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Diagnosis: Unexplained Infertility

Diagnosis: Unexplained Infertility
by Jackie

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.

Diagnostic Process

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.

Treatment Options

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.

Personal Experience

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.


1 Anonymous { 12.11.06 at 1:19 pm }

How many months of ttc before the statistics you quoted apply to “unexplained”? Since I am over 35, I had an evaluation after 6 months. Now I am “unexplained” and I just started clomid.

2 Jackie { 12.11.06 at 10:24 pm }

Anon: Great question. The studies outlined above did not indicate how many months of unexplained infertility the couples experienced in the studies. Because these studies were meta-analyses of several randomized control trials (basically combining the data from 2-5 studies and analyzing all of the data together), I would have to imagine that a heterogeneous, or well mixed population is represented by the data. In each case, I used data only from investigations of unexplained infertility.
It’s also important to remember that these are just statistics. For instance, every I know seems to know at least one person who went on Clomid and !BAM! they were pregnant. So who knows? Maybe it will work for us too.

3 Anonymous { 12.12.06 at 8:06 pm }

Thanks Jackie for this wonderful post. I too am on my first cycle of clomid. RE just wanded me yesterday and said that I had a good response – three medium sized follicles growing. Good luck to you! (PS I also have many friends who got pregnant on first cycle of clomid!)

4 Anonymous { 12.15.06 at 10:07 pm }

I’d just like to add that “unexplained” doesn’t always mean that your tests come back perfectly clean. I had stage one endo that was treated and has never come back. When we found that, we thought “This is it!” but three years later, no luck. I also have a slightly short luteal phase, treatable with progesterone, and also no luck. With intervention, I have picture perfect cycles, but still no successful pregnancy and my official diagnosis is “unexplained.” So it is possible to have a treatable issue and still be unexplained.

5 Anonymous { 01.11.07 at 10:47 am }

I have completed my first set of clomid pills. Unfortunately my ovaries did not react to them, so my Dr. has doubled my dose of clomid to 100g. Good Luck to all!!!!!

6 Amanda Thomas { 02.06.07 at 1:41 pm }

I have read other people’s comments and would like to inform people with ‘unexplained infertility’ that often in these cases Chinese Medicine can help where Western Medicine has been unable to. I am an acupuncturist and Chinese Herbalist, we look at different parameters in terms of making a diagnosis. It is really worth women having at least 3 month’s worth of treatment with acu/herbs. Hope this helps some of you.

7 Anonymous { 01.05.08 at 12:56 pm }

Thanks for all the information regarding unexplained infertility. My husband and I have been trying almost 2 and a half years. I just tried Serophene(clomid) for 3 months with no result. I am leaning toward a natural route. Anyone tried natural essential oils before?

8 Lesley-Ann { 03.12.08 at 3:23 pm }

My husband and I have been trying for nearly 3 years and have been through all the tests stated above and came out with flying colours. I also have a cycle that is like clockwork and have my ovulation dates down pat. Every month is just heartbreaking, but this month in particular I felt sure that this would be it, especially when I had a light coloured bleed on day 25 of my 28 day cycle which I convinced myself was implantation bleeding. Anyone have any words of wisdom?

9 carrie { 07.01.08 at 2:22 pm }

First I have to say I love this blog. It has helped me stay sane, seriously!
I left Eastern Medicine a few months ago (after a miscarriage & I ran out of acupuncture visits per insurance) to try progerstone and it has not worked at all. A combo of bad doctors and bad medical advice, as well, have let me down. I’d love to hear from more women who have had luck/experience with acupuncture/herbs: how long? which herbs? which methods? what was your ‘diagnosis’? etc…
My experience is that when working with Chinese doctors, they sat down and explained more to me, even taught me a lot about the process. They really listened. My experience with Western docs has been just the opposite.
What are your experiences?

10 Anonymous { 07.14.08 at 12:42 pm }

Ok..just went in for my u/s after first cycle of Letrozole to find that 1. I had already ovulated and 2. my eggs are only 10.5 when they should be 18. So my question is: what can I do to increase my mini-eggs?! Been ttc for 1 1/2 years, had one miscarriage at 5 weeks. Totally frustrated. Trying to keep my chin ‘up’ is the hardest thing ever. Advice, please!

11 Anonymous { 10.03.08 at 4:00 am }

going crazy.

Me and and my wife have been trying for two years and no luck, we both did all the tests mentioned above and we are both fine, in previous relationships she had a miscarriage and I had a have got a woman pregnant before (by accident) for us both it was accidents and it was too easy, but now we want, nothing, even after three cycles of clomid. The stress is starting to tear us apart, any words of encouragement appreciated

12 DCHopeful { 07.10.09 at 3:30 pm }

We're over 2 year TTC and passed all tests with flying colours. Cycles are clockwork. We are bypassing low tech and going straight to IVF. 50% success rates and even higher justifies the costs to us. We did all the Mucinex, green tea, acupuncture, etc etc crap and none of it worked. I think everyone has to find the path that works for them. I hope you are all successful (as long as I don't have to know it when it works or see you pregnant on the street). You know how it is, right?

13 Anni { 10.27.09 at 4:29 pm }

I too suffer from unexsplained infertiltiy, sixteen years.. We have had all the tests. Everything is great. We did get pregnant on our own, but lost it at three months. It can happen. We hope it will again.

14 EHR { 01.18.10 at 1:46 pm }

To Leslie-Ann,
If you aren’t already, I would say seriously consider IUI or other fertility treatments as soon as possible. Whatever the reason, and you may never know what it is, things aren’t working and as much as it sucks and it hurts to hear it, the older you get, the more likely you will experience difficulties in getting pregnant. Please don’t let the passing of time be added to your list of regrets and worries and hurdles. If I had known what I do now about infertility, I would have started the whole process a few years earlier. Who knows, maybe I would have been a parent by now.
I am really sorry for your sadness and disappointment. It is heartbreaking. But there is hope.

15 Carly Reego { 03.02.10 at 8:07 pm }

I am on my 2nd iui, did it today. My doctor said I had one big egg that meausred at at 1.92, I have no idea what that means? IS that good, I thought it had to be at a 2???

16 Sarah { 04.26.10 at 6:44 pm }

TTC 6 yrs. Had all the standard tests: all normal. Tried Clomid: didn’t work. Tried Follistim+IUI: 3 conceptions, 3 1st trimester miscarriages (2 with blood thinner, in case of possible blood clotting problem). To others in such a situation, consider reproductive immunology testing. Check out the book by Alan E Beer–Is My Body Baby-Friendly? RE’s don’t usually consider this possibility, since it’s not their specialty. The science is controvercial, but maybe plausible. You need to decide for yourself if it might offer an explanation for your situation. We’re start treatment next week… our last, best hope.

17 Grita { 08.16.10 at 4:37 pm }

Great blog!

Unexplained infertility here too. Hubby and I passed all of our tests with flying colors. But, I’m 40 so even if everything is working as it should be, I’m guessing I’m just short on good eggs.

I did 3 rounds of Clomid with trigger shots and 2 IUI’s (one with daily injections instead of Clomid) and had no luck. I had weekly acupuncture during most of that time too. It was recommended that I take a month off from the meds to give my over-stimulated ovaries a break (but I kept up the weekly acupuncture). I conceived in our month “off”.

I swear the acupuncture helped and I continued the weekly treatments through my 8th week of pregnancy (that was the time period recommend by the acupuncturist). All was well, until we learned at 12 weeks that our baby had a host of problems. They tried to get me to terminate my pregnancy but I couldn’t do it. Our little guy held on until week 17 when his heart stopped beating and I was counseled to delivered him naturally. It was devastating.

Four months later, we’re trying again and I’ve started acupuncture again – and am doing a Clomid challenge test this month. If all goes well, I can do IVF for the first time next month.

18 Mary Anne { 01.04.11 at 1:45 pm }

Great post! Just like you, I have been diagnosed with unexplained infertility. I am regular between day 28 to 31- never fails, my tubes are open, day 3 fsh level good, progesterone is excellent & hubby has normal semen analysis. Very frustrating indeed. 3 cycles of clomid plus follicle scans- no luck. So far, 4 clomid cycles and IUI- currently in the TWW period, but I feel no symptoms- supposed to test this Friday (1/7/11). Afraid that we’ll have to go the IVF route…. Anyway- thanks for the post. I know I’m not alone in this journey.

19 Kelley { 03.18.11 at 6:58 pm }

The most difficult aspect of Unexplained Infertility is the “Unexplained” part. I feel that if there is an explanation, I will feel better about the condition. I tend to explain it by blaming myself. I want to believe that my body is betraying me. As my wonderful husband points out, assigning blame only makes that person feel horrible. I am making myself feel horrible. He also made me realize that an explanation would not change our course of action. It would not deter me from trying again. And so, after our first attempt at IVF ending with a negative result, we are trying again. Our doctor still feels that he can help us and we still have two more attempts with the insurance company. Unexplained Infertility is teaching me how to not take the blame for everything that is unexplained and how to let the frustration pass through me so we can move onto life’s next challenge. I am hopeful that these lessons will only make me a better parent.

20 jlo { 03.13.13 at 7:38 pm }

I have known my whole life I couldn’t conceive. I was never ready so I never sought to find out why . Now I am 25 and I am ready so o saw my gyno. He did a hsg test and it was very painful, they had to inject dye twice and then I saw the left tube fill with dye.. my periods have gotten pretty regular the last year and a half since being .off birth control and I have all the signs of ovulation. This will be my first cycle after hsg. What are my chances that my tubes were just blocked this whole time?

21 Harris { 09.19.13 at 3:31 pm }

We undergo our first iui as soon as this cycles over after five years of expectant management and five years of ” you’re young it’ll happen.”

Good luck!!

22 Sleepingsiam { 09.27.13 at 9:42 am }

Like Harris above it has now been over 5 years we have been through the process of dozens of tests, Clomid etc and are now going for IVF. I have just turned 30 and my husband is 45. TBH I would rather have no hope for IVF as I have already spent so many years crying and am finally starting to accept we will never have a child. I just can’t understand what the problem is, we are both functioning perfectly and fertility is very strong on both sides of the family but I guess there is no point even trying to figure it out. All I know is that if the 1st round of IVF doesn’t work I am giving up forever as I would rather not have kids than continue to put myself through this never ending cycle of hope, disappointment, hope, disappointment. Its just not worth it anymore.

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