Gonadotropin Deficiency
Central hypogonadism, with low levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone in men and estradiol in women, has been reported within hours of brain insult, with eventual recovery of the hypothalamic-pituitary-gonadal (HPG) axis.
24 In a cross-sectional study of 50 men with moderate to severe TBI studied 7 to 20 days postTBI, 79% (N=30) of the subjects had low serum testosterone, which correlated with their Glascow Coma Scores (GCS).
25 This study included subjects with elevated prolactin levels, which may have contributed to low testosterone levels. Another report showed that 14 of 21 subjects (67%) studied 1 week after transfer to rehabilitation had abnormally low testosterone levels.
11 In a cross-sectional study of 102 TBI survivors studied at 6 to 36 months postevent, 11.8% had gonadotropin deficiency and hypogonadism.
9 Seven of 50 (14%) male and female subjects studied 12 to 64 months after TBI were found to have low testosterone or estradiol levels.
7 Although the precise timeline of recovery of the hypothalamic-pituitary-gonadal (HPG) axis has not been established prospectively, hypogonadism was only detected in one of 46 men more than 4 years (49 [SD=8] months) after their initial injury.
5 Another series of subjects evaluated at 6 and 12 months after injury also showed that the majority of them (34/40=85%) regained normal gonadal function by 1 year.
26The mechanisms of suppression of the HPG axis after TBI are multifactorial. Acute, severe illness, and stress are known to adversely affect normal HPG axis function,
27 as are brain damage and dysfunction.
6,
28 TBI-associated hypogonadism may involve decreased LH pulse amplitude, but not pulse frequency, as a result of injury to the pituitary.
12 This is in contrast to a direct injury to the hypothalamic gonadotropin releasing hormone (GnRH) neurons or effects of stress, which would result in a decreased LH pulse frequency. Medications commonly used in the management of TBI and its sequelae, in particular opiates, also can suppress GnRH-induced LH secretion. The inflammatory cascade induced by TBI may also play a role in HPG axis dysfunction at the level of the gonad, as cytokines can suppress Leydig cell function, and thereby the normal production of testosterone in the testis.
27In other models of severe illness, testosterone levels decrease acutely and dramatically into the prepubertal range. Testosterone levels were shown to correlate with APACHE (Acute Physiology and Chronic Healthy Evaluation) scores in a study of 59 men in an ICU.
29 The more severely ill men (APACHE scores of >15) had an average level of 8.2 nmol/liter on admission (healthy age matched comparison subjects ranged from 9.7 to 33.7 nmol/l). Levels fell to 3.7 nmol/liter by day 3 and reached a nadir of 1.2 nmol/liter. Although less dramatic, men with an APACHE score of <10 average level reached a nadir of 7.2 nmol/liter. Another study of ICU admissions found 29 of 30 (96%) of men had testosterone levels below the lower limit of normal for age.
30Recent studies demonstrate that patients with severe burns also have profound hypogonadism. Six men studied approximately 2 weeks after severe burns had an average level of 36.6 ng/dl (normal range=262 to 1593 ng/dl).
31 The authors of this study advocated physiological replacement of testosterone to improve the catabolic state of these subjects. Although hypogonadism can contribute to the catabolic state seen in the critically ill, it is not known if this response is adaptive or detrimental to the recovery process.
27 The effects of hypogonadism on neurological and neurobehavioral function and recovery after TBI also require further investigation.
Identification and treatment of androgen deficiency may be particularly relevant to the treatment of men with TBI. Basic research studies suggest that aromatization of testosterone to estradiol is critical to the neuroprotective effects of testosterone on astroglia after acute brain injury.
32,
33 At the cellular level, estradiol has been shown to have neurotrophic effects.
34 In embryonic hippocampal cells, pretreatment with estrogen before injury improved cell survival.
32 Rats given an aromatase inhibitor by infusion in the cerebral ventricle experienced neuronal loss in the hippocampus to a greater degree than control rats, and additional studies looking at an aromatase knockout mouse confirmed these neuroprotective effects.
33 Others have shown that estrogen blocks secretion of inflammatory mediators, such as inducible NO and prostaglandin E2 and matrix metalloproteinase-9 and complement C3 receptor after liposaccaride-induced neuronal injury.
35 If similar neuroprotection can be extended to persons with TBI, this intervention could afford an opportunity to mitigate the effects of injury and/or facilitate recovery following injury.
Androgen replacement also might improve posttraumatic cognitive impairments, and particularly memory disturbances, by direct action on CNS androgen receptors or via action on the estrogen receptor after aromatization to estradiol.
36 –
40 Testosterone (from the testis or adipose tissue) and the weaker adrenal precursors dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are converted into either more potent androgens by 5-α reductase to dihydrotestosterone, (DHT) or into estrogens via aromatization. In epidemiological cross-sectional studies, estradiol and testosterone levels are correlated with cognitive performance in older men and women.
36 –
40 Free testosterone levels have been shown to predict memory performance and cognitive status in elderly men, and cognitive decline in women has been correlated with free estradiol concentration.
38,
39 In addition to effects on cognition, normal levels of sex steroids may be required for the maintenance of other neurobehavioral functions, and particularly motivation. For example, in chronic schizophrenics, low estradiol levels correlated with lower levels of cognitive performance and increased apathy and anhedonia.
41 If sex steroids afford similar benefits among persons with TBI, their use in this context would be a novel and potentially productive contribution to their postinjury rehabilitation.
Androgens also exert anabolic effects, thereby improving muscle mass and lean body mass.
42 In seven hypogonadal men, treatment with testosterone injections for 10 weeks led to a significant increase in fat-free mass from 56.0 to 60.9 kg. These men also had increases in cross-sectional areas of the triceps and quadriceps muscle.
42 Testosterone has also been used in other ill populations, such as patients with HIV, to increase muscle mass and lean body mass.
43,
44 Treatment of men with TBI using physiological testosterone administration might improve their ability to participate in and benefit from physical therapy, and thereby improve functional outcome after injury.