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PubMed1996

Prostaglandin E2 induces inhibin alpha- and beta A-subunit mRNA and secretion of dimeric inhibin A in cultured human granulosa-luteal cells.

Prostaglandins (PG) E2 and F2 alpha are produced by the human corpus luteum in significant amounts and they are known to exert local luteotrophic and luteolytic effects respectively. The present study determined how PGE2 and PGF2 alpha are involved in the regulation of inhibin A, a granulosa cell-derived glycoprotein hormone that has an endocrine inhibitory effect on hypophyseal gonadotrophin production and a local stimulatory action on thecal cell androgen secretion. The effects of PGE2 and PGF2 alpha on inhibin alpha- and beta A-subunit mRNAs levels and on the secretion of dimeric inhibin A were studied in cultures of human granulosa-luteal cells obtained from patients undergoing an in-vitro fertilization programme. We found that PGE2 induced mRNA of inhibin alpha- and beta A-subunits in a time- and concentration dependent manner, whereas PGF2 alpha had no clear effect. In contrast to the rapidly and transiently induced beta A-subunit mRNA, alpha-subunit mRNA accumulation was stimulated with slower kinetics by PGE2 in a protein synthesis-dependent manner; this was also observed for the mRNA of the cytochrome P450scc enzyme. In the medium of cells cultured for 24 h with PGE2 (1 x 10(-6) M), 1.3-1.6-fold increase (P < 0.05) above basal values in secreted dimeric inhibin A was observed. The results suggest that PGE2 is an important inducer of inhibin A production in granulosa cells and that a local action of PGE2 may partially explain the increase in circulating inhibin A observed during the midluteal phase of the human menstrual cycle.

Cells, Cultured↗
PubMed1993

Inadvertent gonadotrophin-releasing hormone agonist (GnRHa) administration in the luteal phase may improve fecundity in in-vitro fertilization patients.

Spontaneous pregnancies associated with inadvertent periconceptional administration of a gonadotrophin-releasing hormone agonist (GnRHa) occur in approximately 1% of in-vitro fertilization (IVF) cycles. The two main issues to be considered in these circumstances are the luteolytic effect of the agonist and embryotoxicity. In addition, some authors have suggested a higher incidence of ectopic implantations. In view of these concerns, we report on 15 patients who conceived during pituitary desensitization with a GnRHa in the luteal phase of the menstrual cycle, and review the literature on the subject. A detailed analysis of the data available so far, which include 59 pregnancies exposed to GnRHa, shows that: (i) there is no clinical evidence for impaired luteal function, and hormonal supplementation does not improve pregnancy outcome; (ii) with only two cases of reported minor malformations among 37 deliveries, both having a genetic component, there is no evidence of teratogenic effects; and (iii) ectopic implantations in these circumstances are related to tubal disease but not to the drug. Considering the long history of infertility in these patients who had previously been treated unsuccessfully by different therapeutic modalities, it is likely that the occurrence of those pregnancies is not merely coincidental and that GnRHa might have a positive role in fecundity. The improved fecundity may be explained by the mechanisms of luteinizing hormone action in the corpus luteum.

Adult↗
PubMed1983

Alterations in plasma and tissue prostaglandin levels in rabbits during luteal regression.

To determine if ovarian as well as uterine prostaglandin production was associated with luteal regression, tissue and plasma concentrations of prostaglandin F (PGF), prostaglandin E (PGE), 6-keto-PGF1 alpha (6-keto-PGF), and thromboxane B2 (TxB) were measured by radioimmunoassay in uterus, corpora lutea, nonluteal tissue, uterine venous plasma and ovarian venous plasma on Days 8, 12 and 15 of pseudopregnancy in the rabbit. Total prostaglandin levels (PGF + PGE + 6-keto-PGF + TxB) were 4-fold greater in the uterus compared to nonluteal tissue and 8-fold greater than in corpora lutea. Both PGF and PGE levels were increased in uterine tissue on Day 15 compared to Days 8 or 12 (P less than 0.01). The ratio of PGF:PGE was also elevated on Day 15 compared to Days 8 or 12 (P less than 0.05) which suggests that the luteolytic effect of PGF predominates over the possible luteotropic effect of PGE. There were no significant changes in the concentration of TxB or 6-keto-PGF or the ratio of TxB:6-keto-PGF in uterine tissue on any day studied. In nonluteal tissue, PGE was the only PG to vary significantly; PGE levels were elevated (P less than 0.05) on Day 8 of pseudopregnancy compared to Days 12 or 15. Although corpora lutea contain significant quantities of PGF, PGE, TxB and 6-keto-PGF, no alterations in the levels of any of these substances were observed between Days 8, 12 or 15 of pseudopregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Multiple causes of pregnancy failure in hamsters precociously ovulated by human chorionic gonadotropin.

Cycling adult female hamsters can be induced to mate and ovulate 24 h early by the injection of 20 IU human chorionic gonadotropin (hCG) at 1500 h on Day 3 (day before proestrus), but pregnancy is not established. Although there is evidence of decreased sperm transport in precociously ovulated females, this does not appear to be the primary cause of infertility. Reduced size and vascularity of corpora lutea (CL) in treated females suggests incomplete or failed CL activation. Control and hCG-treated females were killed by exsanguination under ether anesthesia at intervals for the first 5 days after mating. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, estradiol, and progesterone were measured by radioimmunoassay. Luteinizing hormone in treated animals was very high at 2200 h on Day 1 after mating (31 h after the hCG injection), due to endogenous release, and dropped below control levels thereafter. Follicle-stimulating hormone, by contrast, was significantly lower than controls at 2200 h on Day 1 and remained low until 2200 h on Day 3 after mating. Prolactin in treated animals was not different from that in controls, except for 1000 h on Day 4, when it showed a significant dip. Estradiol in treated animals was significantly higher than in controls at 2200 h on Day 1 (when LH was also high and FSH was low), and remained high at 1000 h and 2200 h on Day 2, dropping thereafter to control levels. Progesterone was initially at control levels but had dropped significantly by 1000 h on Day 2 and remained low for the next 24 h. These results suggest that pregnancy failure is due to inadequate activation of corpora lutea. This may be due to: 1) immaturity of follicles at the time of ovulation; 2) inappropriate timing of preovulatory events; 3) the luteolytic effects of high levels of LH or estradiol or both; 4) the low level of FSH in the early stages of corpus luteum development; or 5) a combination of the above. Abnormalities of prolactin secretion were not investigated in detail but cannot be ruled out at this time.

Animals↗
PubMed1992

Prolactin stimulates the expression of luteinizing hormone/chorionic gonadotropin receptor messenger ribonucleic acid in the rat corpus luteum and rescues early pregnancy from bromocriptine-induced abortion.

Timed pseudopregnancy (psp) and pregnancy were induced in adult female rats by mating with infertile and fertile males, respectively. Corpora lutea (CL) and the residual parts of the ovaries were isolated and analyzed for luteinizing hormone/chorionic gonadotropin (LH/CG) receptor mRNA by Northern blot and solution hybridization analyses. Several LH/CG receptor mRNA transcripts were detected that could code for an intact functional receptor (6.8, 4.4, and 2.6 kb) as well as several smaller truncated transcripts. LH/CG receptor mRNA abundance in CL varied dramatically during both psp and pregnancy, with peak levels seen during the period of maximal progestational activity (Days 5-10 of psp and Days 7-14 of pregnancy). During the period of functional luteolysis, LH/CG receptor mRNA abundance decreased to low levels. The changes in LH/CG receptor expression could be explained by hormonal regulation. Bromocriptine treatment inhibited pituitary prolactin secretion. This treatment had a potent luteolytic effect by decreasing the levels of LH/CG receptor mRNA and plasma progesterone during early pregnancy, resulting in embryonal resorption in pregnant rats. Exogenous prolactin acted as a anti-luteolysin to reverse these effects by restoring LH/CG receptor mRNA abundance either by increasing gene expression or by stabilizing mRNA transcripts from degradation in young CL.

Abortion, Spontaneous↗
PubMed1993

Comparison of luteinized unruptured follicles and corpora lutea: steroid hormone production and response to luteolytic and luteotropic agents.

Administration of hCG prior to spontaneous ovulation induces the formation of luteinized unruptured follicles (LUFs) in guinea pigs. Serum progesterone (P) in animals with LUFs is significantly lower. This study was designed to determine whether follicular maturity affected the incidence of LUFs and P production as well as to compare isolated LUFs with corpora lutea (CL) in relation to hormone production and response to luteotropic and luteolytic agents. Ovarian histology and serum steroids following injection of hCG at various times during the estrous cycle indicated that greater follicular maturity increased the incidence of ovulation and P production. LUFs and CL contained equivalent amounts of P/mg tissue, but LUFs were significantly smaller than CL. Cells from CL and LUFs responded to hCG in vitro with significant increases in P release, but the response was greatest with LUFs. Prostaglandin F2 alpha (PGF) attenuated the response to hCG in vitro by mid-cycle CL and LUFs, but not by CL obtained during the early luteal phase. We conclude that the attenuated luteal-phase P profile following induction of LUFs is not an intrinsic deficiency in hormone production, but may arise from the smaller mass of luteal tissue and from earlier than normal development of responsiveness to the luteolytic effects of PGF.

Animals↗
PubMed1995

Modulation of cholesteryl ester hydrolase messenger ribonucleic acid levels, protein levels, and activity in the rat corpus luteum.

Previous studies have shown that the induction of functional luteolysis (loss of progesterone production) with either prostaglandin F2 alpha (PGF2 alpha) treatment or hypophysectomy (APX) diminished neutral cholesteryl ester hydrolase (CEH) activity in the corpus luteum (CL) and that prolactin (PRL) replacement of APX animals prevented luteolysis and maintained CEH activity at control levels. More recent studies have shown that CEH is the same protein as hormone-sensitive lipase (HSL) and that CEH/HSL activity may be regulated by phosphorylation. However, the possibility that CEH/HSL activity may be under transcriptional and/or translation control has not been excluded. Therefore, in the present study we examined whether PGF2 alpha treatment, APX, or inhibition of PRL secretion by bromocryptine (BrC) treatment modulated CEH/HSL mRNA and/or protein levels in a coordinate fashion with CEH activity. Furthermore, we examined whether CEH/HSL mRNA and/or protein levels changed after luteinization of the ovary and after natural functional regression. PGF2 alpha treatment and APX significantly reduced CEH activity; and PGF2 alpha treatment, APX, and BrC treatment significantly reduced CEH/HSL protein and mRNA levels. PRL replacement after APX substantially blocked the reductions in CEH activity, CEH/HSL protein, and CEH/HSL mRNA levels. PRL replacement during BrC treatment significantly inhibited the reductions in CEH/HSL protein and mRNA levels. CEH/HSL mRNA levels increased twofold after luteinization. Whereas CEH/HSL mRNA levels remained elevated after natural luteal regression, CEH/HSL protein significantly decreased. In summary, the luteolytic actions of PGF2 alpha, APX, and BrC resulted in coordinate reductions in luteal CEH activity, protein levels, and mRNA levels; PRL replacement significantly reversed the luteolytic effects of APX and BrC; natural luteal regression resulted in a reduction in CEH/HSL protein without a concomitant reduction in CEH/HSL mRNA. These results suggest that ovarian CEH activity is controlled at the level of both transcription and translation, and that PRL is important for continued CEH/HSL mRNA transcription in the CL.

Animals↗
PubMed1999

Sensitivity of bovine corpora lutea to prostaglandin F2alpha is dependent on progesterone, oxytocin, and prostaglandins.

Prostaglandin (PG) F2alpha that is released from the uterus is essential for spontaneous luteolysis in cattle. Although PGF2alpha and its analogues are extensively used to synchronize the estrous cycle by inducing luteolysis, corpora lutea (CL) at the early stage of the estrous cycle are resistant to the luteolytic effect of PGF2alpha. We examined the sensitivity of bovine CL to PGF2alpha treatment in vitro and determined whether the changes in the response of CL to PGF2alpha are dependent on progesterone (P4), oxytocin (OT), and PGs produced locally. Bovine luteal cells from early (Days 4-5 of the estrous cycle) and mid-cycle CL (Days 8-12 of the estrous cycle) were preexposed for 12 h to a P4 antagonist (onapristone: OP; 10(-4) M), an OT antagonist (atosiban: AT; 10(-6) M), or indomethacin (INDO; 10(-4) M) before stimulation with PGF2alpha. Although OP reduced P4 secretion (p < 0.001) only in early CL, it reduced OT secretion in the cells of both phases examined (p < 0.001). OP also reduced PGF2alpha and PGE2 secretion (p < 0.01) from early CL. However, it stimulated PGF2alpha secretion in mid-cycle luteal cells (p < 0.001). AT reduced P4 secretion in early and mid-cycle CL (p < 0.05). Moreover, PGF2alpha secretion was inhibited (p < 0.05) by AT in early CL. The OT secretion and the intracellular level of free Ca2+ ([Ca2+]i) were measured as indicators of CL sensitivity to PGF2alpha. PGF2alpha had no influence on OT secretion, although [Ca2+]i increased (p < 0.05) in the early CL. However, the effect of PGF2alpha was augmented (p < 0.01) in cells after pretreatment with OP, AT, and INDO in comparison with the controls. In mid-cycle luteal cells, PGF2alpha induced 2-fold increases in OT secretion and [Ca2+]i. However, in contrast to results in early CL, these increases were magnified only by preexposure of the cells to AT (p < 0.05). These results indicate that luteal P4, OT, and PGs are components of an autocrine/paracrine positive feedback cascade in bovine early to mid-cycle CL and may be responsible for the resistance of the early bovine CL to the exogenous PGF2alpha action.

Animals↗
PubMed2000

Prolactin-induced expression of intercellular adhesion molecule-1 and the accumulation of monocytes/macrophages during regression of the rat corpus luteum.

Intercellular adhesion molecule-1 (ICAM-1) is thought to facilitate the recruitment and migration of monocytes/macrophages to sites of inflammation. Here we investigated whether the luteolytic effect of prolactin in the hypophysectomized rat is associated with the expression of ICAM-1. In addition, we examined the effect of exogenous testosterone (or its potential conversion to estradiol endogenously) on the corpus luteum to address recent speculation that ovarian steroids might augment luteal regression. Immature, 30-day-old rats were ovulated with eCG and hCG and then hypophysectomized; this resulted in a single cohort of persistent corpora lutea. The rats were assigned randomly into four treatment groups: vehicle treatment without or with testosterone (VEH-T4, VEH+T4) and prolactin treatment without or with testosterone (PRL-T4, PRL+T4). Corpora lutea of control rats exhibited minimal ICAM-1 staining and contained relatively few monocytes/macrophages. In contrast, corpora lutea of prolactin-treated rats exhibited prominent ICAM-1 staining and contained numerous monocytes/macrophages. Testosterone did not overtly affect ICAM-1 staining, numbers of monocytes/macrophages, or concentrations of plasma progestins (progesterone and 20alpha-dihydroprogesterone) in either VEH or prolactin treatment groups; notwithstanding, luteal weights increased significantly in response to testosterone in VEH+T4 rats compared to VEH-T4 rats and prolactin-treated rats. We conclude that ICAM-1 expression and monocyte/macrophage accumulation are associated with prolactin-induced luteal regression in the rat and that these aspects are not influenced by testosterone.

Animals↗
PubMed2001

Endothelin-1 mediates prostaglandin F(2alpha)-induced luteal regression in the ewe.

A diversified series of experiments was conducted to determine the potential role of endothelin-1 (ET-1) in ovine luteal function. Endothelin-1 inhibited basal and LH-stimulated progesterone production by dispersed ovine luteal cells during a 2-h incubation. This inhibition was removed when cells were preincubated with cyclo-D-Asp-Pro-D-Val-Leu-D-Trp (BQ123), a highly specific endothelin ET(A) receptor antagonist. Administration of a luteolytic dose of prostaglandin F(2alpha) (PGF(2alpha)) rapidly stimulated gene expression for ET-1 in ovine corpora lutea (CL) collected at midcycle. Intraluteal administration of a single dose of BQ123 to ewes on Day 8 or 9 of the estrous cycle mitigated the luteolytic effect of PGF(2alpha). Intramuscular administration of 100 microg ET-1 to ewes at midcycle reduced plasma progesterone concentrations for the remainder of the estrous cycle. Following pretreatment with a subluteolytic dose of PGF(2alpha), i.m. administration of 100 microg ET-1 caused a rapid decline in plasma progesterone and shortened the length of the estrous cycle. These data complement and extend previously published reports in the bovine CL and are the strongest evidence presented to date in support of a role for ET-1 in PGF(2alpha)-mediated luteal function in domestic ruminants.

Animals↗
PubMed1982

LHRH analogues can be luteotrophic.

Seven normally menstruating women were treated with consecutive daily supraoptimal doses of the LHRH analogue Hoe 766 initiated in the mid/late luteal phase. This treatment caused immediate increases in circulating levels of LH, FSH, oestradiol (E2) and progesterone. After a few days, the pituitary became unresponsive to Hoe 766 and LH and FSH levels returned to the normal luteal phase ranges while progesterone and E2 levels did not decline to their respective pre-treatment levels until at least 24 h later. As a result of this treatment, the onset of the next menses was delayed in five of the seven women, indicating luteotrophism. These data show that the corpus luteum was responsive to increased LH/FSH during Hoe 766 therapy. Therefore, reported luteolytic effects of short-term treatment with LHRH and/or its analogues were probably not caused by direct inhibitory ovarian action but by reduction of ensuing pituitary gonadotrophin levels.

Adult↗
PubMed1995

Embryo survival following non-surgical embryo recovery in superovulated dairy heifers.

Embryo survival following non-surgical embryo recovery was studied in 66 superovulated dairy heifers. Blood samples were collected at uterine flushing (6.5 days after a single AI), 72 h after flushing and then every 7 days until estrus or until pregnancy diagnosis by palpation per rectum. Luteolytic effect by uterine flushing was detected in three heifers 72 h following flushing (progesterone values < 1 ng/ml plasma). From the remaining animals 11 (17.5%) remained pregnant and 52 returned to estrus. In four heifers, embryo loss was registered 48 days after AI. Seven heifers developed gestation to term: five resulted in single and two in twin normal births. Progesterone concentrations in all samples from heifers in which embryo loss occurred were higher than in those with pregnancy to term. For non-pregnant heifers, the average interval between uterine flushing and the following spontaneous estrus was 16.6 +/- 1.3 days (+/- SEM). It was concluded that uterine flushing did not induce luteolysis in most heifers, and after uterine flushing, embryos remaining in the uterus were capable of developing through pregnancy to term.

Animals↗
PubMed1976

The therapeutic activity, post-treatment fertility and safety of prostaglandin F2alpha-Tham salt in clinically anoestrous mares: a review.

Of 275 mares receiving prostaglandin F2alpha-Tham salt for its luteolytic effect upon the corpus luteum, 231 (84 per cent) exhibited signs of oestrus (range 73-95 per cent). Some mares not exhibiting overt oestrus may, nevertheless, ovulate and post-treatment rectal palpation of mares apparently failing to respond is suggested in these cases. Of 210 mares for which subsequent history was available. 104 (49.5 per cent) became pregnant from breeding at the post-treatment oestrus that immediately followed the induced regression of the corpus luteum (range 42.2-55.5 per cent). Fertility is comparable at this oestrus to that of naturally occurring oestrus in Thoroughbred mares. Side effects with PGF2alpha-Tham are physiological responses to the prostaglandin and include various degrees of sweating, some hypermotility of the gastrointestinal tract, increased pulse and respiratory rates and, occasionally, abdominal discomfort. These signs only occur in a proportion of mares, are transitory in nature and are resolved without treatment. A brief review of a comprehensive toxicity study using 20-160 times the recommended dose level, daily for 8 days, concludes that PGF2alpha-Tham has a 20 times safety margin for a single injection.

Anestrus↗
PubMed1984

Increased conception rate in dairy cows after early post partum administration of prostaglandin F2 alpha THAM.

Commercial dairy cows were given a routine injection of dinoprost tromethamine (prostaglandin F2 alpha THAM) in the early post partum period. The first service conception rate of 64 cows given a single 25 mg injection of dinoprost during the period 14 to 28 days after calving was 68 per cent, that of 64 untreated controls was 43 per cent. The difference was highly significant at the level P = 0.007. In cows with no blood progesterone and with basal progesterone concentrations at the time of treatment, indicating absence of an active corpus luteum, the mean conception rates for 30 treated and 38 control cows were 70 and 44 per cent, respectively, demonstrating that this is not a luteolytic effect. Although that implies a positive myometrial effect, the interval from calving to first service was not shortened in treated cows.

Animals↗
PubMed2006

Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model.

No specific treatment is available for ovarian hyperstimulation syndrome (OHSS), the most important complication in infertile women treated with gonadotropins. OHSS is caused by increased vascular permeability (VP) through ovarian hypersecretion of vascular endothelial growth factor (VEGF)-activating VEGF receptor 2 (VEGFR-2). We previously demonstrated in an OHSS rodent model that increased VP was prevented by inactivating VEGFR-2 with a receptor antagonist (SU5416). However, due to its toxicity (thromboembolism) and disruption of VEGFR-2-dependent angiogenic processes critical for pregnancy, this kind of compound cannot be used clinically to prevent OHSS. Dopamine receptor 2 (Dp-r2) agonists, used in the treatment of human hyperprolactinemia including pregnancy, inhibit VEGFR-2-dependent VP and angiogenesis when administered at high doses in animal cancer models. To test whether VEGFR-2-dependent VP and angiogenesis could be segregated in a dose-dependent fashion with the Dp-r2 agonist cabergoline, a well-established OHSS rat model supplemented with prolactin was used. A 100 microg/kg low-dose Dp-r2 agonist cabergoline reversed VEGFR-2-dependent VP without affecting luteal angiogenesis through partial inhibition of ovarian VEGFR-2 phosphorylation levels. No luteolytic effects (serum progesterone levels and luteal apoptosis unaffected) were observed. Cabergoline administration also did not affect VEGF/VEGFR-2 ovarian mRNA levels. Results in the animal model and the safe clinical profile of Dp-r2 agonists encouraged us to administer cabergoline to oocyte donors at high risk for developing the syndrome. Prophylactic administration of cabergoline (5-10 microg/kg x d) decreased the occurrence of OHSS from 65% (controls) to 25% (treatment). Therefore, a specific, safe treatment for OHSS is now available.

Animals↗
PubMed1982

Relationship of estradiol to luteal function in the cycling baboon.

Since exogenous 17 beta-estradiol (E2) is luteolytic in some primates, it is reasonable to conclude that endogenous E2 is the naturally occurring luteolytic substance. However, a link between endogenous E2 and spontaneous luteolysis has not been demonstrated. In an attempt to understand the function of E2 in spontaneous luteolysis, we employed the antiestrogen clomiphene. We administered E2, clomiphene, or E2 plus clomiphene to baboons during the luteal phase and measured systemic levels of estrone, E2, progesterone (P), and LH, E2 alone depressed the concentrations of P and bioassayable LH prematurely. The length of the luteal phase was significantly shortened (12.8 +/- 0.9 vs. 15.8 +/- 0.4 days for sham controls; P less than 0.01). Clomiphene blocked the luteolytic effect of exogenous E2, resulting in P levels which were not significantly different (P greater than 0.01) from control and a luteal phase of normal length (15.0 +/- 1.0 days). Treatment with E2 alone caused serum LH concentrations to decrease. The administration of clomiphene alone maintained circulating LH at early to midluteal phase levels but did not alter luteal phase P concentrations or prolong the length of the luteal phase (15.6 +/- 0.4 days). The results suggest that E2-induced luteolysis is a result of the withdrawal of luteotropic support from the (corpus) luteum, while spontaneous luteolysis is a result of some other mechanism which may not involve endogenous E2.

Animals↗
PubMed1990

Prostaglandin F2 alpha receptors on enzyme-dissociated pig luteal cells throughout the estrous cycle.

A deficiency of luteal cell prostaglandin F2 alpha (PGF2 alpha) receptors might help explain the well documented refractoriness of pig corpora lutea to the luteolytic effects of PGF2 alpha administered in vivo before day 12 of the estrous cycle. Accordingly, experiments were conducted to measure the levels of [3H] PGF2 alpha-binding sites/receptors on collagenase-dispersed pig luteal cells taken at different stages of the estrous cycle. Pig corpora lutea were obtained surgically at various stages of the estrous cycle and dissociated with collagenase in medium 199. Dissociated mixed luteal cells (approximately 5-15 x 10(4) large luteal cells/tube) were assayed for [3H]PGF2 alpha-binding activity by saturation (Scatchard) analysis. In preliminary experiments it was determined that PGF2 alpha binding was maximal after incubation for 45 min at 30 C in assay buffer of pH 5.75. Additionally, it was determined that [3H]PGF2 alpha binding was displaceable by PGF2 alpha = PGD2 greater than PGE2 greater than 13,14-dihydro-15-keto-PGF2 alpha. Other eicosanoids did not inhibit [3H]PGF2 alpha binding. Two distinct classes of binding sites (high affinity Kd = 19-64 nM; low affinity Kd = 262-3103 nM) were observed at all stages of the estrous cycle. From studies using enriched (by elutriation) large (greater than 30 microns) and small (10-20 microns) luteal cells it appeared that the high affinity binding site was largely confined to large luteal cells, whereas the low affinity binding site was found on both large and small luteal cells. The concentrations (number per large luteal cell) of high affinity PGF2 alpha-binding sites of mixed (unelutriated) luteal cell preparations was low on days 6-8 (0.6 x 10(6) sites/cell) and increased gradually up to 1.4 x 10(6) sites/cell on day 12. The concentrations of binding sites were increased approximately 3-fold on day 13 (4.6 x 10(6) sites/cell; P less than 0.05 vs days 6-12) and remained elevated on days 14 and 16-17 (approximately 3 x 10(6) sites/cell). In summary, these results indicate the existence of a high affinity PGF2 alpha-binding site in pig (large) luteal cells, which is probably the luteal PGF2 alpha receptor. The numbers of these putative PGF2 alpha receptors are low during the early luteal phase (before day 12), but increase thereafter (days 13, 14, and 16-17). This may provide one explanation for the observed refractoriness in vivo of pig corpora lutea to PGF2 alpha before, and increased sensitivity to PGF2 alpha after, day 12 of the estrous cycle.

Animals↗
PubMed1986

The dependency of folliculogenesis and corpus luteum function on pulsatile gonadotropin secretion in cycling women using a gonadotropin-releasing hormone antagonist as a probe.

A potent GnRH antagonist, [Ac-delta 3-Pro1,p-F-D-Phe2,D-Trp3,6]GnRH (4F-Antag), was used as a probe to determine the relative dependency of ovarian cyclicity on pulsatile gonadotropin secretion. 4F-Antag was administered in a dose of 80 micrograms/kg sc twice a day for 3 consecutive days during different phases of the menstrual cycle. This treatment resulted in a prompt attenuation of pulsatile gonadotropin secretion in all women studied. Maximal suppression of gonadotropin levels, expressed as percent change from baseline, averaged 48% for LH and 22% for FSH. The reduced pulsatile gonadotropin release induced by 4F-Antag administration during the early follicular phase resulted in a significant decrease in serum estradiol levels during the period of treatment and was followed by a prolongation of follicular phase (2.4 days) and cycle length (3.5 days), but no alteration of subsequent cyclic ovarian steroid profiles compared to control cycles. Treatment initiated during the midfollicular phase 4-6 days before the expected LH surge resulted in a more dramatic decline in serum estradiol levels and prolongation of follicular phase length by 5-6 days compared to control cycles. Normal luteal function was preserved. These alterations were compatible with induction of the demise of the dominant follicle followed by the reinitiation of follicular recruitment. Administration of 4F-Antag during the midluteal phase resulted in rapid falls in serum estradiol and progesterone levels and the onset of menstrual bleeding in all women. The luteolytic effect of 4F-Antag was completely negated by the administration of hCG. These data indicate that 4F-Antag interferes with ongoing cyclic ovarian function by reducing pulsatile gonadotropin stimulation, which disrupts folliculogenic processes and induces the demise of the corpus luteum. From these findings we infer that the functional integrity of ovarian cyclicity is remarkably sensitive to brief (3 days) and partial reduction in pulsatile gonadotropin secretion.

Adult↗