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Functional evidence for divergent receptor activation mechanisms of luteotrophic and luteolytic events in the human corpus luteum
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
1999 (English)In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 5, no 5, 391-395 p.Article in journal (Refereed) Published
Abstract [en]

Using a dispersed human luteal cell culture model, progesterone synthesis following treatment by incremental doses of human chorionic gonadotrophin (HCG) and the stable prostaglandin F2alpha (PGF2alpha) analogue cloprostenol, alone or in combination, was related to corpora lutea (CL) mRNA transcript abundance coding for the luteinizing hormone (LH)/HCG receptor (LH-R) and PGF2alpha-receptor (FP) by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 33 otherwise healthy women, scheduled for surgery due to benign conditions. CL were grouped according to age, based on the occurrence of a preovulatory LH surge where post-LH days 2-5 were designated as early luteal phase, days 6-10 as mid-luteal phase and days 11-14 as late luteal phase. When exposed to HCG, maximal progesterone output was raised 2.2-fold (P = 0.08, n = 5) compared with untreated controls in the early CL, while it increased 5.7- and 4.6-fold in the mid- and late groups respectively (P<0.05, n = 4 mid-luteal phase, n = 3 late luteal phase). This stimulation pattern was found to be concordant with the value of mRNA coding for LH-R in all groups (n = 6 early luteal phase, n = 5 mid-luteal phase, n = 6 late luteal phase). The integrated response to HCG and cloprostenol showed a dose-dependent 60% inhibition of progesterone production; but only in late luteal phase luteal cells (P<0.01, n = 3). FP mRNA values were lowest in early luteal phase, and increased with the age of the CL. Interestingly, lowest CL tissue concentrations of the natural FP agonist PGF2alpha were found during mid-luteal phase while it increased again 1.6-fold during late luteal phase (P<0.05, n = 8 versus mid-luteal phase, n = 6). Collectively, these data demonstrate that (i) the extrinsic functional control (or rescue of CL in the event of pregnancy) occurs when the sensitivity towards LH/HCG is maximal; and (ii) the demise of CL function is mediated via an acquisition of sensitivity towards the intrinsic luteolytic signal, PGF2alpha in the ageing CL.

Place, publisher, year, edition, pages
1999. Vol. 5, no 5, 391-395 p.
Keyword [en]
corpus luteum, HCG, LH receptor, PGF2α receptor (FP), progesterone
National Category
Obstetrics, Gynecology and Reproductive Medicine
URN: urn:nbn:se:umu:diva-41638DOI: 10.1093/molehr/5.5.391PubMedID: 10338360OAI: diva2:407409
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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