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PubMed1989

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.

Aggression↗

PubMed1998

Testolactone-associated high androgen levels, a pharmacologic effect or a laboratory artifact?

Testolactone, an aromatase inhibitor, blocks conversion of androgens to estrogens. In familial male precocious puberty, slowing of pubertal progression and growth velocity occurs with testolactone and spironolactone. Girls with McCune-Albright syndrome, given testolactone, respond similarly. A 2-yr-old female (case 1) on testolactone for non-McCune-Albright gonadotropin independent precocious puberty had marked elevations of androstenedione (18 ng/mL, normal: 0.2-3.1) and testosterone (3.6 ng/mL, normal < 0.2) but no virilization. Investigations were undertaken to determine whether elevations in testosterone and androstenedione were caused by interference in these RIAs. After a single oral dose of testolactone (5 mg/kg in case 1; 4 mg/kg in case 2, a 3-yr-old boy with familial male precocious puberty; 10 mg/kg in a healthy postmenopausal control), serum testosterone and androstenedione were measured serially by RIA for 24 h. Androstenedione went from normal to a mean peak of 45.4 ng/mL at 1-2 h and returned to baseline by 24 h. Testosterone, undetectable at baseline (case 1 and control) or 1.8 ng/mL (case 2) rose to a mean peak of 6.9 ng/mL and returned to baseline by 24 h. Testolactone, in serial dilutions, cross-reacted in the testosterone assay. Testolactone significantly interferes in these serum RIAs, making their use unreliable in follow-up of patients treated with testolactone.

Androstenedione↗

PubMedDate not supplied

Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover.

The hypothesis that increased estradiol production may be the cause of impaired spermatogenesis in infertile men with idiopathic oligozoospermia was tested by administering the aromatase inhibitor, testolactone, and by assessing its effects on sperm output and fertility. Our study was a randomized, placebo-controlled double-blind crossover trial. Subjects (n = 25) with infertility due to unexplained oligozoospermia were given testolactone (2 g/day) or placebo for 8 months followed by crossover to the other treatment for an additional 8 months. Total estradiol and testosterone levels during testolactone exposure did not change from basal and placebo values. However, sex hormone-binding globulin binding capacity consistently decreased (30%, p less than 0.01) and free testosterone levels increased (36%, p less than 0.01). Free estradiol values increased but not significantly. Additionally, LH and FSH serum levels increased by 15% and 20%, respectively (p less than 0.05), and 17 alpha-hydroxyprogesterone values increased by 90% (p less than 0.05) during drug administration. Sperm output and semen quality remained unchanged during either testolactone or placebo treatment, and no pregnancies occurred during the 16-month study. These data suggest that chronic administration of testolactone at this dose fails to maintain aromatase inhibition despite depression of 17,20-desmolase activity with elevated 17 alpha-hydroxyprogesterone and depressed SHBG binding capacity with elevation of free testosterone. Testolactone is not efficacious in the treatment of idiopathic oligozoospermic infertility.

Adult↗

PubMed1983

Quantitation of testolactone and 4,5-dihydrotestolactone in plasma and urine using high-performance liquid chromatography.

A rapid, sensitive, and selective assay is described for the quantitation of both testolactone and its recently identified metabolite, 4,5-dihydrotestolactone, in plasma and urine using high-performance liquid chromatography. The procedure includes a methylene chloride extraction prior to chromatography and quantitation using peak height ratios (ultraviolet absorbance detection, 242 nm) of testolactone and 4,5-dihydrotestolactone to the internal standard, testosterone. A sensitivity of 20 ng/ml for both testolactone and 4,5-dihydrotestolactone is easily achieved using only 0.5 ml of sample. Mean recoveries for testolactone and its metabolite are 95.0% and 81.8%, respectively, and the mean coefficient of variation of the procedure is 3.5% for the drug and 7.1% for the metabolite. This method is currently being used to study the pharmacokinetics of testolactone and 4,5-dihydrotestolactone in male patients. A steady-state plasma concentration versus time profile from a representative patient is included.

Chromatography, High Pressure Liquid↗

PubMed1986

Treatment of precocious puberty in the McCune-Albright syndrome with the aromatase inhibitor testolactone.

The McCune-Albright syndrome is characterized by café au lait spots, fibrous dysplasia of bones, and sexual precocity. Girls with precocious puberty due to this syndrome have episodic increases in serum estrogen levels together with the formation of large ovarian cysts. The serum gonadotropin levels are typically suppressed, and the precocious puberty has not responded to treatment with long-acting analogues of luteinizing hormone-releasing hormone (LHRH). Encouraged by our initial success in a pilot study of one patient, we have now treated five girls with the McCune-Albright syndrome with the aromatase inhibitor testolactone, which blocks the synthesis of estrogens. Testolactone decreased the levels of circulating estradiol (P less than 0.05) and the ovarian volume (P less than 0.05), and there was a return to pretreatment levels after testolactone was stopped. During treatment, the peak responses of luteinizing hormone and follicle-stimulating hormone to stimulation by LHRH rose above suppressed pretreatment levels--significantly above pretreatment levels for follicle-stimulating hormone (P less than 0.02)--and then returned to pretreatment levels after testolactone was discontinued. Growth rates fell in three patients during treatment but could not be assessed in the other two because of bone deformities. The mean rate of bone maturation decreased and menses stopped in three of the four girls who were menstruating regularly. We conclude that testolactone is an effective treatment of precocious puberty in the McCune-Albright syndrome.

Aromatase Inhibitors↗

PubMed1985

Aromatase inhibition by delta 1-testolactone does not relieve the gonadotropin-induced late steroidogenic block in normal men.

Aromatase inhibition by delta 1-testolactone [(17 oxa-D-homo 1,4 androstanediene-3,17 dione) 500 mg twice daily for 10 days] in nine normal men lowered circulating estradiol (E2) levels by about 25%, enhanced the secretion of FSH, 17-hydroxyprogesterone (17-OHP), and to a lesser degree testosterone (T), but did not affect serum LH levels. Despite E2 lowering there was greater accumulation of 17-OHP than of T after 7 days of treatment, suggesting 17,20-lyase inhibition. Unexpectedly, administration of delta 1-testolactone almost halved the T response to hCG (Pregnyl, 1500 IU), but did not affect the 17-OHP response. Thus, E2 lowering by testolactone aggravated the hCG-induced 17,20-lyase block present before testolactone administration. Although the present data might suggest that estrogens do not play a role in the genesis of the hCG-induced late steroidogenic block, the results suggest that testolactone per se, in addition to its reported antiestrogenic action, inhibits 17,20 lyase.

17-alpha-Hydroxyprogesterone↗

PubMed1993

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.

Age Determination by Skeleton↗

PubMed1996

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.

17-alpha-Hydroxyprogesterone↗

PubMed1999

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.

Adolescent↗

PubMed1987

[Long-term therapy of oligozoospermia with the aromatase inhibitor testolactone].

In a pilot study, 13 subfertile men with idiopathic normogonadotropic oligozoospermia were treated by the aromatase inhibitor testolactone for a period of 6 months. During the administration of 1 g testolactone daily, a significant increase in the sperm count, total sperm output and the absolute number of motile and progressively motile spermatozoa was observed 3 and 6 months after the initiation of therapy, but there were no significant changes in the percentage of motile and progressively motile spermatozoa, sperm morphology or ejaculate volume. The serum hormone levels of testosterone, LH, FSH and oestradiol were assessed before and during testolactone administration; there was a significant increase of testosterone and FSH after 1 and 3 months of treatment, but LH levels increased only during the 1st month of therapy. The oestradiol level showed a significant decrease, while the increase in testosterone/oestradiol ratio was more than twice as expected. The pregnancy rate was 17%. No severe side-effects were reported during testolactone therapy. The results of the study support the hypothesis that oestrogens are involved in the regulation of human spermatogenesis.

Adult↗

PubMed1982

Rapid endocrine effects of tamoxifen and testolactone in prostatic carcinoma patients.

The short-term (6-day) endocrine effects of tamoxifen and testolactone were investigated in men with prostatic carcinoma. Tamoxifen treatment (20 mg/day) did not affect the gonadotropin levels, but it temporarily increased prolactin, induced sex hormone-binding globulin production, and suppressed peripheral serum progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, and 5 alpha-dihydrotestosterone concentrations. These changes were attributed to the estrogenic properties of tamoxifen, since no changes in peripheral serum estradiol concentrations were observed. Testolactone (1000 mg/day) decreased peripheral estradiol concentrations by 50% and increased the concentrations of the neutral steroids measured. The increases in serum FSH and LH were very small. This study corroborates the early estrogen-like action of tamoxifen, and the experiment with testolactone further suggests that endogenous estradiol has physiological functions in man, regulating gonadotropin and androgen production.

Aged↗

PubMed2005

Sertoli cell tumor causing prepubertal gynecomastia in a boy with peutz-jeghers syndrome: the outcome of 1-year treatment with the aromatase inhibitor testolactone.

Peutz-Jeghers syndrome (PJS) is a rare disorder characterized by benign intestinal hamartomatous polyps and mucocutaneous pigmentation, and with an increased risk for intestinal and extra-intestinal neoplasms. Sertoli cell tumors in boys with PJS have been increasingly recognized as a cause of prepubertal gynecomastia. However, an association between nephrocalcinosis and PJS has not been reported before. We report on a 7.25-year-old boy with PJS, bilateral gynecomastia, Sertoli cell tumor and nephrocalcinosis, and present the outcome of 1-year treatment with the aromatase inhibitor testolactone. The patient presented with bilateral breast and testis enlargement, and mucocutaneous pigmentation. Testicular ultrasound revealed parenchymal multiple microcalcifications. Histopathological examination was consistent with Sertoli cell tumors. Nephrocalcinosis due to idiopathic renal hypercalciuria was also detected. The aromatase inhibitor testolactone was begun in an attempt to prevent acceleration in skeletal maturation. One-year treatment with testolactone reduced the breast base diameter from 7 to 3 cm, and bone age advanced 1.2 years during this period. Our case demonstrates that waiting for the effect of aromatase inhibitors on gynecomastia before making a decision for mastectomy may be a reasonable option. We also consider that the association between PJS and nephrocalcinosis may be a coincidence.

Aromatase Inhibitors↗

PubMed2000

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.

Adrenal Hyperplasia, Congenital↗

PubMed1985

Testolactone treatment of precocious puberty in McCune-Albright syndrome.

Current medical and surgical therapies of precocious puberty in McCune-Albright syndrome are often unsatisfactory. We used an aromatase inhibitor, testolactone, to treat precocious puberty in a girl with McCune-Albright syndrome. This child was unresponsive to 28 weeks of treatment with the long-acting agonist of LRH, D-trp6-pro9-NEt-LRH. During testolactone therapy, menses ceased, bone age advancement and height velocity diminished, and plasma oestradiol levels were suppressed. Serum gonadotrophin levels remained in the prepubertal range. Testolactone may be an effective therapy of precocious puberty in girls with McCune-Albright syndrome.

Androstenedione↗

PubMed1987

Short-term effects of testolactone compared to other treatment modalities on longitudinal growth and ovarian activity in a girl with McCune-Albright syndrome.

In a 6 1/2-month-old girl with McCune-Albright syndrome, gonadotropin-independent isosexual precocity and recurrent ovarian cysts, the short-term effects of surgical therapy, cyproterone acetate (120 mg/m2/d), combined medroxyprogesterone acetate (10 mg/d), and spironolactone (50-75 mg/d) treatment, and testolactone (40 mg/kg/d) were evaluated sequentially. No significant reduction of cyst frequency was achieved with any of the medical treatments. The rate of bone maturation (delta BA/delta CA) was increased and the height standard deviation score (SDS) for bone age as a potential indicator of final height was decreased with surgical treatment alone and combined medroxyprogesterone acetate and spironolactone. Both parameters normalized with cyproterone acetate and testolactone. Height velocity SDS, however, was higher with testolactone (0.97 vs. 0.45).

Androgen Antagonists↗

PubMed1980

5-Fluorouracil, methyl-CCNU, and radiotherapy with or without testolactone for localized adenocarcinoma of the exocrine pancreas: a Southwest Oncology Group Study.

Since August 1975, 69 patients with localized pancreatic carcinoma (extent of tumor confined to a 15 cm x 15 cm radiotherapy port) have received either Regimen A, comprising radiotherapy (6,000 rad) to the tumor area with simultaneous combination chemotherapy utilizing methyl-CCNU, 125 mg/m2 orally, every six weeks, and 5-fluorouracil, 400 mg/m2 intravenously, weekly; or Regimen B, comprising Regimen A with the addition of testolactone, 200 mg, orally every day. Thirty-eight patients on Regimen A and 30 patients on Regimen B are currently evaluable. Median survival, which appeared not to be affected by the addition of testolactone, was 38 weeks for those on Regimen A and 30 weeks for those on Regimen B (P = 0.677). The median survival time for all patients was 38 weeks. Good performance status did correlate with improved survival vs. poor performance status (46 weeks vs. 20 weeks, P = .008). Fifteen patients have survived for more than 52 weeks, with the longest survival time being 160 + weeks, and in 3 cases all therapy has been discontinued. However, most patients experienced moderate to severe hematologic toxic reactions. There was one treatment-related death and significant gastrointestinal bleeding developed in 6. Because of the toxic reactions of this program, it should not be considered in favor of similar less aggressive programs.

Adenocarcinoma↗

PubMed1990

Aggressive fibromatosis in the neck. A case treated effectively by testolactone with a long follow-up study.

Extra-abdominal fibromatosis in the neck may occasionally cause serious sequelae when aggressive invasion of the vital structures occurs. However, the principle of wide excision is difficult to apply in some patients because of the important organs surrounding the tumor. We report herein, a woman followed up for 22 years, in whom testolactone showed a definite effect during the course of observation. She first presented, at the age of 52, with a painful tumor in the neck, located behind the right thyroid lobe and fixed to the adjacent structures. Incomplete excision of the tumor was followed by a local recurrence accompanied with recurrent laryngeal nerve palsy and Horner's syndrome on the right side. Prednisolone was administered for 2 1/2 months and external irradiation of 8,000 RAD was given. Enlargement of the recurrent tumor stopped but 2 months later an emergency tracheostomy was required for an airway obstruction. Over the next 3 years, the local findings remained unchanged, but then a painful tumor growth reappeared cephalad which gradually attained a size of 5 cm in diameter, and was fixed to the base. Testolactone 150 to 200 mg was given to the patient daily for 2 months, resulting in marked regression of the tumor. During the last 13 years the patient has been well with the tumor still decreasing in size.

Combined Modality Therapy↗

PubMed1991

Testolactone, sulindac, warfarin, and vitamin K1 for unresectable desmoid tumors.

Ten patients with large inoperable desmoid tumors in various body locations were treated with testolactone. Four tumors (40%) responded with major regressions, i.e., more than 50% reduction in volume. Eight patients received nonsteroid anti-inflammatory drugs (indomethacin, sulindac, or sulindac with warfarin and vitamin K1 [Mephyton]) for periods of 2 to 91 months. There was one major regression, one partial regression, and three instances of tumor growth arrest over periods up to 8 years. Seven patients were treated with nonsteroid anti-inflammatory drugs concurrent with or after testolactone or tamoxifen. There were five major regressions and one partial regression with extensive central necrosis of an enormous intra-abdominal tumor. The last patient has been treated for only 12 months, with no change in tumor volume. It appears that estrogens function as growth factors for desmoid tumors, and that minimization of these effects inhibits tumor growth in some, but not all, cases. In those instances where antiestrogens were not effective as single agents, the tumors usually responded to subsequent nonsteroid anti-inflammatory drug therapy. Withdrawal of estrogen may be followed by inhibition of transcription of genes that support tumor cell proliferation, and sulindac and indomethacin may augment these effects by inhibiting prostaglandin and cyclic AMP synthesis and the activity of protein kinase C. Warfarin may function as a protonophore to acidify the cytoplasm and prevent the alkalinization that is necessary to initiate DNA synthesis and cell cycle progression, again an impairment of the transcription process.

Abdominal Neoplasms↗