BIO 5406 Notes, 3/29/05
FEMALE REPRODUCTIVE ENDOCRINOLOGY
I. History. [Hadley, pg. 445]
A. Removal of ovaries results in uterine atrophy and loss of reproductive
ability.
B. 1895 -- Emil Knauer showed that some effects of ovariectomy could
be reversed by ovarian transplants.
C. 1917 ‑‑ Charles Stockard and George Papanicolaou reported
changes in vaginal cells during estrous cycle of guinea pigs.
D. 1923 ‑‑ First bioassay of estrogens, developed by Edgar Allen and
1. Based on rat vaginal smear.
2. Used to demonstrate the existence of the first female sex hormone ‑‑
an impure preparation of estrogens obtained from follicular fluid of sow
ovaries.
E. 1926 ‑‑ Allen showed that estrogen levels varied with the phases of
the menstrual cycle.
F. 1927 -- Estrogen levels were high in urine of pregnant women.
G. 1929 - 1935 -- Doisy and co‑workers extracted and purified various
estrogens from the urine of pregnant women and determined their
structures.
H. 1934 -- Adolf Butenandt purified progesterone.
II. Ovaries. [pp. 446-447]
A. Paired organs suspended by ligaments from pelvis (fig. 18.1).
1. Human ovaries are 4 cm long, 2 cm wide.
B. Functions.
1. Production of ova.
2. Secretion of estrogen and progesterone.
C. Anatomy (figure).
1. Cortex.
a. Largest portion of ovary.
b. Contains functional units of ovary -- follicles.
2. Medulla.
a. Mostly connective tissue.
3. Hilum.
a. Entry point for nerves and blood vessels.
D. Composition of follicle (figure).
1. Each encloses an oocyte.
2. Oocyte is surrounded by granulosa cells.
3. Outer layers of thecal cells.
III. Secretion of Estrogen and Progesterone. [pg. 451]
A. Secretion begins at puberty.
B. Secreted in a cyclic manner until menopause.
C. Elevated during pregnancy.
D. Very low levels after menopause.
III. Biosynthesis of Female Sex Hormones. [pp. 451-453]
A. Estrogen biosynthesis (fig. 18.6).
1. Precursor ‑‑ cholesterol.
2. Androgen synthesis in thecal cells (fig. 18.5).
a. Products: Testosterone and androstenedione.
3. Aromatization of androgens in granulosa cells.
a. Product: Estradiol.
B. Progesterone biosynthesis.
1. Early intermediate in steroid biosynthesis (figure).
2. Produced in large quantities by corpus luteum of ovary and by
placenta.
IV. Control of Estrogen Secretion. [pp. 456-459]
A. During most of the follicular phase of the menstrual cycle, estrogen
secretion is controlled by a negative feedback loop involving the
hypothalamus and pituitary.
B. Controlled variable is the estrogen concentration in blood.
C. Feedback diagram (fig. 17.3, figure).
1. Thecal cells contain LH receptors.
a. Act via stimulation of adenylate cyclase.
2. Granulosa cells contain FSH receptors.
a. Act via stimulation of adenylate cyclase.
3. Inhibin, secreted by granulosa cells, inhibits FSH secretion.
V. Effects of Female Sex Hormones. [pp. 454-455]
A. Effects of estrogen -- not apparent until puberty (table 18.1).
1. Estrogenic actions.
a. Maturation of female reproductive tract (at puberty).
b. Stimulation of female secondary sex characteristics.
1. Development of mammary glands.
2. Distribution of fat.
3. Female distribution of body hair.
4. Higher voice.
c. Oogenesis.
d. Cyclic changes in uterus.
2. Anabolic actions.
a. Bone growth, followed by closure of epiphyseal discs.
b. Increased synthesis of specific proteins (oxytocin receptors,
thyroid binding globulin).
3. Actions on brain and behavior.
a. Receptive sexual behavior during estrus.
B. Effects of progesterone (table 18.1).
1. The primary function of progesterone is to prepare and maintain the
proper environment for pregnancy.
a. Cyclic changes in uterus.
1. Thick, spongy, and highly vascular.
2. Thickening of cervical mucus.
b. Inhibits uterine contraction.
c. Enlargement of mammary glands.
d. Increases body temperature.
e. Inhibits ovulation.
VI. Mechanism of Action of Estrogen and Progesterone. [pp. 455-456]
A. Binds to cytoplasmic receptors (figure).
B. Hormone-receptor complex is translocated into nucleus.
C. Binds to hormone response elements on nuclear chromatin.
D. Induces synthesis of specific mRNA's and their subsequent translation
into specific proteins.
VII. Oogenesis. [pp. 446-450]
A. Primordial follicles.
1. Oogonia undergo mitosis to form several million primary oocytes at
beginning of third trimester.
2. Primordial follicle = primary oocyte surrounded by a single layer of
flattened granulosa cells (fig. 18.2, figure).
3. At birth, 2 million follicles remain.
a. No new follicles will form after birth.
4. Lose 80% of these by puberty.
5. Will ovulate about 400 times.
B. Primary follicles.
1. Some primordial follicles form primary follicles.
2. Granulosa cells become cuboidal (figure).
C. Secondary follicles.
1. Each month, several follicles begin to grow.
2. Multiple layers of granulosa cells (figure).
3. Surrounded by thecal cells.
3. Secrete fluid into antrum -- liquor folliculi.
4. Only one or two survive.
5. All others degenerate -----> atretic follicles.
D. Mature follicle (Graafian follicle).
a. Oocyte is contained within mound of granulosa cells
b. Fluid-filled antrum.
c. Follicle grows to 1‑2 cm.
d. Bulges on ovarian surface (figure).
e. Shortly before ovulation, primary oocyte undergoes meiosis ----->
secondary oocyte (ovum).
1. Cytoplasm is divided unevenly (polar body).
E. Ovulation.
1. Graafian follicle bursts, releasing ovum, surrounded by granulosa
cells.
2. Second meiotic division is arrested in metaphase until
immediately after fertilization.
3. Follicle changes into corpus luteum.
a. Theca and granulosa cells differentiate into lutein cells.
b. Large, pale‑staining cells with large nuclei.
c. Lipid droplets accumulate within cytoplasm.
VIII. Menstrual Cycle. [pp. 460-463]
A. Characteristics.
1. Primates.
2. About 28 days in length.
3. Controlled by cyclic changes in secretion of gonadotropins.
4. Female is sexually receptive throughout the cycle.
5. Accompanied by changes in the inner epithelial lining of the uterus
(endometrium).
a. Joseph Markee -- direct observation of uterine blood vessels
throughout the menstrual cycle (1940).
1. Transplanted endometrial tissue into anterior chamber of the
eye in monkeys.
6. Changes in vaginal epithelium.
a. Can be identified by vaginal smears.
B. Phases of the menstrual cycle (figure).
1. Menstrual phase (days 1‑5).
a. Day 1 = first day of menstrual bleeding.
b. Menstruation = shedding of endometrium (fig. 18.12).
c. Estrogen and progesterone levels are lowest (fig. 18.11).
d. FSH levels are slightly elevated.
e. Ovary contains only primary follicles.
2. Follicular phase (days 6‑13).
a. FSH stimulates growth of a few follicles.
1. One will become a mature follicle.
b. As follicles grow, they secrete more estrogen.
c. Rising estrogen levels stimulate proliferation of endometrium.
1. Proliferative phase.
d. Estrogen stimulates proliferation of vaginal epithelium.
1. Vaginal smear contains nucleated epithelial cells.
e. Rapid rise in estrogen stimulates surge in LH and FSH (LH surge).
1. Positive feedback loop (figure).
f. Events responsible for the LH surge.
1. Two centers in hypothalamus regulating GnRH secretion.
a. Tonic center ‑‑ pulsatile release of small amounts of
GnRH (every 1 ‑ 2 hr).
1. Stimulates secretion of LH and FSH.
2. Suppressed by testosterone, estrogen, or progesterone.
3. Negative feedback control of testosterone in male and
estrogen in female.
b. Cyclic center ‑‑ releases a large pulse of GnRH in
response to high estrogen levels.
1. Stimulated by a critical level of estrogen.
2. Inhibited by progesterone.
3. Not found in males.
2. Sensitivity of gonadotropes to GnRH.
a. Increased by estrogen (contribute to LH surge).
b. Decreased by continuous administration of GnRH.
1. Down‑regulation after 4 hr.
2. Ends LH surge.
3. Injection of high doses of estrogen can trigger an LH surge in
females, but not in males.
a. Produces LH surge in some homosexual males.
b. Suggests that homosexual males have a cyclic center.
c. Lends support to biological basis of homosexuality.
3. Ovulation (day 14).
a. LH surge causes thin wall of mature follicle to rupture.
b. Ovum is released into oviduct (ovulation) (figure).
c. Cornified cells on surface of vaginal epithelium.
d. Ovulation predictor test measures LH in urine.
1. Ovulation will occur within 36 hours after LH surge.
4. Luteal phase (days 15-28).
a. Empty follicle is stimulated by LH to become corpus luteum (figure).
1. Corpus luteum matures to 1.5 ‑ 4 cm.
2. Stores large amount of cholesterol.
b. Corpus luteum secretes estrogen and large amounts of
progesterone.
c. Progesterone levels peak about 1 week after ovulation.
d. Progesterone causes cervical mucus to thicken, prevents
passage of sperm through cervix.
e. Endometrium becomes thick, spongy, and highly vascular.
1. Secretes a substance known as uterine milk.
2. Prepared to nourish embryo.
3. Secretory phase.
f. Leukocytes invade vaginal epithelium.
g. Progesterone inhibits secretion of LH and FSH.
1. Prevents another ovulation.
h. Corpus luteum requires continued hormonal stimulation.
1. If ovum is not fertilized, corpus luteum degenerates about
10 days after ovulation due to lack of LH.
i. Estrogen and progesterone levels decline.
5. Menstrual phase.
a. Progesterone withdrawal leads to constriction of arteries in
endometrium -----> cell death.
1. Two-thirds of endometrium is shed (menstruation).
IX. Estrous Cycle. [pg. 460; Ovariectomy Lab Handout]
A. Characteristics.
1. Nonprimate mammals.
2. Cycle varies in length from 4 days (rats, mice, hamsters) to 60 days
(dogs, foxes).
3. Sexually receptive only during estrus.
4. Some cycle only during mating season with a long anestrus period
between cycles (sheep).
5. Ovulation is induced by mating in some species (cats, rabbits).
B. Phases of the estrous cycle (figure).
1. Proestrus -- day 1.
(equivalent to follicular phase in menstrual cycle)
a. Prior to ovulation.
b. Ovarian follicles begin to mature.
c. Estrogen levels rise and reach a peak.
d. Rising estrogen levels stimulate surge in LH and FSH.
e. Vaginal smear -- nucleated epithelial cells (figure).
2. Estrus -- day 2.
(equivalent to ovulation in menstrual cycle)
a. Ovulation occurs a few hours after midnight.
b. Receptive to male for 9 - 15 hr.
c. Progesterone surge (unlike menstrual cycle).
d. Vaginal smear -- squamous cornified epithelial cells without
obvious nuclei.
3. Metestrus (early diestrus) -- day 3.
(equivalent to early luteal phase in menstrual cycle)
a. Formation of corpora lutea.
b. Secretion of progesterone by corpora lutea.
c. Gonadotropins are low.
d. Vaginal smear -- increasing numbers of leukocytes.
4. Diestrus (late diestrus) -- day 4.
(equivalent to late luteal phase in menstrual cycle)
a. Corpora lutea regress.
b. Progesterone secretion declines.
c. Gonadotropins are still low.
d. Vaginal smear -- many leukocytes and few epithelial cells.
X. Menopause. [pp. 487-490; Jordan article]
A. About age 50, ovaries run out of oocytes.
1. Estrogen levels decline.
2. Ovulation and menstruation cease.
3. What about FSH?
B. Consequences.
1. Hot flashes -- 75% of women.
2. Decreased vaginal secretions -----> painful intercourse.
3. Emotional changes (fatigue, irritability).
4. Loss of bone mass -----> osteoporosis.
5. Increased LDL cholesterol -----> increased risk of heart attack.
C. Treatment.
1. Estrogen replacement therapy.
a. Increased risk of breast cancer and uterine cancer.
b. Risk is lowered by adding progestin.
c. Women's Health Initiative (J. Am. Med. Assoc. 288: 321, 2002).
1. Enrolled over 160,000 postmenopausal women into a set of
clinical trials of low-fat diet, calcium, vitamin D, or hormone
replacement therapy.
2. 16,608 postmenopausal women with intact uteri were given
estrogen + progestin or placebo in a randomized controlled
trial with a planned duration of 8.5 years.
3. Study was discontinued in 2002 after 5 years of follow-up due
to risks exceeding benefits.
4. Estrogen + progestin reduced risk of colorectal cancer and
hip fracture (hazard ratio significantly below 1).
5. No significant risk of endometrial cancer.
6. Increased risk of breast cancer, coronary heart disease,
stroke, and pulmonary embolism (hazard ratio significantly
above 1).
7. No change in total mortality.
8. Conclusion: Overall health risks exceeded benefits from use of
combined estrogen + progestin for 5 years.
9. Recommendation: Estrogen + progestin should not be initiated
or continued for primary prevention of coronary heart disease.
2. Selective estrogen receptor modulators (SERM).
a. Preparations.
1. Tamoxifen (fig. 18.8).
2. Raloxifine.
b. Bind to estrogen receptors.
1. Block some effects of estrogen.
2. Mimic other effects.
3. Discussion of Jordan article (Jordan, V.C. Designer estrogens.
Sci. Am. 279 (4): 60-67, Oct. 1998).
XI. Treatment of Infertility. [Pace article]
A. One out of seven American couples is infertile.
1. Clinical definition ‑‑ at least one year of unsuccessful
attempts to achieve pregnancy.
B. Drug treatments.
1. Antiestrogens (ex. clomiphene, Clomid).
a. Competitive antagonist of estrogen at tonic center.
b. Blocks feedback inhibition of GnRH secretion.
c. Increases secretion of GnRH and gonadotropins.
d. Administered orally for the first 5 days of each cycle.
e. Increased incidence of multiple births, mostly twins.
2. Gonadotropins.
a. Extracted from the urine of postmenopausal
women (convent in Italy).
b. Daily i.m. injections for 10 days.
1. Stimulate follicular development.
c. Followed by a single injection of chorionic gonadotropin
1. From urine of pregnant women.
2. Mimics the LH surge.
d. 20% multiple births.
3. GnRH agonists.
a. Must be injected in pulsatile fashion (every 90 min).
b. Other uses (continuous GnRH infusion).
1. Prostate cancer.
2. Endometriosis.
3. Precocious puberty.
4. Contraception.
XII. Fertilization. [pp. 474-475]
A. Transport of gametes.
1. Ovum is released into abdominal cavity at ovulation (figure).
a. Surrounded by granulosa cells.
b. Enters oviduct.
c. Propelled by cilia towards uterus.
d. Viable for up to 3 days.
2. Sperm deposited in vagina during intercourse (figure).
a. Must pass through cervix, uterus and enter oviduct.
b. At time of ovulation, cervical mucus is thin and watery.
c. Contractions of uterus and oviduct oppose movement of sperm.
d. About 100 reach each oviduct.
e. Sperm are viable 3‑5 days.
B. Conception.
1. Sperm and ovum meet in upper third of oviduct.
2. Head of sperm contains enzymes which will digest the outer coating
of ovum (figure).
a. After first sperm enters, chemical change in outer coating prevents
entry of other sperm.
3. Sperm and ovum combine.
a. Oocyte completes second meiotic division.
b. Chromosomes combine to form diploid number.
XIII. Pregnancy. [pp. 475-478]
A. First division occurs 30‑36 hr after fertilization.
B. Three days after fertilization, compact mass of cells (morula) enters
uterus.
C. Six days after fertilization, embryo attaches to endometrium ----->
implantation.
D. Outer portion of embryo develops into chorion (figure).
1. Will later become fetal portion of placenta.
2. Secretes chorionic gonadotropin (hCG).
a. Glycoprotein.
b. Same alpha subunit as LH, FSH and TSH.
c. Acts like LH to maintain corpus luteum.
1. LH and hCG receptors on corpus luteum are identical.
2. Corpus luteum continues to secrete estrogen and progesterone.
d. Secretion declines after 10th week -----> corpus luteum degenerates
(figure).
e. Basis of pregnancy test ‑‑ immunoassay of hCG in blood or urine.
E. Placenta.
1. Disc‑shaped structure made up of both maternal and fetal tissue
(figure).
2. Amniotic sac surrounds fetus.
a. Inside is amniotic fluid.
b. Amniocentesis ‑‑ sampling of amniotic fluid (figure).
1. Prenatal diagnosis of Down syndrome, Tay‑Sach's disease.
2. Determine lung maturity before birth
3. Functions.
a. Nutrition ‑‑ exchange of nutrients between maternal blood and
fetal blood.
b. Waste removal -- exchange of waste material between fetal and
maternal blood.
c. Secretion -- of hormones to maintain pregnancy and develop
mammary glands.
1. Progesterone.
a. Maintains endometrium.
b. Stimulates mammary gland development.
c. Suppresses gonadotropin secretion.
d. Suppresses uterine contractions.
2. Estrogen.
a. Placenta lacks 17‑hydroxylase.
b. Estrogen must be synthesized from fetal adrenal androgens.
c. Stimulates uterine development (ex. increases number and
sensitivity of oxytocin receptors..
d. Stimulates mammary gland development.
3. Chorionic somatomammotropin ‑‑ last trimester.
a. GH‑like and prolactin‑like actions.
b. Stimulates breast development.
c. Initiates milk synthesis (also known as placental lactogen).
4. Prolactin.
a. Identical to pituitary prolactin.
b. Stimulates milk production.
XIV. Parturition. [pp. 478-482]
A. Normal gestation in human = 40 weeks.
B. Labor is characterized by powerful contractions of uterine smooth
muscle (figure).
C. Endocrine control of parturition.
1. Fetal adrenal cortex hypertrophies close to term -----> increased fetal
cortisol production.
a. Timing is controlled by fetal brain.
2. Glucocorticoids cause increased production of estrogen from
progesterone in placenta.
3. Increase in estrogen increases sensitivity of uterine smooth muscle.
4. Drop in progesterone removes inhibition of uterine contractions.
5. Local production of prostaglandins soften cervix and stimulate uterine
contractions.
6. Oxytocin secretion increases -----> stimulates uterine contraction
(positive feedback loop).
D. Relaxin.
1. Peptide hormone.
2. Similar in structure to insulin (suggesting common evolutionary precursor).
3. Main source is corpus luteum.
a. In mice and rats, corpus luteum is maintained until late in pregnancy.
1. Relaxin levels peak in the days before parturition (fig. 19.4).
b. In humans, corpus luteum degenerates -----> relaxin levels are
highest in first trimester.
4. Actions.
a. Increased flexibility of birth canal.
1. Softens cartilage in pubic symphysis.
2. Increases distensibility of uterus and cervix.
b. Stimulates nipple growth in mice.
5. Proposed use in induction of labor -- relaxin + mifepristone (RU-486),
an anti-progesterone.
XV. Lactation. [pp. 482-485]
A. Breast development due to E and P.
B. Colostrum ‑‑ first few days.
1. Higher in protein.
2. Contains antibodies from mother.
C. Milk production ‑‑ prolactin.
1. Anterior pituitary hormone.
2. Inhibits secretion of LH and FSH.
D. Milk secretion ‑‑ oxytocin.
1. Milk ejection reflex ‑‑ suckling stimulates production of
prolactin and oxytocin.
XIII. Contraception.
A. Goal ‑‑ to prevent ovulation or fertilization.
B. Sterilization.
1. Male or female sterilization is the most frequently used
contraceptive method in U.S.
2. Tubal ligation.
a. Cut and tie fallopian tubes.
b. Doesn't affect secretion of estrogen, ovulation.
c. Ovum cannot be fertilized.
d. Failure rate = 1/200 to 1/1000 females.
e. Risk ‑‑ pelvic pain in 15%.
C. Rhythm.
1. Timing of anticipated ovulation.
a. Avoid intercourse until a few days after ovulation.
2. Aided by temperature method.
a. Basal body temp decreases slightly about the time of
ovulation ‑‑ effect of estrogen.
b. Increases after ovulation ‑‑ effect of progesterone.
3. Failure rate = 20‑30 pg/100 women/year.
D. Oral contraceptives ‑‑ "the Pill".
1. Development of oral contraceptive.
a. Early observation ‑‑ ovulation is suppressed in mammals
during pregnancy.
1. Linked to corpus luteum.
2. An endocrine function was proposed ‑‑ corpus luteum
secretes a hormone which inhibits ovulation.
b. Ludwig Haberlandt, Austrian physiologist, developed the
concept of reversible hormonal contraception.
1. 1919 ‑‑ Transplanted ovaries from pregnant rabbits
into nonpregnant rabbits ───> they became infertile.
2. Lipid extracts from copora lutea of pregnant cows
rendered rabbits infertile.
3. 1927 ‑‑ Ovarian extracts given orally to mice produced
temporary sterility.
4. 1931 ‑‑ "Of all the methods available, hormonal
sterilization, based on a biological principle, if it
can be applied unobjectionably in the human, is the
ideal method for practical medicine and its future
task of birth control."
5. Died in 1932 and his ideas were forgotten.
XIII. D. 1. Development of oral contraceptive (cont).
c. With the isolation of estrogens and progesterone in the
early 1930's, the next step was to synthesize orally
active steroids in large quantities.
1. Use of plant sterols, such as diosgenin from dioscorea
(related to sweet potato).
2. Two potent progestational agents were developed and
patented in 1952, norethindrone and norethynodrel.
d. The crucial incentive for birth control research came not
from endocrinologists, but from two socially conscious
women.
1. Margaret Sanger, nurse, feminist, and birth control
advocate.
2. Mrs. Page McCormack, a wealthy aristocrat.
3. Mrs. McCormack funded the research of Gregory Pincus,
who began testing norethynodrel in rabbits in 1953.
4. A clinical trial was begun in 1956 in Puerto Rico.
e. Bringing the contraceptive to market.
1. U.S. pharmaceutical companies were very interested
in the new synthetic progestins and estrogens, but
had policies excluding contraceptive research.
2. Primary developer was Syntex N.A., a Mexican
pharmaceutical company.
3. Approved in 1960.
2. Combination of estrogen and progestin for 21 days.
a. Estrogen ‑‑ ethinyl estradiol.
b. Progestins ‑‑ norethindrone or norgestrel.
3. Suppresses the mid‑cycle surge in LH.
4. Last seven pills contain no hormone.
a. Withdrawal of progestin causes menstrual bleeding,
regulates period.
5. Triphasic pill more nearly mimics natural hormonal cycle.
a. Gradually increasing progestin dose.
6. Failure rate = 0.5 pregnancies/100 women/year.
7. Risk ‑‑ low in young, nonsmoking women.
a. Na+ retention, weight gain, hypertension.
b. Breast discomfort, nausea and vomiting.
c. Breakthrough bleeding in low E preparations.
XIII. D. 7. Risks of oral contraceptive use (cont).
d. Blood clotting disorders.
1. Appearance of thrombophlebitis after 5 years of
clinical studies.
2. ^ incidence of stroke, thromboembolism and myocardial
infarction.
3. Risk reduced by reducing dose of estrogen.
4. High risk ‑‑ smokers.
e. Cancer.
1. Do not ^ risk of endometrial or breast cancer in women
of reproductive age.
2. Protects against ovarian cancer.
f. Severe complications of pregnancy are more common.
E. Long‑lasting progestin depots.
1. Norplant contraceptive implant.
1. Contains synthetic progestin.
2. Approved by FDA in 1990.
3. Lasts 5 years.
4. More than 99% effective.
5. Effects are reversed upon removal.
2. Depo‑provera.
a. Given by i.m. injection every 3 months.
b. Used in more than 70 countries.
c. Approved by FDA in 1993.
F. Intrauterine device (IUD).
1. Prevents implantation of fertilized ovum.
2. Inserted by physician.
3. Failure rate ‑‑ 2‑3 pg/100 women/yr
4. Risk
a. Uterine perforation, pelvic infection.
b. A.H. Robins ‑‑ Dalkon shield recall.
c. Withdrawal of Copper 7 and Tatum‑T in 1986.
d. Currently available ‑‑ Progestasert.
G. Barrier contraceptives.
1. Prevent sperm from entering uterus.
2. Diaphragm ‑‑ covers opening of cervix.
3. Must be put on before intercourse. Nuisance.
4. Failure rate = 10‑20 pg/100 women/yr.
5. No risk.
XIII. Contraception (cont).
H. Spermicides.
1. Chemicals which kill sperm.
2. Foam or jelly.
3. Use in conjunction with barrier contraceptives.
4. Vaginal contraceptive sponge.
I. Abortifacients.
1. Drugs which induce abortions.
2. Prostaglandins.
a. Stimulate uterine contractions.
3. RU‑486 (mifepristone) ‑‑ the abortion pill.
a. Antiprogesterone ‑‑ blocks progesterone receptors.
b. Induce menstrual bleeding ───> loss of implanted embryo.
c. Not available in U.S.
XII. Male Contraception.
A. Condoms.
1. Absolutely safe.
2. Failure rate = 10 pg/100 women/year (10%).
B. Vasectomy.
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 males.
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.
a. Suppress gonadotropin release.
b. Decreased libido, feminizing characteristics.
4. GnRH antagonists or high‑dose GnRH analogs.
a. Problem: 9 testosterone ───> loss of libido.
b. Solution: Supplement with testosterone.
c. Problem: Route of administration and toxicity.
5. Androgen alone.
a. Need long‑acting orally‑active androgen without toxicity.
XII. Male Contraception (cont).
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. Read from "Introduction and History of Gossypol".
"In the late 1960's, people in many rural areas of China...complained of fatigue
and of burning of the face, extremities, and other exposed parts of the body. The
farms in the areas raised cotton. The afflicted people could not work in the fields, but
hid in the shade, lying on rocks to get cool. Local doctors were puzzled. The disease
had reached epidemic proportions, but the cause remained unknown. The peasants
called their disease 'the burning fever'.
" Burning fever was especially prevalent in Xingtai, a county in Hebei province.
A local doctor discovered that these affected peasants consumed raw, homemade,
cotton seed oil. Commercially manufactured cotton seed oil had been used in
cooking for many years, but only in the 1960's did the peasants begin to make oil
from uncooked seeds, using their own pressing machines. Raw cotton seeds contain
gossypol which is destroyed by heat. Unlike the commercial process, preparation of
homemade oil does not include heating. Consequently, gossypol remains dissolved
in homemade oil. This substance was discovered to be the cause of the burning
fever.
"As soon as crude cotton seed oil was identified as the source of burning fever,
Xingtai doctors advised their patients to stop pressing their own raw oil. The burning
and fatigue stopped. Several years later, however, many couples were found to be
experiencing fertility problems. A large number of women had amenorrhea, and many
men were impotent. These cases of infertility were regarded as a sequel of burning
fever. When women remained on gossypol‑free diets, many eventually recovered
from amenorrhea. Very few men, despite the elimination of gossypol from their diets,
recovered from their infertility and impotency. Further examination of these men
revealed azoospermia or oligospermia. In addition, some men noted a decrease in
testicular size. Medical and scientific research workers...were sent to the area to
investigate these problems. They confirmed the findings of local doctors. Infertility
was prevalent, and women seemed to recover at a much higher rate than men.
XII. E. 2. "Introduction and History of Gossypol" (cont).
Men who did recover were found to have consumed a lower total amount of cotton
seed oil for shorter periods of time. This information led investigators to hypothesize
whether controlled doses of purified gossypol could be used effectively as a male
fertility‑control agent. Observational studies in the countryside had show that burning
fever, fatigue, and infertility were the most serious effects of gossypol ingestion.
Mortality was not observed as a result of burning fever. Because the rate of recovery
from male infertility was dependent on the amount of cotton oil a man had consumed,
scientists conjectured that infertility would most likely be reversible if the gossypol
dosage could be limited. Cessation of intake would probably lead to restoration of
fertility."
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.
