unexplained infertility

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unexplained infertility
Update on management of
Prof. Aboubakr Elnashar
Benha University Hospital, EGYPT
E-mail elnashar53_at_hotmail.com
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Definition Inability to conceive after one year
with routine (standard, basic) investigations of
infertility showing no abnormality. (RCOG
guidelines,1998 Randolph,2000)
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Prevalence Depend on Evaluation protocol
Referral pattern,
Interpretation of diagnostic
studies 10-20
(Balen,2003) Decreasing (Collins
Crosignani,1992)
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Effect of unexplained infertility on
psychosexual function Depression or history of
depression were significantly higher in women
with unexplained infertility than in the control
group (Meller et al, 2002) Unexplained
infertility prolonged mutual agony sexual
dysfunction . Recognition of the cause of
infertility acceptance of childlessness return
to normal sexual behavior.
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• CAUSES
• It is possible to draw long list of putative
  subtle causes of infertility,
• Many are uncertain
• Many have been found in couples of normal
  fertility.
• Few are actually treatable (Balen,2003) .

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I. Ovarian endocrine factors 1. Abnormal
follicle growth 2. Lutenized unruptured
follicle 3. Hypersecretion of LH. 4.
Hypersecretion of prolactin in the presence of
ovulation 5. Reduced growth hormone
secretion/sensitivity 6. Cytologic abnormalities
of in oocytes. 7. Genetic abnormalities in
oocytes 8. Antibodies to zona pellucida

• Putative
• Subtle
• Uncertain
• Found in fertile couples

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II. Peritoneal factors. 1. Altered macrophage
immune activities. 2. Mild endometriosis 3.
Antichlamydial antibodies III.Tubal factors 1.
Abnormal peristalsis or cilial activity 2.
Altered macrophage immune activity

• Putative
• Subtle
• Uncertain
• Found in fertile couples

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IV. Endometrial factors 1. Abnormal secretion of
endometrial proteins 2. Abnomal integrin/adhesion
molecule 3. Abnormal T cell natural killer cell
activity. 4. Secretion of embyotoxic factors 5.
Abnormalities in uterine perfusion V. Cervical
factors 1. Altered cervical mucus 2. Increased
cell-mediated immunity

• Putative
• Subtle
• Uncertain
• Found in fertile couples

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VI. Male factors 1. Reduction in motility,
acrosome reaction, oocyte binding zona
penetration 2. Ultrastructural abnormalities of
head abnormalities VII. Embryological factors 1.
Poor quality embryo 2. Reduced progression to
blastocyst in vitro 3. Abnormal chromosomal
complement- increased miscarriage rate

• Putative
• Subtle
• Uncertain
• Found in fertile couples

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• DIAGNOSIS
• UI is a diagnosis of exclusion
• To establish the diagnosis of UI the clinician
  should consider the following (Moghissi et
  al,2000)
• Was the infertility evaluation
• 1. complete?
• 2. performed correctly?
• 3.interpreted appropriately?

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European Society of Human Reproduction
Embryology (ESHRE) (2000) Infertility testing
should be classified into 3 groups depending on
correlation with pregnancy rates I. Tests that
have an established association with pregnancy
Conventional semen analysis Tubal patency tests,
Tests of ovulation
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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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STANDARD (BASIC,Routine) INVESTIGATIONS A. Balen
(2003),RCOG Guidelines (1998), Cooke
(1999),National Guideline Clearinghouse (2000)
1. Basic semen analysis. 2. HSG 3. Mid luteal
serum progestrone. There is no value in measuring
thyroid or prolactin in women with regular
menstrual cycle, in the absence of galactorrhea
or symptoms of thyroid disease (RCOG
guidelines,1998).
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B. American Society of Reproductive Medicine
(ASRM)(1992) Randolph (2000) 1. Basic semen
analysis 2. HSG document a normal endometrial
cavity tubal patency but it is less predictive
of pelvic pathology.
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• 3. Assessment of occurrence adequacy of
  ovulation
• Mid-luteal srerum progesterone
• less invasive way to assess luteal function,
• controversy persists regarding the lower limit of
  normal.

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b. LH surge in urine sensitive, relatively
inexpensive, pinpoint the day of ovulation
has reduced the uncertainty in interpretation
of progesterone levels by better-identifying the
time of peak progestrone secretion at which to
obtain serum
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4 . Laparoscopy Indicated in presence of an
abnormal HSG or history or symptoms suggestive
of pelvic disease. In women with normal HSG or
without history suggestive of tubal disease, The
probability of clinically relevant tubal disease
or endometriosis is very low laparoscopy is not
justified or cost effective (Fatum et al, 2002).
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Laparoscopy may reveal minimal or mild
endometriosis or peritubal adhesions. In these
cases either surgery or medical treatment has not
been proven to improve fecunditity. With the
current success rates of ART the relatively low
contribution of diagnostic laparoscopy to the
decision making of treating patients with normal
HSG, laparoscopy should be omitted in couples
with unexplained infertility. These patients
should be treated as UI (by 3 cycles of combined
gonadotropins IUI if unsuccessful ART)
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Treatment What is the treatment? Once the
well-known obvious causes of infertility have
been excluded , the treatment of couples with
unexplained infertility is the same (Balen,2003)
. In UI the disease is not defined, so
treatment is empirical (Soules,2000)
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What aim of the treatment? to increase the
monthly pregnancy rate above the natural rate of
1.5-3 How? improve gamete quality increase
gamete number facilitate gamete interaction.
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When? depend on 1.duration of infertility 2.
woman,s age 3.the previous pregnancy history
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• Combined pregnancy rates per cycle (Guzik et al,
  1998)
• No treatment 1.3
• IUI 3.8
• CC 5.6
• CC with IUI 8.3
• HMG 7.7
• HMG with IUI 17.1
• IVF/ICSI 20.7
• Alternative therapies

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• I.Expectant therapy
• The spontaneous monthly fecundity rate 1.3
• After 3yr 60 will conceive spontaneously
• (Godon Sperof,2002)
• After 5 yr 80 (Randolph,2000)
• Unfortunately, it is not possible to predict
  which couples will conceive spontaneously or in
  what time frame.

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• Expectant therapy for 6-12 mo.
• lt 35yr. or
• lt3 yr. of infertility,
• Aggressive therapy
• gt 35yr. or
• gt3 yr. of infertility (Soules,2000).

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A nonhomogenous hyperechogenic sonographic
endometrial echo pattern predicts lower
fertility potential in women who are not
receiving follicle maturing drugs in unexplained
infertility (Check et al, 2003)
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• II. IUI
• The spontaneous monthly fecundity rate for IUI
  alone
• 3.8 (Guzik et al,1988) to
• 7.4 (Goverde et al,2000)

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• III. Clomiphene citrate
• CC enhances fertility by
• 1.Correcting subtle defect in ovarian
  function-either follicular development or luteal
  phase defect
• 2. Increasing the number of follicles that
  develop consequently oocyte that are released
  (Balen,2003).

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• Pregnancy rate for cycle 5.6
• Although small increase in fecundity,
• the low cost
• ease of administration,
• CC is a sensible first choice treatment
  (Cochrane,2001) .

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IV. Gonadotropins Per cycle pregnancy rate of
7.7 for gonadotrpin alone (Guzick et
al,1998). Oral ovulation induction agents had
significantly reduced odds of pregnancy per women
compared to injectable ovulation induction agents
(Athaullah et al, 2002, Chochrane review)
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V. Stimulation IUI CC with IUI pregnancy
rate of 6.7 per cycle (Guzick et al,1998). It
is cost effective TT.
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Gonadotropins with IUI 18 per cycle pregnancy
rate (Guzick et al,1998). The cycle fecundity in
the first 3 trials of COH IUI was higher than
in cycles 4-6 COH IUI should be limited to 3
trials(Aboulghar et al,2001) .
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VI. IVF/ICSI Rationales 1.To increase the
number quality of oocytes available for
fertilization, 2. To facilitate the sperm-oocyte
interaction enhance fertilization, 3. To
document the occurrence of fertilization, to
evaluate embryo quality (Randolph,2000) . Cycle
fecundity rate 25.7 (ESHRE).
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1. IVF Vs Expectant management There was no
significant difference in clinical pregnancy rate
between IVF expectant management (Pandian et
al,2003, Cochrane review).
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2. IVF Vs IUI There was no evidence of difference
in live birth rates between IVF IUI either
without or with ovulation stimulation. The
effectiveness of IVF in unexplained infertility
remains unproven (Pandian et al,2003, Cochrane
review). The initial treatment of UI should be
IUI as opposed to IVF (Homburg,2003)
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3.IVF Vs ICSI Complete fertilization failure was
higher in conventional IVF (34.3) than ICSI
(10.3) cycles in unexplained infertility
(Jaroudi et al,2003). ICSI should be the first
option for in vitro fertilization in unexplained
infertility (Sertac et al,2000). ICSI should be
the first line therapy for women over 35 yrs
(Balen,2003)
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VII. Alternative therapies 1. Bromcriptine is
not effective (Cochrane,2001) . 2. Danazol is not
effective (Cochrane,2001) . 3. Fallopian tube
sperm perfusion had insufficient evidence to
support use in pooled analysis (Cochrane,2001)
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4. Oil soluble HSG is associated with increased
cycle fecundity when compared with water soluble
(Cochrane,2001). There was a statistically
significantly higher pregnancy rates in couples
with UI randomized to a single tubal flush with
lipiodol compared with no treatment (Nugnet et
al,2002)
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• 5. Letrozole
• an oral, reversible, no-steroidal aromatase
  inhibitor.
• Dose 2.5 mg/d from day 3-7
• Mechanism of action
• 1. Release of the estrogen negative feedback,
  increase GnTR, stimulate ovarian follicle
  development
• 2. Increase sensitivity of follicles to FSH.

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• Advantages of letrozole over CC
• Because of the short half life (45h) absence of
  ER depletion
• No effect on the endometrial thickness or
  cervical mucous

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• Letrozole is effective for increasing follicle
  recruitment in UI (Mitwally Casper,2000)
• Letrozole can replace CC in patients with UI
  undergoing ovulation induction IUI
  (Sammour,2001).
• Letrozole improved response to FSH evidenced by
  lower FSH dose higher number of mature
  follicles in women with UI (Mitwally Casper,
  2003)

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PROGRESSIVE TREATMENT REGIMEN (Soules,2000).
Treatment should follow an orderly progression
of intensity expense The pace intensity of
treatment depend on couple,s desires, anxiety
cost. Some wishing to proceed swiftly to ART
others wanting to avoid ART for as long as
possible
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. Doxycyclin for both partners (effective for
most cases of pyospermia, cervicitis, /or
endometritis) 1. IUI 3 cycles (simple would
treat an undiagnosed cervical or male factor) 2.
Clomifene citrate IUI for 3 cycles. 3.
Gonadotrophins IUI for 2 cycles. 4. ICSI 75 of
couples with UI will conceive after this
treatment.
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Effect of unexplained infertility on obstetric
outcome Women with unexplained infertility are
at higher risk of obstetric complications which
persist even after adjusting for age, parity,
fertility treatment (Pandian et al, 2001) . The
reasons are unclear.
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They had higher incidence of pre-eclampsia,
abrutio placentae, preterm labour, emergency
cesarean section, induction of labour in
comparison with general population.
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Conclusions
1. Incidence of UI is decreasing 2. Many causes
of UI are uncertain few of which are
treatable 3. Tests that have an established
association with pregnancy are semen analysis,
tubal patency tests tests of ovulation
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4. Once the well-known obvious causes of
infertility has been excluded, the treatment of
UI is the same 5. Treatment of UI should follow
an orderly progression of intensity expense. It
includes expectant, CC, GnTR, IUI, COH with IUI,
ICSI other alternative therapies.
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Thank you
www.obgyn.net
Prof.Aboubakr Elnashar Benha University Hospital,
EGYPT
E-mail elnashar53_at_hotmail.com