Infertility is defined as the failure of a couple of reproductive age to
conceive after at least 1 year of regular coitus without contraception.
Primary infertility exists when a woman
has never been pregnant.
Secondary infertility occurs when a woman has a history of one or
more previous pregnancies.
Fecundability is the probability of achieving a pregnancy within one
menstrual cycle. For a normal couple, this is approximately 25%.
Infertility affects about 10% to 15% of
reproductive–age couples in the Unite States.
Half of them (8%) will subsequently conceive without the
need for specialist advice and treatment. Of the remaining 8%
who require input from fertility clinics, half (4%) comprise
couples with primary infertility (no history of a previous
pregnancy) while the other half have secondary infertility
(difficulties in conceiving after an initial pregnancy).
Differential Diagnosis .
The differential diagnoses of infertility encompass five principal
2- cervical factors,
3- ovulatory dysfunction,
4- problems with the uterus or female pelvic organs or both,
5- unexplained causes.
In addition, immunologic factors that involve antiovarian or antisperm
antibodies may adversely affect fertility by impairing fertilization,
destroying gametes, and interfering with embryo cleavage or
Differential diagnosis Percent Basic evaluation
Male factors 30 Semen analysis
25 Basal body
Cervical factors 10 Postcoital test
Unexplained infertility 10 All of the above
the infertility evaluation comprises eight major
(a) history and physical examination;
(b) semen analysis;
(c) spermatic cervical mucus interaction (postcoital
(d) assessment of ovarian reserve;
(e) tests for occurrence of ovulation;
(f) evaluation of tubal patency;
(g) detection of uterine abnormalities;
(h) determination of peritoneal abnormalities.
• After the completion of these steps outlined ,
no abnormality or cause of infertility can be
identified in 10% to 15% of couples. This
group comprises a category known as
• A-History and Physical Examination. The initial
assessment begins by obtaining an extended and
complete history from both partners and
performing a physical examination. A sexual
history should include the frequency and timing
of intercourse, as well as information regarding
menstruation, impotence, dysparonia, the use of
lubricants, and sexually transmitted diseases.
Additionally, modifiable lifestyle factors that
potentially reduce fecundability should be
probed. They include tobacco use, alcohol or
caffeine consumption, body mass index, exercise
habits, and indices of stress.
• The history from the male partner should cover
any pregnancies previously sired; any history of
genital tract infections, such as prostatitis or
mumps orchitis; surgery or trauma to the male
genitalia or inguinal region (e.g., hernia repair);
and any exposure to lead, cadmium, radiation, or
chemotherapeutic agents. Excessive consumption
of alcohol or cigarettes or unusual exposure to
environmental heat should be elicited. Some
medications such as furantoins and calcium
channel blockers reduce sperm quality or
• The normal location of the urethral meatus
should be ensured. Testicular size should be
estimated by comparison with a set of
standard ovoids. The presence of a varicocele
should be elicited by asking the patient to
perform Valsalva's maneuver in the standing
position. Rectal massage of the prostate and
seminal vesicles should bring forth sufficient
secretions at the urethral meatus to allow
microscopic examination for white blood cells.
Exclusion of Male Factor Infertility. The cornerstone of male factor
infertility evaluation is the semen analysis. The semen sample
should be collected after a period of abstinence of at least 48
hours and is best evaluated within 1 hour of ejaculation.
Additionally, the sample is graded for percent motility, sperm
agglutination, and viscosity. If abnormalities are present, the
patient should be referred to a urologist who specializes in
infertility to be evaluated for reversible causes of male factor
Table: Reference values for semen analysis
Parameter Normal value
Volume 2.0 ml or more
Sperm concentration 20 million/ml or more
Motility 50% or more with progressive
Motility (Grade a or b)∗
Viability 75% or more live
White blood cells Fewer than million/ml
∗ Grade a: rapid progressive motility;
Grade b: slow or sluggish motility.
B- Exclusion of Cervical Factor Infertility.
The postcoital test (PCT) or Huhner's test allows direct analysis of
sperm and cervical mucus interaction and provides a rough estimate
of sperm quality. The test is done between days 12 and 14 of a 28- to
30-day menstrual cycle (after 48 hours of abstinence) when
maximum estrogen secretion is present. The mucus is examined
within 2 to 8 hours. Because interpretation of the PCT is subjective,
the validity of the test is controversial, despite its long history of use.
However, a finding of 5 to 10 progressively motile spermatozoa per
high-power field and clear acellular mucus with a spinnbarkeit (the
degree to which the mucus stretches between two slides) of 6-8 cm
generally excludes a cervical factor.
The most common cause of an abnormal PCT is
poor timing. Other causes include cervical stenosis,
hypoplastic endocervical canal, coital dysfunction,
and male factors. The sample can also be assessed
for pH, mucus cellularity, WBC, and ferning.
Clumping and flagellation of sperm without
progression are often suggestive of antisperm
C- Exclusion of Ovulatory Factor Infertility
To exclude ovulatory dysfunction, the presence of
ovulation must be confirmed. In addition, ovarian
reserve should be assessed to exclude oocyte
depletion or aging, and premature ovarian failure
Confirmation of Ovulation
1-The basal body temperature (BBT) chart is a simple means of
determining whether ovulation has occurred. The woman's
temperature is taken daily with a thermometer on awakening,
before any activity, and is recorded on a graph. After ovulation,
rising progesterone levels increase the basal temperature by
approximately 0.4c° through a hypothalamic thermogenic effect.
Because the rise in progesterone may occur anytime from 2 days
before ovulation to 1 day after, the temperature elevation does
not predict the exact moment of ovulation but offers
retrospective confirmation of its occurrence. A temperature
elevation that persists for less than 11 days is suggestive but not
diagnostic of a luteal phase defect.
2-Midluteal phase progesterone level is another test to assess
ovulation. A concentration greater than 3.0 ng/mL in a blood
sample drawn between days 19 and 23 is consistent with
ovulation, whereas a concentration greater than 10 ng/mL
implies adequate luteal support.
3-Daily monitoring of urinary LH has been widely available
given the proliferation of commercial tests for home use.
Using a threshold concentration of 40 mIU/mL, positive
testing for urinary LH has been shown to correlate well with
the surge of serum LH levels that trigger ovulation.
Assessment of Ovarian Reserve
Depleted ovarian reserve adversely impacts fecundability given
the inferior quantity and quality of remaining oocytes. The
following tests help identify both a depleted reserve and the
likelihood of response to controlled ovarian hyperstimulation
during assisted reproduction:
Day 3 FSH concentration: Values under 10 to 15 mIU/mL
suggest adequate ovarian reserve. The exact cutoff
depends on the particular laboratory reference
Clomiphene citrate challenge test (CCCT):
The administration of clomiphene citrate 100 mg orally on
menstrual cycle days 5 to 9 with measurement of Day 3 and
Day 10 FSH. An exaggerated FSH response portends poorly for
spontaneous or assisted conception.
Imaging of antral follicle counts by ultrasonography.
D- Exclusion of Structural Factors (tubal blockage)
The hysterosalpingogram (HSG) assesses uterine
and fallopian tube contour and tubal patency and
is performed in the early follicular phase, within 1
week of cessation of menstrual flow. This timing
minimizes the chances of interrupting a pregnancy.
The procedure is performed by injecting a
radiopaque dye through the cervix.
As more dye is injected, the dye passes through the
uterine cavity into the fallopian tubes and
peritoneal cavity. X-ray films are taken under
fluoroscopy to demonstrate patent or obstructed
tubes. Nonsteroidal anti-inflammatory drugs may
be given to prevent cramping. Prophylactic
antibiotics (e.g., doxycycline, 100 mg orally twice
daily) are advisable when the patient has a history
of pelvic inflammatory disease or when
hydrosalpinges are identified during the study
A diagnostic laparoscopy assesses peritoneal and
tubal factors, such as endometriosis and pelvic
adhesions, and can provide access for simultaneous
corrective surgery. Laparoscopy should be scheduled
in the follicular phase and is the final and most
invasive step in the patient's evaluation, unless the
HSG raised suspicion of abnormalities. Findings on
HSG correlate with laparoscopic findings 60% to 70%
of the time.
Dye (usually a dilute solution of
indigo carmine) should be instilled through
the fallopian tubes (chromopertubation)
during laparoscopy to visually document
tubal patency. Hysteroscopy may also be
included to ensure that no intrauterine
abnormalities were missed on the HSG.
Recently, however, questions have been
raised regarding the propriety and
usefulness of pursuing laparoscopy
following a normal HSG.
1-Anovulation. The WHO stratifies anovulatory women into three
WHO Class I: Hypogonadotropic hypogonadal anovulation encompasses
hypothalamic amenorrhea attributable to low GnRH levels or pituitary
unresponsiveness to hypothalamic GnRH, with resultant low FSH and serum
WHO Class II: Normogonadotropic normoestrogenic anovulation involves
normal levels of estradiol and FSH; LH levels, however, are elevated. This class
includes the polycystic ovarian syndrome (PCOS).
WHO Class III: Hypergonadotropic hypoestrogenic anovulation results from
premature ovarian failure or ovarian resistance.
The vast majority of anovulatory women of reproductive
age fall into WHO class II and, fortunately, this class proves
responsive to ovulation induction.
The agents most commonly used to stimulate multiple
ovarian follicles are
clomiphene citrate (CC),
human menopausal gonadotropins (hMG),
purified follicle-stimulating hormone (FSH).
CC, a synthetic, nonsteroidal estrogen agonist-antagonist,
increases the release of gonadotropin-releasing hormone
(GnRH) and subsequent LH and FSH release.
CC is useful in women with oligomenorrhea and
amenorrhea, with intact hypothalamic-pituitary-ovarian
axes. Patients who are overweight and hyperandrogenic
have decreased responsiveness to CC. Women with PCOS
often respond to metformin administered with or in lieu
GnRH, hMG, and FSH are used primarily in women who
fail to respond to CC or who have hypogonadotropic
amenorrhea or unexplained infertility. Prescription of
these expensive drugs, which are used in the more
complicated protocols for in vitro fertilization , should be
left to specialists trained in their use
to induce ovulation in patients with hyperprolactinemia the use of the
dopamine agonists bromocriptine (Parlodel) or carbergoline (Dostinex
) is the best way.
Bromocriptine is a dopamine agonist that directly inhibits pituitary
secretion of prolactin, which restores normal gonadotropin release. The
usual starting dose is 2.5 mg at bedtime to prevent dopaminergic side
effects, which include nausea, diarrhea, dizziness, and headache. If oral
administration cannot be tolerated, vaginal administration is
recommended. A response is usually seen in 2 to 3 months, and 80% of
hyperprolactinemic patients ovulate and become pregnant. CC is added
if ovulation does not occur within 3 months after beginning treatment.
3-Other, Thyroid problems should be treated
appropriately because both hypothyroidism and
hyperthyroidism may lead to infertility.
Hypothalamic-pituitary axis problems, including
extreme weight gain or loss, excessive exercise, and
emotional stress, can all impact the secretion of
GnRH from the hypothalamus and cause ovulatory
dysfunction. These must be addressed by
appropriate behavioral or psychological intervention.
4-Male Factor Infertility. Although the gynecologist does not
directly treat male patients, therapies to treat male factor
infertility often involve hormonal manipulation in the female
partner. The evaluation is analogous to that in the woman,
with examination of the hypothalamic-pituitary-testicular
axis, outflow tract, and testicular function. Toxins, viruses,
sexually transmitted diseases, varicoceles, and congenital
problems can all influence infertility.. At present, these
abnormalities of volume are most commonly treated with
sperm washing and intrauterine insemination (IUI).
The initiation of intracytoplasmic sperm
injection (ICSI) has revolutionized treatment
of male infertility. As long as viable sperm
can be retrieved by ejaculation, epididymal
aspiration, or testicular biopsy, successful
fertilization and pregnancy can be achieved.
The fertilization rate is 95%, and the
pregnancy rate is comparable to that of in
vitro fertilization (IVF).
3- Endometriosis, the ectopic growth of hormonally
responsive endometrial tissue, may account for 15% of
infertility in women; endometriosis is diagnosed and staged
by laparoscopy, it has a negative impact on fertility, and, once
diagnosed, it should be treated surgically before instituting
infertility therapy. Laparoscopic resection or ablation of even
minimal endometriosis may enhance fecundity in infertile
If pregnancy fails to occur after surgical treatment, the patient
should be directed to an infertility specialist for possible IVF.
GnRH agonists, danazol, and continuous oral contraceptive
pills effectively treat endometriosis-related pelvic pain, but
they all prevent pregnancy
4-Luteal phase defects occur in both fertile and
infertile women, and treatment is highly
controversial. Nevertheless, in a couple with
documented infertility, care should be taken to treat a
presumed luteal phase deficiency with intramuscular
or intravaginal progesterone in the postovulatory
phase of the cycle and if pregnancy occurs until the
luteoplacental shift occurs
5-Uterine factors, such as submucous leiomyomas,
intrauterine synechia (Asherman's syndrome), and
uterine deformities or septa, cause approximately
2% of infertility. The mainstay of treatment for these
conditions is surgical correction, usually via a
6-Infections of the female and male genital tracts
have been implicated as causes of infertility.
Chlamydia infection and gonorrhea are the major
pathogens and should be treated appropriately.
Ureaplasma urealyticum and Mycoplasma
hominis have also been implicated, and, if
positively identified by culture, they should
be treated with oral doxycycline, 100 mg
twice daily for 7 days. This has been shown
to increase the pregnancy rate in patients
with primary infertility.
6-Tubal factor infertility has become more prevalent with the
increased incidence of salpingitis. The frequency of tubal
occlusion after one, two, and three episodes of salpingitis is
reported to be 11%, 23%, and 54%, respectively. Appendicitis,
previous abdominopelvic surgery, endometriosis, and ectopic
pregnancy can also lead to adhesion formation and damaged
tubes. Proximal tubal obstruction is identified on HSG.
Tubal spasm may mimic proximal obstruction,
however, and obstruction should be confirmed by
laparoscopy. Treatment consists of tubal cannulation,
microsurgical tubocornual reanastomosis, or IVF.
Distal tubal disease or distortion can be seen on HSG
and laparoscopy. The success of corrective surgery
(neosalpingostomy) depends on the extent of disease.
Definition of ART
• ART refers to all techniques involving direct
retrieval of oocytes from the ovary
• ART procedures include IVF, GIFT, ZIFT, and
• The simplest ART procedure, IVF has been
around for over 20 years and is perhaps the
most commonly recognized ART of all
Abdulkareem Sultan Al-Olama 39
Abbreviations used in assisted conception
• IVF In-vitro fertilization
• DI Donor insemination
• GIFT Gamete intrafaillopian transfer
• ZIFT Zygote intrafallopian transfer
• SUZI Subzonal insemination
• ICSI Intracytoplasmic sperm injection
• PESA Percutaneous sperm aspiration
• MESA Micro-epididymal sperm aspiration
• TESA Testicular sperm aspiration
Controlled Ovarian Hyperstimulation (COH)
and Protocols for In Vitro Fertilization.
The agents most commonly used to stimulate
multiple ovarian follicles are
CC, hMG, and purified FSH.
are generally given on days 5 to 9 of the menstrual cycle. Response may
be followed by BBT measurement, ultrasonography, and measurement
of LH and estradiol levels. CC is inexpensive and has a low risk of ovarian
hyperstimulation syndrome (OHSS). However, it creates a low oocyte
yield (one or two per cycle) with frequent LH surges that lead to high
cancellation rates in IVF cycles and low pregnancy yield. Most treatment
regimens start with 50 mg per day for 5 days. If ovulation fails to occur,
the dose is increased to 100 mg per day. Human chorionic gonadotropin
(hCG), 5,000 IU to 10,000 IU, may be used to simulate an LH surge.
Eighty percent of properly selected couples will conceive in the first
three cycles after treatment. Potential side effects are vasomotor
flushes, blurring of vision, urticaria, pain, bloating, and multiple
gestation (5% to 7% of cases, usually twins).
increase the number of recruited follicles in patients who do not achieve
pregnancy with CC and in those patients with endometriosis or
unexplained infertility. The hMG, which is a combination of LH and FSH,
is usually given for 2 to 7 days. Although gonadotropin injections prove
more effective at COH than clomiphene, they are more expensive and
can lead to life-threatening OHSS. Trade names for hMG include
Humegon, Pergonal, and Repronex. Attempts to minimize the
potentially deleterious LH component of hMG have led to the
manufacture of purified urinary FSH and, more recently, recombinant
FSH.. Follicle maturation during COH is monitored using sonography and
serial measurement of estradiol levels.
To complete oocyte maturation, hCG is administered
once the follicles have reached 17 to 18 mm in
diameter. Potential disadvantages of gonadotropin
use include premature luteinization, spontaneous LH
surges resulting in high cancellation rates, multiple
gestations, and ovarian hyperstimulation.
analogs/agonists (GnRHa) are used via a flare-up
protocol or a luteal phase protocol.
The flare-up protocol causes an elevation of FSH in the
first 4 days, which increases oocyte recruitment. After 5 days
of administration, the GnRH agonist then down-regulates the
pituitary to prevent premature luteinization and a
spontaneous LH surge.
The luteal phase protocol involves starting GnRHa
administration on the 17th to 21st menstrual day in the cycle
before IVF. GnRHa increase the number, quality, and
synchronization of the oocytes recovered per cycle and
thereby improve the fertilization rate, the number of
embryos, and the pregnancy rate.
Oocyte Retrieval, Culture Fertilization, and Transfer
The two major techniques of oocyte retrieval are
1-ultrasonographically guided follicular
The r is the most widely used technique. Ultrasonographically
guided oocyte retrieval, using a 17-gauge needle passed through
the vaginal fornix, is performed 34 to 36 hours after hCG injection.
The procedure is done under heavy sedation. Potential
complications include risk of bowel injury and injury to pelvic
2-laparoscopic oocyte retrieval
Oocyte Fertilization. Sperm are diluted,
centrifuged, and incubated before 50,000 to
100,000 motile spermatozoa are added to each
Petri dish containing an oocyte. Fertilization is
documented by the presence of two pronuclei and
extrusion of a second polar body at 24 hours. At
that stage, most embryos are cryopreserved for an
unlimited period, with a survival rate of 75%.
Embryo transfer is most commonly carried out 72 hours after
retrieval at the 4- to 10-cell stage. In general, no more than
two embryos are transferred to limit the risk of multiple
gestation and to optimize pregnancy rates. The actual number
of embryos transferred depends on the individual's age and
other risk factors for multiple pregnancy. The common
practice is to supplement the luteal phase with progesterone
given by vaginal suppository, beginning the day of oocyte
release and continuing into the 12th week of pregnancy
. Maternal, Fetal, and Long-Term Effects of ART
Ovarian Hyperstimulation Syndrome (OHSS). Although commonly
self-limited, the OHSS can present as a life-threatening complication
of COH characterized by abdominal bloating, accumulation of ascites,
decreased urine output, hemoconcentration, hypercoagulability,
hydrothorax, ARDS, electrolyte imbalance, and multiple organ failure.
Potentiated by COH cycles using GnRH analogs for down-regulation or
hCG to trigger oocyte maturation, OHSS is classified as mild,
moderate, or severe according to the presenting constellation of
symptoms. Purported risk factors include young age, low body
weight, high or rapidly climbing estradiol levels, large size and number
of follicles, and the presence of PCOS.
Prevention of suspected impending OHSS can be achieved by
lowering or withholding the hCG triggering dose, postponing
embryo transfer, or canceling the cycle.
Inpatient management for moderate-severe cases of OHSS
includes close monitoring of fluid status and laboratory values
of renal and coagulation function, intravascular resuscitation,
thrombosis prophylaxis, paracentesis/thoracentesis as
indicated, and critical care intervention if warranted. One
must remember that OHSS is an entirely iatrogenic entity that
is usually avoidable by vigilance and judicious execution and
alteration of COH regimen.
. Preimplantation Genetic Diagnosis (PGD)
•whereby parents could prevent the transmission of
genetic disorders to their offspring and
simultaneously avoid the emotional angst and ethical
conundrum of pregnancy termination associated with
conventional prenatal diagnosis. The process of PGD
proceeds by biopsy and genetic analysis of one of the
•1 to 2 blastomeres of a cleavage-stage (Days 2 - 3)
embryo derived from IVF
•Polar body biopsy from a metaphase II oocyte
obtained after COH
•Trophectoderm tissue from a blastocyst-stage (Day 5)
•PGD s used in the following
•Single-Gene Disorders. PGD is used for multiple
indications. Using the polymerase chain reaction
(PCR), DNA extracted from the biopsy specimen is
used to screen for a known hereditary disorder”for
example, cystic fibrosis, muscular dystrophy, and
• Aneuploidy Testing. Fluorescence in situ hybridization (FISH) is a
molecular technique predicated on the identification of
chromosome-specific sequences that can be hybridized to
complementary probes attached to differentially colored
•PGD was first used in 2000 to screen for Fanconi anemia and
simultaneously to select for a preimplantation embryo that was
HLA-matched to a pre-existingElective Sex Selection. PGD, via
either PCR or FISH, enables efficient and accurate gender
selection by screening selectively for, or against, the Y
chromosome. Sharp debate over the propriety of such
nonmedical use of reproductive technology has limited the
prevalence of this application.
Who is eligible for ART
• Women with tubal diseases
• Unexplained infertility
• Immunologic causes for infertility
• Women with premature ovarian
• Individuals with male factor
infertility (e.g., abnormalities in
sperm production, function or
transport or prior vasectomy)
Abdulkareem Sultan Al-Olama 54
Methodology of ovulation induction
• The success of ovulation induction in
achieving a pregnancy is highly variable. It
depends on the diagnosis, age, the
medication being used, and numerous
Abdulkareem Sultan Al-Olama 55
• Sperm penetration assay (SPA) is a multi-step
laboratory test that offers a biological
assessment of human sperm fertilizing ability.
Abdulkareem Sultan Al-Olama 56
Abdulkareem Sultan Al-Olama 57
Other techniques Cont’d
– Zygote Intrafallopian Transfer. ZIFT may be recommended if the
husband has severe male fertility factor or if there has been
difficulty confirming fertilization with past procedures. ZIFT has
the advantages of allowing fertilization to be confirmed and it
has demonstrated higher success rates than IVF when used for
the appropriate indications.
– One disadvantage with ZIFT is that the transfer of the zygote
must be performed through a laparoscope.
Other techniques Cont’d
– Gamete intrafallopian transfer was developing in 1984 as a
variation of in vitro fertilization (IVF).
– Gift is recommended when
• unexplained infertility
• infertility due to immunological factors
• selected cases of male infertility
• Tubal infertility
– A requirement for the procedure is that the female partner
having at least one open (patent) fallopian tube.
Other techniques Cont’d
– Tubal Embryo Transfer; the placing of cleaving
embryos into the fallopian tube.
– Peritoneal Oocyte and Sperm Transfer; the
placement of oocytes and sperm into the pelvic
Other techniques Cont’d
– Intracytoplasmic sperm injection, or ICSI, was developed to treat
couples who previously had a very poor probability of achieving
fertilization due to the male partner's extremely low numbers of
– This treatment, when combined with in vitro fertilization, allows
these couples a more favorable probability of achieving
"take home baby rate"
• One of the first questions that most people ask is "what is the
chance for success?" The best estimate is that the birth of a
live baby occurs in approximately 15-25% of women in whom
embryos are transferred into the uterus.
• The 1998 nationwide live birth rate as reported in the IVF-ET
Registry, was 24.9%.
• The corresponding rate for 1989 was 14%.
Success rates Cont’d
• Success varies with many factors, including the number of
embryos that are transferred.
• If one embryo is transferred, there is approximately a 7%
chance of successful implantation; with two embryos, the
success rate increases to 18%.
• The rate peaks with the transfer of three to four embryos.
Presently, the collection of oocytes, fertilization, and early
embryo growth are accomplished with a high degree of
Success rates Cont’d
• The major hurdles to success are implantation after embryo
transfer and early pregnancy loss. The rate of early pregnancy
loss is slightly, but not significantly, higher with ART compared
to spontaneous conception.
• The risk of early pregnancy loss increases with age of the
female partner. Over age 40, ART success rates decline
• Pregnancy complications tend to be higher with ART
pregnancies, primarily because of the much higher rate of
Success rates Cont’d
• Twins occur in about 25% of ART pregnancies versus 1-2%of
spontaneous pregnancies. The risk of more than a twin
pregnancy is less than 5%.
• To put these figures into perspective, studies have shown that
the rate of pregnancy in couples with proven fertility in the
past is approximately 20% per cycle. Therefore, although a
figure of 15-25% may sound low, it is equal to or greater than
the chance that a fertile couple will conceive in any given
Abdulkareem Sultan Al-Olama 66