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U. Zor, B. Strulovici, R. Braw, H. R. Lindner and A. Tsafriri

The aim of this study was to search for direct biochemical effects of highly purified FSH on isolated ovarian follicular theca in vitro. Granulosa cells (GC; approximately 1 × 105 cells per follicle) were flushed from isolated follicles of pro-oestrous rats. The remaining theca layer and the isolated GC were incubated with highly purified ovine FSH. Prostaglandin E (PGE) accumulation was measured by radioimmunoassay. Follicle-stimulating hormone induced a 15-fold increase in PGE accumulation over the basal level in the follicular theca, the stimulated rate exceeding threefold that observed in the GC fraction derived from the same follicle. Follicle-stimulating hormone caused no significant increase in cyclic AMP level or steroidogenesis in the theca layer, but was active on these parameters in the GC. In contrast, LH increased the accumulation of cyclic AMP, progesterone and testosterone, as well as of PGE, in follicular theca. Exogenous 8-bromo cyclic AMP or cyclic GMP also stimulated PGE production in follicular theca or GC, but FSH was without any effect on the level of endogenous cyclic GMP in GC or follicular theca. Antibodies to FSH prevented the effect of FSH (but not that of LH) on PGE formation by follicular theca and GC, while antibodies to the β-subunit of LH blocked the effect of LH but not of FSH. We conclude that highly purified FSH has a stimulatory effect on PGE formation by the follicular theca.

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Mammary explants from two heifers pretreated with oestradiol and progesterone were cultured for 96 h with various combinations of hormones and calf plasma to identify the complement causing mammary tissue development in vitro in the cow. Initial tissue histology, determined by quantitative morphological analysis, was maintained by incubation with insulin, cortisol, oestrogen and progesterone; enlarged lumina were observed after treatment with insulin and cortisol. Lactogenesis was induced in vitro by insulin, cortisol and prolactin, enhanced by adding oestrogen and progesterone at the doses used here and further stimulated by the addition of plasma. The most highly developed mammary alveoli were characterized by an increased luminal area with lipid and stainable secretion, epithelia with large lipid droplets in the apical cytoplasm and a limited stromal area. In a second experiment, samples of plasma were collected from two cows, successfully induced to lactate, on days 6, 15, 17, 19 and 21 after treatment with oestradiol and progesterone. Mammary gland explants from five heifers pretreated with oestradiol and progesterone in vivo were cultured with insulin and cortisol plus these plasma samples (30%, v/v) to test for changes in lactogenic activity. All plasma samples were found equally beneficial in promoting tissue differentiation. These experiments show that low concentrations of ovarian steroids synergize with prolactin at the level of the mammary epithelium and suggest that other plasma components aid the development of bovine mammary epithelium in vitro.

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Sarit Ben-Shmuel, Eyal J Scheinman, Rola Rashed, Zila Shen Orr, Emily J Gallagher, Derek LeRoith and Ran Rostoker

Obesity and type 2 diabetes (T2D) are associated with an increased risk of breast cancer incidence and mortality. Common features of obesity and T2D are insulin resistance and hyperinsulinemia. A mammary tumor promoting effect of insulin resistance and hyperinsulinemia was demonstrated in the transgenic female MKR mouse model of pre-diabetes inoculated with mammary cancer cells. Interestingly, in MKR mice, as well as in other diabetic mouse models, males exhibit severe hyperglycemia, while females display insulin resistance and hyperinsulinemia with only a mild increase in blood glucose levels. This gender-specific protection from hyperglycemia may be attributed to estradiol, a key player in the regulation of the metabolic state, including obesity, glucose homeostasis, insulin resistance, and lipid profile. The aim of this study was to investigate the effects of ovariectomy (including the removal of endogenous estradiol) on the metabolic state of MKR female mice and subsequently on the growth of Mvt-1 mammary cancer cells, inoculated into the mammary fat pad of ovariectomized mice, compared with sham-operated mice. The results showed an increase in body weight, accompanied by increased fat mass, elevated blood glucose levels, and hypercholesterolemia, in ovariectomized MKR mice. In addition, mammary tumor growth was significantly higher in these mice. The results suggest that ovarian hormone deficiency may promote impaired metabolic homeostasis in the hyperinsulinemic MKR female mice, which in turn is associated with an increased growth of mammary tumors.

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E E Connor, D L Wood, T S Sonstegard, A F da Mota, G L Bennett, J L Williams and A V Capuco

Steroid receptors are key transcriptional regulators of mammary growth, development and lactation. Expression of estrogen receptors alpha (ERα) and beta (ERβ), progesterone receptor (PR), and estrogen-related receptor alpha-1 (ERRβ) have been evaluated in bovine mammary gland. The ERRα is an orphan receptor that, in other species and tissues, appears to function in the regulation of estrogen-response genes including lactoferrin and medium chain acyl-CoA dehydrogenase and in mitochondrial biogenesis. Expression of ERα, ERβ, PR and ERRα was characterized in mammary tissue obtained from multiple stages of bovine mammary gland development using quantitative real-time RT-PCR. Expression was evaluated in prepubertal heifers, primigravid cows, lactating non-pregnant cows, lactating pregnant cows and non-lactating pregnant cows (n=4 to 9 animals/stage). In addition, ERα, ERβ, PR and ERRα were mapped to chromosomes 9, 10, 15 and 29 respectively, by linkage and radiation hybrid mapping. Results indicated that expression of ERα, PR and ERRα was largely coordinately regulated and they were present in significant quantity during all physiological stages evaluated. In contrast, ERβ transcripts were present at a very low concentration during all stages. Furthermore, no ERβ protein could be detected in bovine mammary tissue by immunohistochemistry. The ERα and PR proteins were detected during all physiological states, including lactation. Our results demonstrate the presence of ERα, PR and ERRα during all physiological stages, and suggest a functional role for ERRα and a relative lack of a role for ERβ in bovine mammary gland development and lactation.

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L Sivaraman, SG Hilsenbeck, L Zhong, J Gay, OM Conneely, D Medina and BW O'Malley

An early single full-term pregnancy induces a long-lasting protective effect against mammary tumor development in humans and rodents. This protective effect can be mimicked in rats by short-term administration of estrogen and progesterone hormones prior to carcinogen administration. The hormones of pregnancy are able to induce a proliferative block upon carcinogen challenge that is not observed in the age-matched virgin. We wished to determine whether carcinogen is needed to induce a paracrine-to-autocrine shift of proliferation in steroid receptor positive cells or if such a cell population already exists in the age-matched virgin mammary gland. Here we show that estrogen receptor positive (ER+) proliferating cells are rare in the developing mammary gland of the virgin rat but represent the majority of the proliferating cells in the mature (96-day-old) mammary gland of the virgin rat. As the majority of the proliferating cells before carcinogen challenge were ER positive, the ER+ proliferating cells in the mature mammary gland may represent the target cells for carcinogen-induced transformation. Importantly, prior exposure of the mammary gland to pregnancy levels of estrogen/progesterone blocked this positive association. This ability to block the proliferation of the ER+ cells may be one factor by which pregnancy induces protection against breast cancer.

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Prolactin receptors were identified and partially characterized in the mammary gland of the rat. The binding of 125I-labelled ovine prolactin to a subcellular particulate fraction of rat mammary gland decreased between days 30 and 100 of age. Over the same period, binding to the liver increased and there was a significant negative correlation between prolactin binding in the two tissues. Binding to the mammary gland was low during pregnancy, increased in early lactation and declined after the litters were weaned. Binding to the liver was lower during lactation than during pregnancy or the period after weaning suggesting that tissue-specific factors may operate in the control of this receptor. In virgin rats, prolactin binding by the mammary gland was increased by oestrogen. This effect was blocked by hypophysectomy and partially restored by replacement therapy with prolactin. Hypothyroidism and treatment with progesterone also reduced the response to oestrogen. The maintenance of prolactin binding by the mammary gland of lactating rats depends on the presence of the ovaries and pituitary, thyroid and adrenal glands. Examination of the ratio epithelium: stroma suggests that prolactin acts by increasing the number of epithelial cells in the mammary gland and that thyroid, adrenal and ovarian hormones modulate the number of receptors per cell.

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T. R. Koiter, G. C. J. van der Schaaf-Verdonk, H. Kuiper, N. Pols-Valkhof and G. A. Schuiling

The effects of steroid-free bovine follicular fluid (bFF) and sodium phenobarbitone on spontaneous LH releasing hormone (LHRH)-induced secretion of FSH and LH were studied in ovariectomized rats. Luteinizing hormone releasing hormone was administered by infusion to rats anaesthetized with phenobarbitone. Bovine follicular fluid reduced FSH release and synthesis. Luteinizing hormone release remained unaffected after bFF treatment. Phenobarbitone reduced both FSH and LH release. The observed suppressive effects of bFF and phenobarbitone on FSH secretion were additive, suggesting that the basal release of FSH has an LHRH-dependent and an LHRH-independent component. Furthermore, bFF did not affect pituitary responsiveness of LH secretion to LHRH and reduced the responsiveness of FSH secretion only when administered some time before the LHRH challenge. The present observations support the view that in the ovariectomized rat the pituitary gland is the only site of action of inhibin-like activity as present in bFF.

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The response of mouse ovaries maintained in organ culture to follicle-stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotrophin (HCG) was assessed using quantitative histological and radioimmunoassay techniques.

In terms of the induction of preovulatory maturation in follicular oocytes, 1 μg FSH/ml medium was as effective as 10 μg LH/ml. The lowest doses of HCG and LH used (0·2 i.u./ml and 1 μg/ml respectively) had no effect on oocyte maturation, whereas the response to FSH was virtually unchanged irrespective of dose (1–10 μg/ml). When the level of progesterone in the medium at the end of organ culture was used as an index of ovarian response, LH was more effective than FSH and HCG, although all the hormones induced a significant increase, irrespective of dose.

These results are discussed in terms of the mode of action of gonadotrophins in the processes culminating in ovulation.

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S. Purup, K. Sejrsen, J. Foldager and R. M. Akers


Sixteen prepubertal Holstein Friesian heifers were used to study the effect of long-term administration of bovine GH (bGH) on mammary development in intact and ovariectomized heifers. Eight heifers were ovariectomized at 2·5 months of age. Four intact and four ovariectomized heifers received subcutaneous injection of bGH (15 mg/day) for 15 weeks starting at 176 ± 3 days of age (147 ± 3 kg body weight), while the remaining eight heifers received an equal volume of excipient. Blood samples were collected weekly from 2 months of age. Heifers were slaughtered on the day after the last injection of bGH or excipient. Mammary gland development was quantified by dissection, chemical analysis and computer tomographic scanning. Mammary growth response at the time of slaughter was examined in cultures with explants prepared from parenchyma. Histological and histoautoradiographic studies with explants were performed.

Treatment with bGH resulted in a significantly (P<0·05) smaller mammary gland because of a reduced amount of extraparenchymal tissue. Ovariectomy markedly reduced the amount of parenchymal tissue. Growth response in mammary explants showed no treatment differences, suggesting that the decreased amount of parenchyma in ovariectomized heifers was caused by a decrease in mammary cell proliferation occurring some time prior to slaughter. The histological composition of mammary parenchyma was not changed by bGH treatment. However, ovariectomy resulted in less epithelial tissue (P<0·001) and lumen (P<0·05) and more stroma (P< 0·001), expressed as percentage tissue area. Serum hormone concentrations of bGH and insulin-like growth factor-I (IGF-I) were increased by bGH treatment in both intact and ovariectomized heifers. However, despite the fact that mammary growth in ovariectomized heifers was eradicated, the serum concentration of oestradiol was only decreased by one-third compared with intact heifers.

The study therefore confirms the importance of ovarian secretions for mammary growth and development in prepubertal heifers. However, the results give no clear evidence of an interaction between ovarian secretions and GH on the regulation of the development of the mammary parenchyma in heifers.

Journal of Endocrinology (1993) 139, 19–26

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A single injection of 1 mg of a complex of testosterone esters on day 5 of life was used to prepare constantly oestrous rats. Such androgenized female rats were then ovariectomized and submitted to stereotaxical implantation of 1 μg oestradiol benzoate, 5 μg testosterone isobutyrate or, as a control, 10 μg cholesterol in the anterior hypothalamic areas. The effects of the steroids on plasma and pituitary FSH and LH were assessed by radioimmunoassay. As reported previously by us in normal female and male rats, the preoptic–suprachiasmatic area (POA) was able to control synthesis and secretion of both gonadotrophins and did not lose its sensitivity to oestradiol and testosterone in androgenized rats. Evidence for enhanced prolactin secretion in androgenized rats was derived from immunofluorescence studies of the pituitary gland and from histology of the mammary glands. In this respect the condition of the androgenized females was opposite to that of the males. The present work demonstrated that stimulation of prolactin secretion in androgenized female rats resulted from oestrogen action due to permanent oestrus rather than from impairment of hypothalamo-hypophysial relationships. Indeed, prolactin stimulation was suppressed when the androgenized rats were ovariectomized and restored when they were subsequently implanted with oestradiol in the POA.