This Article Abstract Full Text (PDF) All Versions of this Article: 91/4/1561    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brundu, B. Articles by Berga, S. L. Search for Related Content PubMed PubMed Citation Articles by Brundu, B. Articles by Berga, S. L. Related Collections Adrenal and Hypertension Female Endocrinology Neuroendocrinology and Pituitary

Increased Cortisol in the Cerebrospinal Fluid of Women with Functional Hypothalamic Amenorrhea

Department of Gynecology and Obstetrics, Emory University School of Medicine (T.L.L., S.L.B.), Atlanta, Georgia 30322; Department of Anesthesiology (L.J.A.) and Departments of Psychiatry, Cell Biology, and Physiology (J.L.C.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260; Division of Reproductive Sciences, Oregon National Primate Research Center (J.L.C.), Beaverton, Oregon 97006; and Department of Gynecology and Obstetrics IRCCS San Matteo (B.B.), University of Pavia, 65-27100 Pavia, Italy

Address all correspondence and requests for reprints to: Sarah L. Berga, M.D., Department of Gynecology and Obstetrics, Emory University School of Medicine, 1639 Pierce Drive, 4208-WMB, Atlanta, Georgia 30322. E-mail: sberga{at}emory.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: The proximate cause of functional hypothalamic amenorrhea (FHA) is reduced GnRH drive. The concomitant increase in circulating cortisol suggests that psychogenic stress plays an etiologic role, but others have argued for a strictly metabolic cause, such as undernutrition or excessive exercise. Indeed, our finding that the cerebrospinal fluid (CSF) concentration of CRH was not elevated in FHA cast doubt about the extent of hypothalamic-pituitary-adrenal activation in FHA and, therefore, we wondered whether central cortisol levels were elevated.

Objective: We tested the null hypothesis that CSF cortisol levels would be comparable in FHA and eumenorrheic women (EW).

Design: The study is a cross-sectional comparison.

Setting: The study was set in a general clinical research center at an academic medical center.

Participants: Fifteen women with FHA who were of normal body weight and 14 EW participated.

Intervention: Blood samples were collected at 15-min intervals for 24 h, followed by procurement of 25 ml CSF.

Main Outcome Measures: Cortisol, cortisol-binding globulin (CBG), and SHBG levels in blood and CSF were the main outcome measures.

Results: CSF cortisol concentrations were 30% greater when serum cortisol was 16% higher in FHA compared with EW. Circulating CBG, but not SHBG, was increased in FHA and, thus, the circulating free cortisol index was similar in FHA and EW. Because CBG and SHBG were nil in CSF, the increase in CSF cortisol in FHA was unbound.

Conclusions: The hypothalamic-pituitary-adrenal axis is activated in FHA. The maintenance of CRH drive despite increased CSF cortisol indicates resistance to cortisol feedback inhibition. The mechanisms mediating feedback resistance likely involve altered hippocampal corticosteroid reception and serotonergic and GABAergic neuromodulation.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
FUNCTIONAL HYPOTHALAMIC AMENORRHEA (FHA)is a common and reversible form of anovulation not due to discernible organic causes. The proximate cause of anovulation is reduced GnRH drive that manifests in the circulation as decreased LH pulse frequency (1, 2). Several lines of evidence support the notion that FHA, and the suppression of central GnRH drive, is attributable to metabolic and psychogenic stress. First, cortisol concentrations in serum, which reflect limbic-hypothalamic-pituitary-adrenal (LHPA) axis activation and reactivity, are consistently elevated in women with this disorder (3, 4, 5, 6). Second, increased cortisol concentrations were not found in women with other forms of anovulation (7). Third, serum cortisol levels in women with FHA who underwent spontaneous recovery while being studied were lower than in unrecovered women with FHA and were within the range observed in eumenorrheic women (EW) (7). Further, the LH pulse frequency of women recovering from FHA was intermediate between that of unrecovered FHA and EW, suggesting that LHPA axis recovery preceded the full return of GnRH drive (7). Fourth, cognitive behavior therapy (CBT) targeted to ameliorate problematic attitudes fully reversed anovulation and restored ovulation in six of eight women with FHA, whereas only one of eight FHA randomized to observation showed return of ovulation (8). Neither CBT nor reproductive recovery resulted in weight gain. Based on our observations in spontaneously recovering FHA (7), we speculated that CBT reduced hypothalamic-pituitary-adrenal (HPA) activation and allowed for restoration of GnRH drive. Although it has been inferred that HPA activation is required for suppression of GnRH drive, our recent investigation revealed that cerebrospinal fluid (CSF) concentrations of CRH were not increased in FHA compared with EW (9). This unexpected finding led us to question whether the peripheral increase in cortisol was transmitted to the neuraxis. We reasoned that compensatory mechanisms, such as an increase in circulating cortisol-binding globulin (CBG), might buffer the neuraxis from increased cortisol secretion by reducing the free fraction available to transgress the blood-brain barrier. To investigate the null hypothesis that CSF cortisol concentrations would not differ between FHA and EW, we compared the levels of cortisol, CBG, and SHBG in the blood and in the CSF of women with FHA and in eumenorrheic, ovulatory control women (EW).

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Experimental subjects

Women with amenorrhea and eumenorrhea were recruited by advertisement from the local population and screened by telephone. This study was approved by the institutional human subjects review boards of Magee-Womens Hospital and the University of Pittsburgh School of Medicine. All subjects gave written informed consent before the initiation of any study-related procedures. For the subjects in this study, serum levels of LH and cortisol and CSF levels of CRH, ß-endorphin, and arginine vasopressin have been reported (9). To ascertain the cause of amenorrhea and to constrain subject heterogeneity, we employed the same strict entry criteria in this and prior studies (7, 8, 9). Women with FHA were between 90 and 110% of ideal body weight and were carefully evaluated to exclude organic and other functional causes of amenorrhea and anovulation, including eating disorders, excessive exercise (defined as more than 10 h/wk of exercise of any type or running more than 10 miles weekly), weight loss of greater than 10 pounds within the last 5 yr, depression, and other psychiatric conditions. To exclude subjects with current and past psychiatric disorders, we employed the same assessment tools previously described (10). Thus we used both interviews and inventories, including the Structured Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV, the Beck Depression Inventory, the Hamilton Rating Scale for Depression, the Dysfunctional Attitudes Scale, the Self-Control Scale, the Eating Disorder Inventory, and the Bulimia Test-Revised. A provisional diagnosis of FHA (n = 15) was made when amenorrhea persisted for more than 6 months, a urinary pregnancy test was negative, serum levels of LH, FSH, TSH, free thyroxine, and prolactin were within normal range, the LH to FSH ratio was less than 2, and no other cause of secondary amenorrhea, including polycystic ovary syndrome, could be identified. None of the women with FHA displayed phenotypic or biochemical evidence of hyperandrogenism. Specifically, androstenedione, testosterone, dehydroepiandrosterone sulfate, and 17-hydroxyprogesterone levels fell within accepted ranges, and androgen levels were in the low normal range. A final diagnosis of FHA was made if the 24-h LH pulse frequency was less than or equal to 10. EW (n = 14) also were of normal body weight, reported regular menses with 27- to 32-d intervals, and displayed a midluteal serum progesterone level exceeding 30 nmol/liter (9.4 ng/ml) in the current and a preceding menstrual cycle. EW were studied in the early follicular phase, d 3–7 from last menses.

Procedures

Subjects were admitted to the General Clinical Research Center of the University of Pittsburgh School of Medicine at least 1 h before insertion of an iv line. Blood samples were collected every 15 min for 24 h starting at 0900 h (3, 7, 8, 9). A lumbar puncture was performed under sterile conditions at 1100 h on the following day by an obstetrical anesthesiologist (L.J.A.). As previously described, 25 ml CSF were slowly removed and then replaced with artificial CSF to reduce the risk of headaches (9). Each 1-ml aliquot was flash-frozen in a mixture of dry ice and ethanol and stored at –70 C until assay. No significant complications from the lumbar punctures were reported. All subjects who previously underwent CSF sampling for determination of CRH levels are included in the current data set (9).

Assays

Serum concentrations of LH and cortisol were determined in duplicate from each blood sample using standard immunoassays as previously reported (7, 8, 9). All samples from a given subject were analyzed together. The CSF CRH, serum LH, and serum cortisol values from these subjects have been previously analyzed and reported (9). CSF levels of cortisol were determined in two separate runs from aliquots 4 (caudal) and 19 (rostral) by enzyme immunoassay (Salimetrics, State College, PA). This assay was developed for the detection of cortisol in transudates and has a sensitivity of approximately 0.07 ng/ml. CSF samples were batched and analyzed in the same run to eliminate interassay variation. The intraassay coefficient of variation (CV) was 7.9% at 1 ng/ml and 5.8% at 10 ng/ml. Plasma CBG levels were determined at three time points using the plasma pool from 0800–0845 h, 1600–1645 h, and 2400–0045 h by Quest Diagnostics Laboratories (San Juan Capsitrano, CA) using a RIA that employed a ¹²⁵I-CBG ligand and rabbit antihuman CBG antibody (11). Intra and interassay CVs were 8 and 12% at 21 µg/ml, respectively. The sensitivity was 0.1 µg/ml. CSF levels of CBG were measured in aliquot 19 using a modified RIA (Biosource, Nivelles, Belgium) with a sensitivity of 0.1 µg/ml. The intraassay CV was 5.8% at 0.2 µg/ml. Each CSF sample was analyzed in duplicate and all samples were analyzed in the same run to eliminate interassay variability. Serum SHBG was determined once from the morning plasma pool (0800–0845 h) and in CSF in aliquot 19 by immunoradiometric assay (Diagnostic Systems Laboratory, Webster, TX). Plasma samples were diluted according to package instructions, and all samples were assayed in duplicate in the same run. The intraassay CV was 2.1% at 109 nmol/liter and the sensitivity was 3 nmol/liter. CSF samples were assayed without dilution in duplicate in the same run. The intraassay CV was 6.3% at 0.23 nmol/liter and the sensitivity was 0.04 nmol/liter. Free cortisol in the circulation was estimated by calculating the ratio of serum total cortisol in nanomoles per liter divided by plasma CBG in milligrams per liter, which is termed the "free cortisol index" (12). The free cortisol index has been shown to be a robust and reliable estimate of the unbound fraction of cortisol (12).

Statistics

All data are reported as mean ± SEM. Outcome variables were analyzed using SPSS version 10.1 (SPSS Inc., Chicago, IL) to identify between-group differences using a Student’s t test. All distributions were evaluated for normality. When the distribution was borderline for normality, nonparametric tests were performed. The statistical results using parametric and nonparametric test were comparable. In particular, the t test and the Mann-Whitney U test gave the same result for the difference in levels in CSF cortisol between EW and FHA. Main outcome variables were cortisol, free cortisol index, CBG, and SHBG levels in the serum and CSF. Other variables included the previously reported CSF levels of CRH, 24- and 8-h segmental serum cortisol levels, and LH pulse frequency (9). P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
As shown in Table 1, FHA and EW were of comparable age and body mass index. As previously reported (9), LH pulse frequency was significantly reduced in FHA (4.5 ± 0.8 vs. 14.6 ± 0.7 pulses number per 24 h, P < 0.01) and CSF CRH levels were comparable in FHA (38.9 ± 3.7) and EW (39.2 ± 2.1 pg/ml). Mean 24- and 8-h segmental cortisol levels, shown in Table 2, demonstrated activation of the LHPA axis. Serum SHBG levels were comparable in FHA and EW (Table 2). Serum CBG levels were modestly increased in FHA and, thus, the free cortisol index was comparable in FHA and EW (Table 2). However, as shown in Table 3 and in Fig. 1, cortisol levels in the CSF of women with FHA were 30% greater than those of EW (4.71 ± 0.38 vs. 3.60 ± 0.27 ng/ml, P = 0.03). CSF levels of CBG were nil but comparable in FHA and EW (0.20 ± 0.02 vs. 0.18 ± 0.01 µg/ml). Similarly, CSF SHBG levels were quite low but similar in both groups (0.24 ± 0.04 vs. 0.22 ± 0.03 nmol/liter).

View larger version (13K): [in this window] [in a new window]   FIG. 1. Mean (±SE) serum cortisol, serum free cortisol index (total cortisol/CBG), CSF cortisol, and CSF CRH in 15 women with FHA and 14 EW. Increased circulating and central cortisol levels did not suppress CSF CRH, indicating resistance to negative feedback inhibition in FHA. *, P < 0.05.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

To the best of our knowledge, this is the first report of increased CSF cortisol associated with reproductive compromise. The only other report of increased CSF cortisol associated with a stress-related condition was in 2005 by Baker et al. (16). They found increased CSF cortisol in eucortisolemic veterans (men) with posttraumatic stress disorder. Although women with FHA have higher circulating cortisol levels than EW, the increase in CBG in FHA lead to comparable levels of unbound circulating cortisol in FHA and EW. An increase in the free fraction has also been observed in the urine of FHA (4, 13). Although the mechanisms that sustain a gradient between the circulation and CSF are beyond the scope of this investigation, it seems likely that that the blood-brain barrier is more permeable to lipophilic free cortisol than to relatively hydrophilic bound cortisol. Furthermore, lack of CBG in the CSF would abrogate the establishment of a steady state for free cortisol. Together, these mechanisms would favor transfer across the blood-brain barrier of transient increases in free cortisol. Others have suggested that the neuraxis may synthesize and secrete cortisol (17). Furthermore, because women with FHA are relatively hypoestrogenic, one might have expected lower rather than higher CBG on that basis. The isolated elevation of CBG in the face of similar levels of SHBG suggests that the CBG rise reflects a compensatory response to chronic elevations of circulating cortisol. Thus, the rise in CBG buffers the circulatory compartment from glucocorticoid (GR) toxicity without abrogating the opportunity for central feedback. Overall, these data provide further support for the notion that activation of the LHPA is integral to the pathogenesis of FHA. However, LHPA activation does not preclude a metabolic etiology, because Loucks and Thuma (18) have demonstrated that induction of a graded energy deficit proportionately increased circulating total cortisol. Indeed, whereas behaviors that are recognized to be primarily psychogenic may be distinguishable from those that are deemed to be primarily metabolic, especially under experimental conditions, at least some of the endocrine and neuroendocrine responses appear to be common to both forms of stress.

If negative feedback sensitivity remained constant, an increase in central cortisol levels should suppress CRH release. Feedback inhibition permits the stress circuitry to be truncated during or after the response to an acute stressor. Different mechanisms must operate during chronic stress that alter the feedback setpoint and permit sustained LHPA activation. Given the potential for GR neurotoxicity and other health sequalae of chronic stress (19, 20, 21, 22), it would be advantageous to have multiple mechanisms for constraining cortisol elevations elicited by chronic stress. Potential adaptive responses include an increase in CBG, blunting of the adrenal response to ACTH, and/or reduced pituitary responsiveness to CRH. Not unexpectedly, we found that CBG was increased only in the circulation and not in the CSF in FHA. Although the ACTH response to CRH was blunted in major depression (23), we previously showed that the pituitary ACTH response to CRH was preserved in FHA and that the increased circulating cortisol was due to increased cortisol pulse amplitude with preserved pulse frequency in FHA (3). In untreated anorexia nervosa and melancholic depression, CSF CRH levels remained elevated in the presence of high circulating cortisol levels (14, 24), indicating greater compromise or lack of feedback inhibition than in FHA. Taken together, these data suggest that FHA entails a new allostatic setpoint for suppression of the LHPA axis activity by cortisol and that the stress of FHA is not as great as that found in anorexia nervosa or melancholic depression. Other allostatic adjustments also found in FHA include loss of hypothalamic GnRH responsivity to hypoestrogenism (3) and reduced TSH responsivity to reduced thyroxine and thyronine levels (25).

There are several mechanisms governing feedback inhibition of the HPA axis by cortisol. Numerous physiological and pharmacological studies demonstrate that both types of corticosteroid receptors, the mineralocorticoid (MR) and the GR receptors, are abundantly expressed in the hippocampus (26, 27) and that this region serves as a major corticosteroid regulatory site for negative feedback. Because the affinity of cortisol for MR is much greater than for GR, GR are generally occupied only during periods of acute stress. Chronic stress may alter receptor number, MR to GR ratio, and postreceptor events, allowing a change in the setpoint for feedback inhibition (28). Other key mechanisms mediating feedback control likely include neuromodulators such as -aminobutyric acid (GABA) and serotonin. Recent studies indicate that GR up-regulate the GABAergic system (29, 30), whereas corticosterone increases hippocampal GABA receptor expression and promotes the development of a GABAergic phenotype in the monkey hippocampus (31). In addition, the serotonergic system and the HPA axis interact bidirectionally. For example, Andrews et al. (32) demonstrated that hippocampal serotonin down-regulated GR receptor expression. Enhanced central serotonergic function altered secretion of ACTH and cortisol (33, 34), whereas 5-HT_1A and 5-HT_2A receptors regulated CRH neurons via distinct pathways (35). Different stressors activated slightly different constellations of central neural pathways (36), and reactivity to stressors may vary considerably from individual to individual. The contribution of these and other mechanisms to feedback inhibition of the HPA axis in human FHA remains to be clarified.

If the observation that circulating cortisol levels underestimate the extent of HPA activation holds for clinical conditions other than FHA that have been linked to stressful situations, then the clinical significance of these data are heightened because they suggest a mechanism for the link between chronic stress and long-term health burdens (19, 20, 21, 22). These data also illuminate the potential discordance between central and peripheral compartments and highlight the inherent difficulty in quantifying stress noninvasively. Currently, therapeutic options for women with FHA generally address only the reproductive compromise and neglect the potential for long-term health burden from ongoing metabolic and psychogenic stress. Thus, it is commonplace to prescribe oral contraceptives for those not desiring fertility and to employ exogenous gonadotropins for those who do. However, these interventions, which are based on the conceptualization that FHA is an isolated loss of GnRH drive, will not interdict the stress process. Ongoing LHPA activation may compromise neural, bone, cardiovascular, and fetal health (19, 20, 21, 22, 37). We recently demonstrated that CBT targeted to ameliorate problematic attitudes reversed FHA in most women, presumably by reducing LHPA activation and allowing the return of GnRH drive (8). Because women with FHA rarely meet criteria for depression (10, 38), the use of antidepressants in this context is controversial, particularly when conception is being sought. However, because selective serotonin reuptake inhibitors have been shown to inhibit the HPA axis (39, 40), potentially by restoring feedback inhibition, their use might well be indicated in women with FHA who do not respond to CBT or as an adjunct to CBT. Further studies are necessary to clarify the extent to which CBT reverses LHPA activation and the mechanisms by which LHPA disrupts central GnRH drive in FHA.

	Acknowledgments

 
We thank the nurses of the General Clinical Research Center at the University of Pittsburgh School of Medicine and at Magee-Womens Clinical Research Center for their dedicated assistance in the completion of this study, Alicia Corominal for her laboratory expertise, and Kathy Laychak, R.N., for her attention to the study execution and for her devotion to the subjects who participated in this study. We also recognize Rosella Nappi, M.D., Ph.D. (University of Pavia, Pavia, Italy) for her academic guidance.

	Footnotes

 
This work was supported by National Institute of Mental Health Grant RO1MH-50748 (to S.L.B.) and National Center for Research Resources Grant RR-00056 to the General Clinical Research Center at the University of Pittsburgh.

Results from this study were presented in part at the 84th Annual Meeting of The Endocrine Society, San Francisco, CA, June 19–23, 2002.

{smtexp}B.B., T.L.L., L.J.A., and J.L.C. have nothing to disclose. S.L.B. has served as a paid ad hoc medical consultant in the area of menopause therapy to Berlex, Wyeth, Novogyne, and Takeda Pharmaceuticals. She provided an ad hoc medical consult in the area of anovulation to Johnson & Johnson. S.L.B. has received payment from Berlex for CME presentations related to menopause therapy.

First Published Online February 7, 2006

Abbreviations: CBG, Cortisol-binding globulin; CBT, cognitive behavior therapy; CSF, cerebrospinal fluid; CV, coefficient of variation; EW, eumenorrheic women; FHA, (women with) functional hypothalamic amenorrhea; GABA, -aminobutyric acid; GR, glucocorticoid; HPA, hypothalamic-pituitary-adrenal; LHPA, limbic-HPA; MR, mineralocorticoid.

Received November 7, 2005.

Accepted January 30, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Crowley Jr WF, Filicori M, Spratt DI, Santoro N 1985 The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res 41:473–526[Medline]
2. Reame NE, Sauder SE, Case GD, Kelch RP, Marshall JC 1985 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 61:851–858[Abstract]
3. Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P, Yen SSC 1989 Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 68:301–308[Abstract]
4. Biller BMK, Federoff HJ, Koenig JI, Klibanski A 1990 Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 70:311–317[Abstract]
5. Ding JH, Scheckter CB, Drinkwater BL, Soules MR, Bremner WJ 1988 High serum cortisol levels in exercise-associated amenorrhea. Ann Int Med 108:530–534[Medline]
6. Loucks AB, Mortola JF, Girton L, Yen SSC 1989 Alterations in the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes in athletic women. J Clin Endocrinol Metab 68:402–411[Abstract]
7. Berga SL, Daniels TL, Giles DE 1997 Women with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrations. Fertil Steril 67:1024–1030[CrossRef][Medline]
8. Berga SL, Marcus MD, Loucks TL, Hlastala S, Ringham R, Krohn MA 2003 Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavioral therapy. Fertil Steril 80:976–981[CrossRef][Medline]
9. Berga SL, Loucks-Daniels TL, Adler LJ, Chrousos GP, Cameron KL, Matthews KA, Marcus MD 2000 Cerebrospinal fluid levels of corticotropin-releasing-hormone in women with functional hypothalamic amenorrhea. Am J Obstet Gynecol 182:776–784[CrossRef][Medline]
10. Marcus MD, Loucks TL, Berga SL 2001 Psychological correlates of functional hypothalamic amenorrhea. Fertil Steril 76:310–316[CrossRef][Medline]
11. Rosner W, Polimeni S, Khan MS 1983 Radioimmunoassay for human corticosteroid binding globulin. Clin Chem 29:1389–1391[Abstract/Free Full Text]
12. Le Roux CW, Chapman GA, Kong WM, Dillo WS, Jones J, Alaghband-Zadeh J 2003 Free cortisol index is better than serum total cortisol in determining hypothalamic-pituitary-adrenal status in patients undergoing surgery. J Clin Endocrinol Metab 88:2045–2048[Abstract/Free Full Text]
13. Suh BY, Liu JH, Berga SL, Laughlin GA, Yen SSC 1988 Hypercortisolism in patients with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 66:733–739[Abstract]
14. Kaye WH, Gwirtsman HE, George DT, Ebert MH, Juimerson DC, Tomai TP 1987 Elevated cerebrospinal fluid levels of immunoreactive corticotropin-releasing hormone in anorexia nervosa. J Clin Endocrinol Metab 64:203–208[Abstract]
15. Wong ML, Kling MA, Munson PJ, Listwak S, Licino J, Prolo P, Karp B, McCutcheon IE, Geracioti Jr TD, DeBellis MD, Rice KC, Goldstein DS, Veldhuis JD, Chrousos GP, Oldfield EH, McCann SM, Gold PW 2000 Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA 97:325–330[Abstract/Free Full Text]
16. Baker DG, Ekhator NN, Kasckow JW, Dashevsky B, Horn PS, Bednarik L, Geracioti TD 2005 Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder. Am J Psychiatry 162:992–994[Abstract/Free Full Text]
17. MacKenzie SM, Clark CJ, Fraser R, Gomez-Sanchez CE, Connell JM, Davies E 2000 Expression of 11ß-hydroxylase and aldosterone synthase genes in the rat brain. J Mol Endocrinol 24:321–328[Abstract]
18. Loucks AB, Thuma JR 2003 Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J Clin Endocrinol Metab 88:297–311[Abstract/Free Full Text]
19. McEwen BS 1998 Protective and damaging effects of stress mediators. N Engl J Med 338:171–179[Free Full Text]
20. Sapolsky RM 1996 Why stress is bad for your brain. Science 273:749–750[CrossRef][Medline]
21. Chrousos GP, Gold PW 1992 The concept of stress and stress related disorders. JAMA 267:1244–1252[Abstract]
22. Chrousos GP, Torpy DJ, Gold PW 1998 Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med 129:229–240[Abstract/Free Full Text]
23. Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH, Nieman LK, Post RM, Pickar D, Gallucci W, Avgerinos P, Paul S, Oldfield EH, Cutler GB, Chrousos GP 1986 Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N Engl J Med 314:1329–1335[Abstract]
24. Gwirtsman HE, Kaye WH, George DJ, Jimerson DC, Ebert RH, Gold PW 1989 Central and peripheral ACTH and cortisol levels in anorexia nervosa and bulimia. Arch Gen Psych 46:61–69[Abstract]
25. Daniels TL, Cameron JL, Marcus MD, Berga SL, Recovery from functional hypothalamic amenorrhea (FHA) involves resolution of hypothalamic hypothyroidism. Program of the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, 1997 (Abstract P1-378)
26. Reul JM, de Kloet ER 1985 Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117:2505–2511[Abstract]
27. Arriza JL, Simery RB, Swanson LW, Evans RM 1988 The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. Neuron 1:887–900[CrossRef][Medline]
28. Sapolsky RM, Krey LC, McEwen BS 1984 Stress down-regulates corticosterone receptors in a site-specific manner in the brain. Endocrinology 114:287–292[Abstract]
29. Bowers G, Cullinan WE, Herman JP 1998 Region-specific regulation of glutamic acid decarboxylase (GAD) mRNA expression in central stress circuits. J Neurosci 18:5938–5947[Abstract/Free Full Text]
30. Stone DJ, Walsh JP, Sebro R, Stevens R, Panatazopolous H, Benes FM 2001 Effects of pre- and postnatal corticosterone exposure on the rat hippocampal GABA system. Hippocampus 11:492–507[CrossRef][Medline]
31. McMillan PJ, Wilkinson CW, Greenup L, Raskind MA, Peskin ER 2004 Chronic cortisol exposure promotes the development of a GABAergic phenotype in the primate hippocampus. J Neurochem 91:843–851[CrossRef][Medline]
32. Andrews MH, Kostaki A, Setiawan E, McCabe L, Matthews SG 2004 Developmental regulation of 5-HT1A receptor mRNA in the fetal limbic system: response to antenatal glucocorticoid. Brain Res Dev Brain Res 149:39–44[CrossRef][Medline]
33. Fuller RW 1996 Serotonin receptors involved in regulation of pituitary-adrenocortical function in rats. Behav Brain Res 73:215–219[CrossRef][Medline]
34. Lopez JF, Chalmers DT, Little KY, Watson SJ 1998 Regulation of serotonin, glucocorticoid and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 43:547–573[CrossRef][Medline]
35. Mikkelsen JD, Hay-Schmidt A, Kiss A 2004 Serotonergic stimulation of the rat hypothalamo-pituitary-adrenal axis: interaction between 5-HT1A and 5-HT2A receptors. Ann NY Acad Sci 1018:65–70[Abstract/Free Full Text]
36. Romero LM, Plotsky PM, Sapolsky RM 1993 Patterns of adrenocorticotropin secretory release with colchicine blockade of axonal transport. Endocrinology 132:199–204[Abstract]
37. Hansen D, Lou HC, Olsen J 2000 Serious life events and congenital malformations: a national study with complete follow-up. Lancet 356:875–880[CrossRef][Medline]
38. Giles DE, Berga SL 1993 Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison. Fertil Steril 60:486–492[Medline]
39. Jensen JB, Jessop DS, Harbuz MS, Mork A, Sanchez C, Mikkelsen JD 1999 Acute and long-term treatments with the selective serotonin reuptake inhibitor citalopram modulate the HPA axis activity at different levels in rats. J Neuroendocrinol 11:465–471[CrossRef][Medline]
40. Pariante CM, Thomas SA, Lovestone S, Makoff A, Kerwin RW 2004 Do antidepressants regulate how cortisol affects the brain? Psychoneuroendocrinology 29:423–447[CrossRef][Medline]

This article has been cited by other articles:

				S. L. Berga Stress and Reprodution: A Tale of False Dichotomy? Endocrinology, March 1, 2008; 149(3): 867 - 868. [Full Text] [PDF]

				N. R Vulliemoz, E. Xiao, L. Xia-Zhang, J. Rivier, and M. Ferin Astressin B, a Nonselective Corticotropin-Releasing Hormone Receptor Antagonist, Prevents the Inhibitory Effect of Ghrelin on Luteinizing Hormone Pulse Frequency in the Ovariectomized Rhesus Monkey Endocrinology, March 1, 2008; 149(3): 869 - 874. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 91/4/1561    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brundu, B. Articles by Berga, S. L. Search for Related Content PubMed PubMed Citation Articles by Brundu, B. Articles by Berga, S. L. Related Collections Adrenal and Hypertension Female Endocrinology Neuroendocrinology and Pituitary