Implications of Signaling Variance for Physiological Responses
One of the confounding factors that makes it difficult to predict how a given mixture of hormones will affect various physiological processes in the body is that the affinity of a hormone for its receptor—the strength with which it binds to that receptor—does not necessarily determine either the potency of the effect or even the direction of its action (Salahudeen and Nishtala, 2017). Further complicating the assessment of receptor affinity is the extraordinary variability of reported findings based on the source (endogenous versus exogenous) (Fuentes and Silvera, 2019) and the tissue or the cell line used to measure receptor binding (Yaşar et al., 2017). In addition, a given hormone’s binding partners, particularly the coregulators (as noted above), exist in different concentrations in different tissues, producing tissue-specific effects (Smith and O’Malley, 2004). Similarly, the exact mix of steroid hormones present in a given tissue or cell can affect the activity of the individual hormones in that tissue or cell (Uht et al., 1997). A major source of variability in hormone signaling is the genomic context, resulting in variation in the structure and activity of hormone receptors and the enzymes involved in biosynthesis of the steroid hormones themselves (Fuentes and Silvera, 2019). Therefore, the resulting differences in levels of steroid hormones and receptor actions must also be considered in determining the potential benefits and drawbacks of a particular mix of hormones (Ferrell et al., 2005).
It is also important to recognize that hormones within a given class are not going to produce similar effects on all tissues. For example, medroxyprogesterone acetate is a progestogen but has biological effects that diverge from those of progesterone (Frye, 2013; Nilsen and Brinton, 2003). These differences might translate into different effects on brain and estrogen-sensitive tissues such as breast and uterus. In a similar manner, the genomic effects of conjugated equine estrogens—hormone ingredients in FDA-approved drug products—are not identical to those of E2 (Wroolie et al., 2011). Finally, hormone levels tell only part of the story, meaning, they do not permit inferences about tissue levels based on local metabolism nor about cellular effects of those levels in a given tissue (Fuentes and Silvera, 2019; Smith and O’Malley, 2004).
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In summary, the overall effects of steroids are highly context dependent, and they are affected by an individual’s genetic background, current steroid milieu, and prior exposure. The diverse and dynamic signaling produced by steroid hormones emphasizes the need for preclinical and clinical evaluation that would identify potential beneficial and adverse health effects using the specific mixture of hormones that is to be used to treat patients.
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