know definitions of primary and secondary
• understand the causes of infertility
• know the initial investigations of the
Investigate male factor
• Test for ovulation
• Test for tubal patency
• Investigation role of laparoscopy and
Infertility is a common condition with important
psychologic, economic, demographic, and
Infertility is a unique medical condition because
it involves a couple, rather than a single
Demand for infertility services has grown
substantially even though the prevalence of
infertility has been stable.
It is defined as inability 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.
Some clinicians use the term subfertility to
describe this failure to conceive unless the
couple has been proven to be sterile.
5. Primary infertility
is the term used to describe
a couple that has never
been able to conceive ,after
at least 1 year of
the probability of achieving a
pregnancy in one menstrual
cycle, is a more accurate
descriptor because it
recognizes varying degrees
8. NORMAL FERTILITY
A study examined the number of months to
conception in 5574 normal women who had
unprotected intercourse and who became
pregnant . Eighty-five percent of the women
conceived within 12 months.
Five to 15 percent of apparently normal couples
will conceive in the second 12 months of
attempted conception so that after 24 months ,
95 percent of couples will have conceived.
12. The World Health Organization (WHO) task
force on Diagnosis and Treatment of Infertility
performed a study of 8500 infertile couples and
utilized standard diagnostic criteria to determine
the medical conditions contributing to infertility.
female factor : 38 %
Male factor : 20%
Both : 27%
UI : 15%
14. B- Acquired disorders
A Pituitary and hypothalamic tumors (pituitary
Pituitary and hypothalamic infiltrative disorders
(sarcoidosis, histiocytosis, tuberculosis, fungal
Pituitary and hypothalamic lymphocytic
infundibulitis or hypophysitis
Head trauma, intracranial radiation, or surgery
19. C-Systemic illness
Renal failure, hepatic cirrhosis, cancer, sickle
cell disease, amyloidosis, vasculitis, celiac
D-Genetic causes of dysspermatogenesis
Y chromosome microdeletions and related
disordersAutosomal and X chromosome
defectsMutations causing severe defects in
20. D-Sperm transport disorders(5%)
Epididymal dysfunction (drugs,
infection)Abnormalities of the vas deferens
(congenital absence, Young syndrome,
infection, vasectomy)Seminal vesicles and
prostate-Ejaculatory ducts disorders
Infrequent vaginal intercourse, erectile
dysfunction, and premature ejaculation
F-Idiopathic male infertility(10-20%)
27. Causes of ovulatory dysfunction
1-Primary hypothalamic-pituitary dysfunction:
Intense exercise -Eating disorders –Stress
Idiopathic hypogonadotropic hypogonadism
Hyperprolactinemia -Lactational amenorrhea
Pituitary adenoma or other pituitary tumors
Trauma, or radiation of the hypothalamic or pituitary area
Sheehan's syndrome -Empty sella syndrome
Lymphocytic hypophysitis (autoimmune diseases)
28. Causes of ovulatory dysfunction
Polycystic ovary syndrome
Hyperthyroidism or hypothyroidism
Hormone producing tumors (adrenal, ovarian)
Chronic liver or renal disease
Cushing's disease-Congenital adrenal
Premature ovarian failure, which may be
autoimmune, genetic, surgical ,idiopathic, or
related to drugs or radiation
Turner syndrome-Androgen insensitivity S.
30. World Health Organization
classification of anovulation
WHO class 1: Hypogonadotropic
low or low-normal serum (FSH) and
low serum estradiol concentrations due to
decreased hypothalamic secretion of
(GnRH) or pituitary unresponsiveness to
31. WHO class 2: Normogonadotropic
These women may secrete normal
amounts of gonadotropins and estrogens.
However, FSH secretion during the
follicular phase of the cycle is subnormal.
This group includes women with polycystic
ovary syndrome (PCOS). Some ovulate
occasionally, especially those with
32. WHO class 3: Hypergonadotropic
The primary causes are premature ovarian
failure (absence of ovarian follicles due to
early menopause) and ovarian resistance
35. NIH Criteria 1990:
Menstrual irregularity due to
anovulation or oligo-ovulation
Evidence of clinical or biochemical
Hirsutism, acne, male pattern baldness
High serum androgen levels
Exclusion of other causes (CAH,
36. Rotterdam Criteria (2 out of 3)2003:
Menstrual irregularity due to
Evidence of clinical or biochemical
Polycystic ovaries by US
presence of 12 or more follicles in each ovary
measuring 2 to 9 mm in diameter and/or increased
* In addition, other etiologies (congenital adrenal
hyperplasias, androgen-secreting tumors, Cushing's
syndrome) must be excluded.
37. AES criteria 2006:
Presence of three features
Androgen excess (clinical and/or
Ovarian dysfunction (oligo-anovulation
and/or polycystic ovarian morphology)
Exclusion of other androgen excess or
41. Oocyte aging
Age is an important factor affecting a woman's
fertility . The decrease in fecundability with aging
is likely due to a decline in both the quantity and
quality of the oocytes.
The germ cell complement of the ovary reaches
its apex of 6 to 7 million follicles in the
midgestation female fetus, followed by a steady
attrition from 1 to 2 million follicles at birth to
300,000 follicles at the onset of puberty . The
rate of follicle loss accelerates after the woman
reaches her midthirties.
42. Oocyte aging
Other insults to the ovary such as cigarette
smoking, radiation,chemotherapy, and
autoimmune disease also accelerate
Women with a depleted ovarian follicle
pool may continue to ovulate regularly, but
have infertility due to the poor quality of
oocytes remaining in the terminal follicular
43. Oocyte aging
The loss of oocyte quality as a woman ages is
thought to be due to an increase in meiotic
Hypothesized mechanisms involve differences
between germ cells when formed during fetal
life, damage in germ cells that accumulates over
the course of a woman’s life, or age related
changes in the quality of the granulosa cells
surrounding the oocyte.
44. Ovarian cysts
A review of epidemiologic data, drawn
mainly from comparative studies and
cohorts,concluded that it is unclear
whether small (<3 to 6 cm) ovarian cysts
have a role in infertility and that the effects
of surgical treatment are often more
harmful than the cyst itself to the ovarian
45. 2-FALLOPIAN TUBE
Tubal disease and pelvic adhesions
prevent normal transport of the oocyte and
sperm through the fallopian tube.
Previous surgery or nontubal infection (eg,
appendicitis, inflammatory bowel disease),
Pelvic TB, and salpingitis isthmica nodosa
(ie, diverticulosis of the fallopian tube)
46. Women with distal tubal obstruction may
develop hydrosalpinges, which decrease the
success rate of (IVF). In addition to obstruction
to sperm migration, hydrosalpinges appear to
reduce fertility by
retrograde flow of tubal contents into the
endometrial cavity, which creates a hostile
environment to implantation of an embryo.
Removal of the hydrosalpinges increases the
success of IVF
There is good evidence for recommending
proximal tubal occlusion
to improve IVF pregnancy rates.
48. Treatment of hydrosalpinx before IVF
Negative effect on PR, IR, early pregnancy loss
& LBR. LBR are reduced by 50%
The fluid of hydrosalpinx:
1.Mechanical barrier to implantation: embryo to float
2.Deficient to support the developing embryo
3.Toxic to the developing embryo
49. Classification of Tubal disease
British Fertility Society
Proximal occlusion without tubal fibrosis
Distal occlusion without tubal distension
Healthy mucosal appearance at HSG,
Flimsy peritubal/ovarian adhesions.
Unilateral severe tubal damage
Limited dense adhesions of tubes & ovaries
Bilateral severe tubal damage
Extensive tubal fibrosis
Tubal distension >1.5 cm
Abnormal mucosal appearance
Extensive dense adhesion
Impaired implantation, either mechanical or due
to reduced endometrial receptivity, are the basis
of uterine causes of infertility
Uterine leiomyomata:A meta-analysis showed
that only leiomyomata with a submucosal or
intracavitary component were associated with
lower pregnancy and implantation rates.
The likely mechanism is inhibition to normal
53. Uterine anomalies; Uterine abnormalities are
thought to cause infertility by interfering with
normal implantation. Müllerian anomalies are a
significant cause of (RPL), with the septate
uterus associated with the poorest reproductive
Other structural abnormalities associated with
infertility include endometrial polyps, and
synechiae from prior pregnancyrelated
54. ENDOMETRIOSIS —
Mechanisms which decrease fertility in women
with endometriosis include
Anatomic distortion from pelvic adhesions,
damage to ovarian tissue by endometrioma
formation and surgical resection,
and the production of substances such as
cytokines and growth factors which impair the
normal processes of ovulation, fertilization, and
55. 4-CERVICAL FACTORS
Normal midcycle cervical mucus
facilitates the transport of sperm.
Congenital malformations and trauma
to the cervix (including surgery) may
result in stenosis and inability of the
cervix to produce normal mucus,
thereby impairing fertility.
56. 5-IMMUNE FACTORS
Antiphospholipid syndrome :
It may lead to immunological rejection of
the early pregnancy or placental damage.
Evaluation for this disorder depends upon
the patient's medical and family history and
whether infertility is related to recurrent
early pregnancy failure (workup indicated)
or failure to conceive (workup not
57. 6-GENETIC CAUSES
Infertile couples have been shown to have a
higher prevalence of karyotype abnormalities
(trisomies, mosaics, translocations, etc) than the
general population .
The frequency varies according to the cause of
infertility and clinical history.
The most common aneuploidies associated with
infertility are 45, X (Turner syndrome) in women
and 47, XXY (Klinefelter syndrome) in men.
Unexplained infertility is the
diagnosis given to couples after a
thorough evaluation has not revealed
a cause. Many cases of unexplained
infertility may be due to small
contributions from multiple factors.
59. When To start Workup
An infertility evaluation is usually initiated after
one year of regular unprotected intercourse in
women under age 35 years and after six months
of unprotected intercourse in women age 35
years and older.
However, the evaluation may be initiated sooner
in women with irregular menstrual cycles or
known risk factors for infertility, such as
endometriosis, a history of PID, or reproductive
Both couples should be present
Previous pregnancies by each partner
Duration of infertility
Frequency and timing of intercourse
Use of lubricants
66. Very long list of tests, have been
advocated to assist in
determining the cause of the
infertility in the diagnostic
evaluation of infertile couple.
The necessity and cost effectiveness
of performing many of these tests and
correcting the abnormalities found by
them have not been demonstrated.
67. 1-Investigations of Male Factor
Conventional semen analysis
Computer- assisted sperm analysis (CASA)
Strict sperm morphology "Tygerberg strict criteria“
A variety of sperm function tests
- The acrosome reaction test
- Hypo-osmotic swelling test
- Measurement of generation of Reactive oxygen species
- Sperm capacitation assays
- Hemizona-binding assay
- Hamster penetration test
- Human sperm-zona penetration assay
A variety of imaging techniques for detection of varicocele
68. Semen Analysis
Semen analysis is the key laboratory
assessment of the male partner of an infertile
couple. The standard semen analysis
consists of the following:
Semen volume and pH
● Microscopy for
• Sperm concentration, count, motility, and
morphology • Debris and agglutination
• Leukocyte count• Immature germ cells
69. Semen Analysis
The semen sample should be collected
after two to seven days ejaculatory
If possible, the patient should collect the
sample by masturbation at the doctor's
office. If not possible, then the sample may
collected at home and delivered to the
laboratory within an hour of collection.
70. Semen Analysis
Volume – 1.5 ● mL (95% CI 1.41.7)
● Sperm concentration – 15 million
spermatozoa/mL (95% CI 1216)
● Total sperm number – 39 million
spermatozoa per ejaculate (95% CI 33-
● Morphology – 4 percent normal forms
(95% CI 34),
72. Semen Analysis
using "strict" Tygerberg method :
● Vitality – 58 percent live (95% CI 5563)
● Progressive motility – 32 percent (95%
● Total (progressive + nonprogressive)
motility – 40 percent (95% CI 3842)
74. 2-Assessment of ovulation
Basal body temperature
Urine LH kits
Mid luteal serum progesterone
Routine hormonal profile: FSH, LH, Prolactin,TSH
Serial pelvic Ultrasonography.
A variety of tests for assessment of ovarian reserve such as D3
FSH & E2, Inhibin B, Clomid challenge test, Gondotropin
agonist stimulation test, TVS for ovarian volume, antral follicle
count and Stromal blood flow.
75. Evidence of ovulation:
1. Menstrual history of regular cycles.
2. Serum progesterone in the mid-luteal
phase of their cycle (day 21 of a 28-day
cycle) even if they have regular menstrual
3. Serum gonadotrophins ( FSH & LH) on
Day2-3 especially in irregular periods.
(N.B.: No role for basal body temperature
76. Further investigations
-More important in >35 years old, suspected
ovarian failure and to detect response to
1. Total antral follicle count.
2. AMH of less than or equal to 5.4 pmol/l for a
low response and greater than or equal to 25.0
pmol/l for a high response
3. FSH greater than 8.9 IU/l for a low response
and less than 4 IU/l for a high response.
77. D 3 FSH
Both the day 3 FSH level (where day 1 is the
first day of full menstrual flow)and the CCCT,
which is a provocative test for measurement of
FSH, are widely used for screening ovarian
The CCCT involves oral administration of 100
mg clomiphene citrate on cycle days 5 through 9
with measurement of day 3 and day 10 FSH
levels and day 3 estradiol level.
A value less than 10 mIU/mL suggestive of
adequate ovarian reserve.
78. Antral follicle count (AFC)
Ultrasound examination can be used to
determine the number of antral follicles (defined
as follicles measuring 2 to 10 mm in diameter).
On transvaginal ultrasound,
The ovaries are visualized in their transverse
and longitudinal planes and the antral follicles
are counted and measured; the size of the
follicle is the mean of two perpendicular
diameters, one of which should be the largest
dimension of each follicle
A low AFC ranging from <4 to 10 antral
follicles between days two and four of a
regular menstrual cycle suggests poor
Although AFC is a good predictor of
ovarian reserve and response,
it is less predictive of oocyte quality,the
ability to conceive with IVF, and pregnancy
81. Antimüllerian hormone (AMH)
is expressed by the small (<8 mm) preantral and
early antral follicles. The AMH level reflects the size
of the primordial follicle pool, and may be the best
biochemical marker of ovarian function across an
array of clinical situations.
The AMH level appears to be an early, reliable, direct
indicator of declining ovarian function.
AMH level correlates with the number of oocytes
retrieved after stimulation, and is the best biomarker
for predicting poor and excessive ovarian response.
Unlike the day 3 FSH, AMH can be
measured anytime during the menstrual
AMH <0.5 ng/mL predicts reduced ovarian
reserve with less than three follicles in an
● AMH <1.0 ng/mL predicts baseline
ovarian reserve with a likelihood of limited
eggs at retrieval.
● AMH >1.0 ng/mL but <3.5 ng/mL
suggests a good response to stimulation
AMH >3.5 ng/mL predicts a vigorous
response to ovarian stimulation and
caution should be exercised in order to
avoid ovarian hyperstimulation syndrome.
87. Assessment of the uterine cavity
Modalities to assess the uterine cavity
Saline Infusion Sono-
Three dimensional sonography
88. ROLE OF LAPAROSCOPY
Laparoscopy is indicated in women in
whom endometriosis or pelvic
adhesions/tubal disease is suspected
based on physical examination, HSG, or
history (e.g.,, pelvic infection, pelvic
surgery, or ectopic pregnancy).
89. Laparoscopy as a diagnostic tool in
infertility has diminished markedly
Today, we rarely perform diagnostic laparoscopy
in infertile women. (Tulandi, 2017)
1.The benefit of diagnostic laparoscopy with no
risk factors for intra-abdominal adhesions: small.
2.Treatment of stage I or II endometriosis: small
increase in PR.
3.Alternative treatments of infertility are available
1.Abnormal HSG or US
2.Young women with history or symptoms
suggestive of pelvic disease. Even if HSG indicates
patency in one or both tubes
1.A history of PID,
4.Chronic pelvic pain
.5 current dysmenorrhea, pelvic pain, or deep
dyspareunia; previous complicated appendicitis
91. 3. Three cycles of super ovulation with IUI are
diagnostic laparoscopy or
IVF treatment (ASRM, 2012; TulandiT 2017)
4. After failed IVF
-Laparoscopy after failed IVF:(Littman et al., 2005).
Pathology in 50%
endometriosis or adhesions
No RCTs have confirmed this rate.
92. HSG Vs Laparoscopy:
false-negatives are more
tubal blockages are often false-positives
obstructions diagnosed by laparoscopy are
most likely true positives.
Prognosis of a tubal obstruction (unilateral
and/or bilateral) is poorer when diagnosed with
laparoscopy than with HSG (Speroffand Fritz
93. TESTS OF LIMITED CLINICAL
PCT for assessment of the cervical factor.
Chlamydia trachomatis antibodies .
Basal body temperature records
Zonafree hamster oocyte penetration test
Testing for antibodies; antiphospholipid, antisperm,
antinuclear, and antithyroid antibodies.
94. The basic infertility evaluation of
all couples consists of:
Assessment of ovulatory function
Determination of tubal patency and presence or absence
of abnormalities of the uterine cavity,usually by HSG.
Diagnostic laparoscopy is indicated for women with
suspected endometriosis or pelvic adhesions.
Ovarian reserve is assessed with day 3 (FSH) and
estradiol levels in women over 35 years of age and in
younger women with risk factors for premature ovarian
Lack of agreement exists among
trained infertility specialists with regard
to prognostic utility as well as criteria of
normality of many of these tests?
There is no consensus on which tests
are essential before reaching the exact
96. Investigations of infertile couple
Evidence Medicine Based Era
National Evidence-Based Clinical Guidelines
“Assessment and treatment for people with fertility problems
developed by the National Collaborating Centre for
Women and Children's Health on behalf of
the National Institutefor Clinical Excellence (NICE)”
97. Grading – Evidence Based Recommendations
I a- meta-analysis
of RCTs trials,
I b- at least one
II a - at least one
II b - at least one
other type of
studies, such as
studies and case
or opinions and/or
• GPP Good practice point : The view of the Guideline Development Group
•The design of a quasi-experiment relates to a particular type of experiment or other study in which one has little or no control over the
allocation of the treatments or other factors being studied.
98. 1-Semen analysis
• CASA is not superior to conventional
semen analysis (Grade A)
• Screening for antisperm antibodies
should not be offered because there is
no evidence of effective treatment to
improve fertility. (GPP)
99. What To Do if Semen analysis Is
Repeat confirmatory test ( 3 months after
the initial analysis & ttt). (Grade B).
If azoospermia or severe oligozoospermia ,
repeat test as soon as possible. (GPP)
100. Where & When Testicular Biopsy
(TB) be done In Azoospermia?
TB should be performed only in a
tertiary service where there are
Sperm recovery ,
ART( C )
101. 2-Assessment of Ovulation
Women with fertility problems should
be asked about the frequency and regularity
of menstrual cycles.
Women with regular monthly menstrual
cycles are likely to be ovulating. (Grade B)
The use of basal body temperature charts to
confirm ovulation does not reliably predict
ovulation and is not recommended. (Grade B)
102. Assessment of Ovulation
Women with regular menstrual cycles and
more than 1 year’s infertility are offered a
blood test to measure serum progesterone
in the mid-luteal phase of their cycle (day
21 of a 28-day cycle) to confirm ovulation.
103. Ovulation is most easily documented by a
midluteal phase serum progesterone level,
which should be obtained approximately one
week before the expected menses.
For a typical 28day cycle, the test would be
obtained on day 21. A progesterone level >3
ng/mL is evidence of recent ovulation.
104. Assessment of Ovulation
Women with prolonged irregular menstrual
cycles should be offered a blood test to
measure serum progesterone. Depending on the
timing of menstrual periods, this test may need
to be conducted later in the cycle (for example
day 28 of a 35-day cycle) . (GPP)
For such women direct or indirect
measurement of progesterone is unnecessary
until after therapy is initiated.
105. Assessment of Ovulation
Women with irregular menstrual cycles
should be offered a blood test to measure
serum FSH & LH (GPP).
Blood test for prolactin should only be
offered to women who have an ovulatory
disorder, galactorrhoea or a pituitary
tumor. (Grade C)
106. Assessment of Ovulation
Tests of ovarian reserve currently have limited
sensitivity and specificity in predicting fertility.
However, women who have high levels of
gonadotrophins should be informed that they
are likely to have reduced fertility. (Grade C)
The value of assessing ovarian reserve using
Inhibin B is uncertain and is therefore not
recommended. (Grade C)
107. Assessment of Ovulation
Women with possible fertility problems are no
more likely than the general population to have
thyroid disease and the routine measurement of
thyroid function should not be offered.
Estimation of thyroid function should be
confined to women with symptoms of thyroid
disease. (Grade C).
108. Assessment of Ovulation
Women should not be offered an
endometrial biopsy to evaluate the luteal
phase as part of the investigation of
fertility problems because there is no
evidence that medical treatment of luteal
phase defect improves pregnancy rates
109. 3-Assessment of tubal factor
The results of semen analysis and assessment of
ovulation should be known before a test for tubal
patency is performed.
Women who are not known to have co-morbidities
(such as pelvic inflammatory disease, previous
ectopic pregnancy or endometriosis) should be
offered HSG to screen for tubal occlusion because
this is a reliable test for ruling out tubal occlusion,
and it is less invasive and makes more efficient use
of resources than laparoscopy. (Grade B)
110. Assessment of tubal factor
Where appropriate expertise is available,
screening for tubal occlusion using
should be considered because it is an
effective alternative to HSG for women
who are not known to have co-morbidities
111. Assessment of tubal factor
Women who are thought to
have co-morbidities should be
offered laparoscopy and dye so
that tubal and other pelvic
pathology can be assessed at
the same time. (Grade B)
112. 4-Assessing uterine abnormalities
Women should not be offered hysteroscopy on
its own as part of the initial investigation unless
clinically indicated, because the effectiveness of
surgical treatment of uterine abnormalities on
improving pregnancy rates has not been
established. (Grade B)
women with infertility and a normal HSG had no abnormalities of the
uterine cavity when subsequently examined by hysteroscopy.
115. Flushing of the tubes with oil-soluble
media increases subsequent
pregnancy rates (It may flush tubal
The Cochrane Library, Issue 2 2004.
Oil-soluble # Water Soluble Media for HSG
116. Sonohysterography # HSG?
The use of sonohysterography
should be considered as an
effective alternative to HSG
TVS can add evaluation of pelvis.
117. Unnecessary laparoscopy!!!
It is not cost effective to do
diagnostic laparoscopy as part of
the initial infertility evaluation
History, and physical examination,
TVS, HSG, and Midluteal progesterone
are all normal (Grade B)
119. When To Do Laparoscopy For tubal
When associated pelvic co
morbidities (PID, previous Ectopic,
endometriosis ..etc) :evaluation of the
pelvis is required.
122. Indications of Hysteroscopy as workup of
When Laparoscopy is indicated as in
Unexplained infertility ?
Before IVF in cases of
unexplained infertility ?!!!!
After Failed IVF ?
123. No Role for...
1. Postcoital test.
2. Endometrial biopsy
3. Antisperm antibodies
4. Routine cervical cultures
5. Thyroid function ( in absence of symptoms
suggestive of of thyroid disease)
6.Prolactin (in absence of galactorrhoea and
124. Optimum Time For Referral To ART Centers
1. Age > 35 Y.
2. Failed 3 IUI.
3. Severe male subfertility.
4. Number of mature follicles >4 (do not give HCG).
5. Number of follicles (>12 mm) >8 (do not give
6. Extensive endometriosis.
7. Need for cryopreservation of semen.
8. Non optimized office.
Diminished ovarian reserve
Polycystic Ovary Syndrome (PCOS)
Premature Ovarian Failure
History of Pelvic Inflammatory Disease (PID)
Previous ectopic and salpingectomy
Congenital uterine anomaly
Poor cervical mucus quantity/quality
Figure 3 Flowchart summary of algorithm for diagnosis of male infertility. As detailed in section PICO 2 (Is it necessary for all infertile men to undergo a thorough evaluation?) the first line investigations should include Physical Examination, History and Semen Analysis. Abnormalities in these lead to further investigations. YCMD, Y chromosome microdeletion; CFTR, CF transmembrane conductance regulator.