Female infertility,Prof.Salah Roshdy

Salah Roshdy AHMED
Salah Roshdy AHMEDProfessor at Sohag University,Egypt um Sohag University
Female Infertility
Prof.Salah Roshdy,MD
Prof. of Obstetrics & Gynecology
Sohag University
2018
Objectives
 know definitions of primary and secondary
infertility
 • understand the causes of infertility
 • know the initial investigations of the
infertile couple
 Investigate male factor
 • Test for ovulation
 • Test for tubal patency
 • Investigation role of laparoscopy and
hysteroscopy
INTRODUCTION
 Infertility is a common condition with important
psychologic, economic, demographic, and
medical implications.
 Infertility is a unique medical condition because
it involves a couple, rather than a single
individual
 Demand for infertility services has grown
substantially even though the prevalence of
infertility has been stable.
DEFINITIONS
 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.
Primary infertility
is the term used to describe
a couple that has never
been able to conceive ,after
at least 1 year of
unprotected intercourse.
Secondary infertility
Secondary infertility describes
couples who have previously
been pregnant at least once,
but have not been able to
achieve another pregnancy.
Fecundability
the probability of achieving a
pregnancy in one menstrual
cycle, is a more accurate
descriptor because it
recognizes varying degrees
of infertility.
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.
Natural Cumulative Pregnancy
Rate
1
2
3
4
5
6
7
8
9
10
11
12
24
0
10
20
30
40
50
60
70
80
90
1 2 3 4 5 6 7 8 9 10 11 12 24
% pregnant/month
Months of trying
PREVALENCE Of INFERTILITY
ranges from 12 to 18 %.
women 15 to 34 years (7.3 to
9.1 percent)
 35 to 39 years (25 percent)
40 to 44 years (30 percent).
Causes of Infertility
 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%
Male factor
 1-Endocrine and systemic disorders
(hypogonadotropic hypogonadism)2-5%
 A-Congenital disorders
 Congenital GnRH deficiency (Kallmann
syndrome).
 Multiorgan genetic disorders (Prader-Willi
syndrome, Laurence-Moon-Beidl
syndrome, familial cerebellar ataxia).
 B- Acquired disorders
 A Pituitary and hypothalamic tumors (pituitary
macroadenoma, craniopharyngioma)
 Pituitary and hypothalamic infiltrative disorders
(sarcoidosis, histiocytosis, tuberculosis, fungal
infections)
 Pituitary and hypothalamic lymphocytic
infundibulitis or hypophysitis
 Head trauma, intracranial radiation, or surgery
 Vascular (pituitary infarction, aneurysm)
 Hormonal (hyperprolactinemia, androgen
excess, estrogen excess, cortisol excess)
 Drugs (exogenous androgens, opioids and
psychotropic drugs, GnRH agonists or
antagonists)
 C-Systemic disorders:
 Severe systemic illness,Nutritional
deficiencies,Morbid obesity
2-Primary testicular defects in
spermatogenesis(65 to 80 %)
 A-Congenital disorders;
 Klinefelter syndrome (XXY) and its variants
(XXY/XY; XXXY)
 Cryptorchidism
 Myotonic dystrophy-Functional prepubertal
castrate syndrome (congenital anorchia)
 Androgen insensitivity syndromes-5-alpha-
reductase deficiency-Estrogen receptor or
synthesis disorders
 B-Acquired disorders
 Varicocele
 Infections – Viral orchitis (mumps, echovirus,
arbovirus); granulomatous orchitis (leprosy,
tuberculosis); epididymo-orchitis (gonorrhea,
chlamydia)
 Drugs - Alkylating agents, alcohol,
antiandrogens, ketoconazole, spironolactone,
histamine 2 receptor antagonists, ionizing
radiation
 Environmental toxins - Dibromochloropropane,
carbon disulfide, cadmium, lead, mercury,
environmental estrogens and phytoestrogens;
smoking; hyperthermia
 Immunologic disorders, including polyglandular
autoimmune disease and antisperm antibodies
 Trauma
 Testicular torsion
 C-Systemic illness
 Idiopathic dysspermatogenesis
 Renal failure, hepatic cirrhosis, cancer, sickle
cell disease, amyloidosis, vasculitis, celiac
disease
 D-Genetic causes of dysspermatogenesis
Y chromosome microdeletions and related
disordersAutosomal and X chromosome
defectsMutations causing severe defects in
sperm morphology
 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
 E-Sexual dysfunction:
Infrequent vaginal intercourse, erectile
dysfunction, and premature ejaculation
 F-Idiopathic male infertility(10-20%)
 Male factor ----- 26 %
 ● Ovulatory dysfunction – 21 %
 ● Tubal damage – 14 %
 ● Endometriosis – 6 %
 ● Coital problems – 6 %
 ● Cervical factor – 3 %
 ● Unexplained – 28 %
Female Factors
 Ovulatory disorders ● (25 percent)
 ● Endometriosis (15 percent)
 ● Pelvic adhesions (12 percent)
 ● Tubal blockage (11 percent)
 ● Other tubal abnormalities (11 percent)
 ● Hyperprolactinemia (7 percent)
Female infertility,Prof.Salah Roshdy
1-OVARY
 Ovulatory disorders:
Infrequent ovulation (oligoovulation)
or
absent ovulation (anovulation).
Oocyte aging:
 Ovarian cysts:
An
Anovulation
Hypothalamic
Pituitary
Ovarian
Physiologic
• Adolescence
• Perimenopause
• Lactation
• Pregnancy
Hyperandrogenic
• PCOS
• CAH
• Androgen tumors
Hypothalamic Dysfunction
• Primary hypothalamic
• Anorexia Nervosa
• Extreme exercise
• Hyperprolactinemia
• Thyroid disease
• Primary pituitary disease
• Medications
• Premature ovarian failure
• Iatrogenic (chemo/rad)
Hyperinsulinemic
• PCOS
• DM/Pre-diabetes
• Metabolic syndrome
• Obesity
Endometrial
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
 Kallman's syndromeTumors,
 Trauma, or radiation of the hypothalamic or pituitary area
 Sheehan's syndrome -Empty sella syndrome
 Lymphocytic hypophysitis (autoimmune diseases)
Causes of ovulatory dysfunction
 2-Other disorders:
 Polycystic ovary syndrome
 Hyperthyroidism or hypothyroidism
 Hormone producing tumors (adrenal, ovarian)
 Chronic liver or renal disease
 Cushing's disease-Congenital adrenal
hyperplasia
 Premature ovarian failure, which may be
autoimmune, genetic, surgical ,idiopathic, or
related to drugs or radiation
 Turner syndrome-Androgen insensitivity S.
Causes of ovulatory dysfunction
 3-Medications:
 Estrogen-progestin contraceptives
 Progestins
 Antidepressant and antipsychotic
drugs
 Corticosteroids
 Chemotherapeutic agents
World Health Organization
classification of anovulation
 WHO class 1: Hypogonadotropic
hypogonadal anovulation
(hypothalamic amenorrhea):
 low or low-normal serum (FSH) and
 low serum estradiol concentrations due to
decreased hypothalamic secretion of
(GnRH) or pituitary unresponsiveness to
GnRH.
WHO class 2: Normogonadotropic
normoestrogenic anovulation
 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
oligomenorrhea.
 WHO class 3: Hypergonadotropic
hypoestrogenic anovulation:
The primary causes are premature ovarian
failure (absence of ovarian follicles due to
early menopause) and ovarian resistance
(follicular form).
 Hyperprolactinemic anovulation
Anovulation
LHRH
FSHLH
Hypothalamo-
pituitary
WHO Type 1:
Hypogonadotrophic
Nearly everyone conceives
Anovulation WHO Type 2:
Normogonadotrophic
Most women conceive
Ovarian failure WHO Type 3:
Hypergonadotrophic
Conception remote chance
without donated oocytes
The Clues
Hot flushes
Irregular/absent periods
Short cycle
Amenorrhoea
Weight loss/Exercise/Stress
Drug-induced
Other disease
LHRH
FSHLH
Irregular menses
Weight gain
PCOS signs/symptoms
 NIH Criteria 1990:
 Menstrual irregularity due to
anovulation or oligo-ovulation
 Evidence of clinical or biochemical
hyperandrogenism
 Hirsutism, acne, male pattern baldness
 High serum androgen levels
 Exclusion of other causes (CAH,
tumors, hyperprolactinemia)
 Rotterdam Criteria (2 out of 3)2003:
 Menstrual irregularity due to
anovulation oligo-ovulation
 Evidence of clinical or biochemical
hyperandrogenism
 Polycystic ovaries by US
 presence of 12 or more follicles in each ovary
measuring 2 to 9 mm in diameter and/or increased
ovarian volume.
* In addition, other etiologies (congenital adrenal
hyperplasias, androgen-secreting tumors, Cushing's
syndrome) must be excluded.
 AES criteria 2006:
Presence of three features
 Androgen excess (clinical and/or
biochemical hyperandrogenism)
 Ovarian dysfunction (oligo-anovulation
and/or polycystic ovarian morphology)
 Exclusion of other androgen excess or
ovulatory disorders
Female infertility,Prof.Salah Roshdy
Female infertility,Prof.Salah Roshdy
Polycystic Ovaries Cystic Follicles
Uterus
Tube
Anatomic Features of
the Polycystic Ovary
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.
Oocyte aging
 Other insults to the ovary such as cigarette
smoking, radiation,chemotherapy, and
autoimmune disease also accelerate
follicular loss.
 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
pool.
Oocyte aging
 The loss of oocyte quality as a woman ages is
thought to be due to an increase in meiotic
nondisjunction.
 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.
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
reserve.
2-FALLOPIAN TUBE
ABNORMALITIES/PELVIC ADHESIONS
 Tubal disease and pelvic adhesions
prevent normal transport of the oocyte and
sperm through the fallopian tube.
 PID
 Severe endometriosis
 Previous surgery or nontubal infection (eg,
appendicitis, inflammatory bowel disease),
 Pelvic TB, and salpingitis isthmica nodosa
(ie, diverticulosis of the fallopian tube)
 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
Hydrosalpinx:
 There is good evidence for recommending
 laparoscopic salpingectomyor
 proximal tubal occlusion
 to improve IVF pregnancy rates.
 Treatment of hydrosalpinx before IVF
Negative effect on PR, IR, early pregnancy loss
& LBR. LBR are reduced by 50%
 WHY?
 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
Classification of Tubal disease
 British Fertility Society
 Minor
 Proximal occlusion without tubal fibrosis
 Distal occlusion without tubal distension
 Healthy mucosal appearance at HSG,
salpingoscopy
 Flimsy peritubal/ovarian adhesions.
 Intermediate
 Unilateral severe tubal damage
 Limited dense adhesions of tubes & ovaries
 Severe
 Bilateral severe tubal damage
 Extensive tubal fibrosis
 Tubal distension >1.5 cm
 Abnormal mucosal appearance
 Bipolar occlusion
 Extensive dense adhesion
3-UTERUS
 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
implantation.
Female infertility,Prof.Salah Roshdy
 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
outcome .
 Other structural abnormalities associated with
infertility include endometrial polyps, and
synechiae from prior pregnancyrelated
curettage.
 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
implantation.
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.
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
indicated).
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.
7-UNEXPLAINED
 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.
When To start Workup
( investigations)?
 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
tract malformations.
The Most Important
Factor in the
Evaluation of the
Infertile Couple Is:
History
From: The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance—
challenges and future research opportunities
Hum Reprod Update. 2017;23(6):660-680. doi:10.1093/humupd/dmx021
Hum Reprod Update | © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction
and Embryology.This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the
History-General
 Both couples should be present
 Age
 Previous pregnancies by each partner
 Duration of infertility
 Sexual history
 Frequency and timing of intercourse
 Use of lubricants
 Impotence, dyspareunia
 Contraceptive history
History-Female
 Previous female pelvic surgery
 PID
 Appendicitis
 IUD use
 Ectopic pregnancy history
 Endometriosis
 Leiomyoma
History-Female
 Irregular menses, amenorrhea, detailed
menstrual history
 Molimina
 Vasomotor symptoms
 Changes of hair growth.breast discharge
 Stress
 Weight changes
 Exercise-drug –radiation -chemotherapy
 Cervical and uterine surgery
Physical Exam-Female
 Thyroid exam
 BMI
 Hair distribution
 Galactorrhea
 Scar in the abdomen
 Pelvic masses
 Uterosacral nodularity
 Abdominopelvic tenderness
 Uterine enlargement
 Uterine mobility
 Cervical abnormalities
 Abnormal vaginal discharge
 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.
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
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
Semen Analysis
 The semen sample should be collected
after two to seven days ejaculatory
abstinence.
 If possible, the patient should collect the
sample by masturbation at the doctor's
office. If not possible, then the sample may
be
 collected at home and delivered to the
laboratory within an hour of collection.
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-
46)
 ● Morphology – 4 percent normal forms
(95% CI 34),
Female infertility,Prof.Salah Roshdy
Semen Analysis
 using "strict" Tygerberg method :
 ● Vitality – 58 percent live (95% CI 5563)
 ● Progressive motility – 32 percent (95%
CI 3134)
 ● Total (progressive + nonprogressive)
motility – 40 percent (95% CI 3842)
Female infertility,Prof.Salah Roshdy
2-Assessment of ovulation
 Basal body temperature
 Urine LH kits
 Mid luteal serum progesterone
 Routine hormonal profile: FSH, LH, Prolactin,TSH
 Endometrial biopsy
 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.
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
cycles.
 3. Serum gonadotrophins ( FSH & LH) on
Day2-3 especially in irregular periods.
 (N.B.: No role for basal body temperature
charts)
Further investigations
 Ovarian reserve
 -More important in >35 years old, suspected
ovarian failure and to detect response to
ovulation induction.
 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.
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
reserve.
 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.
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
AFC
 A low AFC ranging from <4 to 10 antral
follicles between days two and four of a
regular menstrual cycle suggests poor
ovarian reserve.
 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
outcome.
Female infertility,Prof.Salah Roshdy
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.
AMH
 Unlike the day 3 FSH, AMH can be
measured anytime during the menstrual
cycle.
 AMH <0.5 ng/mL predicts reduced ovarian
reserve with less than three follicles in an
IVF cycle
 ● AMH <1.0 ng/mL predicts baseline
ovarian reserve with a likelihood of limited
eggs at retrieval.
AMH
 ● 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.
Female infertility,Prof.Salah Roshdy
No evidence for:
 - ovarian volume
 - ovarian blood flow
 - inhibin B
 -estradiol (E2)
3-Investigations of tubal factor
 Hysterosalpingography (HSG)
 Hysterosalpingo-contrast sonography
(HyCoSy)
 Laparoscopy with chromotubation
 Hydrolaparoscopy.
 Fluoroscopic/hysteroscopic-
selective tubal cannulation.
 Falloscopy
Assessment of the uterine cavity
 Modalities to assess the uterine cavity
include :
 Saline Infusion Sono-
hysterography (SIS)
 Three dimensional sonography
 Hysterosalpingography (HSG)
 Hysteroscopy
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).
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
 Superovulationwith IUI
 IVF.
Indications
 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,
 2.Ectopic pregnancy.
 3.Pelvic surgery.
 4.Chronic pelvic pain
 .5 current dysmenorrhea, pelvic pain, or deep
dyspareunia; previous complicated appendicitis
 3. Three cycles of super ovulation with IUI are
unsuccessful.
 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.
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
2011).
TESTS OF LIMITED CLINICAL
UTILITY
 PCT for assessment of the cervical factor.
 Chlamydia trachomatis antibodies .
 Endometrial biopsy
 Basal body temperature records
 Zonafree hamster oocyte penetration test
 Mycoplasma cultures
 Testing for antibodies; antiphospholipid, antisperm,
antinuclear, and antithyroid antibodies.
 Karyotype
The basic infertility evaluation of
all couples consists of:
 Semen analysis
 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
failure.
Controversies
 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
diagnosis ?
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)”
February 2004
Grading – Evidence Based Recommendations
A
recommendation
I evidence
B
recommendation
II evidence
C
recommendation
III evidence
D
recommendation
IV evidence
I a- meta-analysis
of RCTs trials,
I b- at least one
RCT.
II a - at least one
controlled study
without
randomization
II b - at least one
other type of
quasi-
experimental
study
non-experimental
descriptive
studies, such as
comparative
studies,
correlation
studies and case
control studies
from expert
committee reports
or opinions and/or
clinical experience
of respected
authorities
• 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.
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)
What To Do if Semen analysis Is
Abnormal?
 Repeat confirmatory test ( 3 months after
the initial analysis & ttt). (Grade B).
 If azoospermia or severe oligozoospermia ,
repeat test as soon as possible. (GPP)
Where & When Testicular Biopsy
(TB) be done In Azoospermia?
TB should be performed only in a
tertiary service where there are
facilities for
 Sperm recovery ,
 Cryopreservation and
 ART( C )
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)
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.
(Grade B)
 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.
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.
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)
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)
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).
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
(Grade B).
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)
Assessment of tubal factor
 Where appropriate expertise is available,
screening for tubal occlusion using
hysterosalpingo-contrast-ultrasonography
should be considered because it is an
effective alternative to HSG for women
who are not known to have co-morbidities
(Grade A)
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)
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.
HSG should
be
performed
Under
Fluoroscopy
( Grade :D)
Removal of the
speculum
before
scanning
Application of
traction by the
tenaculum during
filling of the uterus
often results in
improved uterine
visualization.
. A complete view
of the
endometrial
cavity and
cervical canal
should be the
aim.
Grade D
Flushing of the tubes with oil-soluble
media increases subsequent
pregnancy rates (It may flush tubal
"plugs" ).
The Cochrane Library, Issue 2 2004.
Oil-soluble # Water Soluble Media for HSG
Sonohysterography # HSG?
The use of sonohysterography
should be considered as an
effective alternative to HSG
(Grade A).
 TVS can add evaluation of pelvis.
Unnecessary laparoscopy!!!
 It is not cost effective to do
diagnostic laparoscopy as part of
the initial infertility evaluation
when:
History, and physical examination,
TVS, HSG, and Midluteal progesterone
are all normal (Grade B)
Female infertility,Prof.Salah Roshdy
When To Do Laparoscopy For tubal
evaluation?
 When associated pelvic co
morbidities (PID, previous Ectopic,
endometriosis ..etc) :evaluation of the
pelvis is required.
(Grade B)
Hysteroscopy has NO
role in routine
evaluation
of infertility
Female infertility,Prof.Salah Roshdy
Indications of Hysteroscopy as workup of
infertility?
 Abnormal HSG
 When Laparoscopy is indicated as in
Unexplained infertility ?
 Before IVF in cases of
unexplained infertility ?!!!!
 After Failed IVF ?
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
…)
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
HCG).
6. Extensive endometriosis.
7. Need for cryopreservation of semen.
8. Non optimized office.
Female infertility,Prof.Salah Roshdy
Questions?
1 von 126

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Female infertility,Prof.Salah Roshdy

  • 1. Female Infertility Prof.Salah Roshdy,MD Prof. of Obstetrics & Gynecology Sohag University 2018
  • 2. Objectives  know definitions of primary and secondary infertility  • understand the causes of infertility  • know the initial investigations of the infertile couple  Investigate male factor  • Test for ovulation  • Test for tubal patency  • Investigation role of laparoscopy and hysteroscopy
  • 3. INTRODUCTION  Infertility is a common condition with important psychologic, economic, demographic, and medical implications.  Infertility is a unique medical condition because it involves a couple, rather than a single individual  Demand for infertility services has grown substantially even though the prevalence of infertility has been stable.
  • 4. DEFINITIONS  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 unprotected intercourse.
  • 6. Secondary infertility Secondary infertility describes couples who have previously been pregnant at least once, but have not been able to achieve another pregnancy.
  • 7. Fecundability the probability of achieving a pregnancy in one menstrual cycle, is a more accurate descriptor because it recognizes varying degrees of infertility.
  • 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.
  • 9. Natural Cumulative Pregnancy Rate 1 2 3 4 5 6 7 8 9 10 11 12 24 0 10 20 30 40 50 60 70 80 90 1 2 3 4 5 6 7 8 9 10 11 12 24 % pregnant/month Months of trying
  • 10. PREVALENCE Of INFERTILITY ranges from 12 to 18 %. women 15 to 34 years (7.3 to 9.1 percent)  35 to 39 years (25 percent) 40 to 44 years (30 percent).
  • 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%
  • 13. Male factor  1-Endocrine and systemic disorders (hypogonadotropic hypogonadism)2-5%  A-Congenital disorders  Congenital GnRH deficiency (Kallmann syndrome).  Multiorgan genetic disorders (Prader-Willi syndrome, Laurence-Moon-Beidl syndrome, familial cerebellar ataxia).
  • 14.  B- Acquired disorders  A Pituitary and hypothalamic tumors (pituitary macroadenoma, craniopharyngioma)  Pituitary and hypothalamic infiltrative disorders (sarcoidosis, histiocytosis, tuberculosis, fungal infections)  Pituitary and hypothalamic lymphocytic infundibulitis or hypophysitis  Head trauma, intracranial radiation, or surgery
  • 15.  Vascular (pituitary infarction, aneurysm)  Hormonal (hyperprolactinemia, androgen excess, estrogen excess, cortisol excess)  Drugs (exogenous androgens, opioids and psychotropic drugs, GnRH agonists or antagonists)  C-Systemic disorders:  Severe systemic illness,Nutritional deficiencies,Morbid obesity
  • 16. 2-Primary testicular defects in spermatogenesis(65 to 80 %)  A-Congenital disorders;  Klinefelter syndrome (XXY) and its variants (XXY/XY; XXXY)  Cryptorchidism  Myotonic dystrophy-Functional prepubertal castrate syndrome (congenital anorchia)  Androgen insensitivity syndromes-5-alpha- reductase deficiency-Estrogen receptor or synthesis disorders
  • 17.  B-Acquired disorders  Varicocele  Infections – Viral orchitis (mumps, echovirus, arbovirus); granulomatous orchitis (leprosy, tuberculosis); epididymo-orchitis (gonorrhea, chlamydia)  Drugs - Alkylating agents, alcohol, antiandrogens, ketoconazole, spironolactone, histamine 2 receptor antagonists, ionizing radiation
  • 18.  Environmental toxins - Dibromochloropropane, carbon disulfide, cadmium, lead, mercury, environmental estrogens and phytoestrogens; smoking; hyperthermia  Immunologic disorders, including polyglandular autoimmune disease and antisperm antibodies  Trauma  Testicular torsion
  • 19.  C-Systemic illness  Idiopathic dysspermatogenesis  Renal failure, hepatic cirrhosis, cancer, sickle cell disease, amyloidosis, vasculitis, celiac disease  D-Genetic causes of dysspermatogenesis Y chromosome microdeletions and related disordersAutosomal and X chromosome defectsMutations causing severe defects in sperm morphology
  • 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  E-Sexual dysfunction: Infrequent vaginal intercourse, erectile dysfunction, and premature ejaculation  F-Idiopathic male infertility(10-20%)
  • 21.  Male factor ----- 26 %  ● Ovulatory dysfunction – 21 %  ● Tubal damage – 14 %  ● Endometriosis – 6 %  ● Coital problems – 6 %  ● Cervical factor – 3 %  ● Unexplained – 28 %
  • 23.  Ovulatory disorders ● (25 percent)  ● Endometriosis (15 percent)  ● Pelvic adhesions (12 percent)  ● Tubal blockage (11 percent)  ● Other tubal abnormalities (11 percent)  ● Hyperprolactinemia (7 percent)
  • 25. 1-OVARY  Ovulatory disorders: Infrequent ovulation (oligoovulation) or absent ovulation (anovulation). Oocyte aging:  Ovarian cysts:
  • 26. An Anovulation Hypothalamic Pituitary Ovarian Physiologic • Adolescence • Perimenopause • Lactation • Pregnancy Hyperandrogenic • PCOS • CAH • Androgen tumors Hypothalamic Dysfunction • Primary hypothalamic • Anorexia Nervosa • Extreme exercise • Hyperprolactinemia • Thyroid disease • Primary pituitary disease • Medications • Premature ovarian failure • Iatrogenic (chemo/rad) Hyperinsulinemic • PCOS • DM/Pre-diabetes • Metabolic syndrome • Obesity Endometrial
  • 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  Kallman's syndromeTumors,  Trauma, or radiation of the hypothalamic or pituitary area  Sheehan's syndrome -Empty sella syndrome  Lymphocytic hypophysitis (autoimmune diseases)
  • 28. Causes of ovulatory dysfunction  2-Other disorders:  Polycystic ovary syndrome  Hyperthyroidism or hypothyroidism  Hormone producing tumors (adrenal, ovarian)  Chronic liver or renal disease  Cushing's disease-Congenital adrenal hyperplasia  Premature ovarian failure, which may be autoimmune, genetic, surgical ,idiopathic, or related to drugs or radiation  Turner syndrome-Androgen insensitivity S.
  • 29. Causes of ovulatory dysfunction  3-Medications:  Estrogen-progestin contraceptives  Progestins  Antidepressant and antipsychotic drugs  Corticosteroids  Chemotherapeutic agents
  • 30. World Health Organization classification of anovulation  WHO class 1: Hypogonadotropic hypogonadal anovulation (hypothalamic amenorrhea):  low or low-normal serum (FSH) and  low serum estradiol concentrations due to decreased hypothalamic secretion of (GnRH) or pituitary unresponsiveness to GnRH.
  • 31. WHO class 2: Normogonadotropic normoestrogenic anovulation  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 oligomenorrhea.
  • 32.  WHO class 3: Hypergonadotropic hypoestrogenic anovulation: The primary causes are premature ovarian failure (absence of ovarian follicles due to early menopause) and ovarian resistance (follicular form).  Hyperprolactinemic anovulation
  • 33. Anovulation LHRH FSHLH Hypothalamo- pituitary WHO Type 1: Hypogonadotrophic Nearly everyone conceives Anovulation WHO Type 2: Normogonadotrophic Most women conceive Ovarian failure WHO Type 3: Hypergonadotrophic Conception remote chance without donated oocytes
  • 34. The Clues Hot flushes Irregular/absent periods Short cycle Amenorrhoea Weight loss/Exercise/Stress Drug-induced Other disease LHRH FSHLH Irregular menses Weight gain PCOS signs/symptoms
  • 35.  NIH Criteria 1990:  Menstrual irregularity due to anovulation or oligo-ovulation  Evidence of clinical or biochemical hyperandrogenism  Hirsutism, acne, male pattern baldness  High serum androgen levels  Exclusion of other causes (CAH, tumors, hyperprolactinemia)
  • 36.  Rotterdam Criteria (2 out of 3)2003:  Menstrual irregularity due to anovulation oligo-ovulation  Evidence of clinical or biochemical hyperandrogenism  Polycystic ovaries by US  presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume. * 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 biochemical hyperandrogenism)  Ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology)  Exclusion of other androgen excess or ovulatory disorders
  • 40. Polycystic Ovaries Cystic Follicles Uterus Tube Anatomic Features of the Polycystic Ovary
  • 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 follicular loss.  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 pool.
  • 43. Oocyte aging  The loss of oocyte quality as a woman ages is thought to be due to an increase in meiotic nondisjunction.  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 reserve.
  • 45. 2-FALLOPIAN TUBE ABNORMALITIES/PELVIC ADHESIONS  Tubal disease and pelvic adhesions prevent normal transport of the oocyte and sperm through the fallopian tube.  PID  Severe endometriosis  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
  • 47. Hydrosalpinx:  There is good evidence for recommending  laparoscopic salpingectomyor  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%  WHY?  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  Minor  Proximal occlusion without tubal fibrosis  Distal occlusion without tubal distension  Healthy mucosal appearance at HSG, salpingoscopy  Flimsy peritubal/ovarian adhesions.
  • 50.  Intermediate  Unilateral severe tubal damage  Limited dense adhesions of tubes & ovaries  Severe  Bilateral severe tubal damage  Extensive tubal fibrosis  Tubal distension >1.5 cm  Abnormal mucosal appearance  Bipolar occlusion  Extensive dense adhesion
  • 51. 3-UTERUS  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 implantation.
  • 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 outcome .  Other structural abnormalities associated with infertility include endometrial polyps, and synechiae from prior pregnancyrelated curettage.
  • 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 implantation.
  • 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 indicated).
  • 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.
  • 58. 7-UNEXPLAINED  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 ( investigations)?  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 tract malformations.
  • 60. The Most Important Factor in the Evaluation of the Infertile Couple Is: History
  • 61. From: The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance— challenges and future research opportunities Hum Reprod Update. 2017;23(6):660-680. doi:10.1093/humupd/dmx021 Hum Reprod Update | © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the
  • 62. History-General  Both couples should be present  Age  Previous pregnancies by each partner  Duration of infertility  Sexual history  Frequency and timing of intercourse  Use of lubricants  Impotence, dyspareunia  Contraceptive history
  • 63. History-Female  Previous female pelvic surgery  PID  Appendicitis  IUD use  Ectopic pregnancy history  Endometriosis  Leiomyoma
  • 64. History-Female  Irregular menses, amenorrhea, detailed menstrual history  Molimina  Vasomotor symptoms  Changes of hair growth.breast discharge  Stress  Weight changes  Exercise-drug –radiation -chemotherapy  Cervical and uterine surgery
  • 65. Physical Exam-Female  Thyroid exam  BMI  Hair distribution  Galactorrhea  Scar in the abdomen  Pelvic masses  Uterosacral nodularity  Abdominopelvic tenderness  Uterine enlargement  Uterine mobility  Cervical abnormalities  Abnormal vaginal discharge
  • 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 abstinence.  If possible, the patient should collect the sample by masturbation at the doctor's office. If not possible, then the sample may be  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- 46)  ● 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% CI 3134)  ● 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  Endometrial biopsy  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 cycles.  3. Serum gonadotrophins ( FSH & LH) on Day2-3 especially in irregular periods.  (N.B.: No role for basal body temperature charts)
  • 76. Further investigations  Ovarian reserve  -More important in >35 years old, suspected ovarian failure and to detect response to ovulation induction.  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 reserve.  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
  • 79. AFC  A low AFC ranging from <4 to 10 antral follicles between days two and four of a regular menstrual cycle suggests poor ovarian reserve.  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 outcome.
  • 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.
  • 82. AMH  Unlike the day 3 FSH, AMH can be measured anytime during the menstrual cycle.  AMH <0.5 ng/mL predicts reduced ovarian reserve with less than three follicles in an IVF cycle  ● AMH <1.0 ng/mL predicts baseline ovarian reserve with a likelihood of limited eggs at retrieval.
  • 83. AMH  ● 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.
  • 85. No evidence for:  - ovarian volume  - ovarian blood flow  - inhibin B  -estradiol (E2)
  • 86. 3-Investigations of tubal factor  Hysterosalpingography (HSG)  Hysterosalpingo-contrast sonography (HyCoSy)  Laparoscopy with chromotubation  Hydrolaparoscopy.  Fluoroscopic/hysteroscopic- selective tubal cannulation.  Falloscopy
  • 87. Assessment of the uterine cavity  Modalities to assess the uterine cavity include :  Saline Infusion Sono- hysterography (SIS)  Three dimensional sonography  Hysterosalpingography (HSG)  Hysteroscopy
  • 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  Superovulationwith IUI  IVF.
  • 90. Indications  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,  2.Ectopic pregnancy.  3.Pelvic surgery.  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 unsuccessful.  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 2011).
  • 93. TESTS OF LIMITED CLINICAL UTILITY  PCT for assessment of the cervical factor.  Chlamydia trachomatis antibodies .  Endometrial biopsy  Basal body temperature records  Zonafree hamster oocyte penetration test  Mycoplasma cultures  Testing for antibodies; antiphospholipid, antisperm, antinuclear, and antithyroid antibodies.  Karyotype
  • 94. The basic infertility evaluation of all couples consists of:  Semen analysis  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 failure.
  • 95. Controversies  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 diagnosis ?
  • 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)” February 2004
  • 97. Grading – Evidence Based Recommendations A recommendation I evidence B recommendation II evidence C recommendation III evidence D recommendation IV evidence I a- meta-analysis of RCTs trials, I b- at least one RCT. II a - at least one controlled study without randomization II b - at least one other type of quasi- experimental study non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies from expert committee reports or opinions and/or clinical experience of respected authorities • 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 Abnormal?  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 facilities for  Sperm recovery ,  Cryopreservation and  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. (Grade B)
  • 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 (Grade B).
  • 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 hysterosalpingo-contrast-ultrasonography should be considered because it is an effective alternative to HSG for women who are not known to have co-morbidities (Grade A)
  • 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.
  • 114. Removal of the speculum before scanning Application of traction by the tenaculum during filling of the uterus often results in improved uterine visualization. . A complete view of the endometrial cavity and cervical canal should be the aim. Grade D
  • 115. Flushing of the tubes with oil-soluble media increases subsequent pregnancy rates (It may flush tubal "plugs" ). 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 (Grade A).  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 when: History, and physical examination, TVS, HSG, and Midluteal progesterone are all normal (Grade B)
  • 119. When To Do Laparoscopy For tubal evaluation?  When associated pelvic co morbidities (PID, previous Ectopic, endometriosis ..etc) :evaluation of the pelvis is required. (Grade B)
  • 120. Hysteroscopy has NO role in routine evaluation of infertility
  • 122. Indications of Hysteroscopy as workup of infertility?  Abnormal HSG  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 HCG). 6. Extensive endometriosis. 7. Need for cryopreservation of semen. 8. Non optimized office.

Hinweis der Redaktion

  1. Ovulation Disorders: Aging Diminished ovarian reserve Endocrine Disorder Polycystic Ovary Syndrome (PCOS) Tobacco Use Premature Ovarian Failure Tubal Factors: Obstruction History of Pelvic Inflammatory Disease (PID) Tubal Surgery Previous ectopic and salpingectomy Uterine/Cervical Factors: Congenital uterine anomaly Fibroids Polyps Poor cervical mucus quantity/quality Smoking Infection Uterine synechiae
  2. 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.