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Unexplained Infertility Diagnosis? Delve Deeper

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By Leigh Ann Woodruff, March 6, 2012

One of the most frustrating things a couple experiencing trouble getting pregnant can hear is that their diagnosis is "unexplained infertility." Up to 30 percent of infertility patients will receive this diagnosis, which simply means the couple has had a standard infertility evaluation and the results come back normal.

But how can infertility be unexplained? Isn't that counterintuitive to other health issues where you delve deeper until you find the cause?

"We don't believe in the diagnosis of unexplained infertility, which according to the literature is the diagnosis that roughly up to a third of all infertile patients carry around with them," says Norbert Gleicher, M.D., a fertility doctor and medical director of the Center for Human Reproduction (CHR). "We never see a patient where we don't find the cause of infertility, and it's not often that we can say 'never' or 'always' in medicine, but I can tell you we practically have never seen, in recent years, a patient where we have not been able to find the probable cause for infertility."

Beyond the Standard Fertility Evaluation

Guidelines for a standard infertility evaluation include: a semen analysis, assessment of ovulation, a hysterosalpingogram, and, if indicated, tests for ovarian reserve and laparoscopy.

If the evaluation comes back normal, Dr. Gleicher suggests asking three questions:

  • Have you tested my ovarian reserve according to my age?
  • Have you made sure that my hysterosalpingogram was correctly interpreted?
  • Have you checked me out immunologically?

For patients with unexplained infertility, Dr. Gleicher says he carefully assesses them and most often finds they have one of the following three conditions:

Premature Ovarian Aging

Premature ovarian aging, also known as diminished ovarian reserve, is a condition in which a woman's follicle stimulating hormone (FSH) levels are above where they should be at her age, or her anti-mullerian hormone (AMH) levels are below where they should be at her age.

"In probably 60+ percent of so called unexplained infertility patients, we find unrecognized diminished ovarian reserve," Dr. Gleicher says. "It's usually young women with still normal menstrual periods, with what are considered normal FSH levels. But once they are really properly evaluated, they turn out to have — for their age — abnormal FSH levels or abnormal AMH levels. That is the most frequent finding in women with unexplained infertility."

Dr. Gleicher treats patients with premature ovarian aging with a hormone called DHEA (dehydroepiandrosterone), a natural steroid hormone produced primarily by the adrenal gland. CHR researchers have found that DHEA improves spontaneous pregnancy rates, decreases the amount of time that it takes a woman to become pregnant and increases the amount of eggs retrieved for in vitro fertilization (IVF) treatments. In addition, DHEA had been found to improve egg quality and reduce embryo aneuploidy.

Tubal Disease/Endometriosis

The second most common finding for unexplained infertility in Dr. Gleicher's practice is a missed diagnosis of tubal disease. "That is usually due to the fact that most hysterosalpingograms are done by radiologists, and this is one of those typical clinical situations where different specialties look at things in a different way," Dr. Gleicher says.

He explains that a radiologist considers a hysterosalpingogram normal and the fallopian tubes "patent" (unblocked or unobstructed) if during the hysterosalpingogram the dye goes through the tubes. "But if you push hard enough, for example, if there is a distal tube fibrosis or a distal tube occlusion, if you just push hard enough, the pressure will open it and let the dye go out," Dr. Gleicher says. "So one has to really look in a much more sophisticated way at the hysterosalpingogram and really assess not only whether there is patency, but also whether there is other pathology in the films that would suggest presence of tubal disease.

"And distal tubal disease is a very early sign of endometriosis," he continues. "So there's a statistical linkage between overlooking distal tubal disease and overlooking endometriosis."

Patients with tubal disease often find great success with in vitro fertilization (IVF). "We no longer do surgery," Dr. Gleicher says, "because pregnancy rates with IVF are so high now, especially in patients who only have tubal problems, and surgery is only a very temporary solution at best."

Immune Causes of Infertility

Overlooked immune causes of infertility make up the smallest percentage of unexplained infertility patients that Dr. Gleicher sees. "The classic case is the woman who has unexplained infertility, but had three early chemical pregnancies, and those early chemical pregnancies are overlooked and not considered," he says. "And they usually mean that this woman has an immune problem leading to her having miscarriages."

The relationship between subclinical autoimmunity and decreased fertility is controversial; however. Dr. Gleicher will run an autoimmune panel on patients with unexplained infertility in order to get the full picture. "What we are really looking for is what I call an activated immune system; in other words, patients who have a low level of subclinical autoimmunity will show activation of their immune system. They will show an abnormality here and an abnormality there. It may not be very convincing, and it may just allow you to raise your level of suspicion."

Dr. Gleicher offers treatment; however he explains that there are no well-controlled studies. "Our standard treatment is a combination of baby aspirin, prednisone and and a blood thinner like heparin," he says. "That's our phase 1, and with most patients we succeed with that. With patients where we fail with that or where the immune abnormalities are very blatant, we may add also intravenous gamma globulin to the picture."

Solving the Problem

If you have received a diagnosis of unexplained infertility, it can only help to go and get a second option and additional testing. "In many cases, IVF will solve the problem, but it will solve it quicker if you know what the underlying problem is," Dr. Gleicher says. "There's always an advantage to knowing what you're dealing with rather than shooting in the dark."

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