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Acute and chronic stress may affect fertility. IVF is often described as the most stressful event in the lives of a couple.[150] There is increasing evidence that psychological factors, such as anxiety and depression, may have a negative impact on the IVF outcome,[151] but this evidence is inconclusive. In general, a distinction is made between the direct and indirect effects of stress. The former are the effects mediated by the autonomic nervous system, the (neuro)endocrine system and the immune system; whereas the latter are the health implications of changes in health behavior, for instance smoking.[152]
Despite the known relationship between psychosocial stressors and the activity of the sympathetic medullar system and hypothalamic-pituitary-adrenal axis,[153] little is known about the effect of different types of stressors and the release of stress hormones, especially in relation to IVF outcome. As the treatment itself probably influences psychosocial factors, it is extremely difficult to separate cause and effect of psychosocial factors on the IVF outcome.[152,154] On the other hand, some aspects of the treatment, such as the type of ovarian stimulation employed, could influence the stress hormonal response.[155] A summary of the possible factors by which psychological stress may affect fertility is developed in Figure 3.
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Figure 3. (click image to zoom) Mechanisms by which psychological stress may affect fertility. Psychological stress could influence
fertility by indirect effects derived from changes in health behavior that are detrimental for reproduction, and through direct
effects mediated by the autonomic nervous system, endocrine system and immune system. The sympathetic-adrenal-medulla axis
releases neuroepinephrine in the brain and epinephrine in the adrenal medulla with stress. Catecholamines may induce vasoconstriction
phenomena in the uterus and ovaries, reducing their blood tissue supply. The HPG dysfunction leads to increased serum levels
of prolactin, and CRH-induced pituitary POMC derivatives, which inhibits the control of the hypothalamus over the gonadal
axis. Changes in GnRH and gonadotrophin (FSH and LH) secretion would reduce sex steroid production. The HPA axis releases
high amounts of cortisol in stress conditions, which would also affect the HPG axis and the immune system. The role of increased
serum levels of oxytocin with stress is not well understood. Immune disturbances such as increased levels of TNF and higher
NK cell activity, which may induce apoptosis in ovarian cells, and prolonged activation of T cells has been related to stress.
The persistent activation of T cells may induce a reduced embryo implantation. ACTH = Adrenocorticotrophic hormone; CRH =
Corticotrophic-releasing hormone; FSH = Follicle-stimulating hormone; GnRH = Gonadotrophin-releasing hormone; HPA = Hypothalamic-pituitary-adrenal
axis; HPG = Hypothalamic-pituitary-gonadal axis; LH = Luteinizing hormone; NK = Natural killer; POMC = Proopiomelanocortin.
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Some reports have shown that pretreatment levels of anxiety and depression are significantly related to treatment outcome in IVF.[151] Different stress hormones could impair the chances of successful reproduction. Catecholamines may affect fertility by altering uterine blood flow.[156] Cortisol may affect the immunological conditions needed for implantation and its levels could be related to oocyte quality[157] and pregnancy chances.[158] Other hormones, including elevated prolactin concentrations,[159] and some immune factors, such as high amounts of activated T cells,[160] have been also related to an impaired IVF outcome in women with higher stress levels.
Recently, Smeenk et al. observed that women whose treatment was successful had lower urine concentrations of adrenaline at oocyte retrieval, and lower urine concentrations of adrenaline and noradrenaline at embryo transfer than those whose treatment was unsuccessful.[152] In addition, a significant positive correlation was found between urinary adrenaline concentrations (basal and on the day of embryo transfer) and the basal depression score provided by patient questionnaires. Therefore, adrenaline could be one of the hormonal links between psychosocial stress and IVF outcome.
However, despite the possible negative impact of psychological variables on IVF outcome, the evidence remains inconclusive. This may reflect limitations in study sample size and design, since most studies have been retrospective or cross-sectional, and psychological measurements have usually been limited to a single stress parameter.[150,161,162] Moreover, the majority of related studies have reported clinical pregnancy as an end point, without providing information about spontaneous abortion, premature delivery or other outcomes. Only two reports have considered live birth delivery as an end point. In the first report, live birth rate was negatively influenced by baseline (acute and chronic) stress, but not by procedural (acute) stress.[163] Hence, better results could be achieved if psychological support was offered prior to the procedure. In the second study, surprisingly, women who showed few feelings of anger, depression, uncertainty and/or anxiety (e.g., negative affect) before treatment were less likely to achieve term live birth than those who expressed a moderate level of negative affect.[162] Neither positive affect or negative affect during ovarian stimulation influenced the possibility of a live birth. Therefore, the authors concluded that the expression of negative emotions before starting IVF might not be always detrimental to outcome. High infertility-related stress is harmful, but the expression of moderate infertility-related stress could be more beneficial than extreme low levels of negative affect.
In a recent large multicenter study in which depression and anxiety were measured prior to the initiation of the first cycle of IVF and again 1 day before oocyte retrieval, no associations between stress levels and IVF outcome were found.[164] Anderheim et al. found no evidence of the influence of psychological stress on IVF outcome, and considered this finding of benefit to patients, as it could reduce the stress they experience during treatment.[165] Cooper et al. found that couples who achieved ongoing pregnancies scored higher with measures of a negative view of a child-free lifestyle, need for parenthood and total stress than those who did not.[166] These authors suggested that moderate stress was required for optimal IVF performance.
In summary, the precise impact of stress on infertility remains an open question. The reduction of high levels of stress before IVF is to be encouraged. Enhancing distraction techniques might be more beneficial than interventions enhancing expression of emotions in the management of stress, in order to improve IVF outcome.[167] However, more well-designed studies need to be performed to clarify this controversial issue.
