1. Endocrine Disorders Part 2 Lecture 2 PHBC731 Mohamed Zakaria Gad
Prof. of Biochemistry
16 September 2018
Dr. Mohamed Z Gad

2. Learning Objectives
By the end of this session you should be able to:
Describe Disorders of the Adrenal Cortex and Medulla.
Differentiate between hyper- and hypofunction of adrenal cortex.
Understand disorders of male gonadal function and how to examine male infertility.
Describe normal gonadal function in females and common causes of female subfertility.
16 September 2018
Dr. Mohamed Z Gad

3. Disorders of Adrenal Cortex and Medulla
Adrenal gland consists of 2 distinct tissues of different embryological origin. The cortex secretes glucocorticoids, mineralocorticoids and sex hormones, whilst the medulla secretes catecholamines, principally adrenaline.
Among the glucocorticoids, cortisol (hydrocortisone) is the most important in man.
Hormones of the adrenal gland are
essential for survival
16 September 2018
Dr. Mohamed Z Gad

4. Why Adrenal Cortex have many LDL receptors on their surface ?
Cortisol: Action
Glucocorticoids have widespread metabolic effects on carbohydrate, fat and protein metabolism.
In liver, cortisol stimulates gluconeogenesis, amino acid uptake and degradation, and ketogenesis. Lipolysis is increased in adipose tissue. Therefore, they oppose some insulin actions.
In excess, they impair glucose tolerance and alter distribution of adipose tissue. Also cortisol helps maintain extracellular fluids and normal blood pressure.
Cortisone, sometimes used therapeutically, is not secreted in human body in significant amounts. It is biologically inactive until it has been converted in vivo to cortisol.
Study Questions
Why Adrenal Cortex have many LDL receptors on their surface ?
This enables them to take up cholesterol rapidly, from which the adrenal steroids are synthesized
16 September 2018
Dr. Mohamed Z Gad

5. The hypothalamic-Pituitary-Adrenocortical Axis
Cortisol: Regulation & Transport
Cortisol secretion is under control of hypothalamic-Pituitary-Adrenocortical axis.
Three factors regulate adrenocorticotrophic hormone ACTH (and therefore cortisol) secretion:
1. Negative feedback control: ACTH release from anterior pituitary is stimulated by hypothalamic secretion of corticotrophin-releasing hormone (CRH). Increased plasma cortisol or synthetic glucocorticoids suppress secretion of CRH.
2. Stress (e.g. major surgery, emotional stress): leads to a sudden large increase in CRH (and ACTH) secretion.
3. Diurnal rhythm of plasma cortisol: cortisol levels are highest at start of the working day, falling to lowest levels at onset of sleep.
In circulation, glucocorticoids are mainly protein-bound (~90%), chiefly to cortisol-binding globulin (CBG or transcortin) and to albumin. Plasma CBG is increased in pregnancy and with oestrogen treatment. Biologically active fraction of cortisol in plasma is the free (unbound) form,.
The hypothalamic-Pituitary-Adrenocortical Axis
16 September 2018
Dr. Mohamed Z Gad

6. Hyperfunction of Adrenal Cortex: Excess Cortisol
Known as:
Cushing’s Syndrome
After the American neurosurgeon Harvey Cushing
Causes: four classic conditions
Bilateral adrenal hyperplasia (mostly from increased CRH)
Cancer of the adrenal cortex (cortisol secretion is uncontrolled by pituitary)
Neoplasm of the anterior pituitary (overproduction of ACTH)
Ectopic carcinoma elsewhere that produces ACTH (e.g. carcinomas of the lung).
Cushing’s syndrome may also arise from administration of ACTH or glucocorticoids therapeutically.
Tests:
Plasma cortisol
Plasma ACTH
Urinary free cortisol
Dexamethasone suppression test (dexamethasone suppresses the secretion of CRH)
16 September 2018
Dr. Mohamed Z Gad

7. Congenital Adrenal Hyperplasia (CAH)
Pathways of Steroid Metabolism
Severe virilization in a 46 XX female patient with congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency
Inherited deficiency of one of the enzymes involved in cortisol biosynthesis (e.g. 21-hydroxylase enzyme). This may impair synthesis of cortisol & aldosterone. The low cortisol promotes CRH secretion, so that the adrenal gland becomes hyperplasic. Steroids accumulate before the enzyme block step, and are diverted to moderately strong “androgens” with possibility of female pseudohermaphroditism and precocious sexual development in the male. diagnosis can be established by measurement in plasma of 17-hydroxyprogesterone, or other steroids that accumulate before the block.
16 September 2018
Dr. Mohamed Z Gad

8. Hypofunction of Adrenal Cortex: Cortisol Deficiency
Addison's disease is a rare endocrine disorder that affects about 1 in 100,000 people. It is characterized by weight loss, muscle weakness, fatigue, low B.P, and sometimes darkening of skin in both exposed and nonexposed parts of body. Addison's disease occurs when adrenal glands do not produce enough cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
Causes Failure to produce adequate levels of cortisol, due to different reasons, including problems in the adrenal glands themselves (primary adrenal insufficiency), (e.g. destruction of the gland itself by tuberculosis or autoimmune disease) or to inadequate secretion of ACTH by the pituitary gland (secondary adrenal insufficiency).
16 September 2018
Dr. Mohamed Z Gad

9. Aldosterone Aldosterone Excess
Physiological function: conserve Na+, mainly by facilitating Na+ reabsorption & K+ or H+ secretion in distal renal tubule and in other epithelial cells. Aldosterone is a major regulator of water and electrolyte balance, as well as blood pressure.
Regulation of secretion: renin-angiotensin system is the most important system controlling aldosterone secretion. K+ ions and ACTH are also stimulatory.
1. Renin: a proteolytic enzyme produced by kidney and released into circulation in response to a fall in circulating blood volume or by loss of Na+.
2. Potassium: aldosterone is released in response to increase in plasma [K+]
3. ACTH: not important, except in stress & in congenital adrenal hyperplasia.
*No specific aldosterone-binding protein has been demonstrated. Both glucocorticoids and mineralocorticoids are inactivated by hepatic conjugation with glucouronic acid and sulphate.
Aldosterone Excess
Primary hyperaldosteronism (Conn’s syndrome) due to mainly adrenal adenoma and characterized by low plasma [K+] that may lead to muscle weakness and cardiac arrhythmias.
Secondary hyperaldosteronism more common, and is only associated with hypertension. It is due to conditions that stimulate renin secretion (e.g. congestive heart failure, cirrhosis, Na+ deprivation). The commonest cause is diuretic therapy.
16 September 2018
Dr. Mohamed Z Gad

10. Pheochromocytoma is a catecholamine-secreting tumour of adrenal medulla. They secrete excessive amounts of noradrenaline or adrenaline. Biochemical diagnosis depends on measurement of certain urinary metabolites of catecholamines (e.g. metadrenaline) or urinary free catecholamines. Measurement of plasma catecholamines is not widely available.
Signs and symptoms are those of sympathetic nervous system hyperactivity, including elevated heart rate, elevated blood pressure, headaches, weight loss ……
16 September 2018
Dr. Mohamed Z Gad

11. Disorders of Male Gonadal Function
Male Sex Hormones
The male gonads are the testes. they have a double function:
To produce and secrete testosterone
to produce spermatozoa which are essential for fertilization of ovum
Pituitary LH stimulates Leydig cells in the testis to produce testosterone, and FSH stimulates Sertoli cells to provide other testicular cells with nutrients, and also produce several regulatory proteins such as inhibin and androgen-binding protein. Spermatogenesis requires normal functioning of both the Leydig and the Sertoli cells.
Testosterone circulates in plasma mostly bound to plasma proteins, particularly sex-hormone-binding globulin (SHBG).
Normal female plasma also contains a low concentration of testosterone, about half of which comes from ovary and half from peripheral conversion of androstenedione and dehydroepiandrosterone secreted by adrenal cortex.
16 September 2018
Dr. Mohamed Z Gad

12. Plasma Testosterone
Normal Level: ng/dl [males] ng/dl (females)
All circulating testosterone in males is derived from testis; contribution of adrenal cortex is negligible. Hence, measurement of plasma testosterone concentration is a good way of studying hypogonadism and hypergonadism in males.
Increased in: males: testicular carcinoma or abnormalities of pituitary gonadotrophins. Females: in some cases of virilism or hirsutism.
Decreased in: males: diseases affecting testes, pituitary failure, and in certain chromosomal abnormalities involving sex chromosomes.
16 September 2018
Dr. Mohamed Z Gad

13. Testicular feminization syndrome
Disorder of sex differentiation. An X-linked recessive trait. It is associated with an androgen receptor locus on long arm of X chromosome (Xq11-q12).
Patients have XY karyotype typical of MALES, but develop physically and psychosexually as typical females. Development of secondary sex characteristics (e.g., enlargement of breasts) may be unimpaired, but axillary and pubic hair are typically absent. Individuals with TFS are often diagnosed only when they fail to menstruate at puberty.
Persons with TFS are invariably sterile, with a blind vagina, underdeveloped uterus, and sometimes rudimentary testes. Consequently, the TFS allele is not passed on by XY "male" individuals, but by their asymptomatic heterozygous XX sisters.
TFS is probably due to a receptor defect or end organ resistance to androgens
Plasma testosterone is abnormally high.
16 September 2018
Dr. Mohamed Z Gad

14. Investigation of Male Infertility
History and examination
Normal sperm analysis
Abnormal sperm count
No endocrine tests are
required
Measure testosterone,
gonadotrophins,
prolactin
Low Testosterone
High Prolactin
Hyperprolactinaemia
Low testosterone
Low gonadotrophins
Low Gonadotrophins
Hypogonadotrophic
hypogonadism
High gonadotrophins
High Gonadotrophins
Primary testicular failure
16 September 2018
Dr. Mohamed Z Gad

15. 16 September 2018
Dr. Mohamed Z Gad

16. Case Study
Four adult men were investigated for infertility. The doctor recommended semen analysis and confirmatory tests by determining plasma FSH, LH, testosterone concentrations. Results are as follows:
1st patient
2nd patient
3rd patient
4th patient
Normal values
Sperm count
2.0
millions /ml
Zero/ml
1.5
million/ml
millions/ml
FSH
18 U/L
8 U/L
0.1 U/L
1.2 U/L
2-10 U/L LH
19 U/L
7 U/L
0.3 U/L
1.0 U/L
Testosterone
4 nmol/L
14 nmol/L
1 nmol/L
65 nmol/L
9-30 nmol/L
Select the best diagnosis from the following possible conditions:
(a) Normal reproductive function (b) Pituitary failure
(c) Obstruction of sperm flow (d) Testicular feminization syndrome
(e) Primary testicular failure (f) Virilism
Diagnosis
1st patient
3rd patient
2nd patient
4th patient e b c d
16 September 2018
16 September 2018
Dr. Mohamed Z Gad
Dr. Mohamed Z Gad 16

17. Female Sex Hormones The female ovary has a double function:
Production and secretion female sex hormones.
Production and maturation of ova.
One mature ovum is released once every 4-5 weeks by a non-pregnant woman during the years between onset of menstruation and menopause.
Two different types of steroid hormones are secreted by ovary in non-pregnant females, Oestardiol and progesterone. During pregnancy, the same hormones are produced by ovary, but in different proportions. The placenta also makes the hormones that are necessary for maintenance of pregnancy.
16 September 2018
Dr. Mohamed Z Gad

18. Estrogens Oestardiol is responsible for:
Female secondary sex characteristics
Stimulation of follicular growth
Development of endometrium
Concentrations are low before puberty, but rise rapidly and fluctuate cyclically during reproductive life. Oestardiol circulate in plasma bound to sex hormone-binding globulin, similar to testosterone.
progesterone
Formed in corpus luteum, the body that develops from the ruptured ovarian follicle. Progesterone is secreted after ovulation,
Function: stimulates uterus to undergo changes that prepare it for implantation of fertilized ovum, and suppresses ovulation and secretion of pituitary LH.
Normal Gonadal Function
At puberty the ovaries contain between 100,000 and 200,000 primordial follicles. During each menstrual cycle a small number develop but only one reaches maturation, with extrusion of ovum from the ovary (ovulation).
16 September 2018
Dr. Mohamed Z Gad

19. The average man in a lifetime produces more than 109 sperms.
THINK SCIENCE !!
The average man in a lifetime produces more than 109 sperms.
Woman on average produces only 400 eggs in her lifetime !!!
16 September 2018
Dr. Mohamed Z Gad

20. Normal Gonadal Function
Follicular (Preovulatory) Phase:
At beginning of menstrual cycle ovarian follicles are undeveloped and plasma Oestardiol conc. are low. LH & FSH secretion increase due to diminished -ve feedback by estrogens. LH and FSH cause growth of a group of follicles, by about the 7th day of the cycle one follicle becomes sensitive to FSH and matures while the rest atrophy. LH also stimulates Oestardiol secretion, which stimulates the regeneration of endometrium.
Ovulation:
The dominant follicle develops rapidly and plasma Oestardiol concentrations rise. This triggers a surge of LH release from anterior pituitary by +ve feedback. Ovulation occurs ~16 h later.
Luteal (Postovulatory or Secretory) Phase:
High conc. of LH after ovulation stimulates the granulosa cells of the ruptured follicle to luteinize and to form corpus luteum which synthesizes and secretes progesterone and Oestardiol. The subsequent events depend on whether the released ovum is fertilized. If it is not, the corpus luteum regresses and plasma ovarian hormone concentrations fall; the menstrual cycle takes its course with sloughing of endometrium and menstrual bleeding. As the plasma ovarian hormone concentrations fall, the concentrations of LH and FSH in plasma begin to rise and cycle recommences.
16 September 2018
Dr. Mohamed Z Gad

21. Pregnancy & Lactation
If ovum is fertilized, it may implant in endometrium which has been prepared by progesterone during the luteal phase. Function of LH is taken over by human chorionic gonadotrophin (hCG), produced by chorion of developing placenta. Its concentration in plasma and urine rises steadily from the first week after conception for the next weeks. Early presence of hCG in urine became the basis for a pregnancy test. HCG is similar in structure and action to LH.
During pregnancy, plasma estrogens and progesterone conc. continue to rise and endometrial sloughing is prevented. After the first trimester these hormones are produced by placenta.
Prolactin secretion increases progressively after 8th week of pregnancy, probably because of high plasma estrogen concentrations. High plasma estrogen concentrations inhibit milk secretion. Lactation can only start when plasma concentrations of estrogen fall after delivery of placenta. Absence or inhibition of prolactin production stop milk production.
16 September 2018
Dr. Mohamed Z Gad

22. The Menopause
Occurs when all the follicles have atrophied. Plasma concentrations of estrogens fall and those of FSH and LH increase after the removal of negative feedback.
16 September 2018
Dr. Mohamed Z Gad

23. Hirsutism & Virilism Disorders of Gonadal Function
Plasma progesterone, prolactin, FSH, LH, Oestardiol, TSH, free T4 are common tests to investigate these disorders. Plasma testosterone and androstenedione may need to be measured if there is hirsutism or virilization.
Hirsutism & Virilism
Increased plasma free androgen concentrations, or increased tissue sensitivity to androgens, produce effects ranging from increased hair growth (hirsutism) to marked masculinisation (virilism).
Causes
Congenital adrenal hyperplasia, ovarian tumours, adrenocortical disorders, or even obesity (insulin resistance) often in association with polycystic ovarian disease..
16 September 2018
Dr. Mohamed Z Gad

24. Subfertility in Females
Definition of subfertility: failure of a couple to conceive after 1 year of regular, unprotected intercourse.
Endocrine causes of subfertility in women, in ~1/3 of patients, include:
Excessive androgen secretion by the ovaries in response to insulin resistance
Primary ovarian failure. Elevated FSH & LH, low Oestardiol
Hyperprolactinaemia
Polycystic ovarian disease. Elevated LH, normal FSH, cause of insulin resistance
Cushing’s syndrome
Hypogonadotrophic hypogonadism. FSH & LH low, Oestardiol low. Presence of hypothalamic-pituitary lesion.
Investigations are based whether infertility is associated with amenorrhoea or not.
16 September 2018
Dr. Mohamed Z Gad

25. من لا عمل له ..... أوجد له الشيطان عملا
كلمات باقية
من لا عمل له أوجد له الشيطان عملا
خليل مطران
16 September 2018
Dr. Mohamed Z Gad

26. References:
Clinical Biochemistry: An illustrated colour text, A. Gaw et al., Churchill Livingstone.
Clinical Chemistry, W.J. Marshall, Mosby.
Enzyme Tests in Diagnosis, D.W. Moss & S.B. Rosalki, Arnold.
Clinical Chemistry: Interpretation and Techniques, A. Kaplan & L.L. Szabo, Lea & Febiger, Philadelphia.
Fundamentals of Clinical Chemistry, N.W. Tietz, W.B., Saunders Company, Philadelphia, London, Tokyo ….
Clinical Biochemistry, A.F. Smith, G.J. Beckett, S.W. Walker & P.W. H Rae, Blackwell Science Ltd, London…
Interpretation of Diagnostic Tests, I. Wallach, Little, brown & Company, Boston, London …..
Practical Clinical Biochemistry, H. Varley, A.H. Gowenlock & M. Bell, William Heinemann Medical Books LTD, London
16 September 2018
Dr. Mohamed Z Gad