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. 2006 Feb 1;26(5):1448-56.
doi: 10.1523/JNEUROSCI.3777-05.2006.

The androgen 5alpha-dihydrotestosterone and its metabolite 5alpha-androstan-3beta, 17beta-diol inhibit the hypothalamo-pituitary-adrenal response to stress by acting through estrogen receptor beta-expressing neurons in the hypothalamus

Trent D Lund  1 , Laura R Hinds, Robert J Handa
Affiliations

The androgen 5alpha-dihydrotestosterone and its metabolite 5alpha-androstan-3beta, 17beta-diol inhibit the hypothalamo-pituitary-adrenal response to stress by acting through estrogen receptor beta-expressing neurons in the hypothalamus

Trent D Lund et al. J Neurosci. .

Abstract

Estrogen receptor beta (ERbeta) and androgen receptor (AR) are found in high levels within populations of neurons in the hypothalamus. To determine whether AR or ERbeta plays a role in regulating hypothalamo-pituitary-adrenal (HPA) axis function by direct action on these neurons, we examined the effects of central implants of 17beta-estradiol (E2), 5alpha-dihydrotestosterone (DHT), the DHT metabolite 5alpha-androstan-3beta, 17beta-diol (3beta-diol), and several ER subtype-selective agonists on the corticosterone and adrenocorticotropin (ACTH) response to immobilization stress. In addition, activation of neurons in the paraventricular nucleus (PVN) was monitored by examining c-fos mRNA expression. Pellets containing these compounds were stereotaxically implanted near the PVN of gonadectomized male rats. Seven days later, animals were killed directly from their home cage (nonstressed) or were restrained for 30 min (stressed) before they were killed. Compared with controls, E2 and the ERalpha-selective agonists moxestrol and propyl-pyrazole-triol significantly increased the stress induced release of corticosterone and ACTH. In contrast, central administration of DHT, 3beta-diol, and the ERbeta-selective compound diarylpropionitrile significantly decreased the corticosterone and ACTH response to immobilization. Cotreatment with the ER antagonist tamoxifen completely blocked the effects of 3beta-diol and partially blocked the effect of DHT, whereas the AR antagonist flutamide had no effect. Moreover, DHT, 3beta-diol, and diarylpropionitrile treatment significantly decreased restraint-induced c-fos mRNA expression in the PVN. Together, these studies indicate that the inhibitory effects of DHT on HPA axis activity may be in part mediated via its conversion to 3beta-diol and subsequent binding to ERbeta.

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Figures

Figure 1.
Figure 1.
Verification of ligand pellet placement. The locations of pellets were localized in cresyl-violet-stained sections by identifying pellet location relative to the desired region. A, Typical histology with hormone-containing pellets indicated. B–D, Placement of the pellets from a representative experiment with locations plotted onto atlas diagrams of the brain in the region of the PVN [diagrams adapted from Swanson (1998/1999)]. Each black dot represents the center of a hormone pellet. V3, Third ventricle; PVH, paraventricular hypothalamic nucleus; PVHdp, paraventricular hypothalamic nucleus, dorsal parvicellular part; PVHmpd, paraventricular hypothalamic nucleus, medial parvicellular part; PVHpml, paraventricular hypothalamic nucleus, posterior magnocellular part, lateral zone; PVHpmm, paraventricular hypothalamic nucleus, posterior magnocellular part, medial zone; PVHpv, paraventricular hypothalamic nucleus, periventricular part; PVHlp, paraventricular hypothalamic nucleus, lateral pariventricular part; RE, nucleus reunions; REd, nucleus reunions, rostral division, dorsal part; REl, nucleus reunions, rostral division, lateral part; REm, nucleus reunions, rostral division, median part; PVa, periventricular hypothalamic nucleus anterior part; PVi, periventricular hypothalamic nucleus, intermediate part; SBPV, subparaventricular zone hypothalamus; ZI, zona incerta; fx, columns of the fornix; AHNa, anterior hypothalymic nucleus, anterior part; AHNc, anterior hypothalymic nucleus, central part; AHNd, anterior hypothalymic nucleus, dorsal part; AHNp, anterior hypothalymic nucleus, posterior part; RCH, retrochiasmatic area; sup, supraoptic commissures; ARH, arcuate hypothalamic nucleus; VMHa, ventromedial hypothalamic nucleus, anterior part; VMHc, ventromedial hypothalamic nucleus, central part; VMHdm, ventromedial hypothalamic nucleus, dorsomedial part; VMHvl, ventromedial hypothalamic nucleus, ventrolateral part; MEin, median eminence, internal lamina; MEex, median eminence, external lamina; TU, tuberal nucleus; VM, ventromedial nucleus; SMT, submedial nucleus thalamus; PR, perireuniens nucleus; mtt, mammillothalamic tract.
Figure 2.
Figure 2.
DHT- and ERβ-selective ligands suppress the hormonal response to restraint stress. Wax pellets containing E2, DHT, 3β-diol, DPN, moxestrol (Mox), or PPT were implanted directly above the PVN, and the hormonal response to a 30 min restraint stress was measured. A, Corticosterone levels. B, ACTH levels in stressed animals after central treatment with DHT, the ERβ-selective compounds 3β-diol and DPN with E2, or the ERα-selective ligands moxestrol and PPT. The asterisk indicates groups that were significantly different from vehicle controls (p < 0.05). Each bar represents the mean ± SEM of six or seven animals.
Figure 3.
Figure 3.
Androgen receptor antagonism does not block the effects of centrally administered DHT 3β-diol or DPN on plasma corticosterone response to restraint stress. Corticosterone (A) and ACTH (B) levels were determined 30 min after restraint stress in animals treated centrally with DHT, 3β-diol, or DPN and treated concomitantly with flutamide. *p < 0.05 significant difference compared with control treatment. **p < 0.05 significantly higher corticosterone levels than DHT males not treated with flutamide. Each bar represents the mean ± SEM of 8–10 animals.
Figure 4.
Figure 4.
The estrogen receptor antagonist tamoxifen blocks the effects of centrally administered DHT, 3β-diol, and DPN. Plasma corticosterone (A) and ACTH (B) levels were determined in restrained (30 min) or nonrestrained males with PVN implants containing DHT, 3β-diol, or DPN and then treated with tamoxifen did not differ from controls. *p < 0.05, significant difference compared with control treatment. Double asterisks indicate groups treated with tamoxifen that had significantly higher corticosterone levels than did comparably treated group but without tamoxifen (p < 0.05). Each bar represents the mean ± SEM of 8–10 animals.
Figure 5.
Figure 5.
E2 and DHT influence restraint induced c-fos mRNA expression in the PVN. A, In situ hybridization was used to semiquantitate c-fos mRNA levels in the PVN and to examine the influence of various compounds on the activation of PVN neurons after stress. * indicates groups that were significantly greater relative to the stressed control group (p < 0.05). ** indicates groups that, after restraint, showed c-fos mRNA levels in the PVN that were significantly lower relative to stressed controls (p < 0.05). B, Representative photomicrographs from each of these groups. Each bar represents the mean ± SEM of 8–10 animals. 3V, Third ventricle.
Figure 6.
Figure 6.
The PVN contains relevant steroid hormone metabolizing enzyme mRNAs. Photomicrographs of agarose gels after electrophoresis of RT-PCR products from microdissected PVN of gonadectomized male rats are shown. Bands represent mRNAs for aromatase (A), 5α-reductase (B), 17β-HSD (C), 3α-HSD (D), 3β-HSD (E), and CYP7B (F). Hypo, Hypothalamus.
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References

    1. Alves SE, Lopez V, McEwen BS, Weiland NG (1998). Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study. Proc Natl Acad Sci USA 95:3281–3286. - PMC - PubMed
    1. Bingaman EW, Baeckman LM, Yracheta JM, Handa RJ, Gray TS (1994). Localization of androgen receptor within peptidergic neurons of the rat forebrain. Brain Res Bull 35:379–382. - PubMed
    1. Boudaba C, Szabo K, Tasker JG (1996). Physiological mapping of local inhibitory inputs to the hypothalamic paraventricular nucleus. J Neurosci 16:7151–7160. - PMC - PubMed
    1. Burgess LH, Handa RJ (1992). Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology 131:1261–1269. - PubMed
    1. De Kloet ER, Versteeg DH, Kovacs GL (1983). Aldosterone blocks the response to corticosterone in the raphe-hippocampal serotonin system. Brain Res 264:323–327. - PubMed

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