Sex differences and sex steroids in lung health and disease

Abstract

Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span.

Figure 1.

Publications relating to sex and the lung. A PubMed search was conducted to compare the number of articles published per year related to sex differences in the lung vs. heart. Search terms (title, abstract, and keywords) used were “sex” or “gender” along with “heart, cardiac, vascular (not pulmonary)” to define the broad term “heart” represented in the figure. The search was repeated with “sex” or “gender” and search terms “respiratory, lung, airway, and pulmonary,” which comprise the term “lung.” Searches were conducted annually from 2005 to 2010 (for recent trends), and decade searches 1985–1994 and 1995–2004 (with average numbers of articles per year presented). Over the last two decades, there has been a substantial increase in the number of publications related to sex and lung, with tremendous increases in recent years. However, these numbers remain substantially smaller than those involving sex and heart. Nonetheless, the encouraging upward trend in studies illustrates the recognition that visibility of and research on sex differences in the lung needs to be enhanced. Within this subset is the additional recognition of the role of sex steroids in lung physiology and pathophysiology.

Figure 2.

Sex steroid effects on immune cells. Many lung diseases involve a substantial inflammatory component with key players such as DC and monocytes/macrophages that are particularly important in the initial response to antigens, CD4+ lymphocytes, regulatory T cells (Tregs), B lymphocytes, and other immune cells. In diseases such as asthma, mast cells, CD4+ T lymphocytes, and eosinophils are particularly important. Interactions between antigen-presenting cells and naive CD4 T lymphocytes induces the generation of polarized T lymphocytes characterized at Th1 (predominantly INF-γ secreting) or Th2 (predominantly IL-4 secreting); Th2 polarized cells subsequently have additional downstream effects on B-cell antibody secretion that may further enhance mast cell activation. The effects of estrogen (E), progesterone (P), or testosterone (T) on different types of immune cells have been examined to varying and incomplete extents (see Section IV.E), mostly in the context of autoimmune diseases. This figure schematically summarizes current knowledge of sex steroid effects on specific types of immune cells that are particularly important in lung diseases and illustrates the likely overall complex effect of sex steroids on immune function. An important caveat not represented here (see Ref. 453) is that sex steroid effects on immune cell and function is dependent on concentration, timing and duration, and context of exposure.

Figure 3.

Summary of sex steroid effects on individual cell types of the lung. Many cell types are involved in the pathogenesis of lung disease. Therefore, individual effects of sex steroids must be integrated to achieve a better understanding of sex hormone effects in the manifestation, exacerbation, or alleviation of these diseases as a whole. Androgens, estrogen, and progesterone can have different effects at the cellular level that are concentration-, dose-, and time-dependent (which are described in the text). In general, progesterone and estrogen can either enhance or counterbalance their mutual effects in the female, whereas androgens generally have opposing effects, compared with estrogen, in the male.

Figure 4.

Sex steroid effects in asthma. The complex effects of individual sex steroids on specific cell types of the lung, as well as cooperative vs. opposing effects of different sex steroids within a cell type, are illustrated in the case of asthma (with the caveat that current knowledge of sex steroid effects in asthma is limited). Asthma represents an inflammation-driven response of the airway to environmental or intrinsic allergens, pollutants, and other factors such as cigarette smoke. In response, the airway undergoes structural changes represented by epithelial thickening with increased mucous production, ASM proliferation, and hyperreactivity, as well as remodeling of the extracellular matrix. Sex steroids, especially estrogens, may on the one hand have detrimental effects on airway structure/function by enhancing inflammation or epithelial and ASM proliferation, while also alleviating symptoms via reducing [Ca²⁺]_i in ASM and thus enhancing bronchodilation. Complicating these effects is the sometimes additive, sometimes opposing, effect of other sex steroids. For example, progesterone may also enhance Th2 inflammation and cell proliferation but further bronchodilation. On the other hand, estrogen and progesterone have opposing effects on eNO. In general, testosterone has effects opposite to those of female sex steroids (but note the enhancement of ASM proliferation).