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Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology (K.S.-A., B.A.M.), and Department of Pediatrics (P.C.W.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032; Department of Medical and Surgery Sciences (F.M., F.S.), University of Padua, 35128 Padua, Italy; Department of Obstetrics and Gynecology and Women’s Health (C.V.R.), University of Louisville Health Sciences Center, Louisville, Kentucky 40292; and Department of Physiology (W.E.R.), Medical College of Georgia, Augusta, Georgia 30912
Address all correspondence and requests for reprints to: William E. Rainey, Ph.D., Department of Physiology, Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912. E-mail: wrainey{at}mcg.edu.
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Abstract |
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Objective: The objective of the study was to determine whether APAs express elevated LH receptor, compared with normal adrenal (NA).
Design: Pools of RNA from NA and APAs were hybridized to oligonucleotide microarrays. Data were confirmed using real-time RT-PCR analysis of RNA derived from NA (n = 20) and APAs (n = 18). Aldosterone synthase transcription was studied in H295R adrenocortical cells transfected with an LH receptor expression construct and reporter constructs prepared from CYP11B2 5'-flanking DNA.
Patients: The patient population consisted of 20 normal control adrenals and 18 adenomas from patients with APAs.
Main Outcome Measure: Regulation of CYP11B2 gene expression by aberrant LH receptor expression in aldosterone-producing adrenal adenoma was measured.
Results: LH/choriogonadotropin receptor gene and CYP11B2 are indicated as having greater than 25-fold expression in one pool of APA mRNA samples over NA using microarray analysis. Real-time RT-PCR analyses indicated that one APA sample (APA-LH receptor) exhibited more than 2400-fold elevation in LH receptor expression over NA. Examination of LH receptor mRNA levels in 18 independent APA samples indicated elevated expression in nine samples when compared with NA. In H295R cells transfected with LH receptor, LH treatment caused a concentration-dependent increase in CYP11B2 reporter activity.
Conclusion: LH receptor expression is elevated in many APAs, which makes LH a potential cause of the excessive production of aldosterone in a subset of these adrenal tumors.
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Introduction |
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The LH receptor is expressed primarily in gonadal cells including Leydig cells in testes and differentiated granulosa cells, luteal cells, and theca cells in the ovary. In each of these cell types, LH has been shown to play a critical role in both the regulation of steroid hormone production as well as the expression of steroid-metabolizing enzymes. LH receptor is also expressed in a number of nongonadal tissues including human uterus (7), fallopian tubes (8), prostate (9), and breast cancer biopsies (10), although its role in these tissues is unclear. Interestingly, expression of LH receptor has been documented in the adrenal gland using immunohistochemistry (11). Yet a role for LH in the regulation of normal human adrenal cortisol or dehydroepiandrosterone production has not been supported by in vivo studies or using cells in culture (12, 13).
Aberrant expression of LH receptor in adrenal tumors has been shown to cause some cases of ACTH-independent Cushing’s syndrome (14, 15, 16). However, the role of LH and the aberrant expression of LH receptor in Conn’s syndrome (primary aldosteronism) have not been studied. Herein we present novel findings that suggest that expression of LH receptor is elevated in more than half of aldosterone-producing adenomas (APA). In addition, we demonstrate in an adrenocortical cell model transfected with LH receptor that LH can increase the transcription of aldosterone synthase, which is required for the final reaction in aldosterone synthesis. Together these findings suggest that defining the role of aberrant expression of LH receptor in primary aldosteronism warrants further clinical study.
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Subjects and Methods |
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Normal human adult and fetal adrenals, APAs, ovarian follicles, and corpus luteum tissues were obtained through the Cooperative Human Tissue Network (Philadelphia, PA), Clontech (Palo Alto, CA), the Obstetrics and Gynecology Department of University of Texas Southwestern and/or the University of Padua. The normal adrenal samples came from autopsies performed no more than 6 h after death from causes unrelated to adrenal function. The use of these tissues was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center (Dallas, TX).
Microarray analysis
RNA from an adult adrenal (n = 1) and a pool of APAs (n = 3) were hybridized to an Affymetrix human HG-U133 + 2 oligonucleotide microarray set containing 54,675 probe sets representing approximately 40,500 independent human genes. The arrays were scanned at high resolution using an Affymetrix GeneChip Scanner 3000 located at the University of Texas Southwestern Microarray Core Facility. Results were analyzed using GeneSpring (version 6.1 software; Silicon Genetics, Redwood City, CA) to identify differences in expression of G protein-coupled receptors between normal adult adrenal and APAs.
RNA extraction, cDNA synthesis, and real-time RT-PCR
Total RNA was extracted from tissues (17), and purity and integrity of the RNA were checked spectroscopically. Deoxyribonuclease I (2 µg; Ambion, Inc., Austin, TX)-treated total RNA was reverse transcribed using the high-capacity cDNA archive kit (Applied Biosystems, Foster City, CA) following the manufacturer’s recommendations and stored at –80 C. Primers for the amplification of the target sequences were based on published sequences for human LH receptor and human CYP11B2. The primer set used was designed to target the 5' region of LH receptor: forward, 5'-GCCATCAAGAGAAACATTTGTCAA-3' and reverse, 5'-TTTCTAAAAGCACAGCAGTGGCT-3'. The primer/probe set for CYP11B2 consisted of: forward, 5'-GGCAGAGGCAGAGATGCTG-3', reverse, 5'-CTTGAGTTAGTGTCTCCACCAGGA-3', and probe, 5'-CTGCACCACGTGCTGAAGCACT-3'. PCRs were performed using the ABI Prism 7000 sequence detection system (Applied Biosystems) with a total volume of 30 µl per reaction following the reaction parameters recommended by the manufacturer. For LH receptor the 30 µl total volume consisted of SYBR Green universal PCR master mix (x2) (Applied Biosystems), 50 nM of each primer, and 5 µl of each first-strand cDNA sample. CYP11B2 reaction mix consisted of TaqMan ribosomal RNA reagent (Applied Biosystems), 100 nM of primer/probe mix, and 5 µl of each first-strand cDNA sample. Negative controls contained water instead of first-strand cDNA.
Cell culture, transfection assays, and plasmid constructs
H295R human adrenocortical tumor cells were cultured in DMEM/Ham’s F12 medium supplemented with 10% cosmic calf serum (Hyclone, Logan, UT) and antibiotics. For transfection experiments, cells were subcultured onto 12-well dishes at a density of 400,000 cells/well. Transfections were carried out using the transfection reagent Transfast (Promega, Madison, WI) according to manufacturer’s directions for 6 h. To normalize luciferase activity, cells were cotransfected with 50 ng/well of Renilla plasmid (Promega). After recovery of the cells for 20–24 h, cells were treated with human LH (Sigma, St. Louis, MO) for 6 h before being lysed and assayed for activity using the dual-luciferase assay system (Promega). The 5'-flanking DNA from the human CYP11B2 gene has been previously described (18). The expression construct human LH receptor, encoding the full-length human LH receptor, was a gift from Dr. Ilpo Huhtaniemi (University of Turku, Turku, Finland) (19).
Immunohistochemistry (IHC)
IHC was performed by an avidin immunoperoxidase method using a polyclonal LH/human chorionic gonadotropin (hCG) receptor antibody raised against a human receptor N-terminus amino acid sequence of 15–36 and affinity purified (20). The sections were incubated overnight at 4 C with a 1:200 dilution of the receptor antibody. For the procedural control, the receptor antibody was preabsorbed with excess receptor peptide.
Western analysis
Western analysis was performed by homogenizing tissue in 25 mM HEPES buffer (pH 7.4) containing 10 µg/ml leupeptin and aprotinin and 50 µg/ml 4-(2-aminoethyl)-benzenesulfonyl-fluoride. Thirty-microgram protein aliquots were dissolved in loading buffer [125 mM Tris-HCl (pH 6.8) containing 4% sodium dodecyl sulfate and 20% glycerol] and separated by 8% discontinuous SDS-PAGE under reducing conditions. The separated proteins were electroblotted onto Immobilon P membranes. After blocking the nonspecific binding sites with 5% nonfat dry milk in 5 mM Tris-HCl (pH 7.4) containing 136 mM NaCl and 0.1% Tween 20, the blots were incubated overnight at 4 C with a 1:800 dilution of the LH receptor antibody and washed three times for 10 min each with 5 mM Tris-HCl (pH 7.4) containing 136 mM NaCl and 0.1% Tween 20 buffer. The washed blots were incubated again for 1 h at room temperature with a 1:1000 dilution of horseradish peroxidase-labeled secondary antibody, and then the binding of the LH receptor was detected by an enhanced chemiluminescence detection system.
Statistical analysis
Data were analyzed and compared with control values using the Mann-Whitney rank sum test with the SigmaStat 3.0 software package (SPSS, Chicago, IL). Treatments were considered significantly different when P < 0.05.
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Results |
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) clearly indicate that the aldosterone synthase gene (CYP11B2) as well as the LH receptor were expressed at levels more than 25 times higher in the APA pool than the normal adrenal. Other receptor mRNAs with expression levels more than 25-fold higher in the APA pool than the normal adrenal were the CD47 antigen receptor (56-fold higher), the putative purinergic receptor FKSG79 (29-fold), and the cholinergic receptor CHRM1 (29-fold). Due to the established role of LH receptor in the regulation of ovarian and testicular steroid production, we focused on this G protein-coupled receptor. To confirm the data of the microarray, real-time RT-PCR analyses were performed on the normal adrenal and APA samples used for microarray as well as positive controls for LH receptor expression that included corpora lutea (n = 9) and ovarian follicles (n = 10) and a negative control consisting of whole fetal adrenal (n = 5) for comparison. Analyses were performed with a set of primers that targeted the 5' region (Fig. 2) and 3' region (data not shown) of the LH receptor mRNA. Similar results were obtained using both primer pair sets, and therefore, only the data from the analysis of the 5' region of the mRNA are shown. In Fig. 2A, the normal adrenal sample used in the microarray analysis had an average value of approximately 0.006 attomoles of LH receptor mRNA per microgram of 18s mRNA, compared with the wide range seen with the three APA samples from the microarray, which ranged from 0.0182 to 14.5 attomoles/µg 18s mRNA. The LH receptor expression levels in fetal adrenal were similar to those seen in normal adrenal (0.008 attomoles/µg 18s). As shown in Fig. 2B, although quite variable, the overall expression of LH receptor in corpus luteum was relatively high (3.02 attomoles/µg 18s) with slightly lower values in the ovarian follicles (0.76 attomoles/µg 18s mRNA). A single adrenal adenoma sample that we termed APA-LH receptor exhibited expression levels for LH receptor 2400-fold higher than that seen in normal adrenals (14.5 attomoles/µg 18s).
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), compared with preabsorbed control (Fig. 3B). The APA sample showed groups of intensely staining cells throughout the tumor sample (Fig. 3C). Western analysis confirmed levels of LH receptor expression in APA-LH receptor that were as high as that seen in corpus luteum (Fig. 3D).
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). Surprisingly, 50% (nine of 18) of the APAs examined also exhibited elevated levels of LH receptor, whereas only one of the normal samples was 2 SD above normal LH receptor expression. Using linear regression analysis, there is a correlation between LH receptor and CYP11B2 expression (r = 0.49, P = 0.0256) in the APA samples we studied. In contrast, neither the microarray nor real-time analyses of the ACTH receptor mRNA indicated any difference in expression between normal adrenals and APAs (data not shown).
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, LH was able to mediate CYP11B2 promoter activity in the presence of LH receptor with a maximal 25-fold induction of the promoter over basal with a dose of 50 ng/ml, indicating that LH receptor levels in the adrenal can drive aldosterone production in the presence of LH. No effect of LH was seen in cells that were not transfected with LH receptor expression vectors (data not shown).
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Discussion |
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A number of studies have demonstrated that cortisol-producing adenomas can be under the control of aberrantly expressed membrane receptors. Food-dependent hypercortisolism is a rare form of Cushing’s syndrome that can occur when gastric inhibitory polypeptide receptor (GIPR) is overexpressed in cases of either bilateral macronodular hyperplasia or an adrenal tumor (22). This causes an abnormal cortisol responsiveness to gastric inhibitory polypeptide, which increases after oral intake of glucose. Recent data indicate that GIPR expression is also present in adrenals with nonfood-dependent Cushing’s syndrome but not normal adrenals (23). In addition, it is postulated that chronic ACTH stimulation may cause up-regulation of GIPR (23). Data from our microarray analyses indicate that there were several other G protein-coupled receptors that had elevated mRNA levels in APA arrays, compared with normal adrenals. Serotonin 5HT4R expression levels were at least 3-fold higher in APA samples, compared with normal adrenal, although this has not been confirmed via real-time RT-PCR in individual samples at this point (data not shown). 5HT4R expression levels in three Cushing’s adenoma microarray sets indicate slightly lower-than-normal adrenal expression levels. The major difference in G protein-coupled receptor expression was noted for the LH receptor, although several other genes including CD47 antigen receptor, the putative purinergic receptor FKSG79, and the cholinergic receptor CHRM1 also illustrated expression levels greater than 25-fold over normal in our representative microarray shown in Fig. 1
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LH-responsive Cushing’s syndrome has been described in a number of cases (16, 24, 25, 26) In at least one case (16), Cushing’s syndrome was thought to have developed during pregnancy due to the high levels of circulating hCG, which binds and activates LH receptors. In this particular patient the adrenal disease spontaneously abated after delivery, presumably due to the associated drop in circulating hCG although this hypothesis was not formulated until the patient was seen with similar symptoms at menopause. High LH levels, as seen in postmenopausal women, can also lead to Cushing’s syndrome if the adrenal aberrantly expresses LH receptors (16, 27, 28). Due to the significant number of cases reported with LH regulation of Cushing’s syndrome as a result of aberrant adrenal expression of LH receptor, some clinical algorithms include an LH stimulation test (24).
The potential role of LH in regulation of Conn’s syndrome is far less understood; however, if a role exists, it could be speculated that men (high circulating LH) as well as pregnant (high circulating hCG) or postmenopausal women (high circulating LH) might be likely candidates for LH-regulated hyperaldosteronism. Certainly primary aldosteronism follows a variable course in pregnancy. Normally, aldosterone levels increase in pregnancy 4-fold by 8 wk gestation and continue to increase reaching a 10-fold increase by term. However, this increase is due to increased renin and angiotensin II levels (29). In some women with primary hyperaldosteronism, hypertension improves with pregnancy, and this is thought to be due to an increase in plasma progesterone or other steroids that competitively inhibit the effects of aldosterone on its receptor (30, 31, 32). However, hypertension, hypokalemia, low plasma renin activity, and very high aldosterone levels can appear in the course of pregnancy, suggesting a primary hyperaldosteronism and an adrenal adenoma is sometimes detected (33, 34). In some pregnancies with aldosterone producing adenomas, surgery is required to remove the adenoma (35, 36), whereas in others hypertension is controlled adequately by therapy, and removal of the tumor can occur in the postpartum period (34). No specific information is available on the prevalence of primary aldosteronism in menopause.
The current study used microarray technology to compare expression profiles of G protein-coupled receptors between APAs and normal adrenal glands. This leads to the discovery of an LH-mediated APA with high expression levels of LH receptor taken from a 37-yr-old male patient who presented with uncontrollable hypertension. This patient became normotensive after tumor removal. We verified LH receptor mRNA expression in APA and normal adrenals using real-time RT-PCR. Whereas expression at the level seen in corpus luteum appears rare for APA (one of 18), the expression of LH receptor is elevated above normal adrenal in 50% of APA samples. Previous studies of LH receptor expression in the human adrenal has been limited to IHC and in situ hybridization or nonquantitative RT-PCR for mRNA (11, 37). Immunohistochemical analysis suggested that LH receptor was expressed in the adrenal cortex with higher signal in the inner reticularis zone (11).
An early report suggested that LH/hCG regulated human fetal adrenal steroid production (38). This was an attractive hypothesis because circulating levels of hCG are extremely high in the fetus and apparently correlate with the extremely active fetal adrenal. However, the effects of purified LH or hCG on human fetal adrenal cell steroidogenesis was not confirmed by others (13, 39). Indeed, using the real-time RT-PCR method developed for the present project the expression of fetal adrenal LH receptor was no different from the very low level found in normal adult adrenals, further decreasing the likelihood of a role for hCG in the regulation of the fetal adrenal gland. To better examine the effects of LH/hCG on human adrenal steroid production, a recent in vivo study used GnRH analogs to down-regulate LH production by the pituitary and then examine effects of exogenously administered hCG on circulating adrenal steroids in both healthy premenopausal and oophorectomized postmenopausal women (12). In premenopausal women, hCG increased the serum concentrations of partially or exclusively ovarian steroids such as 17-hydroxyprogesterone, androstenedione, testosterone, and estradiol but had no effect on steroids of exclusively adrenal origin such as dehydroepiandrosterone, dehydroepiandrosterone sulfate, or cortisol. Postmenopausal women were concomitantly treated with estrogen replacement therapy when hCG was administered in an effort to avoid potential LH receptor down-regulation due to chronic high levels of endogenous gonadotrophins. As expected, basal serum concentrations of ovarian steroids were much lower than those of premenopausal women, and hCG treatment did not increase these levels. Nor were adrenal steroid levels increased in these women after treatment with hCG. However, modest increases in dehydroepiandrosterone sulfate secretion with high doses of LH have been observed in human adrenocortical H295R carcinoma cells (40). Thus, the exact role of LH in the function of the normal adrenal remains uncertain.
Nevertheless, it appears likely from previous studies on cortisol-producing adenomas and our current report on APAs that aberrant expression of the LH receptor plays a role in adrenal disease. It is still unclear why aberrant expression of the LH receptor would cause hypercortisolism in some cases and hyperaldosteronism in others. For that reason we examined the effects of LH on the transcriptional activity of CYP11B2. The final step in aldosterone synthesis requires CYP11B2, and no alternative pathways for the synthesis of aldosterone have been found. CYP11B2 is normally regulated by angiotensin II and potassium through the elevation of intracellular calcium and activation of calcium signaling pathways (41, 42, 43). We found that LH increased the promoter activity of CYP11B2, suggesting that in vivo LH could act in adenomas to increase the capacity to produce aldosterone.
In summary, microarray analysis of APAs vs. normal adrenals indicated elevated expression of the LH receptor in the APA pool over normal adrenal. Further confirmation of LH receptor in APA was substantiated by real-time RT-PCR, IHC, and Western blot analysis. We have also demonstrated that LH can increase the transcriptional activity of the aldosterone synthase gene. Analysis of a larger pool of APAs and normal adrenals indicates that elevated expression of LH receptor may be common in APAs. The role of LH as a regulator of certain cases of primary aldosteronism warrants further clinical study.
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Acknowledgments |
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Footnotes |
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Abbreviations: APA, Aldosterone-producing adenoma; GIPR, gastric inhibitory polypeptide receptor; hCG, human chorionic gonadotropin; IHC, immunohistochemistry.
This work was supported by awards (DK43140) from the National Institutes of Health (to W.E.R.).
The authors have no conflict of interest.
Received June 10, 2005.
Accepted November 30, 2005.
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0.001). B, Vertical point scatterplot comparing LH receptor expression in normal adrenal vs. APA samples. Nineteen of 20 normal adrenal samples (95%) fell within normal range vs. only nine of 18 APA samples (50%). The difference in the median values between the two groups is statistically significant (P 