E Micks et al. Bridging progestogens 1–12 4:R81 Review Open Access Bridging progestogens in pregnancy and pregnancy prevention Elizabeth Micks1, Greta B Raglan2 and Jay Schulkin1,2 Correspondence 1Department of Obstetrics and Gynecology, University of Washington, Box 356460, 1959 NE Pacific Street, Seattle, should be addressed Washington, USA to E Micks 2Department of Research, American College of Obstetricians and Gynecologists, 409 12th Street SW, Washington, Email District of Columbia, USA [email protected] Abstract Steroid hormones have been in use for more than a half a century as contraceptive agents, and Key Words only now are researchers elucidating the biochemical mechanisms of action and non-target " progestogens effects. Progesterone and synthetic progestins, critical for women’s health in the US and " pregnancy internationally, appear to have important effects on immune functioning and other diverse " contraception systems. Apart from the contraceptive world is a separate field that is devoted to understanding " preterm birth progesterone in other contexts. Based on research following a development timeline parallel " collaborative research to hormonal contraception, progesterone and 17-hydroxyprogesterone caproate are now administered to prevent preterm birth in high-risk pregnant women. Preterm birth researchers are similarly working to determine the precise biochemical actions and immunological effects Endocrine Connections of progesterone. Progesterone research in both areas could benefit from increased collaboration and bringing these two bodies of literature together. Progesterone, through actions on various hormone receptors, has lifelong importance in different organ systems and researchers have much to learn about this molecule from the combination of existing literatures, and from future studies that build on this combined knowledge base. Endocrine Connections (2015) 4, R81–R92 Introduction Progesterone, progestins, and progestogens gynecologic conditions. As the number of available compounds has grown, so too has our understanding of Progesterone is a C-21 steroid hormone first identified and how they differ in terms of metabolism, pharmacokinetics, characterized by Willard Myron Allen in 1933. C-21 potency, binding affinity for the PR and other steroid steroid hormones contain 21 carbons and are also referred receptors, and effects on diverse cell types. The term to as pregnanes. This class of signaling molecules also ‘progestogen’ encompasses both natural and synthetic includes corticosteroids. Dr Allen named the compound compounds that bind the PR. progesterone, shortened from ‘progestational steroid ketone’. Many different synthetic agents that bind The need for contraceptive technology the progesterone receptor (PR), termed ‘progestins’, are now used for contraception, preterm birth prevention, Half of pregnancies in the USA are unintended (1, 2, 3). hormone therapy, and as treatment for a wide range of About half of women in the USA will have an unintended http://www.endocrineconnections.org Ñ 2015 The authors This work is licensed under a Creative Commons DOI: 10.1530/EC-15-0093 Published by Bioscientifica Ltd. Attribution-NonCommercial-NoDerivs 4.0 International License. Downloaded from Bioscientifica.com at 09/30/2021 06:36:10AM via free access Review E Micks et al. Bridging progestogens 2–12 4:R82 pregnancy by age 45, and one in three will have an Progesterone: diverse roles in different abortion (4). Worldwide, the situation is more dire as systems women with unintended pregnancy often do not have It is estimated that steroid receptors first appeared in living access to safe abortion or obstetric care. Over 280 000 organisms approximately half a billion years ago. The maternal deaths occurred in 2010 and 7.9% were due to mineralocorticoid, glucocorticoid, progesterone, and unsafe abortion (5). Improvements in contraceptive access androgen receptors are very closely related members of the as well as advancements in contraceptive technology are nuclear-receptor super-family, thought to arise in multi- needed to address these issues (6). Reducing unmet need cellular animals (9, 10). Structurally similar receptors exist for family planning represents one of the most effective in all vertebrates, and are present in some invertebrates such strategies for improving maternal health (7), and proges- as mollusks, proving their ancient origins (11, 12). togens remain one of the most promising avenues for Progesterone has diverse effects on myriad systems. It contraceptive research and development. However, there plays a role in pair bonding in birds (13), body fluid balance is evidence indicating that current methods of hormonal in humans (14), sexual differentiation in fish (15), and contraception, particularly injectable progestins, may sexual receptivity in mice (16). In human males and increase women’s risk of HIV acquisition and transmission females, progesterone has been found to have various to male sex partners (8). Lack of other contraceptive reproductive and non-reproductive functions, including options, especially for women at highest risk, is a critical immunomodulation, neuroprotection, and inhibition of barrier to progress towards optimizing women’s reproduc- cholesterol synthesis (17, 18, 19). Progesterone is one of tive health. several hormones, including Vitamin D, aldosterone, and cortisol, which all compete for similar receptor sites in both Progesterone for preterm birth prevention brain and peripheral tissue. Receptor binding and sub- sequent effects depend on the metabolic condition (20). a In 2006, progesterone and 17 -hydroxyprogesterone The role of progesterone in reproductive functioning caproate (17-OHPC) re-emerged as effective therapies for is complex in both pregnant and nonpregnant women. pregnant women at high risk for preterm delivery (delivery In a normal menstrual cycle, progesterone is critical for ! at 37 weeks gestation). In turn, scientists studying the preparing the endometrium for implantation of the mechanisms of normal and preterm birth and the role of Endocrine Connections embryo and, if implantation occurs, it is needed to reproductive hormones made important discoveries maintain the pregnancy (21, 22). If pregnancy does not regarding progestins, the PR, and related steroid receptors. occur, bleeding occurs in response to progesterone with- Research in preterm and normal labor has highlighted the drawal. Progesterone also is responsible for ovulation impact of progesterone on immune functioning. suppression during the luteal phase. In pregnant women, progesterone promotes uterine quiescence but, through Bringing two worlds together different receptors, also makes a contribution to the cascade of events leading to labor (23). Biochemists continue to elucidate the mechanisms of action of different progestins in order to identify the safest and most effective compounds for widespread use in Diverse signaling pathways contraceptives and preterm birth prevention, but research Progesterone was traditionally believed to act only in these areas tends to occur in a vacuum. Researchers in through the progesterone and other steroid receptors via both areas would benefit from following the other gene transcription and translation of genes into proteins. separately evolving field. This article aims to bring The PR is one of the best-described transcription factors. together these two related literatures, discuss the state of However, it also acts through many non-genomic mech- the science of the physiology of progestins and progester- anisms that do not require steroid receptors and protein one for these indications, and determine what conclusions transcription. Such actions are considerably faster and may be drawn about the differential effects of progestins may play crucial roles in several organ systems, especially on various organ systems, particularly the immune the brain. Non-genomic actions of progesterone include system, and how these findings might impact the activation of intracellular signaling pathways through development of contraceptive and preterm birth preven- modulation of cell surface receptors, ion channels, and tion methods. secondary messenger cascades (24).Throughthese http://www.endocrineconnections.org Ñ 2015 The authors This work is licensed under a Creative Commons DOI: 10.1530/EC-15-0093 Published by Bioscientifica Ltd. Attribution-NonCommercial-NoDerivs 4.0 International License. Downloaded from Bioscientifica.com at 09/30/2021 06:36:10AM via free access Review E Micks et al. Bridging progestogens 3–12 4:R83 mechanisms, as well as the traditional PR pathway, ways (19, 29); it both inhibits CRH production in the progesterone helps regulate cell viability in the brain. placenta and attenuates the effects of CRH. Progesterone Other examples of rapid non-genomic effects include also competes with cortisol for the same receptor sites. acceleration of oocyte maturation and stimulation of the The effect of progesterone on CRH activity depends on acrosomal reaction in spermatozoa (25). Some of these gestational age and the ratio of different PRs. effects are mediated through a different kind of PR, The role of progesterone in pregnancy maintenance sometimes referred to as ‘membrane PRs’, which may act and in labor initiation is complex and varies throughout via inhibitory G-proteins (26). pregnancy depending on the state of myometrial receptors and other factors. Nonetheless, clear evidence for the importance of progesterone in pregnancy maintenance Progestins