Horm Mol Biol Clin Invest 2016; aop *Corresponding author: Raj Raghupathy, Faculty of Medicine, Department of Microbiology, Kuwait University, Kuwait, E-mail: raj@hsc.edu.kw Julia Szekeres-Bartho: Department of Medical Microbiology and Immunology, Medical School, University of Pécs, Hungary; MTA – PTE Human Reproduction Research Group, University of Pécs, Hungary; and János Szentágothai Research Centre, University of Pécs, Hungary Raj Raghupathy* and Julia Szekeres-Bartho Dydrogesterone and the immunology of pregnancy DOI 10.1515/hmbci-2015-0062 Received November 11, 2015; accepted December 16, 2015 Abstract: Progesterone is indispensable for the mainte- nance of pregnancy, both via its endocrine effects and its role in creating a favorable immunological environment for the fetus. This review focuses on the immunological effects of progesterone. Progestogens have been shown to have very interesting effects on cytokine production and decidual natural killer (NK) cell activity. The orally- administered progestogen, dydrogesterone, has the abil- ity to modulate cytokine production patterns in a manner that could be conducive to successful pregnancy. The adverse effects of progesterone deficiency and the benefi- cial effects of progesterone supplementation in pregnancy pathologies will be discussed. Keywords: cytokines; dydrogesterone; progesterone; recurrent spontaneous miscarriage. Introduction Progesterone has long been known as a hormone that is indispensable for the maintenance and success of preg- nancy. While its critical roles in the endocrine system are well understood, its perhaps equally important capa- bilities in the immune system are now being unraveled. Progestogens such as progesterone and the orally-admin- istrable dydrogesterone are being explored for their ability to treat pregnancy complications, e.g. threatened miscar- riage, recurrent miscarriage (RM) and pre-term labor. This paper aims to review the possible immunological path- ways affected by progestogens. Spontaneous miscarriage and recurrent miscarriage Thirty to 50% of all conceptions and 10–20% of recognized pregnancies end in miscarriage. Miscarriage is defined as fetal loss occurring before the 20th week of pregnancy. Three or more consecutive miscarriages before the 20th week of gestation (affecting 0.5–1% of couples) are termed RM [1–3]. The underlying mechanisms include both fetal (genetic or developmental abnormalities) and maternal (uterine pathology, endocrine dysfunction, anti-phos- pholipid syndrome and thrombophilic disorders) factors however, the higher the number of the previous miscar- riages, the more likely that the failure is due to maternal and not accidentally occurring fetal factors. In approxi- mately 50% of women with RM neither of the above prob- lems are present, and in many of these cases, the altered immune functions normally associated with pregnancy, are missing. RM is associated with an increased number of endo- metrial natural killer (NK) cells [4], and decidual lym- phocytes from failed pregnancies contain less perforin than those from normal pregnancy deciduas [5] sug- gesting that an increased rate of degranulation takes place in the former case. Other studies have shown that though the proportion of endometrial NK cells was identical in recurrent aborters and normal controls, the CD16-CD56 bright NK cell subset, which is predominant in normal decidua and endometrium, was significantly decreased in favor of CD16+CD56-dim NK cells in recur- rent aborters [6–8]. These data suggest that a proportion of unexplained recurrent miscarriages might have an immunological etiology. Cytokines and recurrent pregnancy loss The large proportion of cases of RM with unidentified etiologies has inspired great interest in the investiga- tion of possible immunologic etiologies. Both humoral and cell-mediated etiologic factors have been explored; Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 2/6/16 1:35 AM