Diagnosis: Unexplained Infertility
What Unexplained Infertility Means and its Impact on Fertility
Unexplained infertility is a diagnosis given after all other possibilities have been excluded. That is to say, after going through the diagnostic process (see below) there is no explanation for the infertility. The male partner has a normal semen analysis. The female partner ovulates and her hormone levels are all within normal limits. In addition, her uterus is free of anatomical abnormalities and the Fallopian tubes are open or patent. In addition to these physical findings, neither the couple’s nor their families’ medical histories indicate any reason why the couple should be infertile. Couples with unexplained infertility have substantially reduced cycle fecundity rates, 1-4% compared to 20-25% for normal couples. Pregnancy rates decrease with increasing maternal age and duration of infertility. Estimates place unexplained infertility at 10-20% prevalence among infertile couples.
Male partner: medical history, family medical history, semen analysis.
Female partner: medical history, family medical history, physical examination, hormone tests (such as Day 3 FSH, estrogen, progesterone, prolactin, thyroid hormone, androgens), demonstration of ovulation (mid-luteal progesterone), hysterosalpingogram (HSG, to determine whether the tubes are patent). Other tests may be performed if indicated by the history. This may include laparoscopy to determine whether endometriosis or adhesions are present. The post-coital test to determine sperm viability in cervical fluid may also be performed although it has been determined that this test has poor predictive value for conception rates.
After the test results come back and no detectable reason for infertility is identified, the unexplained infertility diagnosis is given. This does NOT mean that there isn’t a reason for the infertility. It means that the science and the diagnostic tests are not advanced enough to detect the cause of infertility. Egg quality, fertilization, and implantation factors are difficult to test and may be the underlying problems.
Since there is no known abnormality to remedy in unexplained fertility, all treatments are considered “empiric”. In general, this means the therapies have been observed to be helpful in getting over the infertility, but how? Unknown. All options are possible here and really are only limited by your resources, beliefs and desires.
1. Expectant management: Also known as wait and see, or my favorite term: keep on having the sex. At the end of three years, the pregnancy rate for women with unexplained infertility is about 30-60% without intervention. But can you wait 3 years for a cumulative 30-60% chance of getting pregnant? This is not the same as cycle fecundity rate. In fact, if you have a 28 day cycle, in 3 years, you will have had 39 cycles. My extremely rough math places the cycle fecundity rate at about 0.75-1.5%.
2. Clomid: This drug is a selective estrogen receptor modulator. Basically, it acts on estrogen receptors in the pituitary gland to increase release of FSH and LH and thereby increasing the quality and possibly quantity of mature follicles released from the ovaries. Clomid alone for unexplained infertility increases cycle fecundity rates only a couple of percent over placebo, so from about 1-2% to up to a whopping 4-5%. There is no benefit of using clomid alone for more than 6 cycles with unexplained infertility.
3. Intrauterine Insemination (IUI): One factor that can be difficult to ascertain is hostility of the female environment toward the sperm. The aforementioned post-coital test was more routinely performed until it was determined that the test is not a great predictor of pregnancy rates. To get around any potential hostility, the sperm can be prepared from a semen sample and injected into the uterus bypassing the vagina and cervix altogether. IUI has been found to have a small benefit over timed intercourse in unexplained infertility (5% vs. 2% cycle fecundity rate).
Fallopian sperm perfusion (FSP) also circumvents the vagina and cervix as well as the uterine environment by placing the sperm directly into the Fallopian tube using a laparoscopic procedure. Studies are divided on whether pregnancy rates are improved with FSP compared to IUI in couples with unexplained infertility.
4. IUI following controlled ovarian hyperstimulation (COH): This normally combines Clomid with IUI, but gonadotropins can also be used. Cycle fecundity is improved when ovarian stimulation and IUI are combined over either treatment alone. The average increase in cycle fecundity with combined therapy is about 10%.
5. In Vitro Fertilization (IVF), Gamete Intra-Fallopian Transfer (GIFT), Zygote Intra-Fallopian Transfer (ZIFT): Assisted reproductive technologies offer the highest pregnancy rates among those with unexplained infertility. Most published studies indicate 25-50% pregnancy and live birth rates in those with unexplained infertility. These procedures are more costly and invasive that the other therapies and have somewhat higher incidences of multiple births.
A typical treatment trajectory goes from low cost, low tech for several cycles, advancing from Clomid alone to COH/IUI to IVF. Couples with more resources may opt for the higher cost, higher tech treatments immediately. Since the cause of the infertility is unknown, it is impossible to know how much intervention is necessary to get pregnant.
My husband and I sought assistance after 18 months of unsuccessfully trying to conceive. Our medical histories are normal. I have extremely regular 28 day cycles (almost to the hour), I have never been pregnant, and I have never been diagnosed with endometriosis. For his part the semen analysis was normal. My day 3 hormone levels were spot on. My HSG showed open tubes with bilateral peritoneal spillage of dye. My mid-luteal progesterone was 9.6-definitely ovulating, but sort of mediocre. My RE’s office likes to see it closer to 15. Therefore, my first treatment was Prometrium, which elevated mid-luteal progesterone to about 25.
After 2 unsuccessful cycles, I have opted to try Clomid. In fact, I will take my first dose today. My clinic does not monitor ovulation by ultrasound so I will be peeing on sticks to determine the LH surge. The clinic will draw a mid-luteal progesterone which I expect will be higher than 9.6, but who knows. If Clomid doesn’t work, then we will move on to COH/IUI, and if that doesn’t work, then we will likely undergo IVF. We are definitely taking the low tech, low cost to progressively higher tech, higher cost route. All testing is covered by our insurance including a once-in-a-lifetime laparoscopy which I may elect to have performed sometime this year to definitively rule out any endometriosis.
I must admit that it’s quite frustrating, not knowing WHY. Any more frustrating than knowing why and not conceiving? That’s highly unlikely. And it doesn’t change the treatment options that much from some other “known” types of infertility.