Glucocorticoid-induced muscle atrophy: mechanisms and therapeutic strategies.

OBJECTIVE: To analyze the mechanisms of action of glucocorticoids in causing muscle atrophy and to examine the therapeutic effect of testosterone as well as other treatment modalities in counteracting this adverse effect. METHODS: We reviewed selected publications to analyze the mechanisms of glucocorticoid-induced muscle atrophy in animal models and in humans. The pathophysiologic features of glucocorticoid-induced hypogonadism and the possible relationship to the muscle atrophy in patients receiving glucocorticoids were assessed. The beneficial effects of testosterone on the muscles of hypogonadal and eugonadal men were also reviewed. Other measures such as exercise and glutamine and their possible therapeutic and preventive effects were examined in the context of hypercortisolemia. RESULTS: Glucocorticoids induce rapid muscle breakdown and proximal muscle atrophy. The mechanism of glucocorticoid-induced muscle atrophy relies on the degradation of the myosin heavy chain (catabolic effect), the most important contractile protein in muscle, associated with a decrease of its synthesis (antianabolic effect). One of the contributing factors in the development of muscle atrophy is hypogonadism that is induced by long-term glucocorticoid use. Androgen possesses anabolic and anticatabolic effects in vitro and in animal models. Androgens can be used safely to counteract the catabolic effects of cortisol. Other measures such as exercise, glutamine, and alanyl-glutamine are promising in animal models of glucocorticoid-induced muscle atrophy. CONCLUSION: This study suggests the possible efficacy of testosterone and glutamine on glucocorticoid-induced muscle atrophy. Testosterone and glutamine are natural biologic products with safe pharmacologic profiles, and their bioefficacy merits active research in humans.

Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection.

OBJECTIVE: To chronicle pituitary-testicular axis dysfunction and its clinicopathologic features in homosexual men. METHODS: Between 1984 and 1992, 84 homosexual men underwent longitudinal follow-up for 4 years. At entry into the study, 28 were seronegative and 56 were seropositive for human immunodeficiency virus (HIV). Although 40 subjects remained asymptomatic (nonprogressors), 16 had progression to acquired immunodeficiency syndrome (AIDS). Of those 16 patients with progression, 8 had AIDS within 2 years (early progressors) and 8 demonstrated AIDS within 4 years after enrollment (late progressors), and all died. The testes of five patients were examined at autopsy. The control group had similar follow-up. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and bioavailable testosterone (bio-T) were measured in stored sera collected at 2-year intervals. The last hormonal measurement was between 3 and 24 months before autopsy. Comparison was made between autopsied and nonautopsied patients with AIDS as well as between HIV nonprogressors and control seronegative men. The correlation between pathologic findings and hormonal status was examined by regression analysis. RESULTS: At baseline, testosterone, bio-T, LH, and FSH were not significantly different among all patients and subjects. During the study period, testosterone, bio-T, and serum gonadotropin levels remained unchanged in the seronegative homosexual men. In nonprogressors, serum FSH and LH concentrations remained unchanged, whereas testosterone and bio-T levels decreased significantly during this 4-year period. After progression to AIDS (in both groups of progressors), the serum FSH and LH levels were higher and the serum testosterone and bio-T were lower in comparison with values in the seronegative men. In late progressors to AIDS, FSH and LH increased, whereas serum testosterone and bio-T decreased significantly from baseline. All five patients with AIDS on whom autopsy was done had boundary wall thickening of the seminiferous tubules and decreased spermatogenesis. No significant differences were found in serum testosterone, bio-T, and LH between those in whom autopsy was or was not done; however, FSH was significantly higher in the autopsied cases. The serum testosterone and bio-T levels were negatively correlated with the interstitial inflammation. A significant correlation was also observed between change of bio-T and weight loss. CONCLUSION: We conclude that dysfunction of the pituitary-gonadal axis is common in HIV-infected men. All patients in whom autopsy was done because of AIDS-related diseases had been hypogonadal 3 to 24 months before death. Decreased spermatogenesis, subacute interstitial inflammation, or both were seen at autopsy of patients with AIDS. Pathologic damage to the testes during AIDS was associated with decreased testosterone and bio-T as well as increased serum gonadotropin levels. In a substantial proportion of men with progression to AIDS, compensated hypogonadism (normal serum testosterone and increased serum LH levels) preceded the development of low serum testosterone level.

The genetic basis of male infertility.

Defective spermatogenesis can be the end result of a multitude of causes, such as systemic disease, malnutrition, endocrinologic disorder, genetic defects, anatomic obstruction of the passage of spermatozoa, infections, and environmental toxins. A genetic basis of infertility is thought to exist in a majority of infertile men currently classified as having idiopathic infertility. Despite advances in molecular technology, the pathophysiology of spermatogenic failure in a majority of infertile men remains unknown. Although a large number of genes and loci in experimental animals are associated with sterility, the human homologues of most of these genes have not been cloned yet. Infertility is a heterogeneous syndrome in men; therefore, it is likely that a multitude of genes and loci will be implicated in different infertility subsets.

Pseudohypohyperparathyroidism: a case study of differential resistance to parathyroid hormone.

OBJECTIVE: To present a rare case of a combination of hyperparathyroidism and hypoparathyroidism in a 30-year-old woman. METHODS: We review the laboratory, radiographic, and pathologic findings in a healthy-appearing woman who sustained a patellar fracture after a simple fall at home. RESULTS: Our patient had features of hypoparathyroidism--that is, tetanic crises and hypocalcemia--and also hyperparathyroidism--fracture of the patella, multiple bone cysts, and confirmed osteitis fibrosa cystica on bone biopsy specimens. These features were associated with a high serum level of intact parathyroid hormone (PTH) and parathyroid hyperplasia. A lack of response of nephrogenic cyclic adenosine monophosphate (cAMP) to PTH stimulation was observed along with subnormal serum cAMP responses. In contrast, urine phosphate excretion increased after administration of PTH. CONCLUSION: These results demonstrate a state of renal PTH resistance in a patient with osteitis fibrosa cystica.

Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study.

The effect of testosterone (T) replacement on changes in mood was studied for 60 days in 51 hypogonadal men. All patients were withdrawn from their prior T replacement for at least 6 weeks before enrollment. Of these patients, 18 received T enanthate 200 mg im every 20 days, 16 received sublingual T cyclodextrin (SLT) at a dose of 2.5 mg three times daily, and 17 received SLT at a dose of 5.0 mg three times daily. The total treatment period was 60 days. The patients were asked to respond to a questionnaire on 7 consecutive days before the start of treatment and on 7 consecutive days before their visits to the clinic on days 21, 41, and 60 of treatment. The following mood parameters were assessed using a 7-point Likert rating scale: angry, alert, irritable, full of pep (energy), sad/blue, tired, friendly, nervous, and well/good. When compared with the baseline period, T replacement led to significant decreases in anger (P = 0.0045), irritability (P = 0.0009), sadness (P = 0.0033), tiredness (P = 0.0035), and nervousness (P = 0.0291), and significant improvement in energy level (P = 0.0020), friendliness (P = 0.0072), and sense of well-being (P = 0.024) in all subjects as a group. Analyses of the area under the curve (AUC) of baseline serum T levels before T replacement showed significant positive correlations between serum T (AUC) and friendliness (r = 0.29, P < 0.05) and sense of well-being (r = 0.27, P < 0.05), and significant negative correlations with nervousness (r = -0.27, P < 0.05), irritability (r = -0.29, P < 0.05) and tiredness (r = -0.28, P < 0.05). Similar correlations were found between serum dihydrotestosterone (DHT) and some of the mood parameters. After T replacement in the hypogonadal men, these correlations between AUC of serum T levels and the positive and negative mood scores disappeared. These results were corroborated in a subsequent study in which 30 hypogonadal men were supplemented with SLT 5 mg three times daily for 6 months. The patients were less nervous (P = 0.0025) and more alert (P = 0.0004), friendly (P = 0.042), and energetic (P = 0.0001) during the 6-month treatment period compared with baseline. We conclude that T replacement therapy in hypogonadal men improved their positive mood parameters, such as energy, well/good feelings, and friendliness and decreased negative mood parameters including anger, nervousness, and irritability, and direct correlations between serum T and DHT with mood scores were only observed in the baseline period when serum androgen levels were below the normal range. The latter observation suggests that once a minimally adequate serum T/DHT level was achieved by T replacement therapy, further increases in serum T/DHT levels did not further contribute to the improvement in mood variables.

Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate--a clinical research center study.

We studied and compared the pharmacokinetics and bioefficacy of two doses of sublingual testosterone cyclodextrin (SLT; 2.5 and 5.0 mg, administered three times per day) with testosterone enanthate (TE; 200 mg) given once every 20 days by im injections over a 60-day study period in 63 hypogonadal men. After SLT administration, serum testosterone (T) levels peaked at 20 min and then fell, reaching baseline levels by 360 min. The calculated half-lives were 60.3 +/- 7.5 and 68.8 +/- 5.0 min after a single dose of 2.5 and 5.0 mg SLT, respectively. The mean area under curve (AUC) of serum T was computed over 20-day periods for the 3 treatment groups. The mean net AUC of serum T after TE administration was about 4- and 2-fold higher than that in the 2.5 and 5 mg groups over the last 20 days. Serum estradiol and dihydrotestosterone followed the same pattern as serum T. Serum estradiol to T ratios decreased after T replacement in all 3 groups, whereas serum dihydrotestosterone to T ratios were not significantly changed by T treatment. Suppression of serum LH and FSH levels was more marked in the patients treated with TE than in those given SLT. Similarly, serum sex hormone-binding globulin levels showed significant decreases with androgen replacement only in the TE and SLT 5.0 mg range groups. There were no significant adverse effects based on comprehensive physical examinations, urea, electrolytes, and renal or liver function tests. Hematocrit levels increased in the TE-treated group, but remained slightly lower than baseline levels in the SLT groups. Serum high density lipoprotein cholesterol showed a small, but significant, decrease with time of treatment in all groups. Despite the differences in the AUC of serum T levels achieved by different androgen replacement therapies, all patients showed significant improvements in sexual motivation and performance, with no significant difference between the treatment groups. We conclude that SLT may be a useful addition to the currently available injectable and transdermal delivery systems for treatment of hypogonadal men. Because of the ease of administration, rapid reversibility of effects, and lower AUC of serum T levels achieved compared to those of TE injections, SLT may be especially suitable for treatment of boys with delayed puberty and older men with androgen deficiency.

Alterations in natural anticoagulant levels during allogeneic bone marrow transplantation: a prospective study in 27 patients.

The natural anticoagulants (antithrombin III, protein C, protein S), plasminogen and tissue plasminogen activator antigen (t-PA ag), were measured in 27 consecutive patients following allogeneic BMT. Thrombosis and veno-occlusive disease were not seen in this study. Changes in the levels of these proteins occurred mainly during acute GVHD. There were 14 patients who had no acute GVHD (group I) and 13 patients who had acute GVHD (group II). No changes in antithrombin III (ATIII), protein C, protein S and t-PA levels were found in group II before the appearance of acute GVHD when compared with group I. However, we noted a significant rise in protein S (p = 0.01), antithrombin III (p = 0.001) and t-PA ag (p = 0.0004) levels during acute GVHD. In contrast, protein C levels decreased early in GVHD (p = 0.005), and then increased progressively over the course of a month post-GVHD. No changes in plasminogen levels were observed. These results might reflect activation of and/or damage to endothelial cells during GVHD.

Antithrombin III activity is not related to plasma homocysteine concentrations.

Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients and are responsible for their early deaths. Reduced levels of antithrombin III activity in homocystinuric patients have recently been reported. So, high plasma L-homocysteine concentration could play a role in the low antithrombin III activity level. In the present study, we have studied the relationship between total plasma homocysteine and inhibitors of blood coagulation levels in 16 patients with malignancies who received bone marrow grafts. There were no correlations between homocysteine values and inhibitors of blood coagulation levels. So, while the defect in amino acid transsulfuration that is responsible for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsible for this effect.

Use of phenytoin in healing of war and non-war wounds. A pilot study of 25 cases.

Nineteen patients with war-related missile wounds and six with refractory civilian ulcers were treated with topical phenytoin sodium powder daily for up to 4 weeks. The mean healing time was 2 weeks for missile wounds, compared to historical controls requiring 6-8 weeks. Healing time was 4 weeks for civilian ulcers that had been unresponsive to any treatment over the previous 5 months. Twenty-two patients had complete healing, three required skin grafts. Wider use of this safe, inexpensive, readily available and easy-to-use agent is suggested because of its positive effect on wound healing and rapid pain relief.