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Idiopathic infertility 

Idiopathic infertility
Idiopathic infertility

Eberhard Nieschlag

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date: 26 May 2022

There are a multitude of disorders that lead to hypogonadism and infertility, but despite this the largest group of infertile men are those diagnosed as suffering from ‘idiopathic infertility’. These men constitute about a third of the patients attending infertility clinics (1, 2).

The term ‘idiopathic infertility’ has different meanings in andrology and gynaecology. In gynaecology, the term ‘female idiopathic infertility’ refers to a condition in which clinical examination does not reveal any pathological finding which might explain the infertility of the couple. Here it would be more accurate to speak of ‘unexplained infertility’.

‘Male idiopathic infertility’ does not imply absolute infertility, unless azoospermia is found. Patients with idiopathic infertility might father children, but the likelihood of paternity is reduced and the time taken to achieve pregnancy is extended.

The term ‘idiopathic infertility’ designates diagnosis by exclusion. Only after all other possible causes of infertility have been eliminated can the diagnosis of idiopathic infertility be established. Seminal parameters are frequently abnormal, and may be associated with elevated follicle-stimulating hormone (FSH), indicating spermatogenic failure. No other endocrine abnormalities are usually found. Testicular biopsies often show abnormalities in spermatogenesis or spermiogenesis, which range from complete or focal Sertoli cell-only (SCO) syndrome to spermatid arrest (Chapter 9.4.2). Descriptive histological findings fail to contribute either to the explanation of pathogenesis or to rational treatment.

In recent years, a number of pathological entities were identified that were previously included in idiopathic infertility. Examples include Y-chromosomal microdeletions, CFTR gene mutations, FSH receptor mutations (3), and androgen receptor mutations (4). However, these pathologies appear to be reserved for small groups of patients, as demonstrated by the example of FSH receptor mutations (5). Nevertheless, similar infrequently occurring conditions may be discovered in future, slowly lifting the curtain obscuring idiopathic infertility. Idiopathic spermatogenic defects may result from the lack of, or inappropriate, expression of local and intracellular modulators of germ cell proliferation and development. Very little of clinical relevance is yet known about these factors. An example for such a factor is cyclic AMP (cAMP) responsive element modulator (CREM), which was shown to be lacking in patients with idiopathic round spermatid arrest (6). However, whether the lack of this factor is a symptom or the cause of the arrest remains to be elucidated. Further new insights from investigations of immunological, infectious, or biochemical factors are expected. More research to help patients with idiopathic infertility is clearly needed.

As long as pathogenetic mechanisms fail to be identified, no rational treatment of idiopathic infertility will exist. In past attempts to treat these patients, various empirical approaches have been applied; however, these have to be scrutinized in the context of evidence-based medicine (Chapter 9.5.1).

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