BIO 5406 Notes, 3/23/05
MALE REPRODUCTIVE ENDOCRINOLOGY
I. Introduction and History. [Hadley, pg. 422]
A. Physiological role of the testes has been recognized longer than any other
endocrine gland.
1. Effects of castration in animals and man.
a. Castration of roosters inhibits growth of comb.
b. Castration of bulls makes them less temperamental and their meatmore tender.
c. Castrated men (eunuchs) were used to guard harems.
d. Castrati -- opera singers with high tenor voice.
B. Arnold Berthold's castration and transplantation experiments (1849)
(fig. 1.1).
1. First experimental evidence for the effect of an endocrine gland.
C. 1889 -- Charles-Edouard Brown-Sequard claimed that injecting
testicular extracts restored vigor.
D. First androgen extracted in 1931 by Adolf Butenand.
E. Testosterone was isolated from testicular extracts in 1935 by
Ernst Laquer.
1. Structure determined and synthesized in 1939 independently byButenandt and Leopold Ruzicka.
II. Testes. [pp. 422-423]
A. Functions.
1. Production of spermatozoa.
2. Secretion of testosterone.
B. Located outside of body cavity in scrotum.
1. Descend from abdominal cavity prior to birth (figure).
2. Cooler temperature for spermatogenesis.
3. Evolutionary significance?
4. Cryptorchidism = undescended testes.
a. Decreased fertility.
b. Increased risk of testicular cancer.
C. Seminiferous tubules (fig. 17.1).
1. Network of tubules for production and transport of sperm.
2. Make up 90% of weight of testes.
3. Composed of germ cells (spermatogonia) and Sertoli cells.
4. Base of Sertoli cell is adjacent to the basal membrane of the tubule.
5. Sertoli cell surround developing germ cells.
6. Sertoli cells secrete inhibin.
D. Leydig cells (interstitial cells).
1. Located outside of seminiferous tubules (figure).
2. Secrete testosterone.
III. Androgen Biosynthesis. [pp. 423-424]
A. Occurs in testes (Leydig cells), ovaries (thecal cells), and
adrenal cortex (zona reticularis).
B. Biosynthetic pathway (fig. 17.2).
1. Precursor is cholesterol.
2. Removal of two carbons by 17,20-desmolase diverts pathway from
glucocorticoid (C21) to androgen (C19).
3. Other androgens -- dehydroepiandrosterone (DHEA) and
androstendione.
IV. Feedback Control of Testosterone Secretion. [pp. 425-426]
A. Feedback diagram (fig. 17.3).
B. Gonadotropins.
1. Pituitary gonadotropes secrete both luteinizing hormone (LH) and
follicle-stimulating hormone (FSH).
2. LH and FSH are glycoproteins in the same family as TSH.
3. LH stimulates steroidogenesis in Leydig cells (fig. 17.2).
4. FSH required for spermatogenesis.
C. Gonadotropin-releasing hormone (GnRH).
1. Produced by hypothalamus.
a. Secretion is pulsatile every 1.5 hr.
2. Stimulates secretion of both FSH and LH by pituitary gonadotropes.
3. Decapeptide -- structure identified by Roger Guillemin in 1971.
4. More than a thousand synthetic analogs have been produced.
D. Negative feedback.
1. Secretion of GnRH, LH, and FSH is inhibited by testosterone.
2. FSH secretion is selectively inhibited by inhibin.
a. Peptide hormone secreted by Sertoli cells.
V. Transport of Testosterone. [pg. 426]
A. In blood, 99% bound to plasma proteins.
1. Sex hormone-binding globulin (SHBG).
B. In reproductive tract, bound to androgen binding protein (ABP).
VI. Biological Effects of the Androgens. [pp. 404-411, 427-434]
A. Androgenic actions.
1. Differentiation of male reproductive tract and external genitalia.
2. Growth of prostate gland and seminal vesicle -- basis of bioassay.
3. Stimulation of male secondary sex characteristics.
4. Spermatogenesis.
B. Anabolic actions.
1. Accelerated growth of long bones, followed by closure of epiphyseal
growth plates.
2. Muscular development, especially chest and shoulders.
C. Actions on brain and behavior.
1. Organizational -- maturation and differentiation of brain areas.
a. Sexually dimorphic nucleus in preoptic area of hypothalamus.
1. 5x larger in male than in female.
2. Area is responsible for gonadotropin release and sexualbehavior.
b. Brain areas controlling song are much larger in male birds
(which sing) than in females (which do not sing).
c. Critical period is a few days after birth in rats.
1. Single injection of testosterone in a female rat during this critical
period results in lack of estrous cycles and male sexual behavior
in mature females.
2. Activational -- acute effects on behavior in adults.
a. Reversible, repeatable, not limited to a critical period of development.
b. Song in male canaries.
1. Castrate male canaries ----> no song.
2. Inject ovariectomized female canaries with testosterone ---->song.
c. Libido.
d. Aggression.
VII. Mechanism of Action of Androgens. [pp. 405-410, 414, 434-435]
A. Two-step hypothesis (fig. 17.6).
1. Easily crosses cell membranes.
2. Binds to cytoplasmic receptors.
3. Hormone-receptor complex enters nucleus, binds to nuclear chromatin.
4. Directs synthesis of specific proteins.
B. Modification of testosterone is required in some tissues.
1. Reduction in cytoplasm by 5-a-reductase.
a. Converts testosterone to dihydrotestosterone (fig. 16.7).
b. DHT is required for differentiation of external genitalia and growth
of prostate gland (fig. 16.8).
c. Not required for development of vas deferens and adult secondary
sex characteristics appearing at puberty.
d. DHT mediates male pattern baldness.
2. 5-a-reductase deficiency.
a. Clusters of cases in one village in Dominican Republic.
b. Characteristics.
1. Poorly developed male external genitalia at birth.
a. Raised as females.
2. Normal male internal structures.
3. At puberty, develop male phenotype.
a. Voice deepens.
b. Muscular development.
c. Penis enlarges (guevedoces).
d. Scanty beard growth.
e. Able to produce sperm.
3. Finasteride -- 5-a-reductase inhibitor.
a. Inhibits growth of the prostate.
b. Useful in benign prostatic hyperplasia.
c. Treatment of male-pattern baldness (Propecia).
4. Conversion to estradiol by aromatase.
a. Required for male differentiation of brain (fig. 16.10).
b. Circulating estrogen binding protein levels are high in neonatalfemale prevents exposure to maternal estrogen.
c. Required for sealing of epiphysial growth plates.
1. Based on case studies of aromatase-deficient males
(Carani, C., et al. N. Engl. J. Med. 337: 91-95, 1997).
VIII. Anabolic-Androgenic Steroids. [pp. 432-433]
A. Preparations (figure).
1. Testosterone is rapidly metabolized by liver.
2. Injectables (ex. Deca-Durabolin).
3. Methyl group at C17 allows oral use (ex. Dianabol).
B. Therapeutic uses.
1. Hypogonadism.
2. Hypopituitarism.
3. Chronic debilitating diseases.
C. Abuse by athletes.
1. Increase in muscle mass and strength when combined with training and
proper nutrition.
2. Use condemned by most athletic organizations
(Welcome aboard, Major League Baseball!).
D. Side effects.
1. Depression of spermatogenesis.
2. Liver damage.
a. Only caused by 17-methyl steroids (ex. Dianabol).
b. Range from hepatitis to liver cancer.
3. Increased risk of heart attack.
4. Acne.
5. Aggressive behavior.
6. Addictive.
7. Precocious puberty in young males.
8. Virilization of females.
IX. Antiandrogens [pg. 435]
A. Compete with androgens for receptors (ex. cyproterone acetate)
(fig. 17.7).
B. Therapeutic uses.
1. Hypersexuality.
a. Loss of libido after 2 weeks of daily oral doses.
2. Precocious puberty.
3. Prostate cancer.
a. Present in all men aged 80 or over.
b. Most common treatment -- combination of castration and estrogen
therapy.
X. Spermatogenesis. [pp. 423, 427-428]
A. Spermatozoa were first observed under the microscope by Antonie
von Leeuwenhoek and Stephen Hamm in 1677.
B. Regulation of spermatogenesis (fig. 17.4).
1. Follicle-stimulating hormone (FSH).
a. Binds to membrane receptors on Sertoli cells.
b. Acts via adenylate cyclase.
2. Testosterone.
a. Binds to cytoplasmic receptors in Sertoli cells.
b. Activates specific genes.
C. Sequence of events.
1. Spermatogonia undergo mitotic division and differentiate into
primary spermatocytes (46 chromosomes) (figure).
2. Primary spermatocytes undergo first meiotic division to form two
secondary spermatocytes (23 chromosomes).
a. Requires very high concentrations of testosterone.
3. Second meiotic division occurs rapidly to produce four spermatids.
a. Small, rounded cells (23 chromosomes).
4. Eliminate majority of cytoplasm, form spermatozoa.
a. Tails extend into lumen of tubule.
b. Heads are surrounded by folds of Sertoli cells (figure).
c. Maturation of spermatids requires FSH.
1. No FSH receptors on spermatids.
D. Human spermatogenesis takes about 72 days.
1. Average production 200 million sperm per day.
XI. Sperm Transport through Duct System. [pg. 423]
A. Sperm take about 14 days to pass through the duct system.
1. During this time, they mature and increase motility.
B. Within testis.
1. Seminiferous tubules are connected to the rete testis (fig. 17.1, figure).
2. Drain via the efferent ductules.
C. Mature sperm stored in epididymis.
1. Long, coiled tube attached to the posterior side of each testis.
2. Under influence of testosterone, epididymis secretes substances that
maintain sperm.
3. Testosterone (produced by Leydig cells) and androgen binding
protein (produced by Sertoli cells) are released along with
spermatozoa into epididymis.
D. Vas deferens.
1. Tube extending from epididymis into abdomen behind the urinary
bladder, then joining urethra.
2. Shortly before ejaculation, sperm move through vas deferens and mix with
secretions of prostate gland and seminal vesicles to form semen.
E. Urethra.
1. Tube extending through center of penis.
2. Passage for both urine and semen exits tip of penis.
F. Typical human ejaculate contains 300 million sperm.
XII. Male Contraception.
A. Condoms.
1. Absolutely safe.
2. Failure rate = 10 pregnancies/100 women/year (10%).
B. Vasectomy (figure).
1. Cut and tie vas deferens.
2. Minor surgical procedure.
3. Does not affect secretion of testosterone, spermatogenesis, or
sexual performance.
4. Semen contains no spermatozoa.
5. Failure rate = 1/1000.
6. Risk ‑‑ unknown.
C. Inhibition of spermatogenesis.
1. All methods are experimental.
2. Major drawback ‑‑ large number of sperm produced.
a. Male with 99% reduction of sperm count can still father a child.
3. Estrogens.
4. GnRH antagonists or high‑dose GnRH analogs.
5. Androgen alone.
D. Sugar analogs (ex. 6‑chloro‑6‑deoxyglucose).
1. Block glucose metabolism in spermatozoa ----> necessary for motility.
2. Problems: Potential effects on CNS.
E. Gossypol.
1. Constituent of uncooked cottonseed oil.
2. History -- burning fever in China, followed by infertility.
3. Orally active.
4. Decreases sperm motility within a few days.
5. Decreases spermatogenesis long‑term.
6. 99.9% effective.
7. Mechanism unknown.
8. Problems: Hypokalemia, weakness, reversibility.
