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Recent work from our laboratory suggests that a complex interaction exists between ovarian and adrenal steroids in the regulation of preovulatory gonadotropin secretion. Ovarian estradiol serves to set the neutral trigger for the preovulatory gonadotropin surge, while progesterone from both the adrenal and the ovary serves to (1) initiate, (2) synchronize, (3) potentiate and (4) limit the preovulatory LH surge to a single day. Administration of RU486 or the progesterone synthesis inhibitor, trilostane, on proestrous morning attenuated the preovulatory LH surge. Adrenal progesterone appears to play a role in potentiating the LH surge since RU486 still effectively decreased the LH surge even in animals ovariectomized at 0800 h on proestrus. The administration of ACTH to estrogen-primed ovariectomized (ovx) immature rats caused a LH and FSH surge 6 h later, demonstrating that upon proper stimulation, the adrenal can induce gonadotropin surges. The effect was specific for ACTH, required estrogen priming, and was blocked by adrenalectomy or RU486, but not by ovariectomy. Certain corticosteroids, most notably deoxycorticosterone and triamcinolone acetonide, were found to possess "progestin-like" activity in the induction of LH and FSH surges in estrogen-primed ovx rats. In contrast, corticosterone and dexamethasone caused a preferential release of FSH, but not LH. Progesterone-induced surges of LH and FSH appear to require an intact N-methyl-D-aspartate (NMDA) neurotransmission line, since administration of the NMDA receptor antagonist, MK801, blocked the ability of progesterone to induce LH and FSH surges. Similarly, NMDA neurotransmission appears to be a critical component in the expression of the preovulatory gonadotropin surge since administration of MK801 during the critical period significantly diminished the LH and PRL surge in the cycling adult rat. FSH levels were lowered by MK801 treatment, but the effect was not statistically significant. The progesterone-induced gonadotropin surge appears to also involve mediation through NPY and catecholamine systems. Immediately preceding the onset of the LH and FSH surge in progesterone-treated estrogen-primed ovx. rats, there was a significant elevation of MBH and POA GnRH and NPY levels, which was followed by a significant fall at the onset of the LH surge. The effect of progesterone on inducing LH and FSH surges also appears to involve alpha 1 and alpha 2 adrenergic neuron activation since prazosin and yohimbine (alpha 1 and 2 blockers, respectively) but not propranolol (a beta-blocker) abolished the ability of progesterone to induce LH and FSH surges. Progesterone also caused a dose-dependent decrease in occupied nuclear estradiol receptors in the pituitary.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1992 Mar
PMID:Interaction between ovarian and adrenal steroids in the regulation of gonadotropin secretion. 156 21

Nerve growth factor (NGF), its messenger RNA (mRNA) and its receptor protein and mRNA are found in several brain regions. Little attention has been given to the possibility that the hypothalamus, which controls the endocrine system, may produce NGF and/or express NGF receptors. This would indicate the existence in this brain area of neuronal populations which are either target for NGF-responsive cells or sensitive to NGF, respectively. Blot hybridization of polyadenylated (poly(A)+) RNA to a mouse NGF cRNA probe revealed the presence of NGF mRNA in both the suprachiasmatic region (henceforth, called preoptic area [POA]) and medial basal hypothalamus (MBH) of developing female rats. The mRNA was already detectable on fetal day 18 and reached maximal levels around postnatal day 3 (MBH) and 12 (POA), declining thereafter. This pattern was temporally different than that of areas known to produce NGF, i.e., the neocortex (Cc) and hippocampus (Hc). In agreement with previous reports, NGF mRNA levels in these areas were negligible before birth, became maximal between the second and third week of postnatal life and decreased moderately thereafter. The concentration of NGF protein, measured by a two-site enzyme immunoassay, was 3 times higher in the POA than in the MBH at an infantile age (day 12), increasing 2-fold in the POA of juvenile animals (day 28) but not in the MBH. This developmental pattern was similar to that seen in the Hc, though the NGF concentrations were significantly lower in the POA.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1991 Jan
PMID:The genes encoding nerve growth factor and its receptor are expressed in the developing female rat hypothalamus. 170 76

The decapeptide gonadotropin-releasing hormone (GnRH) and the 56-amino acid GnRH-associated peptide (GAP) are derived from a common precursor translated from the proGnRH-GAP mRNA. Studies using solid-phase hybridization techniques (i.e., Northern blot analysis, dot blot analysis, or in situ hybridization autoradiography) have yielded a controversy as to whether estradiol stimulates, inhibits, or has any effect on proGnRH-GAP gene expression in the preoptic area-anterior hypothalamus (POA-AH) of the ovariectomized (OVX) rat. Using a sensitive and quantitative solution hybridization-nuclease protection assay, which ensures complete hybridization of target RNA to probe RNA, we examined the effects of OVX and estradiol replacement on the amount of proGnRH-GAP mRNA in individual POA-AH dissections. Rats sacrificed at different intervals after OVX showed a significant time-dependent decrease (34-60%) in the levels of POA-AH proGnRH-GAP mRNA relative to sham-operated animals; OVX rats treated with estradiol, however, had proGnRH-GAP mRNA levels comparable to those of sham-OVX animals. To verify these observations, levels of the proGnRH-GAP peptide, measured by radioimmunoassay with antibodies directed against the cleavage and amidation site between the GnRH and the GAP portions fo the precursor molecular, were also found to decrease (37%) after OVX and increase (63-85%) following estradiol replacement, relative to intact rats. These data support the view that estradiol stimulates the levels of both proGnRH-GAP mRNA and its primary translation product in the POA-AH region of the OVX rat.
Brain Res Mol Brain Res 1989 Nov
PMID:Estradiol stimulates preoptic area-anterior hypothalamic proGnRH-GAP gene expression in ovariectomized rats. 269 77

Micropipettes were used to record electrical activity from single neurons in hypothalamic tissue slices, in the hypothalamic arcuate nucleus (ARC), and in the periventricular and suprachiasmatic preoptic nuclei (POA). Responses were measured following in vitro application of luteinizing hormone releasing hormone (LHRH), and two analogues: LHRH models 1 and 3. Model 1 (pyroGlu-His-Trp-Ser-Phe-Thr-Ile-Lys-Ile-ThrNH2) had amino acid substitutions in residues 5-10 designed to form an amphiphilic beta-strand structure. Model 3 (pyroGlu-His-Trp-Ser-Phe-Gly-Ile-Lys-Pro-SerNH2) was also designed to possess amphiphilic characteristics, but also more closely to resemble the native peptide. Electrical recording results showed that LHRH was able both to excite or inhibit different hypothalamic neurons, and that it was more effective in the preoptic area than in the arcuate nucleus. Responses to LHRH model 3 were strongly correlated with responses to LHRH, in their occurrence and their direction, for both of the brain regions studied. Moreover, LHRH models 1 and 3 also retained the neuromodulatory effects of LHRH on cellular responses to norepinephrine and serotonin. Thus, LHRH analogues, designed to possess an amphiphilic beta-structure, preserved some of the properties of LHRH when tested electrophysiologically in the central nervous system.
Mol Cell Endocrinol 1986 Dec
PMID:Electrophysiological test of an amphiphilic beta-structure in LHRH action. 354 30

Excitatory amino acids such as N-methyl-D,L-aspartic acid (NMDA) are thought to play an important role in the regulation of gonadotropin secretion. NMDA induces significant increases in plasma LH in a variety of animal models and these effects occur by activation of neural processes involved in excitation of LHRH neurons rather than by a direct action on the pituitary gland. We have taken advantage of this information to study the effects of NMDA on LH release and on changes in levels of LHRH mRNA in single neurons of adult rats treated neonatally with a high dosage of androgen. While iv NMDA evoked an increase in plasma LH in estrogen-treated ovariectomized control and androgen-sterilized rats (ASR), significantly less LH was released in ASR. LHRH mRNA levels in the organum vasculosum of the lamina terminalis (OVLT), the rostral (r), media (m) and caudal (c) preoptic (POA) regions were quantitated using in situ hybridization histochemistry and quantitative image analysis methods. LHRH mRNA levels in untreated controls and ASR did not differ in any of the brain regions examined. Within 1 h after NMDA, LHRH mRNA had increased significantly in OVLT and rPOA but not in mPOA and cPOA neurons of control rats and these mRNA levels remained elevated for 4 h. In contrast, NMDA treatment of ASR did not affect basal levels of LHRH mRNA in any region of the rostral hypothalamus. These observations suggest that neonatal androgen treatment of female rats either directly or indirectly affects the responsiveness of LHRH neurons to NMDA.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1993 Jan
PMID:N-methyl-D,L-aspartic acid differentially affects LH release and LHRH mRNA levels in estrogen-treated ovariectomized control and androgen-sterilized rats. 838 94

1. Evidence is reviewed which shows that a sexually dimorphic nucleus located in the dorsomedial portion of the male ferret's preoptic area/anterior hypothalamus (POA/AH), called the male nucleus of the POA/AH (Mn-POA/AH), develops during fetal life in response to the action of estradiol, which is formed directly in the nervous system from circulating testosterone over the final quarter of a 41-day gestation. 2. Results are summarized which establish that neurons which make up the Mn-POA/AH are born prior to the critical period of estradiol's action in the male brain. Other data show that some radial glial processes, visualized immunocytochemically using antibodies against GFAP, emanate from proliferative zones at the base of the lateral ventricles in a dorsal-ventral orientation, whereas other glial processes emanate laterally from proliferative zones lining the third ventricle. 3. We suggest that at least some neurons which constitute the dorsomedial POA/AH are born in proliferative zones surrounding the lateral ventricles, raising the question of whether estradiol acts in developing males to influence the migration of these neurons along radial glial guides into the Mn-POA/AH. 4. Finally, evidence is summarized showing that excitotoxic lesions of the dorsomedial POA/AH enhance males' preference to approach and interact with another sexually active male, as opposed to an estrous female, when adult subjects are castrated and treated with estradiol benzoate. These data suggest that the sexually dimorphic Mn-POA/AH is an essential part of a CNS circuit which determines heterosexual partner preference in the male ferret.
Cell Mol Neurobiol 1996 Apr
PMID:Estrogenic control of preoptic area development in a carnivore, the ferret. 874 64

We have characterized the nuclear and cytoplasmic RNA transcripts derived from the gonadotropin releasing hormone (GnRH) gene in a mouse hypothalamic neuronal GT1 cell line. Analyses of nuclear GnRH RNA precursors present in the GT1 cells by RNase protection assay show that there is no particular order of intron excision, suggesting the existence of multiple processing pathways. A similar pattern is observed in mouse preoptic area-anterior hypothalamus (POA-AH). In GT1 cells, approximately 5% of the total GnRH RNA transcripts are found in the nucleus. In contrast, in the POA-AH of mice, nuclear transcripts comprise 40% of the total GnRH transcripts. Thus the GT1 cells, while similar in overall GnRH RNA processing to mouse hypothalamic GnRH neurons, do not exhibit the high abundance of nuclear GnRH RNA transcripts seen in the rodent GnRH neuron in vivo. Quantitative analysis of the nuclear RNA species shows that the GnRH primary transcript comprises more than 90% of the total nuclear GnRH mRNA precursors in both GT1 cells and mouse POA-AH and thus GnRH processing intermediates account for fewer than 10% of these precursors. Using these probes, we have examined changes in GnRH primary transcript expression in GT1-7 cells. In the presence of RNA synthesis inhibitors, the half-life of the GnRH primary transcript was found to be quite short, approximately 18 min, suggesting that the level of primary transcript would reflect levels of GnRH gene transcription. When GT1-7 cells are treated with the phorbol ester PMA (phorbol, 12-myristate, 13-acetate) for 1 h, GnRH primary transcript levels decrease by approximately 70%. Supporting the hypothesis that GnRH primary transcript is a good indicator of GnRH gene transcription is the finding that 1 h of PMA treatment results in a similar (approximately 50%) decrease in GnRH gene transcription, as assayed by nuclear run-on assay. Our observation that GT1 cells resemble mouse hypothalamic GnRH neurons in their pattern of intron excision and in the ratio of primary transcript to other nuclear transcripts emphasizes the utility of these cells for studying the regulation of GnRH gene expression in this immortalized hypothalamic cell line.
Brain Res Mol Brain Res 1996 Dec
PMID:Characterization of gonadotropin-releasing hormone gene transcripts in a mouse hypothalamic neuronal GT1 cell line. 901 81

Opioids have been implicated in sexual differentiation of the brain and in the regulation of reproductive behavior and endocrinology of mammals. Previous studies have indicated that estrogen administration in adults regulates preproenkephalin MRNA levels in several hypothalamic brain nuclei. We have determined preproenkephalin mRNA levels in estrogen-treated juvenile male and female rats to investigate the developmental pattern of estrogenic regulation of enkephalinergic neurons in the medial preoptic area. Rats were treated with estradiol benzoate (20 microgram/kg/day) or oil from day 21 to 23. Sections of the medial preoptic area (mPOA) were studied by in situ hybridization histochemistry at the single cell level and quantified with the assistance of an image analysis system. Our data indicate that males contain higher levels of preproenkephalin mRNA per neuron than females. In addition, our results indicate that estrogen causes an upward shift in the amount of mRNA expressed per cell, females demonstrating a greater response to estrogen than males. An increase in soma cell area following estrogen treatment was observed only in female mPOA enkephalinergic neurons. Taken together, these results indicate a sex difference in total preproenkephalin levels and in estrogenic regulation of preproenkephalin mRNA in the POA of juvenile rats. These results are discussed in relation to the differential role opioids may play in male and female reproductive physiology.
Brain Res Mol Brain Res 1998 Sep 18
PMID:Sex differences in estrogenic regulation of preproenkephalin mRNA levels in the medial preoptic area of prepubertal rats. 974 41

In mammals, NPY is a key factor in the regulation of feeding behavior. In the present study, the effects of refeeding for 1-3 h in 72-75-h food deprived (FD) goldfish on the levels of NPY mRNA in telencephalon-preoptic (TEL-POA), hypothalamus (HYP) and optic tectum-thalamus (OT-THAL) were examined, using Northern blot analysis. Goldfish FD for 72 h exhibited a significant increase in NPY mRNA levels in all brain regions. At 1 h after 72-h FD (73-h FD), NPY mRNA was significantly increased in TEL-POA and OT-THAL, but remained the same as 72-h FD fish in HYP. At 3 h after 72-h FD (75 h), all brain regions exhibited a significant increase in NPY mRNA levels. However, subsequent refeeding for 1-3 h rapidly and completely reversed the effects of FD in all brain regions, reaching fed levels within 1-3 h of refeeding. Serum GH levels were highest in 72-h FD fish, but decreased significantly over 1-3 h after 72-h FD; whereas, refeeding reversed the increase in serum GH levels only at 3 h after refeeding. Taken together, these results further support that NPY is a physiological brain transducer involved in the regulation of daily appetite and feeding in goldfish.
Comp Biochem Physiol B Biochem Mol Biol 2001 Jun
PMID:Effects of food deprivation and refeeding on neuropeptide Y (NPY) mRNA levels in goldfish. 1139 99

Sexually dimorphic brain volumes (sexually dimorphic nucleus of the preoptic area (SDN-POA) and anteroventral periventricular (AVPV) nucleus) are influenced by estrogens. Phytoestrogens, derived from plants (especially soy products), are molecules structurally and functionally similar to estradiol. The purpose of this study was to examine: the consumption of phytoestrogen (using a phytoestrogen-rich (Phyto-600) versus a phytoestrogen-free (Phyto-free)) diets from conception to adulthood (or changing the diets during adulthood) and characterizing (a) circulating plasma phytoestrogen levels, (b) testosterone levels in males, (c) sexually dimorphic brain volumes (i.e. the SDN-POA and AVPV) and (d) the presence of apoptotic cells in these brain structures in Long-Evans rats. Phyto-600 fed animals displayed total serum phytoestrogens levels 37-fold higher compared to Phyto-free values. Circulating testosterone levels were not significantly altered by the diets. Female SDN-POA volumes were not altered by the diets. Whereas, males fed a Phyto-free diet displayed decreased SDN-POA volumes compared to male Phyto-600 values. Females fed the Phyto-600 diet displayed larger AVPV volumes compared to males on the same diet or females on the Phyto-free diet. Males fed the Phyto-free diet had the largest AVPV values compared to Phyto-600 fed males. When the SDN-POA region was examined in lifelong Phyto-free fed males, apoptotic cells were present versus males fed the Phyto-600 diet and in the AVPV region the opposite results were obtained. In summary, consumption of dietary phytoestrogens (estrogen mimics) can alter hormone-sensitive hypothalamic brain volumes in rodents during adulthood.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Estrogens and phytoestrogens: brain plasticity of sexually dimorphic brain volumes. 1294 16


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