Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.
Infertility is defined as the inability to get pregnant after one year of unprotected intercourse if you are a female under the age of 35, or six months if you are 35 or older. Women who get pregnant but who have repeated miscarriages are also considered infertile. Unexplained infertility means that medical tests cannot find any cause for infertility. In some cases, all the tests come back normal even though the couple is unable to conceive. In other cases, the tests may uncover minor abnormalities, but they are not severe enough to result in infertility. It can be frustrating not to know exactly what is causing the problem. If you have unexplained infertility you are not alone: unexplained infertility affects about 1 in 5 couples.
What Causes Unexplained Infertility?
Diagnosed infertility in women may be caused by a number of factors. For example, it might be that the egg is not released at the best time for fertilization or that fertilization does not happen at all. Blocked fallopian tubes, uterine fibroids, or uterine problems may also be the cause. Men can also have fertility problems which result in the couple being unable to conceive. Infertility in men is often due to few or no sperm cells being produced. In some cases, the sperm might be misshapen or they might die before they can reach and fertilize the egg.
A woman is more likely to be diagnosed with unexplained infertility if she is 38 or older. As women get older, the quantity and quality of their eggs diminishes. Most women over 40 have a hard time conceiving, and women over age 44 are rarely fertile even if they ovulate regularly every month. Since there is no test to check for egg quality or quantity, older women with fertility problems are often diagnosed as having unexplained fertility. Women with mild endometriosis may also have fertility problems. Since it is not proven that mild endometriosis causes infertility, some researchers consider those women as having unexplained infertility.
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
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.
