When is azoospermic infertility treatable without intracytoplasmic sperm injection?
Correspondence: Robert I. McLachlan, Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Vic. 3168, Australia. Tel.: 61-3-95943561; E-mail: email@example.com
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. 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, 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. Recently, Tuttelmann et al. 2011 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 or with Klinefelter's syndrome. 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%). 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. Importantly, semen analysis has a detection limit of approximately 100 000/ml 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. 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?
Reversible causes of azoospermia
A complete medical history and examination (including of the genitals), complemented by semen analysis and morning reproductive hormone testing (FSH, LH, T, SHBG, calculated free T, prolactin), assists in identifying remediable causes of infertility (Table 1), and co-existent testosterone deficiency in this ‘at risk’ population. Testicular examination should include volume estimation by orchidometry or ultrasound (normally 15–35 ml); reduced size suggests testicular failure whereas volumes are normal in OA. In some cases of NOA, testis size and serum FSH overlap the normal range, classically germ cell arrest at the spermatocyte stage can ‘masquerade’ as OA, and testicular biopsy is required for diagnosis.[5, 13]
Table 1. Reversible causes of azoospermia
| Secondary testicular failure |
| Kallmann's syndrome, other idiopathic isolated HH|
| Prepubertal HH and combined deficiencies|
|Sex steroid mediated suppression|
|Androgenic steroid misuse or abuse|
|Oestrogen use in transgenderism|
|Opiate use and abuse|
|Sex steroid secreting neoplasia – Leydig cell, adrenal|
|Congenital adrenal hyperplasia|
|Nonfunctioning adenoma, trauma, infiltrative disease|
| Primary testicular failure |
| Obstructive azoospermia |
| Ejaculatory duct obstruction – Mullerian duct cyst.|
Secondary testicular failure
These diagnoses represent the most treatable form of infertility although other pituitary hormone deficiencies may co-exist resulting in significant non reproductive sequelae. Clinical features may include pubertal failure in congenital cases (e.g. Kallmann's syndrome, other types of idiopathic or acquired HH) or severe androgen deficiency in adult-onset disease (pituitary surgery, radiotherapy, trauma and haemochromatosis).
Congenital isolated HH displays a spectrum of severity and may escape detection until presentation with infertility, small testes, azoospermia, features of androgen deficiency and, in the case of Kallmann's syndrome, anosmia and olfactory bulb hypoplasia on MRI. Isolated HH displays only androgen deficiency and pubertal failure, whereas other congenital or prepubertal onset pituitary disorders may feature other hormonal deficiencies.
Natural fertility can often be restored with exogenous gonadotrophins with the prospects being better in those with large initial testicular volumes and no prior cryptorchidism.[14, 15] Treatment with human chorionic gonadotrophin (hCG, an LH substitute; 1000–2000 IU 2–3 times per week sc) alone may restore fertility in men with post pubertal onset HH, whereas co-administration of FSH (75–150 IU three times per week sc) is required in congenital cases. Testicular growth, serum testosterone and semen quality is monitored every 2 months: in congenital cases optimal outcome may not be apparent until 2 years of therapy. Natural fertility can be established in approximately 70% and >90% of congenital and acquired cases, respectively; interestingly the average sperm density at conception is approximately 5 million/ml underscoring the qualitative normality of spermatogenesis. ART/ICSI provides a ‘backup’ should semen quality prove insufficient for timely natural conception.
Acquired gonadotrophin deficiency
Gonadotrophin deficiency may occur in isolation or in conjunction with other pituitary hormone deficiencies; in either event, infertility, androgen deficiency and azoospermia may be the presenting features. Some of the more common causes include the following:
Sex steroid use/abuse
Most anabolic steroid abusers are well aware that this practice reduces testicular size and induces infertility. Usage may be denied, even to the extent of having their partners (some of whom are complicit) undertake ICSI. Non confrontational and non judgmental questioning is essential. Although certain groups have a high prevalence e.g. body builders and security guards, clinical evidence of androgen excess (excess muscularity or acne) or gynaecomastia may be absent, and azoospermia be present despite normal-range testicular volumes.
Azoospermia results from sex steroid negative feedback on gonadotrophin secretion and occurs in about two-thirds of normal men given even modestly supraphysiological testosterone doses in male hormonal contraceptive trials. Sex steroid (pharmaceutical or veterinary) use may be openly declared or be surreptitious: a clue to diagnosis is an undetectable serum LH associated with a low SHBG, and a serum testosterone that is either high (if the native molecule is used) or undetectable (synthetic androgens, such as nandrolone, do not cross react in the immunoassay). The latter profile also suggests hypothalamo-pituitary pathology and further endocrine testing and imaging may be needed. Chromatographic analysis of serum or urine and the ratio of testosterone to epitestosterone, as used for athletic drug detection, will confirm the diagnosis.
The endocrine picture may be complicated by the concomitant administration of drugs, such as tamoxifen (to promote endogenous gonadotrophin release or prevent gynaecomastia) and hCG (to stimulate endogenous androgen and testicular growth), and complex ‘stacking’ regimens aimed at avoiding detection and optimizing perceived benefit. Variable hormonal profiles reflecting ‘disequilibrium’ are seen due to different clearance rates of drugs. When androgens are ceased, sperm output returns over 3–12 months. During this time, transient symptomatic androgen deficiency may occur due to a lagging recovery in gonadotrophin secretion producing a clinical picture suggesting acquired HH. Anecdotal reports of non reversibility after chronic abuse may be due to unrecognized intercurrent illness.
One related clinical point is the misuse of testosterone replacement for newly diagnosed androgen deficiency in men presenting with infertility. Remarkably, well-meaning clinicians still give testosterone to ‘boost sperm counts’. As a rule, even in androgen-deficient NOA men, testosterone therapy should not be commenced until their fertility aspirations have been considered, and if not immediately planned, cryopreservation of testicular sperm considered.
Sex steroid secreting neoplasia
Azoospermia with suppressed gonadotrophins and normal-to-elevated serum testosterone levels also suggest an endogenous source of testosterone secretion. Adrenal or testicular neoplasms can secrete testosterone, oestradiol and a range of metabolites that can suppress gonadotrophins and spermatogenesis.
Leydig cell tumours (LCTs) account for 1–3% of testicular tumours; 90% are benign and 10% are bilateral, and are often detectable only on ultrasound. Excessive oestrogen secretion predominates, producing gynaecomastia or infertility; the return of normal sperm output has been reported in an azoospermic man after removal of a small LCT tumour.
Adrenal neoplasia and infertility are rare, but benign adrenal tumours can be indolent and present similarly to benign LCTs. Detection requires a screen for adrenal androgens (androstenedione, 17-OH progesterone, dehydroepiandrosterone sulfate), imaging, and, possibly, confirmatory venous sampling, given the high incidence of ‘incidentalomas’. Hyperestrogenism leads to feminization and suppressed gonadotrophins, testosterone and spermatogenesis, but rarely azoospermia.
Congenital adrenal hyperplasia
Poorly controlled congenital adrenal hyperplasia (CAH) may induce azoospermia via gonadotrophin suppression by elevated steroid metabolites, such as androstenedione and/or by intra-testicular obstruction from adrenal rest tissue. The latter can be mistaken for testicular neoplasia; the finding of multiple lesions, almost always bilateral, suggests the diagnosis if this has not already been made. Effective glucocorticoid therapy may restore gonadotrophin levels and/or relieve obstruction leading to natural fertility, but persistent intra-testicular obstruction may require ICSI.
Hypothalamo-pituitary gonadotrophin secretion
Prolactinomas are the most common tumours, usually presenting with severe androgen deficiency (loss of libido, erectile failure) and mass effects (headache, visual field defects), but may also present with infertility. Oligospermia rather than azoospermia is found, perhaps as more severe cases are unable to produce an ejaculate. Serum prolactin must be routinely assessed in the setting of suppressed testosterone and gonadotrophin levels. Dopaminergic agents often substantially reduce tumour size and prolactin levels and, depending on stalk anatomy and gonadotrophic cell mass, restore both androgen secretion and spermatogenesis.
A wide range of other neoplasms/cysts, cranial surgery, radiation or trauma can similarly result in severe HH and potentially azoospermia. In post pubertal men with normal premorbid fertility, gonadotrophin therapy as described above will restore fertility.
Chronic opiates use (e.g. chronic pain relief) can profoundly suppress GnRH release, inducing severe HH and oligospermia or potentially even azoospermia. If use is to continue and fertility is sought, hCG will restore both virilization and spermatogenesis.
Primary spermatogenic failure
Azoospermia is frequent during chemo- and radiotherapy underscoring the need for pre treatment cryopreservation. However azoospermia may be transient given the reduced gonadotoxity of modern regimens, e.g. normal fertility is seen in the vast majority of men treated with AVBD for Hodgkin's disease. Regimens using alkylating agents or total body irradiation and pre pubertal exposure, are associated with higher rates of azoospermia. Major disease burden at diagnosis may itself cause of azoospermia which may be reversed by return to good health. Men presenting with testicular cancer have a higher incidence of underlying spermatogenic problems and, as they will lose one testis, and may have subsequent adjuvant therapies, their prospects of eventual natural conception is poor. If an orchidectomy is planned, sperm isolation from an uninvolved section of the testis may provide the last opportunity for fertility preservation.
Although there are many common drugs used in non malignant conditions may impair spermatogenesis (notably salazopyrine, colchicine, methotrexate), azoospermia has not been reported.
The decision to attempt surgical reversal in obstruction to restore natural fertility depends on many factors, both anatomical and pragmatic. In the case of vasectomy, the duration of obstruction and the type of procedure affect the surgical outcome. Commentaries have appeared on the relative cost effectiveness of surgery vs ART/ICSI, especially regarding vasectomy. Microsurgical expertise is critical and treatment outcome must focus on live birth rates over a realistic time frame, not the return of sperm (patency) as semen quality can be poor. The ever increasing age of female partners of men presenting with vasectomy-related azoospermia mean that their fertility window is brief and often the couple elect to go for the immediacy of ICSI. Many factors also play on this decision e.g. desire for only one child, time off work for the male partner, the need for repeat vasectomy and the prevailing health care system.
Less common settings for surgical restoration include vasal repair after transection during hernia surgery, vaso-epididymostomy for traumatic or post-infective epididymal lesions, and ejaculatory duct obstruction due to infection, surgery or Mullerian duct cyst.[30, 31] Occasionally, sperm can be stored at initial surgery for later ICSI, but some obstructive lesions can only be addressed by ICSI, for example bilateral absence of the vas deferens or after extensive prostatic surgery. It is reassuring that, should surgery fail to provide semen quality adequate for natural conception, ICSI remains an effective ‘fall back’ option. Sperm are invariably obtainable by needle aspiration or testicular biopsy and the outcome of treatment is determined largely by the female partner's age and health.
In summary, most azoospermic men have untreatable primary spermatogenic failure and are destined to consider assisted reproductive treatment. However, careful clinical evaluation will identify a significant minority for whom natural fertility can be restored by addressing gonadotrophin deficiency or other endocrinocrinopathies and, in selected cases, by surgery for obstructive azoospermia.
RMcL is a Principal Research Fellow of the Australian NHMRC # 1022327.