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Gonadotropin-Releasing Hormone Regulation of Gonadotropin Subunit Gene Expression in Female Rats: Actions on Follicle-Stimulating Hormone ß Messenger Ribonucleic Acid (mRNA) Involve Differential Expression of Pituitary Activin (ß-B) and Follistatin mRNAs¹

Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Dr. Alan C. Dalkin, University of Virginia Health Sciences Center, Division of Endocrinology, Department of Internal Medicine, 5041 MR4 Building, Lane Road, Charlottesville, Virginia 22908. E-mail acd6v{at}virginia.edu

	Abstract

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GnRH is the primary stimulus in the regulation of gonadotropin subunit mRNA expression. Additionally, local (pituitary) production of activin and follistatin appear to modulate the expression of FSH ß mRNA. The current studies aimed to determine whether GnRH regulation of pituitary activin (ß-B) and follistatin mRNAs could play a role in the differential actions of GnRH pulse pattern on gonadotropin mRNA expression in female rats. In response to altered GnRH pulse amplitude, the expression of FSH ß and follistatin mRNAs followed an inverse pattern. Only high dose GnRH increased expression of follistatin whereas, in contrast, ß-B and FSH ß expression were increased following lower doses of GnRH. To determine whether increased follistatin mRNA expression was correlated with FSH ß mRNA responses, we examined their temporal relationship following high dose GnRH. Both FSH ß and follistatin mRNAs were increased within 2 h and remained increased through 6 h. However, by 12 h FSH ß mRNA levels returned to values seen in controls, suggesting that increased follistatin requires 6–12 h to reduce FSH ß mRNA. In response to altered GnRH pulse frequency, FSH ß expression was increased at all pulse intervals (8–240 min) examined. Rapid GnRH pulse frequencies (8-min intervals) increased follistatin expression, whereas ß-B mRNA was only increased after 30-min pulse intervals, which also resulted in maximal FSH ß mRNA concentrations. These results suggest that changes in pituitary activin (ß-B) and follistatin mRNA expression may be important components of gonadotrope responses to pulsatile GnRH, and potentially imply that GnRH stimulation of activin and follistatin peptide production provides regulatory control over the production of FSH.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
IT IS WELL recognized that changes in the profile of GnRH secretion are essential for the dynamic pattern of gonadotropin (LH and FSH) synthesis and secretion. Following gonadectomy, during sexual maturation, and during the estrous cycle in rats, GnRH release and gonadotrope function are altered in well characterized patterns (for review, see Ref. 1). Additionally, studies of exogenous GnRH have supported the central role of GnRH in reproduction. In both primates and rodents, a pulsatile GnRH is needed to maintain gonadotrope secretory responses. Conversely continuous GnRH results in desensitization and loss of GnRH receptors and LH secretion (2, 3, 4). Extremes of GnRH secretory pattern are likely of physiologic significance as increasing pulsatile release (amplitude and frequency) characterize the proestrus gonadotropin surge, whereas desensitization has been postulated, at least in part, to be responsible for the subsequent decline in LH secretion later on proestrus evening (5, 6, 7). Data such as these support the notion that an understanding of gonadotrope responses to a GnRH signal is essential toward understanding reproductive physiology.

To date, the majority of in vivo studies in which GnRH-deficient animal models were used to assess responses to exogenous GnRH pulse patterns used the castrate/testosterone-replaced adult male rat model (8, 9, 10, 11, 12). In these animals, a pulsatile GnRH signal is required to increase the hormone specific LH ß and FSH ß mRNAs, whereas the common -subunit mRNA is increased by either a pulsatile or continuous pattern. Changes in pulse amplitude selectively regulate LH ß, whereas and FSH ß increase in response to a wide range of pulse doses. In contrast, pulse frequency differentially regulates both ß subunit mRNAs with faster frequencies, favoring only LH ß and subunit mRNAs, whereas slower frequencies increase only FSH ß gene expression.

Notably, gonadotropin synthesis and secretion as well as gonadal hormonal responses are relatively stable in the adult male rat, whereas dynamic changes are well recognized in female rats (as noted above). Hence, considerable effort has been given toward the development of a GnRH-deficient female rat model. We have recently reported that pulsatile GnRH increases , LH ß and FSH ß gene expression in the ovariectomized (OVX)/phenoxybenzamine-treated (PBZ)/testosterone-replaced adult female rat (13). It was the primary purpose of the studies reported here to use this model to explore gonadotrope mRNA responses to changes in GnRH pulse patterns, both in terms of amplitude and frequency in female animals. Moreover, it is becoming increasingly clear that, at least in terms of FSH, local peptide factors may serve either to mediate or modulate GnRH responses. Specifically, activin and follistatin are produced in the pituitary gland by the folliculo-stellate and gonadotrope cells and serve to increase or reduce (respectively) FSH (for review see Ref. 14). In addition, in male rats exogenous GnRH regulates follistatin gene expression (11) and, following gonadectomy, the rise in follistatin (both sexes) and ß-B (females) mRNAs are at least in part prevented by GnRH blockade (11, 15, 16, 17). Therefore, an additional aim of our studies was to determine whether exogenous GnRH could differentially regulate pituitary production of activin and follistatin mRNAs.

	Materials and Methods

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Animal models
Adult female Sprague Dawley rats, 225–250 g BW, were used for all experiments. All surgeries were performed under metofane anesthesia. All animals were OVX, given T implants (plasma levels = 0.4 ng/ml), fitted with indwelling jugular catheters, and treated with phenoxybenzamine (PBZ) 10 mg/kg as previously described (13). This dose of testosterone is similar to levels observed during the estrous cycle at the time of the proestrus gonadotropin surge. The animals were allowed food and water ad libitum and maintained unrestrained throughout the study. Twenty-four hours after OVX/PBZ/T treatment, pulsatile GnRH was initiated using intermittent pulse pumps (Autosyringe) and continued for a duration of 24 h further (except where otherwise indicated).

At the completion of experiments, animals were killed by decapitation; pituitary glands were rapidly removed and snap frozen in liquid nitrogen until RNA extraction (18). The University of Virginia Animal Research Committee approved all animal protocols.

mRNA measurements
The methods for measuring , LH ß, and FSH ß mRNA (dot-blot hybridization assay) and ß-B and follistatin mRNA (quantitative RT-PCR assay) have been previously reported (11, 17, 18, 19). We did not assess changes in inhibin- gene expression in light of prior data revealing that inhibin- mRNA levels do not vary during the estrous cycle (20), increase slowly (days) following ovariectomy (17), and do not increase after exogenous GnRH pulses in male animals (our unpublished data). All mRNA concentrations are expressed as femtomoles of mRNA/100 µg pituitary DNA to allow for comparison between mRNAs and to correct for pituitary size.

RIA
Serum FSH was measured by RIA using reagents kindly provided by the National Hormone and Pituitary Program, with FSH RP-2 as standard. For this assay, the coefficients of variation were 6.3% (intra) and 9.6% (interassay).

Statistical analysis
Treatment-induced effects were examined by one-way ANOVA. Differences between groups were examined by Duncan’s multiple range test.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Exp I—expression of , LH ß, and FSH ß mRNAs following pulsatile GnRH in female rats: effect of pulse amplitude (Fig. 1)
OVX/PBZ/T-treated female rats received GnRH pulses (1, 5, 25 or 125 ng) every 30 min for 24 h. Saline-treated animals served as controls. Serum FSH was increased by all pulse doses (saline: 7.9 ± 0.3, 1 ng: 17.9 ± 1.1, 5 ng: 25.1 ± 1.8, 25 ng: 29.2 ± 3.2, 125 ng: 21.4 ± 4.3 ng/ml) to a similar degree (all P < 0.05 vs. saline control). An optimal response to the 5 ng/pulse dose was observed with all three gonadotropin subunit mRNAs being increased. mRNA was increased at higher (but not lower) pulse doses, whereas LH ß mRNA expression was increased only at lower pulse amplitudes. FSH ß mRNA levels rose at pulse doses from 1–25 ng but did not increase at the highest pulse amplitude (250 ng/pulse) examined.

View larger version (18K): [in this window] [in a new window]   Figure 1. Effect of GnRH pulse amplitude on gonadotropin subunit mRNA concentrations. Animals were treated with saline (open bars) or GnRH (solid bars) pulses every 30 min for 24 h. Results are expressed on a molar basis for comparison between mRNA species. n = 4–6 animals/group. *, P < 0.05 vs. saline-treated animals.

Exp II—expression of FSH ß, follistatin, and ß-B mRNAs following pulsatile GnRH in female rats: effect of pulse amplitude (Fig. 2)

View larger version (16K): [in this window] [in a new window]   Figure 2. Effect of GnRH pulse amplitude on FSH ß, follistatin, and ß-B subunit mRNA concentrations. Animals were treated with saline (open bars) or GnRH (solid bars) pulses every 30 min for 24 h. Results are expressed on a molar basis of cDNA bound (FSH ß) or mRNA (follistatin and ß-B) for comparison between gene products. n = 4–5 animals/group. *, P < 0.05 vs. saline-treated animals.

Exp III—expression of FSH ß and follistatin mRNAs following high dose GnRH pulses (Fig. 3)

View larger version (19K): [in this window] [in a new window]   Figure 3. Time course of GnRH action on FSH ß and follistatin gene expression. Animals were treated with saline (open bars) or GnRH (solid bars) pulses every 30 min for 2–24 h. Saline-treated control animals were killed at each time and values between these control groups were not different (see Results). n = 5 animals/GnRH-treated group with 15 saline-treated control animals. *, P < 0.05 vs. saline-treated animals.

Exp IV—expression of , LH ß, FSH ß mRNAs following pulsatile GnRH in female rats: effect of pulse frequency (Fig. 4)

View larger version (18K): [in this window] [in a new window]   Figure 4. Effect of GnRH pulse frequency on gonadotropin subunit mRNA concentrations. Animals were treated with saline (open bars) or GnRH (solid bars) pulses (5 ng/pulse) for 24 h. Results are expressed on a molar basis for comparison between mRNA species. n = 4–7 animals/group. *, P < 0.05 vs. saline-treated animals.

Exp V—expression of FSH ß, follistatin, and ß-B mRNAs following pulsatile GnRH in female rats: effect of pulse frequency (Fig. 5)

View larger version (16K): [in this window] [in a new window]   Figure 5. Effect of GnRH pulse frequency on FSH ß, follistatin and ß-B subunit mRNA concentrations. Animals were treated with saline (open bars) or GnRH (solid bars) pulses (5 ng/pulse) for 24 h. Results are expressed on a molar basis of cDNA bound (FSH ß) or mRNA (follistatin and ß-B) for comparison between gene products. n = 5–6 animals/group. *, P < 0.05 vs. saline-treated animals.

	Discussion

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The expression of both ß-B and follistatin mRNAs in female rats appears to be regulated by GnRH, though each mRNA responds to a distinct pulse amplitude (Fig. 2). Moreover, there appears to be a positive correlation between ß-B and FSH ß mRNAs and a reciprocal relationship between FSH ß and follistatin mRNAs. Both ß-B and FSH ß mRNAs are increased by low dose GnRH (5 ng), and only FSH ß is increased by an intermediate pulse dose (25 ng) whereas, in contrast, only follistatin mRNA is increased by high amplitude (125 ng) GnRH. These data suggest that increased activin may be important, but not necessary, for increases in FSH ß expression in response to GnRH. Conversely, whether "basal" activin is needed for GnRH responses remains uncertain. Of note, Besecke et al. (23) reported that exogenous follistatin could entirely prevent FSH ß responses to pulsatile GnRH (10 nM every 60 min) in vitro, leading to their conclusion that GnRH acts via activin to regulate FSH ß expression. The 10 nM GnRH concentration in their perifusion system is likely at least 5-fold higher than the peak levels in the peripheral circulation of our in vivo experiments using the supraphysiologic 125 ng pulse (6, 10, 24, 25). An explanation regarding the different FSH ß responses between the two studies remains unknown but may reflect inherent differences between in vivo and in vitro models. Whether low-dose GnRH in vivo that appears to increase in local activin production could increase FSH ß expression in the presence of additional (exogenous) follistatin also remains uncertain. However, our findings that, in response to GnRH there is a positive correlation with the expression of ß-B and FSH ß mRNAs and an inverse correlation with the expression of follistatin and FSH ß mRNAs, support Besecke’s hypothesis that activin mediates (at least in part) gonadotrope responses to GnRH.

As high dose GnRH failed to increase FSH ß mRNA expression (after 24 h of treatment) in female rats, we examined the temporal relationship between GnRH pulses and FSH ß and follistatin mRNA responses (Fig. 3). Using the GnRH-deficient female rat model, within 2 h of initiating treatment with GnRH both FSH ß and follistatin mRNA concentrations were increased. Follistatin mRNA expression remained at similar levels from two through 24 h while, in contrast, FSH ß mRNA concentrations were increased only through 6 h and subsequently returned to levels seen in saline treated control animals. This pattern of mRNA expression is similar to prior reports in vitro in which FSH ß and follistatin mRNAs tended to rise at 4 h with follistatin expression significantly increased at 10 h, whereas FSH ß mRNA levels declined back toward control levels (23). While the later (12 and 24 h) reciprocal relationship between follistatin and FSH ß expression further supports the notion that activin action is important for FSH responses to GnRH, in light of the finding that both FSH ß and follistatin mRNAs can acutely rise in parallel, we also propose that GnRH acts independently of activin to regulate FSH production. This hypothesis is supported by data in castrate animals in which administration of a GnRH antagonist reduces both FSH ß and follistatin mRNAs while ß-B mRNA expression is unchanged (17).

The results obtained in the current studies also provide potential insight toward the in vivo actions of follistatin. Specifically, GnRH-driven increases in follistatin mRNA are observed 6–12 h before inhibition of FSH ß mRNA is noted. While these results potentially indicate that changes in follistatin then alter FSH ß, the current data are limited in that methods to measure pituitary production of follistatin peptide are not widely available. In a prior study addressing this issue, increased pituitary follistatin mRNA did indeed correlate with increased follistatin peptide (26). Moreover, increased pituitary expression of follistatin mRNA was followed 3 h later with an increase in pituitary follistatin content (26), a time course in keeping with the findings presented in the current studies. Of interest, studies conducted in vitro suggest that reductions in FSH ß mRNA concentrations following treatment with follistatin can be observed within 1 h (27). In that light, our data may suggest that the GnRH-regulated pool of releasable follistatin is small and the 6 h delay before changes in FSH ß expression may also reflect an action of GnRH on follistatin synthesis. This temporal relationship between GnRH, follistatin, and FSH ß may be of physiologic importance during the estrous cycle in the rat. On the evening of proestrus, both FSH ß and follistatin mRNAs (but not ß-B) are increased (20, 28, 29) and the rise in follistatin is likely the result of increased GnRH (29). Notably, the increase in follistatin mRNA is noted after 1800 h on proestrus, preceding the decline in FSH ß mRNA (beginning at 0300 h of estrus) by approximately 7 h (20). While a definite link between altered pituitary follistatin peptide and FSH ß awaits the development of an animal model in which follistatin action can be altered, our data support this notion and reveal the important finding that in the presence of an ongoing pulsatile GnRH signal (and the absence of gonadal feedback) a biphasic pattern of FSH ß mRNA expression may result.

It should be recognized that the current studies in female rats use a different model to render the animals GnRH deficient than has been used for experiments in male animals, thereby potentially limiting comparison between genders. In general, however, gonadotropin subunit mRNA responses to changes in GnRH pulse frequency (Fig. 4) in females were similar when compared with our previous studies in male rats (10). mRNA was maximally increased at faster frequencies (8–30') but was not increased at the slower, 240' pulse interval. Similarly, LH ß expression was increased at pulse intervals from 8–120', with the 30' pulse frequency being optimal. In contrast to male animals, FSH ß expression was increased through the range of pulse frequencies examined in this study. In male animals, fast frequency GnRH increases follistatin mRNA expression (11), and hence we measured pituitary ß-B and follistatin mRNA expression to determine whether similar responses could be observed in female rats (Fig. 5). As we have previously observed in males, fast frequency GnRH increased follistatin expression, although the magnitude of change (2-fold) appeared less than in male animals (3-fold, 11). The explanation for the concomitant increases in FSH ß and follistatin mRNAs following 24 h of GnRH pulses (5 ng every 8') remains uncertain. Of note, parallel increases in FSH ß and follistatin mRNAs is seen after ovariectomy (15, 17). Potentially, a longer treatment duration may be needed to observe follistatin effects on FSH ß. Unfortunately, our experimental animal model does not allow studies of 3–4 days duration as the result of cumulative effects of phenoxybenzamine (personal observations). The use of longer term in vitro paradigms may be needed to more fully address this issue. This time-dependent relationship may also relate to FSH release. In the current studies, FSH secretion rose in response to all GnRH pulse patterns examined, and no differences following either changes in pulse amplitude, frequency, or over duration of treatment were observed. This relationship between GnRH and FSH release has been previously reported (10) and is thought to be a function of the relatively long half-life of circulating FSH. As noted above, in vitro approaches may better define whether changes in local activin and follistatin alter pituitary gonadotrope function.

ß-B mRNA expression was increased only at the 30' pulse interval when increases in FSH ß mRNA were maximal. As noted above, these results suggest that, at least in part, GnRH may regulate FSH ß via pituitary-derived activin. However, the increase in FSH ß expression with fast frequency GnRH (8') does not correlate with increased ß-B mRNA. If stable levels of ß-B mRNA do reflect stable levels of activin peptide, these data provide further evidence that GnRH likely also has actions independent of activin on the FSH ß gene.

In conclusion, these studies serve to expand current thoughts on GnRH actions at the pituitary gland. In addition to , LH ß, and FSH ß mRNAs, follistatin and ß-B gene expression are regulated by GnRH in female rats. Moreover, variation in the pattern of GnRH pulses can selectively increase gonadotropin, activin, and follistatin gene products. As a result of this complex hormonal milieu, gonadotrope responses to an ongoing pulsatile GnRH signal can exhibit a pattern of FSH ß and follistatin mRNAs that closely resembles changes during the normal estrous cycle on the evening of proestrus. Specifically, we propose that GnRH increases both FSH ß and follistatin mRNAs on proestrus, with subsequent follistatin action serving as a local feedback mechanism to reduce FSH ß mRNA on the morning of estrus following the gonadotropin surge.

	Footnotes

 
¹ Supported by USPHS Grant HD-11489 (to J.C.M.) and the Reproductive Center Grant HD-28934.

Received April 28, 1998.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

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				D.J. Haisenleder, L.J. Workman, L.L. Burger, K.W. Aylor, A.C. Dalkin, and J.C. Marshall Gonadotropin Subunit Transcriptional Responses to Calcium Signals in the Rat: Evidence for Regulation by Pulse Frequency Biol Reprod, December 1, 2001; 65(6): 1789 - 1793. [Abstract] [Full Text] [PDF]

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