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Stress and Reproductive Function

Sarah L. Berga, MD; Tammy L. Loucks, MPH

The authors present a novel approach to anovulation that takes a more holistic view of the causes and effects of reproductive dysfunction.

Stress is the most common and underappreciated cause of reproductive compromise, including menstrual cycle disturbances and amenorrhea, infertility, and preterm labor. Acute stress elicits transient neuroendocrine, metabolic, and behavioral responses to facilitate homeostatic survival adaptations. Chronic stress provokes more sustained or “allostatic” adjustments in these same physiologic systems. Although allostatic adaptations likely promote survival as well in the short term, they also engender detrimental consequences in the long term (Figure 1). Physical sequelae of long-term stress include osteoporosis, depression, hypertension, and cardiovascular disease, as well as accelerated aging and dementia.

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Figure 1. Psychogenic challenge and metabolic imbalance interact synergistically to suppress ovarian function, activate adrenal secretion of cortisol, and suppress thyroidal secretion of thyroxine.

Gonadal function depends directly on hypothalamic gonadotropin-releasing hormone (GnRH) drive. A decline in endogenous pulsatile GnRH secretion reduces both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Reduced GnRH drive compromises folliculogenesis, and may result in luteal insufficiency or anovulation. Decreased GnRH pulsatility has been shown to cause anovulation and amenorrhea.1 Decrements in central GnRH-LH drive comprise a continuum, varying from day to day to cause a spectrum of ovarian disorders (Figure 2).2 Amenorrhea, polymenorrhea, or oligomenorrhea are more obvious but represent only a small proportion of the spectrum of functional reproductive compromise. Less obvious forms and more common forms include luteal phase deficiency with a preserved menstrual interval and reduced luteal phase length, or a preserved menstrual interval with normal luteal phase length but decreased overall progesterone secretion.

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Figure 2. Continuum of hypothalamic hypogonadism in women, with amenorrhea representing only the tip of the iceberg as related to the incidence of functional forms of hypothalamic hypogonadism.

The most common cause of reduced GnRH drive is functional; that is, it is not due to organic causes such as hypothalamic tumors or pituitary adenomas, but rather to functional hypothalamic hypogonadism. In this theoretically reversible form of gonadal compromise, psychophysiologic and behavioral responses to life stressors activate central neuroregulatory networks, evoking concomitant metabolic mobilization and reproductive suppression due to disruption of GnRH secretion.3

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ETIOLOGY

Stress-induced anovulation (SIA), often termed functional hypothalamic amenorrhea, typically results from chronic psychogenic stress coupled with mild energy imbalance. It is thus an allostatic adaptation, a stable change in behaviors and neuroendocrine secretory patterns that promotes survival at some cost to overall health (Figure 1). Although SIA affects roughly 5% of women of reproductive age, it represents only a small percentage of the incidence of functional forms of hypothalamic hypogonadism (Figure 2). Less severe forms of functional hypothalamic hypogonadism (without complete amenorrhea) are more common and less obvious clinically; indeed, infertility may be the only manifestation.4

Stress-induced anovulation is characterized by reduced hypothalamic GnRH drive, decreased LH and FSH release, and concomitant reductions in folliculogenesis and estradiol release. However, SIA is more than an isolated deficiency in GnRH. It is characterized by a constellation of neuroendocrine adjustments, including activation of the adrenal axis, increased cortisol secretion, thyroidal axis suppression, and decreased thyroxine release in the face of normal levels of thyroid stimulating hormone (TSH). Women with SIA report unrealistic expectations of self and others, poor problem-solving skills, and cognitive distortions related to food and body image. They also display a high need for social approval, often engaging in rigid or perfectionistic behaviors—eg, excessive exercise, high achievement, and/or diet imbalances.5

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ENDOCRINE AND NEUROENDOCRINE CONCOMITANTS

Women with hypogonadotropic hypogonadism demonstrate consistent elevations in cortisol levels.3,6 This situation applies to women with athletic amenorrhea as well.7 Eumenorrheic athletes have decreased luteal progesterone secretion, lower urinary levels of pregnanediol-glucuronide, fewer daily LH pulses, and higher cortisol levels compared with eumenorrheic, sedentary women. Amenorrheic, anovulatory athletes have the fewest daily LH pulses and the highest cortisol levels.

Other hypothalamic outputs also are altered in women with SIA. The hypothalamus generates an endocrine “action plan” to preserve the organism in the face of stress. This involves more than metabolic mobilization via increased cortisol secretion; in SIA, the hypothalamic-pituitary-thyroid (HPT) axis does not increase TSH levels in response to decrements in thyronine and thyroxine. In athletic women, a similar alteration in the HPT axis was seen only in those with compromised ovarian function.8

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BEHAVIORAL AND METABOLIC CONCOMITANTS

The variables that activate the adrenal axis, suppress the thyroidal axis, and halt ovulation are not always readily identifiable. Psychosocial stressors activate the central pathways of perception, whereas exercise and weight loss present metabolic challenges. However, there is no method for clearly differentiating psychogenic from metabolic stress. Psychogenic stress has a metabolic cost, and metabolic stressors (eg, food restriction, excessive exercise) are often initiated to cope with psychogenic stress.

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CLINICAL AND DIAGNOSTIC EVALUATION

The diagnosis of SIA can be established only by excluding other forms of secondary anovulation, including polycystic ovary syndrome (PCOS), premature ovarian failure, organic adrenal and thyroidal conditions, hyperprolactinemia, pituitary tumors, neurologic conditions, and psychological causes (eg, eating disorders, depression, obsessive-compulsive disorder, psychotropic drugs). Diagnosis of clinically occult forms of hypothalamic hypogonadism is more challenging. Oligomenorrhea since menarche suggests PCOS, whereas an abrupt onset following weight loss indicates hypothalamic causes. Adrenal, thyroid, and ovarian disorders can be detected by testing LH, FSH, estradiol, TSH, free thyroxine, prolactin, and testosterone or androstenedione levels. Depending on the index of suspicion, history, and presentation, other screening evaluations may include a 24-hour urinary free cortisol value to exclude Cushing’s disease and serum 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and insulin-like growth factor-1 values to look for congenital adrenal hyperplasia, adrenal dysfunction (Addison disease), and acromegaly, respectively. A normal FSH level with an LH:FSH ratio of less than 1 in the presence of normal levels of other hormones suggests decreased hypothalamic GnRH input. Further testing may involve magnetic resonance imaging to exclude organic causes of hypothalamic hypogonadism, such as pituitary tumors.

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TREATMENT CONSIDERATIONS

The mainstays of therapy for women with SIA are oral contraceptives when fertility is not desired, and ovulation induction or assisted reproduction when it is. The rationale for these interventions is based on the view that SIA represents an isolated compromise of reproductive function, so that only reproductive manifestations need to be treated. Several lines of research invalidate this perspective, including the association of SIA with a constellation of neuroendocrine aberrations.3 This is worrisome because persistent activation of the hypothalamic-pituitary-adrenal axis carries long-term health risks for the woman and, potentially, her fetus.9 The more clinically evident the ovarian compromise, the greater the hypothalamic disruption, and the more profound the associated adrenal and thyroid derangements and sex steroid deprivation.

For a woman with functional hypothalamic hypogonadism seeking conception, ovulation induction can be accomplished via exogenous pulsatile GnRH therapy or gonadotropins. Pulsatile GnRH therapy diminishes the risk of ovarian hyperstimulation and multiple gestation associated with gonadotropins. Clomiphene may not work in these cases because it acts on the hypothalamus, which is already unresponsive. Ovulation induction may also place women with SIA at risk for premature labor and intrauterine growth restriction.10 Women with clinically silent hypothyroidism have a 30% reduction in thyroxine, as do women with SIA. Maternal thyroxine is the dominant source of fetal thyroxine. Because the fetal brain requires thyroxine for neurogenesis, even small deficits may induce neurodevelopmental deficits. Increased maternal cortisol levels may also have independent effects on fetal neuro-development and organogenesis. Further, stress and its endocrine concomitants have been implicated in preterm delivery. It is not known whether the endocrine concomitants of SIA pose a similar risk, but this is clearly a potential hazard.

The most common treatment for a woman with SIA not seeking immediate conception is hormonal, based on the presumption that sex steroid deprivation is the primary issue. There are inherent limitations with this approach, including inadequate promotion of bone accretion or cardioprotection in the presence of ongoing metabolic derangements, continued insults to the brain from chronic amplification of stress cascades, and failure to correct hypothalamic hypothyroidism.11,12 Hormone therapy may also mask other deleterious processes, as SIA is more than an isolated reduction in GnRH secretion.

Essentially, the stress process must be interrupted. Although psychopharmacologic approaches have not been well studied, they probably could be used on an interim basis. A short course of alprazolam might be effective in reducing activation of the hypothalamic-pituitary- adrenal axis and permitting hypothalamic- pituitary-ovarian recovery.13 However, this approach would not be appropriate for a woman hoping to conceive because of the risk of fetal exposure to benzodiazepines.

The optimal intervention is to reverse the stress process so that the hypothalamus recovers and gonadal function resumes. This entails identification and amelioration of the sources of psychogenic and metabolic stress and provision of emotional support while the patient develops healthier coping mechanisms. Nonpharmacologic interventions such as stress management, relaxation training, and/or psychoeducation produce long-term benefits, reversing the endocrine adaptation with appropriate psychogenic and behavioral modifications.

Based on these considerations, a study explored whether cognitive behavior therapy aimed at ameliorating problematic attitudes and behaviors would permit reproductive recovery in normal-weight women with SIA.14 Women with SIA were randomized to observation versus cognitive behavior therapy (CBT) consisting of 16 visits with a physician, therapist, or nutritionist over 20 weeks. The two groups were followed for up to 8 weeks after the intervention for the return of menses. Estradiol and progesterone levels were monitored at weekly intervals for 4 weeks before and after observation versus CBT. About 88% of women who underwent CBT had evidence of ovulation, compared with only 25% of those who were observed. Therefore, CBT offers a focused therapeutic option that avoids the medical risks and costs of ovulation induction and assisted reproduction while reversing neuroendocrine allostasis, at least partially. Because the effect of CBT accrues with time (unlike most pharmacotherapy), CBT should be a mainstay of intervention for stress-related infertility and SIA—even if the patient receives other therapy as well.

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CONCLUSION

Stress is a primary cause of functional hypothalamic hypogonadism that may be clinically obvious, as in amenorrhea or anovulation, or occult, as in luteal insufficiency. Reproductive dysfunction associated with stress is not simply an isolated deficiency in hypothalamic secretion of GnRH, but is associated with metabolic mobilization that can be observed in increased adrenal and decreased thyroidal outputs. When sustained, these adjustments increase the general physical burden. Ideally, treatment approaches that dampen the activation of stress pathways and reverse or ameliorate allostatic neuroendocrine and metabolic adjustments associated with stress-related functional hypothalamic hypogonadism will have a positive impact on overall health for women and promote healthy family building.

Neither author reports any actual or potential conflicts of interest in relation to this article.

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Sarah L. Berga, MD, is James Robert McCord Professor and Chairman; and Tammy L. Loucks, MPH, is Director, Research Projects. Both are in the Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA.

References

1. Berga SL, Daniels TL. Use of the laboratory in disorders of reproductive neuroendocrinology. J Clin Immunoassay. 1991:14:23-28.
2. Reame NE, Sauder SE, Case GD, Kelch RP, Marshall JC. Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation. J Clin Endocrinol Metab. 1985;61(5):851-858.
3. Berga SL, Mortola JF, Girton L, et al. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1989;68(2):301-308.
4. Kaplan JR, Manuck SB. Ovarian dysfunction, stress, and disease: a primate continuum. ILAR J. 2004;45(2):89-115.
5. Marcus MD, Loucks TL, Berga SL. Psychological correlates of functional hypothalamic amenorrhea. Fertil Steril. 2001;76(2):310-316.
6. Biller BM, Federoff JH, Koenig JI, Klibanski A. Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with hypothalamic amenorrhea. J Clin Endocrinol Metab. 1990;70(2):311-317.
7. De Souza MJ, Miller BE, Loucks AB, et al. High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition. J Clin Endocrinol Metab. 1998;83(12):4220-4232.
8. Loucks AB, Laughlin GA, Mortola JF, Girton L, Nelson JC, Yen SS. Hypothalamic-pituitary-thyroidal function in eumenorrheic and amenorrheic athletes. J Clin Endocrinol Metab. 1992;75(2):514-518.
9. Wadhwa PD, Sandman CA, Garite TJ. The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Prog Brain Res. 2001;133:131-142.
10. Van der Spuy ZM, Steer PJ, McCusker M, Steele SJ, Jacobs HS. Outcome of pregnancy in underweight women after spontaneous and induced ovulation. Br Med J. 1988; 296(6627):962-965.
11. olden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR. The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol. 2002;15(3):135-143.
12. Genazzani AD, Gamba O, Petraglia F. Estrogen replacement therapy modulates spontaneous GH secretion but does not affect GH-RH-induced GH response and low T3 syndrome in women with hypothalamic amenorrhea associated to weight-loss. J Endocrinol Invest. 1998;21(6):353-357.
13. Judd SJ, Wong J, Saloniklis S, et al. The effect of alprazolam on serum cortisol and LH pulsatility in normal women and in women with stress-related anovulation. J Clin Endocrinol Metab. 1995;80(3):818-823.
14. Berga SL, Marcus MD, Loucks TL, Hlastala MS, Ringham R, Krohn MA. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril. 2003; 80(4):976-981.

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