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Production a corpus luteum angiogenic factor responsible for proliferation of capillaries and neovascularization of the corpus luteum.

Factors controlling the changes in the vascular pattern of the ovary that occur during the reproductive cycle have been investigated. By using the rabbit cornea, the abilities of ovarian corpus luteum and of follicles to induce neovascularization have been compared. While the corpus luteum is capable of inducing neovascularization, the follicles do not have this ability. It is therefore likely that the corpus luteum actively participates in its own neovascularization by secreting a factor that we have called "corpus leutem angiogenic factor" (CLAF).

Angiogenesis Inducing Agents

Corpus luteum surgery.

The corpus luteum is responsible for a substantial number of emergency operations, some of which prove to be unnecessary and others which are unnecessarily complex. The routine utilization of culdocentesis and pregnancy testing will identify the large majority of those patients who can safely be treated by expectant observation or who should first be investigated by a diagnostic operative technique, such as laparoscopy, before an exploratory laparotomy is performed. When a laparotomy is performed, the ovary should be conserved whenever possible. An analysis of two hundred consecutive emergency operations for ruptured corpus luteum or corpus luteum cyst support these observations.

Corpus Luteum

Interations of gonadotropins with corpus luteum membranes. VII. Association of hCG-binding and adenylate cyclase activities with rabbit corpus luteum plasma-membranes.

Previous studies with rat luteal cell plasma membranes indicated a dissociation of hCG binding sites and adenylate cyclase activity. The hormone binding sites were associated with a light membrane (d 1.13) fraction derived from the microvillous surface while the cyclase enzyme was associated with a heavy membrane (d 1.17) fraction derived from the basolateral surface of the cell. In this study of plasma membranes from 8-day pseudopregnant rabbit corpora lutea both hCG binding and adenylate cyclase activity were associated with a light membrane (d 1.13) fraction. No heavy membrane material was detected.

Adenylyl Cyclases

Prolactin receptors in the mammary gland, corpus luteum and other tissues of the tammar wallaby, Macropus eugenii.

Specific binding of radio-iodinated ovine prolactin to subcellular tissue fractions of the tammar wallaby (Macropus eugenii) was investigated. Specific binding was found, in order of decreasing binding activity, in the lactating mammary gland, corpus luteum, corpus albicans, adrenal gland and ovary. Specific binding was absent in kidney, liver, brain and inactive mammary gland. The mean association constant (Ka at 23 degrees C) was determined as 0.90 x 10(9), 2.20 x 10(9), 2.44 x 10(9), 3.38 x 10(9) and 10.98 x 10(9) l/mol for mammary gland, adrenal, corpus albicans, corpus luteum and ovary respectively. The mean receptor concentration (N) varied from 92.87 x 10(-14) mol/mg protein for the mammary gland to 1.03 x 10(-14) mol/mg protein for the ovary. The concentration in the corpus luteum varied between tissue pools collected at different times of the annual breeding cycle. The specificity for prolactin was shown in the mammary gland and corpus luteum by the failure of ovine FSH, LH, GH and TSH to displace 125I-labelled ovine prolactin, whereas it was displaced readily by both ovine and bovine prolactin.

Animals

Ovarian (corpus luteum) hemorrhage during anticoagulation therapy.

Corpus luteum hemorrhage is a complication of long-term anticoagulant therapy that has rarely been reported in the literature. Within 16 months, we saw six cases in which young women taking anticoagulants to prevent clotting of prosthetic heart valves suffered corpus luteum hemorrhages. Diagnosis was difficult and delayed. Medication stopped the bleeding in three patients; bilateral salpingo-oophorectomy was necessary in the remaining three. Our patients had great difficulty controlling their anticoagulant therapy and had histories of previous bleeding episodes. We believe corpus luteum hemorrhage may become more common as more premenopausal women undergo cardiac valvular surgery.

Adult

Reevaluation of the role of cyclic adenosine 3',5'-monophosphate and protein kinase in the stimulation of steroidogenesis by luteinizing hormone in bovine corpus luteum slices.

Incubation of bovine corpus luteum slices at 37 C with luteinizing hormone showed that 10.0 microng LH/ml caused a maximum rise in tissue cyclic AMP content within 15 min. Slices incubated with 1.0 or 0.1 microng LH/ml showed a much more gradual accumulation of this nucleotide. In the absence of added LH, a marked decline in the amount of cyclic AMP was observed during the first 60 min. The possible role of cyclic AMP in the action of LH was reexamined by studying the dose-response effect of LH on the stimulation of progesterone synthesis, cyclic AMP-dependent protein kinase activation, and cyclic AMP accumulation. After a 2-h incubatin, the results showed that the dose required to elicit a minimal significant stimulation of steroidogenesis was 0.01 microng/ml LH. At this and higher concentrations of LH, a concomitant stimulation of protein kinase activity and progesterone synthesis was also consistently observed. However, significant accumulation of cyclic AMP became consistently detectable only at 0.1 microng/ml LH. This report is the first to show a positive correlation between the activation of cyclic AMP-dependent protein kinase and the stimulation of steroidogenesis in the corpus luteum at the same minimal effective level of LH. These results indicate that cyclic AMP and the cyclic AMP-dependent protein kinase probably play important intermediary roles in the stimulation of steroidogenesis by LH in the bovine corpus luteum.

Animals

Influence of porcine corpus luteum extract on DNA synthesis and proliferation of cultivated fibroblasts and endothelial cells.

The angiogenic activity in corpus luteum (corpus luteum angiogenesis factor--CLAP) reported first by us in 1977 was enriched by ammonium sulfate precipitation and further purified by ion exchange chromatography. Extracts produced in this way from corpora lutea of cyclus synchronized pigs have proven effective to stimulate DNA synthesis and proliferation of both calf aorta endothelial cells and primary mouse embryo fibroblasts cultivated either under optimal or suboptimal (depletion) conditions. The mitogenic action of these extracts has been found to be dose-dependent and similar to that of bovine brain extract produced according to the preparation method published by GOSPODAROWICZ.

Angiogenesis Inducing Agents

Follicular determinants of corpus luteum function in the human ovary.

The corpus luteum is a direct continuation of preovulatory follicle development. Growth and differentiation of a follicle to the preovulatory stage depends on certain endocrine changes taking place within the follicle itself (5). These endocrine changes markedly influence the viability, the rate of proliferation, and the biosynthetic potential of granulosa cells. Therefore, the sequence of endocrine events within the developing antral follicle is likely to be of considerable importance for the formation and secretory activity of the corpus luteum. If granulosa cells in developing antral follicles are exposed to certian hormones in the wrong sequence, the follicle may be prevented from developing into a normal corpus luteum. For example, if granulosa cells in antral follicles are not exposed to FSH, they are unable to generate high levels of oestrogen (Table 1). In the absence of oestrogen, granulosa cells do not increase in number. The same end result may also arise if the granulosa cells are exposed prematurely to elevated levels of LH or to high levels of prolactin: LH blocks granulosa cell mitoses even if the cells are exposed to oestrogen (1, 21); high levels of prolactin in antral fluid are associated with low levels of oestrogen and a reduced rate of granulosa cell proliferation. In women, it is likely that a fully functional corpus luteum is formed from a follicle that was exposed to the most favourable sequence of endocrine changes during its antral stages of development.

Androstenedione

Demonstration of angiogenesis-activity in the corpus luteum of cattle.

The angiogenetic potency of corpus luteum tissue and of extracts of it was tested in three different biological model systems: the chorioallantoic membrane of the chicken (CMA), the ventral subcutaneous pouch of the mouse and the cheeck pouch of the Syrian hamster. The formation of new capillaries after transplantation of the materials was scored macroscopically and stereomicroscopically. In all three systems strong capillary reactions at the periphery of the transplants could be observed indicating the presence of a capillary inducing potency in the tissue of corpus luteum of the cattle.

Angiogenesis Inducing Agents

[Investigations into the hormonal regulation of the corpus luteum function in the human (author's transl)].

In estradiol micro-crystalline suspension was injected into the ovary containing the corpus luteum in women who underwent hysterectomy. The same complete luteaolysis is in women who did not have hysterectomies was obtained. The conclusion is drawn that the prostaglandins which are formed in the uterus have no influence in man on the regulation of the survival of the corpus luteum. As far as we know to date the high excretion of estradiol from the corpus luteum during the maturation of the corpus luteum forms an internal shuttle mechanisms for the survival of the corpus luteum which inhibits the biosynthesis of progesterone by estrogen and blocks the effect of the gonadatropins on the granulosa cells.

Adult

Observations on the human corpus luteum: histochemical changes during development and involution.

Morphologic studies of the developing, gestational, and involuting corpus luteum show that rapid structural changes occur and that involution is not associated with an appropriate inflammatory response. Histochemical techniques were used to demonstrate several patterns of enzyme activity. The luteunized granulosa cells stained with increasing intensity for lactic dehydrogenase, succinic dehydrogenase, cytochrome oxidase, glucose-6-phosphatase, and 3 beta-hydroxysteroid dehydrogenase, but reactivity for these enzymes dropped markedly with early involution, and staining was never conspicuous in the organizing cavity. Reactions for acid phosphatase, glucosaminidase, galactosidase, glucuronidase, and nonspecific esterase were also present in the developing corpus luteum, but staining decreased more slowly during involution and was prominent in the occasional macrophages in the granulosa and the granulation tissue in the cavity. Staining was moderately intense for all of the enzymes in the corpus luteum of pregnancy. The decrease in activity for these metabolic enzymes confirms the histologic impression of degeneration, but the loss of staining for lysosomal enzymes was more rapid than expected. The latter finding complicates the hypothesis of involution of involution of the corpus luteum as an example of programmed cell death.

Corpus Luteum

Histology of the human corpus luteum of early and late pregnancy.

The aim of this investigation has been to examine which histological parameters are of value in the age determination of the corpus luteum of pregnancy. The material comprises representative ovarian biopsies from 16 women from the 10th through 42nd week of gestation. The following histological parameters have been found useful for the age determination of the corpus luteum: 1) the size of the granulosa cells; 2) the number of K-cells, vacuoles and colloid inclusions in the granulosa cell layer; 3) the size of the theca interna cells; (4) the size of the vessels in the theca interna. Futhermore, the differentiation of the corpus luteum of pregnancy from the corpus luteum of menstruation is described, and some indications for a histological age determination of the corpus luteum of pregnancy are mentioned.

Adolescent

Estrogen action in the corpus luteum.

The luteotropic action of estradiol has been studied in the rabbit and rat, and it is proposed that in both species, estradiol may be the "ultimate" luteotropic hormone. The acute dependence of the rabbit corpus luteum upon estradiol is illustrated by the rapid decline in serum progesterone after withdrawal of estradiol (removal of Silastic implant containing 17 beta-estradiol) and by the restoration of serum progesterone to normal values when the estradiol implant is replaced 24 hours later. The identification and characterization of a cytoplasmic and nuclear estrogen receptor in the rabbit corpus luteum and the translocation of the cytoplasmic receptor suggest that estradiol may be acting as it does in other estrogen target tissues. The administration of LH antiserum in pregnant rats causes rapid decreases in luteal estradiol and serum progesterone concentrations, which can be prevented by the administration of low doses of testosterone. This luteotropic effect of testosterone is attributed to an action of estradiol which is formed within the corpus luteum via the luteal aromatase. The rabbit corpus luteum, which has no aromatase, is totally dependent upon estradiol produced by the ovarian follicles and LH is essential to maintain follicular estradiol synthesis. The rat corpus luteum, which is rich in aromatase activity, may produce its own estrogen from an androgen precursor synthesized within the luteal tissue. The essential role of LH may be the stimulation of the synthesis of androgen precursor. As a working hypothesis it is proposed that in these two species LH is necessary to stimulate the synthesis of estradiol which then acts to sustain progesterone secretion.

20-alpha-Dihydroprogesterone

Persistant corpus luteum cyst of pregnancy: sonographic evaluation of cause of third trimester bleeding.

Corpus luteum cysts are frequently observed in pregnant patients evaluated with diagnostic ultrasound. They are usually regarded as incidental findings because of their limited size and usual pattern of regression by ten weeks. The presence and persistence of larger corpus luteum cysts or other extrauterine masses may complicate pregnancy. A case of a large persistent corpus luteum cyst associated with third trimester bleeding is presented.

Adult

In vitro evaluation of corpus luteum function of cycling and pregnant rhesus monkeys: Progesterone Production by dispersed luteal cells.

Corpus luteum function in the cycling and the pregnant rhesus monkey (Macaca mulatta) was evaluated through short term in vitro studies of progesterone production by suspensions of collagenase-dispersed luteal cells in the presence and absence of exogenous gonadotropin (human chorionic gonadotropin, HCG). Cells from mid-luteal phase of the menstrual cycle secreted progesterone, as measured by accumulation of this hormone in the incubation medium, and responded to the addition of 100 ng HCG/ml with a marked increase in progesterone secretion significantly above basal level (63.7 +/- 13.1 versus 24.7 +/- 5.5 ng progesterone/ml/5 x 10(4) cells/3 hr, X +/- S.E., n =6 ; p less than 0.05). However, luteal cells from early pregnancy (23-26 days after fertilization) secreted siginificantly less progesterone than cells of the non-fertile menstrual cycle (3.6 +/- 2.4 versus 24.7 +/- 5.5 ng/ml/5 x 10(4) cells/3 hr, n =3 ; p less than 0.05) and did not respond to HCG with enhanced secretion. By mid-pregnancy (108-118 days gestation ) luteal cells exhibited partially renewed function, and near the time of parturition (163-166 days gestation) basal and HCG-stimulated progesterone secretion (30.2 +/- 5.6 and 63.0 +/- 13.0 ng/ml/5 x 10(4) cells/3 hr, respectively; n = 3) was equivalent to that of cells from the luteal phase of the non-fertile menstrual cycle. The data suggest that following a period around the fourth week of gestation, when steroidogenic activity is markedly diminished, the corpus luteum of pregnancy progressively reacquires its functional capacity and at term exhibits gonadotropin-sensitive steroidogenesis similar to that the corpus luteum of the menstrual cycle.

Animals

Corpus luteum function during the early postpartum interval in lactating rhesus monkeys: in vivo and in vitro response to exogenous gonadotropin.

The response of the postpartum corpus luteum to exogenous gonadotropin was studied in 12 lactating rhesus monkeys given daily injections of either human chorionic gonadotropin (HCG, n = 6) or saline (control, n = 6) for 4 days immediately following parturition. Peripheral blood samples were collected daily. On the 5th day postpartum, luteectomy was performed progesterone production by dispersed luteal cells was examined. Whereas progesterone in the peripheral circulation of control monkeys progressively declined between days 1 and 5 postpartum, progesterone levels increased significantly (p less than 0.025) with the onset of HCG treatment and remained significantly (p less than 0.025) elevated above the controls throughout the period of HCG treatment. However, despite the daily administration of HCG, circulating progesterone levels declined (p less than 0.05) between days 3 and 5 postpartum. The weight of the corpus luteum excised from HCG-treated macaques was significantly (p less than 0.005) greater than that of the controls. Dispersed cells from corpora lutea of saline-treated monkeys produced progesterone in vitro under control conditions (nutrient medium alone) and responded to the addition of high (100 ng/ml), but not low (1 ng/ml), levels of HCG with increased steroidogenesis. Although luteal cells from HCG-treated macaques tended to produce more progesterone in vitro than cells from control monkeys, they also exhibited a 50-fold reduction in sensitivity to HCG in vitro. These data suggest that the corpus luteum of lactating postpartum rhesus monkeys exhibited steroidogenic function which was stimulated by exogenous gonadotropin. However, prolonged exposure of the corpus luteum to high levels of exogenous gonadotropin appeared to produce a state of refractoriness to additional gonadotropic stimuli.

Animals