Transcript sex hormone production by testis and ovary

Endocrine Disorders 3: Reproductive
pathophysiology
CH0576: The Biology of Disease-Dr Richard N. Ranson
Alterations of reproductive
systems: Overview
● Changes in sex hormone levelSynthesis/secretion
● Alterations in receptor
sensitivity/number of receptors
● Congenital
Alterations of reproductive systems:
Timeline
● 6 weeks post conception: Sex Differentiation
-Errors can cause Intersex conditions
● By age 13-14 Puberty (sex hormone production
by testis and ovary)
-May be delayed or precocious – could be due to tumour
sometimes requires hormone treatment.
● Post 14 yrs – First Point of sexual maturity.
-Array of potential disorders – Carcinoma, impotence,
infertility etc.
Endocrinology of Sex
Differentiation and
Development
Sex may be determined by Chromosomes
‘Sex Chromosomes’
XX – female genotype
XY - Male
Key to sex determination
Fig 2.7 Levay Human sexuality
Gene: sex-determining region of the Y chromosome (SRY)
-codes for the protein testis-determining factor (TDF)
● Individuals with Y chromosome with SRY gene will develop as
males
● In the absence of Y Female development is the ‘default pathway’
Sexual differentiation and the role of SRY
Stage 1: Chromosomes dictate development of gonads
When single copies of genes are present SRY overrules DAX-1
SRY (make testis)
DAX-1 (make ovary)
Fig 6.9. Levay. Human Sexuality
● Mesenephros: A transitory embryonic kidney, provides tissue to gonads
● SRY genes produce transcription factor (protein).
● Transcription factor acts on genes in genital ridge cells-sertoli cells –develop
testis
Sex Hormones and critical (time) periods for
sexual differentiation 1.
Development of the reproductive tract:
Prior to 6 weeks both sexes
6 weeks post
conception
Male Gonad
● Sertoli cells- Anti Mullerian Hormone (AMH)
● Leydig cells- Testosterone
Wolffian duct androgen
receptors (normal)
Mutation in PG21 receptor
Intersex condition
Intersex Condition: Androgen insensitivity
syndrome
Look/identify as female
- Characterised by mutation in gene for androgen
receptor
- Mutation- prevents androgen binding to receptor or
receptor binding to DNA response elements
- 1:10000 live born with complete AIS
XY sex chromosomes with SRY
From Human
Sexuality, Levay.
No ovaries
(infertile)
Mullerian
ducts atrophy
AMH
● Amenorrhea (No menstrual periods), No pubic hair
Develop
testes
Testosterone
No effect
● Breast growth due to testis and adrenals secreting estradiol
● Shallow vagina
Sexual Dimorphism
Sex Hormones and critical (time) periods for
sexual differentiation 2.
9 and 12 weeks
testosterone leads
to male genitalia
development
Development
of External
Genitalia
Testosterone
surge in this
period also had
crucial effects on
brain structure
Brain
Dimorphisms
Fig 30.2 B from Purves et al neurosciences
Testosterone and the ‘Masculinization’ of the brain (basis
of sexual dimorphisms?)
During mid gestation (critical period)Testosterone surge
Brain/spinal
neurons
Estradiol (oestrogen)
Testosterone
Aromatase
Binds to estradiol receptors
Enhanced transcription of estrogen
responsive genes
Promotes cell survival, plasticity –
increased dendritic spines- connectivity
Figs from Purves et al Neuroscience
Other human brain regions that are
dimorphic
The cerebral cortex
‘Red’ areas depict regions that are
volumetrically larger in females whilst
‘green’ areas relate to that in males
● Differences linked to cognitive processing
The Hypothalamus
Regions include
SDN, sexually dimorphic nucleus (INAH 1)
INAH, Interstitial nuclei of anterior
hypothalamus-2,3 and 4
SCN, Suprachiasmatic nucleus
SON, supraoptic nucleus
Para ventricular nucleus
Ventromedial nucleus
Sexual dimorphism…Anatomy
INAH3 is much larger
in men than in women
Dendritic
spines
● Neurotransmitter content
● Enzyme activity
● mRNA levels encoding for different proteins
Hippocampal
neurons increase
spine densityEstradiol treatment
Brain nuclei, gender identity and sexual
orientation 1. Hypothalamus
S. Levay (1991).
Science.
253:1034-7
● A more recent study refutes this and finds no link between INAH-3 size
and sexual orientation. (refer Byne et al (2001) Horm. Behav 40, 86-92
● Studies are scant-great care should be drawn in basing conclusions on
small numbers of studies
● Also pathologizing Homosexuality and gender dysphoria raises
many ethical issues!
Brain nuclei, gender identity and sexual
orientation 2. Limbic system
Somatostatin
staining in
bed nucleus
of stria
terminalis
Heterosexual
female
Heterosexual
Man
Homosexual
man
Kruijver et al (2000). JCEM.85, 2034
Male to
female
transsexual
Disorders
Post-Maturation
The Female Reproductive cycle
Disorders of the Female reproductive system: 1.
Primary Amenorrhea (lack of menstruation-16 yrs)
Compartment I : Anatomical defects of outflow tracts.
Congenital absence of vagina and uterus (normal ovarian – 2o sex
traits)
Compartment II: Ovarian defects
Congenital e.g. AIS or Turners Syndrome ( 45 X/46
XX, one X or incomplete)– Ovaries lack gametesno oestrogen secretion-infertile and do not enter
puberty
Compartment III: Anterior pituitary disorders,
tumours- Interruption of FSH and LH release thus
ovary not stimulated to produce oestrogens
Compartment IV: CNS disorders-hypothalamic
Often congenital-Hypothalamic neurons do not
secrete GnRH and thus no action on anterior
pituitary-no FSH/LH release-no oestrogens
Levay
Disorders of the Female
reproductive system: 2. Secondary
Amenorrhea
● Absence of menstruation for 3 or
more cycles (6 months)
Anorexia
Pregnancy is
most common
cause of
secondary
amenorrhea
McCance & Huether
Disorders of the Female reproductive system: 2.
Secondary Amenorrhea- altered gonadotrophin secretion
in female athletes
Weight Loss/decreased body fatlean ratios (availability of
metabolic fuel decreases)
Menstrual Disturbances
GnRH (hypothalamus)
decreased
Exercise
Hypogonadotropic
hypogonadism
Repeated release of stress
and steroid hormones
http://www.endotext.org/female/female4/fi
gures/figure4.jpg
3. Polycystic Ovarian
Syndrome
PCOS details 1-Symptomology
Affects 5-10% of women – resulting in infertility
(inherited)
Characterised by
● Anovulation (absence of ovulation)
● Elevated androgen levels
● Polycystic ovaries
Enlarged
Cyst
http://www.mja.com.au/public/issues/180_03_020204/nor10314_fm.html
PCOS details 2-Pathophysiology: Key role for
Hyperinsulinemia
Obesity
Hirsutism
PCOS, linked to Diabetes mellitus type 2 and cardiovascular disease
Disorders of the Female reproductive
system: 4. Hirsutism and Virilization
Often a consequence
of PCOS
Hyperandrogenic
http://www.mja.com.au/public/issues/180_03_02
0204/nor10314_fm.html
Abnormal Adrenal
Cortex metabolism
Ovarian Tumour
● Increased muscle mass
● Clitoral Enlargement
● Increased libido
Treatment – use of androgen antagonist- Cyproterone
Acetate
Disorders of the
Female
reproductive
system: 5.
Premenstrual
Syndrome (PMS)
and premenstrual
dysphoric disorder
(PMDD)
Disorders of the Female reproductive system: 5.
Premenstrual Syndrome (PMS) and premenstrual
dysphoric disorder (PMDD) - aetiology
PMS: occurs in luteal phase (menstrual cycle) producing
behavioural changes that can affect relationships.
PMDD is PMS in extreme form (2% of women)
Mental:
● Major depression
● Anxiety
● Irritability
● Anger dyscontrol
● Impairment of concentration
Physical:
● Bloating
● Breast tenderness
►No hormonal
pathology discovered
►May be linked to
abnormal response in
CNS- linked to 5-HT
►SSRI’s can treat PMDD
when prescribed in luteal
phase
Hormone
release and
control of male
gonad function
Regulate bone
growth in male
Male reproductive pathophysiology:
● Hypogonadism e.g.
- Adult Leydig cell failure – fall in serum testosteronesexual dysfunction (primary)
- Gonadotropin deficiency - GnRH defect, hypothalamus
(secondary)
● Hypergonadism e.g.
- Virilizing (androgen secreting) tumour - Leydig Cell
- Feminizing (estrogen secreting)
Secondary – tumour in hypothalamus or pituitary
(increased GnRH)
● Benign Prostatic hyperplasia (inflammation of
prostate)
- Up to 80% men, increases with age. May be a
consequence of hormone imbalance
and enhanced
binding of androgen to receptors
● Impotence – lack of circulating testosterone
Postganglionic
Multiple transmitter
release
Prolonged
Stimulation
Viagra
References:
Boron, W. F. and Boulpaep (2005) Medical Physiology. Elsevier saunders
Byne, W. (2001) The interstitial nuclei of the human anterior hypothalamus: An
investigation of variation with sex, sexual orientation, and HIV status. Horm.Behav.
40, 86-92
Hadley, M. C. & Levine (2007) Endocrinology. 6th Edit, Pearson.
Kruijver, FPM et al (2000) male to female transsexuals have female neuron numbers
in a limbic nucleus. Journal of Clinical Endocrinology and Metabolism. 85:2034-2041
Levay S. and Valente, S.M. (2006) Human Sexuality, Sinauer Associates, Inc.
Levay, S. (1991). A difference in hypothalamic structure between heterosexual and
homosexual men. Science. 253:1034-7
McCance, K. L. & Huether, S. E. (2006). Pathophysiology. (The Biologic Basis for
Disease in Adults and Children). 5th Edit. Elsevier Mosby.
Purves et al (2008) Neuroscience, 4th Edit, Sinauer
Sowell, E.R. et al (2007) Sex differences in cortical thickness mapped in 176 healthy
individuals between 7 and 87 years of age. Cereb Cortex. 17 (7):1550-60
Tortora G. J. & Derrickson B.(2006). Principles of Anatomy and Physiology. 11th Edit,
Wiley.