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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3436-3441
Copyright © 2000 by The Endocrine Society

Original Studies

Immunohistochemical Localization of Cyclooxygenase-1 and Cyclooxygenase-2 in the Human Fetal and Adult Male Reproductive Tracts1

Alexander Kirschenbaum, Dara R. Liotta, Shen Yao, Xin-Hua Liu, Adam P. Klausner, Pamela Unger, Ellen Shapiro, Irwin Leav and Alice C. Levine

Departments of Urology (A.K., A.P.K.), Medicine [Division of Endocrinology (D.R.L., S.Y., X.-H.L., A.C.L.)], and Pathology (P.U.), Mount Sinai School of Medicine, New York, New York 100029; Department of Urology, New York University School of Medicine (E.S.), New York, New York 10016; and Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine (I.L.), Boston, Massachusetts 02111

Address all correspondence and requests for reprints to: Alice C. Levine, M.D., Box 1055, Division of Endocrinology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029. E-mail: alice.levine{at}mssm.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The first rate-limiting step in the conversion of arachidonic acid to PGs is catalyzed by cyclooxygenase (Cox). Two isoforms of Cox have been identified, Cox-1 (constitutively expressed) and Cox-2 (inducible form), which are the products of two different genes. In this study we describe the immunohistochemical localization of Cox-1 and -2 in the human male fetal and adult reproductive tracts. There was no Cox-1 expression in fetal samples (prostate, seminal vesicles, or ejaculatory ducts), and only minimal expression in adult tissues. There was no expression of Cox-2 in the fetal prostate. In a prepubertal prostate there was some Cox-2 expression that localized exclusively to the smooth muscle cells of the transition zone. In adult hyperplastic prostates, Cox-2 was strongly expressed in smooth muscle cells, with no expression in the luminal epithelial cells. Cox-2 was strongly expressed in epithelial cells of both fetal and adult seminal vesicles and ejaculatory ducts. The Cox-2 staining intensity in the fetal ejaculatory ducts during various times of gestation correlated with previously reported testosterone production rates by the fetal testis. These data indicate that Cox-2 is the predominant isoform expressed in the fetal male reproductive tract, and its expression may be regulated by androgens. The distinct cell type-specific expression patterns of Cox-2 in the prostate (smooth muscle) vs. the seminal vesicles and ejaculatory ducts (epithelium) may reflect the different roles of PGs in these tissues.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PGs WERE FIRST isolated from seminal fluid and were erroneously thought to be derived from the prostate gland (1, 2). Subsequent studies have demonstrated that the source of seminal fluid PG is primarily the seminal vesicles and ejaculatory ducts, and that the PGs play a pivotal role in human reproduction (3, 4). Cyclooxygenase (Cox), also referred to as PG endoperoxide synthase, is the major enzyme that catalyzes the conversion of arachidonic acid to PGs and other eicosanoids. Two isoforms of Cox have been identified. Cox-1, which has previously been reported to be constitutively expressed in a variety of tissues, was originally characterized from ovine and bovine vesicular glands (5, 6). Cox-2, which was initially identified as a member of the early growth response gene group (7, 8), is inducible by a variety of factors, including cytokines, growth factors, tumor promoters, and steroid hormones (9, 10, 11).

Although both isoforms are expressed during fetal development, Cox-2 expression is more widespread and abundant during fetal life. Targeted gene disruption of Cox-2 yields a more severely altered phenotype than that observed with disruption of Cox-1 (12, 13, 14). In addition to severe renal and cardiac abnormalities, Cox2-/- mice had a predominantly female genotype, implying that male animals lacking Cox-2 gene expression were at a survival disadvantage (13). In the mouse bladder, Cox-2 is strongly expressed during early stages of fetal development and is highly inducible in states of bladder obstruction (15).

There have been several reports demonstrating the expression patterns and importance of the cyclooxygenases in the female reproductive tract (16, 17). Despite evidence implicating PGs and cyclooxygenases as critical factors in male reproductive function, little is known about Cox expression patterns in the human male reproductive tract. We herein report on the cell-specific expression of Cox-1 and Cox-2 in tissue samples derived from fetal, prepubertal, and adult male reproductive organs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues

Tissue sections from human fetal prostates were obtained by Dr. Ellen Shapiro from gestational ages 9.5, 11.5, 13, and 16.5 weeks (n = 2 from each gestational age). Approval for their use was granted by the New York University Institutional Board Review Association. The specimens were fixed in formalin and paraffin embedded. They were serially step-sectioned (3 µm thick). Representative tissue sections from the apex, mid, and base of the prostate were selected for staining. The mid-gland corresponded to the level where the ejaculatory ducts entered the seminal colliculus.

Fetal tissue was obtained from 2 additional male fetuses (16.5 weeks gestation), 3 male fetuses (20–22 weeks gestation), and 3 male fetuses (24–26 weeks gestation) at the time of pregnancy interruption and with the approval of the Mount Sinai Medical Center institutional review board. Specimens of human prepubertal prostate, ejaculatory ducts, and seminal vesicles were obtained from archival tissue collected and stored in the Department of Pathology, New England Medical Center and Tufts University School of Medicine. Adult prostatic tissue was obtained from 10 patients with symptomatic benign prostatic hyperplasia (BPH) undergoing transurethral prostatectomy under the guidelines of the institutional review board. Adult seminal vesicle and ejaculatory duct tissues were obtained from 19 patients undergoing radical prostatectomy for prostate cancer, again under the guidelines of the institutional review board. All samples were fixed in formalin.

Immunohistochemistry for Cox-1 and smooth muscle actin

Immunohistochemical reagents were obtained from Oxford Biomedical Research, Inc. (Oxford, MI). Formalin-fixed tissues were embedded in paraffin. Staining was carried out using an avidin-biotin complex method (18). Briefly, specimens were cut in 5-µm sections, mounted on poly-L-lysine-coated microscope slides, deparaffinized, rinsed with graded alcohol, and washed with water. Slides were then immersed in 3% hydrogen peroxide for 15 min at 22 C to quench endogenous peroxidase activity. After washing in Tris-buffered saline (TBS) twice for 5 min each time, sections were submerged in 10 mmol/L citric buffer, pH 6.0, and microwaved at high power three times for 5 min each time. Slides were then left to cool to room temperature in the buffer solution (20 min). Slides were again washed in TBS twice for 5 min each time, and nonspecific binding was blocked by incubation with normal horse serum for 1 h at 37 C. Cox-1 immunoreactivity was localized with monoclonal mouse anti-human PGHS-1 antibody (Oxford) diluted to 25 µg/ml in 1% FBS in TBS. Sections were incubated with the primary antibody for 1 h at 37 C and at 4 C overnight. Slides were subsequently washed twice with TBS for 5 min each time and then immersed in a biotinylated horse antimouse secondary antibody for 1 h at 37 C. After washing twice in TBS, prediluted strepavidin-horseradish peroxidase was applied for 30 min. After washing twice with TBS, slides were placed in 0.5% Triton X-PBS for 30 s. 3,3'-Diaminobenzidine was used as the chromagen for color development. Sections were counterstained with Harris hematoxylin. Staining for smooth muscle actin ({alpha}-actin) was carried out as described above using monoclonal mouse antiactin (Zymed Laboratories, Inc., South San Francisco, CA) as primary antibody.

Immunohistochemistry for Cox-2

The same procedure described for the immunohistochemical staining of Cox-1 was used for the staining of Cox-2 with the following modifications; specimens were microwaved at high power twice for 5 min each time. Cox-2 immunoreactivity was localized with monoclonal mouse antihuman Cox-2 antibodies (Transduction Laboratories, Lexington, KY) diluted to 25 µg/ml in 1% FBS in TBS. Slides were subsequently washed twice with TBS for 5 min each time and then immersed in a biotinylated horse antimouse secondary antibody for 30 min at 22 C.

Evaluation of immunostaining

Evaluation of immunostaining was carried out by two independent observers (an attending urologist and a genito-urinary pathologist) in a blinded fashion. Cells of different histological types were first analyzed by recording only positive vs. negative immunoreactivity. Histological subtypes were further analyzed in a semiquantitative manner by assigning an immunoreactive intensity of a scale of 0–4 as previously described (19, 20). An intensity of 0 was assigned to cells with no immunoreactivity, and an intensity of 4+ was given to cells with the highest staining intensity. Smooth muscle cells of adult BPH tissue, which uniformly stained with high intensity (4+) for Cox-2, were used as a positive internal reference.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1Go demonstrates the immunohistochemical expression of Cox-1 in fetal, prepubertal, and adult male reproductive tissues. There was no Cox-1 expression detectable in the fetal prostate or ejaculatory ducts at any stage of gestation. Figure 1Go, A and B, demonstrate the negative staining at 11.5 or 22 weeks gestation, respectively. There was also no Cox-1 expression detectable in the seminal vesicles of a prepubertal boy (11 yr of age; Fig. 1CGo) or in prostate specimens from the same case (data not shown). Figure 1DGo demonstrates that there is no detectable Cox-1 expression in either stroma or epithelium of adult hyperplastic prostates.



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  		Figure 1. A–D, Negative Cox-1 Immunostaining in fetal, prepubertal, and adult male reproductive tissues. A, 11.5-week gestation fetal prostate and ejaculatory ducts (arrows; magnification, x40); B, 22-week gestation fetal prostate and ejaculatory ducts (arrows; magnification, x100); C, seminal vesicles of prepubertal male (magnification, x100); D, adult hyperplastic prostate (magnification, x200).

 
In contrast, Cox-2 was strongly expressed in fetal, prepubertal, and adult male reproductive tissues. In the fetus, Cox-2 staining intensity in the ejaculatory ducts varied with gestational age and paralleled reported testosterone production rates by the fetal gonad (21). At 9.5 weeks gestation (n = 2), when androgen levels are low, there was little detectable expression of Cox-2 in either the prostate or ejaculatory ducts (Fig. 2AGo). Cox-2 staining remained negative in the fetal prostate at any stage of gestation. However, Cox-2 was uniformly expressed in the ejaculatory duct epithelium by 11.5 weeks gestation (n = 2; Fig. 2Go, B and C). Staining intensity for Cox-2 in the ejaculatory duct epithelium steadily increased at 13 weeks (n = 2) and 16.5 weeks (n = 4) gestation (Fig. 2Go, D and E, respectively) and remained strong at 21 weeks gestation (Fig. 2FGo), corresponding to the reported peaks in fetal androgen production rates (21). Thereafter, at 24 weeks gestation, Cox-2 staining intensity declined in the ejaculatory duct epithelium (Fig. 2GGo). Staining intensity in all ejaculatory duct specimens examined were as follows: 9.5 weeks (n = 2), intensity = 0; 11.5 weeks (n = 2), intensity = 2+; 13 weeks (n = 2), intensity = 3+; 16.5 weeks (n = 4), intensity = 3+; 21 weeks (n = 3), intensity = 2+; and 24 weeks (n = 3), intensity = 0–1+.



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  		Figure 2. A–F, Cox-2 immunostaining in the fetal prostate and ejaculatory ducts at 9.5–24 weeks gestation. A, Negative Cox-2 expression in prostate and ejaculatory ducts (arrows) of a 9.5-week gestation sample. P.U., Prostatic urethra (magnification, x40). B, Positive Cox-2 expression (2+) in 11.5-week gestation ejaculatory ducts (arrows) with negative prostatic staining (magnification, x40). C, Higher magnification (x100) of positive Cox-2 staining in 11.5-week gestation ejaculatory ducts. D, Positive Cox-2 immunostaining (3+) of 13-week gestation ejaculatory ducts (arrows), with negative staining of surrounding prostatic mesenchyme (magnification, x100). E, Positive Cox-2 immunostaining of 16.5-week gestation ejaculatory ducts (3+), with continued negative staining in surrounding prostatic mesenchyme (magnification, x200). F, Positive Cox-2 immunostaining of 21-week gestation ejaculatory ducts (2+), with no staining of prostatic mesenchyme (magnification, x100). G, Negative Cox-2 immunostaining of 24-week gestation ejaculatory ducts and prostate (magnification, x100).

 
In the prepubertal prostate, there was no Cox-2 expression in prostate epithelial cells of either the peripheral or transition zone (Fig. 3Go, A and B, respectively). However, there was some expression in the smooth muscle cells in the transition zone of the prostate (Fig. 3BGo). Moderate immunostaining of Cox-2 was present in the seminal vesicular epithelia of the prepubertal male that was comparable to the staining intensity found in the fetal ejaculatory ducts at 21 weeks gestation (Fig. 3Go, C and D).



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  		Figure 3. A–D, Cox-2 immunostaining in the prepubertal male reproductive tract. A, Negative Cox-2 immunostaining of prostate epithelial cells of the peripheral zone (magnification, x40). B, Positive Cox-2 immunostaining of prostatic smooth muscle cells (2+; arrows) in the transition zone (magnification, x100). C, Positive Cox-2 immunostaining of seminal vesicle epithelial cells (3+; magnification, x40). D, Higher power (x200) of positive immunostaining of seminal vesicle epithelium.

 
There was intense staining (4+) for Cox-2 in smooth muscle cells in all 10 BPH specimens. The epithelial cells of BPH, however, were generally negative for Cox-2 expression (Fig. 4AGo). Immunostaining of adjacent sections for smooth muscle {alpha}-actin expression demonstrated that it was predominantly the smooth muscle cells of BPH that expressed Cox-2 (Fig. 4BGo). Epithelial cells of adult seminal vesicles and ejaculatory ducts were strongly positive (3–4+) for Cox-2 expression in all samples (Fig. 4Go, C and D, respectively).



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  		Figure 4. A–D, Cox-2 immunostaining in adult reproductive tissues. A, Intense Cox-2 staining (4+) in smooth muscle cells (arrows) of BPH with negative staining in epithelium (magnification, x100). B, {alpha}-Actin staining of smooth muscle cells of an adjacent BPH section (magnification, x100). C, Positive Cox-2 immunostaining (3–4+) of adult seminal vesicle epithelium (magnification, x40). D, Positive Cox-2 immunostaining of adult ejaculatory duct epithelium (4+; magnification, x40).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
PGs are secreted in seminal fluid and have been shown to play key roles in processes involved in human female reproduction, including ovulation (22, 23), menstruation (24), implantation (25, 26), and decidualization (26, 27, 28). The precise roles of PGs and cyclooxygenases in human male reproductive development and function are less clear. The present study indicates that of the two known Cox isozymes that catalyze the conversion of arachidonic acid to PGs, it is the inducible form, Cox-2, that is expressed in the developing human male reproductive tract. These data are in agreement with a previous report that demonstrated that Cox-2 is the predominant isoform expressed in the developing murine fetal bladder (15). Cox-2 expression (and not Cox-1) has also been reported to be induced in embryonic human uterine endometrium (16) and in ovine embryos during the implantation period (29). Mice deficient in Cox-1 are fertile (12), whereas Cox-2-deficient mice are infertile (14), presumably secondary to ovulatory dysfunction and abnormal implantation (17). Taken together, these data indicate that Cox-2 is more highly expressed during development than Cox-1 in both the male and female developing reproductive tracts.

Steroid hormones have been demonstrated to modulate Cox-2 expression in the baboon endometrium (30) and in bovine endometrial cells (11). In one report, which studied the adult rat male reproductive system, Cox-2 expression was localized to the epithelium of the distal vas deferens. In that same report, Cox-2 expression was shown to be androgen dependent (10). Siiteri and Wilson reported that testosterone first becomes detectable in human male fetuses at 8–10 weeks gestation, with peak formation rates at 17–21 weeks gestation and declining levels thereafter (21). The age-specific Cox-2 immunohistochemical staining intensity in the developing ejaculatory duct epithelium, herein described, therefore closely parallels the reported androgen levels in the human male fetus. Cox-2 expression is undetectable by immunohistochemistry at 9.5 weeks gestation, becomes detectable by 11.5 weeks with increased staining intensity at 13, 16.5, and 21 weeks gestation, and decreased staining intensity by 24 weeks gestation. However, although these data may indicate that androgens up-regulate Cox-2 expression, immunohistochemical staining intensity is only a semiquantitative measure of protein expression.

We noted the absence of Cox-1 or Cox-2 expression in fetal prostates. In the prepubertal and adult prostate, Cox-1 expression continued to be undetectable. Moderate Cox-2 immunostaining (2+ staining intensity) was present in prostate smooth muscle cells in the transition zone of an 11-yr-old boy. In adult BPH specimens (n = 10), Cox-2 expression was limited to the smooth muscle cells, with intense immunohistochemical staining (4+). One previous report measured Cox-1 and Cox-2 messenger ribonucleic acid (mRNA) expression in human tissues by RT-PCR (31). In that report, the highest levels of both Cox mRNAs were detected in the prostate, where equal amounts of Cox-1 and Cox-2 transcripts were present. The discrepancy between their findings and those of our present study (in which there was no Cox-1 protein expression in adult BPH with immunohistochemistry) could be due to the greater sensitivity of their RT-PCR technique for detecting low levels of mRNA expression. The prostate tissue samples from which the RNA was derived in the RT-PCR study were from a pool of five adult males. Although the present study demonstrates that noncancerous human prostate epithelial cells do not express Cox-2, we have previously demonstrated that human prostate cancer cell lines express Cox-2 (32). We have also found evidence of up-regulation of both Cox-1 and Cox-2 expression on immunohistochemistry in cancerous prostate epithelial cells (data not shown). The differences in the reported findings of the two studies could also, therefore, be due to the unknown presence of some prostate cancer cells in the pooled prostate samples of the RT-PCR study. Finally, as has been demonstrated with androgen receptor expression (33, 34), there may be differential regulation of Cox-2 expression at the transcriptional and translational levels, accounting for discrepancies in the reported mRNA and protein levels.

PGs are known modulators of smooth muscle function and growth in various hollow organs. Indomethacin, a nonselective Cox inhibitor, was found to lower bladder tone and increase bladder capacity and compliance (35, 36). In the adult mouse bladder, Cox-2 mRNA expression was greatly increased (30-fold) 24 h after obstruction, and this induction was primarily in the stroma (15). One of the sequelae of bladder outlet obstruction secondary to BPH is detrusor muscle hyperplasia and bladder instability. Irritative symptoms of BPH, which are thought to be due to increased smooth muscle tone in the hypertrophied bladder wall, are often the most bothersome and the least amenable to currently available therapies. In the present study the strong immunostaining for Cox-2 in adult prostate smooth muscle cells derived from BPH tissue may have implications in the pathogenesis of BPH, which is believed to be primarily a stromal disease. Selective Cox-2 inhibitors may be effective therapy for BPH, because they hold the promise of decreasing proliferation and inducing relaxation in the smooth muscle cells of both the prostate and the bladder, leading to a decrease in both the obstructive and irritative symptoms of the disease.


   Footnotes
 
1 This work was supported by grants-in-aid from the T. J. Martell Foundation for Leukemia, Cancer, and AIDS Research and the Manfred Lehmann Cancer Research Foundation. Back

Received December 15, 1999.

Revised April 20, 2000.

Accepted May 17, 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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