Management of infertility

Benha University
Hospital, Egypt

When to refer a couple for
investigations?
After 40 y
Immediate evaluation in women.
35-40 Y
After 6 months of unprotected intercourse without
conception
<35 y
After one year
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Incidence
1 in 7 couples
Main causes
Male factors: 30%
Female: 45%
• Tubal: 20%
• Ovulatory disorders: 25%
• Uterine: 10%
• Endometriosis: 5%
Unexplained: 25%
Combined male and female: 40%
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Investigations
(ESHRE, 2000)
I. Tests that have an established association
with pregnancy:
Conventional semen analysis
HSG
Midluteal progesterone
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II. Tests that are not consistently associated
with pregnancy:
Post-coital test
Antisperm antibody tests
Zona-free hamster egg penetration test
III. Tests that have no association with
pregnancy:
Endometrial biopsy
Varicocele assessment
Chlamydia testing
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1. Male factor
infertility
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I. STANDARD SEMEN
ANALYSIS
IV. GENETIC TESTS
1. Karyotyping
2. Y chromosome
microdeletions
3. Cystic fibrosis
conductance regulator
(CFTR) gene mutation
II. SPECIALIZED
SEMEN ANALYSIS
1. Sperm
autoantibodies
2. Semen Fructose
3. Semen culture
4. Sperm function
tests
CASA
SDNAF
III. ENDOCRINE TESTS
1. T
2. LH and FSH
3. Prolactin
INVESTIGATIONS

 Semen analysis: WHO, 2010
:
:
Lower reference limitParameter
1.5 mlVolume
7.2pH
15 million/mlConcentration
39 million/ejaculateTotal sperm number
40% or
PR: 32%
Total motility: (PR+NP)
58% live spermatozoaVitality
4% (strict criteria).Normal forms
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Other consensus threshold values
Peroxidase-positive leukocytes (106/ml)
<1.0
MAR test (motile spermatozoa with bound
particles, %) <50
Immunobead test (motile spermatozoa with
bound beads, %) <50
Seminal zinc (ųmol/ejaculate) ≥2.4
Seminal fructose (ųmol/ejaculate) ≥13
Seminal neutral glucosidase (mU/ejaculate) ≥20
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o Antisperm antibodies
should not be offered
{no evidence of effective treatment}.
• If first semen analysis is abnormal:
repeat 3 months later
{allow time for the cycle of spermatozoa formation to be
completed}
a single-sample analysis will falsely identify about 10%
of men as abnormal, but repeating the test reduces
this to 2%
• if a gross spermatozoa deficiency (azoospermia or
severe oligozoospermia):
repeat as soon as possible
• Post-coital testing:
not recommend {no predictive value on pregnancy rate}Aboubakr Elnashar

TREATMENT
• Hypogonadotrophic hypogonadism: gonadotrophin
drugs {effective}
• Idiopathic semen abnormalities:
No anti-oestrogens, gonadotrophins, androgens, or
bromocriptine {not effective]
• Leucocytes in semen:
No antibiotic treatment unless there is an identified
infection {no evidence that this improves pregnancy
rates]
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Obstructive azoospermia
Diagnosis:
Azoospermia or severe oligospermia +
normal size testis
normal FSH
normal testicular histology.
Surgical correction of epididymal blockage, IF
Experience [likely to restore patency of the duct
and improve fertility}.
ABOUBAKR ELNASHAR

Varicocele:
(AUA&ASRM, 2004 & AFU, 2006)
Imaging examinations: not indicated to
characterize the varicocele.
TT when all of the following conditions are
present:
1. Varicocele: Palpable
2. Semen: Abnormal (at least one abnormality)
3. Couple's infertility: Documented
4. Female infertility problem: Curable

Indications of IUI:
Mild male factor infertility
 up to 6 cycles of IUI
(NICE, 2004; ESHRE Capri Workshop, 2009)
 No IUI, Advise them to try to conceive for a total of
2y (including up to 1y before their fertility
investigations) before IVF will be considered.
Exceptions: Social, Cultural, Religious
(NICE, 2013)

Indications of ICSI
(NICE, 2004; 2014)
1.Severe deficits in semen quality
2.Obstructive azoospermia
3.Non-obstructive azoospermia
5. Mild deficits in semen quality (high resource)
4. Previous IVF cycle with failed or very poor fertilizationa)
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Abnormal semen
ICSI
Palpable varicocele: Varicoceletomy
low FSH &T: Hormonal TT.
Infection: TT ?
Mild
Moderate, Severe
or
Azoospermia
Low Resources
3 trial IUI
H. Resources

INVESTIGATIONS
1. HSG
No co morbidities:
PID
Previous ectopic pregnancy or
Endometriosis
{reliable test for ruling out tubal occlusion
less invasive}
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HS-contrast-US
experience
effective alternative to HSG
Prophylactic antibiotics
before uterine instrumentation if screening for CT
has not been carried out.
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HS-contrast-US
Free fluid collection in the cul-de-sac following
successful demonstration of oviductal patency.
Oviductal fimbria are clearly observed in the collected
fluid.
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2. Laparoscopy and dye test
Co morbidities
{tubal and other pelvic pathology can be assessed
at the same time}.
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3. Hysteroscopy
Not an initial investigation unless clinically indicated
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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
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Hydrosalpinx
well-constrained fluid
accumulation in the adnexae.
In some cases, adhesions
between the oviduct and ovary
may be visualized.
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TREATMENT
I. IVF:
1. Moderate to severe tubal disease
2. Other factors e.g
A. Sperm abnormality
B. Age >36 yr
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Hydrosalpinges
Salpingectomy
Tubal occlusion
{improves the chance of a live birth}.
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II. Laparoscopic surgery:
mild tubal disease
appropriate expertise
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III. Selective salpingography plus tubal
catheterisation, or hysteroscopic tubal
cannulation
Proximal tubal disease
If pregnancy has not occurred within 12 mo:
IVF
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INVESTIGATIONS
1. Midluteal progesterone
{confirm ovulation}
In irregular prolonged cycles
Depending upon the timing of menstrual periods, conducted later in
the cycle (for example day 28 of a 35-day cycle) and repeated
weekly thereafter until the next menstrual cycle starts
2. Basal FSH and LH
• Only in
irregular prolonged cycles
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3. Prolactin
Only in
ovulatory disorder
galactorrhoea
pituitary tumour
4. TSH:
only if
symptoms of thyroid disease
Endometrial biopsy
To evaluate the luteal phase: No
{no evidence that medical tt of luteal phase defect
improves PR]
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5. ORT
Indications
≥ 35 ys
< 35 ys
Endometriosis
Unexplained infertility
Single ovary
Previous ovarian surgery
Poor response to FSH
Previous exposure to chemotherapy or
radiation
(Iii-b) SOGC, 2011
ABOUBAKR ELNASHAR

High responseLow response
16 or more4 or lessTotal AFC
3.5 or more
25
0.8 or less
5.5
AMH
ng/ml
pmol/l
Conversion ratio:7
4 or less8.9 or moreFSH IU/L
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Do not use
1. ovarian volume
2. ovarian blood flow
3. inhibin B
4. E2

Anovulation
% Type Hormonal profile
5-10%
WHO type I
(Hypogonadotropic
Hypoestrogenic)
E2
FSH
75-80%
WHO type II
Normogenadotrophic
Normoestrogenic
Normal E2
Normal FSH
10-20%
WHO type III
(Hypergonadotropic
Hypoestrogenic)
E2
FSH
5-10%
WHO type IV
(Hyperprolactinemia) prolactin
WHO Scientific group, Geneva 1976, Report
514, Rowe et al, 1993

I. Hypothalamic pituitary failure
Amenorrhea or severe oligomenorrhea
FSH & LH: low
Prolactin: normal
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1. Reverse the life style factors:
Increase wt if BMI <19
Moderating exercise if high levels of
exercise.
Treat stress
2. Gnt with LH activity or
Pulsatile GnRH (pump)
 CC:
not effective
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• NI (1990)
 Chronic anovulation.
 Cl and/or biochemical
hyperandrogenism.
Rotterdam (2003)
2 out of 3
 Ch anovulation.
hyperandrogenism.
 PCO on US
AES (2006)
AE-PCOS(2009)
hyperandrogenism.
 Ovarian dysfunction
(anovulation and/or
PCO)
 Exclusion of related ovulatory or other androgen excess
disorders (e.g., thyroid dysfunction, hyperprolactinemia,
androgen-secreting neoplasms, or non classic adrenal
hyperplasia)
8% 18% 12%
Prevalence of PCOS

PCO on ultrasound
Criteria of polycystic ovarian morphology
12 or more follicles, 2 - 9
mm in diameter and/or
Ovarian volume >10 cm3.

Wt reduction
CC
Obese &overweight
Normal weight &No wt loss & No ovulation
LODGnT
No ovulation after 3 cycles.
No pregnancy after 6 cycles.
No pregnancy
after 6 cycles.
No pregnancy after spontaneous,
CC or GnT ovulation
ICSI
Other surgical indication
Difficult follow up
Less aggressive
No desire for
surgery
Add metformin
IGT &IR

III. Hypergonadotropic hypoestrogenic
< 40 yr, 2ndry amenorrhea
Repeated FSH > 20 IU/L
Causes
1. Idiopathic.
2. Genetic.
3. Autoimmune
3. Viral/bacterial infection
4. Pelvic surgery, chemotherapy
5. Galactosemia
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POF.
Only the stroma of the ovary is identified.
A very few follicles ≤1 mm on the inferior aspect of the ovary.
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1. Oral contraceptive suppression of Gnt followed by
discontinuation {allow a rebound in Gnt & ovarian
function}.
2. GnRHa suppression of Gnt secretion followed by
high dose Gnt injection
3. Glucocorticoids suppression of immune system.
Non of these tts has demonstrated efficacy in RCT
(van Kastren et al, 1995)
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IV. Hyperprolactinaemia
I. Idiopathic
.Dopamine agonist (anxiety, pregnancy ).
Stop during pregnancy
II. Microadenoma
. Dopamine agonist (anxiety, pregnancy).
Stop after 2-3 yr.
. Surgery (rapid growth).
III. Macroadenoma
. Dopamine agonist: long term
. Surgery
(No response, suprasellar extension, pregnancy).

INVESTIGATIONS
1. HSG
2. TVS
3. SIS
1. 3DUS
2. MRI
3. hysteroscopy.

1. Uterine myoma
FIGO classification: SM: submucous
O: Other
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Myomectomy:
-Indications:
1. Distorting the uterine cavity
 Submucous:
interfere with fertility and should be removed in infertile
patients, regardless of the size or presence of symptoms
(Gambadauro,2012).
 Intramural:
distorting: reduce the chances of conception
not distorting: controversial results.
 Subserosal:
No evidence supports removal in asymptomatic, infertile
3. >5-7cm
4. Multiple >3 (3-5 cm)
(Bajekal & Li, 2000)
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Intramural fibroid
Examples of fibroids which
compromise the contours of the
endometrial cavity.
Refraction artifacts {tissue
density interfaces and the
texture of the fibroids} often aid
in their identification.
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CAVITY
Distorted
Not distorted
SIZE
≥5 cm ≤5 cm
NUMBER(3-5cm)
≥3 ≤3

2. Septate uterus
Not increased among women with infertility
compared with other women (2–3%).
More common: RM or PTL.
Hysteroscopic metroplasty:
[Evidence level 2b–3]
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3. Intrauterine adhesions
with amenorrhoea
hysteroscopic adhesiolysis
{restore menstruation and improve the chance
of pregnancy}. (C)
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IU adhesions
Bright (hyperechoic) uterine lining - scar tissue in uterine
cavity
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4. Endometrial polyp
Indications of polypectomy
1. Prior to infertility tt
{absence of sufficient data on the effect of polyps
on PR
negative impact of submucosal myomas or
myoma - associated cavity distortion on PR}
2. High risk for endometrial hyperplasia
chronic anovulation
obesity, or
personal history of endometrial hyperplasia.

5. Adenomyosis associated infertility
Conservative tt:
hormone therapy
vessel embolization
Combined surgical and hormonal tts
Successful pregnancies have been reported
for women treated with:
1. GnRHa (depot leuprolide acetate 3.75 mg/4 w
for 24w)
2. Microsurgical resection of adenomyosis followed
by GnRHa.

Inability to conceive after one year with
routine (standard, basic) investigations of
infertility showing no abnormality.
(RCOG guidelines,1998; Randolph,2000)
Dependent on:
Availability of resources
Patients’ age
Duration of infertility.
IUI:
ESHRE (2004)
indicated as empiric treatment
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Protocol for Management
(Ray et al, 2012)

 Cochrane (2012)
• IUI with superovulation increases LBR compared
to IUI alone.
• PR was increased with IUI compared to TI in
stimulated cycles
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• NICE, 2013
 Do not offer oral ovarian stimulation agents
(CC, or letrozole).
{no increase PR or a live birth}.
 Offer IVF after 2 years
 IUI:
 when social, cultural or religious objections to
IVF
without stimulation: no better than EM
with stimulation: better than EM
Aboubakr Elnashar

Benha University Hospital, Egypt
E-mail: elnashar53@hotmail.com
Aboubakr Elnashar
https://www.facebook.com/groups/22774488
4091351/
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OVULATION INDUCTION IN PCOS
NICE, 2013
1. Weigh loss:
If BMI >30 K/m2
 alone may restore ovulation
 improve response to ovulation induction agents,
 positive impact on pregnancy outcomes
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2. One of the following taking into account
•potential adverse effects
•ease and mode of use
•BMI
•monitoring needed:
CC: (not more than 6 m) or
Metformin or
CC + Metformin
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3. CC resistance:
one of the following 2nd line tt, depending on
•clinical circumstances
•woman's preference:
CC and met if not already offered as1st line tt or
LOD or
Gnt
US monitoring
{measure follicular size and number {reduce the risk
of multiple pregnancy and OHSS}
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Infertility workup
1. Ovarian reserve 2. Semen
analysis
3. F tubes
Compromised:
IVF
Not compromised: surgery
Allow 6-18 month
No pregnancy: IVF
No surgery before IVF
except:
Large endometrioma ,
hydrosalpinx,
pelvic pain
de Ziegler et al, 2010Aboubakr Elnashar

I. Minimal and mild
(Aboulghar,2003):
• Medical tt does not enhance fertility &
should not be offered
• Expectant treatment.
• ±COH/IUI.
• Surgical ablation*
• IVF.
*Minimal or mild endometriosis who undergo
laparoscopy should be offered surgical
ablation or resection of endometriosis
plus laparoscopic adhesiolysis
• {improves the chance of pregnancy}.
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II. Moderate & severe
• IVF:
Treatment of choice (Aboulghar, 2003).
• Postoperative medical tt
does not improve PR & not recommended
Moderate or severe:
surgical tt {improves the chance of pregnancy}.
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• Endometrioma:
Laparoscopic cystectomy
{improves the chance of pregnancy}
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A. Open myomectomy
(Bajekal & Li, 2000)
The route of choice:
Large SS or IM(>7 cm)
Multiple fibroids (>5)
When entry into uterine cavity is to be
expected
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B. Hysteroscopic myomectomy:
The route of choice:
SM fibroids.
Compared to laparotomy, it is associated with a
lower risk of scar rupture & no pelvic
adhesion (Bajekal & Li, 2000)
Large (>5 cm) type II SM fibroids may be
unsuitable for hysteroscopic surgery.
A significant benefit of removing SM fibroid
>2cm (Varasteh et al, 1999)Aboubakr Elnashar

C. Laparoscopic myomectomy:
 Pedunculated or SS: not candidate for removal {not
the cause of infertility or recurrent miscarriage}
(Bajekal & Li, 2000).
IM:
 Very experienced laparoscopic surgeon
 Uterine rupture: 2 reports both at 34 w
{inability to effectively close the myometrium
laparoscopically}
Uterine indentation
Uterine fistula Aboubakr Elnashar

Management of infertility

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Management of infertility