By: Sam Najmabadi, M.D.
University of Southern California
Cedar Sinai Medical Center
Center For Reproductive Health & Gynecology (CRH&G)
Director Of CRH&G in Beverly Hills, CA
is defined as the inability to conceive after one year
of sexual intercourse without the use of any contraceptive
methods. A systematic and standard evaluation of all
couples with infertility usually involves three initial
Confirmation of ovulation by History and lab tests.
assessment of the fallopian tubes and the uterus by
the use of an x-ray called Hysterosalpingogram (HSG).
assessment of a semen analysis (SA).
the results of these three tests are normal, and the
couple has been trying to conceive for at least one
year, the diagnosis of unexplained infertility is made.
Of the patients seeking infertility treatment nearly
10 to 15 percent are diagnosed with unexplained infertility.
What this means is that even though the initial tests
we perform to evaluate ovulation, the fallopian tubes
and SA are normal, this couple has difficulty conceiving
due to some inefficiency in the process of conception.
most couples with unexplained infertility get pregnant.
The problem may be an inefficiency that can be overcome
with time and more attempts at conception. Most patients
with unexplained infertility conceive within six to
seven years. Perhaps a younger patient can afford the
wait, but older patients may not have the luxury of
current understanding of what constitutes unexplained
infertility, and the laboratory tests and treatments
recommended for this condition, will be discussed in
is wrong then if everything is normal?
Infertility may be a misnomer since it assumes that
in most cases we do not know what is the cause of infertility.
In fact there is often something wrong at a more basic
level. For example, it is possible that there is something
wrong at the level of the gametes (egg & sperm),
their interaction with each other, or their interaction
with the female reproductive organs.
is also possible to have sperm that appear normal under
a microscope, however not perform the function of fertilization
adequately. Furthermore, one can have normal sperm but
poor quality eggs that do not fertilize or fertilize
at a lower than expected rate. If normal eggs and sperm
meet, one can expect a fertilization rate between 60
to 90 percent. The outer shell of the egg, the Zona
Pellucida, usually hardens after one sperm enters the
egg. It is possible for the outer shell not to allow
a sperm to enter, or allow too many sperm to enter the
egg. Both these situations result in abnormalities that
lead to infertility.
an egg is fertilized, there is an 80 percent chance
of cell division. The rate of division of the resulting
embryo is also of significance. Usually 48 hours after
fertilization, the embryo is between two to four cells
(blastomeres). At 72 hours, they are usually between
six to eight cells. After five days of growth, they
are usually over 120 cells with a fluid cavity in the
middle (Blastocyst). If a larger than expected percentage
of embryos divide slowly or stop dividing at any stage,
this can result in infertility.
can also be problems with normal attachment or implantation
of the embryo once it reaches the uterine cavity. This
can be due to the presence or absence of certain important
factors needed for implantation at the level of the
uterus or the embryo. The outer shell of the embryo
can be too hard or thick and not allow hatching of the
embryo out of its shell (Zona Pellucida). This can result
in a lower chance of implantation. A genetic abnormality
with the embryo can lead to infertility. The embryos
suspected of having a higher chance of a genetic abnormality
are embryos with a higher degree of cell fragmentation
(abnormal looking cells in the embryo).
an evaluation of the fallopian tubes, ovulation, and
a SA are good initial screening tests, they do not identify
all causes of infertility. Unexplained infertility therefore
is not one specific diagnosis, but possibly a combination
of one or many inefficiencies in the processes of conception.
discussed above, one approach in treating couples with
unexplained infertility is reassurance to continue attempting
natural conception if the age of the female is appropriate
(young) Medical intervention has a few disadvantages
including cost, and the increased possibility of a multiple
pregnancy and subsequent sequale. Expectant management
is usually reasonable for a female partner less than
age 35 and short term (less than five years) of unexplained
infertility. Above age 35, it may be prudent to evaluate
ovarian reserve by the means of an ultrasound to count
early ovarian follicles (antral follicles), and measuring
cycle day three Estradiol and FSH levels . Results of
these tests may result in recommendations to proceed
with treatments more aggressive than expectant management.
Clomiphene Citrate (CC) and Intrauterine insemination
or IUI (CC/IUI)
Empiric treatment with fertility pills (CC) is based
on the rationale that increasing the number of eggs
available for fertilization in a given cycle, may increase
the probability of at least one or more released egg,
to produce a viable pregnancy. Based on the review of
the literature, it is clear that CC/IUI improves pregnancy
rates by doubling the couple's chance of getting pregnant
per treatment cycle.
Fertility drugs and IUI
treatment with injectable drugs, gonadotropins (hMG
or FSH) is more aggressive and increases the pregnancy
rates by tripling the baseline rates. This is a reasonable
next step after three to six cycles of CC/IUI has failed
to produce a pregnancy, or unacceptable side affects
resulted from treatment with CC/IUI. Usually three cycles
of injectable fertility drugs with IUI is reasonable
before moving on to a more aggressive treatment option.
Vitro Fertilization (IVF)
is the process by which eggs are recruited by the use
of injectable fertility drugs, and subsequently retrieved
by a process called transvaginal follicle aspiration.
The eggs are then allowed to interact in the laboratory
with sperm, resulting in embryos that are then placed
back into the female partner's body for conception to
occur. With IVF, we can document abnormalities beyond
the routine screening tests and possibly intervene to
correct some problems.
fertilization failure is documented or suspected, we
can inject one sperm into one egg. This process is called
Intracytoplasmic sperm injection (ICSI), and removes
the issue of failed fertilization as a cause of infertility.
In cases where the embryos are slow growing or stop
growing altogether, we can document this in the lab
and propose treatment plans specific to the problem.
cases that present with thickened / hardened outer shell
of the egg, we can perform procedures in the laboratory
to treat these conditions (assisted hatching). Since
we have the opportunity to evaluate the rate of division
and the degree of cell fragmentation of embryos, we
can attempt to select the best morphologic embryos to
result in a viable pregnancy. We can perform genetic
testing on the dividing embryo on the third day of life
and check for the most common genetic abnormalities
that result in infertility and recurrent pregnancy loss.
This process is called Pre- Implantation Genetic Diagnosis
on the review of the available literature on IVF and
unexplained infertility, it is clear that IVF gives
a very high chance of success in these patients (pregnancy
rates of 10 percent to 75 percent depending on the female
partner's age), but at the same time it allows further
evaluation and testing to better diagnose the exact
defect that has led to this couples lower monthly pregnancy
infertility is a diagnosis encompassing many possible
abnormalities resulting in a less efficient conception
process. It defines couples with normal tubes, ovulation
and SA who experience infertility. There are many possible
causes, and some can be treated with assisted reproductive
technology and some abnormalities are beyond the reach
of our current knowledge. Usually, empiric treatment
with inseminations is the most appropriate plan for
three to six months before a more aggressive treatment
with IVF is recommended since many couples will conceive
with less invasive and less costly treatments.