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Unexplained infertility: Treatments and Recommendations

Defining Unexplained Infertility

In the absence of conception despite twelve months of unprotected intercourse, not explained by anovulation, poor sperm quality, tubal pathology, or any known cause of infertility, after going through standard infertility testing, like hormonal tests, sperm analysis, and scans, we have a case of unexplained infertility.

Some couples linger in this space of uncertainty for a short period of time, but others may never reach a diagnosis. Some medical professionals contest this term, saying there is no such thing, but the truth is that there are a lot of patients struggling and lacking answers, despite lengthy testing.

Between 15% and 30% of all cases of infertility are unexplained infertility. Unexplained infertility is one of the most common diagnoses in fertility care. This condition can be particularly nerve-racking because measuring expectations is close to impossible. Management of this condition relies strongly on the duration of infertility and the age of the female partner.

How is it treated

There is no consensus on what tests should be run in case a case of unexplained infertility, and how to later manage and guide the patients. The treatment is mostly empirical, subject to doctors' opinions based on their experience and patient history. Many different regimens have been used and tailored to the patients specifically. However, the norm is always to move from low-technology to high-technology treatment options.

Some more recent authors and doctors state that the prospects for these patients may often be optimistic. So, let's discuss some treatment options.

The alternatives used as the first-line treatment for unexplained infertility are:
  • expectant management,
  • ovarian stimulation,
  • intrauterine insemination (IUI) with or without ovarian stimulation,
  • in-vitro fertilization (IVF).


In 2022, Merviel and colleagues performed a retrospective study in two assisted reproduction techniques centres to compare overall clinical pregnancy, ongoing pregnancy, and live birth rates when using in-vitro fertilization and intrauterine insemination, across different female age groups. And they concluded with the recommendation of IVF treatment rather than IUI for unexplained infertility. If we take a more in-depth look:

  • A significant difference was observed in the pregnancy and live birth rates per cycle between those who did IUI and those who did IVF, overall and in the different female age groups, except in women aged 40 and over was observed.
  • The greatest chances of pregnancy with intrauterine insemination were found in women with secondary unexplained infertility, during the first two cycles, and with a bi-follicular response to stimulation.
  • In in-vitro fertilization pregnancy rates were higher in women with secondary unexplained infertility, in the first two cycles, in in-vitro fertilization, and in women receiving a transfer of two embryos regardless of their embryonic stage.

Also in 2022, Homburg published a study explaining that as IUI is less invasive, less expensive, more comfortable, and safer with a high compliance rate, it should be recommended as the first-line treatment of unexplained infertility for couples in whom the woman' is up to 38 years old.

Summing up

  • It is important to know that unexplained infertility exists, whether it is because the testing process is flawed or because there is genuinely nothing the tests point to as being wrong.
  • This diagnosis is more common than you might think (up to 30% of all cases).
  • There are treatment options for people with unexplained infertility that vary according to how long the person has been trying to conceive (whether the attempts were natural or via assisted reproductive techniques), the age of the woman trying to conceive, and the monetary resources to pursue further treatment.
  • Have fertility hormone levels tested is one important step to get or discard the unexplained infertility diagnosis.
  • Lastly, it is unknown how long a couple with unexplained infertility might take to conceive, thus psychological support is advised, no matter if the couple chooses to continue treatment or stop it.

The Small Book of Fertility Hormones