Chronic stress leads to profound reproductive dysfunction in both men and women, and yet, this subject rarely gets priority status in fertility discussions. As research unwraps more layers of the stress response, governed by the hypothalamic-pituitary-adrenal (HPA) axis, we realize its unique position as a control center for most physiological processes, including reproduction. Once activated, the HPA axis begins shifting metabolic processes and mobilizing energy reserves to prepare the body to combat its threat. It also dictates which physiological processes are helpful for battle and which are not. Unfortunately, reproduction doesn’t make the list because it is energetically expensive and not essential for survival.
Glucocorticoids from the adrenal cortex can powerfully modulate the hypothalamic-pituitary-gonadal (HPG) axis. Their most potent action on female fertility is through their direct actions on the hypothalamus and pituitary. They directly inhibit the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, and prevent luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and release from the pituitary.
More recent studies are suggesting stress-induced infertility may be blamed, in part, on RFamide-related peptide-3 (RFRP3), a hypothalamic inhibitory neuropeptide that rises in response to stress and directly inhibits GnRH. Interestingly, RFRP3 levels fluctuate throughout the ovulatory cycle and may help curb LH during the follicular phase. However, chronic stress elevates RFRP3 throughout the entire menstrual cycle and this persists even after the stressor is removed, presenting a theory for how chronic stress may impact fertility long-term.
In mice studies, stress-induced levels of glucocorticoids impaired oocyte competence. In fact, “the degree of damage to oocyte competence was dependent on the severity of restraint stress, with greater effects found after long-term stress.” Similar studies found changes in the ratio of estrogen to progesterone rooted in increased apoptosis of ovarian epithelial cells following exposure to corticosterone. In a human study of women undergoing in vitro fertilization, “follicular fluid from follicles whose oocytes were not fertilized had levels of cortisol significantly higher than the levels in follicular fluid from follicles containing successfully fertilized oocytes.” Such studies indicate fertilization potential is clearly affected by glucocorticoids.
Glucocorticoids Affect the Testes
In the male, glucocorticoids inhibit testosterone synthesis and release from the testes by binding to glucocorticoid receptors (GR) in the Leydig cells and reducing the number of testicular LH receptors, affecting both gametogenesis and sexual behavior. The GR is present on multiple cell types of the testes. Not only do glucocorticoids inhibit testosterone production, but they induce apoptosis of both Leydig cells in the testis and spermatogonia in the seminiferous tubules.
In a study evaluating the association between psychological stress (measured using Hospital Anxiety and Depression Score (HADS) questionnaire) and seminal quality in the male partner of infertile couples, high HADS scores directly correlated with lower sperm count, motility and morphologically normal spermatozoa. Some of the earliest studies on male gonad and sexual dysfunction were conducted on men with Cushing’s syndrome, giving evidence for the negative affect of cortisol on fertility and reproduction.
Glucocorticoids Affect the Ovary
As already mentioned, glucocorticoids exert their most direct actions on the ovary by suppressing GnRH, and subsequently, LH and FSH from the pituitary. They are also able to suppress the action of LH on the ovary. The result, of course, is decreased oocyte maturation, decreased estrogen production, and inhibited ovulation. Glucocorticoids are also thought to antagonize oocyte maturation.
It is also worth noting that glucocorticoids play a positive role during certain phases of the menstrual cycle. The GR is present in the follicles, corpus luteum, and on the surface of ovaries. Small amounts of glucocorticoids naturally rise during ovulation to protect the ovary from injury while the follicle ruptures, causing acute hemodynamic, cellular, and biochemical changes, as well as protect the corpus luteum. With regards to fertility, stress-induced levels of glucocorticoids will more likely result in negative outcomes, than positive.
Glucocorticoids Affect the Uterus
Stress-induced glucocorticoids appear to affect the ability of the uterus to accept implantation, necessary for a successful pregnancy. Initial mice studies showed reduced uterine receptivity, higher rates of resorbed embryos, and reduced litter sizeswhen restraint or auditory stress was applied. Exogenous cortisol also reduced uterine weight, and decreased uterine cell proliferation prior to implantation as well as electrolyte concentrations, which are critical for successful attachment and implantation. Stress-induced glucocorticoids not only impact the ability to conceive, but may pose significant problems after conception, resulting in an unsuccessful pregnancy.
As the number of couples experiencing infertility rises, and our lifestyles become increasingly stressful, chronic stress and glucocorticoid levels are important to evaluate during the reproductive years. Functional medicine and integrative practitioners have the unique advantage of understanding how chronic stress is a root health concern, as well as possessing skills to address stress-management through lifestyle, dietary, and nutraceutical recommendations. Pantothenic acid, niacin, and pyridoxine (vitamin B-6) support the adrenal glands, while the stress response can be temporarily curbed with the calming neurotransmitter, GABA and its boosters, L-theanine, taurine, and glycine. Encouraging couples to reduce the load on their schedules, find time to meditate and enjoy nature, keep a gratitude journal, and spend time with supportive individuals can all help in ameliorating stress and encouraging the body to know that the environment is right to create new life.