2. LEARNING OBJECTIVES
Identify the type of hormones involve in testicular steroidogenesis and their
origin
Illustrate the pathway of formation of male sex hormones and factors
controlling them
Discuss mode of action of hormone
Explain the pathological consequences due to biosynthetic defects
3. HORMONES
3
◎ hormone is a substance that is synthesized in one organ and transported by
the circulatory system to act on another tissue
◎ hormones can act on adjacent cells (paracrine action) and on the cell in
which they were synthesized (autocrine action) without entering the
systemic circulation
4. 4
GONADAL HORMONES
- Produced by the human gonads: the testis and ovaries
- The primary hormones produced by these organs include:
Androgens: testosterone
Estrogens
progestins
- Part of the hypothalamic –pituitary-gonadal axis
- Regulated by pituitary hormones: FSH and LH (regulated by your GnRH:
hypothalamus)
5. GONADS
◎ Bifunctional – produce:
1. GERM CELLS, AND
2. SEX HORMONES
◎ OVARIES – produce:
1. Ova, and
2. Estrogen and Progesterone
◎ TESTES – produce:
1. Spermatozoa, and
2. Testosterone
6. 6
Paired, ovoid organs serve dual functions
Production of sperm
Production of reproductive steroid hormones
Functional Anatomy of the Male reproductive tract
Testes are located outside the body encased by a muscular sac
Blood flow and contraction of dartos muscle regulate temperature of
testicles to 2 C below core body temperature, which is vital to sperm
production
THE TESTES
7. 7
◎ Sperm develop within the seminiferous
tubules of the testes
◎ The tubules include 2 primary sex cord-
stromal cells
○ Leydig cells – testosterone
○ Sertoli cells- inner lining of the tubules
10. 10
• Spermatic cord can retract testicles into inguinal canal when
injury is threatened
• Composed of 2 anatomic units:
Seminiferous tubules: contain germ and sertoli cells
Interstitium: leydig cells
11. 11
• Physiology of the testicles
• Spermatogenesis
spermatogonia: stem cells that form
sperm
• Undergo mitosis and meiosis; haploid
cells transform to form mature sperm
• Mature sperm has head, body, and tail
so it can swim
20. Steroid Synthesis - Cholesterol to
Precursors)
A. Cholesterol converted to Pregnenolone
1. Stimulated by ACTH release from
anterior pituitary
2. Key enzyme: Cholesterol Desmolase
(Cholesterol Side chain cleavage
enzyme)
B.Pregnenolone converted to Progesterone
1. Pregnenolone is precursor of all steroids
2. Key enzyme: 3-B-Hydroxysteroid
Dehydrogenase
21. Steroid Synthesis - Cholesterol to Precursors
C. Progesterone converted to 17-a-
hydroxyprogesterone
1. Key enzyme: 17-Hydroxylase
2. 17-a-hydroxyprogesterone is precursor
1. Cortisol Synthesis
2. Aldosterone Synthesis
D. 17-a-hydroxyprogesterone converted
to Androstenedione
1. Key enzyme: 3-B-Hydroxysteroid
Dehydrogenase
2. Androstenedione is sex Hormone precursor
1. Estrone
2. Testosterone
3. Estradiol
22. Sex Hormones from Androstenedione
A. Androstenedione converted to Estrone
Key enzyme: Aromatase
B. Androstenedione converted to Testosterone
Key enzyme: 17 B hydroxysteroid
dehydrogenase
1. Testosterone converted to Estradiol
23. HOW IS TESTOSTERONE SYNTHESIZED?
◎ Synthesized by the LEYDIG CELLS
◎ CHOLESTEROL – immediate precursor
◎ RATE LIMITING STEP – delivery of
cholesterol to mitochondria by the
protein StAR (steroidogenic acute
regulatory protein)
◎ Cytochrome P450 side chain cleavage
(P450scc) enzyme - conversion of
CHOLESTEROL to PREGNENOLONE
24. HOW IS TESTOSTERONE SYNTHESIZED?
The conversion of pregnenolone to testosterone requires 5
enzyme activities contained in 3 proteins:
1. 3β-hydroxysteroid dehydrogenase (3β-OHSD) and Δ5,4-isomerase;
2. 17α-hydroxylase and 17,20-lyase;
3. 17β-hydroxysteroid dehydrogenase (17β-OHSD)
25. HOW IS TESTOSTERONE SYNTHESIZED?
2 PATHWAYS:
1. DEHYDROEPIANDROSTERONE PATHWAY
2. PROGESTERONE PATHWAY
31. How is Testosterone metabolized?
1
2
3
4
5
6
7
8
9
1
0
1
9
1
1
1
2
1
3
1
4 1
5
1
6
1
7
1
8
2 pathways:
1. oxidation at 17 position, and
2. reduction of the A ring double bond and the 3
ketone
A
32. How is Testosterone metabolized?
1
2
3
4
5
6
7
8
9
10
19
11
12
13
14
15
16
17
18
◎ First pathway
○ occurs in many tissues (liver)
○ produces less active compounds
33. How is Testosterone metabolized?
1
2
3
4
5
6
7
8
9
10
19
11
12
13
14
15
16
17
18
◎ Second pathway
○ occurs in target tissues
○ less efficient
○ produces the potent metabolite DHT (DIHYDROTESTOSTERONE)
A
34. How is Testosterone metabolized?
◎ Testosterone is as prohormone
◎ It is converted to more potent DHT
A
35. First Pathway Second Pathway
More efficient Less efficient
Produces less potent
metabolite:
17 ketosteroids
Produces potent metabolite:
Dehydrotestosterone (DHT)
Occurs in many tissues like
liver
Occurs in target tissues
37. Dihydrotestosterone (DHT)
◎ The most significant metabolic product of testosterone
◎ Target cells (Highest α reductase activity):
○ Prostate
○ External genitalia
○ Some areas of the skin (genital skin)
38. Dihydrotestosterone (DHT)
◎ Produced ∼400 μg/day
○ compared with 5 mg of testosterone.
○ 50-100 μg – secreted by the testes.
○ The rest – peripherally from testosterone
42. After birth, testes make
only androsterone
(inactive sex hormone)
Ability to produce
testosterone is restored
at puberty and
continues throughout
life
43. REGULATION OF TESTICULAR FUNCTION
Testicular steroidogenesis is
stimulated by lutenizing
hormone and activating adenylyl
cyclase and increasing cAMP
44.
45. Effects of testosterone and other androgens
45
Testosterone and other androgens are responsible for the development of both
primary and secondary male sex characteristics
Stimulates growth of the male reproductive organs
o Enlargement of the penis, testes and scrotum
o Duct and glandular development of the male RS
Stimulates spermatogenesis; without testosterone males become sterile
46. 46
Stimulates the development of secondary sex characteristics
o Androgenic hair (pubic, axillary and facial hairs
o Dermatologic changes :
o skin becomes darker and thicker
o Increase sebum secretion: can lead to acne
o Increase apocrine sweat glands
o Growth of the larynx- deepening of the voice
Musculoskeletal effect:
o Increase bone growth
o Increase muscle mass
o Increase connective tissue
47. Clinical Correlation:
◎ HYPOGONADISM
○ lack of testosterone synthesis
◎ TESTICULAR FEMINIZATION SYNDROME
○ genetically male but lack functional
receptors—feminization of external
genitalia
hormone is a substance that is synthesized in one organ and transported by
the circulatory system to act on another tissue. However, this original
description is too restrictive because hormones can act on adjacent cells
(paracrine action) and on the cell in which they were synthesized
(autocrine action) without entering the systemic circulation
Anatomy of the testis and seminiferous tubules. Note the tubules are created by sertoli cells surrounded by the leydig cells Spermatogenesis takes place within the seminiferous tubules
Spermatogenesis is the process of sperm cell formation, development and maturation
This diagram shows a single seminiferous tubule, and cells in the interstitial tissue outside the tubule. In this connective tissue between the seminiferous tubules there are large cells with eosinophilllic cytoplasm called Leydig cells.
There are also cells called myoid cells surrounding the basement membrane, which are squamous contractile cells, and generate peristaltic waves in the tubules.
All of the gonadal hormones are steroids produced from cholesterol via a series of enzymatic steps
Steroidogenesis process by which some cells can manufacture steroids such as aldosterone, estradiol, testosterone from the parent steroid known as cholesterol. Cholesterol has variety of functions like stabilizing cell membranes over a wide range of temperatures and it is also used in manufacture of bile acids for emulsification of fats… and the most impt function of cholesterol is the conversion of all these steroids shown in this diagram
Yellow – progestagens blue- androgens
Pink – estrogens
Green glucocorticoids
Purple- mineralocorticods: aldosterone red: mitochondrial enzymes green: microsomal enzymes : embedded in the membrane of SER
Side chain cleavage enzyme (also known as cholesterol desmolase) is a cytochrome P450 enzyme encoded by the CYP11A1 gene located at chromosome 15q23-q24. This enzyme converts cholesterol to pregnenolone
Testicular androgens are synthesized in the interstitial tissue by the Leydig cells.
The immediate precursor of the gonadal steroids, as for the adrenal steroids, is cholesterol.
The rate-limiting step, as in the adrenal, is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein
StAR. Once in the proper location, cholesterol is acted upon by the side chain cleavage enzyme P450scc. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis. In the latter two tissues, however, the reaction is promoted by LH rather than ACTH.
The conversion of pregnenolone to testosterone requires the action of five enzyme activities contained in three proteins: (1) 3β-hydroxysteroid dehydrogenase (3β-OHSD) and Δ5,4-isomerase; (2) 17α-hydroxylase and 17,20-lyase; and (3) 17β-hydroxysteroid dehydrogenase (17β-OHSD).
This sequence, referred to as the progesterone (or Δ4) pathway, is shown on the right side of Figure 41–5. Pregnenolone can also be converted to testosterone by the dehydroepiandrosterone (or Δ5) pathway, which is illustrated on the left side of Figure 41–5. The Δ5 route appears to be most used in human testes.
The gonadal hormones particularly the testosterone are lipophilic, so they must be protein bound to travel in the blood. In general, they are bound to SHBG 40%
Testosterone is metabolized by two pathways. One involves oxidation at the 17 position, and the other involves reduction of the A ring double bond and the 3-ketone.
oxidation at 17 position
Metabolism by the second pathway, which is less efficient, occurs primarily in target tissues (Prostate, External genitalia, Some areas of the skin
produces the potent metabolite DHT.
reduction of the A ring double bond and the 3 ketone.
DHT: Dihydrotestosterone
Testosterone can thus be considered a prohormone since it is converted into a much more potent compound (DHT) and since most of this conversion occurs outside the testes.
2 pathways:
oxidation at 17 position, and
reduction of the A ring double bond and the 3 ketone
The most significant metabolic product of testosterone is DHT, since in many tissues, including prostate, external genitalia, and some areas of the skin, this is the active form of the hormone.
The plasma content of DHT in the adult male is about one-tenth that of testosterone, and ∼400 μg of DHT is produced daily as compared with about 5 mg of testosterone. About 50 to 100 μg of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH-dependent 5α-reductase (Figure 41–6).
Some estradiol is formed from the peripheral aromatization of testosterone, particularly in males.
This is the hypothalamic-Pituitary-testicular axis Preoptic neurons in the hypothalamus secretes GnRH GnRH stimulates the anterior pituitary to release LH and FSH LH and FSH stimulate cells in the testes: LH primarily affects the testicular Leydig cells – stimulates the production of testosterone FSH primarily affects the testicular Sertoli cells which stimulates spermatogenesis and synthesizes regulatory peptides (including inhibin) and various growth factors Feedback and regulation of the HPT axis Testosterone inhibits secretion of GNRH, FSH and LH Inhibin selectively inhibits FSH
