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Unexplained Infertility

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Unexplained Infertility  
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Unexplained Infertility

Contributed 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

Infertility 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 tests:

  1. Confirmation of ovulation by History and lab tests.
  2. An assessment of the fallopian tubes and the uterus by the use of an x-ray called Hysterosalpingogram (HSG).
  3. An assessment of a semen analysis (SA).

If 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.

Eventually 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 time.

The current understanding of what constitutes unexplained infertility, and the laboratory tests and treatments recommended for this condition, will be discussed in this article.

What is wrong then if everything is normal?

Unexplained 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.

It 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.

Once 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.

There 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).

Although, 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.

Available Treatments

Expectant management

As 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.

Injectable Fertility drugs and IUI

Empiric 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.

In Vitro Fertilization (IVF)

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.

If 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.

In 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 (PGD).

Based 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 rates.


Unexplained 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.

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