Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

14. Unexplained Infertility

Roy Homburg1


Homerton Fertility Centre, Homerton University Hospital, London, UK


Unexplained or idiopathic infertility can hardly be regarded as a diagnosis but more as a lack of diagnosis and basically one of exclusion. This label is attached to couples in whom all the standard investigations such as tests of ovulation, tubal patency and semen analysis are normal and has been applied to as many as 30–40 % of infertile couples depending on the duration of the infertility from 1 to 3 years. Intervention is generally indicated if the duration of infertility is >2 years or the female age is >35 years. Otherwise, some would recommend expectant treatment. Female age is critical in deciding when to intervene. Treatment with IUI, clomifene and aromatase inhibitors alone are relatively ineffective and the decision usually rests between controlled ovarian stimulation (COS) with gonadotrophins + IUI or IVF. Despite recent guideline recommendations, COS + IUI is a viable option with female age <38 and <3 years infertility (pregnancy rate 8–20 %) before resorting to IVF (15–40 %).


InfertilityUnexplained infertilityOvulationTubal patencySemen analysisSpermZona pellucidaOvumLaparoscopySpontaneous pregnancyPartner’s ageFemale ageMale ageOvarian reserveOvulation-inducing agentsClomiphene citrateAromatase inhibitors gonadotrophinsControlled ovarian stimulationIntrauterine insemination IUIIn-vitro fertilizationIVFOvarian stimulationTubal flushingPerturbationFallopian tube sperm perfusionGamete intra-Fallopian transfer

Unexplained or idiopathic infertility can hardly be regarded as a diagnosis but more as a lack of diagnosis and basically one of exclusion. This label is attached to couples in whom all the standard investigations such as tests of ovulation, tubal patency and semen analysis are normal. Unexplained infertility is a term that has been applied to as many as 30–40 % of infertile couples depending on the duration of the infertility in the definition of unexplained infertility that was applied.

14.1 Diagnostic Tests

The high prevalence of unexplained infertility is a reminder of the lack of accuracy and subtlety of the diagnostic examinations employed. For example, tubal patency does not necessarily indicate normal tubal function, a normal routine semen examination tells us little about the functional capacity of the sperm and its ability to penetrate the zona pellucida and proof of ovulation tells us nothing about the quality of the ovum. The label of unexplained infertility, it could be argued, is dependent on the quality and quantity of the diagnostic tests employed, e.g. the performance of a laparoscopy rather than less invasive tests of tubal patency. The most frequently ‘missed’ diagnoses are probably endometriosis, mild degrees of tubal infertility and impending premature ovarian failure. Though these subtle causes may be responsible for so-called unexplained infertility, it may not be in the best interests of the couples to subject them to a battery of invasive or often very expensive tests. The results may well only fulfil clinical curiosity without helping in better clinical decision making. In the present climate of therapeutic ‘corner-cutting’, regardless of the results of the more sophisticated tests, the decision regarding the treatment options will most often be the same.

14.2 Definition

Most official definitions (e.g. NICE Guidelines [1]), state that a failure to conceive after a period of 2 years of normal, regular, unprotected intercourse should be defined as infertility. A large variation in suggested definitions is seen in the literature including a failure to conceive over a period ranging from 1 to 3 years of unprotected intercourse in the face of normal baseline investigations. Controversially, Gnoth et al. [2] defined infertility as failure to conceive after six cycles of unprotected intercourse irrespective of age.

For the infertile couple, a “diagnosis” of unexplained infertility may be very frustrating and is often interpreted by them as meaning that if there is no explanation for the cause of infertility, there is, therefore, no effective treatment. It may often be difficult for the practitioner to encourage expectant treatment after 1 year’s infertility. Although statistically this may be correct advice, as in the general population of couples attempting conception, 84 % will conceive after one year and 92 % will conceive after 2 years, I have not met many couples who agree to do nothing and wait.

14.3 When to Intervene

It is rare for couples to wait for 2 years before consulting help and they should be referred for investigations after 1 year. If, as a result of the consultation and basic examinations, no cause for the infertility has been forthcoming, a decision as to if and when to start empirical treatment or to employ an expectant policy (i.e. do nothing), has to be taken. In general, prognostic factors related to a higher cumulative spontaneous pregnancy rate during an expectant period are infertility <24 months, a previous pregnancy in the same relationship and female age <30 years. In this case, the couple may be encouraged to wait because they probably have a similar chance of achieving pregnancy with or without any treatment. Treatment is generally indicated if the duration of infertility is >2 years or the female age is >35 year [34]. Importantly, the prognosis is worse when the duration of infertility exceeds 3 years and the female partner is >35 years of age [4]. Female age is critical in deciding when to intervene. For each year of the female partner’s age beyond 30 the pregnancy rate is reduced by 9 %. The definition of unexplained infertility is often a mistaken one in women more than 40 years of age. The main factor for infertility in this group is reduced ovarian reserve which, if found on testing, no longer renders a diagnosis of ‘unexplained’ feasible.

Following a duration of 1 year of infertility, a spontaneous pregnancy rate of 5.9 % was quoted in an unexplained infertility group while on the waiting list [5]. Pragmatically, what is occurring in the field despite some statistically based recommendations that expectant treatment is as effective as various treatment interventions, is that couples with unexplained infertility are being treated, regardless of female age, after 1 year of unexplained infertility in the majority of centres.

14.4 Treatment Options

Traditional treatment options in this group of patients have been expectant management (EM), ovulation-inducing agents (clomiphene citrate, aromatase inhibitors), gonadotrophins (controlled ovarian stimulation, COS) with or without intrauterine insemination (IUI) and in-vitro fertilization (IVF). Currently there is a lack of agreement among infertility specialists with regard to first line treatment of couples with unexplained infertility. Some consider expectant management for young couples with a short period of infertility (1 year). Others consider a short trial of IUI with or without COS with gonadotrophins followed by IVF. Some directly offer IVF, especially to older women or those with a long duration of infertility. Although these couples are tolerant of a short period of expectant management, the majority opts for more active treatment if it proved unsuccessful within a given time period. Although for women >35 years of age and those with poor ovarian reserve and long duration infertility, IVF seems a reasonable first line option, the use of gonadotrophins for COS + IUI is presently widely accepted for all instances of unexplained infertility except for women of age 40 years or more.

Assuming that the female partner of the couple with unexplained infertility is <40 years old, has a duration of infertility <3 years and has an acceptable ovarian reserve, the treatment options employed are listed here in a tentative order of efficiency according to estimated pregnancy rates/cycle.

·               Expectant management (1.8–6 %)

·               IUI (4–8.4 %)

·               IUI with clomifene stimulation (6–7 %)

·               IUI with gonadotrophin stimulation (8–20 %)

·               IVF (15–40 %)

These may be regarded as ‘wild’ estimates taken from a very large number of very heterogeneous trials. They do, however, indicate a rough ‘pecking order’.

The new National Institute for Health and Clinical Excellence (NICE) guidelines on fertility (2012) [1] suggests that COS + IUI should not be offered to women with unexplained infertility of more than 2 years standing through the NHS [1]. They proposed to offer IVF to these couples. A further call for the abandonment of gonadotrophin/IUI treatment for unexplained infertility in favour of IVF has been made recently [6]. However, the evidence on which these recommendations are based is not robust. The possible increase in effectiveness of IVF over IUI + COS should be considered carefully after evaluating its invasiveness and the incremental cost per cycle. Also IUI + COS might be more acceptable to some patients over IVF, medically or financially. Strengthening this point of view, a study from The Netherlands randomised 116 couples with unexplained infertility and a poor prognosis for natural conception into groups receiving either three cycles of IUI-ovarian stimulation or one cycle of IVF with elective single embryo transfer (eSET) [7]. Ongoing pregnancy rates were 24 and 21 % in the IVF and IUI groups respectively with no difference in the number of multiple pregnancies, two and three respectively. The one cycle of IVF was significantly more expensive than three cycles of IUI. The authors concluded that IUI-ovarian stimulation is the preferred treatment and, interestingly, calculated that until IVF eSET results reach >38 % for ongoing pregnancies, this conclusion would hold good.

Details of ovarian stimulation used with IUI and the results are set out in the next chapter. A suggested algorithm for the treatment of unexplained infertility is shown in Fig. 14.1.


Figure 14.1

A suggested algorithm for the management of unexplained infertility

No mention has been made here on the treatment of unexplained infertility by tubal flushing or perturbation, Fallopian tube sperm perfusion or gamete intra-Fallopian transfer (GIFT) as these are methods rarely used today.



NICE Guideline. Fertility: assessment and treatment for people with fertility problems. NICE Clinical Guideline 156. 2013, –4.


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