Histology Flashcards
(233 cards)
1
Q
What is the difference between how hydrophilic and hydrophobic hormones are transported in the blood?
A
Hydrophilics (proteins, glycoproteins, peptides, modified amino acids) can travel straight in the blood
Hydrophobic (steroid and thyroid hormones) must travel bound to protein carriers
2
Q
How does the pituitary gland develop?
A
During the third week of development, a hypophyseal pouch (Rathke’s Pouch) buds up from the roof of the mouth (ectoderm) while a neurohypophyseal bud grows down from the diencephalon (ectoderm from floor of brain).
The mouth pouch becomes the anterior/glandular pituitary or Adenohypophysis (including pars distalis, pars tuberalis, and pars intermedia)
The brain pouch becomes the posterior pituitary or Neurohypophysis (including pars nervosa and infundibulum/stalk attached to the hypothalamus via the median eminence) which secretes hormones via neurons
3
Q
Why do the anterior and posterior pituitary stain differently?
A
Anterior is glandular tissue which is full of hormone granules
Posterior does not produce any hormones because they all come from neurons that originate outside of the pituitary
4
Q
What is the hypothalamic-hypophyseal tract? What hormones are involved?
A
Bundle of axons that travel from the supraoptic and paraventricular nuclei through the infundibulum to the neurohypophysis
Supraoptic nuclei produces ADH while paraventricular nuclei produces Oxytocin
5
Q
Describe the blood supply of the pituitary gland (hypothalamic-hypophyseal portal system). What is the importance of this portal system?
A
The superior hypophyseal artery supplies a plexus that surrounds the median eminence and infundibulum. The hypophyseal portal veins connect the primary plexus to a secondary plexus that surrounds the pars distalis.
The inferior hypophyseal artery supplies a (mostly) separate plexus for only the posterior pituitary
The portal plexuses carry neuropeptides produced by the hypothalamus to the anterior pituitary to either stimulate or inhibit hormones.
6
Q
What are the common features of endocrine organs?
A
Parenchyma: cords or clumps of cells
Highly vascular: fenestrated capillaries
Ductless glands: not like exocrine
Stroma: reticular connective tissue and some nervous tissue
Secretes hormones: peptides, amino acid derivatives, steroids
7
Q
Name the two types of acidophils in the anterior pituitary
A
Somatotrophs: Growth Hormone
Mammotrophs/lactotrophs: Prolactin
8
Q
Name the basophils in the anterior pituitary
A
Thyrotrophs: TSH
Gonadotrophs: FSH and LH
Corticotrophs: ACTH
9
Q
Where do the nuclei in the pars nervosa come from? What are Herring bodies?
A
The only nuclei are from Pituicytes (supporting cells) and capillary endothelial cells
Herring bodies are the neurosecretory vesicles at nerve endings
10
Q
What are chromophobes?
A
Cells of the adenohypophysis that do not stain because they are non-secretory
11
Q
What types of cells are found in the pars tuberalis?
A
Mostly gonadotrophs
12
Q
What is the difference between the corticotrophs of the pars intermedia and those of the pars distalis?
A
The ones in the pars intermedia cleave POMC into two types of melanocyte stimulating hormones (MSH): y-LPH and B-endorphin
The ones in the distalis cleave POMC into ACTH
13
Q
Where are hypothalamic hormones produced? What hypothalamic hormones regulate which hormones of the pars distalis?
A
Paraventricular nucleus, medial preoptic nucleus, arcuate nucleus
TRH (Somatostatin inhibits)—> Thyrotrophs (TSH)
TRH (dopamine inhibits) —> Lactotrophs (Prolactin)
GnRH —> Gonadotrophs (FSH and LH)
CRH —> Corticotrophs (ACTH)
GHRH (somatostatin inhibits) —> Somatotrophs (GH)
14
Q
What type of axons are found in the pars nervosa?
A
Unmyelinated
15
Q
How does negative feedback of hormones work? Use thyroid hormone as an example
How else are pars distalis hormones regulated?
A
TRH stimulates TSH release which stimulates TH release.
Hypothalamus recognizes an increase in body temp and inhibits TRH release. At the same time, TH binds TRH receptors on thyrotrophs and inhibits the release of TSH.
Outside inhibitory (or stimulatory) factors can also regulate hormone release. Ex) ghrelin from the stomach mucosa stimulates somatotropin release
16
Q
What happens to ADH and oxytocin after they are released?
A
They get taken up into fenestrated capillaries
17
Q
What does oxytocin do?
A
Stimulates contraction of uterine smooth muscle during child birth and myoepithelial cells in the mammary gland
18
Q
What regulates the daily rhythms of bodily activity (including light/dark cycles and release of melatonin)?
A
Pineal gland
19
Q
What makes up the Pineal gland? What is corpora arenacea?
A
Stoma: connective tissue capsule (pia mater) and septae (contain blood vessels) that divide it into lobules; fenestrated capillaries; corpora arenacea (calcified concretions that don’t do anything, but they can be used to distinguish the pineal)
Parenchyma: Pinealocytes (90% of cells) arranged in clumps and cords with one to two cell processes that extend to fenestrated capillaries; glial like cells in the interstitium.
20
Q
How is the release of melatonin regulated?
A
Postganglionic sympathetics from the superior cervical ganglion stimulate release of melatonin in response to darkness
21
Q
How can you tell the difference between pinealocytes and astrocytes in the pineal gland?
A
The pinealocytes have euchromatic nuclei and are clumped together
Astrocytes have darker, more elongated nuclei and are only found in the connective tissue septa.
22
Q
What makes up the stroma of the thyroid?
A
Fibroelastic c.t. capsule and septae (which contain blood vessels)
Reticular cells and reticular fibers
Fenestrated capillaries
23
Q
What makes up the parenchyma of the thyroid? What is secreted by the thyroid?
A
Millions of small thyroid follicles lined with simple cuboidal or low columnar epithelium (thyrocytes) and filled with an acidophilic, gelatinous colloid of the protein thyroglobulin
Between the thyrocytes (or between the follicles), large pale-staining C cells (parafollicular cells) can be found which secrete calcitonin for calcium metabolism.
Thyroglobulin is stored within the follicles to later be converted into thyroxine (T4) and tri iodothyronine (T3) which both help determine the basal metabolic rate of the body.
24
Q
What can be found between follicles in the thyroid?
A
Parafollicular cells and capillaries
25
What is the difference between low columnar and squamous follicular cells? Describe the TEM of a follicular cell.
Low columnar represents an active follicle while squamous follicles are hypoactive.
Tight junctional complex at the top, attached to a basal lamina at the bottom. Very well developed RER and Golgi along with many lysosomes. Also have microvilli facing the lumen
26
Where can C cells be found (think about TEM)? What do they look like?
Closely associated with the follicular cells and inside the basement membrane, but often not contacting the lumen.
Large nucleus, large Golgi apparatus, extensive RER, and many dark granules containing calcitonin
27
How is iodide taken up by thyrocytes in order to produce T4 and T3?
Na/I symporters in the basolateral cell membrane.
I-/Cl- transporter (pendrin pumps) pumps I- from the cell into the lumen
28
Describe the process by which thyroid hormones are produced
1) thyrocytes make thyroglobulin and secrete it into the lumen
2) iodide (from the diet) is pumped across the cells into the lumen
3) membrane bound thyroid peroxidases convert iodide to iodine which is then added to tyrosine residues on thyroglobin. This produces MIT and DIT
4) MIT and DIT come together to form T3 and two DITs come together to form T4. However, both T3 and T4 are still attached to the glycoprotein backbone
5) Iodinated Thyroglobulin is endocytosed and degraded into active T3 and T4 which is then released into the capillaries.
29
How do T3 and T4 enhance metabolic activity? Which is more prevalent?
Increase number and size of mitochondria in cells
90% of thyroid hormone is in the T4 form
30
What regulates the function of the thyroid gland?
TSH receptors on the basement membrane of thyrocytes bind TSH which stimulates growth of cell height and stimulates all stages of thyroid hormone synthesis.
Thyroid hormones inhibit release of TSH. Cold exposure increases release of TSH while heat and stressful stimuli decrease it.
31
What is Graves Disease?
Autoimmune disorder in which antibodies cause overstimulation of follicular cells (by binding to TSH receptors and causing cAMP release) and release of thyroid hormones. Marked by weight loss, heat intolerance, sweating, etc.
TSH goes down due to negative feedback by T3 and T4, but it doesn’t matter because this bypasses that system!
32
Hypothyroidism
Reduced thyroid hormone levels caused by inflammation or inadequate secretion of TSH. Results in tiredness, weight gain, intolerance of cold, and decreased concentration.
33
Primary hypothyroidism
Most commonly idiopathic
TSH receptor blocking autoantibodies
34
Hashimoto Thyroiditis
Autoimmune that targets thyroid peroxidase (T3 and T4 can’t be produced)
Causes goiter and hypothyroidism
Lymphoid follicle appears next to thyroid follicles
35
When is calcitonin released? How does it work?
Secreted in response to elevated blood calcium
Directly inhibits osteoclasts which resorb bone
Causes kidney to excrete more calcium and phosphate
36
Parathyroid gland structure
4 ovoid structures on posterior side of the thyroid
Connective tissue capsule and trabeculae
Stroma: reticular cells and fibers
Highly vascular with fenestrated capillaries
37
Parathyroid parenchyma
Chief cells— produce PTH; organelles typical of a protein secreting cell; pale staining
Oxyphils— large, very eosinophilic cells; filled with mitochondria; function unknown; more prevalent in older people. Usually degenerated derivatives of chief cells
Adipocytes— 50% of cells in older patients
38
How does PTH work?
Polypeptide hormone secreted by chief cells
Causes osteoblasts to secrete an osteoclast stimulating factor (RANK) which increases both the number and activity of osteoclasts
The increases resorption of bone matrix increases the levels of blood Ca2+ and serum alkaline phosphatase.
Also indirectly increases Ca2+ by increasing vitamin D activity in small intestine (increases Ca2+ uptake)
Increased Ca2+ inhibits PTH release
39
Primary Hypoparathyroidism vs pseudoparathyroidism
Deficiency in PTH secretion due to damage, hereditary, or autoimmune
Leads to dense bones, spastic muscle contractions, convulsions, tetany, death
Pseudoparathyroidism— rare; abnormal PTH receptors causes hypocalcemia although PTH levels are high
40
Primary hyperparathyroidism vs. malignant tumor
Usually a hormone secreting tumor of chief cells; causes thinning of bones, bone fractures. Deposits of bone in soft tissues
Malignant tumor (breast, lung, ovarian) may secrete a PTH related protein (PTHrP) leading to hypercalcemia
41
What effect does pineal destruction/tumor have on humans?
Precocious puberty in children
Contraception properties as well
A proper functioning pineal is important in defending against breast and prostate cancer
42
What is so nifty about the pineal gland?
It converts sensory information (light) into hormonal information (melatonin)
43
What type of drug might benefit a breast cancer patient with bone metastases?
PTH antagonist
Some breast cancer cells secrete PTHrP because they themselves have a PTH receptor that stimulates cell proliferation by PTHrP. However, the PTHrP also stimulates osteoblasts to oversecrete RANK
44
What is the endocrine function of the pancreas? Where does it occur?
Secrete insulin, glucagon, somatostatin, and pancreatic polypeptide
Occurs in the islets of Langerhans.
45
What makes up the islets of langerhans?
Parenchyma: clusters of cells scattered throughout pancreas
Stroma: reticular cells and reticular fibers
Highly vascularized with fenestrated capillaries
10% of islet cells have autonomic innervation. Gap junctions exist between islet cells.
46
Describe the 4 types of cells found in the parenchyma of the exocrine pancreas
A or alpha cells (20% of cells)— secrete glucagon; react with silver stain; found in periphery of islets
B or beta cells (70% of cells)— secrete insulin; located in interior of islets
D or delta cells (5% of cells)— secrete somatostatin; scattered throughout islet
F cells (<1%)— secrete pancreatic polypeptide which inhibits exocrine secretion of pancreas.
47
Type 1 vs. Type 2 diabetes (beta cells)
Type 1— decreased number of B cells (destroyed by antibodies) and increased leukocyte infiltration
Type 2— variable number of B cells (with amyloid deposits) and islet amyloid polypeptide (IAPP) deposits
48
What do the different zones of the adrenal cortex produce? What properties do all these cells share?
All produce steroid hormones
Zona glomerulosa— mineralcorticoids (aldosterone); stimulated by Ang II and high K+
Zona fasciculata— glucocorticoids (cortisol and corticosterone); stimulated by ACTH; exhibits negative feedback
Zona reticularis— sex steroids (weak androgens), DHEA (gets converted to testosterone in both men and women); stimulated by ACTH; exhibits neg feedback
Steroid producing cells have: Abundant SER, mitochondria with tubulovesicular cristae, lipid droplets (to supply the cholesterol precursor)
49
Primary hyperaldosteronism (Conn disease) affects which zone of the cortex?
Elevated aldosterone due to an adenoma of the zona glomerulosa
50
Cushing syndrome
Caused by administration of large doses of steroids to treat primary disease.
Also caused by ACTH secreting adenoma (corticotrophs) or adrenal cortical adenoma
51
Congenital adrenal hyperplasia
Caused by mutations in genes for steroid synthesizing enzymes—> increased level of androgens
52
Primary adrenal insufficiency (Addison) vs. secondary insufficiency
Primary— caused by autoimmune destruction of adrenal cortex; disrupts glucocorticoid feedback and causes oversecretion of ACTH
Secondary— hypothalamus or adenohypophysis disorder leading to decreased ACTH
53
Chromaffin cells
Make up the adrenal medulla
“Modified sympathetic ganglion” cells that secrete epinephrine and norepinephrine
54
What distinguishes chromaffin cells from adrenal cortex cells? Which is bigger, NE or Epi granules?
Chromaffin cells stain lighter and are larger and clumped together in larger clumps than cortex cells
NE granules are bigger and darker than Epi
55
What is the origin of chromaffin cells? What about adrenal cortex?
Neural crest: they are modified postganglionic neurons that have lost their dendrites and axons
Cortex: comes from mesoderm
56
What neurotransmitter triggers the release of catecholamines from the adrenal medulla?
ACh
57
Pheochromocytoma
Catecholamine producing tumor (secretes both epinephrine and NE) of the adrenal medulla
58
What is the importance of the blood supply of the adrenal gland?
Short arteries supply the cortex but only leave venous blood by the time it reaches the medulla
Long arteries bypass the cortex to supplement the medulla
The short arteries allow glucocorticoids from the cortex to be taken to the medulla because they are needed to for maintenance of the enzyme that produces Epi and NE. Also needed to inhibit development of neuronal cell processes.
59
Neuroblastoma
Neoplasm containing primitive neuro blasts (40% occur in the adrenal medulla)
60
What makes up the structure of the adrenal glands?
Dense connective tissue capsule that sends trabeculae into the parenchyma (that contain blood vessels and neurons probably)
Stroma: reticular fibers and reticulocytes
Parenchyma: cells that produce steroid hormones and catecholamines
61
What’s so special about the mitochondria of the adrenal cortex cells?
Tubulovesicular cristae instead of the shelf like kind.
Not only produce ATP but also contain enzymes for converting cholesterol to pregnenolone (along with the Smooth ER)
62
What primarily increases aldosterone secretion?
Angiotensin II and high K+ levels (only weakly stimulated by ACTH)
63
What are the functions of the ovary?
Production of oocytes
Production of hormones: sex steroids (estrogen and progesterone); protein hormones (relaxin, Inhibin, activin)
64
What are the functions of the ovary?
Production of oocytes
Production of hormones:
Sex hormones: estradiol and progesterone
Protein hormones: activin, Inhibin, relaxin
65
What is the flow of development in the ovary from primordial follicle to corpus luteum?
Primordial follicle-> early primary follicle-> primary follicle-> secondary follicle-> mature Graafian follicle-> ruptured follicle (releases oocyte)-> corpus hemorrhagicum-> corpus luteum
66
How many follicles are you born with? How many lost per cycle? How many at menopause?
Born with 1 million
1,000 lost per cycle
1,000 left at menopause
67
When does the Ovarian cycle start? What are the different phases?
Day 1 of menses (sloughing off of the endometrial wall)
Follicular phase- days 1-14
Ovulation phase- days 14-15
Luteal phase- days 15-28; luteal regression usually begins around day 24
Any variation in cycle length is due to follicular phase. Luteal phase is always 14 days
68
What happens during the follicular phase? What phases of the uterine cycle does it correspond with?
FSH stimulates growth and maturation of a follicle (LH helps a little bit) until ovulation
Menstrual phase (days 1-5) and Proliferative phase (days 6-14)
69
What happens during the luteal phase? What uterine phases does it overlap with?
LH promotes ovulation (with help of FSH) and proliferation of the corpus luteum
Secretory phase (days 15-26) and Pre-menstrual phase (days 27-28)
70
What are the different layers of the ovary?
Outer epithelium (mesothelium) of simple cuboidal cells
Tunica albuginea (like testes)— dense connective tissues capsule
Cortex— cellular connective tissue where primordial follicles reside
Medulla— inner loose connective tissue with blood vessels entering from the hilum
71
Primordial follicle
Present since fetal life; arrested in Prophase of Meiosis I since week 11-12 of development (46, 4N)
Found in cortex of ovary; 25um in diameter with large nucleus in the middle (primary oocyte arrested in prophase)
Single layer of flat, squamous follicular cells surround oocyte; separated from vascularized stroma by basal lamina
72
Primary Follicle
Stimulated by FSH (only during follicular phase), a primary oocyte starts to increase in size and number of organelles (but stays in Prophase I)
Unilaminar primary follicle— follicular cells undergo mitosis and become single cuboidal layer. Bigger than primordials.
Multilaminar primary follicle— continues to grow and follicular cells develop into multiple cell layers called granulosa cells. Cells communicate through gap junctions. Still a vascular and retains basal lamina. Zona pellucida (a glycoprotein layer required for sperm binding and fertilization) separates the oocyte and the granulosa layer. Oocyte and granulosa can communicate through this layer. Stroma surrounding follicle starts to differentiate into theca interna and theca externa. Bigger than unilaminar.
73
What does the theca interna do? Theca externa?
Theca interna is well vascularized endocrine tissue that secretes androstenedione. Molecule diffuses through basement membrane where granulosa cells convert it into estrogen via aromatase. This is FSH dependent. The estrogen then leaves back into the theca layer and into the capillaries.
Theca externa is a layer containing fibroblasts and smooth muscle that blends into the stroma around it.
74
What happens to multilaminar primary follicles as they continue to grow?
They move deeper into ovarian cortex and antri (antrum) start to appear and fill with follicular fluid containing GAG, plasminogen, fibrinogen, heparin sulfate, and high concentrations of steroids (progesterone and estrogen)
Now called Secondary Follicle. Primary oocyte still in Prophase I
75
Cumulus oophorus and corona radiata?
As the secondary follicle matures, the antrum starts to outgrow the granulosa layer and the layer becomes thinner. The oocyte juts out into the antrum while staying surrounded by a layer of granulosa known as the Cumulus oophorus
The corona radiata is the layer that immediately surrounds the oocyte and stays with it after ovulation. Cell processes from the corona and microvilli from the oocyte extend into the zona pellucida and communicate with one another.
76
Mature Graafian follicle (and polar body)
Once a follicle reaches a certain size (2cm) it is considered a mature follicle. It pushes up against the wall of the ovary and forms a bulge that is visible through ultrasound. Just before ovulation, this bulge becomes ischemic and is called the STIGMA.
Just before ovulation, the oocyte becomes a secondary oocyte by completing meiosis I (becomes 23, 2N). One daughter oocyte is much larger than the other. The smaller is called the first polar body and undergoes atresia. The larger oocytes is ovulated but remains suspended in metaphase of meiosis II until fertilization.
77
Follicular atresia
Begins during fetal life and continues partly into menopause. Can occur at any stage of follicular development.
Of the 1000 follicles that start during each menstrual cycle, 999 undergo atresia while 1 is ovulated (but they can still secrete hecka estrogen for a while before they die).
Includes apoptosis of granulosa cells, loss of zona pellucida, autolysis of oocyte, and invasion by macrophages to clean up.
78
Where does GnRH originate? How does puberty onset?
Arcuate and Preoptic nucleus; pulsatile release stimulates release of FSH and LH (especially during ovulation)
Pulsatile release of GnRH leads to onset of puberty
79
How is GnRH regulated during follicular development? What are the roles of estrogen and progesterone?
At low levels, estrogen exhibits neg feedback on GnRH during the follicular phase but once a mature follicle, it reaches a threshold and starts to positively feedback causing GnRH release to increase and an LH surge (triggers ovulation). During the luteal phase, progesterone exhibits negative feedback on FSH and GnRH
Other inhibitors: dopamine, endorphins, melatonin, CRF
Other stimulators: norepinephrine
Estrogen (from the granulosa cells) increases endometrium proliferation during the follicular phase while progesterone and estrogen (from corpus luteum) stimulate endometrium proliferation even more during luteal phase.
80
Why doesn’t estradiol positive feedback also result in an FSH surge?
During the follicular phase, granulosa cells also secrete Inhibin B which has a negative feedback effect on FSH release (as well as low levels of estrogen). During the luteal phase, progesterone and Inhibin A from corpus luteum have negative feedback effects on both FSH and GnRH
Nothing directly inhibits LH secretion
81
How does estradiol synthesis decrease as a result of the LH surge?
LH receptors on theca cells become completely occupied during LH surge which leads to suppression of LH induced androgen precursor synthesis.
Loss of androgen precursors leads to decrease in estradiol synthesis after LH surge.
82
What happens during ovulation?
Cause by LH surge
Meiosis I is completed
Granulosa cells secrete more prostaglandins and hyaluronan which causes the antrum to swell and loosens the outer layer of cells
Ovarian wall weakens due to plasminogen from capillaries
Smooth muscle contractions begin in the theca externa stimulated by the prostaglandins.
The cells of the ovulated follicle give rise to the corpus luteum under stimulation of LH.
83
Corpus Luteum (of menstruation). What effect does it have on FSH?
After ovulation and under stimulation of LH, the granulosa layer and theca layer fold in on themselves and blood clots appear in the antrum
Granulosa cells increase in size, become well vascularized, and are called granulosa lutein cells which take up 80% of the corpus luteum. LH stimulates these cells to synthesize progesterone and estradiol that target the reproductive tract for preparation of fertilization, preimplantation development and implantation.
The theca interna becomes theca lutein cells which are half as big as granulosa lutein cells. LH causes these cells to make large amounts of weak androgens
The LH surge causes corpus luteum to secrete progesterone for 10-12 days. After that, if no pregnancy occurs, it undergoes apoptosis. This is called the Corpus luteum of menstruation. The decrease in progesterone after apoptosis causes sloughing of the endometrial lining (menstruation).
The estrogen produced by the corpus luteum inhibits FSH. FSH also stimulates Inhibin A to inhibit itself. So after it is gone, FSH goes back up.
84
What happens if GnRH secretion becomes continuous? Which is more important in GnRH secretion, magnitude or frequency?
FSH and LH levels are not maintained (they require pulsatile stimulation).
Frequency
85
What does FSH do in the early and later follicular phases?
Targets granulosa cells:
Early follicular phase: NO effect on primordial follicle (it grows spontaneously). Begins at primary follicle;
- stimulates mitosis and cell proliferation
- induces FSH receptors
- induces gap junction formation
- induction of aromatase to produce estradiol
- stimulates Inhibin B synthesis which stimulates androgen production by theca interna and decreases FSH release through negative feedback
Late phase: estrogen levels are elevated— induces LH receptors on granulosa cells resulting in low level progesterone production.
86
What does LH do during the early follicular phase and late follicular phase?
Targets both theca and granulosa cells
Early Follicular phase: targets theca interna— stimulates steroid hormone production (mainly androgens)
Late follicular phase: targets granulosa cells to initiate luteinization and progesterone synthesis
- LH surge: high occupancy of LH receptors on theca cells blocks androgen precursors needed for estradiol synthesis
87
How is estrogen created through side-chain cleavage?
Cholesterol side-chain is cleaved to 21 carbon progesterone. Cleaved some more into 19 carbon androstenedione or testosterone. Aromatase cleaves those into 18 carbon estradiol
88
What changes occur in the dominant follicle due to the LH surge?
Oocyte completes first mitotic division resulting in secondary oocyte and first polar body
Transformation of granulosa cells into lutein cells with an increase in progesterone production
Activation of proteolytic enzymes that degrade the follicular wall with formation of the stigma
Oocyte with cumulus detaches from the wall of the follicle and floats in the liquor follicular
Rapid accumulation of fluid in the antrum
89
Corpus albicans
Without LH, the corpus luteum dies
LH surge causes increase in progesterone from granulosa cells which exhibits negative feedback on GnRH release and down regulates GnRH receptors in pars distalis
LH secretion decreases. Corpus luteum degenerates into inactive corpus albicans that has NO NUCLEI
90
Corpus luteum of pregnancy
Human chorionic gonadotropin (hCG) from the implanting blastocyst RESCUES the corpus luteum (hCG acts similar to LH)
Steroid hormone production is continued and maintains the endometrial lining in the uterus
Corpus luteum of pregnancy continues to enlarge and increase hormone production throughout the first trimester
91
What’s the difference between Inhibin B and Inhibin A?
Inhibin B— granulosa cells; inhibits FSH secreting gonadotrophs
Inhibin A— granulosa lutein cells; inhibits both FSH and LH secreting gonadotrophs
92
What can a granulosa lutein cell make that a granulosa cell can’t? Why? What is weird about progesterone and estrogen synthesis in granulosa lutein cells?
FSH allows granulosa cells to convert androgens into estradiol via aromatase BUT LH allows granulosa lutein cells to take up cholesterol and form progesterone
HOWEVER, the granulosa lutein cells do not have the enzyme necessary to turn progesterone into androgens. Therefore, the androgens that become estradiol in the granulosa lutein cells still comes from theca lutein cells.
93
Clinical considerations of the ovary
Ovarian cysts— fluid filled cavities resulting from unruptured Graafian follicles
Polycystic ovary syndrome— elevated androgens and LH but no FSH means bilateral ovarian enlargement due to follicular cysts (that never matured)
Ovarian tumors
Menopause— ovarian follicles fail to develop
94
Why are FSH and LH levels increased in menopause? Where do low levels of estrogen still come from? How can you counteract menopause?
Menopause= cessation of menses. Follicles do not develop in response to FSH/LH
Reduced estradiol, progesterone, and Inhibin B means loss of negative feedback so FSH/LH levels rise.
Estrogen deficiency causes bone loss, hot flashes, increased coronary artery disease
Low levels of estrogen are produced via aromatase and androgen precursors in peripheral tissue
Hormone replacement therapy
95
What are the different layers of the oviducts (Fallopian tubes)? What happens as you move from the ampulla to the isthmus?
Highly folded mucosa, poorly defined muscularis with both circular and longitudinal layers, and highly vascular serosa/adventitia. It’s just like the ESOPHAGUS
Internal luminar diameter decreases, highly folded mucosa reduced to fewer folds, muscularis becomes thicker
96
What makes up the mucosa of the oviducts?
Two types of simple columnar cells:
- ciliated cells: beat in unison towards the uterus to move oocyte
- peg cells: secrete a nutrient rich fluid to enrich secondary oocyte, spermatozoa, and preimplantation embryo
Lamina propria- highly vascular and highly cellular loose connective tissue
97
What effects do estradiol and progesterone have on the oviducts?
Estradiol
- Epithelium: stimulates ciliogenesis and ciliary beat, stimulates secretory activity
- Lamina Propria: increases vascularity
- Muscularis: increases vascularity and contractions
Progesterone
- Epithelium: maximizes ciliary beat, stimulates secretory activity
- Muscularis: decreases contraction
98
What happens to the secondary oocyte at the time of fertilization?
Zona pellucida: receptor for sperm; initiates acrosome reaction— enzymes associated with the acrosome digest a path through the zona pellucida
Cortical rxn prevents polyspermia (release of granules by egg makes ZP impenetrable to sperm)
Entry of sperm nucleus triggers completion of second meiosis division to form mature ovum and second polar body
Nuclei of ovum and sperm fuse to form zygote
99
Which is higher in childhood FSH or LH? Adult reproductive period? Senescence? What about overall levels?
Childhood and puberty: FSH > LH
Adult Reproductive Years: LH > FSH
Senescence: FSH > LH
Overall levels increase with age
100
When do the following hormones peak? FSH, LH, Estradiol, Progesterone, Inhibin B, Inhibin A
FSH, LH, Estradiol- at or just before ovulation
Progesterone- 7 days after ovulation
Inhibin B- at ovulation (same time as FSH peak)
Inhibin A- 7 days after ovulation
101
Where does fertilization usually occur?
Antrum of oviduct
102
Amenorrhea
Absence of menses
103
A woman comes in complaining of no period over the past 6 months. She has 14 follicles in the left ovary. What would you expect to see?
LH/FSH ratio > 2, increased androgens
menstrual irregularities, insulin resistance, obesity, hirsutism, infertility
Multiple cysts would be seen
104
3,3,5 triiodothyronine
Reverse T3 (rT3); inactive form of T3 that is secreted instead of T4 when the need for thyroid hormone is low
105
What are the four major steps in the synthesis and release of thyroid hormones?
Uptake and concentration of dietary iodide within the gland
The oxidation and incorporation of iodide into tyrosine residues
The coupling of two iodinated tyrosine residues to form either T3 or T4
Secretion and release of T3 and T4
106
How much iodide do we need vs how much do we ingest? Describe the first step of thyroid hormone synthesis
Requirement is 150mg/day while average intake in US is 400-500mg/day (we have about 100 times excess)
Iodide is actively transported into the follicular cells via Na+/I- cotransporter known as iodide trap. This maintains a high intracellular iodide concentration relative to the concentration in the plasma. The iodide is transported into the follicle lumen via pendrin
Dietary deficiency of iodide leads to thyroid hormone deficiency despite maximal operation of the trap
107
Describe the second step of thyroid hormone synthesis. Where does it take place? What is thyroglobulin? What is thyroid peroxidase? What are the products?
Follicular cells synthesize and secrete thyroglobulin into the follicular lumen as the source of tyrosine for thyroid hormone.
In the follicular lumen, thyroid peroxidase enzyme oxidizes iodide via locally generated H2O2 and incorporates it onto specific tyrosine residues of thyroglobulin.
Monoiodotyrosine (MIT) and diiodotyrosine (DIT) result from iodination
108
What occurs during step 3 of thyroid hormone synthesis? What is the ratio of products normally and when iodine is deficient?
Tyrosine peroxidase catalyzes the coupling of two iodinated tyrosines within thyroglobulin (still in the colloid lumen)
DIT + DIT = T4
MIT + DIT = T3
Ratio of T4/T3 is normally 10/1 but T3 production increases if iodide is deficient
109
Describe the fourth step of thyroid hormone synthesis. What is Megalin? What is deiodinase?
Iodinated tyrosines (on thyroglobulin) are stored in the follicular lumen colloid until needed.
Thyroglobulin complex (with its MITs, DITs, T3s and T4s) is endocytosed into the follicular cell via Megalin receptors.
Lysosomal enzymes release T3 and T4 from thyroglobulin and they are then released into capillaries
MIT and DIT are deiodinated by deiodinase and the components are recycled for incorporation into new hormones
110
What do thyrouracils do?
Block the enzyme thyroid peroxidase which is useful in treating hyperthyroidism.
111
What are the layers of the uterus? What type of epithelium lines the mucosa of the uterus?
Endometrium, myometrium, and perimetrium (serosa/adventitia)
Simple columnar
112
Describe the structure of the myometrium
Thickest of the three layers. Made up of huge smooth muscle cells interlaced with connective tissue: collagen fibers, vessels and lymphatics
Three layers: middle layer is the thickest and contains arcuate arteries
113
Hormonal regulation of myometrium: estrogen, progesterone, relaxin, oxytocin?
Estrogen: proliferation (by itself during proliferative phase); maintains/increases contractility; formation of gap junctions
Progesterone: decreases contractility
Relaxin: inhibits uterine contractions
Oxytocin: stimulates uterine contractions
During pregnancy, myometrium undergoes hyperplasia and hypertrophy. Increased collagen as well. Apoptosis of SM occurs after pregnancy
114
Two layers of the endometrium?
Stratum functionale— this layer changes in response to hormones; the lamina propria contains the length of the uterine glands; spongier lamina propria with more ground substance. Supplied by spiral arteries (when proliferated)
Stratum Basale— doesn’t change or slough off; more cellular lamina propria; contains the deep ends of the glands; straight arteries supply here (constantly)
115
When is the menstrual phase of the uterine cycle? Describe the endometrial structure
Days 1-5 when progesterone and estrogen are crashing; endometrium can’t be maintained
Thickness of endo: 3 mm —> .5 mm
Glands: short, collapsed (undergoing apoptosis)
Stroma: dense with leukocytes and red blood cells (because the vasculature and lymphatics are breaking down and dumping out)
Epithelium: columnar
Mitosis: absent
116
When is the proliferative phase of the uterine cycle? What is the endometrial structure like? Stimulated by what?
Days 5-14; estrogen from developing follicle stimulates this phase
Thickness of endo: 1 mm —> 4 mm
Glands: narrow and straight, no secretory activity (still growing)
Stroma: proliferating, no leukocytes are present
Mitoses: numerous
Epithelium: columnar (cells from basal end of glands proliferate and come up to become surface cells)
117
When is the secretory phase of the uterine cycle? What is the endometrium like?
Days 15-26; caused by estrogen but mostly progesterone in this phase
Thickness of endo: 4-6 mm
Glands: wide, sacculated, secretory. Glycogen rich secretions essential for survival and development of the embryo (all of this stimulated by progesterone)
Stroma: edematous, no leukocytes; secretions and edema cause the swelling
Epithelium: tall columnar
Mitoses: confined to coiled arteries
118
When is the premenstrual phase? What is the endometrium like?
Days 27-28; progesterone and estrogen start to decline
Thickness of endo: 4-5mm
Glands: wide, irregular in outline
Stroma: dense, leukocytes, RBCs
Epithelium: columnar
Mitoses: absent
119
Functions of the cervix?
At ovulation, cervical glands secrete a watery mucus that facilitates entry of sperm into the uterus (therefore, it is stimulated by estrogen)
At other times of cycle and during pregnancy, glands secrete viscous mucus preventing entry of sperm and microorganisms into the uterus (progesterone)
120
What are the layers of the cervix?
Mucosa:
- simple columnar epithelium (endocervical); switches to non-keratinized stratified squamous at a certain point
- Thick lamina propria (more fibrous than cellular)
- Branched, tubular glands (mucus)
Muscularis: dense collagen opus c.t. with elastic and smooth muscle fibers
Adventitia
121
Nabothian cysts
Secretions from cervical glands stuck beneath the surface of the epithelium
122
Transformation zone
Simple columnar to strat. squamous epithelium in the cervix. Located just outside the external os during reproductive age
123
Pap smear
Swab of the stratified squamous cells of the exocervical mucosa to determine if there is an cervical carcinoma
Most common cause is HPV 16-18
124
Hormonal regulation of the cervix
Estrogen: stimulates formation of watery mucus (lysozyme)
Progesterone: induces formation of a very viscous mucus
Relaxin: stimulates softening of the cervix by lysis of collagen fibers at the time of parturition (giving birth). Produced by corpus luteum and placenta
125
Layers of the vagina
Mucosa: numerous transverse folds
- epithelium: mucosal, stratified squamous epithelium (small amount of keratohyalin forms)
- basal layer of cells (constantly renews stratified layers due to stimulation by estradiol)
- Lamina propria: loose fibroelastic c.t., highly vascular, NO GLANDS, neutrophils, lymphocytes, few sensory nerve endings
Muscularis: smooth muscle and elastic fibers
- Thin inner circular layer
- Thicker outer longitudinal layer
Adventitia: dense fibroelastic c.t.
126
What chain molecule is often preserved on the surface of the vaginal mucosa when stained?
Glycogen (stains red)
127
Hormonal regulation of the vagina
Estradiol:
- maintains thickness of epithelium
- stimulates production of glycogen which is converted to lactic acid by vaginal flora to maintain an acidic pH
Progesterone:
-Decreases proliferation and increases differentiation
128
Give a summary of the sex steroid regulation of the female reproductive tract (estrogen and progesterone on oviducts, uterus, and vagina)
Estrogen:
- (oviducts) incr. cilia formation and activity, incr. contractility
- (uterus) incr. proliferation of endo, incr. growth and contractility of myo, watery secretion by glands
- (vagina) epithelial proliferation, incr. glycogen deposition
Progesterone:
- (oviducts) incr. secretion, decr. Contractility
- (uterus) incr. differentiation and secretion, decr. Contractility, dense viscous glandular secretions
- (vagina) incr. differentiation, decr. Proliferation
129
Endometriosis
Some Endometrium goes up into peritoneal cavity instead of sloughing out; can cause severe pain and formation of cysts
May lead to sterility because the ovaries and oviducts become deformed and embedded in scar tissue
130
Describe the mammary glands prior to puberty
Same in both sexes
Only contain lactiferous sinus just below nipple (areola) with small ducts
131
Describe the mammary glands at puberty
Rise in estrogen in girls causes adipocytes accumulation and ductal growth:
Nipple and areola enlarge
Proliferation of duct system and epithelial cells (that make up the duct)
Increase in stroma (collagenous c.t. and fat)
132
Compound tubuloalveolar gland
Describes the adult mammary gland structure:
Contains 15-20 lobes each of which has its own lactiferous duct and sinus. Separated from other lobes by dense connective tissues and adipose tissue
Each lobe contains multiple functional units called lobules (which are made up of glandular alveoli when stimulated by pregnancy and child rearing); each lobule attaches to its own branching duct. Within the lobule are found multiple terminal ducts (which lead to alveoli when there)
133
Describe the nipples/areola, stroma, and duct system of the adult resting mammary tissue
Nipples/areola: keratinized strat. squamous epithelium; areola has sweat and sebaceous glands; dermis is dense irregular conn tissue with smooth muscle fibers; highly innervated
Ductal system:
- Lactiferous sinuses: stratified columnar/cuboidal epithelium
- Lactiferous ducts: simple columnar/cuboidal and stratified columnar/cuboidal
- Terminal ducts: simple columnar/cuboidal (these lead to the acini/alveoli)
- intralobular ducts
- myoepithelial cells to project milk out
Stroma:
- interlobar and interlobular c.t. — dense irregular c.t. and adipose tissue
- intralobular c.t. — loose c.t. with plasma cells, lymphocytes, eosinophils
134
What surrounds the cells of each terminal ductule/acinus? When does breast carcinoma become really dangerous?
Myoepithelial cells and a basement membrane
When the carcinoma pushes outside of the basement membrane it can start spreading to vessels and other regions, etc.
135
How does the mammary gland change in response to menstruation? How does it compare to pregnancy?
First half: estrogen causes slight ductal proliferation
Second half: progesterone causes slight development of secretory units (alveoli)
Very minuscule growth compared to the hormone flood during pregnancy
136
To which lymph nodes do mammary glands drain normally? What is peau d’orange?
Axillary nodes
When a tumor blocks lymphatic drainage, the lymphatic ducts dilate and cause the skin of the breasts to swell looking like an orange peel
137
Generally, what happens to mammary tissue during the first half of pregnancy vs. the second half?
First half: proliferative— secretory alveoli develop at the ends of terminal ductules
Second half: Lobules enlarge from hypertrophy of alveoli and secretion of colostrum
138
During pregnancy, what happens to the nipple/areola, duct system, stroma, and glandular tissue? What do the alveoli do?
Nipple/areola: enlarge and become more pigmented
Ductal System: completes development
Stroma: c.t. and adipose tissue are reduced
Glandular tissue: develop; ALVEOLI FILL LOBULES
-Alveolar cells= simple cuboidal/columnar that secretes milk lobules; secrete colostrum in second half of pregnancy
139
What is the difference, histologically, between resting adult mammary tissue, pregnant adult mammary tissue, and lactating adult mammary tissue?
Resting: lobules appear as connective tissue islands with small, sparse ductules within them
Pregnant: alveolar proliferation has completely filled in the lobule territory. Many more lumen and nuclei can be seen. The connective tissue between lobules is reduced
Lactating: milk secretion fills the numerous alveoli and ductules. Connective tissue is hard to see except for septa because it has been crowded out
140
What is colostrum?
Late in pregnancy the glandular alveoli and ducts are dilated by an accumulation of colostrum in the intralobular connective tissue.
Fluid rich in protein and containing leukocytes. Produced under the influence of prolactin. IgA antibodies made by plasma cells enter colostrum and will help confer immunity on to the baby through breast feeding
141
How can you tell the difference between alveoli and ducts on a slide?
Ducts= columnar epithelium; spaced out; smaller lumens
Alveoli= cuboidal epithelium; tons of them around each other; bigger lumens starting to fill with milk
142
What happens to adult mammary tissue during lactation? After lactation?
Glandular tissue:
- secretory unit— alveoli
- alveoli (and ducts) dilated with secretory product, milk
- epithelium is compressed (cuboidal)
Thin c.t. septae
No further changes in ducts, nipples, areola
143
What do the alveoli secrete days 1-3 of lactation? Day 4 and beyond?
Colostrum
- rich in protein
- rich in Vit A
- rich in IgA
Day 4: Milk
- protein (1.5%)
- fat (4.0%)
- lactose (7%)
- IgA
144
What are the effects of estradiol, progesterone, and prolactin on mammary glands? What other hormones have an effect?
Estradiol: stimulates duct proliferation (puberty and pregnancy)
Progesterone: stimulates development of secretory units (alveoli)
Prolactin:
- dopamine suppresses prolactin in nonpregnant women
- increases during pregnancy although action on mammary gland suppressed by high E and P
- stimulates pubertal development of breast tissue and further hyperplasia during pregnancy
- stimulates milk synthesis and secretion after drop in E and P after pregnancy
Oxytocin: stimulates milk ejection by contraction of myoepithelial cells
Background of hormones: glucocorticoids, insulin, thyroxine, GH, IGFs
145
Milk ejection vs milk let-down
Prolactin is secreted in response to sucking child— prolactin causes milk synthesis (let down)
Oxytocin secreted in response to sucking child— milk ejection
146
What is lactational amenorrhea?
Prolactin released due to sucking child inhibits GnRH release (negative feedback); FSH and LH blocked, no follicular development, no menses
147
What happens to the mammary glands after cessation of lactation? What about at menopause?
Post-lactation: Resorption of glandular tissue; reestablishment of c.t. and adipose tissue
Menopause: connective tissue decreases in amount and density increases (cells replaced with fibrous tissue); further involution of ducts and secretory units
148
Describe some hormonal therapies for breast cancer (either ductal carcinoma or terminal (lobular) carcinoma)
Estrogen receptor blockers: blocks estrogen dependent ductal proliferation
Estrogen receptor destruction
Aromatase inhibitors: prevents conversion of androgens to estrogen
Oophorectomy
Chemical castrations (GnRH analogs): continuous stimulation of pituitary prevents FSH/LH release
149
What could happen if a woman had prolactin excess?
Infertility and complete loss of menses (GnRH inhibitor)
150
What is the function of the testis?
Production of sperm (spermatogenesis)
Production of androgens for reproduction and development of secondary male characteristic (steroidogenesis); only 5% of androgens are produced by adrenals
151
Intratesticular and excurrent ducts, accessory glands (what do they all do)?
Intratesticular duct: straight tubules, rete testis (sperm transport, maturation and storage)
Excurrent: efferent ductules, ductus epididymis, vas deferens (sperm transport, maturation, and storage)
Accessory glands (secretion to nurture sperm and facilitate transport): seminal vesicles, prostate, bulbourethral glands
152
Describe the external structure of the testis
Tunica Albuginea— thick, dense irregular connective tissue capsule
Mediastinum testis— involution of thickened tunica albuginea on posterior surface of testis (excurrent ducts, blood vessels, and lymphatics run through here)
Septa— connective tissue projecting from the capsule separating testis into 250 lobules
153
Describe the tubule system within the testes
1-4 convoluted, seminiferous tubules in each lobe (where sperm collects after synthesis)
Straight tubules (one per lobule) also called tubuli recti that connect seminiferous tubules to rete testis
Rete testis— maze of interconnecting channels within mediastinum testis
154
What is found in the interstitial connective tissue stroma between seminiferous tubules? What is important about this area?
Loose connective tissue containing:
Fibroblasts— cigar shaped nuclei.
Leydig cells— Found in clusters. Round or polygonal. Large, acidophilic cytoplasm full of SER and lipid droplets because it SYNTHESIZES AND SECRETES TESTOSTERONE. Primary endocrine function of the testes. Nucleus is also large and round.
155
What makes up a seminiferous tubule? What are myoid cells? What type of epithelium is the seminiferous epithelium?
Lamina (tunica) propria— 3-5 layers of myoid cells (flat, smooth muscle like cells that help move sperm and fluid to the excurrent ducts) and collagen fibrils
Basal lamina
Seminiferous Epithelium— Complex stratified
- Sertoli cells (supporting cells with tight junctions and large nuclei with prominent nucleolus); extend from basement membrane to lumen— provide structure
- Spermatogenic cells— replicate and differentiate into sperm; poorly defined layers but most immature on basement membrane and most mature closest to lumen (apical surface of Sertoli cells)
156
What are the five types of spermatogenic cells? What are the three phases of Spermatogenesis? What is spermiogenesis?
```
Spermatogonia
Primary Spermatocytes
Secondary Spermatocytes
Spermatids
Spermatozoa (mature)
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1) Spermatogonia undergoes mitosis to replicate and differentiate into a Primary Spermatocyte.
2) two round of meiosis: primary spermatocyte—> 2 secondary spermatocytes—> 4 spermatids
3) Spermiogenesis: spermatids transform into mature spermatozoa (does NOT require mitosis or meiosis)
157
What is the cytoplasmic bridge? When does it disappear?
Connection of cytoplasm between developing spermatocytes (stay linked even after cell division) so that they can share gene products among haploid cells so that they can be supplied with RNA and proteins from complete diploid genome. Allows synchronous development
Only disappears upon completion of spermiogenesis as mature spermatozoa disconnect from the Sertoli cells
158
Describe Spermatogonia. What are the three types?
Type A dark (Ad), Type A pale (Ap), Type B
Most immature sperm cell; relatively large, round or ellipsoid; always connected to the basement membrane. Rounded nuclei with different patterns of chromatin
Differentiate into primary spermatocytes
159
Primary Spermatocytes. How do these give way to genetic variation?
Largest germ cell present; spherical or ovoid; nucleus contains strands of heterochromatin;
Primary spermatocytes undergo first meiotic division which allows crossing over and random assortment
160
Secondary Spermatocytes
Half the size of Primaries; rarely seen because they undergo meiosis II almost immediately. Each secondary spermatocyte produces two spermatids
161
Spermatids (early vs late)
Going through spermiogenesis to produce spermatozoa; no more cell division
Early— small size; round nuclei with condensed chromatin
Late— Elongated, condensed nucleus; has a tail; attached to apical side of Sertoli cells
These guys make up most of the thickness of the seminiferous tubules
162
What are the four components of spermiogenesis?
1) Nuclear condensation and elongation (as small as possible)
2) Acrosome formation— cap filled with hydrolytic enzymes
3) Flagellum formation— mitochondria connects head to a microtubule flagellum
4) Cytoplasmic reduction by Sertoli cells and Spermiation— breaking of the cytoplasmic bridge as sperm are released into the seminiferous tubules
163
Spermatozoon (spermatozoa); where are they stored and when do they gain the capability to move?
“Stripped down” cell
Most of cytoplasm has been phagocytosed by Sertoli cells; no longer attached to each other; free in the lumens of the tubules
Are not motile when they are first released! They gain that function in the epididymis although they are inhibited by inhibitory proteins until ejaculation
Stored in the distal portion of the duct of the epididymis until ejaculation
Can live there for several weeks but only 2-3 in the female repro tract
164
What is the function of Sertoli cells? What is the blood-testis barrier?
Structural organization of seminiferous tubules
Support and nurse maturing sperm (by exchanging waste and metabolic substrates)
Phagocytose unneeded cytoplasm and failed spermatogenic cells
Form tight junctions via cellular processes that separate the epithelium into a basal and adluminal compartments; also forms the blood-testis barrier which keeps spermatogenic cells from entering blood (they are antigenic because they are haploid)
Exocrine and endocrine secretion
165
What do Sertoli cells secrete?
Exocrine:
- Fluid— facilitates passage of mature sperm through seminiferous tubules
- Androgen Binding Protein— promoted by FSH; binds to testosterone to make it less lipophilic and highly concentrated in the lumen of tubules to stimulate development of sperm
Endocrine:
- Estradiol— aromatase in Sertoli cells (in neonatal and prepubescent mammals) converts testosterone to estradiol to regulate spermatogenesis and inhibit testosterone production from Leydig cells
- Inhibin B— to provide negative feedback for FSH from adenohypophysis
- Mullerian Inhibiting Factor (MIF)— inhibits formation of female reproductive tract (VERY IMPORTANT ONE)
- Growth factors— maintain the numbers of spermatogonia
166
Structure of Sertoli cells
Tall, columnar
Nucleus is ovoid or triangular, large and lightly stained; NUCLEOLUS is large and prominent; cell limits not visible
Well developed SER, RER, mitochondria, and Golgi cause it secretes shiz
167
When and how do spermatogenic cells get through the blood-testis barrier?
Early spermatocytes need to pass through because meiosis and spermiogenesis occurs on the adluminal side of the barrier
New barrier forms on the basal side of the spermatocytes luminal side barrier dissipates
168
What is the effect of temperature on Spermatogenesis? What are the protective mechanisms against this? What is the danger of Cryptorchidism?
- All spermatogenic cells (besides spermatogonia) are very heat sensitive so they dangle to maintain 2-3 degrees below body temp
- The pampiniform plexus of veins surrounds the descending testicular artery and acts as a heat exchanger to cool the arterial blood slightly
- Cremaster reflex pulls testis up into the body cavity to protect from cold; Dartos fascia has a thin layer of muscle that also contracts when cold and causes scrotum to wrinkle
Cryptorchidism (undescended testes) could lead to destruction of all cells besides spermatogonia leaving only interstitial spaces
169
Why is the smooth muscle so thick around the veins of the pampiniform plexus? How can they be recognized histologically?
It has to propel blood against gravity to reach the abdominal veins
Thick smooth muscle vessels surrounding an even larger testicular artery
170
When does implantation occur? What is the role of hCG? What is the decidual reaction?
Days 21-24 of cycle;
hCG from the syncytiotrophoblasts (blastocyst) rescues and maintains the corpus luteum
Endometrial stroma cells hypertrophy
171
Why is it so important to maintain the progesterone and estrogen levels during pregnancy?
Because we need them to maintain that endometrial lining
172
A woman has regular 28 day cycles. She comes in at day 40 since her last period. Took a positive pregnancy test at day 31 and 32. How many days since conception?
25 days
173
Decidual Reaction. What is the function of the decidua?
Fibroblasts within the lamina propria (stroma) of the endometrium hypertrophy and contain large amounts of glycogen and lipid in response to the continued secretion of progesterone and estrogen
1) Initially, cells serve as a nutrient source for embryo until the vascular connections are made
2) Also forms a barrier to keep embryo from entering myometrium
3) Also functions as endocrine organ: releases prolactin, relaxin, prostaglandins that act on uterine muscle, cervix, and the embryo
174
What are the functions of the decidual hormones?
Relaxin: produced by corpus luteum of pregnancy, and placenta, AND decidua
- stimulated by hCG
- Early pregnancy— suppresses myometrium contractions to protect embryo
- Late pregnancy— softening of the cervix in preparation of parturition (breaks down connective tissue fibers)
Prolactin: major source is maternal pituitary, but locally produced prolactin depresses immune response to the fetus
Prostaglandins:
-Late Pregnancy— contraction of the smooth muscle and softening of the cervix
175
What are the tissue layers of a blastocyst?
Trophoblast— the peripheral cells of the blastocyst that attach the fertilized ovum to the uterine wall and contribute to the placenta. The inner cell layer is the cytotrophoblast and the outer layer is the syncytiotrophoblast
Cytotrophoblast— the mitotically active inner cell layer producing cells that fuse with the syncytiotrophoblast
Syncytiotrophoblast— outer layer that is not mitotically active. Multinucleate cytoplasmic cell mass that erodes and invades the epithelium and the underlying stroma of the epithelium (and starts to capture the maternal blood from within)
176
What are the functions of the Placenta?
Quintessential hormonal organ
Unique and transient endocrine function:
- secretes hormones that affect maternal and fetal metabolism
- not subject to regulation by maternal or fetal signals
Acts as fetal gut supplying nutrients
Acts as fetal lung exchanging gases
Acts as fetal kidney eliminating waste and regulating fluid volumes
177
Describe the development of the placenta
Blastocyst implants and syncytiotrophoblast starts capturing maternal blood and projecting villi into the endometrium. Chorionic shell forms around syncytiotrophoblastic layer. Maternal blood trapped in the intervillous spaces
Fetal portion: Chorion
- chorionic plate
- chorionic villae: free and anchoring villae
- cytotrophoblastic shell
Maternal portion: decidua basalis
- basal plate
- placental septa
178
Histologically, where are the syncytiotrophoblasts, cytotrophoblasts, fetal blood, and maternal blood?
Syncytiotrophoblasts— dark, group nuclei around the perimeter of the villi
Cytotrophoblasts— larger, light nuclei within the villi
Maternal blood in the intervillous spaces
Fetal blood within fetal blood vessels INSIDE the villi
179
What is an anchoring villus?
Where the villus meets the cytotrophoblastic shell and thus physically connects to the maternal decidua
180
What is the placental barrier?
The layers that blood/toxins must cross to get to the fetal blood
- syncytiotrophoblasts
- cytotrophoblasts
- extraembryonic mesenchyme
- endothelial cells (blood vessels)
181
What crosses the placental barrier?
Exchange of gases and nutrients (glucose and proteins)
Transferrin (carries iron to fetus)
Steroid hormones
Fetus eliminates waste
Maternal antibodies (IgG)
Alcohol or other drugs
182
What is the “placental hypothalamic-pituitary unit”? What hormones does each layer secrete?
The inner cytotrophoblastic layer acts as the hypothalamus and releases:
-GnRH
-CRH
-TRH
-Somatostatin
As well as IGF-I and IGF-II to stimulate proliferation and differentiation
The outer syncytiotrophoblast layer acts as the pituitary gland and releases:
- hCG (similar to FSH/LH)
- human chorionic ACTH
- human placental GH
- human chorionic thyrotropin
```
As well as the big ones:
Progesterone
-inhibits maternal immune response
-provides precursors to fetal adrenal glands
-Quiets uterine contractions
-Stimulate mammary gland development
Estrogen
-stimulates growth of uterine smooth muscle
-stimulates mammary gland development
-cannot synthesize androgen precursors for estradiol synth; relies on fetal androgen gland
Human Chorionic Somatomammotropin (hCS)
-Shunts nutritional substrates to fetus
Inhibin A
-suppress unwanted follicle development
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183
Why does PLACENTAL steroidogenesis require a coordinated interaction between the mother and the fetus?
The placenta CAN make progesterone from Cholesterol from the maternal liver
However, it does not have the enzymes to convert progesterone to estrogen so Pregnenolone (before progesterone) must be converted to DHEA by the fetal adrenals to 16a-OHDEAS by the fetal liver where is goes back to the placenta to be converted to estriol
Summary:
(Placenta) Cholesterol—> Pregnenolone—> (fetus) DHEA—> 16a-OHDEAS—> (placenta) Estriol
184
When does hCG stop regulating E and P secretion?
After 1st trimester
Corpus luteum secretes E and P for first trimester
Placenta takes over for 2nd and 3rd trimester
-high levels of sex steroids prevents maternal hypoth/pituitary axis preventing ovulation
185
To determine fetal health, which is the BEST hormone to measure?
Estriol (estrogen)
Progesterone will be made by the placenta independently of the fetus, but Estrogen requires a healthy fetus for the placenta to maintain the high levels
186
A 5 month pregnant woman is referred to your office with newly diagnosed hypertension. You are concerned that the fetus and placenta may be compromised. To assess fetal and placental health, which hormone measurements would be most informative?
Urinary Estriol and serum hCG
Why not progesterone? Because the corpus luteum of pregnancy might be present still and producing progesterone. hCG only comes from the syncytiotrophoblasts of the placenta which is a better measure of fetal health
187
LH stimulates Leydig cells to produce testosterone. What effect does FSH have on Sertoli cells? What type of feedback does the testosterone demonstrate? What is activin?
Causes them to secrete:
- Estrogen (provides a negative feedback on Leydig cells to inhibit T production)
- ABP (to increase local T levels)
- Growth Factors (to regulate mitosis and meiosis)
- Inhibin B (to induce and regulate spermatogenesis; negative feedback on FSH production)
Test has a negative feedback on hypothalamus to inhibit GnRH release and LH production/release (but not FSH I guess?)
Activin in the anterior pituitary antagonizes Inhibin B action and increases FSH synthesis
188
What other functions (besides secretion) does FSH have on Sertoli cells? What can be measured as an index of spermatogenesis?
Controls Sertoli cell proliferation and seminiferous tubule growth and thus control testicular size
Important in the initiation of spermatogenesis during puberty
Necessary for the development of the blood-testis barrier
Inhibin B levels correlate with spermatogenesis, total sperm count, and testicular volume
189
How is estrogen synthesis in the testicles similar to that of the ovaries?
Androgens have to cross the basement membrane into the functional space to be converted by aromatase into estrogen
190
How is testosterone transported in the blood? What happens to it in the tissues?
50% bound loosely to albumin
44% bound to sex hormone-binding globulin (SHBG)— NOT bioavailable T
2-3% free
In peripheral tissues gets converted to DHT (super strong form of T) or estrogen
If not converted, gets degraded by the liver
191
What are the physiological roles of testosterone?
Principal circulating androgen
Binds to receptors
Intratesticular function: high local levels in the testis required for spermatogenesis
Peripheral function: required for masculine characteristics
192
How does T secretion change over life? What is diurnal rhythm
During fetal life, the testes are stimulated by hCG from the placenta to produce moderate amounts of T
Essentially no T produced in childhood until about 10-13 years old
At puberty, triggered by pulsatile release of GnRH resulting in increasing amplitude of FSH and LH
Diurnal rhythm: FSH and LH increase during sleep in the early parts of puberty. This is lost by age 16-18
After age 40, T declines by 2% per year while SHBG increases further decreasing the amount of available T; aging is associated with decreased T to E ratio, decreased LH pulse frequency, and diminished DHT in reproductive tissues
193
What can cause hypergonadism? What are the effects?
Androgen overproduction:
- before puberty: leads to precocious puberty
- after puberty: early hair loss
Causes:
- hypothalamic tumors (incr. GnRH)
- activating mutations of LH receptors
- congenital adrenal hyperplasia
- androgen producing tumors (Leydig cell tumor)
- Pinealoma (destroys pinealocytes which decr. melatonin—> incr. GnRH)
194
What effect does melatonin have on T production throughout life?
From early in development (3 months), melatonin is secreted at night and inhibits GnRH secretion
GnRH axis stays inhibited until puberty when body mass increases and causes decreasing concentrations of melatonin. GnRH pulse then gets reactivated
195
Primary vs. Secondary Hypogonadism
Both cause decreased T production
Primary Hypogonadism (hypergonadotropic)- testicular dysfunction problem. Low T but high LH; testicular damage, cryptorchidism, gonadal dysgenesis, enzyme defects in T biosynthesis, or LH receptor defects
Secondary (hypogonadotropic)— problem at the hypothalamus/pituitary level— low FSH, LH, and T; genetic defects, adrenal hypoplasia, mutations in GnRH receptor, LH or FSH B-subunits; pituitary tumors (including prolactinoma which increases prolactin and inhibits GnRH); trauma or surgery
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What should be injected to determine a Secondary hypogonadism at the level of the hypothalamus vs pituitary
Inject GnRH
If LH goes up, its hypothalamic
If nothing changes, LH won’t go up
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What lines the straight tubules (of the intratesticular ducts)?
Early portion, lined only by Sertoli cells
Later portion becomes simple cuboidal epithelium
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Histologically, how do you tell a vein from rete testis?
Rete testis is lined by simple cuboidal epithelium (more basophilic)
Veins are lined by squamous endothelium (more acidophilic)
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What is the function of the efferent ductules (excurrent system)? How does its epithelium reflect its function? What other layers exist?
- 20 ductules transport sperm from the rete testis to the proximal portion of epididymis
- reabsorbs most of the fluid secreted in the seminiferous tubules
Epithelium: pseudostratified columnar (most common type of epithelium in the male reproductive tract)
- alternating clumps of tall, ciliated columnar cells (movement) and short cells with microvilli (absorption)
- basal cells on basement membrane possess little cytoplasm and serve as stem cells
Thin smooth muscle layer surrounds it all and helps with movement of sperm
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What does the epididymis do? What are the three parts of the epididymis? What are their layers?
Sperm transport
Reabsorb fluid that wasn’t reabsorbed in the efferent ductules
Place of sperm maturation (gain the ability to move and fertilize but are inhibited by proteins in the body)
Storage reservoir for matured sperm
Head— efferent ductules; surrounded by single layer of smooth muscle that contracts spontaneously
Body— duct of the epididymis; site where spermatozoa mature; surrounded by single layer of smooth muscle
Tail— duct of the epididymis; principal reservoir for mature spermatozoa; 3 layers of smooth muscle— circular, inner longitudinal, outer longitudinal; not spontaneous but controlled by ejaculation
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How is the epithelium of the epididymis different from the efferent ductules?
Also pseudostratified but only one two cell types:
- basal cells
- tall ‘principle’ cells with stereocilia— not for motility, only absorption
Lumen appears regular because the cells are all one height
This doesn’t start until the body of the epididymis
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Vas Deferens
Longest part of excurrent system— direct continuation of tail of the epididymis
Enters abdomen as part of spermaticord
Function: Strong peristaltic contractions following neural stimulation and ejaculation to expel sperm to ejaculatory duct
Lumen: deep longitudinal folds
Mucosa: stereociliated pseudostratified columnar epithelium (shorter cells than tail of epididymis; moderately thick lamina propria of loose connective tissue with elastic fibers
Muscularis: 3 layers
- inner longitudinal
- middle circular (very thick)
- outer longitudinal
Adventitia: slightly denser than usual; blends in with the general fibrous connective tissue of the spermatic cord; contains nerves and vessels
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What prize does the vas deferens win?
Muscular wall is (relatively) the thickest wall of any tube in the body
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Ejaculatory Duct
Connects the end of the vas deferens to the urethra through the prostate; mixes sperm and seminal fluid
Same mucosa as vas deferens but no muscularis layers (instead surrounded by the stroma of the prostate); fibroelastic tissue and smooth muscle of prostate
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What happens to sperm produced by someone with a vasectomy?
Fluid absorbed by epididymis and solid product broken down by macrophages
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Does a vasectomy have any effect on testosterone production?
Nope; happens in interstitial spaces of testis
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After a vasectomy, could there be anti-sperm antibodies detected in the blood? If that is the case, could this person ever be fertile again if the vasectomy is reversed?
Maybe. If spermatozoa leaked into the blood from the severed vas deferens
Yes because the blood testis barrier would reform
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What are the accessory glands of the male reproductive system?
Seminal vesicles, prostate, bulbourethral (cowper’s) glands
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Describe the function of seminal vesicles
Paired, elongated, highly-coiled glands (15cm) located on the posterior wall of the bladder
Function:
- secretions form 60-70% of seminal fluid; whitish-yellowish; expelled in the second half of ejaculation to wash out urethra and dilute the thick mass of sperm
- fluid is slightly alkaline which helps neutralize acidic vagina
- secretions are mostly fructose (nutrients for spermatozoa)
- also secretes prostaglandins (to cause smooth muscle contractions in female and male reproductive tracts) and fibrinogen (cleaved to fibrin; holds sperm in the deep parts of vagina)
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Describe the structure of seminal vesicles
Paired, elongated, highly-coiled glands (15cm) located on the posterior wall of the bladder
Lumen: one large lumen; stores the fluid secretion between ejaculations (no spermatozoa here though)
Mucosa:
- arranged into highly convoluted folds to increase the secretory surface area
- Pseudostratified columnar epithelium with tall non-ciliated cells and basal cells
- also some simple columnar epithelium
- connective tissue lamina propria which contains elastic fibers; can be found within the folds of the lumen
Muscularis: (can sometimes be seen crossing the lumen within the deep luminal folds)
- inner circular and outer longitudinal layers to eject fluid
- secretory function and morphology are under control of testosterone
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What is the function of the prostate? Describe prostatic fluid
Stores and secretes a thin, milky, alkaline which makes up 25-30% of seminal fluid
Largest accessory sex gland in men (size of walnut)
Expelled in the first ejaculate fractions with most of the spermatozoa
- neutralizes acidic vagina
- also contains clotting enzymes (to form a fibrin clot to help anchor sperm in vagina) and fibrinolysin (liquifies clot 15-30 minutes later to release motile sperm within the female tract)
- contains PSA
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What is PSA? PAP?
Prostate Specific Antigen is normally produced by prostate epithelial cells; normally released into prostatic secretion as a serine protease and helps liquify coagulated semen to provide for slow release of sperm after ejaculation; small amount leaks into blood
In prostate cancer patients, large amounts of PSA are secreted and released into the blood
PSA can also be elevated in benign conditions like prostatitis
Prostatic Acid Phosphatase— elevated levels found in serum of patients with metastatic prostate cancers. These levels were measured before PSA was around
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Describe the overall structure of the prostate
Contains 30-50 compound tubuloalveolar exocrine glands which empty into 15-25 independent excurrent ducts; these ducts open into the urethra
Glands are embedded into a dense fibromuscular stroma which mainly consists of smooth muscle separated by dense connective tissue
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What type of epithelium is found in the prostate? What does testosterone do here?
Mostly simple columnar, but....
.. there may be patches of cuboidal, squamous, or pseudostratified columnar
Changes to a transitional epithelium near the openings to the urethra
Testosterone is converted to DHT by 5a-reductase; DHT stimulates epithelial growth in the prostate including during BPH and prostatic cancer
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What are Corpora Amylacea in the prostate?
Lamellated prostatic concretions found in the alveoli
Precipitations of secretory material around cell fragments; vary in size and shape; unique to prostate
Their numbers increase with age
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Although they look slightly similar, what are the differences between prostatic glands and mammary glands?
Prostate has smooth muscle in the stroma and lamellated prostatic concretions
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What are the four zones of the adult prostate?
Peripheral zone
Central zone
Transition zone
Periurethral zone
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Peripheral urethra
Surrounds distal urethra and occupies posterior and lateral parts of the urethra; most common site of prostate cancer (64%); most susceptible to inflammation
Palpable on digital exam
Cancer here is hard to find at first because it does NOT impinge the prostatic urethra
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Central Zone
Surrounds ejaculatory ducts; resistant to carcinoma and inflammation
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Describe Transitional Zone. What is BPH?
Surrounds proximal prostatic urethra
Account for 34% of prostate cancers
Also responsible for benign prostatic hyperplasia (BPH)— outgrowth of both epithelial and stromal cell compartments BUT does not leave the basement membrane like cancer does; formation of nodular masses can compress flow through the prostatic urethra
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Periurethral Zone
Thin sleeve around the prostatic urethra; may undergo pathological growth from stromal compartment in later stages of BPH; also increases urine retention in bladder by compressing urethra
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Which part of the prostate isn’t in a “zone”?
Anterior portion
Made of fibromuscular stroma
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Why does a biopsy have to be performed to confirm prostate cancer?
Because PSA is also elevated in BPH
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Which structure is lost in prostate cancer? What are the treatment options for prostate cancer? (Be specific)
The nice alveoli (because cells penetrate the basement membrane)
Surgery
Radiation therapy
Hormone Therapy:
-reduce circulating androgens by performing orchiectomy (surgical removal of testis); decreases T and DHT but increases FSH/LH
-use GnRH antagonist (duh) or GnRH agonist (causes initial spike in FSH/LH, T, and DHT but then the continued non-pulsatile presence of GnRH down regulates GnRH receptors)
-block action of androgens via androgen receptors antagonist
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Bulbourethral glands
Size of a pea; behind the prostate
Secrete clear, mucus-like pre-ejaculate to lubricate the penile urethra for spermatozoa to pass through. Neutralizes traces of acidic urine. Helps flush out any residual or foreign matter
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Composition of Semen
10% sperm, 90% seminal plasma from pre-ejaculate, prostatic secretions, and seminal vesicular secretions.
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Is PSA always elevated in BPH? What treatments could be done?
No
Inhibitors to 5a-reductase would reduce conversion of T to DHT and thus reduce size of prostate
Surgical removal of hyperplastic regions of prostate
Themotherapy (laser, microwave, etc.) to destroy prostate tissue
a-blockers to relax smooth muscle and ease urination
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What makes up the erectile tissue of the penis?
2 dorsal masses— corpus cavernosum (separated by pectiniform septum)
1 ventral mass— corpus spongiosum (penile urethra runs down the middle of this one)
Tunica albuginea (a dense, fibroelastic layer) binds all three together and forms a capsule around each. Much thicker around cavernosums.
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Describe the structure of the corpus cavernosum
A pair of sponge like regions of erectile tissue containing most of the blood during erection
Almost all of it is made up of irregular vascular spaces lined by endothelium and separated by thin layers of trabeculae containing collagen, elastic fibers and smooth muscle
Each is supplied by a central artery which gives off multiple corkscrew shaped helicine arteries that fill the vascular spaces during erection
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Describe the structure of the corpus spongiosum
The mass of spongy tissue surrounding the penile urethra; function is to prevent compression of penile urethra during erection in order to maintain a functioning urethra for ejaculation
Also contain numerous irregular vascular spaces lined with endothelium
These spaces are surrounded by thick layer of connective tissue and smooth muscle bundles— “subendothelial cushions”
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How does erection work?
Parasympathetic release of ACh—> NO released from SM and endothelial cells—> activation of cGMP in SM cells—> vasodilation—> relaxation and vasodilation of helicine arteries SM cells—> increased blood flow into corpus cavernosum—> compress the venues against the thick tunica albuginea (can’t flow out)—> tunica albuginea also compresses larger vessels to prevent back flow—> maintains erection
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When does Viagra work for erectile dysfunction? When does it not?
Viagra inhibits cGMP phosphodiesterase (breaks down cGMP); preserves SM relaxation and prolonging the erection period
If the ED is due to parasympathetic nervous system dysfunction, this won’t work
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Termination of Erection
Sympathetic stimulation—> contraction of trabeculae SM cells and of helicine arteries—> decr. blood flow to corpus cavernosum—> reduce BP in corpus cavernosum to normal venous pressure—> allow veins to open and drain blood
