Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia.

Treatment outcome in congenital adrenal hyperplasia is often sub-optimal due to hyperandrogenism, treatment-induced hypercortisolism, or both. We previously reported better control of linear growth, weight gain, and bone maturation in a short term cross-over study of a new four-drug treatment regimen containing an antiandrogen (flutamide), an inhibitor of androgen to estrogen conversion (testolactone), reduced hydrocortisone dose, and fludrocortisone, compared to the effects of a control regimen of hydrocortisone and fludrocortisone. Twenty-eight children have completed 2 yr of follow-up in a subsequent long term randomized parallel study comparing these two treatment regimens. During 2 yr of therapy, compared to children receiving hydrocortisone, and fludrocortisone treatment, children receiving flutamide, testolactone, reduced hydrocortisone dose (average of 8.7 +/- 0.6 mg/m2 x day), and fludrocortisone had significantly (P < or = 0.05) higher plasma 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels. Despite elevated androgen levels, children receiving the new treatment regimen had normal linear growth rate (at 2 yr, 0.1 +/- 0.5 SD units), and bone maturation (at 2 yr, 0.7 +/- 0.3 yr bone age/yr chronological age). No significant adverse effects were observed after 2 yr. We conclude that the regimen of flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone provides effective control of congenital adrenal hyperplasia with reduced risk of glucocorticoid excess. A long term study of this new regimen is ongoing.

Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset.

Short term treatment with spironolactone, testolactone, and, after the onset of central puberty, deslorelin can normalize the rate of growth and bone maturation in boys with familial male-limited precocious puberty. To test the hypothesis that this treatment can achieve long term normalization of the growth and development of these children, we examined the growth rate, bone maturation rate (change in bone age/change in chronological age), and predicted adult height of 10 boys who were treated with spironolactone (5.7 mg/kg x day) and testolactone (40 mg/kg x day) for at least 6 yr. Deslorelin (4 microg/kg x day) treatment was initiated 2.6 +/- 1.3 yr after beginning spironolactone and testolactone treatment. The growth rate normalized within 1 yr of starting treatment and remained normal during the next 5 yr of treatment (P < 0.001). The rate of bone maturation normalized during the second year of treatment and remained normal thereafter (P < 0.001). Predicted height increased from 160.7 +/- 14.7 centimeters at baseline to 173.6 +/- 10.1 centimeters after 6 yr of treatment (P < 0.05 during the fourth through the sixth year of treatment compared to baseline). We conclude that long term treatment with spironolactone, testolactone, and, after central puberty, deslorelin normalizes the growth rate and bone maturation and improves the predicted height in boys with familial male-limited precocious puberty. The ultimate effect of this approach on adult height will require further study.

A preliminary study of flutamide, testolactone, and reduced hydrocortisone dose in the treatment of congenital adrenal hyperplasia.

Treatment outcome in congenital adrenal hyperplasia is often suboptimal due to hyperandrogenism, treatment-induced hypercortisolism, or both. As a new approach, we hypothesized that the effects of androgen could be blocked by an antiandrogen (flutamide) and an inhibitor androgen to estrogen conversion (testolactone), thus allowing the hydrocortisone dose to be reduced. We conducted a short term pilot study in 12 children with congenital adrenal hyperplasia in a randomised cross-over open design to determine whether flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone are more effective than hydrocortisone and fludrocortisone treatment in normalizing linear growth, weight gain, and bone maturation. Each regimen was administered for 6 months, with a 3-month washout period, consisting of hydrocortisone and fludrocortisone treatment, between regimens. Compared to hydrocortisone and fludrocortisone treatment, the regimen of flutamide, testolactone, reduced hydrocortisone dose (from 12.9 to 7.9 mg/m2 day), and fludrocortisone produced an increase in plasma 17-hydroxyprogesterone levels (P < 0.05) and a decline in urinary cortisol (P < 0.01), linear growth rate (-0.9 +/- 0.5 vs. 1.4 +/- 0.6 SD U; P = 0.003), weight velocity (-0.80 +/- 4.0 vs 0.6 +/- 0.4 SD U; P = 0.01), and bone maturation (0.6 +/- 0.6 vs. 1.4 +/- 0.9 yr bone age/yr chronological age; P = 0.02). Although no important adverse effects were observed, the known potential for flutamide-induced hepatotoxicity made frequent monitoring essential. We conclude that the regimen of flutamide, testolactone, reduced hydrocortisone does, and fludrocortisone improve the short term control of growth and bone maturation in children with congenital adrenal hyperplasia. Long term studies are required to determine whether this approach can improve these children's growth and development.

First generation aromatase inhibitors--aminoglutethimide and testololactone.

Aminoglutethimide and testololactone may be considered the first generation aromatase inhibitors for the endocrine treatment of breast carcinoma. Initially, both of these agents were designed and used clinically based on different concepts of their mechanisms of action. Only later were they both demonstrated to inhibit aromatase. Curiously, testololactone was earlier and more widely used than aminoglutethimide in treating advanced breast carcinoma. The discovery of the peripheral aromatase inhibition as the proper mechanism of action was delayed for both the agents but was relatively more timely for aminoglutethimide. Paradoxically, the clinical use of testololactone has become already obsolete since its true mechanism of action was discovered. Aminoglutethimide is still the most widely used aromatase inhibitor in treating advanced breast carcinoma. Due to the initial misinterpretation of its mechanism of action, aminoglutethimide was used for a long time at a relative high daily dose, always combined with hydrocortisone. Subsequent phase II and then randomized phase III studies demonstrated an equivalent efficacy using half (500 mg) of the previous conventional daily dose (1000 mg), with hydrocortisone. Very recently, a randomized clinical trial demonstrated that administering this lower dose without hydrocortisone did not significantly decrease the clinical efficacy. By decreasing the dose of aminoglutethimide, the incidence of side effects has been reduced. So, the last paradoxical aspect of the aminoglutethimide story is that this agent seemed initially very toxic but finally, with the new schedules, shows a very low toxicity profile, especially after the first few weeks of treatment.

Long-term testolactone therapy for precocious puberty in girls with the McCune-Albright syndrome.

We used the aromatase inhibitor testolactone (40 mg/kg.day) to treat 12 girls with precocious puberty due to the McCune-Albright syndrome for periods of 0.5-5 yr. In the 7 girls who received testolactone for at least 3 yr, the mean +/- SD serum estradiol level was 618 +/- 268 pmol/L at the start of therapy and fell to 156 +/- 84 pmol/L at 1 yr, 116 +/- 48 pmol/L at 2 yr, and 241 +/- 260 pmol/L at 3 yr (P < 0.05 compared to the start of therapy), with recurrent ovarian cysts at 3 yr in 2 patients. These 7 girls averaged 8 menses/yr before therapy. The average frequency of menses decreased to 2 episodes/yr during the first year of treatment, 3/yr during the second year, and 4/yr during the third year. The mean +/- SD testosterone levels were slightly above the normal prepubertal range (0.51 +/- 0.2 nmol/L) before treatment and did not change significantly during treatment. The mean +/- SD androstenedione levels rose from 1.1 +/- 0.6 nmol/L before treatment to 2.1 +/- 0.1 nmol/L at 2 yr and 2.8 +/- 0.1 nmol/L after 3 yr of treatment (P < 0.05 compared to before treatment) and were consistent with normal adrenarche. The mean predicted adult stature was 143.0 +/- 7.8 cm before treatment and 147.3 +/- 11.5 cm at 3 yr (P = NS). In 3 of 12 girls, all with bone age greater than 12 yr, the gonadotropin responses to LHRH indicated early central precocious puberty after 1-4 yr of treatment. The adverse effects of testolactone were transient abdominal pain, headache, and diarrhea in 3 girls and elevated hepatic enzymes in 1 girl who had abnormal liver function before treatment. Six families acknowledged difficulty in adhering to the daily dosing schedule. We conclude that testolactone can be effective in the treatment of LHRH-independent precocious puberty in girls with McCune-Albright syndrome, but that some patients exhibit an escape from the effects of treatment after 1-3 yr.

Treatment of intra-abdominal and abdominal wall desmoid tumors with drugs that affect the metabolism of cyclic 3',5'-adenosine monophosphate.

A female patient with Gardner's syndrome was treated with delta1-testololactone (200 mg daily) because of growth of a large desmoid tumor in the pelvis and lower abdomen and a tumor in a scar from a previous laparotomy. There was also pain and swelling of the left leg. An immediate effect of the drug therapy was complete relief of pain followed shortly thereafter by disappearance of the edema of the leg. After two months, the numerous sebaceous cysts were less prominent. The gross measurements of the diameter of the pelvic and lower abdominal tumor clearly demonstrated tumor shrinkage following therapy. Small polyps scattered over the rectal mucosa and numerous osteomata were not demonstrably affected. After one year of treatment with delta1-testololactone, a laparotomy for partial small bowel obstruction was necessary. Obstruction was caused by the involvement of small bowel mesentery and the bowel itself in a contracted residuum of dense fibrous tissue. Substitution of theophylline and chlorothiazide for the testololactone in Januray 1974 was followed by further diminution of the measurable abdominal and pelvic desmoids. All of these compounds synergize the action of 3',5'-adenosine monophosphate and at least the latter two may function by inhibiting the action of 3',5'-adenosine monophosphate diesterase.