Definition of unexplained infertility: Infertility cases in which the standard infertility testing has not found a cause for the failure to conceive.

The definition of what “standard testing” consists of is not agreed upon by all experts. Unexplained infertility is also referred to as idiopathic infertility. 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 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 more couples in the unexplained category. The current rate of unexplained infertility is probably about 50% for couples with a female partner under age 35 and about 80% by age 40 (see discussion below about female age issues).

In reality, there are probably hundreds of “causes” of infertility. What this means is that there are a lot of things that have to happen perfectly in order to conceive and have a baby. As a simplified example:

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 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 into the uterus The embryo must continue to develop into a blastocyst The blastocyst must hatch from 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 chain can this 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 function properly in order to have a pregnancy develop. The standard tests for infertility barely scratch the surface and are really only looking for very obvious factors, such as blocked tubes, abnormal sperm counts, ovulation regularity, etc. These tests do not address the molecular issues at all. That is still for the future…2

The subtle causes of sub fertility that have been proposed as underlying unexplained infertility are as follows3

Ovarian and endocrine factors

Abnormal follicle growth

Luteinized unruptured follicles and ovarian cysts

Hyper secretion of LH

Hypersecretion of prolactin in the presence of ovulation

Reduced growth hormone secretion /sensitivity

Cytological abnormalities in oocytes

Genetic abnormalities in oocytes

Antibodies to zona pellucida

Peritoneal factors

Altered macrophage and immune activity

Mild endometriosis

Antichlaydial Ab

Tubal factors

Abnormal peristalsis or cilliac activity

Altered macrophage and immune activity

Endometrial factors

Abnormal secretion of endometrial proteins

Abnormal intergrin/adhesion molecules

Abnormal t cell and natural killer cell activity

Secretion of embryo toxic factors

Abnormalities in uterine perfusion

Cervical factors

Altered cervical mucous

Increased immunogenicity

General immune factors

Altered cell mediated immunity

Male factors

Reduction in motility, acrosome reaction, oocyte binding ,and zona penetration

Ultrasructural abnormalities of head morphology

Embryological factors

Poor quality embryos

Reduced progression to blastocyst

Abnormal chromosomal complement-increased miscarriage rate

Unexplained infertility and female age

Women are born with certain number of eggs and when they attain menarche they start releasing these eggs cyclically. As the woman ages they run out of there eggs and quality of eggs will become poorer too. Therefore the likelihood of a diagnosis of unexplained infertility is increased substantially in women 35 and over – and greatly increased in women over 38. 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”.2

Unexplained infertility and Mild endometriosis

It is not quite clear whether mild endometriosis causes infertility and treating mild endometriosis improve the fertility rates. Some recent studies has shown surgical treatment for mild endometriosis increases the fertility. 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 31.4

Treatment options for unexplained infertility

Ovarian stimulation and/or intrauterine insemination (IUI)

Intrauterine insemination vs. timed intercourse – no medications involved

Studies have been shown that chances of pregnancy is increased with intrauterine insemination compared to timed intercourse.

Clomid and timed intercourse

Glazener et al .treated 100women,43% of whom were porous ,with either clomid 100mg from days 2-6 and placebo in a randomized cross over study. Overall there was a 50% increase in pregnancy rates after 3 cycles of treatment. Benefit was seen in after 3 years of infertility and more so in parous women.The same study showed that there were no conception in women over 35 years.5 This suggest that these women are not suitable candidates for clomid treatment and should be treated vigorously with assisted conception methods.

Clomid plus IUI

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.

Deaton et al carried out a randomized study between timed intercourse or clomid with IUI, and showed that monthly fecundity was 9.5% in clomid plus IUI group compared to control group- a significant difference.6 In the same study it has been showed that there was no difference in number of follicles between conception and non conception cycles, suggesting that the insemination component have a more important influence than the Clomid does on outcome- but success rates are higher when both are used together.

Collating all studies together a recent systematic review, Hughes et al. reported that treatment with clomid is superior to no treatment or placebo (95% CI 1.5-4.65).7

Injectable gonadotropins plus intercourse

This is less extensively studied. However a study by Mascarenhas et al demonstrated that super ovulation with gonadotrophins significantly increased the pregnancy rates in unexplained infertility.8

Injectable gonadotropins (shots of FSH hormone) plus IUI

Several studies showed improved pregnancy success rates with injectable FSH plus IUI treatment as compared to no treatment. A meta-analysis by Hughes9 indicated that FSH plus IUI increases the pregnancy rate by 2.3 times than compared to FSH plus timed intercourse.

It is most likely that super ovulation and IUI both independently increase fertility potential, with relatively more fertility benefit coming from the IUI component.