This Article Abstract Full Text (PDF) All Versions of this Article: 90/2/695    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 Google Scholar Google Scholar Articles by Bloch, M. Articles by Cizza, G. Search for Related Content PubMed PubMed Citation Articles by Bloch, M. Articles by Cizza, G. Related Collections Female Endocrinology Neuroendocrinology and Pituitary

Cortisol Response to Ovine Corticotropin-Releasing Hormone in a Model of Pregnancy and Parturition in Euthymic Women with and without a History of Postpartum Depression

Department of Psychiatry (M.B.), Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel 64239; Behavioral Endocrinology Branch (D.R.R., P.J.S.), National Institute of Mental Health, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland 20892-1276; and Pediatric and Reproductive Endocrinology Branch (A.L., G.P.C., G.C.), National Institute of Child Health and Human Development, NIH, U.S. Department of Health and Human Services, Bethesda, Maryland 20892-1853

Address all correspondence and requests for reprints to: David R. Rubinow, M.D., National Institute of Mental Health, Building 10, Room 3N238, 10 Center Drive, MSC 1276, Bethesda Maryland 20892-1276. E-mail: rubinowd{at}intra.nimh.nih.gov.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hypothalamic-pituitary-adrenal axis abnormalities have been reported in depressed women and those with postpartum blues, compared with nondepressed women.

We investigated the effect of gonadal steroids on the hormonal response to ovine CRH in women with (n = 5) and without (n = 7) a past history of postpartum depression (PPD) by creating an endocrine model of pregnancy and the postpartum. Ovine CRH (1 µg/kg) stimulation tests were performed in the baseline follicular phase, during hormone addback (leuprolide acetate plus supraphysiologic doses of estradiol and progesterone-mimicking pregnancy), and after precipitous withdrawal of hormone replacement (mimicking the puerperium).

Significant phase by time (P < 0.005) and phase by diagnosis (P < 0.05) interactions were observed, reflecting increased stimulated cortisol during the supraphysiologic phase, particularly in subjects with a history of PPD. Cortisol area under the curve also showed a significant phase by diagnosis effect (P < 0.05). Significant increases during the supraphysiologic phase were also seen for urinary free cortisol (P < 0.05), cortisol area under the curve (P < 0.001), and plasma corticosteroid-binding globulin (P < 0.05).

Our data show that in humans, as in animals, supraphysiologic gonadal steroid levels enhance pituitary-adrenal axis activity, and, further, that women with a history of PPD have an enhanced sensitivity of the pituitary-adrenal axis to gonadal steroids.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ABNORMALITIES OF THE hypothalamic-pituitary-adrenal (HPA) axis have been associated with the pathogenesis of depression in women. Studies of the effects of estrogen on the HPA axis have demonstrated extensive interactions and generally show a stimulatory effect of estrogen on the HPA axis (1, 2, 3, 4). However, in a prior study, we demonstrated that progesterone rather than estradiol appeared responsible for the increased HPA axis activity observed during the luteal phase (1). The third trimester of pregnancy is characterized by very high estrogen and progesterone plasma levels and a hyperactive HPA axis with high plasma cortisol levels (5). During this period, total and free cortisol concentrations and 24-h urinary free cortisol excretion increase to levels similar to those seen in a mild form of Cushing’s syndrome (6). Conversely, the postpartum period is associated with suppressed hypothalamic CRH secretion attributed to dysregulation of the hypothalamic CRH neuron together with the postnatal hypoestrogenic state (7).

About 10% of women develop a form of depression during the postpartum period, and a much higher percent experience the blues. Magiakou et al. (7) reported that women affected by the blues or depression (PPD) in the postpartum period experienced a more blunted ACTH response to ovine CRH (oCRH) stimulation compared with nondepressed women. In a pharmacological model that attempts to partially simulate pregnancy, parturition, and the postpartum period (8), we demonstrated that in vivo manipulation of gonadal steroid concentrations differentially affects mood in women with and without a predisposition for postpartum depression. In the present study, we used a subsample of women from the earlier study to further evaluate the potential involvement of the pituitary-adrenal axis in the pathogenesis of PPD.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

This study was part of a research project exploring the potential effects of gonadal steroids on mood and the susceptibility to PPD [for a detailed description of the study design, see Bloch et al. (8)]. The main inclusion criteria were healthy, euthymic, medication free (including oral contraceptives) women, 22–45 yr old, with regular menstrual cycles (n = 12). All women had one or more biological children and were at least 1 yr past their most recent childbirth. A complete psychiatric diagnostic evaluation was performed using the Structured Clinical Interview for DSM-IV (9) and the Schedule for Affective Disorders and Schizophrenia-Lifetime (10). Subjects with past or present psychiatric illness, with the exception of past PPD for the study group, were excluded. Subjects with premenstrual dysphoric disorder were also excluded based on prospective screening performed over two menstrual cycles.

Two experimental groups were studied: women with a history of at least one episode of PPD who were euthymic for the past year or longer (subjects, n = 5), and age-matched (within 3 yr) controls with no history of past or present psychiatric illness (controls, n = 7). The age and body mass index (BMI) of subjects and controls were as follows: age 32.2 ± 7.6 and 30.1 ± 6.2 yr, respectively, and BMI 27 ± 5.8 and 26.8 ± 4.9, respectively.

The study was approved by the NIMH intramural research panel, and all subjects gave oral and written informed consent before their participation.

Study design

The study comprised three distinct, consecutive phases with a total duration of 4 months: a hypogonadal phase (4 wk), a supraphysiologic phase (8 wk), and a withdrawal phase (4 wk). The first phase (hypogonadal) consisted of the induction of a hypogonadotropic hypogonadal state by using an open-label injection of depot leuprolide acetate (Lupron, 3.75 mg im; TAP Pharmaceuticals, Deerfield, IL). This agent is a long-acting GnRH agonist known to suppress the endogenous production of gonadal steroids, achieving a state of medical gonadectomy. A total of four injections were administered during the study, maintaining the suppression of endogenous production of gonadal steroids. During the hypogonadal phase, subjects also received daily oral placebo estrogen and progesterone tablets in a blind fashion. In the second (supraphysiologic) phase, micronized progesterone (Women’s Health Pharmacy, Madison, WI) and estradiol (Estrace, Bristol-Myers Squibb, Princeton, NJ) were substituted for placebo. The number of tablets prescribed was adjusted biweekly on a random basis during baseline (placebo) and according to plasma hormone levels during active treatment. Estradiol was started at a dose of 4 mg/d and was progressively increased up to 10 mg/d in three divided doses. Progesterone was started at 400 mg/d in three divided doses and increased progressively according to plasma levels. Plasma levels were monitored after 1 wk, 2 wk, and every 2 wk thereafter, in an effort to reach maximal levels after 2–4 wk. Target plasma levels for estradiol and progesterone were approximately 300 pg/ml and 50 ng/ml, respectively. In the third (withdrawal) phase, the active medications were switched in a blinded fashion to placebo, inducing a sharp drop in plasma estradiol and progesterone levels. During this phase subjects continued to take the same number of tablets (placebo) they had received at the end of the supraphysiologic phase. After the withdrawal phase of 4 wk, subjects were followed up for an additional 8 wk while unmedicated (follow-up).

To ensure that the subjects were kept blind to gonadal steroid treatment, several measures were taken. First, active and placebo medication were packaged to look identical. Second, whether on placebo or active medication, the number of tablets prescribed was the same. Third, subjects were not informed of the onset of active treatment. Fourth, to prevent the subject from identifying the study phase by the occurrence of any spotting/bleeding, subjects were told that such a phenomenon could occur at any time throughout the study. Fifth, the research nurse administering study drug and rating scales (and monitoring adverse events biweekly) was blind to treatment phase and the presence or lack of a history of PPD.

oCRH stimulation test

oCRH stimulation tests were performed three times throughout the study using a dose of 1 µg/kg body weight, as previously described (11): during the early follicular phase before the first leuprolide injection (baseline), between wk 6 and 8 of active estradiol and progesterone (plus leuprolide) addback (supraphysiologic), and 2 wk after the last leuprolide injection and switch of active medication to placebo (withdrawal). The oCRH test was performed starting between 0700 and 0900 h.

Subjects were instructed to fast from midnight before the test and present to the clinic between 0700 and 0800 h. Subjects were weighed and then placed in a semirecumbent position. An iv catheter was inserted in the antecubital space, and the subjects rested for 40 min before receiving 1 µg/kg oCRH by iv push. Blood samples for ACTH and cortisol were drawn at –15, 0, 5, 15, 30, 60, 90, 120, 150, and 180 min. Blood samples were collected in prechilled tubes containing EDTA, centrifuged, and aliquoted promptly, and plasma was stored at –70 C until assayed.

Hormone assays

Plasma levels of cortisol were measured by RIA on the samples collected during the oCRH test. In addition, corticosteroid-binding globulin (CBG) was measured by competitive assay and plasma leptin by RIA on the 15-min sample of the CRH test, as previously described (12). Plasma estradiol and progesterone were measured by RIA biweekly starting at baseline on samples collected in the morning. Finally, 24-h urine collection was performed once at each phase of the study, before the oCRH test, for further determinations of urinary free cortisol (UFC), norepinephrine, epinephrine, and dopamine. Assay characteristics were previously reported (12).

Statistical analyses

All data are expressed as mean ± SD. The effect of oCRH injection on cortisol response was analyzed by repeated-measures ANOVA, with diagnosis (PPD–, PPD+) as the between-subjects factor and treatment phase (baseline, supraphysiologic, withdrawal) and time of sampling (–15 to 180 min) as within-subjects factors.

The area under the curve (AUC) was then calculated using the trapezoidal integration method by subtracting the time-integrated basal hormone levels from the total time-integrated levels throughout the sampling period. The AUC cortisol and UFC data were analyzed using 2 x 3 repeated-measures ANOVAs, with a between-subjects factor of diagnosis and a within-subjects factor of treatment phase. Significant findings were decomposed by Duncan post hoc tests (where permitted by the results of the ANOVA). Significance was accepted at a P < 0.05 level. Correlations between UFC and CBG levels were performed with Pearson product moment correlation coefficients with Bonferroni corrections for multiple correlations. Diagnostic differences in age and BMI were determined with Student’s t tests. Estradiol and progesterone levels were compared in the two subject groups across the three treatment phases with repeated-measures ANOVA.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
From the series of 16 participants reported in the psychological study (8), we performed the oCRH stimulation test and the other endocrine measurements reported here on 12 consecutive euthymic women, five with (PPD+) and seven without (PPD–) a history of PPD. Subjects in the two groups did not significantly differ in age or BMI. Our pharmacological model, as described previously, was overall well tolerated. Elevated plasma levels of estradiol and progesterone were sustained during the addback phase in the two subject groups (estradiol, 269 ± 92.2 vs. 290 ± 77.7 pg/ml; and progesterone, 46.6 ± 19.6 vs. 73.1 ± 32.2 ng/ml mean ± SD in women with a history of PPD vs. comparison group, respectively), with no significant between group differences observed across the three study phases (baseline, supraphysiologic, withdrawal). The symptoms attributable to the hormonal manipulations performed in this study included mood symptoms (in the PPD+ subjects only) during the supraphysiologic and withdrawal phases, hot flushes in the hypogonadal and withdrawal phases, and sporadic bleeding observed throughout the study. The incidence of the somatic symptoms did not differ between groups: hot flushes did not precede the mood symptoms (observed only in the PPD+ subjects), and spotting was not phase specific and thus did not compromise the blind.

A significant phase effect was observed for UFC levels (F_2,9 = 5.8, P < 0.01) (Fig. 1A), largely reflecting a 2-fold (but insignificant) increase during the supraphysiologic phase, compared with the baseline phase. A significant phase effect was observed for plasma CBG levels (F_2,9 = 3.9, P < 0.05) (Fig. 1C), reflecting approximately 36% higher levels during the supraphysiologic phase, compared with the baseline phase.

View larger version (21K): [in this window] [in a new window]   FIG. 1. UFC (A), cortisol AUC (B), and cortisol binding globulin (C) (means + SD) in women with (PPD+) and without (PPD–) a history of PPD.

Significant phase by time (F_8,126 = 2.3, P < 0.005) and phase by diagnosis (F_2,14 = 5.0, P < 0.05) interactions were seen for oCRH stimulated cortisol, reflecting increased stimulated cortisol during the supraphysiologic phase, with greater increases seen in the PPD+ subjects (Fig. 2). A significant phase (baseline, supraphysiologic, withdrawal) by diagnosis (PPD+ vs. PPD–) effect also was seen for cortisol AUC (F_2,8 = 7.6, P < 0.05) (Fig. 1B). Post hoc analysis within PPD+ subjects revealed a significant increase of cortisol at the supraphysiologic phase, compared with both baseline (P < 0.01) and withdrawal (P < 0.01) phases. No significant changes in cortisol levels were present in the PPD– group (all P > 0.10). Comparison between phases in PPD+ subjects revealed a significant difference in cortisol AUC at the supraphysiologic phase compared with baseline (P < 0.05). No group by phase interactions were observed for UFC or CBG.

View larger version (20K): [in this window] [in a new window]   FIG. 2. Cortisol plasma level responses (mean ± SE) to an oCRH stimulation test in women with (PPD+) and without (PPD–) a history of PPD.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The second finding of this study is that stimulated cortisol concentrations increased to a greater extent in the pregnancy-like phase of the study in women with a history of PPD (PPD+), compared with those without (PPD–). This difference cannot be attributed to emotional stress elicited in PPD+ women, because such mood symptoms were observed to a greater extent in the withdrawal phase of the study in which, contrary to the supraphysiologic phase, no difference in cortisol level was observed between the two groups. The fact that levels of stimulated cortisol rose to a larger extent in PPD+ women, compared with controls, while receiving supraphysiologic doses of gonadal steroids may have potential consequences in subjects with such history who use oral contraceptives or take hormone replacement therapy. It should be noted, however, that because neither the oral contraceptive nor hormone replacement therapy preparations commonly used translate into supraphysiological estrogen or progesterone levels (but rather mimic physiological levels), the relevance of our findings for the hormonal therapy of PPD+ subjects is uncertain. Supraphysiologic doses of estrogens or progestins in PPD+ subjects may, however, induce an exaggerated stress-related increase in cortisol levels. Such increased levels of cortisol have been associated with several adverse consequences, including osteoporosis, in women with major depression (17).

Our observation of differential response in women with a history of PPD is consistent with several possible explanations. The experience of a prior depression may alter the subsequent modulatory effect of gonadal steroids on stimulated pituitary-adrenal response. Abnormal cortisol response to the dexamethasone-CRH test, for example, has been described in remitted depressed patients (18). Whether antecedent puerperal and nonpuerperal depressions would have similar subsequent effects on the pituitary-adrenal axis is unclear.

Alternatively, gonadal steroids may have a differential modulatory effect on the HPA axis (i.e. enhanced reactivity) in women who are also vulnerable to the development of PPD. It is of interest that many women who eventually develop PPD become partially symptomatic during the third trimester (19, 20). From the present data, one can speculate that these early depressive symptoms may be a consequence or concomitant of dysregulation of the HPA axis secondary to the elevation in gonadal steroids that occurs during pregnancy. Whereas we have previously shown that progesterone increases exercise-stimulated HPA axis function (1), progesterone levels in the PPD+ subjects were, if anything, lower than those obtained in the control subjects and hence cannot explain the enhanced reactivity seen in the PPD+ subjects.

Because maternal leptin is elevated during pregnancy (21), we measured this hormone during the different phases of the study. No changes were observed in leptin levels resulting from pharmacological manipulation of the gonadal axis, suggesting that the increase in leptin observed during pregnancy is mainly due to the production of leptin from the placenta rather than the increased estrogen levels observed during pregnancy. Furthermore, no differences in leptin were observed in this small sample between subjects with a history of PPD and controls. Some reports indicate that leptin may be increased, especially at night, in subjects with major depression (11). Because leptin secretion is pulsatile, the observation that single-time determinations of leptin did not differ between subjects and controls does not necessarily rule out the possibility that leptin may differ between patients and controls (22).

The differential response in the HPA axis was not observed in the withdrawal phase, which mimics the postpartum period when, clinically, most cases of PPD begin. Furthermore, in her study Magiakou et al. (7) found prolonged blunting of the HPA axis in women with the blues or depression in the hypogonadal postpartum period, a finding we did not replicate in our model. This discrepancy may reflect the obvious limitations of a pharmacological model of pregnancy. In our model we were able to attain supraphysiological levels of gonadal steroids, but these levels are much lower than those reached during pregnancy and further are maintained for a relatively short duration (8 wk). As such, the withdrawal phase induced in our model is certainly not identical with the postpartum period. Furthermore, pregnancy is characterized by the production of very high concentrations of CRH by the placenta, causing the down-regulation of the hypothalamic CRH neuron, which results in a blunting of the HPA axis in the postpartum period (23). The absence of this blunting effect in our model may explain our inability to detect a differential effect of the (hypogonadal) withdrawal phase on the HPA axis in the group of women with a history of PPD.

The underlying biological mechanisms responsible for cortisol hyperresponsiveness to oCRH in the presence of increased gonadal steroids need to be elucidated. Such mechanisms could include increased arginine vasopressin secretion, up-regulation of pituitary CRH receptors, or increased steroidogenesis through effects on adrenal steroid synthetic enzymes (24). Similarly, the exaggerated responsivity in women with a history of PPD, although of unknown cause, may represent the effect of polymorphic variants in steroid synthetic genes or other genes in the pituitary-adrenal regulatory pathway (25, 26). As a caveat, the fixed rather than randomized order of the conditions in this study precludes detection of possible order effects. Other limitations of the current study included the following: the sample size was small; ACTH levels were not determined; the model simulated only endocrine change and did not mimic environmental factors (e.g. maternal stressors) (27) that affect pregnancy and parturition; given the uniform time of pituitary-adrenal testing, possible differences in diurnal modulation of the axis could not be determined; and the oCRH test is only one measure of pituitary-adrenal axis activity, the results of which have uncertain relationships to behavior. Despite these limitations, this study demonstrated by using a novel pharmacological model of pregnancy and parturition that women with a history of PPD, although euthymic, exhibit increased cortisol responses to a pharmacological challenge, oCRH, in the context of increased levels of gonadal steroids. Such a trait may compromise behavioral adaptation or predispose to the long-term consequences of hypercortisolism.

	Footnotes

 
First Published Online November 16, 2004

Abbreviations: AUC, Area under the curve; BMI, body mass index; CBG, corticosteroid-binding globulin; HPA, hypothalamic-pituitary-adrenal; oCRH, ovine CRH; PPD, postpartum depression; UFC, urinary free cortisol.

Received July 15, 2004.

Accepted November 5, 2004.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Roca CA, Schmidt PJ, Altemus M, Deuster P, Danaceau MA, Putnam K, Rubinow DR 2003 Differential menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls. J Clin Endocrinol Metab 88:3057–3063[Abstract/Free Full Text]
2. 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]
3. Lindholm J, Schultz-Moller N 1973 Plasma and urinary cortisol in pregnancy and during estrogen-gestaten treatment. Scand J Clin Lab Invest 31:119–122[Medline]
4. Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J, Pirke KM, Hellhammer DH 1996 Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. J Clin Endocrinol Metab 81:3639–3643[Abstract]
5. Nolten WE, Lindheimer MD, Rueckert PA, Oparil S, Ehrlich EN 1980 Diurnal patterns and regulation of cortisol secretion in pregnancy. J Clin Endocrinol Metab 51:466–472[Medline]
6. Magiakou MA, Mastorakos G, Rabin D, Margioris AN, Dubbert B, Calogero AE, Tsigos C, Munson PJ, Chrousos GP 1996 The maternal hypothalamic-pituitary-adrenal axis in the third trimester of human pregnancy. Clin Endocrinol (Oxf) 44:419–428[CrossRef][Medline]
7. Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW, Chrousos GP 1996 Hypothalamic cortico-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab 81:1912–1917[Abstract]
8. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR 2000 Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 157:924–930[Abstract/Free Full Text]
9. First MB, Spitzer RL, Gibbon M, Williams JBW 1996 Structured clinical interview for DSM-IV axis I disorders–patient edition. New York: Biometrics Research Department, New York State Psychiatric Institute
10. Spitzer RL, Endicott J 1979 Schedule for affective disorders and schizophrenia–lifetime version. New York: Biometrics Research Department, New York State Psychiatric Institute
11. Antonijevic IA, Murck H, Frieboes RM, Horn R, Brabant G, Steiger A 1998 Elevated nocturnal profiles of serum leptin in patients with depression. J Psychiatr Res 32:403–410[CrossRef][Medline]
12. Cizza G, Lotsikas AJ, Licinio J, Gold PW, Chrousos GP 1997 Plasma leptin levels do not change in patients with Cushing’s disease shortly after correction of hypercortisolism. J Clin Endocrinol Metab 82:2747–2750[Abstract/Free Full Text]
13. Altemus M, Roca C, Galliven E, Romanos C, Deuster P 2001 Increased vasopressin and adrenocorticotropin responses to stress in the midluteal phase of the menstrual cycle. J Clin Endocrinol Metab 86:2525–2530[Abstract/Free Full Text]
14. Linton EA, Perkins AV, Woods RJ, Eben F, Wolfe CD, Behan DP, Potter E, Vale WW, Lowry PJ 1993 Corticotropin releasing hormone-binding protein (CRH-BP): plasma levels decrease during the third trimester of normal human pregnancy. J Clin Endocrinol Metab 76:260–262[Abstract]
15. Vamvakopoulos NC, Chrousos GP 1993 Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression: potential implications for the sexual dimorphism of the stress response and immune/inflammatory reaction. J Clin Invest 92:1896–1902
16. Vamvakopoulos NC, Chrousos GP 1994 Hormonal regulation of human corticotropin-releasing hormone gene expression: implications for the stress response and immune/inflammatory reaction. Endocr Rev 15:409–420[CrossRef][Medline]
17. Cizza G, Ravn P, Chrousos GP, Gold PW 2001 Depression: a major, unrecognized risk factor for osteoporosis? Trends Endocrinol Metab 12:198–203[CrossRef][Medline]
18. Zobel AW, Nickel T, Sonntag A, Uhr M, Holsboer F, Ising M 2001 Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: a prospective study. J Psychiatr Res 35:83–94[CrossRef][Medline]
19. Righett-Veltema M, Conne-Perreard E, Bousquet A, Manzano J 1998 Risk factors and predictive signs of postpartum depression. J Affective Disord 49:167–180[CrossRef][Medline]
20. Stowe ZN, Nemeroff CB 1995 Women at risk for postpartum-onset major depression. Am J Obstet Gynecol 173:639–645[CrossRef][Medline]
21. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K 1997 Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3:1029–1033[CrossRef][Medline]
22. Licinio J, Mantzoros C, Negrao AB, Cizza G, Wong ML, Bongiorno PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW 1997 Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 3:575–579[CrossRef][Medline]
23. Gomez MT, Magiakou MA, Mastorakos G, Chrousos GP 1993 The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome. J Clin Endocrinol Metab 77:173–177[Abstract]
24. Nowak KW, Neri G, Nussdorfer GG, Malendowicz LK 1995 Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical cells of the rat adrenal cortex. Life Sci 57:833–837[CrossRef][Medline]
25. Stevens A, Ray DW, Zeggini E, John S, Richards HL, Griffiths CE, Donn R 2004 Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype. J Clin Endocrinol Metab 89:892–897[Abstract/Free Full Text]
26. Wust S, van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH 2004 Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab 89:565–573[Abstract/Free Full Text]
27. Glover V, O’Connor TG, Heron J, Golding J, The ALSPAC Study Team 2004 Antenatal maternal anxiety is linked with atypical handedness in the child. Early Hum Dev 79:107–118[CrossRef][Medline]

This Article Abstract Full Text (PDF) All Versions of this Article: 90/2/695    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 Google Scholar Google Scholar Articles by Bloch, M. Articles by Cizza, G. Search for Related Content PubMed PubMed Citation Articles by Bloch, M. Articles by Cizza, G. Related Collections Female Endocrinology Neuroendocrinology and Pituitary