2. OUTLINE
1. Mechanisms of Hormone Action and Second Messenger Systems
2. Hormone Types
3. Hypothalamus and Pituitary
4. Pineal Gland
5. Reproductive Hormones
6. Puberty
7. Leptin
8. Pregnancy
9. Menopause
10. Growth
11. Pancreas
12. Thyroid
13. Adrenal gland
14. Calcium homeostasis
3. Mechanisms of Hormone Action and Second Messenger Systems
01
Cell surface receptors
• Hormones may act in an autocrine, paracrine or endocrine manner
• Steroids, IGFs & thyroid → carrier proteins; free hormone → bind to specific receptors →
associated with effects directly on DNA to mRNA
• Peptide hormones & neutrotransmitter 4 main groups:
1. 7 trans membrane domain (LH, FSH, TSH, B-adrenergic)
2. single transmembrane domain growth factor receptors (insulin, IGFs)
3. cytokine receptors (GH, prolactin)
4. guanylyl cyclase-linked receptors
5. G-protein receptor activation represented by a ß-adrenergic
receptor
• There are multiple types of G-protein, which
are heterotrimers made up of an α-, ß-, y-
subunit
• ß-adrenergic activation is thus associated with
↑ in intracellular cyclic adenosine
monophosphate (cAMP)
• The deactivated GDP—a-subunit complex re-
associates with the ß- & y-subunit
6. The guanylyl cyclase-linked receptors can be activated in three ways:
1. They may be activated by nitric oxide (NO) produced by nitric oxide synthase (NOS).
2. iNOS is present predominantly in immune cells but is also found in vascular smooth muscle cells.
3. Guanylyl cyclase is also linked to peptide receptors and the ligand—receptor interaction activates
it directly
7. Nuclear receptors
• has a critical role in development, general
physiology, fertility & disease
• include steroid hormones, thyroid hormones,
retinoic acid & vit.D
• Nuclear receptor activation by ligand G2, which
passes through the cell wall & binds to its
receptor in the cytoplasm before passing into the
nucleus to bind to its response element on
deoxyribonucleic acid. I-ISP, Heat shock protein.
8. Hormone Types
02
Peptide hormones
• initiated by the transcription of DNA into a
specific mRNA.
• Passes from the nucleus into the cytoplasm,
where it binds to ribosomes in the rough
endoplasmic reticulum (RER) and is translated
into the peptide sequence
Synthesis of insulin
9. The synthesis of the
key reproductive
steroids
(highlighted).
Glucocorticoids (stress &
metabolism), aldosterone (fluid
balance) & progesterone
(reproduction) have 21 carbon
atoms; testosterone & other
androgens have 19 carbon atoms,
while oestrogens have 18
10. Steroid hormone synthesis.
• The synthetic pathways are the same in the ovary, testis & adrenal, but the dominant product varies
from tissue to tissue
• The pathway always starts from cholesterol
Steroid hormones
11. Ovary
• The main source of circulating oestrogens,
• During follicular phase of the cycle, the ovary produces oestrogens predominantly
• luteal phase: oestrogen and progesterone
Adrenal
Divided into three zones:
(1) the outer zona glomerulosa (zG)
(2) middle zona fasciculata (zF), which consists of cells full of cholesterol
(3) the inner zona reticularis (zR).
regulated by the control of the renin— angiotensin pathway
Testis
• The Leydig cells of the testis produce testosterone in response to LH → circulates 97% to SHBG
& to a lesser extent, to albumin.
• In other tissue, testosterone has to be converted to DHT by the enzyme 5a-reductase → bind to a
cytoplasmic receptor
12. Fetus lacks sulphatases, 3ßHSD & aromatase, therefore produces DHEAS, which it exports
to the placenta, which possesses these enzymes & produces El, E2 & oestriol E3.
Placenta
Feto-placental oestrogen production
Chol, Cholesterol; Prog, progesterone;Prg, pregnenolone.
13. Steroid binding & metabolism
→ All steroid hormones circulate bound to various proteins; occurs in the liver
In the circulation, all steroid hormones circulate bound to
various proteins (Table 11.1). Steroid hormone metabolism
occurs in the liver
Steroid binding profile
14. Amino acid hormones
• thyroid (tyrosine), catecholamines (tyrosine) & melatonin (tryptophan) are derived
from amino acids, and stored in granules.
• Activities are regulated by their release & by the expression of the enzymes
necessary for their synthesis.
16. Hypothalamus and Pituitary
03
Embryology
Both the thalamus and the
hypothalamus develop in the lateral
walls of the diencephalon, the cavity
that becomes the third ventricle
Embryonic development of the hypothalamus
Moore KL 1993 The developing human—
clinically oriented embryology, 5th edn.
WB Saunders, Philadelphia
17. The development of the pituitary
(C)
The pituitary develops in close association with the
hypothalamus & made up of two parts:
(1) the anterior or adenohypophysis
(2) the posterior or neurohypophysis
Anterior pituitary is formed from the ventral ridges of
the primitive neural tube, which are pushed forward by
the developing Rathke's pouch
18. The pituitary portal system and its connections
The portal system carries all the hypothalamic hormones that regulate the
function of the anterior pituitary
19. Relations of the pituitary.
A small part of the anterior pituitary
immediately opposed to the
neurohypophysis becomes the
intermediate lobe
20. Anatomy
Boundaries
• The thalamus lies superior to the hypothalamus,
separated from it by the hypothalamic sulcus.
• The pituitary lies within the sella turcica; the
cavernous sinus laterally, the clinoid processes
posteriorly of the sphenoid bone & pituitary stalk
superiorly, which merges into the hypothalamus
21. Blood supply
• The hypothalamus, pituitary stalk & the pituitary are supplied by the carotid arteries via the superior & inferior
hypophyseal arteries
• The superior hypophyseal arteries form a primary plexus called the median eminence.
• The plexus forms into the portal vessels where they form a secondary plexus.
• The nerves from the hypothalamic nuclei end close to primary plexus & release regulatory hormones
• The posterior pituitary is supplied by the inferior hypophyseal artery.
22. Structure
• The hypothalamus is made of nuclei arranged
around the third ventricle
• the axons pass to the area of the median
eminence
• The axons of the paraventricular & supraoptic
nuclei pass down the pituitary stalk to the
posterior pituitary.
• Both synthesise and release oxytocin &
vasopressin
Diagrammatic representation of the hypothalamus
& pituitary.
Passmore R, Robson J
(eds). Companion to
medical studies.
23. Hypothalamic Product
Regulation of anterior pituitary function
Hormone Source
Amino
Acids
Role
GnRH Pre-optic area 10
Stimulates LH and FSH release
GHRH Anterior paraventricular
nucleus
41 Stimulates ACTH release
GRH Arcuate nucleus 44 Stimulates GH release
Somatostatin Periventricular area 14 Inhibits GH release
TRH Medial paraventricular
nucleus
3 Stimulates TSH release
Dopamine Arcuate nucleus Inhibits prolactin release
24. Anterior pituitary hormones
Hormone Type
Amino
Acids
Size Role
LH Glycoprotein 204 30,000 Stimulates ovarian hormone synthesis
and oocyte release
FSH Glycoprotein 204 30,000 Stimulates follicle maturation
TSH Glycoprotein 201 28,000
Stimulates thyroid hormone release
ACTH Protein 39 4500 Stimulates cortisol synthesis in the
adrenal
GH Protein 191 21,500 Stimulates hepatic IGF-II synthesis and
release
Prolactin Protein 198 22,000 Stimulates lactation
25. Posterior pituitary hormones
Hormone Source
Amino
Acids
Role
Oxytocin
Lateral and superior
paraventricular and
supraoptic nuclei
9 Stimulates contraction of the
myoepithelial cells of the breast
causing milk let-down, and of the
uterine myocytes in labour
Vasopressin Lateral and superior
paraventricular and
supraoptic nuclei
9 Retains water by altering the
permeability of the collecting ducts
in the kidney; cardiovascular
regulation; enhances CRH-
stimulated
ACTH release
26. Pineal Gland
04
• The pineal gland lies in the roof of the third ventricle at the posterior end & produces
melatonin, with roles in the regulation of the 'body clock' and puberty.
• Pineal gland tumours associated with signs of a space-occupying lesion with deficiency of
hypothalamic hormones or occasionally with precocious puberty.
• With age, the pineal gland calcifies and may be visible on an x-ray of the skull.
27. Reproductive Hormones
05
• The levels of the gonadotrophins vary with age
• Before puberty they are low; ↑ at puberty, in both sexes; with menopause, the levels of both
rise markedly.
• During the follicular phase, FSH and LH stimulate oestrogen synthesis by the developing
follicle.
• During mid cycle: oestogren ↑, leading to a marked positive effect.
• GnRH ↑ : results in an LH & FSH peak → ovulation & initiation of luteinisation of the follicle.
Function
28. Regulation of the hypotalamic –pituitary-gonadalaxis.
Schematic diagram of the hypothalamic-
pituitary-gonadal axis showing neural
systems that regulate GnRH secretion &
feedback of gonadal steroid hormones
at the level of the hypothalamus and
pituitary.
29. Oestrogen & Progesteron
Properties of Oestrogen
Structure Stimulates endometrial growth, maintenance of vessels and skin,
reduces bone resorption, increases bone formation, increases
uterine growth
Protein synthesis
Increases hepatic synthesis of binding proteins
Coagulation Increases circulating levels of factors Il, VII, IX, X, antithrombin Ill
and plasminogen; increases platelet adhesiveness
Lipid Increases HDL and reduces LDL, increases triglycerides, reduces
ketone formation, increases fat deposition
Fluid balance Salt and water retention
Gastrointestinal Reduces bowel motility, increases cholesterol in bile
HDL, High density lipoproteins; LDL, low density lipoproteins.
30. Properties of Progesterone
Structure Enhances endometrial receptivity, maintains myometrial
quiescence, breast development
Respiration Increases respiratory drive
Lipid Reduces HDL and increases LDL
Fluid balance
Promotes sodium exertion
Bowel Reduces bowel motility
Metabolism Increases body temperature
31. Androgens
• In ♀ → androgens are synthesised ovary & adrenal glands
• Remainder is derived directly from the adrenal (25%), or indirectly through peripheral
conversion predominantly of androstenedione (50% from the ovary and 50% from the adrenal)
and of DHEA
• androgens responsible for the maintenance of pubic & axillary hair, & controlling libido.
32. Sex differentiation in utero
• default phenotype: ♀
• ♂ phenotype determined by the sex determining region Y (SRY) → regulated another key transcription
factor SOX9.
• SRY & SOX9 develop into Sertoli cells, become spermatogonia,
• Wolffian & Müllerian systems initially develop in parallel.
• Secretion of AMH → regression of the Müllerian system.
• Sex differentiation occurs with the secretion of testosterone.
• Testosterone promotes the development of the Wolffian ducts into the vas deferens, seminal vesicles
epididymis & external ♂ genitalia.
→ development of the external ♂ genitalia promoted by DHT converted from the testosterone secreted
by the Leydig cells (5a-reductase)
• absence of testosterone → DSDs
33. Puberty
06
Female
Stage I
The prepubertal stage. No development has occurred yet
Stage II
The breast bud begins to grow beneath the nipple
Stage III
The breast is more rounded and begins to resemble the adult breast in
appearance, but is much smaller
Stage IV Greater development has taken place, and the breast is larger than at stage Ill.
In addition, the nipple and areola project forward in front of the contour of the
breast as a secondary mound
Stage V Full adult breast size and form has been achieved
Stages of Breast Growth
34. Stages of Pubic Hair Development
Stage I Prepubertal stage. No terminal hair is visible
Stage Il Terminal hair appears on the vulva and in the midline of the mons
Stage III
The narrow triangular area of the pubis shows darker hair, which is still
sparse in amount
Stage IV A wider triangular area of the pubis is covered, and the density is
greater. The lateral angles of the triangle still have to be filled in
Stage V The adult stage has been achieved
35. Male
Stage I: testis size ↑
Stage II: FSH-induced ↑ in the seminiferous tubules.
Stage III: scrotum reddens, penis’ length ↑, pubic hair starts to appear
Stage IV: penis, testes & scrotum size ↑.
Stage V: testes length 5 cm, scrotum is pigmented & thickened at stage Ill and is
of an adult pattern at stage V
36. Endocrinology of puberty
• Hypothalamus in childhood is sensitive to sex steroid inhibition of GnRH secretion
• In puberty: inhibition reduces → secretion of GnRH & gonadotrophins ↑
• in females, the initial endocrine change → ↑ in the nocturnal pulse frequency of GnRH → FSH
secretion → multi-cystic ovaries & oestrogen secretion.
• In puberty: LH also ↑.
• in late puberty: secretion of gonadotrophins loses its diurnal pattern & the levels remain elevated.
• Of the initial cycles, 90% are anovulatory, with time the number falls (4-5 years after menarche:
<20%)
• ↑ oestrogen → maturation of the female genital tract, breasts, the initial growth spurt followed
• adrenal gland ↑ in puberty, as shown ↑ DHEAS
37. Leptin
07
• Leptin is the 167-amino-acid product of the Ob-gene in white adipocytes.
• mutation of the Ob-gene → obesity & hypogonadotropic infertility.
• Replacement with leptin → weight loss & the restoration of fertility (by ↑ GnRH levels)
• Leptin expression ↑ by insulin, glucocorticoids, noradrenaline & food
38. Menstrual cycle
Follicular maturation form (A) 10 to (B) 20 to the mature 3 0
(C) graafian follicle
Reproduced with permission from Johnston MH 1988 Essential reproduction, 3rd edn.
Blackwell Scientific, Oxford
• At puberty: 300,000 - 600,000 primordial follicles (<25
um)
→ maturation is independent of gonadotrophins until
reaches secondary follicle stage
• Follicle contains steroid-rich, fluid-filled antrum &
rapidly grows to become a pre-ovulatory, or graafian
follicle (2.0 to 2.5 cm).
• Ever cycle ±10 secondary follicles are recruited.
• Following ovulation, granulosa cells luteinise & vessels
from theca invade, the remnant of the follicle becomes
the corpus luteum.
39. Diagrammatic representation of changes in
hormone levels during the menstrual cycle.
• Oestrogen ↑ through the follicular (peak day 12 &14)
• This trigger LH → ovulation.
• Progesterone ↑ towards the end of the follicular phase
• After ovulation, the follicle remnant becomes the corpus
luteum & produces oestrogen & progesterone, relaxin,
inhibin-A and inhibin-B
40. Inhibin & Activin
• Belong to the same family
• During menstrual cycle: activin is undetectable or present at very low levels
• During pregnancy: circulating levels of inhibin-A & activin-A are derived from the feto-placental
unit.
• Activin has been linked with embryo implantation
• ↑ inhibin have been linked with adverse pregnancy outcomes
41. The subunits forming activin & inhibin
• Inhibin is a heterodimer made up of an a and ß subunit.
• There are two ß-subunits, A and B.
• Activin is a homodimer of the ß-subunit, and thus may exist as activin-A, activin-B or activin-AB
42. Pregnancy
08 Levels of hcg during pregnancy
• Placenta: source of circulating oestrogen & progesterone
(8-9 weeks)
• produces several peptides hCG, HPL & all the
hypothalamic-releasing
• hCG rises & peaks at 10 -12 weeks
• HPL is a member of the GH—prolactin family, antagonises
the effect of insulin & promotes lipolysis, ↓ glucose
utilisation & enhances amino acid transfer across the
placenta → ↑ nutrient supply to fetus
• Prolactin ↑ throughout pregnancy → promotes breast
development, regulates fat metabolism
43. Biochemistry of human labour (1)
• During pregnancy: uterus expands, cervix remains firm & closed.
• Throughout pregnancy: 'pro-pregnancy' factors operate to inhibit myometrial contractility & allow
myometrial hypertrophy until, 'pro-labour' factors begin to operate
→ allow cervix to efface, dilate & stimulate the uterus to begin coordinated contractions
• Labour : result of the activation of a 'cassette of contraction-associated proteins'
• Factors that control the activation of 'cassette of contraction-associated proteins' also activate
factors in the fetal membranes → production of prostaglandins & cytokines associated with labour,
factors within the cervix → cervical remodelling &ripening.
44. 4 parturitional phases of pregnancy:
• 1st phase: during 1st & 2nd trimesters, dominated by 'pro-pregnancy factors' & the period
of myometrial growth and quiescence.
• 2nd phase: during the early and midthird trimester, phase of myometrial quiescence
• 3rd phase: phase of labour & has the character of an inflammatory reaction. the 'brake' on
myometrial contractility is released & spontaneous contractility of the uterus is augmented
• 4th phase: state of the intrauterine tissues after the process of labour.
Biochemistry of human labour (2)
45. Pro-pregnancy factors
• Progesterone is the principal
• Has negative regulatory effect upon many of the 'contraction-associated proteins' associated
with connexins & interleukin-8)
• ↓ uterine sensitivity to oxytocin
• inhibition of progesterone (RU486) causes cervical ripening & ↑ myometrial contractility.
• No functional withdrawal of progesterone prior to labour in humans; rather, its 'pro-pregnancy
action is simply overwhelmed by 'pro-labour' factors
