Luteinizing hormone and luteinizing hormone-releasing hormone secretion is under locus coeruleus control in female rats

doi:10.1016/S0006-8993(02)03471-6

Brain Research

Volume 955, Issues 1–2, 15 November 2002, Pages 245-252

https://doi.org/10.1016/S0006-8993(02)03471-6 Get rights and content

Abstract

It has been suggested that norepinephrine (NE) from the locus coeruleus (LC) plays an important role in triggering the preovulatory surge of gonadotropins. This work intended to study the role of LC in luteinizing hormone (LH) secretion during the estrous cycle and in ovariectomized rats treated with estradiol and progesterone (OVXE₂P) and to correlate it with LH releasing hormone (LHRH) content in the medial preoptic area (MPOA) and median eminence (ME). Female rats on each day of the estrous cycle and OVXE₂P were submitted to jugular cannulation and LC electrolytic lesion or sham-operation, at 09:00 h. Blood samples were collected hourly from 11:00 to 18:00 h, when animals were decapitated and their brains removed to analyze LC lesion and punch out the MPOA and ME. Plasma LH levels and LHRH content of MPOA and ME were determined by radioimmunoassay. During metestrus, diestrus and estrus, LC lesion did not modify either LH plasma concentrations or LHRH content, but completely abolished the preovulatory LH surge during proestrus and the surge of OVXE₂P. These blockades were accompanied by an increased content of LHRH in the MPOA and ME. The results suggest that: (1) LC does not participate in the control of basal LH secretion but its activation is essential to trigger spontaneous or induced LH surges, and (2) the increased content of LHRH in the MPOA and ME may be due to a decreased NE input to these areas. Thus, LC activation may be required for depolarization of LHRH neurons and consequent LH surges.

Introduction

The luteinizing hormone (LH) preovulatory surge is the key event in the estrous cycle. Its release depends on hypothalamic luteinizing hormone releasing hormone (LHRH) secretion from nerve terminals into the median eminence (ME) [29]. Ovarian steroids classically control LHRH and LH secretion by positive and negative feedback [35] but the precise mechanisms by which estradiol (E₂) and progesterone (P) exert their effects are not completely established.

Since either E₂[43] or α-estradiol receptors (αER) [17] are not co-localized in the LHRH neurons, it has been suggested that the estrogen influence on LHRH secretion occurs by indirect mechanisms. On the other hand, recent studies demonstrated the expression of β-estradiol receptors (βER) in LHRH neurons in rodents [23]. However, since there was no difference in the number of βER immunoreactive neurons between female rats in different hormonal states and male rats, the βER expression seems not to be steroid-dependent. It is possible that these receptors could be involved in the negative feedback mechanism, since they can exert opposite effects to αERs [32]. According to this result, it seems reasonable to consider that the positive feedback could be exerted by indirect actions of E₂ modulating neurotransmitter secretion.

Its well known that one of the major neurotransmitters that controls LH secretion is norepinephrine (NE). The NE turnover in the preoptic area parallels changes in circulating LH concentrations [21]. Moreover, direct infusion of NE as well as methoxamine, an α₁-adrenergic agonist, into the ME stimulates LHRH secretion [47] whereas administration of an α₁-adrenergic antagonist eliminates the preovulatory LH surge [27] and the one induced by sexual steroids in ovariectomized rats [8].

The noradrenergic innervation of the hypothalamus is extrinsic [38] and comes from terminals originating in cell bodies located in the brain stem. The locus coeruleus (LC) is the major noradrenergic nucleus and has extensive efferent projections throughout the entire central nervous system (CNS) [14], [46] including areas involved in LH and LHRH synthesis and release [10].

Electrical stimulation of the LC in ovariectomized rats treated with E₂ amplifies the LH surge induced by electrochemical stimulation of the medial preoptic nucleus [12] while electrolytic lesions of the LC block the preovulatory surge of LH [2], [11]. This blockade of LH surge is accompanied by a decrease in the NE content in the medial preoptic area (MPOA) and medial basal hypothalamus (MBH) [2].

These findings strongly suggest that NE from the LC plays an important role mediating the positive feedback action of E₂ on LH secretion. However, the role of LC in basal LH secretion has not been studied. Thus, the aim of this study was to evaluate the effect of LC lesion on basal LH secretion, which occurs during metestrus, diestrus and estrus as well as on the LH surges in the afternoon of proestrus and in ovariectomized rats treated with E₂ and progesterone (OVXE₂P). Also, by measuring LHRH content in the cell bodies of the MPOA, as well as in the terminals in the ME, we investigated whether the effects of LC lesion on LH secretion might be due to alterations in LHRH secretion.

Section snippets

Animals

Adult female Wistar rats weighing 250–300 g from the animal house of the Ribeirão Preto Campus of the University of São Paulo were maintained under controlled lighting (lights on from 06:00 to 18:00 h) and temperature (24±0.5 °C). Food (standard rat chow, Nuvilab) and tap water were provided ad libitum.

Experimental design

Experiment I examined the effect of LC lesion on LH and LHRH secretion during the estrous cycle. Experiment II examined the effect of LC lesion on LH and LHRH secretion in ovariectomized rats

Results

Most of the missed lesions were located posterior to the LC. However, there were lesions dislocated to the right (lateral to the LC on the right side and medial on the left side) or to the left (lateral to LC on the left side and medial on the right side) and a few of them were also located dorsal to the LC (Fig. 1A, left). The size of the missed lesions did not differ from that of successful lesions. A complete lesion of the LC is shown in Fig. 1A (right). Fig. 1B shows the photomicrographic

Discussion

The present data demonstrate that LC lesion did not modify LHRH content or basal plasma LH during metestrus, diestrus and estrus; however, it completely abolished the preovulatory LH surge in proestrus, as well as the one induced by gonadal steroids in ovariectomized rats. These blockades were accompanied by an increased content of LHRH in the MPOA and ME.

Since lesions located laterally, medially, dorsally or posteriorly to the LC did not block the preovulatory surge, one may hypothesize that

Acknowledgements

We are grateful to Rute Ap. Freitas Marcon and Sonia M. Zanon Baptista for technical assistance, and to Fabricio Viviani for his help. Financial support: FAPESP; CNPq.

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In stressful situations, LH release seems to be facilitated by the progesterone secreted by the adrenal gland since progesterone secretion induced by stress is not abolished by ovariectomy (Kalil et al., 2013; Andersen et al., 2004; Budec et al., 2002; Romeo et al., 2004), while adrenalectomy completely abolishes the ACTH-induced increase in progesterone and LH secretion (Putnam et al., 1991). Noradrenaline is also an important neuromodulator of LH surge regulating the activity of hypothalamus-pituitary-ovarian axis (Helena et al, 2002; Szawka et al, 2007, 2009, 2013). Locus Coeruleus (LC; A6), A1 and A2 noradrenergic neurons project to the preoptic area, regulating the release of GnRH and therefore, of LH (Campbell and Herbison, 2007).
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Other cells in the rostral brainstem also respond to estradiol-17β (as indicated by Fos production), but we have demonstrated that these cells do not project to the BNST. There is some evidence to suggest that in the rat cells of the locus coeruleus (LC) are involved in regulation of GnRH neurons (Helena et al., 2002; Martins-Afferri et al., 2003), and in a previous study in sheep (Rawson et al., 2001) we demonstrated that LC neurons were retrogradely labelled from the POA, and therefore could be involved in the control of GnRH secretion, although these cells were found not to be noradrenergic. In the sheep we did not find any cells in this region that projected to the BNST, therefore LC cells involved in such GnRH regulation are likely to project directly to the POA.
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Research reportLuteinizing hormone and luteinizing hormone-releasing hormone secretion is under locus coeruleus control in female rats

Abstract

Introduction

Section snippets

Animals

Experimental design

Results

Discussion

Acknowledgements

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Neuroscience

Neuroscience

Mol. Cell. Endocrinol.

Brain Res.

Recent Prog. Horm. Res.

Mol. Brain Res.

Trends Endocrinol. Metab.

Brain Res. Bull.

Brain Res.

Mol. Brain Res.

The effect of locus coeruleus lesion on stress induced alterations in anterior pituitary hormone release in the rat

Locus coeruleus lesions block pulsatile release in ovariectomized rats

Brain Res.

A neural circuit for circadian regulation of arousal

Nat. Neurosci.

A rapid and sensitive method for quantitation of microgram quantities of protein utilizing the principle of protein dye binding

Anal. Biochem.

Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors

Endocrinology

A 24 h periodicity in the ‘LH release apparatus’ of female rats, disclosed by barbiturate sedation

Endocrinology

Nucleus locus coeruleus: new evidence of anatomical and physiological specificity

Physiol. Rev.

Effect of locus coeruleus lesion on luteinizing hormone secretion under different experimental conditions

Neuroendocrinology

A rapid and simple procedure for chronic cannulation of the rat jugular vein

J. Appl. Physiol.

Research report
Luteinizing hormone and luteinizing hormone-releasing hormone secretion is under locus coeruleus control in female rats