ART
Assisted reproductive technology
Dithawut Khrutmuang MD.
Assisted reproductive technology
• All treatments or procedures which include the handling of human
oocytes or embryos, including in vitro fertilization, gamete
intrafallopian transfer, zygote intrsifallopian transfer, and such other
specific technologies as the Secretary may include in this definition.
1992 Fertility Clinic Success Rate and Certification Act
Assisted Reproductive Technology (ART)
• In vitro fertilization-embryo transfer (IVF-ET)/intracytoplasmic sperm
injection (ICSI)
• Gamete intrafallopian transfer (GIFT)/ Zygote intrafallopian transfer (ZIFT)
• Frozen embryo transfer (FET).
• ART may be recommended when other treatments (such as intrauterine
insemination) have not been successful or when there is severe male factor
infertility, severe endometriosis or tubal obstruction.
2011 the American Society for Reproductive Medicine
Evaluation before ART
• General
• Before starting ART, each patient is evaluated to help maximize her chances for
success and a healthy pregnancy.
• Chronic medical conditions such as diabetes, hypertension and asthma should be
well controlled before attempting to conceive.
• Women planning an IVF cycle should optimize their weight. Obesity has been
associated with infertility, a reduced chance of success with IVF, and an increase
in the risk of miscarriage and preterm birth.
2011 the American Society for Reproductive Medicine
Ovarian
reserve test
J Hum Reprod Sci. 2011 Sep-Dec; 4(3): 108–113.
Evaluation before ART
• Uterus
• The uterus is usually evaluated prior to an IVF. Three methods can be used: HSG,
SIS or hysteroscopy.
• Prior to IVF, a trial or “mock” transfer may be done. The purpose of this procedure
is to determine the length and direction of the uterus.
• Semen
• A semen analysis should be reviewed. Changes in sperm quality may occur over
time that could affect IVF success.
2011 the American Society for Reproductive Medicine
Prerequisite test before ART
• Female
HIV
Hepatitis B antigen
Hepatitis C antibody
VDRL/RPR
Pap smear
Blood group, Rh, and antibody screen
• Male
HIV
Hepatitis B antigen
Hepatitis C antibody
VDRL/RPR
Complex semen analysis, antisperm
antibodies, and strict morphology
2011 the American Society for Reproductive Medicine
STRONGLY RECOMMENDED PRENATAL TESTS
• Female
• Male
• Rubella titer
• Hemoglobin electrophoresis
Varicella titer
Hemoglobin electrophoresis
Cervical swab for Gonorrhea and
Chlamydia
2011 the American Society for Reproductive Medicine
ART Cycle
• Pre-stimulation treatment
• Ovarian stimulation with gonadotropins
• Monitoring follicle development
• Final oocytes maturation
• Transvaginal oocyte retrieval
• Insemination
• Embryo transfer
• Progesterone supplementation
• Pregnancy test Early pregnancy follow-up
2011 the American Society for Reproductive Medicine
Ovarian stimulation with gonadotropins
Santos M A et al. 2010;139:23-34
©2009 by Society for Reproduction and Fertility
Ovulation induction VS. Controlled ovarian hyperstimulation
Ovulation induction
Controlled ovarian hyperstimulation
• Use in anovulatory infertility.
• Superovulation
• Restore physiologic of cyclic
• Stimulation of multiple follicular
ovarian function.
• Aim : Ovulation of single follicle
development
• Aim : multiple follicular
development for ART
2011 the American Society for Reproductive Medicine
Controlled ovarian hyperstimulation
Long agonist
Antagonist
Merck & Co., Inc
GnRH agonist / antagonist
used to inhibit a premature LH surge
GnRH Agonists
• Gonadotropin releasing hormone (GnRH) is a hormone produced in the brain
that indirectly stimulates ovarian function.
• Agonists of GnRH are synthetic forms of this hormone
• Mechanism Of Action
• Agonists of GnRH initially stimulate the pituitary gland to release all the stored
gonadotropins (LH and FSH -the hormones that normally stimulate ovarian function).
• Over the course of a week to 10 days, GnRH analogs suppress the production of any new LH
and FSH. This effect appears to prevent the ovaries from receiving mixed signals from the
patient's own LH and FSH and from the medications that are administered to stimulate
follicle development.
• The result for many patients is a more synchronized development of mature oocytes.
2011 the American Society for Reproductive Medicine
Days of cycle ( CD)
Duration administration
GnRH agonist protocol
Route of
administration
Ultrashort
NS / SC
2,3 – 4,5
Short
NS / SC
2,3 until day of hCG
8 -12 days
Menstrual early cessation
NS / SC
21 until menses
7 -12 days
Follicular early cessation
NS / SC
21 until stimulate D6,7
13 -20 days
Long follicular
NS / SC
2 until day of hCG
28 -35 days
Long follicular(depot)
Depot
2
Long luteal
NS / SC
21 until day of hCG
Long luteal(depot)
Depot
21
Ultralong
NS / SC / Depot
2 or 21
3 days
Once
21 -28 days
Once
8-12 weeks , depot 2-3
times
GnRH agonist protocol
Advantasge
Disadvantage
Ultrashort
Patient’s comfort, Poor responders
Low PR, Low oocyte quality
No programming
Short
Patient’s comfort, Poor responders
Low PR, Low oocyte quality
No programming
Menstrual early cessation
Inconclusive
Low E2 level, high cancel rate
Follicular early cessation
Inconclusive
Low E2 level, high cancel rate
Long follicular
Good PR, High number oocytes, programming
Long duration
Long follicular(depot)
Patient’s comfort
Too long duration of action
Long luteal
Good PR , programming
Long duration
Long luteal(depot)
Patient’s comfort
Too long duration of action
Ultralong
Endometriosis
Sideeffects due to estrogen deficiency
GNRH Antagonists
• Antagonists of GnRH are directly and immediately inhibit FSH and LH
production.
• Ultrasound measurements of follicular growth are used to determine
when to start these medicines.
• Mechanism of Action
• GnRH antagonists bind to the receptor for gonoadotropin releasing hormone
on the pituitary, preventing the natural luteinizing hormone surge and
ovulation.
2011 the American Society for Reproductive Medicine
GnRH antagonist protocols
Gonadotropins ; use in ovarian stimulation
• Complex heterodimeric glycoproteins
• 2 non-covalent linked proteins:
α -subunit:
β -subunit: unique, specific hormonal function
Exogenous gonadotropins
• Pregnant mare serum
• Pig pituitary gland extracts
• Human menopausal gonadotropin (hMG)
• Recombinant human gonadotropins
Corifollitropin alfa ;New long-acting gonadotropins
Luteinzing hormone
• A heterodimeric glycoproteins
• Bind to receptor on the theca cells and granulosa cells (late follicular phase)
• Main role:
• Stimulate androgen production from the theca cells
• Triggering ovulation
• Supporting the corpus luteum
• Indication:
• Hypogonadotropic hypogonadism
• Profound pituitary & ovarian desensitization (GnRH agonist)
• Poor responder, age > 35 years
COH monitoring : Why ?
• Predict the ovarian response to gonadotropins.
• Monitor effect of pituitary down-regulation.
• Evaluate whether the dose of gonadotropin is
adequate.
• Avoid OHSS
• Find the optimal time to give hCG
2011 the American Society for Reproductive Medicine
Final oocytes maturation / trigger ovulation
• Trigger ovulation; When?
• 3 follicles of 18 mm (mean of 2 diameters) on Day 9 -10 of stimulation and
• fewer than 15 follicles and
• Endometrial thickness : ≥ 7 mm.
• Drug used to trigger ovulation
• Urinary human chorionic gonadotrophin (uhCG)
• Recombinant hCG (rhCG)
• Recombinant LH (rLH)
• GnRH agonist
Merck & Co., Inc
Merck & Co., Inc
Merck & Co., Inc
Success rate
• Success varies with many factors.
• Age of the woman is the most
important factor
• Quality of embryos
• Number of embryos transferred
J Hum Reprod Sci. 2011 Sep-Dec; 4(3): 108–113.
Success rate
Age
<35
35-37
38-40
41-42
>42
38662
19599
18410
10167
6224
Percentage of cycles resulting in pregnancies
46.7
37.8
29.7
19.8
8.6
Percentage of cycles resulting in live births
40.7
31.3
22.2
11.8
3.9
Percentage of cancellations
6.3
9.2
12.7
15.8
21.5
Average number of embryos transferred
1.9
2.0
2.4
2.9
2.9
29.5
25.0
20.3
13.4
9.0
1.1
0.7
0.7
0.7
0.4
Number of cycles
Percentage of live births with twins
Percentage of live births with triplets or more
2014 SART