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Home Care Services↗
Biomedical subjects
N R Adams
Publications and source records attributed to N R Adams.
Detection of the effects of phytoestrogens on sheep and cattle.
Cows and ewes fed estrogenic forage may suffer impaired ovarian function, often accompanied by reduced conception rates and increased embryonic loss. Males are relatively unaffected, but the mammary glands in females and castrate males may undergo hypertrophy of the duct epithelium, accompanied by secretion of clear or milky fluid. In cows, clinical signs resemble those associated with cystic ovaries. The infertility is temporary, normally resolving within 1 mo after removal from the estrogenic feed. However, ewes exposed to estrogen for prolonged periods may suffer a second form of infertility that is permanent, caused by developmental actions of estrogen during adult life. The cervix becomes defeminized and loses its ability to store spermatozoa, so conception rates are reduced, although ovarian function remains normal. Importantly, both temporary and permanent infertility in ewes often occur without observable signs and can be detected only by measurement of phytoestrogens in the diet, or measurement of their effects on the animal. Low background concentrations of dietary phytoestrogens are suggested to play an important role in prevention of disease in humans and laboratory rats, but subclinical effects of phytoestrogens in cattle have not yet been described. Effects of low concentrations of phytoestrogens on reproductive function in ruminants are likely to receive increasing attention.
Animals↗
Organizational and activational effects of phytoestrogens on the reproductive tract of the ewe.
Ewes exposed to phytoestrogens may display two forms of infertility, categorized as temporary or permanent. Temporary infertility results from actions of estrogen that are similar to the activational effects of estrogen in most species of mammals. The permanent infertility results from changes to the cervix which are analogous to the organizational effects of estrogen reported in other species treated during organogenesis. However, in the ewe these effects may be produced after organogenesis by prolonged treatment during adult life. It has recently become apparent that the level of nutrition and metabolic hormones influence the degree of uterus-like histological change in the cervix produced by prolonged treatment with estrogen. It is hypothesized that, under some nutritional conditions, the hormonal milieu in adult ewes may simulate hormonal patterns that are normally experienced by fetal lambs in utero, thereby allowing the cervix of the adult ewe to give an organizational response to estrogen.
Animals↗
Effect of diet on the clearance of estradiol-17 beta in the ewe.
The twinning rate of ewes is poorly related to plasma concentrations of gonadotropins. In this study, we tested an alternative hypothesis for the control of twinning rate, by testing whether nutritional treatment sufficient to affect twinning could alter estrogen metabolism, with a particular focus on the enterohepatic recirculation. Groups of 5 ovariectomized ewes were fed either above maintenance (supplemented) or below maintenance (restricted). The metabolism of estradiol-17 beta was examined by following the fate of a single i.v. injection of 1.45 micrograms [3H]estradiol-17 beta. In both groups, 74% of the radioactivity was recovered from the feces within 10 days, predominantly as free estradiol-17 alpha, but excretion was slower in the nutritionally restricted ewes. A further 6% of injected radioactivity was excreted in the urine, mostly within 24 h, with no effect of dietary group. Radioactivity in plasma was characterized by ion-exchange chromatography and HPLC. Within 30 min of injection, the main circulating radioactive compound was estradiol-17 alpha sulfate. This remained at a greater concentration than free steroid for the next 48 h, and was greater after 16 h (p < 0.05) in plasma of nutritionally restricted ewes than in the supplemented group. At 0.5 and 2 h, the free steroid was almost entirely estradiol-17 beta, but a polar compound, which appeared by 4 h and probably arose by recirculation from the intestine, remained the major unconjugated metabolite in plasma for the next 24 h. Plasma concentrations of this compound were higher (p < 0.05) in the restricted ewes than in the supplemented ewes during this period.(ABSTRACT TRUNCATED AT 250 WORDS)
Animal Nutritional Physiological Phenomena↗
A model for follicle selection and the determination of ovulation rate in the ewe.
A model for folliculogenesis is proposed that is based as far as possible on a knowledge of physiological, rather than anatomical, changes taking place during follicle development. The model is therefore functional, rather than descriptive, and consists of five classes of follicles that have been defined by their dependency and sensitivity to gonadotrophins. These classes are: primordial, committed, gonadotrophin-responsive, gonadotrophin-dependent and ovulatory. The model is an attempt to encourage discussion and to promote the integration of morphological models of folliculogenesis with recent advances in the molecular endocrinology of the ovarian follicle. Two hypotheses for the mechanisms that determine ovulation rate are developed in light of the model. In the first, multiple ovulation results when the viability of gonadotropin-dependent follicles is enhanced. In the second, multiple ovulation is caused by increasing the number of gonadotrophin-responsive follicles available for further development; this results from the increasing rate of folliculogenesis and the throughput of follicles. The final section of this paper examines how these two hypothetical mechanisms, which are not mutually exclusive, appear to account for most of the known genetical and environmental effects on ovulation rate of sheep. In particular, the effects of nutrition, genotype, exogenous gonadotrophins, immunity to both oestrogens and androgens, and immunity to inhibin are discussed.
Animal Nutritional Physiological Phenomena↗
Frequent blood sampling changes the plasma concentration of LH and FSH and the ovulation rate in Merino ewes.
During earlier studies we observed that ewes housed and sampled intensively to measure pulses of LH in plasma had a higher ovulation rate than similar ewes housed outside. In Expt 1, we pursued this observation by testing whether the increase was due to effects of housing or collection of blood samples. Ewes sampled at intervals of 4 h for 2 days before progestagen sponge removal and 2 days after sponge removal, and every 20 min for 12 h the day before sponge removal and every 10 min for 4 h on the day of sponge removal had a higher ovulation rate than ewes that were not sampled (1.72 versus 1.41; P < 0.05). The ovulation rate of the ewes housed indoors but not sampled was similar to that of ewes that remained in the paddock (1.43). In Expt 2, we studied the effects of blood sampling in three groups of 20 ewes sampled every 20 min for different periods of 24 h. Ewes from all three groups were sampled the day before sponge removal (day -1) and, in addition, one group of ewes was sampled for the previous 48 h (i.e. days -3 to -1) and another group was sampled on day -8. The frequency of LH pulses was lower (P < 0.05) in ewes sampled for the first time on day -1 compared with the frequency of LH pulses in groups also sampled earlier in the cycle (day -8 or days -3 and -2). In ewes sampled on days -3 to -1, the frequency of LH pulses was low for the first 24 h and then increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Improved feed intake and body weight change in sheep treated with dexamethasone at entry into pens or feedlots.
Treatment with the synthetic glucocorticoid dexamethasone sodium phosphate increased the feed intake of sheep within 24 h. A single treatment with the longer-acting compound dexamethasone trimethylacetate had a slower effect, but resulted in improved feed intake and enhanced body weight gain over a period of 7 to 14 days. Treatment was effective in sheep housed individually and in sheep penned in groups. The improvement in body weight gain disappeared 15 to 20 days after a single treatment, but in most studies treated sheep had less variability in weight change than untreated sheep at this time. A statistically significant increase in body weight gain was observed in 8 of 11 trials; in the other 3 trials, it appeared that the feed intake of the untreated sheep was already maximal. Wethers treated with dexamethasone trimethylacetate on arrival at an assembly point for live export arrived in the Middle East 23 days later with a lower mean weight loss, partly because fewer sheep lost a significant amount of weight.
Animals↗
Permanent infertility in ewes exposed to plant oestrogens.
In Australia, more than 1 million ewes have permanently damaged reproductive tracts because they have been grazed on oestrogenic pasture. These effects occur in the absence of classical clinical "clover disease". The lesions result from an "organisational" action of oestrogen, causing a mild sexual transdifferentiation to occur in ewes during adult life, with the main lesion being found in the cervix. Diagnosis of the problem depends primarily on detection of the pathological changes, rather than history or clinical signs. On average, affected flocks have around a 10% increase in non-pregnant ewes, but most farmers can achieve an acceptable lambing rate by increasing their management and feed inputs to produce more twin lambs. Agronomic approaches have been used in the past to combat "clover disease", but further progress with the present problem may depend on the development of animal-based solutions.
Animals↗
Immunization of ovariectomized ewes against progesterone, oestrogen or cortisol to detect effects of adrenal steroids on reproduction.
Ovariectomized ewes were immunized against cortisol, oestrogen or progesterone to determine whether steroids of non-ovarian origin occur in sufficient amounts to influence the reproductive system. Ewes immunized against oestrogen (oestrone + oestradiol) had smaller uteri (P less than 0.05) and a lower concentration of oestradiol in uterine tissue (P less than 0.05), while the adrenal gland was heavier (P less than 0.05). In the peripheral plasma of immunized ewes, the concentration of FSH, but not LH, was increased (P less than 0.05). Ewes immunized against cortisol also had smaller uteri (P less than 0.05) and heavier adrenal glands (P less than 0.05), but gonadotrophins and the concentration of oestradiol in the uterus were unaffected. Immunization against progesterone, or injection with synthetic glucocorticoids, did not affect any of the characteristics measured. We conclude that the adrenal gland of the ewes produced sufficient oestrogen or aromatizable androgen to have significant effects on the reproductive system. In contrast, adrenal production of progesterone did not produce detectable biological effects. Immunization against cortisol did affect the reproductive system, but the mechanism of this action could not be determined.
Adrenal Glands↗
LH, FSH and ovulation rate in ewes treated with exogenous oestradiol.
In two experiments, mature Merino ewes were fitted with subcutaneous implants containing oestradiol-17 beta or empty implants (control). Peripheral concentrations of LH and FSH were measured during luteal and follicular phases, which were synchronized by means of intravaginal progestagen-impregnated sponges. The ovulation rates of the ewes were determined by laparoscopy, 1 week after luteolysis. In Exp. 1, small implants (3 mm) decreased the LH pulse frequency before luteolysis. In the ewes with oestradiol implants, the amplitude of the preovulatory surge of LH was reduced and the onsets of the LH and FSH surges were delayed. There was no effect of oestradiol on LH baseline, LH pulse amplitude or in the concentration of FSH during the luteal or follicular phases. In Exp. 2, larger implants (10 mm) were inserted for the luteal, follicular, or luteal + follicular phases. The control ewes had empty implants. In the ewes with oestradiol implants, LH pulse frequencies were decreased during the luteal phase. This decrease persisted throughout the follicular phase, even though the oestradiol implants had been removed. There were no differences in the other measures of LH or FSH in the luteal or follicular phases. Ovulation rates were not affected by oestradiol treatment in either experiment, indicating that the regulation of LH pulse frequency is not a critical factor in the determination of ovulation rate in ewes. This was supported by retrospective analysis of the gonadotrophin profiles of single and twin-ovulating ewes, in which all measures of LH were similar between the two groups. However, twin-bearing ewes had slightly higher circulating concentrations of FSH during the luteal phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of oestradiol implants on the ovulation rate of the ewe.
In a series of 5 experiments, ewes were treated with implants releasing oestradiol-17 beta and the effects on ovulation rate were observed. Large doses of oestradiol-17 beta (greater than 20 micrograms/day) produced anovulation while smaller amounts only reduced the proportion of twin ovulations. Amounts of exogenous oestradiol comparable to ovarian production rate in the luteal phase (less than 1 microgram/day) produced a significant (P less than 0.01) suppression in ovulation rate. Treatment during the follicular phase of the oestrous cycle was most effective, but treatment during the luteal phase alone also appeared to suppress ovulation rate. Furthermore, in 2 of 3 experiments ewes treated with low amounts of oestradiol during the first half of the luteal phase were less likely to have multiple ovulations at the subsequent oestrous period. The results support the hypothesis that oestrogen is involved in the physiological control of ovulation rate in the ewe, but this action is probably not restricted to the assertion of dominance by a maturing follicle during the follicular phase.
Animals↗
Persistent infertility in ewes after prolonged exposure to oestradiol-17 beta.
Merino ewes were treated with implants which released 300 micrograms oestradiol-17 beta per day or 5 mg progesterone per day, or both, for 9 months (Months 1-9), and after an 11-month intermission were treated again for 6 months (Months 20-26). Ewes were run with rams at Months 16, 28 and 40. Fertility was not affected by the first exposure period, but the second exposure to oestradiol reduced the fertility of ewes at both subsequent mating periods. Affected ewes returned to service more frequently (P less than 0.01) and were less likely to conceive (P less than 0.05). After mating, a normal population of spermatozoa was established in the caudal cervix, but transport through the cervix was impaired in affected ewes and there were fewer spermatozoa (P less than 0.01) in the cranial cervix. In affected ewes, the spinnbarkeit of cervical mucus was reduced (P less than 0.05), and the histological appearance of the cervix changed, looking like that of the uterus. Treatment with progesterone did not affect fertility, cervical mucus or sperm transport, but diminished the histological abnormalities produced by oestradiol (P less than 0.05). These results show that oestradiol-17 beta given after puberty can cause the same kind of permanent sexual transdifferentiation that is produced by the oestrogenic isoflavones in ewes with clover disease. The results suggest that this change may require more than a single exposure to oestrogen.
Animals↗
Adrenal glands alter the concentration of oestradiol-17 beta and its receptor in the uterus of ovariectomized ewes.
To investigate the effects of adrenal hormones on oestrogen activity in the uterus, ovariectomized ewes were either adrenalectomized, administered glucocorticoid-like preparations (CORT), or remained as controls. The adrenalectomized ewes were maintained with a corticoid-replacement therapy and monitored daily for plasma glucose and Na+/K+ concentrations. Blood samples were collected from all ewes at 15-min intervals for 4 h and assayed for LH and FSH. The adrenalectomized ewes were killed 9 days after adrenalectomy, while the CORT ewes were killed after 3 weeks of drug therapy. The control ewes were killed simultaneously with the CORT ewes. Uterine tissues were homogenized and the numbers of oestradiol receptors and tissue concentrations of oestradiol-17 beta were measured. The adrenalectomized ewes had significantly higher concentrations of cytosolic oestrogen receptors in the uterus than did the control ewes, which had significantly higher concentrations than the CORT ewes (0.95 +/- 0.06, 0.76 +/- 0.02 and 0.60 +/- 0.02 (S.E.M.) mumol/kg protein respectively). The concentrations of oestradiol-17 beta measured in uterine tissues were significantly lower in adrenalectomized and CORT ewes than in control ewes (37.4 +/- 5.5, 61.7 +/- 25.7 and 135.5 +/- 12.8 pmol/kg respectively). There were no significant differences between any groups in the peripheral concentrations of LH or FSH. These results indicate that the adrenal gland affects the concentrations of both oestrogen and its receptor in the uterus of ovariectomized ewes, probably by different mechanisms. These effects are not mediated by gonadotrophins.
Adrenal Glands↗
Cytosol type II sites in the rat uterus: interaction with an endogenous ligand.
Previous studies from our laboratory demonstrated that normal, but not malignant tissues, contain a ligand which competes for [3H]estradiol binding to nuclear type II sites in the rat uterus. Since elevated nuclear levels of type II sites are correlated with estrogen stimulation of uterine growth and DNA synthesis, we believe this ligand may regulate cell growth. The present studies show that the ligand for nuclear type II sites also interacts with type II sites in uterine cytosol. This was demonstrated by dilution experiments which show that greater quantities of type II sites are measured in dilute (10 mg/ml) than in concentrated (40 mg/ml) uterine cytosol. Furthermore, stripping of uterine cytosol with 1% dextrancoated charcoal, or pre-binding cytosol type II sites to hydroxylapetite (HAP) prior to binding analysis, removed the ligand from these preparations such that high levels of type II sites were measured. Following charcoal stripping, cytosol type II sites demonstrated good specificity for estrogenic hormones but not progesterone, corticosterone, or the triphenylethylene anti-estrogen, nafoxidine. Since the level of type II sites in the cytosol always preceded and exceeded the level of this site measured in uterine nuclei at all times following estrogen treatment (0-96 h), we believe cytosol type II sites may function as an type II-ligand binding protein (LBP) which regulates the availability of the ligand for interaction with nuclear type II sites. This is consistent with our observation that type II sites are not depleted from uterine cytosol by estrogen treatment and nuclear type II sites are very tightly associated with the nuclear matrix.
Animals↗
Measurement of estrogen receptors in the ovariectomized ewe is affected by body condition and secondary binding sites.
Two studies were carried out to examine possible causes of the variability that occurs in studies on estrogen receptors in sheep. In the first study, the concentration of estrogen receptors in the uterus of a group of 16 ovariectomized ewes was inversely related to their live weight (r = -0.52, p less than 0.05). A second study examined 8 ovariectomized controls and 7 ewes that were permanently infertile after prolonged exposure to estrogenic clover pasture. The concentration of estrogen receptors in the pituitary of these ewes was inversely related to a measure of body fatness (r = -0.67, p less than 0.05), and there were no differences between control and clover-affected ewes. In addition to the classical estrogen receptor with a dissociation constant of 0.03 X 10(-9) mole/L, there were secondary binding sites with dissociation constants of about 0.9 X 10(-9) mole/L in the pituitary. The amount of this binding varied among sheep and appeared to increase as the cytosol was diluted. It is suggested that a failure to distinguish the presence of these sites may have led to apparent differences between experimental groups in the amount of affinity of receptors in previous studies. The effect of body condition on the number of cytosolic receptors may also have confounded previous studies.
Adipose Tissue↗
The effect of zeranol and testosterone on Merino wethers exposed to highly oestrogenic subterranean clover pasture.
Groups of Merino wethers treated with 2 doses of zeranol (6 mg and 12 mg), or testosterone cyclopentyl propionate (150 mg) and untreated controls were grazed at 2 sites, one an oestrogenic subterranean clover (Trifolium subterraneum) pasture and the other a low oestrogen medic (Medicago truncatula) pasture. The influence of oestrogenic subterranean clover on these treatments was assessed by measuring changes in teat length, bulbourethral gland weight and pathology, bodyweight, carcase weight, dressing percentage and greasy and clean fleece weights. Teat lengths were increased by all treatments except 6 mg of zeranol where increases were not significant, and although increased by exposure to oestrogenic pasture this effect were not additive. Bulbourethral gland weights were increased by both of the zeranol treatments and by oestrogenic pasture, and these effects appeared to be additive. Differences observed histologically indicated that testosterone protected whereas zeranol exacerbated the influence of oestrogen. The bodyweights of all treated groups were heavier than the controls, but carcase weights were not significantly different. However an effect was seen in the group given the 6 mg dose of zeranol on the low oestrogen site, where the dressing percentage was significantly lower than in the control and testosterone treated groups. Differences in greasy and clean fleece weights were not significant except that the washing yield of the testosterone-treated group was significantly lower at the low oestrogen site.
Animal Feed↗
Measurement of histological changes in the cervix of ewes after prolonged exposure to oestrogenic clover or oestradiol-17 beta.
Morphometric methods were used to measure abnormalities in histological architecture of the endocervix in ewes with infertility after prolonged exposure to oestrogenic clover pastures. Similar measurements were made on the cervix of ewes exposed to oestradiol-17 beta for 6 months. In both cases the changes in histological appearance were essentially similar, and were most easily measured by counting the number of cervical crypts. Ewes treated with either phyto-oestrogens or oestradiol also had significantly wider cervical folds, greater areas of lamina propria, and more cervical glands. The results provide a basis for measuring the severity of permanent oestrogenic change in different flocks or after different experimental treatments.
Animal Feed↗
Changed control of cervical secretion from infertile ewes previously exposed to oestrogenic clover pasture.
The amount of cervical mucus recovered from control ovariectomized ewes increased with increasing doses of oestradiol benzoate (OB), while the maximum Spinnbarkeit of mucus occurred at an intermediate dose of OB. Neither the amount nor the Spinnbarkeit of mucus varied with the dose of OB in ewes with permanent infertility caused by grazing oestrogenic pasture (clover-affected ewes). Furthermore, the increase in Spinnbarkeit of cervical mucus seen in normal ewes treated over a 3-day period with OB or with implants containing oestradiol did not occur in affected ewes. In control ewes treated repeatedly with OB, production of mucus declined within 5 days, but no change in secretion was detectable in clover-affected ewes. Therefore, neither the amount nor the duration of oestrogenic stimulation affected the cervical mucus in ewes with clover disease. Affected ewes produced more mucus than did controls in the absence of oestrogenic stimulation. It is concluded that the relatively normal volume of mucus in affected ewes treated with OB results largely from autonomous production. The Spinnbarkeit does not increase in these ewes because the ability of the cervix to respond to oestrogen is impaired.
Animals↗