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608
Journal of Andrology, Vol. 15, No. 6, November/December 1994Copyright 2) American Society of Andrology
Effect of Low-Dose Testicular Irradiation on SpermCount and Fertility in Patients with Testicular Seminoma
GRACE M. CENTOLA,* JAMES W. KELLER,ff MARGARET HENZLER,* AND PHILIP RUBINt
From the Departmenl of Obstetrics and Gynecology; the Department of Radiation Oncology; and the §Physics
Section, Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York
ABSTRACT: The treatment of seminoma with radiation therapy riskstransient infertility. We have prospectively followed eight patientswith stage I seminoma of the testicle. All patients underwent radical
orchiectomy of the affected testis. The mean age of the patients was32.9 years (range 24-40). Each patient was treated with megavol-tage radiation with a 10- or 18-MV linear accelerator. The remainingtesticle was shielded using a standard lead enclosure, and the meantesticular dose was 44 cGy (range 20.8-78.2). Semen specimenswere delivered to the lab within 30 minutes of ejaculation. All spec-
imens were analyzed using a computer-assisted sperm analyzer.Pretreatment parameters were within normal limits for all but onepatient; one patient presented with a borderline normal sperm countat 18 and 22 x 1 0#{176}/mI.Following treatment, there was a decreasein sperm count, detected at 3 months, to <10 x 10#{176}/mi(range 4.4-
8.6 x 106) in all patients except one, who presented with an initialpretreatment count of 189 x 10#{176}/mI,which decreased to 58 x 1 0#{176}/ml at 3 months, 32 x 10#{176}/mIat 6 months, and rose to 325 x 106/
ml by 12 months following treatment. Although the sperm count forthis patient (D.L.) was within the normal range, the post-radiation
sperm count was less than 20% of the pretreatment count. Therewas no difference in the motility at 3 months, the mean of which was51.3%. One patient’s (F.C.) wife conceived at 9 months following
treatment, one at 12 months (J.R.), and one (J.S.) at 14 months, and
all have delivered normal infants. Of the remaining patients, fourpatients recovered sperm counts within the normal range by 1 year
(range 38-325 x 10#{176}/mI),one by 18 months, and one by 30 months.Of the two remaining patients, one did not return for sperm analysisafter the couple had a child using banked sperm, and the secondwas able to conceive a child at 14 months and believed that a spermcount was superfluous. The earliest recovery was seen at 12 months.In the present study, recovery was seen at doses of �65 cGy,
although the one patient receiving a dose of 90 cGy conceived nat-
urally and did not return for follow-up sperm analysis after a sperm
count at 12 months (4.3 x 10#{176}/mi).There is thus a transient decreasein sperm count following megavoltage radiation treatment with tes-
ticular doses between 28 and 90 cGy, with recovery of normal spermcount or the ability to father offspring by a maximum of 30 months
after treatment. A study of serial semen analyses in patients withHodgkin’s disease (and two patients with testicular seminoma) from
this institution was updated to serve as a comparison for this study.
Key words: Testicular cancer, radiation treatment, sperm bank-
ing, fertility.
J Androl
C hemotherapy and radiation therapy are known to have
a toxic effect on testicular function (Sandeman, 1969;
Sposto and Hammond, 1985; Jewett and Jarvi, 1986;
Aubier et al, 1989; Pryant et al, 1993). The long-term
effects, however, are not clearly known, because recovery
depends on the type and dose of the drug, length of treat-
ment, and the dose and time course of the radiation treat-
ment. Most patients with curable cancers are in their re-
productive years, or are approaching this lifetime event,
Presented at the 17th Annual Meeting of The American Society of
Andrology, March 27-30, 1992, in Bethesda, Maryland.
Present address: Department of Radiation Oncology, The EmoryClinic, 1365 Clifton Road, N.E., Atlanta, Georgia 30322.
Correspondence to: Dr. Grace M. Centola, Department of Obstetrics
and Gynecology, Box 668, University of Rochester Medical Center, 601Elmwood Avenue, Rochester, New York 14642.
Received for publication February 17, 1994; accepted for publicationJune 2!, 1994.
and therefore the impact of treatment on fertility is of
major concern. Sperm banking has evolved as a means
of “fertility insurance,” although the value of this “in-
surance” is often limited (Centola, 1989).
Germ cell tumors of the testes constitute only 0.5% of
all new cancers in the United States; they occur especially
in young males. Pure seminoma testicular cancers con-
stitute approximately 40% of these cases, and most of
these patients present with stage I (70-90%) or stage II
(10-20%) disease, which is highly curable with surgery
and adjuvant radiation. Radiation is generally given to
the para-aortic and/or ipsilateral pelvic lymph nodes.
Usually the remaining testicle is shielded during the ra-
diation. However, spermatogenesis is still affected by scat-
tered radiation. Modern megavoltage irradiation is thought
to be associated with less radiation to the testicle and
shorter periods of oligozoospermia (Hahn et al, 1982;
Bei-thelsen, 1984). This is related to less internal scatter,
shielding of the remaining testicle during simulation and
Centola et al . Effect of Testicular Irradiation on Sperm Count 609
Table 1. Treatment and fertility stat us of Hodgk in’s disease and testicular sem inoma patien ts (data from Speiser et aI 1973, updated)
LastTesticle Sperm count analy-
Age dose before treat- sis Last sperm countInitials (years) Diagnosis Stage (cGy) ment (xl 06/mI) (months) (xl 0#{176}/mI) Status
J.K. 26 Hodgkin’s ? 260* 51 47 0 NEDP.W. 28 Hodgkin’s 1A 24O1 90 40 0 NEDJ.F. 31 Hodgkin’s 1A 234t 96 35 0 NEDM.C. 32 Hodgkin’s 1A 160t 22 29 0 RELD.R. 26 Hodgkin’s lilA 212t 25 17 0 NEDP.S. 33 Hodgkin’s hA 168t 55 43 0 NEDED. 24 Hodgkin’s hA 143* 64 29 0 REL
R.G. 29 Seminoma 1 116t 31 31 Child conceived at 30 months NEDK.H. 26 Seminoma 1 120* Not done 36 Child conceived at 43 months NED
NED, no evidence of disease; REL, relapsed.* Estimated dose.
t Measured using thermoluminescence dosimetry (TLD).
treatment to avoid stray radiation from the housing, and
avoidance of open fields with beam and verification films.
Measurements of testicular dose have often been esti-
mated in the past by relating the radiation energy and
distance from the lower level of the field to the remaining
testicle. Direct measurements can now be made with ease
using thermoluminescence dosimetry.
The current data would suggest that 20-100 cGy of
fractionated radiation to the testicle, in most cases, leads
to oligozoospermia or azoospermia, and that recovery
takes 12-24 months (Sandeman, 1969; Jewett et al, 1986;
Meistrich and VanBeek, 1990). A certain percentage, in
some series 30%, of patients with testicular tumors may
be oligozoospermic (count <20 x 1 0#{176}/mI)prior to treat-
ment (Hahn et al, 1982; Berthelsen, 1984).
This prospective study was undertaken to examine the
semen parameters of patients with stage I testicular sem-
inoma. We have followed eight patients prospectively with
stage I seminoma and several patients retrospectively with
seminoma and Hodgkin’s disease. This report details the
effects of low-dose irradiation on semen parameters.
Materials and Methods
Study Patients
Between 1967 and 1987, 75 patients were treated in the De-
partment of Radiation Oncology for seminoma. Sixty-two were
stage I. The median age was 35 years (range 23-70). The median
follow-up was 8.3 years. Staging tests consisted of chest x-ray(100%), lymphogram (74%), abdominal computerized tomog-
raphy (CT) scan (30%), and lymphogram and CT scan (15%).
Radiation fields for patients with stage I disease consisted ofpara-aortic and pelvic fields in 56 patients (90%) and an addi-
tional mediastinal field in 6 patients (10%).Eight patients with stage I disease agreed to participate in a
protocol to study fertility. Radiation portals for these patients
consisted of para-aortic and ipsilateral pelvic fields. All patients
had radical orchiectomy performed on the affected testis andwere staged with chest x-ray, abdominal CT scan, and marker
studies (alpha fetoprotein and beta human chorionic gonadotro-
pin [hCG]). The mean age of these patients was 32.9 years (range
24-40). Semen analyses and sperm banking were performed in
the Andrology Laboratory, Rochester Regional Cryobank, De-partment of Obstetrics and Gynecology, University of RochesterMedical Center. Semen analyses were performed after orchiec-
tomy but prior to initiation of radiation treatment and at regular
intervals until recovery of normal parameters (see below). Sperm
banking, if requested, was done after orchiectomy, but prior toradiation treatment.
Between 1970 and 1973, there were 19 patients who entereda seminoma!Hodgkin’s disease fertility study. Some of these datawere reported in 1973 by Speiser et al. These data were reviewed
for the present report (Table I). Seven of the original individualswith Hodgkin’s disease had semen analyses done prior to any
abdominal radiation, five had measured doses of radiation, twodoses were estimated, and all had no subsequent chemotherapy.Further semen analysis data were available, and clinical statuswas determined from chart reviews. Included in these data were
two patients with seminoma treated with abdominal radiation,one of whom had pretreatment semen analysis (Table 1). In sixof the Hodgkin’s/seminoma patients, the testicular dose wasmeasured using thermoluminescence dosimetry (TLD) in thesame manner as the current series; the others were estimated
(see Table 1). The testicular doses in this series were higher than
the current series because the total given doses were higher.
Radiation Treatment
The seminoma patients in the current series were all treated with
an 18-MV linear accelerator, except one treated with a 10-Mv
beam. All treatments and port films were performed with a 1-cm-thick low melting alloy “clam shell” testicular shield in place.The shield was also used at the time of simulation so that any
impact on positioning was included. This also allowed confir-mation that the entire shield was inferior to the inferior border
of the field. The “clam shells” are effective in shielding against
scattered radiation only and must never be included in the pri-mary beam. TLD measurements were made using pairs of dis-
610 Journal of Andrology November/December 1994
Table 2. Sperm count pnor to and after radiation treatment for testicular seminoma. The mean dose and range of doses received are alsoindicated for each study patient. Range of doses refers to variation in different measurements
Initials AgeDose (cGY)
(range)
Sperm count (xl 0#{176}/mI)
Pretreatment
Post-treatment (months)
3 6 12 18 30
D.D. 34 - 46 - - 47.5 - -
J.L. 24 65 57 7.6 - 8.9 9.6 62.7F.C. 28 28 (24-32) 49 4.4 - 38 - -
J.R. 33 32.5(26-39) 40 - 7.3 - 95 -
E.A. 42 37 (32-42) 27 8.6 - 42 - -
J.S. 33 90 (82-98) 15, 22 - 4.3 - - -
D.L. 40 49 (45-53) 189 58 32 325 - -
P.S. 29 39.5(31-48) 40 - 7.1 - - -
F.C. conceived children at 9 months and 35 months following cessation of treatment. J.R. conceived a child at 12 months following cessation oftreatment. J.S. conceived a child at 14 months following cessation of treatment. P.S. conceived a child using banked sperm.
posable lithium fluoride (LiF) TLD capsules placed inside the
clam shell shield, one pair on the ipsilateral side of the remainingtesticle and the other pair on the contralateral side. Because thefield was a “hockey stick” shape, the distance from the lower
edge of the field to the ipsilateral TLD capsules and remaining
testicle was less than to the contralateral inguinal region. There-
fore a dose gradient was expected and indeed was measured with
the two sets of TLD capsules. The reported doses are the averageof the four TLD readings. The TLD measurements were donethree times on one patient, and twice on two patients. The repeatreadings relative to the prescribed dose were within 1% of theinitial readings in all cases but one.
In one case, the dose was calculated using the distance betweenthe lower edge of the field and the beam energy. Several inves-
tigators have shown that the dose outside the radiation fielddepends primarily on the distance from the edge of the field,with the dose falling off approximately exponentially (Kubo andShipley, 1982; Fraass and van de Geljn, 1983; Fraass et al, 1985).
Semen Analyses
Semen samples were obtained by masturbation and delivered tothe laboratory within 30 minutes of ejaculation. The specimenswere kept at 37#{176}Cfor no more than an additional 10 minutesprior to analysis. Routine semen analysis was performed using
a Hamilton-Thorn 2030 motion analyzer (HTM-2030, Hamil-
ton-Thorn Research, Danvers, Massachusetts) with standard set-up parameters (Centola et al, 1990). Computer-aided semen
analysis (CASA) provided data on sperm count and motility.Specimens from those patients desiring sperm banking were pro-cessed for cryopreservation. Sperm morphology was assessed by
placing 40 zl of semen onto a prestained BluStan slide (IrvineScientific, Irvine, California). To determine the percent live anddead, eosin-nigrosin staining was used. The hypoosmotic swell-ing test is a routine part of the semen analysis. This test deter-mines the ability of a sperm cell to swell (by movement of waterinto the cell) in a hypoosmotic buffer. The ability of the sperm
to swell under these conditions indicates that the cell membraneis functionally intact; it has been correlated with the sperma-tozoa’s ability to fertilize human oocytes (VanDerVen eta!, 1986).
Results
Table 2 shows the sperm counts prior to treatment and
at intervals following irradiation. All data are reported as
the mean ± standard error of the mean (SEM). The nor-
mal sperm count is generally >20 x 10#{176}/mi,with values
less than this considered oligozoospermic and subfertile(World Health Organization, 1992). Pretreatment sperm
counts varied between 18.5 and 189 x 106/ml (53.8 ±
17.5). Following radiation therapy, the sperm count de-
creased to <10 x 106/ml (range 4.3-8.6 x 106) in six
patients. In one patient, who started therapy with an ex-
ceptionally high sperm count of 189 x 10#{176}/ml,the post-
therapy nadir was 32.0 x 10#{176}/miat 6 months following
cessation of therapy.
By 12 months following treatment, the sperm count
increased to within normal limits in four patients (50%);
in one patient the sperm count was within normal limits
by 18 months. One patient (J.L.) remained oligozoosper-
mic until 30 months after treatment, when the sperm
count was within normal limits (62.7 x 10#{176}/ml);however,
it is quite possible that he recovered before this, but he
refused to submit a specimen until then.
Table 3 demonstrates additional semen parameters as-
sessed by CASA. The sperm motility and percent normal
morphology were within normal limits prior to treatment
and following irradiation, except for motility at 6 months
for two patients (D.L. and J.R.). The sperm motilities for
these two patients increased to within normal limits when
the sperm count reached the normal range. The mean
percent motility following treatment, however (Table 3),
was not significantly different than the pretreatment value
or the motilities at all other observation times. The per-
cent live sperm (by vital dye exclusion) and the hypoos-
motic swelling test were also within normal limits both
prior to and after treatment.
Centola et al . Effect of Testicular Irradiation on Sperm Count 611
Table 3. Semen parameters (mean ± SEM) prior to and after radiation treatment for testicular seminoma
No. ofpatients
Count(xl 0#{176}/mI)
Motility(%)
Morphology(%)
HOS(%)
Live(%)
Pretreatment 8 53.8(17.5) 59.4(3.8) 81.0(5.1) 74.2(3.2) 64.0(3.6)
3 Months 4 19.7 (12.8) 15.5 (11.8) 78.7(3.6) 73.7(8.7) -
6 Months 3 12.7(6.5) 27.7 (hi .0) 77.0(3.2) 73.0(17.2) 69(3.0)12 Months 6 92.3(58.7) 60.2(6.0) 83.8(2.1) 80.0(1.1) 74(2.0)18 Months 2 52.3(43.1) 71.5(9.6) 85.0(3.0) 78.3(5.1) 72(2.6)30 Months 1 62.7 56.0 86.0 70.0 -
HOS, hypoosm otic swelling test (see VanDerVen et al, 1986).
Three patients had documented fertility following ces-
sation of radiation treatment. One patient (F.C.) con-
ceived a child 9 months after cessation of treatment (his
12-month sperm count was 38 x 106/ml); one patient
(J.R.) conceived at 12 months; and one patient (J.S.) con-
ceived at 14 months following treatment (his 6-month
sperm count was 4.3 x l0#{176}/ml).
Two seminoma patients, prior to initiation of this study,
received 116 and 120 cGy of radiation to the testis (Table
1).Children were conceived at 30 and 43 months follow-
ing completion of radiation treatment. A similar group
of seven Hodgkin’s disease patients who received higher
doses of testicular radiation (range 143-260 cGy) re-
mained azoospermic throughout the period of observa-
tion (Table 1).
Discussion
Recovery of sperm count and “fertility” after radiation
is important information for young males who are re-
ceiving a course of radiation therapy for testicular neo-
plasms and Hodgkin’s disease. Regaud and Ferroux (1927)were the first to comment on the difference between a
single dose of radiation to the testicle and fractionated
radiation. They noted that a single dose of radiation to a
ram’s testicles did not produce sterility, but did injure
scrotal skin, whereas fractionated radiation did not dam-
age the skin but did produce sterility. In a more controlled
study, Rowley et al (1974) found that single doses of < 100
cGy led to full recovery in 9-18 months, 200-300 cGy of
radiation resulted in approximately 30 months to recov-
ery, and 400-600 cGy required >5 years to recover, with
only one individual showing recovery at that time.
Studies in animals have demonstrated more stem cell
killing with fractionated radiation than with single-dose
radiation (Thames and Hendry, 1987). Fractionated ra-
diation to the human testes has not been studied as ex-
tensively as single-dose radiation. Most of the data re-
garding fractionated radiation to the testicle have resulted
from studies such as ours, on patients with testicular can-
cer or Hodgkin’s disease whose fields are generally above
the level of the testes but who receive scattered radiation.
Early work in this field contained dose estimates depen-
dent upon the energy of the radiation source and the dis-
tance from the lower edge of the beam, based on phantom
measurements. Several factors make estimates of ab-
sorbed dose to the testicle less precise (Hahn et al, 1982).
Direct measurement using TLD is more accurate.
The present study supports previous studies in the lit-
erature demonstrating that low-dose radiation treatment
does cause a transient decrease in sperm counts. This
study is a small, prospective study that has fairly complete
information from serial sampling. We did not encounter
any patients in this series who were azoospermic or se-verely oligozoospermic after orchiectomy and prior to
radiation. Others have noted that as many as half their
patients presented with azoospermia or oligozoospermia
prior to treatment (Berthelsen, 1984; Fossa et al, 1986).
In the present study we have clearly demonstrated a tran-
sient decrease in sperm count and no effect on other sperm
parameters following megavoltage radiation treatment for
stage I testicular seminoma. The threshold dose of frac-
tionated radiation capable of producing transient oligo-
zoospermia has been given as 20-60 cGy (Hansen et al,
1990). However, those reporting the 20-cGy dose do notgive enough data to make this judgement. Schlappack et
al (1988) reported one patient who had a normal baseline
sperm count and a reduced count after radiation, followed
by recovery to >20 x 1 06 sperm/ml after a measured
dose of 34 cGy. Using these criteria, our patient who
received 28 cGy would be the lowest threshold. In one
patient, the sperm count remained well within normal
limits for the entire time before and following irradiation.
This patient had the highest sperm count pretreatment,
and although the post-treatment sperm count was withinnormal limits, the actual post-treatment count decreased
to <20% of the pretreatment count. One patient finally
recovered sperm production within normal limits by 30months. There may also be a definite time to nadir fol-
lowing irradiation, although this was not determined from
the present data. In the sequence of spermatogenesis, type
B spermatogonia are the most sensitive to radiation, sper-
matocytes intermediate, and spermatids the most resis-
tant (Lusbaugh and Casarett, 1976). The mechanism of
azoospermia produced by low-dose radiation is probably
612 Journal of Andrology . November/December 1994
directly related to the number of stem cells or spermatogo-
nia killed. A complete spermatogenic cycle is approxi-
mately 60-90 days, and thus cessation of sperm produc-
tion (and availability to ejaculation) takes about this much
time, plus perhaps an epididymal reservoir factor. Fur-
thermore, although spermatids may be radioresistant,
mutagenic changes could occur, although the incidence or
the effects of a parent’s radiation treatment in the offspring
were not studied. Because of the possibility of radiation
injuries to the genome, we mnke a standard recommen-
dation to avoid conception during treatment time, until
maturation depletion occurs and for 1 year to be safe.
Recovery of sperm count and “fertility” appears to be
dose dependent. In this study, the radiation doses were
relatively low, well tolerated, and resulted in complete
recovery in all patients. Patients receiving higher doses
of testicular radiation (116, 120 cGy) exhibited fertility
(conceived a child) at 30 and 43 months following treat-
ment, although we do not have data on their potential for
fertility prior to that time. Patients receiving even higher
doses of radiation (143-240 cGy) remained azoospermic
at least to 40 months following treatment, the period of
observation. Previous studies contained dose estimates
based on phantom measurements, whereas the present
study was able to determine direct testicular dose based
upon TLD. Hahn et al (1982) reported a dose-dependent
recovery of sperm count, with fractionated scattered doses
of <150 cGy resulting in oligozoospermia or azoosper-
mia. Recovery occurred in 7.5-22 months following treat-
ment. Schlappack et al (1988) did not find a correlation
between sperm recovery and doses of <100 cGy. Our
numbers are too small to perform a good correlation.
Hansen et al (1990) found that the time to sperm re-
covery was related to: 1) absorbed testicular dose, 2) pre-
treatment sperm count, 3) age, and 4) chemotherapy. All
of our patients had normal pretreatment sperm counts,
no chemotherapy, and low levels of absorbed dose (<90
cGy); all but one recovered by 2 years, and he recovered
by 30 months. Higher doses (>120 cGy) of testicular
radiation may be associated with longer times to recovery
of sperm production, as demonstrated by our retrospec-
tive data from patients with Hodgkin’s disease, although
none of the patients receiving higher doses of radiation
recovered sperm production. It is suspected that with more
time some of these patients should recover also (Pedrick
and Hoppe, 1986; Pryant et al, 1993). Whether patients
who receive >300 cGy of fractionated radiation will even-
tually demonstrate recovery if followed for many years is
not clear.
Current megavoltage irradiation results in a transient
decrease in sperm count. Nonetheless, sperm banking
should still be considered in those patients desiring fer-
tility prior to complete recovery and those concerned about
possible genetic effects of scattered radiation. We rec-
ommend, as others, appropriate contraception for 1 year
following cessation of radiation treatment in order to (rea-
sonably) ensure no genetic effects of the irradiation on the
remaining germ cells. Furthermore, in the event of sub-
sequent chemotherapy for recurrences prior to complete
recovery, banked sperm may indeed provide “fertility
insurance.”
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New Investigator- 1994
Student Awards-i 994
Linda R. Johnson Sperm from t25/+ Mice Are Defective in Sperm-EggInteractions: A Possible Mechanism for Transmission RatioDistortion. Patricia J. Olds-Clarke, PhD
Merit Awards- 1994 (alphabetical order)
Haolin Chen
Sarah Jensen
Budhan Pukazhenthi
Deborah Ricker
Robert Viger
Leydig Cell Steroidogenesis in the Aging Rat. Barry R.Zirkin, PhD
P450 Aromatase in the Rat Testis and Epididymis. LynnJanulis, Janice M. Bahr, David Bunick, Yoshio Osawa and
Rex A. Hess
Role of Protein Tyrosine Kinase on Cat Sperm Function.D. E. Wildt, M. A. Ottinger, Patricia M. Sailing and JoGayle Howard, DMV, PhD
Evidence That Neuronal Input from the Inferior MesentricPlexus Affects Sperm Transport Through the Rat Cauda
Epididymidis. Thomas S. K. Chang, PhD
Expression of Steroid 5a-Reductase Type 1 mRNA andImmunocytochemical Localization of the Type 1 Proteinin the Rat Testis During Sexual Maturation. Bernard
Robaire, PhD
Richard V. Clark, MD, PhDChairman, Awards Committee