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E. PEREL and H. R. LINDNER

Summary.

The phyto-oestrogens coumestrol (7,12-dihydroxycoumestan) and genistein (5,7,4′-trihydroxyisoflavone) induced uterine growth in ovariectomized rats, but failed to induce ovum implantation in mated ovariectomized, gestagen-maintained rats and in intact lactating rats when given at dose levels effective in uterine weight assays. Oestradiol17β, under similar conditions, induced ovum implantation even at dose levels below those required for a uterine weight response. Diethylstilboestrol and large doses of oestradiol-17α (5 to 10 μg) were effective in both assays. It is suggested that different uterine receptors may be involved in mediating the uterine-growth-promoting and implantationinducing actions of oestrogen.

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M. SHEMESH, H. R. LINDNER and N. AYALON

Summary.

The non-steroidal phyto-oestrogens, coumestrol and genistein, were able to compete with oestradiol-17β (Oe2) for binding sites on a macromolecular component of the uterine cytosol from 6-day-pregnant rabbits. Binding affinity for these compounds was related to their reported oestrogenic potency: approximately one part by weight of Oe2, seventy of coumestrol and 175 of genistein produced equivalent inhibition of the uptake in vitro of [3H]Oe2 by this uterine receptor. Biochanin-A, formononetin, 12-O-methylcoumestrol, sativol and medicagol did not significantly inhibit Oe2 binding, suggesting that free hydroxyl groups in both position 7 and 12 (= 4') of coumestans and isoflavones are essential for effective interaction with the oestrogen receptor. The 7- and 12-methoxy-coumestans and isoflavones tested appear to be pro-oestrogens, able to bind to the uterine receptor only after O-demethylation in vivo.

A rapid competitive protein-binding radioassay for phyto-oestrogens in the blood that makes use of the uterine cytosol receptor is described. Its useful range is 0·5 to 40 ng for coumestrol and 2·5 to 200 ng for genistein. Prior chromatographic separation is required to discriminate between plant-derived and endogenous steroidal oestrogens. Coumestrol was present in the blood of goats (2·0 to 3·9 ng/ml) after feeding alfalfa hay at a rate supplying 12 mg coumestrol/24 hr/animal.

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SUMIE TACHI, C. TACHI and H. R. LINDNER

Summary.

Morphological features of the interaction between the implanting blastocyst and the uterine endometrium were studied by electron microscopy, using material fixed in situ. The observations extended from the pre-attachment stage to the completion of trophoblastic erosion of the uterine epithelium and early decidual transformation of the stromal cells.

After shedding of the zona pellucida, the blastocyst establishes contact with the tips of microvilli and with bleb-like cytoplasmic protrusions of the epithelial cells. Attachment occurred during the afternoon of the 5th day post coitum (p.c.). Patches of`bristle-coated' membrane appeared on the trophoblast membrane at that time. A lattice-like substructure was discernible in the cytoplasmic plaques, which are abundant in the early blastocyst. Sperm-tail inclusions were observed in both trophoblast and inner cell mass as late as Day 5 p.c.

By the 6th day p.c., the epithelial microvilli were usually lost and the trophoblast membrane interlocked with that of the epithelial cells, with frequent formation of tight junctions. Leucocytes were occasionally seen in the epithelial layer at the attachment site. Unusually electron-dense cells were often found wedged between the trophoblast and epithelial cells; their possible relation to Wilson bodies is discussed.

The earliest morphological response of the stromal cells to blastocyst attachment was the appearance of changes in nuclear shape, chromatin distribution and nucleolar structure in the subepithelial layer. The deeper subepithelial stroma became oedematous, and diapedesis, erythro-phagocytosis and later the formation of sinusoids could be observed.

During Day 7 p.c., the basement membrane generally disappeared and the trophoblast cells were then in close contact with stromal cells : the distance between the two unit membranes was in the range 100 to 200 Å. A `periplacental fibrinoid barrier' could not be recognized at this stage, but the existence, or later development, of such an immunological barrier could not be excluded.

Stromal cells undergoing decidual transformation showed an abundance of membrane-bound ribosomes and a striking accumulation of fibrils, 80 to 90 Å in diameter, displacing the cytoplasmic organelles.

The development of Reichert's membrane was traced from its first appearance as an amorphous deposit along the inner wall of the trophoblast on Day 6 p.c., to the formation of a stratified, membranous structure on the 8th day.

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C. TACHI, SUMIE TACHI and H. R. LINDNER

Summary.

Progesterone pretreatment (5 mg/day) of ovariectomized— adrenalectomized rats for at least 12 hr abolished the response of the uterine luminal epithelium to oestradiol (0·2 μg) with respect to (i) mitotic activity, (ii) nucleolar enlargement, and (iii) [3H]uridine uptake, and suppressed the uptake of [3H]oestradiol by the epithelial cells, as judged by dry-mount autoradiography.

Progesterone pretreatment for periods exceeding 36 hr redirected the mitogenic action of oestradiol and its stimulatory action on [3H]uridine uptake from the epithelium to subepithelial stromal cells. The latter are not responsive to the action of oestradiol on its own. High resolution (EM) autoradiography revealed preferential accumulation of [3H]uridine over the stromal nucleoli, supporting the view that the bulk of the RNA synthesized as an early response to oestradiol is ribosomal precursor RNA.

In the glandular epithelium, progesterone prevented the induction of mitotic activity, but not the stimulation of [3H]uridine uptake, by oestradiol; the ability to accumulate [3H]oestradiol remained unaffected.

Rats injected with oestradiol during delayed implantation showed a mitotic response in the stroma, but not in the luminal or glandular epithelium, and failed to accumulate [3H]oestradiol in the luminal epithelium. In pregnant and pseudopregnant rats, mitotic activity declined sharply in epithelial and glandular cells after Day 2 post coitum. This was followed by a sharp rise in the rate of thymidine incorporation and cell division of the subepithelial stromal cells. The reciprocal changes in these tissues, previously described in the pregnant mouse, are ascribed to an interaction between progesterone and oestradiol. It is inferred that significant oestrogen secretion commences late on Day 2 post coitum, i.e. well before the time postulated for the preimplantation `oestrogen surge.'

The rate of DNA synthesis in pseudopregnant rats reached a peak on Day 5 post coitum, coinciding with maximal uterine sensitivity to deciduoma-inducing stimuli, but mitotic rate in both pregnant and pseudopregnant rats declined sharply before the morning of Day 5, suggesting a prolongation of the G2 phase of the mitotic cycle at that time.

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J. F. STRAUSS III and H. R. LINDNER

The prolongation of pseudopregnancy in the rat as a result of hysterectomy (Melampy, Anderson & Kragt, 1964) or massive deciduoma (Velardo, Olsen, Hisaw & Dawson, 1953; Melampy et al., 1964) suggests that a luteolyticprinciple is produced by the uterine endometrium. There is evidence that the proposed luteolysin acts locally: pseudopregnancy is extended in rats following excision of one uterine horn and of the contralateral ovary, while no extension results when the ovary adjacent to the excised horn is removed (Anderson, Melampy & Chen, 1966; Barley, Butcher & Inskeep, 1966). Pseudopregnancy is also prolonged by spatial separation of the uterine horns from their related ovaries (Anderson, Melampy & Chen, 1966; Barley et al., 1966). We have been able to confirm these observations.

A local luteolytic action has been observed in the unilaterally pregnant gilt (Du Mesnil du Buisson, 1961) and the Canadian porcupine (Erethizon dorsatum)(Mossman 8c Judas, 1949). Although unilateral pregnancy has been described in the intact rat (Deanesly & Parkes, 1931), the possibility of a local luteolytic action has not been investigated and this is the subject of the present study.

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M. SHEMESH, H. R. LINDNER and N. AYALON

Summary.

A rapid radiometric assay based on thin-layer-chromatography and the competition by progesterone for binding sites on the corticosterone-binding globulin of human plasma was used to determine changes in the level of progesterone in peripheral bovine plasma during the oestrous cycle. The blood level (ng/ml, mean ± S.E.) of the hormone was minimal (0·6± 0·15 to 0·8± 0·20) from Day −2 to +2 of the cycle (Day 0 = day of oestrus), rose steeply between Day 3 and Day 7, and either continued to rise very slowly or maintained a plateau fluctuating about a mean of 5·4± 0·16 for 8 to 10 days, before declining; the most abrupt fall in plasma progesterone concentration occurred on Day −4 or −3. The results agreed well with control data obtained by sequential paper- and gas-chromatography (r = 0·93).

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M. SHEMESH, N. AYALON and H. R. LINDNER

Progesterone levels in jugular venous blood are being measured by us in cycling (unmated) and inseminated (pregnant or non-pregnant) cows as part of a comparative study of cows with normal and difficult breeding histories. Hawk, Wiltbank, Kidder & Casida (1955) reported a high incidence of embryonic death in cows during the period 16 to 25 days after insemination. The 3rd week of gestation may indeed be a critical phase in the regulation of luteal function, since towards the end of this week regression of the corpus luteum normally occurs in the absence of a conceptus. This note records that in a herd of normal Friesian cattle with a cycle length of 21·2 days±1·5 s.d. the presence of a conceptus in the uterus first exerted a significant

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C. TACHI, SUMIE TACHI and H. R. LINDNER

Summary.

Intraluminal injection of pyrathiazine, promethazine and benadryl into the uterus of pseudopregnant rats at dose levels reported to suppress the decidual reaction (1 mg/horn) caused extensive necrosis of the endometrium. Suppression of the decidual reaction by these agents when applied locally cannot, therefore, be attributed unequivocally to their antihistaminic properties and, hence, does not provide evidence for a rôle of histamine in the mediation of decidual induction.

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B. P. SETCHELL, G. M. H. WAITES and H. R. LINDNER

Summary.

The food intake of six rams was restricted for 3 months, resulting in a reduction of body fat to less than 12% of live weight, compared with 25 to 49% in well-fed controls. At the end of this period of undernutrition, blood flow and the uptake of oxygen and glucose in unit weight of testis, when estimated during anaesthesia, were lower than in the controls, and testis weight was reduced. The fraction of oxygen uptake that could be accounted for by the oxidation of glucose was unchanged, although the respiratory quotient was slightly higher in the underfed rams. Oxygen uptake by homogenates and mitochondria from the testes of underfed rams was lower under most conditions of incubation applied.

Testosterone output (mg/ram/day±s.e.m.) was 0·4±0·2 in the underfed rams and 3·5±0·7 in well-fed controls; in six other well-fed rams, sampled while conscious, testosterone output was 2·8±0·3. Spermatogenic activity, as indicated by the diameter of the seminiferous tubules and the sperm content of the epididymis, and accessory gland activity, as indicated by the weight and fructose content of the seminal vesicles, were lower in the underfed rams. All these indices appeared to be related to testosterone output when the latter was less than 2·5 mg/ram/day, but tended to attain maximal values at higher rates of hormone production

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A. TSAFRIRI, H. R. LINDNER, U. ZOR and S. A. LAMPRECHT

Summary.

Isolated Graafian follicles cultured intact were used as a test-system for the meiosis-inducing action of hormonal preparations and for analysing the mediation of this hormone effect.

When enlarged follicles were explanted from rats on the day of pro-oestrus before 14.00 hours, i.e. before the preovulatory lh-surge, the oocytes remained in the dictyate state of meiosis throughout an 18-hr culture period. Completion of the first meiotic division could be induced by addition of lh or prostaglandin E2 to the culture medium, or by microinjection of dibutyryl cyclic AMP into the antrum of the cultured follicle. Addition of hcg or fsh to the culture medium was also effective, though possibly due to lh-like activity present in these preparations. Prostaglandin F, at 2·8 × 10−5 m, was only partly effective; prolactin, progesterone, 20α-dihydroprogesterone, oestradiol-17β, linolenic acid and adenosine-5′-monophosphate were completely ineffective. The maturation-inducing action of lh was not blocked by cyanoketone, an inhibitor of steroid synthesis.

Addition of lh to the culture medium stimulated the formation of cyclic AMP by the isolated follicles. Exogenous cyclic AMP enhanced protein kinase activity in the supernatant fraction of follicular homogenates.

It is proposed that the action of lh on oocyte maturation involves the mediation of the adenyl cyclase/cyclic AMP system and possibly of the prostaglandins. An action of steroids could not thus far be implicated. The experimental model described permits study of the mechanism of the meiosis-inducing action of lh under controlled conditions in vitro.