Unexplained Infertility -- Kaylen M. Silverberg, MD -- 09/25/02
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About 10% to 15% of infertile couples are diagnosed as having unexplained infertility. It doesn't mean that there is no reason for the infertility -- just that the reason is unidentified at that time. What options do these couples have? As part of National Infertility Awareness Week, WebMD joined with RESOLVE: The National Infertility Association, to bring you the Trying to Conceive (TTC) Cyber Conference. Kaylen M. Silverberg, MD, joined us to discuss unexplained infertility.
Moderator: Welcome, Dr. Silverberg. Thanks for being our guest this hour. First, can you please define unexplained fertility?
Silverberg: Unexplained infertility is the inability to conceive or carry a pregnancy following one year of unprotected intercourse when the infertility evaluation is completely negative.
Member: Is age-related infertility in the category of unexplained? Or is age itself the explanation?
Silverberg: Age itself is the explanation.
Member: I have been diagnosed with unexplained infertility. Had my first IUI last week. What is the success rate with Clomid + hCG shot + IUI? How many times should I try IUI?
Silverberg: Clomid plus hCG plus IUI is 8-12% per cycle. You should not take clomiphene more than six ovulatory cycles.
Member: What can you do when it's been two and a half years and no baby? Doctors say nothing is wrong with husband or me. So frustrating.
Silverberg: Make sure the evaluation has been completed. So you need to make sure you have had a laparoscopy. Then the next step is probably gonadotropin therapy plus IUI and if all that's been done, you need to go to IVF.
Member: My husband and I have been unable to conceive for the past two years. All of our tests thus far have come back normal. My doctor recently suggested that my husband have his sperm DNA fragmentation levels checked with the sperm chromatin structure assay or SCSA. Have you heard of this test, and what do you think it might tell us about our chances to conceive?
Silverberg: Yes, I have heard of it. It is experimental and there is no good data supporting routine use. And make sure the routine evaluation has been completed before you delve into the esoteric.
Moderator: What are all of the routine tests that a couple should have before it's decided they have unexplained infertility?
Silverberg: At a minimum a semen analysis, documentation of ovulation, ultrasound of uterus and ovaries, and an HSG. HSG is the X-ray that evaluates the fallopian tubes and the uterine cavity. A semen analysis is a sperm test. The ultrasound looks at the uterus and ovaries to rule out severe endometriosis. Documentation of ovulation just proves that ovulation happens.
Member: My husband and I have been trying to conceive for five years, to no avail. He has a child from a previous relationship and doctors have told me that I have a healthy reproductive system. We've done all the traditional methods to conceive. Could it be something psychological? Could I be allergic to his sperm?
Silverberg: No. You need to undergo evaluation. Just because people have proved fertile in the past does not mean they are still fertile.
Member: Are some of us with unexplained fertility possibly normal, just taking longer to conceive?
Silverberg: Yes. Unexplained infertility is referred to by some as subfertility. The purpose of therapy is to shorten the time to conception.
Member: What are the "not-so-routine" tests? What about those of us who are still unexplained?
Silverberg: Hysteroscopy. If your husband has had an issue with sperm in the past, maybe sperm antibody testing.
Member: How do we obtain documentation of ovulation?
Silverberg: You can use an ovulation prediction kit. You can do ultrasound to document ovulation. You can do a mid-luteal blood progesterol level.
Member: What plan do you recommend for a 32-year-old with unexplained infertility? How many cycles of just Clomid? When to do IUI or IVF?
Silverberg: Clomiphene for not more than six ovulatory cycles. Add IUI if there is poor cervical mucus or abnormal semen analysis. The next step would be injectable drugs plus IUI. And if that fails, you go onto IVF.
Member: Is 35 when age is the sole factor in unexplained infertility? Does race impact that cut-off?
Silverberg: Race does not. And 35 is not an abrupt cliff. There is a gradual decrease in fertility.
Member: I have unexplained infertility and have gone through two unsuccessful IVFs. Would you recommend IVF again?
Silverberg: Yes. We did the biggest study in the U.S. on IVF on 55,000 cycles. IVF pregnancy rates are the same on the first four cycles. Assess why the IVF did not work, if possible. For example, if it's poor fertilization and you did not do ICSI, then you should consider doing ICSI.
Member: Is it possible that unexplained infertility is just that a person's blood tests fall within the normal range, but that the range is too broad (or narrow, depending). For example, my doctor thought from my symptoms that I may have PCOS; however, my blood insulin and testosterone levels were fine, and I had no diabetic markers and am not overweight (I'm thin), though I do have some acne. My LH was 9.6 and my FSH was 5.8. I was told that my LH was high compared with my FSH but it would need to be a 2:1 ratio to be considered PCOS. Could it still be PCOS but just not fit into the generally accepted range?
Silverberg: It's not PCOS without an increase in androgen levels, but just a type of ovulatory dysfunction. There is too much focus on the diagnosis of the term PCOS. The bottom line is unless androgen levels are very high, you treat all types of ovulatory dysfunction the same, anyway.
Member: I've had all the routine fertility tests you mentioned and the doctors can't find anything wrong with either of us. I have had 21-day cycles for many years and have been trying to conceive for five years. Is it possible that my short cycle length and light period can point to a problem?
Silverberg: Absolutely. That may very well be the problem.
Member: I have had unexplained infertility for four years. What effect do arthritis drugs like Voltaren have on conceiving, because I was on a lot of these meds about four years ago?
Silverberg: If you are not on them currently, it should be out of your bloodstream. Undergo a basic fertility evaluation.
Member: I'm 32 and just finished a round of Clomid/IUIs. We've been trying for two years. Should someone with unexplained infertility with no symptoms of endometriosis, the basic workup done, and safe Clomid cycles running out move on to injectables/IUIs or IVF? There may be a cost-benefit reason for moving to IVF for under-35 unexplaineds. Do you agree?
Silverberg: That study was already done. In fact, moving onto IVF immediately was not shown to be cost-effective. Move on to gonadotropin or IVF, but a professional should assess your specific issues.
Member: I, too, have unexplained fertility. How many times should a couple go through insemination? We have done it six times so far. I'm finally with a real specialist and she says to try one more time. What do you think?
Silverberg: You should not do inseminations without meds for more than six cycles. Nor should you do clomiphene plus inseminations for more than six cycles.
Member: Why only six cycles of Clomid? I have a friend who's been using Clomid for almost one year now.
Silverberg: Very Important: 95% of all pregnancies on clomiphene occur in the first six cycles. Chances in seventh cycle or beyond, while greater than zero, is not great.
Member: What does clomiphene do?
Silverberg: Clomiphene induces ovulation. Some use it for unexplained infertility but there is only one study in the literature from Vermont that shows it improves pregnancy rates for unexplained infertility. Most specialists believe clomiphene should be left to induce ovulation.
Member: What is the success rate with IVF for unexplained fertility (I am 31) after Clomid, HCG, and IUI did not work.
Silverberg: The options would be FSH --IUI or IVF. Chance for success with FSH -- IUI varies from 15-30% and chance for pregnancy with IVF depends on the program, and that should be checked out at www.CDC.gov.
Member: When should an unexplained couple move to laparoscopy for diagnosis of endometriosis? Can diagnosis and treatment of even mild or moderate endo affect IVF success rates?
Silverberg: You can't truly be diagnosed with unexplained fertility until you have had a laparoscopy. Absolutely, the treatment of even minimal or mild disease is associated with marked improvement in pregnancy rates.
Member: What does the laparoscopy look for?
Silverberg: Laparoscopy looks for endometriosis, and for scar tissue.
Member: I had a laparoscopy when I was 19 that showed no endometriosis. I no longer have very painful periods, but that's the only test we haven't done. I'm 32, should I ask to have it repeated?
Silverberg: After 13 years, absolutely. It is more than reasonable to go through laparoscopy again. A lot of things can change.
Member: The only thing my RE can find wrong with me is some cervical stenosis. Could this cause infertility?
Silverberg: Probably not, but IUI or cervical dilatation is an easy way to get around it.
Member: My doctor did not recommend a laparoscopy, maybe because I am still young (early 30s), but said I'd get the same answers through IVF so it is an extra procedure that is not necessary.
Silverberg: I don't agree with that. IVF does not tell anything about endometriosis or your fallopian tubes. It bypasses the tubes but does not bypass the endometriosis issue. I would go on to say that pregnancy rates through IVF for women with endometriosis goes up after endometriosis has been treated.
Member: My partner and I (we are both 32) have been TTC for two years. Sixteen months ago we had a miscarriage at 10 weeks. We have had a semen analysis performed three times (separate clinics) and the results are deemed adequate (I can't find any results). Two ovulation tests have been positive. Last month I underwent a laparoscopy and there was no evidence of endometriosis or past pelvic infection, with the fornices clear of any mass of induration -- overall a normal uterus. What should be our next step? Our doctor advises us to continue with natural conception ("statistically, 90% of couples will become pregnant after two years"). We realize though that this natural process isn't getting any easier as we get older. Should we push for superovulation and IUI? Anything else?
Silverberg: Yes. I would push for superovulation IUI. IUI is intrauterine insemination. Superovulation means you add gonadotropin or clomiphene citrate.
Member: Do you know of any alternative therapies for treating unexplained infertility? I've heard of some success with traditional Chinese medicine.
Silverberg: I have never seen improved success rates attributable to Chinese medicine published in a peer-reviewed journal. Having said that, I know of many anecdotal reports demonstrating improved success with Chinese medicine therapy. If interested, I would refer Daoshing Ni, my friend, who is the dean of the California College of Chinese (Oriental) Medicine. (telephone 310-917-2200). He's one of the most widely respected experts in the field of Chinese medicine in the U.S.
Member: In what study did you see pregnancy rates for IVF go up after endometriosis was treated? Many doctors in my region are now referring to a recent study in Canada that looked at this same issue and found the opposite results.
Silverberg: Your information is backwards. The study in Canada is called the ENDOCAN, and it showed patients with stage 1 and stage 2 endometriosis had significantly greater pregnancy rates once the endo was treated than did control patients. This was a prospective, randomized, blinded study that was of very high quality. A subsequent study from Italy failed to show the same thing. So controversy persists.
Member: However, I believe the ENDOCAN study showed this was only true after no treatment, and for a long period of time.
Silverberg: I was actually the judge at the meeting where ENDOCAN was presented. The study was very clear and straightforward. I can't go into the details of the study, but I suggest you get a copy of the study and read it for yourself. It is a very clear-cut study.
Member: Is diet important in treating infertility?
Silverberg: You should eat a well-balanced diet, but there is no evidence a specific kind of diet can help you. You know, high-carb or high-protein -- that's not specifically effective.
Member: I've had my second endometrial biopsy. The first one indicated that I had too much progesterone in my uterine lining to sustain a pregnancy. Changed protocol for second biopsy using estrogen injection twice a week and Crinone gel starting day 14 or so. No results yet. What questions should I be asking?
Silverberg: First, show me the data that luteal phase inadequacy is associated with infertility. The original study by Wentz and Jones that described luteal phase inadequacy has been recanted and even those authors (who are world experts) no longer believe that luteal phase defect causes infertility. My concern is that you may be chasing a phantom diagnosis and complicating the picture by adding additional hormones.
Moderator: Dr. Silverberg, we are just about out of time. Do you have any final comments for us?
Silverberg: Unexplained Infertility is frustrating for both patient and medical professional. I encourage you to stick to the basics before chasing the esoteric. And the data suggest that with appropriate treatment, at least 80% of patients with unexplained infertility eventually conceive.
Moderator: Thanks to Kaylen M. Silverberg, MD, for being our guest. For more information on fertility issues, be sure to explore all the TTC info here at WebMD, including our message boards and regular live chats with Amos Grunebaum, MD.
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