Louisa Laue

Treatment of Familial Male Precocious Puberty with Spironolactone and Testolactone

Because the pubertal growth spurt in boys appears to be mediated by both androgens and estrogens, we hypothesized that blockade of both androgen action and estrogen synthesis would normalize the growth of boys with familial male precocious puberty. To test this hypothesis, we studied nine boys (age range, 3.3 to 7.7 years) during treatment with an antiandrogen (spironolactone) or an inhibitor of androgen-to-estrogen conversion (testolactone), followed by treatment with both agents. After six months of observation without treatment, the first four boys received spironolactone for six months, followed by spironolactone and testolactone. The next five boys received testolactone for six months, followed by spironolactone and testolactone. Neither spironolactone nor testolactone, given alone, was satisfactory as a treatment for this condition. However, a combination of spironolactone and testolactone, given for at least six months, restored both the growth rate and the rate of bone maturation to normal prepubertal levels and controlled acne, spontaneous erections, and aggressive behavior. The combined therapy was associated with a significantly lower growth rate than testolactone alone (P less than 0.05) and a significantly lower rate of bone maturation than spironolactone alone (P less than 0.05). No important adverse effects were observed during combined treatment. Six of the nine boys continued to receive the combined therapy for an additional 12 months and maintained normal prepubertal rates of growth and bone maturation. The mean predicted height (+/- SEM) increased progressively during the combined treatment although the difference between the pretreatment and post-treatment predictions was not significant (169.5 +/- 2.8 at the end of treatment vs. 166.2 +/- 4.5 cm before treatment; P = 0.29). We conclude that blockade of both androgen action and estrogen synthesis with the combination of spironolactone and testolactone is an effective short-term treatment for familial male precocious puberty. Further study will be required, however, to assess the long-term outcome in boys who receive this treatment.

Glucocorticoid Antagonists and the Role of Glucocorticoids at the Resting and Stress State

Glucocorticoids act on almost all organs and tissues. Their levels are rarely constant, showing both pronounced circadian variations and/or a rise during stressful situations. It is thought that glucocorticoids evoke an adaptation to stress via a variety of mechanisms including mobilization of fuel for metabolism, enhancement of cardiovascular function, and production of euphoria or behavioral activation. Glucocorticoids also suppress the immune system. It has been argued that this effect helps prevent autoimmune activation following “fight or flight” situations that result in trauma and inflammation.

Abnormal Growth Hormone Secretory Dynamics in Children with Familial Hypercholesterolemia

Growth hormone secretory dynamics and plasma somatomedin C concentrations were assessed in four prepubertal patients with defects in the low-density lipoprotein (LDL) receptor pathway before and after 2 months of treatment with mevinolin, an HMG-CoA reductase inhibitor that reduces intracellular cholesterol. Pre- and posttreatment mean 24-hour growth hormone levels and pulse amplitude were similar and tended to be higher than in age-matched prepubertal controls. Pre- and posttreatment somatomedin C levels were also similar and lower than in age-matched prepubertal controls. All patients responded to growth hormone provocative testing with a peak response of greater than 7 ng/ml, independent of treatment status. Growth velocity was not significantly altered in any patient following 2 months of treatment with mevinolin, and was within the normal range for age. Thus, children with defects in the LDL receptor pathway express abnormalities in growth hormone secretion and somatomedin C generation comparable to those seen in other chronic diseases. Treatment with mevinolin has no apparent effect on these biochemical abnormalities, suggesting that it may not have long-term effects on growth. Regardless of mevinolin therapy, children with defects in the LDL receptor pathway may manifest a degree of growth retardation and, hence, growth rate and skeletal maturation should be closely monitored.