Stress and infertility. (Editorial).

"I'm under a great deal of stress at work. Will this affect my upcoming IVF cycle?" Patients commonly ask this question in my practice, and Lovely et al (1) address the subject in this issue of Southern Medical Journal. In their study, Lovely et al measured cortisol and 6-sulfatoxy-melatonin during an in vitro fertilization (IVF) treatment cycle. In addition, study patients completed the State-Trait Anxiety Inventory (STAI) to measure subjective stress. The choice of an appropriate marker for stress is a challenge for any research in this area. Of these three variables, 6-sulfatoxy-melatonin concentrations have not been studied previously in this context. The study of a metabolite of melatonin, and thus an assessment of pineal gland function, is a novel idea. As the authors state, this potentially avoids the influence of endocrine changes associated with IVF on the measurement of stress indicators. Previous studies primarily used the measurement of cortisol and prolactin, which may change with increasing estr adiol or other hormones during therapy, as end points.

The authors did not find a difference in any of these three variables in a comparison with a control group of donor IVF patients. (Qocyte donors are a logical choice for controls, because they experience the stress of the treatment but not the condition of infertility.) Their conclusion is that stress does not play a role in IVF outcome. This study is an important one that adds to the body of literature regarding this complex issue. It undoubtedly will not put the issue to rest.

Patients with extreme stress who present with amenorrhea are the classic example linking stress to infertility. Eating disorders, low body weight, and extreme exercise are all factors that cloud the presentation of amenorrhea in the setting of stress. Women with functional chronic anovulation have an increased cortisol secretion and a blunted response to administration of corticotropin-releasing hormone. (2) Animal studies show a link between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-ovarian axis in that acute corticotropin-releasing hormone administration to ovariectomized monkeys inhibits gonadotropin-releasing hormone and luteinizing hormone. (3) Human studies fail to show such a direct demonstration of the effect of the adrenal axis on reproductive function. The inability to separate the multiple interactions of the hormonal and neuroendocrine systems in human reproduction makes such a distinction difficult.

Human clinical studies of IVF treatment and the measurement of mediators of stress are contradictory. Facchinetti et al (4) reported in a small sample that women who failed to become pregnant after IVF were more likely to have an exaggerated response to stress testing in terms of increased blood pressure and heart rate. Women who worked outside the home had a lower pregnancy rate.

Harlow et al (5) demonstrated that prolactin levels, cortisol levels, and STAL scores increased throughout the menstrual cycle in women undergoing a stimulated IVF cycle compared with women undergoing noninfertility laparoscopy. However, nonstimulated IVE patients did not show a similar increase in mediators of stress. Pregnancy rates were not different between the groups.

Sanders and Bruce (6) reported a positive correlation between pregnancy after multiple IVF attempts and a low STAI score or presumably a lower stress level. Csemiczky et al (7) showed that infertile women undergoing IVF had higher levels of prolactin and cortisol throughout the menstrual cycle than did women who were fertile. There was no statistical difference in STAL scores between those who became pregnant and those who did not.

Although the current study and the ones cited above focus on stress and IVF success, it may be that stress is more likely to play a role in the genesis of infertility and affect therapies other than IVF. The use of gonadotropin-releasing hormone agonists during IVF treatment may disconnect the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-ovarian axis. In the analysis of stress research, a practical problem occurs for the clinician and the patient. If we had clear evidence that stress plays a role in infertility, which we do not, how could we change the situation? Certainly, all patients would prefer to undergo complex infertility treatments at a time when they are calm and relaxed. Aside from the fact that infertility treatment itself is stressful, most people cannot easily change the external factors that create added stress in their lives. I often advise patients undergoing IVF therapy against engaging in multiple life-changing events, such as buying a new house or tackling a major pro ject at work. Other than this advice, clinicians can encourage patients to eat sensibly, get moderate exercise and plenty of sleep, and know that stress probably will not be the determining factor in whether they become pregnant as a result of IVF therapy.

Accepted September 13, 2002.

References

(1.) Lovely LP, Meyer WR, Ekstrom, RD, Golden RN. Effect of stress on pregnancy outcome among women undergoing assisted reproduction procedures. South Med J 2003;96:548-551.

(2.) Ferin M. Clinical Review 105: Stress and the reproductive cycle. J Clin Endocrinol Metab 1999;84:1768-1774.

(3.) Olstcr DH, Ferin M. Corticotropin-relcasing hormone inhibits gonadotropin secretion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab 1987;65:262-267.

(4.) Facehinetti F, Matteo ML, Artini GP, Volpe A, Genazzani AR. An increased vulnerability to stress is associated with a poor outcome of in vitro fertilization-embryo transfer treatment. Fertil Steril 1997;67:309-314.

(5.) Harlow CR, Fahy UM, Talbot WM, Wardle PG, Hull MG. Stress and stress-related hormones during in-vitro fertilization treatment. Hum Reprod 1996;11:274-279.

(6.) Sanders KA, Bruce NW. Psychosocial stress and treatment outcome following assisted reproductive technology. Hum Reprod 1999;14: 1656-1662.

(7.) Csemiczky G, Landgren BM, Collins A. The influence of stress and state anxiety on the outcome of IVF-treatment: Psychological and endocrinological assessment of Swedish women entering IVF-treatment. Acta Obstet Gynecol Scand 2000;79:113-118.

From thc Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS.

Reprint requests to Randall S. Hines, MD, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216. Email: [e-mail].

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9606-0533