Chapter 1 16 symptoms in the 1940s (Stefanick, 2005) and the development and approval of the first oral contraceptive pill in 1960 (Junod & Marks, 2002). Nowadays, exogenous hormones are used for a wide range of indications, ranging from fertility (e.g. contraception or fertility treatments) to symptom relief when endogenous sex hormone levels are outside of the eugonadal physiological range (e.g. hormone therapy for hypogonadism or menopausal symptoms) or to change physical characteristics in transgender persons (e.g. use of gender-affirming hormones). Exogenous hormones have similar effects to endogenous hormones, since they can bind to and activate the same hormone receptors. Due to the negative feedback mechanism in the HPG-axis, exogenous hormones can also suppress endogenous sex hormone production, as shown in Figure 1.1. However, exogenous hormones can differ from endogenous hormones in terms of potency, selectivity and systemic effects, which depends on the chemical composition and administration route of the hormones. Firstly, the potency of hormones can differ between hormone formulations. For example, ethinylestradiol, which is a non-bioidentical form of estradiol, is 100 times more potent than bioidentical estradiol (Jeyakumar et al., 2011). Secondly, differences in selectivity of hormone forms can change the effects of hormone formulations: the progestin levonorgestrel, which is present in many forms of hormonal contraceptives, not only binds to progesterone receptors but also to testosterone and cortisol receptors (Kuhl, 2005). These effects also seem to affect cortisol dynamics, since levonorgestrel-containing hormonal contraceptives were found to affect cortisol responsivity (Aleknaviciute et al., 2017; Herrera et al., 2019). Thirdly, differences in the hormone administration form can also influence the systemic effects of hormones: use of oral estradiol is associated with an increase in sex hormone-binding globulin (SHBG), which can bind to sex hormones and reduce the amount of free estradiol and testosterone, whereas the use of transdermal estradiol was not found to affect SHBG concentrations (Campagnoli et al., 2002; Ropponen et al., 2005). Lastly, effects of exogenous hormones could also be dependent on the timeframe in which they are used. Some exogenous hormones are used daily, which results in a relatively stable hormone level with small day-to-day fluctuations, while other exogenous hormones can be used weekly, monthly or every 3 months, resulting in stronger fluctuations in hormone levels. Differences in day-to-day sex hormone dynamics are during use of exogenous hormones also illustrated in Figure 1.2.
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