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
Altered macrophage and immune activity
Abnormal peristalsis or cilliac activity
Altered macrophage and immune activity
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
Altered cervical mucous
General immune factors
Altered cell mediated immunity
Reduction in motility, acrosome reaction, oocyte binding ,and zona penetration
Ultrasructural abnormalities of head morphology
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
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.
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.
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.
Dr. Lester De Silva ( Registrar Obstetrics & Gynaecology )
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