1 ENDOCRINE SYSTEM

DEFINITIONS HORMONES (ENDOCRINES) are secreted by the cells and glands of the endocrine system into the blood and exert an effect distant from their site of release. Some cells release chemical messengers into the ECF and exert influences on neighbouring cells withouit entering the circulation. This is PARACRINE secretion. AUTOCRINE secretion is the local release of chemical messengers that influence the cells from which they were released. NEUROCRINE secretion is the release of chemical messengers by nerves eg transmitters. CYTOKINES are chemicals that may act locally or at a distance. They are released on demand and are not pre-stored. Eg immune system. 3. (ACTH) ADRENOCORTICOTROPHIC HORMONE Stimulates the adrenal cortex to secrete hormones involved with carbohydrate metabolism. Also controls growth of the cortex. Secretion stimulated by hypothalamic CRH. 4. (FSH) FOLLICLE STIMULATING HORMONE In females stimulates growth and development of ovarian follicles. Also promotes secretion of oestrogen by the ovaries. In males is required for sperm production. Controlled by hypothalamic GnRH (Gonadotrophin Releasing Hormone) 5. LUTEINISING HORMONE (LH) _ In females is responsible for ovulation and development of the corpus luteum that secretes oestrogen and progesterone. In males stimulates testes to secrete testosterone. Also controlled by GnRH. 6. PROLACTIN In females enhances breast development and milk production. In males role uncertain but may induce development of LH receptors. Controlled by Hypothalamic PIH (Dopamine). NEUROHORMONES from the Posterior Pituitary. 1. A.D.H. Controls water balance. 2. OXYTOCIN Stimulates milk secretion and uterine contractions.

ENDOCRINE SYSTEM The Hypothalamus is an important homeostatic control centre. It co-ordinates autonomic functions and controls these functions by exerting influence over the hormones of the pituitary gland. The link between the hypothalamus and pituitary is both neural, to the posterior pituitary (neurohypophysis) and circulatory to the anterior pituitary (adenohypophysis). Negative feedback is an important element of control in the system. FUNCTIONS OF THE HYPOTHALAMUS Control of Body temperature Thirst and urine output Food intake Uterine contractions Milk ejection Co-ordination of autonomic functions Emotion and behaviour Anterior pituitary hormone secretion. PITUITARY GLAND HORMONES 1. GROWTH HORMONE Primary role is the regulation of body growth. Also has an influence on metabolic processes. Growth effects also mediated by somatomedins secreted by the liver. Secretion stimulated by GHRH from the hypothalamus. 2. THYROID-STIMULATING HORMONE stimulates the thyroid gland to secrete its hormones and also controls growth of the gland. Secretion stimulated by TRH from the hypothalamus.

2 HORMONES AND SIGNAL TRANSDUCTION

Depending upon the nature of the hormone, hormones either exert their influence by binding to cell surface receptors eg adrenaline, peptide hormones, or they penetrate the cells of their target organ and exert an influence directly, usually at a nuclear level eg thyroid hormone, steroid hormones. Hormones that bind to extracellular receptors initiate their cellular response by triggering the release of second messengers inside the cells. Receptors may be linked via G-proteins (GTP binding proteins) to membrane bound enzymes that generate the second messenger The second messenger c-AMP is produced when the G protein is linked to adenylate cyclase. The effect of increasing intracellular c-AMP is to activate the phopsphorylating enzyme Protein Kinase A. (Note A for AMP) The second messengers Inositol TriPhosphate (IP3) and Diacylglycerol (DAG) are produced when the G protein is linked to phospholipase C. IP3 stimulates the release of calcium from intracellular stores. The rise in intracellular calcium activates the calcium-binding protein calmodulin. This then activates Protein Kinase C (Note C for calcium). DAG can activate Protein Kinase C directly but its effect is amplified when calcium concentration rises. Receptors may be linked to Tyrosine Kinase which phosphorylates intracellular messenger molecules making them active. Insulin acts in this way. Receptors may be linked by G proteins to ion channels causing an influx of Ca++. Adrenalin works in this way when increasing the force of contraction of the heart. The influx of calcium then activates the molecule calmodulin. G proteins are not always excitatory. In the case of insulin secretion for example glucagons receptors are linked via excitatory G proteins to adenylate cyclase so that the response to glucagons is an increase in intracellular c-AMP and activation of Protein Kinase A. On the other hand hormones that inhibit insulin secretion eg somatostatin have their receptors linked to an inhibitory Gprotein. When this becomes active the

enzyme adenylate cyclase is inhibited and intracellular c-AMP concentration falls. HORMONE ACTION ON TARGET CELLS The hormone must be recognised An intracellular signal must then be generated One or more intracellular processes must be increased or decreased. Hormones that freely enter the cell such as steroids combine with receptors that are large proteins located in the cytoplasm and nucleus. MECHANISM OF CELL-PERMEABLE HORMONES The hormone combines with a nuclear receptor protein The C-terminal of the receptor is different for different hormones The mid portion of the receptor has DNAbinding sites The hormone/receptor complex binds to DNA and either stimulates or inhibits gene transcription. Gene transcription may involve the synthesis of a range of functionally related enzymes. Eg the hormone cortisol stimulates gluconeogenesis by inducing the enzymes necessary for this process. The site on DNA to which the hormone binds (the operator locus) controls the transcription of all the enzymes required for the metabolic pathway.

PANCREATIC ISLET HORMONES PANCREATIC ISLET PEPTIDES 1. Insulin secreted by the cells 2. Glucagon secreted by the cells 3. Somatostatin secreted by the cells
This causes the release of Ca++ from intracellular stores. As [Ca++] is increased insulin secretion is stimulated. Other hormones use cyclic AMP as their second messenger to stimulate insulin secretion eg Glucagon BETA CELL RESPONSE TO GLUCOSE AND HORMONES

4. Pancreatic polypeptide secreted by F cells. ACTIONS: Insulin reduces blood glucose concentration Glucagon increases blood glucose concentration Somatostatin influences gut activity and indirectly reduces blood glucose concentration. Pancreatic polypeptide stimulated by low blood glucose concentration MAY reduce pancreatic enzyme secretion.

Glucose Glucose-6-PO4 Pyruvate ATP

FACTORS STIMULATING SECRETION Plasma glucose concentration. Plasma amino acid concentration.

INSULIN

Duodenal hormones eg G.I.P. (entero-insular axis). Vagus nerve stimulation. 1. psychic effect 2. appetite centre in hypothalamus. ACTION OF GLUCOSE ON BETA CELLS Following a meal when the circulating glucose concentration is elevated, glucose enters the beta cells via a GLUT 2 transporter. Beta cells possess ATP-regulated K channels. In the presence of ATP these channels are closed. When ATP is low the channels are open. The entry of glucose into the cells increases the ATP concentration. This closes the K channels. Closure of the K channels causes membrane depolarisation. Membrane depolarisation opens up voltage gated Ca channels. An influx of Ca stimulates the secretion of the vesicles containing insulin. (Compare this with neurotransmitter release) Acetylcholine and CCK also stimulate insulin secretion. They bind to their cell surface receptors which activates a G protein that results in the production of Inositol Tri Phosphate (IP3).

Closes K ATP channel causing depolarisation Ca++ channels open

K+

Ca++

[Ca++ ]

IP3

CCK & Ach

Insulin released by exocytosis

INSULIN AND MUSCLE CELLS Uptake of glucose is stimulated by insertion of glucose transporters into the membrane (GLUT). Glycogen formation from glucose -6phosphate is stimulated by stimulation of glycogen synthase. Amino acid uptake is also stimulated. INSULIN AND LIVER CELLS Liver cells do not need insulin for the uptake of amino acids and glucose. Stimulation of metabolic enzymes such as glucokinase traps glucose in the cells and maintains the diffusion gradient for glucose entry. INSULIN AND FAT CELLS Insulin stimulates the uptake of glucose, amino acids and fats into adipose tissue (fat cells). Fat is transported in the blood within chylomicrons and VLDLs as triacylglycerols. Absorption of triacylglecerols by fat cells is dependent upon activation of lipoprotein lipase. This is activated by insulin and is found in the endothelial cells of the capillaries that supply adipose tissue. HDL from the liver facilitate uptake of lipids by transferring apoproteins to chylomicrons and VLDLs.

PLASMA INSULIN CONCENTRATION Note that there is a relationship between plasma glucose and plasma insulin Following a meal plasma glucose rises to 110 180 mg%. This is associated with a marked rise in insulin secretion. As glucose is removed from the circulation the concentration drops back to resting 60 100 mg%.(3.3 5.5 mM) Following a long-term fast, plasma glucose falls to 50 70 mg% and insulin secretion drops also. Little or no insulin is secreted if plasma glucose is < 50 mg% (2.8mM). EFFECT OF INSULIN ON CELLS. Binding of insulin to its receptor causes autophosphorylation of the receptor. The receptor hormone complex becomes an active tyrosine kinase which phosphorylates other intracellular proteins and enzymes. Metabolism shifts towards glycogen and pyruvate Glucose transporter (GLUT4) is inserted into the membrane.

GLUCAGON
Function Promotes mobilisation of metabolic fuel especially glucose. Actions Stimulates glycogenolysis in the liver by activation of glycogen phosphorylase. Stimulates gluconeogenesis in the liver from amino acids by activating a number of enzymes eg fructose-1,6-diphosphatase. In adipose tissue, stimulates lipolysis thereby increasing delivery of F.F.A. to liver Secretion stimulated by hypoglycaemia. inhibited by hyperglycaemia and insulin.

Liver uptake of amino acids lowers their plasma concentration but makes them available for gluconeogenesis. The main thrust of glucagons effect is to release stored fuel. Therefore when the balance of metabolic hormones favours glucagons the metabolic process is shifted towards release of fuel rather than storage. INTER-RELATIONSHIP BETWEEN ENDOCRINE AND EXOCRINE FUNCTIONS OF THE PANCREAS Endocrine and exocrine secretions are stimulated by gut nutrients. Islet hormones are secreted into the portal circulation together with the products of nutrient digestion and absorption. Within the liver, islet hormones influence the metabolism of substrates. In peripheral tissues, Islet hormones influence the deposition and/or release of substrates. As Islet hormones pass through the liver before entering the systemic circulation, hepatocytes are exposed to higher concentrations of these hormones than are peripheral cells.

EFFECT OF INSULIN ON FUEL FLOW Tissue uptake of glucose, FFA and amino acids keeps their plasma concentration low. Amino Acids are stored in the form of proteins, carbohydrates as glycogen and fats as triglycerides in adipose tissue. Release of stored fuel is inhibited by insulin. Therefore when the balance of metabolic hormones favours insulin the metabolic process is shifted towards fuel storage rather than fuel useage. EFFECT OF GLUCAGON ON FUEL FLOW Release of glucose, FFA and keto-acids from tissues elevates their plasma concentrations.

ADRENAL CORTEX The physiological role of the adrenal cortex can be determined by considering diseases in which the function of the gland is abnormal. Addisons Disease is an autoimmune disease in which adrenal cortex tissue is destroyed. Symptoms: Inability to maintain blood sugar. Low blood pressure (postural hypotension) Loss of fluid and sodium Hypersensitivity to stress. Cushings Syndrome results from an overproduction of cortisol. Symptoms: Elevated blood glucose Glucosuria Elevated nitrogen excretion. Anatomy 1. Made up of 3 regions, Inner, Middle and Outer. Secretes 2 types of hormone Mineralcorticoids: Major example is aldosterone which is secreted by the cells of the outer region. Role is the control of plasma sodium and potassium concentration. Glucocorticoids: Major example is cortisol which is secreted by cells of the inner region. Cells of the middle region store cholesterol. This is the precursor molecule for all steroid hormones. Biosynthesis of steroid hormones involves hydroxylation reactions. Cells of the outer region do not respond to ACTH. Cortisol Function: Long term control of metabolism Permissive effect on the action of noradrenaline. Control of secretion Glucocorticoid secretion is controlled by the hypothalamus. Stress and circadian signals stimulate the secretion of CRH into the portal circulation linking the hypothalamus to the pituitary. CRH stimulates the secretion of ACTH from the anterior pituitary which acts on the adrenal cortex to release glucocorticoids. As the concentration of glucocoticoids in the plasma rises, negative feedback occurs at both the hypothalamus and pituitary to control the hormone concentration. STRESS CIRCADIAN RHYTHM STIMULATE INHIBIT HYPOTHALAMUS

Corticotropin-releasing Hormone (CRH) ANTERIOR PITUITARY Adreno-Corticotrophic Hormone (ACTH) ADRENAL CORTEX Cortisol Blood Glucose by stimulation of gluconeogenesis and inhibition of glucose uptake Blood Amino Acids by stimulation of protein breakdown Blood Fatty Acids by stimulation of lipolysis
Negative Feedback

2.

Circadian Variation in cortisol secretion is due to the circadian variation in ACTH secretion.

Adrenal Cortex and Stress A fall in blood glucose is not the only stressor that stimulates the hypothalamus to secrete CRH. CRH is secreted and hence cortisol in response to both physical and mental stress. The protective effect of cortisol in these situations is due to the shift from fat and protein storage to carbohydrate storage. Amino acids are made available not only for gluconeogenesis but also for tissue repair. Fat is made available as an alternative energy source thereby sparing carbohydrates. Chronic stress leads to the suppression of the immune response by cortisol. Therefore chronically stressed individuals are prone to infection eg overtraining. Mechanism Of Cortisol Action The liver possesses enzymes for both the anabolism and catabolism of glucose. By providing the liver with substrate for the anabolic pathway, gluconeogenesis is stimulated. Cortisol induces the synthesis of the enzymes necessary for the anabolic pathway. It crosses the cell membrane, enters the nucleus and switches on the genes to transcribe their messenger RNA. This passes to the ribosomes where synthesis of new enzymes occurs. Summary of Cortisol Action Liver
Enzymes A.A. Glucose (2)

Mineral corticoid secretion is controlled by 1) The renin-angiotensin system and 2) The plasma [K+]. Cortisol has four main sites of action. 1. Liver It stimulates gluconeogenesis, ie synthesis of glucose from amino acids. Liver glycogen stores are depleted between meals. Therefore synthesis of new glucose is essential to replenish these stores. 2. Muscle This is the main source of amino acids. Cortisol suppresses protein synthesis and the free amino acids enter the circulation and are taken up by the liver. 3. Tissues Uptake of glucose by tissues is suppressed by cortisol (anti-insulin effect). The brain is not affected. This action ensures that sufficient glucose is present in the circulation to support brain metabolism. 4. Adipose Tissue Cortisol stimulates lipolysis in adipose tissue. This releases fat stores so that circulating FFA increases. This can be utilised by tissues such as the heart. Circulating glycerol also rises which can be converted to glucose by the liver.

Blood
Glucose (3) Amino Acids

Muscle
Enzymes A.A. Protein (1)

(1) (2) (3)

Reduction in protein synthesis Stimulation of gluconeogenesis Reduction in glucose uptake

THYROID HORMONES
The thyroid gland is located immediately below the larynx on either side of and anterior to the trachea. (Refer to a text book for a diagram of this). The thyroid gland secretes 2 hormones. Thyroxine (T4) and Tri-iodothyronine (T3). T4 is the most abundant. However, most of the biological actions of the thyroid hormones is due to T3. T4 is converted to T3 at the target sites. Thyroid hormone secretion is controlled by the hypothalamus. Thyrotrophin releasing hormone (TRH) is released by the hypothalamus into the portal circulation in response to thermal and caloric signals. As the TRH reaches the anterior pituitary it stimulates the secretion of thyroid stimulating hormone (TSH). Negative feedback by T3 on the pituitary and hypothalamus provides the control loop. TSH secretion is under tonic inhibition from the hypothalamus due to somatostatin and dopamine secretion. Stress - Hypothalamus + TRH Anterior Pituitary TSH Thyroid Gland T3 & T4 Cold EFFECT OF TSH TSH is a glycoprotein hormone. It comprises alpha and beta sub-units. The alpha sub unit is common to FSH and LH. Although the thyroidspecific unit is the beta sub-unit, both sub-units have to be present and be recognised by the TSH receptor for TSH to be effective. There are 2 major effects of TSH. One is to stimulate hormone synthesis by the thyroid and the other is to stimulate growth of the thyroid. Growth involves both an increase in cell number as well as cell size. Not surprisingly a range of second messengers are released when TSH binds to its receptor. These include Ca++, c-AMP, IP3 and DAG. SYNTHESIS OF THYROID HORMONES The two hormones synthesised are triiodothyronine T3 and thyroxine T4 which contain iodine. Synthesis occurs on thyroglobulin a glycoprotein synthesised and secreted by follicular cells into the colloid. Iodide is actively pumped from blood then moves passively into colloid. Uptake is TSH sensitive. During passage into the colloid it is oxidised to molecular iodine (I). Tyrosine within the thyroglobulin molecule is iodinated. to yield monoiodotyrosine (MIT). Further iodination yields di-iodotyrosine (DIT). Combination of 2 DIT yields thyroxine (T4), combination of MIT + DIT yields tri-iodothyronine (T3). These molecules remain attached to the thyroglobulin parent structure and are stored in the colloid component of the thyroid follicle. SECRETION OF T3 & T4 Thyroglobulin is taken back into the follicular cells and the thyroid hormones are split off by lysosomal enzymes. T3 & T4 pass into the blood. MIT and DIT are de-iodinated and the iodine is reused. Hormones transported in the blood mainly by thyroxine binding globulin (70-80% of T3 & T4) but also by serum albumen. Production of T3 = 35 g/day, 75% by conversion of T4. Production of T4 = 90 g/day.

Increased oxygen consumption and heat production. Influences on protein, carbohydrate and lipid metabolism. Facilitation of sympathetic activity. Enhancement of growth and central nervous system development.

MODE OF ACTION

T3 & T4 enter cells. T3 binds to intranuclear receptors which influence gene transcription. T4 is converted to T3 before binding. EFFECTS OF THYROID HORMONES

expression of growth hormone, and normal growth & development. Thyroid deficiency in children leads to cretinism. Cardiovascular Effects Heart An important effect of thyroid hormone is to increase cardiac output. This ensures adequate O2 delivery to tissues where metabolism has been stimulated. Rate and Stroke volume are increased. Speed and force of contraction are increased. Rate is increased by T3 as a consequence of upregulation of 1 receptors. Heart rate used clinically as an indicator of either under or over secretion of thyroid hormones. Blood Flow Metabolic products dilate blood vessels and there is O2 utilisation. In the skin dilation helps to dissipate heat. Blood Pressure in heart rate contributes to in cardiac output Therefore blood pressure should increase. However, as many vascular beds are dilated the P.R. is reduced. Therefore B.P.changes little. Systolic pressure may rise by 10 20 mmHg. in P.R. causes fall in diastolic pressure. Overall effect is a rise in pulse pressure. Some Features of Hyperthyroidism Weight loss in spite of good appetite Fatigue Sweating and heat intolerance Palpitations, tachycardia. Cardiac failure Muscle Weakness Prominence of eyes Goitre Agitation & Tremor Diarrhoea Some Features of Hypothyroidism Dry skin and alopecia Puffy face, puffy eyes and oedema Slurred speech and ataxia. Anaemia Goitre Slow pulse rate Constipation

Tissue response correlates with nuclear receptor occupancy. Oxygen consumption is stimulated. Hence basal metabolic rate is determined by the amount of thyroid hormone present. When in excess O2 usage increases and when reduced O2 usage decreases. T3 stimulates Na/K ATP-ase activity. The ADP resulting from this may be the intracellular messenger that stimulates other metabolic events. Many of the effects of thyroid hormone stem from its influence on metabolism. Hence ventilation is increased to supply increased O2 demand, red cell production is increased, thermogenesis triggers heat loss mechanisms eg increased sweating and cutaneous vasodilation. Carbohydrate Metabolism

Two effects 1. glucose absorption in the gut 2. glucose utilisation by cells Cause: Stimulation of enzyme systems by T3 Fat Metabolism in metabolism. This is secondary to carbohydrate metabolism. If carbohydrate fuels are used up quickly then the switch to fat as an alternative occurs earlier. Stimulates biosynthesis of cholesterol, its oxidation and its conversion to bile acids and biliary secretion. Net effect is to reduce the body pool and plasma concentration of cholesterol Protein Metabolism and Growth Both protein synthesis and breakdown are stimulated. Thyroid hormones are essential for full

Deafness and hoarse voice.

CALCIUM CONTROL
Consists of 2 elements 1. Maintenance of day to day calcium balance 2. The response to acute changes in calcium. Three agents are involved. 1. Parathyroid hormone 2. Calcitonin 3. Vitamin D in its active form of 1,25dihydroxy vitamin D3 Three target organs 1. Skeleton 2. Small intestine 3. Kidney PARATHYROID HORMONE 1. 2. Secreted by the 4 parathyroid glands located in the mass of the thyroid gland. Secreted in response to a fall in [Ca++] Causes release of Ca from bone by Fast efflux from the small labile pool of Ca++ Stimulation of osteoclasts that cause the dissolution of hydroxyapatite crystals in bone thereby releasing Ca++ Stimulates increased absorption of Ca++ from the kidney. Stimulates increased excretion of PO42from the kidney. Stimulates the activation of Vitamin D CALCITONIN Secreted by C cells of the thyroid Stimulated by a rise in plasma [Ca++] Decreases Ca flux from bone Inhibits osteoclast activity Stimulates renal excretion of Ca++ Note: Under normal circumstances calcitonin is of little importance in the maintenance of calcium balance. 1,25-DIHYDROXY VITAMIN D3 Vitamin D is produced in the skin on exposure to UV light. The majority of Vitamin D comes from the diet. Conversion of Vitamin D to Vitamin D3 requires 2 hydroxylation steps. One occurs in the liver, the other in the kidneys. The hydroxylation reaction in the kidney is stimulated by parathyroid hormone. + Kidneys Major effect of Vitamin D3 is to increase intestinal absorption of Ca++. Also facilitates the effect of parathyroid hormone on bone. Inhibits excretion of Ca++ by the kidneys. Plasma Ca++ + Parathyroid glands PTH + Bone

Renal Tubular Ca++ reabsorption

Activation of Vitamin D

Mobilisation of Ca++ from bone

+
Intestine Absorption of Ca++ in intestine

Urinary excretion of Ca++

Plasma Ca++

FEMALE SEX HORMONES AND THE MENSTRUAL CYCLE FEMALE SEX HORMONES 1. 2. 3. Follicular Phase Ovulation Luteal Phase

Major hormones are the oestrogen oestradiol

and progesterone. Dehydroepiandrosterone. This is an androgen secreted by the adrenal cortex which causes 1. growth of pubic and axillary hair. 2. growth spurt at puberty. 3. maintenance of sex drive.

The cycle is controlled by 2 gonadotrophic hormones from the pituitary, Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH). The secretion of these hormones is under the control of the hypothalamus through Gonadotrophin Releasing Hormone (GnRH). During the first half of the cycle (follicular phase) oestrogen is secreted by the granulosa cells of the follicle. In the second half of the cycle (luteal phase) the ruptured follicle forms a corpus luteum (yellow body so called because of the yellowish appearance resulting from abundant cholesterol) and secretes progesterone in addition to oestrogen.

Oestrogen and progesterone are central to the monthly cycle of ovum release. Oestrogen also responsible for secondary sexual characteristics eg breast development and stimulation of particular growth areas eg pelvis. Oestrogens also influence calcium and nitrogen metabolism. REFER TO A TEXT BOOK DIAGRAM OF THE CHANGES THAT TAKE PLACE IN THE UTERUS DURING THE MENSTRUAL CYCLE. Ovary and egg development In the foetus the oogonia which are the female germ cells equivalent to the male spermatogonia, divide to give rise to 6 7 x 106 oogonia by the 5th month of gestation. These develop into PRIMARY OOCYTES and develop no further until they are prepared for ovulation. However, before birth each oocyte is surrounded by a single layer of Granulosa Cells thus forming a PRIMARY FOLLICLE. Oocytes that do not form into follicles degenerate. At birth about 2 x 106 primary follicles remain each containing a single primary oocyte capable of producing a single ovum. No new oocytes form after birth. Therefore those in the ovaries provide the reservoir from which all ova arise during the reproductive life of the female. Of the 2 x 106 follicles only about 400 will mature and release their ovum. This is because during the period between birth and puberty developing follicles degenerate and form scar tissue on the ovary, a process known as atresia. OVULATORY CYCLE At puberty there is onset of a cyclical release of an ovum. Classically this cycle lasts 28days but there is variation between individuals. The cycle can be divided into 3 phases.

FOLLICULAR PHASE At the onset of the follicular phase FSH is secreted from the pituitary. This stimulates mitosis in the granulosa cells and formation of a fluid filled antrum. Oestrogen secretion begins. Oestrogen is generated from androgens that are secreted by the thecal cells of the follicle. The androgens pass to the granulosa cells where they undergo conversion to oestrogen. Theca cells are controlled by LH. Granulosa cells are controlled by FSH. Therefore significant oestrogen secretion requires the presence of both LH and FSH. As oestrogen concentration rises it has a number of effects. 1. Within the follicle it contributes to granulosa cell proliferation. 2. In the circulation it acts upon target tissues eg uterus 3. Exerts negative feedback on the pituitary. This reduces the sensitivity of FSH secreting cells to hypothalamic GnRH. Therefore during the latter stages of the follicular phase FSH secretion declines. LH is not affected. Inhibin is secreted by the developing follicle which also exerts negative feedback on FSH secretion. The oestrogen secreted during this phase is responsible for stimulating the endometrium of the uterus. It begins to thicken, its glands enlarge and the arteries supplying the tissue increase in number.

As the oestrogen concentration continues to rise, its feedback effect on the pituitary changes from being negative to being positive. This positive feedback occurs when

Late Follicular Phase and Ovulation

oestrogen concentration is >150pg/ml for > 36 hrs. The effect of this positive feedback is to cause the LH surge. Early Follicular Phase - Hypothalamus GnRH Pituitary - FSH LH Inhibin Follicle + Granulosa Thecal Cells Cells Androgen Oestrogen
OVULATION Ovulation is caused by the LH surge. The surge results from the +ve feedback effect of oestrogen. This stimulates the hypothalamus to secrete GnRH and increases the sensitivity of LH-secreting cells in the pituitary to GnRH. Therefore there is an increase in LH secretion. There is also a surge in FSH secretion but this is less pronounced. The surge causes 4 major changes in the follicle. 1. Inhibits oestrogen synthesis by the follicular cells. 2. Stimulates meiosis in the oocyte. 3. Stimulates local release of prostaglandins that increase blood flow to the follicle. This causes rapid swelling and subsequent rupture. 4. Causes differentiation of follicular cells into luteal cells.

+ Hypothalamus GnRH Pituitary + FSH LH + Inhibin Follicle + Granulosa Thecal Cells Cells Androgen Increased Oestrogen
LUTEAL PHASE Following ovulation the ruptured follicle forms a corpus luteum and secretes both oestrogen and progesterone under the influence of LH. High levels of progesterone inhibit +ve feedback of oestradiol. Progesterone also inhibits follicular development. In the absence of Human Chorionic Gonadotrophin from the placenta, corpus luteum regresses and progesterone secretion declines. In the absence of progesterone the endometrial lining sloughs off = menstruation. Inhibitory effect of progesterone removed and therefore new follicles grow and FSH and LH secretion increases. Cycle starts again. Note that a rise in progesterone stimulates metabolism. This causes a small increase in body temp. Therefore by monitoring body temp it is possible to identify when ovulation has occurred. Early to Mid Luteal Phase - Hypothalamus GnRH

- Pituitary FSH LH

Corpus Luteum

Oestrogen Progesterone Inhibin