ANDROGENS

TESTOSTERONE AND OTHER ANDROGENS

Testosterone- the principal secreted androgen in men synthesized by the Leydig cells

- probably the principal androgen in women synthesized in the corpus luteum and adrenal cortex

Androstenedione and dehydroepiandrosterone

- Weak androgens converted peripherally to testosterone

Secretion and Transport of Testosterone

First trimester in utero

- Fetal testis begin to secrete testosterone, the principal factor in male sexual differentiation

Beginning of Second trimester

- Serum testosterone concentration is close to that of mid-puberty,~ 250 ng/dL

Secretion and Transport of Testosterone

End of the Second trimester

- Serum testosterone concentration falls

By birth

- Rises to again to ~ 250 ng/dL

Early adulthood

- 500 to 700ng/dL in men, 30 to 50 ng/dL in women

The testosterone value falls again in the first few days after birth, but it rises and peaks again at ~250 ng/dL at 2-3 months after birth and falls to < 50 ng/dL by 6 months, where it remains until puberty

Secretion and Transport of Testosterone

LH - secreted by the pituitary gonadotropes

- the principal stimulus of testosterone secretion men

- stimulates the corpus luteum to secrete testosterone in women

Metabolism of Testosterone to Active and Inactive Compounds

Testosterone has many different effects in many tissues:

1. Mediated by metabolism of testosterone to two other active steroids, dihydrotestosterone and estradiol

2. By testosterone itself

3. By dihydrotestosterone

4. By estradiol

Metabolism of Testosterone to Active and Inactive Compounds

Testosterone

- is metabolized in the liver to androsterone and etiocholanolone

Dihydrotestosterone

- is metabolized to androsterone, androstanedione, and androstanediol

Physiological and Pharmacological Effects of Androgens

Testosterone

- can act as an androgen directly by binding to the androgen receptor

- or indirectly by conversion to dihydrotestosterone, which also binds to the androgen receptor

- can also act as an estrogen by conversion to estradiol, which binds to the estrogen receptor

Consequences of Androgen Deficiency During Fetal Development

During first trimester in utero

-Incomplete sexual differentiation

-Results from testicular disease (17a-hydroxylase deficiency)

-Complete deficiency of testosterone secretion results in entirely female external genitalia

-Less severe testosterone deficiency results in incomplete virilization of the external genitalia

The consequences of androgen deficiency depend on the stage of life during which the deficiency first occurs and on the degree of the deficiency

Consequences of Androgen Deficiency Before Completion of Puberty

Failure to complete puberty

-When a boy secretes testosterone in utero but loses the ability to do so before the age of puberty

-All the pubertal changes (external genitalia, sexual hair, muscle mass, voice and behavior) are impaired to a degree proportionate to the abnormality of secretion

Consequences of Androgen Deficiency Before Completion of Puberty

Eunuchoid

-Longer arms and legs relative to the trunk as a result of normal growth hormone secretion and subnormal testosterone secretion

Gynecomastia

-Enlargement of glandular breast tissue, another consequence of subnormal testosterone secretion

Consequences of Androgen Deficiency After Completion of Puberty

Libido and energy decrease (within a week or two)

Decrease in muscle mass and strength (within a few months)

Decrease in hematocrit and hemoglobin (within several months)

Decrease in bone mineral density (within two years)

Loss of sexual hair (Many years)

Consequences of Androgen Deficiency In Women

Decrease in sexual hair (many years)

Therapeutic Androgen Preparations

Ingestion of testosterone is not an effective means of replacing testosterone deficiency

The rapid hepatic catabolism ensures that hypogonadal men cannot ingest sufficient amounts and with sufficient frequency to maintain normal serum testosterone concentration

Most preparations of androgens are designed to bypass hepatic catabolism

Therapeutic Androgen Preparations Testosterone Esters

*Testosterone enanthate or cypionate

-Administered IM every 2-4 weeks

-Results in serum testosterone concentration higher than normal in the first few days of injection to low normal just before the next injection

*Undecanoate ester of testosterone

-when dissolved in oil and ingested is absorbed in the lymphatic circulation bypassing initial hepatic catabolism

Testosterone undecanoate in oil also can be injected and produces stable serum concentration for two months

Therapeutic Androgen Preparations Alkylated Androgens

17a-alkylated androgen

-Hepatic catabolism is retarded hence are androgenic when administered orally

-However less androgenic than testosterone itself and can cause hepatoxicity

Therapeutic Androgen Preparations Transdermal Delivery Systems

ANDRODERM

-In patches

ANDROGEL OR TESTIM

-Gel preparation

STRIANT

-buccal tablet

All these preparations produce mean serum testosterone concentrations within normal range in hypogonadal men

Testosterone undecanoate in oil also can be injected and produces stable serum concentration for two months

Therapeutic Uses of Androgens Male Hypogonadism

- The best established indication for administration of androgens

- The goal of treatment is to mimic the normal serum concentration

- Normalization of serum testosterone concentration induces normal virilization in prepubertal boys

Therapeutic Uses of Androgens Male Senescence

- Increasing serum testosterone concentration of men whose serum levels are subnormal due to their age will increase their bone mineral density and lean mass and decrease their fat mass

- -However it is uncertain if such treatment will worsen benign prostatic hyperplasia or increase the incidence of prostate cancer

Therapeutic Uses of Androgens Female Hypogonadism

Little data exist on increasing the serum testosterone concentration of women whose levels are below normal will improve their libido, energy, muscle mass, and strength or bone mineral density (BMD)

-In a study of women with low serum testosterone levels due to panhypopituitarism, increasing the level to normal was associated with small increases in BMD, fat-free mass and sexual function compared to placebo

Therapeutic Uses of Androgens Enhancement of Athletic Performance

Because androgens for this purpose are usually taken surreptitiously, information about possible effects is not as complete as that for androgens

FDA has recommended against the use of body-building products containing steroids or steroid-like substances due to serious health risks

Therapeutic Uses of Androgens Male Contraception

Androgens inhibit LH secretion by the pituitary and decrease endogenous testosterone production

Scientists have tried to use androgen alone or in combination with other drugs as a male contraceptive

Suppression of testosterone production greatly diminishes spermatogenesis

However, testosterone alone required supraphysiologic doses

Addition of GnRH antagonist daily injections

A more promising approach is a combination of progestin with physiological dose of testosterone to suppress LH secretion and spermatogenesis but provide a natural serum testosterone secretion

Therapeutic Uses of Androgens Catabolic and Wasting States

Generally not effective but with one exception in the treatment of muscle wasting associated with AIDS which is often accompanied with hypogonadism

Therapeutic Uses of Androgens Angioedema

Chronic androgen treatment of patients with angioedema effectively prevents attacks

Stanozolol and Danazol stimulate the hepatic synthesis of esterase inhibitor

Therapeutic Uses of Androgens Blood Dyscrasias

Once employed to stimulate erythropoiesis in patients with anemia with various etiologies

But the availability of erythropoietin has supplanted that use

Androgens still are used as adjunctive treatment for hemolytic anemia and ITP refractory to first line agents