Population Briefs | February 2003, Vol. 9, No. 1 | Biomedical Research: Mirena-Induced Drop in Menstrual Bleeding Studied

Population Briefs February 2003

February 2003, Vol. 9, No. 1

Biomedical Research
Mirena^®-Induced Drop in Menstrual Bleeding Studied

Researchers have known for years that the contraceptive Mirena^® drastically reduces the excessive menstrual bleeding experienced by some women with uterine fibroids, the most common benign uterine tumors. They did not know for certain, however, what molecular mechanism accounted for this marked improvement in symptoms. Recent studies have begun to provide insight into this mystery.

Mirena, a progestin-releasing intrauterine system (IUS), was co-developed and tested by the Population Council, its International Committee for Contraception Research, and the pharmaceutical company Leiras. Mirena is now approved for use in more than 80 countries and is being used by more than 2 million women. Mirena is an extremely effective contraceptive, with fewer than 1 in 100 women becoming pregnant during five years of using the device. Berlex Laboratories, Inc., the U.S. subsidiary of Schering AG, Germany, markets Mirena in the United States under a license from the Council. Schering AG markets Mirena globally.

Severe symptoms
Women with uterine fibroids and adenomyosis of the uterus (growth of the lining of the uterus, or endometrium, into the uterine muscle) often suffer from excessive menstrual bleeding. Extreme menstrual bleeding, also known as menorrhagia, often interferes with daily activities and can leave sufferers anemic. One treatment for menorrhagia has been therapy with gonadotropin-releasing hormone (GnRH) agonists, which induce a reversible menopause-like state. GnRH agonists, however, can have severe side effects, such as osteoporosis and hot flashes. Another common treatment, hysterectomy, leaves women permanently infertile. “Mirena offers a safe, nonsurgical alternative for the management of excessive menstrual bleeding that also preserves women’s fertility,” says Elof D.B. Johansson, director of the Population Council’s Center for Biomedical Research.

Previous investigators have shown that in women who use Mirena, the endometrium thins. This thinning reduces the material, including blood, that is shed through menstruation. Obstetrician and gynecologist Takeshi Maruo of Kobe University collaborated with Johansson, Council researcher Irving M. Spitz, and others to determine the underlying molecular cause of changes in the endometrium of women using Mirena. Maruo is a member of the Council’s International Committee for Contraception Research. The researchers examined cellular changes in the endometrium, analyzing samples taken from 15 women before and three months after the insertion of the Mirena IUS.

Radical transformation
In mammals, including humans, the endometrium is regulated in part by genetically programmed cell death, also known as apoptosis. The endometrium goes through a radical transformation during each menstrual cycle, which can be divided into three parts: the proliferative phase, the secretory phase, and the menstrual phase. During the proliferative phase, which starts at the end of menstrual bleeding and lasts until ovulation, increasing levels of estrogen induce the endometrium to thicken. During the secretory phase, which ranges from ovulation until the start of menstrual bleeding, the hormone progesterone causes endometrial glands to secrete mucus and other substances that would help sustain a pregnancy. If pregnancy does not occur, however, estrogen and progesterone levels drop and mass cell death begins in the endometrium. During the menstrual phase, the uterus sheds the endometrium. "Apoptosis helps refresh the endometrium, readying it for growth during the next cycle," explains Maruo.

The researchers looked at four factors related to apoptosis in the endometrium. PCNA, a marker of cell proliferation, was less abundant in the endometrium three months after IUS insertion than it was before insertion. Bcl-2 protein, which is known to prevent apoptosis, was present in endometrial glands before the insertion of Mirena, but became scanty three months after insertion. Conversely, Fas antigen, which promotes apoptosis, was scarcely apparent before Mirena insertion, but three months after insertion Fas antigen expression became predominant in the endometrium. Finally, the number of cells observed to be undergoing apoptosis in the endometrium was greater three months after IUS insertion than it had been prior to insertion.

"The increased apoptosis in the endometrium after Mirena insertion, which we detected using multiple measures, may represent an underlying molecular mechanism that causes the endometrium to atrophy," says Maruo. "This in turn leads to improved management of menorrhagia.

Sources
Laoag-Fernandez, J.B., T. Maruo, P. Pakarinen, I.M. Spitz, and E. Johansson. 2003 "Effects of levonorgestrel releasing intrauterine system on the expression of vascular endothelial growth factor and adrenomedullin in the endometrium," Human Reproduction 18(4): 694–699.

Maruo, T., J.B. Laoag-Fernandez, H. Matsuo, T. Samoto, O. Kurachi, S. Takeuchi, I.M. Spitz, P. Pakarinen, P. Lähteenmäki, and E. Johansson. 2002. "Effects of levonorgestrel-releasing intrauterine system on the endometrium and the relevance to the management of menorrhagia caused by uterine myoma and adenomyosis," in T. Maruo, D. Barlow, H. Marndon, and S. Kennedy (eds.), Cell and Molecular Biology of Endometrium in Health and Disease. Osaka: Soeisha, pp. 193–207.

Maruo, T., J.B. Laoag-Fernandez, P. Pakarinen, H. Murakoshi, I.M. Spitz, and E. Johansson. 2001. "Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium," Human Reproduction 16(10): 2103–2108.

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