Expression and hormonal regulation of aquaporins in the human uterus

BACKGROUND: Aquaporins (AQPs) are water channels present in the cell wall, allowing water – and occasionally other molecules – to pass the cell membrane. So far 13 AQPs have been found in humans. Their function is to maintain the cell internal milieu by regulating water and ion equilibrium. AQPs can be found in virtually all cell types and tissues and are essential to the normal function of cells and organs. Malfunction of the water channels can cause disease.

The uterine wall consists of three layers of which the endometrium is the innermost portion, facing the uterine cavity. The endometrium undergoes structural changes during the menstrual cycle, influenced by the hormones estrogen (E) and progesterone (P), as a preparation for implantation of a fertilized egg. Angiogenesis is the formation of new blood vessels from existing ones. This process is essential for regeneration of the endometrium after shedding during menstruation.

Excessive uterine bleeding, also called menorrhagia, is a common gynecological disorder, presenting with large menstrual bleedings and reduced quality of life for those affected. Several organic diseases can lead to excessive uterine bleeding, but in most of the cases the cause is unknown. Mifepristone is a synthetic steroid which has the ability to bind to P-receptors, thereby mainly blocking the effect of P. Mifepristone treatment improves menstrual bleeding pattern and has an effect on endometrial vessels.

OBJECTIVES OF THE STUDIES: The general objective of the studies was to gain knowledge about the expression and hormonal regulation of AQPs in the uterus as well as to investigate the connection between AQPs and uterine function in healthy subjects and patients diagnosed with excessive uterine bleeding.

RESULTS AND CONCLUSIONS: AQP1 and AQP2 are present in human endometrium; AQP1 in endothelial cells (lining the interior surface of blood vessels) and AQP2 in epithelial cells (lining cavities, surface structures, and glands). They can be assumed to be involved in events where water transport is essential, e.g. menstruation and reduction of uterine fluid volume at the time of implantation. AQP1 levels in the endometrium are reduced in women with excessive uterine bleeding, indicating that an impaired expression of AQP1 could be a cause to this condition.

Mifepristone treatment increases AQP1 expression in human endometrium, which could imply a regulation by P. In cell culture, it was possible to show a hormonal regulation of certain AQPs: AQP1 protein-expression was up-regulated in endothelial cells when exposed to E, as well as to P; AQP2 mRNA levels increased after exposure to E + IC, and P combined with mifepristone, and AQP7 protein-expression increased after treatment with E + IC, and E + P, suggesting a role for these AQPs in increased endometrial secretion after ovulation.

List of scientific papers

I. Anna Hildenbrand, Luther Lalitkumar, Soren Nielsen, Kristina Gemzell-Danielsson, Anneli Stavreus-Evers. Expression of aquaporin 2 in human endometrium. Fertil Steril. 2006; 86:1452–8.
https://doi.org/10.1016/j.fertnstert.2006.03.058

II. Miriam Mints, Anna Hildenbrand, Luther PG Lalitkumar, Sonia Andersson, Soren Nielsen, Kristina Gemzell Danielsson, Anneli Stavreus-Evers. Expression of aquaporin-1 in endometrial blood vessels in menorrhagia. Int J Mol Med. 2007; 19: 407-411.
https://pubmed.ncbi.nlm.nih.gov/17273788

III. Anna Hildenbrand, Anneli Stavreus-Evers, PGL Lalitkumar, Soren Nielsen, Miriam Mints, Kristina Gemzell Danielsson. Aquaporin 1 is expressed in the human endometrium during normal cycle and increases after mifepristone treatment. Int J Mol Med. 2008; 22: 49-53.
https://pubmed.ncbi.nlm.nih.gov/18575775

IV. Anna Hildenbrand, PGL Lalitkumar, Anneli Stavreus-Evers, Baiju Surendran, Kristina Gemzell-Danielsson. Hormonal control on aquaporins 1, 2, and 7 in human uterine endothelial cells by estrogen and progesterone: An in vitro study. [Manuscript]