Epigenetics of functional hypothalamic amenorrhea.

Functional hypothalamic amenorrhea (FHA) is a temporary infertility characterized by the suppression of the hypothalamic-pituitary-gonadal (HPG) axis, induced by the inhibition of the hypothalamic pulsatile secretion of the gonadotropin-releasing hormone (GnRH), in the presence of stressors, including eating disorders, excessive exercise, and psychological distress. Although the stressful factors that may lead to FHA are well-established, little is known about the inter-individual variability in response to stress and the consequent inhibition of the HPG axis. Not all women, indeed, manifest FHA in presence of stressful conditions. Recent studies highlighted a genetic contribution to FHA. Rare or polymorphic variants in genes that control the development and/or function of GnRH neurons may contribute, indeed, to the adaptability of the reproductive axis to stress factors. Also epigenetic changes have been associated with different pathways involved in the HPG axis and therefore, take part in FHA and confer a personal predisposition to anovulation consequent to a stressful event, or represent biological markers of response to stress. This review summarizes recent advances in the identification of the contribution of (epi)genetics to FHA and to long-term complications of functional amenorrhea, and reports insights into the involvement of additional genetic loci in FHA development on the bases of the clinical and molecular overlap with other gynecological and/or psychological conditions. Finally, we describe the promising application of induced pluripotent stem cells (iPSCs) as a new approach to investigate the molecular pathways involved in FHA.

Lack of expression of endometrial prolactin in early implantation failure: a pilot study.

BACKGROUND: Animal models and experimental studies suggest a role for paracrine prolactin (PRL) signalling in decidualization and embryo implantation. We investigated the expression of endometrial prolactin (e-PRL) and prolactin receptor (PRL-R) in the endometrium of women affected by unexplained infertility (UI) and repeated miscarriages (RM). METHODS: Patients (n = 24) were divided into three groups: RM, n = 5; UI, n = 11; controls, n = 8. Endometrial samples were collected at the time of hysteroscopy in the late luteal phase. The presence of transcripts of e-PRL and PRL-R was investigated by qualitative RT-PCR. Pattern and site of expression of e-PRL were studied by immunohistochemistry. RESULTS: PRL-R mRNA was detected in all endometrial samples of the three groups. PRL gene expression was detected in all control samples, only in three of five samples of the RM group and in four of 11 samples of the UI group. RT-PCR results were largely confirmed by immunohistochemistry, study groups showing a defect of expression of e-PRL. CONCLUSIONS: In this pilot study we report a lack of expression of endometrial prolactin during the 'implantation window' in some patients affected by unexplained infertility and repeated miscarriages. These data, in association with those obtained in experimental animals, suggest that the lack of endometrial PRL expression is involved in reproduction failure.

Macrophage migration inhibitory factor in the human endometrium: expression and localization during the menstrual cycle and early pregnancy.

Macrophage migration inhibitory factor (MIF) was discovered as an activated T-lymphocyte-derived protein that inhibits the random migration of macrophages in vitro. Subsequently, knowledge of the physiological actions of MIF was extended to include its role as a proinflammatory cytokine that affects several functions of macrophages and lymphocytes. Previous reports have suggested an involvement of MIF in reproduction. However, no data are currently available on the presence of this cytokine in the human endometrium. In this study, the expression and tissue localization of MIF was evaluated in specimens of cycling endometrium, first trimester placenta bed biopsy, and isolated endometrial glands by Western blot analysis, immunohistochemistry, ELISA, and reverse transcription-polymerase chain reaction. The results demonstrated that MIF is expressed in human endometrium across the menstrual cycle and in early pregnancy. Immunohistochemical localization identified the protein in glandular epithelium, in stromal and predecidualized stromal cells of cycling endometrium, as well as in the decidua of first-trimester placenta. The proinflammatory features and specific actions of MIF on lymphoid cells suggest its potential involvement in several aspects of endometrial physiology.