Testolactone aqueous suspension (Teslac).
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Animals↗
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Anti-estrogens and aromatase inhibitors: tamoxifen and testolactone.
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Animals↗
Analysis of testolactone and its formulations by high-performance liquid chromatography.
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Chromatography, High Pressure Liquid↗
Musculo-aponeurotic fibromatosis treated by surgery and testolactone.
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Adult↗
Aromatase inhibitors for male infertility.
PURPOSE: Testosterone-to-estradiol ratio levels in infertile men improve during treatment with the aromatase inhibitor, testolactone, and resulting changes in semen parameters. We evaluated the effect of anastrozole, a more selective aromatase inhibitor, on the hormonal and semen profiles of infertile men with abnormal baseline testosterone-to-estradiol ratios. MATERIALS AND METHODS: A total of 140 subfertile men with abnormal testosterone-to-estradiol ratios were treated with 100 to 200 mg. testolactone daily or 1 mg. anastrozole daily. Changes in testosterone, estradiol, testosterone-to-estradiol ratios and semen parameters were evaluated during therapy. The effect of obesity, diagnosis of the Klinefelter syndrome, and presence of varicocele and/or history of varicocele repair on treatment results was studied. RESULTS: Men treated with testolactone had an increase in testosterone-to-estradiol ratios during therapy (mean plus or minus standard error of the mean 5.3 +/- 0.2 versus 12.4 +/- 1.1, p <0.001). This change was confirmed in subgroups of men with the Klinefelter syndrome, a history of varicocele repair and those with varicocele. A total of 12 oligospermic men had semen analysis before and during testolactone treatment with an increase in sperm concentration (5.5 versus 11.2 million sperm per ml., p <0.01), motility (14.7% versus 21.0%, p <0.05), morphology (6.5% versus 12.8%, p = 0.05), and motility index (606.3 versus 1685.2 million motile sperm per ejaculate, respectively, p <0.05) appreciated. During anastrozole treatment, similar changes in the testosterone-to-estradiol ratios were seen (7.2 +/- 0.3 versus 18.1 +/- 1.0, respectively, p <0.001). This improvement of hormonal parameters was noted for all subgroups except those patients with the Klinefelter syndrome. A total of 25 oligospermic men with semen analysis before and during anastrozole treatment had an increase in semen volume (2.9 versus 3.5 ml., p <0.05), sperm concentration (5.5 versus 15.6 million sperm per ml., p <0.001) and motility index (832.8 versus 2930.8 million motile sperm per ejaculate, respectively, p <0.005). These changes were similar to those observed in men treated with testolactone. No significant difference in serum testosterone levels during treatment with testolactone and anastrozole was observed. However, the anastrozole treatment group did have a statistically better improvement of serum estradiol concentration and testosterone-to-estradiol ratios (p <0.001). CONCLUSIONS: Men who are infertile with a low serum testosterone-to-estradiol ratio can be treated with an aromatase inhibitor. With treatment, an increase in testosterone-to-estradiol ratio occurred in association with increased semen parameters. Anastrozole and testolactone have similar effects on hormonal profiles and semen analysis. Anastrazole appears to be at least as effective as testolactone for treating men with abnormal testosterone-to-estradiol ratios, except for the subset with the Klinefelter syndrome, who appeared to be more effectively treated with testolactone.
Anastrozole↗
The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity.
Stanozolol, an oral 17 alpha-alkylated androgen, increases hepatic triglyceride lipase activity (HTGLA) and decreases high-density lipoprotein cholesterol (HDL-C) levels, whereas intramuscular testosterone has comparatively little effect. In the present study, we tested the hypothesis that aromatization of androgen to estrogen blunts the lipid and lipase effects of exogenous testosterone. Fourteen male weightlifters received testosterone enanthate (200 mg/wk intramuscularly), the aromatase inhibitor testolactone (250 mg four times per day), or both drugs together in a randomized cross-over design. Serum testosterone level increased during all three drug treatments, whereas estradiol level increased only with testosterone alone (+47%, P < .05), demonstrating that testolactone effectively inhibited testosterone aromatization. Testosterone decreased HDL-C(-16%, P < .05), HDL2-C(-23%, NS), and apoprotein (apo) A-I (-12%, P < .05) levels, effects that were consistently but not significantly greater with simultaneous testosterone and testolactone administration (HDL-C, -20%; HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast, both testosterone regimens decreased HDL3-C levels by 13% (P < .05 for both). HTGLA increased 21% during testosterone treatment and 38% during combined testosterone and testolactone treatment (P < .01 for both). Lipoprotein lipase activity (LPLA) increased only during combined testosterone and testolactone treatment (+31%, P < .01), suggesting that estrogen production may counteract the effects of testosterone on LPLA. Testolactone alone had little effect on any lipid, lipoprotein, apoprotein, or lipase concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Flutamide decreases cortisol clearance in patients with congenital adrenal hyperplasia.
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is characterized by a defect in cortisol and aldosterone secretion and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenal androgen secretion. Satisfactory adrenocortical suppression often requires supraphysiological doses of hydrocortisone, which may produce an unacceptable degree of hypercortisolism. A new four-drug treatment regimen of flutamide, testolactone, reduced hydrocortisone dose, and 9alpha-fludrocortisone has been shown to achieve normal growth and development after 2 yr of therapy and may, therefore, represent a potential alternative approach to the treatment of children with classic congenital adrenal hyperplasia. We investigated the effect of flutamide and testolactone, and flutamide alone, on cortisol clearance by performing clearance studies twice in 13 children (6 males and 7 females; age range, 7.0-14.5 yr) with classic 21-hydroxylase deficiency. All studies were conducted at least 3 months after institution of the four-drug treatment regimen. In eight patients (group 1), the first cortisol clearance study was performed on the four-drug regimen, and the second study was performed after a 48-h washout period off flutamide and testolactone. In five patients (group 2), the first study was conducted 1 wk after discontinuation of testolactone and while patients were receiving flutamide, hydrocortisone and 9alpha-fludrocortisone, and the second study was performed after a 48-h washout period off flutamide. Oral hydrocortisone was held on the day of the clearance studies, and all patients received a continuous infusion of hydrocortisone (0.6 mg/m(2).h) from 1800 h to 0200 h, with cortisol concentrations measured once hourly. In addition, an in vitro study was conducted to exclude the possibility of an analytical interference of flutamide, 2-hydroxyflutamide, and testolactone with the serum cortisol immunoassay. Total body cortisol clearance was significantly lower during treatment with the four-drug regimen than during treatment with hydrocortisone and 9alpha-fludrocortisone (153.5 +/- 26.8 vs.355.4 +/- 65.8 ml/min; P = 0.001). Similar results were obtained comparing flutamide, hydrocortisone, and 9alpha-fludrocortisone therapy to hydrocortisone and 9alpha-fludrocortisone therapy (155.8 +/- 26.5 vs. 281.8 +/- 96.2 ml/min; P = 0.037). The in vitro study indicated that an interference with the serum cortisol immunoassay was unlikely. These findings indicate that the addition of flutamide and testolactone to the treatment regimen of hydrocortisone and 9alpha-fludrocortisone decreases cortisol clearance in patients with classic 21-hydroxylase deficiency, and this effect seems to be due to flutamide. Glucocorticoid replacement doses should be reduced when flutamide is added to the treatment regimen of patients receiving hydrocortisone.
Adrenal Hyperplasia, Congenital↗
Use of aromatase inhibitors in precocious puberty.
During puberty, estrogen causes breast maturation and growth of the uterine lining in girls, and accelerates linear growth and bone maturation in both boys and girls. Decreasing the biosynthesis of estrogen can attenuate these processes. In 12 girls with the McCune-Albright syndrome (MAS), in which precocious puberty is due to production of estrogen from ovarian cysts, testolactone (40 mg/kg per day) decreased the volume of ovarian cysts, the frequency of menses, and the rates of growth and bone maturation, for periods of 1-4 years. In a 6-month pilot study of 12 children (eight boys; four girls) with congenital adrenal hyperplasia, testolactone, in combination with an antiandrogen (flutamide), a mineralocorticoid (fludrocortisone acetate, Florinef), and a reduced glucocorticoid dose, improved the control of growth and bone maturation compared with conventional therapy. In a 6-year study of 10 boys with familial male precocious puberty, testolactone, in combination with an antiandrogen (spironolactone), decreased rates of growth and bone maturation, and increased predicted adult height. All patients who developed evidence for gonadotropin-dependent puberty were also treated with a GnRH analog. Testolactone had no important adverse effects in any group of patients, although the need for a four-times-daily dosing schedule made compliance difficult for many families. We conclude that suppressing of estrogen with testolactone was effective therapy, and that more potent and specific inhibitors of aromatase could further improve the treatment of these disorders.
Adrenal Hyperplasia, Congenital↗
Evidence of a treatable endocrinopathy in infertile men.
PURPOSE: We establish whether a subset of infertile men have decreased serum testosterone-to-estradiol ratios and whether this condition can be corrected with an oral aromatase inhibitor. MATERIALS AND METHODS: The serum testosterone-to-estradiol ratios of 63 men with severe male factor infertility or hypergonadotropic hypogonadism (mean follicle-stimulating hormone 21.2 +/- 1.8) were compared with those of an age matched, fertile, control reference group. Of the 63 men 43 were azoospermic with biopsy proved severe male infertility and 20 were oligospermic. The men with the lowest ratios (less than 20th percentile) were treated with 50 to 100 mg of the aromatase inhibitor testolactone orally twice daily. Testosterone-to-estradiol ratios and semen analyses were evaluated during testolactone therapy. RESULTS: Men with severe male infertility had significantly lower testosterone (328 versus 543 ng/dl, p <0.01) and higher estradiol (58.4 versus 43.5 ng/l, p = 0.01) than fertile control reference subjects, resulting in a decreased testosterone-to-estradiol ratio (x10(-1) = 6.9 +/- 0.6 versus 14.5 +/- 1.2, respectively, p <0.01). Of the 45 men treated with testolactone a correction of these abnormalities was seen and ratios (x10(-1)) increased into the normal range (5.0 +/- 0.3 to 12.7 +/- 1.2, p <0.01). Semen analyses were considered evaluable only in men with sperm in the ejaculate before aromatase inhibitor treatment. Semen analyses before and during testolactone treatment revealed significant increases in sperm concentration (16.1 to 28.9 million sperm per ml, p = 0.03) and motility (27.1% to 45.3%, p <0.01) in 12 oligospermic men. CONCLUSIONS: We identified an endocrinopathy in men with severe male factor infertility that is characterized by a decreased serum testosterone-to-estradiol ratio. This ratio can be corrected by aromatase inhibition, resulting in a significant improvement in semen parameters in oligospermic patients.
Endocrine System Diseases↗
Aromatase inhibitors in precocious puberty: rationale and experience to date.
Aromatase inhibitors have been used in the treatment of selective forms of precocious puberty since the mid-1980s. The primary aim of therapy is attenuation of the effects of estrogen on growth, skeletal maturation, and secondary sexual development. The first-generation agent, testolactone, has been demonstrated to be tolerable and effective in the treatment of familial male precocious puberty, while mixed results with testolactone have been achieved in girls with McCune-Albright syndrome. A favorable outcome with the use of testolactone in conjunction with conventional therapy in children with congenital adrenal hyperplasia has also been suggested. Although a few anecdotal reports of the use of newer generation aromatase inhibitors in precocious puberty exist, the extreme rarity of the relevant disorders remains a limiting factor in clinical investigation. In this review, the pathophysiology, presentation, and treatment of precocious puberty are described. Particular attention is devoted to the specific disorders in which aromatase inhibitors have been utilized, which are forms of peripheral (gonadotropin-independent) precocious puberty. The impact of untreated precocious puberty on growth and adult stature is discussed, and the actions of estrogen in the human skeleton are summarized. Finally, a detailed description of the existing literature pertaining to aromatase inhibitors in the pediatric population is provided. Emerging potential new indications are discussed. In conclusion, aromatase inhibitors, particularly testolactone, have a proven track record in the treatment of a few forms of precocious puberty. Continued exploration with new generation aromatase inhibitors in these disorders is ongoing. The wider application of aromatase inhibitors for the purposes of delaying skeletal maturation and increasing adult height in several conditions leading to short stature is currently a subject of intense investigation.
Aromatase Inhibitors↗
Metabolism of androgens in human benign prostatic hyperplasia: aromatase and its inhibition.
As an extension of our studies on androgen metabolism in epithelium and stroma of human benign prostatic hyperplasia (BPH) tissue our attempts to demonstrate the presence of aromatase are described. Additionally, the question is raised whether the aromatase inhibitor 17 alpha-oxa-D-homoandrosta-1.4-diene-3.17-dione (testolactone) might also act by inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSDH). In vitro metabolism and inhibition were analyzed by TLC. The main results were: (1) Two aromatase assays (estrone formation and tritium release) were tested with placenta microsomes. Identical results were obtained (Km = 43 +/- 7 nmol/l n = 5; Vmax = 100 resulted in recovery of the aromatase activity added. (3) In BPH tissue alone, formation of estrone from androstenedione could not be detected (less than 7 x 10(-17) mol/min per mg protein, n = 8). (4) 4-Hydroxyandrostenedione inhibited placental aromatase (Ki = 37 nmol/l) distinctly better than 17 beta-HSDH from human BPH (Ki = 18 mumol/l), whereas the Ki values for testolactone (3.7 and 29 mumol/l, respectively) were more similar. It is concluded that aromatization of androgens is not an important pathway in BPH tissue. An alternative mode of action of testolactone by inhibition of 17 beta-HSDH is discussed.
17-Hydroxysteroid Dehydrogenases↗
An in vitro method to determine the selective inhibition of estrogen biosynthesis by aromatase inhibitors.
Potency and selectivity of aromatase inhibition are parameters which ultimately influence the therapeutic efficacy of aromatase inhibitors. This report describes an in vitro model which allows an assessment of the selectivity with which aromatase inhibitors inhibit estrogen biosynthesis. Estrogen production was stimulated by incubating adult female hamster ovarian tissue with ovine LH. The production rates of estrogens (E), testosterone (T) and progesterone (P) were determined using radioimmunoassays to measure the amount of these steroids released into the incubation medium over a 4-hour incubation period. The selectivity of aromatase inhibition was assessed by determining the IC50S with which each inhibitor inhibited the production of E (end product), T (immediate precursor of E) and P (early precursor of E). Selectivity was studied for each of the 4 aromatase inhibitors, CGS 16949A (a new non-steroidal compound), 4-OH-androstenedione, aminoglutethimide and testolactone. CGS 16949A was the most potent of the four, followed by 4-OH-androstenedione, aminoglutethimide and testolactone. As far as selectivity was concerned, both CGS 16949A and 4-OH-androstenedione selectively inhibited aromatase judging from the IC50s for E and P production (CGS 16949A: IC50 for E & P = 0.03 & 160 microM, resp.; 4-OH-androstenedione: IC50 for E & P = 0.88 & greater than or equal to 330 microM, resp.). Aminoglutethimide was the least selective inhibitor of aromatase (IC50 for E & P = 13 & 60 microM, resp.). For testolactone, the least potent of the four (IC50 for E = 130 microM), no conclusive data were obtained concerning the selectivity of aromatase inhibition. Thus a simple, effective and reproducible method is described for assessing the selectivity with which aromatase inhibitors inhibit aromatase.
Aminoglutethimide↗
The effect of supraphysiologic doses of testosterone on fasting total homocysteine levels in normal men.
Elevated total homocysteine (tHcy) levels are associated with increased risk for atherosclerotic cardiovascular disease. tHcy levels are higher in men than in women, and estrogen replacement therapy may reduce tHcy levels in postmenopausal women. The effect of androgenic hormones on tHcy levels in men has not been examined. The present study determined the effect of supraphysiologic doses of testosterone, with or without its aromatization to estradiol, on fasting tHcy levels in 14 normal male weightlifters aged 19-42 years. Subjects received testosterone-enanthate (200 mg/week intramuscularly), the aromatase inhibitor, testolactone (1 g/day orally), or both drugs together in a crossover design. Each treatment lasted 3 weeks and each treatment was separated by a 4-week washout. Both testosterone regimens increased serum testosterone levels, whereas estradiol increased only during testosterone alone. Mean tHcy levels were not significantly altered when testosterone was given alone or together with testolactone. Testolactone did not significantly influence tHcy levels. We conclude that short-term, high-dose testosterone administration does not affect fasting tHcy levels in normal men.
Adult↗
Use of aromatase inhibitors to increase final height.
During puberty in both sexes, the mechanism involved in epiphyseal fusion is mediated by the action of estrogen through a cascade of events including proliferation, differentiation, and apoptosis of chondrocytes. The enzyme P450 aromatase catalyzes the aromatization of C19 androgens (androstenedione and testosterone) to C18 estrogens (estrone and estradiol). Inhibition of estrogen action by aromatase inhibitors (AIs) appears to decelerate the process of growth plate fusion, and thus AIs may be used therapeutically to increase adult height. The clinical experience with AIs in the pediatric setting is limited to testolactone, fadrozole, letrozole, and anastrozole. Testolactone, a nonselective steroidal AI, has been used successfully as an adjunct to antiandrogen and gonadotropin-releasing hormone analogue (GnRHa), therapy for children with familial male-limited precocious puberty (FMPP) and congenital adrenal hyperplasia (CAH), and with some success in girls with McCune-Albright syndrome. The limitations of testolactone include its relatively low potency and the need for frequent dosing. Results of a randomized placebo-controlled trial in boys with delayed puberty treated with letrozole, a selective nonsteroidal AI, found that boys treated with letrozole + testosterone experienced delayed bone maturation and good growth response and achieved an increase in predicted adult height. In this study, only minor differences in bone density were seen between the placebo and letrozole treatment groups, both of which were receiving concomitant testosterone therapy. No adverse effects on testis size or inhibin B concentration were noted. The therapeutic value of AIs in growth promotion now remains to be substantiated in future controlled clinical trials.
Aromatase Inhibitors↗
Tamoxifen treatment of progressive precocious puberty in a patient with McCune-Albright syndrome.
Treatment of progressive precocious puberty in patients with McCune-Albright syndrome (MAS) has traditionally been with aromatase inhibitors, such as testolactone. However, the use of these agents has been characterized by problems with both efficacy and compliance. We report a case of MAS in which tamoxifen proved to be a successful alternative in the treatment of progressive precocious puberty. An African-American female presented with MAS at 2-5/12 years. Frequent menses, skeletal maturation and growth acceleration prompted initiation of therapy with testolactone at 22 mg/kg/d. Over the next 13 months, the patient's puberty advanced unchecked, despite progressive increases in the dose of testolactone. At age 4 years, medication was discontinued due to treatment failure. At 4-6/12 years, bone age was 10 years, predicted adult height was 137 cm, and monthly bleeding continued. Tamoxifen was then begun on an experimental basis. In response, the patient experienced immediate cessation of menses, and had an abrupt decrease in the rates of pubertal progression and linear growth. This patient has now been maintained on tamoxifen for over three years with no apparent adverse effects. GnRH analogue therapy was begun when the onset of central precocious puberty was noted. Predicted adult height has improved to 154 cm and growth velocity and skeletal maturation remain stable. Our results suggest that tamoxifen may have a valuable role in the treatment of precocious puberty in patients with MAS and may lead to superior results compared with those achieved with aromatase inhibitors.
Body Height↗
Modulation of prolactin responses to gonadotropin releasing hormone by acute testosterone infusions in normal women.
The administration of gonadotropin releasing hormone (GnRH) has been shown to stimulate prolactin (PRL), suggesting its role as an inducer of PRL release. This study addresses whether testosterone may modulate the release of PRL with GnRH during the early follicular phase when this stimulatory effect is not usually observed. Chromatographically pure testosterone was administered intravenously to 13 women in 2 doses (100 micrograms and 1000 micrograms) over a 6-hour period. GnRH (100 micrograms) was administered as a bolus 2 hours before and 4 hours after beginning testosterone. In addition, 3 women received testosterone twice, 3 months apart, with testolactone pretreatment on the second occasion. Serum testosterone rose in all patients and achieved maximum steady-state levels by 120 minutes. Serum estradiol (E2) was increased in subjects receiving the larger dose of testosterone but was unchanged with the lower dose and with the addition of testolactone. PRL did not increase significantly after GnRH before testosterone infusion but showed a significant increase after testosterone as well as after testosterone with testolactone. This effect did not appear to be dose-related.
Adolescent↗
Effective aromatase inhibition by anastrozole in a patient with gonadotropin-independent precocious puberty in McCune-Albright syndrome.
Testolactone is used to treat conditions with excessive estrogen synthesis, e.g. gonadotropin-independent precocious puberty in McCune-Albright syndrome (MAS). Unfortunately, daily treatment with testolactone requires 3 to 4 doses (10-20 tablets) and even at these doses it is sometimes ineffective. We treated a patient with MAS (café-au-lait spots; thelarche at age 2- 6/12 yr; menarche at 5- 5/12 yr; accelerated bone age [BA 10 yr]) with the highly selective aromatase inhibitor anastrozole (1 mg once per day). Tamoxifen 1 mg/kg per day was added for 1 year but was discontinued when an ovarian cyst developed with markedly elevated estradiol levels. Estradiol levels returned to normal after resuming anastrozole-only treatment and accelerated BA progressed only 6 months during 2 1/2 years of treatment. The potent estrogen suppressive action and simple dosage regimen of anastrozole suggest it may be advantageous compared to other aromatase inhibitors such as testolactone or anti-estrogens.
Anastrozole↗
Comparative studies of aromatase inhibitors in cultured human breast cancer cells.
The presence of aromatase activity, estrogen receptors, and estrogenic responsiveness in MCF-7 human breast cancer cells has allowed this cell line to be used as a unique in vitro system for investigating the biological activities of potentially therapeutic aromatase inhibitors. We now report the results of studies which have examined the cytotoxicity, antiaromatase, and intrinsic estrogenic activities of aminoglutethimide, 1,2-dehydrotestolactone (testolactone), dihydrotestosterone, 4-hydroxy-4-androstene-3,17-dione, and 10-propargylestr-4-ene-3,17-dione within MCF-7 monolayer cultures. Cell viability was determined by trypan blue exclusion, and aromatase activity was assessed by quantifying the amounts of [3H]estradiol formed from [3H]testosterone. Estrogenic activity was assessed by examining the ability of each inhibitor to increase cytoplasmic progesterone receptor and deplete cytoplasmic estrogen receptor concentrations in these cells during a 5-day incubation period. Cytoplasmic progesterone and estrogen receptors were measured by the single-saturating-dose technique using [17 alpha-methyl-3H]-17 alpha, 21-dimethyl-19-norpregna-4,9-diene-3,20-dione and [3H]estradiol as the labeled ligands for each assay, respectively. The results showed that all of these compounds were noncytotoxic aromatase inhibitors in MCF-7 cells but that these agents demonstrated marked differences in inhibitory potency (10-propargylestr-4-ene-3,17-dione greater than 4-hydroxy-4-androstene-3,17-dione much greater than dihydrotestosterone much greater than testolactone = aminoglutethimide). The incubation of cells with 4-hydroxy-4-androstene-3,17-dione resulted in cytoplasmic progesterone and estrogen receptor responses that were similar in magnitude to those observed in other cultures incubated with equimolar concentrations of estradiol. None of the other four agents demonstrated estrogenic activity in this system. However, we have previously observed that dihydrotestosterone has substantial antiestrogenic action in this system. Taken together, these results indicate that some aromatase inhibitors may influence the hormonal regulation of human breast cancer cells by more than one mechanism.
Aminoglutethimide↗