May 9, 2022
National Women’s Health Week
Stress and the HPA Axis: Balancing Homeostasis and Fertility
By Abigail Blake
Editor’s Note: To mark National Women’s Health Week, we are featuring research examining how stress response systems may impact fertility and fetal development. While a medical student in our FACTS elective, Abigail Blake reviewed the 2017 article, Stress and the HPA Axis: Balancing Homeostasis and Fertility, published in the International Journal of Molecular Sciences.
To learn more about the role fertility awareness-based methods may play in monitoring and managing women’s health, be sure to sign up for our 2022 FACTS Virtual Conference series, which kicks off in just 10 days! Also, in honor of our Executive Director’s birthday today, we will give you all an additional 10% off the registration fee if you sign up TODAY – May 9th and use the promo code BIRTHDAY10!
Introduction
Stress can be defined as a “state of real or perceived threat to homeostasis that may challenge an organism’s well-being”(1). The stress response consists of endocrine, nervous, and immune system activation in response to this threat, prioritizing survival over other physiological functions such as growth and reproduction. The hypothalamic-pituitary-adrenal (HPA) axis is the primary mediator of the stress response. Activation of the HPA axis triggers the release of corticotropin-releasing hormone (CRH) from the hypothalamus, stimulating the production and secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. ACTH modulates the synthesis and secretion of many important molecules in the body, including glucocorticoids such as cortisol, mineralocorticoids like aldosterone, and adrenal androgens. Rising levels of cortisol in the bloodstream act as a negative feedback loop inhibiting release of CRH and ACTH. This enables the HPA axis to return to normal physiological function after an acute activation.
As part of this stress response, the HPA axis also mediates the reproductive system via the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis is mediated via endocrine signaling much like the HPA axis. Hypothalamic secretion of gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, which act on the ovary to stimulate oocyte maturation, ovulation, and steroid hormone production. Ovarian production of inhibins, steroid hormones such as estradiol and progesterone, and activins all act to regulate secretion of GnRH. Stress signaling impacts this axis at all levels. High levels of cortisol can inhibit GnRH secreting neurons, LH and FSH secreting cells, and activity of the gonads resulting in reproductive dysfunction.
Impact of Stress throughout the HPG Axis
It has been suggested that increased levels of CRH exert negative effects on reproductive function by reducing endogenous levels of LH and FSH. These can return to baseline once CRH levels also return to baseline. Stress can inhibit GnRH release, which has a multitude of downstream effects, including suppression of GnRH and GnRH receptor synthesis, disruption in pituitary release of LH, and increased function of gonadotropin inhibitory hormones. These downstream effects will inhibit the LH surge that is crucial for healthy ovulation in females. Additionally, secretion of FSH can increase as a result of increased glucocorticoids, raising the FSH:LH ratio. A high FSH:LH ratio has been shown to have a negative impact on follicular development and oocyte quality.
“Stress can inhibit gonadotropin-releasing hormone (GnRH) release, which has a multitude of downstream effects …These downstream effects will inhibit the LH surge that is crucial for healthy ovulation in females.”
Figure 1: HPA axis activation by various stressors alters the activity of the HPG axis. HPA-axis: hypothalamic-pituitary-adrenal axis, FSH: follicle stimulating hormone, LH: lutenizing hormone, GnRH: gonadotropin-releasing hormone, GnIH: gonadotropin-inhibitory hormone [1]
Effects in Female Reproductive Tract Organs
One of the main effects stress can have in females is impaired oocyte competence. One study of women undergoing in vitro fertilization showed that follicular fluid from unfertilized follicles has higher concentrations of cortisol than fluid in fertilized follicles, suggesting that high levels of cortisol could influence how easily a follicle is fertilized. Mice studies have shown that stress impairs fertility through poor embryo development, fewer blastocysts per mouse, and increased apoptosis in the oviduct. Moreover, stress in mice significantly reduced pregnancy rates and litter size and increased anxiety-like behaviors.
Placenta and Parturition
Pregnant women have 1,000 to 10,000 times the CRH concentrations as non-pregnant women. Most of this is bound by CHR-binding protein, rendering it inactive, but during the third trimester there is a CRH surge which has been hypothesized to act as a “placental clock” responsible for the duration of gestation. CRH produced in the placenta can stimulate ACTH production, resulting in a positive feedback loop and increased production of glucocorticoids. This is one mechanism that could cause stress-induced preterm labor.
Other Markers of the Stress Response
Salivary α-amylase (sAA) is secreted as part of the stress response, and in one study, women with the highest levels of sAA exhibited a significant decrease in fertility rates. This suggests that stress is associated with lower fecundity among affected women. Stress may also significantly reduce the probability of conception each day during the fertile window.
Stress Impact on Fetal Programming
Increased glucocorticoid exposure can permanently affect tissue and organ function, reduce birth weight, and increase risk of cardiometabolic disease, stress-related anxiety, and HPA affective disorders later in life. These effects may persist for many generations. Maternal stress can also increase risk for developmental disorders, including temperament, cognition, language skills, and motor functioning. This is evidenced by several studies of pregnant women and their offspring following the Dutch famine, the World Trade Center collapse, the 1998 Ice Storm in Quebec, and more.
Sex Differences in the Response to Stress
There is evidence suggesting that male and female infants differ in their response to prenatal stress while in utero. Female placenta has been shown to respond to changes in glucocorticoid concentration with changes in cortisol metabolism, adrenal function and growth, and placental cytokine expression. This response involves adaptations that result in decreases in growth in order to promote survival. Male placenta appears to be glucocorticoid resistant as the pathways typically responsive to cortisol listed above remain unaffected. However, the male response was associated with a greater risk of preterm delivery, intrauterine growth restriction, or death in utero. Some of the sex differences seen could be a result of altered 11β-HSD1 and 11β-HSD2 signaling in the female placenta.
Prenatal maternal stress can affect outcomes for each sex beyond the neonatal period as well. Female fetal exposure to stress has been associated with increased levels of childhood anxiety, impaired executive function, and significant enlargement of the amygdala. These effects are not demonstrated in males.
“Prenatal maternal stress can affect outcomes for each sex beyond the neonatal period as well.”
Conclusion
Glucocorticoids are essential for fertility and fetal survival yet can negatively impact fertility and fetal outcomes. Increased HPA axis activity can alter the functions of the hypothalamus, pituitary, and gonads. It is not well understood whether the dysfunctions arise from direct actions on target tissue or endocrine effects of stress signaling, but it is clear that HPA axis activity can cause reproductive dysfunction. Given the current COVID-19 pandemic and its associated stressors there could be an increased rate of reproductive dysfunction in the general population as a result of increased chronic stress.
Charting with an FABM can give women insight as to how stress is affecting their menstrual cycles. Stress could cause a prolonged follicular phase, impaired oocyte quality, or decrease fecundity rates in women of reproductive age. Further research on stress and its effects on reproductive health is necessary to see how we can best support our patients in difficult times.
References
[1] Joseph DN, Whirledge S. Stress and the HPA Axis: Balancing Homeostasis and Fertility. Int J Mol Sci. 2017;18(10):2224. Published 2017 Oct 24. doi:10.3390/ijms18102224.
About the Author
Abigail Blake
Abigail Blake is a second year medical student at the University of New England College of Osteopathic Medicine. She earned her undergraduate degree at Northeastern University in Boston and completed her Master of Public Health degree at Southern New Hampshire University. Abigail participated in The Role of FABMs in Restorative Reproductive Women’s Health elective through FACTS in 2021 and hopes to continue furthering her knowledge of FABMs throughout her medical career. She hopes to practice Family Medicine.
