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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 11 5325-5331
Copyright © 2002 by The Endocrine Society

Original Article

Progesterone Production and Actions in the Human Central Nervous System and Neurogenic Tumors

Tsukasa Inoue, Jun-Ichi Akahira, Takashi Suzuki, Andrew D. Darnel, Chika Kaneko, Kazuhiro Takahashi, Masahito Hatori, Reizo Shirane, Toshihiro Kumabe, Yoshimochi Kurokawa, Susumu Satomi and Hironobu Sasano

Department of Pathology (T.I., J.A., J.T., T.S., A.D.D., C.K., H.S.), Second Department of Surgery (T.I., Y.K., S.S.), and Departments of Applied Physiology and Molecular Biology (K.T.), Orthopedic Surgery (M.H.), and Neurosurgery (R.S., T.K.), Tohoku University School of Medicine, Sendai 980-8575, Japan

Address all correspondence and requests for reprints to: Tsukasa Inoue, M.D., Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: tsukasai{at}gonryo.med.tohoku.ac.jp.

Abstract

Progesterone has been suggested to be involved in the functions of the nervous system, but it has yet to be examined in humans. Progesterone has also been postulated to be involved in the biological behavior of various human neurogenic tumors via progesterone receptors A and B (PR-A and PR-B). In this study we examined the expression of PR and the enzymes responsible for progesterone biosynthesis (P450scc, 3ßhydroxysteroid dehydrogenase, and steroidogenic acute regulatory protein) in human brain. We also examined the distribution of PR isoforms in neurogenic tumors using immunohistochemistry and RT-PCR analysis. The presence of PR and mRNA for P450scc, 3ß-hydroxysteroid dehydrogenase, and steroidogenic acute regulatory protein was detected in human brain. PR isoforms were detected in neurogenic tumors. PR-A and PR-B were equally expressed in meningiomas, but PR-B was the predominant isoform compared with PR-A in astrocytic tumors and Schwannomas. There was a statistically significant inverse correlation between PR-A and the proliferation index in meningiomas and astrocytic tumors. These findings suggest that progesterone is locally synthesized and exerts its actions through PR in the human central nervous system, and that progesterone may be involved in regulation of the growth and development of neurogenic tumors via PR, especially in the inhibition of tumor cell proliferation via PR-A.

PROGESTERONE HAS BEEN demonstrated to exert its effects not only in reproductive organs, such as the endometrium and breast, but also in several nonreproductive organs (1). Especially, progesterone has been reported to be synthesized in the central and peripheral nervous system and is considered to be a neurosteroid (2). The enzymes responsible for progesterone biosynthesis [cytochrome P450scc, which converts cholesterol to pregnenolone, and 3ß-hydroxysteroid dehydrogenase (3ß-HSD), which converts pregnenolone to progesterone] have been identified in the brain and spinal cord of the rat (2). These enzymes have been localized to the glial and Schwann cells of the rat nervous system (3, 4). In addition, the biosynthesis of steroid hormones, such as progesterone, is known to take place within the mitochondria. Steroidogenic acute regulatory protein (StAR) plays an important role in the process of steroidogenesis and appears to be the factor that results in the movement of cholesterol within the mitochondria (5), but its presence in the nervous system has been a topic of dispute. Progesterone synthesized in the nervous system is postulated to play essential roles in this system, including the regulation of myelin formation and the modulation of type A {gamma}-aminobutyric acid receptor function (2, 6). Progesterone has also been found to activate myelin synthesis in the neurons of the rat (7). These relatively diverse effects of progesterone are all mediated through its binding to a specific intranuclear receptor, the progesterone receptor (PR) (8).

PR belongs to the nuclear receptor superfamily, and to date, two isoforms of this receptor have been identified, PR-A and PR-B (94 and 114 kDa in size, respectively) (9). The PR-B isoform is a full-length receptor, whereas the PR-A isoform lacks 164 amino acids in the N terminus of the PR-B isoform. Both PR-A and PR-B are derived from transcripts initiated from two distinct estrogen-inducible promoters within a single copy of the PR gene (10). Both isoforms have been demonstrated to function as ligand-activated transcription factors, but they are not always equal in their functional properties and progesterone actions (11). PR-B is, in general, transcriptionally more active than PR-A, but compared with PR-A, PR-B activity is also cell specific (12). In addition, the PR-A isoform has been demonstrated to repress the transcriptional activities of other steroid hormone receptors, including the estrogen receptor and PR-B (11, 13, 14, 15). Therefore, the relative levels of PR-A and PR-B within target cells may contribute to the nature and magnitude of functional responses to progesterone. Examination of the relative levels of these two isoforms in progesterone-responsive tissues, therefore, has become a very important topic of study, as it leads to a better understanding of progesterone actions.

In this study we first examined the presence of P450scc, 3ß-HSD, StAR, and PR subtypes in the human central nervous system (CNS) to evaluate the status of possible progesterone biosynthesis and actions, i.e. whether progesterone may also serve as a neurosteroid in the human brain.

Progesterone has also been reported to influence the biological behavior of human neurogenic tumors. For instance, the incidence of meningiomas is twice as high in females as in males (16), and their growth has been observed to be accelerated during pregnancy (17). To date, several investigations have examined the expression of PR in meningiomas and astrocytomas (18, 19). The presence of PR in meningioma has been reported to be involved in its histological features, tumor grade, and prognosis (18, 20, 21). In addition, an association between the histological grade for astrocytic tumors and PR has been reported (22, 23). These studies all suggest that progesterone may contribute to the proliferation of meningioma and astrocytic tumors via PR.

However, the expression of PR isoforms, PR-A and PR-B, has not been studied in neurogenic tumors. Therefore, in this study we examined the distribution of PR-A and PR-B in human neurogenic tumors using immunohistochemistry and RT-PCR analysis. We also examined the relationship between PR isoforms and the proliferation index (Ki-67), one of the most important clinicopathological parameters that describes the biological behavior of these tumors, to evaluate the possible biological significance of progesterone in the growth and development of these neurogenic tumors. In addition, we used RT-PCR analysis to evaluate the presence of cytochrome P450scc and 3ß-HSD in these tumors to elucidate a possible mechanism of progesterone synthesis on tumor proliferation.

Materials and Methods

Tissues

Seventy-seven cases (36 males and 41 females) of neurogenic tumors were retrieved from the surgical pathology files at Tohoku University Hospital (Sendai, Japan). These tissues were obtained during surgery at Tohoku University Hospital between 1990 and 1999. The mean age of the patients was 48.6 ± 18.7 yr (range, 6–85 yr). All specimens for immunohistochemical examination were fixed in 10% neutral formalin for 18 h at room temperature and then embedded in paraffin. These specimens were subsequently sectioned at 3 µm and mounted onto silane-coated glass slides (Matsunami Co. Ltd., Tokyo, Japan).

Fresh-frozen specimens of both adult brain tissues (n = 5; 2 males and 3 females; mean age, 53.2 ± 15.6 yr) obtained from autopsy and neurogenic tumors (n = 27; 14 males and 13 females; mean age, 41.3 ± 19.0 yr) obtained from surgery were available for RNA extraction. Total RNA was extracted from tissues by the guanidine thiocyanate-cesium chloride method. Informed consent was obtained from the patients or the families of the patients. The ethics committee at Tohoku University School of Medicine (Sendai, Japan) approved this research protocol.

RT-PCR analysis

cDNA synthesis was performed using an RT-PCR kit (Superscript preamplification system, Life Technologies, Inc., Grand Island, NY). First-strand cDNA was synthesized from 1 µg total RNA in a 20-µl reaction volume containing 50 mM Tris-HCl (pH 8.3), 55 mM KCl, 3 mM MgCl2, 0.02 M dithiothreitol, 0.5 mM deoxy-NTP, 62.5 mg/ml oligo(deoxythymidine), and 100 U Superscript II ribonuclease H- reverse transcriptase at 42 C for 50 min. The reaction mixture was subsequently inactivated for 15 min at 70 C. An aliquot of each RT reaction product (1 µl) was amplified with gene-specific primers (Table 1Go) in a solution containing 1x PCR buffer, 1.5 mM MgCl2, 0.1 mM deoxy-NTP, and 1.25 U Taq DNA polymerase (PCR Reagent System, Life Technologies, Inc.) in a total volume of 25 µl. PCR was performed on a DNA Engine Thermocycler (MJ Research, Inc., Cambridge, MA). A 35-cycle amplification profile consisted of denaturation at 94 C for 45 sec, annealing at 55 C for 30 sec, and extension at 72 C for 1.5 min. The amplified DNA products were then resolved on a 1.8–2.0% agarose gel and visualized by ethidium bromide staining. Negative controls without RNA and without reverse transcriptase were also included in the PCR reaction to test for exogenous DNA contamination. To assure that the PCR-amplified DNA observed in the agarose gel represented the gene-specific product of interest, we isolated, extracted, and purified the gene-specific bands of anticipated size from agarose gels, then cloned and sequenced them.


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  		Table 1. Oligonucleotide primer sequences used for RT-PCR analysis

 
Primary antibodies

The primary antibodies used in the present study were hPRa7, hPRa2 (Neomarkers, CA), and Ki-67 (MIB-1, Immunotech, Marseilles, France). hPRa7 and hPRa2 are monoclonal antibodies raised in mice against PR isoforms obtained from a human endometrial carcinoma (EnCa 101). In a previous investigation we reported an immunohistochemical study using hPRa7 and hPRa2 (1). The hPRa7 antibody employed in this study recognized both PR-A and PR-B in immunoblot analysis (24). However, Mote et al. (25) reported that hPRa7 did not recognize PRB in their immunohistochemistry study of fixed tissues even after antigen retrieval, as evidenced by the absence of immunostaining for this antibody in the PR-B-expressing MDA-MB-231/PR-B cell line. This may be due to the inaccessibility of the epitope on PR-B recognized by hPRa7 in 10% formalin-fixed and paraffin-embedded tissue specimens (25), which, in turn, may be due to an alteration in the conformation of the molecule in such a way that the hPRa7 epitope is located in a manner that reduces its accessibility during immunohistochemistry. Ki-67 is monoclonal antibody that reacts with a nuclear protein expressed in the G1, G2, S, and M phases of the cell cycle (26). Therefore, immunostaining for Ki-67 is effective in predicting the biological behavior and prognosis of neoplasms of the nervous system (27, 28).

Immunohistochemistry

Immunohistochemistry was performed using the streptavidin-biotin amplification method employing a Histofine Kit (Nichirei, Tokyo, Japan), which has been previously described in detail (29). The hPR-7 antibody was used at a dilution of 1:100, the hPR-2 antibody at 1:200, and the Ki-67 antibody at 1:50. The antigen-antibody complex was visualized with 3,3'-diaminobenzidine solution [1 mM 3,3'-diaminobenzidine, 50 mM Tris-HCl buffer (pH 7.6), and 0.006% H2O2] and counterstained with hematoxylin. Tissue sections of invasive ductal carcinoma of the breast were used as positive controls for PR isoforms. PBS (0.01 M) and normal mouse IgG were used instead of primary antibodies as a negative control. No specific immunoreactivity was detected in these tissue sections.

Scoring of immunoreactivity

All of the immunolabeled cells were evaluated as positive regardless of the degree of immunointensity (30). For statistical analyses of PR-A, PR-B, and Ki-67 immunoreactivity, we determined the percentage of positive cells in each tumor, as described by Sasano et al. (31) with some modification. Scoring of PR-A, PR-B, and Ki-67 in tumor cells was performed with high power fields (x400) using a standard light microscope. In each case more than 500 tumor cells were counted independently (double-blind) by two of the authors (T.I. and T.S.), and the percentage of immunoreactivity, i.e. the labeling index (LI), was determined. In our present study interobserver differences were less than 5%, and the mean of the two values was obtained.

Statistical analysis

LI values for PR-A, PR-B, and Ki-67 were presented as the mean ± 95% confidence interval. An association between PR and Ki-67 immunoreactivity was evaluated using a Spearman rank correlation. P less than 0.05 was considered significant.

Results

RT-PCR analysis

RT-PCR analysis revealed bands corresponding to the expected sizes for PR-AB (196 bp), P450scc (182 bp), 3ß-HSD (181 bp), and StAR (199 bp) in human adult brain tissues, including cerebral cortex and cerebellum, regardless of age or gender. Breast carcinoma (PR-A and PR-B) and adrenal cortex (P450-scc, 3ß-HSD, and StAR), employed as positive controls, were also shown to express the respective amplified gene product of the expected size. A band corresponding to the expected size for glyceraldehyde-3-phosphate dehydrogenase (GAPDH; 307 bp) was detected in all tissues examined in this study (Fig. 1Go).



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  		Figure 1. RT-PCR analysis of human PR-AB, 3ß-HSD, P450scc, and StAR. Bands corresponding to the amplified PCR products for PR-AB (196 bp) 3ß-HSD (181 bp), P450scc (182 bp), and StAR (199 bp) were clearly detected in all human brain tissues we examined. GAPDH (307 bp), an internal positive control, was demonstrated in all tissues. 1–5, 70-yr-old female; 6–9, 66-yr-old male; 1, frontal lobe; 2, pons; 3, cerebellum; 4, temporal cortex; 5, hippocampus; 6, frontal lobe; 7, pons; 8, cerebellum; 9, temporal cortex; 10, positive control.

 
RT-PCR analysis also revealed bands corresponding to the expected sizes for PR-AB and PR-B (429 bp) in human neurogenic tumors, as well as in breast carcinoma (Fig. 2Go), but amplified gene products for P450scc and 3ß-HSD were not detected. The sequences of all of these PCR products were confirmed by direct sequencing analysis (data not shown).



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  		Figure 2. RT-PCR analysis of human PR-AB, PR-B, 3ß-HSD, and P450scc. Bands corresponding to the amplified PCR products for PR-AB (196 bp) and PR-B (429 bp) were clearly detected in all human neurogenic tumors we examined, but bands for 3ß-HSD (181 bp) and P450scc (182 bp) were not detected in these tumors. GAPDH (307 bp), an internal positive control, was shown to be amplified in all tissues.

 
Immunohistochemistry

Immunoreactivity for PR isoforms was confined exclusively to the nuclei of tumor cells (Fig. 3Go). The median percentage of astrocytic tumor cells expressing PR-B was 88.4 ± 18.1%, whereas that expressing PR-A was 17.5 ± 21.0%. The median percentage of meningioma tumor cells expressing PR-B was 56.5 ± 27.3%, whereas that expressing PR-A was 41.6 ± 28.2%. The median percentage of Schwannoma tumor cells expressing PR-B was 46.6 ± 29.4%, whereas that expressing PR-A was 18.9 ± 18.8% (Table 2Go). The PR-A LI was higher in meningiomas than in astrocytic tumors and Schwannomas (P < 0.05). There was no significant correlation between PR isoform immunoreactivity, and gender or menopausal status in patients with human neurogenic tumors (Tables 3Go and 4Go).



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  		Figure 3. Immunoreactivity for PR-A and PR-B in human neurogenic tumors. In astrocytoma, compared with PR-A (A), PR-B (B) was predominantly expressed. In meningioma, PR-A immunoreactivity (D) was as high as that of PR-B (E). In Schwannoma, compared with PR-A (G), PR-B (H) was predominantly expressed. A control study was performed using normal mouse IgG in astrocytoma (C), meningioma (F), and Schwannoma (I). Original magnification, x400.

 

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  		Table 2. The relative expression of PR-A and PR-B in the human neurogenic tumors

 

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  		Table 3. The percentage of PR isoforms in the human neurogenic tumors of male and female cases

 

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  		Table 4. Correlation between PR isoform immunoreactivity and clinical parameters in the human neurogenic tumors

 
Immunoreactivity for Ki-67 (MIB1) was detected in the nuclei of tumor cells. There was a significant inverse correlation between PR-A and Ki-67 LIs in astrocytic tumors and meningiomas (P < 0.05; Fig. 4Go), but not between PR-B and Ki-67 LIs. No correlation was detected between either of the PR isoforms and Ki-67 LI in Schwannomas.



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  		Figure 4. Correlation between PR-A LI and Ki-67 LI in astrocytic tumors (A) and meningiomas (B). A, There was a significant inverse correlation between PR-A LI and Ki-67 LI in astrocytic tumors (P < 0.05). B, There was a significant inverse correlation between PR-A LI and Ki-67 LI in meningiomas (P < 0.05).

 
Discussion

A neurosteroid is defined as a steroid hormone produced from cholesterol in the nervous system, first proposed by Baulieu et al. (2). Progesterone has recently been reported to be one of the neurosteroids influencing various functions of both central and peripheral nervous systems as a modulator of neurotransmission (32). Progesterone is synthesized particularly in myelinating Schwann cells (3) and regulates myelin synthesis through PR in the nervous system by activating transcription (6). All studies to date, however, have previously been performed in the rat and mouse, and thus little is known about the status of progesterone biosynthesis, actions, and function as a neurosteroid in the human brain.

In our present study the number of cases examined was limited due to the nature of the study, but PR as well as the enzymes involved in progesterone biosynthesis were detected in some regions of the human brain. Therefore, progesterone may also function in the human CNS as a neurosteroid. Robel and colleagues (32) reported that neurosteroids such as progesterone could influence memory processes by modulating type A {gamma}-aminobutyric acid neurotransmission. Investigations by Baulieu et al. (6) and Chan et al. (33) reported that progesterone might enhance myelin formation of the nerve. Progesterone that is locally produced in the human brain may also promote new myelin sheath formation and contribute to regeneration and repair of the nerve cells, but further investigations are required to clarify the role that progesterone has as a neurosteroid in the human brain.

Two isoforms of human 3ß-HSD, the enzyme responsible for converting pregnenolone to progesterone, have been identified to date, type I and type II. 3ß-HSD type I is detected in the placenta and skin, whereas the type II isoform of 3ß-HSD is detected in the adrenal glands, ovaries, and testes. Functionally, no differences are known to exist between the two isoforms of 3ß-HSD (34). In this study the sequences of the amplified PCR products for 3ßHSD in human brain were consistent with 3ß-HSD type II. Therefore, of the two isoforms of 3ß-HSD, we believe it is the type II isoform of 3ß-HSD that is expressed in the human nervous system. In this study StAR was also detected in the human brain. StAR plays an essential role in steroid hormone biosynthesis through the import of cholesterol into mitochondria (5). Previous studies have demonstrated the absence of StAR in human and rat brains (35, 36), but Furukawa and co-workers (37) have recently identified StAR in the rat brain. Results from our present study suggest that StAR may also be involved in the synthesis of progesterone in the human brain. Cholesterol is known to be transported into mitochondria via StAR. The conversion of cholesterol to pregnenolone via P450scc and that of pregnenolone to progesterone via 3ß-HSD are likely to be one mechanism of progesterone synthesis in the human CNS. However, further investigations are required to fully characterize progesterone biosynthesis and actions in the human CNS.

Human neurogenic tumors have been demonstrated to express PR. However, the biological significance of PR in these tumors has not been fully characterized. The analysis of PR subtypes can provide new insights into the biological roles of various progesterone-responsive lesions, including neurogenic tumors. Immunohistochemical evaluation of receptor subtypes can provide important information in these studies. As described previously, Mote et al. (25) have demonstrated that the mouse monoclonal antibody hPRa7, which was also employed in this study, recognized only PR-A based on immunofluorescence immunostain analysis in MCF-7 M11/PR-A cells expressing only PR-A protein and PR-B-expressing MDA-MB-231/PR-B cells (25). They subsequently examined immunolocalization of PR-A and PR-B subtypes in human endometrium during the menstrual cycle using dual immunofluorescent histochemistry (25). However, it is also possible that MCF-7 M11/PR-A cells employed in the study by Mote et al. (25) contained protein or factors that blocked the PR-B-binding site of hPRa7. In addition, it is true that accessibility of the epitopes on antigen molecules may be influenced by various factors of tissue preparations, such as the duration of fixation and others. Therefore, further investigations are required to clarify the specificity of hPRa7 in recognizing PR-A in all of these 10% formalin-fixed and paraffin-embedded tissue sections, including those from neoplastic cases examined in this study. Our present study of immunohistochemistry of PR-A and PR-B subtypes was associated with limitation in interpreting the results as described above, but the PR-B LI was significantly higher than the PR-A LI in astrocytic tumors and Schwannomas, whereas the PR-B LI was as high as the PR-A LI in meningiomas. The discrepancy detected between these different types of neoplasms may represent a possible difference in the effects and/or roles of progesterone among different subtypes of human neurogenic tumors. Previous studies describing PR expression have demonstrated that the relative distributions of PR-A and PR-B in uterine leiomyoma, malignant endometrium, ovarian cancer, and breast cancer may be associated with the biological behavior and/or malignant grade of the tumor (38, 39, 40, 41, 42). Several investigators have reported that there was a significant correlation between histological grade and PR level in meningiomas and astrocytic tumors (18, 20, 21, 22, 23). In meningiomas, aggressive biological behavior, including frequent recurrences and infiltrative growth associated with or without bone destruction, is highly correlated with negative PR status (20, 21), whereas high grade astrocytic tumors are correlated with the presence of PR (22).

Brain tumors are, in general, known to not metastasize outside of the cranial cavity, and thus, the status of cell proliferation is considered the most important predictor of biological behavior of these tumors. However, the correlation between the proliferation of tumor cells and PR isoforms has not been examined in these tumors. In our present study a significant inverse correlation between PR-A level and proliferation index was detected in meningiomas and astrocytic tumors. Michelsen et al. (17) reported the growth of neurogenic tumors that were accelerated during pregnancy. Therefore, it is likely that a female sex steroid hormone may be playing an important role in the proliferation of neurogenic tumors, possibly acting as a growth factor. These data also suggest that progesterone contributes to the cell proliferation and development of neurogenic tumors via PR-A and PR-B. Therefore, progesterone may promote the growth of tumor cells via PR-B while inhibiting the growth via PR-A in meningiomas and astrocytic tumors. An introduction of selective progesterone receptor modulators can therefore contribute to the treatment of these tumors in the future. We could detect the presence of mRNA for 3ß-HSD and P450scc, both of which are required for the synthesis of progesterone in the human nervous system. However, neither 3ß-HSD nor P450scc immunoreactivity or protein was detected in these tumors in these tissues. Therefore, progesterone, in addition to its presence in the circulation, may be synthesized in the nonneoplastic nervous tissue surrounding these neurogenic tumors and may exert its effects through PR in neurogenic tumors.

In summary, progesterone may be synthesized and may act through PR in the human nervous system, possibly as a neurosteroid, and may also be involved in regulation of the growth and development of human neurogenic tumors via its binding to PR.

Acknowledgments

Footnotes

Abbreviations: CNS, Central nervous system; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; 3ß-HSD, 3ß-hydroxysteroid dehydrogenase; LI, labeling index; PR, progesterone receptor; StAR, steroidogenic acute regulatory protein.

Received January 3, 2002.

Accepted August 16, 2002.

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