Review
Progesterone and autoimmune disease

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Abstract

Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.

Introduction

At roughly the same time 500 million years ago, two major adaptations arose in primitive vertebrates: the adaptive immune system and highly specific steroid hormone receptors [1], [2]. The subsequent development of placental reproduction posed immunological “problems” for the adaptive immune system, as Sir Peter Medawar, pioneer in transplantation immunology, put it in 1953 [3]. He posited that the fetus might avoid attack from its mother's immune system by means of physical barriers, immunological inertness and suppression of maternal immune responses. As Medawar himself suspected [3], physical separation of maternal and fetal circulations is critical, but so too are certain adaptations of the mother's immune system. Accordingly, the human immune system bears evidence of sexual selection. This is most obvious in the female predominance of certain autoimmune diseases (ADs) (Fig. 1), and to a lesser extent, sexual dimorphism in responses to infections. Several theories attempt to explain the female predominance of ADs: immunomodulatory effects of sex hormones; sex-dependent genetic factors; microchimerism; and gender-related factors [4]. The importance of sex hormones, particularly the sex steroids, in human AD is supported by considerable observational and experimental evidence. In this regard, much attention has been given to estrogen (Es) and androgens, important determinants of sexual dimorphism, but far less has been given to progesterone (Pg), the hormone of pregnancy. Long known for its immunoregulatory properties, Pg's impacts on human AD are not well understood. This review article will summarize what is known about Pg and AD.

First, I will outline observations supporting a role for female sex steroids in AD, correlating them with recent genetic discoveries. Next, I will briefly discuss the molecular actions of Pg, followed by a more detailed description of how Pg impacts functions of select components of the immune system. With this framework in place, I will discuss what is known about Pg, individual ADs and their animal models.

Section snippets

Progesterone and mammalian biology

Pg is a cholesterol-derived hormone critical to pregnancy [5]. Indeed, the name ultimately derives from the prefix pro and the Latin gestāre to carry. Through a variety of mechanisms, Pg is required for normal function at multiple stages of mammalian reproduction: oocyte maturation, differentiation of the endometrium, implantation of the embryo, growth of the placenta, quiescence of uterine muscle during fetal development and differentiation of mammary gland tissues. Pg also contributes to some

Sexual dimorphism in human AD

The female predominance of AD remains unexplained, but several non-competing hypotheses have been proposed. The first idea is that female sex hormones modulate the immune system to increase risk of AD in genetically susceptible individuals; the converse is that male sex steroids are protective. While this may be the most intuitive explanation, it is not the only one. X-linked immune genes, particularly if they escape inactivation or are duplicated [8], could play a major role in female

Progesterone — mechanisms of action

Steroid hormones exert their influence on physiological processes via direct effects on cellular functions. Sex steroids are synthesized primarily in the gonads, adrenal glands and, during pregnancy, the placenta. They are delivered via the bloodstream, largely protein-bound, to target tissues. Steroid hormones signal via highly specific receptors found in the plasma membrane, cytosol and nucleus of cells. [5]

Pg utilizes both cell surface and intracellular receptors. Best characterized are

Effects of progesterone on immune functions

Four general lines of evidence together indicate that Pg modulates immune functions in vivo: 1) post-pubertal female predominance of ADs; 2) systemic immunomodulation during times of high circulating Pg (pregnancy, luteal phase of the ovulatory cycle); 3) immunomodulation after Pg treatment; and 4) in vitro experiments showing direct effects on immune cells. In this section, I will discuss these last three lines of evidence, reserving the first for Section 6, “Progesterone and Autoimmune

Progesterone and autoimmune disease

As summarized in the previous section, Pg can impact many immune pathways involved in AD. This section will examine what is known about Pg and the female-predominant ADs, drawing on the previous sections to highlight possible mechanisms and future lines of investigation. For general review of the topic of female sex steroids and AD, see McCombe et al. [4] and Matocchia et al. [23]

Summary and future directions

The evolutionary requirements of placental reproduction have driven sexual dimorphism in mammalian immune systems. This dimorphism is most obvious in the extreme female predominance of certain human ADs. Sexual immune dimorphism almost certainly involves modulatory actions of sex steroids like T, Es and Pg. Pg exerts these effects via direct actions on immune cells and induction of immunomodulatory molecules in non-hematopoietic tissues. The effects of Pg and synthetic progestins depend greatly

Acknowledgments

I would like to thank Edward A. Clark, Ph.D., Peter Thomas, Ph.D., and Parul Sharma, D.O., for their helpful comments during the writing of this review.

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