When Is Azoospermic Infertility Treatable Without Intracytoplasmic Sperm Injection?

Robert I. McLachlan


Clin Endocrinol. 2013;78(2):176-180. 

In This Article

Abstract and Introduction


Infertility with azoospermia requires a diligent search for reversible factors and treatment to restore natural fertility, even though most cases are due to untreatable primary spermatogenic failure and are destined to require consideration of assisted reproductive treatment (ART) options. Complete clinical and diagnostic evaluation is essential for avoiding both unnecessary ART and overlooking important co-morbidities. Gonadotrophin deficiency is the most treatable cause, resulting from drug effects or congenital or acquired disease, and medical therapy is highly efficacious. A range of uncommon endocrinocrinopathies may also result in reversible azoospermia. Finally, obstructive azoospermia may be surgically remediable in selected cases.


Assisted reproductive treatments (ART), and intracytoplasmic sperm injection (ICSI) in particular, are remarkably effective in allowing fatherhood in men previously considered sterile, provided a few motile sperm can be isolated in the semen, epididymis or testis.[1] However a pragmatic 'default to ICSI' approach that circumvents a diligent search for reversible factors must be avoided; ART carries substantial heath, psychological and financial burdens, and safety concerns are not fully resolved: clearly couples aspire to conceive naturally. The clinician must critically consider the clinical features and investigations to identify reversible causes and seek to restore natural fertility where possible.

A male factor is the sole or contributory cause in half of the one in eight couples who are infertile. About 10% of infertile men present with azoospermia,[2] a finding that produces despair in the couple who assume they will never have children. An expeditious and thorough evaluation[3,4] will determine if the problem is primary spermatogenic failure (also termed 'non-obstructive azoospermia', NOA), the rare, but critical diagnosis of hypogonadotrophic hypogonadism (HH) due to hypothalamo-pituitary disease, or obstructive azoospermia (OA).

Reflecting severe testicular disease, NOA typically features small testes and an elevated serum FSH, but these are not invariably present and may overlap with normal ranges.[5] Recently, Tuttelmann et al. 2011[2] reported the prevalence of causes and associations of azoospermia in 1583 infertile men. Common associations (rather than necessarily being the singular definitive cause) included cryptorchidism (17%), varicocele (10%) or urogenital infection (10%). Defined causes included chromosomal disorders (15%, overwhelmingly Klinefelter's syndrome), Y chromosomal microdeletions (2%), effects of malignancy or its treatment (15%), and other causes of testicular damage (2%). Although a precise figure cannot be given, no definitive cause for spermatogenic failure (idiopathic infertility) can be identified in about half of men with NOA. As yet, unrecognized genetic or environmental insults affecting the sperm number, motility or function may underlie idiopathic infertility and its association with cryptorchidism and increased testicular cancer risk. In the absence of evidence for effective medical treatments to restore natural fertility, these conditions can be considered irreversible and referral for ART is appropriate. Remarkably, testicular biopsy provides sperm in approximately 50% of men with NOA, even those post chemotherapy[6] or with Klinefelter's syndrome.[7] Neither testicular volume or serum FSH are useful predictors of sperm recovery, but when sperm are available fertility outcomes approach those of the general ART population.

Of the remaining 20% of azoospermic patients, most are accounted for by obstruction (11%), HH (2%) or are associated with systemic disease and its treatments (7%).[2] These populations may present the opportunity to restore natural fertility by medical or surgical means.

Azoospermia is defined as the absence of sperm in the ejaculate based on centrifugation and examination of the pellet.[8] Importantly, semen analysis has a detection limit of approximately 100 000/ml[9] meaning there may well be sperm present in an 'azoospermic' sample. This fact, combined with the intrinsic variability in sperm output, accounts for the well recognized phenomenon of 'intermittent azoospermia'. Increased sensitivity of sperm detection (e.g. fluorescent labelling) reduces the apparent incidence of azoospermia.[10] In any event, at least two analyses are needed to confirm azoospermia; the finding of any sperm on any occasion substantially increases the likelihood that sperm will be available for ICSI in either semen or biopsy tissue by pointing to the presence of active spermatogenesis.

What clinical and laboratory features suggest reversibility of azoospermia? In what setting does one see recovery of fertility by the withdrawal of spermatogenic toxins or agents that suppress gonadotrophins, or that allow effective intervention to stimulate spermatogenesis using gonadotrophin therapy?