Endocrinology III
Reproductive Endocrinology
I. Biochemistry
A. Steroid Producing Cells
1. Adrenocortical: The adrenal cortex is the site for production of the steroids
a. Z. glomerulosa
b. Z. fasiculata
c. Z. reticularis
d. These produce a group of hormones: aldosterone (mineral corticoids), cortisol and cortisone (glucocorticoids)
2. Ovarian: Produces estrogen
a. Follicular: Produced during
follicular development – First 14 days of cycle
b. Luteal Steroids: Produced during days 14-28 of
cycle
3. Testicular (Leydig cells): Produce androgens
B. Pathways
1. Cholesterol is modified in one form or another to form different steroids
2. There is a difference between steroids but it’s just a simple difference between androgens and estrogens – Have an affect on receptors
Male Endocrinology
II. The Testis: The primary reproductive structure in the male – Has dual functions: Produces sperm (spermatogenesis) and androgens (steroidalgenesis)
A. Embryology
1. The testis develop in the rear of the abdominal cavity – Around the 7th month or so they descend from the abdominal cavity through the abdominal wall through the inguinal canal into the scrotum
2. The descent of the testes is complete by the 7th month or so and following the descent the opening of the inguinal closes tight around the spermatic cord (contains blood vessels and nerves)
a. If this opening is not closed tightly an inguinal hernia could result – Part of the viscera or gut can become strangled and surgical repair will be needed
b. Need surgery so the gut doesn’t poke through the opening – Can get an inguinal hernia by tearing the viscera
3. The testes descend in the scrotum because the temperature in the scrotum is 2-3 degrees lower than the temperature in the abdominal cavity
a. In order for normal spermatogenesis to occur the temperature has to be less than normal body temperature
b. The temperature has to be 2-3 degrees less is needed for sperm production not androgen production
4. There are two systems responsible for maintaining the temperature of the testes:
a. Pampiniform Plexus: Counter current flow mechanism that supplies the testes and keeps the blood that bathes the testes cooled so that the testes stay cool
i. Problem: Vericoele is when there is a problem with the Paminiform Plexus (a wrong structure) and it doesn’t operate properly so doesn’t cool the testes – Men that suffer from this tend to be sterile
b. Muscle called the cremasteric responds to changes in temperature by contracting and relaxing – When the temperature is too hot the muscle relaxes so that the testes will be further down in the scrotum – When the temperature is too cool the muscle contracts and pulls the testes closer to the body
i. Problem: Crytochidism is uncommon in full term pregnancies – Occurs in premature babies and it is when the testes don’t descend and they’re still in the abdominal cavity (cryptos: hard to see, obscure & orchios: testes)
B. Histological Morphology
1. Longitudinal Section: There are 2-3 hundred lobules within each teste
a. Seminiferous Tubules: There are 2-3 within each lobule and they are the sperm production apparatus – There are 800 feet of seminiferous tubules in the male testes (in a bull there is 15000 feet of seminiferous tubules)
2. X-Section
a. Seminiferous tubules: The seminiferous tubules produce various germ cells – There are different cell types within tubules, germ cells, which are in various stages of development
i. Germ
Cells: These cells are all in different stages of differentiation or maturation
or meiosis (diploid to haploid)
ii. Sertoli Cells: These cells are the substance of
the seminiferous tubules – These cells have a number of different functions
such as:
-Blood testes barrier: (Immune system learns what is self and not self) In the male spermatogenesis does not occur until puberty - These sperm cells are suddenly in the body where the immune system could attack them but sertoli cells create this blood testes barrier
-They nourish the germ cells
-They phagocytize germ cells that haven’t developed properly
-They produce a tubular fluid which help transport the sperm through the tubules
-They produce an androgen binding protein which allows the testes to maintain an increased concentration of androgens (spermatogenesis has to have a high amount of testosterone in order to occur)
-They produce the hormone inhibin
-They increase the enzyme P450 aromatases activity
-They produce Plasminogen activating factor which helps free the sperm from the edge of the lumen of the seminiferous tubules (plaminogen activating factor à plasma)
-They increase the synthesis of transferrin
b. Interstitial Cells of Leydig: Found between in the spaces between the seminiferous tubules and produce androgens
i. Testosterone: The predominant androgen is testosterone which can go to the target tissue and have its affect on that tissue or it can be converted by 5-alpha-reductase into dihydrotestosterone (DHT)
ii. DHT: This can also affect
target tissues – 5-alpha-reductase is found in target tissues (penis, scrotum,
etc.,)
iii. Estrogens: Testosterone can be aromatased into
estrogens (in fat tissues) – Testosterone also produces significant quantities
of estrogen – There are high levels of estrogen circulating during early
follicular stages (usually equal to testosterone) – There are higher amounts of
androgens so the androgens are expressed – Estrogens are expressed when there
is androgen resistance by the body (body builders) and this could cause gynacomastia which is breast development in males (anabolic
steroids could cause this)
III. The Ductile System: 3 elements: The convoluted pathway which take sperm from the testes to outside the urethra, the glands contribute to the semen, and the penis which is designed to put the sperm in the vagina
A. Epididymis: (on the twins) Set on each of the testes and are comma shaped and are 4-5 meters long
1. The sperm are stored and mature in the epididymis
2. The maturation process is important because if you take the sperm from the seminiferous tubules they’re not fertilizable
B. Vas Deferens: (ductus deferens) A tube
1. Vasectomy: Go in on either side of the vas deferens and tie off and cut – Sperm can now no longer get from the epididymis to the urethra – This can be reversed
C. Seminal Vesicles: Contributes 60% to the volume of the semen and create a nutrient rich secretion
1. Nutrients:
Fructose, prostaglandins, and fibrinogen
D. Prostate: Located where the urethra comes out of the bladder
1. In older men, prostatic hypertrophy can occur and this causes the urethra to become strangled and they have difficulty urinating
2. The prostate produces a thin, milky secretion that is quite alkaline and this is important because it make the semen alkaline
a. The vagina is an acidic environment so that microbial growth is retarded but this environment is not good for the motility and life of the sperm
b. Since the sperm are alkaline, they can survive better in the vagina
3. The prostate produces enzyme that create fibrinogen into fibrin – This helps to form a clot at the time of ejaculation so that the semen is trapped in the vagina
4. All secretions contribute to the semen – Men who’ve had a vasectomy can still produce an ejaculate but it is sperm free
IV. Male Sex Act: Tactile stimulation of the glands penis and psychological stimulation
A. Erection: A parasympathetic phenomenon which causes the dilation of the arterioles that supply the penis – These are the only arterioles that are parasympathetically innervated
1. Corpus cavernosum: Cells which help create spongy tissue in the penis and when they are engorged with blood it causes an erection
2. When the sympathetic sexual stimuli is sufficient it causes the contraction of the epididymis, the vas deferens, etc., and this causes ejaculation
V. Female Sex Act
VI. Testosterone
A. Titers - See Figure
1. Plasma testosterone levels as a function of age
2. There is a surge of testosterone during fetal life (in fetal testes) at 8 weeks or so until 18 weeks – This is a critical time for normal development of the male reproductive tract
3. Testosterone levels are low in the neonat after birth
4. Around 3 months there is a surge in testosterone but this has no known function
5. Over the next 10 years testosterone levels are very low
6. At the onset of puberty there is a dramatic increase in the plasma testosterone levels and they continue at this high level until 21 or so and then they decline slightly
7. Start to see a more pronounced decline around the age of 60 or so – There is never an abrupt decline of androgens
B. Role in Sex Determination: For normal male development
1. Genetic Sex: The sex of the child is determined by the type of sperm fertilizing the ovum:
a. Y: Male
b. X: Female
2. Gonadal Sex - testicular determining factor: After
genetic sex is determined all embryos (up to 6 weeks) have the potential to
develop in either direction – The gonads are indifferent
a. If the Y chromosome is present it contains the testes determining gene, the SRY gene – The SRY gene codes for the protein testicular determining factor which causes the gonad to develop into testes and to begin the secretion of androgens
3. Phenotypic: The apparent anatomical sex
a. External genitalia: These come from the same embryonic structure (indifferent) – The genital tubercles, genital fold, urogenital sinus, and the genital swelling are all part of the indifferent and common pathway – They then go to form either female or male genitalia
i. Something directs the common pathway on which was to go – The default if always female – If the indifferent gonad is not exposed to the protein DHT then the gonad will develop into a female
ii. Exposure to DHT determines the male direction but if gonad is not exposed to DHT the gonad will go in the female direction
b. Reproductive tract: Each embryo can go either way, male or female – There is an undifferentiated Wolffian system and Mullerian system
i. The Wolffian system goes towards the male development and the Mullerian goes toward female development
ii. Fetal testes begin producing testosterone and stimulate the Wolffian system to cause the gonad to develop along male lines
iii. The fetal testes produce Mullerian Inhibiting Factor and the gonad develops according to the Wolffian system and represses the Mullerian system and vice versa
iv. Peripherally testosterone is converted by 5-alpha-reductase into DHT which influences the common external genitalia pathway so it makes the pathway go towards the male lines
v. The hormone HCG causes the fetal tissues to produce testosterone
vi. Problems: Some HY fetuses lack 5-alpha-reductase so the gonad would develop testes and the male reproductive tract but the external genitalia would be female
-Adrenogenital Syndrome: (related to adrenal gland) Instead of making cortisol, androgens are being made and cause a problem in the female embryos – Embryos would have ovaries but because of androgens the external genitalia would be male – Would think the girl was a boy until breast development occurred
vii. Androgens have a very important role in the sex development of the reproductive tract and the external genitalia
4. Role in Masculinization of Brain: Fetal androgens cause the male brain
a. The female brain is cyclic because of the cyclic reproduction cycle but the male brain is a-cyclic
b. The default system is towards the female (cyclic brain)
c. The testes produce androgens but they’re converted to estrogens and estrogens convert the male brain into a female brain
d. Male brains have an alpha-fetal protein and it binds to estrogen so that estrogen’s not available to convert the male brain into the female brain
e. Female is the default because males are continuously exposed to estrogen while in their mother’s womb but only females are exposed to androgens
5. Role in Descent of Testes:
Testosterone plays a role in the descent of the testes
6. Role in Sexual Characteristics: Testosterone is very low until you hit
puberty – Androgens play a role in primary and secondary sexual characteristics
– Androgens enhance spermatogenesis but you must have a high level of androgens
present
a. Primary: Causes the growth and maturation of reproductive tract and the internal and external genitalia at puberty and the maintenance of all of the above in the adult
i. This is responsible for libido (sex drive) and has a role in a number of animals (estrogens play a bigger role)
ii. If you castrate a male dog early it doesn’t show the characteristics of a usual male dog but if the dog reaches sexual maturity and it’s then castrated it will act like a non castrated dog (around female dogs and fight with male dogs)
b. Secondary: Responsible for the distribution of body hair and the sexual hair development (face, chest, trunk, and pubic hair) under the influence of testosterone
i. In some cases, androgens cause hair loss (marginal baldness) – Genetic background has an affect on the androgens – Could treat baldness by castration
ii. Causes the enlargement of the larynx and the deepening of the voice and has an affect on the skin (thickening)
iii. Increases the secretion of sebaceous glands
iv. Responsible for bone growth and causes the closure of the epiphyseal plates
v. Responsible for protein synthesis – Nitrogen retention – An increase in muscle development
vi. Causes erythropoiesis
vii. Increases the basil metabolic rate (BMR)
viii. Causes an increase in LDLs – Not an advantage
ix. Responsible for an increase in the synthesis of androgen binding protein (in testes) and helps keep an increased concentration of androgens in the testes (seminiferous tubules)
x. Responsible for fat deposition especially in the abdomens
c. In the male fetus: Testosterone has an affect on the epididymis, vas deferens, seminal vesicles, and the seminiferous tubules
i. DHT has an affect on or is responsible for the penis, scrotum, and the prostate
d. In the adult male: Testosterone has its affect on and is responsible for the penis, seminal vesicle, sperm production, skeleton and muscle, libido, and larynx
i. DHT is responsible for and has its affect on scrotum, prostate, hair, and sebaceous gland
VII. Regulation
A. The hypothalamus makes Gnrh which has its affect on FSH and LH (produced by the anterior pituitary)
B. LH: It gets into the blood and goes to the Leydig cells and has an influence on testosterone
1. Testosterone has lots of affects but has an affect on the Sertoli cells which cause an increased concentration of the androgen binding protein which then has its affect on testosterone
a. This is a classic negative feedback system
C. Gnrh causes the production of FSH which has an affect on the Sertoli cells and causes an increase in the androgen binding protein and causes spermatogenesis
1. Spermatogenesis strongly shuts off FSH but not LH (Gnrh is not affected)
2. Inhibin shuts off FSH and also represents a potential birth control pill for men
D. Could there be a substance to inhibit Gnrh? No because inhibiting Gnrh would take care of the sperm but would cause testosterone production to stop and would stop the demasculinating affect
1. Inhibin just affects FSH and spermatogenesis
VIII. Age Related Changes
A. Pre-puberty to puberty:
1. During the pre-puberty period testosterone levels are very low and there is decreased activity due to hormonal and neuronal mechanisms
2. There is an incredible sensitivity in the hypothalamus and the pituitary to testosterone and the production of it
3. Neuronal Regulation: There is direct neuronal inhibition which directly inhibits Gnrh
B. At the onset of puberty what happens in the body? Not sure what happens but they think that the onset of puberty is related to body weight and at the amount of fat present in the body
1. There is some evidence for women that are lean and stop their cycles that if food is limited then it makes no sense to make offspring especially if the parents don’t have sufficient body energy
2. Melatonin: They think that this has something to do with the onset of puberty – If you remove the pineal gland in animals, they experience an early puberty (pinealectomy) – In normal individuals there is a decrease in melatonin secretion at the onset of puberty
a. Melatonin has a negative influence in the gonad
b. Melatonin is thought to be influenced by light – Light inhibits melatonin and darkness stimulates melatonin
3. Senescence: There are some changes in testosterone levels and there is a lack of the gonad’s acceptability for LH and FSH – The hypothalamus and anterior pituitary aren’t affect but the testes loose their sensitivity to LH and FSH
IX. Xenoestrogens (xeno: foreign) so foreign estrogens
A. There is some evidence that we are being exposed to chemicals that are estrogenic (bi-product of industrialization) or that mimic estrogens such as petroleum, insecticides, food preservatives, and chemicals that make plastics soft
1. There is evidence that the exposure to estrogenics are linked to abnormalities in male reproductive tract
2. Since 1940 there has been a declining sperm count (sperm per ml of ejaculate) and a decline in the volume of ejaculate
a. There is half the number of sperm today then from 50 years ago
3. Increases chances for testicular cancer
4. Increases reproductive tract abnormalities
5. Increases cryptorctimism and hypospadia which is when the penis does not form completely (urethral folds do not complete close) – Results in gender bending (like hermaphroditic fish)
6. Also causes an increased chance for breast cancer in women
Female Reproductive System
I. Introduction
A. Cyclic activity: Periodic production of ova or eggs and fluctuations in the sex hormone secretions and the length of the cycle varies
1. EX: Mice have a cycle every 4-6 days and bats just once a year but in humans the cycle is about every 28 days
2. Ovarian cycle produces cyclic changes in the lining of the uterus and causes changes because it is preparing for the reception and implantation of the sperm to the egg
a. If no zygote or fertilized egg comes together in the uterus the endometrium is sloughed off (only in higher primates does the cycle lead to bleeding or menstruation so referred to as the menstrual cycle) – In other species is called an estrous cycle (similar in regulation to the menstrual cycle)
b. In the estrous cycle there is no bleeding from the endometrium – Is a defined period of heat called the estrus period
3. Follopia was an anatomist in
a. Keep in mind that during estrous the vulva enlarges and there is vaginal discharge in dogs
b. Every time he found ova he found vaginal discharge so Follopia concluded that ovulation occurs when there is vaginal discharge – There is menstrual discharge and ovulation in humans also
c. Follopia’s work was then used for a socio-biological phenomena by the Roman church and he was asked for advice about avoiding pregnancies in women so Follopia encouraged sexual intercourse when the sperm was farthest away form the oviduct and he said that the best day to avoid pregnancy was at day 14
d. This is not right!
4. Menarche: Starts around 9-15 years old – The cycle is active for 30-40 years unless a pregnancy occurs until menopause
II. Functional and Anatomical Overview: Looking at menarche
A. The Ovary: There are 2 ovaries that are paired glands – They’re about the size of an unshelled almond
1. The outer portion of the ovary is the germinal epithelium
a. People used to think that the germinal epithelium is where the ova were produced – Not true
2. The outer zone is the cortex and contains the ova
3. The germ cells are found to be associated with follicles
4. The ova in the follicles are in varying stages of development
5. Inside the ovaries is the medulla or the center portion
6. Ovaries
produce mature ova and sex steroids or hormones
B. The Oviducts: There is 1 on each side of the ovaries and they have
fingerlike extensions called Fimbriae
1. The fimbriae beat back and forth and help direct the ova in to the oviduct and they help create a current
2. The oviducts extend down and are about 4-5 inches long
3. Fertilization occurs in the first 1/3 portion of the oviduct
4. The oviduct goes down to the uterus
C. The Uterus: The uterus is pear shaped and is composed of several different
layers
1. Its overall role is to provide an appropriate environment for the developing fetus
2. It also provides a mechanical force for forcing the fetus through the cervix during parturition
3. There are 3 layers: Epimetrium (outside), Myometrium (muscular layer), and the Endometrium (the inner portion)
4. These layers are under hormonal control
5. The myometrium helps to expel the fetus and is under endocrinological control (menstrual cramping)
6. The endometrium sloughs off during menstruation
D. Vagina: Passageway for menstrual flow, childbirth, and sperm
1. It is a tubular fibrous organ and is lined with mucus secreting cells
2. There are folds of vascularized tissue at the end of the vagina that forms a border around the opening, partially occluding it, called the hymen
a. The extent and durability of the hymen varies
b. The hymen may be torn due to athletic activities, tampons, or intercourse for the 1st time
E. Vulva: A collective term for all the external genitalia
1. Mons pubis: An elevation of
adipose tissue covered by skin and hair and serves as a cushion for the pubic symphisis – From the mons pubis extend 2 longitudinal folds
of skin:
2. The labia: The labia majora and the labia minora
3. Clitoris: A small cylindrical mound/mass of tissue (like the penis) that
engorges with blood and erects during sexual activity
4. Vestibule: A cleft space between the labia minora
a. Within the vestibule are the hymen, the vaginal orifice, the external urethral orifice, and openings to several mucus producing cells and glands
b. The mucus producing cells and glands provide mucus during sexual stimulation for lubrication for the penis
III. The Ovarian Cycle: The ovarian cycle is everything in the ovary
A. Follicular Phase: During embryological development there are primordial germ cells which produce oogonia by mitotic division
1. At weeks 20-24 of fetal development in the female there are about 7 million oogonia and during this same time and until about 6 months after parturition the oogonia begin prophase of the 1st meiotic division (primary oocyte)
2. After the 1st meiotic division of the 1st prophase the process is arrested and you have a primary oocyte
3. The next step is the conversion of the naked oocyte into a primary follicle (a laying down of cells around the outside: granulosa cells) or primordial follicle
4. During this time a significant amount of attrition takes place so at about 6 months of age there are only about 2 million primordial follicles
5. The 2 million primordial follicles have one of two fates:
a. To become a mature follicle and ovulate
b. To be atretic and degenerate
6. Before puberty, many follicles begin to develop and may reach the primary follicle state but more will become atretic so that only about 400,000 ova are still viable (out of the 7 million)
7. From puberty to menopause various follicles begin to develop but only if the hormonal environment is ideal will they become a mature follicle and ovulate
8. Out of the 400,000 only about 400 will ovulate – The rest become atretic – There is an enormous loss of ova
9. At the time of birth females have all the ova that they are going to ever have
a. Some of the ova are in meiotic arrest during birth and may not ovulate for 40 years or so
10. The primordial follicle (oocyte in the middle and a single layer of granulose cells around it) – The oocyte grows and the granulosa cells proliferate (more than one layer) and the zona pellucida (layer between the ova and the granulosa cells) does too at the primary follicle – This is an hormonally independent action
11. From the primary follicle to the secondary follicle: Under the influence of FSH get an additional proliferation of granulosa cells and an outer layer develops: the thecal layer
12. The thecal layer and the granulosa layer begin to produce estrogens which causes a definite move from the primary follicle to the secondary follicle
13. From the secondary follicle to the tertiary follicle: There is one dominant tertiary follicle that develops over the others – The other follicles begin to shrink back and become atretic
a. The one tertiary follicle continues its secretion of estrogen
b. There is a cavity in the middle, the actrum, and the thecal cells are developed into the theca internoa and theca externa
14. Finally, get a Graafian follicle or a mature follicle with the granulosa cells, the theca interna, and the theca externa and the follicle is destined to ovulate
15. At the time of ovulation there is a surge of LH which signals the ova to complete meiotic division and causes the release of plasminogen activating factor (which makes plasmin) produced by the granulosa cells
a. Plasmin causes the follicle to burst and the ova can go out into the oviduct and the fimbriae direct it (ova really goes out in the abdominal cavity but the oviduct is right there next to ovaries)
16. All of the above happens in the follicular phase and happens between days 1-14 of the cycle – Once the follicle ruptures this signals the end of the follicular phase
B. Luteal Phase: After ovulation the ruptured follicle undergoes biological changes and it is transformed into the corpus luteum which produces estrogen and progesterone – The corpus luteum continues to do so for several days (10 or so) beyond ovulation unless pregnancy occurs
1. The corpus luteum becomes less active or degenerates – It finally degenerates enough so that it no longer produces estrogen or progesterone and becomes the corpus albicans
2. The granulosa and thecal cells form the corpus luteum which then hypertrophies and degenerates into the corpus albicans
IV. The Endometrial Cycle: Composed of 3 phases
A. The menstrual phase: The sloughing off of the endometrium – Days 1-5 of cycle
B. The proliferative phase or the estrogen demand phase: Days 6-14 – Influenced predominantly by the developing follicle – The endometrium is getting thicker
C. The secretory phase or the progesterone demand phase: Days 15-28 – The endometrium is well vascularized and lush and is ready to receive the sperm
V. Cervical Mucus Cycle: There is mucus within the cervix that goes through a cycle that is influenced by hormones
A. Estrogen phase: The mucus is thin and watery and alkaline
1. If you want the sperm to fertilize the ova then you need a thin and alkaline environment
B. Luteal phase: Later you want the egg to be protected so a thick, viscous, and acidic mucus is what is needed
VI. Breast cycle
A. Follicular phase: Under the influence of estrogen there is a deposition of fat in the breast due to fluid accumulation
1. There is an increase in the nipple growth and the pigmentation of the nipple
B. Progesterone phase: Sustains the above until menstruation occurs and then after menstruation the tissues return to their baseline values
C. In order to lactation to occur there must be exposure to estrogen and progesterone for long periods
VII. Function of Estrogens
A. Role on Primary Sex Characteristics: Estrogen causes the growth and maintenance of the female reproductive tract
1. Cause vaginal thickness in the epithelium so the vagina is not damaged during sex
2. Causes endometrium proliferation
3. Causes myometrium excitability
4. Causes the motility of the oviducts
5. Causes the deposition of fat in the breasts
6. Stimulates the ductile system development
7. Causes the thinning of the cervical mucus
8. Causes the formation of LH receptors in the granulosa cells
B. Role on Secondary Sex Characteristics
1. Has an affect on the skeletal system:
a. Estrogen influences the shape of the pelvis and favors bone deposition
b. When women go through menopause there is little or no estrogen so bones become thin and weak and osteoporosis sets in
c. Estrogen also favors the closure of the epiphyseal plates more so than androgens do and this is why males are taller than females
2. Muscle: Estrogen favors protein deposition but not as much as androgens do
3. Increase the fat deposition beneath the skin, thighs, and hips
a. Estrogen causes the softening of the skin and increased vascularation of the skin
4. Causes an increase in HDLs and a decrease in LDLs – A good affect
5. Causes increased production of clotting factors
a. Was a big issue because birth control pills caused thromboemboluli since the pills contained a lot of estrogen and caused the blood to clot
6. There is not much influence on hair deposition – Hair deposition is mostly due to androgens from the adrenal gland
7. Estrogen may play a role in libido
VIII. Functions of Progesterone: Progesterone is not a hormone to do with pregnancy
A. Uterine Effects: Progressively
increases the secretory capacity and causes the
myometrium to not be active
B. Breasts: Responsible for the development of the lobules and the alveoli
C. Cervix: Causes a thickening of the cervical mucus
D. Electrolytes: Progressively causes a decrease in Na+ retention
E. Causes a decrease in body temperature
IX. Regulation of Female Cycle
A. The early stages (primordial to the primary follicle) are not dependent on hormones
1. For the proliferation of the granulosa cells and the thecal cells you need an increase in FSH which causes the follicle to develop into a primary and secondary follicle (a well differentiated thecal and granulosa cell layer)
2. Estrogen begins its steady climb
3. Have to have thecal cells and granulosa cells cooperating
B. Thecal cells under the influence of LH make androgens and granulosa cells under the influence of FSH makes aromatase (also makes progesterone and inhibin)
1. The combination of androgens and aromatase make estrogens
2. Granulosa cells cannot produce down the pathway to estrogen just down to progesterone so need thecal cells to produce androgens which in combination with aromatase produce estrogen
3. Granulosa cells also produce inhibin
4. The estrogen concentration increases and see an influence in the endometrium and get proliferation of the endometrium – As estrogen levels increase see an affect on FSH, a negative feedback on FSH and then decrease FSH levels
5. Estrogen is feeding back to the anterior pituitary to inhibit FSH
6. Granulosa cells produce inhibin which inhibits FSH and during this tie estrogen levels reach some appropriate level with a little bit of progesterone
a. When increase estrogen with a little bit of progesterone the hypothalamic anterior pituitary flips over to a positive feedback mode
b. Now estrogen causes more production of FSH and LH and you see a spike of LH and FSH
c. The spike of LH is essential for ovulation to occur and causes the activation of plasmin via plasminogen activating factor which causes the rupture of the follicle on day 14 and ovulation
d. The corpus luteum is formed and begins to produce estrogen and lots of progesterone and begins the proliferative phase of endometrial development
7. Then FSH and Lh levels begin to do down because of the large amounts of progesterone and estrogen which inhibits LH and FSH
a. The corpus luteum degenerates and decrease estrogen and progesterone levels and now have the corpus albicans
b. The endometrium is sloughed off and FSH and LH go up again and you begin another cycle
X. Birth Control
A. Inhibit Ovulation: Mechanism that inhibits ovulation
1. Birth control pill: Contains a synthetic estrogen-like substance and synthetic progesterone (the liver breaks real estrogen and progesterone down quickly)
a. Take for 3 weeks and then take a placebo for 1 week
b. Increase estrogen and progesterone
c. Gnrh levels decrease (stay low)
d. FSH and LH stay low so that normal follicular development doesn’t occur
e. There is still a development of the endometrium but when the hormones are removed it sloughs off
f. The hormones keep the cervical plug viscous so that sperm can’t get through
g. Patient has to be vigilant for the birth control to work so there is a problem with patient compliance
B. Barrier
1. Condom: Provides a barrier between the sperm and the ova
a. There are varying efficacies: (number of pregnancies per year per 100 normally sexually active women) 10 - The condom is not safe sex, there is safer sex
2. Diaphragm: Device inserted into the vagina
3. Cervical Caps: Vaginal pouches
4. Contraceptive Sponges
5. Minipill: Progesterone only preparation – It interrupts the interaction and keeps Gnrh levels low
a. The cervical mucus prevents sperm penetration
C. Chemical: Products that contain spermatocide such as foams, creams, jellies that are put in the vagina – Usually used in combination with barrier devices
1. Nonoxnol-9: The active ingredient in most spermatocides
a. Efficacies vary but are better if a barrier is used
D. Sterilization
1. Vasectomy: Cut and tie the vas deferens and the ejaculate is sperm free
2. Tubuligation: Tie off the oviducts so that the ova cannot get to the oviducts (fertilization)
E. Prevent Implantation
1. IUD: Intra Uterine Device
a. Copper is inserted into the uterus by a physician while the cervix is dilated
b. It disturbs the environment of the uterus
c. There is a problem with pregnancies and bleeding
d. IUD’s raise moral issues because they’re abortifisions
e. Day 8 or so implantation occurs but IUD’s prevent implantation
2. Morning After Pill: Increases estrogen and increases the motility of the oviducts and the uterus
a. They hasten the transport of the zygote through the reproductive tract (no implantation)
3. RU 486 (mifepristone): A prostaglandin agonist and an abortifision
a. Increases the motility of the uterus and displaces the fetus before implantation (day 8)
4. Prostaglandins: Increases motility
F. Avoid Fertile Period
1. Rhythm Method: 30 or 40 efficacies (pregnancies per 100 women)
a. Fertilization takes place when the sperm and the eggs get together
b. No sex during ovulation (day 14) but ovulation is not always day 14
c. Not very successful
d. 90 out of 100 women become pregnant because they’re without birth control
XI. Pharmacology
A. Estradiol (Estrase) (Climara)
1. Prescribed predominantly for females that are post menopausal and they prevent the symptoms of menopause
2. A therapy against osteoporosis
3. Not naturally occurring estrogen
B. Conjugated (Premarin)
1. Naturally occurring estrogen from pregnant mares
C. Progestin (Provera) (Cycrin)
1. Progesterone
2. For abnormal bleeding during cycles
D. Combination (Prempro) (Estratest)
1. A combination of estrogen and progesterone
2. Menopausal symptoms: Estrogen alone is sometimes not sufficient to treat
3. Estrogen alone increases endometrial carcinoma
4. Endometrial carcinoma chances decrease with progesterone
XII. Implantation (See Figure)
A. Hormones
1. After intercourse the sperm goes to the ends of the oviducts in about 5 minutes (not just by swimming)
2. Proposed reason for getting there so quickly: Prostaglandins in the semen and they increase the motility of the myometrium and force the sperm through
3. Oxytocins are released by the sperm to increase motility of the myometrium
B. Sperm and Egg Coming Together
1. Sperm are viable in the reproductive tract for 2-3 days but are maximally viable for only 24 hours
2. 2-6 million are deposited in the vagina but only about 200 reach the vicinity of the ovum
3. Many sperm are needed to prepare the ovum and get through it
4. Only 1 fertilizes the ovum and occurs at the first 1/3 of the oviduct
5. Flagella are active at the oviduct and direct the ova into the oviduct
6. The ova are viable for 12-24 hours but are only maximally viable for about 8-12 hours
7. 2-3 days are required to go down the rest of the oviduct and reach the uterus and another 3 to 4 days before implantation – This is important at the blastocyst stage
8. Implantation occurs in the properly prepared endometrium
9. Basically, the cells of the blastocysts (tropoblastic cells) eat a hole in the endometrium and attach to it and the pregnancy is its way
XIII. Hormones of Pregnancy
A. Human Chorionic Gonadotropin
1. Days of Cycle: 1-3 or 5 is Menstruation
5-14 is Proliferation
14 or so is Ovulation
2. It takes 3 days to get out of the oviduct so about day 17 and then another 3 to 4 days
3. At day 22 the corpus luteum decreases to the corpus albicans and the endometrium is sloughed off beginning menstruation
4. Something has to interrupt the cycle for pregnancy
5. Initially the tropoblastic cells cause the placenta to produce HCG
6. HCG functions:
a. In the mother: HCG is very similar to LH (is structure and biochemistry) – The corpus luteum gets bigger and continues producing estrogen and progesterone through the first trimester of pregnancy – The endometrium is maintained
i. The HCG hormone is what’s detected in pregnancy test kits (molecule looking for) – Only pregnant females produce HCG – Early on it may not be dictated in urine tests but blood tests detect HCG easily – Male urine tests positive
b. In male fetus: A role in embryonic testes to produce testosterone (important that testes produce testosterone) – Adult testes produce testosterone by LH (anterior pituitary)
i. 8 week old fetus’ don’t have an anterior pituitary so HCG stimulates the secretion of testosterone from the testes
B. Estrogens: The estrogens of pregnancy
1. During the 1st trimester the estrogen is predominantly produced in the corpus luteum
a. 2nd trimester: Estrogen produced in the placenta
b. Not produced in the placenta in the 1st trimester because the placenta is small and the placenta is incapable of producing estrogen all the way from cholesterol
2.
The 2nd to 3rd trimester: The fetal placental unit 
a. Fetus provides the raw material for producing estrogen – This can’t happen in the 1st trimester because there isn’t much fetus here
b. Placenta can get cholesterol from the mother and make a little and makes pregnenolone which then makes progesterone and then makes DHEA (gets from the fetus) which diffuses across the placenta and then makes androstendione and then makes estradiol (the most common estrogen in non-pregnant females) or via 16-OH DHEA (which also diffuses across the placenta from the fetus) makes estriol (most common estrogen in pregnant females)
3. There has to be cooperation between the placenta and the fetus
a. Even with the placenta, estrogen couldn’t be produced because there is no adrenal
b. During pregnancy estrogen is most responsible for the estrogen effects is estriol
4. Special functions:
a. Enlargement of the external genitalia and enlargement of the uterus
b. Enlargement of the breasts
c. Specific for the growth of the ductile system
d. Relaxation of the pubic ligaments
C. Placental Progesterone
1. 1st trimester: Corpus luteum
a. 2nd and 3rd trimester: Placenta
2. Progesterone causes the decidual cells to produce nutrients
3. Functions:
a. The decidual cells (special cells of the uterus) are induced to produce nutrients by progesterone
b. Progesterone is responsible for the substrate that causes the fetus to produce cortisol and aldosterone synthesis
c. Decreases myometrial activity
d. Inhibits oxytocin sensitivity
e. Decreases prostaglandin activity (all work to maintain pregnancy)
f. The development of the alveolar pouches in breast
g. Causes the thickening of the cervical plug
h. Stimulates the maternal respiratory center
D. Human Chorionic Somatomammotropin (Human Placental Lactogen) (HCS): Produced by the placenta (size of the placenta depends on levels of HCS)
1. Prepare the breasts for lactation and the stimulation of the mammary glands
a. HCS levels are used to access the growth and health of the fetus
2. Increase fetal somatomedins (insulin like growth factors)
a. In the fetus, there is high HGH but HCS stimulates growth because the fetus is anacephalic (no brain) so the HCS is not stimulated by HGH
3. Decrease the insulin sensitivity in the mother and this benefits the fetus because glucose levels increase but this may cause pregnancy induced diabetes – HCS is a hormone working against insulin
E. Relaxin: Produced by the corpus luteum and the decidual cells
1. Causes the relaxation of the pelvic floor
2. Causes the softening of the cervix
3. Reduces the myometrial contractions
XIV. Parturition: The length of gestation varies considerably and in humans it is 38 weeks (elephants: 20 months, dogs/cats: 9 weeks) – No one knows for sure what happens – In sheep, the mechanism is well known and the fetus signals the onset of parturition – In humans, it is more complex (hormonal and mechanical factors)
A. Hormonal Factors: Progesterone and estrogen ratios
1. Progesterone decreases uterine motility and estrogen increase uterine motility
a. In many species you see a change in the concentrations
a. At the end of pregnancy there is a decrease in estrogen and an increase in progesterone so there is an increase in motility of the uterus
b. In humans there is no change in estrogen and progesterone concentrations in the plasma
c. Locally the production of estrogen and progesterone is by the membranes of pregnancy
d May be having an affect on the myometrium and never reflected in plasma levels
2. Oxytocin: Released in response to the stretching of the cervix
a. The uterus is properly prepared
b. Oxytocin levels don’t rise until after the onset of parturition
c. Changing the estrogen and progesterone levels can change oxytocin receptor sensitivity
d. Recent evidence: Uterus synthesizes oxytocin but this will not be reflected in the plasma concentration
e. The levels in the plasma don’t go up until after the onset of parturition
3. Prostaglandins:
a. Increase uterine motility
b. The exact role in the initiation of parturition is unknown
c. Increases progesterone levels in the fetal membrane before the onset of labor
d. All these hormonal signals are coming from the mother
4. Fetal Endocrine Signals
a. In sheep: Fetal pituitary releases Acth which causes the production of cortisol which affects the increase of estrogen synthesis and the net effect increases estrogen and decreases progesterone
b. Cortisol does other things: Increases the lung maturation, closes ductus arteriosis (shunt between the pulmonary artery and the aorta)
c. If you inject Atch into sheep, they should prematurely parturate (cortisol too)
d. In humans, it is more complicated (Atch and glucocorticoids) and does not induce parturition
e. In humans, anacephalic gestation is longer so there is some affect
B. Mechanical
1. As the fetus develops it crowds the uterus and causes it to stretch and toward the end of the pregnancy the uterus “drops”
a. The head turns downward and stretches the cervix which causes the myometrium to contract and pushes the fetus more downward
b. When the myometrium contracts again it pushes the fetus more downward and then contracts more and pushes and so on
c. Multiple births ten to have a shorter gestation than in single births because of the mechanical stretching of the uterus
XV. Lactation: Mammary glands or breast are present in both sexes
A. Gynacomastica: Males develop breasts
B. Breasts develop in females because of estrogen and progesterone
1. Each gland has 20 lobules and each of these radiate via the ductile tissue to the nipples
2. Each lobule has a number of alveoli (unit of the breast) that produce milk
a. Alveoli: Gland like structure which produces milk
b. In non-pregnant females the milk production apparatus is rudimentary and there is very little ductile development
C. During pregnancy the size of the breast is due to adipose tissue
a. Exposure to estrogen and progesterone cause the transformation into the milk production glands
b. Layer secretory epithelium and the myoepithelium cells
D. Hormones:
1. Estrogen responsible for:
a. Growth of the breast
b. Deposition of fat
c. Development of the ductile system
2. Progesterone responsible for:
a. Cells that are secretory in nature
b. Increases the development of the alveoli
3. Prolactin:
a. Essential for the expression of estrogen and progesterone causes the secretion of milk from the epithelial cells into the lumen
4. HCS (HPL): Similar to prolactin but it’s not as effective but is not as potent
a. By the end of pregnancy the breast is ready for milk production but there is no secretion of milk into the alveoli without prolactin (needed to get secretion)
b. Estrogen and progesterone inhibit prolaction and the source of estrogen and progesterone is placenta
c. At parturition the placenta is expelled from the uterus so the prolactin can be secreted and the milk can be released into the alveoli but the milk has to be let down to the level of the nipple
5. Oxytocin is released from the posterior pituitary in response to sucking by the infant
a. Affect myoepithelial cells to contract and milk is let down into the ductile system where it is available to the infant
b. Cholestrium: The first milk which is lower in fat and lactose than true milk – An increase in proteins (immunoglobulin) - Several hours before milk is available: If mothers are going to milk, nurses bring the baby in soon after parturition to nurse even though nothing much is happening – There is not much milk in the alveoli but it reduces the amount of bleeding in the uterus and the suckling baby causes the mother to release oxytocin which causes the myometrium to contract down and starts restoring the size of the uterus
XVI. Pathologies
A. A.M.I. (Athletic Menstrual Irregularity): A number of female athletes have irregular menstrual periods, or stopped or infrequent cycles where there is a period but no ovulation
1. 50% or more AMI
2. Study: 28 women (college age) athletic but not in training (with normal cycles) were exposed to the first 4 weeks of running 4 miles a day and then 5-8 weeks they ran 10 miles a day and at the end only 4 had normal menstrual cycles but all of the women returned to their normal menstrual cycles after 6 months
3. There is decreased FSH and decreased progesterone in the luteum phase and decreased estrogen in the follicular phase
4. Has to do with the percent of body fat
5. Problems: Women affectively become menopausal and start risks of osteoporosis
B. Endometriosis: Unusual
1. Functional endometrial tissue where it doesn’t belong (ovaries, outside the uterus, uterine ligaments, vagina, intestines) and in more bizarre places like the nostril, lungs, or limbs
2. The cause is unknown
3. Theories:
a. Retro-Grade Menstrual Theory: During menstruation the flow goes out of the oviducts and the tissue finds a site outside the uterus to begin functioning
b. Embryogenic Implantation Theory: Undeveloped endometrial tissue gets misplaced during embryological development and later becomes active
c. Endometrial Metastasis: Gets in the lymphatic or circulatory system and is transported to cells elsewhere and the endometrial tissue is often functional
4. Undergoes menstruation and the sloughing off (cycle) and causes severe pain, scarring, adhesions and sterility (blocked oviducts so there is no fertilization)
5. Demographic data: This is higher in higher socioeconomic levels, women between ages 20-40, higher in developed countries, common in goal oriented, over achievers (Type 1 personalities)
6. Treatment: Treated with contraceptives (birth control) and the symptoms are alleviated or could just treat the pain but birth control pills are not taken like they normally are
a. Drug: Danocrine: Synthesized androgen suppresses FSH and LH so don’t get a cycle anymore but the side effects are menopause or mascularation (facial hair)
b. Surgery where the endometrium tissue is cut away (lyposcopic) or more radical surgery like hysterectomy and ovurectomy
C. Ectopic
pregnancy: Fertilized ovum implants somewhere else besides the uterus (in the
oviducts) and is destined for failure because the fetus outgrows the space
D. Dysmenorrhea: Painful menstruation
1. Prostaglandins are responsible and have a stimulatory effect on the myometrium
2. Use a prostaglandin inhibitor and take it before menstruation occurs
a. Motrin or Aspirin
E. P.M.S: A distinct clinical phenomena
1. Physiological and psychological symptoms
2. Occurs during the pre-menstrual period (10 days or less)
3. The cause is unknown and is common in females (around 30 yo) and is less common in teens and women in their 20’s
4. Bloating, abdominal pain, swelling breasts, depression, headache
5. Treatment: Multi-factorial, dietary changes, anti-depression and treated symptomatically
F. Osteoporosis
1. Pathology: In post menopausal females but could occur in athletes
a. Estrogen favors the deposition of bone mass and as it decreases bones fracture easily
2. Pharmacology:
a. (EVISTA): Estrogen receptor
modulator and has an estrogen like affect on bones
b. (FOSAMAX): Inhibits bone reabsorption and inhibits osteoclasts
(breaking down of bone)
c. (MIACALCIN): The hormone Calcitonin, humans don’t
have much but it works to decrease bone reabsorption and favors the deposition
of bone
i. Calcitonin/Miacalcin are from salmon (a protein) and in a nasal spray because can’t swallow it