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  • br Clinical realities br Commentary on uses of

    2023-03-14


    Clinical realities
    Commentary on uses of selective 17,20 lyase inhibitors If continued monitoring of these same parameters along with tracking of circulating ACTH in human trials confirms these new drugs are the long sought after 17,20 lyase inhibitors, then we may for the first time be able to control both circulating C19 androgen precursors (and so androgens) that initially drive tumor growth, and alternatively derived steroids in drug resistant tumors without diminishing circulating Deoxycholic acid sale and thus elevating circulating ACTH (with all its deleterious side effects). The immediate relevance is first and foremost improving the treatment of castration resistant prostate cancer, and hopefully the second would be extending life beyond the ∼5 months achieved so far with abiraterone in clinical trials (see above). Given the availability now of drugs showing greater 17,20 lyase selectivity, we should know the answer to this question quite soon. There are also other diseases of androgen, but not cortisol, excess which may also benefit from treatment with such new compounds. One prevalent example is polycystic ovary syndrome (PCOS), a condition afflicting ∼15% of women. Ovarian androgen excess is present in the majority of women with PCOS and comprises one of the key diagnostic criteria, namely hyperandrogenism, intermittent or absent menstrual cycles and polycystic ovaries (at least two out of these three required for diagnosis) [79]. The excess androgen results in hirsutism, acne and disrupted ovarian, hypothalamic and adipose function [80]. Oral contraceptives effectively lower androgens and block the effect of androgens via suppression of ovarian androgen production and by increasing sex hormone-binding globulin. To especially block the effects of androgen in skin pilosebaceous units or hair follicles, androgen action is diminished either through the use of competitive androgen receptor antagonists such as spironolactone, cyproterone acetate and flutamide, or by using finasteride to inhibit 5α-reductase and preventing the conversion of testosterone to its more potent form, 5α-dihydrotestosterone. The selection of antiandrogen therapy is guided by presenting symptoms [81]. Another area where selective lyase inhibition may also be of value is in premature adrenarche. The past decade of study suggests that in such subjects premature elevation of adrenal androgens is coincident with premature expression of Cytb5 and reduction of HSD3B2 [82] within the ZR. Recent studies also suggest that bioactive androgens may be derived from adrenal androstenedione itself or 11BOH-androstenedione, but both are still dependent on 17,20 lyase activity. It is therefore highly likely that the use of a selective lyase inhibitor would moderate premature symptoms and avoid the need for subtype specific HSD17B inhibitors which are proposed for use but do not yet exist. One reason this approach may be appealing is while the increased expression of HSD17B5 is observed in ZR development [82], [83], it is also widely expressed in other tissues including kidney, bladder as well as prostate and testis [84]. Thus while a specific HSD17B5 inhibitor may be attractive as a treatment, it may also have undesired side effects. It is more likely the best approach is a combined use of CYP17A1 lyase inhibitor alone or in combination with a selective HSD17B isoform inhibitors at more modest doses, so avoiding unwanted side effects. In closing, it is important to recognize that only by considering decades of biomolecular study of CYP17A1 expression and function in the normal and abnormal adrenal that we can fully understand the true action of CYP17A1 inhibitors. As we now approach the third generation of inhibitors, namely those truly selective for 17,20 lyase activity, we may finally be turning the corner in our battle to treat castration resistant prostate cancer (and potentially other hyperandrogenic responses) with a scalpel-like approach instead of a hammer because we considered both basic science and clinical outcomes together.