Unexplained Infertility & Effective Fertility Treatments

Unexplained infertility at a glance

  • “Unexplained infertility” is a clinical diagnosis given to couples and individuals whose cause of infertility cannot be determined with history, typical tests, and exams.
  • It is the diagnosis given in up to 30% of infertility cases after initially evaluating the male’s sperm, the female’s eggs and the reproductive anatomies of both partners.
  • Unexplained infertility is indicative of both the complex nature of infertility causes and the importance of continuing infertility research to improve our diagnostic abilities.
  • Having unexplained infertility does not mean a couple or person cannot get pregnant; it just means that it is challenging to determine the best course of treatment.
  • We can use treatments to attain pregnancy in many cases, including ovarian stimulation with intrauterine insemination (IUI) and in vitro fertilization (IVF).

What is unexplained infertility?

When the history, tests, physical examinations and professional evaluation of couples or individuals having difficulty conceiving do not indicate a clear cause, a fertility doctor will give a diagnosis of unexplained infertility. This does not mean the infertility has no cause. It just can’t be pinpointed, and further efforts are needed to arrive at appropriate treatments.

In the meantime, fertility doctors usually encourage unexplained infertility patients to keep trying to conceive naturally. Different studies cited by the American Society for Reproductive Medicine (ASRM) indicate that many couples finally do conceive with no treatment after a diagnosis of unexplained infertility. ASRM reports that anywhere from 10%-30% of infertile couples have unexplained infertility.

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Fertility testing before arriving at an unexplained cause of infertility

The fertility testing begins by focusing on the major issues, such as the male’s semen with a semen analysis and the female’s ovulation. If the periods are regular, ovulation is almost a certainty. Other medical conditions like chronic illnesses or past sexually transmitted diseases that could be causing infertility are also ruled out.

The female has a physical exam and an ultrasound of the uterus and ovaries is performed, looking for issues with her reproductive system. Some examples could be issues with the uterus such as abnormalities from birth or uterine fibroids. Imaging tests by x-ray and hysterosalpingogram (HSG) check for blocked fallopian tubes.

Unidentified doesn’t mean undiscoverable – or untreatable

Unexplained infertility couples have normal anatomy and male factor yet are sub fertile. The underlying cause or causes of infertility may have eluded a fertility team on the first pass, but fertility doctors are not likely to give up there.

A subgroup of patients with diminished ovarian reserve can now be separated out from the conventionally undiagnosed group. The ovarian ultrasound can count antral small follicles and the anti-Müllerian hormone (AMH) test predicts those who have premature ovarian aging.

In women younger than 35 with unexplained infertility, fertility doctors may offer laparoscopy to look for endometriosis, which can hamper embryo implantation. This is highly indicated in women with significantly painful periods.

For men, if the semen analysis is normal, male examination is not helpful. The function of tests of sperm such as DNA fragmentation remain controversial. 

Deciding to move forward with infertility treatment

The fertility specialist will discuss the advisability of such tests and exams with the couple or individual, depending on their circumstances. Most patients want to move forward with treatment. Others with an unexplained infertility diagnosis may wish to continue to try conceiving naturally.

Getting a diagnosis of unexplained infertility can be very frustrating and cause even more stress than learning a definitive cause. Trying to decide on attempting a specific treatment when the doctor is not sure of the cause may seem like a leap of faith. But it’s no different than with many medical situations when patients trust in their physician’s experience, skills and professional judgment, even when outcomes are uncertain.

Still, these can be difficult decisions. A fertility doctor will help the patients make the choice that is right for them on a personal level, considering all factors.

Fertility treatments for unexplained infertility

Primary treatments for unexplained infertility are ovarian stimulations, intrauterine insemination (IUI) and in vitro fertilization (IVF). These treatments are offered, depending on the individual’s or couple’s conditions and desires, weighing the costs, risks, and benefits of each.

In general, fertility doctors will try the least invasive treatment methods first. These may include advising the patient, as appropriate, about lifestyle changes, such as the following, that could improve fertility.

  • Timing sexual intercourse with predicted ovulation using over-the-counter kits can help.
  • Stopping smoking and drinking excess alcohol, which can inhibit fertility.
  • Striving for a healthy weight, since being underweight, overweight or obese can contribute to infertility.

Fertility drug treatments like Clomid, letrozole and gonadotropins

Clomid (clomiphene citrate) with IUI

The oral fertility medication, clomiphene citrate (brand name Clomid) is often the first drug used for unexplained infertility cases. Clomid increases the number of eggs a woman’s ovaries produce each month for fertilization. An ultrasound is used to pinpoint follicle development and ovulation is triggered with an injection. Then IUI is performed.


Like Clomid, letrozole can be used to increase the number of eggs a woman’s ovaries produce, and hence the chance for pregnancy. Letrozole accomplishes this in a different manner than Clomid, with fewer side effects. Both letrozole and Clomid enhance a woman’s ovulation and chance of conception.

IUI is the process of placing sperm into the upper part of a woman’s uterus near the fallopian tubes. IUI increases the odds of pregnancy by making it more likely that sperm will reach and fertilize the egg in the fallopian tubes.

IUI can sometimes be used alone, but it is most often used for unexplained infertility in conjunction with medications. Taking Clomid or Letrozole alone or IUI alone are ineffective. The combination of ovulation induction (OI) and IUI is the best procedure.


Fertility doctors may also use injectable gonadotropin medications, which are the reproductive luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In males, gonadotropins stimulate sperm production, and in females they stimulate ovulation. Because of risk of triplets, gonadotropins is only uncommonly used in IUI.

IVF and combinations with fertility drugs

IVF has three times the success of OI/IUI. IVF is the most successful treatment for unexplained infertility because it works around a variety of both male and female factors that can be at play.

Risks of treatments

Fertility medications increase the likelihood of having a multiple pregnancy, which is twins or more. A multiple pregnancy adds risks to the mother and child during birth and to the child’s development. IVF carries risks of a hyperstimulation of the ovaries, damage to organs, bleeding and pain.