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D. R. LINDSAY and R. J. SCARAMUZZI

SUMMARY

Fourteen synthetic steroids and androstenedione were examined in ovariectomized ewes for oestrogenic activity when administered alone and with oestradiol benzoate by intramuscular injection. None of the compounds investigated was active when administered alone, as assessed by the vaginal smear assay, and only androstenedione produced a behavioural response. Androstenedione had a MED of 8·8 mg. but was less active when administered intravenously. Several steroids acted as anti-oestrogens when injected with oestradiol benzoate. Eight steroids inhibited the behavioural response and four the vaginal response. An additive response was found with androstenedione for behavioural response and with 17β-ethyl-17-hydroxy-19-nor-4-androsten-3-one (SC-5914) for vaginal response.

Vaginal and behavioural responses were not necessarily related, and responses obtained in the ewe to particular steroids were not identical with those obtained in laboratory animals by other workers using similar tests.

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I. C. FLETCHER and D. R. LINDSAY

SUMMARY

The effects of dose of oestrogen and season on the expression of oestrous behaviour was studied in 60 spayed and 16 intact ewes.

In progesterone-primed spayed ewes the incidence and duration of oestrous behaviour increased and the interval between injection of oestrogen, and onset of oestrous behaviour decreased as the dose of oestrogen was increased. The linear regression of duration of oestrus on log dose of injected oestrogen provided the most precise measure of the effect of changing dose level of oestrogen on oestrous behaviour.

The sensitivity of spayed ewes to constant levels of oestrogen increased to a maximum near the middle of the breeding season and then declined to a minimum during the non-breeding season. In progesterone-synchronized intact ewes the interval between the end of progesterone treatment and onset of oestrus was at a minimum, and duration of oestrus at a maximum, near the middle of the breeding season. By bioassay it was estimated that endogenous oestrogen production was greater near the middle of the breeding season than at either the beginning or end.

It is concluded that seasonal variation in the expression of oestrous behaviour in intact ewes is controlled by changes in both the production of endogenous oestrogen and the sensitivity of ewes to it.

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R. J. SCARAMUZZI, D. R. LINDSAY and J. N. SHELTON

SUMMARY

The effects of repeated injections of oestradiol benzoate (ODB) on the behavioural oestrous responses of ovariectomized ewes were studied using a pool of 144 animals. Oestradiol benzoate (15·6–421·2 μg) injected at intervals of 4 or 6 days produced a gradual decrease in the number of ewes showing induced oestrous behaviour. The response eventually fell below 10% at which time the ewes were defined to be refractory to oestrogenic stimulation of behavioural oestrus. When a continuous variable was used as a measure of response an immediate effect was observed; after the second injection of ODB the duration of oestrous behaviour decreased while the time to onset of oestrous behaviour showed a corresponding increase when compared with the first injection. However the proportion of ewes responding remained unaltered, indicating that continuous variables are a more sensitive measure of refractoriness. Treatment of refractory ewes with the progestagens progesterone, SC-9880 or Nilevar restored normal oestrous behaviour. These results are interpreted to mean that oestrogens (15–400 μg) act to increase thresholds for subsequent oestrogen stimulation of behavioural oestrus, while progestagens (1–10 mg) act to decrease this threshold.

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R. J. SCARAMUZZI, D. R. LINDSAY and J. N. SHELTON

Most investigators studying oestrous behaviour in sheep use the incidence of such behaviour as a quantal response, an animal being scored as showing or as not showing behavioural oestrus. This procedure has been useful in studying the endocrinology of oestrus in this species but has not clarified the effects of the ovarian hormones on certain quantitative aspects of oestrus such as its duration. In only one study (Lindsay, 1966) have quantitative measurements of the duration of oestrous behaviour in the ovariectomized ewe been recorded and these results suggest that the length of the induced oestrus might be related to the dose of oestradiol benzoate.

Fifty Border Leicester × Merino ewes, ovariectomized 2 years previously, were randomly divided into five groups. The ewes were then injected with 20 mg progesterone every second day for 10 days, followed by a final injection of 10 mg progesterone 2 days later. Forty-eight hours after

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I. C. FLETCHER, A. J. ALLISON and D. R. LINDSAY

Seasonal variation in the incidence and duration of behavioural oestrus in spayed ewes treated with progesterone and oestrogen has been attributed to changes in the sensitivity of ewes to oestrogen (Reardon & Robinson, 1961; Fletcher & Lindsay, 1971). This interpretation is open to question, however, in view of suggestions from Lamond & Bindon (1962) and Lamond (1964) that intact ewes showed seasonal changes in sensitivity to progesterone. The investigation reported here was designed to determine whether changes in sensitivity to progesterone contributed to seasonal variation in the expression of oestrous behaviour in spayed ewes.

The experiment was of factorial design with three different doses of progesterone for priming, two breeds of ewe and two seasons of observation. Sixty spayed Merino and 60 spayed Border Leicester × Merino cross-bred ewes were each allotted at random to three groups of 20. They were injected daily with 5, 10 or 20 mg progesterone

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T R Arnett, R Lindsay, J M Kilb, B S Moonga, M Spowage and D W Dempster

Abstract

We investigated the actions of the trans- and cis-isomers of tamoxifen on the function of neonatal rat osteoclasts in vitro. Both compounds inhibited resorption pit formation by osteoclast-containing mixed bone cell cultures incubated for 24 h on cortical bone slices. Cell counts revealed that the inhibition was closely related to a cytotoxic effect, to which osteoclasts appeared particularly sensitive. Partial inhibition of resorption was seen in the presence of 2 μm trans-tamoxifen, whereas complete abolition of resorption and osteoclast viability occurred with 10 μm trans-tamoxifen; survival of mononuclear cells was unimpaired at either concentration. Cis-tamoxifen appeared to be slightly more toxic, with significant inhibitions of osteoclast viability and thus resorption pit formation at a concentration of 2 μm, and also of mononuclear cell numbers at 10 μm. Time-lapse video observations indicated that osteoclast death occurred rapidly (within 2–3 h) following exposure to 10 μm of either trans-tamoxifen or cis-tamoxifen. The morphological appearance of the dying cells was consistent with apoptosis. These results may help to explain the anti-resorptive action of tamoxifen seen in vivo in rats and humans. In contrast, oestradiol-17β consistently exerted no significant effects on resorption pit formation by rat osteoclasts over 24 h, even at grossly supraphysiological concentrations (up to 10 μm).

Journal of Endocrinology (1996) 149, 503–508

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A Iida-Klein, S Shou Lu, R Kapadia, M Burkhart, A Moreno, D W Dempster and R Lindsay

Parathyroid hormone (PTH) stimulates bone resorption as well as bone formation in vivo and in organ culture. The catabolic actions of PTH have been recognized in patients with hyperparathyroidism, or with acute infusion of the N-terminal 1–34 fragment of human PTH (hPTH1–34). Whereas the anabolic actions of daily injection with PTH have been well studied in both humans and mice, the catabolic actions of PTH on murine bone remain to be defined. To do this we sought to create a model with short-term, sustained hyperparathyroidism using osmotic infusion pumps. We treated 10-week-old female C57BL/J6 mice with continuous infusion of hPTH1–34 (8.1 pmol/0.25 μl per h, equivalent to 40 μg/kg per day) or vehicle for 2 weeks, using Alzet osmotic pumps. Bone mineral density (BMD), serum total calcium, hPTH1–34, mouse intact PTH (mPTH1–84), osteocalcin and mouse tartrate-resistant acid phosphatase (mTRAP) activity, and microarchitectural variables of the distal femur were measured. Separately, we compared the effects of intermittent daily injection of hPTH1–34 (40 μg/kg per day) with continuous infusion of hPTH1–34 on BMD and bone markers. Exogenous hPTH1–34 was detected only in the PTH-infused mice. Both intermittent and continuous treatment with hPTH1–34 markedly suppressed endogenous mPTH1–84, but only the latter induced hypercalcemia. Daily PTH injection significantly increased both serum osteocalcin and mTRAP, while continuous PTH infusion showed a strong trend to stimulate mTRAP, with a slight but non-significant increase in osteocalcin. There were significant differences in BMD at all sites between animals treated with the same daily dose of intermittent and continuous hPTH1–34. Microcomputed tomography (μCT) analysis of the distal femurs revealed that hPTH1–34 infusion significantly decreased trabecular connectivity density (P<0.05). Thus, the murine bone response to continuous PTH infusion was quite different from that seen with daily PTH injection. Short-term infusion of hPTH1–34 appears to be a good model to study the mechanisms underlying the catabolic action of PTH in mice.