Unexplained Infertility Background, Tests and Treatment Options
Page author Richard Sherbahn MD
Definition of unexplained infertility
Infertility cases in which the standard infertility testing has not found a cause for the failure to get pregnant. Unexplained infertility is also referred to as idiopathic infertility. Another way to explain it is the "doctors can't figure it out" group.
What is standard infertility testing?
The definition of what "standard testing" consists of is not agreed upon by all experts. Medical studies have reported that 0-26% of infertile couples have unexplained infertility. The most commonly reported figures are between 10-20% of infertile couples.
However, those percentages are from studies in which all the women had laparoscopy surgery to investigate the pelvic cavity for pelvic scarring and endometriosis. Laparoscopy surgery is no longer done as part of the routine fertility workup. Therefore, we are not finding all of the causes of infertility that we used to - leaving many more couples in the unexplained category.
- The current rate of unexplained infertility is about 50% for couples with a female partner under age 35, and about 80% by age 40 (see discussion below about age)
- In reality, there are probably hundreds of "causes" of infertility
- There are a lot of things that have to happen perfectly in order to get pregnant and have a baby
As an overly simplified example of the science involved:
- The hormones that stimulate egg development must be made in the brain and pituitary and be released properly
- The egg must be of sufficient quality and be chromosomally normal
- The egg must develop to maturity
- The brain must release a sufficient surge of the LH hormone to stimulate final maturation of the egg
- The follicle (eggs develop in structures called follicles in the ovaries) must rupture and release the follicular fluid and the egg
- The tube must "pick up" the egg
- The sperm must survive their brief visit in the vagina, enter the cervical mucous, swim to the fallopian tube and "find" the egg
- The sperm must be able to get through the cumulus cells around the egg and bind the shell (zona pellucida) of the egg
- The sperm must undergo a biochemical reaction and release their DNA package (23 chromosomes) into the egg
- The fertilized egg must be able to divide
- The early embryo must continue to divide and develop normally
- After 3 days, the tube should have transported the embryo down into the uterus
- The embryo must continue to develop and expand into a blastocyst
- The blastocyst must hatch out of its shell
- The endometrial lining of the uterus must be properly developed and receptive
- The hatched blastocyst must attach to the endometrial lining and "implant"
- Many more miracles in early embryonic and fetal development must then follow...
A weak link anywhere in this chain will cause failure to conceive
The above list is very oversimplified, but the point is made. There are literally hundreds of molecular and biochemical events that have to happen perfectly in order to have a pregnancy develop.
The standard tests for infertility barely scratch the surface and are really only looking for obvious factors, such as blocked tubes, abnormal sperm counts, ovulation problems, etc. These tests do not address the molecular issues at all. That is still for the future.
Unexplained infertility and female age
The likelihood of a diagnosis of unexplained infertility is increased substantially in women 35 and over - and greatly increased in women over 38. The reason for this is that there are more likely to be egg quantity and quality problems as women age. Since we do not have a "standard category" called egg factor infertility, these couples sometimes get lumped in to the "unexplained" infertility category.
Most women over 40 who try to get pregnant will have difficulty, and fertility over age 44 is rare - even in women who are ovulating regularly every month. The point is that the older the female partner, the more likely that there is an egg related issue causing the fertility problem. Unfortunately, there is currently no specific test for "egg quality".
Some experts would also consider infertility associated with mild endometriosis to be in the "unexplained" category. This is because a cause and effect relationship has not been definitely established between mild endometriosis and fertility problems.
Chance for getting pregnant on own - without fertility treatment - for couples with unexplained infertility
The duration of infertility is important. The longer the infertility, the less likely the couple is to conceive on their own. After 5 years of infertility, a couple with unexplained infertility has less than a 10% chance for success on their own.
One study showed that for couples with unexplained infertility and over 3 years of trying on their own, the cumulative pregnancy rate after 24 months of attempting conception without any treatment was 28%. This number was found to be reduced by 10% for each year that the female is over 31.
(Reference: Collins, JA and Rowe, TC. Fertility and Sterility 1989;52:15-20.)
Treatment options for unexplained infertility
Ovarian stimulation and/or intrauterine insemination, IUI
Intrauterine insemination vs. timed intercourse (sometimes called sex, or BD, baby dance) - no medications involved
This has been studied and there is an increased chance for pregnancy with IUI for unexplained infertility as compared to timed intercourse. However, intercourse should be more fun than IUI - and should be cheaper too.
Clomid and timed intercourse for unexplained infertility
3-6 months of treatment with Clomid pills (clomiphene citrate) might improve fertility by as much as 2 times as compared to no treatment. This is a very low level infertility treatment. Infertility specialists do not usually recommend Clomid treatment( without insemination) for unexplained infertility for women over the age of about 35. Most fertility specialists do not use it (without IUI) on any couples with unexplained infertility. If a woman is already having regular periods and ovulating one egg every month, giving Clomid, which will probably stimulate the ovaries to release 2 or 3 eggs per month (instead of one) is not really fixing anything that is broken - and is not likely to be successful.
Clomid plus insemination, IUI for unexplained infertility
Treatment with Clomid tablets plus IUI improves fertility rates. For unexplained infertility, studies have shown that for women under 35, monthly success rates for Clomid plus insemination are about 10% per cycle. This pregnancy rate holds up for about 3 tries and the success rate is considerably lower after that. More about success rates with IUIs is on the insemination page and on the Clomid for unexplained infertility page. The insemination component boosts fertility more than the Clomid does - but success rates are higher when both are used together.
Letrozole or Femara is another oral medication that is sometimes used to stimulate development of multiple follicles during infertility treatment
Injectable gonadotropins (shots of FSH hormone) plus intrauterine insemination, IUI
Several studies showed improved pregnancy success rates with injectable FSH plus IUI treatment as compared to no treatment.
Injectable gonadotropins plus intercourse
This is less extensively studied. It is not yet known whether the ovarian stimulation and the insemination have independent beneficial effects or whether their beneficial effects are only seen when they are used in combination. Most likely they both independently increase fertility potential, with relatively more fertility benefit coming from the IUI component.
Assisted reproductive technologies and IVF as treatment for unexplained infertility
In vitro fertilization (IVF) has high success in young women with normal ovarian reserve testing and unexplained infertility. Most couples with unexplained infertility with a female partner under age 40 will try about 3 artificial inseminations and if not pregnant - do IVF.
IVF also can give us clues as to the cause of the infertility. For example, we may see low fertilization rates per egg, or we may see slow embryo development, excessive fragmentation of the embryos, abnormal eggs, abnormal egg shells (zona pellucida), etc...