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Flashcards in Infertility & PCOS & IVF Deck (36):
1

Infertility epidemiology

30-34: 1/7
35-39: 1/5
40-44: 1/4
generally 1/6 couples

Incidence increasing

2

Cumulative fertility and maternal age

20-24: 86% conceive within one year
25-29: 78
30-34: 63
35-39: 52

3

When to investigate for infertility

4

Ovarian reserve testing


Day 3 FSH/estradiol (FSH

5

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

6

Anovulation causes

PCOS
Hypothalamic hypogonadism (low BMI, FHS/LH/estradiol low)
Hypothyroidism (increased TRH can affect pituitary function)
Hyperprolactinemia
Premature ovarian failure
menopause

7

Establishing tubal patency

hysterosalpingogram
laparoscopy

8

Semen analysis

2 separate samples, >2 wks apart
volume >1.5 ml
concentration>15 mil/mL
motility >32%
normal morphology >4%

9

Female work up for infertility

ovarian reserve testing: day 3 FSH and estradiol/AMH
Hysterosapingogram
TSH, prolactin
pelvic ultrasound
luteal phase progesterone

10

PCOS incidence

5-10% of women
one of most common hormonal disorders

11

PCOS diagnosis

2/3 of:
Oligo/amenorrhea (oligo >35 days)
Clinical/laboratory evidence of elevated androgens - hirsutism, acne
Polycystic ovaries on US

12

PCOS diagnosis: rule out

CAH - 17OHP
Cushing's: clinical signs, AM cortisol
Hyperprolactinemia: galactorrhea, elevated PRL
Hypothyroidism: TSH

13

Presenting complaints of PCOS

infertility
hirsutism/male pattern hair loss
acne
irregular cycles

14

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

15

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

16

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

17

PCOS etiology

likely heritable
some rare single gene disorders
likely complex multigenic
intrauterine environment????

18

Infertility in PCOS

not ovulating regularly
weight loss can improve insulin status

19

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

20

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

21

Letrozole MOA

aromatase inhibitor (decrease androgen level)
take day 3-7 of cycle

22

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

23

FSH injection

expensive - need 10-20 injecitons at $50-100/day just to ovulate
chance of multiples ~30%

24

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

25

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

26

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

27

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

28

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)

29

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

30

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

31

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

32

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

33

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)

34

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

35

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

36

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