Shimonovitz, S., Hurwitz, A., Hochner-Celnikier, D., Dushnik, M., Anteby, E., & Yagel, S. (1998). Expression of gelatinase B by trophoblast cells: down-regulation by progesterone. American journal of obstetrics and gynecology, 178(3), 457-461. https://doi.org/10.1016/s0002-9378(98)70420-x
Shimonovitz S, Hurwitz A, Hochner-Celnikier D, Dushnik M, Anteby E, Yagel S. Expression of gelatinase B by trophoblast cells: down-regulation by progesterone. Am J Obstet Gynecol. 1998;178(3):457-461. doi:10.1016/s0002-9378(98)70420-x
Shimonovitz, S., et al. "Expression of gelatinase B by trophoblast cells: down-regulation by progesterone." American journal of obstetrics and gynecology, vol. 178, no. 3, 1998, pp. 457-461.
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It is now accepted that gelatinase B (92 kd type IV collagenase) is involved in blastocyst implantation and trophoblast invasion. However, little is known about the regulation of this enzyme at the fetomaternal interface. Progesterone has been demonstrated to inhibit gelatinase B secretion from endometrial cells, myometrium, and cervical fibroblasts. Interestingly, the promotor of gelatinase B contains a progesterone-responsive element that may explain transcriptional activation of this metalloproteinase by progesterone. It may be hypothesized that progesterone secreted from trophoblast cells, representing the fetal part of the fetomaternal interface, may have a role in the regulation of gelatinase secretion and blastocyst implantation.
Study Design
To this end, use was made of first-trimester trophoblast cells obtained from first-trimester pregnancy terminations. The trophoblast cells were separated by trypsin degradation and fractionation on Percoll gradients. Metalloproteinase activity was measured by zymography, and the expression of the gelatinase B messenger ribonucleic acid was determined by the solution hybridization/ribonuclease protection assay.
Results
Primary cell cultures of trophoblasts from first trimesters of pregnancy constitutively elaborated two species of type IV collagenases (gelatinase A and B) as assessed on a gelatin matrix. Treatment with progesterone decreased the accumulation of a gelatinase B species in a dose-dependent fashion. Administration of a progesterone receptor antagonist onapristone (ZK-98.299) neutralized the progesterone inhibitory effect on the gelatinase B in a dose-dependent fashion, thus supporting the presumption that the progesterone effect is receptor mediated. Progesterone significantly attenuated the expression of gelatinase B by trophoblast cells, an effect that was neutralized by ZK-98.299.
Conclusion
These observations provide strong indirect support for the participation of progesterone in the regulation of gelatinase B in trophoblast cells. It may be an important regulator of gelatinase production at the fetomaternal interface.
We report the results of a first exploratory study testing the use of vaginal microbiome transplantation (VMT) from healthy donors as a therapeutic alternative for patients suffering from symptomatic, intractable and recurrent bacterial vaginosis (ClinicalTrials.gov NCT02236429 ). In our case series, five patients were treated, and in four of them VMT was associated with full long-term remission until the end of follow-up at 5-21 months after VMT, defined as marked improvement of symptoms, Amsel criteria, microscopic vaginal fluid appearance and reconstitution of a Lactobacillus-dominated vaginal microbiome. One patient presented with incomplete remission in clinical and laboratory features. No adverse effects were observed in any of the five women. Notably, remission in three patients necessitated repeated VMT, including a donor change in one patient, to elicit a long-standing clinical response. The therapeutic efficacy of VMT in women with intractable and recurrent bacterial vaginosis should be further determined in randomized, placebo-controlled clinical trials.
To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.
Sato T et al., 1991·Biochem J·Free full text on PubMed Central
Rabbit uterine cervical fibroblasts produced a large amount of matrix metalloproteinases (MMPs) such as collagenase (MMP-1) and stromelysin (MMP-3) and a small relatively amount of tissue inhibitor of metalloproteinases (TIMP). When cells were treated with progesterone or oestradiol-17 beta, both steroids concurrently decreased the level of procollagenase and prostromelysin in the culture media and the steady-state levels of the respective mRNAs. On the other hand, the level of TIMP in the culture media and the steady-state level of its mRNA were simultaneously increased by these steroids. Similarly, the suppression of production of MMPs and the augmentation of TIMP production by both steroids were observed with interleukin 1 (IL-1)-treated cells, but the action of progesterone was more effective than that of oestradiol-17 beta in the IL-1-untreated and -treated cells. These results suggest that collagenolysis in uterine cervical fibroblasts is negatively regulated by steroid hormones via the acceleration of TIMP production and the suppression of synthesis of MMPs at the pretranslational level.
DeMayo FJ et al., 2020·Journal of molecular endocrinology·Free full text on PubMed Central
Progesterone's ability to maintain pregnancy in eutherian mammals highlighted this steroid as the 'hormone of pregnancy'. It was the unique 'pro-gestational' bioactivity of progesterone that enabled eventual purification of this ovarian steroid to crystalline form by Willard Myron Allen in the early 1930s. While a functional connection between normal progesterone responses ('progestational proliferation') of the uterus with the maintenance of pregnancy was quickly appreciated, an understanding of progesterone's involvement in the early stages of pregnancy establishment was comparatively less well understood. With the aforementioned as historical backdrop, this review focuses on a selection of key advances in our understanding of the molecular mechanisms by which progesterone, through its nuclear receptor (the progesterone receptor), drives the development of endometrial receptivity, a transient uterine state that allows for embryo implantation and the establishment of pregnancy. Highlighted in this review are the significant contributions of advanced mouse engineering and genome-wide transcriptomic and cistromic analytics which reveal the pivotal molecular mediators and modifiers that are essential to progesterone-dependent endometrial receptivity and decidualization. With a clearer understanding of the molecular landscape that underpins uterine responsiveness to progesterone during the periimplantation period, we predict that common gynecologic morbidities due to abnormal progesterone responsiveness will be more effectively diagnosed and/or treated in the future.
Microsomal membranes sedimented at 40 000 g were prepared from human myometrium samples. The progesterone binding properties of microsomal suspensions were determined by incubating microsomes and [3H]progesterone at 4 degrees C. Dextran-coated charcoal was used for the separation of bound and free steroids. Membrane-associated progesterone binding sites of high affinity were identified in microsomes prepared from pregnant and nonpregnant uteri. The binding was saturable (Kd approximately 4 X 10(-9) M, concentration of binding sites 400-900 fmol/mg microsomal protein) and specific for natural progesterone. Of 21 steroids tested only 21-hydroxy-4-pregnene-3,20-dione, 17 alpha-hydroxyprogesterone and testosterone showed moderate competition against progesterone with relative affinities between 7.0-20.0% (R.A. of progesterone 100%). 5 alpha-Dihydroprogesterone and 5 alpha-dihydrotestosterone showed weak cross reaction (relative affinities 2.5 and 2.0%, respectively). Corticosteroids, estrogens and the 5 synthetic progestins tested showed only weak competition with relative affinities lower than 1.0%. These microsomal progesterone binding sites of high affinity and limited capacity resemble steroid hormone receptors but they are different from the soluble cytosolic progesterone receptor of human uterus in terms of steroid specificity. The physiological function of this microsomal progesterone receptor is unknown.
SUMMARY 1. The action of progesterone on the development of the mouse ovum from the eight-celled stage to the blastula has been studied in vitro . 2. Concentrations of progesterone below 2 μg/ml. produced no observable effect, whereas some toxicity was observed at 4 μg/ml. and few ova survived higher concentrations. 3. Herniation of the zona pellucida by the developing blastula is described; this process was inhibited by 4 μg/ml., but not by 2 μg/ml. of progesterone. 4. Blastulae appear to be more sensitive to the action of progesterone than are earlier stages. 5. Oestrogens afforded no demonstrable protection against the toxic action of progesterone when added to the culture medium. 6. The possible physiological significance of these findings is discussed.
Reproductive Endocrinology › Ovarian Hormones › Progesterone · Pregnancy › Early Pregnancy › Progesterone Support
Simcha Yagel
S Yagel
PMID 9539508 9539508 DOI 10.1016/s0002-9378(98)70420-x 10.1016/s0002-9378(98)70420-x Shimonovitz et al. 1998, Shimonovitz 1998
Cite this article
Shimonovitz, S., Hurwitz, A., Hochner-Celnikier, D., Dushnik, M., Anteby, E., & Yagel, S. (1998). Expression of gelatinase B by trophoblast cells: down-regulation by progesterone. American journal of obstetrics and gynecology, 178(3), 457-461. https://doi.org/10.1016/s0002-9378(98)70420-x
Shimonovitz S, Hurwitz A, Hochner-Celnikier D, Dushnik M, Anteby E, Yagel S. Expression of gelatinase B by trophoblast cells: down-regulation by progesterone. Am J Obstet Gynecol. 1998;178(3):457-461. doi:10.1016/s0002-9378(98)70420-x
Shimonovitz, S., et al. "Expression of gelatinase B by trophoblast cells: down-regulation by progesterone." American journal of obstetrics and gynecology, vol. 178, no. 3, 1998, pp. 457-461.
