Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.
Objective To investigate the association between lifetime breast feeding, exclusive breast feeding, postpartum amenorrhea, and incidence of endometriosis among parous women.Design Prospective cohort study.Setting Nurses' Health Study II, 1989-2011.Participants 72 394women who reported having one or more pregnancies that lasted at least six months, 3296 of whom had laparoscopically confirmed endometriosis. For each pregnancy, women reported duration of total breast feeding, exclusive breast feeding, and postpartum amenorrhea. Main outcome measures Incident self reported laparoscopically confirmed endometriosis (96% concordance with medical record) in parous women. Multivariable Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for diagnosis of endometriosis.Results Duration of total and exclusive breast feeding was significantly associated with decreased risk of endometriosis. Among women who reported a lifetime total length of breast feeding of less than one month, there were 453 endometriosis cases/100 000 person years compared with 184 cases/100 000 person years in women who reported a lifetime total of ≥36 months of breast feeding. For every additional three months of total breast feeding per pregnancy, women experienced an 8% lower risk of endometriosis (hazard ratio 0.92, 95% confidence interval 0.90 to 0.94; P<0.001 for trend) and a 14% lower risk for every additional three months of exclusive breast feeding per pregnancy (0.86, 0.81 to 0.90; P<0.001 for trend). Women who breastfed for ≥36 months in total across their reproductive lifetime had a 40% reduced risk of endometriosis compared with women who never breast fed (0.60, 0.50 to 0.72). The protective association with breast feeding was strongest among women who gave birth within the past five years (P=0.04 for interaction). The association with total breast feeding and exclusive breast feeding on endometriosis was partially influenced by postpartum amenorrhea (% mediated was 34% (95% confidence interval 15% to 59%) for total breast feeding and 57% (27% to 82%) for exclusive breast feeding).Conclusion Among women who experienced at least one pregnancy that lasted at least six months, breast feeding was inversely associated with risk of incident endometriosis. This association was partially, but not fully, influenced by postpartum amenorrhea, suggesting that breast feeding could influence the risk of endometriosis both through amenorrhea and other mechanisms. Given the chronic and incurable nature of endometriosis, breast feeding should be further investigated as an important modifiable behavior to mitigate risk for pregnant women.
An important feature of the mammary gland is its ability to undergo repeated morphological changes during each reproductive cycle with profound tissue expansion in pregnancy and regression in involution. However, the mechanisms that determine the tissue’s cyclic regenerative capacity remain elusive. We have now discovered that Cre-Lox ablation of Rac1 in mammary epithelia causes gross enlargement of the epithelial tree and defective alveolar regeneration in a second pregnancy. Architectural defects arise because loss of Rac1 disrupts clearance in involution following the first lactation. We show that Rac1 is crucial for mammary alveolar epithelia to switch from secretion to a phagocytic mode and rapidly remove dying neighbors. Moreover, Rac1 restricts the extrusion of dying cells into the lumen, thus promoting their eradication by live phagocytic neighbors while within the epithelium. Without Rac1, residual milk and cell corpses flood the ductal network, causing gross dilation, chronic inflammation, and defective future regeneration.
To estimate the effectiveness and safety of thyroid hormone treatment among pregnant women with subclinical hypothyroidism.
While many studies have shown that maternal weight and nutrition in pregnancy affects offspring’s breast cancer risk, no studies have investigated the impact of paternal body weight on daughters' risk of this disease. Here, we show that diet-induced paternal overweight around the time of conception can epigenetically reprogram father’s germ-line and modulate their daughters' birth weight and likelihood of developing breast cancer, using a mouse model. Increased body weight was associated with changes in the miRNA expression profile in paternal sperm. Daughters of overweight fathers had higher rates of carcinogen-induced mammary tumors which were associated with delayed mammary gland development and alterations in mammary miRNA expression. The hypoxia signaling pathway, targeted by miRNAs down-regulated in daughters of overweight fathers, was activated in their mammary tissues and tumors. This study provides evidence that paternal peri-conceptional body weight may affect daughters' mammary development and breast cancer risk and warrants further studies in other animal models and humans.
Lactation duration has shown weak protective associations with incident diabetes (3%-15% lower incidence per year of lactation) in older women based solely on self-report of diabetes, studies initiated beyond the reproductive period are vulnerable to unmeasured confounding or reverse causation from antecedent biochemical risk status, perinatal outcomes, and behaviors across the childbearing years.
In recent years, a greater appreciation for the microbes inhabiting human body sites has emerged. In the female mammary gland, milk has been shown to contain bacterial species, ostensibly from the skin. We decided to investigate whether there is a microbiome within the mammary tissue. Using 16S rRNA sequencing and culture, we analysed breast tissue from 81 women with and without cancer in Canada and Ireland. A diverse population of bacteria were detected within tissue collected from sites all around the breast in women aged 18 to 90, not all of whom had a history of lactating. The principal phylum was Proteobacteria. The most abundant taxa in the Canadian samples were Bacillus (11.4%), Acinetobacter (10.0%), unclassified Enterobacteriaceae (8.3%), Pseudomonas (6.5%), Staphylococcus (6.5%), Propionibacterium (5.8%), unclassified Comamonadaceae (5.7%), unclassified Gammaproteobacteria (5.0%) and Prevotella (5.0%). In the Irish samples the most abundant taxa were unclassified Enterobacteriaceae (30.8%), Staphylococcus (12.7%), Listeria welshimeri (12.1%), Propionibacterium (10.1%) and Pseudomonas (5.3%). None of the subjects had signs or symptoms of infection, but the presence of viable bacteria was confirmed in some samples by culture. The extent to which these organisms play a role in health or disease remains to be determined.
Pregnant women with epilepsy frequently experience seizures related to pregnancy complications and are often prescribed anti-epileptic drugs (AEDs) to manage their symptoms. However, less is known about the comparative safety of AED exposure in utero. We aimed to compare the risk of congenital malformations (CMs) and prenatal outcomes of AEDs in infants/children who were exposed to AEDs in utero through a systematic review and Bayesian random-effects network meta-analysis.
The mammary gland represents a unique tissue to study organogenesis as it predominantly develops in the post-natal animal and undergoes dramatic morphogenetic changes during puberty and the reproductive cycle. The physiological function of the mammary gland is to produce milk to sustain the newborn. Here we view the lactating gland through three-dimensional confocal imaging of intact tissue. We observed that the majority of secretory alveolar cells are binucleated. These cells first arise in very late pregnancy due to failure of cytokinesis and are larger than mononucleated cells. Augmented expression of Aurora kinase-A and Polo-like kinase-1 at the lactogenic switch likely mediates the formation of binucleated cells. Our findings demonstrate an important physiological role for polyploid mammary epithelial cells in lactation, and based on their presence in five different species, suggest that binucleated cells evolved to maximize milk production and promote the survival of offspring across all mammalian species.
Probiotic supplementation to women during pregnancy and lactation can modulate breast milk composition, with immune benefits being transferred to their infants.