Stress Induced Anovulation 615 Stress Induced Anovulation S L Berga and T L Loucks Introduction Emory University School of Medicine, Atlanta, GA, USA A wealth of scientific and clinical evidence supports ã 2007 Elsevier Inc. All rights reserved. the notion that stress causes reproductive compro- mise and increases health burden. Neuroendocrine, Introduction metabolic, and behavioral responses to acute stress Neuroendocrine Mechanisms Linking Cognition, Mood, represent transient homeostatic adaptations that Behavior, and Gonadotropin-Releasing Hormone Drive promote survival in the face of perceived challenge; Pathogenesis of Stress-Induced Anovulation chronic stress elicits allostatic (sustained) adjustments Behavioral, Nutritional, and Metabolic Influences on the that also promote survival but at greater health cost Reproductive Axis (Figure 1). Reproductive compromise impedes popu- Synergism among Stressors lation replenishment and increases acute and chronic Treatment Considerations health burden in women, men, and children due to Summary metabolic dysfunction, obesity, diseases of aging, pre- term delivery, birth defects, costly and risky infertility therapies, and, through epigenetic mechanisms, it Glossary imprints the next generation. Stress is the most com- Allostasis A sustained adjustment that promotes mon and most commonly underappreciated cause survival in response to chronic challenge; of reproductive dysfunction (Table 1). Stress-induced may increase long-term health burden. anovulation (SIA), often termed functional hypotha- Anovulation The cessation of ovulation. lamic amenorrhea (FHA) or functional hypothalamic Cognitive- A form of psychoeducation or talk chronic anovulation, causes infertility and increases behavior therapy that addresses nonadaptive acute and chronic health burden. therapy thoughts, cognitions, attitudes, and Behaviors that chronically activate the limbic- conceptualizations. hypothalamic-pituitary-adrenal (LHPA) axis and/or Eumenorrhea A normal pattern of menstrual bleeding; chronically suppress the hypothalamic-pituitary- can occur in the absence of ovulation. thyroidal (HPT) axis compromise the hypothalamic- Gonadotropin- Decapeptide produced and released in a releasing hor- pulsatile mannner from hypothalamic pituitary-gonadal (HPG) axis in both women and mone (GnRH) neurons; stimulates the release of pitui- men by reducing hypothalamic gonadotropic-releasing tary lutenizing hormone (LH) and folli- hormone (GnRH) drive. Individuals with functional cle stimulating hormone (FSH). (not due to defined organic conditions) forms of Hypothalamic A condition characterized by suppres- hypothalamic hypogonadism typically engage in a hypogonadism sion of GnRH drive and, in turn, pitui- combination of behaviors in response to psychogenic tary LH and FSH, resulting in reduced stress that concomitantly induce intermittent or or absent gonadal steroidogenesis and chronic energy imbalance. Further, chronic adrenal gametogenesis. activation may increase the energetic cost of common Hypothalamic An allostatic adjustment in thyroidal activities such as running. In women, functional hypo- function that conserves energy expendi- hypothalamic hypogonadism exists on a spectrum thyroidism ture and is characterized by relatively nor- that includes polymenorrhea (menstrual interval mal levels of pituitary thyroid stimulating < hormone (TSH) in the presence of sup- 24 days), eumenorrhea with reduced luteal proges- pressed levels of thyroid hormones triio- terone secretion, and anovulatory eumenorrhea, dothyronine (T3) and thyroxine (T4). oligomenorrhea (menstrual interval 735 days), or Limbic- Neuroendocrine circuit that mediates amenorrhea (absence of menstruation for >3–6 hypothalamic- stress perception and stress responses. months). In men, oligoasthenospermia (very low pituitary- sperm count with low motility and abnormal mor- adrenal axis phology) may result, but this is typically not clinically Metabolism Biochemical processes that regulate evident unless fertility is being sought or severe energy expenditure and storage. testosterone deficiency results in muscle wasting or Secondary Cessation of menses in a woman of other phenotypic alterations. amenorrhea reproductive age who was previously eumenorrheic. This article focuses primarily on SIA/FHA in Stress Physical and psychological stimuli that women. SIA/FHA typically results from psychogenic challenge the status quo and elicit homeo- stress coupled with a mild energy imbalance and static or allostatic behavioral responses. represents an allostatic adaptation, that is, a stable 616 Stress Induced Anovulation Homeostasis Chronic stress Allostasis Cognitive-behavior therapy Metabolic challenge Psychogenic challenge –Excessive exercise –Performance pressure –Undernutrition –Unrealistic expectations –Nutrient deficiency –Poor coping strategies Central neuromodulation Hypothalamic adjustment Pituitary Glands Thyroid, parathyroid, gonads, adipocytes, pancreas, adrenal Figure 1 Conceptualization of synergism between metabolic and psychogenic stress in the pathogenesis of stress-induced anovulation. Table 1 Common causes of anovulation/amenorrheaa not promote recovery from allostatic endocrine adjustments in the adrenal and thyroidal axes. In- Percentage deed, the rationale for the use of sex steroid replace- Stress-induced anovulation/ functional 34 ment is based on the erroneous assumption that hypothalamic amenorrhea functional forms of hypothalamic hypogonadism rep- Hyperandrogenism/PCOS 29 resent only or primarily a loss of sex steroid exposure Hyperprolactinemia 13 due to reduced GnRH drive. Further, the replacement Premature menopause 12 Asherman’s syndrome 5 of sex hormones masks deficits that accrue from Other 7 chronically altered adrenal and thyroidal functions. a Long-term deleterious consequences of SIA/FHA Based on data presented in Reindollar, R. H., Novak, M., Tho, probably include an increased risk of cardiovascular S. P. T., et al. (1986), Adult-onset amenorrhea: a study of 262 patients, American Journal of Obstetrics and Gynecology 155, disease, osteoporosis, depression, other psychiatric 531–543. PCOS, polycystic ovarian syndrome. conditions, dementia, and neurodevelopmental com- promise in offspring. Although fertility can be restored with exogenous administration of gonado- change in behaviors and secretory patterns that pro- tropins or pulsatile GnRH, fertility management motes acute survival but at some health cost. SIA/FHA alone does not engender adrenal and thyroidal recov- affects roughly 5% of women of reproductive age; less ery. Pregnancy in the face of ongoing psychogenic severe forms of hypothalamic hypogonadism are more stress and metabolic imbalance may increase the like- common and are less clinically evident (Figure 2). lihood of poor obstetrical, fetal, or neonatal out- Stress-induced anovulation is theoretically revers- comes. In contrast, behavioral and psychological ible, but reproductive recovery appears to depend on interventions that address problematic behaviors the restoration of eucortisolemia and at least partial and attitudes have the potential to facilitate repro- recovery from functional hypothalamic hypothyroid- ductive recovery along with adrenal and thyroidal ism. Hormone replacement strategies have limited recovery. In short, full endocrine recovery offers bet- benefit for women with SIA/FHA because they do ter individual, maternal, and child health. Stress Induced Anovulation 617 250 30 250 30 25 25 200 200 20 20 1 1 1 − 1 − − 150 − 150 15 15 100 LH IU l FSH IU l 100 LH IU l 10 10 FSH IU l 50 50 5 5 0 0 0 0 12 3 4 5 6 7 8 9 10 1112131415161718192021222324252627282930 1 2 3 4 5 6 7 8 9 10111213141516171819202122232425262728293031 350 20 350 20 300 300 1 − 1 − 1 15 1 − 250 − 15 250 200 200 10 10 150 150 100 5 100 Estradiol pg ml 5 Progesterone ng ml Estradiol pg ml 50 50 Progesterone ng ml 0 0 0 0 12 3 4 5 6 7 8 9 10 1112131415161718192021222324252627282930 1 2 3 4 5 6 7 8 9 10111213141516171819202122232425262728293031 (a) Cycle day (b) Cycle day 250 30 250 30 25 25 200 200 20 1 20 − 1 1 1 − − 150 − 150 15 15 LH IU l 100 100 FSH IU l LH IU l FSH IU l 10 10 50 50 5 5 0 0 0 0 12 3 4 5 6 7 8 9 10 1112131415161718192021222324252627282930 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536 350 20 350 20 300 300 1 1 − − 1 15 − 250 1 15 − 250 200 200 10 10 150 150 100 Estradiol pg ml 5 100 Progesterone ng ml Estradiol pg ml 5 50 Progesterone ng ml 50 0 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536 (c)Cycle day (d) Cycle day LH FSH Estradiol Progesterone Figure 2 Continuum of ovarian function in women with preserved menstrual cyclicity. a, Ovulatory eumenorrhea; b, luteal insufficiency; c–d, eumenorrheic anovulation. Pituitary gonadotropin (LH and FSH) and ovarian sex steroid (estradiol and progesterone) levels were obtained daily for one cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone. Note that FSH > LH, but FSH < 20 IU/L, thus the cause of hypogonadism is hypothalamic rather than reduced ovarian reserve. Neuroendocrine Mechanisms Linking The proximate cause of hypothalamic forms of Cognition, Mood, Behavior, and hypogonadism, including SIA/FHA, is reduced hypo- Gonadotropin-Releasing Hormone Drive thalamic GnRH input. Gonadal function depends directly on secretion from the hypothalamus of Our conceptualization of the bidirectional interaction GnRH as pulses.