Biomedical subjects

J R Brawer

Publications and source records attributed to J R Brawer.

At least 37 records · Page 2Linked to original sources

PubMed1990

Induction of Stein-Leventhal-like polycystic ovaries (PCO) in the rat: a new model for cystic ovarian disease.

An injection of estradiol valerate (EV) in the rat produces an anovulatory polycystic ovarian (PCO) condition. Chronic estrogen exposure, produced by subcutaneously implanted, estradiol (E2)-containing chronic release capsules, results in acyclicity and in hypothalamic changes similar to those seen in the EV-injected rat. We, therefore, examined the ovarian histology and plasma gonadotropin patterns in the E2-implanted rat and found that this model exhibits a polycystic ovarian condition and a plasma gonadotropin pattern very different from those in the EV-treated model. The plasma patterns of LH and FSH are bimodal consisting of small frequent pulses as well as less frequent large episodes of long duration. The ovaries contain multiple small cysts, characterized by an extensively hypertrophied theca interna, and vast chords of hypertrophied secondary interstitial cells. In contrast, cystic follicles in EV-treated rats are fewer in number, but much larger than those in the E2-implanted animals. The cystic theca and the secondary interstitial cell clusters are also far less extensive in the EV-induced polycystic ovary. These and other differences between the two types of PCO indicate that they are produced by fundamentally different morphogenic mechanisms. The cystic ovary produced by the E2 implants is similar in appearance to that seen in the human Stein-Leventhal condition, and thus provides a new model for the study of cystic ovarian disease.

Animals↗

PubMed1990

Estrogen effects on the synaptology and neural membranes of the rat hypothalamic arcuate nucleus.

The concept of estrogen-induced "sexual differentiation of the brain" has been a useful focus for investigation. However, it has become clear that the action of estrogen on the rat brain is lifelong, including effects on neurogenesis in the fetus, synaptogenesis in the newborn, and synaptic remodeling in the adult. Estrogen imparts sex differences in the rat's brain by shaping synaptology, postsynaptic membranes, and glia within the arcuate nucleus. These effects of estrogen on the arcuate nucleus also could underlie sexual maturation in both sexes and the development of senescent constant estrus in females.

Animals↗

PubMed1990

Plasma gonadotropin patterns characterizing the development of polycystic ovaries in the estradiol valerate treated rat.

Polycystic ovaries (PCO) develop in female rats within 4 weeks of an injection of estradiol valerate (EV). The final morphological transition from a noncystic to a cystic state occurs in the presence of estrous (control) mean serum gonadotropin concentrations, suggesting that gonadotropin patterns rather than mean concentrations are causal to PCO. We have examined plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) patterns in female rats at estrus and on days 5, 11, 16, and 21 following EV treatment. Estrous animals displayed large amplitude LH pulses of short duration, interspersed among frequent, low amplitude pulses of similar duration, and infrequent, broad-based LH episodes. Following EV treatment, there was a progressive decline in the frequency and magnitude of the large amplitude LH pulses, such that by day 16, they ceased altogether. Conversely, the frequency of the low amplitude pulses increased such that the total pulse frequency remained constant. The onset of this pattern coincides with the wave of atresia that precedes the emergence of cystic follicles. The pulsatile plasma pattern of FSH seen at estrus remained unaltered at all time intervals examined after EV treatment. We conclude that there is a specific LH pattern responsible for the generation and maintenance of the PCO condition.

Animals↗

PubMed1990

Alterations in opioid parameters in the hypothalamus of rats with estradiol-induced polycystic ovarian disease.

The distribution and density of selectively labeled mu-, delta-, and kappa-opioid binding sites were examined by in vitro radioautography in the hypothalamus of normal, estradiol valerate (EV)-injected, and estradiol (E2)-implanted female rats. Hypothalamic beta-endorphin concentration was also examined by RIA in these three groups of animals. Quantitative analysis of film radioautographs demonstrated a selective increase in mu-opioid binding in the medial preoptic area of EV-treated, but not of E2-implanted rats. However, both these estrogenized groups exhibited a reduction in the density of delta-opioid binding in the suprachiasmatic nucleus. Statistically significant changes between either estrogenized groups were not observed for kappa-opioid binding. Results on the hypothalamic concentration of beta-endorphin indicated a marked reduction in EV-injected animals with respect to controls. In contrast, the E2-implanted animals exhibited beta-endorphin concentrations similar to controls. The present results confirm the increase in opioid receptor binding previously reported in the hypothalamus of EV-treated rats and further demonstrate that this increase is confined to the medial preoptic area and exclusively concerns mu-opioid receptors. The concomitant reduction in beta-endorphin levels observed in the same group of animals suggests that the observed increase in mu-opioid binding could reflect a chronic up-regulation of the receptor in response to compromised beta-endorphin input. Given the restriction of this effect to the site of origin of LHRH neurons and the demonstrated inhibitory role of opioids on LHRH release, it is tempting to postulate that such up-regulation could lead to the suppression of the plasma LH pattern that characterizes polycystic ovarian disease in the EV-treated rat.

Animals↗

PubMed1989

Development and maintenance of a polycystic condition in ovaries autotransplanted under the kidney capsule.

A single injection of estradiol valerate (EV) produces a polycystic ovarian (PCO) condition in the rat. The development of the PCO condition coincides with alterations in the endogenous plasma gonadotropin patterns, suggesting that PCO may be a response to abnormal gonadotropin stimulation. Other factors, however, such as direct autonomic innervation, also contribute significantly to the regulation of the ovary and could be important in generating and/or maintaining PCO. We have, therefore, removed and autotransplanted one ovary in each of eight rats under the capsule of the ipsilateral kidney, thus totally disrupting its innervation. The animals were injected with EV and both ovaries of each animal were examined 8 weeks later. In a second group of animals, we induced the PCO condition, autotransplanted one polycystic ovary in each animal under the kidney capsule, and examined the ovaries 2 weeks later. In both groups the autotransplanted ovaries exhibited the full range of polycystic morphology, as did the intact ovary in each animal. We conclude that since a major perturbation in innervation affects neither the development nor the maintenance of PCO, autonomic innervation does not play a crucial role in this disorder.

Animals↗

PubMed1989

The role of aberrant hypothalamic opiatergic function in generating polycystic ovaries in the rat.

Treatment of adult female rats with estradiol valerate produces an intractable hypothalamic impairment that ultimately results in anovulatory acyclicity and polycystic ovaries. Evidence from our laboratory suggests that the hypothalamic impairment compromises regulation of the endogenous opioid system engendering a persistent opiatergic suppression of gonadotropin-releasing hormone secretion, which is subsequently reflected in a chronically low pituitary content of gonadotropin-releasing hormone receptors. If such is the case, inhibition of opiatergic transmission should improve the gonadotropin-releasing hormone pattern resulting in an improvement in the pituitary content of gonadotropin-releasing hormone receptors, and in an amelioration of the polycystic condition. We, therefore, treated rats with the polycystic ovarian condition, with daily injections of naltrexone. Within 1 week, there was a significant increase in the pituitary content of gonadotropin-releasing hormone receptors and a marked improvement in ovarian morphology, indicating that the hypothalamic opiatergic system is chronically active, and contributes significantly to the polycystic ovarian condition.

Animals↗

PubMed1988

Light and electron microscopic study of tyrosine hydroxylase-immunoreactive neurons within the developing rat arcuate nucleus.

The topography, fine structure, and patterns of connections of tyrosine hydroxylase (TH)-immunoreactive tubero-infundibular dopaminergic (TIDA) neurons were examined by light and electron microscopic immunocytochemistry in the arcuate nucleus of 2-, 15- and 30-day-old female Wistar rats. In 2-day-old animals, TH-immunoreactive perikarya were mainly located in the ventrolateral portion of the arcuate nucleus. In 15-day-old rats numerous TH-positive cell bodies were still present ventrolaterally, but a cluster of labeled cells was also apparent in the mediodorsal segment of the nucleus. In the 30-day-old rats, most TH-immunoreactive neurons were concentrated mediodorsally, as seen in the adult. At the ultrastructural level, TH-immunoreactive somata exhibited, in all age groups, a large nucleus surrounded by a thin rim of cytoplasm containing mitochondria, Golgi apparatus, endoplasmic reticulum, multivesicular bodies and lysosomes. These labeled somata were synaptically contacted by unlabeled axon terminals and often laid adjacent to either labeled or unlabeled dendrites. Similarly, in all age groups, labeled dendrites were synaptically contacted by unlabeled axon terminals and were often directly apposed to either labeled or unlabeled perikarya and dendrites, or to tanycytic processes. These results indicate that TIDA neurons establish extensive connections early in development, and that their pattern of intercellular relationships remains qualitatively unchanged from 2 days to adulthood. It is suggested that TIDA neurons may be already functional at birth, and could therefore, influence the maturation of other arcuate neuronal populations.

Aging↗

PubMed1988

Pituitary gonadotropin-releasing hormone receptor content in rats with polycystic ovaries.

A single injection of estradiol valerate (EV) induces, after a lag period of 4-6 wk, a chronic anovulatory polycystic ovarian (PCO) condition in adult rats. This condition is associated with a selective compromise of luteinizing hormone (LH) release and/or synthesis reflected in low basal serum LH concentrations, decreased pituitary content of LH, and decreased gonadotropin-releasing hormone (GnRH)-stimulated LH secretion. The present study was undertaken to determine to what extent the aberrant LH release in rats with PCO could be related to alterations in pituitary content of GnRH receptors. Pituitary GnRH-receptor content was assessed by the evaluation of saturation binding of a GnRH analog, [125I]-D-Ala6-des-Gly10-GnRH, to pituitary membrane preparations. The receptor content of pituitaries from rats with PCO was compared to that obtained from intact animals at estrus and diestrus. Receptor levels in ovariectomized normal rats and rats with PCO were also assessed. The pituitary GnRH receptor content in PCO rats was similar to that observed in normal controls at estrus and was significantly lower than that for rats at diestrus. Although a twofold increase in pituitary GnRH receptor content was observed at 28 days following the castration of control rats, GnRH receptor content in the pituitaries of PCO rats, at 28 days following ovariectomy, remained unchanged. Although, castration-induced elevations in mean serum LH and follicle-stimulating hormone (FSH) concentrations were observed in both the PCO and control animals, the rise in both gonadotropins was significantly attenuated in the PCO-castrates when compared to the ovariectomized controls. Since GnRH is a major factor in the regulation of pituitary GnRH receptor content, these findings suggest that hypothalamic GnRH release is impaired in rats with PCO and that this impairment is independent of any influences from the polycystic ovaries.

Animals↗

PubMed1987

An intractable, ovary-independent impairment in hypothalamo-pituitary function in the estradiol-valerate-induced polycystic ovarian condition in the rat.

A single injection of estradiol valerate (EV) produces anovulatory acyclicity and polycystic ovaries (PCO) in the rat. Basal serum luteinizing hormone (LH) concentrations are attenuated whereas serum follicle stimulating-hormone (FSH) concentrations are in the high normal range in these animals. Subsequent unilateral ovariectomy restores ovulatory cycles and normal histology in the remaining ovary without correcting the aberrant basal serum gonadotropin concentrations. This suggests that although the blocked surge mechanism is correctable, a second relatively intractable, ovary-independent impairment compromises basal gonadotropin production. To identify and characterize this second component, we have examined hypothalamic-pituitary function in PCO rats after bilateral ovariectomy. Adult (200-250 g), normal cyclic Wistar rats were injected with 2 mg EV or with vehicle (control). Nine weeks later all animals were ovariectomized and PCO was confirmed in the EV-treated animals. Animals were killed at 0, 2, 7, 14, and 28 days after ovariectomy, and hypothalamic content of luteinizing hormone-releasing hormone (LHRH) and pituitary and serum concentrations of LH and FSH were measured. LH and FSH responses to exogenous LHRH were assessed. Serum progesterone, testosterone, and estradiol concentrations were determined at 28 days. Hypothalamic LHRH decreased significantly in all animals over the 28-day period. Although LHRH values did not differ at Time 0, by 28 days there was significantly less LHRH in the hypothalami of control than in PCO rats. This pattern of depletion was mirrored by corresponding reciprocal patterns of increasing serum gonadotropin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Plasma patterns of LH, FSH and prolactin in rats with a polycystic ovarian condition induced by oestradiol valerate.

The patterns of plasma LH, FSH and prolactin concentrations were investigated in rats with a polycystic ovary condition (PCO). The condition was induced by treatment with oestradiol valerate 9 weeks before blood sampling. Serial blood samples were taken at 10-min intervals for 4 h from ten rats with PCO. All samples were assayed for LH, those from five animals for FSH and those from the remaining five animals for prolactin. In addition, five control animals with normal oestrous cycles were sampled during oestrus and the samples assayed for LH. Mean concentrations of LH, FSH and prolactin in rats with PCO were 140 ng/l, 76 micrograms/l and 7.6 micrograms/l respectively. All three hormones exhibited an episodic pattern. The mean peak amplitudes of LH, FSH and prolactin were 120 ng/l, 25 micrograms/l and 3.5 micrograms/l respectively. All three hormones exhibited a similar mean frequency of four or five episodes per 4 h. The LH and FSH patterns were closely synchronized; nearly all FSH peaks coincided with LH peaks. The prolactin pattern did not, however, correlate with that of the gonadotrophins. Despite the persistent oestrous condition of the animals with PCO, it was clear that their pattern of LH did not resemble that of cyclic animals in normal oestrus; in the normally cyclic animals in oestrus the pulse period was nearly twice as long and the pulse amplitude was more than sixfold greater than those in animals with PCO. We conclude that the unique episodic patterns of gonadotrophins are more important than mean blood concentrations of these hormones in establishing and maintaining the polycystic ovary syndrome.

Animals↗

PubMed1986

Development of the polycystic ovarian condition (PCO) in the estradiol valerate-treated rat.

A wide range of experimental manipulations results in an anovulatory polycystic ovarian (PCO) condition in the rat. Although PCO has been studied in a number of these models, research has centered on the condition after it is well established rather than as it develops. Consequently, it is still not clear exactly what follicular cysts are or how and why they form. Therefore, we studied the development of PCO in rats treated with estradiol-valerate (EV). In this model, definitive cysts were present 8-9 wk after a single injection of EV. Animals were killed at 5, 11, 16, 21, 28 and 56 days after EV treatment. Serum was assayed for luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Ovaries were weighed and prepared for histologic examination. The ovaries were serially sectioned such that the number and size distribution of normal and atretic follicles could be assessed quantitatively. Oviducts were examined for the presence of ova. Immediately after EV treatment, ovulatory cycles ceased; by 16-20 days posttreatment, all animals exhibited persistent vaginal cornification. Basal concentrations of serum LH and FSH fell to a nadir at 11 days posttreatment, after which both gonadotropins exhibited a trend toward recovery. Within the first 28 days after treatment, ovarian weights declined significantly as did the total number of healthy follicles. Atretic follicles of all sizes were particularly numerous at 16 days. By 28 days, the decline in the number of healthy follicles reached a plateau. Numerous atretic, large secondary follicles were particularly prominent on the background of the decreasing number of normal follicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

The fine structural organization of tyrosine hydroxylase immunoreactive neurons in rat arcuate nucleus.

The fine structure of the tyrosine hydroxylase (TH) immunoreactive neurons of the hypothalamic arcuate nucleus was examined by means of immunocytochemistry [peroxidase-antiperoxidase (PAP) method], utilizing an antibody against TH. Immunolabeled axon terminals were observed infrequently and were located predominantly in the lateral region, whereas numerous labeled perikarya and dendrites were found throughout the nucleus. The labeled terminals, containing primarily clear and occasionally dense core vesicles, were never observed in synaptic contact. On the other hand, unlabeled axon terminals were frequently seen synapsing on labeled dendrites. In addition, the labeled dendrites were often seen in direct apposition to other neuronal elements such as both labeled and unlabeled perikarya. In contrast, unlabeled dendrites were never seen apposed to labeled perikarya. Labeled dendrites also occurred in direct contact with one another and with unlabeled dendrites. Moreover, numerous labeled dendrites were encountered along tanycytic processes. Dendrites engaged in tanycytic appositions were occasionally partially encompassed by thin sheaths emanating from the tanycytic process. The extensive contact made by the labeled dendritic profiles on both labeled perikarya and dendrites suggests that tubero-infundibular dopaminergic (TIDA) cells may communicate with each other by means of dendritic release of dopamine. The presence of appositions between labeled dendrites and both unlabeled perikarya and dendrites suggests that the TIDA system also influences other neuronal populations through its dendrites. Finally, the dendrotanycytic relationship suggests that the TIDA system may play some role in the regulation of tanycytic function.

Animals↗

PubMed1985

Gonadal steroid-induced modification of opiate binding sites in anterior hypothalamus of female rats.

It has been previously shown that treatment with estradiol valerate (EV) or 17 beta-estradiol produces enhanced tritiated naloxone binding in the hypothalamus of the rat. In the present study, the following questions were addressed: Does this effect occur in the preoptic and anterior hypothalamic areas (regions associated with the cyclic gonadotropin surge)? Is chronic estradiol (E2) exposure essential in producing a long-term elevation in opiate binding? Is the effect steroid specific? The results indicated that chronic, but not acute, exposure to estradiol induces and maintains enhanced binding in the anterior hypothalamus. E2 exposure was most effective in this regard, testosterone (T) significantly less so, and 5 alpha-dihydrotestosterone (DHT) caused no elevation in binding above castrate control levels. Furthermore, both T and DHT significantly inhibited the estradiol effect. In addition, intact animals showed significantly less binding than their ovariectomized counterparts, suggesting that the ovary normally produces a factor that suppresses opiate binding. Enhancement of anterior hypothalamic opiate binding is therefore dependent on chronic exposure to E2, and the marginal effects of T are probably due to in situ aromatization. E2 enhancement of opiate binding may be causal in producing the hypothalamic aberration that results in the EV-induced polycystic ovarian condition.

Animals↗

PubMed1985

Unilateral ovariectomy restores ovulatory cyclicity in rats with a polycystic ovarian condition.

An acyclic polycystic ovarian condition can be induced in adult rats with a single injection of estradiol valerate (EV). The ovaries are small and contain multiple cystic follicles and no new corpora lutea. In the early stages of the condition, both basal plasma luteinizing hormone (LH) and LH responses to luteinizing hormone-releasing hormone (LHRH) are attenuated. Plasma androgens are indistinguishable from normal controls. The present study examines the effect of unilateral ovariectomy (ULO) on this condition. Removal of one cystic ovary results in almost immediate resumption of vaginal cyclicity that persists for at least 3 wk. At 1 or 3 wk after ULO the remaining ovary contains fresh corpora lutea, appears histologically normal, and is significantly heavier than the cystic ovary removed at ULO, indicative of compensatory hypertrophy. Despite the resumption of apparently normal cyclic function, basal plasma LH concentrations and LH responses to LHRH are not significantly better than those in intact animals with polycystic ovaries. Thus, the previously polycystic ovary is fully capable of normal ovulatory function despite obvious impairments in the hypothalamo-pituitary axis. Since ovulatory function resumes on a background of continued poor pituitary responsiveness, the primary defect, which ULO corrects, is probably at the hypothalamic level. Finally, the cystic ovary clearly contributes to the hypothalamic aberration to which it subsequently responds.

Animals↗

PubMed1984

Polycystic ovarian condition in estradiol valerate-treated rats: spontaneous changes in characteristic endocrine features.

A chronic anovulatory polycystic ovarian (PCO) condition can be induced in rats with estradiol valerate (EV). We have previously shown that the early stages (8-10 wk after EV treatment) of the condition are characterized by low basal plasma luteinizing hormone (LH) and estradiol concentrations, as well as poor LH responsiveness to LH-releasing hormone (LHRH). These observations suggested that alterations in pituitary LH secretory activity may be involved in induction and maintenance of the PCO condition. In order to examine this possibility we have measured basal plasma LH and follicle-stimulating hormone (FSH) concentrations at various times (6, 15, 20 and 22 wk) after treatment with EV. AT 22 wk animals were subjected to a double LHRH pulse or equivalent treatment with saline. Basal plasma LH concentrations in EV-treated animals doubled between 6 and 22 wk. Despite this sharp increase, basal plasma LH concentrations at 22 wk were still significantly lower in EV-treated animals compared to proestrous controls. Basal FSH in EV-treated animals, remained in the proestrous range throughout the 22-wk period. Pituitary FSH and LH secretions in response to the LHRH challenge were significantly greater in EV-treated animals compared to proestrous controls. Plasma estradiol was significantly greater at 22 wk post-EV treatment than at 9 wk and this difference was reflected in the histology of the endometrium. These results indicate that a PCO condition is compatible with radical alterations in basal LH, and responsiveness to LHRH. Thus, aberrations in the ability to secrete LH do not appear to be causal in maintaining the condition.

Animals↗

PubMed1983

Prolonged estrogen treatment induces changes in opiate, benzodiazepine and beta-adrenergic binding sites in female rat hypothalamus.

Exposure of the rat brain to estradiol is known to modify certain neurotransmitter binding sites. We have now examined the influence of long-term (3 months) treatment with this steroid. Opiate and benzodiazepine receptors are both elevated in hypothalamus but not in amygdala or cerebral cortex. In contrast, the affinity, but not maximum binding, of hypothalamic beta-adrenergic sites is reduced 5-fold. Our results confirm and extend previous reports that hypothalamic neurotransmitter binding sites are particularly sensitive to estrogen feedback.

Amygdala↗

PubMed1983

Pituitary and ovarian responses to luteinizing hormone releasing hormone in a rat with polycystic ovaries.

Female rats injected with a single dose of 2 mg estradiol valerate (EV) develop anovulatory acyclicity characterized by persistent vaginal cornification and the formation of multiple large cystic follicles on the ovaries. In order to determine if these effects of EV are accompanied by changes in ovarian and/or pituitary function, the following studies were conducted. Ovarian androgen production was determined by the measurement at 4, 5 and 6 weeks after EV treatment of circulating dehydroepiandrosterone, androstenedione and testosterone. The capacity of the polycystic ovary to ovulate in response to luteinizing hormone releasing hormone (LHRH) stimulus was assessed. Ovarian histology was examined at the termination of the study (9 weeks after EV treatment). Pituitary function was assessed 9 weeks after the EV treatment by examining the acute changes in plasma luteinizing hormone (LH) concentration in response to a double pulse of LHRH. Plasma concentrations of the androgens were unchanged over the 3-week sampling period and were similar to those found in sesame-oil-treated normal cycling control rats. The ovaries from EV-treated animals were smaller than those of controls and the cystic follicles exhibited marked thecal hypertrophy and attenuation of the granulosa cell layer. The basal plasma LH concentration at 9 weeks after EV treatment were significantly lower than in proestrus controls and plasma concentrations of LH elicited by LHRH pulses was significantly lower than in controls. The relative increase in plasma LH following the LHRH stimulus was, however, greater in the EV-treated animals than in controls. In spite of the diminished LH surge elicited in response to LHRH, the EV-treated animals ovulated as indicated by the presence of fresh corpora lutea on the ovaries. These results indicate that androgens are not responsible for the polycystic ovarian condition in this system and that the polycystic ovary is capable of ovulatory function when appropriately stimulated.

Animals↗

PubMed1982

Response of tanycytes to aging in the median eminence of the rat.

Age-related changes in tanycytes of the median eminence were observed at both the light and electron microscopic level in male and female rats at ages 4 weeks to 14 months. The most obvious changes involved a marked progressive increase in number and size of droplets identified histochemically as neutral lipid and the development of complex degenerate bodies in the perivascular contact zone. These degenerate bodies consisted of large multiple complexes of myelin figures containing intercalated channels and pools of electron-dense material. They often occurred interspersed among large lipid droplets. The degenerate bodies (myelin figure complexes) and associated lipid droplets occupied much of the contact zone in the older animals. Evidence of axonal degeneration and tanycytic phagocytosis of deteriorating neural elements was also present. These age-related changes occurred independent of sex and were not affected by gonadectomy. This tanycyte response to aging in the median eminence is very similar to the response of neurohypophysial pituicytes to axonal degeneration, suggesting a phagocytic glial role for tanycytes.

Aging↗