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
