What is there to know about the effects of progestins on the human brain and cognition?

Progestogens are a broad class of steroid molecules that bind to and activate progesterone receptors (PRs). There is a whole family of natural (progesterone and its metabolites) and synthetic progestogens. The synthetic progestogens are called progestins (Giatti et al., 2016). Progestins are used by millions of women daily, sometimes for many years, as they are an important part of hormonal contraceptives (HCs), (post)menopausal hormone replacement therapy (HRT) and other medications used for the treatment of diseases of the reproductive system. According to information provided by the United Nations (2019), 16% of women of reproductive age around the world currently use oral contraceptives (OCs: pills and minipills), 17% use intrauterine devices (IUDs; this number includes both users of copper (nonhormonal) and levonorgestrel (LNG) IUDs), 8% use injectable HCs, and 2% use HC implants to avoid unplanned pregnancies or to cure female reproductive system diseases. Numerous factors influence contraceptive use, such as accessibility to family planning facilities, social policy, religion, education, costs and age; therefore, the prevalence of specific contraceptive methods varies widely between countries (United Nations, 2019). In contrast to HC users, the number of women using HRT is declining because of findings emerging from clinical trials that show that the long-term use of HRT poses serious health risks (Parkin, 2011, Rosenberg et al., 2021, Stagnitti and Lefkowitz, 2011). Nevertheless, it is still a popular method to relieve menopausal symptoms (e.g., hot flashes, night sweats, sleep disturbances, and vaginal and urinary tract changes) (Grant et al., 2015). In parallel to growing numbers of HC users (United Nations, 2019) and health concerns related to HRT use (Parkin, 2011, Rosenberg et al., 2021), the number of studies designed to investigate the effect of these medications on the human nervous system (i.e., brain morphology and function, cognitive performance, emotions and mood, and mental health) and general wellbeing is growing (for recent reviews about the effect of HCs, see Brønnick et al., 2020, Lewis et al., 2019, Montoya and Bos, 2017, Pletzer and Kerschbaum, 2014, Taylor et al., 2021, Warren et al., 2014; regarding the effects of HRT, see Del Río et al., 2020, Dye et al., 2012, Maki, 2012, Maki, 2005, Spark and Willis, 2012, Stanczyk et al., 2013). These studies and reviews provide accumulating evidence that medications created and used to deal with needs or problems related to the reproductive system have significant impacts on women’s nervous system and its related functions. Moreover, in regard to the effects of HCs and HRT on the brain and cognition, the focus is currently on women, although it is expected that the target group to which this knowledge is relevant will expand when the use of HCs in men moves from clinical trials to regular use. Recent male HC research has focused on drugs that combine novel oral androgen/progestin compounds and topical gels and has shown promising results (Thirumalai and Amory, 2021, Thirumalai and Page, 2020).

The vast majority of HCs or HRTs contain progestins, often in combination with ethinyl estradiol (EE), estradiol valerate or conjugated equine estrogen (CEE; used in HRT). The literature on the effects of progestins and estradiol substitutes on the brain and cognition is very limited. The effects of estrogen substitutes on brain function have been investigated in a few animal (Lacreuse and Herndon, 2003, Mennenga et al., 2015) and human (Beltz et al., 2015, Espeland, M.A., Tindle, H.A., Bushnell, C.A., Jaramillo, S.A., Kuller, L.H., Margolis, K.L., Mysiw, W.J., Maldjian, J.A., Melhem, E.R., Resnick, S.M., for the Women’s Health Initiative Memory Study, 2009) studies. The situation with progestin effects is complicated because of the large variety of progestins that differ in chemical structure and properties related to pharmacokinetics, metabolism and serum concentrations, and therefore, these compounds have different clinical outcomes (Bick et al., 2021). Nevertheless, Giatti et al. (2016) published a comprehensive review discussing progestin effects in the brain. In this review, progestin types, chemical structures, molecular mechanisms underlying their actions in the brain, relationships to brain function and dysfunction, i.e., neuroprotective and anti-inflammatory effects, and possible protection against neurodegenerative diseases were described. In addition, this review disclosed the variability in the effects of progestins on the brain, cognition, and mood. Analysis of data from ovariectomized animal studies revealed that treatment with different types of progestins might affect mitochondrial function differentially through impact on ATP synthase α-subunit expression, related to neuroprotective effects or through increased Bax/Bcl-2 ratio related to apoptosis (Liu et al., 2010). In addition, the levels of β-endorphin and allopregnanolone in the brains of ovariectomized rats changed differently after treatment with different progestins (e.g. Genazzani et al., 2007; Nicola Pluchino et al., 2009). The overview of studies involving postmenopausal women in this review suggested that progestin type may be an important factor to consider when applying postmenopausal HRT to improve, or at least not worsen, cognitive function. Additionally, it has been shown in animal models that LNG in combined oral contraceptives (COCs) is responsible for specific changes in the expression of GABAA receptors (Porcu et al., 2012). However, the situation regarding the effects of different progestins in female HC users was called complicated, as there were no studies at that time allowing an evaluation of the effects of different progestins on the brain or cognition of healthy women of reproductive age. An exception was the initial evidence that the androgenicity of progestins may be an important factor that should be taken into consideration when the effects of HCs are evaluated (Giatti et al., 2016). However, animal studies have demonstrated that clinically relevant progestins significantly differ in their neurogenic and neuroprotective efficacy (Liu et al., 2010), and clinical evidence from women has shown unexpected and broad side effects (from reproductive and cardiovascular symptoms to negative mood and depression) of synthetic progestins used in HCs and, even more, in HRTs. Taken together, these findings suggest that the choice of progestin may be important in determining risk outcomes with regard to various aspects of physical and mental health (Koubovec et al., 2005, Martin et al., 2018).

Several recent reviews (Henderson, 2018, Rehbein et al., 2021, Sundström-Poromaa et al., 2020) have emphasized the importance of progesterone, a hormone that was often disregarded previously, on brain function, cognition and mental health. In addition, knowledge of sex steroids, including progestogens, on women’s mood and emotions was recently reviewed (Lewis et al., 2019, Osório et al., 2018). However, despite recent years of increasing HC use, which is even more promoted by the World Health Organization, especially among adolescents in low- income regions (Chola et al., 2020) and despite intensive research on progestogens, to the best of our knowledge, there are no recent reviews dedicated specifically to the effect of progestins on the human brain and cognition. Therefore, the purpose of our review is to summarize the recent knowledge about the effects of different progestin types on human brain structure, function, and cognition. Purely progestin-related studies are rare, as progestins are usually used as part of HCs, HRT alone or in combination with estrogens. Therefore, the main focus of our article is on studies focused on the effects of HCs and postmenopausal HRT and the management and treatment of premenstrual disorders. As the main target of progestins are PRs, we start from a short overview of the known effects of natural ligands of these receptors (progesterone and its main metabolites) on the human brain and cognition. Then, we briefly describe the properties of progestins used in different types of hormonal therapies. Finally, we review studies that evaluated the effects of different types of medications (HCs, premenstrual disorder treatments, and HRTs) on the brain and/or cognition while taking progestins into consideration.

Hormonal therapies containing progestins may apply to all individuals across genders (including cis women, cis men, non binary individuals, and transgender men). In this review, we mainly focus on HCs and HRTs used by cis women.

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