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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