82 - Sexual Differentiation Flashcards
How is “sex” determined?
Biologically - genotypic or c’somal
How is “gender” determined?
Socially-determined (usually related to appearance)
- Independent of genotype, hormones, and phenotype
Describe the “hierarchy” of sexual development.
Chromosome determines gonads, determines genitalia, determines gender identity
How would you confirm someone’s biological sex?
Karyotype analysis
Generally, what is gonadal development determined by?
Genes only (c’somes)
Generally, is genitalia development determined by genes, internal/external structures, environment, hormones, social behavior, or a combo of them?
- Hormones
- Internal and external structures
- Social behavior
What c’some is required for testicular development?
Y c’some (“Y defines the guy”)
What important gene is found on the Y c’some in the region that determines sex?
What’s its other name?
- SRY: sex-determining region Y
- AKA TDF: testes-determining factor
SRY is a TS factor, it’s major target being:
SOX9
What specifically determines gonadal sex?
(C’somes)
Determined by normal differentiation and especially activation of SRY/TDF gene to yield male vs female
What what week in pregnancy is the gonad male?
When is it female?
- Male by 7 weeks
- Female by 11 weeks
Although you can determine c’some sex by genomic (karyotype) analysis, what’s the only way you can determine gonadal sex?
Histology of the gonad (ouch)
What specifically determines the genitalia?
(gonadal sex)
Determined by activation and integration of:
- Neuroendocrine axis
- Paracrine, endocrine control of genital tract devo
How would you determine someone’s gender identification?
Observation/psychoanalytical tests
XY mice w/no functional SRY develop ________.
Ovaries
XX mice w/added functional SRY develop ________.
Testes
What c’some encodes the androgen receptor?
X c’some
What cells migrate to the gonadal ridge at 5-6 weeks gestation?
Primordial gene cells (PGCs)
Before gonads become testes or ovaries, what are they known as?
Primordial (indifferent) gonad
bipotential for testis or ovary
What 2 genes are responsible for development of the testes from the primordial gonad?
+ Sry
+ Sox9
What genes are responsible for development of the ovary from the primordial gonad?
Neither, just need the absence of the testes!
Although absence of testes is the deciding factor for the primordial gonad to become an ovary, what 2 genes are responsible for the appropriate differentiation into an ovary?
+ Rspo1
+ Wnt4
What part of the embryo (foregut, midgut, or hindgut) do the gonads develop in?
Hindgut
What are the 2 areas of the gonadal ridge called?
Cortex (anterior) and medulla
Female internal genitalia develop from the ________ of the gonadal ridge.
cortex
Male internal genitalia develop from the ________ of the gonadal ridge.
Medulla
“m” for male = medulla
Describe the 4 steps of the embryologic development of the male gonad.
- Indifferent gonad = primitive sex cords
- Proliferation of sex cords (SRY, SOX9)
- Penetration of medulla by sex cords
- Differentiation of medullary cords – becomes testes
Describe the 4 steps of the embryologic development of the female gonad.
- Indifferent gonad = primitive sex cords
- Sex cords disorganize – cortical epithelial cells proliferate (due to absence of SRY)
- Cortical cords develop from cortical epithelium
- Cells form clusters around germ cells – epithelial cells become follicular cells – ovary develops
What are the 3 types of cells of the testes?
- Gametes
- Sertoli cells
- Leydig cells
What are male gametes called?
Sperm
What are female gametes called?
Ovum
What do Sertoli cells (of the testes) do?
Secrete antimullerian hormone (AMH) and inhibin B
What do Leydig cells (of the testes) do?
Synthesize and secrete testosterone/DHT (androgens)
What are the 2 cell types of the early ovary?
- Gametes
2. Follicular cells
Together, the gametes and the follicular cells of the early ovary make up the:
Follicle
Follicular maturation results in formation of what 2 cell types w/in the ovary?
- Granulosa cells
2. Thecal cells
What do granulosa cells (of the mature ovarian follicle) do?
Secrete and synthesize estrogens and progesterone
What do thecal cells (of the mature ovarian follicle) do?
Make androgens
The germ cells of the male are called ________________, and those of the female are called _______________.
- Spermatogonia
- Oogonia
The coelomic epithelium of the male will become ___________ cells, and that of the female will become _____________ cells.
- Sertoli (secrete AMH, inhibin B)
- Granulosa (secrete estrogens/progesterone)
The mesenchymal cells of the male will become ___________ cells, and that of the female will become _____________ cells.
- Leydig (secrete testosterone/DHT)
- Theca cells (make androgens)
AMH + androgens will result in development of the:
Male genital tract/external genitalia
No AMH + no androgens will result in development of the:
Female genital tract/external genitalia
Name the 3 parts of the “sexually indifferent duct system” of the developing fetus.
- Mesonephros
- Mullerian Duct
- Wolffian Duct
What is the mesonephros and when does it start working?
Transient kidney
- 6-10 weeks gestation
Which of the 2 sexually indifferent ducts undergoes further development in females?
Mullerian duct
recall: males have anti-mullerian hormone
Which of the 2 sexually indifferent ducts undergoes further development in males?
Wolffian duct
What’s another name for the Wolffian duct? Mullerian duct?
W: Mesonephronic duct
M: Paramesonephronic duct
What does AMH do?
Anti-Mullerian hormone induces regression of the Mullerian duct
Recall: Leydig cells make/secrete testosterone and DHT (androgens). What, generally, is the purpose of this?
Stimulates the formation of genitalia from the Wolffian duct.
What 4 specific parts of the male internal/external genitalia does release of testosterone from Leydig cells form?
(top, middle, bottom)
- Top: epididymis
- Middle: ductus deferens (vas)
- Base: seminal vesicle, ejaculatory duct
What (2) specific parts of the male internal/external genitalia does release of DHT from Leydig cells form?
Prostate and external genitalia
Recall: what induces the regression of the Wolffian ducts?
Absence of Testes (not presence of ovary)
- No AMH, no androgens
What do the top, middle, and bottom of the Mullerian ducts differentiate into?
- Top: Fallopian tubes (oviducts)
- Middle: fuses to become uterus
- Bottom: Cervix + upper 1/3 vagina
When contrasting patterns of male and female differentiation of the internal genital ducts, what duct develops when you castrate the male? Female?
Male castration: Mullerian (instead of Wolffian)
Female castration: Still get Mullerian
During male castration, why do Mullerian ducts develop instead of Wolffian ducts?
Lack of AMH (AMH induces regression of the Mullerian duct)
During female castration, why do Mullerian ducts still develop?
Because AMH would never be released anyways…further evidence that absence of testes induces regression of the Wolffian ducts
In male early castrates + testosterone, what ducts would you expect to develop?
Both because no AMH so no regression of the Mullerian duct, + testosterone induces
How would you alter the normal female development of her normal internal genitals in order to get both Mullerian and Wolffian ducts?
- Absence of testicles and lack of AMH induces Mullerian ducts.
- Then just add testosterone to induce presence of the Wolffian ducts as well.
The genital tubercle becomes the __________ in the male and the __________ in the female.
- Glans penis
- Clitoris
The urogenital folds become the __________ in the male and the __________ in the female.
- Ventral penis
- Labia minora
The urogenital sinus becomes the __________ in the male and the __________ in the female.
- Prostate
- Lower vagina
The labioscrotal folds become the __________ in the male and the __________ in the female.
- Scrotum
- Labia majora
What hormone is converted into DHT?
Testosterone
What 3 male genital parts things require DHT for their development?
- Penis
- Scrotum
- Prostate
What enzyme is required to convert testosterone into DHT?
5alpha-reductase
A mutation in 5alpha-reductase would cause what problems?
Defects in external male genitalia (penis, scrotum, prostate)
What general class of cells undergoes meiosis?
Germ cells
What’s another name for gender identity + external genitalia?
Phenotypic sex
How do daughter cells differ in mitosis?
They are identical (somatic cells only)
What is accomplished during meiosis I?
- Duplication of DNA.
- Recombination of chromosomes = genetic diversity.
- Chromosomes split
At the end of meiosis I, what is the ploidy of the cells?
What about after meiosis II?
- 2x diploid
- 4x haploid
What are the names of the male and female gametes?
- Male: spermatozoa
- Female: ovum
Name the 4 different names for the sperm cells during their meiotic process, and what happens for each to form + the ploidy.
- Spermatogonium (diploid)
- Primary spermatocyte (diploid, after DNA duplicates)
- Secondary spermatocyte (haploid, after 1 cell division)
- Spermatids (haploid, after 2 cell divisions, half of gamete DNA)
- Then become spermatozoa
Name the 4 different names for the egg cells during their meiotic process, and what happens for each to form + the ploidy.
- Oogonium (diploid)
- Primary oocyte (diploid, after DNA duplicates)
- Secondary oocyte + 1 polar body (haploid, after 1 cell division)
- Ovum + 3 polar bodies (haploid, after 2 cell divisions, half of gamete DNA)
What 2 things are contained in the primordial follicle?
- 1 daughter cell/germ cell
2. polar bodies
What happens to the oogonia before birth?
None are present–all have been converted to primary oocytes or are subject to atresia
What step is the female meiosis arrested at until puberty?
Meiosis I is arrested at diplotene of prophase
What compound is responsible for the arrest of female meiosis I at diplotene of prophase until puberty?
What cells secrete it? (think)
Oocyte maturation inhibitor (OMI)
- Small peptide secreted by follicular cells
Female meiosis __ is arrested at __________ __ until fertilized by sperm.
Meiosis II, metaphase II (then completes meiosis)
m2 m2’s are waiting to get pregnant
When does male spermatogenesis generally end?
“old age”
What’s a translocation?
Equal or unequal exchange of c’somal material b/w c’somes
When a translocation occurs, what is the reason an XX female develop a male phenotype?
SRY gene inserted (eg from Y tralocation w/female X)
- X inactivation can cause a variety of presentations
How could an XY male develop female genitalia?
Translocation of SRY off of Y gene, so no SRY on either.
How many c’somes does a normal karyotype have?
46
In terms of the sex c’some, what is Turner’s syndrome?
45 XO
In terms of the sex c’some, what is Klinefelter’s syndrome?
47 XXY
What is Turner syndrome characterized by (in terms of sex devo)?
What other sx characterize Turner’s syndrome?
45 XO
- Gonadal dysgenesis–ovaries don’t develop and become a “streak” of fibrous tissue (both X chromosomes are required during development for oogonia).
- Systemic issues due to aneuploidy: very short stature, “shield chest,” webbed neck, upper torso deformities, amenorrhea, lack of puberty
Although both X chromosomes are required during development for oogonia and early differentiation of the ovary, why are 2 copies of X no longer required later in life?
X inactivation (duh)
What is Klinefelter’s syndrome characterized by (in terms of sex devo)?
What other sx characterize Turner’s syndrome?
47 XXY
- Testes are present but small and hyalinated; infertile, low T (due to testes disfunction); micropenis
- Eunuchoid body (lower segment greater than upper); short arms; gynecomastia (elevated estradiol); other issues due to aneuploidy
What is usually the cause of Klinefelter’s syndrome?
How common is it?
- Usually due to meiotic nondisjunction
- Most common chromosomal disorder in boys (1:500 to 1:1000)
What are the (2) different general etiologies of hermaphroditism?
Chromosomal (genetic); Hormonal (development)
What distinguishes male pseudohermaphroditism?
Testes present, but some or all female internal/external genitalia also present
What distinguishes female pseudohermaphroditism?
Ovaries present, but some or all male internal/external genitalia also present
What distinguishes true hermaphroditism?
Both testes and ovaries present “gonadal” sex. Phenotypic sex ambiguous.
What is the genotypic number and cause of complete male pseudohermaphroditism?
How is hormonal balance affected?
46, XY
- Loss of X-linked AR gene (androgen resistance gene)
- Androgen levels are high (lack of feedback, estrogen levels high (for male). Gonadotropins?
What is the sexual phenotype of complete male pseudohermaphroditism?
(there are lots of details here, try to name some. What ducts are present?)
Phenotype: female with blind vaginal pouch
- Y chromosome induces mullerian duct regression, testes (undescended); lack of androgen effects (no Wolffian duct development, no external genitalia)
- High estrogens induce development of female body characteristics
What is the cause of partial male pseudohermaphroditism?How is hormonal balance affected?
Partial: AR mutation – partially functional
- Same as complete: Androgen levels are high (lack of feedback, estrogen levels high (for male). Gonadotropins?
What is the sexual phenotype of partial male pseudohermaphroditism?
(there are lots of details here, try to name some. What ducts are present?)
- Phenotype: ambiguous with blind vaginal pouch (under masculinized)
- Y chromosome – induces Mullerian duct regression, testes (undescended); Wolffian duct develops, gynecomastia
What are the (4) most common causes of female pseudohermaphroditism?
- Fetal congenital adrenal hyperplasia (most common)
- Maternal androgen excess
- Adrenal or ovarian tumors
- Progestational drugs (eg BCP while pregnant)
What is the phenotype of female pseudohermaphroditism?
- Retention of the urogenital sinus
- Fusion of labia
- Virilization via increased androgens: advanced skeletal “age”, clitoromegaly, and other ambiguities of genital anatomy
What are the gonads often referred to as w/true hermaphrodites?
Ovotestis
For true hermaphrodites, XX are generally raised as (male/female)?
Does spermatogenesis occur?
What genetic sx are common?
- Female
- No, because Y genes not present
- Ambiguous genitalia; cryptocordism (undescended testes), and hypospadias are common (penis opening not at tip but underside)
What are some possible genetic causes of true hermaphroditism?
Possible SRY translocation or loss of Rspo1 gene (testes repressor)
- No spermatogenesis because other Y genes not present
