Purpose Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate—a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis—was pursued. Patients and Methods Chemotherapy-naive men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts. Results Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess—namely hypertension, hypokalemia, and lower-limb edema—were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9)...

https://ascopubs.org/doi/pdf/10.1200/JCO.2007.15.9749

Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven

Masculinization depends on adequate production of testosterone by the fetal testis within a specific "masculinization programming window." Disorders resulting from subtle deficiencies in this process are common in humans, and environmental exposures/lifestyle could contribute causally because common therapeutic and environmental compounds can affect steroidogenesis. This evidence derives mainly from rodent studies, but because there are major species differences in regulation of steroidogenesis in the fetal testis, this may not always be a guide to potential effects in the human. In addition to direct study of the effects of compounds on steroidogenesis, information also derives from study of masculinization disorders that result from mutations in genes in pathways regulating steroidogenesis. This review addresses this issue by critically reviewing the comparative timing of production and regulation of steroidogenesis in the fetal testis of humans and of rodents and its susceptibility to disruption; where there is limited information for the fetus, evidence from effects on steroidogenesis in the adult testis is considered. There are a number of fundamental regulatory differences between the human and rodent fetal testis, most notably in the importance of paracrine vs. endocrine drives during masculinization such that inactivating LH receptor mutations block masculinization in humans but not in rodents. Other large differences involve the steroidogenic response to estrogens and GnRH analogs and possibly phthalates, whereas for other compounds there may be differences in sensitivity to disruption (ketoconazole). This comparison identifies steroidogenic targets that are either vulnerable (mitochondrial cholesterol transport, CYP11A, CYP17) or not (cholesterol uptake) to chemical interference.

/pdf/steroidogenesis-in-the-fetal-testis-and-its-susceptibility-19p4rksil9.pdf

Steroidogenesis in the Fetal Testis and Its Susceptibility to Disruption by Exogenous Compounds

Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiencies in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5alpha-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several comparative differences exist between rat and human LCs that may contribute, at least in part, to the greater susceptibility of the rat to both spontaneous and xenobiotic-induced LCTs; (3) endocrine disease states in man (such as androgen-insensitivity syndrome and familial male precocious puberty) underscore the marked comparative differences that exist between rats and man in the responsiveness of their LC's to proliferative stimuli; and (4) several human epidemiology studies are available on a number of compounds that induce LCTs in rats (1,3-butadiene, cadmium, ethanol, lactose, lead, nicotine) that demonstrate no association between human exposure to these compounds and induction of LC hyperplasia or adenomas. (ABSTRACT TRUNCATED)

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

P450-dependent enzymes as targets for prostate cancer therapy

The purpose of the article is to review the current concepts regarding the etiology and treatment of male-factor infertility. The following general conclusions can be drawn: (a) conventional parameters for sperm quality and male fertility are inadequate and any assessment should involve several different tests of sperm cell function to increase the fertility prognosis; (b) the causes of disturbed sperm quality are still poorly understood; (c) the role of the varicocele is still controversial but some of the discrepancies reported in the literature may be explained by the negative influence of other factors such as smoking, epididymal pathology or glandular infections operating either in conjunction or independent of the varicocele; (d) the role of chronic inflammatory processes in the reproductive organs, in particular the involvement of chronic chlamydial infections, has been underestimated, largely because it is often asymptomatic and difficult to demonstrate objectively; (e) partial androgen insensitiv...

Male Infertility: Current Concepts

Ketoconazole is an antifungal azole derivative which also inhibits the cytochrome P-45017α, catalyzing the conversion of progestins into androgens. The effects of ketoconazole on human, dog and rat testosterone biosynthesis were compared using short term incubations of dispersed testicular cells. The results showed that ketoconazole inhibited androgen biosynthesis at lower concentrations in dispersed human testicular cells (IC50: 0.08μmol/l) than in canine (IC50: 0.1μmol/l) and rat cells (IC50 ±0.2μmol/l). Furthermore, they demonstrated that ketoconazole first inhibited the 17,20-lyase activity and then the 17-hydroxylation in rat and dog cells whereas only the 17-hydroxylation was affected in human cells.

Comparative effects of ketoconazole on rat, dog and human testicular steroidogenesis

Clinical aspects in the surgical treatment of varicocele in subfertile men. II. The role of the epididymal factor

Clinical aspects in the surgical treatment of varicocele in subfertile men. I. Comparison of observed and expected pregnancy rates.

Ketoconazol ist ein oral wirksames Breitband-Anti-mykotikum. Bei niedrigen Konzentrationen (nM) hemmt dieser Stoff die Ergosterinsynthese bei Hefen und Pilzen. Bei hoheren Konzentrationen (0,1 bis 10 μM) hemmt dieses Imidazolderivat bei Saugetieren mehrere zytochrom-P-450-abhangige Enzyme, vor allem aber solche, die bei der Steroidogenese eine Rolle spielen [3]. Diese Ergebnisse haben zu weiteren Studien angeregt, die auf die Bedeutung hoher Ketoconazol-Dosen (d.h. 400mg dreimal taglich) bei der First- und Second-line-Behandlung von Patienten mit Prostatakrebs hinwiesen (Ubersichten s. [1, 2]).

Vergleich der Wirkungen von Ketoconazol auf die testikuläre Steroidogenese bei Ratte, Hund und Mensch

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Comparative effects of ketoconazole on rat, dog and human testicular steroidogenesis

Clinical aspects in the surgical treatment of varicocele in subfertile men. II. The role of the epididymal factor

Clinical aspects in the surgical treatment of varicocele in subfertile men. I. Comparison of observed and expected pregnancy rates.

Vergleich der Wirkungen von Ketoconazol auf die testikuläre Steroidogenese bei Ratte, Hund und Mensch