With drawal of which hormone is the immediate cause of menstruation
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With drawal of which hormone is the immediate cause of menstruation
Progesterone
The menstrual cycle is regulated by two hormones secreted from the pituitary gland, Follicle stimulating Hormone [FSH]
Progesterone withdrawal causes endothelin release from cultured human uterine microvascular endothelial cells.
[The monthly human menstrual bleed is an intricately and highly regulated event involving the endocrine, cardiovascular and haemostatic systems. Despite enormous advances in molecular biology during the last decades, details of the regulation of menstrual bleeding are still not known. The shedding of the endometrium follows in the absence of or at failed implantation. It is preceded by the demise of the corpus luteum and, as a consequence thereof, a fall in circulating progesterone. The progesterone withdrawal initiates a sequence of events that ultimately lead to the shedding of the endometrium and menstrual bleeding.
Past and present theories regarding the mechanisms of menstruation involve, to some extent, vasoconstriction in the coiled arteries (also called spiral arteries) of the endometrium. In the early works by Markee, this constriction was suggested to precede menstrual bleeding ( Markee, 1940 ). For >60 years, scientists have searched with increasingly advanced methods for a link between progesterone withdrawal and the regulation of menstrual bleeding. However, the link between progesterone withdrawal and the subsequent coiled artery vasoconstriction has been poorly studied and is not at all clear. Many factors have been suggested to be involved; hormones, enzymes, inflammatory mediators, haemostatic factors and growth factors. We have focused our interest on the 21 amino acid polypeptide endothelin (ET). Endothelins consist of a group of three peptides, ET‐1, ET‐2 and ET‐3, with potent biological properties. ET‐1 is produced mainly by endothelial cells and is the most potent vasoconstrictor peptide known to date ( Yanagisawa et al ., 1988 ). Other tissues produce ET‐2 and ET‐3.
The ETs appear to act primarily by a direct effect on vascular smooth muscle cells ( Gude et al ., 1991 ). Thus, the main site of action of ET in the endometrium is likely to be the vascular smooth muscle cells of the small endometrial vessels. Normally, circulating ET levels, as well as production of the peptide in isolated blood vessels, are rather low due to the absence of stimuli and the presence of potent clearance mechanisms. Important stimulators of ET production are thrombin, angiotensin, arginine, vasopressin and transforming growth factor‐β, as well as certain cytokines and physicochemical factors such as hypoxia ( Luscher et al ., 1993 ).
We hypothesized that uterine microvascular endothelial cells might release endothelin in response to progesterone withdrawal, and that ET therefore could be one agent that contributes to endometrial vessel contraction. The resulting endometrial ischaemia could then be one of the regulators of menstrual bleeding.
Menstrual bleeding also intimately involves the coagulation system. As a candidate for the link between progesterone withdrawal, ET release and the coagulation system, we have studied thrombin. Progesterone has been found to regulate synthesis of the G protein‐coupled protease‐activated receptor‐1 (PAR‐1), the receptor for thrombin, in the human endometrium ( Hague et al ., 2002 ) and in the arterial wall of the aorta ( Herkert et al ., 2001 ). Thrombin is known to upregulate endothelin‐converting enzyme (ECE‐1) in human endothelial cells ( Eto et al ., 2001 ). Furthermore, thrombin is one factor that stimulates ET release, as shown by several authors ( Yanagisawa and Masaki, 1989 ; Ohlstein and Storer, 1992 ). One endothelial cell response to stimulation by thrombin through the thrombin receptor is release of the contents of the Weibel–Palade bodies. These contain several locally effective proteins, including von Willebrand factor ( Wagner et al ., 1982 ) and ET ( Russell et al ., 1998 ). Thrombin also induces secretion of another storage particle containing tissue plasminogen activator (tPA) ( Emeis et al ., 1997 ). Following progesterone withdrawal, there is an increase of tPA ( Lockwood and Schatz, 1996 ) possibly as a response to an increased thrombin response.
To test the hypothesis that endothelial cells in the uterine small arteries might upregulate thrombin receptors and release ET in response to progesterone withdrawal, we have cultured uterine microvascular endothelial cells (UtMVEC‐Myos) in the presence of estrogen and progesterone, and analysed ET levels in the culture supernatants as well as thrombin receptor occurrence in the cells under conditions simulating progesterone withdrawal. In order to compare the reactions to progesterone withdrawal in UtMVECs with another endothelial cell type commonly used for studies of endothelial production of vasoactive substance, we also performed the same experiment in human umbilical vein endothelial cells (HUVECs). There are documented differences between the two endothelial cell types ( Lang et al ., 2003 ).]