Human steroid biosynthesis for the oncologist

Abstract

In 2005, results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial ushered in a new era of endocrine therapy for hormone-responsive malignancies. This study demonstrated that, compared with tamoxifen (a selective estrogen receptor modulator), anastrozole (aromatase inhibitor [AI]) prolonged time to recurrence and disease-free survival for postmenopausal women with breast cancer. The advantage was even greater for those with estrogen receptor-positive (ER) tumors, and anastrozole was better tolerated than tamoxifen. Since then, AIs have become first-line adjuvant therapy for ER breast cancer in postmenopausal women.In late 2010, a trial comparing abiraterone acetate (a 17-hydroxylase/17,20-lyase [CYP17A1] inhibitor) plus prednisone versus prednisone alone in men with castration-resistant prostate cancer (CRPC) previously treated with docetaxel chemotherapy was terminated early because of the survival benefit in the abiraterone acetate arm. This result not only validated a new therapy for CRPC but also, with the antecedent phase I-II abiraterone studies, shattered our understanding of the molecular mechanisms underpinning CRPC development and progression.Aromatase inhibitors and CYP17A1 inhibitors will be widely used by oncologists, yet fellowship programs provide little training in steroid biosynthesis, compared with training in the biology of standard chemotherapies. Consequently, these drugs might be used without an appreciation of their caveats and pitfalls. The purpose of this review was to acquaint practicing oncologists with the fundamental principles and pathways of steroid biosynthesis, to improve their understanding of how and why these drugs work, and to alert these physicians to potential problems related to the drugs' mechanisms of action.

FIGURE 1

A, A conceptual model for steroid biosynthesis. Classical steroid production begins with a tropic stimulus, which drives the conversion of cholesterol to pregnenolone and maintenance of the downstream enzymes in the steroidogenic cell. Peripheral tissues and target cells further metabolize these steroids. B, Major steroidogenic pathways in human beings. Enzymes are indicated above and aside arrows, and main product steroids of the adrenals, testis, and ovary are underlined. Thin line from 17-hydroxy-(17OH)-progesterone to androstenedione indicates minor pathway. C, Canonical terminal steps of T synthesis from DHEA(S) and fates of T in different tissues. T acts directly on AR or indirectly after metabolism to DHT, and aromatase changes the biological activity of T via metabolism to E2.

FIGURE 1

A, A conceptual model for steroid biosynthesis. Classical steroid production begins with a tropic stimulus, which drives the conversion of cholesterol to pregnenolone and maintenance of the downstream enzymes in the steroidogenic cell. Peripheral tissues and target cells further metabolize these steroids. B, Major steroidogenic pathways in human beings. Enzymes are indicated above and aside arrows, and main product steroids of the adrenals, testis, and ovary are underlined. Thin line from 17-hydroxy-(17OH)-progesterone to androstenedione indicates minor pathway. C, Canonical terminal steps of T synthesis from DHEA(S) and fates of T in different tissues. T acts directly on AR or indirectly after metabolism to DHT, and aromatase changes the biological activity of T via metabolism to E2.

FIGURE 1

A, A conceptual model for steroid biosynthesis. Classical steroid production begins with a tropic stimulus, which drives the conversion of cholesterol to pregnenolone and maintenance of the downstream enzymes in the steroidogenic cell. Peripheral tissues and target cells further metabolize these steroids. B, Major steroidogenic pathways in human beings. Enzymes are indicated above and aside arrows, and main product steroids of the adrenals, testis, and ovary are underlined. Thin line from 17-hydroxy-(17OH)-progesterone to androstenedione indicates minor pathway. C, Canonical terminal steps of T synthesis from DHEA(S) and fates of T in different tissues. T acts directly on AR or indirectly after metabolism to DHT, and aromatase changes the biological activity of T via metabolism to E2.

FIGURE 2

Initiation of steroid biosynthesis in the mitochondria via StAR and CYP11A1. Stimulated by increased cAMP, StAR induces the movement (large solid arrow) of cholesterol in the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM), where FdR and CYP11A1 reside. Electrons from NADPH flow (open arrows) to the flavin (three hexagons) in FdR, to the iron-sulfur cluster (dots and lines) in the soluble mitochondrial matrix protein Fdx to the heme (Maltese cross and dot) of CYP11A1. These electrons plus molecular oxygen enable CYP11A1 to convert cholesterol to pregnenolone (small solid arrow) in three cycles, and pregnenolone is then liberated into pathways, which lead to specific steroids (cortisol, T, etc.).

FIGURE 3

Termninal steps of androgen biosynthesis from DHEA. In this pseudo-three-dimensional diagram, reactions to the right (3βHSD) and to the back (5α-reductase) are irreversible, whereas vertical reactions are reversible and catalyzed by several 17βHSD enzymes. Flux from DHEA to DHT might follow several pathways, and an individual steroid molecule might cycle vertically many times before finally moving through the 3βHSD and/or 5α-reductase reactions.

FIGURE 4

Hypothalamic-pituitary-target gland axes for the A, adrenal; B, testis; and C, ovary. Block arrows indicate actions of hormones, and flat end to lines indicate negative feedback. Curved block arrow in panel C indicates that androstenedione from the theca cell diffuses to the granulosa cell, where aromatization occurs.

FIGURE 4

Hypothalamic-pituitary-target gland axes for the A, adrenal; B, testis; and C, ovary. Block arrows indicate actions of hormones, and flat end to lines indicate negative feedback. Curved block arrow in panel C indicates that androstenedione from the theca cell diffuses to the granulosa cell, where aromatization occurs.

FIGURE 4

Hypothalamic-pituitary-target gland axes for the A, adrenal; B, testis; and C, ovary. Block arrows indicate actions of hormones, and flat end to lines indicate negative feedback. Curved block arrow in panel C indicates that androstenedione from the theca cell diffuses to the granulosa cell, where aromatization occurs.

FIGURE 5

Endocrine therapy strategies for prostate cancer, which all inhibit androgen production or antagonize the androgen receptor. Flat end to lines indicate site of action on process or tissues, including hypothalamus and pituitary (top), adrenal (triangle in middle), and testis (oval at bottom). Block arrows indicate receptor activation.

FIGURE 6

Physiology of genetic 17-hydroxylase deficiency, equivalent to abiraterone acetate monotherapy. Loss of CYP17A1 activities (dashed arrows with X) eliminates production of all steroids in grey box, including androgens, estrogens, and cortisol. Loss of cortisol negative feedback increases ACTH and flux of cholesterol to pregnenolone (block arrow). The only available pathways (thick arrows) go to DOC and corticosterone (B), which expand blood volume, increase blood pressure, and suppress both plasma renin activity and aldosterone production (block arrows).