Role of 5areductase in androgen physiology and pathophysiology

18.1.1 Normal androgen metabolism

During the last century, the identification and characterization of the major sex steroids, which include androgens, estrogens, and progestins, helped define their biologic functions. Androgens were demonstrated to be essential for normal male sexual differentiation in utero and for development and maintenance of male secondary sexual characteristics, including terminal body hair growth, muscle mass, sexual behavior and fertility. Androgens are steroid hormones and, as such, produce effects by binding to an intracellular receptor, forming a hormone-receptor com-plexthat interacts with DNAto modulate protein transcription (Mainwaring 1977). Testosterone, the major circulating androgen in adult men, was logically suspected to be the hormone responsible for these effects. Observations in 46XY subjects with inborn androgen insensitivity (syndrome of testicular feminization) confirm that the sexual phenotype in humans is predominantly female in the absence of androgen effects (Morris et al. 1963, see Chapter 3). Specifically, despite normal circulating levels of testosterone, subjects with androgen insensitivity who have impaired responses to androgens secondary to a dysfunctional androgen receptor manifest female external genitalia (with blind vaginal pouch, cryptorchid testes and infertility) and breast development, no terminal sexual body hair growth, and a pre-pubertal pattern of scalp hair growth. Due to the absence of androgen action, no androgen-related disorders typical of aging men, such as disorders of the prostate or male pattern hair loss over the scalp, are observed. The latter finding is consistent with Hamilton's conclusions regarding the androgen dependence of typical male pattern scalp hair loss, based on observations of eunuchs compared to normal subjects (Hamilton 1942; 1951). Each of these examples suggested that the lack of testosterone, or the lack of its biologic action, was responsible for the observed effects, although effects due to decreased activity of metabolites of testosterone (Fig. 18.1) could not be ruled out. Subsequent observations demonstrated that specific androgens other than testosterone were, in fact, crucial for effecting biologic functions and contributing to the pathophysiology of androgen-related disorders.

18.1.2 Evidence for role of 5a-reductase in pathophysiology of androgen disorders

In the 1970s, remarkable findings, based on observations of kindreds harboring mutations in the gene coding for steroid 5a-reductase (5aR), the enzyme that catalyzes the conversion of testosterone to dihydrotestosterone (DHT), were reported. The presence of 5aR activity had first been identified in the prostate in preclinical species, and DHT had been identified as a potent androgen with greater affinity (approximately 5-fold) for the androgen receptor than testosterone, although

DEHYDROEPIANDROSTERONE

ANDROSTENEDIONE

NADPH

NADPH

ANDROSTENEDIONE

ANDROSTANEDIONE

NADH OH

ANDROSTENEDIOL

NADH OH

NADH OH

NADPH O

ANDROSTANEDIONE

NADH OH

DIHYDROTESTOSTERONE

TESTOSTERONE

NADPH O

17ß-ESTRADIOL

DIHYDROTESTOSTERONE

17ß-ESTRADIOL

Fig. 18.1 Androgen metabolic pathways in skin (adapted from Kaufman 1996).

its precise role in androgen biology was not fully understood (Anderson and Liao 1968; Fang etal. 1969; Mainwaring 1969; Saunders 1963; Wilson 1972; Wilson and Gloyna 1970; Wilson and Lasnitzki 1971). The findings in subjects with genetic deficiency of 5aR led to a significantly greater understanding of how the specific androgen DHT participates in fetal development and sexual maturation and contributes to the pathogenesis of disorders associated with aging men.

18.1.2.1 Genetic 5a-reductase deficiency

In 1974, two independent groups, using classical clinical observation and pre-molecular biochemical techniques, reported on cohorts of subjects harboring genetic mutations affecting androgen metabolism (Imperato-McGinley etal. 1974; 1979; Walsh et al. 1974). Subjects with these mutations were characterized by impaired activity of 5aR, with marked reductions in the levels of 5a-reduced steroid metabolites, including decreased levels of DHT, the 5a-reduced metabolite of testosterone. Males homozygous for genetic 5aR deficiency are born with ambiguous genitalia and initially reared as girls; with puberty, virilization occurs, presumably due to high circulating levels of testosterone, along with the transition from a female to a male sexual identity, development of male muscle mass and normal skeletal integrity. As adults, these men are otherwise healthy, with sparse facial and body hair and apparent protection against development of common

Scalp - Sebaceous Glands

Type 1 5a-Reductase

Sebaceous Glands

Chest/Back Skin

Adrenal Glands Kidney

Scalp - Sebaceous Glands

Sebaceous Glands

Chest/Back Skin

Adrenal Glands Kidney

Testis/Epididymis

Chest Skin

- Liver

Seminal Vesicles Prostate

Scalp - Hair Follicle Beard

Foreskin/Scrotum

Type 2 5a-Reductase

Fig. 18.2 5a-reductase enzyme activity in adult human tissues (adapted from Gormley 1995).

Testis/Epididymis

Chest Skin

- Liver

Seminal Vesicles Prostate

Scalp - Hair Follicle Beard

Foreskin/Scrotum

Type 2 5a-Reductase

Fig. 18.2 5a-reductase enzyme activity in adult human tissues (adapted from Gormley 1995).

androgen-relateddisorders associatedwith aging, includingbenign prostatic hyperplasia (BPH), prostate cancer and male pattern hair loss, despite normal or supranormal circulating levels of testosterone. Subsequent reports of normal spermato-genesis and fertility in these subjects strengthened the theory that testosterone, rather than DHT, is the key androgen supporting reproductive capacity in men. Females with genetic 5aR deficiency can be detected by biochemical assay and are considered phenotypically normal, although subtle physiological alterations, such as delayed onset of menarche and decreased body hair growth, have been reported (Katz etal. 1995).

It was subsequently discovered, and later confirmed through genetic sequencing, that two distinct isoenzymes of 5aR, referred to as types 1 and 2, exist in humans and most other species studied (Andersson et al. 1991; Russell and Wilson 1994). DNA sequencing analysis demonstrates that subjects with genetic 5aR deficiency harbor mutations in the gene coding for the type 2 isoenzyme while their type 1 gene is normal. This is consistent with localization studies that subsequently identified differing amounts of the two isoenzymes in specific tissues (Harris et al. 1992; Russell and Wilson 1994; Thigpen et al. 1993). For example, while both isoenzymes are prominent in the liver, contributing to circulating levels of DHT, type 2 5aR is predominant in the genitourinary tract, including the prostate, while type 1 5aR is predominant in sebaceous glands of the skin (Fig. 18.2). Subsequent genetic studies have failed to identify functional mutations in the gene coding for the oh oh

type 1 5aR enzyme (Russell and Wilson 1994). Taken together, the presence of two distinct 5aR isoenzymes accounts for the fact that suppression of DHT formation is incomplete in subjects with 5aR deficiency, even in those harboring mutations that yield no measurable type 2 enzymatic activity, while the differing amounts of the two isoenzymes in individual tissues provide insight into the observed sequelae of the genetic syndrome.

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