 17 position. This is for oral activity If it is compared to testosterone (bottom), we can see the only chance between them (ignoring the 17 substituent) is the lack of the methyl group on the 19
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them (ignoring the 17 substituent) is the lack of the methyl group on the 19 position Because it's only a minor change, the older generations of progestins have androgenic activity Which means women can grow beards, get acne etc. New generations have reduced androgenic effects But they give a higher risk of CVD, a second generation one is recommended

Drospirenone is quite interesting Produced from spironolactone instead of a testosterone backbone Gives antimineralocorticoid activity (like spirinolactone) Causes reduced breast tenderness and blood pressure

Cytoproterone goes further 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)

Pharmacokinetics Again, first pass metabolism is something we need to keep in the back of our minds Along with enterohepatic recycling Sex hormones are bound to Sex Hormome Binding Globulin (SHBG) 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 in COCs Little distribution into the milk occurs 10 (plasma):2 (milk) for levonogestrel and 10:1 for norethindrone Misc. hormones
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Misc. hormones Tibolone is a pro drug used in hormone replacement therapy 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

Clomiphene is very interesting due to its isomerism The E isomer is anti-estrogenic (antagonist) 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 Z isomer is estrogenic (agonist)

Misoprostol is a synthetic form of prostaglandin E1 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 It is also able to cause uterine contractions Uncouples the placenta, pushes it out Good for either abortions, or helping induce contractions during childbirth

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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 Alkylation at the 17 position in pretty much all steroids allows a orally active form to be made At least in androgens, this causes a drop in activity, but at least it's orally active 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 Although it is not shown on the diagram below, removing the 19 carbon (the methyl group above the double bond) will improve the anabolic effects 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 And finally, the 3 ketone is essential for activity

Erectile dysfunction 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 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 Alpha antagonists can work here to prevent erections Treat pripratism (painful, long lasting erections) PHENTOLAMINE is a potent antagonist which can be injected 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 Alloprostadil (synthetic E1) works here Although it is not shown here, nitric oxide (NO) will stimulate cGMP production, which has the same effect as increasing cAMP Lastly, cGMP is broken down by phosphodiesterase (PDE) 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

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the penis

Phosphodisesterase (PDE) inhibitors Again, they break down cGMP. Remember: keeping cGMP allows the male to have an erection by keeping the vascular smooth muscle relaxed Notice the far right ring (two heterocyclic rings, called a pyrimidinone)

So it's not surprising to see caffeine is a weak inhibitor of this enzyme See how the two heterocyclic rings are similar to caffeine

Papaverine is a antispasmodic Weak PDE inhibitor Long term use can cause fibrosis of the penis

Sildenafil is a popular PDE-5 inhibitor 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 Tertiary nitrogen is basic enough to allow the citrate salt to be produced for greater solubility The ring on the right copies the pyrimidinone in cGMP, and it gives selectivity against PDE-5 Vardenafil uses a electronically rich ring compared to sildenafil, gives greater selectivity against PDE-5 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) It's ironic because Viagra comes as blue pills Has a half-life of around 4 hours for both Class I BCS drug High solubility and permeability However, they are extensively cleared by first pass metabolism CYP3A4 is the major metaboliser of both drugs Metabolites are active Beware of CYP3A4 inhibitors and inducers
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 Beware of CYP3A4 inhibitors and inducers Avoid grapefruit juice Sildenafil (but not vardenafil) is affected by the food effect Taking a dose after a fatty meal reduces absorption AND delays absorption (as tmax) as well

Taladafil is another popular PDE-5 inhibitor Looks nothing like sildenafil Salt formation is not possible Potent and selective for PDE-5 No blue vision Classified as Class II BCS drug Low solubility/high permeability Remember: no salt formation, may lead to this low solubility Half-life is at least 4 times longer (17 hours) than the other two One for the weekend, keeps it up Is also metabolised by CYP3A4 Inactive catchecol metabolite May be glucouridated (enterohepatic recirculation?) Avoid grapefruit juice Has a larger volume of distribution and lower clearance compared to the other two drugs Very long half-life

It appears both tadalafil and vardenafil have advantages over sildenafil: 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... All PDE-5 inhibitors have a very important contraindication 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 Other side effects include Headache
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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

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

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 However, the problem is, because it's a dopamine agonist, it also hits the vomiting centers in the brain Give sublingually to reduce this effect somehow 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 The most common treatment is to monitor the growth to prevent it from causing too much trouble They don't have much life left anyway, why put them through quality of life reducing treatments Non-pharmacological treatment includes Microwaving to destroy tissue Surgically removing the prostate Pharmacological options include: Alpha-1 receptor antagonists Relaxes muscles at the urethra to let urine pass through more easily 5-alpha reductase inhibitors 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

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Infections of the reproductive tract

Intro Bacteria aren't the only type of pathogens which can cause an infection. Need to consider Viruses Fungi Protozoa Some activities will increase the risk of getting a STI Being born from a mother who has an active STI infection Which is why screening for STIs is important in pregnancy, some infections like Chlamydia are slient Victims of sexual abuse Sexually active people Drug use is linked to sex (especially amateur prostitutes who don't get STI information as much as ones who work in registered premises) Students are also quite sexually active, high risk The group who has it the worst is young and drunk people though (what a surprise) Chlamydia trachomatis Bacteria Gram negative cocci Non-motile Has intracellular and extracellular forms BUT Obligate intracellular pathogen to replicate (extracellular forms just used to get from cell to cell) By far the most common STI Symptoms Very commonly asymptomatic in both sexes (silent) 75% in females, 50% in males If untreated, can lead to infertility in both sexes In females, it can travel all the way up the tract to cause infection of the cervix, uterus, Fallopian tubes and ovaries In males, it can also reach the testes, causing epididymitis (swollen, painful testicles) and infertility Can also cause ectopic pregnancies Both sexes may experience urethritis (purulent discharge and pain on urination) Can smell foul Males can get proctitis, which is a rectal infection Pain, bleeding and discharge from site Importantly, it also affects infants Chances of premature birth increases Conjunctavitis Pneumonia And remember: this infection tends to be asymptomatic, NEED TO SCREEN MOTHERS! Diagnosis Culturing isn't possible because it's an obligate intracellular parasite Remember: normal agar has no cells
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 Remember: normal agar has no cells Instead, we could use PCR to confirm an infection Extracellular forms too hard to see under microscope Intracellular forms can be observed with a dye Treatment and prevention The person AND their sexual partner(s) need to be treated Antibiotics- azithromycin. 2 per OP. One for you, one for your partner Or doxycycline or amoxicillin for 7 days Dont forget to choke back your laughter whenever you see it. Resistance is low, treatments are effective Need to have good patient education to prevent spread Screening programmes are being set up for high-risk patients Vaccines are very hard to make Have an intracellular and extracellular form to target Need to stimulate the immune system in a specific way to produce IgA at the mucosal surfaces to prevent spread (not sure if it's possible yet) Gonorrhoea Nesseria gonorrhoeae Gram negative diplococci Infects mucus membranes with columnar epithelium most of the time But in immunocompromised patients, it can become a systemic infection So normally it affects the urinary tract, rectum, parynx and conjunctiva No evidence of spreading due to toilet seats, requires person-to-person contact Symptoms Can be asymptomatic as well 50% in females, 30% in males But this is lower compared to chlamydia Extreme pain on urination Burning feeling Purulent discharge may be present Can also spread around Up the tract to cause infections in the sex organs causing infertility Spread systematically, which can lead to meningitis and endocarditis Since it can infect the conjunctiva, if an infant gets this from the mother, they could become blind Diagnosis and treatment Can be cultured or observed under a microscope Again, need to use antibiotics But some strains are resistant, check cultures Concurrent chlamydia infections are common Treat for chlamydia while treating for gonorrhoea Trichomonas vaginalis Protozoa Twitches around to get to places Obligate Human pathogen (i.e. humans only) But it grows fine on triptic soy so it can't be an obligate parasite... Commonly found with other STIs
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 Commonly found with other STIs Other STIs will reduce the physical defences so it's able to cause an infection easier Symptoms Females tend to have it worse compared to males and infants Because female hormones are linked to growth of these organisms So infections tend to be self-limiting in both males and infants Women may experience: Thin, frothy green-yellow discharge Foul odour (like fish) Red and swollen vulva Post-coital bleeding (i.e. bleeding after sex) Cervical haemorrhage Abdominal pain Can lead to infertility as well if untreated, as it can damage the Fallopian tubes BUT about 50% of the women may be asymptomatic Men can experience May be asymptomatic But can have similar symptoms (urethritis, thin yellow-green discharge) Pain on urination Self-limiting infection Neonates may experience Infection of the vagina if the mother has an active infection But it tends to be asymptomatic and self-limiting as well Diagnosis and Treatment Culturing is also possible Can also observe them directly under a microscope Treatment: antibiotics as well Metronidazole Large single dose (2g) or 7 day course (400mg bd) Very high cure rate 95%, low resistance Systemic routes better compared to topical treatments Remember: people can be asymptomatic, treat contacts as well Treponema palladium- Syphilis Spiral shaped bacteria Gram negative Obligate human pathogen as well Increases risk of other STIs Especially HIV, because it causes open sores, which means the virus can easily reach the systemic circulation Can cause miscarriage and infections in the newborn Which is nasty, because if this goes systemic, it can cause a whole bunch of symptoms, including CNS effects (see below) Because it's a obligate human pathogen as well, it can't be cultured ELISA Direct microscopy Treatment is very easy One IM injection of penicillin Fun fact: one of the earlier uses of penicillin was to cure soldiers from syphilis. Earlier treatments meant entire units could be kept off the field for a long time, but now with a single injection of penicillin, they were returned to good health in no time at all. Of course, not everyone was
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returned to good health in no time at all. Of course, not everyone was happy with this... Stages of infections Primary (early, local symptoms) Ulcerative sores which are painless on the genitals, trademark of syphilis Can be internal or external (seen outside of the body) Will heal on their own in 3-6 weeks (but the bacteria are still there) Secondary ( systemic spread begins) Skin rash with brown ores Palms of the hands, soles of the feet Highly infectious The rash will heal on their own Mild fever, aches Latent Everything is quiet, no symptoms, not infectious, but the bacteria are there Tertiary (late stage, severe systemic spread) Damage to brain Neurosyphilis Mental illness Fun fact: quite a few geniuses in history are suspected of having suffering from neurosyphilis, e.g. Vincent van Gogh Heart Eyes Death Genital warts Human papillomavirus (HPV) i.e. similar to the virus which causes cervical cancer Very common STI (75% in sexually active people) Can be latent as well Not as infectious compared to having active warts (highly infectious otherwise) Signs and symptoms Clusters of warts For women they tend to be internal (i.e. not seen from outside the body) Except for the warts, doesn't cause anything else But some strains (16, 18, 45) cause higher risks of cancer, but less likely to cause external warts However, it's not the same in infants Can cause infections in the wart, can lead to death (choking) Diagnosis and treatment Diagnosis can be made directly by visual inspection Other possible diagnostic methods are: PCR Pap smear is an indirect detection method, because it detects cancerous cells which are due to the virus So it's not an ideal detection method Treatments are based on cosmetic correction, no need to treat the virus because it's relatively harmless Liquid nitrogen (freeze it off) Surgery Wart paint (acetic acid) Podophyllotoxin (antimitotic, not for pregnancy) and imiquimod (immune
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 Podophyllotoxin (antimitotic, not for pregnancy) and imiquimod (immune stimulatory) can be used as well HPV vaccines exist for the high-risk cancer strains, but they won't protect against the strains which cause warts Genital herpes Caused by herpes simplex virus (types 1 and 2) Type one causes oral sores Type 2 causes genital sores Slightly hard to get infected due to two conditions which need to be met Need to have broken skin for infection The person who is passing on the joy needs to have an active breakout Not curable, remains latent because it stays in the nerve endings Signs and symptoms Mostly asymptomatic (plus it's latent disease as well) Primary Flu-like symptoms Fever, headache, malaise) Local symptoms Pain, itching Discharge Lesions Outbreaks Local symptoms only Can lead to meningitis if unlucky (or immunocompromised) Especially bad for neotates, mortality rate of 65% Harsh considering the infection rates from mother to child are approximately 50% during the primary infection Drops to less than 5% during an outbreak Diagnosis and treatment Lesions would indicate infection Can swab for DNA samples ELISA remains an option as well Treatment is just aciclovir, 5 times daily for 5 days Not a cure, just reduces the time for the outbreak to resolve Can be used during pregnancy to prevent transmission, but only on specialist advice (classified B3 by the TGA) Non-conventional treatments may include L-lysine The virus makes the cell absorb Lysine (amino acid) but the normal amino acid is R-Lysine. It's theorized that giving L-lysine will tip the ratio of usable to non-usable amino acid to prevent replication Vaccines are currently unavailable against it Candida albicans (Thrush) Fungal infection Technically not an STI, it's from commensal fungi Most common cause of vaginitis (itchy vagina) Symptoms Women May have a discharge 'Curd like' White No smell (very important)
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 No smell (very important) Could be very high up in the vagina, so no discharge could be seen Swelling and redness of the area Notice: if women come into the pharmacy complaining of an itchy vagina, it could be due to candidiasis or menopause. Check for symptoms of menopause if there's vaginal itching but no discharge. Men Rash Redness Burning sensation Treatment Oral antifungals Could be a single dose or one given over a few days Topical creams Easy for men to use Pessaries Obviously for women only

Genital Epstein-Barr virus (EBV)

Herpesviridae family EBV infection however is rather common (up to 95% infection rate!) Not curable, remains latent in red blood cells Usually transmitted in saliva to infect B cells and epithelial cells Not too sure how it gets sexually transmitted though Uncommonly, it can cause painful genital ulcers Urethritis in men No cure, so we have to focus on symptoms Anti-inflammatories and analgesics Corticosteroids for severe cases Since it's also in the Herpesviridae family, aciclovir also works against them Only reduces the amount of viruses shedded though Summary
Name Chlamydia trachomatis What Symptoms Diagnosis PCR Treatment 1x Azithromycin STAT Low resistance

Asymptomatic G- cocci Intra/extracellula Urethritis Protitis r Obligate parasite Discharge Infertility Pneumonia Conjunctivitis

Neisseria gonorrheae

G- diplococci

Asymptomatic Pain Discharge Conjuctavitis

Culture Microscopy

High resistance strains exist Use antibiotics

Trichomonas vaginalis

Protozoa Green-yellow Culture discharge Obligate parasite Microscopy Motile Vaginitis Post-coital bleeds Self-contained in males Spiral G Burning feeling Obligate parasite Primary Secondary Tertiary ELISA Microscopy

Metronidazole 1 stat or 7 days Low resistance

Treponema pallidum (gonorrhoea)

1 IM penicillin

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 Tertiary HPV (warts) HSV Virus Bunches of warts Visual Internal or PCR external Pap smear Sores Internal or external Oral or genital Creamy No odour Itching Sores Visual PCR ELISA Visual Culture Visual Remove warts Aciclovir L-lysine

Herpes virus

Candida albicans EBV

Fungus

Antifungals

Herpes Virus

Aciclovir

Fill this out for practice (no peeking!)

Name Chlamydia trachomatis Neisseria gonorrheae Trichomonas vaginalis Treponema pallidum HPV HSV Candida albicans EBV What Symptoms Diagnosis Treatment

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Therapeutics
Pre-eclampsia High blood pressure AND protein in the urine during pregnancy Need to have both, no protein in urine is just pregnancy-induced hypertension Women with pre-existing diabetes or hypertension are more likely to have it 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 Notes about diabetics and pregnancy: 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 all the extra glucose into fat, which makes the baby much larger, and harder to give birth to.

Signs and symptoms Hypertension 140/90 can be cut-offs Proteinurea 300mg/day Peripheral odema May be caused by a protein imbalance in the blood HELLP syndrome Hemolysis Hb levels decreased, free Hb causes kidney damage Elevated Liver enzymes Low Platelets Severe pre-eclampsia also has: Headaches Even more severe odema Higher blood pressure Spots in vision (due to micro-haemorrhages in the blood vessels of the eyes) The disease progresses to eclampsia where seizures and organ failure occur if untreated Tonic-clonic seizures (affects the whole brain, bad news for the baby as well)
Treatments Alpha-methyldopa Orally, 500mg tid Alpha 2 antagonist Works at the brain, presynaptically to trigger a negative feedback mechanism to slow down sympathetic activity This leads to a decrease in blood pressure Caution: renal failure patients need a smaller dose (renally secreted) Contraindicated with hepatic disease and depression Side effects: Haemolytic anaemia (watch for headaches, tiredness, paleness,
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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) Magnesium sulfate Given IV as an emergency measure for severe pre-eclampsia Prevents seizures from occuring Labetalol Beta-1 antagonist Can be given IV during severe pre-eclampsia to counter high blood pressure Safe for pregnancy Caesarean section (C-section) Used as a last-ditch attempt to prevent eclampsia if the symptoms can't be controlled by the IV drugs Betamethasone is given IV to encourage surfactant production in the foetal lungs (make them a bit more mature) so the baby can breath properly Only needed in premature babies Oral contraceptives There are two general types of oral contraceptives available: Combined Oral Contraceptives (COC) Progestin only pill (POP) 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 COCs have a 12 hour window, while POPs have a 3 hour window (Cerazette doesn't count) COCs are given as a first line treatment, unless there's an absolute contraindication present: Migranes with aura History of heart or cardiovascular disease (includes hypercoagulability) Smokers over 40 Suspected breast cancer Liver damage/dysfunction Obese and/or hyperlipidemia And we have to be cautious in certain cases: Smoking Taking CYP3A4 inducers Being overweight So if there is a contraindication present, the POP is given Advise women the COC will increase chances of: Breast cancer Increased exposure to estrogen Deep Vein thrombosis and other CVD Hypercoagulability of the blood Note: risk of DVT is higher in pregnancy anyways...

COC (and POP) timing

Timing is very important for contraceptives Start pills on the same day as menstruation 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 If you miss pills:
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 If you miss pills: Circumstance Missed one on days 8-21 in COC Missed one on days 1-7 in COC Missed 2 COC pills within 7 days (during days 1-14) When to take pill Other recommendations

Take pill soon as you remember Extra precautions not (within 12 hours) or take two needed the next day Same as above As above 7 day rule (->) Consider ECP if unprotected intercourse Extra precautions for 7 days (until 7 active pills taken) Consider ECP if unprotected intercourse

Missed 2 COC pills Start next pack immediately during 15-21 (last week) (pills during 22-28 are inactive anyway, we're skipping it) Missed POP by 3 hours/12 hours with Cerazette Take as soon as possible, can combine 2 pills, carry on as normal Varies, check on pack (generally extra protection)

Vomiting and diarrhoea: COC + vomiting/diarrhoea for >24h POP + vomiting/diarrhoea As above ? Addition contraceptive method + 7 day rule Varies, check info on pack

What about antibiotics? Normal antibiotics will not cause failure of the medicine Originally thought to cause failure due to reduced enterohepatic recycling of the estrogen But antibiotics which will cause CYP3A4 induction can cause failure of the COC 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) In addition, antibiotics can cause vomiting and diarrhoea, follow instructions as above Non-pharmacological treatments Intrauterine devices 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 Surgery Tie the fallopian tubes Erectile dysfunction

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 Tends to be experienced by older males Has two causes: Psychogenic The body is fine, brain is not Stress, anxiety and reduced libido etc. Organic 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) But can also be a mix of the two Pharmacological treatments

PDE-5 (phosphodiesterase-5) inhibitors 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 WARNING: contraindicated with nitrates Which is a shame, people who are on nitrates tend to need it If nitrates are taken, it causes systemic vasodilation and death Can cause vascular, GI or psychiatric disorders Postural hypotension (because of vasodilation) Nausea and headaches Vomiting Sildenafil: Warning: can cause blue vision Fatty foods should be avoided Avoid grapefruit juice and its products
Alprostadil 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) Apomorphine (not really used) Dopamine agonist at D1 and D2 Works at brain and penis Mostly the brain, not so much at the penis Given sublingually or injected into the penis Strong emetic ability Remember: these receptors exist in the CTZ of the brain Also contraindicated in CVD and nitrate use Non-pharmacological treatments Lifestyle modification Reduce smoking and drinking Increase exercise Psychotherapy/ couples counselling Good for psychogenic causes Penis pump Most effective non-pharmacological treatment for organic causes
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 Most effective non-pharmacological treatment for organic causes Potentially painful Surgery Insertion of things into the penis Last line measure

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Patient Assessment
Soon TM

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Pharmacokinetics, drugs, pregnancy and milk

Intro Pregnant women are going to have to take drugs from time to time Although the general rule it to try and reduce the number of drugs, we could try to recommend safer alternatives Which is why there are classifications made by several agencies in the world to help prescribers make decisions This includes OTC sales There are some common areas where pregnant women will try to look for OTC products Reflux Common due to the foetus pushing up on the stomach to cause reflux Recommend raft antacids Morning sickness Common early in pregnancy Paracetamol/metoclopramide are both classified as 'A' by the TGA This combo is known as Paramax Stretch marks Whatever is good Bio-oil seems to be heavily marketed right now Cough and colds Paracetamol (NOT ibuprofen, it's an NSAID) Saline nasal spray only for congestion Bromhexine could be used for coughs Constipation Pressure on the intestines and lots of fluids taken by the foetus causes this We could recommend fibre and lots of water No stimulant laxatives! It's probably a good idea to memorise the above, I got a feeling it's going to be in the orals this year Pharmacokinetics We need to consider three things about pharmacokinetics if pregnancy is involved Maternal PK The drug can affect the pregnancy The pregnancy can affect the drug Foetal PK Will the drug reach the foetus? If the drug reaches the foetus, it is important? Transfer into breast milk Same as foetal PK Drugs affecting the foetus- Risk factor categories Taking some drugs can screw up the development of the foetus We can look up the risk factor categories for drugs and determine if they are safe for use in pregnancy These categories give us an idea as to how teratogenic a drug is Although there are several risk factor categories in the world, we will be working
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 Although there are several risk factor categories in the world, we will be working off TGA (Australia) categories Some drugs are slightly different, methotrexate is classified as D by the TGA, and X by the FDA Category A Has been shown to not show defects after it's been taken by a large number of women New drugs can't get category A, because it needs to have been used by a lot of pregnant women (which will take a long time) before being given category A Category B Taken by a limited number of women, no increase in harmful effects B1- Animal models show no harmful effects B2- Animal models are lacking, but shows no harmful effects B3- Animal models show some harmful effects, not sure in humans Category C The drug might cause harmful effects on the foetus Could be reversible Need to weight up the risks and benefits (probably a specialist would do that) e.g. NSAIDs- can cause premature closing of the Ductus arteriosus Connects the pulmonary artery to the aorta because there's no point pumping blood through the lungs because there's no gas exchange yet Category D The drug might/will expect to cause harmful effects on the foetus Irreversible Needs a VERY good reason why a woman needs to take this (probably specialist advice) e.g. Efavirenz (NNRTI) Category X No. Don't give it to them under any circumstances Contraception is required while using this medication Pregnancy must be ruled out before starting the medication e.g. thalidomide Very important: pregnancy is hard to detect in the first trimester, but it's also the time the foetus is at its most vulnerable point Avoid drugs if people are trying to get pregnant Don't guess, if it doubt, look it up. Maternal pharmacokinetics Absorption GI motility Under the control of progesterone Low concentrations during early pregnancy increases motility High concentrations during late pregnancy reduces motility Remember: GI motility is important because it determines how quickly and how long a drug gets to the small intestine, where most of the absorption for most drug occurs Can lead to a slower or faster onset of action (slower or faster tmax respectively) Although the rate of absorption is changed, the extent of absorption usually remains unchanged i.e. AUC is the same Gastric acid Secretion is reduced, which leads to reduced acidity (increased pH)
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 Secretion is reduced, which leads to reduced acidity (increased pH) Some drugs require an acidic stomach to be absorbed properly (atanzavir is such a drug) Reduction in absorption of such drugs Acid labile drugs (such as penecillins) will be absorbed better as they'll be broken down less Nausea and vomiting Major concern because vomiting will mean the oral dose is lost, leading to underdose

Distribution The volume of fluid increases overall, leading to an increase in Vd of most hydrophilic drugs Amniotic fluid, placenta and foetus all add to the Vd increase 8L increase 60% in the foetus, placenta and amniotic fluid 40% in maternal tissues (breasts etc.) Plasma volume of the mother needs to expand to accommodate for all these extras Hypoalbuminemia (lower concentrations of plasma albumin) will occur due to dilution Remember: acidic drugs are the ones which tend to bind to albumin Will lead to increase in the fraction free Increased Vd Increased elimination Increased pharmacodynamic effects Increase in body fat Increased Vd for lipophilic drugs Increased cardiac output Increased renal blood flow Increased excretion Increased uterine blood flow Overall: Vd increases for both lipid and water soluble drugs Decreased plasma protein binding Since Vd increases, we need to consider the loading dose Loading dose is:
As you can see, Vd has changed, so we need to make adjustments to the loading dose BUT for maintenance doses, assuming there's no change in the clearance, we don't need to make adjustments, because Vd doesn't play a major factor:

Metabolism/Excretion Hepatic clearance is altered Estrogens and progesterone Renal clearance may be altered

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