Early Life Stress Affects the HPT Axis Response in a Sexually Dimorphic Manner

Thyroid hormone (TH) is critical to life as it is essential during development of all vertebrate species (1). In adulthood, TH signaling is key to communicating the environment to the cells of different tissues so they can adapt to heat or cold, energy needs, illness, and other stressors. Traditionally, research on TH and the hypothalamic-pituitary-thyroid (HPT) axis has assumed male and female responses to external stressors to be similar. However, recent work by the Joseph-Bravo group and others has highlighted the dynamic differences and the sexually dimorphic nature of the HPT axis response (2-4). This work emphasizes the need to include sex as a biological variable when studying the HPT axis. Furthermore, it underscores the role of sex in developing a thyroid disorder. Indeed, women are 5 to 9 times more likely than men to develop thyroid disease.

TH is regulated by the HPT axis in a classical negative-feedback loop (1). Thyrotropin-releasing hormone (TRH) is released from hypophysiotropic neurons in the paraventricular nucleus (PVN) of the hypothalamus to the median eminence where it stimulates release of thyroid-stimulating hormone (TSH) from the pituitary. TSH stimulates the thyroid to regulate the production and release of THs, both the prohormone thyroxine (T4) and the active hormone triiodothyronine (T3). TH targets both TRH and TSH in a suppressive manner to keep TH levels in tight control. In addition to increasing levels of TH, the HPT axis is suppressed by fasting and diet, illness, and stress. Conversely, physical activity and cold exposure and other stimuli that require energy stimulate the HPT axis.

The HPT axis response to suppressive or activating stimuli is reprogrammed by early life stressors. Indeed, it has been known for 40 years that the neonatal exposure of male or female rats to high levels of TH leads to persistent central hypothyroidism in adulthood (5). However, the response to additional stressors including maternal malnutrition and exposure to drugs or environmental toxins is sexually dimorphic. Previous work determined early life stress increases Trh expression in the PVN, decreases the serum TSH concentration, and increases white adipose tissue weight in female rats only (2). Conversely, this same paradigm reduced serum TSH concentrations, increased TRH-degrading enzyme expression in the median eminence, and blunted HPT axis suppression during fasting in male rats. In a second study, early life stress coupled with juvenile exposure to high fat, high carbohydrate diet, and acute restraint suppressed T4, T3 and TSH levels in male rats compared to elevated T4 and T3 in female rats (3). Together these studies demonstrate that exposure to great stress during development can dramatically alter the activity of the HPT axis.

In their recent study, Jaimes-Hoy et al further explore the effects of early life stress on the dynamic response of HPT axis (4). Early life stress blunted cold exposure stimulation of the HPT axis in male rats. Acute cold exposure response was not measured in female rats, but these experiments can be done either by timing estrous cycles or by standardizing estrogen levels with ovariectomy and 17β-estradiol replacement (6). Early life stress had no effect on the HPT axis response to wheel running in either male or female rats. Interestingly, early life stress (maternal separation) produced epigenetic changes within the Trh gene locus. Whereas methylation patterns were similar in nonstressed male and female rats, early life stress in male rats hypomethylated a TH receptor (THR) binding site in the Trh locus that may be important to negative regulation of Trh by T3. Decreased methylation may increase THR binding either by reducing Trh expression or increasing suppression of Trh in response to lower concentrations of T3. Conversely, early life stress in female rats hypermethylated 3 sites in the Trh locus including a conserved THR-binding site (site 4) in the human and rodent genes. This increase in methylation could decrease THR binding, thus reducing suppression of Trh by T3 and/or increasing Trh expression as seen in female rats. Of note, these methylation changes were small, but that does not exclude their efficacy. Second, TRH neurons in the PVN are a diverse population and are not all hypophysiotropic. To determine the particular subset of TRH neurons that undergo these methylation changes, sorting of neuroendocrine TRH neurons from the other populations will be necessary.

The authors suggest early life stressors dampen the dynamic response of the HPT axis to the environment and could lead to symptoms of subclinical hypothyroidism, where TSH levels are high but TH levels are still normal. A recent meta-analysis concluded that nonpregnant adults with subclinical hypothyroidism treated with TH therapy did not experience improved general quality of life or hypothyroid symptoms (7). Therefore, further work needs to be done to determine the root causes of subclinical hypothyroidism to reveal more effective treatments. Additionally, follow-up studies are needed to understand the TH response of rats subjected to early life stress: are these rats able to appropriately respond to exogenous TH?

Notably, subclinical hypothyroidism affects 4% to 8% of all women of child-bearing age. Research has yet to determine the full effect of subclinical hypothyroidism on women’s health and currently, there is conflicting research about the role of subclinical hypothyroidism in fertility. Jaimes-Hoy et al and other previous studies detail the greater effect of early life stress on the response of the female rat HPT axis (2,3). Further studies should investigate the link between early life stress and subclinical hypothyroidism and fertility. Additionally, this work underlines the need for greater focus on the effect of aging and reductions in sex steroids on the HPT axis in both men and women. The reductions in sex steroids can critically impact the body’s ability to regulate TH signaling and adapt to the environment (8). Furthermore, how does the stress of aging affect the actions of TH on target cells? Moreover, women undergoing menopause have drastic shifts in their ability to regulate their metabolism and body temperature. Do early life stresses further complicate the loss of estrogen on women’s metabolism and HPT axis function?

Acknowledgments

Financial Support: This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK056123 (ANH), R01 DK117940 (ANH), and R01 DK105029 (ANH).

Additional Information

Disclosures: The authors have no conflicts of interest to declare.

Data Availability

Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study