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Sex Differences in Neurosteroid and Hormonal Responses to Metyrapone in Posttraumatic Stress Disorder

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Sex Differences in Neurosteroid and Hormonal Responses to Metyrapone in Posttraumatic Stress Disorder Psychopharmacology (2014) 231:3581–3595 DOI 10.1007/s00213-014-3621-3 ORIGINAL INVESTIGATION Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder Sabra S. Inslicht & Anne Richards & Erin Madden & Madhu N. Rao & Aoife O’Donovan & Lisa S. Talbot & Evelyn Rucker & Thomas J. Metzler & Richard L. Hauger & Thomas C. Neylan Received: 10 December 2013 /Accepted: 10 May 2014 /Published online: 21 June 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract HPA axis responses and account for sex differences in PTSD Rationale Mechanisms contributing to sex differences in the has not been previously examined. regulation of acute stress responsivity and their effect on the Objective The present study examined the effects of sex and increased incidence of posttraumatic stress disorder (PTSD) in PTSD on adrenocorticotropic hormone (ACTH), progester- women are poorly understood. The reproductive hormone, one, and allopregnanolone responses to metyrapone and progesterone, through conversion to allopregnanolone whether progesterone and allopregnanolone reactivity could (ALLO), suppresses the hypothalamic pituitary adrenal affect the ACTH response in PTSD. (HPA) axis and has potent anxiolytic effects. The potential Methods Healthy medication-free male and premenopausal that progesterone and allopregnanolone reactivity modulate follicular phase female participants with chronic PTSD (n= 43; 49 % female) and controls (n=42; 50 % female) complet- S. S. Inslicht (*) : A. Richards : E. Madden : M. N. Rao : ed an overnight metyrapone challenge and ACTH, progester- A. O’Donovan : L. S. Talbot : E. Rucker : T. J. Metzler : one, and allopregnanolone were obtained by repeated blood T. C. Neylan sampling. Stress and Health Research Program, San Francisco VA Medical Results TheincreaseinACTHresponsetometyraponewas Center, 4150 Clement St. (116P), San Francisco, CA 94121, USA e-mail: [email protected] higher in PTSD subjects compared to controls and in women compared to men. Contrary to our initial prediction of an : : : ’ : S. S. Inslicht: A. Richards: E. Madden: A. O Donovan inverse relationship, progesterone and allopregnanolone were L. S. Talbot E. Rucker T. J. Metzler T. C. Neylan positively associated with ACTH. Progesterone and Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA allopregnanolone partially mediated the relationship between PTSD and ACTH. : : : : S. S. Inslicht A.: Richards E.: Madden :M. N. Rao : Conclusions Our findings of increased ACTH to metyrapone A. O’Donovan L. S. Talbot E. Rucker T. J. Metzler in PTSD and in women may reflect heightened hypothalamic T. C. Neylan CRF hypersecretion. Progesterone and allopregnanolone par- Northern California Institute for Research and Education (NCIRE), The Veterans Health Research Institute, San Francisco, CA 94121, tially mediated the ACTH response in PTSD. Further charac- USA terizing sex differences in these processes will advance our understanding of the pathophysiology of PTSD, and may M. N. Rao ultimately lead to better-targeted, more effective treatment. Department of Medicine-Division of Endocrinology, University of California, San Francisco, San Francisco, CA 94143, USA Keywords Sex differences . Posttraumatic stress disorder . R. L. Hauger Progesterone . Allopregnanolone . ACTH . Metyrapone Center of Excellence for Stress and Mental Health, San Diego VA Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA Background R. L. Hauger Department of Psychiatry, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, Traumatic stress exposure that involves threat to life or phys- CA 92093, USA ical integrity often results in posttraumatic stress reactions in a 3582 Psychopharmacology (2014) 231:3581–3595 proportion of exposed individuals. Posttraumatic stress disor- to 4:00 p.m. Gulf War Veterans with PTSD had a significantly der (PTSD) is estimated to affect approximately 8–10 % of the higher ACTH response to metyrapone than veterans without US general population and 13–22 % of returning US veterans PTSD, although they did not differ from non-exposed control from Iraq and Afghanistan (Boscarino 2006; Dohrenwend subjects (Golier et al. 2009). In two additional studies, one et al. 2006; Friedman 2004;Hogeetal.2004; Kessler 2000; including male combat veterans and one of female civilian Kessler et al. 1995). Several epidemiological studies have trauma survivors, metyrapone was administered in the evening suggested that women develop PTSD at twice the rate of before sleep and ACTH was measured the following morning, men, despite greater trauma exposure in men (Adamson in order to avoid disturbing sleep (Neylan et al. 2003; Otte et al. et al. 2008; Breslau et al. 1998). Preclinical studies have 2007). In both of these studies, subjects with PTSD had a shown that differences in hypothalamic–pituitary–adrenal significantly smaller increase in ACTH response compared to (HPA) axis regulation and corticotropin releasing factor PTSD-free controls. However, it is unclear whether the PTSD (CRF) receptor signaling confers stress hypersensitivity in subjects and controls had the same immediate peak and recov- female compared to male rodents (Bangasser and Valentino ery of the ACTH response soon after metyrapone administra- 2012); however, the mechanisms that contribute to sex differ- tion, since blood was drawn 8–9.5 h after the final metyrapone ences in the regulation of acute stress responsivity in humans dose. The discrepancy in findings across studies may be due to and their effect on the increased incidence of PTSD in women differences in metyrapone dosage, the timing of ACTH mea- are poorly understood. surement, time of day, and gender. PTSD is associated with increases in both extrahypothalamic Growing literature also suggests that HPA axis activity and hypothalamic CRF neurotransmission (Baker et al. 1999; differs between men and women. Several studies have shown Bremner et al. 1997, 2003a;Heimetal.2001; Sautter et al. that premenopausal women have lower mean cortisol levels 2003;Smithetal.1989). Hypersecretion of CRF by neurons compared to men in the same age range (Van Cauter et al. is believed to be an important component of PTSD patho- 1996) and smaller HPA responses to psychological stress physiology based on studies that have detected abnormally (Kirschbaum et al. 1999, 1992). A study in which metyrapone high CRF levels in the cerebrospinal fluid of PTSD patients, wasadministeredat4p.m.andevery4hthroughnoonthe with the highest CRF concentrations being associated with next day found that both depressed and control women had a greatest illness severity, suicide, and psychosis (Baker et al. greater ACTH response compared to depressed and control 1999; Bremner et al. 1997;Haugeretal.2012; Sautter et al. men. Analyses within each gender revealed that depressed 2003). Furthermore, chronically elevated hypothalamic women had an increased initial evening ACTH response CRF activity in PTSD is thought to contribute to the blunted compared to control women, and that depressed men had adrenocorticotropic hormone (ACTH) response to CRF in an overall decreased ACTH response over the course of PTSD found in most (Bremner et al. 2003a;Heimetal. 24 h compared to control men (Young and Ribeiro 2006). 2001; Smith et al. 1989), but not all studies (Kellner et al. No studies to date have examined sex differences in 2002; Rasmusson et al. 2001). Also, increased CRF may be ACTH responses to metyrapone in men and women with involved in the increased ACTH and cortisol response to PTSD. psychological challenge in PTSD (Bremner et al. 2003b; Studies have also shown that sex differences in HPA axis Elzinga et al. 2003;Heimetal.2000). responses are influenced by aging. Whereas age-related ele- Metyrapone has been used diagnostically as a challenge vations of cortisol during the nocturnal nadir occurs in both that allows evaluation of the integrity of the HPA axis. men and women, older postmenopausal women also showed Metyrapone blocks cyp11B1 (11β-hydroxylase) and hence increased plasma cortisol levels in the morning acrophase blocks the conversion of 11-deoxycortisol to cortisol resulting (Van Cauter et al. 1996). Studies have also shown that older in reduced cortisol synthesis and increased levels of 11- women had higher cortisol responses to CRF administration deoxycortisol and other adrenocortical steroids prior to the (Greenspan et al. 1993; Luisi et al. 1998), decreased HPA inhibitory step. Reduced cortisol concentrations result in re- feedback sensitivity to cortisol (Wilkinson et al. 1997), and an moval of glucocorticoid negative feedback to the hypothala- increased ACTH and cortisol response to psychological chal- mus and pituitary, which can lead to increased hypothalamic lenge (Seeman et al. 1995, 2001). However, there are also a CRF drive and the stimulation of pituitary ACTH release. A few studies showing that older postmenopausal women have study of male combat veterans in which metyrapone was lower urinary free cortisol in response to mild laboratory stress administered in the morning and ACTH was assessed at blood (Prinz et al. 2000) in addition to lower ACTH and free salivary draws obtained at 1, 3, and 5 h later found that those with cortisol responses to acute stress than men (Kudielka et al. PTSD had a greater ACTH response compared to non-combat 1998). Despite some inconsistencies, the finding of HPA axis exposed controls (Yehuda et al.
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