Director’s Note: This week, we feature research [1] summarized by Dr. Cassidy Berg, a family medicine resident and FACTS Ambassador who participated in the elective as a medical student. The female cycle is the fifth vital sign, and stress has well-documented effects on various biomarkers of a woman’s cycle, including ovulation. Previous research has identified elevated cortisol levels in women with anovulation secondary to functional hypothalamic amenorrhea (FHA). The study by Berga et al [1] summarized below explores the role of cortisol in other instances of anovulation.
Introduction
Stress impacts a woman’s menstrual cycle and is associated with disruptions of cycle length and bleeding patterns as well as anovulation-induced amenorrhea, also known as functional hypothalamic amenorrhea (FHA). While increased levels of cortisol, the body’s “stress hormone,” have been found in women with FHA, it is unclear whether cortisol is also elevated along with other causes of anovulation, such as hyperandrogenism and hyperprolactinemia. [1] In FHA, anovulation is caused by decreased gonadotropin releasing hormone (GnRH) from the hypothalamus. If the GnRH suppression characteristic of FHA is uniquely caused by stress-induced elevation of cortisol, this would present an important target to restore ovulation in women with FHA.
“Stress impacts a woman’s menstrual cycle and is associated with disruptions of cycle length and bleeding patterns as well as anovulation-induced amenorrhea, also known as functional hypothalamic amenorrhea (FHA).”
Methodology
In this study by Berga et al, 44 women with amenorrhea were recruited along with 19 women with eumenorrhea. Among those with amenorrhea, 19 were diagnosed with FHA, 19 had other causes of anovulation (OA), and 6 were designated as “ovulatory hypothalamic amenorrhea” (OVHA), meaning there was serologic evidence of restored ovulation in these women during the study period. All participants, including those with eumenorrhea, were classified in their study groups according to relevant lab values drawn prior to the study, such as urinary β-hCG and serum LH, FSH, TSH, PRL, E2, P, androstenedione, T, and 17α-OH P. Inclusion and exclusion criteria were also applied, including age, smoking, medication/drug use, exercise habits, % of ideal body weight (IBW), recent weight loss or gain, and no current diagnosis of an eating disorder or other major psychiatric disorder. [1]
The participants were admitted to the research center for a 24-hour period during which blood samples were drawn every 15 minutes via an indwelling IV catheter with extension tubing to avoid sleep disturbance overnight. Meals and sleep hours were all standardized. Mean 24-hour cortisol levels were calculated for each patient as well as the mean cortisol level for each 8-hour segment of the sleep-wake cycle. Cortisol values were the main outcome of interest, although additional hormone levels were also analyzed to control for confounding variables and to consider possible secondary effects of FHA. [1]
Results
In participants with FHA, mean 24-hour cortisol levels were significantly higher (p < 0.05) compared to women with eumenorrhea (EW) or other causes of anovulation (OA). Mean cortisol levels from midnight to 7:30am were also significantly higher in FHA vs. all other groups (EW, OA, and OVHA). Mean LH pulse number per 24 hours was significantly lower in FHA vs. EW and OVHA. Finally, TSH was significantly higher in the OVHA group compared to all others. [1]
Discussion
The finding of increased cortisol levels only in subjects with FHA may support the hypothesis that elevated cortisol is unique to the etiology of decreased GnRH secretion in FHA compared to other causes of anovulation. This is further supported by the fact that subjects in the OVHA group had lower levels of cortisol as well.
“The finding of increased cortisol levels only in subjects with FHA may support the hypothesis that elevated cortisol is unique to the etiology of decreased GnRH secretion in FHA compared to other causes of anovulation.”
The finding of elevated TSH levels in patients with restored ovulation appears consistent with recovery of central hypothalamic drive resulting from lowered cortisol levels. The increased number of LH pulses in the OVHA group is also consistent with this, as LH pulses are an indicator of GnRH secretion. Taken together, the hypothalamic-pituitary-adrenal axis is clearly linked in an important way to both the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-thyroidal axes. Thyroid dysfunction is a well-known treatable cause of ovulatory dysfunction, and the results of this study point to stress (a proxy for elevated cortisol) as a similarly treatable cause of FHA.
The study participants were not tracking their menstrual cycles with a fertility awareness-based method (FABM), which presents a significant opportunity for further research. Since internal hormonal activity is reflected by specific external signs in a woman’s body, charting with FABMs would allow for more precise identification of restored ovulation in participants with OVHA [2], as progesterone levels could be drawn on particular days after ovulation was identified on the woman’s chart. This contrasts with the standard draw on day 21 which could easily miss the true luteal phase for many women, especially those with irregular cycles.
“Since internal hormonal activity is reflected by specific external signs in a woman’s body, charting with FABMs would allow for more precise identification of restored ovulation in participants with OVHA, as progesterone levels could be drawn on particular days after ovulation was identified on the woman’s chart.”
Furthermore, FABMs offer a unique form of feedback for researchers when studying any form of ovulatory dysfunction, including FHA. For example, as cortisol levels decrease, participants would be able to report observations of physical signs indicating a return to fertility. This would provide valuable data about the clinical course and treatment of FHA that could be directly applied to patient care.
Further research on the relationship between actual and perceived stress, cortisol levels, and FHA should be done. Utilizing FABMs in future studies would provide a more holistic understanding of how FHA develops and resolves with treatment. Future studies should also compare women diagnosed with FHA who fall within distinct groups of exercise habits, % of IBW, and history of weight loss/gain to investigate the hypothalamic setpoint defining the stress level at which an individual woman’s body will or will not ovulate.
Editor’s Note: The fascinating article by Berga et al [1] was published in Fertility and Sterility in 1997. To learn more about the modern, evidence-based role of cycle charting and fertility awareness-based methods in FHA, read Haley Wissler’s summary, “Functional Hypothalamic Amenorrhea Clinical Practice Guidelines: A Review.”
Cassidy Berg, MD is a first-year resident at the University of Minnesota – Woodwinds Hospital Family Medicine Residency Program. Prior to medical school, she completed her undergraduate education at South Dakota State University, followed by a Master of Nutrition degree at the University of Minnesota. Dr. Berg is interested in the impact of lifestyle factors and nutrition on the female menstrual cycle and is excited to begin caring for patients from this perspective. She enrolled in the FACTS elective to gain a better understanding of natural fertility awareness methods and ways they can be used to provide restorative reproductive medical care to patients, helping them achieve their family planning and health goals.
