Chronic Stress and Ovulatory Dysfunction: Implications in Times of COVID-19

Abstract

Stress is known to be associated with adverse health outcomes. The COVID-19 pandemic and its associated lockdowns are examples of chronic stressors. Lockdown measures inadvertently caused significant psychological distress and became a powerful source of anxiety/stress, sleep disturbances, nutritional changes and weight gain. Stress is known to impact women's health specifically, through hypothalamic-pituitary-gonadal (HPG) axis dysfunction and resultant ovulatory dysfunction. Such dysfunction may manifest in menstrual irregularities and/or infertility due to hypothalamic hypogonadism. Here, we review the key physiological mediators of stress and associated ovulatory dysfunction. The kisspeptinergic system is comprised of sets of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and the arcuate nucleus (ARC). This system links nutrition, reproductive signals and stress. It plays a key role in the function of the HPG axis. During chronic stress, the kisspeptinergic system affects the HPG axis, GnRH pulsatility, and, therefore, ovulation. Leptin, insulin and corticotrophin-releasing hormone (CRH) are thought to be additional key modulators in the behavioral responses to chronic stress and may contribute to stress-related ovulatory dysfunction. This mini-review also summarizes and appraises the available evidence on the negative impact of chronic stress as a result of the COVID-19 pandemic lockdowns. It proposes physiological mechanisms to explain the observed effects on women's reproductive health and well-being. The review suggests areas for future research.

Keywords: anxiety; kisspeptin; menstrual cycle; obesity; ovulation; stress.

Figure 1

An increase in FSH levels leads to recruitment and development of ovarian follicles. Selected follicles produce rising estradiol levels. Estradiol and inhibin exert a negative feedback upon the HPG axis, thus decreasing FSH levels. Estradiol also causes a negative feedback upon the Kiss^ARC neurons. Kisspeptin-neurokinin B-dynorphin (KNDy) neurons present in the hypothalamus's arcuate nucleus (ARC), co-express neurokinin B (NKB) and dynorphin (Dy) and are essential for GnRH pulse generation and secretion. Low frequency hypothalamic GnRH pulses lead to a release of FSH and LH from the anterior hypophysis. One of the selected ovarian follicles becomes dominant, and secretes increasingly high levels of estradiol. This rapid and sustained increase in estradiol values gives the required signal to activate the Kiss^RP3V/POA neurons. This activation triggers the GnRH pulsatility and release, necessary for the LH/FSH surge. The LH surge is initiated, which causes follicular luteinization and an initial progesterone rise. Progesterone maintains the LH peak and is necessary for follicular rupture and adequate ovulation. After ovulation, estradiol levels abruptly decrease. This “turns off” the Kiss^RP3V/POA neurons, ending the LH/FSH surge.

Figure 2

Kisspeptinergic neurons from the “preoptic area” and “arcuate nucleus” release kisspeptin to stimulate GnRH neurons to release GnRH. Under proper nutritional conditions, the presence of metabolic signals such as insulin and leptin will activate anorexigenic neurons, as the POMC neurons that release α-MSH, causing satiety. On the other hand, insulin and leptin will inhibit the orexigenic neurons, which release NPY and AgRP, causing hunger. Proper metabolic signals will stimulate the release of kisspeptin and promote ovulation. On the contrary, signs of starvation and/or stress will inhibit the release of kisspeptin, affecting ovulation and the reproductive process.