Partnership Between the Patient, the
ObGyn, and the Fertility Specialist
ObGyn
Patient
Fertility
Specialist
1
There Are Multiple Causes
of Infertility
Causes of Infertility
14%
18%
Tubal factor
Ovulatory dysfunction
6%
6%
Diminished ovarian reserve
Endometriosis
Uterine factor
13%
7%
Male factor
Other causes
1%
Unexplained
11%
Multiple female factors
6%
19%
Multiple factors male + female
Centers for Disease Control. http://www.cdc.gov/ART/ART02/sect2_fig14-24.htm#Figure%2014. 2006.
2
Assisted Reproductive Technology (ART)
Infertility treatment options
In vitro fertilization
Associated technology
Efficacy of ART
Partnership
for better outcomes
• Weight management
• Surgical interventions
• Pharmacologic interventions
•
•
•
•
Ovulation induction (CC)
Ovulation induction (gonadotropin)
Controlled ovarian stimulation protocols
ICSI
• Preimplantation genetic diagnosis
• Cryopreservation
• Oncology considerations
• Pregnancies/deliveries IVF
• Pregnancies/deliveries ICSI
• Rate of complications
•
•
•
•
Need for partnership
Management algorithm
Recommendations
Transition of patient
3
Treatment Options for Female Infertility
● Weight management
● Surgical interventions
– Tubal reconstruction/flushing
– Adhesiolysis, salpingectomy, laparoscopic treatment of endometriosis
– Correction of uterine abnormalities
● Pharmacologic interventions (non–ovulation induction)
– Selective estrogen receptor modulators, insulin-sensitizing agents, aromatase
inhibitors, etc
● Ovulation induction
– Natural or intrauterine insemination
● Assisted reproductive technologies
– In vitro fertilization
• Controlled ovarian stimulation
• Intracytoplasmic sperm injection
4
Managing Obesity in Women Can
Improve Fertility
Odds ratio for subfertilitya
2.0
1.7%
1.5
1.4%
1.0%
1.0%
<18.5
18.5 to <25.0
1.0
0.5
0
25.0 to <30.0
≥30
BMI (kg/m2)
aTime
to pregnancy >12 months.
Ramlau-Hansen et al. Hum Reprod. 2007;22:1634.
5
PCOS
BMI >25
Anovulatory infertility
Anthropometric and
echographic evaluation
Diet 1200 kcal
BMI reduction by 5%
then by 10%
Ovulation
Anthropometric and
echographic evaluation
Anovulation
Residual time for
spontaneous conception
End of the study
Rate of regular cycles, ovulatory
cycles, and pregnancy
Weight Loss as Treatment for Infertility
1.0
0.8
Ovulatory cycles
0.6
Regular menstrual
cycles
0.4
0.2
Pregnancy
0
0
2
4
6
8
10
Months
Treating obesity appears to reinstate normal ovulatory functions
Crosignani et al. Hum Reprod. 2003;18:1928.
6
Tubal Reconstruction
● Tubal reconstruction appears less effective than IVF for
treatment of tubal factor infertility
– Series of 83 women with distal tube occlusion treated surgically and
followed for 1 year1
• Pregnancy within 1 year: 15.7%
• Live births from the above pregnancies: 9.6%
– Overall delivery rate per transfer for IVF patients with tubal
factor: 28.9%2
1. Nichols and Steinkampf. Prim Care Update Ob Gyns. 1998;5:168.
2. Benadiva et al. Fertil Steril. 1995;64:1051.
7
Adhesions Can Affect Infertility
Origin
● Endometriosis
● Pelvic inflammatory disease
(PID)
● Peritoneal infections
– Appendicitis
– Tuberculosis
● Surgery
Effects
● Distortion of tubo-ovarian
relationships, preventing ovum
capture
● May hinder oocyte
development and maturation
– Decreased ovarian blood
supply
– Inadequate delivery of
gonadotropins and growth
factors to follicles
Diamond and Freeman. Hum Reprod Update. 2001;7:567.
8
Uterine Structural Abnormalities
● Congenital abnormalities
(Incidence %)
–
–
–
–
–
–
Hypoplasia/agenesis (n/a)
Unicornuate (6.2%)
Bicornuate (20.3%)
Didelphys (6.2%)
Arcuate (32.8%)
Septate (33.6%)
Didelphys
● Endometrial polyps
● Myomas (fibroids)
Taylor and Gomel. Fertil Steril. 2008;89:1.
Raga et al. Hum Reprod. 1997;12:2277.
9
Uterine Abnormalities, Reproductive
Effects, and Common Treatments
Abnormality
Effects on
Reproduction
Treatment
Congenital Uterine
Abnormalities
Unicornuate
45% loss of pregnancies
Removal of rudimentary horn by
laparotomy or laparoscopy
Bicornuate
45% loss of pregnancies
Rarely requires surgical treatment
Didelphys
42% loss of pregnancies
Resection of vaginal septum, Strassman
reunification
Septate
79% loss of pregnancies
Hysteroscopic resection
Polyps
28% pregnancy rate
Myomas
-
Polypectomy
GnRH agonist, mifepristone, uterine
artery embolization, myolysis,
myomectomy
Taylor and Gomel. Fertil Steril. 2008;89:1.
10
Possibly Useful Pharmacologic
Interventions
● Selective estrogen receptor modulator
(clomiphene/tamoxifen)—antagonizes estrogen
feedback activity at hypothalamic-pituitary axis
● Insulin-sensitizing drugs
(metformin/troglitazone)—insulin resistance
may play a key role in the pathogenesis of
ovarian dysfunction
● Aromatase inhibitor (letrozole)—blocks
conversion of androstenedione and
testosterone to estriol and estradiol
Stadtmauer et al. Fertil Steril. 2001;75:505.
Mitwally and Casper. J Soc Gynecol Investig. 2004;11:406.
11
Indications for In Vitro Fertilization
● Absent or blocked fallopian tubes
● Failed tuboplasty
● Concomitant pelvic disease
● Severe male factor infertility
● Endometriosis
● Diminished ovarian reserve
● Unexplained infertility
– Failed intrauterine insemination (IUI)
Diedrich et al. Hum Reprod. 1992;7(suppl 1):115.
12
Ovulation Induction
● Useful in patients with anovulatory infertility as well as
unexplained infertility
– WHO class I: hypogonadotropic hypogonadism
– WHO class II: PCOS
● Goal
– Stimulate development of a single follicle that will be able to
reach preovulatory size and rupture
● Options
– Clomiphene citrate (CC)
– Gonadotropins (LH, FSH, gonadotropin-releasing hormone
[GnRH], human chorionic gonadotropin [hCG])
Messinis. Hum Reprod. 2005;20:2688.
13
Pharmacology of Clomiphene
Citrate (CC)
● Nonsteroidal triphenylethylene derivative
● Binds to estrogen receptors (ER) throughout the
reproductive system
– Both agonist and antagonist properties
– Efficacy in ovulation induction attributed to binding to hypothalamic
ER
– Increases both LH and FSH
– Considered best initial treatment for the majority of women whose
infertility is associated with ovulatory dysfunction
● Some deleterious effects on endometrium and cervical
mucous (due to systemic antiestrogen effects)
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(suppl 5):S187.
Sereepapong et al. Fertil Steril. 2000;73:287.
14
Clomiphene
50-250 mg/d
5 days
Standard CC Treatment Regimen
5 days Coitus
every other day
7 days
Progesterone
LH
FSH
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Menses
Clomiphene therapy
Home Fertility Network. Ovulation induction. http://www.homefertility.com/ovulind.htm. 2007.
15
Efficacy of CC: Meta-Analysis of
Clinical Results
70
69.4%
% of patients
60
50
40
30
20
6.2%
10
8.8%
0
Ovulation per cycle Pregnancy per cycle
Pregnancy per
ovulatory cycle
Steiner et al. Hum Reprod. 2005;20:1511.
16
CC Summary
● Simplest initial treatment for majority of women
● Reported outcomes are variable, but in general, pregnancy
rates 6% per cycle
● Limit treatment to 6 (3 if poor ovulation induction) cycles
(low probability of success beyond this)
● Monitor patients to ensure effectiveness of ovulation
induction (basal body temperature, urinary LH, serum
progesterone)
● Principal risk associated with CC is multifetal gestation
(<10%)
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(suppl 5):S187.
National Institute for Clinical Excellence. http://www.nice.org.uk/nicemedia/pdf/CG011fullguideline.pdf. 2004.
Hanson and Dumesic. Mayo Clin Proc. 1998;73:681.
Imani et al. J Clin Endocrinol Metab. 1999;84:1617.
17
Gonadotropin Therapy
● Represents a more physiologic approach to multifollicular
recruitment than CC
● Agents
– Purified or recombinant human FSH
– Human menopausal gonadotropins (hMG): 75 IU each of FSH
and LH
– Human chorionic gonadotropin (hCG)
● Gonadotropin preparations constitute the principal agents for
ovulation induction and COS
– Significantly higher odds of pregnancy per woman (OR=0.41,
95%CI: 0.17-0.80) vs antiestrogen induction
– Maximum control
• Ovarian response
• Risk of multiples
Davis and Rosenwaks. Sem Reproductive Med. 2001;19:207.
Athaullah et al. Cochrane Database Syst Rev. 2002:CD003052.
18
Ovulation Induction:
Gonadotropin Treatment
● Starting dose of FSH usually 50 or 75 IU
● Increments of 25-50 units after 7-14 days
● May include IUI or natural intercourse
OI
hCG
Homberg and Insler. Hum Reprod Update. 2002;8:449.
Lambalk et al. Hum Reprod. 2006;21:632.
19
Ovulation Induction vs In Vitro Fertilization
● Ovulation induction (OI)
– Goal: induce growth of 1 or 2 mature follicles
– Low doses of gonadotropins
– Clomiphene citrate (CC)
– Natural insemination or IUI fertilization
● In vitro fertilization (IVF)/COS
– Goal: induce growth of multiple mature follicles
– Higher doses of gonadotropins
– Oocytes removed, fertilized in laboratory setting,
then returned to uterus
20
In Vitro Fertilization (IVF)
Procedure
● Initially used in women with fallopian
tube blockage or damage
Risks
●
–
● Now employed for many causes of
infertility (eg, endometriosis, male
factor)
● Involves
– Controlled ovarian stimulation (COS)
– Egg retrieval
– Insemination, fertilization, embryo
culture
– Embryo transfer
– Cryopreservation of extra embryos
Ovarian hyperstimulation syndrome
(OHSS)
–
–
Usually not serious and resolves with
outpatient management
1%-2% severe requiring hospitalization
Dose-dependent, avoided by careful
titration
●
Anesthesia
●
Multiple births
●
Ectopic pregnancy
●
Psychologic distress
American Society for Reproductive Medicine. http://www.asrm.org/Patients/patientbooklets/ART.pdf. 2008.
21
Typical IVF Protocol
Controlled
ovarian
stimulation
Embryo
cryopreservation
PGD screening
Follicular aspiration
IVF
or
ICSI
Oocyte freezing
Embryo
cleavage
Embryo
transfer
Pregnancy
diagnosis
Oehninger. J Soc Gynecol Investig. 2005;12:222.
22
Key Concepts in Controlled Ovarian
Stimulation
● Prospective identification of ovarian response
(high, intermediate, low)
● Individualization of treatment
● Prevention of complications by careful dose
titration:
– Ovarian hyperstimulation syndrome (OHSS)
● Optimization of the total reproductive potential
by embryo cryopreservation
Arslan et al. Fertil Steril. 2005;84:555.
23
Gonadotropin Releasing Hormone (GnRH)
● Released from the hypothalamus in small amounts
about once every 90 minutes
● Stimulates the pituitary gland to secrete LH and FSH
● A GnRH analogue often is used to prevent spontaneous
ovulation when gonadotropins are given to women
undergoing IVF
– Agonists
• Leuprolide, nafarelin, goserelin, buserelin,
deslorelin, triptorelin
– Antagonists
• Ganirelix, cetrorelix
American Society for Reproductive Medicine. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. 2006.
van Loenen et al. Semin Reprod Med. 2002;20:349.
24
Native GnRH
pGlu
His
Trp
Ser
Tyr
Gly
Leu
Arg
Pro
Gly
NH2
● Synthesized and secreted in the hypothalamus
● Released in coordinated pulses by the hypothalamus
● Reaches the pituitary via the HP portal system
● Stimulates the release of FSH, LH, and GnRH
receptors of the anterior pituitary
● Quickly metabolized with a half-life of <5 minutes
25
Controlled Ovarian Stimulation (COS):
Gonadotropin Treatment
● Starting dose of FSH usually 150 or 225 IU
● Needs GnRH analogue treatment to prevent premature
LH surge
● Ovarian stimulation followed by oocyte pick-up, in vitro
fertilization, and transfer of embryos
COS
hCG
Arslan et al. Fertil Steril. 2005;84:555.
Borini and Dal Prato. Reprod Biomed Online. 2005;11:283.
Yong et al. Fertil Steril. 2003;79:308.
26
Potential Adverse Effects of
Gonadotropin Treatment
● Deliveries after IVF and ICSI combined are multiple
– Twins: 21.7%
– Triplets: 1%
● Premature delivery
● OHSSa
● Breast tenderness
● Swelling or rash at the injection site
● Abdominal bloating and/or pain
● Mood swings
aDose-dependent.
Andersen et al. Hum Reprod. 2008;23:756.
American Society for Reproductive Medicine. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. 2006.
27
Typical GnRH Agonist Protocols
Long follicular protocol
FSH
Agonist
Cycle day M
3
5
7
9
11
13
hCG
Long luteal protocol
FSH
Agonist
Cycle daya 15
17
19
21
23
25
27
M
3
5
7
9
11
hCG
Short/flare-up protocol
FSH
Agonist
hCG
Ultrashort protocol
FSH
Ag
Ag
hCG
FSH
Early cessation protocol
Agonist
hCG
aPrior
cycle.
van Loenen et al. Semin Reprod Med. 2002;20:349.
28
GnRH Antagonist Protocols
Single-dose protocol
FSH
Antagonist
hCG
Multiple-dose protocol
FSH
Antagonist
hCG
van Loenen et al. Semin Reprod Med. 2002;20:349.
29
Antagonist Protocol Is Shorter Than
Agonist Protocol
Day 2 or 3
of menses
hCG
Day 6 of FSH
Embryo transfer
GnRH antagonist
Cycle day
21-24
rFSH
IVF
or
Luteal phase
support
GnRH agonist
rFSH
ICSI
Downregulation
Luteal phase (prior cycle)
Luteal phase (current cycle)
Start of cycle
30
GnRH Agonists vs Antagonists: No
Difference in Live-Birth Outcomes
Citation
Year
Albano
European
0.01
0.1
Effect
P Value
2000
0.83
0.56
2000
0.75
0.12
Olivennes
2000
0.80
0.61
North American
2001
0.78
0.32
Middle East
2001
0.97
0.91
Akman
2001
0.76
0.71
Hohmann
2003
0.93
0.86
Martinez
2003
1.57
0.59
Franco
2003
0.55
0.57
Hwang
2004
1.11
0.87
Sauer
2004
1.07
0.91
Xavier
2005
0.85
0.76
Loutradis
2005
0.70
0.47
Malmusi
2005
1.00
1.00
Marci
2005
10.36
0.06
Cheung
2005
1.55
0.64
Check
2005
1.82
0.35
Barmat
2005
0.65
0.36
Bahceci
2005
0.84
0.60
Badrawi
2005
0.80
0.64
Schmidt
2005
1.00
1.00
Lee
2005
0.70
0.52
0.86
0.08
Favor agonists
1
10
100
Favor antagonists
Kolibianakis et al. Hum Reprod Update. 2006;12:651.
31
GnRH Agonists vs Antagonists:
Other Outcomes
Outcome
Duration of treatment
Difference (Antagonist vs Agonist)
Shorter for antagonist (difference >19 days)
FSH requirement
No difference
Oocytes retrieved
Lower for antagonist (difference 1.2 per cycle)
OHSS associated with hospital admission
Lower with antagonist (odds ratio = 0.46)
LH surge
Higher with antagonist (odds ratio = 4.05)
LH rise
Higher with antagonist (odds ratio = 8.27)
Kolibianakis et al. Hum Reprod Update. 2006;12:651.
32
Intracytoplasmic Sperm Injection (ICSI)
Success Rate and
Complications
Indications
●
Very low numbers of motile sperm
●
Severe teratospermia
●
Problems with sperm binding to and
penetrating the egg
●
Antisperm antibodies
●
Prior or repeated fertilization failure with
standard IVF methods
●
Frozen sperm limited in number
and quality
●
Obstruction of the male reproductive tract not
amenable to repair
●
Fertilization rate: 50%-80%
●
Live offspring: 20%-40% (40% in
younger women, success declines
with maternal age)
American Society for Reproductive Medicine. http://www.asrm.org/Patients/FactSheets/ICSI-Fact.pdf. 2001.
Palermo et al. Sem Reprod Med. 2000;18:161.
Campbell and Irvine. Br Med Bull. 2000;56:616.
33
Oocyte Retrieval
● Transvaginal ultrasound-guided oocyte retrieval (TVOR) during IVF
treatment is the gold standard for IVF therapy1,2
– May be performed without general anesthesia
– Generally well tolerated
● Complications1
– Aspiration needle injury to adjacent pelvic organs and structures leading to
serious complications1
– Infection3
– Hemorrhage3
– Adnexal torsion3
– Rupture of endometriotic cysts3
– Hyperprolactinemic stress when performed under general anesthesia4
– Vertebral osteomyelitis3
1.
2.
3.
4.
El-Shawarby et al. Hum Fertil (Camb). 2004;7:127.
Yuzpe et al. J Reprod Med. 1989;34:937.
Bennett et al. J Assist Reprod Genet. 1993;10:72.
Robinson et al. Hum Reprod. 1991;6:1291.
34
Preimplantation Genetic Diagnosis
(PGD) and Screening
Indications
● Recurrent miscarriage or
unsuccessful IVF cycles
● Unexplained infertility
● Advanced maternal age
● Male factor infertility
● Fertile couples carrying single
gene disorders
Evaluations
● Mosaicism
● Chromosome aberrations
– Aneuploidy
– Structural chromosome
aberrations
– Reciprocal translocations
– Robertsonian translocations
– Inversions
– Deletions
– Duplications
– Genomic imprinting and
uniparental trisomy
– Single gene disorders
Kearns et al. Semin Reprod Med. 2005;23:336.
35
ESHRE Consensus Meeting on Genetic
Risks and Complications in ART
● Both partners should be examined (female by a gynecologist, male by
an andrologist)
● All couples with severe male subfertility or repeated fertilization failure
should be counseled by a genetically trained specialist
● Genetic counseling should be offered
● Possible laboratory testing
– Chromosomal analysis and microdeletion testing in nonobstructive
azoospermia and oligozoospermia
– Karyotype is suggested when sperm count is <5 million/mL and highly
recommended when sperm count is <1 million/mL
– Cystic fibrosis transmembrane regulation (CFTR) gene analysis in
congenital bilateral absence of the vas deferens and related conditions
– In pregnancy, mid-trimester ultrasound screening for congenital
malformations and amniocentesis may be considered
Land and Evers. Hum Reprod. 2003;18:455.
36
Common PGD Single-Gene Testing
● Autosomal dominant
– Myotonic dystrophy = 35%
– Huntington disease = 29%
– Charcot-Marie-Tooth = 8%
– Other = 29%
● X-linked
– Fragile X = 26%
– Duchenne/Becker muscular dystrophy = 23%
– Hemophilia = 9%
– Other = 42%
Image courtesy of David Hill. Ph.D.
Most common PGD single-gene tests performed
● Autosomal recessive
– Cystic fibrosis = 38%
– Thalassemia = 18%
– Spinal muscular dystrophy = 17%
– Other = 27%
Kearns et al. Sem Reprod Med. 2005;23:336.
37
Two Basic Techniques Developed for
Cryopreservation
Slow Freezing
Vitrification
Physiologic
solution
Before
cooling
Cryoprotectant
solution
Vitrification
solution
Ice seeding
After
cooling
Slow cooling
Rapid cooling
Rapid cooling
In LN2
Kasai and Mukaida. Reprod Biomed Online. 2004;9:164.
38
Pregnancy and Deliveries After IVF in
Europe (2004)
Pregnancies
Deliveries
40
35
30.1%
% of patients
30
25
20
26.6%
24.1%
17.4%
18.8%
21.1%
15
10
5
0
Per cycle
Per aspiration
Per transfer
Andersen et al. Hum Reprod. 2008;23:756.
39
Pregnancy and Deliveries After ICSI in
Europe (2004)
Pregnancies
Deliveries
40
35
% of patients
30
29.8%
27.1%
25.1%
25
20
17.2%
18.4%
19.8%
15
10
5
0
Per cycle
Per aspiration
Per transfer
Andersen et al. Hum Reprod. 2008;23:756.
40
Complications and Fetal
Reductions With ART in Europe (2004)
Number of cases
(incidence rate)
(From 29 countries, 785 clinics reported 367,066 cycles)
3000
2858
2500
(0.77%)
2000
1500
1125
1000
(0.30%)
500
520
(0.14%)
0
OHSS
Oocyte
Bleeding
retrieval
complications
526
362
(0.09%)
4
(0.14%)
Infection
Maternal
death
Fetal
reduction
Andersen et al. Hum Reprod. 2008;23:756.
41
Assisted Reproductive Technologies:
Summary
● Improvement in knowledge and technology has
made it possible to optimize ovarian
development, retrieve and fertilize oocytes, and
preserve embryos with a minimal risk to patient
● Despite all these advances, younger maternal
age has the most successful impact on
outcomes
42
How can the ObGyn and fertility specialist together
make sure that patients get the most appropriate
treatment as soon as possible?
ObGyn
Patient
Fertility
Specialist
43
Management Algorithm for ObGyn
Couple attempting conception
Female <35 years of age
1 year of infertility
Female >35 years of age
6 months of infertility
Determine progesterone level 7 days after presumed ovulation
Ovulation
Anovulation or oligo-ovulation without hirsutism
Consider referral for
COS
Female physiology: serum sensitive TSH, FSH, and
prolactin levels
Abnormal
Refer to fertility
specialist
Normal
Male evaluation: semen analysis
Abnormal
Female anatomy: hysterosalpingography
Abnormal
Treatment: clomiphene citrate 50-100 mg/d orally for 5 days during
menses, for 3 cycles
Unsuccessful
Successful
Initiate prenatal care
Hanson and Dumesic. Mayo Clin Proc. 1998;73:681.
44
Lifestyle Changes Can be
Recommended
● Avoid smoking and secondhand smoke to
improve fertility (both male and female)
and to reduce required dose of fertility
medication
● Lose weight
● Reduce stress
Kelly-Weeder and O’Connor. J Am Acad Nurse Pract. 2006;18:268.
Younglai et al. Hum Reprod Update. 2005;11:43.
45
Reasons for Referral to
a Fertility Specialist
● Factors indicating immediate referral to a
fertility specialist
– Older female age
– Tubal occlusion
– Abnormal semen parameters
– Insulin resistance
– Abnormal ovarian reserve testing
– CC failure
– Suspected or confirmed infertility
Potter. http://www.infertilityspecialist.com/acrobat/The%20Contemporary%20Fertility%20.pdf. 2008.
Olive and Hammond. Postgrad Med. 1985;77:205.
46
Transition From Clomiphene Citrate (CC) to
Specialist-Guided Therapy and Back
● CC is widely used for ovulation induction in women with
PCOS and in couples with unexplained infertility to
induce follicular development
● Because of the potential side effects associated with
CC, all patients should be monitored to assess
response to treatment
● Without ultrasound monitoring, the number of CC
cycles should probably be limited to 3 (or less), and
early referral should be considered
● After successful ART, transition of patient back to
ObGyn and prenatal care should be initiated
PCOS = Polycystic ovary syndrome.
Case. Can Fam Physician. 2003;49:1465.
47
Summary
● Infertility treatment protocol depends on female age
● Conduct diagnostic tests after
– 1 year of infertility for female aged <35 years
– 6 months of infertility for female aged >35 years
● Refer to fertility specialist after 3 (or fewer)
unsuccessful CC cycles
48