Download Chapter (3) Unexplained Infertility

Chapter (3)
Unexplained Infertility
Chapter (3)
Unexplained Infertility
Human beings are not very fertile mammals. Evaluation of the fertile
status is generally indicated in women attempting pregnancy who fail to
conceive after a year or more of regular, unprotected intercourse;or six
months in women over 35 years, with an average monthly fecundity rate
of only 20 percent, 85 percent of couples will achieve pregnancy without
assistance in one year (The Practice Committee of the American
Society for Reproductive Medicine, 2013).
However, most couples seeking therapy for infertility are not truly
sterile but have some degree of subfertility and can achieve pregnancy
without treatment (Evers, 2002).
Inability to conceive remains unexplained in 15–30 percent of fully
investigated couples. The delay in conception may represent a chance
delay or may be the result of an abnormality in the reproductive process.
Unexplained infertility (UI) is reached when whatever diagnostic workup
has been chosen reveals no obvious cause for a couple‟s infertility. Thus,
it cannot be assumed that the pregnancy that occurs after treatment for
subfertility is attributable solely to the treatment because it may occur by
chance. Such treatment-independent pregnancies are more likely to occur
in couples having unexplained infertility (Evers, 2002).
However, for infertility of greater than three years duration, monthly
fecundity rates in untreated couples are 1–2 percent (Collins et al., 1995).
The veracity of ‘unexplained infertility’ term has been challenged by
many clinicians and researchers; they emphasize that the assignment of
this title to an infertile couple is much dependent on the quantity, quality
and nature of the applied diagnostic tests (Gelbaya et al ., 2014).
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Chapter (3)
Unexplained Infertility
The incidence of unexplained infertility varies with the population
studied and with the criteria used. Different potential factors may
contribute to unexplained infertility, including age of the partners,
duration of infertility, coital frequency, and professional status (Collins,
2004).
Among all of the potential contributing factors, female age over thirty
years is the only significant predictor. A couple in which the female
partner is thirty years or more is 1.7-fold more likely to have unexplained
infertility. In fact, the distribution of the age of female partners with this
condition is significantly more advanced than the age distribution with
other diagnoses (Collins, 2004).
Therefore, unexplained infertility seems to arise mainly from
undetectable reproductive defects, some of which may be associated with
an age-related decline infertility (The ESHRE Capri Workshop Group,
2005).
Our inability to find the causes of couples’ infertility does not mean that
there is no cause for the disorder. Extensive research on other possible
causes of failed conception such as ovarian and testicular dysfunctions,
sperm and oocyte quality, fallopian transport defects, endometrial
receptivity,
implantation
failures,
and
endometriosis
should
be
conducted(Hatasaka et al ,.2011).
Diagnosis of unexplained infertility
The infertility evaluation is typically initiated after 1 year of trying to
conceive, but in couples with advanced female age (>35 years), initiate
diagnostic evaluation after 6 months. The Practice Committee of the
American Society for Reproductive Medicine (ASRM) has published
guidelines for a standard infertility evaluation. It includes a semen
analysis, assessment of ovulation, a hysterosalpingogram,or laparoscopy .
However, there are controversial opinions about the value of endometrial
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Chapter (3)
Unexplained Infertility
biopsy, ovarian reserve (AMH, AFC), post-coital test and serum prolactin
levels (The Practice Committee of the American Society for
Reproductive Medicine, 2006a).
Unexplained infertility is a diagnosis made by exclusion after a
complete infertility evaluation , it is approximately estimated to be 15% to
30% (The Practice Committee of the American Society for
Reproductive Medicine, 2006b).
It is therefore important to seek agreement on which diagnostic tests
are required to be done prior to concluding that a couple has unexplained
infertility. The standard testing should include 3 items: semen analysis
(evaluated according to the WHO criteria 2010), assessment of ovulation,
and hysterosalpingography which is considered as the best method to
assess tubal patency as well as size and shape of the uterine cavity)
(Collins, 2004).
At present, other additional investigations contribute relatively little
to effective diagnosis of unexplained infertility. Laparoscopy is required
to make a diagnosis of endometriosis or adnexial adhesions, but in the
presence of tubal patency, these lesions seem to be of lesser significance.
The medical treatment of endometriosis does not improve pregnancy rates,
and intraoperative destruction of the lesions has only a small and shortlived beneficial effect (The ESHRE Capri Workshop Group, 2004).
Assessment of Male Infertility:
Male factor infertility is the only cause of infertility in approximately
30% of couples and a contributing factor in another 20% to 30% (Kolettis,
2003).
Assessment of the infertile couple includes evaluation of the male
partner by history, examination, and semen analysis. Important elements
of the history include prior paternity, a history of cryptorchidism, surgical
history, sexual dysfunction, and any use of medications, tobacco, alcohol,
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Chapter (3)
Unexplained Infertility
or illicit drugs. On the physical examination, testicular abnormalities such
as varicocele or absence of the vas deferens can be detected. If the semen
analysis is abnormal, it should be repeated after at least 1 month by a
laboratory that
adheres
to
World
Health
Organization
(WHO)
guidelines,or 3 months by NICE. Guidelines from WHO criteria was
shown in Table (A).
(Lab. Manual of the WHO for the examination of human semen,2010)
.
Table (A): WHO (2010) criteria
A number of commercial laboratories use a variety of ranges for the
semen analysis but Careful attention should be paid to these ranges.
Despite its limitations, semen analysis remains the most important
tool in the investigation of male factor infertility. If any abnormalities are
repeatedly detected on a semen analysis, referral to andrologist may be
warranted (Quaas and Dokras, 2008).r
Assessment of Ovulation
Ovulatory defects are present in 40% of infertile women (The
Practice Committee of ASRM,2006a).Often a defect in ovulatory
function manifests itself in menstrual disturbances and can be identified
by history in the majority of women.
A patient with menstrual abnormalities should be investigated for
underlying causes such as polycystic ovarian syndrome, thyroid disease,
hyperprolactinemia, and hypothalamic causes secondary to weight
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Chapter (3)
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changes. Normal menstrual cycles by history is a highly accurate marker
of ovulation and anovulatory levels of serum progesterone (3 ng/mL) are
found in only a very small minority of these patients (Malcolm and
Cumming, 2003).
In addition to a thorough menstrual history, other methods used to
evaluate ovulation include basal body temperature (BBT) recordings,
urinary luteinizing hormone (LH) ovulation predictor kits, mid luteal
serum progesterone testing, and endometrial biopsy to assess for secretory
endometrial development (Quaas and Dokras, 2008).
Ovulation predictor kits are useful for women who do not have very
long menstrual cycles and can be used by couples to appropriately time
intercourse. Mid luteal progesterone levels are measured around day 21 in
women with regular (28 day) cycles. However, they are often poorly timed
if they are drawn on cycle day 21 in women with irregular menses. In such
women it is better to use an ovulation kit and measure the progesterone
levels 7 to 8 days after the LH surge is detected. Serum progesterone
levels higher than 3 ng /mL suggest that ovulation has occurred and levels
higher than 10 ng /mL are optimum. Although endometrial biopsy results
were previously used to diagnose luteal phase defect, they do not correlate
with fertility status and hence are no longer recommended (Coutifaris
etal., 2004).
Assessment of Ovarian Reserve
Another test added to the workup of couples with infertility includes
assessment of ovarian reserve. Women with advanced age or history of
prior ovarian surgery are at risk for diminished ovarian reserve.
The testing includes a cycle day 3 serum follicle-stimulating hormone
(FSH) and estradiol level, clomiphene citrate challenge test, anti mullerian
hormone and/or an ultrasonographic ovarian antral follicle count. The
results of these tests are not absolute indicators of infertility but abnormal
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Chapter (3)
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levels correlate with decreased response to ovulation induction
medications and lowered live birth rates after IVF (The Practice
Committee of ASRM, 2006a).
Assessment of Uterus and Fallopian Tubes
Assessment of the uterine contour and the tubal patency is an
integral part of the basic infertility evaluation. This may be achieved by
hysterosalpingography (HSG).
However, patent fallopian tubes on HSG do not confirm that ovum
pickup will occur. For example, women with severe endometriosis may
have adherent ovaries in the cul de sac with normal fallopian tubes. Also
HSG is descriptive only and tubal function cannot be assessed (The
Practice Committee of ASRM, 2006a).
Ultrasound evaluation in the follicular phase is used to identify
uterine fibroids, polyps, and congenital cavitary anomalies such as a
septate uterus. At the same time, information on ovarian volume and antral
follicle counts can be obtained, making pelvic ultrasound part of the initial
workup for infertility. A complete cavitary assessment, however,
necessitates either sonohysterography for conditions such as uterine
polyps, submucus leiomyomas, or Asherman‟s syndrome (uterine
synechiae) (Roma et al., 2004). Some practitioners prefer diagnostic
office hysteroscopy as it allows direct visualization of the uterine cavity
(Quaas and Dokras, 2008).
The Role of Laparoscopy in the Infertility Evaluation
The role of laparoscopy in the investigation of infertility has changed
over the past decade. Whereas laparoscopy use as a part of the basic
infertility workup is now reserved for selected cases. Given that it allows
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Chapter (3)
Unexplained Infertility
direct visual examination of the pelvic reproductive anatomy, it is the test
of choice to identify otherwise, unrecognized peritoneal factors that
influence fertility, specifically endometriosis and pelvic adhesions.
According to the guidelines of the ASRM, laparoscopy should be
performed in women with unexplained infertility or signs and symptoms
of endometriosis (The Practice Committee of ASRM, 2006a) .So, in
conclusion, except for laboratory assessments for ovulation, assessment of
tubal patency and semen analysis, „... other additional investigations
contribute relatively little to effective diagnosis of unexplained infertility
and so are not mandatory‟ (Crosignani et al., 1993).
The principle causes of misdiagnosis
As previously noted, a specific cause of infertility is never certain.
The complexities in reaching correct diagnoses have, therefore, to be
acknowledged, and the literature provides considerable evidence that final
diagnoses are often inaccurate. The four below discussed medical
conditions appear to contribute most often to the non-diagnosis of UI
(Gleicher and Barad, 2006).
Endometriosis
The prevalence of endometriosis in infertile females has remained
controversial and it was to be as low as 5–10% (Smith et al., 2003)and as
high as 30–50%. Even in the hands of experienced laparoscopists, an
accurate diagnosis can be difficult because the disease is often
microscopic in nature and presents visually with a variety of atypical
lesions (Cook and Rock, 1995).
Many investigators have pointed towards similar patient profiles in
women with mild cases of endometriosis and UI. Suggestions have,
therefore, been made, that endometriosis may be under diagnosed and that
UI may, in many cases, represent a non-visible and/or only microscopic
precursor stage of endometriosis (Guidice and Kao, 2004).Some
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Chapter (3)
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authorities have argued that the mere presence of mild endometriosis, in
the absence of visible secondary organic disease, such as tubal
involvement, is not associated with infertility. Consequently, they consider
a diagnosis of UI in such cases as appropriate (Moen, 1995)
There is a growing evidence in the literature that endometriosis
affects IVF outcomes in all aspects of the process (Guidice and Kao,
2004).If endometriosis does so in vitro, it can be expected to exert the
same effects in vivo, as well. Also in mild cases of endometriosis,
pregnancy outcomes were impacted by subtle tubal abnormalities (Guzick
et al., 1994b).This observation is reflective of microscopic endometriotic
disease in fallopian tubes or other organs, which can never be fully ruled
out, even by laparoscopy (Cook and Rock,1995).The logical conclusion
from these findings, therefore, has to be that mild endometriosis can affect
normal tubal function, as well as other reproductive processes (Guidice
and Kao, 2004).
Tubal disease
The inaccuracy of HSG in defining normal tubal physiology and
anatomy has been well established. Consensus exists that HSG is less
accurate in detecting and evaluating tubal disease than laparoscopy
(Tanahatoe et al., 2003). Despite that HSG is widely considered a corner
stone of infertility diagnosis and still represents the principle first line tool
to assess tubal status (Crosignani et al., 1993).Yet, as the consensus
shows, routine HSG has limited value in assessing tubal patency and
basically no value in determining tubal function. Tubal function can be
impaired in the presence of tubal patency (Papaioannou et al., 2003).
Routine HSG misses at least one anatomical or physiological tubal
abnormality in 84% of the cases (Karande et al., 1995a)and detection of
the physiological function abnormality of an elevated tubal perfusion
pressure is, in 85% of cases, associated with the laparoscopically
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Chapter (3)
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confirmed endometriosis so UI may be due to undiagnosed endometriosis
(Karande et al.,1995b).
Premature ovarian Insufficiency:
This concept of premature ovarian insufficiency (POI) appears to be
statistically correlated with the total number of remaining follicles within
the ovary (Faddy, 2000).
The literature suggests that approximately 10% of women experience
early menopause before age 45 years and 1% before age 40 years (Van
Noord et al.,1997).These women can be assumed to have followed a
premature ovarian ageing curve based on which they hit points of
subfertility (age 31–32 years) and accelerated decline (age 37–38 years)
early. In other words, these women would present with evidence of
diminished fertility when nobody would expect such a decline, based on
their age. For lack of symptoms, such women will frequently be tagged
with a diagnosis of UI (Nikolaou and Templeton, 2004).Women with
POI can be correctly diagnosed if carefully investigated for signs of POI.
The most reliable of such signs are age atypical resistance to ovarian
stimulation with gonadotrophins, (Beckens et al.,2002)and prematurely
elevated baseline( day 3) FSH levels, low level of anti mullerian hormone,
low antral follicle counts and a family history of early menopause
(NICE,2013).
Subclinical autoimmune disease
Controversies surround the possible association between abnormal
autoimmune function and female infertility, although proposed treatments
failed to demonstrate outcome benefits. Many investigators have reported
a clustering of subclinical autoimmune abnormalities in infertile
populations (Gleicher, 1999).
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Chapter (3)
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Women at pre-clinical stages of their impending autoimmune diseases
already demonstrated decreased fecundity (Sicman and Black, 1998).
One has to assume that at least some cases of UI may be a reflection of
decreased fecundity because of abnormal immune function. To define
such patients as unexplained infertility would appear dishonest (Gleicher
and Barad, 2006).
Other recently suggested causes:
1) Abnormal Zona pellucida:
There is a published case study of an UI (unexplained infertility)
couple due to abnormal Zona Pellucida. The oocytes of the woman
collapsed during the preparation of the oocytes for sperm injection. These
oocytes suffered from irregular ZP and abnormal appearance. Only after
gentle treatment of the oocyte cumulus complex and ICSI fertilization,
embryo development and delivery of normal newborn was achieved. This
woman and others who suffer from UI did not conceive in a natural way
since the ZP of the ovulated eggs did not bind sperm cells and, thereby,
were not fertilized. One of the reasons for the deformatted ZP is the
malfunction of the gene that encodes the 4 glycoproteins, which compose
the ZP. This is now under investigation (Paz et al., 2008)
2) Vascular Endothelial Growth Factor (VEGF):
A case controlled study investigated the role of vascular endothelial
growth factor (VEGF) and its naturally occurring circulating antagonist,
soluble VEGF receptor-1 (sVEGFR-1). In infertility, VEGF is a key
angiogenic factor in the endometrial and ovarian cyclic processes that are
crucial for fertility and sVEGFR- 1 impairs its function and fertility in
animals. This is not proved as regards human fertility (Wathen et al.,
2008).
Plasma VEGF concentrations showed no cyclicity in fertile women,
but were higher in the infertile group at the midluteal phase. Serum
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Chapter (3)
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sVEGFR-1 concentrations were similar between the groups and between
natural and IVF cycles. In the follicular phase infertile women had a high
ratio of VEGF/sVEGFR-1, which was decreased in the luteal phase. Both
findings were associated with failure to achieve pregnancy in subsequent
IVF cycles. The conclusions were: One cause of unexplained infertility
may be unbalanced secretion of sVEGFR-1 with concomitant changes in
free VEGF during the transition from the follicular to the luteal phase.
This aberration may be related to impaired implantation (Wathen et al.,
2008).
3) Leukaemia inhibitory factor (LIF):
The frequency of functionally relevant mutations of the leukaemia
inhibitory factor (LIF) gene in infertile women is significantly enhanced in
comparison with fertile controls (Novotny et al., 2009). Also is found that
LIF expression is decreased in mid-luteal phase in women with
unexplained infertility and repeated implantation failure in comparison
with fertile controls (Jason et al.,2014).
4) Proprotein convertase 5/6 (PC6):
Embryo implantation requires a healthy embryo and a receptive
uterus. Uterine incompetence contributes significantly to implantation
failure and infertility. Proprotein convertase 5/6 (PC6) is tightly regulated
in the uterus and critical for receptivity and implantation; its secretory
nature predicts PC6 to be secreted into the uterine cavity.
A study examined PC6 detection in uterine lavage and whether there
is any correlation between secreted PC6 levels and uterine receptivity
using Western blotting technique, this assay was applied to 103 lavages
collected from different phases of the menstrual cycle from women with
proven fertility or unexplained infertility. PC6 levels were significantly
higher in fertile women, and in a subgroup of women with unexplained
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Chapter (3)
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infertility were significantly lower than in the fertile counterparts.
Detection of PC6 in uterine fluid may lead to the development of a rapid
and relatively non invasive assessment of uterine receptivity (Heng et al.,
2011).
5) Antiphospholipid Antibodies:
The prevalences of antiphospholipid antibodies (APAs) among 1,325
women with a history of unexplained infertility and 676 women
experiencing recurrent implantation failure were compared with 789
women experiencing recurrent pregnancy loss and 205 fertile control
women. Eight percent and 9% of women with a history of unexplained
infertility and recurrent implantation failure had more than one positive
APA compared with 1.5% of fertile negative control women and 11% of
positive control women experiencing recurrent pregnancy loss (Sauer et
al., 2010).
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