Progesterone Induces Calcitonin Gene Expression in Human Endometrium within the Putative Window of Implantation¹

Abstract

The human endometrium acquires the ability to implant the developing embryo within a specific time window that is thought to open between days 19-24 of the secretory phase of the menstrual cycle. During this period the endometrium undergoes pronounced structural and functional changes induced by the ovarian steroids, estrogen and progesterone, that prepare it to be receptive to invasion by the embryo. The identification of reliable biochemical markers to assess this critical receptive phase in the context of the natural cycle remains one of the major challenges in the study of human reproduction. Our previous studies in a rat model system demonstrated that the expression of calcitonin, a peptide hormone involved in calcium homeostasis, is transiently induced by progesterone in the glandular epithelium at the onset of implantation. Attenuation of calcitonin synthesis in the uterus during the preimplantation phase by administration of calcitonin antisense oligodeoxynucleotides severely impairs implantation of rat embryos, suggesting that this peptide hormone plays a critical role in uterine receptivity. To investigate whether calcitonin is also expressed in the human endometrium during implantation, we monitored the spatio-temporal expression of calcitonin on various days of the menstrual cycle. Our studies employing RT-PCR showed that calcitonin messenger ribonucleic acid is expressed in human endometrium during the postovulatory midsecretory phase (days 17-25) of the menstrual cycle, with maximal expression occurring between days 19-21. Very little calcitonin expression was detected in the endometrium in either the preovulatory proliferative (days 5-14) or the late secretory (days 26-28) phase. In situ hybridization and immunocytochemical analyses localized the calcitonin expression predominantly in the glandular epithelial cells of the endometrium. Our studies further showed that calcitonin expression in the human endometrium is under progesterone regulation. Treatment of women with an antiprogestin, mifepristone (RU-486), drastically reduced calcitonin expression in the endometrium. Collectively, these findings reveal that progesterone-induced expression of calcitonin in the secretory endometrium temporally coincides with the putative window of implantation in the human.

Calcitonin administration improves endometrial receptivity via regulation of LIF, Muc‐1 and microRNA Let‐7a in mice

“…Recent studies have shown that CT can also be synthesized and secreted by other organs such as the uterus (Ding, Zhu, Bagchi, & Bagchi, 1994). It has been reported that after fertilization the endometrium begins to express the CT, and the CT mRNA expression reaches the highest level during the implantation window (Ding et al, 1994;Kumar et al, 1998;Zhu, Cullinan-Bove, Polihronis, Bagchi, & Bagchi, 1998). The expression of CT is regulated by P4 and occurs in the middle secretory phase of the menstrual cycle, which coincides with the implantation window.…”

Implantation: Cross Talk of the Developing Embryo and Endometrium

“…Intracellular Ca + is essential in the E-cadherin regulation and assembly, in which a rise in intracellular Ca + induces a signaling cascade that results in cytoskeletal reorganization and the disassembly of E-cadherins between cellular junctions. Consequently, calcitonin expression is induced by increased progesterone secretion, which results in an increase in intracellular Ca + concentrations [18]. This specifically seems to take place during the mid-secretory phase, at which time the window of implantation is implicated to occur.…”

In search for an ideal marker of endometrial receptivity: from histology to comprehensive molecular genetics-based approaches

“…Это белки клеточной адгезии, цитокины, факторы роста и другие регуляторные и структурные молекулы [20,[22][23][24]32]. Их изучение в образцах эндометрия преимущественно основано на использовании иммуногистохимических методов и в некоторых случаях, когда необходимо исследовать экспрессию белка на уровне мРНК, флуоресцентной гибридизации in situ (FISH) [74][75][76]. Наиболее изученным белком, экспрессию которого связывают с установлением периода «имплантационного окна», является интегрин αvβ3 [77][78][79].…”

“…В группе белков клеточной адгезии есть и другие молекулы, кроме интегрина αvβ3, которые рассматривают в качестве способных влиять на рецептивность эндометрия: CD44, trophinin, cadherin-11 [83][84][85]. Другие возможные маркеры, определяющие рецептивное состояние эндометрия, включают: цитокин LIF (leukemia inhibitory factor -ингибирующий фактор лейкемии), факторы роста HB-EGF (heparin-binding epidermal growth factor-like factor -гепаринсвязывающий EGF-подобный фактор роста) и IGF-II (insulin-like growth factor-II -инсулиноподобный фактор роста-II) [20,23,32,86], кальцитонин [74,75], транскрипционные факторы HOXA10 и HOXA11 [76,[87][88][89], L-селектин и лиганд L-селектина [90].…”

“…Для анализа всего пула молекул мРНК в клетке используют микроматричный анализ или высокопроизводительное секвенирование (next generation sequencing -NGS) -современные генетические технологии, которые в рамках одного эксперимента позволяют исследовать экспрессию сотен и тысячи генов. Так, во многих работах наряду с иммуногистохимическим окрашиванием проводили исследование количества и распределения соответствующих мРНК, например, фактора LIF [36,102,103], интегрина αvβ3 [32,104], кальцитонина [74] и других. В частности, было показано, что мРНК фактора LIF может быть обнаружена в клетках эндометрия на протяжении 18-28 дней цикла, при этом пик экспрессии приходится на 20-й день [102,103].…”