Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2

The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed to possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Uterine-specific deletion of Notch2 did not affect female fertility. Nevertheless, the expression of decidual Prl8a2, a member of the prolactin family, was downregulated due to Notch2 ablation. Subsequently, we interrupted pituitary prolactin function to determine the luteotropic role of the decidua by employing the lipopolysaccharide-induced prolactin resistance model, or blocking the prolactin signaling by prolactin receptor-Fc fusion protein, or repressing pituitary prolactin release by dopamine receptor agonist bromocriptine, and found that Notch2-deficient females were more sensitive to these stresses and ended up in pregnancy loss resulting from abnormal corpus luteum function and insufficient serum progesterone level. Overexpression of Prl8a2 in Notch2 knockout mice rescued lipopolysaccharide-induced abortion, highlighting its luteotropic function. Further investigation adopting Rbpj knockout and DNMAML overexpression mouse models along with chromatin immunoprecipitation assay and luciferase analysis confirmed that Prl8a2 was regulated by the canonical Notch signaling. Collectively, our findings demonstrated that decidual prolactin members, under the control of uterine Notch signaling, assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and maintenance.

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PROLACTIN IN MAINTENANCE OF THE CORPUS LUTEUM OF EARLY PSEUDOPREGNANCY IN THE GOLDEN HAMSTER

Journal of Endocrinology ◽

10.1677/joe.0.0900145 ◽

1981 ◽

Vol 90 (2) ◽

pp. 145-150 ◽

Cited By ~ 7

Author(s):

K. H. HARRIS ◽

B. D. MURPHY

Keyword(s):

Single Dose ◽

Corpus Luteum ◽

Golden Hamster ◽

Peripheral Blood ◽

Plasma Levels ◽

Progesterone Level ◽

Control Group ◽

Blood Samples

The role of prolactin in the maintenance of the corpus luteum of pseudopregnancy was studied in the golden hamster. Nine groups of seven to fourteen animals each received 1 mg bromocriptine at 11.00 h on days 1, 2 or 3 of pseudopregnancy (three groups for each day). On each day of treatment with bromocriptine, one group of hamsters was injected with bovine prolactin 4 h before bromocriptine, and one group received prolactin 4 h before bromocriptine for three consecutive days following treatment with bromocriptine. One group received bromocriptine only. These nine groups were compared with a control group of animals given 0·85% saline instead of bromocriptine and prolactin. Peripheral blood samples were taken from all hamsters at 11.00 h on days 3, 4, 5 and 6 of pseudopregnancy and plasma levels of progesterone were determined by radioimmunoassay. Luteolysis, indicated by a decline in progesterone level by 24 or 48 h after treatment with bromocriptine, occurred in all hamsters given bromocriptine alone, whether it was administered on day 1, 2 or 3. Pretreatment with a single dose of prolactin did not mitigate the bromocriptine-induced fall in progesterone. In the majority of cases, pretreatment with prolactin plus daily doses of prolactin maintained the progesterone at levels not different from saline-treated hamsters. These data suggest that prolactin is a necessary luteotrophin during early pseudopregnancy without which luteolysis ensues.

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Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Deficient Mice Display Reduced Serum Progesterone Levels during Corpus Luteum Development

Endocrinology ◽

10.1210/en.2002-220963 ◽

2003 ◽

Vol 144 (1) ◽

pp. 5-8 ◽

Cited By ~ 22

Author(s):

Warren B. Nothnick

Keyword(s):

Corpus Luteum ◽

Tissue Inhibitor Of Metalloproteinase ◽

Wild Type ◽

Serum Progesterone ◽

Multifunctional Protein ◽

Progesterone Production ◽

In The Wild

Abstract TIMP-1 is a multifunctional protein that is abundantly expressed within the ovary during the period of early corpus luteum formation. TIMP-1 has been suggested to play a role in progesterone production, but reports are conflicting. To more thoroughly examine the role of TIMP-1 in steroidogenesis during early luteal development in vivo, immature wild-type and TIMP-1 null female mice were primed with gonadotropins. Mice were sacrificed at 0, 24, and 48 h post hCG administration and serum was collected for determination of estradiol (E2) or progesterone (P4) concentrations. In the 24 h hCG groups, ovulation was assessed by counting the number of shed ova. Serum P4 concentrations were significantly lower in the TIMP-1 null mice, both at 24 and 48-h post hCG compared to wild-type counterparts. No differences were detected in the number of ovulations between genotypes at the 24 h time point. In both the 24 and 48 h post-hCG groups, null mice had significantly higher ovarian wet weights. Interestingly, ovarian MMP activity was greater in the null mice at 24 h post hCG but higher in the wild-type at 48 h post hCG administration. These observations suggests that expression of TIMP-1 during early luteal development may participate in regulation of progesterone production via its ability to regulate ovarian MMP activity.

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Transient development and function of rabbit corpora lutea after hypophysectomy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1984.247.6.e808 ◽

1984 ◽

Vol 247 (6) ◽

pp. E808-E814

Author(s):

K. C. Yuh ◽

C. H. Bill ◽

P. L. Keyes

Keyword(s):

Estrogen Receptor ◽

Corpus Luteum ◽

Pituitary Hormones ◽

Corpora Lutea ◽

Serum Progesterone ◽

Lh Receptor ◽

Luteal Tissue ◽

Wet Weight ◽

And Function

The requirement of the pituitary gland and the role of 17 beta-estradiol in the early development of the corpus luteum was investigated in rabbits hypophysectomized the day after sterile mating (day 1). Serum progesterone in hypophysectomized rabbits was normal for 2 days after hypophysectomy. Luteal tissue from hypophysectomized and sham-hypophysectomized rabbits had similar wet weight (4.0 +/- 0.4 vs. 5.3 +/- 0.2 mg/corpus luteum) and similar concentrations of available cytoplasmic estrogen receptor (1.2 +/- 0.2 vs. 1.5 +/- 0.3 fmol/micrograms DNA) and luteinizing hormone (LH) receptor (4.0 +/- 0.2 vs. 6.1 +/- 1.4 fmol/micrograms DNA) on day 4 of pseudopregnancy. Serum progesterone in hypophysectomized rabbits began to decline on day 4 and was undetectable by day 6. Estrogen receptor and luteal weight in hypophysectomized animals also declined after day 4 to low values by day 6, and serum estradiol was undetectable. However, if estradiol was administered by Silastic capsule implanted subcutaneously at the time of hypophysectomy or 3 days after hypophysectomy, serum progesterone, luteal weight, estrogen receptor, and LH receptor were maintained on day 6 of pseudopregnancy. These results indicate that after a preovulatory gonadotropin surge, the function of newly formed corpora lutea is normal for 3–4 days in the absence of pituitary hormones. However, by 4 days after ovulation, estradiol is required to sustain the structural and functional integrity of corpora lutea.

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Role of matrix metalloproteinase 2 in the ovulatory folliculo-luteal transition of ewes

Reproduction ◽

10.1530/rep.0.1240347 ◽

2002 ◽

pp. 347-352 ◽

Cited By ~ 26

Author(s):

ML Gottsch ◽

EA Van Kirk ◽

WJ Murdoch

Keyword(s):

Matrix Metalloproteinase ◽

Corpus Luteum ◽

Basement Membranes ◽

Extracellular Proteins ◽

Cellular Migration ◽

Matrix Metalloproteinase 2 ◽

Corpora Lutea ◽

Serum Progesterone ◽

Ovulatory Follicle

Tissue dissolution and remodelling are associated with the processes of rupture of the ovulatory follicle and formation of the corpus luteum. Matrix metalloproteinase 2 (MMP-2) belongs to a family of endopeptidases that cleave extracellular proteins; its primary substrate is the lattice network of basement membranes that support epithelial cells and endothelium. The aim of this study was to ascertain a putative regulatory role of MMP-2 relevant to the folliculo-luteal transformation in ewes. Luteal regression and the preovulatory surge of gonadotrophins were synchronized by administration of PGF(2alpha) and GnRH on days 14.0 and 15.5 of the oestrous cycle, respectively. Dominant antral follicles present during pro-oestrus consistently ovulate approximately 24 h after GnRH administration. Normal IgG or a bioactivity-neutralizing MMP-2 monoclonal antibody was injected into the antral cavity of preovulatory follicles at 8 h after GnRH administration. Jugular blood samples were obtained for serum progesterone analysis and ovaries were removed for light microscopic morphometry on day 8. A definitive ovulation stigma was evident in control ewes. The antra of ruptured follicles had largely been supplanted with luteal tissue. In contrast, the ovarian surface contiguous with follicles injected with anti-MMP-2 was smooth and undisturbed, which is indicative of a failure of ovulation. Luteinized unruptured follicles were filled with (entrapped) fluid. Corpora lutea of control animals contained numerous connective tissue projections that provided a framework for cellular migration and angiogenesis. Luteal tissues that surrounded the cavity of antibody-treated follicles lacked trabeculae and were deficient in blood vessels. Systemic venous progesterone concentrations were lower in ewes with a luteinized unruptured follicle compared with those with a corpus luteum. It is proposed that MMP-2 is a mediator of ovulation and luteal development.

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The Role of Activated NOTCH Signaling in Childhood T-ALL

Klinische Pädiatrie ◽

10.1055/s-0030-1270328 ◽

2010 ◽

Vol 223 (01) ◽

Author(s):

AE Kulozik ◽

C Kox ◽

M Remke ◽

S Breit ◽

M Zimmermann ◽

...

Keyword(s):

Notch Signaling

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ZUR BEDEUTUNG DES HYPOPHYSÄREN LUTEINISIERUNGSHORMONS FÜR SCHWANGERSCHAFT, GEBURT UND LACTATION BEI DER RATTE

Acta Endocrinologica ◽

10.1530/acta.0.065s005 ◽

1970 ◽

Vol 65 (3_Suppl) ◽

pp. S5-S32 ◽

Cited By ~ 2

Author(s):

K. Loewit

Keyword(s):

Luteinizing Hormone ◽

Early Pregnancy ◽

Hydroxysteroid Dehydrogenase ◽

The State ◽

Termination Of Pregnancy ◽

Progesterone Level ◽

Corpora Lutea ◽

Regulatory Properties ◽

Duration Of Pregnancy

ABSTRACT The role of luteinizing hormone (LH) for the maintenance of pregnancy, parturition and lactation was investigated by immunological and histochemical methods in the rat. Neutralisation of endogenous rat-LH with Rabbit-Anti-Bovine-LH-Serum (selective hypophysectomy) from days 7-12 of pregnancy resulted in reabsorption of the foetuses and the reappearance of strong 20α-hydroxysteroid-dehydrogenase (20α-OHSD) activity in the corpora lutea (CL) of pregnancy, which normally show no such activity at that time. This effect could be prevented in part by concurrent pregnenolone administration and fully by progesterone, but was not influenced by oestrogen or prolactin. It is concluded that in early pregnancy LH is the main luteotrophic hormone in the rat even though prolactin might act synergistically with it. Antiserum treatment after the 12th day of gestation had no influence on the state or duration of pregnancy or on parturition. LH-injections during the first half of pregnancy had no luteolytic effects i. e. they did not activate 20α-OHSD activity. After day 16 they advanced the reappearance of the enzyme, but delayed parturition or resulted in stillbirths. Neither LH nor antiserum seemed to alter lactation. Since progesterone prevented both the termination of pregnancy and the recurrence of 20α-OHSD activity, it should have some regulatory properties on the enzyme. It is discussed whether the gonadotrophin-dependent progesterone level could regulate the 20α-OHSD activity rather than result from it.

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GESTOGENS IN CORPUS LUTEUM OF CATTLE

Acta Endocrinologica ◽

10.1530/acta.0.xxxiii0417 ◽

1960 ◽

Vol XXXIII (III) ◽

pp. 417-427 ◽

Cited By ~ 19

Author(s):

John Kristoffersen

Keyword(s):

Corpus Luteum ◽

Average Value ◽

Spectrophotometric Methods ◽

The Third ◽

Quantitative Measurements ◽

Before And After ◽

Luteal Tissue ◽

In Pregnancy

ABSTRACT By means of chromatographic and spectrophotometric methods progesterone and a substance closely similar to 20β-hydroxy-pregn-4-ene-3-one has been detected in luteal tissue from non-pregnant and pregnant cows. In 21 animals quantitative measurements based on a method giving an average net recovery of 56 per cent showed that in pregnancy the average progesterone content in the corpus luteum reached a maximum in the third to fifth month, with low values before and after this period. For 6 nonpregnant cows, the average value was 20.2 μg/g tissue, which is considerably higher than previous values reported in the literature. The relation between these findings and the bovine dependence on a functional corpus luteum in pregnancy is discussed, and it is pointed out that more information about the metabolism of progesterone in cattle is highly desirable.

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