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A putative stimulatory role of progesterone acting via progesterone receptors in the steroidogenic cells of the human corpus luteum
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2000 (English)In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 62, no 3, 655-663 p.Article in journal (Refereed) Published
Abstract [en]

To further explore the proposed auto-regulatory role of progesterone action in the human corpus luteum (CL), the expression and functional roles of progesterone receptor (PR) isoforms A and B during the luteal phase (LP) of the menstrual cycle were investigated. A total of 27 otherwise healthy patients previously scheduled for surgery were recruited after informed consent. An LH rise was detected, and CL were grouped according to age (Days 2-5 post-LH-rise, early LP; Days 6-10, mid LP; Days 11-14, late LP). Using a semiquantitative reverse transcription-polymerase chain reaction assay, the PR-B mRNA levels, which were 100- to 1000-fold lower than PR-A/B mRNA, were 46% lower (P < 0.05, n = 24) in mid LP, compared to early and late LP. CL tissue levels of progesterone and PR-A/B protein levels were inversely correlated to increasing CL age; i.e., significantly reduced levels were observed in the late LP (r(2) = 0.34, P < 0.01, n = 23). Expression of PR-A/B mRNA as well as PR-A/B protein were detected by in situ hybridization and immunohistochemistry, respectively. Both methods revealed a clear and distinct localization to cells in the steroidogenic layer of the CL. Freshly obtained mid-luteal CL cells were cultured in vitro, and media were analyzed for progesterone concentrations after treatment by incremental doses of hCG and the stable PR antagonist mifepristone, alone or in combination. Mifepristone did not per se alter progesterone synthesis, but when it was added in conjunction with hCG, a dose-related inhibitory response was seen, with a maximal 47% reduction in progesterone output at a 10 microM addition (P < 0.05, n = 3). Collectively, these data implicate a stimulatory role of progesterone receptor-mediated action in the steroidogenic cells of the human CL, which may serve as an important pathway for maintaining functional homeostasis during early pregnancy.

Place, publisher, year, edition, pages
2000. Vol. 62, no 3, 655-663 p.
National Category
Obstetrics, Gynecology and Reproductive Medicine
URN: urn:nbn:se:umu:diva-41640DOI: 10.1095/​biolreprod62.3.655PubMedID: 10684807OAI: diva2:407413
Available from: 2011-03-30 Created: 2011-03-30 Last updated: 2011-09-17Bibliographically approved
In thesis
1. Intraovarian mechanisms influencing the human corpus luteum
Open this publication in new window or tab >>Intraovarian mechanisms influencing the human corpus luteum
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: The human corpus luteum (CL) is a transient endocrine gland, only functionally active for about 14 days. Its principal function is to produce and secrete progesterone and thereby support the endometrium for implantation of a blastocyst and prevent rejection of the developing embryo. In the event of a non-conceptive cycle, functional and structural demise of the CL follows and a new ovulatory cycle begins. The aims of the thesis were to study different mechanisms involved in the extrinsic and intrinsic regulation of the CL and correlate these findings to available clinical investigations tools.

Materials and methods: Sixty women volunteered to donate their CL prior to scheduled surgery due to benign conditions. They were grouped according to CL-age, based on the occurrence of a preovulatory luteinizing hormone (LH) surge where days 2-5 post LH surge were designated as early luteal phase, days 6-9 as mid luteal phase and days 11-14 as late luteal phase. The CL bearing ovary was investigated using transvaginal ultrasonographical B-mode and color Doppler imaging prior to surgery. Following excision, the CL was further characterized using anatomical and morphological measurements, in vivo and in vitro hormone synthesis, isolation and cultures of steroidogenic luteal cells. Moreover, active transcription of putative regulatory genes of interest was targeted using semi-quantitative reverse-transcription polymerase chain reaction, in situ hybridization and Northern blots, and these genes' respective translation products were characterized by immunocytochemistry.

Results: The bulk of progesterone is stimulated by human chorionic gonadotropin (hCG) in the peripheral (steroidogenic) layer of the CL, where the LH/hCG receptor, as well as progesterone receptor (PR) isoform A/B and estrogen receptor type β (ER-β), but not ER-α, was localized. The sesitivity towards hCG was highest during the mid luteal phase in concordance with the value of LH/hCG receptor coding mRNAs. During this phase, despite low levels of PR-B mRNA, hCG treatment initiated a significant rise in progesterone output which could be blunted by the PR antagonist mifepristone. Increased amounts of prostaglandin (PG) F and its respective receptor (FP) mRNA were detected during the later developmental stages of the CL. However, steroidogenic luteal cells were unresponsive to added PGF until late luteal phase, indicative of an acquisition of sensitivity to the proposed luteolytic signal during this stage. Intraluteal vascular density was highest in early luteal phase and dramatically decreased during the course of CL development, a finding which was inversely correlated to resistance to blood flow in intraovarian blood vessels supplying the CL. Furthermore, a high degree of agreement between ultrasonographical and anatomical measurements of the CL was found.

Conclusions: Based on the novel findings herein, the hypothesis of steroid influence, acting within or near the steroidogenic luteal cells is confirmed. Alongside the classical extrinsic signals (e.g. hCG) and locally produced factors (e.g. PGF) these findings may further explain their modulatory roles during luteolysis or very early pregnancy. Furthermore, transvaginal ultrasonography in combination with color Doppler measurements may serve as a clinical tool to evaluate CL function.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2000. 44 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 695
Corpus luteum, steroidreceptors, progesterone, LH/hCG, PGF2α, ultrasonography
National Category
Obstetrics, Gynecology and Reproductive Medicine
urn:nbn:se:umu:diva-46975 (URN)91-7191-915-5 (ISBN)
Public defence
2000-10-27, Hörsal E04, by 6E, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Available from: 2011-09-17 Created: 2011-09-17 Last updated: 2011-09-17Bibliographically approved

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Ottander, UlrikaHosokawa, KenichiLiu, KuiBergh, AndersNy, TorOlofsson, Jan I
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