Lifestyle and fertility: the influence of stress and quality of life on female fertility

The reasonable association between woman’s stress response and fertility potential made literature to accumulate studies with conflicting results [19‐29]. However, there is likewise converging evidence on female body-stress response and hormones involvement [30‐32] (Fig. 1).

Stressful stimuli cause the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis [33]. The hormones secreted by these systems after stressful stimuli result in an abnormal, prolonged and/or excessive stress-induced body’s set-up that can potentially produce long-term neuroendocrine changes, affecting female fertility [34‐39]. Biologically, neurons of the hypothalamic paraventricular nucleus of HPA axis release vasopressin and corticotropin-releasing hormone (CRH) to mediate the secretion of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary gland [33, 40]. In turn, ACTH mediates the secretion of cortisol and glucocorticoid hormones by the adrenal cortex [33, 40].

Differentially, the preganglionic sympathetic fibers of SAM axis, in response to environmental stressful stimuli, activate the adrenal medulla to release epinephrine and norepinephrine into the blood [33]. Experimental data showed that statistically significant reductions in the probability of conception across the fertile window during the first cycle attempting pregnancy were observed for women whose salivary concentrations of α-amylase were in the upper quartiles in comparison with women in the lower quartiles [41]. Even if the salivary α-amylase is considered only a surrogate marker of stress and SAM activity, these data seem to confirm the ability of stress to exert its effect on female fecundity through the SAM pathway [41].

All stress-induced hormones from the adrenal cortex and medulla are responsible for several physiological and mental consequences, which cause the individual to fight with or flight from the stressor. Differences in individual responses could be explained by findings from ewes showing that animals with divergent cortisol responses to ACTH exhibit functional differences in the HPA axis due to innate differences in the gene expression/function of HPA molecules [42]. Further results from female cynomolgus monkeys, exposed to mild combined psychosocial and metabolic stress, show a selected and specific (rather than generalized) increased activity in the adrenal framework significantly related to stress-induced reproductive dysfunction [43].

Increased glucocorticoid release/concentrations leads to profound dysfunction of the hypothalamic-pituitary-ovary (HPO) axis [31, 43‐47]. Specifically, distress concentrations of glucocorticoids in the bloodstream reach high levels acting directly on hypothalamus altering the physiologic release of gonadotropin releasing hormone (GnRH) [48, 49]. The synthesis and release of gonadotropins from the pituitary are thus indirectly inhibited, even if a direct pituitary effect of glucocorticoid has been also demonstrated [48, 49]. Accordingly, evidences from animal models are available [41]. In sheep model the infusion of cortisol at concentrations comparable to those produced in humans under stress generates a delay in follicular maturation and ovulation by attenuating or blocking the expected increase of estrogens and luteinizing hormone (LH) surge [41].

However, the signaling pathway by which this occurs remain unclear and is further complicated by the recent findings of kisspeptin (KISS1) and gonadotropin-inhibitory hormone (GnIH). These two neuropeptides induce opposite effects on hypothalamic GnRH release being sensitive to high levels of glucocorticoids [32]. KISS1 exerts stimulatory effects on GnRH secretion [50]. In mouse model, corticosterone administration reduced hypothalamic expression of KISS1 during the estradiol-induced LH surge and decreased the activation of KISS1 neurons [51]. Differentially, GnIH neurons inhibit the activity mediated by either GnRH and KISS1 molecules [52]. Experimental data in ewes demonstrated a direct relationship between both acute and chronic stress and inhibiting GnIH effects on hypothalamus [53] up to inhibition of LH release from the pituitary [54].

Consequently, the stressful stimuli on the female adrenal and HPO axis impact more than one physiological event of fertility including ovulation, fertilization and the implantation rate [34, 48], independently of stimulus origin. Anomalies in the LH pulses induce and inhibition of the ovulatory function directly or thought an effect on sex steroid synthesis/secretion in the ovary [45, 55]. This circumstance can be produced by job-induced stress that exerts its effect through increased LH-plasma concentrations in both the follicular and luteal phases of the ovarian cycle [56].

Both in general and infertile population, distress was respectively associated with decreased conception rates and long menstrual cycles (≥35 days) and lower outcomes of reproductive medicine, including oocytes retrieved, fertilization, pregnancy and live birth rates [11, 41, 57‐59]. In addition, in infertile women “chronic” lifetime psychosocial stressors were also identified as detriments to ovarian reserve. Specifically, they were predictive of an enhanced likelihood for diminished ovarian reserve [60]. To this regard, a low socioeconomic status aggravated by sources of stress such as undernutrition and financial hardships potentially plays a key role in affecting ovarian reserve [61].

Of note, the distress can act on female fecundity acting on uterine receptivity also independently from ovarian function. Using a mouse implantation model, the distress induced a poorer endometrial receptivity even if the hormone supplementation was administrated [62].

Depression, high active coping, avoidance and expression of emotions may produce the same consequences on female fecundity [58]. Depression is significantly correlated with the alternative manifestation of stress, i.e. anxiety, affecting cortisol release [44] and symptoms are observed in approximately 37% of infertile women [63]. Consistently, both emotions are prevalent in female partners of infertile couples [64] and more common among females suffering from infertility compared to fertile females [65‐67]. The role of emotional distress and anxiety is not still understood, but a small body of evidence suggests that the induction of oxidative stress may be the mechanism by which psychosocial stressors affect oocyte quality through impairment of the overall female health [12, 68, 69].

Many women undergoing reproductive medicine report depressive symptoms prior to beginning their treatments, reflecting a prior history of mood/anxiety disorders independent of infertility itself [63]. Of interest, resilience, i.e. psychosocial stress-resistance, in infertile couples acts as a protective factor against infertility-specific distress and impaired QoL [70] probably through its effect on freedom from anxiety [71]. Moreover, data on psychological interventions or counseling interfering with depression and anxiety are reliable to speculate that the less women are physiologically reactive to distressing stimuli the more they potentially become capable of alleviating their negative consequences on reproductive system [38, 44, 72‐83]. Nonetheless, albeit these interventions are effective to optimize natural fertility and outcomes of reproductive medicine strong clinical evidences are still lacking [67, 84, 85].

Although a variety of patient self-reported outcome (PRO) measures are available to investigate the intriguing aspects on the relationship between QoL and infertility (Table 1), only the two Fertility Quality of Life (FertiQoL) and Fertility Problem Inventory (FPI) questionnaires are recently acknowledged as the best useful tools to address this issue in interventional studies [86]. Specifically, the FertiQoL questionnaire is the most widely applied tool and it was developed to tackle limitations of the FPI and other questionnaires designed for specific subpopulations and therefore unable to be used as generic measures for female infertility [87, 88]. The FertiQoL items capture the key life domains affected by fertility problems, including the emotional, mind-body (cognitive and physical), relational and social domains together with the individual perception of the treatment environment and tolerability [87, 88].

Moreover, there is reasonable evidence for adequate linguistic validation of FertiQoL [86] as confirmed by a plethora of data collected from several populations [8, 89‐92]. This support that PROs of FertiQoL reliably measures QoL in women facing infertility and prove that infertility significantly reduces female QoL by increasing anxiety and depression levels [6‐8, 89‐92]. Both conditions belong to the emotional domain independently of the infertility cause and constitute stressful stimuli (namely distress) acting on the HPA and SAM frameworks as previously described.

For women who have ever met the criteria for infertility and perceive a fertility problem, life satisfaction is significantly lower and the association is weaker for employed women. On the contrary, for women with infertility who do not perceive a problem, not being mother is associated with higher life satisfaction [93]. As consequence, if becoming pregnant is a priority that cannot to be voluntary achieved, this denied attempt affects female QoL and identity with long-term effects and significant higher levels of distress compared to voluntary childlessness women [94].

Unsatisfied motherhood may have implications on female QoL for stress related to marital life too, hampering also couple’s attitude towards successful infertility treatments [59]. Consistently, partnered women who give up a strong intention to have children show more depressive symptoms when relinquished fertility intentions occur in the context of declining relationship quality [95, 96] and in the relational domain, female sexual function positively correlates with male partner sexual function [64]. In addition, infertile women are more likely to underestimate the importance of sexual intimacy in marital life [97] and this is consistent with the deleterious effect of the infertility on sexual dysfunction and poor QoL in women [98, 99]. This scenario can constitute a negative event in women’s life with an impact on QoL because it may potentially trigger chronic distress and subsequently reduce the changes of successful infertility treatments [100]. However, this pathway still needs further clarification [101].

QoL can be impaired in case of reproductive illness at which women are faced to during fertile lifespan. For instance, the polycystic ovary syndrome (PCOS) may be a factor favoring the occurrence of mood disorders as there is evidence that infertile women with PCOS experience high psychological distress and difficulties with coping with their condition as well as poor QoL [102‐104]. These and other variables including body mass index, woman’s job, menstrual cycle intervals and sexual satisfaction appear to define QoL in women with PCOS [105]. The validated questionnaire for evaluating the impact of PCOS on health-related QoL in affected women revealed that how weight decrease is of relevance for the overall phenotypic spectrum improvement and a relative decrement in psychological distress [106]. Co-morbidities (for example obesity) may impact many patient’ characteristics, such as social and patient perspective reflected in well-being and QoL individual perception [107].

Moreover, QoL argument is of relevance in Eastern [108, 109] and African [110] societies, where social parenthood cognitions as well as community and family pressure consistently interfere with QoL of infertile women due to the cultural importance of bearing children.

Although the influence of stress and distress (measured as anxiety and depression) on ART outcomes was appeared somewhat limited up to 2011 [84], four years later the European Society of Human Reproduction and Embryology (ESHRE) acknowledged the clinical weight of stress and QoL in female reproduction and prompted to incorporate psychosocial assistance into clinical practice of reproductive medicine [111]. In fact, each specific step of ART treatment seems to be closely related to increased levels of distress [112, 113].

This picture seems to be gender-related [114]. During an ART cycle, women show lower levels of QoL compared to men and the number of ART failures in becoming pregnant influences more women’ QoL rather than men [92, 114, 115]. Before knowing ART outcome, women undergoing a cognitive coping and relaxation in their first in vitro fertilization (IVF) cycle showed improved QoL as compared with patients undergoing routine care [116]. From a different perspective, many ART women may report depressive symptoms prior to beginning their cycle, which likely reflects the impact of repeated, unsuccessful, less invasive forms of treatment, but may reflect also a prior history of mood/anxiety disorders independent of infertility [117]. Interestingly, lower concentrations of norepinephrine and cortisol in serum and follicular fluid on the oocyte retrieval day were found in women whose treatments were successful suggesting that both stress-induced biomarkers may negatively influence the clinical pregnancy rate in IVF treatment [118]. Similar findings whereby stress levels where measured in terms of circulating prolactin and cortisol levels suggest that infertile women have a different personality profile in terms of more suspicion, guilt and hostility as compared to the fertile controls [119]. To this regard, the infertility status or its awareness could influence the hormonal release of prolactin/cortisol. On the other hand, the psychological stress may affect the outcome of IVF treatment since anxiety levels in patients who do not achieve pregnancy are higher than in those who become pregnant [119]. Furthermore, women with successful treatment have lower concentrations of adrenaline at oocyte retrieval and lower concentrations of adrenaline and noradrenaline at embryo-transfer day, compared with unsuccessful women [58]. That data emphasizes the positive relationship between adrenal stress-related biomarkers concentrations and pregnancy and depression [58].