Gynecological surgery in adulthood imparts cognitive and brain changes in rats: A focus on hysterectomy at short-, moderate-, and long-term intervals after surgery.

Premenopausal hysterectomy is associated with a greater relative risk of dementia. We previously demonstrated cognitive impairments in adult rats six weeks after hysterectomy with ovarian conservation compared with intact sham-controls and other gynecological surgery variations. Here, we investigated whether hysterectomy-induced cognitive impairments are transient or persistent. Adult rats received sham-control, ovariectomy (Ovx), hysterectomy, or Ovx-hysterectomy surgery. Spatial working memory, reference memory, and anxiety-like behavior were tested either six-weeks post-surgery, in adulthood; seven-months post-surgery, in early middle-age; or twelve-months post-surgery, in late middle-age. Hysterectomy in adulthood yielded spatial working memory deficits at short-, moderate-, and long-term post-surgery intervals. Serum hormone levels did not differ between ovary-intact, but differed from Ovx, groups. Hysterectomy had no significant impact on healthy ovarian follicle or corpora lutea counts for any post-surgery timepoint compared with intact sham-controls. Frontal cortex, dorsal hippocampus, and entorhinal cortex were assessed for activity-dependent markers. In entorhinal cortex, there were alterations in FOSB and ΔFOSB expression during the early middle-age timepoint, and phosphorylated ERK1/2 levels at the adult timepoint. Collectively, results suggest a primary role for the uterus in regulating cognition, and that memory-related neural pathways may be modified following gynecological surgery. This is the first preclinical report of long-term effects of hysterectomy with and without ovarian conservation on cognition, endocrine, ovarian, and brain assessments, initiating a comprehensive framework of gynecological surgery effects. Translationally, findings underscore critical needs to decipher how gynecological surgeries, especially those involving the uterus, impact the brain and its functions, the ovaries, and overall aging from a systems perspective.

Investigating racial disparities in quality-of-life years after pediatric hematopoietic stem cell transplant.

BACKGROUND: While racial disparities in the clinical outcomes of hematopoietic stem cell transplant (HSCT) patients have been explored, racial disparities in quality of life (QoL) during the re-adjustment phase after transplant are yet to be investigated in pediatric patients. The objective of this study was to examine the role of patient race in QoL at least 2 years after pediatric HSCT. PROCEDURE: We conducted a retrospective chart review of patients under 21 years of age at diagnosis who received an allogeneic transplant at our institution between January 2007 and December 2017. Patient QoL was assessed using the Pediatric Quality-of-Life Inventory Generic Score Scales (PedsQL TM 4.0) at least 2 years post transplant. Patient demographic, treatment, and transplant outcome data were obtained for subsequent analysis, where patient race was categorized as either Black, White, Hispanic, or Native American. RESULTS: Data were collected on 86 pediatric patients who underwent HSCT. Forty patients (46.5%) were non-Hispanic White, 29 (33.7%) Hispanic, 10 (11.6%) Black, and seven (8.1%) Native American. Where preliminary analyses indicated a difference in QoL by patient race, there were no significant differences in physical, emotional, social, and school functioning by patient race after adjusting for transplant characteristics (age at transplant, sex, diagnosis, donor type, and conditioning regimen) and determinants of socioeconomic status (insurance type, estimated household income). CONCLUSIONS: Pediatric patients had comparable QoL, regardless of race, at a median of 3 years after HSCT in our study cohort.

Evaluations of memory, anxiety, and the growth factor IGF-1R after post-surgical menopause treatment with a highly selective progestin.

Progestogens are a key component of menopausal hormone therapies. While some progestogens can be detrimental to cognition, there is preclinical evidence that progestogens with a strong progesterone-receptor affinity benefit some molecular mechanisms believed to underlie cognitive function. Thus, a progestin that maximizes progesterone-receptor affinity and minimizes affinities to other receptors may be cognitively beneficial. We evaluated segesterone-acetate (SGA), a 19-norprogesterone derivative with a strong progesterone-receptor affinity and no androgenic or estrogenic-receptor activity, hypothesizing that it would enhance cognition. Middle-aged rats underwent Sham or Ovariectomy (Ovx) surgery followed by administration of medroxyprogesterone-acetate (MPA; used as a positive control as we have previously shown MPA-induced cognitive deficits), SGA (low or high dose), or vehicle (one Sham and one Ovx group). Spatial working and reference memory, delayed retention, and anxiety-like behavior were assessed, as were memory- and hormone- related protein assays within the frontal cortex, dorsal hippocampus, and entorhinal cortex. Low-dose SGA impaired spatial working memory, while high-dose SGA had a more extensive detrimental impact, negatively affecting spatial reference memory and delayed retention. Replicating previous findings, MPA impaired spatial reference memory and delayed retention. SGA, but not MPA, alleviated Ovx-induced anxiety-like behaviors. On two working memory measures, IGF-1R expression correlated with better working memory only in rats without hormone manipulation; any hormone manipulation or combination of hormone manipulations used herein altered this relationship. These findings suggest that SGA impairs spatial cognition after surgical menopause, and that surgical menopause with or without progestin administration disrupts relationships between a growth factor critical to neuroplasticity.

Surgical Menopause and Estrogen Therapy Modulate the Gut Microbiota, Obesity Markers, and Spatial Memory in Rats.

Menopause in human females and subsequent ovarian hormone deficiency, particularly concerning 17ß-estradiol (E2), increase the risk for metabolic dysfunctions associated with obesity, diabetes type 2, cardiovascular diseases, and dementia. Several studies indicate that these disorders are also strongly associated with compositional changes in the intestinal microbiota; however, how E2 deficiency and hormone therapy affect the gut microbial community is not well understood. Using a rat model, we aimed to evaluate how ovariectomy (OVX) and subsequent E2 administration drive changes in metabolic health and the gut microbial community, as well as potential associations with learning and memory. Findings indicated that OVX-induced ovarian hormone deficiency and E2 treatment had significant impacts on several health-affecting parameters, including (a) the abundance of some intestinal bacterial taxa (e.g., Bifidobacteriaceae and Porphyromonadaceae), (b) the abundance of microbial short-chain fatty acids (SCFAs) (e.g., isobutyrate), (c) weight/BMI, and (d) high-demand spatial working memory following surgical menopause. Furthermore, exploratory correlations among intestinal bacteria abundance, cognition, and BMI underscored the putative influence of surgical menopause and E2 administration on gut-brain interactions. Collectively, this study showed that surgical menopause is associated with physiological and behavioral changes, and that E2-linked compositional changes in the intestinal microbiota might contribute to some of its related negative health consequences. Overall, this study provides novel insights into interactions among endocrine and gastrointestinal systems in the post-menopausal life stage that collectively alter the risk for the development and progression of cardiovascular, metabolic, and dementia-related diseases.