androgens -- with notes
TRANSCRIPT
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