Endocrinology Flashcards
1
Q
Endocrine Signaling
A
- Involves hormone secretion into the blood by an endocrine gland.
- The hormone is transported by the blood to a distant target site
e.g. Anterior Pituitary gland –> blood vessels –> Gonads (target site) –> Cells of ovary and testis –> or steroid hormones , Estrogens(female) and Androgens (male).
2
Q
Neuroendocrine Signaling
A
-cell type that releases the hormone is a nerve. In this case it is the hypothalamus
3
Q
Paracrine Signaling
A
Long distance signaling
4
Q
Autocrine Signaling
A
cell releases hormone that acts on self
5
Q
Communication by hormones (or neurohormones) can involves six steps
A
- Synthesis: of the hormone by endocrine cells (or neurons in case of neurohormone
- Release: of the hormone by the endocrine cells (or the neurohormones by the neurons)
- Transport: of the hormone or neurohormone to the target site by the blood stream
- Detection of the hormone or neurohormone by a specific receptor protein on the target cells
- A change in cellular metabolism triggered by the hormone receptor interactions
- Removal of the hormone, which often terminates the cellular response
*each step has a regulatory aspect to it
6
Q
How most hormones are transported?
A
Transported via binding protein
7
Q
The “Classical” endocrine organs
A
- Brain: Hypothalamus w/ Anterior and Posterior Pituitary Gland
- Thyroid and parathyroid glands
- Heart: Atrial natriuretic peptides (ANP)
- Adrenal glands: Cortex and medulla
- Pancreas: islets of Langerhans
- ovaries and testis
8
Q
Hypothalamic-Pituitary Signaling
A
- via blood vessels of the pituitary stalk
- hypothalamic-Hypophyseal Portal System- from the hypothalamus to the adenohypophysis (anterior pituitary)
- hypothalamic neurohormones either activate or inhibit activity of one of the six types of hormone-producing celling in the anterior pituitary
- called either releasing hormones (releasing factors) or inhibiting hormones (inhibiting factors).
- hypothalamus and pituitary are almost continuos tissues.
- hypothalamus hormones have two functions: inhibit the release of something, or tell the pituitary to release something.
9
Q
Classes of Hormones Based on Structure
A
Glycoproteins -FSH -LH -TSH Polypeptides -GH -Insulin -Glucagon Steroids -Aldosterone -cortisol -progesterone Amines -epinephrine -melatonin
10
Q
Synthesis of Protein Hormones
A
-by definition, if its secreted it’s a hormone.
- Synthesis on ribosomes: preprohormones
- Rough endoplasmic reticulum –> prohormones
- Golgi Apparatus: prehormones packaged into secretory vesicles: prehormone –> hormone + other peptide
- Vesicles: storage of hormone
- Co-release of hormone + other peptides.
11
Q
Structures of some steroid hormones
A
-common four carbon ring structure
12
Q
“lock and key” mechanism for a hypothetical membrane receptor
A
- the hormone acts as a key for a lock
- the lock being the receptor that is a chemical and physically specialized for the hormone
- Receptor hormone reaction are very specific
13
Q
Properties of Hormone Receptors
A
a. Specificity: recognition of single hormone or hormone family
b. Affinity: binding hormone at its physiological conc.
c. Should show saturability; i.e. a finite number of receptors
d. Measurable biological effect: a measurable biological response due to interaction of hormone with its receptor
14
Q
Receptor Regulation
A
a. Receptors can be upregulated either by increasing their activity in response to hormone or their synthesis
b. Receptors can be down-regulated either by decreasing their activity or their synthesis
* it makes no physiological sense for a receptor with a micromolar conc. to have affinity for a hormone at a nanomolar conc. Same goes vice versa
15
Q
3 mechanisms by which a hormone can exert effects on target cells
A
- Direct effects on function at the cell membrane
- Intracellular effects mediated by second messenger systems
- Intracellular effects mediated by genomic or nuclear action
16
Q
Direct effect
A
Hormone acts on a receptor –> receptor directly attach to a regulatory protein –> result is seen in the effect on what happens to the protein
17
Q
Signaling via an intracellular second messenger
A
- a lot of second messengers are kinases
Hormone interacts with receptor –> changes the activity of a protein –> protein released into cytoplasm –> can influence the function on other proteins
18
Q
Intracellular genomic signaling
A
e.x. Estrogen stimulate the transcription of certain genes –> more certain proteins are made, oppresses other genes –> more of wanted genes and less of unwanted genes.
TO be clear
Estrogen is a steroid. Steroid is very lipophilic meaning it can cross the membrane. Hormone goes directly into the nucleus of the cell and binds with a receptor. Receptor will change the way gene translation is regulated in the target cell. Ultimately changes the protein content of the cell
19
Q
Feedback Control of Hormone Secretion
A
- Hormone secretion is precisely regulated by feedback mechanisms
- an excess of hormone, or excess hormonal activity, leads to a diminution of hormone secretion
- conversely, a deficiency of hormone leads to an increase in hormone secretion
20
Q
e.x. of Feedback control of hormone secretion
A
- plasma Ca conc. goes down –> parathyroid glands are stimulated –> the synthesis and release of the parathyroid hormone will increase –> secretion will increase –> kidney will filtrate less Ca –> Ca will be saved from the bone and more will be taken out of the Gut
- Ca conc. will go up –> when there is enough, Ca will bind to the Ca receptor to tell the parathyroid gland to stop stimulation
21
Q
Need to Know about endocrine glands and their secretions
A
- Anatomic Location
- Hormones secreted
- Chemical Nature of Hormones
- Effects
- Mechanism of Action
- Control of Release
- Problems
- Treatment
22
Q
Pituitary Gland
A
Anatomy: two distinctly different tissues
- Adenohypophysis (aka Anterior pituitary) - endocrine tissue
- Neurohypophysis (aka posterior pituitary) - neural tissue
23
Q
Hormones that the Hypothalamus releases
A
- Gonadotropin releasing hormone (GnRH)
- Growth Hormone releasing Hormone (GHRH)
- Somatostatin (SS)
- Thyrotropin releasing hormone (TRH)
- Prolactin release inhibiting Hormone (PIH)
- Prolactin releasing hormone (PRH)
- Corticotropin releasing Hormone (CRH)
24
Q
Hormones that Anterior Pituitary Hormones releases:
A
- FSH and LH (+ affected by GnRH)
- Growth hormone (+ by GHRH and - by SS)
- TSH (+ TRH and - by SS)
- Prolactin (+ by TRH and PRH and - by PIH)
- ACTH (+ by CRH)
25
Target Organ: Gonads
- Germ cell development; hormones: estrogen, progesterone, testosterone
- Stimulated by FSH and LH
26
Target Organ: Liver and other Cells w/ Many organs are tissues
Liver: secretes IGF-I
Organs and Tissues: growth and organic metabolism
stimulated by Growth Hormone
27
Target Organ: Thyroid
- Secretes thyroxine, triiodothyronin
| - stimulated by TSH
28
Target Organ: Breast
- breast development, milk production, (males: facilitates reproductive function)
- stimulated by prolactin
29
Target Organ: Adrenal Cortex
- secretes cortisol
| - stimulated by ACTH
30
FSH
Follicle stimulating hormone
31
LH
Lutenizing hormone
32
IGF-1
insulin-like growth factor 1
33
Posterior Pituitary Gland (Neurohypophysis)
- outgrowth of hypothalamus connected by the pituitary stalk
- secretes oxytocin and vasopressin
- oxytocin and vasopressin synthesized in two hypothalamic nuclei (supraoptic nucleus and paraventricular nucleus), whose axons run down the pituitary stalk and terminate in the posterior pituitary close to capillary blood vessel.
- Prohormones processed in secretory granules during axonal transport
- Mature hormones liberated from the carrier molecules, neurophysins
- Circulating half lives: 1-3 min.
34
Oxytocin
Females
a. Parturition: uterus extremely sensitive to oxytocin at end of pregnancy. Dilation of uterine cervix by fetal head causes release of oxytocin --> uterine contraction, which assists the expulsion of fetus and then placenta
b. Milk ejection: in lactating mother - response to the stimulus of suckling. Oxytocin cuases milk filled ducts to contract and squeeze milk out
c. Behavioral effects: local oxytocin release in the brain reduces anxiety and enhances bonding and prosocial behavior
Males
a. Ejaculation: oxytocin surge during sexual activity assists epididimal passage of sperm and ejaculation
b. Behavioral effects: local oxytocin release in the brain reduces anxiety and enhances bonding, and pro social behavior.
35
Thyroid Gland: Coloid
- major component is thyroglobulin, a large protein 700,000 Da
- contains thyroid hormones thyroxine(T4) and triiodothyronine(T3)
- T4 and T3 are split off the thyroglobulin, and enter blood where they bind to special plasma proteins
36
Thyroglobulin
- synthesis of thyroglobulin under control of TSH of pituitary gland
- provides a type of storage for T4 and T3 prior release
37
Thyroid hormones and Iodine
- hormones contain iodine
- availability of iodine to terrestrial vertebrates limited
- cellular mechanisms developed for conc., utilization and conservation of iodine in thyroid gland
- thyroid follicular cells are able to trap iodide and transport it across the cell against a chemical gradient(active transport)
38
Synthesis of thyroid hormones
- Iodine(I2) used for iodination of tyrosine residues of thyroglobulin (TGB) to form monoiodotyrosine (MIT) and diiodityrosine (DIT)
- Oxidative coupling of two DIT forms thyroxine (T4) while oxidative coupling of one MIT with one DIT forms triiodothyronine (T3)
- These hormones are stored linked to thyroglobulin
- rate of all steps of T4 and T3 formation is increased by TSH
39
Control of Thyroid activity
- without TSH, thyroid has very low turnover of thyroid hormones
- synthesis of release of TSH controlled by hypothalamic thyrotropin releasing hormone (TRH)
- When T4 and T3 in blood increase they exert a negative feedback at both hypothalamic and pituitary levels to decrease release of TRH and TSH
- TSH interacts with specific receptors located on follicular cells, leading to increased production of T4 and T3.
40
Iodine Deficiency
- when the supply of iodide is deficient, synthesis of thyroid hormones decreases and T4 and T3 in circulation decrease
- release of TSH increases and the thyroid follicular cells are constantly stimulated
- thyroid enlarges and may form a visible lump, a goiter
- since the enlarged thyroid is unable to synthesize biological active thyroid hormones due to the iodine deficiency, known as non-toxic goiter.
41
Summary of the Effects of Thyroid Hormones
Stimulation of calorigenesis in most cells
- Increase cardiac output: rate and strength of cardiac contractions
- Increase oxygenation of blood
- Increase rate of breathing; increase number of red blood cells in the circulation
Effects of carbohydrate metabolism
-promote glycogen formation in liver; increase glucose uptake into adipose and muscle
Effects on Lipid Turnover
-increased lipid synthesis; increased lipid mobilization; increased lip oxidation
Effects on protein metabolism
-stimulate protein synthesis
Promote Normal Growth
- Promote neural branching and myelinization of nerves
- Stimulate growth hormone (GH) secretion; Promote bone growth; Promote IGF-1 production by the liver
- Promote development and maturation of the nervous system
42
Molecular Mechanisms of Action of Thyroid Hormone
1. T3 and T4 work like steroid hormones and alter trasncription
2. may induce some effects by interactions with plasma membrane and mitochondria. A specific receptor for T4/T3 located in inner mitchondreal membrane
3. T4/T3 act directly at plasma membrane and increase uptake of amino acids. This effect is also independent of protein synthesis
43
Hypothyroidism
-hypofunction of the thyroid gland. Characterized by low levels of thyroid hormones
44
Hyperthyroidism
-hyperfunction of the thyroid gland. High levels of thyroid hormones.
45
Primary Hypothyroidism
- At level of thyroid, inability to synthesize active thyroid hormones
causes: atrophy, autoimmune thyroiditis, goitrous hypothyroidism or non-toxic goitre
46
Secondary Hypothyroidism
-at the level of the hypothalamus; synthesis of little or no thyroid stimulating hormone (TSH)
47
Tertiary Hypothyroidism
at level of the hypothalamus, synthesis of little or no thyrotropin releasing hormone (TRH)
48
Treatment for Hyprothyroidism
-effectively treated by administration of thyroid hormones
49
Primary Hyperthyroidism
toxic diffuse goiter (graves disease)
50
Secondary Hyperthyroidism
- level of the anterior pituitary gland
| - no negative feedback from increased levels of T3/T4 and synthesize autonomously thyroid stimulating hormone(TSH)
51
Tertiary Hyperthyroidism
- at level of hypothalamus
| - often due to presence of a hypothalamic tumor
52
Treatment for Hyperthyroidism
- surgery plus replacement therapy
- administration of radioactive iodide
- Administration of antithyroid drugs
53
Calciums role in fundamental biological processes
- essential structural component of the skeleton
- important in normal blood clotting
- with Na+ and K+ helps maintain transmembrane potential of cells
- important in excitability of nervous tissue
- important in conctraction of muscles
- important in release of hormones and neurotrasnmitters
54
Hormonal Control of Calcium
- maintenance of plasma Ca is achieved mainly by exchange between bone and plasma under influence of hormones
- hormones also affect intestinal absorption of Ca and excretion of by kidneys
55
3 hormones in particular are importance in Calcium regulation
1. Parathyroid hormone (PTH): protein and is produced by parathyroid glands - increases circulation levels of Ca++
2. Calcitonin: protein and is produced by the parafollicular or "C" cells of the thyroid gland - lowers the circulating levels of Ca++
3. Vitamin D: increases the circulating levels of Ca++
56
Where does Ca goes from the plasma
-some will be deposited in bone or cells of other tissues
0some will go through the kidney and into the urine.
-Stable conc. in blood is achieved mainly by exchange of Ca between bone and plasma under hormonal influence.
57
Parathyroid Hormone
- secreted from parathyroid chief cells embedded in surface of thyroid
- 4 parathyroid glands, located on the backside of thyroid gland
- removal of parathyroid: sever drop in plasma calcium levels causing tetanic convulsions and death
58
Parathyroid Hormone (PTH) structure
- 84 amind acid polypeptide
- Synthesized as part of a larger protein, preproparathyroid hormone, which undergoes proteolytic cleavage to produce PTH
- Very short half-lie - 3-18 min.
59
Functions of PTH
Increase the concentration of plasma Calcium:
1. Bone reabsorption: increases bone demineralization - increases Ca++ in body fluids
2. Kidney: increase the reabsorption of Ca++ in proximal convoluted tubule
3. Vitamin D synthesis: stimulates the conversion of 25 hyrdoxyvitamin D3 to 125 Dihydroxyvitamin D3 primarily in kidney
4. Gut: PTH and 1,25D3, facilitate the absorption of Ca++ from the gut
60
Control of PTH release
controlled directly by the circulation conc. of Ca
61
Mechanism of PTH activity
-binds to cognate receptor on target cells exerts
62
Case of Low Calcium
Ca++ parathyroid glands stimulated --> increase in PTH tp decrease bone reabsorption --> in kidney will decrease urine excretion of Ca
opposite mechanism for when Ca is too high
63
Vitamin D
- available from limited dietary sources
| - can be synthesized from a cholesterol metabolite, so strictly speaking, it is not a vitamon
64
Synthesis of Vitamin D
1. UVB light + 7-dehydrocholesterol in skin
2. 25-hydroxylation in liver followed by..
3. 1-hydroxylation in kidney and several tissues --> 1,25 - dihydroxyvitamin D3
65
Physiological Function
1. Primary function: increase calcium absorption from the intestine
2. also regulates the immune system -> anti-inflammatory
3. Anticancer properties
66
Regulation of Vitamin D synthesis in Kidney
- increased in conditions of low calcium, when PTH is also increased
- depressed by high calcium
67
Rickets
- causes: incapacity to produce the hormonal vitamin D. Lack of the enzyme that converts 25 D to 1-25 D.
- Hair does not get recycled , leaves to balding
68
Calcitonin:
- 32 amino-acid calcium-lowering peptide hormone
- manufactured in parafollicular or "C" cells of the thyroid gland
- lowers plasma Ca by promoting transfer of Ca++ from blood to bone and increasing urinary excretion of Ca++
- rise in plasma Ca++ increases release of Calcitonin
- decrease in plasma Ca conc. decreases the release of calcitonin
69
Adrenal Glands
- located adjacent to upper surface of kidneys
- heavier in the male than female
- two distinct types of tissue- cortex and medulla
70
Cortex
- large lipid containing epithelial cells
- derived from the mesoderm
- produces steroid hormones; glucocorticoids(major one being cortisol in human, corticosterone in rodents) and mineralocorticoids and progestins
71
Medulla
- chromaffin cells-fine brown granules when fixed with potassium bichromate
- derived from neural crest
- produces catecholamines, epinephrine, and norepinephrine and some peptide hormones (enkephalins, dynorphins, and atrialnatriuretic peptides)
72
Adrenal Cortex 3 morphologically and functionally different layers
1. Zona glomerulosa, most mineralocorticoids (aldosterone)
2. Zona fasciculate, produces mainly glucocorticoids (cortisol)
3. Zone reticularis, glucocorticoids, progestins, androgens, and estrogens
73
What controls the synthesis of adrenal steroids
-pituitart hormone adrenocorticotropin (ACTH)
74
Molecular Mechanisms of action of steroid hormones:
- function to regulate (increase or decrease) the transcription of hormone/receptor - specific target genes
* genes regulated vary with each target tissue, and relate specifically to those functions regulated by each steroid hormone and the physiological function of the tissue.
75
Adrenal Roles of Adrenal Hormones: Aldosterone
-Sodium metabolism - increases the reabsorption of Na+ by the kidney
- also affects the plasma conc. of K+ and H+
- loss of K+ and H+ in urine balance reabsorption of Na+
76
Adrenal Roles of Adrenal Hormones: Glucocorticoids
1. Salt Retention
- Some activity but less effective than aldosterone. Can be important under pathological conditions when plasma cortisol remains elevated
2. Effects on proteins and carbohydrate metabolism
- stimulate the synthesis of a number of gluconeogenic enzymes in hepatocytes...
- released amino acids enter liver and are converted to glucose and glycogen.......
- LEADS TO INCREASED BLOOD GLUCOSE LEVELS
3. Lipid metabolism
4. Anti-inflammatory and immunosuppressive actions of glucocorticoids
5. Effects of glucocorticoids on bone:
- decrease the protein matrix of the bone through the protein catabolic effect.
77
Control of glucocorticoid secretion
- controlled by pituitary adrenocorticotropin (ACTH) a 39 amino acid polypeptide, synthesized as part of larger protein known as POMC
- feedback control of cortisol secretion is via hypothalamus and anterior pituitary
78
Congenital Adrenal Hyperplasia
- where enzyme deficiencies where cortisol is not produced, ATCH secretion is unchecked
- treatment: administration of cortisol, which a. corrects the deficiency and b. normalized the ACTH secretion.
79
Mechanism of action of ACTH
- binds to specific ACTH receptor on membrane of zona fasciculata and zona reticularis cells
- stimulation of adenylyl cyclase leading to increased production of cyclic AMP
- activates steroidogenic enzymes leading to increased synthesis and release of steroid hormones
Daily rhythm of plasma cortisol and ACTH:
-diurnal rhythm and ACTH and cortisol secretion - minimum at midnight and maximum at morning
-rhythm may be independent of sleep and abolished by stress and Cushing's disease.
80
Addison's Disease
- hypofunction of the adrenal cortex
- characterized by failure of the adrenal cortex to produce adrenocortical hormones
- may involve total destruction of the gland
-mostly due to atrophy of the adrenal glands due to tuberculosis and involves medulla as well as the cortex
81
Cushing's Disease
- hyperfunction of the adrenal cortex
- characterized by hyperplasia of the adrenal cortex due to increased circulation levels of ACTH
- excessive production of glucocorticoids as well as increased production of mineralocorticoids
82
Pancreas as an endocrine organ
- located behind the stomach
- 99% of pancreas is exocrine and secretes the digestive enzymes
- however, scattered within the exocrine pancreas are small endocrine structures, the islets of Langerhans - compact mass of cells with good vascularization
83
Islets of Langerhans
- about 60% of these cells know as beta cells -synthesize insulin.
- About 25% of the cells are alpha cells - synthesize glucagon
84
Control of Insulin secretion
- most important: beta cells respond to blood glucose levels, secreting little or no insulin when blood glucose is low, secreting more when blood glucose if high.
85
Growth Hormone:
- single chain polypeptide produced by anterior lobe of the pituitary
- responsible for growth
- increases protein synthesis in many tissues such as bone, muscle, kidney, liver by enhancing amino acid uptake by cells and by accelerating the transcription and translation of mRNA
- also increases the rate of liplysis and utilization of free fatty acids as a source of energy. This is a direct effect of GH not mediated by somatomedins
86
Somatomedins
- produced by the liver under stimulation of GH - Somatomedins
- are structurally similar to insulin and are name insulin-like growth factors I and II (IGF-I and IGF-II).
- increase protein synthesis and stimulate growth
87
Control of GH release
Complex feedback mechanism mediated by two hypothalamic neurohormones:
a. growth hormone releasing hormone (GRH) also known as somatoliberin, which stimulates growth hormone release
b. Somatostatin (growth hormone inhibiting hormone) which inhibits growth hormone release.
* GRH and somatostatin tightly regulated by an integrated system of neural, metabolic, and hormonal factors
88
Pathophysiology of growth hormone
GH deficiency: in the young, absence of GH leads to decreased physical growth
Excess of GH: in young, leads to gigantism
Excess of GH in later life: produces the condition of acromegaly, in which many bones, get longer and heavier
89
Two functions of the Gonads
1. Gametogenesis: the production of reproductive cells known as gametes; spermatozoa in male and ova in female
2. Secretion of sex hormones (specific steroids); testosterone (androgen) in the male, and estrogen and progesterone in the female.
90
Effects of estrogen in males
-estrogen in males produced locally in tissues by the conversion by aromatase of testosterone to estrogen estradiol
Estrogen deficiency in males
- leads to increased body fat
- contributes to sexual desire and erectile function
91
Control of Reproductive Function
A similar chain of signals function in males and females
1. Gonadotropin releasing hormone (GnRH), secreted by hypothalamus, travels to anterior pituitary via hypothalmo-pituitary portal vessels,
2. Stimulates the release of pituitary gonadotropins: follicle-stimulating hormone(FSH) and luteinizing hormone (LH).
3. FSH and LH stimulate development of spermatozoa or ova, and secretion of sex steroids.
4. Sex steroids exert effects in gonads in other parts of the reproductive system and the body
92
Male Reproductive System: Function of the testes
- the principal function of testes is production of mature germ cells and steroid hormones.
- the process of spermatogenesis takes place within the coiled seminiferous tubules of the testes
93
Two cell types that are critical for maturation of spermatozoa
1. Laydig cells
| 2. Sertoli cells
94
Laydig cells
- located outside the seminiferous tubules
| - in response to LH, Leydig cells synthesize androgens
95
Sertoli cells
- located within the seminiferous tubules
- they are intimately involved with the sperm maturation process- envelop the germ cells throughout their development
* In response to FSH, these cells synthesize Androgen Binding Protein (ABP) and inhibin
96
Spermatogenesis
- critically dependent on androgen conc. within seminiferous tubules, which must be approximately 10x higher than androgen conc. in circulation otherwise spermatogenesis ceases.
- presence of ABP synthesized by sertoli cells ensures that high androgen conc. within semniferous tubules
97
Testicular Androgen Synthesis regulated by two negative feedback loops
a. Hypothalmic-pituitary-Leydig cell axis: GnRH stimulates release of LH and FSH stimulate Leydig cells and Sertoli cells, Leydig cells produce androgen, which inhibit the release of GnRH, LH and FSH
b. Hypothalmic-pituitary-seminiferoous-tubules axis: non steroidal inhibin secreted by the sertoli cells inhibits FSH release only
98
Female Reproductive System: Ovarian Function
- principal functions: produce mature eggs, and steroid hormones which regulate the reproductive tract and influence sexual behavior
- at birth ovary contains non-proliferating pool of germ cells or oocytes
- oocytes are surrounded by a single layer of granulosa cells and basement membrane making uo the structure called primordial follicles - fundamental reproductive units of the ovary
- growth of the primordial follicles into primary follicles begins by an unknown initiating event. Once intitiated, growth controlled by gonadotropins and steroid hormones until the follicles either ovulate or degenerate (atresia)
99
Follicular growth - development of oocytes suitable for ovulation but also development for new endocrine organ.
1. Initially enlargement and differentiation of the oocyte which grows and elaborates zona pellucida(an acellular layer rich in glycoproteins surrounding the oocyte)
2. Granulosa cells divide and increase to 2 or more layers - primary follicles. Influenced by FSH and estrogens. Estrogens important for expression of LH receptors on granulosa cells.
3. Under influence of FSH and LH, primary follicle develops into a secondary follicle which expresses receptors for FSH, estrogens, and LH. ALso appearance of the follicular antrum which contains secretions from the granulosa cells.
4. Under the combined influence of FSH and LH the granulosa cells elaborate follicular fluid, which takes up the larger portion of the preovulatory follicle (also know as late secondary follicle)
*theca cells produce higher amounts of estrogen.
100
Follicular development leads to one of two events
1. Follicular Atresia
| 2. Ovulation
101
Follicular Atresia
Although many follicles initiate growth and development in each reproductive cycle, in humans usually only one follicle will ovulate in each reproductive cycle - remaining secondary follicles degenerate in a process known as atresia.
102
Ovulation
Mechanism of follicular rupture poorly understood - possible that increase in intrafollicular pressure and proteolysis of ovarian wall of mature Graafian follicle lead to ovulation.
103
Luteinization (after ovulation)
-Ruptured follicle transformed into Corpus Luteum – secretes progesterone.
-Both theca and granulosa cells contribute to formation of the corpus luteum, a temporary endocrine structure within the ovary that synthesizes progesterone and estrogens.
Progesterone and estrogens are produced in large amounts by corpus luteum for few days following ovulation but then drop off unless implantation of the fertilized ovum occurs.
-Upon implantation, corpus luteum transformed into corpus luteum of pregnancy, responsible for synthesis of progesterone and estrogens and creation of proper endocrine environment for maintenance of pregnancy until progesterone and estrogen synthesis by placenta established.
104
Luteolysis
In absence of implantation, life span of corpus luteum limited. Luteal regression may be induced by prostaglandins which decrease LH binding and thus steroidogenesis.
-Decrease of plasma progesterone and estrogen may be trigger for initiation of next reproductive cycle.
105
The menstrual cycle
- Prior to day one, endometrium thickens under influence of estradiol.
- Progesterone induces the appearance of specialized glycogen-secreting glands.
- Day 1 - first day of detectable vaginal bleeding - deterioration of uterine endometrium. -Menses (bleeding) begins when estradiol and progesterone very low in circulation, when the blood vessels supplying endometrium constrict reducing the blood supply. -endometrium deteriorates, flows through the cervix into the vagina.
- Bleeding occurs for ~5 days during which, ovaries are endocrinologically rather inactive.
- Low estradiol and progesterone lead to increased pituitary FSH secretion (lack of –ve feedback loop).
- Also, decrease in non-steroidal ovarian inhibin, which selectively inhibits secretion of FSH, may contribute to elevation in FSH release.
- Under influence of FSH, cohort of ovarian follicles develop. FSH stimulates granulosa cells of follicles to proliferate -> production of estrogen, which further stimulates granulosa cell proliferation.
- Day 8, one follicle becomes dominant and committed to further development. Remaining follicles begin to degenerate by atresia. In humans, how one follicle becomes dominant still unknown.
- Dominant follicle produces increasingly more estradiol, which becomes important in Fig. 5.2 late stages of cycle.
- increasing estradiol stimulates uterine endometrium proliferation.
- By day 13, the endometrium very thick. Estradiol induces production of endometrial progesterone receptors.
106
Estradiol Effects on brain and Pituitary
Moderate estradiol concentrations:
-negative feedback on FSH release
-stimulate synthesis of LH by pituitary and increase sensitivity of pituitary to GnRH -> stimulates LH synthesis. Note, although moderate estradiol concs. stimulate LH synthesis, they inhibit LH release. Therefore, LH accumulates to high levels within pituitary.
High estradiol concentrations.
-Under influence of developing follicle estrogen concs. continue to build.
Elevated estrogen concs. stimulate LH release - LH surge ~day 14 (small increase in FSH release also occurs). -Stimulation of LH synthesis by estradiol and increased sensitivity of the anterior pituitary to GnRH leading to increased LH synthesis by anterior pituitary known as estrogen +ve feedback control mechanism.
Figure. 5.3
-Thus, estrogens exert -ve feedback - decreased GnRH and LH release and +ve feedback - increased sensitivity of anterior pituitary cells to GnRH and increased LH synthesis.
-Meanwhile, at the ovary the follicle has become huge. The sudden surge of LH causes the follicle to rupture (mechanism unclear) and the ovum is ejected.
107
Corpus Luteum
Under the influence of LH the follicle becomes corpus luteum -produces large amounts of
estradiol and progesterone induce endometrial growth of the uterus. In addition, under the influence of progesterone the endometrium becomes glandular. The endometrium is now fully prepared to receive and support the development of a growing embryo.
108
Luteal Phase
No fertilization - egg degenerates, corpus luteum degenerates (luteolysis). Lasts a constant 14
days, known as the luteal phase of cycle since steroids produced by corpus luteum dominate. After 14 days in absence of implantation corpus luteum degenerates, steroid levels drop, uterine endometrium degenerates, menstruation begins and pituitary starts to increase its secretion of FSH, and we are back to the beginning of the cycle.
109
Fertilization and Implantation
- At ovulation, unfertilized egg is taken by the fimbria of the oviduct (or fallopian tube) and is being propelled towards the lumen of the uterus.
- If sexual intercourse takes place around this time, some spermatozoa deposited in the vagina will travel as far as the oviduct and one of these will fertilize the egg.
- Egg starts dividing to the stage of blastocyst during its transport down the oviduct into the uterine lumen
110
After Implantation
Blastocyst differentiates into trophoblast (becomes the placenta) and the inner cell mass (which will form the embryo). Trophoblast invades uterine mucosa -> embedding of developing embryo in endometrium.
Around time of implantation, trophoblast starts to synthesize human chorionic gonadotropin (HCG) which has LH-like properties and stimulates the corpus luteum to continue secreting gonadal steroids.
After about 12th week of pregnancy endocrine function of corpus luteum taken over entirely by placenta, which together with developing fetus forms the fetoplacental unit.
Close functional interdependence between the fetal and maternal compartments, and fetal liver acquires an important function in the synthesis of estriol (an estrogen).
-Placenta also produces human chorionic somatotropin, progesterone, and relaxin
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Lactation
The secretion of milk by the breast (mammary glands) is termed lactation. Normal mammary development required for lactation - under endocrine control.
Mature non-pregnant mammary glands (Ductal)
-With onset of puberty under the action of increasing levels of estrogens, marked enhancement of duct growth and duct branching but relatively little development of the alveoli. -Progesterone stimulates growth of alveoli. -However, most breast enlargement due to fat deposition under the glandular tissue.
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Lactational Amenorrhea
Maintained nursing stimulates prolactin production, which inhibits the secretion of FSH and LH. This blocks the resumption of the reproductive cycle. Actually, nursing used to be a natural method of contraception. However, the intensity and frequency of suckling appears to be an important parameter for the maintenance of the blockade on the reproductive cycle and ovulation. Thus, if suckling is not frequent then ovulation, and pregnancy, may occur.
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Menopause - loss of ovarian steroid production:
- At the end of reproductive period, most ovarian follicles have disappeared by atresia and a few hundred have been ovulated during successive menstrual periods.
- Depletion of follicles results in loss of capacity for steroid (estrogen and progesterone) hormone production by the ovary.
- Lack of estrogens often induces number of symptoms: hot flashes, dry vagina, restlessness, bone loss (osteoporosis - long term), etc.
- Cessation of ovarian steroid hormone production eliminates –ve feedback loop and rise in levels of plasma gonadotropins FSH and LH. The constantly high levels of plasma FSH is most reliable indicator for onset of menopause.
- Symptoms caused by estrogen lack respond readily to estrogen replacement therapy. However, because follicular depletion is primary cause of menopause, fertility cannot be restored by steroid replacement therapy.
