Gonadal Differentiation Flashcards
What is sexual differentiation in mammals driven by?
- presence of androgens in males and their decreased amounts in females
What does the presence of androgens induce in males?
- irreversible changes
- genital differentiation, secondary sex characteristics
What does the lower amount of androgens induce in females?
- female genital differentiation, secondary sex characteristics
What is sex?
- biological and physiological characteristics that define men and women
- male and female
What is gender?
- socially constructed roles, behaviours, activities, and attributes that a given society considers appropriate for men and women
- masculine and feminine
What is this section “gonadal differentiation” about?
- conditions that leave people with a reproductive inability not a health abnormality
In what chromosomal gene/region is FISH helpful?
- ID
What initiates testes development?
- sex-determining region Y (SRY) protein, is a DNA-binding protein
What is SF-1 important for?
- gonadal and adrenal development, reproduction and anti-mullerian hormone
What do mutations in SF-1 lead to?
- range of problems
- adrenal insufficiency i 46, XY females (low androgens), gonadal dysgenesis
What does translocation of SRY cause?
- 46, XX males (SRY functional), but mutation of SRY leads to 46XY females (loss of SRY function)
What are testicular and ovarian differentiation influenced by?
- combination of hormonal and environmental factors
What does the undifferentiated gonad have the unique characteristic of?
- has potential o form either of two organs: testes or ovaries
Currently, how many genes have been identified that regulate sex differentiation processes? What do these genes do?
- more than fifty genes
- encode transcription factors, gonadal steroids, peptide hormones and tissue-specific receptors
Currently, how many genes have been identified that regulate sex differentiation processes? What do these genes do?
- more than fifty genes
- encode transcription factors, gonadal steroids, peptide hormones and tissue-specific receptors
What are mullerian ducts?
- paired ducts of the embryo that run down the lateral sides of the urogenital ridge
What do the mullerian ducts develop into?
- in female: form the fallopian tubes, uterus, and the upper portion of the vagina
- in male: lost
When is the default form female?
- when there is no exposure or sensitivity to androgens
What is the wolffian duct?
- paired organ also found in humans during embryogenesis
What does the wolffian duct develop into?
- males: epididymis, vas deferens and seminal vesicle
What must wolffian ducts be exposed to? When?
- testosterone during embryogenesis for development
What controls stabilization of wolffian ducts?
- anti-mullerian hormone (or mullerian inhibiting factor) produced by sertoli cells and leydig cells
Testicular differentiation precedes ___ ____.
ovarian differentiation
What are some of the conditions associated with females?
- amenorrhea: GnRH deficiency, functional hypothalamic amenorrhea, hyperprolactinemia
- menopause
What is amenorrhea? What could this be a possible sign of?
- lack of menstrual cycle after age 16 or 3 missed periods
- genetic, endocrine or anatomic abnormalities
What is GnRH deficiency (Kallmann’s syndrome)?
- example of amenorrhea
- adhesion molecule gene mutation
- no migration of GnRH producing cells or olfactory neurons to the hypothalamus
- no sexual maturity or smell
What is Functional hypothalamic amenorrhea?
- reduced GnRH pulse frequency and amplitude
- low FSH and LH, leptin implicated, minor activation of HPA axis and incidences of psychological stress, strenuous exercise or poor nutrition precede
What is hyperprolactinemia?
- example of amenorrhea
- usually dopamine not inhibiting prolactin release
What is menopause?
- ovary ceases to function at average age 51
Which country made a third gender option legal?
Germany
What is Klinefelter’s syndrome? What are the conditions associated with it?
- male 47, XXY
- gonadal dysgenesis, low testosterone, sometimes no clear secondary sex characteristics, may be mental retardation
How common is Klinefelter’s syndrome?
- 1/500 males
- most common form of male hypogonadism
- most common found human sex chromosomal abnormality
- low androgens
What is Turner’s syndrome? What are the conditions associated with it?
- female 45, X
- gonadal dysgenesis, almost no estrogen or progesterone, no secondary sex characteristics
- numerous developmental problems: short, web neck, hearing and kidney loss of function
How common is Turner’s syndrome?
- mostly fatal to fetus so 1/5000
What is the cause of Turner’s syndrome?
- father did not pass on a sex chromosome
Are Klinefelter’s syndrome and Turner’s syndrome treatable?
- both treatable with hormones for secondary sex characteristics
- will always be infertile
What is male hypogonadism?
- developmental default is female so hypogonadism in males leads to female characteristics
What is female 46, XX DSD - intersex (female pseudohermaphrodism)?
- prenatal exposure to androgens resulting from genetic pathogenesis
- both ovarian and testicular tissue in one or both gonads (ambiguous genitalia)
What is the difference between early androgen exposure and at 12 weeks?
- early androgen exposure: no ovaries
- androgen exposure at 12 weeks: penis and ovaries
What is intersex 46, XY DSD (male pseudohermaphroditism)?
- have testes but genital ducts or external genitalia not fully masculinized
What causes intersex 46, XY DSD?
- defect in testosterone secretion
What are the symptoms of intersex 46, XY DSD?
- testicular dysgenesis
- impaired T or MIF secretion
- gonadal target tissue not responsive
- no T –> DHT conversion
What are the symptoms of androgen insensitivity syndrome (AIS, resistance)?
- testes present, absent wolffian ducts, female-appearing external genitalia
- at puberty: female secondary sex characteristics, no menarche
What is the cause of androgen insensitivity syndrome?
- increase LH secretion results in increase in T and E2
- androgen receptor mutation is common
What are the three causes of androgen biosynthetic dysfunction in 46, XY individuals?
- luteinizing hormone (LH) receptor mutation
- 17alpha-hydroxylase deficiency
- 5alpha-reductase deficiency
What results from LH receptor mutation?
- decreased androgen production
- hypogonadism
- intersex 46, XY DSD
What results from 17alpha-hydroxylase deficiency?
- can’t make androgens
- ambiguous gonads or feminization
- intersex 46, XY DSD
What results from 5alpha-reductase deficiency?
- can’t make DHT
- 46, XY DSD
What are the three causes of androgen excess in 46, XX individuals?
- 21 alpha-hydroxylase deficiency
- aromatase deficiency
- increased androgen exposure in utero
What results from 21 alpha-hydroxylase deficiency?
- build up of androstenedione and DHEA
- increase T, masculinization
- intersex 46, XX DSD
What results from aromatase deficiency?
- lack of estrogen
- 46, XX DSD
What results from increased androgen exposure in utero?
- androgenic drugs
- 46, XX
At 37-45 days of gestational age the gonads are?
- biopotential - default is female
What initiates the testes in males?
- SRY protein
What stabilizes the wolffian ducts?
- anti-mullerian hormone
What receptors do estrogens bind to and activate?
- ERalpha and ERbeta
Where is ERalpha expressed? What does it mediate?
- in reproductive tissues
- the majority of the sexually dimorphic and reproductive functions
Where is ERbeta expressed?
- exhibits a distinct pattern of expression in prostate, brain and immune cells
What are the domains and functions of the estrogen receptor structure?
- A/B: transactivation, activation function (AF-1 ligand independent)
- C: DNA binding domain, dimerization
- D: hinge
- E: ligand binding domain, dimerization (AF-2, ligan dependent)
- F: function unknown
In what domains of the estrogen receptor can phosphorylation occur?
- in all domains
- affects functions
Do ERalpha and ERbeta have similar roles?
- overlapping yet unique roles in E2 signalling
What is tamoxifen?
- an antagonist of the estrogen receptor in breast tissue
What is estrogen receptor signalling also known as?
- nuclear initiated steroid signalling
What are the specifications of estrogen receptor signalling (classical nuclear action)?
- activation of txn of target gene by E2/ER
- or no activation by antagonist tamoxifen/ER
- with recruitment of coactivators or corepressors
What are the specification of estrogen receptor signalling (non-classical nuclear action)?
- ER regulates gene txn on genes without HRE
- interacts with TF such as SP-1, fos, jun
What is non-genomic estrogen receptor signalling?
- aka membrane initiate steroid signalling
How is non-genomic estrogen receptor signalling mediated?
- through GPCR, increase production EGF, p cascade
How are ERalpha membrane associated?
- by lipid rafts
- also direct activation of Gbetagamma leads to kinases
What does activation of the non-genomic estrogen receptor signaling activate?
- leads to pylation of nuclear ER and activation of mitogenic pathway
- E2 signalling through GPCR30
