Understanding Infertility,

Evaluations,
and Treatment Options
Prof. Medhat E Helmy
Email:medhathelmy@hotmail.com
 DEFINITIONS
• Infertility is a unique medical condition
because it involves a couple, rather than a
single individual.
• It is defined as failure of a couple to
conceive
– after 12 months of regular intercourse without
use of contraception in women less than 35
years of age;
– and after six months of regular intercourse
without use of contraception in women 35
years and older [1].
• Some clinicians use the term subfertility
to describe this failure to conceive unless
the couple has been proven to be sterile.
• Fecundability, the probability of achieving
a pregnancy in one menstrual cycle, is a
more accurate descriptor because it
recognizes varying degrees of infertility.
• The large majority (80 to 90 percent) of
apparently normal couples will conceive
within the first year of attempted
conception.
• Five to 15 percent of apparently normal
couples will conceive in the second 12
months of attempted conception so that
after 24 months of trying to become
pregnant, 95 percent of couples will have
conceived.
• Fecundability was 0.25 in the first three
months of observation, and then
• decreased to 0.15 during the next nine
months of observation.
• The fecundability of the cohort decreases
over time and with increasing age of the
female partner. Thus, the possibility of
infertility may be suspected after only six
months of unprotected intercourse
without conception.
• Patients who have not achieved
pregnancy after 12 months have even
lower fecundability.
 Prognosis
The best prognosis for treatment-
independent conception [8].
•Under age 30,
•A less than two-year history of infertility,
•A previous pregnancy,
•do not have tubal disease,
– anovulation,
– partners with male factor infertility, or
– endometriosis,
 PREVALENCE OF INFERTILITY
• From 1982 to 2002, the percentage of
infertile women fell from 8.5 to 7.4 percent.
This figure is lower than the incidence of
infertility estimated from prospective
studies in the United States, which ranges
from 12 to 18 percent [10].
 PREVALENCE OF INFERTILITY
•In the United States, 7.3 million women
(12% of women of reproductive age) had
difficulty or were unable to get pregnant or
carry a baby to term.2 (Based on data from
2002)
•Only half of those couples will actually seek
and receive treatment, but with treatment, 2
of 3 couples will succeed in having a child.
 PREVALENCE OF INFERTILITY
• Worldwide, the prevalence of infertility is highest in
Eastern Europe, North Africa/Middle East, Oceania,
and Sub-Saharan Africa [12].
• It is not known whether fecundity varies among racial
and ethnic groups when adjusted for confounders.
• The National Survey of Family Growth found that
married black women had about twice the odds of
infertility as married white women, after adjustment
for education, income, and self-reported history of
pelvic inflammatory disease [9].
• Others have shown that this disparity cannot be
explained by differences in common risk factors for
infertility, such as smoking, obesity, fibroids, or ovarian
volume.
 CAUSES OF INFERTILITY
• Some causes of infertility are easily
identifiable, such as azoospermia (no
sperm cells in the ejaculate),longstanding
amenorrhea, or bilateral tubal obstruction.
• However, the situation is less clear in
most couples. It is often difficult to weigh
or prioritize these findings when
counseling infertile couples or planning
treatment programs.
• Adding to the complexity of the situation,
there are few data regarding the predictive
validity of these tests despite their
widespread use. Thus, an abnormal test
result cannot be said to be the cause of
infertility in a particular couple.
• One population-based study reported the
following results [15]:
– Male factor (hypogonadism, post-testicular
defects, seminiferous tubule dysfunction) — 26
percent
– Ovulatory dysfunction — 21 percent
– Tubal damage — 14 percent
– Endometriosis — 6 percent
– Coital problems — 6 percent
– Cervical factor — 3 percent
– Unexplained — 28 percent
• The frequency of these factors in infertility
is similar whether infertility is primary or
secondary, and has not changed
significantly over the past 25 years in
developed countries [16].
 CAUSES OF INFERTILITY
• In developed countries (WHO),
– female factor infertility was reported in 37 %
– male factor infertility in 8 %
– both male and female factor infertility in 35 %.
– Five % of couples had unexplained infertility
 There Are Multiple Causes of Infertility
Causes of Infertility

Tubal factor
14%
Multiple factors 18%
(male + female)
Ovaluatory dysfunction
6%

Diminished ovarian reserve

Multiple factors 6%
(female only) 13%

7%
Endometriosis

1%
Uterine factor
Unexplained
11%
Male factor
19%
Other causes 6%

Arlene
Centers for Disease Control and Prevention. 2006 Assisted J. Morales,
Reproductive M.D., Success
Technology FACOGRates: National Summary and Fertility Clinic Reports.
2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.
 Decline in Fertility With Age:
The Fixed Ovarian Pool Becomes
Depleted as Time Passes
Monthly Fertility Rate
1 .2

1 .0

0 .8

0 .6
Relative rate

0 .4

0 .2

20 25 30 35 40 45 50

Broekmans et al. Trends Endocrinol Metab. 2007;18:58.

 ART:
Pregnancy and Birth Rates Still
Decrease With Women’s Age
60

50

40

30

20
Percent

10

0 <21 22 24 26 28 30 32 34 36 38 40 42 44 46 48 >48
Age (years)
Pregnancy Live birth Singleton live birth

*For consistency, all percentages are based on cycles started.

Centers for Disease Control and Prevention. 2006 Assisted Arlene J. Morales,
Reproductive M.D., Success
Technology FACOGRates: National Summary and Fertility Clinic Reports.
2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.
 Determinants of Declining Fertility
With Advancing Age in Women
• Higher incidence of age-related
• Declining oocyte number and gynecologic problems, including
ovulatory disturbances uterine fibroids and polyps
• Declining oocyte quality and • Declining sexuality
increasing chromosomal and • Increased pregnancy wastage
genetic mutations • Early implantation failures and
• preclinical losses
Luteal phase dysfunction
• Clinical losses
• Impaired fertilization rates
• Increased incidence of general
• Implantation failures medical problems accompanying
aging (eg, type 2 diabetes mellitus,
• Poor-quality embryos and genetic hypertension)
abnormalities • High incidence of obstetric
• Impaired endometrial receptivity complications and poor
pregnancy outcomes

Pal and Santoro. Endocrinol Metab Clin North Am. 2003;32:669.

 Indications and timing of the
infertility evaluation
• 1. Initiate evaluation after 12 months of unprotected and frequent
intercourse:
– Women under age 35 years without risk factors for infertility.
• 2. Initiate evaluation after six months of unprotected and frequent
intercourse:
– Women age 35 to 40 years.
• 3. Initiate evaluation upon presentation despite less than six
months of unprotected and frequent intercourse:
– Women over 40 years of age.
– Women with oligomenorrhea/amenorrhea.
– Women with a history of chemotherapy, radiation therapy, or advanced
stage endometriosis.
– Women with known or suspected uterine/tubal disease.
– Women whose male partner has a history of groin or testicular surgery,
adult mumps, impotence or other sexual dysfunction, chemotherapy
and/or radiation, or a history of subfertility with another partner.
 Evaluation is initiated promptly
• if the female partner has:
– A history of risk factors for premature ovarian
failure (previous extensive ovarian surgery,
exposure to cytotoxic drugs or pelvic radiation
therapy, autoimmune disease, smoking, strong
family history of early menopause/premature
ovarian failure),
– Advanced stage endometriosis, or
– known or suspected uterine/tubal disease [28].
 TIMING OF INFERTILITY
EVALUATION
• Male factors can also be indications for
initiating early evaluation of the male
partner. These factors include
– A history of testicular trauma requiring
treatment,
– adult mumps,
– impotence or other sexual dysfunction,
– chemotherapy and/or radiation, or
– A history of subfertility with another partner.
 TIMING OF INFERTILITY
EVALUATION
• For younger couples who present with
fewer than 12 months of attempted
conception, we suggest focusing the
initial intervention on:
– Teaching timed intercourse with the aid of a
urinary ovulation predictor kit,
– Advising that they wait at least 12 months
before initiating the infertility evaluation.
• This recommendation may be modified to
fit the specific circumstances of the
• Recommend changes in lifestyle factors
that may improve fertility, including:
– Achieving an ideal body mass index,
– Cessation of smoking,
– limiting exposure to caffeine and alcohol.
 Infertility evaluation – history-1
Male Female Female

Duration of infertility Duration of infertility

Fertility in other Number and outcome of any prior pregnancies (including

relationships ectopic and miscarriages) with the same or a different
partner
Medical and surgical Gynecologic history, including history of pelvic
history, including inflammatory disease, fibroids, endometriosis, cervical
testicular surgery dysplasia; surgery of the cervix, ovary, uterus, fallopian
and history of mumps tube, pelvis, or abdomen; intrauterine device use, other
prior contraceptive use, diethylstilbestrol exposure in
utero, uterine anomalies.
Menstrual history (age at menarche, cycle length, and
regularity), presence of molimina or vasomotor symptoms
(hot flashes),dysmenorrhea
Changes in hair growth, body weight, or breast discharge
Other medical and surgical history
 Infertility evaluation – history- 2
Male Female

Medications Medications

History of chemotherapy or History of chemotherapy or radiation

radiation
Cigarette smoking, alcohol, marijuana Cigarette smoking, alcohol, marijuana and
and other drug use; environmental and other drug use;
Occupational exposures environmental and occupational exposures

Sexual dysfunction or impotence Exercise and dietary history

Frequency of Frequency of intercourse, use of lubricants
intercourse, use of (which may be toxic to sperm). presence of
lubricants(which may deep dyspareunia suggestive of
be toxic to sperm) endometriosis

Previous infertility testing and therapies Previous infertility testing and therapies
 Infertility evaluation – history-3
Male Female

Family history of birth Family history of birth defects, mental

defects, mental retardation, or
retardation, or reproductive failure
reproductive failure
Pelvic or abdominal pain, symptoms of
thyroid disease
 INFERTILITY EVALUATION
"Psychological stress and
infertility”
• The recognition, evaluation, and treatment
of infertility are stressful for most couples.
• The clinician should not ignore the
couple's emotional state, which may
include depression, anger, anxiety, and
marital discord.
 INFERTILITY EVALUATION
• It is important to remember that the
couple may have multiple factors
contributing to their infertility
• Evaluation of both partners is performed
concurrently
• complete initial diagnostic evaluation,
including a complete history and physical
examination, should be performed.
 Initial basic investigations of the
infertile couple
• Semen analysis to assess male factors
• Menstrual history, assessment of LH
surge in urine prior to ovulation, and/or
luteal phase Progesterone level to assess
ovulatory function
• Hysterosalpingography to assess tubal
patency and the uterine cavity.
(Day 3 serum FSH and estradiol levels.)
 Additional tests
• Pelvic ultrasound to assess for uterine
myomas and ovarian cysts
• Laparoscopy to identify endometriosis or
other pelvic pathology
• Assessment of ovarian reserve in women >35
years of age; this may involve
– a clomiphene challenge test,
– ultrasound for early follicular antral follicle count,
– day 3 serum inhibin B level, or antimüllerian
hormone measurement.
• Assessment of thyroid function.
Therapeutic interventions for
treatment

– drug therapy,
– surgery, and/or
– procedures such as
• intrauterine insemination or
• in vitro fertilization.
 Contraindications to infertility
therapy
• The only absolute contraindications to
infertility therapy are contraindication to
pregnancy and contraindication to use of the
drugs or surgery used to enhance fertility.
• The ethics of restricting infertility therapy for
other reasons, such as parental child-rearing
ability, severe obesity, life-style issues
(tobacco smoking, alcohol consumption), are
controversial
• The parent's marital status, sexual orientation,
and HIV status should not be used to deny
infertility treatment
• Women who use infertility therapies (IVF
or non-IVF) appear to have a small but
statistically significant increase in risk of
some pregnancy complications, such as
preterm birth [34,35].
• Compared to the general population, an
increased risk of adverse pregnancy
outcomes has also been observed among
untreated subfertile women who
conceived naturally.
 Treatment Options for Infertile Couples
Condition Treatment Options
Female infertility
Ovulatory failure or dysfunction OI
Tubal factor COS with IVF
Endometriosis IUI (patent tubes), or COS with IVF

Male infertility
Male subfertility IUI with or without OI
Male factor COS with ICSI
Female and/or male infertility
Unexplained IUI, COS with IVF, or ICSI

OI = ovulation induction; COS = controlled ovarian stimulation; IVF = in vitro fertilization;

IUI = intrauterine insemination; ICSI = intracytoplasmic sperm injection.
National Institute for Clinical Excellence. Fertility assessment and treatment for people with fertility problems. 2004. http://www.nice.org.uk/
nicemedia/pdf/CG011fullguideline.pdf. Accessed April 20, 2009.
 TREATMENT
• The couple is counseled on lifestyle
modifications to improve fertility, such as
– Smoking cessation,
– Reducing excessive caffeine and alcohol
consumption,
– Appropriate timing and frequency of coitus
(every one to two days around the expected
time of ovulation or according to an ovulation
predictor kit).
 Ovulation induction
• Ovulatory disorders can be identified in the
woman in 18 to 25 percent of couples
presenting with infertility [1].
• Most of these women have
oligomenorrhea, arbitrarily defined as
menstruation that occurs at intervals of 35
days to six months. While ovulation may
occasionally occur, spontaneous
conception is unlikely.
• The goal of therapy in these women is
monofollicular development and
subsequent ovulation.
• This approach should be differentiated
from stimulation of multiple follicle
development in ovulatory women, as is
done with assisted conception techniques.
The method of ovulation induction selected
by the clinician should be based upon:
– the underlying cause of anovulation
– efficacy,
– costs,
– risks, and
– potential complications associated with each
method.
 Methods of ovulation induction
• Antiestrogens,
• Metformin,
• Gonadotropins,
• Pulsatile GnRH therapy,
• Aromatase inhibitors,
• Opiate antagonists, and
• Dopamine agonists
 Ovulation Induction

• OI is useful in patients with anovulatory infertility

– WHO class I: hypogonadotropic hypogonadism
– WHO class II: polycystic ovary syndrome (PCOS)
• Goal
– Stimulate development of a single follicle that will be able to
reach preovulatory size and rupture
• Options
– Clomiphene citrate (CC)
– Gonadotropins (hMG/FSH followed hCG)
– GnRH analogue

Messinis. Hum Reprod . 2005;20:2688. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90
(5 suppl):S7. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S187.
Ovulation Induction: Clomiphene Citrate
• CC is an antiestrogen that binds to estrogen receptors and interferes
with estrogen-negative feedback
– Results in an alteration in pulsatile GnRH secretion
– Leads to increases in gonadotropin secretion and follicular development
• CC is widely used for ovulation induction in women with PCOS and in
couples with unexplained infertility
• CC treatment successfully induces ovulation in about 80% of properly
selected candidates
– Pregnancy rates are much lower (30%-40% per cycle)
– 40%-45% of couples can become pregnant within 6 cycles
– Failure to conceive after successfully induced ovulation is indication for
further evaluation
• Patient characteristics predictive of poor response to CC:
– Hypothalamic disorder
– Low estrogen levels
– Obesity
American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/
patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009.
Case. Can Fam Physician . 2003;49:1465. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86:S187.
 Limitations and Risks With CC for OI

• CC is generally well tolerated, although some side effects may limit its
efficacy and safety
– Short-term, reversible side effects include: hot flashes, mood swings, visual
disturbances, breast tenderness, pelvic discomfort, and nausea
– The antiestrogenic effects may negatively impact the uterine lining, leading
to lower pregnancy rates
– Risk of multiple pregnancy is increased
– Risk of cancer is increased among women who were treated with CC
• Uterine fibroid risk increases with CC treatment
• Risk of ovarian cancer increases among women treated with prolonged
CC
• Treatment should be limited to no more than 6 cycles or fewer in
consideration of woman’s individual situation
– Age, baseline characteristics, etc

Althuis et al. Am J Epidemiol. 2005;161:607.

Case. Can Fam Physician . 2003;49:1465.
For women with hypogonadotropic
amenorrhea (WHO class 1),
• Pulsatile GnRH as first line therapy in countries where
it is available.
• Because clomiphene citrate is easy to administer, it is
reasonable to give one course of clomiphene prior to
initiating pulsatile GnRH. However, very few women in
this group respond.
• Gonadotropin therapy should be initiated, with both LH
and FSH (these women do not respond to FSH alone).
Both low-dose step-up and step-down protocols are
reasonable.
• To minimize the risk of multiple gestation and ovarian
hyperstimulation syndrome, gonadotropin cycles
should be stopped if there are an excess number of
follicles or extremely high serum estradiol
concentrations.
 WHO class 2 anovulation
(most of whom have PCOS)

• Clomiphene citrate is the first line infertility

treatment. Doses, regimens, and monitoring
• The addition of metformin may be useful in
women who do not respond to clomiphene
alone.
– Correction of hyperinsulinemia with metformin
has been shown to have a beneficial effect in
anovulatory women with PCOS by increasing
menstrual cyclicity and improving spontaneous
ovulation.
– However, it does not appear to improve live birth
rates when given alone or in combination with CC.
 Other Strategies for improving the efficacy
of clomiphene induction of ovulation for
clomiphene-resistant patients..)

• Most clinicians go directly to FSH injections if

clomiphene alone fails.
• However, the addition of
– dexamethasone,
– pretreatment with oral contraceptives, or
– metformin
is an alternative for those who value low cost
and low risk of multiple gestation.
• Although data are limited, women may
benefit from the addition of
dexamethasone, even if they have a
normal serum DHEAS concentration.
• Women with hyperprolactinemic
anovulation should be treated with
dopamine agonists.
 WHO class 2 anovulation
-Cont.

• If none of the clomiphene strategies are

successful, then gonadotropin therapy
should be started (in this case, FSH alone
is sufficient).
• Strict attention to follicle number is
essential to avoid complications (multiple
gestation and ovarian hyperstimulation).
 Multistep approach to treatment of
anovulatory infertility associated PCOS
Step Intervention Cost Risk of multiple gestation
pregnancy

1 Weight loss (if Low Not increased

baseline
weight is elevated)

2 Clomiphene Low Modest increase in risk

3 Clomiphene plus Low Modest increase in risk

adjuvants*

4 FSH injections Resource Markedly increased

intensive
5 Ovarian surgery Resource Not increased
intensive
6 In vitro fertilization Resource Potentially increased but
intensive controllable
(eg, single embryo transfer)•
 WHO Class 3 anovulation
(hypergonadotropic hypogonadism, ie, ovarian failure)

• No ovulation induction strategy has been

shown to be effective.
• However, in vitro fertilization with donor
oocytes has high success rates.
 The mechanism of action of
antiestrogens
• The mechanism of action of antiestrogens
remains poorly understood.
• These agents are thought to occupy estrogen
receptors in the hypothalamus and pituitary,
thereby blocking the negative feedback action of
estradiol.
• Consequently, serum FSH concentrations rise by
around 50 percent, resulting in the stimulation of
follicle growth and follicular estradiol production.
However, other mechanisms, such as induced
changes in the insulinlike growth factor system
and SHBG levels, may also contribute
 Tamoxifen
• Tamoxifen, like clomiphene, is a nonsteroidal
antiestrogen capable of inducing ovulation
[10].
• However, it has less of an antiestrogenic
effect at the uterine level. The usual starting
dose is 20 mg daily given for five days
starting on day three to five of the cycle.
• In a randomized comparison between
tamoxifen and clomiphene, no significant
difference between ovulation and pregnancy
rates were observed [11].
Antiestrogen therapy-Monitoring
The goal of antiestrogen therapy is to induce mono-ovulation.
• A biphasic basal body temperature (BBT)
• Resumption of regular menstrual cyclicity
• Evidence of a preovulatory increase in urinary LH on a home
monitoring kit
• An elevated serum progesterone concentration during the mid-
luteal phase of the cycle
• Pelvic ultrasound evidence of preovulatory follicular growth
followed by collapse of the follicle
• Transvaginal ultrasound can also be used to monitor for the
presence of multiple follicular development, and the potential
risk of multiple pregnancy and ovarian hyperstimulation
syndrome (OHSS).
– Some advocate ultrasound monitoring of just the first CC cycle
in order to exclude multiple follicular development
 Outcomes
• Sixty to 85 percent of anovulatory women ovulate
in response to CC (most typically WHO class 2
patients, or women with polycystic ovary
syndrome).
• Of those who ovulate, approximately 50 percent
do so at a dose of 50mg.
• Predictors of ovulation include
– a lower free androgen index (FAI), a calculation of
testosterone not bound to SHBG,
– lower body mass index (BMI),
– presence of oligoamenorrhea (as opposed to
amenorrhea)
– lower ovarian volume.
 Outcomes
• Of those who ovulate, 30 to 40 percent
conceive.
• Predictors of pregnancy with clomiphene
include
– younger age,
– low BMI,
– low FAI, and
– oligomenorrhea rather than amenorrhea.
 Outcomes
• After six months of treatment, the pregnancy
rate per cycle falls substantially despite
regular ovulation.
• In addition, pregnancy rates are lower among
women who ovulate only after receiving
higher doses of clomiphene.
• Failure to conceive despite ovulatory cycles,
particularly at higher doses, may be due to
clomiphene‘s antiestrogenic effects on the
quantity and quality of cervical mucus and on
the endometrium.
 Outcomes
• Twin and triplet gestations occur in
approximately 7 to 9 and 0.3 percent,
respectively, of clomiphene-induced
pregnancies.
• The incidence of miscarriage and birth
defects appears to be similar to that in
spontaneous pregnancies.
• The rate of ectopic pregnancy is probably not
increased.
• The risk of ovarian hyperstimulation
syndrome is less than 1 percent.
 Aromatase inhibitors
• While aromatase inhibitors appear to be
effective in some studies, their precise
role for ovulation induction remains
unclear. Thus, we currently do not
recommend their routine use.
Gonadotrophines
 Ovulation Induction:
Gonadotropin Treatment
• Optimal for women who have failed CC or who cannot risk
waiting
• Used in women with inadequate pituitary secretion of LH and FSH
(hypogonadotropic amenorrhea) or PCOS
• Agents: FSH, hCG, human menopausal gonadotropin (hMG)
• Success rates
– WHO class I: 30% per cycle
– WHO class II: 17% per cycle
• May include
OI IUI or natural intercourse
hCG

American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/
patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009.
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S7.
Increased risk of ovarian cancer ?
• While there has been concern about a
possible increased risk of ovarian cancer
with ovulation induction drugs, it appears
that the risk may be due to the infertility
diagnosis rather than the medications
themselves.
• However, because one study suggested an
increase after 12 cycles of clomiphene
citrate, women should not receive more
than 12 cycles.
Increased risk of Breast cancer ?
• There does not appear to be an increased
risk of breast cancer with ovulation
induction drugs.
 Use of IUI in OI Protocol
• Indications
– Unexplained infertility
– Male subfertility—mild
oligozoospermia,
asthenozoospermia, or
teratozoospermia
– Failure to conceive after
ovulation induction treatment
– Ejaculatory failure
– Retrograde ejaculation
• Procedure
– Washed prepared sperm are
deposited in the uterus just
before the release of an egg or Image on file with Schering-Plough/Organon.
eggs in a natural or stimulated
cycle
• Success rate: up to 15% per
cycle
• Significant risk for multiple
pregnancy

Rowell and Braude. BMJ . 2003;327:799.

 In Vitro Fertilization
Procedure Risks
• Initially used in women with • Ovarian hyperstimulation
fallopian tube blockage or syndrome (OHSS)
damage – Usually not serious and
• Now employed for many resolves with outpatient
causes of infertility (eg, management
endometriosis, male factor) – 1%-2% severe requiring
hospitalization
• Involves – Dose-dependent, avoided by
– COS careful titration
– Egg retrieval • Anesthesia
– Insemination, fertilization,
embryo culture
• Multiple births
– Embryo transfer • Ectopic pregnancy
– Cryopreservation of extra • Cost
embryos • Psychologic distress

American Society for Reproductive Medicine. Assisted reproduction technologies: a guide for patients. 2008. http://www.asrm.org/Patients/
patientbooklets/ART.pdf. Accessed April 20, 2009.
 Intracytoplasmic Sperm Injection
Indications Success Rate and
• Very low numbers of motile Complications
sperm • Fertilization rate: 50%-80%
• Severe teratospermia • Live offspring: 20%-40%
• Problems with sperm (40% in younger women;
binding to and penetrating success declines with
the egg maternal age)
• 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
American Society for Reproductive Medicine. Intracytoplasmic sperm injection (ICSI). 2008. http://www.asrm.org/Patients/FactSheets/ICSI-Fact.pdf.
Accessed April 20, 2009. Campbell and Irvine. Br Med Bull. 2000;56(3):616. Palermo et al. Sem Reprod Med. 2000;18(2):161.
 Controlled Ovarian Stimulation:
Gonadotropin Treatment
• Starts with higher dose of gonadotropins than for OI (COS: 150-225 IU
of FSH; OI: 50-75 IU of FSH)
• Needs GnRH analog treatment to prevent interference by endogenous
hormones
• COS is followed by oocyte retrieval, IVF, and transfer of embryos

COS

hCG

Arslan et al. Fertil Steril. 2005;84(3):555.

Borini and Dal Prato. Reprod Biomed Online. 2005;11:283.
 Common Procedures: COS

hCG
Day 2 or 3
of menses
Embryo Transfer
Day 6 of FSH

GnRH antagonist
Cycle day
21-24 rFSH/hMG IVF
Luteal phase
support
or
GnRH agonist
ICSI
rFSH/hMG

Down regulation
 Ovarian hyperstimulation
syndrome (OHSS)
• Ovarian enlargement due to multiple ovarian
cysts as a result of multifollicular development.
• an acute fluid shift out of the intravascular
space.
• The most severe manifestations include
massive ovarian enlargement
hemoconcentration and third-space
accumulation of fluid;
• These changes may be complicated by renal
failure, hypovolemic shock, thromboembolic
episodes, acute respiratory distress syndrome,
and death
 OHSS
• OHSS occurs after luteinization of a large
number of follicles.
• Such massive follicular luteinization is
usually only observed in exogenous
gonadotropin cycles following
administration of hCG, or after
administration of GnRH agonist;
• It rarely occurs in women treated with CC.
• The clinical symptoms usually appear 5 to
10 days following the first dose of the
ovulatory trigger (hCG, GnRH agonist).
 OHSS
• Mild ovarian hyperstimulation also rarely
develops following an endogenous LH
surge
• in a setting of spontaneous multifollicular
development. This has been described in
case reports, particularly in
• women with polycystic ovarian syndrome
or hypothyroidism
 OHSS
• Severe, recurrent, spontaneous OHSS during
pregnancy has been described in several reports.
• In these instances, the OHSS was due to a
mutation in the serpentine region of the FSH
receptor that resulted in a broadening of ligand
specificity, thereby allowing stimulation by
endogenous hCG.
• The persistent stimulation of the FSH receptor
during pregnancy resulted in excessive follicular
recruitment and subsequent ovarian
hyperstimulation.
 OHSS
• Development of massive ascites and
hypovolemia due to increased capillary
permeability are the cardinal clinical
events in the pathogenesis of OHSS .
• Hypovolemia results in
hemoconcentration, decreased central
venous pressure, low blood pressure, and
tachycardia
 OHSS
• Vascular endothelial growth factor (VEGF) of
follicular origin is the main, although possibly not
the only, component responsible for development
of OHSS .
• This peptide has two actions:
– it is a potent promoter of neovasculogenesis; and
– it may increase permeability of blood vessels walls
(mediated by in part by nitric oxide), thereby disrupting
functional integrity of the vascular bed [10-14].
• In addition, VEGF can induce changes in cellular
actin fibers, which may compromise the integrity of
tight cell junctions.
• VEGF levels correlate with both the presence and
 CLASSIFICATION AND
CLINICAL MANIFESTATIONS
• Grade I (mild hyperstimulation)
• Grade II (moderate hyperstimulation)
• Grade III (severe hyperstimulation)
 Grade I (mild hyperstimulation)
• It is characterized by bilateral ovarian
enlargement with multiple follicular and
corpus luteum cysts measuring up to 5 by 5
cm.
• Serum estradiol (E2) concentration greater
than 1500 pg/mL (6000 pmol/L) and
progesterone concentration greater than 30
ng/mL (115 nmol/L) in the early part of the
luteal phase.
 superovulation" or "controlled
ovarian hyperstimulation
• Mild hyperstimulation has been renamed "
superovulation" or "controlled ovarian
hyperstimulation" to distinguish it from
excessive ovarian stimulation associated
with morbid sequelae.
• However, mild hyperstimulation also
raises the incidence of high-order multiple
pregnancy , which can result in more
spontaneous abortions and perinatal
complications.
 Grade II (moderate
hyperstimulation)
• Ovaries enlarged up to 12 by 12 cm,
accompanied by abdominal discomfort
and gastrointestinal symptoms (eg,
nausea, vomiting, and diarrhea).
• A sudden increase in weight of more than
3 kg may be an early sign of moderate
hyperstimulation.
 Grade III (severe
hyperstimulation)
• The presence of large ovarian cysts (more
than 12 by 12 cm), ascites, and, in some
patients, pleural and/or pericardial
effusion,
• Electrolyte imbalance (hyponatremia,
hyperkalemia), hypovolemia, and
hypovolemic shock.
• Marked hemoconcentration, increased
blood viscosity, and thrombo-embolic
phenomena, including DIC.
• Spontaneous regression occurs over 10 to
14 days, but may take longer if
implantation occurs.
• The incidences of moderate and severe
ovarian hyperstimulation are 3.1 to 6
percent and 0.25 to 1.8 percent,
respectively.
• In one study, the pregnancy rate in
hyperstimulated cycles was threefold
higher than in nonhyperstimulated cycles
 TREATMENT of OHSS
• The best treatment of OHSS is primary
prevention.
• Preventing ovulation by withholding hCG
is an effective method of avoiding
hyperstimulation in overstimulated ovaries.
• Alternatively, aspiration of follicles 36
hours after administration of the ovulatory
dose of hCG may lower the risk of
developing clinical hyperstimulation by
reducing the mass of luteinized granulosa
• Medical therapy suffices for most patients,
• laparotomy reserved for catastrophic
complications, such as ovarian torsion or
rupture and internal hemorrhage.
• Women with severe symptoms often
require intensive medical care.
• Vaginal intercourse is restricted in all
grades of OHSS because of the risk of
cyst rupture.
• Patients should also avoid impact-type
 Treatment of mild
hyperstimulation
• Treatment is supportive, as needed.
• However, mild ovarian hyperstimulation can
develop into moderate or severe disease,
especially if conception ensues.
• observed for enlarging abdominal girth, acute
weight gain, and abdominal discomfort on an
ambulatory basis for at least two weeks or until
the appearance of menstrual bleeding.
 Treatment of moderate
hyperstimulation
• Observation, bed rest, provision of adequate
fluids, and sonographic monitoring of cyst size.
• Serum electrolytes, hematocrit, and creatinine
should also be evaluated.
• Some clinicians have outpatients keep track of
their fluid intake and output; intake or output less
than 1000 mL/day or a discrepancy in fluid
balance greater than 1000 mL/day would be a
cause for concern
• Initiation of resolution
– the cysts become smaller on two consecutive
ultrasound examinations
– clinical symptoms recede.
• Early detection of
– continuous weight gain (two pounds or more a
day),
– increase in severity of existing symptoms, or
– the appearance of new symptoms, such as
vomiting, diarrhea, and dyspnea.
 Medical treatment of severe
hyperstimulation
• Maintaining blood volume while correcting
the disturbed fluid and electrolyte balance
• Relieving secondary complications of
ascites and hydrothorax
• Preventing thromboembolic phenomena
 Clinical findings in women with
ovarian hyperstimulation syndrome
• Bloating • Hyponatremia,
• Nausea, vomiting, hyperkalemia
diarrhea • Pleural and
• Lethargy pericardial effusions
• Shortness of breath • Ascites
• Oliguria • Hypercoagulability
• Rapid weight gain and thrombosis
• Hemoconcentration • Adult respiratory
distress syndrome
• Leukocytosis
 Laboratory monitoring in
women with grade 3 OHSS
Daily Once, repeat as
• Leukocyte count indicated
• Hemoglobin and • Liver function tests
hematocrit • Prothrombin and
• Electrolytes partial thromboplastin
time
• Chest radiograph (if
respiratory symptoms
are present)
 Fluid balance
• net fluid flow (intake/output record),
• weight and girth measurements, and
• hematocrit examinations.
• A central venous pressure catheter may
be required in women who are
hemodynamically unstable
• one to two liters of isotonic fluid is given
to such women in the first hour to rapidly
restore tissue perfusion.
• Further fluids optimally should be given
while monitoring the central venous or
pulmonary capillary wedge pressure.
• Fluid repletion should continue at the
initial rapid rate as long as the cardiac
filling pressures and the systemic blood
pressure remain low.
• Plasma expanders such as dextran, human
albumin (200 mL of 25 percent albumin over
four hours), and plasma (500 to 1000 mL over
24 hours) supplemented with appropriate
electrolytes should be administered early and
repeated as needed
• Oral indomethacin, which blocks prostaglandin
synthesis and reduces capillary permeability.
• Hematocrit should be monitored every four
hours; plasma expanders can be stopped when
the hematocrit is less than 38 percent
 Diuretics
• Diuretic agents are not recommended
since
– fluid in the third space is not affected by these
drugs.
– most diuretics act at the distal tubule with
minimal effect on the proximal tubule
• Renal failure may respond to a dopamine
drip (0.18 mg/kg per hour) [27]. Oral
docarpamine administration could be one of the options
in the management of patients with OHSS requiring
dopamine therapy
 Ascites
• Sonographically guided Paracentesis
resulted in a marked improvement of renal
function (due to increased venous return),
blood osmolarity, and hemoconcentration,
as well as relief of dyspnea and abdominal
discomfort
• Other authors have reinfused the
withdrawn ascitic fluid (after
microfiltration) and reported relief of
symptoms and improvement of renal
 Pleural effusions
• Pleural effusions should be drained to
relieve dyspnea.
• Paracentesis may also be useful in
alleviating breathing difficulties in patients
with ascites and hydrothorax
 Thromboembolism
• Thromboembolic events are the most serious,
but rarest, complications of OHSS.
• Thromboses can occur in either the arterial (25
percent) or venous (75 percent) circulations and
may lead to permanent neurologic injury or death.
• Prophylactic anticoagulation with heparin or low
molecular weight heparin, antiembolism
stockings, and or intermittent pneumatic
compression boots should be considered to
minimize the risk of venous thrombosis
• Anticoagulant therapy is usually
unnecessary if above therapies are
promptly employed.
• Blood coagulation may be monitored
because of the danger of disseminated
intravascular clotting.
 Resolution
• After a period of several days, third space fluid
begins to re-enter the intravascular space,
hemoconcentration reverses, and natural
diuresis ensues.
• The patient feels better and her appetite and
ability to take oral fluids improve.
• Intravenous fluids are tapered as oral intake
increases. Some clinicians limit oral intake to
1000 mL/day at this time to facilitate diuresis
and maintain euvolemia [2].
• Complete resolution typically takes 10 to 14
days from the onset of initial symptoms.
 Risk factors
• Young age
• High serum estradiol concentrations
immediately prior to human chorionic
gonadotropin (hCG) administration
• Polycystic ovary morphology tend to have
the most exuberant response to
exogenous gonadotropins)
 Treatment for reducing the
incidence and/or severity of OHSS
in high risk cycles
• Withholding hCG. Exogenous hCG, which mimics
an ovulatory luteinizing hormone (LH) surge, also
contributes to hyperstimulation risk due to the
pharmacologic doses that are used, as well as
its prolonged biologic half-life.
• The GnRH agonists are capable of evoking an LH
surge sufficient for inducing ovulation, but, in
general, not long enough to provoke ovarian
hyperstimulation. However, some risk of ovarian
hyperstimulation remains (Antagonist)
 Treatment for reducing the incidence
and/or severity of OHSS
• However, corpus luteum function
following GnRH agonist induced ovulation
may be inadequate to sustain nidation and
continuation of pregnancy,
– Pharmacologic luteal support should be given.
– Clinical pregnancy rate was lower.
• Another prevention strategy is
administration of recombinant human LH
(rhLH) as the ovulatory trigger rather than
hCG. There were no episodes of OHSS in
those receiving a single dose of up to 30,
 Treatment for reducing the
incidence and/or severity of
OHSS
• hCG may be given with a low risk of OHSS
to women with estradiol levels less than
1500 pg/mL in the presence of no more
than two follicles above 17 mm and less
than four smaller follicles.
 Reducing the incidence and/or
severity of OHSS
• Coasting [22-24]
• Transforming
• Replacing hCG with a GnRH agonist [25-27]
• Replacing hCG with recombinant LH [17]
• Performing follicular reduction [21]
• Intravenous albumin [28-33]
• Dopamine agonist administration
 Intravenous albumin for the
prevention of OHSS
• human albumin administration proximate
to oocyte retrieval reduced the risk of
severe OHSS in high risk women.
• Absolute risk reduction was 5.5 percent
and 18 women would need to be treated to
prevent one case of severe OHSS
• data on the efficacy of intravenous
albumin for the prevention of OHSS are
conflicting.
 Hydroxyethyl starch
• The possible efficacy of hydroxyethyl
starch in prevention of OHSS was reported
in two prospective,randomized, placebo-
controlled trials including over 350
patients; the magnitude of benefit was
similar to that noted in the meta-analysis
of intravenous albumin trials
• There is insufficient data to recommend
use of corticosteroid prophylaxis at this
time.
• Cabergoline (0.5 mg daily) or placebo until
the day of hCG administration prevented
the increase in vascular permeability and
reduced the rate of moderate OHSS
 Intrauterine insemination (IUI)
• IUI alone is a useful technique for
achieving pregnancy in couples with
severe sexual dysfunction, but can also be
useful in patients with cervical factor
infertility as long as at least one fallopian
tube is patent.
• When IUI is performed during an
unstimulated (natural cycle) or a
clomiphene stimulated cycle, we suggest
use of an over-the-counter ovulation
predictor kit to schedule the optimum time
 IUI
• For patients with mild male factor, early
stage endometriosis, or unexplained
infertility, we suggest controlled ovarian
hyperstimulation with IUI rather than
natural cycle IUI (Grade 2B). Ovarian
stimulation may employ clomiphene or
gonadotropins.
• Semen processing for IUI is not difficult to
learn and can be adapted to use in clinical
offices, but care must be taken to ensure
 The management of couples
with unexplained infertility
• Unexplained infertility refers to the
absence of a definable cause for a
couple's failure to achieve pregnancy after
12 months of attempting conception (six
months in women 35 years and older)
despite a thorough evaluation.
• The infertility is probably due to subtle
functional abnormalities in oocyte, sperm
or endometrial function.
 The management of couples
with unexplained infertility
• It usually starts with treatments that consume
few resources and are low risk and patient
directed (eg, lifestyle changes), and
• then moves sequentially to treatments requiring
proportionately greater resources and risks
(intrauterine insemination, clomiphene,
clomiphene plus intrauterine insemination), and
• finally to higher risk and high resource intensive
interventions (gonadotropin injections plus
intrauterine insemination, IVF)
 The management of couples with
unexplained infertility
• Lifestyle changes, such as discontinuing
cigarette smoking and achieving a normal
weight may increase fertility in women with
unexplained infertility.
• Approximately 1 percent of these couples will
become pregnant per cycle with no intervention.
• Expectant management may be an appropriate
therapy for couples where the female partner is
less than 32 years of age.
• For women over 37 years of age, however, the
ovarian follicular pool can become depleted
during expectant management, resulting in
untreatable infertility. Typically women 37 years
 Empiric treatment of
unexplained infertility
• Three to four cycles of clomiphene citrate
and intrauterine insemination (IUI) (Grade
2C).
• The second step is either
– one to three cycles of gonadotropin and IUI
– or
– in vitro fertilization, depending on patient
specific factors (eg, personal costs and
insurance coverage, convenience and
availability of treatment).
 Empiric treatment of
unexplained infertility
• IVF is the intervention that will result in the
highest per cycle pregnancy rate in the
shortest time interval.
• It is also the most costly intervention and
has a high rate of high order multiple
pregnancy.