Male and Female Idiopathic Infertility: What Are the Available Options?

What is idiopathic infertility or unexplained infertility (UI)?

Infertility is defined as the inability to achieve pregnancy after 12 months of regular unprotected sexual intercourse (or after 6 months in women over 35 years of age).

Unexplained infertility refers to the same situation, but without an apparent cause; in other words, when all the basic fertility investigations performed in both partners yield completely normal results. This definition is supported by the leading scientific societies in the field, including the European Society of Human Reproduction and Embryology (ESHRE), the American Society for Reproductive Medicine (ASRM) and the Spanish Fertility Society (SEF).

It is therefore a diagnosis of exclusion, established only after ruling out the known pathophysiological causes of infertility through the standard fertility assessment, which includes semen analysis (seminogram) in the male partner, confirmation of ovulation in the female partner and assessment of Fallopian tube patency. According to ESHRE, even when standard investigations are normal, abnormalities that current diagnostic methods are unable to detect may still be present.

This has an important implication: it does not mean that everything is normal, but rather that the underlying problem exists below the detection threshold of the diagnostic tools currently available.

Statistics on male and female idiopathic infertility

From an epidemiological perspective, the Spanish Fertility Society (SEF) estimates that 10% of infertility cases are idiopathic (while the remaining cases are distributed as approximately 30% female factor, 30% male factor and 30% mixed factor infertility).

A male factor is involved in around 50% of infertile couples, and approximately 30% of these men present abnormalities in semen quality without an identifiable cause. In women, unexplained infertility is estimated to account for between 10% and 17% of cases.

In the following sections, we explore the possible mechanisms that may explain why pregnancy does not occur in both men and women.

Causes of idiopathic male infertility

In men, idiopathic infertility is defined as the presence of abnormalities in semen quality without an identifiable cause based on the medical history, physical examination of the male reproductive system or standard complementary investigations. It may also refer to men with apparently normal semen parameters whose partners are diagnosed with unexplained infertility.

It is important to note that the seminogram evaluates only the basic sperm parameters, such as concentration, motility and morphology, but it cannot assess the functional capacity of sperm. Therefore, even when the seminogram is normal, alterations may still exist that impair the sperm’s ability to fertilise an egg or negatively affect embryo development, including the following:

• Sperm DNA fragmentation: a man may have a completely normal seminogram while presenting high levels of DNA damage in his sperm. For this reason, the European Association of Urology recommends evaluating sperm DNA fragmentation in couples diagnosed with unexplained infertility.
• Seminal oxidative stress: an excess of reactive oxygen species within the testes may damage sperm DNA, motility and morphology.
• Genetic factors: the possible involvement of genetic mutations that have not yet been identified is currently under investigation.
• Environmental and lifestyle factors: exposure to endocrine-disrupting chemicals, heat, tobacco, obesity and subclinical genital infections may impair spermatogenesis.

Causes of idiopathic female infertility

In women, unexplained infertility means that the standard fertility assessment—including confirmed ovulation, patent Fallopian tubes, a uterine cavity without apparent abnormalities and a normal hormonal profile—does not reveal any cause that could explain the absence of pregnancy.

However, current research points to several possible pathophysiological mechanisms that may underlie this condition but remain undetectable using today’s diagnostic methods.

Uterine factor

The uterus is clearly one of the key organs required for pregnancy to occur. It is a dynamic microenvironment whose receptivity at the appropriate stage of the menstrual cycle is essential for embryo implantation.

One possible explanation for unexplained infertility is impaired endometrial receptivity that cannot be detected by standard diagnostic tests.

Another mechanism currently under investigation is abnormal uterine peristalsis. The uterus is composed mainly of muscle tissue known as the myometrium. Contractions of this tissue facilitate sperm transport towards the Fallopian tubes. Disruption of these contractions may hinder fertilisation despite the absence of any obvious uterine pathology.

The role of the uterine immune system, particularly endometrial plasma cells, is also being investigated. Successful pregnancy requires maternal immune tolerance towards the embryo. An imbalance in this immune tolerance could compromise embryo implantation.

A recent study found that a significant proportion of women previously classified as having unexplained infertility were diagnosed with endometriosis following diagnostic laparoscopy, raising the question of how many cases of unexplained female infertility may actually correspond to minimal or mild endometriosis that remains undetected using conventional diagnostic techniques.

Cervical factor

Cervical mucus plays an important role in achieving pregnancy because it facilitates the passage of healthy sperm, allowing them to ascend through the female reproductive tract towards the Fallopian tubes.

Although less extensively studied in unexplained infertility, alterations in cervical mucus—such as changes in its composition or viscosity—are believed to impair sperm transport without being detectable through standard fertility investigations.

Treatments for unexplained infertility

A diagnosis of unexplained infertility does not mean that there are no treatment options available. Reproductive medicine offers a range of assisted reproductive treatments, which should be tailored according to the couple’s prognosis, the woman’s age and the duration of infertility.

Expectant management

Expectant management for approximately six months is the first option for couples with a favourable prognosis. During this period, couples are advised on healthy lifestyle habits, sexual intercourse is optimised and clinical follow-up is provided.

Intrauterine insemination

This is the first-line active treatment. It is indicated for couples with a less favourable prognosis or for those who have not achieved pregnancy after six months of expectant management.

Between three and six treatment cycles are generally recommended before proceeding to IVF, unless there are circumstances that justify earlier escalation.

In vitro fertilisation

This is the second-line treatment and is indicated when intrauterine insemination has not been successful or in selected cases where IVF is recommended as the initial treatment, such as advanced maternal age or diminished ovarian reserve.

It has been shown to improve live birth rates compared with expectant management in these patients.

IVF also makes it possible to identify certain causes of infertility that would otherwise remain undetected, such as fertilisation failure or impaired embryo development.

Frequently asked questions

How many types of infertility are there?

From an aetiological perspective, there are four types of infertility: female infertility (tubal, ovulatory, uterine, cervical factors, etc.), male infertility (testicular, genetic causes, etc.), mixed infertility, when both partners present fertility disorders, and unexplained infertility.

From a clinical perspective, infertility is also classified into two types: primary infertility, in couples who have never achieved a pregnancy, and secondary infertility, when there has been a previous pregnancy, including pregnancy loss.

Can unexplained infertility disappear?

Yes, this can occur in some cases.

A proportion of couples diagnosed with unexplained infertility achieve spontaneous pregnancy, particularly those with a favourable prognosis. This is why expectant management is one of the recommended therapeutic approaches in these situations.

It is also possible that, as new scientific evidence and diagnostic tools become available, some cases currently classified as unexplained infertility will eventually receive a specific diagnosis.

How can you maintain a positive attitude during infertility?

A diagnosis of unexplained infertility carries a particular emotional burden because it is accompanied by the uncertainty of not knowing the underlying cause.

First of all, it is important to understand what this diagnosis means. It does not mean that there is no problem or that everything is “fine”; rather, it means that, at present, we are unable to detect the underlying cause. However, this does not mean that there are no treatment options or that pregnancy is impossible.

It is also important to remember that couples facing this diagnosis are not alone. Thousands of couples experience unexplained infertility, and specialised support resources are available throughout the process.

Some recommended strategies include maintaining good communication as a couple, seeking specialised psychological support and adopting healthy lifestyle habits. In this regard, how to cope with a diagnosis of unexplained infertility can provide useful tools and recommendations for managing the uncertainty associated with this diagnosis.

Dr Sofía Olalla, Gynaecologist at Instituto Bernabeu Madrid.