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Reproductive system
    physiology

          By
    Khorrami Ph.D.


          khorrami4@yahoo.com
   http://khorrami1962.spaces.live.com
Testis
• Seminiferous tubules
   – 900*50cm …..450m
   – 80% volume of testis
• Rete testis(anastomosing tubule)
• Efferent ductules
• Epididymis
   –   5m long
   –   Head …immature sperm
   –   Body….sperm maturation
   –   Tail ….sperm maturation
• Vas deferens …. Decapacitation
• Ejaculatory duct
Spermatogenesis needs
•   Sertoli
•   Leydig
•   Germ cells
•   Myoepithelial cells
•   Epithelial cells
Spermatogenesis
•   Mitosis
•   Miosis
•   Spermiogenesis
•   spermiation
Spermatogenesis

• Spermatogenesis: The production of
  spermatozoa in the sertoli cells
• Spermiogenesis: Conversion of the
  spermatids into spermatozoa
• Spermiation: Release of the
  spermatazoon into the lumen
• Capacitation: Final maturation of the
  spermatazoon in the female genital tract
Spermatogenesis
•   Stem cells
•   Mitosis
•   Spermatogonia
•   First spermatocyte
•   First miosis
•   Second spermatocyte
•   Second miosis
•   Spermatid
•   sperm
SPERMATOGENESIS

       SPERMATOGONIA (DIPLOID)



            MITOSIS



                PRIMARY
            SPERMATOCYTES
               (DIPLOID)


       12
SPERMATOGENESIS
             PRIMARY SPERMATOCYTES

            MEIOSIS I



            SECONDARY SPERMATOCYTES
                   (HAPLOID)
             MEIOSIS II

                SPERMATIDS (HAPLOID)
               SPERMIOGENESIS
              SPERMATOZOA (HAPLOID)
       13
FROM SPERMATID TO SPERM




           15
16
SERTOLI CELL
           17
Spermatogenesis
• Inhibited by:
• Toxiphole
• Hypokalemia
Functions of Sertoli cells
• Blood-testis barrier(sertoli-cell barrier) by
  tight junction
  – Adluminal compartment
  – Basal compartment
• Supportive effects on germ cells
• Nutritive effects on germ cells
• Secretions
FUNCTIONS OF SERTOLI CELLS
•    Secrete ANDROGEN BINDING PROTEIN &
     LUMINAL FLUID.
•    Secrete PARACRINE AGENTS Stimulating
     proliferation & differentiation.




                      23
FUNCTIONS OF SERTOLI CELLS
• Secrete the regulatory protein INHIBIN.
• Secrete paracrine agents: FACILITATING
  LEYDIG CELL FUNCTION.
• PHAGOCYTOSIS of defective sperm
• Secrete MULLERIAN INHIBITING
  HORMONE(MIH)




                      24
Secretions of Sertoli cells
•   Mullerian inhibitory factor (MIF)
•   Aromatase
•   Androgen binding protein (ABP)
•   Inhibin
•   Estrone/estradiol
•   DHT
•   GnRH-like peptide
•   Ceruloplasmin
•   Plasminogen activator
•   Follistatin
•   IGF-1
•   TGF
•   Transferrin
•   Cytokines
Functions of leydig cells
• Steroidogenesis …8-18th week of gest.
• LH receptor/PRL(potentiate LH function)
• Testosteron ..5-7mg/day
• Androstenedione
• Relaxin-like factor
• A good marker for fully differentiated adult-
  type Leydig cells
• Weakly expressed in prepubertal
• Immature Leydig cells
    – By insulin-like factor 3 gene
Relaxin-like factor 3(RLF)
• In estrogen-induced cryptorchidism, RLF
  levels in the testis are significantly reduced
• RLF secreted by theca cells of small antral
  follicles
• RLF secreted by the corpus luteum of the
  cycle and pregnancy
Testicular steroidogenesis
MALE REPRODUCTION: HORMONAL REGULATION
                              HYPOTHALAMUS




                                                             - ve feedback
                          GONADOTROPIN RELEASING HORMONE


                             ANTERIOR PITUITARY
 - ve feedback




                             FSH            LH
                 TESTES

                     S
                     E                 LEYDIG CELL
                     R
                     T
                     O               TESTOSTERONE
                     L
                     I                                     REP.TRACT
                     CELL       SPERMATOGENESIS
                                                           & OTHER ORGANS
      INHIBIN                          29
SEMEN ANALYSIS
• A test for infertility
• Semen contain:
  – Sperms
  – Secretions:
     •   Seminal vesicles
     •   Prostate
     •   Cowper’s glands
     •   Bulbo-urethral glands

                           30
SEMEN ANALYSIS
• Volume: 2.5 to 3.5 ml/ejaculate
• Sperm count: 100 M/ml.
• <20% abnormal.
• <20 M/ml, sterile
• Sperm speed: 3mm/min.
• Reach fallopian tube 30- 40 min after coitus.



                        31
SEMEN: COMPOSITION

• Color: white, opalescent
• Specific gravity: 1.028
• Ph : 7.35 – 7.50




                   32
SEMEN
• Liquid when ejaculated
• Coagulates:
  – In vitro
  – In vagina
• Undergoes secondary liquefaction after
  15 min.

                    33
SPERMATOZOA
• Fertile up to 24 to 48 hrs after deposition.
• Motile, for 48 – 60 hrs.`




                         34
Semen production
•   Seminal vesicle (60%)
•   Prostate (30%)
•   Bulbouretral gland (cowper)
•   Seminiferous tubule
Semen composition
•   Fructose (for anaerobic metabolism of sperm )….sem.ves
•   Glucose, A.A. and sorbitol (for aerobic metabolism of sperm ) ….sem.ves
•   Hormones (androgens, estrogens, progesterone)
•   Decapacitation factors (cholesterol/esterol) ….sem.ves
•   Prostoglandins ….sem.ves
•   Citrate
•   Ascorbic acid ….sem.ves
•   Lecithin ….sem.ves
•   Phosphoryl choline ….sem.ves
•   Potassium
•   Acid phosphatase
•   Phosphate
•   HCO3-
•   Acrosin inhibitor
•   Spermine (odor- coagulation) .....prostate
•   Sperm coating proteins.....prostate
•   Fibrinolysin .....prostate
•   Zinc .....prostate
Testosterone & other steroids in
             man
•   Testis     95%
•   Adrenal    5%
•   Total:     5-7mg/day
•   DHT        50-100µg/day
•   17α-OH-progesterone 1-2mg/day
•   Estradiol  10-15µg/day
Testosterone & other steroids
• Castration →increase in LH & FSH
• Castration+ androgen →increase in FSH only
• Role of inhibin
Androgen in plasma
• SHBG         40%
• Albumin      47%
• Other proteins
Metabolism of androgens
•   By urine
•   Excreted as 17KS      50%
•   Gluco & sulphoconjugation in liver
•   ↓
•   Urinary 17-KS
    – Testis     30%
    – Adrenal    70%
FUNCTION OF PENIS IN COITUS
    (SEXUAL INTERCOURSE)

• Erection
• Ejaculation




                50
ERECTION
• VASCULAR:
  – SMALL ARTERIAL DILATATION
  – VENOCONSTRICTION
• PARASYMPATHETIC FACILITATION
• SYMPATHETIC INHIBITION
  – SMOOTH MUSCLES RELAX




                    51
PENILE ERECTION: REFLEX PATHWAYS
                                       INPUT FROM
   THOUGHTS                         MECHANORECEPTORS
   EMOTIONS                              OF PENIS
  SIGHT, SMELL


               NEURONS TO PENIS
            NEURONS RELEASE nonCholinergic
               NEUROTRANSMITTER (NO)

             INHIBITION ON SYMPATHETIC NEURONS



        PENIS
          ARTERIAL DILATATION + VENOCOMPRESSION
                        = ERECTION
                           52
EJACULATION
•   Sympathetic facilitation
•   Skeletal muscles contract
•   Two events:
    1. EMISSION: Smooth muscles contract &
       semen sent into urethra
    2. EXPULSION: Rapid contraction of
       urethral smooth muscles.



                      53
MALE REPRODUCTIVE
    ABNORMALITIES
• CRYPTORCHIDISM (UNDESCENDED
  TESTES)
 – THE DESCENT OF TESTES IS INCOMPLETE IN
   10% OF NEONATES
 – SPONTANEOUS DESCENT OCCURS LATER
 – INCIDENCE: 2% AT INFANCY & 0.3% AFTER
   PUBERTY
 – COMPLICATIONS: INCREASED INCIDENCE OF
   TESTICULAR MALIGNANCIES & INFERTILITY.

                    54
Testosterone /effects
Synthesis of the male sex hormones in Leydig
cells of the testis. P450SSC, 3b-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..
LH & FSH during life of a woman
HL: FSH>LH
Follicles
•   At 20th week …..20mil
•   At birth …………1-2 mil
•   At puberty ……..300-400k
•   During reproductive period..400-500
Uterine cycle
• Proliferative
• Secretory
• Ischemic
• Bleeding
Estrogen in proliferation phase
•   Cell proliferation in endometrium
•   Growth of ER & mitochondria in endometrium
•   Increase glycogen storage
•   Endometrial glands
•   Dilation of arteries and coiled
•   Increase in progesterone receptors
•   Increase sensitivity & contractility of myometrium
Secretory phase
• Secretion of mucus
• Continue to proliferation
• Edema of endometrium
• Decrease contraction of myometrium
Menstrual cycle
Ovarian cycle
•   Follicular phase
•   Preovulatory phase
•   Ovulatory phase
•   Luteal phase
•   Luteolysis phase
Steroidogenesis in ovary
Follicle graaf
• Theca interna is rich in Scc450(desmolase)
• Theca interna cells have LH receptors
• Granulosa cells are rich in aromatase
• Granulosa cells have LH & FSH receptors
Synthesis of the major female sex hormones in the ovary. Synthesis of testosterone and
androstenedione from cholesterol occurs by the same pathways as indicated for
synthesis of the male sex hormones.
Hohlweg effect
• Critical plasma concentration for estrogen
  – 200pg/ml
  – For 36 hrs
  – No response to 100pg/ml
• Increase GnRH receptor on gonadotrops (est &
  PGE2)
• Increase the enzymatic activity of
  gonadotrops(est)
• Increase amplitude & frequency of GnRH(est &
  PGE2)
PGs & follicular rupture
Ovulation
•   Androgen to estrogen microenvironment
•   More FSH receptors
•   Hohlweg effect
•   Less OMI concentration
•   Plasminogen activator
•   Plasmin
•   Fibrinolysin
•   Collagenase
•   Inhibin
•   FSH & LH…..increase in cAMP
•   Prostaglandin F2α( 2-5 hrs before ovulation)
    – Completion of first miosis
    – Contraction of ovarian smooth muscles
• Oxytocin
Ovulation
Luteal phase
•   Progesterone secretion
•   Negative Fern test
•   LH support
•   Maximum activity: 6-8 days after ovulation
Luteolysis
• PGF2α:
  –   Reduction in blood flow of corpus luteum
  –   Increase estrogen secretion
  –   Reduce response of corpus luteum to LH
  –   Increase OT secretion from CL
Menstrual cycle
Capacitation
• Remove of HMW glycoprotein (polylactoseamine) &
  peptides
• Whiplash-like pattern of hyperactivation of sperm
• Removing sterol & cholesterol from the surface
• Rearrangement of surface molecules
• Increase permeability to calcium
• Hyaloronidase activity
• Galactosyl-transferase activity
Acrosome reaction
• Calcium entrance- Ca-cal
• Increase cAMP
• Activation of phospholipaseA2
• Increasing lysophospholipids
• Adhesion
• pH: 5.2 to 7:00
• Segmentation of acrosome
Syngamy
•   After enter the sperm, 2nd polar body
•   After 30 min, disperse of sperm nucleus
•   After 6-8 hrs, pronucleus & syngamy
•   After 27-43 hrs, first division
Origin of testosterone in women
Factors affecting SHBG

Stimulator          Inhibitors
• Estrogen          • Progestins (except OH-
• Hyperthyroidism     prog)
• Ageing            • GH
                    • Glucocorticosteroids
                    • Hypothyroidism
Relation of MCR of steroids & affinity to SHBG
DHEA-S concentration versus age
Distribution of plasma testosterone &
                estadiol
Aromatase activity in
•   Muscle (25-30% in normal conditions)
•   Adipose tissue
•   Skin fibroblasts
•   Hair follicles
•   Brain

• Aromatase has more affinity to androstenedione than
  testosterone
Sources of estrone in women




         Aromatase
Strogens
• Estradiol; 95% by ovary
• Estrone; peripheral conversion
• In normal women: E2/E1 >1
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Reproductive Male Female

  • 1. Reproductive system physiology By Khorrami Ph.D. khorrami4@yahoo.com http://khorrami1962.spaces.live.com
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  • 5. Testis • Seminiferous tubules – 900*50cm …..450m – 80% volume of testis • Rete testis(anastomosing tubule) • Efferent ductules • Epididymis – 5m long – Head …immature sperm – Body….sperm maturation – Tail ….sperm maturation • Vas deferens …. Decapacitation • Ejaculatory duct
  • 6.
  • 7. Spermatogenesis needs • Sertoli • Leydig • Germ cells • Myoepithelial cells • Epithelial cells
  • 8. Spermatogenesis • Mitosis • Miosis • Spermiogenesis • spermiation
  • 9. Spermatogenesis • Spermatogenesis: The production of spermatozoa in the sertoli cells • Spermiogenesis: Conversion of the spermatids into spermatozoa • Spermiation: Release of the spermatazoon into the lumen • Capacitation: Final maturation of the spermatazoon in the female genital tract
  • 10. Spermatogenesis • Stem cells • Mitosis • Spermatogonia • First spermatocyte • First miosis • Second spermatocyte • Second miosis • Spermatid • sperm
  • 11.
  • 12. SPERMATOGENESIS SPERMATOGONIA (DIPLOID) MITOSIS PRIMARY SPERMATOCYTES (DIPLOID) 12
  • 13. SPERMATOGENESIS PRIMARY SPERMATOCYTES MEIOSIS I SECONDARY SPERMATOCYTES (HAPLOID) MEIOSIS II SPERMATIDS (HAPLOID) SPERMIOGENESIS SPERMATOZOA (HAPLOID) 13
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  • 15. FROM SPERMATID TO SPERM 15
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  • 18. Spermatogenesis • Inhibited by: • Toxiphole • Hypokalemia
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  • 22. Functions of Sertoli cells • Blood-testis barrier(sertoli-cell barrier) by tight junction – Adluminal compartment – Basal compartment • Supportive effects on germ cells • Nutritive effects on germ cells • Secretions
  • 23. FUNCTIONS OF SERTOLI CELLS • Secrete ANDROGEN BINDING PROTEIN & LUMINAL FLUID. • Secrete PARACRINE AGENTS Stimulating proliferation & differentiation. 23
  • 24. FUNCTIONS OF SERTOLI CELLS • Secrete the regulatory protein INHIBIN. • Secrete paracrine agents: FACILITATING LEYDIG CELL FUNCTION. • PHAGOCYTOSIS of defective sperm • Secrete MULLERIAN INHIBITING HORMONE(MIH) 24
  • 25. Secretions of Sertoli cells • Mullerian inhibitory factor (MIF) • Aromatase • Androgen binding protein (ABP) • Inhibin • Estrone/estradiol • DHT • GnRH-like peptide • Ceruloplasmin • Plasminogen activator • Follistatin • IGF-1 • TGF • Transferrin • Cytokines
  • 26. Functions of leydig cells • Steroidogenesis …8-18th week of gest. • LH receptor/PRL(potentiate LH function) • Testosteron ..5-7mg/day • Androstenedione • Relaxin-like factor • A good marker for fully differentiated adult- type Leydig cells • Weakly expressed in prepubertal • Immature Leydig cells – By insulin-like factor 3 gene
  • 27. Relaxin-like factor 3(RLF) • In estrogen-induced cryptorchidism, RLF levels in the testis are significantly reduced • RLF secreted by theca cells of small antral follicles • RLF secreted by the corpus luteum of the cycle and pregnancy
  • 29. MALE REPRODUCTION: HORMONAL REGULATION HYPOTHALAMUS - ve feedback GONADOTROPIN RELEASING HORMONE ANTERIOR PITUITARY - ve feedback FSH LH TESTES S E LEYDIG CELL R T O TESTOSTERONE L I REP.TRACT CELL SPERMATOGENESIS & OTHER ORGANS INHIBIN 29
  • 30. SEMEN ANALYSIS • A test for infertility • Semen contain: – Sperms – Secretions: • Seminal vesicles • Prostate • Cowper’s glands • Bulbo-urethral glands 30
  • 31. SEMEN ANALYSIS • Volume: 2.5 to 3.5 ml/ejaculate • Sperm count: 100 M/ml. • <20% abnormal. • <20 M/ml, sterile • Sperm speed: 3mm/min. • Reach fallopian tube 30- 40 min after coitus. 31
  • 32. SEMEN: COMPOSITION • Color: white, opalescent • Specific gravity: 1.028 • Ph : 7.35 – 7.50 32
  • 33. SEMEN • Liquid when ejaculated • Coagulates: – In vitro – In vagina • Undergoes secondary liquefaction after 15 min. 33
  • 34. SPERMATOZOA • Fertile up to 24 to 48 hrs after deposition. • Motile, for 48 – 60 hrs.` 34
  • 35. Semen production • Seminal vesicle (60%) • Prostate (30%) • Bulbouretral gland (cowper) • Seminiferous tubule
  • 36. Semen composition • Fructose (for anaerobic metabolism of sperm )….sem.ves • Glucose, A.A. and sorbitol (for aerobic metabolism of sperm ) ….sem.ves • Hormones (androgens, estrogens, progesterone) • Decapacitation factors (cholesterol/esterol) ….sem.ves • Prostoglandins ….sem.ves • Citrate • Ascorbic acid ….sem.ves • Lecithin ….sem.ves • Phosphoryl choline ….sem.ves • Potassium • Acid phosphatase • Phosphate • HCO3- • Acrosin inhibitor • Spermine (odor- coagulation) .....prostate • Sperm coating proteins.....prostate • Fibrinolysin .....prostate • Zinc .....prostate
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  • 42. Testosterone & other steroids in man • Testis 95% • Adrenal 5% • Total: 5-7mg/day • DHT 50-100Âľg/day • 17Îą-OH-progesterone 1-2mg/day • Estradiol 10-15Âľg/day
  • 43. Testosterone & other steroids • Castration →increase in LH & FSH • Castration+ androgen →increase in FSH only • Role of inhibin
  • 44. Androgen in plasma • SHBG 40% • Albumin 47% • Other proteins
  • 45. Metabolism of androgens • By urine • Excreted as 17KS 50% • Gluco & sulphoconjugation in liver • ↓ • Urinary 17-KS – Testis 30% – Adrenal 70%
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  • 49.
  • 50. FUNCTION OF PENIS IN COITUS (SEXUAL INTERCOURSE) • Erection • Ejaculation 50
  • 51. ERECTION • VASCULAR: – SMALL ARTERIAL DILATATION – VENOCONSTRICTION • PARASYMPATHETIC FACILITATION • SYMPATHETIC INHIBITION – SMOOTH MUSCLES RELAX 51
  • 52. PENILE ERECTION: REFLEX PATHWAYS INPUT FROM THOUGHTS MECHANORECEPTORS EMOTIONS OF PENIS SIGHT, SMELL NEURONS TO PENIS NEURONS RELEASE nonCholinergic NEUROTRANSMITTER (NO) INHIBITION ON SYMPATHETIC NEURONS PENIS ARTERIAL DILATATION + VENOCOMPRESSION = ERECTION 52
  • 53. EJACULATION • Sympathetic facilitation • Skeletal muscles contract • Two events: 1. EMISSION: Smooth muscles contract & semen sent into urethra 2. EXPULSION: Rapid contraction of urethral smooth muscles. 53
  • 54. MALE REPRODUCTIVE ABNORMALITIES • CRYPTORCHIDISM (UNDESCENDED TESTES) – THE DESCENT OF TESTES IS INCOMPLETE IN 10% OF NEONATES – SPONTANEOUS DESCENT OCCURS LATER – INCIDENCE: 2% AT INFANCY & 0.3% AFTER PUBERTY – COMPLICATIONS: INCREASED INCIDENCE OF TESTICULAR MALIGNANCIES & INFERTILITY. 54
  • 55.
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  • 58. Synthesis of the male sex hormones in Leydig cells of the testis. P450SSC, 3b-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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  • 66. LH & FSH during life of a woman
  • 68. Follicles • At 20th week …..20mil • At birth …………1-2 mil • At puberty ……..300-400k • During reproductive period..400-500
  • 69. Uterine cycle • Proliferative • Secretory • Ischemic • Bleeding
  • 70.
  • 71. Estrogen in proliferation phase • Cell proliferation in endometrium • Growth of ER & mitochondria in endometrium • Increase glycogen storage • Endometrial glands • Dilation of arteries and coiled • Increase in progesterone receptors • Increase sensitivity & contractility of myometrium
  • 72. Secretory phase • Secretion of mucus • Continue to proliferation • Edema of endometrium • Decrease contraction of myometrium
  • 73.
  • 75. Ovarian cycle • Follicular phase • Preovulatory phase • Ovulatory phase • Luteal phase • Luteolysis phase
  • 77. Follicle graaf • Theca interna is rich in Scc450(desmolase) • Theca interna cells have LH receptors • Granulosa cells are rich in aromatase • Granulosa cells have LH & FSH receptors
  • 78.
  • 79. Synthesis of the major female sex hormones in the ovary. Synthesis of testosterone and androstenedione from cholesterol occurs by the same pathways as indicated for synthesis of the male sex hormones.
  • 80.
  • 81.
  • 82. Hohlweg effect • Critical plasma concentration for estrogen – 200pg/ml – For 36 hrs – No response to 100pg/ml • Increase GnRH receptor on gonadotrops (est & PGE2) • Increase the enzymatic activity of gonadotrops(est) • Increase amplitude & frequency of GnRH(est & PGE2)
  • 83. PGs & follicular rupture
  • 84.
  • 85.
  • 86. Ovulation • Androgen to estrogen microenvironment • More FSH receptors • Hohlweg effect • Less OMI concentration • Plasminogen activator • Plasmin • Fibrinolysin • Collagenase • Inhibin • FSH & LH…..increase in cAMP • Prostaglandin F2Îą( 2-5 hrs before ovulation) – Completion of first miosis – Contraction of ovarian smooth muscles • Oxytocin
  • 88.
  • 89. Luteal phase • Progesterone secretion • Negative Fern test • LH support • Maximum activity: 6-8 days after ovulation
  • 90. Luteolysis • PGF2Îą: – Reduction in blood flow of corpus luteum – Increase estrogen secretion – Reduce response of corpus luteum to LH – Increase OT secretion from CL
  • 92.
  • 93. Capacitation • Remove of HMW glycoprotein (polylactoseamine) & peptides • Whiplash-like pattern of hyperactivation of sperm • Removing sterol & cholesterol from the surface • Rearrangement of surface molecules • Increase permeability to calcium • Hyaloronidase activity • Galactosyl-transferase activity
  • 94.
  • 95. Acrosome reaction • Calcium entrance- Ca-cal • Increase cAMP • Activation of phospholipaseA2 • Increasing lysophospholipids • Adhesion • pH: 5.2 to 7:00 • Segmentation of acrosome
  • 96.
  • 97.
  • 98.
  • 99. Syngamy • After enter the sperm, 2nd polar body • After 30 min, disperse of sperm nucleus • After 6-8 hrs, pronucleus & syngamy • After 27-43 hrs, first division
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  • 104.
  • 106. Factors affecting SHBG Stimulator Inhibitors • Estrogen • Progestins (except OH- • Hyperthyroidism prog) • Ageing • GH • Glucocorticosteroids • Hypothyroidism
  • 107. Relation of MCR of steroids & affinity to SHBG
  • 109. Distribution of plasma testosterone & estadiol
  • 110. Aromatase activity in • Muscle (25-30% in normal conditions) • Adipose tissue • Skin fibroblasts • Hair follicles • Brain • Aromatase has more affinity to androstenedione than testosterone
  • 111. Sources of estrone in women Aromatase
  • 112. Strogens • Estradiol; 95% by ovary • Estrone; peripheral conversion • In normal women: E2/E1 >1