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The effects of hormonal contraceptives on structural features of the hypothalamus and pituitary are incompletely understood. One prior study reported microstructural changes in the hypothalamus with oral contraceptive pill (OCP) use. However, effects on hypothalamic volume have not been reported. One prior study reported volumetric changes in the p...
Context in source publication
Context 1
... women (mean age ± standard deviation; 22.1 ± 3.7 years) comprising of 21 OCP users (age range, 19-29) and 29 NCW (age range, 18-36) were enrolled. There was no significant difference in age, BMI, and smoking history between NCW and OCP users (Table 1). More OCP users consumed alcohol when compared to NCW (p = 0.001), but no participant consumed more than 7 drinks per week. ...Citations
... In fact, the third interstitial nucleus of the anterior hypothalamus (INAH-3) displays the largest sex-related volumetric difference in the human brain, 9 and volumetric sex differences have been observed in various hypothalamic substructures. [10][11][12][13] Changes to hypothal amic volume have been shown under oral contraception 14 and analyzed across the menstrual cycle. 14,15 Tight interplay between the hypothalamus and sex hormones makes the hypo thalamus a target for studies on disorders, such as depression, in which sex hormones mediate risk. ...
... [10][11][12][13] Changes to hypothal amic volume have been shown under oral contraception 14 and analyzed across the menstrual cycle. 14,15 Tight interplay between the hypothalamus and sex hormones makes the hypo thalamus a target for studies on disorders, such as depression, in which sex hormones mediate risk. [16][17][18] Gender-affirming hormone therapy (GHT) 19 allows for investigation of the effects of highly dosed sex hormones on the human brain. ...
Background:
Among its pleiotropic properties, gender-affirming hormone therapy (GHT) affects regional brain volumes. The hypothalamus, which regulates neuroendocrine function and associated emotional and cognitive processes, is an intuitive target for probing GHT effects. We sought to assess changes to hypothalamus and hypothalamic subunit volumes after GHT, thereby honouring the region's anatomical and functional heterogeneity.
Methods:
Individuals with gender dysphoria and cisgender controls underwent 2 MRI measurements, with a median interval of 145 days (interquartile range [IQR] 128.25-169.75 d, mean 164.94 d) between the first and second MRI. Transgender women (TW) and transgender men (TM) underwent the first MRI before GHT and the second MRI after approximately 4.5 months of GHT, which comprised estrogen and anti-androgen therapy in TW or testosterone therapy in TM. Hypothalamic volumes were segmented using FreeSurfer, and effects of GHT were tested using repeated-measures analysis of covariance.
Results:
The final sample included 106 participants: 38 TM, 15 TW, 32 cisgender women (CW) and 21 cisgender men (CM). Our analyses revealed group × time interaction effects for total, left and right hypothalamus volume, and for several subunits (left and right inferior tubular, left superior tubular, right anterior inferior, right anterior superior, all p corr < 0.01). In TW, volumes decreased between the first and second MRI in these regions (all p corr ≤ 0.01), and the change from the first to second MRI in TW differed significantly from that in CM and CW in several subunits (p corr < 0.05).
Limitations:
We did not address the influence of transition-related psychological and behavioural changes.
Conclusion:
Our results suggest a subunit-specific effect of GHT on hypothalamus volumes in TW. This finding is in accordance with previous reports of positive and negative effects of androgens and estrogens, respectively, on cerebral volumes.
... Despite well-known health risks and benefits for metabolic, neoplastic, and gynecological processes, the effects of oral contraceptives on the brain are not well-defined despite they may carry important risks (Gingnell et al. 2013;Skovlund et al. 2016Skovlund et al. , 2018. Oral contraceptives intake induces structural and functional changes in the brain as evidenced by resting-state functional connectivity studies of the amygdala, hippocampus, PFC, and hypothalamus (Chen et al. 2021;Lisofsky et al. 2016). Notably, oral contraceptives users have lower amygdala reactivity and greater dorsal anterior cingulate cortex and insular reactivity to traumatic stimuli when compared to normally cycling women . ...
Fear extinction memories are strongly modulated by sex and hormonal status, but the exact mechanisms are still being discovered. In humans, there are some basal and task-related features in which male and female individuals differ in fear conditioning paradigms. However, analyses considering the effects of sex hormones demonstrate a role for estradiol in fear extinction memory consolidation. Translational studies are taking advantage of the convergent findings between species to understand the brain structures implicated. Nevertheless, the human brain is complex and the transfer of these findings into the clinics remains a challenge. The promising advances in the field together with the standardization of fear extinction methodologies in humans will benefit the design of new personalized therapies.KeywordsEstradiolFear extinctionProgesteroneSex differencesSex hormones
... A closer look to which phase of the natural cycle and phase of OC-intake were compared, is provided in Table 1. Moreover, the brain structures producing estrogen and progesterone, the hypothalamus and pituitary gland, have decreased volumes in women using OCs when compared to naturally cycling women (Chen et al., 2021). ...
... itksnap.org/) is a semi-automatic segmentation using both manual and automated delineation to segment structures in MRI images. Chen et al. (2021) used this method to segment the hypothalamus and the pituitary gland and reported decreased volumes in women using OCs compared to naturally cycling women. The authors chose this segmentation method as the hypothalamus and the pituitary gland are known to be very small structures of the human brain. ...
... However, the pituitary gland cannot be assessed by FreeSurfer as of yet. The gland is being removed during the process of making the mask of the brain to strip the skull and needs to be delineated either manually or via semi-automated segmentation, as performed by Chen et al. (2021) mentioned above. ...
... Furthermore, based on lack of pertinent clinical history of the majority of patients, there was paucity of data in the electronic medical record regarding FSH, menopause, TSH, oral contraception (OCP) use, BMI, and other forms of exogenous hormones, which precluded us from further investigation of the relationship between these variables and pituitary [68 Ga]-DOTATATE avidity. Pituitary gland volume may change with oral contraceptive use, pregnancy, nulliparity, hormone replacement therapy, obesity, and primary hypothyroidism [41][42][43][44][45][46][47]. Future studies in relation to the aforementioned variables will further enhance our understanding of [68 Ga]-DOTATATE PET in various clinical settings. ...
Purpose
The pituitary gland has the fourth highest physiologic avidity of [68 Ga]-DOTATATE. In order to guide our understanding of [68 Ga]-DOTATATE PET in clinical contexts, accurate characterization of the normal pituitary gland is first required. This study aimed to characterize the normal pituitary gland using dedicated brain [68 Ga]-DOTATATE PET/MRI as a function of age and sex.
Methods
A total of 95 patients with a normal pituitary gland underwent brain [68 Ga]-DOTATATE PET examinations for the purpose of diagnosing CNS SSTR2 positive tumors (mean age: 58.9, 73% female). Maximum SUV of the pituitary gland was obtained in each patient. SUV of superior sagittal sinus was obtained to calculate normalized SUV score (SUVR) of the gland. The anatomic size of the gland was collected as maximum sagittal height (MSH). Correlations with age and sex were analyzed.
Results
The mean SUV and SUVR of the pituitary gland were 17.6 (range: 7–59.5, SD = 7.1) and 13.8 (range: 3.3–52.6, SD = 7.2), respectively. Older females had significantly higher SUV of the pituitary gland compared to younger females. When stratified by age and sex, both older and younger females had significantly higher pituitary SUV than older males. SUVR did not differ significantly by age or sex. MSH of the pituitary gland in younger females was significantly greater than in younger males at all age cutoffs.
Conclusion
This study provides an empiric profiling of the physiological [68 Ga]-DOTATATE avidity of the pituitary gland. The findings suggest that SUV may vary by age and sex and can help guide the use of [68 Ga]-DOTATATE PET/MRI in clinical and research settings. Future studies can build on these findings to investigate further the relationship between pituitary biology and demographic factors.
... Additionally, to re ect the pituitary gland's vast regulatory role in the body, we initially sought to investigate relationships between pituitary [68Ga]-DOTATATE uptake and clinical variables such as FSH, menopause, TSH, oral contraception (OCP) use, BMI, and other forms of exogenous hormones, where were not included in the nal analysis due to di culties accessing the data, inconsistent documentation, and general scarcity of such information in the electronic medical record. Pituitary gland volume may change with oral contraceptive use, pregnancy, nulliparity, hormone replacement therapy, obesity, and primary hypothyroidism [35][36][37][38][39][40][41]. Future studies in relation to the aforementioned variables will further enhance our understanding of [68Ga]-DOTATATE PET in various clinical settings. ...
Purpose
The pituitary gland has the fourth highest physiologic avidity of [68Ga]-DOTATATE. In order to guide our understanding of [68Ga]-DOTATATE PET in clinical contexts, accurate characterization of the normal pituitary gland is first required. This study aimed to characterize the normal pituitary gland using dedicated brain [68Ga]-DOTATATE PET/MRI as a function of age and sex.
Methods
A total of 95 patients with a normal pituitary gland underwent brain [68Ga]-DOTATATE PET examinations for the purpose of diagnosing CNS SSTR2 positive tumors (mean age: 58.9, 73% female). Maximum SUV of the pituitary gland was obtained in each patient. SUV of superior sagittal sinus was obtained to calculate normalized SUV score (SUVR) of the gland. The anatomic size of the gland was collected as maximum sagittal height (MSH). Correlations with age and sex were analyzed.
Results
The mean SUV and SUVR of the pituitary gland were 17.6 (range: 7-59.5, SD = 7.1) and 13.8 (range: 3.3–52.6, SD = 7.2), respectively. Older females had significantly higher SUV of the pituitary gland compared to younger females. When stratified by age and sex, both older and younger females had significantly higher pituitary SUV than older males. SUVR did not differ significantly by age or sex. MSH of the pituitary gland in younger females was significantly greater than in younger males at all age cutoffs.
Conclusion
This study provides an empiric profiling of the physiological [68Ga]-DOTATATE avidity of the pituitary gland. The findings suggest that SUV may vary by age and sex and can help guide the use of [68Ga]-DOTATATE PET/MRI in clinical and research settings. Future studies can build on these findings to investigate further the relationship between pituitary biology and demographic factors.
... In veterans with post-traumatic stress disorder, the bilateral amygdala and hippocampus were shown to be significantly smaller compared to controls [45]. The hypothalamus was noted to be significantly smaller in women using oral contraceptive pills [46]. In patients with multiple sclerosis, the hypothalamus, hippocampus, and anterior thalamus were significantly smaller compared to healthy controls [42]. ...
Purpose:
Literature is scarce regarding volumetric measures of limbic system components across the pediatric age range. The purpose of this study is to remedy this scarcity by reporting continuous volumetric measurements of limbic system components, and to provide consistent stratification data including age-related trajectories and sex-related differences in the pediatric age range in order to improve the recognition of structural variations that might reflect pathology.
Methods:
In this retrospective study, MRI sequences of children with normal clinical MRI examinations of the brain acquired between January 2010 and December 2019 were included. Isotropic 3D T1-weighted were processed using FreeSurfer version 7.3. Total brain volume and volumes of the limbic system including the hippocampus, parahippocampal gyrus, amygdala, hypothalamus, cingulate gyrus, entorhinal cortex, anteroventral thalamic nucleus, and whole thalamus were assessed. Parcellated output was displayed with the respective label map overlay and images were visually inspected for accuracy of regional segmentation results. Continuous data are provided as mean and standard deviation with quadratic trendlines and as mean and 95% confidence intervals. Categorical data are presented as integers and percentages (%).
Results:
A total of 724 children (401 female, 55.4%), with a mean age at time of MRI of 10.9 ± 4.2 years (range: 1.9-18.2 years), were included in the study. For females, the total brain volume increased from 955 ± 70 mL at the age of 2-3 years to 1140 ± 110 mL at the age of 17-18 years. Similarly, the total brain volume increased for males from 1004 ± 83 mL to 1263 ± 96 mL. The maximum volume was noted at 11-12 years for females (1188 ± 90 mL) and at 14-15 years for males (1310 ± 159 mL). Limbic system structures reached their peak volume more commonly between the 13-14 years to 17-18 years age groups. The male cingulate gyrus, entorhinal cortex, and anteroventral thalamic nucleus reached peak volume before or at 9-10 years.
Conclusion:
This study provides unique age- and sex-specific volumes of the components of the limbic system throughout the pediatric age range to serve as normal values in comparative studies. Quantification of volumetric abnormalities of the limbic system on brain MRI may offer insights into phenotypical variations of diseases and may help elucidate new pathological phenotypes.
... Most studies evaluating the impact of COCs on the brain structure and/or cognitive function of women have been observational crosssectional studies (e.g., Beltz et al., 2015Beltz et al., , 2022Bianchini et al., 2018;Chen et al., 2021;De Bondt et al., 2013;Garrett and Elder, 1984;Gingnell et al., 2016;Griksiene et al., 2018;Griksiene and Ruksenas, 2011;Gurvich et al., 2020;Larsen et al., 2020;Petersen et al., 2015b;Pletzer et al., 2010Pletzer et al., , 2015Rumberg et al., 2010;Wharton et al., 2008). There are few double-blinded, randomized studies with pre-and posttreatment evaluations (Gingnell et al., 2016;Petersen et al., 2021) or quasiexperimental studies that involved participants before and after the initiation of COC use (e.g., Lisofsky et al., 2016). ...
... All three of these retrospective studies showed significant and usage durationdependent effects of previous COC use: (i) the duration of previous COC treatment was positively related to gray matter volume in the hippocampus and the basal ganglia, while the time since discontinuation was negatively related to gray matter volume in the hippocampus but not in the basal ganglia ; (ii) ever users of COCs performed significantly better than never users in the domains of visuospatial ability and speed and flexibility, with duration-dependent increases in performance, especially in ever users with ≥ 15 years of use (Egan and Gleason, 2012); (iii) women with short-term use (≤5 years) of COCs had 26 % lower odds of having cognitive impairment compared with those who had never used COCs, whereas the association was not statistically significant (although it was 13 % lower) for those who used for more than 5 years (Song et al., 2020). Unfortunately, there is no information about the progestins used by all (Egan and Gleason, 2012;Song et al., 2020) or the majority of participants in these retrospective studies, as in many other studies that evaluated the effects of COCs on the brain structure,function and cognitive function of women (e.g., Beck et al., 2008;Chen et al., 2021;De Bondt et al., 2013, 2015Hamstra et al., 2014;Holloway et al., 2011;Kuhlmann and Wolf, 2005;McFadden, 2000;Miedl et al., 2018;Mihalik et al., 2009;Nielsen et al., 2011;Petersen et al., 2015b;Pletzer et al., 2010;Rosenberg and Park, 2002;Rumberg et al., 2010;Wen et al., 2021). Some studies provided information about the type of progestins but did not take this factor into consideration in data analyses (Gogos, 2013;Gravelsins et al., 2021;Hamstra et al., 2015;Høgsted et al., 2021;Kerschbaum et al., 2017;Kimmig et al., 2022;Lisofsky et al., 2016;Merz, 2017;Mordecai et al., 2008;Plamberger et al., 2021;Pletzer, 2019;Pletzer et al., 2014a;Sharma et al., 2020), and other studies combined data from participants using different types of HCs (COCs, minipills, IUDs, implants, vaginal rings, etc.) (e.g., Bernal et al., 2020;Nobile et al., 2021;Petersen et al., 2015a). ...
Progestins are an important component of hormonal contraceptives (HCs) and hormone replacement therapies (HRTs). Despite an increasing number of studies elucidating the effects of HCs and HRTs, little is known about the effects of different types of progestins included in these medications on the brain. Animal studies suggest that various progestins interact differently with sex steroid, mineralocorticoid and glucocorticoid receptors and have specific modulatory effects on neurotransmitter systems and on the expression of neuropeptides, suggesting differential impacts on cognition and behavior. This review focuses on the currently available knowledge from human behavioral and neuroimaging studies pooled with evidence from animal research regarding the effects of progestins on the brain. The reviewed information is highly relevant for improving women’s mental health and making informed choices regarding specific types of contraception or treatment.
... A closer look to which phase of the natural cycle and phase of OC-intake were compared, is provided in Table 1. Moreover, the brain structures producing estrogen and progesterone, the hypothalamus and pituitary gland, have decreased volumes in women using OCs when compared to naturally cycling women (Chen et al., 2021). ...
... itksnap.org/) is a semi-automatic segmentation using both manual and automated delineation to segment structures in MRI images. Chen et al. (2021) used this method to segment the hypothalamus and the pituitary gland and reported decreased volumes in women using OCs compared to naturally cycling women. The authors chose this segmentation method as the hypothalamus and the pituitary gland are known to be very small structures of the human brain. ...
... However, the pituitary gland cannot be assessed by FreeSurfer as of yet. The gland is being removed during the process of making the mask of the brain to strip the skull and needs to be delineated either manually or via semi-automated segmentation, as performed by Chen et al. (2021) mentioned above. ...
Worldwide over 150 million women use oral contraceptives (OCs), which are the most prescribed form of contraception in both the United States and in European countries. Sex hormones, such as estradiol and progesterone, are important endogenous hormones known for shaping the brain across the life span. Synthetic hormones, which are present in OCs, interfere with the natural hormonal balance by reducing the endogenous hormone levels. Little is known how this affects the brain, especially during the most vulnerable times of brain maturation. Here, we review studies that investigate differences in brain gray and white matter in women using OCs in comparison to naturally cycling women. We focus on two neuroimaging methods used to quantify structural gray and white matter changes, namely structural MRI and diffusion MRI. Finally, we discuss the potential of these imaging techniques to advance knowledge about the effects of OCs on the brain and wellbeing in women.
... Finally, it remains unclear how influences of age and physical health in the hypothalamus are temporally related, how one affects the other, and which other participant characteristics could further explain hypothalamic microstructure. For example, potential effects of sleep and hormonal medication (e.g., oral contraceptive use) need to be considered [57,58]. Longitudinal investigations could shed light onto these mechanisms to better understand their individual and shared contributions to better target interventions aiming at healthy aging. ...
Physical, mental, and cognitive resources are essential for healthy aging. Aging impacts on the structural integrity of various brain regions, including the hippocampus. Even though recent rodent studies hint towards a critical role of the hypothalamus, there is limited evidence on functional consequences of age-related changes of this region in humans. Given its central role in metabolic regulation and affective processing and its connections to the hippocampus, it is plausible that hypothalamic integrity and connectivity are associated with functional age-related decline. We used data of n = 369 participants (18–88 years) from the Cambridge Centre for Ageing and Neuroscience repository to determine functional impacts of potential changes in hypothalamic
microstructure across the lifespan. First, we identified age-related changes in microstructure as a function of physical, mental, and cognitive health and compared those findings to changes in hippocampal microstructure. Second, we investigated the relationship of hypothalamic microstructure and resting-state functional connectiv-ity and related those changes to age as well as physical health. Our results showed that hypothalamic micro-structure is not affected by depressive symptoms (men-tal health), cognitive performance (cognitive health), and comparatively stable across the lifespan, but affected by body mass (physical health). Furthermore, body mass changes connectivity to limbic regions including the hippocampus, amygdala, and nucleus accumbens, suggesting functional alterations in the metabolic and reward systems. Our results demonstrate that hypotha-lamic structure and function are affected by body mass, focused on neural density and dispersion, but not inflammation. Still, observed effect sizes were small, encouraging detailed investigations of individual hypothalamic subunits.
... In a recent MRI study of midlife women at risk for AD, OC users exhibited greater GM volume in medial temporal lobe, precuneus, fusiform gyrus, parietal and frontal cortex as compared to never-users , which is in line with findings in younger women . However, other studies reported reduced GM volume of amygdala, parahippocampal gyrus, hypothalamus, pituitary gland, posterior cingulate cortex and orbitofrontal cortex of OC users compared to non-users (Petersen et al., 2015;Lisofsky et al., 2016;Chen et al., 2021). When comparing the follicular phase of naturally cycling women with the inactive phase of androgenic progestins or antiandrogenic pills, OC users had lower GM volume in cingulate gyrus and bilateral culmen, although these effects did not survive correction for multiple comparisons (De Bondt et al., 2016). ...
Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women’s brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer’s disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women’s health practices.
