FERTILITY AND STERILITY
59, No, 1, January 1993
Copyright 10 1993 The American Fertility Society
The use of clomiphene citrate in the treatment of azoospermia
secondary to incomplete androgen resistance
James W, Akin, M.D.*
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
The phenotype of patients with androgen insen-
sitivity syndrome may range from a 46,XY sex re-
versed female to a 46,XY infertile male (1). The un-
derlying problem in these patients is thought to be
an abnormal androgen receptor (AR) resulting from
either aberrations in one of the eight exons con-
tained within the AR gene or from post-translational
errors, all in the presence of normal androgen pro-
duction. As the severity of the androgen receptor
abnormality increases, so does the likelihood for de-
velopment of a female phenotype.
Recently, Akin et al. (2) described an azoospermic
phenotypic male found to be missing exon four
within the AR gene. The AR in this individual must
have had some function because the phenotype was
male; however, that function must not have been
complete enough to allow normal spermatogenesis
to occur. Although correction of the abnormal AR
is not possible, an increase in the substrate reaching
that receptor may result in a more normal biological
effect as demonstrated by the following case report.
CASE REPORT
A 23-year-old black male presented with azo-
ospermia diagnosed by semen analysis on three sep-
arate occasions (average pH of 7.4; average volume
of 3.4 mL) over the course of 1 year. Laboratory
evaluation revealed a normal follicle-stimulating
hormone, luteinizing hormone, testosterone (T),
prolactin, and thyroid functions. A peripherallym-
phocyte karyotype was 46,XY. Physical examination
Received June 12, 1992; revised and accepted September 21,
1992.
* Reprint requests: James W. Akin, M.D., Department of Ob-
stetrics and Gynecology, Indiana University Hospital, Room 2440,
926 West Michigan Street, Indianapolis, Indiana 46202-5274.
Vol. 59, No.1, January 1993
Vol.
Printed on acid-free paper in U.S.A.
revealed a small left varicocele but otherwise a nor-
mal exam. The patient underwent a bilateral testic-
ular biopsy, high ligation of the gonadal vein, and a
right-sided vasostomy with vasogram that was
normal.
On testicular biopsy, most of the tubules con-
tained only Sertoli cells and a slightly thickened tu-
nica propria. Only occasional tubules had germ cells
present with varying stages of spermatogenesis.
Leydig cells were seen in slightly increased numbers
(Fig. 1). Follow-up semen analysis postoperatively
still revealed the presence of azoospermia up to 3
years later. The patient and his wife were offered
donor insemination for a pregnancy attempt but
they declined.
Subsequent deoxyribonucleic acid (DNA) study
of this patient was accomplished by Southern anal-
ysis using oligonucleotide probes specific for the hu-
man AR gene. The polymerase chain reaction was
also used to confirm the findings. A deletion of exon
4 within the AR gene was found, as has been de-
scribed elsewhere (2).
Treatment with clomiphene citrate (CC) was
started at doses of 25 mg/d for 4 months. A subse-
quent semen analysis revealed 50,000 sperm/mL
with 33% motility (total volume was 2.1 mL). The
treatment was continued for up to 9 months, but
the sperm count did not improve further. No preg-
nancy was achieved. It was felt that not enough mo-
tile sperm were present to perform routine in vitro
fertilization (IVF). Potentially, this patient may be
a candidate for micromanipulation techniques in the
future.
DISCUSSION
Aiman et al. (1) published a report in 1979 that
first suggested that phenotypically normal infertile
Akin Communications-in-brief 223

Figure 1 Testicular biopsy demonstrating predominance of
Sertoli cells.
males were a part of the androgen insensitivity
spectrum. His conclusions were based on AR binding
activity analysis from genital fibroblasts. More re-
cently at the DNA level, Akin et al. (2) demonstrated
a molecular deletion of exon 4 within the AR gene
in an azoospermic individual with a normal male
phenotype. Exon 4 of the AR gene encodes for a
protein subunit that facilitates the transport of the
AR-androgen complex from the cytoplasm to the
nucleus in the target cell. In the absence of exon 4,
this process continues but not as efficiently.
Phenotypically normal males with azoospermia
secondary to androgen resistance may represent a
subpopulation of infertile males who might respond
to medical therapy. If the AR is present but its com-
plete function is only slightly impaired, the flooding
of the receptor with increased levels of endogenous
androgen substrate may be sufficient to overcome
some problems with spermatogenesis. Although a
serum T level in this patient was not obtained during
treatment, Sokol et al. (3) have previously demon-
strated that the T level rises with CC particularly
if Leydig cells are present.
Gooren (4) described a 32-year-old black male
with oligospermia who had undergone surgical cor-
rection for hypospadius, unilateral cryptorchidism,
and gynecomastia. Studies on fibroblasts from this
patient revealed a decreased AR receptor function.
The patient was treated with tamoxifen (10 mg 2
times a day), and his wife conceived after about 20
weeks of therapy. This treatment was repeated two
additional times over a 5-year period with successful
conception each time.
224 Akin Communications-in-brief
Perhaps the patient reported by Gooren (4) did
1
not have as severe androgen resistance as did the
patient in the present case report because oligo-
spermia and not azoospermia was present. Motile
sperm were still found in this patient after 4 months
of CC therapy, although the ultimate goal of preg-
nancy was not reached.
This case report is not meant to imply that all
patients with oligospermia or azoospermia would
benefit from CC therapy or even that empiric treat-
ment should be tried. The patients having androgen
resistance as the etiology of their infertility are the
most appropriate ones on which to try this therapy.
The frequency of androgen resistance among azo-
ospermic and oligospermic patients is not known,
but a preliminary report based on genital skin fi-
broblast receptor analysis suggests it is as high as
40% (5). As more infertile males are screened for
androgen resistance, the true incidence may become
more evident.
SUMMARY
An infertile male with a deletion within the AR
gene is discussed. The patient presented with azo-
ospermia and, after daily CC treatment, was found
to have sperm within his ejaculate. However, the
ultimate goal of pregnancy was not achieved, nor
were there enough sperm present to warrant an IVF
attempt.
Key Words: Azoospermia, male infertility, an-
drogen insensitivity syndrome.
REFERENCES
1. Aiman J, Griffin JE, Gazak JM, Wilson JD, MacDonald PC.
Androgen insensitivity as a cause of infertility in otherwise
normal men. N Engl J Med 1979;300:223-7.
2. Akin JW, Behzadian A, Tho SPT, McDonough PG. Evidence
for a partial deletion in the androgen receptor gene in a phe-
notypic male with azoospermia. Am J Obstet Gynecol
1991;165:1891-4.
3. Sokol RZ, Steiner BS, Bustillo M, Petersen G, Sweidloff RS.
A controlled comparison of the efficacy of clomiphene citrate
in male infertility. Fertil Steril 1988;49:865-70.
4. Gooren L. Improvement of spermatogenesis after treatment
with the antiestrogen tamoxifen in a man with the incomplete
androgen insensitivity syndrome. J Clin Endocrinol Metab
1989;68:1207-10.
5. Aiman J, Griffen JE. The frequency of androgen receptor
deficiency in infertile men. J Clin Endocrinol Metab 1982;54:
725-32.
Fertility and Sterility