Gonadal Steroids in Critical Illness

Crit Care Clin 22 (2006) 87 – 103

Gonadal Steroids in Critical Illness Jeffrey I. Mechanick, MDa,T, David M. Nierman, MD, MMMb a

Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, 1192 Park Avenue, New York, NY 10128, USA b Medical Intensive Care Unit, Mount Sinai School of Medicine, Box 1232, One Gustave L. Levy Place, New York, NY 10029, USA

For nearly a decade, clinical studies have demonstrated sexually dimorphic responses to critical illness; some favor a potentially protective effect of being male [1,2] and others a potentially protective effect of being female [3–6]. Other studies have failed to detect a gender difference [7]. Croce and coworkers [8] studied 12,756 (73%) men and 4833 (27%) women for 52 months after trauma and failed to demonstrate any outcome difference by gender or age. George and colleagues [9] found that with blunt trauma, men had a statistically significant higher mortality than women b 50 years old, but not with women 50 years old. The opposite pattern was seen with penetrating trauma: men had a survival advantage compared with women 50 years old, but not with women b 50 years old [9]. Recent attempts to model critical illness have invoked paradigms of nonlinear complexity [10] and allostatic regulation [11,12], and gender differences have not been well elucidated. The complex interplay and coupling among biological oscillators (organ systems) by the immune-neuroendocrine axis (INA) depends, in part, on gonadal steroids (Fig. 1). Generally speaking, estrogens have been associated with improved immune and cardiovascular function, whereas androgens are associated with suppression of these functions [13–15]. In the early, acute phases of critical illness, anterior pituitary function is activated by the INA and a host of other allostatic pathways, which protect vital homeostatic regulation [11,16]. However, if the patient fails to recover quickly

T Corresponding author. E-mail address: [email protected] (J.I. Mechanick). 0749-0704/06/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2005.08.005 criticalcare.theclinics.com

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Fig. 1. Allostasis model of critical illness, which highlights the role of gonadal steroids. Components of the immune-neuroendocrine axis (cytokines) and the limbic system impinge onto the hypothalamicpituitary axis. Steroid production occurs in gonadal and adrenal tissue. Gonadal steroids exert feedback onto the INA. Gonadal steroids also modulate activity of various organ systems: cardiovascular, intestinal, hepatic, and immune. Allostasis is achieved through the complex interactions of these different regulatory axes to preserve the integrity of vital homeostatic pathways. DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; HPA, hypothalamic-pituitary-adrenal; HPG, hypothalamic-pituitary-gonadal; HPT, hypothalamic-pituitary-thyroidal; IGF-1, insulin-like growth factor-1.

and critical illness is prolonged, a state of allostatic overload and chronic critical illness (CCI) ensues. This is characterized by protein hypercatabolism, preservation of adipose tissue, fatty infiltration of vital organs, and downregulation of the hypothalamic-pituitary-gonadal (HPG) axis [16]. Although end-organ hormonal therapies, such as androgens and estrogens, seem logical, their use has not been convincingly beneficial, possibly because of exacerbation of allostatic overload. Alternatively, it has been postulated that more proximate interventions directed toward brain-INA pathways in CCI, such as using hypothalamic releasing factors, might be more advantageous [16]. Gonadal steroids are primarily synthesized in the testes or ovaries, though the adrenal gland, brain, liver, pancreas, adipose tissue, integument and immune cells also express gonadal steroidogenic enzymes [17,18]. In postmenopausal women, nearly 100% of active gonadal steroids are synthesized locally in peripheral target tissues from inactive steroid precursors [17]. These substrates are derived from the adrenals and gonads but more so from the adrenals [17]. The active steroid

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GONADAL PRODUCTION ESTRONE ESTRADIOL TESTOSTERONE

ADRENAL PRODUCTION DHEA(S)

3β -HSD1

17β -HSD3,5

∆4-androstenedione

testosterone

DHT

AROMATASE

estrone

17β-estradiol 17β-HSD1,7

ER

AR

INTRACRINE EFFECTS

GENOME

CYTOKINES AND OTHER HUMORAL FACTORS Fig. 2. Peripheral intracrine steroidogenic pathways affecting androgens and estrogens. Gonadal and adrenal steroids are converted within target cells into active steroids that interact with estrogen and androgen receptors. AR, androgen receptor; ER, estrogen receptor; 3b-HSD1, 3b-hydroxysteroid dehydrogenase type-1; 17b-HSD3, 5 and 1, 717b-hydroxysteroid dehydrogenase types 3 and 5, and 1 and 7.

products act within the target cell, without being released into the extracellular space or general circulation and thus exert an ‘‘intracrine’’ effect (Fig. 2) [17]. In adult males, approximately 50% of active gonadal steroids are synthesized locally [17]. With septic shock in males, peripheral aromatization of adrenal or testicular androgens is potentiated resulting in increased 17b-estradiol (E2) and decreased testosterone levels [19]. Hence, the peripheral metabolism of gonadal steroids may play an important regulatory step in the physiologic response to stress.

Mechanisms of hypothalamic-pituitary-gonadal axis dysfunction in critical illness In men, critical illness is associated with hypotestosteronemia caused by direct effects of cytokines on Leydig cell function [1], increased peripheral aromatiza-

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tion of androgens [2], and downregulation of the HPG axis [3]. Acute critical illness is associated with mildly low testosterone levels, which become more severely reduced with chronic critical illness [20]. In a retrospective study of men who had CCI, 96% had decreased age-adjusted bioavailable testosterone levels [21]. The severity of hypotestosteronemia is directly related to mortality among critically ill men [22]. Low dehydroepiandrosterone (DHEA) sulfate (DHEAS) and androstenedione levels were also found in men with CCI [20]. Moreover, gonadotropin levels were higher in patients who were discharged from the intensive care unit, which indicates that neuroendocrine suppression may portend a worse prognosis [22]. Suppression of gonadotropin secretion lags behind hypotestosteronemia with CCI [23]. Dopamine [24], opiates [25], and interleukin-1 [26] (IL-1) may act in concert to preserve luteinizing hormone (LH) pulse frequency while suppressing pulse amplitude. Consistent with the allostasis model of critical illness in which proximate, multipronged interventions are theoretically better than a single drug, androgen therapy in CCI has failed to demonstrate conclusive clinical benefit [27]. LH-releasing hormone (LHRH) pulsatile therapy alone demonstrated minimal benefit [28], but LHRH pulses plus continuous growth-hormone-releasing peptide-2 and thyrotropin-releasing hormone infusions improved target organ responses and anabolic effects [29]. In critically ill women, the ‘‘hypothalamic amenorrhea of stress’’ results from complex INA events (Fig. 3). Central to this model is the bidirectional crosstalk between the hypothalamic-pituitary-adrenal (HPA) axis, and corticotrophinreleasing hormone (CRH) in particular, and the HPG axis. Stress-induced eutopic (hypothalamic) and ectopic (immune cell and reproductive tissue) corticotrophinreleasing factor (CRF) production inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion while glucocorticoids inhibit pituitary LH [30] (by way of the type-2 corticoid receptor [31]), ovarian estrogen secretion, and ovarian progesterone secretion [32]. Estrogen also influences neuronal allostatic pathways that involve the HPG axis, HPA axis, and cortical behavior centers [33]. In rats, E2 sensitizes CRH-induced suppression of LH pulses [34]. This effect localizes to the locus coeruleus, which is innervated by CRH neurons—that act through the CRF-R2 receptor [35]—and inhibits LH pulsatility by way of GABAergic neurotransmission [36]. E2 also rapidly uncouples m-opioid and g-aminobutyric acid (GABA)B receptors from G-protein gated inwardly rectifying K+ channels in proopiomelanocortin and dopamine neurons [33]. In addition, E2 enhances a1-adrenergic inhibition of small conductance, Ca2 +-activated K+ channels in preoptic GABAergic neurons [33]. Furthermore, E2 modulates hippocampal CA1 pyramidal cells (a site of neuronal plasticity potentially mediating allostatic responses to chronic immobilization stress in rats [37]) and GnRH neurons in the amygdala and arcuate nucleus, by way of effects on G-protein signaling [33]. E2-modulation of hypothalamic neurotransmission was found to involve the following critical proteins: gec-1, PI3-kinase p55g, rab11aGTPase, synaptobrevin-2, synaptogyrin, taxilin, Ca2 +-dependent activator protein for secretion, and pleckstrin homology-domain

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Fig. 3. Complex INA mechanisms producing the hypothalamic amenorrhea of stress. 17b-estradiol potentiates the HPG axis suppression by the limbic system (emotion/behavior, cognitive stress), HPA axis (noncognitive stress), and cytokines (inflammation, noncognitive stress). CR-2, type-2 corticoid receptor; CRH-R2, type-2 CRH receptor; DA, dopamine; NE, norepinephrine; POMC, proopiomelanocortin; TYR-OH, tyrosine hydroxylase.

containing proteins [38]. The genes encoding these proteins represent potential therapeutic targets in critically ill patients.

Gonadal steroid action in target tissues Steroid hormone receptors, including the androgen receptor (AR) and estrogen receptor (ERa and ERb), are part of the nuclear receptor superfamily of transcription factors. These gonadal steroid receptors form ligand-induced homodimers and transactivate target genes by binding specific inverted repeat DNA response elements. Their function depends on (1) ligand and non-ligand activation, (2) complexing with chaperones like heat-shock proteins 70 (Hsp70) and 90 (Hsp90), (3) translocation to the nucleus, and (4) subnuclear coregulator interaction and compartmentalization (Fig. 4) [39]. Functional polymorphisms in the AR/ER have been associated with normal and pathological aging phenomena, such as various malignancies, coronary heart disease, osteoporosis, and depression, and could represent a potential prognostic marker in critical illness [40].

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Fig. 4. Complex subcellular trafficking of the androgen and estrogen receptor. Gonadal steroid ligands interact with membrane bound receptors (AR/ER) which dimerize, complex with various regulators and transcription factors and then exert genomic effects by way of transactivation of androgen (ARE) or estrogen (ERE) response elements on DNA. Alternatively, AR/ER may complex with other factors involved with signal transduction, in the absence of gonadal steroid ligands, and exert nongenomic effects. EGF, epidermal growth factor; GR, glucocorticoid receptor; KGF, keratinocyte growth factor; PKA, protein kinase A.

In addition to steroid ligand activators, such as androgens and estrogens, nonsteroidal ligand activators of the AR/ER include protein kinase A activators, cytokines, such as interleukin-6 (IL-6), and certain polypeptides, such as insulinlike growth factor 1, keratinocyte growth factor, and epidermal growth factor [41,42]. These activators crosstalk with ligand-independent activators, and induce nongenomic androgenic effects, such as activation of the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3V-kinase (PI3K)/Akt, and Janus kinases /signal transducers and activators of transcription (JAK/STAT) intracellular signaling networks [41]. In rats, androgen-, but not estrogen-, mediated p38 MAPK activation may be responsible for the sexually dimorphic immune response following trauma-hemorrhage [43]. Coregulators exert control over AR/ER transcriptional activity by way of ligand selectivity, recruitment of histone deacetylases and chromatin-modifying complexes, and scaffolding for other transcriptional factors [44,45]. Exploitation of coregulator activity by selective ER modulators (SERMs), selective tissue estrogenic activity regulators (STEARs), selective AR modulators, and other selective receptor modulators present a unique opportunity for drug development for critically ill patients [46,47].

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Another facet of the complex function of gonadal steroid receptors relates to the intersection between the cellular inflammatory response mediated by nuclear factor kB (NFkB) and the cellular anti-inflammatory response mediated by steroid hormone receptors. The AR heterodimerizes with the glucocorticoid receptor [48], interacts with and represses activator protein-1 (AP-1) [49], and also participates in mutual transcriptional antagonism with the p65 (RelA) polypeptide component of the NFkB heterodimer [50]. The implication here is that first, androgens may modulate glucocorticoid-mediated anti-inflammatory events, second, normal androgen signaling may be attenuated with inflammation and third, inflammatory pathways may be attenuated in androgen responsive tissue [51]. Similar reciprocal interactions have been determined for the ER. NFkB p65 represses ERa-mediated transactivation [50] and ERa activation inhibits NFkB p65 nuclear translocation [52]. Thus, the protective effects of estrogen on immune and cardiovascular function in the critically ill patient may, at least in part, be caused by inhibition of NFkB-mediated events.

Androgen therapy in critical illness Testosterone therapy in critically ill men Clinically, the intuitive advantage of androgen therapy as an anabolic agent in critical illness, supported by improvement in certain biochemical and laboratory markers, must be weighed against preclinical and clinical evidence demonstrating harm. In female mice treated with 5a-dihydrotestosterone (DHT), there was significant depression in macrophage IL-1 and IL-6 production [53]. In a followup study, castration was associated with improved wound healing in male mice [54]. Use of the AR antagonist, flutamide, was associated with improved vascular endothelial function and regional hemodynamics following trauma-hemorrhage in male rats [55]. Vasodilating effects by flutamide were observed in isolated aortic rings from male rats, with a lesser effect observed in those from female rats [56]. This suggests direct, gender-specific mechanisms of flutamide on blood flow. On the other hand, studies with male rabbits have demonstrated a beneficial effect of androgens on atherosclerosis, but these effects appear to be because of intracrine effects caused by local aromatization in the vessel wall [57,58]. Gender-specific androgenic effects are further supported by male-selective AR expression and AR-mediated stimulation of vascular cell adhesion molecule-1 in endothelial cells [59]. Intestinal endothelial function also exhibits gender-specific differences in rats [60]. In murine macrophages, testosterone inhibits inducible nitric oxide synthase (iNOS), which could increase platelet aggregation and thrombosis risk [61]. Testosterone also induces human vascular endothelial cell apoptosis by way of AR agonism but not aromatization [62]. The diverse effects of testosterone in clinical studies are dependent on dose, gender, age, disease state, and other factors. In a small clinical study of six severely burned male patients, testosterone enanthate treatment, 200 mg intra-

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muscular per week for 2 weeks, was associated with improved amino acid balance, which was not affected by an intravenous amino acid infusion [63]. Within the physiological range, testosterone impairs flow-mediated vascular dilatation (FMD), though intracrine (aromatization and 5a-reduction) and nongenomic androgen effects remain unclear [64]. However, with supraphysiological dosing, testosterone may increase FMD [65], though concomitant intense exercise, as with bodybuilders, can produce the opposite effect [66]. Additionally, in healthy men N60 years, androgen replacement therapy did not have significant effects on vascular reactivity [67]. Thus, the routine use of testosterone therapy in critically ill men is not supported by the clinical literature. Nevertheless, potential uses in select critically ill men would include situations where catabolic rates are very high and parenteral testosterone therapy might render improved nitrogen retention, as long as cardiovascular and fluid retention risks are minimal. Oral testosterone therapy should not be used in the critically ill because of the higher risk of hepatic injury. Testosterone therapy in women Data describing the effects of testosterone therapy in females are limited. In female-to-male transsexuals treated with long-term testosterone, brachial artery diameter was increased with a reduced nitrate response, but FMD was unchanged compared with age-matched female controls [68]. In estrogen-treated postmenopausal women, testosterone therapy that produced supraphysiological blood levels increased FMD slightly [69]. As more women with female androgen insufficiency or sarcopenia are treated with androgens, extrapolation of relevant information to the critically ill woman might be possible. At present, there are insufficient controlled clinical data to support the routine use of androgens in critically ill women. Benefits of parenteral testosterone therapy on nitrogen balance might outweigh potential cardiovascular and fluid retention risks in women who have resolved critical illness but have severe body cell mass depletion. Dehydroepiandrosterone therapy in critical illness DHEA and DHEAS represent the most abundant adrenal androgens in the circulation. They exert androgenic action by way of conversion into active androgens and estrogens in peripheral tissue. They do not directly exert negative feedback on the HPA axis and regulation of their synthesis involves factors other than corticotropin. The maximal response of DHEA to corticotropin stimulation normally declines with age. Moreover, during periods of stress, cytokines such as tumor necrosis factor (TNF)-a, IL-1b, and transforming growth factor (TGF)-b reduce expression of cytochrome p450c17, availability of cofactors (cytochrome b5 and nicotinamide-adenine dinucleotide phosphate oxidoreductase) and DHEA sulfotransferase, thus decreasing DHEA and DHEAS production [70–73].

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Teleologically, this has the benefit of diverting limited steroid precursors away from androgen synthesis and toward glucocorticoid synthesis. DHEA [74–76], and its metabolite androstenediol [77], which has estrogenlike activity, have both been shown to improve cardiovascular and hepatocellular function and lower cytokine production in rats. DHEA also increases long-chain fatty acid oxidation and antioxidant activity by way of peroxisome proliferators activated receptor a activation [78]. By decreasing the availability of reactive oxygen species (ROS), DHEA decreases NFkB [79] and AP-1 [80] nuclear translocation and DNA-binding, thus opposing inflammatory cellular cascades. DHEA also prevents glucocorticoid-induced lymphocyte and thymocyte apoptosis [81]. DHEA improves insulin sensitivity in animal studies by way of increased phosphatidylinositol 3-kinase and protein kinase C activities [82]. In early sepsis, DHEAS levels are low [83]. Nonsurvivors have lower DHEAS levels compared with survivors and levels decline further with late sepsis in survivors and nonsurvivors despite preservation of cortisol secretion [83,84]. In contrast, the nonsulfated androgen precursor, DHEA, increases with early sepsis but, with late sepsis, normalizes only in survivors [85]. Is there a role for DHEA or DHEAS therapy in critically ill patients? Not yet. Even though there are attractive preclinical data indicating that DHEA(S) therapy may oppose the catabolic effects of glucocorticoids and the pro-inflammatory effects of cytokines, there are insufficient controlled clinical data to support its routine use [86].

Oxandrolone in critical illness Oxandrolone is an oral anabolic, minimally androgenic steroid that has been used with dietary protein and energy supplementation to improve body cell mass and muscle strength in patients with chronic malnutrition. Based on many clinical studies, including those involving recovering burn patients [87], the Food and Drug Administration has approved oxandrolone for use as an adjunctive therapy to promote weight gain after extensive surgery or severe trauma [88]. Nevertheless, in one prospective, randomized, double-blind, placebo-controlled trial (PRCT) of 62 patients who required enteral nutrition during the acute phase after traumatic injury, oxandrolone therapy, 10 mg orally twice a day for 28 days, was not associated with any nutritional or clinical outcome benefit [89]. Recently, Bulgar and coworkers [90] conducted a PRCT of 41 surgical trauma patients who required more than 7 days of mechanical ventilation and received 21–23 kcal/kg/d and 1.2–1.5 gm protein/kg/d. Those randomized to receive oxandrolone during their ICU stay had a more prolonged course of mechanical ventilation. This detrimental effect of oxandrolone was thought by the authors to be caused by increased collagen deposition and fibrosis in the later stages of acute respiratory distress syndrome. Oxandrolone is contraindicated with concurrent prostate or male breast cancer, or hypercalcemia. Oxandrolone is also associated with increased international normalized ratio and prothrombin time in patients who are

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treated with warfarin [91]. Thus, oxandrolone is not recommended for use in patients with acute or chronic critical illness.

Estrogen therapy in critical illness Contrary to the generalized detrimental effects of androgens, the current preclinical and clinical data point toward benefit and potential therapeutic utility of estrogen therapy in critically ill patients. In the rat, E2 administration is associated with significant improvements in cardiovascular and hepatocellular function after experimental trauma-hemorrhage [92,93]. Specifically, E2 increases intestinal bloodflow and protects splanchnic organs by way of increased nitric oxide production, cytokine modulation, decreased vasoconstrictor synthesis (like endothelin–1) [94], decreased neutrophil adhesion, and decreased ROS formation [95,96]. These mechanisms can theoretically improve gut mucosal function and decrease bacterial translocation. When E2 is chronically administered to male-to-female transsexuals [97], older men castrated because of advanced prostate cancer [98], or to young healthy men [99], vascular reactivity is increased. The constitutively expressed endothelial isoform of nitric oxide synthase is activated by E2 via genomic and nongenomic effects of ERa [100]. The latter is mediated by steroid receptor fastaction complexes in endothelial cell caveolae that activate downstream MAPK and Akt signaling pathways [100]. E2 also reduces iNOS expression and thus limits excessive nitric oxide production, ischemia- or endotoxemia-mediated inflammation, and lung injury [101]. Another mechanism of E2-mediated protection from organ injury with traumahemorrhage is by way of induction of the inducible isoform hemeoxygenase-1, also known as heat shock protein–32, mRNA expression [102]. This protein catabolizes heme into carbon monoxide, biliverdin and bilirubin, which may decrease hypoperfusion or reperfusion injury by way of vasodilation and immunomodulatory/antioxidant (biliverdin, bilirubin) effects [102]. The activity of another heat shock protein (HSP72) has been associated with post-ischemic recovery of left ventricular function [103]. Here, the effects of E2 are detrimental because they inhibit HSP72 gene expression [104]. However, E2 also has salutary effects on myocardial function, which may be associated with increased IL-6 levels [105]. Furthermore, girls have higher perioperative levels of the anti-inflammatory, macrophage deactivating cytokine IL-10 than boys following cardiac surgery [106]. IL-10 also modulates the HPA axis [107]. Progesterone may also have direct effects on the heart; its administration to ovariectomized rats improves cardiovascular responses to trauma and hemorrhagic shock [108]. Unlike male mice, the ability of female mice to maintain competent immune function with trauma-hemorrhage is because of estrogen and ER [109]. In a two-hit animal model of trauma-sepsis, E2 treatment suppressed proinflammatory cytokine production and improved monocyte-macrophage function

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[110]. Splenic T-lymphocytes not only elaborate IL-2 and IL-6, but also express ER as well as aromatase and 17b-hydroxysteroid dehydrogenase (HSD), which form E2 [111]. Splenic T-lymphocytes also express 3bHSD, which converts DHEA into D4-androstenedioe, and 5a-reductase, which converts testosterone into DHT [112]. Intracrine actions of splenic T-lymphocyte-derived E2, acting through ERb-binding to specific promoter response elements, modulate splenic T-lymphocyte-derived cytokine production [111]. Thus, sustained local production of E2 improves immune function after trauma. Therapeutically, the SERM idoxifene exerts beneficial effects in an ischemiareperfusion animal model of shock by improving endothelial and immune function [113]. In septic male mice, the aromatase inhibitor, 4-hydroxyandrostenedione, increases ER expression, improves the immune response, and decreases mortality [114]. Also in male rodent splenic T-lymphocytes, 5a-reductase, and 17bHSH type IV activities are increased when compared with females, which leads to increased androgenic action and immunosuppression [112]. In female rodent splenic T-lymphocytes, aromatase activity, but not gene expression, is increased compared with males [112]. Interestingly, 3bHSD activity was similar between male and female rodents which indicates that the salutary effects of DHEA are caused by its conversion into D4-androstenedione [112]. Indeed, gender dimorphism in activities of immune cell enzymes that mediate the intracrine effects of gonadal steroids may contribute to the gender differences in survival with critical illness. EXPIRE

ACUTE CRITICAL ILLNESS

EXPIRE

CHRONIC CRITICAL ILLNESS

RECOVER

DECREASED NITROGEN RETENTION HYPOGONADAL MALE ?FEMALE NO CONTRAINDICATIONS NOT FUTILE

CONSIDER: TESTOSTERONE ENANTHATE 100 MG IM Q WEEK OXANDROLONE 2.5 – 10 MG ENTERALLY BID

RECOVER

OPTIMAL NITROGEN RETENTION EUGONADAL MALE FEMALE

NO ANABOLIC THERAPY

Fig. 5. Proposed use of gonadal steroids in critical illness.

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Summary The implementation of gonadal steroid therapy in the management of critically ill patients is not routine, though emerging clinical evidence may eventually change this. If critical illness can be conceptualized as an acute phase, a chronic phase, and a recovery phase, then a rational and evidence-based framework for the use of gonadal steroids can be constructed (Fig. 5). In the acute and chronic phases, preclinical experimental data and clinical observational data argue against the use of androgens or anabolic steroid analogs. Investigational protocols may eventually demonstrate a beneficial role for estrogens (most likely with SERMs or STEARs) in these phases, but their use, however attractive, should be dissuaded at present. On the other hand, during the recovery phase, in which anabolism is critical for survival and INA setpoints have normalized, administration of anabolic agents, such as testosterone or oxandrolone, may be useful. Although this approach has not been supported by clinical evidence, a rational approach would be to limit these anabolic agents to those patients who have (1) no or minimal signs of active inflammation, (2) a reasonable expection for recovery with acceptable quality of life (subjective assessment), (3) biochemical hypotestosteronemia, (4) biochemical evidence of decreased nitrogen retention (increased urinary nitrogen excretion), and (5) no contraindications (prostate cancer, male breast cancer, elevated PSA requiring further evaluation).

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