PF-06835919, a ketohexokinase inhibitor intended for the treatment of non-alcoholic fatty liver disease, caused decreased/absent corpora lutea in the ovary in a 6-month rat repeat-dose toxicity study. These findings occurred in the presence of liver and thyroid effects, and it was hypothesized that the decreased/absent corpora lutea was due to hypothyroidism secondary to PF-06835919-related UGT (UDP-glucuronosyltransferase) enzyme induction. An investigative study was conducted to evaluate the onset of ovarian changes by monitoring daily estrous cycles with daily administration of 100mg/kg/day, and thyroid hormone levels were also measured. Estrous cycle disruption (persistent estrus) was noted in 10 of 15 females, with onset occurring between days 33 and 81. Higher TSH (3.8x control) and altered T3 and T4 were noted on day 37, indicating that thyroid hormone dysregulation preceded the estrous cycle disruption. Recovery of the estrous cycle disruption occurred in 30% of the animals before the study was terminated due to onset of reproductive senescence. Liver UGT enzyme induction, including UGT1A1, was confirmed to be induced in a separate 2-week rat study. All available data support the hypothesis that PF-06835919-related induction of one or more UGT enzymes and consequent thyroid dysregulation were the cause of ovarian changes in the rat.

Lithium excretion into breastmilk and concentrations in infant serum are highly variable. Although lithium appears on some lists of drugs contraindicated during breastfeeding,[1] many sources do not consider it an absolute contraindication in healthy-full-term infants, especially in infants over 2 months of age and during lithium monotherapy.[2-9] Numerous reports exist of infants who were breastfed during maternal lithium therapy without any signs of toxicity or developmental problems. Most were breastfed from birth and some continued to nurse for up to 1 year of maternal lithium therapy. Some reports suggest that lithium in milk can adversely affect the infant acutely when its elimination is impaired, as in dehydration or in newborn or premature infants. Neonates may also have transplacentally acquired serum lithium levels. Lithium levels in these infants decline whether they are breastfed or not, although serum levels may fall more slowly in exclusively breastfed infants.[10] The long-term effects of lithium on infants are not certain, but limited data indicate no obvious problems in growth and development.[9-11] Lithium may be used in mothers of fullterm infants who are willing and able to monitor their infants. Because maternal lithium requirements and dosage may be increased during pregnancy, maternal serum levels should be monitored frequently postpartum and dosage reduced as necessary to avoid excessive infant exposure via breastmilk.[12] Discontinuing lithium 24 to 48 hours before Cesarean section delivery or at the onset of spontaneous labor and resuming the prepregnancy lithium dose immediately after delivery should minimize the infant's serum lithium concentration at birth.[13] Some investigators recommend monitoring infant serum lithium, serum creatinine, BUN, and TSH in intervals ranging from "periodic" to every 4 to 12 weeks during breastfeeding and maternal lithium therapy.[4,14] One group recommends monitoring maternal and infant serum lithium at 2, 10, 30 and 60 days postpartum.[15] A systematic review recommends infant lithium serum level, thyroid and renal function tests only at 10 days postpartum, then only if the infant’s serum lithium is 0.3 mEq/L or greater or if clinical signs of toxicity appear.[16] However, others recommend close pediatric follow-up of the infant and only selective laboratory monitoring (i.e., serum lithium, TSH, BUN) if clinically indicated by unusual behavior, restlessness, feeding difficulties, sedation or abnormal growth and development. Infants who are preterm, dehydrated, or have an infection, should receive hydration and be assessed for lithium toxicity.[6,7] If the infant serum lithium level is elevated, reducing the percentage of breastfeeding can decrease it.[9]

Environmental pollutants adversely affect both adult organisms and their offspring. Prednisone, a synthetic glucocorticoid frequently detected in surface water, harms aquatic organisms like sheepshead minnows, tadpoles, and zebrafish (Danio rerio). However, data on its effects on the thyroid endocrine system of zebrafish and its intergenerational toxicity are currently lacking. This study exposed adult male zebrafish to environmentally relevant prednisone concentrations (0-500 ng/L) for 60 days to explore potential thyroid endocrine disruption in both parents and offspring. Research findings show that compared with the control group, zebrafish in the high-dose (H) group had significantly reduced body length and weight. Their swimming speed decreased by 20.9-32.7%, the time spent stationary at the bottom of the tank decreased by 139.1-152.1%, and the frequency of this behavior dropped by 84.6-94.2%. As prednisone concentrations increased, the plasma levels of T4 in parental zebrafish decreased significantly, while the levels of T3 and TSH increased significantly. Thyroid follicular epithelial cells exhibited hyperplasia and hypertrophy along with a depletion of colloid cells. These effects were associated with abnormal transcriptional levels of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis (i.e., crh, pax8, tpo, tg, ttr and dio1 and dio2). Additionally, parental exposure to prednisone impaired F1 larvae: 82.3% increased mortality, 14.3-32.2% reduced hatching rates, abnormal heart rates, 29.16-38.76% reduced swimming activity, decreased thyroid hormones, and dysregulated transcription of HPT axis-related genes. The study confirms that prednisone induces intergenerational toxicity in parents and offspring by disrupting thyroid endocrine function, enhancing understanding of the risks posed by prednisone to fish.

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated not only with tumor progression but also with profound metabolic and nutritional disturbances. Thyroid hormone homeostasis may reflect this systemic response; however, perioperative data in PDAC remain limited. We aimed to assess perioperative changes in thyroid-related parameters in patients with PDAC undergoing different types of surgical management and to explore their associations with nutritional, metabolic, and tumor-burden variables. Methods: We performed a retrospective single-center study including 101 patients with PDAC. Thyroid-related and metabolic laboratory parameters were assessed before surgery and again 4-6 weeks later. The analyzed variables included thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), the FT3/FT4 ratio, albumin, total protein, glucose, insulin, HbA1c, lipid parameters, and CA 19-9. Patients were analyzed according to resectional versus non-resectional treatment and according to four procedure types. The primary endpoint was perioperative change in the FT3/FT4 ratio. Results: At baseline, resectional patients had significantly higher FT3 and FT3/FT4 ratio values and lower FT4 and CA 19-9 levels than non-resectional patients. In the whole cohort, FT3 and the FT3/FT4 ratio decreased significantly after treatment, whereas TSH increased, and FT4 remained unchanged. These endocrine changes occurred in parallel with significant declines in albumin, total protein, glucose, insulin, HbA1c, and HDL cholesterol, together with an increase in triglyceride levels. Baseline FT3 and FT3/FT4 ratios correlated positively with albumin and total protein and negatively with CA 19-9. Although perioperative changes did not differ significantly between resectional and non-resectional groups except for triglycerides, significant procedure-dependent differences were observed across the four surgical categories for FT3, FT4, TSH, and the FT3/FT4 ratio; glucose; insulin; and triglycerides. The prevalence of low-T3 syndrome increased from 11.1% preoperatively to 38.7% postoperatively. Conclusions: In PDAC, perioperative changes in thyroid hormone indices are pronounced and strongly depend on the type of surgical management. FT3 and the FT3/FT4 ratio appear to reflect systemic metabolic and nutritional adaptation as well as disease burden rather than acting as tumor-specific markers.

The U.S. Army Ranger Training Course (RTC) is a multi-stressor environment including cognitive and physical stress coupled with repeated sleep and energy deficits over 61+ days. Previous investigations of physiological responses to RTC operational stressors were conducted exclusively in males, leaving female responses uncharacterized. Therefore, this study aimed to identify changes in metabolic, growth, and sex hormones, inflammatory and iron markers in males and females undergoing RTC. Blood samples and body composition assessments (DXA) were collected at the start of RTC (Baseline (BL)) and at the end of each phase (Phase (P)1 - general field, P2 - mountains, P3 - swamp). During each phase, daily urine sampling and measures of energy balance (doubly labeled water method) occurred. Females experienced physiological changes primarily in P2, with reductions in estradiol (mean difference [95% Confidence Interval]: -79.29 [-115.32, -43.26]), progesterone (-1.48 [-2.70, -0.26]), testosterone (-0.74 [-1.43, -0.04]), free testosterone: -12.70 [-23.23, -2.17]), thyroid stimulating hormone (TSH; -0.54 [-1.03, -0.05]), and insulin-like growth factor 1 (IGF-1; -92.58 [-121.28, -63.88]) compared to BL. Males demonstrated significant decreases in free testosterone, TSH, triiodothyronine (T3), IGF-1, hemoglobin, and hematocrit across all three phases compared to BL (all, p < 0.05), with the largest changes in P3 for TSH (-0.66, [-1.21, -0.11]), T3 (-0.30 [-0.41, -0.20]), IGF-1 (-104.70 [-116.52, -92.88]), hemoglobin (-1.32 [-1.71, -0.94]), and hematocrit (-3.89 [-5.02, -2.75]). Ferritin increased across all phases compared to BL regardless of sex (p < 0.05). These findings indicate that multi-stressor environments may disproportionately affect male physiological markers, whereas females exhibited fewer, phase-specific changes.

Previous epidemiological studies have established associations between fine particulate matter (PM2.5) exposure and maternal thyroid hormone suppression. However, as PM2.5 is a complex chemical mixture, the specific contribution of metallic constituents to PM2.5-induced thyroid disruption remains poorly characterized. This study aimed to evaluate the relationship between maternal thyroid function and exposure to metallic and metalloid components of PM2.5 during pregnancy. In a longitudinal study of 847 pregnant women recruited from three maternal and child healthcare hospitals, we collected fasting blood samples at 10, 17, and 32 weeks of gestation for thyroid hormone assessment. Concurrently, ambient PM2.5 monitoring stations near participating hospitals quantified 11 metallic/metalloid elements. Linear mixed-effects regression models assessed individual element associations with thyroid parameters, while weighted quantile sum (WQS) regression evaluated combined effects of metal mixtures. Significant inverse associations were observed between lead (Pb) exposure and serum thyroid stimulating hormone (TSH) levels. Multiple elements - including aluminum (Al), arsenic (As), cadmium (Cd), lead (Pb), antimony (Sb), selenium (Se) and thallium (Tl) - demonstrated negative correlations with free thyroxine (FT4) and free triiodothyronine (FT3) concentrations. WQS analysis revealed that each inter-decile rise in mixed metal exposure was associated with a 0.52% decrease in TSH (95% CI: -3.84%, 2.91%), a 1.52% reduction in FT4 (95% CI: -1.95%, -1.09%), and a 1.18% decline in FT3 (95% CI: -1.60%, -0.77%). Tl, Al, and As emerged as primary contributors to these effects, collectively accounting for 86%- 97% of the weighted mixture impact. These findings demonstrate that metallic components of PM2.5, particularly Tl, Al and As are significantly associated with suppressed maternal thyroid function during pregnancy. This highlights the importance of metal-specific toxicity in PM2.5-related endocrine disruption.