Test Three - Steroidogenesis, Adrenal & Reproductive Glands Flashcards
A ____________________ is a chemical possessing the steroid nucleus, which is also known as the ____________________________ nucleus.
Steroid
Cyclopentanoperhydrophenanthrene
What is another name for the steroid nucleus?
Cyclopentaoperhydrophenanthrene
Steroid hormones are not packaged but _____________ and immediately ____________ from cells. In other words, steroid hormones are not stored in cells.
Synthesized
Released
Are steroid hormones stored in cells?
No, they are synthesized and immediately released
What are steroid hormones derived from?
Cholesterol
Where are enzymes that produce steroid hormones from cholesterol located?
Mitochondria
Smooth ER
Do steroid hormones travel freely in the blood?
No, they must be bound to carrier proteins
Why must steroid hormones be bound to carrier proteins?
Because they are highly hydrophobic
In some cases, a steroid is secreted by one cell and converted to an active steroid in the target cell. For example, __________, which is secreted by a gonad, is converted into __________ in the brain.
Androgen
Estrogen
Cholesterol is composed of phenanthrene attached to a pentano ring and a side chain.
You must be able to draw cyclopentanoperhydrophenanthrene (sterane) and cholesterol. You must also be able to number each carbon.
What is this?
Cholesterol
How many carbons are in cholesterol?
27 carbons
Which three steroid groups have 21 carbons?
Progestins
Glucocorticoids
Mineralocorticoids
Which groups of steroids have 19 carbons?
Androgens
Which groups of steroid hormones have 18 carbons?
Estrogens
Which derivative of cholesterol has 27 carbons?
Vitamin D
Which groups of steroid hormones have 24 carbons?
Bile acids
There are 5 classes of steroid hormones. What are they?
- Glucocorticoids
- Mineralocorticoids
- Androgens
- Estrogens
- Progestins
How many carbons does each class of steroid hormones contain?
Glucocorticoids have 21 carbons
Mineralocorticoids have 21 carbons
Androgens have 19 carbons
Estrogens have 18 carbons
Progestins have 21 carbons
What is the major role of glucocorticoids like cortisol?
Normal stress response
Utilization of carbohydrates, fats, and proteins
What is the major role of the mineralocorticoids, like aldosterone?
Salt and water balance
What is the major role of androgens, like testosterone?
Male attributes
What is the major role of estrogens, like estradiol?
Female attributes
What is the main role of the progestins, like progesterone?
Fertilization
Implantation
Pregnancy maintenance
What is the major cellular site of steroidogenesis for the glucocorticoids (cortisol)?
Zona fasciculata of the adrenal cortex
What is the major cellular site of steroidogenesis for the mineralocorticoids (aldosterone)?
Zona glomerulosa of the adrenal cortex
Outermost layers of zona fasciculata of the adrenal cortex
What is the major cellular site of steroidogenesis of the androgens (testosterone)?
Leydig or interstitial cells of the testis
Zona fasciculata and reticularis of the adrenal cortex
What is the major cellor site of steroidogensis of the estrogens (estradiol)?
Granulosa cells of the ovary
Small amounts in the zona fasciculata and reticularis of the adrenal cortex
What is the major site of steroidogenesis of the progestins (progesterone)?
Corpus luteum of the ovary
Placenta
Small amounts from the adrenal cortex
What are the three cellular origins of cholesterol?
- De novo biosynthesis from acetate
- Circulating lipoprotein in serum
- Hydrolysis of cholesterol esters within lipids cells of steroidogenic cells
___________ cholesterol synthesis refers to making cholesterol from _________ by linking carbon atoms together, but it is not common - only 10 to 15 percent of cholesterol is synthesized this way.
De novo
Acetate
HMG-CoA reductase is the enzyme that catalyzes the ______________ step of de novo cholesterol synthesis.
Rate-limiting step
What enzyme is the rate-limiting step for the de novo synthesis of cholesterol?
HMG-CoA reductase
HMG-CoA converts HMG-CoA to ______________.
Mevalonate
What is the primary way to regulate de novo synthesis of cholesterol?
By regulating the enzyme HMG-CoA reductase
What causes Smith-Lemli-Optiz Syndrome?
Defects in de novo synthesis of cholesterol
What are the symptoms of Smith-Lemi-Oprtiz Syndrome?
- Psychomotor and growth retardation
- Distinct craniofacial features
Smith-Lemli-Optiz is an ____________________ genetic disorder characterized by a defect in de novo cholesterol synthesis. Severe cases can result in miscarriage or stillborn birth. It affects mostly _____________________ of _____________ descent.
Autosomal recessive
White people
European descent
How do low-density lipoproteins (LDL) deliver cholesterol to the cell?
- LDL particles bind LDL receptors and scavanger receptor BI (SRBI), HDL receptors, triggering endocytosis
- The endosome fuses with a lysosome, breaking down the lipoproteins and releasing cholesterol via de-esterification
- Cholesterol diffuses into cytosol from lysosome
- Free cholesterol is converted back to cholesterol ester via ACAT (acetyl-CoA-cholesterol acyl transferase), making the cholesterol less soluble and held in storage cells
What is one way in which HMG-CoA reductase is inhibited?
Lots of free cholesterol in cell - the cell do not need to produce cholesterol de novo if excess cholesterol is already present
LDL brings cholesterol _______ peripheral tissues while HDL brings cholesterol ______ peripheral tissues.
To
From
________________ ___________ are the preferred form of cholesterol transport in bloodstream and storage in the cytosol; they usually do not contribute to plasma membrane structure.
Cholesterol esters
How are cholesterol esters released?
Hydrolysis
What enzyme hydrolyzes cholesterol esters?
Cholesteryl ester hydrolase
____________ ____________ _____________ hydrolyzes cholesterol ester, producing free cholesterol and _________ ________.
Cholesteryl ester hydrolase
Fatty acids
In the steroidogenic pathway, cholesterol is converted first to _____________________ by PC450scc or ____11A1.
Pregnenolone
CYP11A1
Free cholesterol must move to the _____________ for steroidogenesis to occur because the first enzyme in the pathway is found there: _______________.
Mitochondria
P450scc
P450cc is located within the inner or outer mitochondrial membrane?
Inner
What is StAR?
StAR is a protein that transports cholesterol from the cytosol across the outer mitochondrial membrane and through the inner membrane space to the inner mitochondrial membrane, where P-450scc is located
What does StAR stand for?
Steroidogenic Acture Regulatory Protein
P450scc and StAR together comprise the_____________ ______________ step of steroidogenesis. As such, they are often ___________________.
Rate-limiting or rate-determing step
Regulated
Sterodogenic enzymes can be divided into two subgroups: _____________ ___________ ___________ (CYPs) and _____________ ___________ (HSDs).
Cytochrome p450 oxidases
Hydroxysteroid dehydrogenases
Cytochrome p450 oxidases (CYPs) are steroidogenic enzymes that contain a single _____ group. Most are found in the _____________ _____________, but some are also found in the mitochondria. They primarily function in the ________ to metabolize endogenous and exogenous toxins, drugs, xenobiotics, and enivironmental pollutants. There are ____ distinct p450 enzymes involved in steroidogenesis.
Heme
Endoplasmic reticulum
Liver
Six
What are the six p450 enzymes involved in steroidogenesis?
- p450scc
- p450c11β
- p450c11AS
- p450c17
- p450c21
- p450arom
Hydroxysteroid dehydrogenases (HSDs) have no heme group but require _________ or ___________ as cofactors. Each reaction catalyzed by HSDs can be catalyzed by two or more ___________. There are two families of HSDs: ______ _____ dehydrogenases and aldo-keto ____________
NADH
NADPH
Isozymes
Short-chain dehydrogenases
Aldo-keto reductases
Cleavage of the cholesterol side chain of cholesterol via P-450scc forms pregnenolone, and the fate of pregnenolone is determined by the presence of _____________ within the cell.
Enzymes
There are two primary steroidogenic pathways: _______ and _________. The pathway taken is often species-specific but usually result in the same products.
Δ5 pathway
Δ4 pathway
What is the primary difference between the Δ5 and Δ4 pathways?
In the Δ5 pathway, pregnenolone is converted to 17α-hydroxyprenenolone by 17α-hydroxysteroid dehydrogenase while in the Δ4 pathway pregnenolone is converted to progesterone first by 3β-hydroxysteroid dehydrogenase before being converted to 17α-hydroxyprenenolone
In the Δ5 pathway, pregnenolone is converted to 17α-_________________ by ______________________ while in the Δ4 pathway pregnenolone is converted to _____________ by 3β-hydroxysteroid dehydrogenase before being converted to 17α-hydroxyprenenolone
17α-hydroxypregnenolone
17α-hydroxysteroid dehydrogenase
Progesterone
In the Δ5 pathway, pregnenolone is converted to 17α-hydroxyprenenolone by 17α-hydroxysteroid dehydrogenase while in the Δ4 pathway pregnenolone is converted to progesterone first by 3β-hydroxysteroid dehydrogenase or ________ before being converted to 17α-hydroxyprenenolone
3 beta-HSD
The Δ5 pathway is usually found in _____________, rabbits, dogs, and ________ while the Δ4 pathway is usually found in rats, _______, mares, and macaques.
Humans
Cows
Ferrets
Which pathway do humans usually follow?
Δ5 pathway
There is ________ ____________ of steroidogenic enzymes within each region of the adrenal cortex.
Differential expression
You should be generally familar with these enzymes.
Estrane, androstane, and pregnane are steroid nomenclatures that designate the placement of what functional group?
Methyl groups
Estrane indicates a basic steroid skeleton with 18 carbons and methyl groups at carbons ____ and _____.
13 and 17
Androstane indicates a steroid skeleton with 19 carbons and methyl groups on carbons ___ and ___.
13 and 10
Pregnane indicates a basic steroid skeleton with 21 carbons and methyl groups on carbons ____ and ___ with a two-carbon atom side chain attached to carbon ____.
13 and 10
17
The adrenal glands are also known as the ________ glands because of their location near the kidneys.
Suprarenal
The adrenal glands are heavily ____________.
Vascularized
Each adrenal gland is structurally and functionally two endocrine glands: ____________ and ____________.
Adrenal medulla
Adrenal cortex
The adrenal medulla is associated with the ___________ nervous system and releases _____________. The adrenal cortex makes up most of the gland and releases ___________.
Sympathetic nervous system
Catecholamines
Corticosteroids
The majority of the adrenal gland is composed of the adrenal cortex (______%)
80 - 90%
The adrenal medulla is site of __________ and _________ synthesis and is associated with the “__________” response. The adrenal cortex is site of glucocorticoid steroid synthesis and is ssociated with “_____” response.
Epinephrine
Norepinephrine
Fight or flight
Alarm
The cells of the zona glomerulosa or ________ layer of the adrenal cortex are _______ to _______ in shape and arranged in rounded clumps, glomeruli, surrounded by capillaries. The round cell nucleus is ______ stained and the cytoplasm is ______.
Outermost
Cuboidal to columnar
Darkly stained
Acidophilic
The middle zona _________ is the broadest layer and consists of cells that are arranged in ________ cords, surrounded by capillaries. The shapes of the cells are ________ or polygonal with a _______ stained cytoplasm. ______ _______ give the cells a foamy appearance. The nucleus is round and darkly stained.
Zona fasciculata
Parallel
Cuboidal
Poorly stained
Lipid droplets
The ______ zona reticularis consists of cells arranged in less parallel cords, giving it a _________ pattern. The cells of the zona reticularis are ________ and _______ stained than the ones in zona fasciculata.
Inner
Reticular
Smaller
Darker stained
These zones of the adrenal cortex cannot be surgically separated because there is no clear boundary between each of them. We do not understand the differing __________ of the three zones, but one theory is that progenitor cells located underneath the capsule migrate into the interior.
Morphologies
The zona glomerulosa produces mineralocorticoids namely _______________, the major control mechanism of which is _______-___________. The zona fasciculata produces glucocorticoids namely _________, the major control mechanism of which is ___________. The zona reticularis produces androgens namely _______________ (DHEA), the major control mechanism of which is unknown but includes ______.
Aldosterone
Renin-angiotensin
Cortisol
Adrenocorticotropic hormone
Dehydroepiandrosterone
What does ACTH stand for?
Andrenocorticotropic hormone
What does DHEA stand for?
Dehydroepiandrosterone
Before puberty and sexual maturity, the zona reticularis is the main source of ________, which are thought play central role in _____________, which may kickstart puberty
Androgens
Andrenarche
Edward Calvin Kendall, Tadeus ____________, and Philip Showalter Hench won the Nobel Prize in Physiology or Medicine in 1950 for their discoveries relates to the hormones of the adrenal cortex.
Reichstein
What three scientists were awarded the Nobel Prize in 1950 for their work on adrenal hormones?
Edward Calvin Kendall
Tadeus Reichstein
Philip Showalter Hench
Kendall and Reichstein independently isolated and characterized _____________ hormones while Hench gave ________ to ameliorate symptoms of rheumatoid arthritis.
Cortical
Cortisone
Which enzymes does the zona glomerulosa express?
Aldosterone synthetase or CYP1182
What does aldosterone synthetase or CYP1182 catalyze?
The formation of aldosterone
Which enzyme does the zona glomerulosa not express?
17α-hydroxylase/17,20 lyase or CYP17
The zona fasciculata expresses the enzyme ______________ but not _____________.
17α-hydroxylase (CYP17)
17,20 lyase (CYP17)
Which enzyme does the zona reticularis produce?
17,20 lyase or CYP17
What is the primary function of 17,20 lyase (CYP17)?
The production of androgens
What is the major function of 17α-hydroxylase?
The formation of corticoids
Progesterone, cortisol, and aldosterone have ____ carbons; testosterone has ___ carbons; and estradiol has ____ carbons. As a result, progesterone, cortisol, and aldosterone are structurally similar and can bind each other’s receptors at high enough concentrations; when they bind, they generally function as ________.
21 (C-21)
19 (C-19)
18 (C-18)
What functional groups at which carbons are essential for the function of progesterone?
Keto groups at C-3 and C-20
Which functional groups are essential for cortisol?
Two hydroxyl groups on C-11 and C-17
What functional group is essential for aldosterone functioning?
A hydroxyl group at C-21
It is believed that the ___________ receptor evolved first followed by the ______________ receptors.
Estrogen
Mineralocorticoid
____________ is a uniquely terrestrial hormone, first appearing in lungfish, which have both gills and lungs. Mineralocorticoid receptors (MRs), on the other hand, evolved much earlier, and are found in cartilaginous and bony fish.
Aldosterone
Eustachius – 1560s: adrenal glands first identified and noted
T. Addison – 1850s: began looking at diseases of the adrenal glands
Brown-Sequard – 1850s: adrenalectomy
Walter Cannon – 1925: coined term “homeostasis;” described flight or fight response
Hans Seyle – 1936: described alarm response
There are three sources of cholesterol for adrenal steroidogenesis: (1) de novo synthesis from acetate, where HMG-CoA reductase catalyzes the ___-_________ step; (2) circulating lipoproteins in serum; and (3) hydrolysis of chesterol esters stored within lipid droplets and catalyzed by ________________.
Rate-limiting step
Cholesterol esterase
Over ___% of adrenal steroidogenic hormones are synthesized from circulating lipoprotines and/or stored cholesterol esters.
80%
Which two sources of cholesterol for adrenal steroidogenesis are stimulated by ACTH?
- Receptors for LDL and HDL are upregulated, enabling the cell to obtain cholesterol from circulating lipoproteins
- Hydrolysis of cholesterol esters is stimlated
We know cholesterol esterase (releases cholesterol from lipid droplets) and import of lipoproteins are stimulated by ACTH, most notably in the _____________________; the other zones can be stimulated by ACTH but to a lesser extent
Zona fasciculata
Mineralocorticoids are produced in the _________________ and function in the regulation of electrolytes, notably ________ and potassium, which are important in regulation of blood pressure and volume. ____________ is the major mineralocorticoid produced by the adrenal gland, and it acts on the _________ to increase blood levels of ____ by decreasing the ion’s excretion from the body and increasing the ion’s reabsorption.
Zona glomerulosa
Sodium or Na+
Aldosterone
Kidneys
Na+
Sodium is a key electrolyte in the body. Why is it more so than other ions?
Water tends to follow sodium
What strimulates aldosterone release from the adrenal cortex?
- Increase blood K+
- Decrease blood Na+
- ACTH (stress)
What decreases aldosterone secretion?
Atrial natriuretic peptide (ANP)
What mechanism controls the release of aldosterone?
The Renin-Angiotensin system
What is the functional unit of the Renin-Angiotensin System (RAS)?
The juxtoglomerular cell
Where is the juxtoglomerular cell located?
The kidneys
What do juxtoglomerular cells secrete?
Renin
What does renin do?
Raises blood pressure
What cells signal to the juxtoglomerular cells that blood pressure is low?
The macula densa cells
How do the macula densa cells determine if blood pressure is low?
They detect low sodium concentrations; low levels of blood will have low levels of sodium, therefore blood pressure will be low
What do the macula densa cells secrete when they detect that blood pressure is low?
Prostaglandins
_________ ___________ cells in the distal nephrons of the kidney detect low ____ concentrations, which indicate low blood pressure. In response, they release _____________, which are paracrine signals that move to the _______________ cells or the functional units of the Renin-Angiotensin System (RAS). When stimulated, these cells release renin, which ______ blood pressure. Renin does so by traveling to the liver, which produces the pro-hormone _____________________. Renin cleaves this pro-hormone into angiotensin I (A1). A1 travels to the lungs where it encounters _____________________________________________ (ACE) and is cleaved into angiotensin II (A2), a more potent hormone. A2 has many targets, most notably the adrenal cortex, which releases ________________ in response to A2 binding. This mineralocorticoid causes the distal tubules of the nephrone to reabsorb more ____ and therefore _________.
Macula densa cells
Low Na+ concentrations
Prostaglandins
Juxtoglomerular cells
Raises blood pressure
Angiotensinogen
Angiotensinogen converting enzyme (ACE)
Aldosterone
Na+
Water
Besides the adrenal gland, what other areas of the body does angiotensin II act upon?
- Directly cause arteries to constrict and increase cardiac output
- Directly decrease glomerular filtration rate, leading to water retention
- Directly increases thirst
- Stimulates ADH (vasopression) release from the posterior pituitary, which increases aquaporin expression in nephrone collecting duct cells and increases sodium reabsorption in the medulla of the kidney
Be sure to refresh your memory of how ADH stimulates aquaporin 2 expression.
Besides renin, what else can affect aldosterone release?
Increase potassium or decreased sodium in the blood
ACTH release by the anterior pituitary in response to stress
Atrial natriuretic peptide (ANP) inhibits release (ANP secreted by heart when blood pressure or volume is increased)
In the circulation aldosterone (A) is mainly bound to cortisol-binding globulin (CBG) or _________. Free aldosterone enters the tubule cells of the kidney and binds to the _________ ________. This induces release of a ___________ _________ _____________, dimerization of two MRs and translocation to the nucleus where the dimers bind to a ____________ ____________ ____________ (GRE) on the DNA and, along with other transcription factors, initiates protein synthesis. The aldosterone-induced proteins include factors that regulate the luminal Na+ channel and components of the Na+/K+ ATPase pump.
Albumin
Mineralocorticoid receptor (cytosol)
Heat shock protein
Glucocorticoid response element
____________ cells are modified smooth muscle cells which secrete _______. The macula densa are tubular cells of the thick ascending limb of the loop of Henle which can detect circulating concentrations of ___________. In response to the indicated stimuli renin is secreted and converts ________________ (synthesized in the liver) to _______________. Angiotensin-converting enzyme (ACE ) converts ________________ __ to ___ which acts on AT1 receptors in the adrenal cortex (glomerulosa) to stimulate aldosterone secretion.
Juxtoglomerular cells
Renin
Na+
Angiotensinogen
Angiotensin I
Angiotensin I to II
Another graphic
The renin/angiotensin system stimulates aldosterone secretion, and angiotensin II potentiates the release of ________________ (ADH) and stimulates thirst. Vasopressin secretion is also directly stimulated by hypothalamic osmoreceptors and volume receptors in the cardiovascular system. __________ is released in response to atrial stretch and also inhibits the synthesis and release of aldosterone, and inhibits renin production and AVP release.
Antidiuretic hormone or vasporessin
Atrial natriuretic peptide
Where are the glucocorticoids produced?
The zona fasciculata of the adrenal cortex
What is the primary glucocorticoid?
Cortisol
What are the four functions of cortisol?
- Maintain blood pressure and cardiovascular function
- Reduce inflammatory response
- Maintain blood sugar levels by balancing effects of insulin (stimulates gluconeogenesis)
- Regulates metabolism of proteins, carbohydrates, and fats
Cortisol levels are highest when?
The early morning
_________________ stimulates the hypothalmus to produce corticotropic-releasing hormone (CRH), which travels to the anterior pituitary and binds _________________ that then release adrenocorticotropic hormone (ACTH). ACTH travels to the adrenal cortex and binds receptors on cells in the zona fasciculata, stimulating the activity of _________________ ____________ and ________________ (StAR) that will ultimately lead to increased secretion of ________________.
Stress
Corticotrophs
Cholesterol esterase
Steroidogenic acute regulatory protein (StAR)
Cortisol
Cortisol inhibits stress, the _____________, and the ___________ __________.
Hypothalamus
Anterior pituitary
Cortisol has specific metabolic effects in muscle, liver, and fat cells. In muscle cells, cortisol stimulates the degradation of _________ into its constitutive amino acids, which can then be utilized to make both glucose and the enzymes required for glucose synthesis in the liver. In liver cells, cortisol stimulates _________________, ultimately leading to increased glycogen stores. In fat cells, cortisol stimulates the breakdown of fat into _____ _____ _____ and ____________, which can also be used by the liver to create more glucose
Cortisol also directly decreases glucose uptake in peripheral tissues by inhibiting _______ receptors.
Protein
Gluconeogenesis
Free fatty acids
Glycerol
GLUT4
Cortisol _____________ glucose intake in ___________ tissues via GLUT4 receptors. It increases glucose production and release from the __________. In this way, cortisol is known as a ____________________, like epinephrine and glucagon.
Decreases
Peripheral
Liver
Diabetogenic
The glucocorticoid receptor (GR) is a nuclear steroid receptor with three main domains: a ligand or steroid binding domain, a ________ _________domain, and a regulatory or transcriptional domain. The GR is a ___________ nuclear receptor, and it shares a great deal of homology with other such receptors, including the mineralocorticoid receptor; their homology is greater than ____%, specifically when looking at the DNA binding domain
Type I nuclear receptor
DNA-binding domain
90% homology
The glucocorticoid receptor is typically found sequestered in the cytosol by ______ ______ _________; when cortisol diffuses across the membrane, it binds GR, causing a __________________ ________ in GR that exposes its ____________ __________ _________. GR bound to cortisol then translocates to the nucleus where it _________ with another activates GR and binds the __________ _____________ _____________, leading to increased transcription of genes related to glucose synthesis .
Heat shock proteins
Conformational change
Nuclear localization signal
Dimerizes
Glucocorticoid response element (GRE)
Like the androgen and progesterone receptors, but unlike thyroid hormone receptors, unliganded GRs are located in the cytoplasm attached to heat shock proteins (hsp-__, hsp-70 and hsp-__).
When hormones bind to these receptors hsps are released and, through an ______-dependent process, the hormone receptor complexes translocate to the nucleus. These complexes form homo- or heterodimers and the _____ fingers of their DNA-binding domains slot into the glucocorticoid response elements (GREs) in the DNA helix.
Hsp 90
Hsp 70
Energy
Zinc
Be familiar with this figure.
Where are the gonadocorticoids produced?
The zona reticularis of the adrenal cortex
What is the primary sex hormone produced by the zona reticularis?
Androgens
Androstenedione
Dehydroepiandrosterone (DHEA)
Adrenal androgens are converted to _________ in males and ___________ in females. The exact role for adrenal sex hormones is unknown, but they are believed to contribute to the onset of puberty, secondary sex characteristics, and sex drive in females
Testosterone
Estrogen
______________, a period of high adrenal androgen production, precedes puberty and is believed to lead to puberty (e.g., causes underarm and pubic hair)
Andrenarche
We don’t know exact regulatory mechanism of the adrenal androgens, but we do know that ___________ stimulates adrenal androgen production, specifically DHEA and androstenedione.
ACTH
DHEA and androstenedione are converted to testosterone via __________________________. Testosterone can be further converted in males into 5α-dihydrotestosterone (5α-DHT), a more potent androgen, via ______________. Testosterone can be further converted in females and males into estradiol via _________.
17β-hydroxysteroid dehydrogenase (17β-HSD)
5α reductase
Aromatase
Because adrenal androgens are stimulated by ACTH, they mimic ____________ release.
Cortisol
Conn’s Syndrome caused by excess _____________ production from a benign tumor of the adrenal gland, likely the __________________ _____________. Common symptoms include hypertension and hypoalkaemia or _________________.
Aldosterone
Low blood potassium levels
What cause secondary aldosterone excess?
Low blood volume, usually due to edema
How does edema lead to secondary aldosterone excess?
Low blood volume activates the renin-angiotensin-aldosterone system, ultimately increase aldosterone production; aldosterone will continue to increase blood volume, but blood volume will continue to register as low because fluid pools in the peripheral tissues due to damage in blood vessels
What are two disorders of aldosterone excess?
Conn’s Syndrome (primary)
Secondary
Be familar with this figure.
________________________________ is caused by a mutated gene for CYP21 or _______________, which is necessary for the production of aldosterone and ___________. When the enzyme is defective, intermediates of the steroidogenic pathway are transformed into androgens because the lack of ______________ results in no negative feedback to the hypothalamus and pituitary gland. The lack of negative feedback results in increased _________ and thus steroidogenesis in the adrenal cortex and the upregulation of _______, which converts pregnenolone into DHEA.
Congential adrenal hyperplasia
21β-hydroxylase
Cortisol
Cortisol
CYP17 (17α-hydroxylase, 17,20-lyase)
Babies with congenital adrenal hyperplasia are usually born with ambiguous genitalia; the image shown is of a female baby who has developed __________ genitalia because adrenal androgens have been converted into ______________ (DHT). Treatment of CAH is simple: the individual is given exogenous aldosterone and cortisol.
5α-dihydrotestosterone
Individuals with congenital adrenal hyperplasia often have severe hypovolemia, hyponatremia, and hyperalkemia. Why does this occur?
CYP21 (21β-Hydroxylase) is mutated, so progestorone can not be converted into the precursors for aldosterone and cortisol. Aldosterone stimulates the kidneys in the Renin-Angiotensin-Aldosterone System (RAAS) to increase Na+ and water absorption. Without aldosterone, then, low blood volume (hypovolemia) and low Na+ (hypoatremia). If there is low Na+ in the blood, the sodium-potassium pump will be dysregulated (usually for every 3 Na+ pumped out of the cell, 2 K+ are pumped inside), thereby resulting in hyperalkemia (high blood K+).
Patients with cogenital adrenal hyperplasia often have increased levels of ACTH, 17-OH progesterone, and androgens. Why is this?
CYP21 (21β-Hydroxylase) is defective and cannot transform progesterone into aldosterone precursors or 17-OH progesterone into cortisol precursors. Without cortisol production, there is no negative feedback to the hypothalamus, so ACTH is continuously stimulated. This causes the steroidogenic pathways of the adrenal glands to be continuously stimulated, ultimately leading to more progesterone and 17-OH progesterone and androgens.
What are two disorders that result from adrenal hypofunction?
Primary hypofunction (Addison’s Disease)
Secondary hypofunction
______________________ is a disorder characterized by low levels of cortisol (markedly) and aldosterone. In the past, it was due to destruction of the adrenal cortex by ____________, but today, it is most often seen as a result of an __________ disorder. The symptoms of this disease include fatigue, loss of appetite, ____________ weight, hypoglycemia, decreased blood pressure, _________ craving for salty foods, and ____________ pigmentation.
Addison’s Disease
Tuberculosis
Autoimmune disorder
Decreased
Increased
Increased
Why do patients with Addison’s Disease often have hyperpigmentation?
Low levels of cortisol are unable to engage in negative feedback with the hypothalamus and pituitary gland; therefore, the pituitary gland continues to synthesize POMC or pro-opiomelanocortin, the precursor for ACTH; when POMC is cleaved, ACTH is formed as is melanocyte-stimulating hormone (MSH), which stimulates melanocytes and leads to hyperpigmentation
Secondary adrenal hypofunction is not as problematic as primary adrenal hypofunction and is the result of impaired hypothalamic-pituitary-adrenal regulation, notably decreased __________.
ACTH
_______________’s syndrome is caused by excess cortisol, the most common cause of which is use of glucocorticoids to treat other disorders. A secondary cause is ___________ overproduction that can be either ACTH-dependent (the syndrome) or ACTH-independent. . The syndrome is most often caused by tumors in the adrenal or pituitary glands.
Cushing’s syndrome
Endogenous (Cushing’s is ACTH-dependent)
What are the common symptoms of Cushing’s Syndrome or hyperadrenocorticisim?
Common symptoms of Cushing’s Syndrome include a
- Redistribution of fat to the abdomen
- thinning of the limbs (muscle wasting as cortisol causes breakdown of proteins in muscle)
- buffalo hump
- Thinning of skin
- Striations
- hypertension (mineralocorticoid effects)
- easy bruising
- Purpure
People with Cushing’s Syndrome are at increased risk for diabetes and cardiovascular problems. Why?
Cortisol increases insulin resistance and increases blood glucose levels
The adrenal medulla is made up of modified ganglionic sympathetic neurons called ____________ cells. These cells secrete epinephrine and norepinephrine, which are _________. Secretion of these hormones results in increased blood glucose levels, blood vessel constriction, heart rate, bronchial dilation and oxygen intake, and blood diverted to the _______, __________, and skeletal muscle.
Chromaffin
Catecholamines
Blood, heart
_______________ is the primary product of the adrenal medulla.
Epinephrine “fight or flight”
Chromaffin cells are clustered with faint basophilic cytoplasm and granules of catecholamines. They are highly _________ and _________ in nature - their products are released directly into circulation.
Vascularized
Neurosecretory
Catecholamines are _________ derivatives. This amino acid is first transformed into DOPA via __________ __________, which is the rate-limiting step, and then to dopamine via aromatic amine acid decarboxylase, norepinephrine via dopamine β hydroxylase and finally epinephrine via phenylethanolamine N-methyl transferases.
Tyrosine
Tyrosine hydroxylase
Tyrosine is first converted to DOPA by tyrosine hydroxylase. DOPA is converted to dopamine via __________ _______ ________ decarboxylase (AAD). Dopamine is converted to norepinephrine via dopamine β‐hydroxylase. Norepinephrine is converted to epinephrine via _______________ _________ ___________ (PNMT).
Aromatic amine acid decarboxylase (AAD)
Phenylethanolamine N-methyl transferase
Catecholamine synthesis is stimulated by the nervous system. Stress triggers higher brain centers to signal the release of ____________ from the sympathethic nervous system. This neurotransmitter binds ___________ _________, which then increase secretion of epinephrine and norepinephrine that enter circulation. The catecholamines have _____ half lives. Most are taken back up and reused by the cells that produce them and target cells.
Acetylcholine
Chromaffin cells
Short half-lives
What does each enzyme acronym stand for?
TH = tyrosine hydroxylase
AAD = aromatic amin acid decarboxylase
DβH = dopamine β‐hydroxylase
PNMT = phenylethanolamine N‐methyl transferase
·What is the fate of secreted catecholamines?
- reuptake by catechol-secreting cells for reuse or metabolism
- uptake by receptors on effector cells
- metabolized by inactivating mechanisms, mostly in liver
What are the actions of epinephrine?
The response depends on type of adrenergic receptor, but in general, epinephrine causes arousal: alerting, pupillary dilation, piloerection, sweating, bronchiodilation, tachycardia, smooth muscle inhibition in GI, sphincter contraction, relaxation of uterine muscles; increased metabolic actions (glycogenolysis, lipolysis); and increased cardiovascular actions (stimulates HR and vasoconstriction, ↑ BP)
Differential localization of adrenergic receptors leads to different cellular responses. Beta1 receptors are localized to the _______. Beta2 receptors are localized to _______ and ________ ___________ cells. Beta3 receptors are localized to ___________ tissue and ___________. Alpha receptors are largely but not exclusively localized to the _________ and reproductive system
Heart
Smooth and skeletal muscle
Adipose tissue and fat
GI tract
What disorder of the adrenal medulla did we discuss in class?
Pheochromocytomas (benign tumors of the adrenal medulla)
What do pheochromocytomas cause?
They cause excess catecholamines and therefore decreased insulin production; hypertension, tachycardia; sweating; tremor, palpitations; nervousness; weight loss; hyperglycemia
How are pheochromocytomas diagnosed
Free plasma catecholarime levels
Urinary catecholamine metabolite (metaneprhines)
CT scan
What do pheochromocytomas often present similarly to?
Hyperthyroidism
The long-term stress response is also known as the “______” system and stimulates the adrenal __________ to produce cortisol and aldosterone. Aldosterone works to increase sodium and water reabsorption in the kidneys and to increase blood volume and blood pressure. Cortisol works to increase glucose levels and to suppress the immune system
The short-term stress response is also known as the “__________” system and stimulates the adrenal _________ to produce catecholamines. Catecholamines work to increase heart rate, increase blood pressure, convert glycogen to glucose and increase blood glucose levels, increase bronchiole dilation, decrease digestion and urine production, and increase metabolic rate.
Alarm
Adrenal cortex
Fight or flight
Adrenal medulla
What is sexual differentation?
Process by which bipotential gonad develops into testis or ovary which is determined by presence/absence of Y chromosome
The ____________ paradigm of sexual differentiation was established via experiments on rabbits; rabbits castrated before development developed into females, thereby establishing female sex as the “default” sex. The paradigm states that the establishment of chromosomal/genetic sex occurs at fertilization, which then influences the development of gonads (gonadal sex) and ultimately external and internal genitalia (phenotypic sex).
Jost
What does the Jost paradigm of sexual differentation propose?
The paradigm states that the establishment of chromosomal/genetic sex occurs at fertilization, which then influences the development of gonads (gonadal sex) and ultimately external and internal genitalia (phenotypic sex).
How many chromosomes do human somatic cells contain?
46 (including sex chromosomes)
Human somatic cells are diploid but gametes are __________.
Haploid
The ___________ determines chromosomal sex.
Sperm
Females are ______________; males are heterogametic
Homogametic
Humans have an X and Y chromosome, but other species may have different sex chromosomes (e.g., male birds are __ and female birds are __
ZZ
ZW
The ___ chromosome is the critical determinant of chromosomal and genetic sex
Y chromosome
XY or XXY or XXYY or XXXY or XXXXY = ______
XX or XXX = ___________
XO = _________ with incomplete ____________ development
XXY or XXYY or XXXY or XXXXY = ________ but impaired _________ production
Male (testis)
Female (ovary)
Female but incomplete ovarian development
Male but impaired sperm production
How is dosage compensation achieved in females?
X inactivation
How does X inactivation occur in women?
X inactivation occurs by condensing one of the two X chromosomes in women; the Barr Body is the heterochromatized X chromosome (i.e., heterochromatin is condensed chromatin where genes are unable to be expressed)
The _____ _____ is the heterochromatized X chromosome
Barr Body
The X chromosome marked for inactivation expresses the _____ gene, a non-protein coding gene that codes for RNA. The mRNA product coats the X chromosome; this coat then recruits chromatin remodeling complexes to the X chromosome, condensing the X chromosome into the Barr Body and leading to dosage compensation. If you increase the number of X chromosomes, you increase the amount of ____ expression
The other X chromosome expresses _____, which codes for an _________mRNA that prevents the remodeling of the X chromosome.
XIST
XIST
TSIX
Antisense
Once X inactivation occurs, it is reflected or not reflected in remaining cells?
Reflected
Alligators do not have sex chromosomes; instead, sex is dependent upon ________. At temperatures greater than 34 degrees Celsius, an egg will incubate into a _______. At temperatures lower than 30 degrees Celsius, an egg will incubate into a ________.
The same is true for turtles, except the temperature restrictions are flipped (high temperatures result in _________, low temperature result in _________).
Temperature
Males
Females
Females
Males
In alligators and turtles, __________ regulates the expression of enzymes necessary for gonad formation and sexual differentiation.
Temperature
In other species, sex determination is based on social and behavioral factors (e.g., fish) that stimulate hormonal changes that result in sexual differentiation of phenotype. _________ results when a male changes to female. _________ results when a female changes to male.
Protandry (male to female)
Protogyny (female to male)
The Y chromosome contains the ______ gene (_____________________). This gene produces the __________ _________ __________.
SRY
Sex determining region on the Y chromosome
Testis determining factor (TDF)
Besides the sex-determining region on the Y chromosome (SRY) gene, which contains the testis-determining factor (TDF), what else is interesting about the Y chromosome?
It is smaller (less than 100 genes). It also contains genes important in skeletal growth and spermatogenesis, and pseudo-autosomal regions are located on the ends of the chromosome so that pairing with the X chromosome can occur
The SOX9 gene expresses the SOX9 protein, which regulates skeletal development and sex determination; it is stimulated by the ______ gene (e.g., TDF), fibroblast growth factor 9, and prostaglandin D synthetase, ultimately leading to testis development. In women, SOX9 must be inhibited, usually by ____________.
SRY gene (sex-determining region of the Y chromosome)
FOXL2 (forkhead box L2)
What does SOX9 stand for?
SRY Box 9
What stimulates SOX9?
The SRY gene
FGF9
PGDS (prostaglandin D synthetase)
What inhibits SOX9?
FOXL2 (forkhead box L2)
Activation of SOX9 leads to __________ development.
Testis
The mammalian ovary and testis develop from ___________ ____________ gonads.
Bipotential primordial gonads
Germ cells move to the _________ _________ where they form bipotential cells and develop germinal epithelium. If male, the primary sex cords continue to elongate and develop into the seminiferous tubules where sperm will develop, and testosterone will be produced. If female (lack of Y chromosome), the primary sex cords will degenerate, and the secondary sex cords will develop, ultimately forming the ovarian cortex and follicles. Gonads form from the _________ tubules (pre-pre-kidneys)
Genital ridge
Mesonephric
REMEMBER: THE Y CHROMOSOME and the SRY GENE as well as the testis ARE THE PRIMARY DETERMINANTS OF SEX
In males, we see the regression of the Mullerian ducts due to the presence of ____________ hormone, which is expressed specifically in the ________; this leaves the male with the _________ ducts that then develop into the ____________ and accessory glands as the testes produce androgens.
Anti-Mullerian hormone (AMH)
Testes
Wolffian ducts
Vas deferens
In females, we see the continuation of the _____________ ducts and the degeneration of the _________ _________ (i.e., there are no androgens present because there are no testes, so these ducts do not continue development); the ________ ducts will continue to develop into the oviducts, uterus, cervix, and the upper part of the vagina.
Mullerian
Wolffian ducts
Mullerian
The development of external genitalia is dependent upon _________ availability. The genital ________ will form either the penis or clitoris. The ________folds will form either the underside of the penis (penile ____) or the labia minora. The _________ swellings will form either the scrotum or labia majora.
Hormone
Genital tubercle
Urogenital folds
Penile raphe
Labiosacral swellings
What are the five steps of internal male development discussed?
- Organization of testes into spermatogenic cords, containing fetal Sertoli cells and primordial germ cells (~7wks)
- Regression of müllerian ducts caused by AMH, produced by the fetal Sertoli cells (~8wks)
- Mesenchymal cells differentiate into Leydig cells which synthesize testosterone (~8-9wks)
- Male genital tract (epididymis, vas deferens, and seminal vesicles) develops from the Wolffian ducts in response to increased testosterone
- Prostate gland development begins at ~10wks (and continues even after birth)
____________ cells will produce AMH, leading to the regression of the Mullerian ducts in males
_________ cells will produce testosterone, leading to the elongation of the Wolffian ducts into the epididymis
Sertoli cells
Leydig cells
Be familiar with this picture
What are the three stages of external male development discussed in class?
- Genital swellings enlarge and migrate posteriorly to form scrotum; genital folds fuse over urethral groove to form penile
urethra; prepuce develops to cover glans penis (9‐12th wks)
- Growth of external genitalia
- Testicular descent
a. Transabdominal phase (10‐15wks)
b. Inguinoscrotal phase (26‐35wks)
In the _____________ phase, the testes descend, stimulated by ____, which is produced by the testes; the gubernaculum swells, which contributes to testes descent, in response to androgen production. The second phase of testicular descent, the ___________ phase, corresponds to the migration of the testes and epididymis through the inguinal canal into the ______; it is stimulated by _________ produced by the testes.
Transabdominal phase
IGF3
Inguinoscrotal phase
Scrotum
Androgens
__________________ is responsible for Wolffian development, spermatogenesis, and gonadotropin regulation while __________________ is responsible for external virilization, prostate development, and pubertal maturation
Testosterone
5α-dihydrotestosterone (DHT)
___________ converts testosterone to 5α-dihydrotestosterone (DHT), which has a higher affinity for the androgen receptor; DHT is a much __________ androgen and is central to ___________.
In fact, males without this enzyme are unable to transform testosterone into DHT, ultimately leading to the development of a micropenis and __________, where the urethral opening develops on the underside of the penis
5α-reductase
Stronger androgen
Virilization
Hypospadias
What are the five stages of internal female development discussed in class?
- Cortical cords appear in indifferent gonads, and primordial germ cells concentrate along the cords
- Müllerian ducts form the oviducts, the uterus, cervix, and the upper 1/3 of the vagina. (~10 wks)
- The Wolffian ducts regress (~10wks)
- Estrogen is produced by the fetal ovary but is not believed to play a large role in female sexual differentiation
- Follicular development begins (~15wks)
In females, the lack of _________ results in the regression of the ___________ ducts and the lack of __________ results in the persistence of the ___________ ducts
Androgens
Wolffian ducts
Anti-Mullerian hormone (AMH)
Mullerian ducts
Be familiar with this figure.
We should be able to go through this figure.
What are two disorders of chromosal sex discussed in class?
Klinefelter Syndrome (47, XXY)
Turner Syndrome (45, XO)
___________ Syndrome (47, XXY) affects 1/500 newborn males. Before puberty, the testes are ______ and have _________ numbers of spermatogonia. After puberty, incomplete virilization, sterility, and breast enlargement. Patients will usually have low to normal testosterone but increased ____________.
Klinefelter
Small
Decreased
Estradiol
__________ Syndrome (45, XO) is rarer than Klinefelter Syndrome. Patients present phenotypically __________ but are often of short statuture and lack menstrual cycles and secondary sexual characteristics. This syndrome is associated with multiple cogenital abnormalities and may present with __________ ________ gonads.
Turner
Female
Bilateral steak gonads
Individuals with Turner Syndrome often have a characteristically wide __________ neck.
Webbed
What disorder of gonadal sex did we discuss in class?
Gonadal dysgenesis
What is gonadal dysgenesis?
Occurs in individuals who are genotypically male or female but abnormal gonadal development
Individuals with gonadal dysgenesis (46 XX or XY) will often have bilateral streak gonads and display an immature _________ phenotype since gonadal development is arrested before _________ and ___________ are produced.
46, XY complete gonadal dysgenesis can result from mutations in any number of genes including SRY, Wilms’ Tumor-Related 1, Steroidogenic Factor 1 (SF1), SOX9, and DAX-1.
Female
AMH
Androgens
____________ is an important gene in steroidogenic pathways; it affects production of androgens and other steroidogenic genes; it can cause defects elsewhere including adrenal gland. SOX9 defects can lead to gonadal dysgenesis and congenital hyperplasia (skeletal development problems).
SF1 (Steroidogenic Factor 1)
Be familiar with this figure.
What disorders of phenotypic sex did we discuss in class?
Pseudohermaphroditism and hermaphroditisim
_____________ pseudohermaphroditism possess ovaries and Müllerian derivatives amd have varying degrees of virilization of the external genitalia. It is usually caused by in utero exposure to _________ (ex. Congenital adrenal hyperplasia, placental aromatase deficiency).
Female pseudohermaphroditism
Androgens
_______ Pseudohermaphroditism results from defects in ________ synthesis in testes, defects in __________ action in target cells, and defects in ____________ duct regression.
Male
Androgen
Androgen
Mullerian
Hermaphroditism results when a person has an ambiguous __________ or one that disagrees with genetic and gonadal sex.
Phenotypic sex
True hermaphroditism is __________, and patients present with both ovarian and testicular tissue or ______________. True hermaphroditism can result in an error in fertilization where half the cells are 46:XX and the other are 46:XY; however, most have 46:___ karyotypes.
Rare
Ovatestis
46:XX
What are the three functions of the male reproductive system?
To produce testosterone, male gametes, and sperm (and its delivery)
The accessory glands have __________ function.
Exocrine
The accessory glands form the ________ in which sperm travels.
Fluid
The testes are found inside the scrotum, which hangs below the body and consists of skin and _______________ _____________. There is a ____________ that divides the scrotum. Sperm is produced in the tests and then travels to the ______ testis, the epididymises, vas deferens, ejaculatory duct, and finally urethra. The accessory glands include the __________ vesicles, the __________ gland, and the ___________ glands.
Superficial fascia
Septum
Rete testis
Seminal vesicles
Prostate gland
Bulbourethral gland
The testes is surrounded by two protective layers: the outer ___________ __________ and the inner, thicker ____________ _____________, which divides the testes into _________ each of which contains between 2 and 4 seminiferous tubules.
Tunica vaginalis
Tunica albuginea
Lobules
The ____ _____ is the site in which sperm enters prior to entering the epididymis.
Rete testis
The seminiferous tubules extend throughout the testes and are arranged into _____________. They are lined with a ______________ membrane. Inside are the Sertoli cells, which nurse developing ____________ cells, and the ___________ cells themselves. Outside are the Leydig cells, which produced androgens, and the __________ cells, responsible for contracting and moving sperm through the seminiferous tubules.
Lobules
Basement membrane
Sperm cells
Sperm cells
Myoid cells
The testes is vascularized but located outside or inside the seminiferous tubule?
Outside
The seminiferous tubules are tightly coiled structures composed of germ cells (developing sperm cells), Sertoli cells, and __________ cells. Their most important function is the production of _________.
Peritubular tissue
Sperm
Sertoli cells are held together by __________ junctions near the ________ side of the seminiferous tubules, essentially preventing the movement of any external substances into the seminiferous tubule. These junctions are referred to as the “blood-testis barrier”
The Sertoli cells are the functional unit of the seminiferous tubules, and sperm develops in between the Sertoli cells, moving from the basal membrane to the lumenal space
Tight junctions
Basal
Spermatogenesis refers to the formation of _______________. As the bipotential gonads are forming, the germ cells move to the genital ridge, and as they do so, they undergo proliferation so that by the time they arrive at the genital ridge, approximately _______ germ cells are present. By the time of __________, cell proliferation results in about 6 million germ cells present; these germ cells are _____________. Around puberty, these cells are triggered to begin preparing for meiosis II; they undergo cell growth and DNA replication, transforming into _________ _____________, diploid cells, just before entering meiosis I. After the first round of meiosis, the primary spermatocytes are transformed into __________ spermatocytes that enter meiosis II. Here, the sister chromatids are split apart during anaphase II, resulting in daughter cells called _____________, which will undergo cell differentiation to become spermatozoa.
Spermatozoa
3,000
Puberty
Spermatogonia (diploid)
Primary spermatocytes (diploid)
Secondary spermatocytes (haploid)
Spermatides
The cell differentiation process of spermatides is called ___________________. The spermatids are remodeled into spermatozoa; this includes the condensation of the nucleus, the rearrangement of organelles, the elongation of the cell and formation of the flagellum. The Golgi will eventually develop into the ________; the mitochondria will relocate to base of flagellum; and most of the cytoplasm will be lost, forming the “______ body”. This process occurs toward the basal end of the tubule.
Spermiogenesis
Acrosome
Residual body
All spermatogonia are located in the basal compartment; they undergo mitosis in the basal compartment and then become primary spermatocytes here; once the become primary spermatocytes, they begin moving into the ___________ compartment during prophase I of meiosis I. The remainder of spermatogenesis and spermiogenesis occurs in the ____________ compartment
Adlumenal
Adlumenal
Spermatozoa are released into the ________ of the seminiferous tubules; they remain underdeveloped at this point and will undergo maturation as they move through the male reproductive tract with further maturation occuring once they enter the female reproductive tract. Spermatozoa will enter the ____ __________ and move into the ______ epididymis and through the body and tail epididymides; at the tail epididymis, spermatozoa will remain until _______ __________. Once this occurs, spermatozoa move into the vas deferens, which wraps behind the urinary bladder and ends at the __________ duct; at the ___________ duct, seminial fluid from the seminal vesicles will mix with the sperm prior to ejaculation through the urethra.
Lumen
Rete testes
Head
Sexual stimulation
Ejaculatory duct
Ejaculatory duct
How long do spermatozoa travel through the epididymis?
Movement through the epididymis takes about 12 days, and a great deal of maturation occurs during this time
___% of seminal fluid is produced by the seminal vesicles
60%
The seminal vesciles produce a yellowish, ___________ solution high in __________, __________, and prostaglandins. The prostate gland secrets a _______, alkaline fluid. The bulbourethral glands secrete far less than the other glands, and they produce a ________, thick mucus that is critical for _________ the urethra for sperm travel.
Alkaline
Vitamin C
Fructose
Milky
Clear
Lubricating
Know this general figure.
Testosterone production follows the delta ______ pathway.
Delta 4
The gonadotropins LH and FSH regulate testosterone production and spermatogenesis. LH binds its receptor on _______ cell, which express and produce the LHR. The LHR is a GPCR, and once activated, it leads to increased _____ and activation of _____ (i.e., CREB - cyclic AMP response element) ultimately leading to increased expression of steroidogenic genes (e.g., StAR, P450c17, and growth factors) required for converting ________ to _________ to testosterone
Leydig cells
cAMP
PKA
Cholesterol
Pregnenolone
FSH binds its receptor on ________ cells; the FSHR is a GPCR that once activated increases cAMP levels and PKA activation (i.e., CREB), ultimately leading to increased transcription of genes related to __________ and _________ regulation (e.g., _______, a peptide protein hormone; AMH, growth factors, ________ _________protein (ABP), and others)
The testosterone produced by the Leydig cells can bind the _________ receptor within Sertoli cells, which help regulate the events occurring within the Sertoli cells.
Sertoli cells
Spermatogenesis
Reproductive regulation
Inhibin
Adrogen binding protein
Androgen receptor
GnRH is regulated by _________-1, a hormone produced by ____ neurons in the _______ nucleus. This hormone is required for activation of the hypothalamic-pituitary-testicular axis. Testosterone negatively feedbacks to the __________ pituitary gland and the ________ nucleus of the hypothalamus, thereby inhibiting the production of __________-1
Kisspeptin-1
KNDy neurons
Arcuate nucleus of the hypothalamus
Anterior pituitary gland
Arcuate nucleus
Inhibiting production of kisspeptin-1
___________ _, produced by the Sertoli cells, negatively feedbacks to the anterior pituitary gland with its primary effects inhibiting FSH production.
Inhibin B
In ___________, testosterone levels rise late in first trimester in association with male sexual differentiation.
Embryogenesis
During the neonatal period, testosterone levels rise in the first ___ months of life and decline by age _____, remaining low until puberty (due to increased LH, Sertoli, Leydig, and germ cells).
Six
1 year
___________ is the age at which individuals reach sexual maturity, where they can reproduce
Puberty
In males, _______________ occurs around age 6‐7 years and _________ occurs around 11-12 years.
Adrenarche
Puberty
The onset of puberty is associated with _____________ sleep surges of ________ with secretion later increasing throughout the day. This surge results in maturation of Leydig cells and initiation of spermatogenesis, as well as testicular enlargement, reddening and wrinkling of scrotal skin, pubic hair growth; later increase in penis, prostate, seminal vesicles, and epididymis size; characteristic hair growth, enlarged larynx and thickened vocal cords, enhanced rate of linear growth
Increased
LH
Increased _____ production results in increased _________ levels; pulses and amplitude of ____ increase at night with secretion increasing throughout the day until maturity is reached
LH
Testosterone
LH
Pre-puberty, _______________ completely inhibits GnRH production despite the presence of __________, a strong stimulator of GnRH. In early puberty, _____ neurons increase and produce _____________, neurokinin B, and dymorphin, which are believed to have strong stimulatory effects on GnRH, even in presence of GABA.
Gamma aminobutyric acid (GABA)
Glutamate
KNDy
Kisspeptin-1
In men, puberty is usually completed by age 16‐18 years. _____ growth is not maximal until mid‐ to late‐20s. As men age, ________ decrease, slowing beard growth, causingregression of reproductive accessory organs and some skeletal muscle, and decreasing male sex drive.
By age 40, men see a gradual decrease in free ___________ and an __________ in SHBG. Elderly men have decreased _______ __________ and elevated ___ and ____. Betwen 50 and 80 years of age, sperm production is decreased by 30%. You usually see a decline in sexual activity.
Hair
Androgens
Free testosterone
Increase in sex-hormone binding globulin
Total testosterone
LH and FSH
The ______________ layer is the site of implanation.
Endometrial
What lines the ovary?
Tunica albuginea
What lines the uterus?
Germinal epithelium, simple cuboidal epithelial cells
The follicle houses the ______, which is surrounded by _______ cells
Oocyte
Granulosa
____________________ granulosa cells directly surround the oocyte and form the _________ _________.
Cumulous granulosa cells
Corona radiata
_________ granulosa cells do not directly surround the oocyte.
Mural granulosa cells
Granulosa cells are important in producing ___________; they have tight communication with the oocyte facilitated by __________ between granulosa cells and with the oocyte; this communication influences follicle and oocyte development
Estradiol
Gap junctions
Surrounding the granulosa cells is the __________ membrane; all vascular components are outside of this membrane; therefore all nutrients and gases must diffuse across
Basement
As the follicle develops, theca cells develop, ultimately resulting in a theca _____ layer and a theca ________ layer. Theca cells are important in producing ________ but are converted into estradiol by the granulosa cells.
Interna
Externa
Androgens
Ovarian steroids are derived from dietary cholesterol, mostly LDL, where it is taken into ovarian cells and stored as cholesterol esters in lipid droplets until stimulation occurs. Ovarian steroidogenesis requires both the granulosa and theca cells in a process called the ______________________________________ meaning that ovarian steroidogenesis requires both two cell types and two gonadotropin hormones. During follicular development, theca cells will express ____ receptors, and granulosa cells will express ____ receptors. When ___ binds to its receptors on theca cells, it promotes steroidogenesis via the Δ5 pathway, ultimately leading to the upregulation of StAR and production of _____________, which diffuses across the basement membrane into the granulosa cells. ____ binds its receptors on granulosa cells and upregulates production of __________, the enzyme that converts androstenedione into estradiol, which will enter circulation.
Two-Cell, Two-Gonadotropin Theory
LH receptors
FSH receptors
LH
Androstenedione
FSH
Aromatase
What is folliculogenesis?
The growth of the follicle from the primordial to ovulatory stage
The early stages of follicular development are gonadotropin _________________.
Independent
Provide an overview of folliculogenesis.
- Primordial follicles: the oocyte surrounded by single layer of flattened epithelial cells (precursor granulosa); basement membrane surrounds this layer; in utero
- Oocyte stimulates primary follicle by secreting local growth factors, promoting differentiation pre-granulosa into granulosa cells; flattened epithelial layer to single layer of cuboidal epithelium,
- Growth factors from the oocyte continue; additional layer of granulosa cells, secondary follicle. A more well-developed zona pellucida, a layer of glycoprotein-rich extracellular matrix secreted by the oocyte . Stromal cells begin to form theca cells. Movement from primordial to secondary follicular stages can take months (average >120 days)
- Granulosa cells continue to proliferate, developing more layers; does not become antral follicle until antrum
- Graafian follicle develops; very few follicles reach this stage; follicle is ready to receive stimulus and to release. Well developed theca interna, externa; multiple layers of granulosa cells; a well-developed antrum; an oocyte with a surrounding corona radiata connected to the rest of the mural granulosa cells via a stalk; at this stage these granulosa cells have started to express LH receptors, which is key to what occurs next
It is only when we reach the __________ follicular stage that the theca and granulosa cells become responsive to gonadotropins
Antral
___________ refers to ovarian degeneration or death.
Atresia
- The initial recruitment of ovarian follicles occurs throughout a woman’s life, and before gonadotropin-dependent, they will eventually die by atresia
- LH and FSH at puberty allow antral follicles to be recruited and become Graafian follicles, and after puberty, every month, 8 to 10 follicles may be recruited, but typically only one follicle makes it to the Graafian stage and is released; initial recruitment continues throughout a women’s life
- The combination of initiation and cyclic recruitment ultimately leads to ovarian follicle depletion, and menopause occurs
What is ovulation?
The release of a mature oocyte from a dominant follicle
Prior to ovulation, the outer wall of the follicle protrudes from the ovary forming a….?
Stigma
What causes rupture of the follicle?
Proteases
The oocyte is released into the ____________ cavity along with follicular fluid during ____________.
Perioteneal cavity
Ovulation
The oocyte remains surrounded by the __________ __________ immediately following ovulation.
Corona radiata
The ruptured follicle fills with blood forming the _________ ___________.
Corpus hemorrhagicum
The corpus hemorrhagicum is absorbed and the _________ ________ forms.
Corpus luteum
What is luteinization?
The process by which granulosa cells differentiate into progesterone-producing cells
The corpus luteum degenerates by a process called _____________, leaving nothing more than a scar also called a ______ _____________.
Involution
Corpus albicans
When we look at conversion of steroidogenesis, we go from the Δ5 to Δ4 pathway as we shift from the theca/granulosa cells to the luteal cells
The ovarian cycle begins at ___________. It normally lasts 28 days. It consists of two phases: __________ (1 - 14 days) and ___________ (14 - 28 days).
Puberty
Follicular
Luteal
Which phase of the ovarian cycle involves growth and differentiation of the follicles?
Follicular phase
Which phase of the ovarian cycle involves formation and demise of the corpus luteum?
Luteal phase
GnRH is produced in hypothalamus, released into the hypophyseal portal system, etc. Higher brain centers moderate the release of GnRH, including ___________. Initially, LH binds theca cells to produce androstenedione, and FSH binds granulosa cells to stimulate aromatase, which leads to androgen conversion to estradiol. Estradiol _________ feedbacks to the _________ pituitary, slowing LH and FSH production. Once an estradiol threshold is reached, a __________ feedback loop begins, resulting in a surge of LH and FSH. The ___ surge stimulates ovulation and luteinization. If pregnancy does not occur, the resultant _____ ________ will degenerate.
Kisspeptin-1
Negatively
Anterior pituitary
Positive
LH surge
Corpus luteum
When estradiol levels reach more than _________ picograms/ml, the ____ surge occurs.
200 pg/ml
LH surge
Two higher brain centers are involved in GnRH regulation: the arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). The ARC regulates GnRH pulsatility (GnRH must be released in a pulsatile fashion for proper functioning). The AVPV regulates GnRH surge. Together, these nuclei produce kisspeptin-1, which stimulates the release of GnRH, and GnRH stimulates production and release of LH (pulsatile) and FS. Negative feedback on the hypothalamus by estradiol occurs at the ARC while positive feedback occurs at the AVPV – therefore we are able to have both positive and negative feedback in GnRH regulation
What nucleus regulates GnRH pulstaility?
Arcuate
Which nucleus regulates GnRH surge?
AVPV (anteroventral periventricular nucleus)
What does AVPV stand for?
Anterventral periventricular
Glycoproteins are also important in regulation. _____________ __ is produced in the developing follicle; inhibin A is produced by the ______ ______. As follicles are stimulated by FSH, an increase in _________ ___ expression occurs, which engages in a ______ feedback loop with the anterior pituitary and inhibits FSH synthesis and release
Inhibin B
Corpus luteum
Inhibin B
Negative
__________ is a local glycoprotein in the pituitary, and it has same beta subunit as inhibin. It locally _________ FSH synthesis and release.
Activin
Stimulates
Activin can be inhibited by _________ (also produced in the pituitary), which binds and prevents activin from stimulating FSH production
Follistatin
Oogenesis begins before birth in utero as germ cells migrate to the bipotential gonads in early development around week 5; as they migrate, oogonium undergo mitosis and proliferate, ultimately forming _________ ___________ that are then incorporated into _____________ follicles – this also occurs during infancy and childhood, where the ________ _________ are arrested in ________ I, which can be visualized by the presence of a nuclear envelope around the oocyte. The oocyte remains arrested in ________ I as it moves from a primary to secondary follicle and is not restimulated into meiosis until the ____ surge, which triggers the resumption of meiosis; a key marker of this is the __________ __________ breakdown or nuclear envelope breakdown. After the primary oocyte is stimulated to resume meiosis, it becomes a _____________ oocyte and arrests in __________ II. The _________ oocyte will be released and ovulated from the ___________ follicle; if and only if it is _________ will the __________ oocyte undergo complete meiosis
Primordial oocytes
Primordial follicles
Primary oocytes
Prophase I
Prophase I
LH surge
Germinal vesicle
Secondary oocyte
Metaphase II
Secondary oocyte
Graffian follicle
Fertilized
Secondary oocyte
Important notes:
- Primary oocytes arrests in prophase I
- Primary oocyte resumes meosis I after LH surge
- Secondary oocyte arrests in metaphase II
- Secondary oocyte will not complete meiosis unless fertilization occyrs
- After meiosis I, we get our first polar body
Female duct system includes the _________ (fallopian/uterine tubes), _______, and vagina. Cilia on _________ create currents within peritoneal fluid to carry oocyte into ______. Oocyte carried towards uterus by combination of _______ and beating of cilia. Fertilization usually occurs within the ___________. __________cells within oviduct keep oocyte (and sperm if present) moist and nourished
Oviducts
Uterus
Fimbrae
Oviducts
Peristalsis
Ampulla
Mucosa
The ___________ is the site of sperm reception, and the lower part of the vagina forms the _________ _______.
Vagina
Birth canal
The __________ is a hollow, pear-shaped, muscular organ (~7cm long) that functions to receive, retain, and nourish a fertilized ovum.
Uterus
The wall of the uterus has ____ layers: the ________________ or outermost layer, the ______________ or the bulky, middle layer, and the _____________ endometrium or the mucosal lining of uterine cavity and site of implantation.
Three
Perimetrium
Myometrium
Endometrium
Which layer of the uterine wall is composed of interlacing bundles of smooth muscle that contract during childbirth?
Myometrium
What is the cervix?
narrow neck of uterus, projecting into vagina
What is the purpose of cervical mucus?
·prevents spread of bacteria from vagina into uterus, blocks entry of sperm except at midcycle, lubricates vagina
Around day 14, we see the thinning of the cervical mucus, coinciding with increased estradiol production and __________.
Ovulation
There are two layers of the _______________. Stratum ______________ undergoes cyclic changes and is shed during menstruation, and the tratum __________ forms new functionalis after menstruation
Endometrium
Stratum functionalis
Stratum basalis
The uterine artery breaks off into ___________ arteries. The ____________ artery supplies blood to the stratum basalis. The coiled artery supplies blood to the stratum _____________. It is the ________ arteries that respond to changes in progesterone and estradiol. When the corpus luteum degrades, the decreased production of progesterone causes the _______ arteries to undergo _________ and death, ultimately leading to menstruation.
Radial
Straight
Stratum functionalis
Coiled or spiral arteries
Coiled or spiral arteries
Ischemia
The endometrial veins are thin walled with ___________ (or swellings)
Sinusoids
There are three phases to the uterine or endometrial cycle: _____________, _____________, and __________________.
Menstrual
Proliferative
Secretory
The secretory phase of the __________ cycle can be divided into two subphases: ________ and ___________.
Uterine
Early
Late
If no fertilization occurs, we see a decrease in the corpus luteum and progesterone and an increase in ________ arteries that kink and spasm, resulting in shedding of the __________ _____________.
Coiled arteries
Stratum functionalis
The menstrual cycle is composed of both the _________ and __________ cycles. Estrogen acts in the uterus to induce proliferation of the __________. Estrogen and FSH induce ________ growth and differentiation, resulting in higher estrogen levels. Estrogen reaches a threshold concentration causing a surge of both ___ and ____ to be released from the anterior pituitary. The ___ surge results in ______________ and formation __________ _________, which produces large amounts of ____________, which stimulates the further build-up of the cells in the endometrium and the uterine glands to secrete substances that maintain the endometrium. High estrogen and progesterone levels strongly ______ LH and FSH release, ultimately leading to the demise of the ___________ __________. These decreased estrogen and progesterone levels also lead to ________ and eventual shedding of endometrium.
Ovarian
Uterine
Endometrium
Follicular
LH and FSH
LH surge
Ovulation
Corpus luteum
Progesterone
Inhibit
Corpus luteum
Ischemia
Take a look.
More menstrual cycle stuff.
What are some of the extraovarian functions of estrogen?
Maintain normal vasculature, decrease bone resorption, increase blood-clotting factors, increase blood coagulation, increase HDL and triglyceride turnover.
Ultimately estrogen has many protective effects for vasculature, bone, and neuron development.
What are some extraovarian functions of progesterone?
Contributes to insulin resistance, increases body temperature, and increase minute ventilation
Pre-puberty, FSH and LH are synthesized as early as 5 weeks gestation and peak in the pituitary between 25-29 weeks before LH declines
Postnatally, serum FSH increases and remains elevated for 2-4 years (decrease likely due to CNS events)
By 8-10 years, gonadotropin secretion increases again, with rise in FSH before LH
- Adrenarche (7-8 years)
- Amplification of a sleep-related pattern of LH release, followed by more permanent increase
- Increased estradiol production (& testosterone)
- Menarche (first menstruation; 12 years)
- Ovulation occurs 6-9 months after menarche
- Adolescent growth spurt (skeleton, muscle, viscera)
- Increase in hip width and body composition (fat)
- Breast development
- Growth of axillary and pubic hair (pubarche)
These are all actions that occur during puberty
Be familiar.
__________________ is the entire period during which estrogen levels decrease due to depletio of ovarian follicles.
Climacteric
___________ is the time at which the final menstrual bleeding occurs (~52 years)
Menopause
Menopause before the age of 35 is considered ___________ _________ _______.
Premature ovarian failure
Menopause diagnosis is _______________, meaning it occurs approximately 6 - 12 months after the last menses and confirmed via increased FSH levels.
Retrospective
Why do we see increased FSH levels in menopause?
As estrogen levels decrease due to ovarian reserve depletion, there is no longer estradiol formed to engage in negative feedback with the arcuate nucleus of the hypothalamus
What are some early consequences of estrogen depletion (menopause)?
Vasomotor instability (hot flashes), flushing, sweating, increased heart rate, sleep disturbance, fatigue, urogenital atrophy, painful intercourse, thin skin, decreased axillary/pubic hair
What are some long-term consequences of estrogen depletion (menopause)?
Loss of bone mass, osteoporotic fractures, increased central obesity
Don’t forget the positive feedback system for childbirth!
