Background

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.

Assisted reproductive technologies

IVF

In vitro fertilization (IVF) has high success in young women with normal ovarian reserve (normal FSH levels) and unexplained infertility. Most couples with unexplained infertility with a female partner under age of 35 could try about 3 artificial inseminations and if fail to pregnant  it is sensible to have IVF. On the other hand women over 35 years should have been offered IVF as a first line treatment.

GIFT

Gamate intrafallopian transfer goes one step further than superovulation/IUI as it involves the collection of oocytes and sperm into fallopian tubes. The main disadvantage compared to IUI is the need of laparoscopy and more complicated ovarian stimulation regimes. Compared with GIFT the main advantages of IVF are, that being able to study the fertilization, gives the opportunity to transfer best quality embryos to the uterus, and it also gives couple with surplus fertilized oocytes which can be cryo preserved for future use.

A large multi-center randomized study performed by European Society of Human Reproductive and Emryology to compare five treatments for unexplained fertility .The study concluded that there was no significant difference in outcome between them.(super ovulation 15% per cycle, super ovulation 27%,superovulation/IUI 27%,GIFT28%,IVF26%.10

In summary, strategic management of unexplained infertility should focus on the efficacy of the method ,cost effectiveness and invasiveness of the procedures involved. Evidence suggest that there would be little or no benefit if treatment start in  a woman less than 35 years. Therefore it is worth considering superovulation and/or IUI for 3 cycles after 3 years of infertility, and if not successful go for IVF. However for older women (over 35) to consider IVF straight away.

References

1. Hull MGR, Glazener CMA, Kelly NJ et al.(1985), Population study of causes,

2. Unexplained Infertility

http ;//www.advancedfertility.com/unexplain.ntm( accessed 11/03/2008).

3. Adam, H.B. & Howard, S.J, (2003), Infertility In Practice, Churchill Livingstone, London.

4. Collings JA ( 1989), Natural course of unexplained infertility, Proceedings of the Serono symposium on unexplained infertility : basic and clinical aspects. Serono Aries Publishers, Rome.

5. Glazener CMA, Coulson C, Lambert PA et al, ( 1990), Clomiphene treatement for women with unexplained infertility : placebo-controlled study of hormonal responses and conception rates. Gynecol Endocrinol 4: 75-83

6. Deaton JL, Gibson M, Blackmer KM, Nakajima ST, Badger GJ & Brumsted JR, (1990), A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 54 : 1083- 1088.

7. Hughes E, Collins J, & Vandekerchhove P (2002),Clomiphene citrate for unexplaine subfertility in women. Cochrane Database of systematic Reviews, Issue 1, 2002.

8. Mascarenhas L, Khastgir G, Davies WAR & Lee S, ( 1994),Superovulation and timed intercourse: can it provide a reasonable alternative  for those unable to afford assisted conception ? Hum Reprod  9: 67 -70

9. Hughes EG (1997), The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility : a meta-analysis. Hum Reprod 12 : 1865-1872

10. Crosignani PG, Walters DE & Soliani A, (1991), ESHERE multicentre trail on the treatment of unexplained infertility : a preliminary report. Hum Reprod 6: 953-958.

So what are the male infertility treatment options available to men? Before we take a look at some of them let’s look at the most common cause of male fertility issues and that’s varicoceles.

Varicoceles is simply a group of veins which become dilated around the testis area of the man. Between 15-20% of men suffering infertility will have this as the major reason. If varicocele issues are not at play then it could be any number of other problems including:

- blockages
- infections
- hormonal disorders
- exposure to substances that are toxic for sperm

Male Infertility Treatment

It’s important to note that with many forms of male infertility treatment, men can still introduce semen into the reproductive tract of the female. So what are some of the treatment options available?

A very high percentage of men can be treated. There are a number of treatments depending on the infertility issue.

- Intracytoplasmic sperm injection was introduced not long ago giving hope to almost every man with a fertility problem. Since in the majority of cases the man still has some sperm present in his ejaculate, the issue really is when to start the treatment rather than which treatment to apply.

- Gluco-corticoid therapy for sperm auto-immunity and gonadotrophin treatment for gonadotrophin deficiency result only with 50% success.

- The simplest of treatments in male fertility treatment is artificial insemination. This is usually done with almost 100% success of insemination.

There are other male infertility treatments which involve surgery:

- Transrectal Ultrasound (TRUS)
- Vasography
- Testis biopsy

Male Infertility Testing

Treatment for male infertility will only take place after extensive tests. This is done because unless the cause is established, then there really can be no treatment offered. There isn’t too much which is left out during the investigation stage.

If you’re serious about getting to the bottom of your infertility issue then leave nothing out. Things like a full history check which will include anything from sexual practices, diet and taking of harmful substances will be noted. This all helps in determining any possible causes.

It’s ok to be optimistic during the analysis stage but remember, male infertility treatment can be a long process and in many cases, for no result. You’ll need a steely resolve and plenty of support.

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After six months, it may be time to at least speak to your doctor just for some preliminary testing. This is when both the male and female should undergo some preliminary infertility testing. One of the biggest mistakes couples can make is to assume it’s the woman’s problem.

In about 40% of cases, men will be the ones suffering from fertility issues and the good news is that once it’s determined where the problem lies, it can usually be rectified.

Infertility Treatment

The initial infertility treatment phase will commence with the usual exams. Your part in this initial testing believe it or not should be to maintain a positive outlook and not to dwell on the negative aspects.

Do not try to think to far ahead because this will only mess with your emotions. If ovulation is an issue then your doctor may recommend things such as therapy to induce ovulation. This will mean taking prescription medication and is an inexpensive treatment for infertility.

The numbers of women who experience ovulation issues in regards to infertility is quite high. Some estimates put it at 50%. These are usually rectified following the initial treatment and many end with a happy story to tell.

In the case of fibroid issues, surgery may be a requirement. You will be guided by your doctor here but if issues such as fibroids and endometriosis are hampering your efforts to conceive then surgery could be the initial recommendation.

Advanced Treatments

Plan your treatment program with your doctor. In the majority of cases, the advanced infertility treatment options don’t come into play but if you happen to get to this stage, you need to really think about a couple of issues before proceeding.

Firstly, the cost of these advanced treatments is high. ART(Assisted Reproductive Technologies) for example are expensive.

Secondly, be clear in your own mind whether the expense will be worth it. By this, will it all be a wasted exercise if you don’t become pregnant. Consider the cost factors. Yes, this is an emotional time and you want your own child but commonsense must also prevail.

Consider the risk and success options and the odds of you actually being able to conceive against your financial commitments. It may sound tough but needs to be thought out.

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This is a mistake which is all too common and in recent years, education directed to male infertility testing has gathered momentum.

Home testing kits are available for both men and women. Men with low sperm counts are a real issue in the world of infertility and it’s important to consider all options when trying to find an underlying cause for fertility problems.

Male Infertility

There are many reasons which could contribute to a low sperm count in men. Substance abuse and stress are two of the more common causes. Home testing is not a daunting thing at all. You can have your result in just several minutes. This procedure is painless and involves screening the sperm for quantity, quality and lifespan of the sperm.

Essentially, testing is simply a way of finding the level of concentration of the sperm in the male semen. This method of infertility testing will measure the sperm as being above or below the cut-off of twenty million sperm cells per milliliter.

It may require several tests but if the majority indicate the sperm count as being less than twenty million cells per milliliter, this may be an indication that the male has fertility issues.

Once you have established this then it’s time to visit your doctor. In many cases, low sperm count issues could be turned around quickly depending on the issues causing it. On the other hand, if testing reveals no abnormalities then you have eliminated one possible source of fertility problems.

Female Infertility

Once the male has undergone testing and has met all the requirements to determine there are no fertility problems, then it’s time concentrate on the female.

Again, home infertility testing methods are available but before you begin, it may be beneficial to visit your doctor and discuss your concerns with them. To assume after only several months of trying to conceive that you are infertile is premature.

History shows despite the mental trauma couples facing these issues go through, in most cases, they are resolved with a happy ending.

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