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Abstract
Millions of people take hormonal contraceptives (HCs), often starting during adolescence when ovarian hormones influence brain and behavioral maturation. However, there is a fundamental lack of information about the neurobehavioral consequences of hormonal alterations via adolescent HC use. To begin addressing this gap, we validated a rodent model of adolescent HC administration and characterized its impact on endocrine, transcriptional, and behavioral endpoints. Cohorts of intact post-pubertal female Sprague-Dawley rats received daily subcutaneous injections of either vehicle or HC [10 μg ethinyl estradiol (EE) + 20 μg levonorgestrel (LNG)] for the duration of adolescence from postnatal day (PND) 35 to PND56. Blood and brain tissue was collected at PND57. Other cohorts received daily injections of vehicle or HC from PND35 until behavioral assays were completed on PND57-64. HC treatment was effective, as vaginal lavage indicated disrupted estrous cycling and ELISA indicated suppressed serum luteinizing hormone in HC-treated rats. Liquid chromatography-mass spectrometry analysis showed EE and LNG in serum and brain as well as diminished serum and brain levels of allopregnanolone and testosterone in HC-treated rats. NanoString nCounter analysis indicated that adolescent HC administration impacted expression of genes related to synapses, white matter, neuroimmune, monoamine, and hormone signaling in the hypothalamus and medial prefrontal cortex. While no effects of HCs were seen on sociability in the social preference test or stress coping behavior in the forced swim test, adolescent HC administration diminished risk-assessment behaviors in the novelty-induced hypophagia paradigm and altered anxiety-like behavior in the open field test and elevated plus maze. Overall, these data suggest that exposure to contraceptive hormones during the critical developmental period of adolescence may shape the brain and behavior.
Bronnick MK et al., 2020·Frontiers in Psychology·Free full text on PubMed Central
Hormonal contraceptive drugs are being used by adult and adolescent women all over the world. Convergent evidence from animal research indicates that contraceptive substances can alter both structure and function of the brain, yet such effects are not part of the public discourse or clinical decision-making concerning these drugs. We thus conducted a systematic review of the neuroimaging literature to assess the current evidence of hormonal contraceptive influence on the human brain. The review was registered in PROSPERO and conducted in accordance with the PRISMA criteria for systematic reviews. Structural and functional neuroimaging studies concerning the use of hormonal contraceptives, indexed in Embase, PubMed and/or PsycINFO until February 2020 were included, following a comprehensive and systematic search based on predetermined selection criteria. A total of 33 articles met the inclusion criteria. Ten of these were structural studies, while 23 were functional investigations. Only one study investigated effects on an adolescent sample. The quality of the articles varied as many had methodological challenges as well as partially unfounded theoretical claims. However, most of the included neuroimaging studies found functional and/or structural brain changes associated with the use of hormonal contraceptives. The included studies identified structural and functional changes in areas involved in affective and cognitive processing, such as the amygdala, hippocampus, prefrontal cortex and cingulate gyrus. However, only one study reported primary research on a purely adolescent sample. Thus, there is a need for further investigation of the implications of these findings, especially with regard to adolescent girls.
Pletzer BA et al., 2014·Frontiers in Neuroscience·Free full text on PubMed Central
Hormonal contraceptives are on the market for more than 50 years and used by 100 million women worldwide. However, while endogenous steroids have been convincingly associated with change in brain structure, function and cognitive performance, the effects of synthetic steroids contained in hormonal contraceptives on brain and cognition have barely been investigated. In this article we summarize the sparse findings, describing brain structural, functional and behavioral findings from the literature and suggest that synthetic steroids may contribute to masculinizing as well as feminizing effects on brain and behavior. We try to identify methodological challenges, explain, how results on endogenous steroids may transfer into research on hormonal contraceptives and point out factors that need to be controlled in the study of hormonal contraceptive dependent effects. We conclude that there is a strong need for more systematic studies, especially on brain structural, functional and cognitive changes due to hormonal contraceptive use. The hormonal contraceptive pill is the major tool for population control. Hence, such behavioral changes could cause a shift in society dynamics and should not stay unattended.
Cognitive abilities, such as verbal fluency and mental rotation, are most sensitive to changes in sex steroids but poorly studied in the context of hormonal contraceptive usage. Therefore, we investigated the performance of mental rotation and verbal fluency in young (21.5±1.8 years) healthy oral contraceptive (OC) users (23 women) and non-users (20 women) during the follicular, ovulatory and luteal phases of the menstrual cycle. Salivary 17β-estradiol, progesterone and testosterone levels were assayed to evaluate hormonal differences between groups and the phases of the menstrual cycle. To assess the effects of progestins having androgenic/anti-androgenic properties, OC users were subdivided into the third and new generation OC users. In addition, positive and negative affects as factors possibly affecting cognitive performance were evaluated. Salivary 17β-estradiol and progesterone levels were significantly lower in hormonal contraception users. Level of salivary testosterone was slightly lower in the OC users group with significant difference only during ovulatory phase. Naturally cycling women performed better on verbal fluency task as compared to OC users. Subjects who used the third generation (androgenic) OCs generated significantly fewer words as compared to new generation (anti-androgenic) OC users and non-users. The third generation OC users demonstrated significantly longer RT in MRT task as compared to non-users. The MRT, verbal fluency and mood parameters did not depend on the phase of menstrual cycle. The parameters of the PANAS (Positive and Negative Affect Schedule) scales did not differ between OC users and non-users. Our findings show that hormonal contraception has an impact on verbal and spatial abilities. Different performances between users of oral contraceptives with androgenic and anti-androgenic properties suggest an essential role for the progestins contained in OCs on cognitive performance.
Vigil P et al., 2016·Linacre Q·Free full text on PubMed Central
This review explains the main effects exerted by sex steroids and other hormones on the adolescent brain. During the transition from puberty to adolescence, these hormones participate in the organizational phenomena that structurally shape some brain circuits. In adulthood, this will propitiate some specific behavior as responses to the hormones now activating those neural circuits. Adolescence is, then, a critical "organizational window" for the brain to develop adequately, since steroid hormones perform important functions at this stage. For this reason, the adolescent years are very important for future behaviors in human beings. Changes that occur or fail to occur during adolescence will determine behaviors for the rest of one's lifetime. Consequently, understanding the link between adolescent behavior and brain development as influenced by sex steroids and other hormones and compounds is very important in order to interpret various psycho-affective pathologies. Lay Summary : The effect of steroid hormones on the development of the adolescent brain, and therefore, on adolescent behavior, is noticeable. This review presents their main activational and organizational effects. During the transition from puberty to adolescence, organizational phenomena triggered by steroids structurally affect the remodeling of brain circuits. Later in adulthood, these changes will be reflected in behavioral responses to such hormones. Adolescence can then be seen as a fundamental "organizational window" during which sex steroids and other hormones and compounds play relevant roles. The understanding of the relationship between adolescent behavior and the way hormones influence brain development help understand some psychological disorders.
Contraception › Adverse Effects › Mood and Libido · Reproductive Endocrinology › Neuroendocrinology › Hypothalamic Pituitary Axis · Research Methods › Preclinical Research › Animal Models
Rachel A Gilfarb, Sanjana Ranade, Marissa Smail, Lynde Wangler, Meredith Stewart, Abhishek Rajesh, Kathryn M Lenz, Benedetta Leuner
R Gilfarb, S Ranade, M Smail, L Wangler, M Stewart, A Rajesh, Kathy Lenz, Kate Lenz, K Lenz, B Leuner
PMID 40188588 40188588 DOI 10.1016/j.yhbeh.2025.105725 10.1016/j.yhbeh.2025.105725 Gilfarb et al. 2025, Gilfarb 2025