• Spermiogenesis: From Spermatid to Spermatozoon
  

• The Role of Sustentacular Cells (Antigen Barrier)
  

• Sustentacular cells (Sertoli cells) - with tight junctions, divide the seminiferous tubule into "basal compartment" and "adluminal compartment"
  

• blood-testis barrier - these cells prevent leakage of proteins from "new genetic cells" (from crossing over) to stimulate an autoimmune response, which would kill the gametes
  
• absorb excess cytoplasm "sloughed off"
  
• chemical signals that regulate entire process
  

• Effects on Spermatogenesis and Fertility
  

• Autoimmune disorder - immune system attacks "new" sperm cells which are different from somatic cells due to crossing over during mitosis
  
• Other factors: radiation, lead poisoning, some pesticides, marijuana, alcohol can lead to abnormal sperm production
  

• Erection of the Penis

1. impotence - inability to attain/maintain erection
   

• Ejaculation of Sperm
  

• Brain-Testicular Hormone Axis

• Mechanism and Effects of Testosterone
  

1. Mechanism of Action
• testosterone passes through cell membrane (lipid)
• binds to "hormone receptor" in the nucleus
• "hormone-receptor complex" binds to acceptor on gene
• DNA of gene is translated into mRNA
• mRNA directs protein synthesis in cytoplasm
2. Synthesis of sex hormones in males
• Prostate testosterone -> dihydroxytestosterone
• Some neurons - testosterone -> estrogen
3. Effects of Targets
   

• testes - stimulates spermatogenesis
• ducts, glands, penis - essential for growth/maintain
• secondary sex characteristics - develop at puberty

• pubic, axillary, facial, chest hair growth
• increase in bone & muscle size
• sex drive for Males & Females

• all potential gametes produced before birth
• Meiotic divisions unequal, leading to the formation of polar bodies (eventually destroyed)
• puberty releases the "arrested state" of primary oocytes, leading to ovulation
• Meiosis II does not occur until fertilization of the secondary oocyte by mature sperm
• ovulation and reproduction naturally end during menopause

• spermatogenesis from spermatogenic cells starts at puberty and continues through life
• Meiotic divisions are equal, leading to 4 spermatozoa from original spermatogenic cell
• Meiosis II completed before the sperm leads to fertilization

• Follicular phase (days 1-10 of cycle)

• 1. primordial follicle ------> primary follicle (squamous cells) (cuboidal cells)
• 2. primary follicle ------> secondary follicle; follicle cells ------> stratified epithelium (granulosa)
• 3. ovary cortex forms theca folliculi around granulosa ;theca folliculi & granulosa produce estrogens
• 4. granulosa form jelly-like zona pellucida
• 5. fluid-filled space called antrum develops
• 6. primary follicle now becomes a secondary follicle ;granulosa cells begin to form corona radiata ;secondary (vesicular) follicle reaches ovary surface

• Ovulatory phase (days 11-14 of cycle)
  

• fluid filled antrum increases in size ;corona radiata begins to separate from wall
  
• ovulation - secondary oocyte (surrounded by the corona radiata) bursts from the ovary -->into the peritoneal cavity (fimbriae pick up!)
  
• mittelschmerz - pain associated with ovulation
  

• Luteal phase (days 14-28 of cycle)
  

• corpus luteum forms from granulosa and thecal cells remaining from the bursting site; it secretes progesterone and some estrogen
• YES pregnancy -> secrete more progesterone
• NO pregnancy -> whole structure will degenerate (no more progesterone)

• childhood ovaries secrete small amounts of estrogens ------>

• block hypothalamic release of GnRH
• (no FSH or LH secreted from anterior pituitary)
  

• early puberty hypothalamus less INHIBITED by estrogens ----->

• gradually more GnRH is released ------>
• gradually more FSH and LH released
  

• late puberty GnRH released more cyclicly ----->

• FSH and LH released cyclicly ----->
• menarche - first menstrual period (bleeding)
  

2. Hormonal Interactions During Ovarian Cycle
   

• GnRH, LH, FSH and their Role in Estrogen Level
  

1. increasing release of GnRH from hypothalamus -----> increased release of FSH and LH from ant. pituitary ----->
   

• FSH stimulates growth/division of follicle cells
• LH stimulates development of thecal cells
  

• LH stimulates thecal cells to produce androgens
• FSH stimulates granulosa to convert to estrogens
  

2. temporary NEGATIVE FEEDBACK - these low levels of estrogens briefly inhibits more release of FSH and LH (although it is still being produced and stored!)
   
3. temporary POSITIVE FEEDBACK - these low levels of estrogens briefly enhance FSH stimulation of granulosa
   

• Higher Estrogen Leads to Actions of LH
  

1. estrogen levels eventually get higher and higher
2. suddenly, high estrogen creates POSITIVE FEEDBACK to brain increasing GnRH, FSH, LH levels
3. LH and FSH levels rise very quickly (MIDCYCLE)
4. high LH level increases fluid level in antrum, and rupture/release of the secondary oocyte
5. estrogen level drops immediately after ovulation, but soon begins to rise again
6. LH stimulates "corpus luteum" to secrete progesterone to prepare the endometrium for implantation and pregnancy.
   

• Continuation Depends on Corpus Luteum and Progesterone
  

1. progesterone and estrogen levels rise, leading to a NEGATIVE FEEDBACK on LH and FSH from anterior pituitary
   
2. LH levels decline, corpus luteum starts to degenerate, and less progesterone released

• PREGNANCY -------> placenta releases Human Chorionic Gonadotropin, (maintaining progesterone levels for pregnancy)

1. Proliferative phase of Uterine Cycle (days 6-14)
1. rising levels of estrogen allow "repair" of stratum basalis of the endometrium; also causes thickening of stratum functionalis, increasing vasculature, making progesterone receptors
2. Secretory phase of Uterine Cycle (days 15-28)
1. rising levels of progesterone (from corpus luteum) increase thickness and vasculature to the endometrium
3. Menstrual phase of Uterine Cycle (days 1-5)
   

• NO PREGNANCY -------> no Human Chorionic Gonadotropin -------> no more progesterone (corpus luteum gone) -------> endometrium “sloughs off” and bleeding occurs

Role of Estrogens

• cause maturation of sex organs at puberty
• cause increased growth in girls aged 11-13
• Secondary Sex Characteristics: breast growth, increased fat on hips & breasts, widening of pelvis, axillary & pubic hair, facilitate Ca++ uptake
  

Role of Progesterone

• regulates uterine cycle with estrogens
• prepares uterus for pregnancy
• prepares breasts for lactation

• same autonomics (S2,3,4) stimulate excitation of clitoris, vagina, breasts, and lubrication
• multiple orgasms possible, but not essential for pregnancy to occur

• •Peak age 8-13 years
• •Female > male
• •70% on face & neck
• •3.5% multiple
• Adnexal tumor differentiating toward hair matrix
• –Internal root sheath
• –Hair shaft

1. –Early: cystic
2. –Late: bluish hard nodule, chalky white on cut section
3. –Blue: basaloid matrical cells, Pink: ghost/shadow cells
4. –Osseous metaplasia
5. –Mitoses common in matrical cells

• –Gardner’s
• –Myotonic dystrophy
• •

1. Autosomal dominant
2. •
3. Myotonia, muscle wasting, cardiac conduction defects, cataracts, testicular atrophy, frontal baldness

Variations:
• giant form, proliferating, malignant
• Beta-catenin mutation
  
• Shadow cells are non-specific
• •Desmoplastic trichoepithelioma
• •Mixed tumor
• •Matrical carcinoma

There are more than 250 proteins that function as hormones, that range in length from 3 to 192 amino acids, for example the growth hormone.

There are 4 main modes of action for hormones:

1. Endocrine- secreted by specific glands, travel through blood stream to reach remote target site. Only few select glands capable. Example, Thyroid gland.

2. Paracrine- act in vicinity of releasing cell, normally on neighboring cells, can work on either same cell or different cell type, hormone acts via diffusion through gap junctions or intercellular fluid channels. Many cells capable.

3. Autocrine- a cell releases hormone that then effects the releasing cell itself. Nearly all known tissues are capable

4. Neuroendocrine- hormones within neurological pathways and also functioning as neurotransmitters.

Peptide hormone evolution

Primitive forms of life contain hormones, i.e. insulin. Specific segments of peptide hormone synthesis has been preserved throughout evolution.

DNA is translated into RNA

Transcription starts Poly-adenylation

5’-end____________|_____________________________________|________3’-end

Regulatory region Structural region Transcription

Termination

Structural region is made up of exons interdispersed with introns, a cap site, and a polyadenylation signal (AATAAA)

Regulatory Region has 3 parts

1.) Variable region contains

a.)MRE-metabolic response

-response element to cAMP

-steroid receptors

-thyroid

b.)TSS/E- tissue specific silencers/enhancers

2.)TATA Box

Sequence of TATAA present 30 nucleotides upstream to make sure that transcription is initiated properly. Binds to a complex of several proteins, including RNA polymerase II and at least 6 other proteins (IIA, IIb, IIC ,IID, IIE, IIF, IIH ),referred to as TATA box transcription factors These proteins form the machinery required for initiation of RNA synthesis

Among TATA box transcription factors, TFIID is a key factor. It consists of the TATA box binding protein (TBP) and at least 12 associated proteins (TBP –associated factors- TAFs).

The binding of TBP alone to TATA supports basal transcription.

However, upregulation or downregulation of transcription requires the presence (binding) of TAFs. TAFs serve as coactivators or corepressors for enhancer or silencer binding proteins.

3.) Upstream Promoter Region

Alteration in expression

In the basal state, the cAMP response element (CRE) binds a CRE binding protein (CREB).When CREB is phosphorylated by cAMP- dependent protein kinase A, the phosphoCREB recruits the coactivator designated as CREB- binding protein CBP.

CBP couples with TBP-associated factors, leading to marked increase in transcription rate

Steps in expression of protein:

Evolutional processes- rearrangement and transposition of DNA segments.

1.)Transcription: formation of RNA copies from the two alleles; catalyzed by

RNA- polymerase II- associated transcription factors

2.)Post-transcriptional processing: specific modifications of RNA such as the

formation of mRNA from precursor RNA via the excision of introns and rejoining of exons; modification of the 3’ end of RNA by polyadenylation (poly A tail- stability?) and of the 5’ end by addition of7-methylguanine “caps”.

Receptors for GHR, growth hormone differ between species.

Growth Hormone Binding Protein, GHBP, circulate within blood and bind Growth Hormone, this serves as a resevior for Growth Hormone. GHBP result from alternate splicing of the RNA that codes for Growth Hormone Receptor, by splicing the end that inserts into the cell membrane.

This is an example how a single gene can give rise to different hormones or receptors depending on the splicing

Pre-hormone

Hormones that still need to be cleaved and processed after transcription in order to become an active hormone. They contain a signal.

Pre-Prohormone

Signal| Cryptic| Bioactive| spacer| Bioactive|

Signal- NH2 terminus sequence. Upon emergence from the large ribosomal subunit, the signal sequence associates with a signal recognition complex containing 6 different proteins + a 7S RNA located at the endoplasmic reticulum and cytoplasm. This results in translational arrest. It remains in translational arrest until it binds to a high – affinity binding protein on the endoplasmic reticulum termed the signal recognition particle receptor or docking protein. Block is released, protein synthesis resumes, and the peptide prehormone is then transferred across the membrane of the endoplasmic reticulum. The NH2 terminal signal sequence is cleaved by SIGNAL HYDROLASE. The removal of the hydrophobic signal sequence frees the prohormone so it may now assume its secondary structure during further transport in the ER and Golgi apparatus.

Spacer functions as a pusher for hormone to leave ribosome

Conversion of Prohormone

-Occurs in the Golgi Appratus. The translocation of prohormone from rough ER to Golgi requires microtubules. This is known because we can block the translocation with vinblastin.

-Requires prohormone convertases endopeptidases, proteases that cleave specific sites.

Examples:

PCI- converts proinsulin to insulin, is associated with a specific disease where proinsulin is high.

PCII- converts proglucagon to glucagons.

Proopimelanocortin- responsible with formation of ACTH and MSH, difiency disease results in growth retardation, obesity.

Post translational processing

Conversion-prohormones to intermediate or final protein.

Derivatization-glycoslation, phosphorulation, or acetylation.

Folding- to achieve native conformation

Amidation- enhances stability when active site is close to C-terminal

Secretory Granules and Secretion

-Formation begins at the tran-Golgi

-Hormone concentration/ aggregation is facilitated by changes in pH,

calcium concentration and proteins such as chromogranins, sulfated proteoglycans.

-contain one or more hormones

-Secretory granules release their contents by cytoskeletal protein-

mediated movement of the granule to the cell surface followed by exocytosis of stored hormones.

Additional sites of Hormone Regulation

-elongation or termination of transcription

-variation of RNA splicing

-hormonal mRNA stability (prolactin effect on breast casein mRNA stability, thyroid hormone effect on TSH beta subunit mRNA stability)

-effect on translocation

Angiotensin II-example of proteolysis after release from granule to change effect of hormone.

Secretion Regulation- extracellular stimuli

-regulated by other hormones (inhibited or stimulated)

-changes in extracellular environment (electrolytes, minerals, or Osmolarity)

- extracellular glucose, amino acids, or nutrients

Hormone Receptors- General Principle

Responsible for the recogination and binding of hormone

1. Provides specificity- recoginition domain provides for the affinity of binding, i.e. the better the fir of the hormone at the binding site the better the affinity of the receptor for the hormone. Experiments have shown the more you alter a hormone from its native conformation the more of a decrease in its receptor affinity will be observed.

2. Contains the coupling machinery- which allows signal transduction, i.e. is what allows the stimulation of cell from hormone, effect of hormone on cell.

2 major ways of hormone coupling

1.) binding of hormone to receptor on cell membrane generates signals that regulate cell systems

2.)Nuclear receptos superfamily- hormone enters cells and interacts with receptors within the cell, and travel to nucleus, i.e. steroid, retinoic acid, and thyroid.

Signaling pathways regulating genomic actions of nuclear receptors. Ligand binds to receptor. It modifies receptors and allows binding to other peptides. Which intiates transcription.

Surface receptors

-utilize second messengers to interact (directly or indirectly) with DNA elements within the gene.

Surface receptors that use cAMP as second messenger

α2 adrenergic catecholamines(inhibitory) glucagon

β2 adrenergic catecholamines TSH

ACTH PTH

Angiotensin II(inhibitory) somatostatin

ADH (inhibitory)

Calcitonin

chorionic gonasdotropin

CRH

FSH

LH (inhibitory= inhibits adenylate cyclase)

MSH

Generation of cAMP

ATP react with Adenylate cyclase and Mg²⁺ leading to cAMP, which then reacts with phosophodiesterase to form 5’ AMP.

Cell surface receptors with cGMP as second meesenger

atrial naturetic peptides

nitric oxide

G-protein signaling

Ligand binds to extracellular receptor, GDP is released from alpha subunit, GTP binds to alpha subunit, alpha subunit releases from receptor and attaches to effector, E_A, and can initiate cascade. The α -subunit has GTPase activity, and bound GTP is hydrolyzed to GDP and Pi. Hydrolysis of GTP, which is typically slow, causes dissociation of the effector- alpha-subunit complex and terminates the regulatory signal.

• GTPase-activating proteins (GAPs) may regulate the rate at which GTP is hydrolyzed. In this way GAPs may serve as regulators of G protein signaling (i.e., RGS proteins).

Calmodulin

• 17 kDa protein, homologous to muscle troponin C

• major calcium dependent regulatory protein

• has 4 calcium binding sites

• Full calcium occupancy leads to conformational changes which capacitate

calmodulin to associate with and activate other proteins.

• Many kinases are acivated by calmodulin, some are specific calmodulin – dependent protein kinases, another is a multifunctional calmodulin- dependent protein kinase.Other enzymes are regulated directly(adenyl cyclase, phosphodiesterase)or indirectly (glycogen synthase, caMg-ATPase).

• The calcium- calmodulin system also affects the activity of structural cell elements such as the actin myosin complex in VSMC, microfilament- mediated processes etc.

Two examples calmodulin mediated cell responses

Nutrients: glucose enters the ß-cell on the GLUT2 transporter and is metabolized with a consequent generation of ATP and closure of KATP channels. The decreased efflux of K+ leads to depolarization of the ß-cell with the consequent opening of VDCCs and an influx of extracellular Ca2+ down its concentration gradient. The Ca2+ binds to CaM, and the Ca2+/CaM complex binds to the inactive kinase (CaMKi), which becomes enzymatically active (CaMKa). The active CaMK phosphorylates (PO4) ß-cell substrate proteins, and these phosphorylation events stimulate the secretory process.

Nonnutrients: agonists bind to cell-surface receptors that are coupled via the heterotrimeric GTP-binding protein Gq to PLC. hydrolysis of membrane inositol phospholipids. IP3 releases stored Ca2+ from the endoplasmic reticulum, and the elevation in intracellular Ca2+ activates CaMK, as described above

Binding of ligand (L) to G protein-coupled receptor (R) causes association between receptor and heterotrimeric G protein (alpha-beta-gamma subunit). After association, GDP, which is tightly bound to the alpha - subunit in the unstimulated state, dissociates from guanine nucleotide binding site. GTP quickly takes its place.

G-protein coupled receptor signaling (con’t):

Binding of GTP induces a conformational change, causing dissociation of the effector alpha subunit complex and terminates the regular signal. Alpha subunit has GTPase activity, can be turned on by GAP’s, regulatory step where receptor activator can be modulated. If GAP’s are activated and cleaves GTP to GDP and Pi, when this occurs activating mechanism is no longer in effect, and receptor activator is being turned off.

Some receptors can be turned off by GRK (G protein receptor kinase) phosphorlation dependent desensitization (inactivation).

Once GTP cleaved by alpha subunit GTPase activity (maybe enzyme linked) changes from GTP to GDP allows dissociation from effector and re-association with beta-gamma subunit and recycles the protein.

Other mechanisms that are responsible for receptor inactivation, termination mechanisms are very important. 1^st example was GRK (see above) after GRK did its job it can bind beta-arestin allowing receptor to be internalized. Can generate signaling inside cell and then be recycled and reused (dephosporlated in the cell).

There are many families of G protein subunits alpha subunit most studied, some stimulatory, some inhibitory, etc. work by a whole array of mechanisms: cAMP, phospholipids, PIP2, etc.

Activation of alphas lead to increase of cAMP , effector enzyme is adenalin cyclase. cAMP interacts and frees protein kinase A to work in cell and phosporlates (removes block).

Phospholipid Breakdown:

Backbone structure of triglyceride composed of Fatty Acid. Arachidonic acid (important signaling molecule synthesized heats, prostaglandins and many other) in position. Activation of different phospholipase: A - cleaves unsaturated fatty acids in position two releases arachidonic acid. C – cleaves FA in position three linked to cholin, insitol or ethanolamine. Serine release leaves you with diacyleglycerol (DAG) and inositol with phosphate (IP3). This cleavage into DAG and IP3 signaling event to many G protein receptors.

Phospholipase C (PLC) – highly preserved catalytic domain (X and Y), and a varying docking domain that can be activated by different elements, acting on different sites.

Beta-Gamma subunit of protein G can couple with docking unit of PLC this leads to formation of IP3 and DAG. There are several different isoforms of PLC and what it associates with downstream. PLC can also be activated by PTK (phosphotryosine) receptor. PTK receptor auto phospholates itself which then activates PTK and PLC.

These mechanisms work simultaneously making the effect of the ligands more potent. Activation by Ach --- PLC --- IP3 --- Ca++ --- PKC (allows certain kinases to be activated). PKC binds DAG direct activator (some require intracellular Ca++ increase). PKC once activated is another mechanism by which downstream reactions take place (insulin release).

Caveoli – Caveolae are vesicular invaginations of the plasma membrane. The chief structural proteins of caveolae are the caveolins. Caveolins form a scaffold onto which many classes of signaling molecules can assemble to generate preassembled signaling complexes. In addition to concentrating these signal transducers within a distinct region of the plasma membrane, caveolin binding may functionally regulate the activation state of caveolae-associated signaling molecules.

Some hormones use the same mechanism with general intracellular events. Thus it’s a question of specificity which is believed to be achieved by caveoli – one hormone one effect. Caveoli are highly enriched with caveli 1 and 2, it is an area that concentrate hormone action into a location. Receptor can only enter caveoli if ligand has binded to receptor and allow for compartment action they are not random but in substructure that improve downstream specificity. Another mode of action is receptor already in caveloi and can only act once ligand binds.

Variety in structure, regulation and physical distribution allows specificty of overall response: There is a great variety of each molecular component. Each component is represented by several isoforms, Each isoform can be differentially regulated, for example, by phosphorylation or by Ca2+, and be ticketed to a specific place within the cell, presumably because of special signal sequences or domain specificities.

Differential distribution of β-adrenergic receptors: A change in single AA makes a big difference in terms of response, known from studies in lab or human disease (tyrosine not present at specific site) hormone won't exert its effect. Several isoforms to each components and can be regulated allows different down stream targeting.

REMEMBER that we can have simultaneous activation of different mechanisms

Family of hormones that bind membrane and use Kinase / Phoshotase as "second messenger": erythroprotein, EGF, GH, insulin, IGF-I/II, nerve growth factor, oxytocin, prolactin.

LDL, EGF and Insulin (homodimmer) receptors: similar mode of action, receptor has tyrosine kinase activity in cytoplamic portion activated once hormone binds receptor.

Activation of PLC leads to rise in intracellular Ca++ and activation of PKC. Insulin activates several mechanisms for different purposes.

Insulin regulates uptake of glucose into cell by glucose transportase (Glut's). Insulin needs to move glut's to membrane where it can load glucose into the cell. 1^st event depends on tyrosinkinase moiety on intracellular domain once phosphorlation took place it can bind downstream molecules. 1^st is IRS (insulin preceptor substrate), then it's phosphorlated and associated with SH2 which activates PI-3K. Via action of PI-3K we end up with PI3,4,5P this molecule can activate different downstream molecules PKC, PDK (phosphatidle insoitol dependent kinase) allows activation of PKB both required to allow Glut 4 to associate with cell membrane.

IRS are linkers between receptor and signaling best known are IRS1, 2, 3, 4. IRS1 works in muscle, IRS2 works mainly in liver. PI-3K dependent root of activation of PKC and PDK, although other pathways are also activated and are important in activation of Glut4.

Out of PowerPoint presentation:

Two potential insulin receptor–dependent signal transduction pathways. Insulin stimulation results in the activation of a PI 3-kinase–dependent pathway that is necessary but not sufficient to induce GLUT4 translocation. In parallel, the insulin receptor activates an additional pathway leading to Cbl tyrosine phosphorylation through its interaction with the CAP protein. Syn4, syntaxin 4; PI3-K, PI 3-kinase

The phosphorylated insulin receptor binds and phosphorylates IRS proteins and Shc, which bind differentially to various downstream signaling proteins. PI3-kinase is critical for metabolic actions of insulin, such as glucose transport, glycogen synthesis, and protein synthesis, whereas Grb-2/SOS complex, which activates the MAP kinase cascade, is critical in mitogenic response. PI3-kinase probably modulates the mitogenic response as well. Spatial compartmentalization of insulin signal transduction: IRS binds to, and activates the regulatory unit of PI3- kinase and the complex translocates to internal membranes which contain substrate for PI3-kinase and close to GLUT4 which translocates,in response to this process, to the cell membrane

Major signaling pathway of insulin action –

IRS's proteins associated with PI-3K outcome dependents on downstream molecules glucose transport, glycogen synthesis, protein synthesis. Insulin activating the mechanisms of Grb2 and SOS, leading to cell replication (acts as a growth factor).

Insulin Receptor: auto-phosphorlation binds IRS protein and phosphorlate downstream catalytic subunit of PI-3K then the whole complex phosphorylates a specific target in the internal cell structure where Glut 4 resides. Glut 4 is released and traslocated to the cell membrane. Mutation at any point can lead to loss of function.

Hormones with cell membrane receptor for which calcium or/and phosphoinositides serve as second messengers (PLC dependent): α1 adrenergic catecholamines, acetylcholine (muscarinic), angiotensin II, ADH, EGF, GnRH, PDGF (platelet derived growth factor), TRH (tyrotropin releasing hormone --- stimulate TSH).

Regulation of Polypeptide Hormone Synthesis The steroid/retinoic acid/thyroid hormone (nuclear) receptor superfamily example:

Hormone Regulatory Elements (HRE) in the regulatory region of the transcription unit have already been characterized for: glucocorticoid receptor, estrogen receptor, androgen receptor, progesterone receptor, vitamin D receptor, retinoic acid receptor, thyroid hormone receptor (THE NUCLEAR RECEPTOR SUPERFAMILY). Receptor found in cytoplasm once activated it travels to DNA

In each case a DNA element of 8-20 nucleotides confers hormonal regulation to its associated structural region.

Hormones such as steroids and thyroid hormones interact with nuclear receptor proteins which, in turn, interact directly with DNA elements to modulate gene transcription

For example, glucocorticoid ligands bind to inactive glucocorticoid receptor in the cytoplasm which is present in complex with hsp90, hsp70 and other peptides.

Activated receptor- ligand complexes interact as a trans- acting factor to bind to the DNA element GRE.

Cortisol - Steroid Receptor Example: steroid hormone outside cell get through cell membrane (lipophilic) quickly. Cortisol in cytoplasm bind the receptor and causes a conformational change. Receptor is normally in inactive state, bound by hsp70 (heat shock protein) and cannot exert its effect on DNA. Hsp70 is a dimmer linked to receptor preventing downstream action, cortisol induces conformational change, hsp70 dissociates. Complex of receptor and steroid moving freely to nucleus bind hormone response element on DNA (GRE, glucocorticoid response element) induces another conformational change and leads to DNA synthesis.

Phosphorlation must take place for activation

Vitamin D Example: 1alpha,25(OH2)D3 is active form different mode of action.

In inactive form linked as hetrodimer to RXR (retinoic receptor) binding of Vitamin D moves to nucleus still bound VDRE (co-activators) lead to target gene increased transcription rate.

Anatomy of nuclear receptor an d typical gene structure:

LBD – bind steroid (ligand) receptor

DBD – DNA binding domain has zinc fingers and carboxyl terminal with hinge between critical elements at beginning and end AF1 (N-terminus) and AF2 (C-terminus), AF stands for activation functions. Most nuclear receptors superfamily differs in sequence thus binding different activators and co-activators.

Zinc fingers are a part of receptor that is in direct contact with DNA usually has one or two zinc fingers. Zinc fingers are sequence of AA with multiple cystein and histadine this allows for unique folding where Zn binds. There are different arrangements of receptors allowing different association with DNA: monodimmer, homodimmer, RXR heterdimmer. Receptor variations improve specificity, and minimize errors.

Once nuclear receptor bound VDRE (vitamin D response element) with VDR and REX this induces binding of cofactors (activators) in many cases leading to physical folding of area get into direct contact with TATA box. Physical touch of TATA box activating machinery increases transcription rate of RNA polymerase.

In recent years another concept was developed that takes way from the nuclear receptor mode. Particular steroids can also work by interaction with cell membrane directly and generate effects like classical membrane associated receptors. The difference is in the time involved, nuclear activation is a timely process between 30-40min to hours. Cell membrane receptors effects are very rapid, estrogen and testosterone can act within seconds. Therefore there must be another pathway other than the classic nuclear receptor root. For example immediate increase in intracellular Ca++ must be membrane response explains some of the effects. What was initially thought to be two separate modes of action might not be separate but receptors have yet to be identified.

The tract of Endocrine system are CNS, hypothalamus, pituitary, end organ.

The anterior and posterior pituitary develop from 2 different tissues. Anterior pituitary develops from the ectoderm of the roof of the mouth. Whereas the Posterior pituitary develops form the neural tissue of the third ventricle.

A tumor in the pituitary can cause diplopia by putting pressure on the optic nerves.

The volume of pituitary decreases with age, and increases by up to 50% during pregnancy due to the production of prolactin.

Vascular connections

Posterior pituitary- direct arterial supply from inferior hypophyseal artery

The median emmience and upper stalk- superior hypophyseal artery

Anterior pituitary- supplied by capillary plexus that is derived from portal veins

that carry blood from the superior hypophyseal artery. (through this connection hypothalamus releases hormones into portal veins to effect pituitary) prone to hypoxia when blood pressure drops

Sheehan’s- drop in blood pressure causes necrosis of pituitary.

Hypothalamus

-is responsible for various basic functions : hunger, thrist, blood pressure, temperature regulation, water balance, metabolic rate.

Communication

-the brain sends signals to the hypothalamus, which then regulates the anterior and posterior pituitary via neurotransmitters, mainly dopamine, or hormones.

Characteristics of hypothalamic releasing hormones p.878 Levy 4^th ed.

1. secretion in pulses

2. Action on specific plasma membrane receptors.

3. Transduction of signals through calcium, membrane phosopholipid products,

and cyclic AMP (cAMP) as second messengers.

4. Stimulation of release of stored target anterior pituitary hormones via

exocytosis.

5. Stimulation of synthesis of target anterior pituitary hormones at the

transcriptional level.

6. Modification of the biological activity of target anterior pituitary hormones by

post-translational effects such as glycosylation.

7. Stimulation of hyperplasia and hypertrophy of target cells.

8. Modulation of effects by up-or down-regulation of their own receptors.

-peptide hormones that react on posterior piruitary

-argnine vasopressin (Shapiro) or ADH (Levy)

-oxytocin

-hormones that act on anterior pituitary

• -Thyrotropin Releasing Hormone (TRH)-acts on anterior pituitary to release thyroid hormone, a tripeptide
• -Gonadotropin Releasing Hormone (GnRH)-releases gonadotropin hormone that acts on the ovaries and testis.
• -Somatostatin-inhibitory hormone of Growth hormone
• -Growth Hormone Releasing Hormone (GHRH)- stimulates the release of Growth Hormone.
• -Prolactin Inhibitory Hormone (PIF)- structure is dopamine, prolactionrhea, the flowing of milk at wrong times, can be stopped by the administration of this hormone.
• - Prolactin Releasing Hormone (PRF)-stimulates the release of prolactin
• -Corticotropin Releasing Hormone (CRH)-stimulates the release of ACTH (adrenal cortex hormone).

Pituitary Cells (major)

Corticotroph- releases ACTH, acts on adrenal gland

Thyrotroph-releases TSH, acts on thyroid

Gonadotroph-releases LH and FSH, acts on gonads(ovaries and testes)

Somatotroph-releases GH, acts on all tissues

Mammotroph-releases prolactin, acts on mammary glands and gonads

Anterior Pituitary Hormones Groups

Corticotropnin-lipotropin- all come from a common precursor, hypothalamus PONC

ACTH

Beta-lipoprotein

Beta-endophin

Glycoprotein-alpha and beta subunits, alpha common to all hormones, beta differentiates them

LH

FSH

TSH

Somatomamotrop-evolved from common hormone

GH

PRL

Anterior Lobe

TSH-Thyroid Stimulating Hormone-stimulates thyroid secretion and growth

ACTH-Adrenal Cortex Hormone-stimulates zona fasculata and reticularis

G.H., somatotroph-accelerate body growth and IGF-1 (insulin like growth factor) stimulates growth cartilage

FSH-females ovary follicle growth, males spermatogenesis

LH- stimulates female ovulation and estrogen secretion, males testerone secretion.

PRL-stimulates secretion of milk and maternal hormones

Beta lipotropin- don’t know

Alpha- MSH-causes pigmentation, and shuts off appetite

Genes for alpha and beta parts of hormone are separate, excess of alpha or beta chains may indicate tumor. Hypothyroidism because of mutation in beta genes.

Prolactin inhibits GnRH on Pituitary, which causes less LH and FSH, which leads to no period and loss of libido

TSH regulation (Levy p.880 Fig. 49-6)

Regulation of thyroid-stimulating hormone (TSH) secretion. Thyroxine (T₄) and triiodothyronine (T₃) from the thyroid gland exert negative feedback on the pituitary by blocking the action of thyroid-releasing hormone (TRH). Negative feedback of T₄ and T₃ also occurs at the level of the hypothalamus. Somatostatin and dopamine each inhibit TSH secretion tonically. TRH down-regulates its own receptor, and the releasing hormone loses effectiveness. Growth Horomone will reduce TSH secretion, therefore GH is used as a treatment for overproduction of TSH. Hormone secretion is episodic, pulses intricate multiple rythms of hormone secretion.

CRH (cytokine releasing hormone)

Releases ACTH, as does ADH (anti-diurteic hormone). Some cells co-secrete CRH and ADH. ADH functions to retain fluid. CRH receptors are in the brain, spinal cord, immune cells, and GI tract. On immune cells, CRH stimulates the release of cytokines. CRH causes central nervous system arousal, increased blood pressure, and increased sympathetic system activity. CRH decreases synthesis of gonadotropin-releasing horomone (GnRH)(which causes a decrease in reproductive function), feeding behavior, and growth. CRH is a stress hormone, so women who were in concentration camps had high CRH levels, which lead to a decrease in GnRH, which then caused amonorhea (no monthly period).

ACTH and MSH

ACTH has 39 amino acids, only need the first 24 to be biologically active, which is the synthetic form used for clinical purposes (called Synacthin or Cortrisyn)

Alpha-MSH-most important pigmentary hormone, cleaved from ACTH

Beta –MSH- found in mammals, cleaved from gamma lipotropin

Gamma MSH- cleaved from the N-terminal peptide.

Regulation of ACTH

CRH release from the hypothalamus is stimulated by stress, sleep/wake, norepnephrine, acetylcholine, and serotonin. CRH is inhibited by endorphins. ADH release is stimulated by sleep/wake. ADH and CRH stimulate the release of ACTH from pituitary, which then stimulates the adrenal to release Cortisol.. ACTH acts as negative feed back on the hypothalamus to decrease CRH secretion via short feed back loop. Cortisol can either work via short feed back loop and inhibit the pituitary from releasing ACTH, or long feedback loop and inhibit hypothalamus from secreting CRH. CRH can also act via ultra short feedback loop and shut off its own secretion.

Stimulation of ACTH Inhibition of ACTH

CRH Cortisol increase

Cortisol decrease

Adrenalectomy

Metyrapone

Stress

Psychiatric disturbances

Depression

Neurotransmitters

Serotonin

Acetylcholine

Metyropoine drug causes a drop (block) in Cortisol, which causes an increase in ACTH.

Prolonged use of steroids cause lack of response to ACTH, leads to atrophy of adrenal cortex.

Factors of ACTH secretion

Stress vs. Diurnal rhythm vs. feedback

Stress will over-ride the other 2

Diurnal rhythm overrides feedback

Chronic inhibition of CRH, due to hypersecretion of Cortisol or therapeutic administration of Cortisol analogs, will eliminate stress response, and one can die without steroid administration. Can take up to one year for recovery after removal of inhibition.

Posterior Pituitary (magnocellular)

ADH (Anti-diuretic or arginine vasopressin)-primary role is to conserve body water and regulate the Osmolarity of body fluids.

Oxytocin (OCT)- primary role is to eject milk

Both are secreted with a protein carrier (neurophysins).

ADH

Synthesis : 1. SON and PVN ( hypothalamus)

Migration down supra-optico-hypophysial tract

Storage + release: Posterior lobe ( Magnacellular)

Axons of PVN reach Median eminence and secreted into portal circulation stimulating ACTH

Also: Co-synthesis of ADH with CRH

For permanent DI need destruction of nuclei

Metabolized in liver and kidney

1/2t: 15- 20 min

ADH Action

• This is all about control of water balance to maintain normal osmolality and normovolemia

• Primary determinant of rate of free water excretion

• Augment water permeability of luminal membranes of cortical and medullary collecting tubules.

• Attain osmotic equilibrium with hypertonic interstitium of kidney

• (Osmolality in urine can go from <100> 1200 – Maximal effect of ADH depends on maximal concentration in the kidney interstitium. Urine goes from dilute to concentrated.

• countercurrent mechanism

Stimuli of ADH

• Osmotic changes of 1% , Most sensitive factor

• Osmotic Threshold – 280 mmol\kg (normal 275 – 295 mmol\kg)

• Osmoreceptor in hypothalamus

• Peak renal action 5pg/ml, very sensitive

• Volume 8 - 10% change, less sensitive

• Greater response of VP, hypovolemia – levels over 100pg/ml, does want

• Nausea

• Low cardiac output

• Nicotine

• Hypoxia, Pain (post op), stress

Osmotic Stimuli

• Osmoreceptors 3thd ventricle region hypothalamus, (organum vasculosum lamina terminalis) – stimulate SON

• Cholinergic neurons outside blood barrier go to SON and PVN

• Chronic catecholaminergic inhibitory fibers from arterial baroreceptors going to tractus solitarium in medulla.

Osmoreceptors

• Measure osmotic gradient between plasma and osmoreceptor cell.

• Cell: water permeable: Hypernatremia shrinks cell = activation cation channels = depolarization = increased ADH secretion.

• Hyponatremia: dilates cell = polarization = suppression ADH secretion

• Plasma sodium primary osmotic determinant (very important)

• Urea – ineffective osmole

• Glucose enters cell immediately and usually not effective. In insulin deficiency = increase of ADH

• Posm <>

• Maximal urine concentration: 1200 mosmol/kg

Hydroosmotic Action of ADP

AVP receptor in renal collecting duct cells

G protein receptor activation AC – V2 R

AC = CAMP = PKA activation, inactivated by phosphodiesterase

PKA activation activates mRNA of AQ-2 water channels and translocation of AQ-2 to plasma membrane

AQP-2

• AQP-2 is AVP regulated water channel

• Present in cytoplasmic vesicles and have trafficking to membrane under AVP.

• Water loading leads to internalization, aggregation in clathrin pits and back to vesicles in cytoplasm

• PKA phosphorylation of serine 256 in C-terminal of AQP-2 makes the action

• Osmotic water movement in cell = systemic circulation across basolateral membrane

Summation

As Osmolarity increases, vasopressin secretion increases, which in turn increases urine Osmolarity.

Thrist

• Thirst center is in hypothalamus

• Hyperosmolar state stimulates thirst

• Osmotic threshold 2 -5 osmol/kg above ADH

• Oropharyngeal mechanoreceptors involved. Large fluid intake drops thirst sensation.

• Thirst + ADH = decrease osmol and increase intervesicular Volume

Summation

As Osmolarity increases, water intake increases, plasma Osmolarity increases, vasopressin increases, which leads to thrist.

Volume and Pressure

Volume depletion: vomiting, cirrhosis, heart failure secret ADH in spite of low Posm.

(Shapiro skipped the rest but they were in the slides and text)

Parasympathetic afferent in carotid sinus = vasomotor center medulla = PVN.

Mean arterial pressure = cardiac output x systemic vascular resistance

Release of renin and norepinephrine more sensitive than AV

The hormone works by activating a receptor that then activates Phospholipase C, which through a cascade activates protein kinase C.

Summation

As blood volume decreases, vasopressin increases. A larger stimulus is required, thus the release is larger.

Hypovolemia

• Stimulates the generation of brain rennin and Angiotension II

• Brain Angiotension II enhances release of ADH on addition to increasing thrist sensation

Hypervolemia

Causes the release of atrial naturetic peptide (ANP) from cardiac myocyte with brain NP from SON. This inhibits ADH to give diuressis.

Interaction osmotic and volume stimuli

Volume depletion enhances output in presence of hyperosmolar state

Hypovolemia and hypoosmolar state – volume over rides osmolar state = hyponatremia

Chronic hypervolemia shifts osmotic threshold upward = elevation Posm and sodium

concentration

Agents that alter vasopressin release

Stimulate Inhibit

Vincristine Alcohol

Cyclophosphamide ANP

During the first 5 weeks the fetal gonads are indistinguishable, which means the cells are not committed to either sex yet.. However between the 6-7 week of gestation gametogenesis starts. The SRY gene on the short arm of the Y chromosome is responsible for male phenotype development. This gene codes for TDF (testis determining factor). After testis development, they release two factors that then push on the development of the male reproductive tract, MIF and Testosterone.

MIF- mullerian-inhibiting factor is responsible for stopping the formation of the female reproductive tract. Testosterone- is then responsible for pushing the male reproductive tract to form.

There are two types of cells that responsible for the development of the male reproductive tract Sertoli and Leydig cells.

Sertoli cells

These cells produce MIF or also called AMH (antimullerian hormone) which cause the mullerian ducts to atrophy (mullerian ducts later develop into the fallopian tubes, uterus, and vagina)

Leydig cells

Are the testosterone secreting cells of the testis. Testosterone promotes the wolffian or mesonephric ducts to develop into epididymis, vas deferens, seminal vesicles, and ejaculatory ducts. Testosterone is converted to its active form, dihydrotestosterone, by 5alpha- reductase,

The female tract development is governed by the gene DAX-1 found on the X-chromosome.

For male tract development there are 3 integral pituitary hormones:

LH- goes to Leydig cells and stimulates them to produce testosterone.

FSH- stimulates sertoli cells to start spermatogenesis and start the transport of sperm to the epididymis.

Prolactin- is really only needed in females to produce milk, however in males it can cause them to become desensitized to gonadotropin hormone (GnRH) and cause impotence.

Accessory glands are controlled by testosterone and alpha D testosterone.

In couple’s seeking help for infertility, a physician may perform a post-coital test (PCT), which is a physiological test for:

• Was intercourse really there

• Was there ejaculation

• How many sperm and what quality

• Was there interaction of sperm with nucleus

You may be wondering why such a test is necessary, I mean if a couple is seeking help for infertility, they’re going to be having sex, right? Well guess what, some patients do lie, and a physician needs to know if infertility is really due to lack of coitus.

GnRH is released from hypothalamus, acts on anterior pituitary to release LH and FSH (these hormones are released from same gonadotroph cells). LH acts on Leydig cells and FSH acts on Sertoli cells.

LH causes the release of testosterone in males and estrogen in females

Then FSH and Testosterone together cause spermatogenesis and release of inhibin from sertoli cells.

Inhibin is part of a feedback loop. It acts back on anterior pituitary to discontinue release of FSH. Therefore, if you have a male who has high testosterone and FSH, it is a sign that he is not producing sperm and inhibin.

The frequency and amplitude of GnRH can change ratio of FSH and LH example polycystic ovary or sperm quality. (Can change ratio by pumping in exogenous GnRH to fix the ratio artificially). Obstructive azosperma is caused by obstruction in the vas deferens.

Testis should be 3 degrees below body temperature, because the testis blood barrier is only efficient in hypothermic conditions. The testis are cooled by air circulating around the scrotum. Now blood supply to the testes consists of a network of veins and artery, in which the veins kind of form this meshwork around the artery. This allows the blood to warm up on its way back into the body. Now in some cases a varicocele forms in the veins, this is similar to a varicose vein in leg, where a valve fails and blood pools in the vein causing a bulge. Because there is now blood pooling in the testis, the temperature raises in the testis, causing a decrease in the quality of the sperm. Now this rarely happens on the right side, is more common on the left side, due to the difference in their connection to the inferior vena cava. They can perform a surgery to correct the varicocele, which does increase the quality of the sperm. However, case studies have shown that men who have the surgery and those who do not have the same fertility rates. Therefore it is only necessary to have the corrective surgery for pain or discomfort.

Testis

• Length = 4.5 cm

• Volume~ 20 mL

  • 70% volume seminiferous tubules

  • 30% interstitial tissue

Mesenchymal cells

Leydig cells- proliferation depends on LH

hCG (human chroinic gonadotroph) is governed by LH, hCG causes increase in production of testosterone.

In females, testosterone gets converted to estrodial almost immediately, in males high levels of testosterone will get converted to estrodial. Therefore if there is a problem with the cell receptor for testosterone, and the cells can not take up and metabolize the testosterone. The levels of testosterone will be high, it will get converted to estrodial, and the cells will then take up estrodial and the genetic male will develop female characteristics. Any defect in testosterone receptor will cause inactivation of the receptor.

In the testes you will find Leydig cells surrounding blood vessels and tubules. Leydig cells excrete testosterone into the blood stream for its exocrine action. In tubules, Leydig cells have a paracrine action of testosterone, and the testosterone level is 400 times higher around tubules than in serum.

There are two binding proteins for testosterone:

• SHBG- sex hormone binding globulin- it’s produced by the liver and found in the blood

• ABP- androgen binding protein- found in sertoli cells.

There are two pathways and sites for testosterone production

1. In adrenal (makes 5% of testosterone) Cholesterol is converted to pregnenolone, which is then converted to 17-alpha-hydroxypregnenolone, then to dehydroepiandrosterone, then to Androstenedione, then to Testosterone.

2. In testes, (95% of testosterone) Cholesterol is converted to pregnenolone, which is then converted to progesterone, then to 17-alpha-hydroxyprogesterone, then to androstenedione, then to testosterone

In the formation of testosterone, LH binds to the receptor and causes increase in formation of cholesterol from cholesteryl esters via cAMP, and via PKA causes conversion of cholesterol to pregnenolone.

Action of Testosterone

• Gonadotropin regulation

• Spermatogenesis

• Sexual Differentiation

• Sexual Maturation at Puberty

In circulation, 60% of testosterone is bound to SHBG, 40% is bound by Albumin, and only about 2% is free testosterone (I know the numbers don’t add up but this is what he gave in class). The testosterone avalible to receptor (Bioavailability) is about 40%, the free will be used first and then the testosterone bound to albumin, (it is much harder to get it released from SHBG).

Spermatogenesis

Takes place in the tubules, walls are 3-5 layers of myeloid cells, germ cells develop to sperm cells and are released into the lumen, takes about 3 months.

There are 3 phases

• Proliferation -2n cells

• Meiosis- 4n cells

• Spermatogenesis-1n spermatids

The Sertoli cells are important for spermatogenesis, for endo, para, and genetic control. These cells are controlled by LH and testosterone. The meiosis phase has essential need for testosterone. Therefore, if infertility is thought to be due to low levels of testosterone. You give hCG instead of testosterone. Because hCG stimulates the Leydig cells to release testosterone right next to the Sertoli cells instead of having to go through circulation.

Erection of the penis is under parasympathetic control. It is due to vasodilatation of the arterioles and muscle relaxation. Viagra activates cGMP, the second messenger for vasodilatation.

Ejaculation is under sympathetic control. It is due to the contraction of the vessels in reflex to fluid in the posterior urethra. There are 3 glands involved in ejaculation, seminal vesicle, prostrate, and Cowper ’s gland.

A. Glands without ducts

1. Secrete HORMONES (“ to set in motion ”) into the intercellular spaces and they pass directly into the blood and is then distributed to all parts of the body via they circulatory system.

2. Hormones – chemical secretions of the endocrine glands.

   1. chemical types -

1). proteins and polypeptides (endodermal origin)

2). amines (endodermal origin)

3). steroid (mesodermal origin)

3. Hormones – act to maintain homeostasis by altering cellular activity.

4. Hormones – can effect
   

a. organ or groups of organs directly (“target organ(s)”)

b. other endocrine glands called “target glands”

[these hormones are called trophic hormones]

B. Nervous System vs. Endocrine System

Controls muscles & glands activities of cells:

1. metabolism

2. reproduction

3. stress responses

4. fluid-electrolyte balance

5. acid-base balance
   

6. energy balance

A. Location

1. in Sella Turcica of sphenoid bone
   

2. attached to Hypothalamus by a stalk called Infundibulum

B. Structure

1. Anterior lobe – [glandular part] – Adenohypophysis

2. Posterior lobe – [neural part] - Neurohypophysis
   
   

C. Anterior Pituitary - (Adenohypophysis)

1. Hormone secretions controlled by secretions from the hypothalamus

- produced by nerve cells and control the release of hormones by

Endocrine glands; these hormones are called releasing factor

2. Growth Hormone (GH) – Somatotrophic Hormone (STH)

1. Increases Growth and Maintenance of Organs by:
   

1. stimulating protein anabolism

2. promotes fat catabolism (use of fat rather than sugars for energy)

2. Abnormal Secretions of STH

1. Gigantism -- hypersecretion during childhood ( before epiphyseal plates close)

2. Acromegaly -- hypersecretion durion adulthood

3. Dwarfism -- hyposecretion during childhood

4. Cachexia (Simmond’s Disease) – hyposecretion during adulthood

causes premature ageing and

atrophy of organs

B. Prolactin - (Lactogenic Hormone)

1. promotes breast development during pregnancy

2. stimulates mammary glands to produce milk after delivery

C. Thyriod Stimulating Hormone (TSH) - (Thyrotropin)

1. promotes growth of the Thyroid Gland

2. stimulates the secretion of the Thyroid Hormone

D. Adrenocorticotropin -- (ACTH)

1. promotes growth of the Adrenal Cortex

2. stimulates the secretion of Cortical Hormones

3. stimulates Fat Catabolism & Glycogenesis

E. Gonadotropins – FSH and LH

1. Follicle Stimulating Hormone (FSH)

a. female - stimulates the Ovarian Follicles to Develop and produce ova

- stimulates the Ovarian Follicles to secrete Estrogens

b. male - stimulates the production of sperm

- stimulates the secretion of Testosterone

2. Luteinizing Hormone (LH)

   1. female - associated with FSH in development of the Ovarian Follicles

- stimulates development of the Corpus Luteum following ovulation

- stimulates Corpus Luteum to secrete Progestrone

2. male - stimulates the Inerstitial Cells to secrete Testosterone

(also called Interstitial Cell Stimulating Hormone [ICSH])

D. Posterior Pituitary Lobe (Neurohypophysis)

1. Antidiuretic Hormone (ADH) - produced in the hypothalamus and collected and secreted by the posterior lobe

a. increases the permeability of the kidney tubules to water

b. promotes the reabsorption of the water from the urinary filtrate resulting in a smaller volume of urine

c.Diabetes insipidus - condition resulting in larger volumes of urine produced - may be treates with vasopressin

2. Oxytocin

1. stimulates powerful contractions of the pregnant uterus at the time of delivery

2. causes milk ejection from the lactating breast