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INTRODUCTION:The Endocrine System is a complex network

of glands.Glands act in concert with the nervous

system –linked by the hypothalamus Control & coordinate the myriad chemical

reactions associated with storage, release of energy, growth, maturation, reproduction and behaviour

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INTRODUCTION Cont.Many glands- endocrine, neurocrine,

paracrine and exocrine glands produce secretions.

Endocrine glands-ductless glands that release their secretory products (hormones) directly into the bloodstream for distribution to distant tissues responsive to hormones.

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INTRODUCTION Cont.located in the Hypothalamus, Anterior and

Posterior Pituitary, Pineal, Thyroid, Parathyroid, Adrenal Cortex and Medulla, Heart, Ovary, Testis, Placenta, Pancreas, Gastrointestinal tract and Kidney etc.

discrete e.g thyroid and adrenal or groups of cells within other organs e.g.

cells in the pancreas that produce insulin.

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HORMONESEach gland may produce one or more

hormones; - The Pituitary for instance is known as the master endocrine gland since many of its hormones influence the activity of other glands, including many endocrine glands.

Hormones (derived from the Greek word hormon) are chemical substances secreted by the endocrine glands & conveyed in blood so regulating the function of another tissue or gland.

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Hormones cont.Hormones- vary widely in composition but

can be grouped into three main classes namely,Steroids e.g. cortisol, polypeptides or proteins e.g ACTH and GH and substances derived from amino acids e.g thyroxine and cathecholamines.

Hormones possess a high degree of structural specificity. An alteration in the molecular composition of a hormone may cause significant changes in its physiological activity e.g oestradiol and oestriol.

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HORMONE FUNCTIONHormone functions are complex and diverse and may beregulatory,morphogenetic and integrative.

a)Regulatory Function:- Hormones maintain constancy of chemical composition (homeostasis) of extracellular and intracellular fluids for proper and efficient function and growth of the organisms.

b)Morphogenesis:- hormones function in the control of growth and development of an organism.

c)Intergrative Action:- although each hormone has a specific action, other hormones produced by different endocrine glands may be important for regulating a single function. A hormone can also exert its effect on more than one organ at the same time.

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PRINCIPLES OF HORMONE FUNCTION

Hormones exert their effects on certain organs known as target organs.

These target organs have cells with special receptor molecules on their surfaces.

The appropriate hormone can fit into these receptor molecules and bring about its effects,

-by affecting the cell permeability to certain substances

- promoting protein synthesis or increasing the activities of certain enzymes usually through second or third messenger on cell membranes and cytoplasm for peptide hormones or directly in the nucleus for steroids.

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Hormone function cont.The secretion of these hormones may be -direct e.g insulin secreted from the

pancreatic islet cells or growth hormone secreted from the anterior pituitary gland, influence tissue metabolism directly or

-indirect e.g trophic hormones from the pituitary gland stimulate target endocrine gland to synthesize and secrete further hormones.

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CONTROL OF HORMONE SECRETION1. The anterior pituitary, for instance, like the

hypothalamus occupies a central position in the control of hormone secretion and secretes several trophic hormones that in turn stimulate and maintain other target endocrine organs.

2. In the absence of these trophic hormones, the target glands are unable to maintain a normal rate of secretion and atrophy. The main target organs are the thyroid glands, adrenal cortex and gonads.

3. The body needs small amounts of hormones to bring about their effects. However, endocrine glands may secrete excessive or deficient amounts of hormone.

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4. Abnormalities of target glands may be primary or secondary to dysfunction of the controlling mechanism, usually located in the hypothalamus or the anterior pituitary gland.

5.In abnormalities of secondary nature, the target gland is essentially normal.

6.The secretion of hormones is controlled by tightly regulated mechanisms - negative feedback inhibition, circadian and episodic secretion, and physiological stimuli sometimes through the hypothalamus and higher centres.

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Control of anterior pituitary

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Six different hormones produced by the anterior lobe Three of these have direct effects on the body, the other three control other glands.

                                                                  

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Gonadal Hormones production.LH and FSH from the anterior pituitary

stimulate the gonads (ovaries and testes).LH stimulates the testes to produce several

kinds of steroid hormones called androgens. One of these androgens is testosterone, the main sex hormone in males.

LH stimulates the ovaries produce estrogen and progesterone, the female sex hormones.

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Gonadal hormones cont.Sex hormones are responsible for the

development of secondary sex characteristics, which develop at puberty. Some examples of secondary sex characteristics in males are deepening of the voice (due to a large larynx), growth of facial hair, and muscle development.

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Effect of sex hormones.Some secondary sex characteristics in

females are development of the breasts and broadening of the pelvis. Both sexes show increased activity of sweat glands and sebaceous glands (oil glands in the skin), and growth of pubic and axillary (armpit) hair.

FSH controls gamete (egg or sperm) production.

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Gonadal Steroid Hormones

Gonadal Steroid HormonesAlthough many steroids are produced by the

testes and the ovaries, the two most important are testosterone and estradiol.

These compounds are under tight biosynthetic control, with short and long negative feedback loops that regulate the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary and gonadotropin releasing hormone (GnRH) by the hypothalamus.

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Biosynthesis of sex steroids.The biosynthetic pathway to sex hormones in

male and female gonadal tissue includes the production of the androgens---androstenedione and dehydroepiandrosterone.

Testes and ovaries contain an additional enzyme, a 17B-hydroxysteroid dehydrogenase, that enables androgens to be converted to testosterone.

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In males

In malesLH binds to Leydig cells, stimulating production of the principal Leydig cell hormone, testosterone.

Testosterone is secreted to the plasma and also carried to Sertoli cells by androgen binding protein (ABP). In Sertoli cells the D-4 double bond of testosterone is reduced, producing dihydrotestosterone.

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Low levels of circulating sex hormone reduce feedback inhibition on GnRH synthesis (the long loop), leading to elevated FSH and LH.

Peptide hormones-FSH and LH bind to gonadal tissue and stimulate P450ssc activity, resulting in sex hormone production via cAMP and PKA mediated pathways.

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Testosterone and dihydrotestosterone are carried in the plasma, and delivered to target tissue, by a specific gonadal-steroid binding globulin (GBG).

In a number of target tissues, testosterone can be converted to dihydrotestosterone (DHT). e g androgen-binding protein (ABP), which transports testosterone and DHT from Leydig cells to sites of spermatogenesis.

There, testosterone acts to stimulate protein synthesis and sperm development.

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DHT is the most potent of the male steroid hormones, with an activity that is 10 times that of testosterone. Because of its relatively lower potency, testosterone is sometimes considered to be a prohormone.

Testosterone is also produced by Sertoli cells but in these cells it is regulated by FSH, again acting through a cAMP- and PKA-regulatory pathway.

In addition, FSH stimulates Sertoli cells to

secrete testosterone.

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Synthesis of the male sex hormones in Leydig cells of the testis. P450SSC, 3-DH, and P450c17 are the same enzymes as those needed for adrenal steroid hormone synthesis. 17,20-desmolase is the same as 17,20-lyase of adrenal hormone synthesis

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In femalesLH binds to thecal cells of the ovary, where it

stimulates the synthesis of androstenedione and testosterone by the usual cAMP- and PKA-regulated pathway.

An additional enzyme complex known as aromatase is responsible for the final conversion of the latter 2 molecules into the estrogens.

Aromatase is a complex endoplasmic reticulum enzyme found in the ovary and in numerous other tissues in both males and females.

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In females cont.Its action involves hydroxylations and

dehydrations that culminate in aromatization of the A ring of the androgens.

Aromatase activity is also found in granulosa cells, but in these cells the activity is stimulated by FSH.

Normally, thecal cell androgens produced in response to LH diffuse to granulosa cells, where granulosa cell aromatase converts these androgens to estrogens.

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As granulosa cells mature they develop competent large numbers of LH receptors in the plasma membrane and become increasingly responsive to LH, increasing the quantity of estrogen produced from these cells. Granulosa cell estrogens are largely, if not all, secreted into follicular fluid.

Thecal cell estrogens are secreted largely into the circulation, where they are delivered to target tissue by the same globulin (GBG) used to transport testosterone.

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DISORDERS OF THE ANTERIOR PITUITARY SYNDROMES Associated with primary abnormalities of anterior pituitary hormone secretion

Hormone Excess Deficiency

GH Acromegaly,Gigantism

Short stature

Prolactin Amenorrhoea Infertility Galactorrhoea

Lactation Failure

ACTH Cushing’s Disease Secondary Adrenal Hypofunction

TSH Hyperthyroidism Secondary Hypothyroidism

LH/FSH Precocious Puberty Secondary hypogonadism Infertility.

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DISORDERS OF MALE GONADAL FUNCTIONAltered Hormone Associated clinical disorder

Androgen deficiency

-Primary testicular dysfunction

Testo LH (Hypergonadotrophic hypogonadism)-Dysfunction secondary to pituitary or hypothalamic diseases- Testo LH (hypogonadotrophic hypogonadism)

Infertility

(sertoli cell function dependent on FSH and testosterone)

-1o testicular failure

Testo Inhibin FSH

-Failure of spermatogenesisFSH,Testo – anterior pituitary failure

LH Testo -leydig cell failure

LH Testo-Lesser damage with compensatory increase in LH secretion

Hyperprolactinemia -Pituitary tumour, Klinefelter’s syndrome

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DISORDERS OF FEMALE GONADAL FUNCTION

Presentation

Cause Comment

Amenorrhoea

•Ovarian failure

pituitary Gonadotrophins-

(hypergonadotrophic

hypogonadism)

Pituitary gonadotrophins

(hypogonadotrophic

hypogonadism)

•Hyperprolactinemia

-inhibits GnRH gonadal steroid hormone synthesis

( FSH, LH E2)

Other causes of 20 amenorrhoea-Pregnancy-Menopause-Severe illness-Hyperprolactinemia-Hyperthyroidism-Cushing’s syndrome

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DISORDERS OF FEMALE GONADAL FUNCTION

Presentation Cause Comment

Hirsutism

(Excessive growth of hair in a male distribution)

-Polycystic ovary syndrome

-Congenital adrenal

hyperplasia

Testo, SHBG , Prol.

21– hydroxylase deficiency

DHA, DHAS

Virilism

(excessive androgen secretion )-masculinity

-Ovarian tumours – (secrete androgens – Testosterone

-Adrenocortical disorders

Testo

DHA,DHAS

Menopause

(all the follicles have atrophied)

E2 FSH (LH increases to a lesser extent after removal of negative feedback)

-Identical with 1o gonadal failure

Infertility (may occur despite having a

normal,subnormal or abnormal cycle)

-Ovulatory failure

-Impaired luteal function

Progesterone (on day 21 for a normal menstrual cycle)

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Investigation of Amenorrhoea Clinically, assess pt fully to determine 1o and 2o cause with any severe disease. Distinguish primary from secondary from lab tests. Perform pregnancy test before

investigations. If negative , proceed as follows. Measure plasma FSH,LH,E2 FSH LH E2 is suggestive of ovarian failure (Do chromosone studies) FSH, LH E2 is suggestive of testicular feminization (Measure Test and do

chromosone studies)E2 gonadotrophin suggests hypothalamic or pituitary cause.2) Measure plasma prolactin 3 hrs after waking up.Prol suggests hypothalamic or pituitary cause Repeat to confirm & exclude drugs,3)Perform GnRH test gonadotrophin suggests probable hypothalamic cause perhaps involving only GnRH.

gonadotropin suggests a pituitary lesion4) Do a combined pituitary stimulation test.

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Hirsutism & VirilismAim of test after full clinical assessment is to detect

cases with significant elevation of plasma androgen and identify source as ovary or adrenal cortex.

-Perform Total and free testoterone tests.-DHAS or DHA -17 hydroxyprogesterone – if late onset congenital

adrenal hyperplasia is suspected. (there may be an exaggerated response of 17 -hydroxyprogesterone to tetracosactrin).

-LH and FSHFindings may be supplemented with other

investigations such as ovarian ultrasound.

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Plasma findings and InterpretationTesto DHAS LH FSH 17-OH-Prog

N or slight N or slight N N N Simple hirsutism

N N or N polycystic

ovaries

N N or N or N ovarian tumour

N or slightly N or N or N Adrenocortical

tumour

N or N or Congenital

adrenal hyperplasia

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Investigation of infertility : Female infertility.A woman may be infertile despite having - clinically normal menstrual cycle, amenorrhoea, oligomenorrhoea

Determine occurrence of ovulation and normal luteal development even if cycle seems regular.

If patient is menstruating regularly, measure serum progesterone during luteal phase on day 21 or 22 of cycle.

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Female infertility: Interpretation of results.Normal Progesterone suggests strong

evidence of ovulationLow progesterone – suggests ovulatory

failure or impaired luteal function. (Repeat to confirm).

2) Follicular development and ovulation may be monitored by ovarian ultrasound examination.

3) Histological examination of an endometrial biopsy specimen should indicate whether luteal function is normal.

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Investigation of Male infertility.

Laboratory investigations may detect early hormonal deficiency or distinguish between testicular and pituitary causes.

1) Measure plasma testosterone, LH and FSH concentrations and perform a semen analysis.

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Interpretation of results. LH Testosterone is indicative of leydig

cell failure. LH Testosterone suggests lesser degree

of damage with compensatory increase in LH secretion

LH and Testosterone suggests pituitary or hypothalamic disease

FSH indicates seminiferous tubular failure (irrespective of plasma testoterone concentration)

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Interpretation cont.There is usually oligospermiaOligospermia with FSH suggests pituitary

or hypothalamic disease and patient should be investigated for the condition.

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Interpretation cont. FSH indicates seminiferous tubular failure

(irrespective of plasma testoterone concentration)

There is usually oligospermiaOligospermia with FSH suggests pituitary

or hypothalamic disease and pt should be investigated for the cond

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Management of male infertility Measure plasma prolactinMarked prolactin is suggestive of pituitary

tumour Perform a combined pituitary stimulation test

if clinically indicated.

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Conclusion

• Reproductive endocrinology is very complex but important.

• The understanding depends on a good well furnished clinical laboratory that will produce dependable results.

• Variations in laboratory methods and performances exist depending on the reagents being used.

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