PHARM - Reproduction Flashcards
Major organs of the menstrual cycle?
Hypothalamus
Anterior pituitary
Ovary
Manipulatable Hormones?
GnRH
LH
FSH
Estrogens
Progesterone
GnRH and the menstrual cycle
Hypothalamus controls anterior pituitary via PULSATILE RELEASE of GnRH
Regulates the cycle
If GnRH is constantly released in high amounts, the system would downregulate
First half of Cycle –> BEFORE ovulation –> there is a series of RAPID-PULSE, LOW AMPLITUDE release of GnRH
Second half of Cycle –> AFTER ovulation –> the amplitude of release is MUCH HIGHER, but the FREQUENCY decreases
GnRH on anterior Pituitary
GnRH from the hypothalamus then gets into the PITUITARY which activates a GPCR on the gonadotropes and RELEASES FSH and LH
These hormones activate steroid hormone generation AT THE OVARIES –> E + P
E + P and Feedback
E + P have NEGATIVE FEEDBACK LOOPS in both the ANTERIOR PITUITARY and the HYPOTHALAMUS
P feeds back on the hypo and causes the changing of amplitude and frequency of GnRH release
E feeds back on the PITUITARY –> HIGH LEVELS OF E INHIBIT THE RELEASE OF FSH and LH –> only exception is the LH SURGE that is caused by E
ADMINISTERING ESTROGEN PHARMACOLOGICALLY IS USUALLY INHIBITORY
Menstrual Cycle Beginning
Day 0 = Day of menstruation at the end of last cycle = FSH slightly elevated –> this causes a number of follicles to begin growing inside the ovary
ONLY ONE follicle becomes predominant for release
Under influence of FSH, follicle begins secreting ESTROGEN
First half of cycle
Before Ovulation –> level of E SLOWLY increases
Days 7-10 –> level of E SUDDENLY RISES RAPIDLY
Rapid increase primes anterior pituitary for a HUGE RELEASE OF LH and FSH in the middle of the cycle
PEAK release of LH causes the growing follicle to RELEASE THE OOCYTE!! OVULATION!!!!!
(only instance where E does not INHIBIT)
Second half of cycle
Under the influence of LH during the second half of the cycle, the remaining CORPUS LUTEUM (remnants of follicle) begins secreting A LOT OF PROGESTERONE with some estrogen
As the levels of LH DROP (if no fertilization), the CORPUS LUTEUM begins to atrophy and turns into the scar-tissue-like CORPUS ALBICANS (no more progesterone and estrogen)
When the level of PROGESTERONE dips below certain level –> MENSTRUATION
Endometrium in the cycle
In the first half –> ENDOMETRIUM PROLIFERATES UNDER INFLUENCE OF ESTROGEN
When PROGESTERONE becomes more dominant (2nd half), the ENDOMETRIUM BECOMES SECRETORY
If fertilization occurs, the endometrium will remain intact and maintained by P
If no fertilization –> P drops, MENSTRUATION/sloughing off of the endometrium
Cervix in the cycle
Under the influence of E during the first half, the cervix secretes THIN, ALKALINE SUBSTANCE (pro-fertility/pro-sperm!)
In the SECOND HALF –> Increase in P causes the cervical secretions to be THICK and VISCOUS
Anti-sperm!!! More adept for IMPLANTATION
Structures of GnRH, LH, FSH etc
GnRH is a PEPTIDE –> DEGRADED if given ORALLY, so to INDUCE OVULATION, must give it in ANOTHER FORM
LH, FSH, hCG are all large GLYCOPEPTIDES (can’t be given orally either) and they all have TWO CHAINS –> ALPHAS are identical, the BETAS make them unique
Beta chains in LH and HCG –> VERY SIMILAR –> they are ESSENTIALLY INTERCHANGEABLE IN THEIR ACTIONS!!!!!! Release of oocyte and their effect on the CL
Drugs for STIMULATING OVULATION
To stimulate a “normal cycle” –> give a BOLUS OF FSH AND LH for a number of days to INDUCE FOLLICLE GROWTH
When the time comes for the LH SURGE we can give a BOLUS OF HCG –> more POTENT than LH!!!! (can also use this for egg retrieval in IVF)
FSH and LH work in the ABSENCE OF A PITUITARY OR HYPOTHALAMUS!!!! Obviously still need a functioning ovary
Side effects of FSH, LH, HCG as drugs?
Can HYPERSTIMULATE the ovary, resulting in RUPTURE!!!!!
Can also get MULTIPLE BIRTHS (7 or 8!!!) –> can give test doses to avoid this; females differ in their sensitivity!
Effectiveness of FSH, LH, HCG?
75% will ovulate, 1/3 will get pregnant
Miscarriage rate is ~normal (10-25%)
GnRH as a drug for ovulation?
It is VERY HARD to deliver it in the correct PULSATILE FASHION, thus it isn’t used anymore in the US
Continuous GnRH administration will DOWNREGULATE and DESENSITIZE receptors of the anterior pituitary (where GnRH works)
If we have administered too much FSH and LH, we can use GnRH to switch it off!!! Allows the system to re-sensitize to LH, FSH, HCG –> “re-boot”
LEUPROLIDE and GOSERELIN
Leouprolide – GnRH analog, can be used if given in the correct pulsatile fashion
GOSERELIN –> used to suppress the production of the sex hormones (E) in the treatment of BREAST CANCER (can also suppress T for Prostate cancer)
These drugs are just SUPER POTENT GnRH analogs and are used to LIMIT SEX STEROID PRODUCTION!!!!
Selective Estrogen Response Modulators (SERMS)
Estrogen ANTAGONISTS
CLOMIPHENE –> DRUG OF CHOICE FOR INFERTILITY
Binds with HIGH AFFINITY to E receptors in the anterior pituitary (BLOCKS)
When administered, NEGATIVE FEEDBACK of E on the anterior pituitary is TURNED OFF (results in a LARGE INCREASE IN FSH and LH) –> HPA AXIS MUST BE INTACT!!!!
Very SAFE DRUG –> some women can get hyperstimulation, but not enough to cause rupture like LH, FSH, HCG
Only 8% of births are multiple, usually twins
About 75% ovulate, 1/3 get preggo, normal miscarriage rate
Best infertility drug?
CLOMIPHENE
This is a SERM! Blocks E
Breast Milk and Infertility
Breastfeeding is a NATURAL METHOD OF BIRTH CONTROL
Breast milk production depends on HIGH PROLACTIN –> some women have high circulating levels EVEN WHILE NOT BREASTFEEDING which results in amenorrhea and inappropriate milk production
HYPOTHYROIDISM could be a culprit (decreased thyroid –> release of thyrotropic releasing hormone –> high TRH leads to PROLACTIN RELEASE)
Pituitary tumor could also cause lots of prolactin
HIGH PROLACTIN = LOW ESTROGEN
If prolactin returns to normal, SO DOES FERTILITY
DOPAMINE acts as a PROLACTIN INHIBITOR!!!! Using a DA receptor agonist specific to D2 and D3 on lactotrophs can BLOCK PROLACTIN RELEASE
BROMOCRIPTINE
DA receptor agonist specific for D2 and D3 found on lactotrophs, so PROLACTIN RELEASE GETS BLOCKED!!
Can be given orally to reduce prolactin in the blood
Main side effect is POSTURAL HYPOTENSION (antagonizes SNS, prevents release of NE)
May also see some CNS effects (hallucinations, psychosis) – rarely but makes sense (DA!)
HIGHLY EFFECTIVE – almost 100% of women will ovulate!!!
NOT a curative drug (Prolactin will increase after taking it)
How do we MAINTAIN infertility drugs?!
Have to make sure the baby matures LONG ENOUGH!!! 37 weeks
Can give TOCOLYTICS to prevent contractions/premature labor!
Uterine Contraction Review
Smooth muscle in uterus –> anyting that INCREASES CALCIUM will cause CONTRACTION –> calcium channel blockers could prevent this!
Prostaglandins can also cause contractions –> COX blockers to prevent!!
Increasing cAMP or cGMP within the muscle will cause INHIBITION of the myosin light chain kinase –> DEACTIVATES myosin light chain and thus relaxation
TOCOLYTICS - What are the first line drugs?
To prevent contractions/prevent premature labor
RITRODINE/TERBUTALINE are FIRST LINE
These are BETA adrenergic receptor agonists –> Promote smooth muscle RELAXATION; increase cAMP within the smooth muscle –> inhibit MLCK, deactivate MLC, relax
SIDE EFFECTS = HTN and Tachycardia (beta agonists!!!) Contraindicated in CV patients
Other Tocolytics?
Magnesium sulfate – blocks influx of calcium; nausea, vision defects, lethargy, pulmonary edema, possible fetal death, beta agonists first line!!
COX blockers –> INDOMETHACIN can be used, but can cause PREMATURE CLOSURE OF DUCTUS ARTERIOSUS
Oxytocin receptor ANTAGONISTS –> more receptor later in pregnancy when oxytocin receptors are more potent
Nitric Oxide –> causes an increase in cGMP –> inhibits MLCK –> deactivates MLC –> relax
Drugs to INDUCE labor?
OXYTOCIN –> works particularly well at the LATER STAGES of pregnancy when receptors are upregulated
When oxytocin binds, it causes STRONG UTERINE CONTRACTION through cAMP-dependent release of Ca2+ in smooth muscle
GIVEN IV or with PGE1/MISOPROSTOL…
PGE1 (MISOPROSTOL) –> Intravaginally given to cause CERVICAL RIPENING and UTERINE CONTRACTIONS, also through an upregulation of Ca2+ in the myometrium
Should probably be used sparingly (can close ductus arteriosus)
First line for Infertility?
CLOMIPHENE – SERM (estrogen antagonist - no neg feedback, increased LH and FSH)
BROMOCRIPTINE if patient is producing too much prolactin!!!
First line for PREVENTING contractions?
RITRODINE and TERBUTALINE (beta receptor agonists) - increase cAMP within uterine smooth muscle –> lower MLCK, lower MLC, relaxation
First line for INDUCING LABOR?
OXYTOCIN –> strong uterine contractions/influx of calcium; given IV
PGE1(MISOPROSTOL) –> cervical ripening and uterine contractions, increases Ca2+ –> contraction! intravaginally
Often given together
Idea behind Birth Control
Giving HIGH LEVELS OF ESTROGEN and PROGESTERONE will potentiate NEGATIVE FEEDBACK in the HYPO and PITUITARY, thus INHIBITING THE RELEASE OF FSH and LH
Effects –> Suppresses follicle development (no FSH), Prevents OVULATION (no LH surge), Endometrium stays secretory (high P, prevents implantation), Cervical secretions maintain ANTI-SPERM properties (high P), interferes with normal fallopian tube movement (high E)
ESTROGENS ALONE for BC
Give estradiol continuously and it will BLOCK OVULATION, and thus pregnancy
Problem is that it has a HUGE FIRST PASS and can only be given effectively IM
ETHINYL ESTRADIOL –> eventually found that adding ethinyl group will INCREASE BIOAVAILABILITY to 40-50% and achieve high enough levels for 1x/day dosing
MESTRANOL –> Metabolized in the liver to ethynil estradiol
PROGESTINS ALONE for BC
First try were drugs similar to PROGESTERONE and then we switched to 19-norestrone –> SIGNIFICANT ANDROGENIC EFFECTS (weight gain, hair growth, acne)
Newer drugs DECREASE ANDROGENIC SIDE EFFECTS
DROSPIERNONE (yaz, yasmin) –> ANALOG OF SPIRONOLACTONE –> hypotension is a relatively severe side effect!
COMBINATION PREPARATIONS for BC
These include a SYNTHETIC ESTROGEN with slow metabolism and a PROGESTIN
Work because ESTROGEN maintains proliferative endometrial state until withdrawal bleeds, and PROGESTIN maintains anti-sperm cervical secretions
At first, HIGH DOSE 21/7 preps (21 days on, 7 off for bleeding)
The doses were 3-4x bigger than what women were used to!!! Caused FSH and LH to be COMPLETELY SUPPRESSED and BLOCK FOLLICLE DEVELOPMENT
BUT, such high doses can be stored in ADIPOSE TISSUE, allowing for CONTINUOUS RELEASE of hormone and preventing withdrawal periods!!!
patients wouldn’t always restore normal fertility probably due to some atrophy of the HPA
Current Combo Preps
Now we use a MUCH LOWER DOSE –> 0.02-0.1 mg synthetic E and 1-2 ug P
This is still VERY EFFECTIVE, though we see some abnormal LH surges once in a while (constant E should block it)
We can also see BREAKTHROUGH BLEEDS if we cannot sustain endometrium whole 21 days, give more E if this happens
COMBO preps can be MONO or BIPHASIC
Mono - E and P constant throughout
Biphasic – vary the E dose throughout to try and maintain a relatively normal cycle (for the sake of other organs like breast and bone that receive the stimulation too)
BUT since the whole point of BC is to interrupt the normal cycle and prevent ovulation, Biphasic seems pretty unnecessary
Mini Pills
PROGESTIN ONLY –> eliminates some of the severe side effects of excess E
35-75 ug doses –> primarily works by PREVENTING FERTILIZATION via maintenance of the anti-sperm secretions
Not as effective, but good for those who cannot use E
Breakthrough bleeds, irregular menses
MEDROXYPROGESTERONE
Depoprovera (Progestin)
150 mg IM dose EVERY 3 MONTHS
Side effects –> decreased bone density, possible infertility in future
Norplant and Implanon
Work for 3 years!!!!
Arm implants (filled with levornegestrel-progestin)
Both have good restoration of fertility after the drug is ceased
Good Effects of OCPs
Regulated cycles, decreased blood loss with menstruation, decreased cramps, correction of anemia, decreased tension, increased libido, decreased ovarian cysts, decreased acne, decreased ovarian and endometrial gain
Bad Effects of OCPs
N/V, headache, tension, breast discomfort, anxiety, fatigue, depression, weight gain, adenitis, amenorrhea, cholasma (brown spots)
Very bad effects –> decreased GLUCOSE TOLERANCE, reversible HTN, benign hepatomas, cervical cancer (HPV+ patients), breast cancer (giving lots of E!), venous thrombotic events (increased clotting factors, aggregation, etc)
< 35 –> HYPERCOAGUABILITY is worse in PREGNANCY than on the pill
> 35 –> CONTRAINDICATED because the hypercoaguability of taking it outweighs pregnancy
EMERGENCY CONTRACEPTION - Overview and Levonogestral
Morning After Pill! Can be used after HIGH RISK SEX and REDUCE ODDS OF PREGGO by 60-80%
Super high dose of PROGESTERONE which stops ovulation if it has not yet occurred –> inhibits sperm with ANTI-SPERM SECRETIONS, fallopian tube motility and blastocyst implantation if it has already occurred
ULIPROSTOL –> single 30 mg dose can be given within 5 days
LEVONOGESTRAL (progestin) –> Plan B –> can be a single 1.5 mg dose or two 0.75 mg doses and must be taken within 72 hours; OTC for women over 17; more side effects N/V, H/A, abdominal pain, dysmenorrhea, dizziness
MIFEPRISTONE (RU-486)
Anti-Progesterone ABORTIFICANT that can be taken AT ANY POINT IN FIRST TRIMESTER to terminate a pregnancy
When pregnant, P is required for MAINTENANCE of the endometrium early –> BLOCK P’s EFFECTS at its receptor –> Causes DETACHMENT OF UTERINE LINING –> fetus detaches too
MUST BE GIVEN WITH MISOPROSTOL IN ORDER TO FACILITATE CONTRACTIONS (remember?!?!) and EXPEL THE LINING
Post-menopausal side effects
MAINLY DUE TO LOW ESTROGEN
Hot flashes
Vasomotor effects
Osteoporosis
Urogenital Atrophy
Hormone Replacement Therapy
ESTROGEN REPLACEMENT (no uterus)
COMBO THERAPY (uterus - P protects endometrium from E!)
These therapies given in E doses less than 25% that of normal OCPs
Can be conjugated equine estrogen, estrone sulfate, estradiol transdermal patch, vaginal cream (cream for women on aromatase inhibitors because it stays more LOCAL)
ERT and HRT both VERY EFFECTIVE at decreasing menopausal symptoms, get more effective at high doses
WHI study no increase of breast cancer risk, DECREASE colon cancer risk!
Side Effects of HRT
CV effects – stroke, MI, VTE –> because of this, only recommended for patients who have DEBILITATING menopausal symptoms; could be worse in elderly
Increased DEMENTIA, cognitive loss
Increase ENDOMETRIAL CANCER RISK only on HRT which is approved for patients with a uterus only
Estrogen proliferation in the UTERUS so there is an increased risk of uterine cancer
TERATOGENS
TERATOGENS
Inadvertent Exposure
50% of US pregnancies are UNPLANNED
Women may be taking drugs that are fine for them but teratogenic to their unborn baby if they don’t know they are pregnant
A lot of detrimental effects occur in the FIRST TRIMESTER (critical period of organogenesis) so this is a significant problem
Fetal Risk Summary
A good alternative to the categories –> Super blunt and says “this drug will harm your baby” or “this drug increases risk of cardiac malformations” –> will also say WE DONT KNOW (better than category C or D)
Let’s us know what it’s based on (animal studies, human studies) and where to ACCESS data
Clinical considerations too –> risk of inadvertent exposure, risk of untreated comorbidities, dosage changes for medications already taken
THALIDOMIDE
Marketed as a NON-BARBITUATE sedative
Used for nausea, available without prescription; FDA never approved its use here in the US, so most cases were in Europe
Epidemic of infants born with ABNORMAL LIMBS (PHOCOMELIA)
20-30% of the babies were affected, but this just shows that NOT EVERYONE IS SUSCEPTIBLE TO TERATOGENS
PLACENTA was thought to be protective, but THALIDOMIDE PROVED THIS WRONG
Thalidomide and Animals
Was tested in animals, but it just precipitated, never really getting into the system
This DOES NOT MEAN that animal studies aren’t relevant
MOST DRUGS THAT ARE TERATOGENIC IN HUMANS ARE TERATOGENIC IN ANIMALS TOO –> Misoprostol is an exception
BUT, the reverse is not always true –> A drug that is NOT teratogenic in animals doesn’t mean it won’t be in humans
Nowadays, also very important to prove that drugs are not only non-teratogenic, but GOOD FOR THEIR INDICATED USE TOO
How many babies are born with birth defects and how many are due to teratogens?
3-4% are born with birth defects while 4-5% of those are due to drugs/chemicals
Four criteria for establishing teratogenicity?
GENETICS - fetus’ susceptibility depends on the genotype and the way it interacts with environment; not all thalidomide embryos had problems; CYP enzymes differ in racial groups, may be SPECTRUM of effects
TIMING - Susceptibility to teratogens varies; depends on the developmental stage at time of exposure
SPECIFICITY - Some drugs act in specific ways on developing cells and tissues, causing characteristic malformations (Thalidomide - limbs, Topiramate - cleft lip, Valpro - Neural tube defects)
DOSE EFFECT - Manifestations of abnormal development increase in degree as the dose increases –> from no effect to totally lethal; more drug more seal babies
Teratogens and Study Types
Animal studies - generally use HIGHER DOSES for animals; also the same effects don’t occur in animals/humans (they have TAILS for example)
Case Reports - important for thalidomide, but WE DONT KNOW THE DENOMINATOR (3/3000? 3/300? 3/50?)
Case-Control - Generally better than case reports; RETROSPECTIVE (start with outcome, work back to exposure); relies on RECOLLECTION; good for moderate risk teratogens
Cohort - Tend to be PROSPECTIVE and start with exposure; takes out recollection aspect; but the limit is that we are EXPOSING a woman to find a trend!!!
Human studies also only consider LIVE BIRTHS - don’t talk about babies killed in utero!
Some teratogenic effects may be very long term, like cognitive or cancers, and we won’t be able to trace it back to being teratogenic in nature
Alcohol
Causes CNS effects, facial changes; 30-50% risk in chronic binge drinkers
Most common cause of drug-induced birth defects and a leading cause of intellectual/developmental disability
FAS – flat midface, indistinct philtrum, low set ears, think upper lip, low nasal bridge
ACEI, ARBS, RENIN INHIBITORS
Can all cause CV malformations in the FIRST TRIMESTER, prolonged renal failure, decreased skull ossification, renal tubular dysgensis in 2nd/3rd
EQUALLY AS BAD (all Anti-HTN) –> they are CATEGORY D in the 2nd or 3rd, and CATEGORY C in the 1st
Anti-thyroid drugs
PROPYLTHIOURACIL, METHIMAZOLE
Fetal/neonatal goiters and hypothyroidism
HYPERthyroid MUST be treated during pregnancy!! But these drugs may cause adverse effects, oh well
Recommended to use PROPYLthiouracil in the FIRST TRIMESTER and then switch to METHIMAZOLE
Carbamezapine
Neural tube defects!
Cocaine
Small for gestational age!
Diethylstilbestrol (DES)
Vaginal CARCINOMA for girls exposed in utero!!!!
GU defects in female and male offspring
50% females
Hypoglycemic Drugs
Neonatal hypoglycemia
NEED TO KNOW DM status of mother
Was it BEFORE preggo? If so –> Type I are kept on normal insulin
If type II – oral hypoglycemic are SWITCHED TO INSULIN during pregnancy –> insulin has been shown to CONTROL BLOOD SUGAR better and we want to have VERY TIGHT CONTROL as high blood sugar is bad for the baby)
Maternal diabetes can cause CAUDAL REGRESSION SYNDROME, congenital heart defects, neural tube defects
LITHIUM
EBSTEINS ABNORMALITY –> atrialized right ventricle
METHOTREXATE
Folic acid inhibitor –> CNS and Limb malformations!!!!
NSAIDs
Constriction of the DUCTUS ARTERIOSUS
Also INHIBIT prostaglandins which can SLOW LABOR (PGs can be used to induce labor) –> this can increase bleeding risk
PHENYTOIN
Facial and CNS defects; 10% full blown, 30% partial
PSYCHOACTIVE DRUGS (Benzos, Opioids, Barbs)
Neonatal WITHDRAWAL syndrome if taken late
Withdrawal from alcohol/barbs can be fatal!
SMOKING
Small for gestational age
Causes vasoconstriction –> OXYGEN DEPRIVATION IN FETUS
Nicotine ALONE IS NOT TERATOGENIC –> have them on the patch during pregnancy!!!
Spontaneous abortion, perinatal death, premature birth, general pregnancy complications, intrauterine growth retardation, congenital malformations
FASTEST GROWING SET OF NEW SMOKERS IS ADOLESCENT GIRLS
SYSTEMIC RETINOIDS –> ISOTRETINOIN and ETRETINATE
CNS, craniofacial, CV or other defects
25% have anomalies
40% miscarriage rate
CATEGORY X!!!!! No safe dose ever justified when pregnant; need to take pregnancy tests when taking it to make sure you aren’t pregnant/reduce risk of inadvertent exposure
VALPROIC ACID
Neural tube defects (spina bifida) –> 1% risk
Inhibits folate absorption
WARFARIN
Skeletal and CNS defects; DANDY WALKER syndrme
17-30%
USE LOW MOLECULAR WEIGHT HEPARIN
Anti-Epileptics
Can cause OCP FAILURE (carbamezapine, Valpro, Phenytoin, Phenobarb)
Be advised to use TWO FORMS OF BIRTH CONTROL or to INCREASE ESTROGEN in OCP –> these drugs INDUCE CYP450 THAT METABOLIZES ESTROGEN!!!!
SSRI and Teratogenicity
Seem to have a “class effect” like ANTI-HTN
May be a very small increase in CV abnormalities when using PAROXETINE during 1st trimester
SERTRALINE may cause pulmonary HTN during 3rd
When it comes to depression and the terrible effects it could have, then the benefit probably outweighs the risk
Drugs that when GIVEN TO THE MOM similarly AFFECT THE FETUS
Antithyroid
Enzyme inducers
Drugs producing dependence
Oral hypoglycemics
Anticoagulants
CNS depressants
Ototoxic agents
HORMONE THERAPY OF CANCER
HORMONE THERAPY OF CANCER
Overview of Hormone Therapy
Seeks to manipulate the production and/or action of specific, endogenous hormones that typically promote malignancy
MAINLY FOR BREAST AND PROSTATE CANCER
Goal is to PREVENT PROLIFERATION OF PRIMARY TUMORS or METASTASIS in response to ESTROGENS (Breast) or ANDROGENS (Prostate)
Drugs designed to either BLOCK their action or PREVENT their synthesis
Found when women with breast cancer started showing smaller tumors when their OVARIES were removed!!!
In 60-70% of breast cancers, malignant cells express ESTROGEN RECEPTORS!!!!!!!
HPA Review
GnRH released from HYPOTHALAMUS (pulsatile fashion!)
GnRH travels to ANTERIOR PITUITARY and acts on GONADOTROPIC RECEPTORS
LH and FSH ARE STIMULATED and these ACT ON THE OVARIES OR TESTES
Stimulates the PRODUCTION OF ESTROGEN and PROGESTERONE or ANDROGENS
These steroids have secondary actions on BREAST TISSUE (mammary glands) OR THE PROSTATE
BLOCKING STEROID ACTION (one of two mechanisms of hormone therapy)
BLOCK STEROID ACTION
All roids exhibit a flat, planar structure; after they are produced, they FREELY DIFFUSE ACROSS MEMBRANES and enter the cytoplasm of nucleus
Sometimes they are converted to HIGHER AFFINITY HORMONES (T –> DHT via 5-a-reductase)
These then bind a SPECIFIC RECEPTOR –> conformational change that transports the complex to the nucleus and BINDS THE DNA
SO! Steroids can act as DNA ENHANCERS!!! Increasing transcription/translation
Since a large majority of steroid-targeted genes are involved in tissue-specific proliferation, excess hormones can ultimately promote TUMOR GROWTH –> THIS IS WHY WE BLOCK STEROID ACTION
PREVENT STEROID SYNTHESIS (one of two mechanisms of hormone therapy)
All steroids come from a COMMON CHOLESTEROL PRECURSOR –> this includes sex hormones
We generally tend to target the END STAGE STEPS to prevent side effects of having no steroids at all, as long as we still block SEX STEROIDS then all is good!
3 ENZYMES TARGETED
AROMATASE: Androgens –> Estrogen
5-ALPHA-REDUCTASE: T –> DHT
17-ALPHA HYDROXYLASE (earlier step)
What is the SERM for breast cancer?
Selective Estrogen Response Modulators
TAMOXIFEN!!!!! RALOXIFENE (less side effects)!!!!
FULVESTRANT –> estrogen antagonist!
TAMOXIFEN
Selectively targets estrogen receptors in the mammillary epithelial tissue
PREVENTS A CONFORMATIONAL CHANGE SO NO COACTIVATORS CAN BIND –> HALTS TRANSCRIPTION!!!!!!
Blocks ALL ESTROGEN STIMULATED PROTEINS FROM BEING TRANSLATED
Indicated as FIRST LINE ADJUVANT (usually with aromatase inhibitors) following resection of an estrogen sensitive tumor to prevent residual disease and metastasis; 5-10 year course
Metastatic Breast Cancer
CHEMOPREVENTATIVE agent in those predisposed!!
Metabolism of Tamoxifen
CYP450 metabolizes Tamoxifen extensively (6 metabolites)
MAJOR = N-desmethyltamoxifen
MINOR = 4-hydroxytamoxifen
N-des is then broken to ENDOXIFEN WHICH IS THE ACTIVE METABOLITE
CYP2D6 mediates Tamox –> 4hydroxy and N-des –> Endoxifen steps: Patients may have polymorphism that determines the efficacy! HIGH ACTIVITY CYP2D6 IS BETTER (more metabolism to the active metabolite)
SSRI may BLOCK CYP2D6 so that there is POOR CONVERSION
VERY LONG HALF LIFE!!! Parent = 7 days, N des = 14 days (can “forget” to take the drug and it won’t matter for a couple days”
Positive and Negative Effects of Tamoxifen
Positive besides treating breast cancer = DECREASES LDL and LIPOPROTEINS
SLOWS DEVELOPMENT OF OSTEO
Side effects –> systemic estrogen receptor binding will cause: INCREASED INCIDENCE of ENDOMETRIAL CANCER (pro-estrogen in uterus!!!!); eye diseases, frequent HOT FLASHES, thrombocytopenia, CV problems
After 5-10 years, most tumors DEVELOP RESISTANCE TO TAMOXIFEN
RALOXIFENE
Oral SERM with less side effects than Tamoxifen
Binds to BOTH ALPHA AND BETA ESTROGEN RECEPTORS WITH HIGH AFFINITY
In the breast tissue, it is an ESTROGEN ANTAGONIST, preventing proliferation
Estrogen agonist in BONE!!! Good! Prevents osteoporosis!!!!!
Used for INVASIVE BREAST CANCER, PREVENTION IN HIGH RISK, AND OSTEOPOROSIS!!!
FULVESTRANT
Extremely effective ESTROGEN ANTAGONIST
Indicated for POST-MENOPAUSAL WOMEN who have progressed to METASTATIC WHILE ON TAMOXIFEN
Simultaneously causes DEGRADATION OF RECEPTORS WHILE ALSO ANTAGONIZING IT!!!!
Side Effects –> GI effects, headache, back pain, hot flashes
IM once/month
AROMATASE INHIBITORS
Aromatase is involved in the synthesis of estrogen and converts ANDROSTENIDIONE –> ESTRONE and TESTOSTERONE to ESTRADIOL
Inhibit this, so ESTROGENS ARE NOT PRODUCED
ANASTRAZOLE, LETROZOLE (non-steroidals)
EXEMESTANE (steroidal)
Steroidals (EX) –> substrate analogs that act as “suicide” inhibitors, IRREVERSIBLY INACTIVATING AROMATASE
Non-steroidals –> interact REVERSIBLE with the heme group of CYP enzymes
VERY EFFECTIVE! After one week serum estrogen is brought BELOW DETECTABLE LEVELS (and does not affect cholesterol or aldosterone)
Shown to INCREASE DISEASE FREE & OVERALL SURVIVAL and decrease risk of CONTRALATERAL TUMORS!
FIRST LINE TREATMENT FOR ESTROGEN POSITIVE BREAST CANCERS (60-70%)
Used instead of or AFTER tamoxifen
EXEMESTANE good for PREVENTION
Aromatase specifically for who…
***POST MENOPAUSAL WOMEN ONLY!!!!!!!
If given to PRE menopausal women, the estrogen reduction would be SO SIGNIFICANT that the anterior pituitary would give out MASSIVE LH AND FSH!!!
This would stimulate the ovary to abnormally hyperproliferate and hyperovulate, potentially RUPTURE
Side Effects of Aromatase inhibitors
Generally well tolerated
Minor effects due to the significant drops in estrogen, closely resemble MENOPAUSAL symptoms
Enhanced osteoporosis and joint pain
Long term use associated with RESISTANCE
Anti-Androgens for PROSTATE CANCER
FLUTAMIDE
BICALUTAMIDE
Non-steroidal, oral, FIRST LINE FOR ADVANCED METASTATIC
Side effects - both metabolized by the liver to active compound, thus they can cause HEPATIC TOXICITY and LIVER FAILURE
GYNECOMASTIA (larger amounts of estrogen relative to T –> alters mammary tissue)
Loss of LIBIDO
GI effects
Bicalutamide has less side effects
Mechanism of Anti-androgens
Bind to androgen receptors in the prostate and seminal vesicles –> competitively inhibit the actions of T and DHT
Blocks the proliferation/DNA enhancement
Also block androgen-regulated NEGATIVE feedback on the anterior pituitary –> Massive LH and FSH surge that can target the testes and secrete a LOT of Testosterone in the peripheral circulation; could theoretically wash out the inhibition
GIVE WITH GnRH ANALOGS to PREVENT THIS (downregulates the HPA)
GnRH analogs in BREAST AND PROSTATE CANCER
GOSERELIN
LEUPROLIDE
Persistent elevation of GnRH –> Gonadotrope receptors in anterior pituitary DOWNREGULATE so that FSH and LH production DECREASES –> has a DOWNSTREATM EFFECT on the PRIMARY SEX ORGANS –> Limits Steroid Hormone Production
80-100x more potent than GnRH itself! Essentially acts as a chemical oophorectomy or orchidectomy in patients with breast/prostate cancer
Initially, may have a BRIEF STIMULATION before the downregulation/inhibition sets in –> TUMOR FLARES can be painful, especially in metastatic bone disease; so give with HORMONE ANTAGONISTS TO SHUT IT OFF AT ONCE
Side Effects –> Hypogonadism, loss of libido, hot flashes, dryness, vaginal atrophy
BPH DRUG?
FINASTERIDE
Orally administered steroid
Alternative to surgery for BPH
Targets receptors in HAIR FOLLICLES so it can cause baldness!!
Could potentially PREVENT BPH –> but the tumors that DID emerge (even though there were less overall) were MORE aggressive
Competitively inhibits 5-ALPHA REDUCTASE in selective target tissue; this will PREVENT T–>DHT
Decreasing DHT HALTS EXCESSIVE PROLIFERATION –> improves urinary outflow, shrinks the prostate
ORAL PREDNISONE
Glucocorticoids in cancer
Indicated at EXTREMELY HIGH DOSES in combo therapy for: ALL, CLL, MYELOMA, HODGKINS/NHL
Complete remissions with chemo are SIGNIFICANTLY improved when prednisone is added
Metabolism –> Immediately comverted to PRENISOLONE –> acts directly on lymphocytes, stimulating receptor-mediated apoptosis
Side effects –> extensive, affects almost every organ; continuous administration –> RESISTANCE
Breast Cancer Drugs
SERMS - TAMOXIFEN, RALOXIFENE (estrogen antagonists)
FULVESTRANT – extremely effecting estrogen antagonist
Aromatase Inhibitors for Breast Cancer
ANASTRAZOLE
LETROZOLE
EXEMSTANE
Prevent T –> estradiol conversion
POST MENOPAUSAL WOMEN ONLY!!!!!! in premenopausal, no inhibition, massive LH/FSH, hyperstimulated ovaries!
Prostate Cancer Drugs
FLUTAMIDE and BICALUTAMIDE (anti-androgens!!!!)
Breast AND prostate cancer drugs
GnRH analogs (DOWNREGULATE SYSTEM)
GOSERELIN
LEUPROLIDE
BPH Drug?
FINASTERIDE (inhibits 5-alpha reductase – so no conversion of T –> DHT)
Steroid for cancers?
GLUCOCORTICOID –> ORAL PREDNISONE
