Unexplained Infertility: True Diagnosis or Cop Out?

08 Jan
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For about 10% of all infertile couples, the cause of the infertility cannot be readily determined using conventional diagnostic methods. Such cases are often referred to as “unexplained infertility.” The truth, however, is that in most such cases, this diagnosis is in fact “presumptive” because a more in-depth evaluation would have revealed a cause.

This having been said, people diagnosed with so called “unexplained infertility” fall into two broad groups:

a. Those couples who don’t have any biological problems interfering with pregnancy

b. Those who do, but the reason cannot be found, due to insufficient medical information or technology

It is in group b that improved testing techniques have made infertility easier to diagnose and treat. In order to make even a presumptive diagnosis of “unexplained infertility” the answers to the following questions must be in the affirmative.

  • Is the woman ovulating normally?
  • Is the couple having intercourse regularly in the periovulatory phase of the cycle?
  • Are the fallopian tubes normal and open?
  • Can endometriosis be excluded?
  • Does the male partner have normal semen parameters (most specifically with regard to sperm count and motility)?
  • Is the post coital “Huhner” test(a periovulatory examination of cervical mucous, done 6-18 hours after intercourse) normal?

The fewer tests performed, the more likely a presumptive diagnosis. The definitive diagnosis of “unexplained infertility” has a lot to do with the thoroughness of the health care provider in excluding all possible causes.

For Example:

Abnormalities of the fallopian tubes: Adhesions or developmental defects of the finger-like “petals” at their outer ends of the tubes that help sweep eggs inside (fimbriae) can prevent eggs from being collected and transported to the awaiting sperm.

  • Chromosomal abnormalities of eggs or embryos: Eggs must be euploid (contain the right number of chromosomes) to be successfully fertilized; embryos must also be euploid in order to implant successfully in the uterine lining. Until recently, there was no reliable method for determining whether eggs and embryos were euploid. The recent introduction of genetic tests such as comparative genomic hybridization (CGH) now allows for identification of all chromosomes in the egg and embryo. As such, CGH represents an important addition to the diagnostic armamentarium.
  • Luteinized Unruptured Follicle (LUF) Syndrome: Here, the eggs can become trapped in the follicle and not be released (“trapped ovulation”). In such cases, routine tests done to detect ovulation (temperature charting, urine LH testing, blood progesterone levels) may be normal, resulting in false interpretation that ovulation is actually occurring.

  • Ovulation (hormonal) Dysfunction: Abnormalities in ovarian hormone production in the preovulatory phase of the cycle (follicular phase defect) and/or in the postovulatory phase (luteal phase defect) can negatively affect preparation of the uterine lining (endometrium), thus thwarting normal implantation.

  • Immunologic implantation dysfunction (IID): Sometimes, the male or female partner’s own immune system can attack sperm cells, killing them or causing them to become immobilized. Also, immunologic dysfunction involving the uterine lining can cause the implanting embryo to be rejected so early that the woman does not even recognize that she had in fact conceived.

  • Cervical infection – Ureaplasma urealyticum: Infection of the cervical glands can prevent sperm from migrating through the cervix and uterus to reach the egg in the fallopian tube(s). Such infection will usually not be detectable through routine examination and/or cervical culturing methods.

  • Mild or Moderate Endometriosis: Endometriosis is, in 100% of cases, associated with the production of “pelvic toxins” that reduce the fertilization potential of otherwise normal eggs by a factor of 3-5x. In addition, about 1/3 of women with endometriosis (regardless of its severity) have immunologic implantation dysfunction (IID). Furthermore, mild and even moderately severe endometriosis can often only be accurately diagnosed by direct visualization of the lesions through laparoscopy or laparotomy. The detection of IID requires highly sophisticated tests that can only be adequately performed by a handful of Reproductive Immunology Reference Laboratories in the United States. Finally, a condition called nonpigmented endometriosis, in which the endometrium may be growing inside the pelvic cavity with many of the same deleterious effects as overt endometriosis, cannot be detected even by direct vision (at laparoscopy/laparotomy). The fertility of these patients may be every bit as compromised as if they had detectable endometriosis.

  • Psychological Factors: The entire reproductive process is governed by the brain. Thus it should come as no surprise that stress and negativity can interfere with hormonal balance and decrease the ability to conceive.

Management of “Unexplained Infertility”

Successful management of “Unexplained Infertility” requires that a very individualized approach be taken. Wherever possible, the underlying cause should first be identified. Problems that involve ovulation dysfunction (hormonal imbalance) require ovulation induction with oral or injectible fertility drugs. Cervical mucous hostility due to infection with ureaplasma (which is transferred back and forth sexually to both partners) requires specific and concurrent antibiotic therapy. In other cases involving younger women (under 39 years) where there is a problem with sperm migration via the cervix and uterus to the fallopian tube(s), intrauterine insemination (IUI) with or without ovulation induction, is indicated.

When these treatments fail, in vitro fertilization (IVF) is needed. This is also generally the case in women over the age of 39 years, women with IID, men or women who harbor antisperm antibodies in significant concentrations, and in cases associated with tubal abnormalities, All cases of intractable, moderate or severe male infertility call for injecting sperm directly into the egg to achieve forced fertilization (intracytoplasmic sperm injection or ICSI).

It is an indisputable fact that most causes of infertility can be diagnosed. In my opinion, it is a great pity that the diagnosis of “unexplained infertility” is often used as an excuse for not having performed a full and detailed evaluation of the problem. Couples should not simply accept a diagnosis of “unexplained infertility” at face value since treatment is most likely to be successful when the specific cause of the problem can be fully identified.


  • Lenny says:

    Dr. Sher

    We are a couple that has been trying to conceive for 3 yrs. I’m 35, my husband is 33. I’ve had 3 IUI and one IVF in a natural cycle with a 3rd day, 6-cell embryo, transfer with no pregnancy. Our diagnosis is ‘unexplained infertility’.
    During our battle with infertility I’ve discovered a LUFS in 6 out of 8 monitored cycles with blood tests and ultrasound that resolved by itself in the next cycle without the need for extra medication. My 3rd day cycle hormone levels are normal, HSG test normal, thyroid levels normal. Sperm count and motility also normal. We tested for STDs, all clear. I’m told I don’t have endometriosis because my CA-125 levels are normal (but without a laparascopy in my opinion there really isn’t any way to be sure). In the country I live in, the doctors refuse to do or even recommend additional test until I have 3 more unsuccessful IVF attempts or at least two miscarriages. I refuse to wait until I fill the required quota and I can’t simply believe that LUFS is just something happening to me because I have bad luck. If you could advise me in which direction to search for my diagnosis I would very much appreciate it since I’m planning to take my fertility treatment abroad and I don’t want to waste any time. Thank you in advance.

    • Geoffrey Sher says:

      Frequently, when following vigorous and often repeated flushing of follicles at egg retrieval they fail to yield eggs, it is ascribed to “Empty Follicle Syndrome.” This is a gross misnomer, because all follicles contain eggs. So why were no eggs retrieved from the follicles? Most likely it was because they would/could not yield the eggs they harbored.

      This situation is most commonly seen in older women, women who have severely diminished ovarian reserve, and in women with polycystic ovarian syndrome (PCOS). In my opinion it is often preventable when an optimal, individualized and strategic protocol for controlled ovarian stimulation (COS) is employed and the correct timing and dosage is applied to the “hCG trigger shot.”

      Normally, following optimal ovarian stimulation, the hCG “trigger shot” is given for the purpose of it triggering meiosis (reproductive division) that is intended to halve the number of chromosomes from 46 to 23 within 32-36 hours. The hCG trigger also enables the egg to signal the “cumulus cells” that bind it firmly to the inner wall of the follicle (through enzymatic activity), to loosen or disperse, so that the egg can detach and readily be captured at egg retrieval (ER).

      Ordinarily, normal eggs (and even those with only one or two chromosomal irregularities) will readily detach and be captured with the very first attempt to empty a follicle. Eggs that have several chromosomal numerical abnormalities (i.e., are “complex aneuploid”) are often unable to facilitate this process. This explains why when the egg is complex aneuploid, its follicle will not yield an egg…and why, when it requires repeated flushing of a follicle to harvest an egg, it is highly suggestive of it being aneuploid and thus “incompetent” (i.e., incapable of subsequently propagating a normal embryo).

      Older women, women with diminished ovarian reserve, and those with polycystic ovarian syndrome, tend to have more biologically active LH in circulation. LH causes production of male hormone (androgens, predominantly testosterone), by ovarian connective tissue (stroma/theca). A little testosterone is needed for optimal follicle development and for FSH-induced ovogenesis (egg development). Too much LH activity compromises the latter, and eggs so affected are far more likely to be aneuploid following meiosis.

      Women with the above conditions have increased LH activity and are thus more likely to produce excessive ovarian testosterone. It follows that sustained, premature elevations in LH or premature luteinization (often referred to as a “premature LH surge”) will prejudice egg development. Such compromised eggs are much more likely to end up being complex aneuploid following the administration of the hCG trigger, leading to fruitless attempts at retrieval and the so called “empty follicle syndrome.”

      The developing eggs of women who have increased LH activity (older women, women with diminished ovarian reserve, and those with PCOS) are inordinately vulnerable to the effects of protracted exposure to LH-induced ovarian testosterone. Because of this, the administration of medications that provoke further pituitary LH release (e.g., clomiphene and Letrazole), drugs that contain LH or hCG (e.g., Menopur), or protocols of ovarian stimulation that provoke increased exposure to the woman’s own pituitary LH (e.g., “flare-agonist protocols”) and the use of “late pituitary blockade” (antagonist) protocols can be prejudicial.

      The importance of individualizing COS protocol selection, precision with regard to the dosage and type of hCG trigger used, and the timing of its administration in such cases cannot be overstated. The ideal dosage of urinary-derived hCG (hCG-u) such as Novarel, Pregnyl and Profasi is 10,000U. When recombinant DNA-derived hCG (hCG-r) such as Ovidrel is used, the optimal dosage is 500mcg. A lower dosage of hCG can, by compromising meiosis, increase the risk of egg aneuploidy, and thus of IVF outcome.

      There is in my opinion no such condition as “Empty Follicle Syndrome.” All follicles contain eggs. Failure to access those eggs at ER can often be a result of the protocol used for controlled ovarian stimulation.

      Please go to the home page of this blog, http://www.IVFauthority.com . When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.

      1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)

      2. Ovarian Stimulation for IVF: The most important determinant of IVF Outcome” (Nov. 2103)

      3. “Agonist/Antagonist Conversion Protocol”

      4. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)

      5. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)

      6.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)

      7. “IVF success: Factors that influence outcome”

      8 “Use of the Birth Control Pill in IVF”

      Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype with me so we can discuss your case in detail.

      Finally, perhaps you would be interested in accessing my new book (recently released). It is the 4th edition (and a re-write) of “In Vitro Fertilization: The ART of Making Babies”. The book is available through “Amazon.com” as a down-load or in book form. It can also be obtained from most bookstores.

      Geoff Sher

      P.S: Please go to http://www.youtube.com/watch?v=Vp3GYuqn2eM&feature=youtu.be
      To view a video-tutorial by Linda Vignapiano RN, Clinical Manager at SIRM-Las Vegas.

  • I like looking through a post that will make men and women think.
    Also, thank you for allowing me to comment!

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