Impact of Stress on Ovulation during COVID-19: A Research Review

By: Jessica Pickard

Director’s Note: As we continue to witness the repercussions of COVID-19 on everything from mental health to physical wellbeing, this research published in 2022 in Frontiers in Global Women’s Health adds a unique perspective. [1] The study by Vigil et al provides an in-depth review of the literature on stress and COVID-19 with a focus on its implications for women’s hormonal health and ovulatory function. The research was summarized by Jessica Pickard, a fourth-year medical student who participated in the online FACTS fertility awareness elective offered at Georgetown University School of Medicine.

Introduction

The COVID-19 pandemic had varying effects on populations worldwide, many of which are only now being appreciated. The spread of disease impacted millions of people through periods of quarantine, mass lockdowns, and even the collapse of entire healthcare entities. A common impact seen across the globe was increased rates of chronic stress manifesting as elevated rates of anxiety, depression, nutritional changes, and sleep disturbances. [1] The impact of chronic stress is different in women in both their psychological and physiological responses compared to men. The timely review by Vigil et al summarized below explores the neurochemical pathways related to chronic stress, how the COVID-19 pandemic contributed to increased stress levels, and the unique physiologic impact this had on women’s reproductive health, particularly ovulatory dysfunction.

“The impact of chronic stress is different in women in both their psychological and physiological responses compared to men.”

Methodology

The authors conducted an extensive literature review of available data collected during and shortly following the lockdown phases of the COVID-19 pandemic. They hypothesized the pandemic fostered an environment conducive to chronic stress and that this stress had a unique impact on women’s psychological health, hormonal axes, and subsequent ovulatory dysfunction. In addition, the authors provide an in-depth review of the human response to stress, including hormones, neural pathways, and metabolic effects.

Of the studies reviewed, 13 evaluated the impact of COVID-19 on levels of chronic stress. These studies were used to define chronic stress and establish the relationship between the pandemic and physiologic distress using survey techniques. These surveys included self-rated levels of anxiety, depression, and sleep disturbances, and self-reported changes in diet and exercise patterns noted by women during and after lockdown phases of the pandemic.

A number of cross-sectional studies were analyzed to investigate the link between physiologic stress experienced during the pandemic and altered menses. Specific changes to the menstrual cycle included the duration of menses, heaviness of menstrual flow, cycle irregularity, new dysmenorrhea, and worsening of premenstrual symptoms. The accuracy of survey data, reliant on self-selection and proper recall of cycle characteristics, was improved in these studies, as 75% of respondents utilized a period tracking application to increase precision. Women with regular cycles for one year prior to the pandemic were included while women on hormonal birth control were excluded.

Results

The COVID-19 pandemic has been linked to psychologic distress mainly due to social isolation experienced during lockdowns and periods of quarantine. The most notable changes were seen in nutritional habits, sleep patterns, and physical activity routines. [1] Specific symptoms endorsed by women in the review included increase in low mood, poor appetite, binge eating, poor concentration, anxiety, loneliness, poor sleep, and excess alcohol use. [1] [4] Overall, this review suggests a positive correlation between COVID-19 and rates of chronic stress among women.

The disruption of the hypothalamic-pituitary-gonadal (HPG) axis results in a state of hypoestrogenism and anovulation. [2] [3] In a study published in 2021 of 952 female healthcare workers in Turkey, all participants had regular cycles for at least 1 year pre-pandemic. [5] During the pandemic, 23% of the women reported cycle irregularities, and those with cycle irregularity had statistically significant higher stress scores. Another study reported similar findings during the pandemic: 53% of women had worsening premenstrual symptoms, 46% noted a change in their cycle, and one third of women reported new onset dysmenorrhea. [1] [6] These findings from various studies strongly suggest a relationship between the stress experienced during the pandemic and changes in the female cycle.

“These findings from various studies strongly suggest a relationship between the stress experienced during the pandemic and changes in the female cycle.”

Discussion  

The female population has been found to be biologically more vulnerable to stress than males. Corticotropin releasing hormone (CRH) is released upon activation of the sympathetic nervous system in response to stress. [1] Studies show women have increased levels of CRH-producing neurons and a heightened response to CRH, thus amplifying their biologic reaction to distress. [1]

During periods of stress, CRH preferentially stimulates production of β-endorphins from the pro-opiomelanocortin and cocaine and amphetamine-regulated transcript (POMC/CART) neurons in the arcuate nucleus. [1] Along with CRH, these β-endorphins inhibit the kisspeptinergic neurons in the preoptic area and arcuate nucleus. [2] Kisspeptin stimulates release of gonadotropin releasing-hormone (GnRH) from the hypothalamus, which stimulates release of follicular stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, stimulating the ovaries to produce estrogen and progesterone. [2] These hormonal relationships within the HPG axis are disrupted during times of stress due to kisspeptin’s inhibition of hypothalamic GnRH production, thereby inhibiting all downstream signals. [2]

“These hormonal relationships within the HPG axis are disrupted during times of stress due to kisspeptin’s inhibition of hypothalamic GnRH production, thereby inhibiting all downstream signals.”

Women have a greater concentration of CRH neurons in their hypothalamus than men and, in general, this heightened response to CRH is linked to the increased levels of anxiety reported and diagnosed in women. When potentiated, these neurons have a strong inhibitory impact on GnRH release from the hypothalamus, which decreases FSH and LH production. The lack of FSH results in a lack of follicular development within the ovary, and thus a lack of estradiol production from developing follicles. [7] Without a rise in estradiol and its peak to crucial levels, there is no LH surge and, thus, no ovulation. As a result, during the pandemic, many women experienced irregular cycles, worsening premenstrual symptoms, new onset dysmenorrhea, and more or less anovulatory cycles. [1]

The studies reviewed were limited by the self-selecting nature of survey data, recall bias of cycle characteristics, lack of rigorous controls, and lack of clinical laboratory data for objective measures of stress. These findings are also difficult to generalize because many participants in the studies were from women of high socioeconomic background with high levels of education. Future studies would benefit from broadening the reach of their surveys to include more women of color, women from lower socioeconomic backgrounds, and women with lower levels of education. Additionally, objective laboratory values could provide a benefit when comparing levels of stress rather than relying on self-reported scores.

All women were subject to the stress caused by COVID-19 to some degree; thus, the reproductive health of all women has been impacted, particularly those utilizing fertility awareness-based methods (FABMs) for health maintenance or fertility monitoring. Further research is needed to more objectively define stress using biochemical markers and to correlate those values with changes in the female cycle. Studies regarding planned and unplanned pregnancy rates during COVID-19 due to skewed data from FABMs would be interesting as well.

References

[1] Vigil P, Meléndez J, Soto H, Petkovic G, Bernal YA, Molina S. Chronic Stress and Ovulatory Dysfunction: Implications in Times of COVID-19. Frontiers in Global Women’s Health. 2022;3. doi:https://doi.org/10.3389/fgwh.2022.866104.
[2] Sills ES, Walsh AP. The GPR54-kisspeptin complex in reproductive biology: neuroendocrine significance and implications for ovulation induction and contraception. Neuro Endocrinol Lett. (2008) 29:846–51. Available online at: www.nel.edu.
[3] Barsom SH, Mansfield PK, Koch PB, Gierach G, West SG. Association between psychological stress and menstrual cycle characteristics in perimenopausal women. Women’s Health Issues. (2004) 14:235–41. doi: 10.1016/j.whi.2004.07.006.
[4] Sohn JW. Network of hypothalamic neurons that control appetite. BMB Rep. (2015) 48:229–33. doi: 10.5483/BMBRep.2015.48.4.272. doi:10.1016/s0010-7824(97)00040-1.
[5] Takmaz T, Gundogmus I, Okten SB, Gunduz A. The impact of COVID-19-related mental health issues on menstrual cycle characteristics of female healthcare providers. J Obstetrics Gynaecol Res. (2021) 47:3241–49. doi: 10.1111/jog.14900.
[6] Phelan N, Behan LA, Owens L. The Impact of the COVID-19 Pandemic on Women’s reproductive health. Front Endocrinol. (2021) 12:1–8. doi: 10.3389/fendo.2021.642755.
[7] Matsuda F, Ohkura S, Magata F, Munetomo A, Chen J, Sato M, et al. Role of kisspeptin neurons as a gnrh surge generator: comparative aspects in rodents and non-rodent mammals. J Obstetrics Gynaecol Res. (2019) 45:2318– 29. doi: 10.1111/jog.14124.

ABOUT THE AUTHOR

Jessica Pickard

Jessica Pickard is a fourth-year medical student at Ohio University’s Heritage College of Osteopathic Medicine in Dublin, OH. She completed her undergraduate studies at Ohio State University in Columbus, OH, where she also worked as a patient care associate for the James Cancer Hospital. She plans to complete residency training in internal medicine and a fellowship in cardiology. She has a passion for women’s health and, specifically, how the pathophysiology and presentation of cardiovascular disease differs in women. She enrolled in the FACTS elective to learn more about hormonal patterns in women and their impact on fertility and family planning, and to apply this knowledge in future research in women’s health.