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Division of Endocrinology, Department of Internal Medicine, and the Center for Research in Reproduction, University of Virginia, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Laura L. Burger, University of Virginia, Department of Internal Medicine, P.O. Box 801412, Charlottesville, Virginia 22908. E-mail: lburger{at}virginia.edu.
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Introduction |
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-subunit and a unique ß-subunit. The subunit genes are differentially regulated by GnRH pulse frequency, fast frequencies favoring and LH-ß and slow frequencies favoring FSH-ß (1), and also by gonadal steroids. Steroids act both at the hypothalamus to alter GnRH pulsatility and/or directly on the pituitary. Differential regulation of the subunit genes by steroids was first reported in gonadectomized (GDX) rats. Both estradiol (E2) and testosterone (T) suppressed the post-GDX increases in pituitary and LH-ß mRNAs. In contrast, the post-GDX increase in FSH-ß mRNA was abolished by E2, but T either had no effect or enhanced FSH-ß responses in a dose-dependent manner (2, 3, 4, 5). Studies in castrated (CAST) and GnRH antagonist-treated (CAST + GnRH-A) rats showed that the effects of T on LH-ß and FSH-ß were in part at the level of the pituitary. In both GnRH-deficient CAST rats (6, 7, 8) and cultured rat pituitary cells (4, 9, 10), T suppressed LH-ß mRNA and increased FSH-ß mRNA. The mechanism(s) by which androgens differentially regulate LH-ß and FSH-ß gene expression are not completely known. Gonadotropes contain androgen receptor (AR), and T increases translocation of the AR from the cytosol to the nucleus (11). To date, consensus androgen response elements have not been reported in the promoter of either the rat LH-ß or FSH-ß genes. Curtin et al. (12) have recently reported that AR is required for androgen suppression of rat LH-ß promoter activity in transgenic mouse pituitary cells. Studies using rat or ovine LH-ß promoter-reporter constructs have revealed that the AR suppresses LH-ß promoter activity through protein-protein interactions with other transcription factors (12, 13).
The mechanism of T action on FSH-ß gene expression is less well understood, and the effects of androgens on the FSH-ß promoter are unknown. In an earlier study we proposed that T regulated FSH-ß mRNA stability because T increased the half-disappearance time of FSH-ß mRNA from 20 to 50 h in CAST + GnRH-A rats but did not significantly increase FSH-ß mRNA synthesis, as measured by nuclear runoff assays (7).
In addition, androgens may regulate FSH-ß transcription indirectly via changes in the availability of intrapituitary activin. The activins are homo-/heterodimers of the inhibin ß-subunits (ßA or ßB). The activin ßB subunit is produced by the gonadotropes (14, 15), and activin increases both FSH-ß transcription (16) and FSH-ß promoter activity (17, 18). Activin activity is modulated by follistatin (FS), a glycoprotein produced in the pituitary by both the gonadotropes and folliculostellate cells (19), that binds to and bioneutralizes activin (20). Testosterone decreases both pituitary FS mRNA expression (21, 22, 23, 24, 25) and secretion (26). Therefore, T may increase FSH-ß gene expression indirectly by decreasing FS and increasing activin availability.
The aims of this report were to investigate androgen regulation of LH-ß and FSH-ß transcription in normal rat pituitary cells, by using sensitive quantitative RT-PCR assays to measure primary transcripts (PTs). Furthermore, we aimed to determine whether T actions on FSH-ß PTs were effected directly or involved modulation of pituitary FS and activin ßB.
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Materials and Methods |
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Experiment 1: the effects of GnRH-A and T on FSH-ß transcription and FS gene expression after castration
To determine the time course of changes in FSH-ß transcription after CAST and the roles of GnRH and T, male rats (n = 5–9/group) were CAST and treated with 1) nothing (CAST), 2) GnRH-A LRF-147, or 3) GnRH-A + T. Rats were killed 0, 8, or 24 h later. The water-soluble GnRH-A LRF-147 was synthesized by Dr. Jean Rivier (The Salk Institute, La Jolla, CA) and has been shown to abolish the post-CAST rise in LH (7) and partially block the increase in pituitary FS mRNA expression (22, 24). In this experiment, we treated rats with 200 µg LRF-147 (in 0.5 ml 0.9% saline/0.1% BSA, sc) beginning 12 h before CAST and every 12 h thereafter to maximally suppress LH. Subsequently we found that pretreatment was unnecessary and 100 µg LRF-147 prevented the post-CAST increase in serum LH. Testosterone was administered at the time of CAST via SILASTIC brand (Dow Corning, Midland, MI) implants (20 mm; two implants per rat) designed to achieve serum T levels of approximately 3.5 ng/ml (27). Pituitary FSH-ß and LH-ß PTs and mRNAs, FS and activin ßB mRNAs, and serum gonadotropins were measured.
Experiment 2: time course of T action on pituitary FSH-ß transcription and FS mRNA in GnRH-deficient CAST male rats
To determine the time course of FSH-ß transcription after T, groups of male rats were CAST (n = 4–7/group) and given the LRF-147 (100 µg, sc) every 12 h. Four days after CAST, rats received T implants and were killed 0, 3, 8, 24, and 48 h later. Control groups were sham (blank implants) killed after 48 h and intact males. Pituitary FSH-ß and LH-ß PTs and mRNAs, FS and activin ßB mRNAs, and serum gonadotropins and T were measured.
Experiment 3: to determine whether the effects of T on FSH-ß transcription are androgen specific
As T can be aromatized to estradiol (E2), we determined whether the effects of T on FSH-ß transcription were androgen specific. Male rats (n = 5–6/group) were CAST and given LRF-147 (100 µg, sc) every 12 h. Twenty-four hours after CAST, rats received implants containing nothing (sham controls), T, DHT, or E2. DHT implants (20 mm; two implants per rat) were designed to achieve serum DHT levels of 250 pg/ml (5). E2 implants [two per rat; 27-mm column of 1 mg/ml E2 in sesame oil (Sigma Chemical Co., St. Louis, MO); SILASTIC brand tubing 1.6 mm inner diameter, 3.2 mm outer diameter] produced serum E2 concentrations 4-fold greater than intact males. Rats were killed 8 h after steroid treatment. Intact male rats were included as controls. Pituitary FSH-ß and LH-ß PTs and mRNAs, FS and activin ßB mRNAs, and serum gonadotropins were measured.
Experiment 4: to determine whether T inhibition of FS mRNA is required to increase FSH-ß transcription
To determine whether T increases FSH-ß transcription directly or by decreasing pituitary FS concentrations, we administered androgen in the presence of exogenous FS in vitro. Pituitaries from adult male Sprague Dawley rats (225–250 g) were cultured as previously described (28), except that both the fetal calf serum (10%) and horse serum (5%) were charcoal stripped to remove steroids. After culturing cells for 24 h, coverslips were transferred to fresh medium containing T (4 ng/ml), DHT (250 ng/ml), recombinant human FS (30 ng/ml; R&D Systems, Minneapolis, MN) or T + FS (3 or 30 ng/ml recombinant human FS). Control medium contained the appropriate vehicle (0.04% ethanol). After 24 h, cells were recovered and total RNA extracted.
Measurement of serum hormones, RNA preparation, subunit mRNAs, and subunit primary transcripts
Serum LH and FSH were measured by RIA using the standards NIDDK RP-3 for LH and NIDDK RP-2 for FSH (National Hormone and Pituitary Program). The sensitivities for the LH and FSH assays are 0.09 ng/ml and 0.8 ng/ml, respectively. The coefficients of variation are 10.9% and 16.1% (intra- and interassay) for LH and 5.3% and 12.4% for the FSH assay. T, DHT, and E2 were measure by RIA using kits available from Diagnostic Systems Laboratories (Webster, TX). The sensitivities of the assays are 0.1 ng/ml, 4 pg/ml, and 4.7 pg/ml, respectively. The coefficients of variation are 11.5% and 18.7% (intra- and interassay) for T and 6.2% and 14.8% for E2. The intraassay coefficient of variation for DHT was 12.4%; all samples were measured within a single assay.
Total pituitary RNA was extracted using the acid guanidinium method (29). Residual genomic DNA was removed by treatment with 1 U RNase-free DNase I/µg RNA (Roche Molecular Biochemicals, Indianapolis, IN) at 37 C for 1 h. RNA preparations were confirmed to be DNA-free by PCR in the absence of a preceding RT reaction. Subunit mRNA concentrations were determined by dot blot hybridization assays using 4 µg pituitary RNA per dot (30, 31) and a sense-strand RNA standard curve spotted on each nitrocellulose filter (32). Subunit PTs, FS mRNA, and ßB mRNA were measured by quantitative RT-PCR assays (22, 32, 33). Briefly, regions of intron/exon for PT assays (32) or portions of the mature mRNAs for FS and ßB (22, 33) were amplified using specific oligonucleotide primers and a size-altered competitive template (CT) RNA specifically made for each gene. A four-point standard curve was generated by adding a fixed amount of pituitary RNA (5–400 ng/reaction) to a graduated amount (2, 10, 50, and 250 fg) of CT. The pituitary and CT RNA were reverse transcribed followed by 35 cycles of PCR in the presence of [32P]dCTP. The PCR products were separated by electrophoresis in 3% agarose, the bands excised, and [32P]dCTP incorporation determined by scintillation counting.
Analysis
All data were examined by ANOVA. Significant differences (P < 0.05) were determined post hoc by Duncan’s multiple range test. Before analyses, all measurements were transformed to the logarithmic scale to attain equal variation among treatments.
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Results |
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. Serum LH concentrations are shown in Table 1. Serum LH increased 2- and 8-fold by 8 h and 24 h post-CAST, respectively, and was prevented by GnRH-A. LH-ß PT also increased 4- and 8-fold at 8 and 24 h after CAST, respectively (Fig. 1), and GnRH-A suppressed LH-ß PT to 60% of intact animals (0 h) at 24 h. T further decreased LH-ß PT to 30% of intact (0 h) values after 24 h. LH-ß mRNA increased 2-fold 24 h after CAST, GnRH-A abolished the increase at 24 h, and T had no additional affect.
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Experiment 2: time course of T action on pituitary FSH-ß- transcription and FS mRNA in GnRH-deficient CAST male rats
The time course of T action on ß-subunit mRNAs and PTs and FS and ßB mRNAs, in 4-d GnRH-deficient CAST rats are shown in Fig. 2. Serum LH and FSH are shown in Table 2. The rats killed before steroid treatment (0 h T) and the 48-h CAST + GnRH-A + sham steroid groups were not different on any of the parameters measured; the two groups were combined (as 0 h) for analysis. GnRH-A prevented the post-CAST rise in both serum LH and FSH (Table 2). T had little effect on serum LH but significantly increased FSH. LH-ß mRNA concentrations did not change significantly after T. In contrast, FSH-ß mRNA increased after T, with maximal changes (2-fold) occurring at 8 h. Gonadotropin ß-subunit PTs showed similar changes; T reduced LH-ß PT (40% of controls at 8 h) and increased FSH-ß PT (2.5- to 3.5-fold) between 3 and 48 h. As in experiment 1, the rise in FSH-ß PT was associated with a decline in FS mRNA. The post-CAST rise in FS mRNA was not fully suppressed by GnRH-A but was reduced to 30% of controls by T. Pituitary ßB mRNA levels were elevated in CAST + GnRH-A controls (vs. intact), but were unaffected by T.
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. Serum LH and FSH were suppressed by GnRH-A. Steroids had no effect on LH, but T and DHT increased FSH 1.5- to 2-fold (vs. sham; data not shown). LH-ß PT was suppressed by GnRH-A (vs. intact) in all CAST groups and further suppressed by DHT (vs. sham control). GnRH-A prevented the post-CAST increase in LH-ß mRNA, and steroids had no additional effect. GnRH-A reduced FSH-ß PT and mRNA, but T and DHT returned both FSH-ß PT and mRNA to intact levels; E2 further reduced FSH-ß PT (30% of sham controls). FS and to a lesser degree ßB mRNAs were increased in sham controls vs. intact rats. Both T and DHT suppressed FS and ßB mRNAs, whereas E2 had no effect.
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. Due to limited RNA recovery, we could not measure gonadotropin ß-subunit mRNAs in these samples. There were no differences between the groups treated with T and FS at 3 or 30 ng/ml for any of the parameters measured; for clarity, only the T + FS (30 ng/ml) group is shown in Fig. 4. Media FSH was suppressed (60% of controls) by FS (30 ng/ml) but was unaffected by T (with or without FS) or DHT (data not shown). In contrast to the in vivo experiments, neither T nor DHT suppressed LH-ß PT in cultured rat pituitary cells. FS alone did not affect LH-ß PT, but LH-ß PT increased slightly in the FS + T-treated groups (vs. controls). Both T and DHT increased FSH-ß PT vs. control. FS suppressed FSH-ß PT to 60% of controls, but the addition of T (FS + T) resulted in marked (6-fold) elevation of FSH-ß PT (vs. FS only). Neither FS nor ßB mRNAs were affected by androgens or FS.
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Discussion |
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FSH-ß and LH-ß transcription after CAST sharply contrast the changes that occur after ovariectomy (OVX). We previously reported that after OVX, FSH-ß PT increased within 12 h, and LH-ß PT did not increase until 24–48 h later, coincident with enhanced GnRH secretion (34). In contrast, after CAST, LH-ß PT increased 4- to 8-fold at 8 and 24 h followed by a 2-fold increase in LH-ß mRNA at 24 h. Although the increase in LH-ß mRNA immediately post CAST lagged the change in PT, by d 7, we have previously reported that both LH-ß PT and mRNA were increased 6-fold (32). FSH-ß PT did not change acutely after CAST, but FSH-ß mRNA was increased 2-fold at 24 h. The mechanism(s) for the increase in FSH-ß mRNA at 24 h without an increase in FSH-ß PT is unknown and may reflect enhanced mRNA stability. In OVX females the acute increases in FSH-ß PT and mRNA largely reflect the loss of circulating inhibin. In adult males inhibin plays little, if any, role in regulating FSH-ß expression (35, 36, 37). Hence the lack of changes in FSH-ß PT within 24 h of CAST may reflect a suboptimal GnRH input, increased pituitary FS, and/or the loss of circulating T.
GnRH is a primary regulator of LH-ß and FSH-ß gene expression, and treatment with a GnRH-A suppresses the post-GDX increases in both LH-ß and FSH-ß PT (32, 34). In the present study, GnRH-A suppressed FSH-ß transcription below intact levels, abolished the post-CAST rise in LH-ß PT, and partially suppressed the rise in FS mRNA. GnRH differentially regulates FSH-ß and LH-ß gene expression via changes in GnRH pulse frequency, acting at the level of transcription. We have recently reported that GnRH pulses every 30 min in CAST + T rats resulted in a rapid and sustained increase in LH-ß PT (34). In contrast, FSH-ß PT increased only transiently (2–4 h) after 30-min GnRH pulses, and the decline in FSH-ß PT coincided with an increase in FS mRNA. Only slow-frequency (every 240 min) GnRH pulses resulted in a robust and sustained increase in FSH-ß PT. Because GnRH pulses in CAST rats are approximately every 30 min (38), GnRH input may not be optimal to stimulate FSH-ß PT acutely after CAST.
GnRH pulses every 30 min also stimulate FS mRNA (22, 33), and pituitary FS mRNA increases rapidly after CAST (22, 24). In our male rat in vivo studies there appears to be an inverse relationship between FSH-ß PT and FS mRNA levels; therefore the increase in FS mRNA, and presumably FS protein, after CAST may restrain the acute increase in FSH-ß PT. However, the inverse relationship between FS mRNA and FSH-ß PT is not maintained in long-term CAST rats. FS mRNA continues to increase after CAST (21, 22), and we have reported that by d 7 after CAST FSH-ß PT is 3-fold greater than in intact rats (32), which indicates that FSH-ß transcription increases after CAST despite elevated pituitary FS gene expression. In these studies FS mRNA increased acutely after CAST, was partially suppressed by GnRH-A, and was completely suppressed by GnRH-A + T. The suppression of FS mRNA by T has been shown previously both in vivo (21, 22, 24) and in vitro (23, 25).
The administration of T to GnRH-deficient CAST rats also had differential actions on FSH-ß and LH-ß gene expression. T rapidly increased FSH-ß PT but suppressed LH-ß PT (by 40–70%). T did not suppress LH-ß mRNA, which may reflect both its long half-life (44–65 h) (7, 39) and that T slightly increases the stability of the mRNA (7). The effects of T on FSH-ß transcription were androgen specific. FSH-ß PT increased 2-fold (vs. control) after T and DHT and decreased 70% after E2, which is in agreement with previous reports for the effects of T (or DHT) and E2 on FSH-ß mRNA both in vivo (3, 6) and in vitro (9). However, the data conflict with our earlier findings that T does not act transcriptionally to increase FSH-ß mRNA (7). Paul et al. (7) reported that T increased FSH-ß mRNA but did not increase FSH-ß mRNA synthesis as measured by nuclear runoff assays. We believe that the measurement of primary transcripts by quantitative RT-PCR is a more sensitive method for assessing FSH-ß transcription in normal gonadotropes, although it remains possible that T also stabilizes PT as well as the mature FSH-ß mRNA.
In vivo, the increases in FSH-ß PT with androgen were associated with a decline in FS mRNA and suggested that T increased FSH-ß transcription indirectly via changes in pituitary FS/activin activity. However, despite the presence of exogenous FS, treatment of rat pituitary cells with androgen significantly increased FSH-ß transcription. These data support the concept that T does not increase FSH-ß PT via modulating FS/activin but rather exerts a direct action on FSH-ß gene transcription. The mechanism by which androgens increase FSH-ß transcription remains unknown, and to date the regulation of the rat FSH-ß promoter by androgens has not been investigated.
In contrast to the limited information on the mechanism of androgen regulation of the FSH-ß gene, the mechanism by which androgens suppress LH-ß transcription is better studied. Jorgensen et al. (13) found that androgen bound to AR suppressed the activity of a bovine LH-ß promoter-reporter construct, transfected into the LßT2 gonadotrope cell line, by protein-protein interactions with SF-1 in the proximal portion of the promoter. Curtin et al. (12) reported that DHT (or T) suppressed GnRH-stimulated rat LH-ß promoter activity, in LßT2 cells, by protein-protein interaction between AR and Sp1 (and possibly Egr-1) at the distal portion of the GnRH-responsive region of the promoter, but did not suppress basal LH-ß promoter activity. We also observed that neither T nor DHT reduced LH-ß PT in cultured pituitary cells, which is in contrast to the marked suppression of LH-ß PT by androgens in vivo, and possibly reflects a prolonged absence of GnRH stimuli. Alternatively, the conditions in culture do not mimic the environment in vivo; we cultured pituitary cells in steroid-free media, and it is also possible that other factors necessary for the regulation of LH-ß transcription were lost.
Another difference between cultured pituitary cells and studies performed in vivo was the loss of androgen action on FS. In vivo, both T and DHT consistently suppressed FS mRNA 50–70% vs. CAST + GnRH-A rats, yet in culture neither steroid had any affect on FS mRNA. This is consistent with a recent report by Bilezikjian et al. (26) in which T did not affect FS mRNA in an immortalized rat folliculostellate cell line. However, this is in contrast to other studies from this lab in which T suppressed FS mRNA expression in cultured male rat pituitary cells (23, 25). The differences between our results and Vale and co-workers are likely due to differences in cell culture parameters (we examined the effects of T on cells cultured for 48 h vs. 96 h) and/or T dose [our dose (4 ng/ml) is similar to T levels in intact male rats, whereas Vale and co-workers (23, 25) used a dose that was 3-fold greater]. Additionally, there are several possible explanations for the differences we observed in vivo vs. in vitro. First, as stated above, the conditions in cell culture and in vivo are not the same, and it is possible that in our attempts to ensure that the media was steroid free we removed some factor that is important for the regulation of FS. Second, FS expression may be regulated in part by hypothalamic input, other than GnRH, that is androgen sensitive. Winters and co-workers (40, 41) have reported that the hypothalamic peptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates FSH-ß gene expression through FS. PACAP decreases FSH-ß mRNA and increases FS mRNA in rat pituitary cells (26, 40, 41), and T prevents the post-CAST increase in hypothalamic PACAP mRNA in Xenopus laevis (42). Therefore, T may regulate pituitary FS mRNA in vivo, in part, via hypothalamic secretion of PACAP.
In addition to the lack of regulation of FS mRNA in vitro by T, exogenous FS also had no effect on FS mRNA. This contrasts with earlier reports where administration of FS suppressed its own mRNA (23, 43). The differences between our data and the previous studies may be related to either FS dose [Dalkin et al. (43) used a dose that was 8-fold greater] and/or timing [Bilezikjian et al. (23) found that FS maximally suppressed FS mRNA after 6 h]. Despite the lack of FS mRNA suppression, FS was biologically active; both FSH secretion and FSH-ß transcription (FS only group) were suppressed to 60% of controls.
In conclusion, we have shown that androgens differentially regulate FSH-ß and LH-ß transcription, increasing FSH-ß and suppressing LH-ß transcription. The increase in FSH-ß PT in response to T was androgen specific and in vivo was correlated to a decrease in pituitary FS mRNA. However, the fact that FSH-ß PT increased in vitro in the presence of excess FS indicates that T stimulation of FSH-ß transcription occurs independently of modulation of FS. The divergent effects of T on gonadotropin subunit gene transcription provide an additional mechanism whereby differential regulation of LH and FSH can occur in males.
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Acknowledgments |
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Footnotes |
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Abbreviations: AR, Androgen receptor; CAST, castrated (or castration); CT, competitive template; DHT, dihydrotestosterone; E2, estradiol; FS, follistatin; GDX, gonadectomized; GnRH-A, GnRH antagonist; OVX, ovariectomized; PACAP, pituitary adenylate cyclase-activating polypeptide; PT, primary transcript; T, testosterone.
Received August 13, 2003.
Accepted for publication September 15, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit gene expression. Endocrinology 131:3027–3033[Abstract]
and luteinizing hormone ß messenger ribonucleic acid (RNA) of male and female rats after castration: quantitation using an optimized RNA dot blot hybridization assay. Endocrinology 119:691–698[Abstract]
and gonadotropin ß subunits in cultured rat pituitary cells. Mol Cell Endocrinol 88:143–151[CrossRef][Medline]
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