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REPRODUCTIVE SYSTEM PHYSIOLOGY

By
H. Khorrami PhD.

http://khorrami1962.spaces.live.com
khorrami4@yahoo.com
http://www.scribd.com/khorrami4
REPRODUCTIVE ENDOCRINOLOGY
Ò  Chromosome & genetic determinants, related abnormalities & syndromes.
Ò  Enzymes that influence steroidogenesis.
Ò  Brain, male type & female-type brain. sex and gender
Ò  Puberty; theories & mechanisms involved
Ò  Male reproductive organ, testis, spermatogenesis
Ò  Female reproductive organ.
Ò  Menstrual cycle; Ovulation, premenstrual syndrome ,follicle, hirsutism
Ò  Fertilization; theories, decapacitation and capacitation.
Ò  Placenta; hormonal action
Ò  Physiologic changes during pregnancy
Ò  Physiologic changes during pregnancy, endocrine disorders during pregnancy
Ò  Parturition; pain, endocrinology of parturition
Ò  Lactation; physiological functions of prolactin
Ò  Menopause/ andropause
Ò  Steroid hormones
Ò  Growth factors
Ò  Physiological actions of prostaglandins, pathological & their therapeutically usage
Ò  Stem cell, cloning & related articles
SEXUAL REPRODUCTION

Ò  Since 1 billion years ago


Ò  Most important factor in development of life
STAGES IN SEXUAL DEVELOPMENT

Ò  Genetic

Ò  Gonadal sex


Ò  Phenotypic sex

Ò  Neuronal sex

Ò  Gender identity

É  What is going on.. This or that is happening?


CYTOGENETIC TECHNIQUES
Ò  Q-bands: identification of Y & 21, 22
É  Quinacrine hcl
É  UV

Ò  G-bands: identification of all chromosomes


É  Giemsa
É  Based on bands in homologous chromosomes
Ò  C-bands: reflect constitutive heterochromatin
É  Repetitive DNA without specified message
É  Alkaline denaturation
É  Interstitial location in Y
É  Determine the origin of fault
SEXUAL DIFFERENTIATION

Ò  Gonadal differentiation


Ò  Internal organ diff.

Ò  External organ diff.

Ò  Brain diff.

Ò  Puberty
CHROMOSOMAL FAULTS

Ò  Mosaicism (often in a single gene)


Ò  Chimerism
É  Eyecolor
É  Hermaphrodism
GONADAL DIFERENTIATION

Ò  SRY gene


Ò  SRY gene expression (in all sertoli cells)
CHRONOLOGY OF SEX ORGANS
Autosomal gene Sox9
Ch;17 for sertoli cell
differentiation
SRY

Ò  Gender verification in Olympic (1992-2000)


Ò  Makes a protein that controls Dopamine
É  Schizophrenia

É  Parkinson’s disease


SOX9 GENE

Ò  Chondrocyte differentiation


É  Def:
Campomelic dysplasia with sex reversal in
males
Ò  Regulate transcription of AMH gene
Ò  Steroidogenic factor 1(SF1)
É  Nuclear receptor family
É  Regulates transcription of key genes in H-P-G axis,
adrenal and gonads
GENITAL DIFFERENTIATION
JOST(1953-1973)ON RABBIT
Ò  Castrated fetuses at different stages then continue the
pregnancy
É  Castration of male
Ð  Int. & ext. genitalia → female

Ò  Castration of female


É  No appreciable effect/ normal female genitalia

Ø  Presence of ovary is not essential for development of fallopian


tube & uterus
Ø  Female is default sex in human
GENITAL DIFFERENTIATION
JOST(1953-1973)ON RABBIT
Ò  Castrated fetuses at different stages then continue the
pregnancy
É  Castration of male + testosterone
Ð  fian duct development
Ð  Failed to regression of muller

Ò  Josso(1974)→ sertoli cells→ a macromolecule→ MIH


SEXUAL DEVELOPMENT
GENITAL DEVELOPMENT

Ò  Mesonephric duct(Wolfian Ò  Paramesonephric


duct) duct(Mullerian duct)
É  Vasa deferent É  Fallopian tube
É  Seminal vesicle É  Uterus
É  Epididymis É  Upper portion of vagina

Ò  Urogenital sinus Ò  Urogenital sinus


É  Prostate É  Lower vagina
É  Cowper’s gland É  Bartholien glands
SEX DIFFERENTIATION
SEXUAL DEVELOPMENT
SEXUAL DEVELOPMENT
TRUE HERMAPHRODISM

Ò  XX karyotype
TESTICULAR FEMINIZATION
Ò  X-linked recessive
Ò  End pouch vagina
Ò  Testes
Ò  No internal female organ
Ò  Breast development
Ò  Paucity of pubic hair
ABNORMAL DEVELOPMENT OF REPRODUCTIVE SYSTEM
PATHWAYS OF STEROID HORMONE BIOSYNTHESIS
ESTRONE

Estradiol
ADRENAL/GONADAL ANDROGENS
STEROID ACTIVITY
STEROIDOGENESIS IN ADRENAL

DHT androstenediol
5-αreductase
ANDROGEN PRODUCTION

Ò  5α-reductase in:


É  prostate

É  Scrotum

É  Penis

É  Liver

É  Hair follicles


É  Skin

É  Glial cells


DHT

Ò  5-α reductase


Ò  Finasteride (5-α reductase inhibitor)
É  for hair growth
É  To treat Benign prostate hyperplasia, but may cause
prostate cancer(by masking the symptoms)
É  Male breast cancer
ADRENOGENITAL SYNDROME

Ò  21β-hydroxylase deficiency


Ò  Enlarged phalus
Ò  Fused labioscrotal folds

Ò  Hi MSH

Ò  Tan skin


METABOLISM OF STEROIDS:
Synthesis of the various adrenal steroid hormones from cholesterol. Only the terminal hormone structures are included.
3b-DH is 3b-dehydrogenase, P450c11 is 11b-hydroxylase, P450c17 is 17a-hydroxylase, P450c21 is 21b-hydroxylase.
Abbreviations: CYP11A1, cholesterolmside-chain cleavage enzyme; desmolase; CYP17, 17a-
hydroxylase/17,20-lyase; 3b-HSD, 3b-hydroxysteroid dehydrogenase; CYP21A2, 21-hydroxylase;
CYP11B1, 11b-hydroxylase; CYP11B2, aldosterone synthase, corticosterone 18-methylcorticosterone
oxidase/lyase.
18-11-15

BARON-COHEN THEORY
Ò  Based on brain potential
É  Empathy
É  Systemize
Ò  From Simon Baron-Cohen

58
SYSTEMIZING

Ò  Analyze

Ò  Understand

Ò  Predict

Ò  Control

Ò  Construct rule-based systems


EMPATHIZING

Ò  Identify
another person’s emotions & thoughts
Ò  Respond with an appropriate emotion
AUTISM

Ò  Lack of joint attention at 14 months


Ò  Lack of pretend play at 24 months

Ò  Impaired knowing test at 3yr

Ò  Problem in understanding deception

Ò  Savant Syndrome


AUTISM CAUSING MEDICATIONS

Ò  Antidepressants (2015)

Ò  Androgens

Ò  ….
MECHANISMS IN BRAIN DIFFERENTIATION

Ò  Altering neuronal genomic expression


Ò  Regional cell growth

Ò  Proliferation

Ò  Death, cell number, size, or packing density

Ò  Early migrational patterns

Ò  Dendritic growth

Ò  Neuronal myelination


BRAIN TYPES
Ò  Sexually dimorphic nucleus of medial preoptic area
(SDN-POA) male>2.5female
Ò  Preoptic-anterior hypothalamic area
Ò  Men: higher proportion of gray matter to cranial volume
Ò  Women: higher proportion of white matter
Ò  Women: larger corpus callosum
Ò  No sex differences in general IQ
Ò  Men typically excel in spacial & quantitative abilities
Ò  Women: on tasks involving verbal abilities, perceptual
speed and accuracy, and fine motor skills
Ò  Men: more specialized skill
Ò  Women: never backbite & life-time store secrets!
LEFT BRAIN (MOSTLY) RIGHT BRAIN(MOSTLY)

Ò  Uses logic detail oriented Ò  Uses feeling "big picture“
facts rule oriented imagination rules
Ò  Academic Ò  Artistic & creative
Ò  words and language Ò  Symbols and images
Ò  Present and future
Ò  present and past
Ò  Philosophy & religion
Ò  math and science
Ò  Meaning, believes, appreciates
Ò  knows object name
Ò  Spatial perception
Ò  Knows object function

HEMISPHERES
ALPHA-FETO-PROTEIN
Ò  Isa globulin
Ò  Produced by
É  Fetal liver
É  Yalk sac

Ò  Startsat 4th week


Ò  Max secretion at 24th week
Ò  Absent after 24th week
Ò  Regulate steroid hormones
ESTROGEN ON BRAIN

Ò  Timing

Ò  AFP

Ò  SHBG
BRAIN DIFFERENCES
BRAIN TYPES
Ò  Maletype brain
Ò  Homosexuality
É  Fraternal birth order effect
Ð  Blanchard and Bogaert(1996):

Ò  Maternal immune hypothesis


NEUROSTEROIDS

Ò  Sexual behavior


Ò  Developmental enhancing effect

Ò  Memory enhancing effect

Ò  Pregnancy

Ò  Stress
PROGESTERONE & NEUROSTEROIDS

Ò  Schwann cells secrete progesterone, important


in myelination
Ò  Progesterone stimulate myelin protein synthesis

Ò  Convert to 5α-OH prog. by 5α-reductase

Ò  Then to 3α,5β-OH-prog. by 3α-OHS-


oxidoreductase in glial cells,
É  Act on GABA & NMDA receptor(potentiate)
AROMATASE & BREAST CANCER

1 Schematic of metabolic pathways in an ER-positive cell that can be affected by AIs. The left side represents the active
pathways and cellular responses under normal estrogen control. The right side depicts the blockade of pathways involving
ERs and the resultant cellular responses. AI, aromatase inhibitor; E2, estradiol; ER, estrogen receptor; MAP, mitogen-
activated protein; PI-3, phosphoinositide-3; RTK, receptor tyrosine kinase; SERD, selective estrogen receptor down-
regulator; SERM, selective estrogen receptor modulator
THESE FACTORS ARE ESSENTIAL FOR:

TDF & SOX9 Testosterone DHT MIH Estradiol


Wolf Seminiferous External Muller Male type brain
tubule genitalia regression
Testicular Seminal vesicle Testicular Libido
differentiation descending

Ejaculatory duct prostate Bone fusion


GONADOTROPIN SECRETION

Ò  Testis activity: at 7th week


Ò  Ovary activity: at 14th week

Ò  Portal system is intact at 11.5th week

Ò  Functional fetal LRH at the end of first trimester

Ò  Axon fibers of LRH in ME at 16th week


GONADOTROPIN SECRETION
Ò  FSH & LH are detectable at 10th week
Ò  Increase sharply until 25-29th week
Ò  Then decline(increase H-P sensitivity)
Ò  At birth: hi level of hCG and estrogen(breast budding)
É  Low level of gonadotropins
Ò  After a week: decline of hCG and estrogen
É  Rising of gonadotropins
Ò  In boys: More response of LH to GnRH
É  start to decline before 4th month
Ò  In girls: More response of FSH to GnRH
É  start to decline before 4th year
PUBERTY

Ò  Factorsaffecting
Ò  Mechanisms involved

Ò  Gene or chromosome?

Ò  Stages
FACTORS AFFECTING PUBERTY

Ò  Genetic

Ò  Geographic

Ò  Socioeconomic

Ò  Inheritance

Ò  Altitude

Ò  Lifestyle(activity)
Ò  Nutrition
GONADOTROPIN SECRETION PATTERN

Ò  Tonic

Ò  Cyclic
CONTROL OF HT ON GONADOTROPIN SECRETION

Ò  Maturation of sex steroid receptors in LRH


neurons
Ò  Maturation of sex hormone-independent
inhibitory pathways
CYCLIC SECRETION OF GONADOTROPINS

Ò  In men: LH: every 90-120min


É  1µg/min for 6min every hr
Ò  Mid and late luteal phase: every 3-4 hrs
GONADOTROPINS
Ò  Stimulator Ò  Inhibitor
(on GnRH pulse) (on GnRH pulse)
Ò  Adrenalin Ò  Histamine
Ò  Noradrenalin Ò  Bradykinin

Ò  Dopamine Ò  5-HT

Ò  Estrogen Ò  Opioids

Ò  PGs Ò  Endorphin

Ò  Enkephalin

Ò  Progesterone

Ò  Melatonin
PUBERTY GENE

Ò  GPR54 defect


Ò  In Saudi family

Ò  Hypogonadotrophic hypogonadism

Ò  Puberty delay

Ò  Sexual infantilism

Ò  Low GnRH but responsible pituitary to


exogenous GnRH
PUBERTY GENE
Ò  GPR54
Ò  On chromosome 19
Ò  Encodes a G protein–coupled receptor
Ò  A member of rhodopsin family of G-pr coupled
receptor
Ò  This receptor is essential for normal GnRH
physiology and for puberty.
Ò  Metastin(kisspeptin-1) is an agonist on the same
receptor
É  Secreted by placenta
Ð  Normal delivery
É  Defect in X-linked kallmann’s syndrome
GONADOTROPIN REGULATION

Ò  Sex hormone dependent


É  In MBH & arcuate nucleus
Ò  Sex hormone independent
PUBERTY STAGES

Ò  Adrenarche (prepubertal)


É  2year before second event
É  SHBG increase in both sexes

Ò  Gonadarche
É  SHBG decrease more in boys
SHBG

Ò  Stimulator: Ò  Inhibitor:


Ò  Estrogen Ò  GH (Acromegaly)

Ò  Thyroid hormones Ò  Glucocorticoids (Cushing)

Ò  In old ages Ò  Androgens

Ò  Obesity Ò  Progestin


É  Estrogen ↑
É  Androgen ↓
NEGATIVE FEEDBACK
SLEEP-INDUCED LH PULSE
CONTROL OF ADRENAL CORTEX
GROWTH OF ADRENAL
ADRENAL CORTEX DEVELOPMENT
DHEA-S SECRETION
HORMONES DURING PUBERTY
Hormone Sex Prepubertal Pubertal
male 6ng/ml 5.5ng/ml
prolactin
female 7.2 8.5
male increase increase
somatostatin
female increase increase
DHEA & male increase Increase(15-25peak)
DHEA-S
female increase Increase(15-25peak)
male increase increase
GH
female increase increase
male E1>E2 E1>E2
Estrogens
female E2>E1 E2>E1
GROWTH SPURT DURING PUBERTY

Ò  Peripuberty

Ò  Peak height velocity(PHV)


Ò  Decrease velocity, epiphyseal fusion
SATIETY HORMONES

Ò  Ghrelin

Ò  Leptin

Ò  Orexin

Ò  Amylin

Ò  Obestatin
É  Obestatin/Ghrelin ratio is important in obesity, IBS
& DM type II
LEPTIN

Ò  A hormone produced primarily by the fat cells in


white adipose tissue
Ò  An inhibitory (anorexigenic) effect on appetite,
by inducing a feeling of satiety
GHRELIN & OBESTATIN

Ò  An appetite inducing (orexigenic) hormone


Ò  Produced in the stomach and the upper portion
of the small intestine
Ò  Oral androgens decrease high-density
lipoprotein (HDL) cholesterol and increase low-
density lipoprotein (LDL) cholesterol
Ò  Selective estrogen receptor modulators
(SERMs), tamoxifen and raloxifene
PINEAL GLAND

Ò  Pinealocytes: produce and secret melatonin


Ò  Peptidergic neuron-like cells

Ò  Interstitial cells

Ò  Perivascular phagocytes

Ò  Pineal neurons

Pineal calcification is hi in regions with hi frequency of breast cancer


MELATONIN

Ò  Melatonin was discovered in 1958


Ò  By American physician Aaron B. Lerner

Ò  Derivative of tryptophan


MELATONIN SECRETION
LIGHT SIGNAL TRANSMITION
Ò  Retina

Ò  SCN of HT
Ò  PVN

Ò  Intermediolateral cell column


Ò  Superior cervical ganglia

Ò  Pineal gland

Ò  Inhibition of Mel.


MELATONIN RECEPTORES

Ò  Most abundant in SCN & anterior pituitary( pars


tuberalis)
Ò  Mel1A & Mel1B

Ò  Block
out the blue rays of light to avoid
postpartum depression