Hypogonadism induced by surgical stress and brain trauma is reversed by human chorionic gonadotropin in male rats: A potential therapy for surgical and TBI-induced hypogonadism?

Introduction: Hypogonadotropic hypogonadism (HH) is an almost universal, yet underappreciated, endocrinological complication of traumatic brain injury (TBI). The goal of this study was to determine whether the developmental hormone human chorionic gonadotropin (hCG) treatment could reverse HH induced by a TBI. Methods: Plasma samples were collected at post-surgery/post-injury (PSD/PID) days -10, 1, 11, 19 and 29 from male Sprague-Dawley rats (5- to 6-month-old) that had undergone a Sham surgery (craniectomy alone) or CCI injury (craniectomy + bilateral moderate-to-severe CCI injury) and treatment with saline or hCG (400 IU/kg; i.m.) every other day. Results: Both Sham and CCI injury significantly decreased circulating testosterone (T), 11-deoxycorticosterone (11-DOC) and corticosterone concentrations to a similar extent (79.1% vs. 80.0%; 46.6% vs. 48.4%; 56.2% vs. 32.5%; respectively) by PSD/PID 1. hCG treatment returned circulating T to baseline concentrations by PSD/PID 1 (8.9 ± 1.5 ng/ml and 8.3 ± 1.9 ng/ml; respectively) and was maintained through PSD/PID 29. hCG treatment significantly, but transiently, increased circulating progesterone (P4) ~3-fold (30.2 ± 10.5 ng/ml and 24.2 ± 5.8 ng/ml) above that of baseline concentrations on PSD 1 and PID 1, respectively. hCG treatment did not reverse hypoadrenalism following either procedure. Conclusions: Together, these data indicate that (1) craniectomy is sufficient to induce persistent hypogonadism and hypoadrenalism, (2) hCG can reverse hypogonadism induced by a craniectomy or craniectomy +CCI injury, suggesting that (3) craniectomy and CCI injury induce a persistent hypogonadism by decreasing hypothalamic and/or pituitary function rather than testicular function in male rats. The potential role of hCG as a cheap, safe and readily available treatment for reversing surgery or TBI-induced hypogonadism is discussed

Progesterone treatment shows benefit in a pediatric model of moderate to severe bilateral brain injury.

Controlled cortical impact (CCI) models in adult and aged Sprague-Dawley (SD) rats have been used extensively to study medial prefrontal cortex (mPFC) injury and the effects of post-injury progesterone treatment, but the hormone's effects after traumatic brain injury (TBI) in juvenile animals have not been determined. In the present proof-of-concept study we investigated whether progesterone had neuroprotective effects in a pediatric model of moderate to severe bilateral brain injury.Twenty-eight-day old (PND 28) male Sprague Dawley rats received sham (n = 24) or CCI (n = 47) injury and were given progesterone (4, 8, or 16 mg/kg per 100 g body weight) or vehicle injections on post-injury days (PID) 1-7, subjected to behavioral testing from PID 9-27, and analyzed for lesion size at PID 28.The 8 and 16 mg/kg doses of progesterone were observed to be most beneficial in reducing the effect of CCI on lesion size and behavior in PND 28 male SD rats.Our findings suggest that a midline CCI injury to the frontal cortex will reliably produce a moderate TBI comparable to what is seen in the adult male rat and that progesterone can ameliorate the injury-induced deficits

Progesterone Treatment Shows Benefit in Female Rats in a Pediatric Model of Controlled Cortical Impact Injury

<div><p>Purpose</p><p>We recently showed that progesterone treatment can reduce lesion size and behavioral deficits after moderate-to-severe bilateral injury to the medial prefrontal cortex in immature male rats. Whether there are important sex differences in response to injury and progesterone treatment in very young subjects has not been given sufficient attention. Here we investigated progesterone’s effects in the same model of brain injury but with pre-pubescent females.</p><p>Methods</p><p>Twenty-eight-day-old female Sprague-Dawley rats received sham (n = 14) or controlled cortical impact (CCI) (n = 21) injury, were given progesterone (8 mg/kg body weight) or vehicle injections on post-injury days (PID) 1–7, and underwent behavioral testing from PID 9–27. Brains were evaluated for lesion size at PID 28.</p><p>Results</p><p>Lesion size in vehicle-treated female rats with CCI injury was smaller than that previously reported for similarly treated age-matched male rats. Treatment with progesterone reduced the effect of CCI on extent of damage and behavioral deficits.</p><p>Conclusion</p><p>Pre-pubescent female rats with midline CCI injury to the frontal cortex have reduced morphological and functional deficits following progesterone treatment. While gender differences in susceptibility to this injury were observed, progesterone treatment produced beneficial effects in young rats of both sexes following CCI.</p></div

Effects of progesterone (PROG) on learning and memory task as assessed by latency to locate the Morris water maze (MWM) platform.

<p>During Run 1 <b>(a)</b> on the acquisition phase there was a significant effect of controlled cortical impact injury. Eight mg/kg PROG proved beneficial by decreasing the mean latency to find a hidden platform in the MWM compared to the CCI+vehicle-treated group. There was no clear effect of PROG treatment on Run 2 <b>(b)</b> or during the reversal phase (<i>p</i> > 0.05). The Sham+PROG group was given 16 mg/kg doses of PROG. * = different from Sham+Vehicle; # = different from CCI+Vehicle (<i>p</i>’s < 0.05). ‡ = different from baseline within each group; n = 6–11.</p

Dose-response effect of progesterone on mean velocity in the MWM.

<p>During Run 1 (<b>a</b>) in the acquisition phase there was a significant effect of CCI injury. While progesterone treatment eventually improved performance, when collapsed across trials the 4–16 mg/kg CCI+PROG groups were not statistically different from CCI+ vehicle-treated rats. During Run 2 (<b>b</b>) swim speed for the CCI+ vehicle group compared to Sham Vehicle was significantly different. PROG (16 mg/kg)+CCI groups showed the most improvement on swim speed during reverse phase learning. * =  significantly different from CCI+ vehicle; # =  significantly different from CCI+8 mg/kg (<i>p</i>'s<.05). n = 8–9. PROG =  progesterone.</p

Tabulated comparative deficits between male and female controlled cortical impact injury.

<p>Bold numbers with asterisk (<b>*</b>) indicate differences between treatment groups within the same gender, <i>p</i> < .05. Darker-shaded cells indicate where male rats either found the hidden MWM platform faster or made fewer visits to the closed arm of the EPM than similarly treated female rat pups (between-gender analysis), <i>p</i> < .05. Lighter-shaded cells indicate where female rat pups either weighed less, had smaller lesions, spent less time in the open arm of the EPM, tended to travel longer distances (Open Field), remained on the rotarod longer, or found the MWM platform faster than similarly treated male counterparts (b/w gender analysis), <i>p</i> < .05; PID 0 = day of injury but prior to surgery; PID -1 = day(s) before surgery; MWM: Morris Water Maze; CCI: controlled cortical impact; Mean +/- SEM; n = 6–11. Male data (columns 3, 5, 7, and 9) were previously published [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0146419#pone.0146419.ref026" target="_blank">26</a>].</p

Dose-response effect on Spontaneous Activity test.

<p>Mean distance travelled (<b>a</b>), mean time spent at rest (<b>b</b>), Ambulatory responses (<b>c</b>) and stereotypic responses (<b>d</b>). Although CCI had a significant effect on spontaneous activity across test days, across the group there was no observed significant effect of Lesion/Treatment. * =  significant difference from baseline within each group. Values are mean ±SEM (n = 8–9). PROG =  progesterone.</p

Dose-response effect of progesterone on learning and memory task as assessed by latency to locate the MWM platform.

<p>During Run 1 (<b>a</b>) on the acquisition phase there was a significant effect of CCI injury and all three doses of progesterone proved beneficial by decreasing the mean latency latency to find a hidden platform in the MWM compared to the CCI+ vehicle treated group. There was no clear effect of CCI injury on Run 2 (<b>b</b>) or during the reversal phase (p>0.05). * =  mean values are significantly different from sham; n = 8–9. PROG =  progesterone.</p

Effect of progesterone (PROG) treatment on vestibulomotor function in female CCI rats treated with PROG vs. vehicle.

<p>PROG (8 mg/kg) -treated CCI rats showed improvement in balancing and walking on the rotarod tasks. The Sham+PROG group was given 16-mg/kg doses of PROG. * = different from sham + vehicle; # = different from CCI + vehicle (<i>p</i>’s < 0.05). ‡ = different from baseline within each group. Values are mean ± SEM (n = 6–11).</p

Lesion reconstruction analysis of juvenile female rats with controlled cortical impact (CCI) treated with progesterone (PROG) vs. vehicle.

<p>Mean percent (± SEM) of volumetric tissue loss at 6 anterior-to-posterior (A/P) levels at 4 weeks post-injury. # = difference between the CCI+vehicle-treated group and CCI rats given 8 mg/kg PROG. Values are mean ± SEM (n = 6–11 / group).</p