Chapter 49_ Androgens and the Male Reproductive Tract.pdf

Testosterone

What is the principal secreted androgen in men?

Leydig cells

Which testicular cells synthesize the majority of testosterone in men?

Corpus luteum and adrenal cortex

Where is testosterone synthesized in women?

Androstenedione and dehydroepiandrosterone

Which weak androgen precursors can be converted peripherally to testosterone?

AR

What is the medical abbreviation for androgen receptor?

CYP

What is the medical abbreviation for cytochrome P450?

FSH

What is the medical abbreviation for follicle-stimulating hormone?

GnRH

What is the medical abbreviation for gonadotropin-releasing hormone?

hCG

What is the medical abbreviation for human chorionic gonadotropin?

LH

What is the medical abbreviation for luteinizing hormone?

NO

What is the chemical abbreviation for nitric oxide?

PDE5

What is the abbreviation for phosphodiesterase type 5?

PKG

What is the abbreviation for protein kinase G?

sGC

What is the abbreviation for soluble guanylate cyclase?

~250 ng/dL

What is the serum testosterone concentration in male fetuses near birth and again at 2 to 3 months of age?

Luteinizing hormone from the fetal pituitary gland

What drives the secretion of testosterone in the fetus near birth?

Less than 50 ng/dL

What is the serum testosterone concentration in male infants from 6 months of age until puberty?

12 to 17 years

During what age range does the pubertal increase in serum testosterone typically occur in males?

300 to 800 ng/dL

What is the normal serum testosterone concentration range in early adult men?

30 to 50 ng/dL

What is the normal serum testosterone concentration range in early adult women?

Gradual decrease

What is the characteristic trend of serum testosterone levels as men age?

Luteinizing hormone

What is the principal pituitary hormone that stimulates testosterone secretion in men?

Pituitary gonadotroph cells

Which cell type secretes luteinizing hormone and follicle-stimulating hormone?

Follicle-stimulating hormone

Which gonadotropin potentiates the effect of LH on testosterone secretion?

Gonadotropin-releasing hormone

Which hypothalamic hormone stimulates the pituitary secretion of LH?

Direct negative-feedback inhibition

What is the feedback mechanism by which testosterone regulates LH secretion?

Pulsatile every ~2 hours

What is the frequency and pattern of LH secretion in men?

8 AM

At what time of day does the diurnal peak of plasma testosterone concentration occur in young men?

8 PM

At what time of day does the diurnal trough of plasma testosterone concentration occur?

Morning peaks diminish

What happens to the diurnal peak of testosterone secretion as men age?

Sex hormone–binding globulin

Which plasma protein binds about 38% of circulating testosterone with high affinity?

Biologically unavailable

What is the functional availability of testosterone that is bound to SHBG?

Albumin

Which plasma protein binds approximately 60% of circulating testosterone with low affinity?

About 2%

What percentage of circulating testosterone exists in the unbound or free state?

Corpus luteum

Which female reproductive structure is stimulated by LH to secrete testosterone?

Estradiol and progesterone

In women, what are the principal hormonal inhibitors of LH secretion under normal physiological circumstances?

5α-reductase

Which enzyme catalyzes the conversion of testosterone to dihydrotestosterone?

Dihydrotestosterone

Which metabolite binds to the androgen receptor with higher affinity and activates gene expression more efficiently than testosterone?

Type I 5α-reductase

Which 5α-reductase isoenzyme is located predominantly in nongenital skin, liver, and bone?

Type II 5α-reductase

Which 5α-reductase isoenzyme is located predominantly in urogenital tissue in men and genital skin in men and women?

Aromatase complex

Which enzyme complex catalyzes the conversion of testosterone to estradiol?

About 85%

What percentage of circulating estradiol in men is derived from the peripheral conversion of testosterone?

Direct testicular secretion

Where does the remaining ~15% of circulating estradiol in men originate?

Androsterone and etiocholanolone

What are the main inactive hepatic metabolites formed from testosterone?

Androsterone, androstanedione, and androstanediol

What are the major metabolites of dihydrotestosterone?

Direct binding to AR, conversion to DHT binding AR, and conversion to estradiol binding ER

What three primary cellular mechanisms mediate the physiological and pharmacological effects of testosterone?

Heat shock protein complex

In the absence of a ligand, what complex is associated with the androgen receptor in the cytoplasm?

Dissociation from heat shock proteins, dimerization, and nuclear translocation

What structural changes occur to the androgen receptor upon ligand binding?

Androgen response elements

To what specific DNA sequences does the activated AR dimer bind on responsive genes?

Recruitment of coactivators to act as a transcription factor complex

How does the liganded AR dimer regulate gene expression after binding DNA?

Incomplete male sexual differentiation and pubertal development

What is the developmental outcome of mutations in the hormone- or DNA-binding regions of the AR in utero?

Spinal and bulbar muscular atrophy / Kennedy disease

What inherited neuromuscular and endocrine disorder is caused by AR mutations?

Expansion of CAG repeats coding for glutamine

What specific genetic abnormality at the amino terminus of the AR causes Kennedy disease?

Gynecomastia and progressive motor neuron atrophy

What are the primary clinical manifestations of Kennedy disease?

Continued expression and active ligand-independent signaling of AR

Why does metastatic prostate cancer often relapse after initial androgen deprivation therapy?

Abiraterone

Which inhibitor of adrenal androgen synthesis can produce tumor responses when prostate cancer becomes resistant to standard androgen deprivation?

Anastrozole

Which drug acts as an inhibitor of CYP19 (aromatase)?

Sexual desire, erectile function, and decrease in fat

Which physiological effects of testosterone replacement require conversion to estradiol?

Lean mass and muscle strength

Which physiological effects of testosterone replacement do NOT require conversion to estradiol?

Human chorionic gonadotropin

Which hormone stimulates the fetal Leydig cells to begin secreting testosterone around the 8th week of gestation?

Wolffian ducts

Which embryonic structures are stimulated by local high concentrations of testosterone to differentiate into the epididymis, vas deferens, and seminal vesicles?

Dihydrotestosterone

Which androgen drives the embryological development of the male external genitalia?

Further phallic growth

What is the main developmental effect of the surge in fetal testosterone near the end of gestation?

LH acting on Leydig cells and FSH acting on Sertoli cells

Which two pituitary hormones act on specific testicular cells to stimulate seminiferous tubule development and spermatogenesis at puberty?

Enlargement in length and width

What anatomical changes happen to the phallus during male puberty?

Increased sebum production making skin coarser and oilier

What mechanism causes acne development during male puberty?

Pubic and axillary hair first, followed by lower leg, body, and facial hair

What is the chronological sequence of male sexual hair growth during puberty?

Shoulder girdle

In which region of the body is muscle mass and strength gain most prominent during male puberty?

Epiphyseal bone growth acceleration followed by epiphyseal maturation and closure

How does pubertal testosterone affect bone growth and height?

Increased erythropoiesis

Why do adult men have higher hematocrit and hemoglobin concentrations than preadolescent boys or women?

Laryngeal thickening

What structural change causes voice deepening in pubertal males?

Spatial relations and aggressiveness

Which cognitive and behavioral characteristics tend to be enhanced in men following pubertal testosterone increases?

Complete absence of androgen action resulting in a female phenotype

What clinical phenotype results from the most severe form of androgen receptor loss-of-function mutations?

Incomplete virilization of external genitalia with normal male internal genitalia

What genital presentation occurs in infants with 5α-reductase deficiency?

Microphallus

What phallic condition results from testosterone deficiency during the third trimester of gestation?

Subnormal LH secretion due to abnormalities of GnRH secretion or action

What underlying neuroendocrine defect commonly causes microphallus and cryptorchidism in boys?

Cryptorchidism

What term describes undescended testes that fail to enter the scrotum?

Failure to complete puberty

What is the clinical result when a boy loses the capacity to secrete testosterone before the anticipated age of puberty?

Continued lengthening of long bones resulting in disproportionately long limbs relative to the trunk

What skeletal abnormality occurs if growth hormone is normal but testosterone is deficient during expected pubertal years?

Gynecomastia

What term describes the enlargement of glandular breast tissue caused by subnormal testosterone during puberty?

1 to 2 weeks

How quickly do libido and energy decline after postpubertal loss of testosterone?

Several months

How long does it take for a pronounced decrease in hemoglobin to manifest after postpubertal androgen loss?

Within 1 year

How soon can a decrease in bone mineral density be detected following postpubertal androgen deficiency?

Several years

How many years does it take for a clinically detectable decrease in muscle mass to appear after postpubertal castration?

Many years

How long does the complete loss of male sexual hair or increased fracture incidence take following postpubertal androgen deprivation?

Testosterone, testosterone esters, and 17α-alkylated androgens

What are the three main chemical categories of therapeutic androgen preparations?

Testosterone cypionate, testosterone enanthate, and testosterone undecanoate

What are three clinically available testosterone esters?

Methyltestosterone, oxandrolone, stanozolol, fluoxymesterone, and danazol

What are five 17α-alkylated androgens listed for therapeutic use?

Retards hepatic metabolism allowing oral administration

What is the primary pharmacological reason for adding an alkyl group to the 17α position of testosterone?

Hepatotoxicity and lower androgenic potency compared to native testosterone

What are the major toxicities and drawbacks of 17α-alkylated androgens?

Rats

In which animal species did 17α-alkylated androgens demonstrate greater anabolic than androgenic effects in laboratory tests?

Recommends against their use due to potentially serious health risks

What is the FDA position on body-building products marketed as containing steroids or steroid-like substances?

Testosterone replacement for male hypogonadism

What is the best-established clinical indication for androgen administration?

Serum testosterone concentration

What is the most important parameter to measure when monitoring the efficacy of testosterone replacement?

Relatively constant

How stable is the serum testosterone concentration from day to day when using transdermal gels?

Midway between doses

When should serum testosterone levels be measured in a patient receiving testosterone enanthate every 2 weeks?

Normalization of serum LH within 2 months

What indirect laboratory marker indicates adequate testosterone replacement in primary testicular failure?

Erythrocytosis, salt and water retention, and peripheral edema

What adverse effects can occur if excessive doses of physiological testosterone are administered?

Benign prostatic hyperplasia and prostate cancer

Which two androgen-dependent diseases must be monitored in men over 40 receiving testosterone?

Cholestasis, peliosis hepatis, and lowered HDL cholesterol

What specific hepatic and lipid side effects are caused by 17α-alkylated androgens?