US Pharm. 2012;37(6):39-42.
Approximately 15% of couples do not achieve pregnancy within one year of unprotected sexual intercourse.1-3 A male infertility factor is identified in about 50% of these cases and is solely responsible in 20% of couples.1,2
Male infertility has been attributed to a variety of causes including
lifestyle factors, gonadotoxin exposure, hormonal dysfunction,
chromosomal disorders, varicoceles, testicular failure, ejaculatory
disorders, and obstruction. Evaluation of male infertility is important
to identify a cause and provide treatment if the etiology is
correctable. If a specific treatment is not available or the origin of
the male factor infertility is not correctable, other options such as
assisted reproductive techniques (ART) may exist. The pharmacist plays a
vital role in identifying medications that contribute to male
infertility, counseling the couple on medications used to treat
infertility, and promoting healthy lifestyles that minimize infertility
factors. The purpose of this article is to provide a broad overview of
the etiology, evaluation, and treatment of male infertility.
Definitions and Epidemiology
Infertility is defined as the inability to achieve conception despite one year of regular, unprotected intercourse.4 In the United States, approximately 8 million couples are affected by infertility.5
For healthy young couples, the probability of achieving pregnancy
within the first year of fertility-focused sexual activity is 84%.6 Despite advances in the diagnosis and treatment of infertility, the conception rate remains stable.6
A recent increase in demand for infertility services has been
attributed to a greater awareness of treatment options, increased
acceptance of infertility, and a trend toward delayed marriage and
childbirth leading to more fertility issues.6
Male Reproductive Physiology
The testicles contain Leydig, Sertoli, and germ cells,
which are responsible for the production of sperm and the synthesis of
testosterone. The Sertoli cells line the seminiferous tubules in the
testicles along with primitive germ cells. The principal role of the
Sertoli cells is to provide germ cell support, initiate and sustain
spermatogenesis, and regulate pituitary gland function. Leydig cells are
responsible for the production of testosterone necessary for
The hypothalamic-pituitary-gonadal (HPG) axis is a complex
system that regulates gonadal and sexual function. The hypothalamus is
the integrative center for the reproductive hormonal axis; it secretes
gonadotropin-releasing hormone (GnRH), which releases luteinizing
hormone (LH) and follicle-stimulating hormone (FSH) from the anterior
pituitary. After release from the pituitary, LH interacts with receptors
on the Leydig cell membrane in the testes to synthesize and secrete
testosterone. FSH binds to Sertoli cell membrane receptors to initiate
and maintain spermatogenesis. Synthesis and release of gonadotropins are
regulated by neuroendocrine signals from the central nervous system.7,8
Human reproduction requires fertilization of a mature ovum
through introduction of sperm-containing semen via the vagina. During
this event, penile erection and ejaculation are essential. The
parasympathetic nervous system controls erectile function while the
sympathetic nervous system is responsible for emission and ejaculation.
The seminiferous tubules, a tubular network within the testes, carry
seminal fluid containing mature spermatozoa to the epididymis through
the vas deferens to the ejaculatory ducts and into the urethra.
Periurethral muscle contractions expel the seminal fluid out of the
urethra and into the female reproductive tract.7,8
Azoospermia is defined as the absence of spermatozoa in the seminal fluid.
Causes of infertility in the azoospermic male may be categorized as pretesticular, testicular, or post-testicular.
Pretesticular Deficiency: As a less
common etiology than other causes of male infertility, hypogonadotropic
hypogonadism (HH) is caused by insufficient GnRH and/or FSH and LH
secretion.2 These insufficiencies result in deficient
androgen secretion and spermatogenesis. HH can arise from congenital
GnRH deficiency, hemochromatosis, genetic disorders, pituitary and
hypothalamic tumors, hormonal abnormalities, or medications. In
addition, systemic disorders such as chronic illnesses, nutritional
deficiencies, and obesity have been identified as causes of HH.9
Testicular Deficiency: Testicular deficiency, sometimes referred to as nonobstructive azoospermia,
is spermatogenic failure caused by conditions other than obstruction or
HPG dysfunction. This category of dysfunction can be further subdivided
into congenital, acquired, or idiopathic testicular failure. Congenital
failure can manifest as anorchia, testicular dysgenesis,
cryptorchidism, or genetic abnormalities. Acquired testicular failure
can be the result of trauma, testicular torsion, orchitis, exogenous
factors (e.g., medications, systemic diseases, varicocele), or surgeries
that damage the vascular structure of the testes.3 About 15% of the general male population and approximately 40% of men presenting with male infertility have varicoceles.10
Post-testicular Deficiency: Often referred to as obstructive azoospermia,
post-testicular deficiency is due to either ejaculatory dysfunction or
obstruction of sperm delivery. This form of male infertility is less
common than non-obstructive azoospermia, but occurs in approximately 40%
of men presenting with azoospermia.2 The obstruction can arise from the epididymis, vas deferens, or ejaculatory duct and can be acquired or congenital.3
Idiopathic Infertility: In approximately 30% to 40% of men who are infertile, no male infertility factor can be identified.3
These men frequently have no previous history of infertility,
unremarkable physical examination, and normal endocrine laboratory
evaluation. Semen analysis reveals a decreased number of spermatozoa,
reduced sperm motility, and many abnormal forms of sperm. These findings
commonly occur together and are termed oligo-astheno-teratozoospermia or OAT syndrome.
Idiopathic male infertility can be attributed to endocrine disruption
due to environmental pollution, reactive oxygen species, or genetic
Medications and Lifestyle Factors
Numerous substances have been implicated as causes of
infertility. Establishing cause and effect of medications is difficult
due to confounding factors and small sample sizes. Drugs may affect male
infertility through direct gonadotoxic effects, alteration of the HPG
axis, impairment of ejaculation and/or erectile function, and changes in
libido.11 Recreational and illicit drugs including alcohol,
tobacco, marijuana, cocaine, and amphetamines are cited as causes of
infertility. A number of medications have been identified as causes of
male infertility including chemotherapy, antihypertensives, hormones,
psychotropics, antidepressants, and antibiotics (TABLE 1).11,12
Testosterone replacement therapy is a common medical etiology of male
factor infertility and has an adverse effect on spermatogenesis. In
addition, many vaginal lubricants have been shown to inhibit sperm
motility and velocity potentially leading to infertility.
Hydroxyethylcellulose-based lubricants, mineral oil, and canola oil lack
these effects on sperm and may be recommended as alternatives.13
A pharmacist can review the medication profile of patients presenting
with infertility to identify potential drug therapy causes and reduce
the need for further evaluation.
The American Urological Association (AUA) recommends an
initial screening evaluation of the male partner of an infertile couple
if pregnancy has not occurred within one year of regular, unprotected
intercourse. An earlier evaluation is reasonable if a known infertility
factor exists or a male doubts his fertility potential.2 A
previous history of fertility does not exclude the possibility of
secondary infertility. Men with secondary infertility are evaluated in
the same manner as men who have never initiated pregnancy. The female
partner should also undergo evaluation during this time period.
The basic components for the evaluation of male infertility include a detailed review of patient history (TABLE 2),
physical examination, at least two semen analyses, and hormonal
assessment of the HPG axis. The patient’s history may identify risk
factors and/or behavior patterns that affect fertility potential. During
the physical examination, particular attention is given to body habitus
and secondary sex characteristics. The scrotum, testes, and prostate
are evaluated for signs of infection, obstruction, or varicocele.
Additional tests include transrectal or scrotal ultrasonography,
post-ejaculatory urinalysis, and genetic testing, which
are obtained on an individual basis when indicated.
Semen analysis is the fundamental laboratory test in the evaluation of male infertility.14
It provides information about semen quality and volume, sperm
concentration, motility, and morphology. These results may be compared
with reference ranges and used to identify men with abnormal semen
parameters who may benefit from ART such as intrauterine insemination
(IUI) or in vitro fertilization (IVF) with or without intracytoplasmic
sperm injection (ICSI). Men with normal semen analyses rarely have sperm
that contribute to infertility.1
Some infertile men will have medically or surgically
correctable causes, making natural conception possible with appropriate
intervention. Treatment is dependent on the underlying etiology and thus
requires an accurate diagnosis for proper treatment. If a treatable or
correctable infertility factor is identified, it should be corrected
using appropriate medical or surgical therapies. Men with uncorrectable,
untreatable, or unknown etiologies may benefit from ART.
ART procedures have been used in the U.S. since 1981 and
have dramatically improved fertility rates. IVF-ICSI is a type of ART
used to overcome severe oligospermia or azoospermia by injecting a
single sperm into the cytoplasm of a mature egg. IVF-ICSI is a treatment
option for males with azoospermia, yielding live birth rates comparable
to those achieved with IVF without ICSI.15 Azoospermic men
require microdissection testicular sperm extraction to surgically
retrieve sperm that may be usable for IVF-ICSI; the couple must be
counseled on the success rates of sperm harvest as well as IVF-ICSI
success rates using this sperm. The risks associated with IVF-ICSI
include ovarian hyperstimulation syndrome, multiple gestation, perinatal
complications, and genetic disorders.16 Some couples undergo
ART without an appropriate evaluation by an infertility specialist;
this is dangerous because approximately 6% of males evaluated have a
serious underlying medical condition.5,17
Pretesticular Deficiency: Hyperprolactinemia
is the most common endocrine disorder of the hypothalamic-pituitary
axis and is a known cause of HH. Fertility may be restored by
normalizing prolactin serum concentrations. Several drugs including
dopamine antagonists, selective serotonin reuptake inhibitors, tricyclic
antidepressants, and high-dose estrogen therapy cause
hyperprolactinemia and should be discontinued if possible in this
situation.18 A dopamine agonist such as cabergoline or bromocriptine is the treatment of choice for most patients with hyperprolactinemia.18
Gonadotropins may be used to treat HH caused by
hypothalamic or pituitary disease not associated with
hyperprolactinemia. Human chorionic gonadotropin (hCG) has biological
activity similar to LH but has a longer half-life. It is usually
initiated alone at 1,500 to 2,000 IU 3 times per week given
intramuscularly or subcutaneously in the thigh for 18 to 24 weeks and
then titrated at 2-week intervals to achieve serum testosterone
concentrations between 300 and 500 ng/dL. Seminal fluid is evaluated for
spermatogenesis every 2 to 4 weeks. If sperm concentrations are
unsatisfactory after 6 to 12 months of therapy, an FSH preparation
should be added to hCG. Men using hCG should be warned of possible side
effects such as gynecomastia, headaches, and mastalgia.19
FSH is available as human menopausal gonadotropin (hMG) or
recombinant human FSH (r-hFSH). hMG contains purified extracts of LH
and FSH, while r-hFSH consists of only FSH. It is preferred because of
similar efficacy and substantially lower costs when compared with
r-hFSH. The initial dose of hMG is 75 IU administered 3 times weekly and
may be titrated to 150 IU. Although the hMG is generally well
tolerated, headache, mastalgia, and injection site reactions have been
Pulsatile GnRH therapy is an off-label use for the
treatment of HH caused by hypothalamic disease. GnRH is administered via
a subcutaneous pump that delivers GnRH over 60 minutes every 2 hours.
The typical starting dose is 25 ng/kg/bolus titrated based on serum
testosterone levels at 2-week intervals. Once target testosterone levels
are achieved, the dose is held constant; testicular volume
seminal fluid analyses are performed each month. Catheter-site
complications such as phlebitis, hematoma, and infection occur in
approximately 7% of patients.21 Men receiving GnRH therapy
should be instructed by their health care professional to monitor the
needle-insertion site daily and report any redness, pain, or drainage.
Testicular Deficiency: Hypergonadotropic
hypogonadism is due to dysfunctional testes and is characterized by
elevated gonadotropins, low testosterone, and oligospermia or
azoospermia. This is also known as primary testicular failure. These patients rarely achieve paternity through natural conception due to seminiferous tubule damage.22 Gonadotropin therapy is not effective under this circumstance and IVF-ICSI is typically necessary for successful fertilization.
The treatment of varicocele has traditionally been
considered controversial, and no consensus about the efficacy of
interventions exists. Results from a recent randomized, controlled trial
suggest that varicocelectomy in men with palpable varicocele(s)
improves semen parameters and increases the odds of spontaneous
pregnancy within 1 year when compared with observation.23
AUA suggests varicocele repair be offered to the male partner of a
couple attempting to conceive when the varicocele is palpable, the
couple has documented infertility, the female is fertile, and the male
partner has one or more abnormal semen or sperm parameters. IVF with or
without ICSI may be considered when there is the need to treat a female
infertility factor, regardless of the presence of varicocele and
suboptimal semen quality.10
Post-testicular Deficiency: Treatment
options for infertility due to obstructive azoospermia include IVF-ICSI
and microsurgical procedures (vasectomy reversals).24
Ejaculatory dysfunction, more specifically failure of emission, can be
treated with alpha-adrenergic agonists that facilitate ejaculation.25
This approach can convert a patient with failed emission to retrograde
ejaculation and sperm can then be retrieved for insemination.
Idiopathic Infertility: There is no
consensus on the correct management of idiopathic infertility. A variety
of empiric medical therapies have been attempted
to improve pregnancy rates (TABLE 3)
despite a lack of proven efficacy. According to an AUA survey of
fertility specialists, clomiphene citrate, hCG, and anastrazole are the
most commonly prescribed medications for idiopathic male infertility.26
Infertility affects 8 million couples in the U.S., with
many requiring medical intervention to achieve pregnancy. It is
essential that both partners be thoroughly evaluated for causes to
optimize treatment and minimize morbidity associated with possible
underlying medical conditions. The pharmacist’s role in health care
affords the opportunity to identify medications with potential adverse
effects on fertility, recommend alternative drugs, and counsel patients
on the proper use of medications. Advances in ART have improved outcomes
for severely infertile couples, but further research is needed to
better understand unknown causes of male infertility and to develop more
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