Infertility, as defined by the failure to conceive after one year of unprotected intercourse, affects 15-20%
of couples with a male-related problem wither directly responsible or contributory in up to 50% of all
cases. Infertility is a couple phenomenon and evaluation and treatment for both male and female factors
should be carried out at the presentation to maximize the couple’s reproductive potential. Age related
decline in female fertility has been well documented and as the general population continue to postpone
childbearing, previously compensated male factor cases are likely to become more apparent as the
female partners get older.
Recent advances in assisted reproductive technology, namely in vitro fertilization with intracytoplasmic
sperm injection (IVF/ICSI), has offered hope for couples with severe male factor infertility previously
considered not manageable; this initial success has led some to suggest that evaluation and treatment for
male factor infertility is no longer pertinent provided that minute quantity of sperm are available for
IVF/ICSI. This “IVF for all” approach was based on premature enthusiasm using “best case scenario”
pregnancy rate and failed to consider the following facts:
1. Significant medical conditions, including life threatening ones such as testis cancers, may present as
male infertility. Diagnosis and cause-specific treatment of these conditions is possible only after a
thorough male factor evaluation.2. The progressive and potentially irreversible nature of varicocele-induced testicular injury: varicocele
may lead to the progressive deterioration of semen quality as shown by Cheval and others. Despite
the fact that varicocele repair in the subfertile, males is unequivocally beneficial as demonstrated by
Madgar’s cross-over study, not all men showed improvement following varicocele repairs. In a large
retrospective review of 15 papers encompassing 2466 men, Pryor and Howards reported an overall
rate of improvement in semen quality of 66% with an overall pregnancy rate of 43%. As such,
varicocele-related subfertility should be promptly treated to prevent progressive testicular injury and to
maximize the chance of recovery.
3. The significant cost advantage of cause-specific treatment for male infertility when compared with
IVF/ICSI: the cost per live birth following varicocelectomy ($26,268) and vasectomy reversal
($25,475) was significantly lower when compared to IVF/ICSI ($72,521 to $89,091).
4. The potential for both short and long term female side effects following ovarian hyper stimulation for
IVF. It is then logical that a potential male factor should be considered as an integral part of a
couple’s infertility evaluation and if present, be investigated and specifically treated if possible.
Despite our increasing understanding of male infertility, many men with abnormal seminal analyses for
whom no definitive explanation exist; evaluation in these men nevertheless serves to exclude the
presence of any treatable conditions and allows for the selected use of empiric medical treatment, ART or
other reproductive options such as donor insemination and adoption. It also serves to avoid unnecessary
expenditure in time and valuable resources on measures, which are unlikely to be productive.
The evaluation for male infertility is straightforward and can be promptly accomplished in most men. The
standard approach has not changed significantly and is familiar to all urologists. Recent advances with
IVF/ICSI and our increasing understanding in the genetics of male reproduction have allowed us to
modify the traditional approach to reflect these advances. As with the investigation of other medical
conditions, a cost effective approach requires the working knowledge of the male reproductive biology,
detailed history and physical examination (H&P) and the selective use of available tests in order to
formulate a streamlined diagnostic and treatment strategy; especially if one considers the fact that many
couples are self-paying due to the constraints imposed by managed care.
Several recent developments in male infertility warrant brief discussion:
1. Cystic Fibrosis (CF) and vasal agenesis: CF mutations may result in congenital bilateral or unilateral
absence of vas deferens (CBAVD/CUAVD) and congenital vaso-epididymal or intratesticular
obstruction. Most men with vasal agenesis will be carriers of CF mutations and do not require renal
imaging studies unless otherwise indicated. This is in contrast to those with non-CF related vasal
agenesis in whom co-existing renal anomalies are frequent due to a common development defect of
the mesonephric duct. We proceed initially with CFTR blood test (CF Transmembrane conductance
Regulator) and if the CFTR is negative, we then obtain either renal ultrasound or IVP. Careful
physical examination is all that is necessary to confirm the diagnosis of vasal agenesis without the
need for surgical exploration.
2. Y-chromosome microdeletion and male infertility: Numerical and structural chromosomal abnormality,
such as Klinefelter’s, has long been associated with male infertility. Recent advances in molecular
biology have found portions of the Y-chromosome critical in the normal spermatogenesis. Deletions
of sequences within this region (AZF) in men with normal karyotype are responsible for up to 13% of
men with non-obstructive azoospermia (NOA, or testicular failure) and to a lesser extent, men with
severe oligospermia. AZF testing is based on polymerase chain reaction (PCR) using DNA obtained
from peripheral lymphocytes and is available at several research institutions. Y-microdeleted men
may present with various testis size, FSH levels and testis histology; some of the azoospermic men
may be managed with testicular sperm extraction (TESE) in conjunction with IVF/ICSI.
3. Testis Biopsy in men suspected of NOA: The dictum that significant testicular pathology exists in
azoospermic men with elevated serum FSH levels and small testes continues to be valid and testis
biopsy is not indicated unless the couple is interested in pursuing TESE with IVF/ICSI. We obtain
karyotype and AZF testing in men suspected of NOA prior to testis biopsy since the finding of a
genetic factor may influence the couple’s decision to proceed. In addition to the standard testis
biopsy for histology, one to two additional samples are also submitted to the andrology lab for
attempted TESE in order to further identify those with whom IVF/ICSI will be feasible (Table 1);
previously successful TESE has a 80% predictive value for subsequent sperm retrieval provided that
a 6 moths waiting period is allowed for testicular recovery. Testis tissue is cryopreserved for future
IVF/ICSI use if sperm are found.
4. Partial Ejaculatory Duct (EJD) Obstruction: Incomplete obstruction of the EJD is being increasingly
recognized in the infertile men. Complete EJD obstruction presents with the classic findings of low
volume azoospermia with normal testes and FSH levels. Semen analysis in partial EJD obstruction is
more variable and should be suspected in men with low or normal volume ejaculates with either
severe oligospermia and/or low motility. TRUS is the initial test and the presence of distended SV
(>1.5cm AP diameter) and/or dilated EJDs with or without a centrally located EJD cyst or calcification
is the most common findings. Some cases may not exhibit significant TRUS abnormalities and other
studies such as SV aspiration, seminal track washout and empiric TUR-EJD may be needed.
Vasogram alone in partial EJD obstruction is less helpful since the sperm sampling for motility and
count comparison to the ejaculates; significant disparity between the two supports the presence of
partial EJD obstruction.
Clinical evaluation of male infertility:
1. Pre-visit preparation: Most sub-fertile men are referred to the urologists with semen analysis already
performed, typically via the wife’s gynecologist. As a university center, we also see men from afar
with evaluations already initiated. Every effort is made to review all the pertinent information,
including the actual testis biopsy, prior to or at the time of the initial visit. Such preparation also allows for provisions to be made for additional diagnostic studies such as TRUS at the initial visit.
Wives are always encouraged to be present to provide pertinent female history.
2. History: The reproductive history of both partners should be considered. Decision to repair a
varicocele in a man with borderline semen analysis or to surgically reconstruct previously failed
vasectomy reversals may be dependent on coexisting female factors, including her age. A male
infertility questionnaire is time saving and ensures completeness. Secondary male factor may be
seen with varicocele due to progressive testicular injury; obstructions at the epididymal or EJD levels
should also be considered in these men.
3. Physical Examination: The male reproductive track lends itself well to physical examinations, which is
much more than simply determining the presence of varicocele. Reduction in testicular size and
consistency with collapsed epididymis is an azoospermic or severely oligospermic man is like due to
testicular failure whereas azoospermia with normal feeling testes and epididymal distention, ductal
obstruction is more likely. Similarly, agenesis of the scrotal vas should be readily apparent on
physical exam. Chinn Urology diagnosis varicoceles by palpation and reserve color Doppler ultrasound (CDU)
for those whose physical exam is indeterminate. We do not use CDU to screen for subclinical
varicoceles since repair of these “varicoceles” have not been shown to be beneficial and are not
being sought as a diagnostic entity in our practice