Before discussing the effects of cancer treatment on male
fertility, an understanding that the malignancy itself may be
associated with impaired male fertility even prior to cancer treatment
is critical. Testicular cancer is the most common malignancy in
men aged 15 to 40, with about 8,000 new cases each year in the
United States (Garner, Turner, Ghadirian, & Krewski, 2005).
It is more common in men who have cryptorchidism (i.e., undescended
testes), a condition that is also related to infertility. Additionally,
many men diagnosed with testicular cancer have tissue abnormalities
and reduced sperm production in the contralateral testis, even
when it appears normal (Hoei Hansen, Holm, Rajpert-De Meyts, &
Skakkebæk, 2003). Bilateral testicular cancer is present
in less than 1% of newly diagnosed men, and less than 1.9% may
develop a second, invasive cancer in their remaining testicle
within the 15 years following their initial diagnosis (Fossa,
Chen, et al., 2005). A Danish registry study found significantly
lower fertility in a cohort of 3,530 men born between 1945 and
1980 who developed testicular cancer compared to all other Danish
men born in the same era (Jacobsen et al., 2000). Fertility was
significantly reduced in the 2 years leading up to the cancer
diagnosis and in men with nonseminomatous tumors (i.e., tumors
arising from sperm cell precursors). In 3,847 men in an American
infertility clinic who had abnormal semen analyses (defined as
semen with low sperm concentrations and with defects in sperm
morphology and motility), the rate of testicular cancer was 20
times higher than expected, reinforcing the need for infertility
specialists to be watchful for this cancer (Raman, Nobert, &
Goldstein, 2005).
In addition to testicular cancer, other malignancies that may
occur in teens and young men include non-Hodgkin’s lymphoma,
Hodgkin’s disease, leukemia, sarcomas, melanoma, colorectal
cancer, and central nervous system tumors (Pearce, Parker, Windebank,
Cotterill, & Craft, 2005; Wu et al., 2005). In Hodgkin’s
disease, up to 70% of male patients are found to have defects
in semen quality at the time of diagnosis (Wallace, et al., 2005).
In general, young men diagnosed with cancer are more likely to
have reduced sperm counts and motility, perhaps due to recent
fevers, anesthesia for diagnostic procedures, or other tumor-related
factors (Chung et al., 2004). The semen quality of young teens,
older teens, and men in their early 20’s is equally affected
by these factors (Wallace et al., 2005). Moreover, the sperm of
men recently diagnosed with cancer also show more DNA damage than
the sperm of healthy controls (Kobayashi et al., 2001; O’Donovan,
2005). Tests for DNA damage in sperm measure strand breakage or
the condensation of genetic material in the nucleus. These abnormalities
are associated with poor fertilization rates in natural and assisted
conception (Morris, 2002).
A number of cancer treatments damage male fertility either temporarily
or permanently. For instance, surgery for pelvic or genital cancers,
such as bilateral orchiectomy for testicular cancer or advanced
prostate cancer, may remove a critical portion of the male reproductive
system. Although many people think of men with prostate cancer
as beyond reproductive age, the average age of diagnosis has decreased
due to prostate-specific antigen screening; therefore, some men
are still interested in having children at the time they are diagnosed
with prostate cancer (Varenhorst et al., 2005). Radical surgery
for prostate or bladder cancer removes the prostate and seminal
vesicles, eliminating the production of semen. Retroperitoneal
lymphadenectomy performed to diagnose the extent of testicular
cancer can impair fertility by causing retrograde ejaculation,
but nerve-sparing surgical techniques can usually prevent this
complication. However, nerves are often damaged when similar surgery
is performed to remove residual disease after chemotherapy (Saxman,
2005). Surgery for colorectal cancer may cause similar impairment
(Havenga, Maas, DeRuiter, Welvaart, & Trimbos, 2000).
Chemotherapy drugs and radiation therapy directed near the testes
can also impair male fertility (Agarwal & Allamaneni, 2005;
Howell & Shalet, 2005). Alkylating chemotherapy drugs, including
platinum agents (Saxman, 2005), are the most destructive to spermatogenesis.
The higher the chemotherapy agent dose, the greater the chance
that all the spermatogonia (i.e., stem cells that produce maturing
sperm cells) will be destroyed, causing permanent azoospermia
(i.e., complete absence of sperm cells in the semen). Although
some chemotherapy regimens, such as ABVD (doxorubicin, bleomycin,
vinblastine, and dacarbazine) for Hodgkin’s disease, have
been designed in an attempt to replace other highly gonadotoxic
regimens and reduce the rates of permanent azoospermia, recurrent
or advanced disease may necessitate treatment with a more toxic
regimen (Grigg, 2004).
The damage to male gonads caused by radiation therapy can be
permanent and depends on the total dose, fractionation schedule,
and field of radiation. The higher the dose of radiation to which
the testes are exposed, the greater the damage to spermatogenesis,
but even doses as low as 0.1 to 1.2 Gy may impair spermatogenesis.
Men receiving total-body irradiation prior to a bone marrow transplant
commonly experience permanent azoospermia (Howell & Shalet,
2005). Therefore, patients receiving total-body irradiation are
considered at high risk (>80%) for impaired fertility (Wallace
et al., 2005). Testicular radiation in prepubertal boys with leukemia
is also quite destructive to fertility and permanent azoospermia
is an invariable consequence when testes are exposed to radiation
doses of 24 Gy (Brougham & Wallace, 2005; Thomson et al.,
2002). Recently, however, good recovery of spermatogenesis has
been reported in men treated with brachytherapy for prostate cancer
(Grocela, Mauceri, & Zietman, 2005; Mydlo & Lebed, 2004).
Cancer survivors, as a group, tend to have decreased sperm counts
and motility after chemotherapy or pelvic irradiation (Bahadur
et al., 2005; Howell & Shalet, 2005). However, the degree
of damage to sperm counts and motility that may occur even before
cancer treatment does not accurately predict recovery of fertility
after cancer treatment. For instance, men with testicular cancer
have the lowest sperm concentrations (i.e., sperm count per milliliter
of semen) prior to treatment, but are most likely to have some
sperm cells in their semen after treatment (Bahadur et al., 2005).
However, men with the lowest sperm counts after cancer have the
longest times to fertility recovery. Nonetheless, in a recent
study of 42 men with azoospermia at cancer diagnosis who were
followed for a median of 9 years, 12 of 17 who wanted to father
a child achieved that goal (Ragni et al., 2005).
Sperm DNA damage may also occur as a result of cancer treatment
(Morris, 2002; O’Donovan, 2005), although DNA repair can
eventually occur. Most DNA defects are found in sperm during the
first weeks after cessation of cancer treatment; abnormalities
typically diminish over the next 2 years (Wyrobek, Schmid, &
Marchetti, 2005). For this reason, sperm banking is not recommended
once a man has been exposed to chemotherapy or pelvic radiotherapy,
and most oncologists suggest waiting 6 to 12 months after cancer
treatment to attempt conception (Morris, 2002; Wyrobek et al.,
2005). In a clinical study comparing 33 long-term survivors of
childhood cancer to 66 healthy controls, no excess DNA abnormalities
were found in the sperm of cancer survivors (Thomson et al., 2002).
However, 30% of the cancer survivors were azoospermic and only
33% had normal semen quality.
In animal studies, sperm with DNA damage is associated with birth
defects or unusual cancer rates in offspring (Morris, 2002). However,
no excess rate of birth defects has been observed in children
conceived during or after the father’s cancer treatment
(Fossa, Magelssen, et al., 2005; Meistrich & Byrne, 2002).
In a study of more than 4,000 adult male survivors of childhood
cancer, significantly fewer had live-born children compared to
their brothers (Green et al., 2003), but no excess birth defects
or other health problems were identified in their offspring. Moreover,
no unusual rates of cancer are seen in the children of cancer
survivors, except in families with inheritable cancer syndromes
(Winther et al., 2004). Theoretically, a genetically defective
sperm would not be capable of fertilizing the oocyte or an embryo
produced with a defective sperm would fail to develop. Therefore,
there is no basis to recommend that male cancer survivors forego
fatherhood or to advocate conception using cryopreserved sperm
obtained before cancer treatment versus fresh sperm produced years
later out of concern over the risk of birth defects or increased
rates of cancer in offspring.
Although banking sperm before cancer treatment has been an option
for many years, its practicality was limited in the past. Some
sperm always died during freezing, and few cancer patients had
semen of high enough quality to achieve success with the infertility
treatments that were available. Fortunately, since IVF with intracytoplasmic
sperm injection (ICSI) became available in 1992, conception often
only requires that small numbers of live sperm survive banking
(Shin, Lo, & Lipshultz, 2005). The embryologist can choose
one normal appearing sperm to inject into each oocyte obtained
for IVF. Additionally, one ejaculate can be divided into small
vials for use in several IVF cycles. Another barrier was overcome
when researchers discovered that semen of adequate quality for
banking could be obtained when samples were collected on consecutive
days, rather than after 36 hours of abstinence as previously recommended
(Agarwal, Sidhu, Shekarriz, & Thomas, 1995). Therefore, even
men with an urgent need to begin cancer treatment can often collect
one or two samples before initiating therapy. Moreover, since
sperm from cryopreserved semen may remain viable for many years
(sperm has been successfully used after being frozen for up to
25 years), banking is increasingly offered to adolescent cancer
patients (Wallace et al., 2005).
Because it is difficult to predict whether any individual will
recover spermatogenesis after cancer therapy, the Ethics Committee
of the American Society for Reproductive Medicine (2005) has endorsed
the recommendation that any man whose fertility is at risk be
offered sperm banking. In countries like Norway and Japan, where
sperm banking is part of socialized medical benefits, about one
half of men decide to bank sperm (Magelssen et al., 2005; Saito,
Suzuki, Iwasaki, Yumura, & Kubota, 2005). Japanese men have
reported overwhelmingly that banking sperm helped them cope emotionally
with their cancer (Saito et al., 2005). In contrast, only approximately
one fourth of eligible men in the United States bank sperm (Chung
et al., 2004; Schover, Brey, Lichtin, Lipshultz, & Jeha, 2002a).
In a survey of over 200 young male patients seen in major cancer
centers, only one half recalled being told about sperm banking
(Schover et al., 2002a). This is particularly unfortunate because,
among men interested in having children in the future, the most
common reason for not banking sperm, cited by 25%, was lack of
information. Men were more likely to bank sperm if they were referred
by a physician and if they were childless at the time of their
cancer diagnosis. However, a companion survey of oncology physicians
revealed that despite endorsing the idea of discussing sperm banking
with all eligible men, 48% of physicians either never mentioned
it or did so less than 25% of the time (Schover, Brey, Lichtin,
Lipshultz, & Jeha, 2002b). One half of these physicians cited
a lack of time to discuss the topic in a busy clinic, not knowing
where to find a convenient sperm bank, and believing that most
patients could not afford the fees; in fact, only 7% of male patients
cited cost as a factor in deciding not to bank sperm (Schover
et al., 2002a).
Efforts to protect spermatogenesis during chemotherapy have included
the use of gonadotropin-releasing hormone (GnRH) analogues with
or without testosterone, but despite promising results in animals,
human trials have been disappointing (Shetty & Meistrich,
2005). For prepubertal boys, a future option may be to harvest
spermatogonial stem cells from the immature testes and cryopreserve
them either in a suspension that could later be injected back
into the testes to repopulate the sperm-producing tubules, or
embedded in tissue that could later be autografted back into the
body or even xenografted onto a mouse so mature sperm cells could
be harvested for infertility treatment (Orwig & Schlatt, 2005).
These techniques are not yet ready for clinical trials in humans.
When cancer survivors are azoospermic, exploratory microsurgery
can sometimes identify islands of spermatogenesis, yielding sperm
for IVFICSI (Chan, Palermo, Veeck, Rosenwaks, & Schlegel,
2001). This procedure is called testicular sperm extraction and
is available for males before or after puberty, although it is
experimental for prepubertal boys. Additional parenthood options
available for male cancer survivors with impaired fertility after
cancer treatment include the use of donor sperm and adoption.
Until recently, less than 10% of cancer patients who banked sperm
used their samples for infertility treatment, but this rate appears
to be increasing (Agarwal et al., 2004; Chung et al., 2004). Live
birth rates resulting from assisted reproduction using cancer
patients’ cryopreserved samples are excellent and at least
equal to the rates achieved with the use of samples from men with
impaired fertility from other causes (Revel et al., 2005). Although
IVF-ICSI produces the highest success rate per cycle of treatment,
the less expensive intrauterine insemination technique (with or
without hormonal stimulation to induce multiple ovulations in
the female partner) can be used for men whose semen samples contain
over 2 million sperm per milliliter after freezing and thawing
(Agarwal & Allamaneni, 2005; Chung et al., 2004; Revel et
al., 2005; Schmidt et al., 2004).
Men usually discontinue storage of cryopreserved samples if they
have conceived all the children they desire or have agreed to
discard samples upon their death (Hallak, Sharma, Thomas, &
Agarwal, 1998), but some men prefer to will their samples to a
family member who might use the sperm to conceive a posthumous
child (Chung et al., 2004). Very few wives who consider conceiving
posthumous children actually carry out their plan, but all men
should create an advance directive stating their wishes regarding
the cryopreserved samples (Bahadur, 2002; Ethics Committee of
the American Society for Reproductive Medicine, 2005).
Men with cancer may suffer impaired fertility due to either the
malignant process itself or cancer therapy. Although most oncologists
recommend allowing an interval of 6 to 12 months after cancer
treatment to attempt conception, there is no evidence that offspring
of male cancer survivors exhibit more birth defects or are otherwise
less healthy than offspring of men who have never had cancer.
Sperm banking should be offered to any man facing fertility risks
due to cancer treatment. Additional options to preserve fertility
in male cancer patients include harvesting and cryopreserving
spermatogonial stem cells from the immature testes (for prepubertal
boys) and testicular sperm extraction.
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