Infertility & PCOS & IVF Flashcards
Infertility epidemiology
30-34: 1/7
35-39: 1/5
40-44: 1/4
generally 1/6 couples
Incidence increasing
Cumulative fertility and maternal age
20-24: 86% conceive within one year
25-29: 78
30-34: 63
35-39: 52
When to investigate for infertility
Ovarian reserve testing
Day 3 FSH/estradiol (FSH
Documenting ovulation
regular cycles - 95% women are ovulating
basal body temperature charting
urniary LH kit
Luteal phase progesterone = gold standard
- measure 7 days before anticipating menses, since luteal phase is fixed
Anovulation causes
PCOS
Hypothalamic hypogonadism (low BMI, FHS/LH/estradiol low)
Hypothyroidism (increased TRH can affect pituitary function)
Hyperprolactinemia
Premature ovarian failure
menopause
Establishing tubal patency
hysterosalpingogram
laparoscopy
Semen analysis
2 separate samples, >2 wks apart volume >1.5 ml concentration>15 mil/mL motility >32% normal morphology >4%
Female work up for infertility
ovarian reserve testing: day 3 FSH and estradiol/AMH Hysterosapingogram TSH, prolactin pelvic ultrasound luteal phase progesterone
PCOS incidence
5-10% of women
one of most common hormonal disorders
PCOS diagnosis
2/3 of:
Oligo/amenorrhea (oligo >35 days)
Clinical/laboratory evidence of elevated androgens - hirsutism, acne
Polycystic ovaries on US
PCOS diagnosis: rule out
CAH - 17OHP
Cushing’s: clinical signs, AM cortisol
Hyperprolactinemia: galactorrhea, elevated PRL
Hypothyroidism: TSH
Presenting complaints of PCOS
infertility
hirsutism/male pattern hair loss
acne
irregular cycles
Pathogenesis of PCOS
not simple!
increased LH, androgens, insulin
Hypothalamus rapid GnRH pulsatility
–> preferential release of LH over FSH
LH increases androgens from theca cells, lower FHS can’t recruit dominant follicles
Causes of increased LH in PCOS
thecal cells stimulated –> preferential production of androgens
Granulosa cells have less FSH, don’t aromatise as much to estrogen
elevated local androgens - inhibit follicular development
Increased insulin in PCOS
directly works synergistically with LH to increase theca cell androgen production
indirectly decreases sex-hormone binding globulin to increase circulating testosterone
PCOS etiology
likely heritable
some rare single gene disorders
likely complex multigenic
intrauterine environment????
Infertility in PCOS
not ovulating regularly
weight loss can improve insulin status
tx of PCOS
1) clomiphene citrate
letrozole
metformin
others: FSH injections, IVF, ovarian drilling
if NOT trying to conceive - OCP to regulate cycles, reduce hirsutism/acne, protect endometrium, etc
Clomiphene citrate MOA
blocks estrogen feedback at hypothalamus/pituitary, also at uterine lining
increased FSH release, possibility of ovulation
Anti-estrogen effects on uterine lining/cervica lmucous –> thin endometrial lining, thick mucus
Rate of multiples - 8%
cost - $100/mo
May need to bring on a period with Provera
10 days with progesterone to mimic luteal phase, then stop to signal beginning of another cycle
start at 50, then 100, then 150
Letrozole MOA
aromatase inhibitor (decrease androgen level) take day 3-7 of cycle
Metformin MOA in PCOS
decreases hepatic glucose production
decreases intestinal glucose absorption
increases insulin sensitivity
Reducing insulin –> reduction of effect of LH on theca cells
does not work as well as clomiphene
500 mg three times a day
FSH injection
expensive - need 10-20 injecitons at $50-100/day just to ovulate
chance of multiples ~30%
Hirsutism/acne treatment
due to elevated androgens
Oral contraceptives:
- estrogen increases SHBG and reduces LH production
- progesterone: can be anti-androgenic
Anti-androgens: cyproterone acetate, spironolactone, flutamide
Long-term health implications of PCOS
Endometrial cancer:
- hyperplasia of endometrium due to chronic unopposed estrogen
- OCP/cyclic progesterone q3 mo
Hypertension
Dyslipidemia
Type II DM - 30-40% have impaired glucose intolerance; 10% will have T2DM by 40s
Sleep apnea
IVF overview
1) ovaries stimulated with drugs to produce multiple eggs
2) harvested when ready
3) inseminated with sperm
4) fertilized eggs matured into embryos
5) one or more embryos are replaced into uterus
6) extra embryos frozen for future use
7) pregnancy test performed 2 weeks later to confirm
Investigations to be done prior to IVF
Ovarian function and reserve - Day 3 FSH, E2, AMH
Uterine cavity architecture - HSG, SHG or hysteroscopy
Tubal status (rule out hydrosalpinx) - HSG, contract SHG/larparoscopy
thyroid status (aim for 1-2.5, miscarriage risk increases with abnormal TSH)
Semen parameters
Antral follicle count - for initial FSH dosage
BMI - affect treatment outcome significantly if >35
Other - prophylactic antibiotics, concomitant meds, prenatal supplements, herbs, other supplements
IVF - oocyte recruitment and growth
FSH/LH administered by daily s/c injection –> promote growth of several ovarian (antral) follicles
Each follicle at maturity will contain 1 oocyte
Generally require between 9-12 d befoer majority of follicles reach mature size (17-18mm in mean diameter) >3 reach mature size
FOllicular number and growth monitored during stimulation using ultrasound/serum estradiol
Concomitant medication - prevent developing oocytes from ovulating spontaneously before retrieval (prevent own LH surge)
IVF - Triggering of oocyte maturity
majority of follicles reach mature size
hCG administered by s/c injection
–> mimics biological effect of LH in natural menstrual cycle
- oocyte undergo first meiotic division with extrusion of first polar body (haploid oocyte)
oocyte to break away from follicular wall and float freely in follicular fluid
Oocyte retrieval
performed 34-36 hours after the trigger shot
each follicle aspirated using an aspiration needle connected to a collection tube
performed vaginally with ultrasound guidance
- aspiration needle passed through a needle guide attached to US probe
Needle advanced through vaginal wall into ovary, then into a follicle (ovary adjacent to vaginal wall)
needle then passed form one follicle to next and fluid from each drained into collection tube
Oocyte identification
each follicular aspirate passed to an embryologist for immediate examination
When a cumulus-oocyte complex is identified, some of excess cumulus is cut away/oocyte then placed into oocyte culture medium
Oocyte insemination
Semen sample obtained/thawed from bank
Preparation process of sperm
Depending on quality/quantity of semen, oocytes are then exposed to sperm by either:
- adding a number of sperm to culture medium containing each egg (IVF)
- single sperm is selected and injected into each egg (ICSI)
ICSI is employed when sperm quality/quantity is less than ideal, and fertilization could potentially be impaired if IVF was used
Oocyte culture
Inseminated sperm placed into an incubator which is strictly controlled for temperature as well as CO2, O2 and nitrogen concentration
Fertilization confirmed by examining each oocyte after 18 h of incubation
Presence of 2 pronuclei = fertilization
Replaced into incubator, grown to 3rd or 5th day of development
- on day 3, genetics of embryo must be functional, so sperm genetics must be working at this time
Embryo development monitored by various means - daily examination (appearance/morphology) or by a continuous method (morphokinetics/embryoscope)
Morphokinetics
quantifying dynamics of morphological changes correlates with embryo’s sustained implanatation potential
Time of pronuclei appearance TIming of cell divisions Synchrony of cell divisions Duration of cell cycles Aneuploidy prediction strategies based on morphokinetic algorithms
Embryo replacement/transfer
Not all embryos have potential to develop to 5th day (blastocyst stage)
If an embryo reaches day 5 –> best chance of implantation
Many factors influence decision regarding # of embryos to replace/timing of transfer
Always best to balance chance of pregnancy against risk of a multiple pregnancy since multiple pregnancy considered a complication of IVF
Choice of transfer catheter personal
embryos deposited between 1-1.5 cm from top of endometrial cavity
Woman receives progesterone either vaginally/im for support of luteal phase, and for a variable length of time afterward depending on pregnancy status
Extra embryos frozen by vitrification
Elimination of disease in IVF
pre-implantation genetic diagnosis (PGD)
- single gene defects, chromosomal abnormalities
Pre-implantation genetic screening (PGS, CCS)
recurrent pregnancy loss, recurrent failed implantations of embryos, women over 40
oocyte rejuvenation - ovarian stem cells
embryonic stem cell research
gene therapy
