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Journal of Endocrinological... Nov 1988
Review
Topics: Animals; Antineoplastic Agents; Aromatase Inhibitors; Breast Diseases; Chemical Phenomena; Chemistry; Estrogen Antagonists; Female; Gynecomastia; Hormones; Humans; Hyperplasia; Infertility; Male; Pregnancy; Prostate; Puberty, Delayed; Puberty, Precocious; Tamoxifen; Testolactone
PubMed: 3068293
DOI: 10.1007/BF03350940 -
The Journal of Clinical Endocrinology... Mar 1998Testolactone, an aromatase inhibitor, blocks conversion of androgens to estrogens. In familial male precocious puberty, slowing of pubertal progression and growth...
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.
Topics: Androstenedione; Artifacts; Child, Preschool; Cross Reactions; Female; Humans; Infant; Male; Middle Aged; Postmenopause; Puberty, Precocious; Radioimmunoassay; Reference Values; Testolactone; Testosterone; Time Factors
PubMed: 9506727
DOI: 10.1210/jcem.83.3.4623 -
Zebrafish Apr 2020Testolactone is a potent steroid aromatase (CYP19A1) inhibitor, and its main effect is a reduction in estradiol and estrone and an increase in testosterone and...
Testolactone is a potent steroid aromatase (CYP19A1) inhibitor, and its main effect is a reduction in estradiol and estrone and an increase in testosterone and androstenedione levels. In this work, we evaluated a zebrafish water tank (ZWT) as a model to investigate testolactone biotransformation and the possibility to increase knowledge regarding the applicability of the ZWT on steroid hormone elimination research, as well as on the impact of steroid hormones on the endogenous metabolism of zebrafish. High-resolution mass spectrometry combined with SIEVE software was used to discriminate the peaks of interest based on significant changes in the relative signal intensity of the values between different ZWT experiments. The metabolites, 4,5-dihydrotestolactone and 1,2,4,5-tetrahydrotestolactone, the same metabolites as those described in humans, were detected in ZWT, both in quite similar proportions. The presence of testolactone in the ZWT caused a rise in testosterone and androstenedione in the water tank, similar to that in human serum. These data suggest that, while the concentration of testolactone was high enough to inhibit the aromatase enzyme, an accumulation of androgens in the water occurred, indicating that the ZWT can be considered a model to investigate the impact of steroids on live organisms.
Topics: Animals; Aromatase Inhibitors; Biotransformation; Gonadal Steroid Hormones; Testolactone; Zebrafish
PubMed: 32096703
DOI: 10.1089/zeb.2019.1791 -
American Journal of Surgery Apr 1991Ten patients with large inoperable desmoid tumors in various body locations were treated with testolactone. Four tumors (40%) responded with major regressions, i.e.,...
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.
Topics: Abdominal Neoplasms; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fibroma; Gardner Syndrome; Humans; Indomethacin; Male; Remission Induction; Sulindac; Tamoxifen; Testolactone; Time Factors; Vitamin K 1; Warfarin
PubMed: 2035759
DOI: 10.1016/0002-9610(91)91102-o -
Human Reproduction Update Dec 2021Infertility affects 15% of men and contributes to nearly half of all cases of infertility. Infertile men usually have impaired spermatogenesis, presenting as azoospermia... (Review)
Review
BACKGROUND
Infertility affects 15% of men and contributes to nearly half of all cases of infertility. Infertile men usually have impaired spermatogenesis, presenting as azoospermia or various degrees of asthenospermia and oligozoospermia. Spermatogenesis is a complex and coordinated process, which is under precise modulation by the hypothalamic-pituitary-gonadal (HPG) axis. An aberrant hormone profile, especially an imbalance between testosterone (T) and estradiol (E2), plays an essential role in male infertility. In the male, E2 is produced mainly from the conversion of T by the aromatase enzyme. Theoretically, reducing an abnormally elevated T:E2 ratio using aromatase inhibitors (AIs) could restore the balance between T and E2 and optimize the HPG axis to support spermatogenesis. For decades, AIs have been used to treat male infertility empirically. However, owing to the lack of large-scale randomized controlled studies and basic research, the treatment efficacy and safety of AIs in male infertility remain controversial. Therefore, there is a need to summarize the clinical trials and relevant basic research on the application of AIs in the treatment of male infertility.
OBJECTIVE AND RATIONALE
In this narrative review, we summarized the application of AIs in the treatment of male infertility, including the pharmacological mechanisms involved, clinical trials focused on patients with different types of infertility, factors affecting treatment efficacy and the side-effects.
SEARCH METHODS
A literature search was performed using MEDLINE/PubMed and EMBASE, focusing on publications in the past four decades concerning the use of AIs for treating male infertility. The search terms included AI, male infertility, letrozole, anastrozole, testolactone, azoospermia, oligozoospermia, aromatase polymorphisms, obesity and antiestrogens, in various combinations.
OUTCOMES
Clinical studies demonstrate that AIs, especially nonsteroidal letrozole and anastrozole, could significantly inhibit the production of E2 and its negative feedback on the HPG axis, resulting in increased T and FSH production as well as improved semen parameters in infertile men. Large-scale surveys suggest that obesity may result in symptoms of hypogonadism in both fertile and infertile males, such as decreased semen quality and attenuated sexual function, which can be improved by AIs treatment. Polymorphisms of the aromatase gene CYP19A1, including single nucleotide polymorphisms and tetranucleotide TTTA repeats polymorphism (TTTAn), also influence hormone profiles, semen quality and treatment efficacy of AIs in male hypogonadotropic hypogonadism and infertility. The side-effects of AIs in treating male infertility are various, but most are mild and well tolerated.
WIDER IMPLICATIONS
The application of AIs in treating male infertility has been off-label and empirical for decades. This narrative review has summarized the target patients, dose, treatment duration and side-effects of AIs. Polymorphisms of CYP19A1 that may affect AIs treatment efficacy were also summarized, but a full understanding of the mechanisms involved in AIs action requires further study.
Topics: Anastrozole; Aromatase; Aromatase Inhibitors; Humans; Infertility, Male; Letrozole; Male; Semen Analysis
PubMed: 34871401
DOI: 10.1093/humupd/dmab036 -
European Urology 198840 patients with oligoasthenozoospermia in infertile marriages were subjected to randomized treatment with 30 mg tamoxifen/day (n = 20), or with 30 mg tamoxifen/day and... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
40 patients with oligoasthenozoospermia in infertile marriages were subjected to randomized treatment with 30 mg tamoxifen/day (n = 20), or with 30 mg tamoxifen/day and 150 mg testolactone/day (n = 20), to prevent elevation of estradiol levels during monotherapy with tamoxifen. In both groups there was a significant increase in FSH, LH and testosterone. The elevation of estradiol serum levels was significant (p less than 0.0001) in the tamoxifen group, and not significant in the group with combination therapy. The increase in sperm density was significant in both groups (p less than 0.001; p less than 0.002, respectively), but no differences were seen between both groups. No improvement of the other ejaculate parameters was seen in either groups. The incidence of gravidity was the same under additional testolactone therapy (n = 3).
Topics: Drug Therapy, Combination; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Oligospermia; Random Allocation; Sperm Count; Tamoxifen; Testolactone; Testosterone
PubMed: 3141194
DOI: 10.1159/000473006 -
Pediatric Endocrinology Reviews : PER Dec 2005Testotoxicosis is a form of gonadotropin-independent (peripheral) precocious puberty in which boys experience early onset and progression of puberty. Patients have... (Review)
Review
Testotoxicosis is a form of gonadotropin-independent (peripheral) precocious puberty in which boys experience early onset and progression of puberty. Patients have accelerated growth, early development of secondary sexual characteristics and usually reduced adult height. Testotoxicosis is caused by an activating mutation of the luteinizing hormone (LH) receptor, leading to increased levels of sex steroids in the context of low LH. Therapy has, therefore, traditionally targeted steroidogenesis. However, the drugs used have been associated with side effects. More recently, a combination of an oral anti-androgen (spironolactone) and an aromatase inhibitor (testolactone) decreased height velocity and improved predicted height. A phase II study in testotoxicosis is currently underway,exploring the combination of a highly selective anti-androgen, bicalutamide, and the potent aromatase inhibitor, anastrozole. These agents are well tolerated in the populations in which they have been studied and effectively inhibit testosterone activity and estrogen production, in adult patients.
Topics: Anastrozole; Androgen Antagonists; Anilides; Aromatase Inhibitors; Body Height; Child; Clinical Trials, Phase II as Topic; Humans; Male; Nitriles; Point Mutation; Puberty, Precocious; Receptors, LH; Tosyl Compounds; Triazoles
PubMed: 16361981
DOI: No ID Found -
Acta Endocrinologica Jun 1985Current medical and surgical therapies of precocious puberty in McCune-Albright syndrome are often unsatisfactory. We used an aromatase inhibitor, testolactone, to treat...
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.
Topics: Androstenedione; Child, Preschool; Endocrine System Diseases; Estradiol; Estrone; Female; Fibrous Dysplasia of Bone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Puberty, Precocious; Syndrome; Testolactone; Testosterone; Triptorelin Pamoate
PubMed: 3925675
DOI: 10.1530/acta.0.1090254 -
Journal of Chromatography Oct 1983A rapid, sensitive, and selective assay is described for the quantitation of both testolactone and its recently identified metabolite, 4,5-dihydrotestolactone, in plasma...
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.
Topics: Chromatography, High Pressure Liquid; Humans; Male; Testolactone; Time Factors
PubMed: 6643639
DOI: 10.1016/s0378-4347(00)84825-2 -
Nihon Rinsho. Japanese Journal of... Jun 2006
Review
Topics: Aromatase Inhibitors; Aspartic Acid; Cyclic AMP; Diagnosis, Differential; Drug Therapy, Combination; Humans; Leydig Cells; Male; Mineralocorticoid Receptor Antagonists; Mutation; Prognosis; Puberty, Precocious; Receptors, LH; Spironolactone; Testolactone; Testosterone
PubMed: 16817479
DOI: No ID Found