repro 1: exam 3 applied phys

Three phases of sexual differentiation

1) Chromosomal (X or Y), 2) Gonadal (initiated by SRY in the bipotential gonad), 3) Phenotypic (induced by sex steroids)

What determines chromosomal sex?

The sperm. The oocyte always carries X; sperm carry X or Y

Homogametic vs heterogametic sex

XX females are homogametic; XY males are heterogametic

SRY = ?

Sex-determining Region of the Y chromosome = Testis Determining Factor (TDF)

What does SRY code for?

A transcription factor that turns on male-determining genes (e.g., SOX9)

Is sex determined by the Y chromosome or by SRY?

SRY itself, not the Y chromosome as such (explains XX males and XY females)

Role of SOX9

Transcription factor turned on by SRY; turns on more male genes (e.g., FGF9) and drives Sertoli cell differentiation. Mutations can alter phenotypic sex

First cells in the bipotential gonad to differentiate in response to SRY expression are

Sertoli cells

What do Sertoli cells induce neighboring cells to become?

Germ cells become spermatogonia; mesenchymal cells become Leydig cells

due to change of sertoli cells, the indifferent gonad becomes a

testis (induced)

in the absence of SRY what occurs?

ovarian differentiation (default)

Sertoli cell secretions

AMH/MIS, which regresses Müllerian ducts and induces Leydig differentiation

Leydig cell product

Testosterone

What does AMH do?

Causes degeneration of the Müllerian (paramesonephric) ducts and induces Leydig cell differentiation

AMH = ?

Müllerian Inhibiting Substance (MIS) = Müllerian Inhibiting Factor (MIF)

Müllerian ducts = ?

Paramesonephric ducts (female duct system)

Wolffian ducts = ?

Mesonephric ducts (male duct system)

Memory hint for Müllerian

Latin mulierem, Portuguese mulher, Spanish mujer all mean woman, so Müllerian = female

What does testosterone do in fetal development?

Promotes survival of the Wolffian ducts (male duct system), which form the epididymis, ductus deferens, ejaculatory duct, and seminal vesicles

once leydig cells differentiate testosterone is obviously a product, but what else arises with the help of 5-alpha reductase enzyme? what does this do?

dihydrotestosterone (DHT) which develops penis, scrotum, and accessory sex glands

What does DHT do in fetal development?

Drives differentiation of the external genitalia (penis, scrotum) and accessory sex glands such as the prostate

Enzyme that converts testosterone to DHT

5-alpha reductase (in the target tissue)

Testosterone vs DHT: which acts where?

Testosterone acts on internal ducts (Wolffian). DHT acts on external genitalia

Derivatives of the urogenital sinus (male)

Bladder, urethra, prostate, bulbourethral glands

Derivatives of the urogenital sinus (female)

Bladder, urethra, lower vagina

Derivatives of the Wolffian ducts (male)

Epididymis, ductus deferens, ejaculatory duct, seminal vesicles

Derivatives of the Müllerian ducts (female)

Oviducts, uterus, cervix, upper vagina

What is the default pathway of sexual differentiation?

Female. Without SRY, ovaries develop which means no AMH which means paramesonephric ducts become the oviducts, uterus, cervix, and part of the vagina which complete the female tract

Genes supporting ovarian development

Wnt4 and Rspo1

genes supporting testis development and gene supporting sertoli cells

SRY and Sox9
FGF9

Female tract: what happens without AMH?

Müllerian ducts persist and develop

Female tract: what happens without testosterone?

Wolffian ducts degenerate and external genitalia form a clitoris and labia

what is phenotypic sex determined by?

presence or absence of masculinizing hormones

what is gonadal sex determined by?

presence of absence of SRY gene

what is genetic sex determined by?

depends on combination of sex chromosomes

once ____ sex is established, the leydig cells of the testis begin to produce testosterone

gonadal

after gonadal sex determination (formation of testes) either the

male (wolffian) or female (mullerian) ducts will differentiate while the other will degenerate

Is female differentiation dependent on estrogen?

No. Estrogen is high in the maternal environment for both sexes and does not drive differentiation

absence of what and what leads to wolffian duct regression

androgens and MIS

Role of aromatase in the male

Converts testosterone to estradiol, which drives brain sexual differentiation

External genital precursors (7 weeks)

Genital tubercle, urethral folds, genital swellings (identical in both sexes)

Male external genitalia from the genital tubercle, urethral folds, and swellings

Glans penis and shaft, fused urethral folds, scrotum (via DHT)

Female external genitalia from the same precursors

Clitoris, labia minora, labia majora

Where do primordial germ cells (PGCs) originate?

The yolk sac, outside the gonad

PGC migration route

Yolk sac to hindgut and mesentery to the gonadal ridge. In humans, complete by about day 53-58

Is gonadal sex determined when PGCs arrive?

No. PGC generation and migration are identical in males and females

What determines PGC fate?

Somatic cells of the gonad (the stem cell niche), not the PGC itself

Role of somatic cells (evolutionary view)

Generation, proliferation, protection, and dissemination of germ cells

responsible for generating genetic diversity through meiosis and transmitting DNA to subsequent generations

germ cells

PGCs in the testis become

Spermatogonia (mitotic, embedded in seminiferous cords with Sertoli cells)

PGCs in the ovary become

Oogonia

Spermatogonia in the fetal testis

Remain mitotic, then quiescent until puberty

Oogonia in the fetal ovary

Proliferate by mitosis, enter meiosis I during fetal life, then arrest (meiotic arrest, diplotene)

Oocytes stay arrested until

Puberty

Male vs female germ cell timing in the fetus

Male: mitotic then spermatogonia are quiescent til puberty. Female: enter meiosis in the fetus, then meiotically arrest til puberty

Lineage of gametes

PGC to spermatogonia/oogonia (diploid, mitotic) to meiosis to sperm/oocyte (haploid)

Two sources of genetic diversity in meiosis

Homologous recombination and independent assortment

What does fertilization restore?

Diploid number (46); the embryo becomes mitotic again

Sperm sex chromosomes

Half carry X, half carry Y

Gonadal support cells: male vs female

Sertoli (male) vs granulosa (female)

Gonadal steroid cells: male vs female

Leydig (testosterone converted to estradiol) vs theca (androstenedione, converted to estradiol)

Klinefelter syndrome

XXY. Male phenotype because SRY is present
Sex chromosome DSDs

Turner syndrome

XO. Sex chromosome DSDs

Swyer syndrome

XY with SRY absent or non-functional. Female phenotype, normal uterus and tubes, non-functional gonads

XX male syndrome (de la Chapelle)

XX karyotype with SRY translocated onto an X. Male phenotype

Ovotesticular DSD

Rare (~1:20,000). Both ovarian and testicular tissue (true hermaphroditism). Can occur in XX or XY
Sex chromosome DSDs

DSD where certain male-determining genes (SOX9, MIS, 5-alpha reductase) are non-functional and ambiguous external genitalia and phenotypes ranging from simple infertility to intersexuality

XY DSDs

DSD where ovaries present but external genitalia appear male or mixed. The internal female reproductive glands are usually normal

XX DSDs

DSD that includes: (XX/XY mosaicism, XO Turners syndrome, XXY Klinefelter syndrome, SRY mutation/translocation)

• Ovotesticular DSD (rare, ~1:20,000 births)

• True hermaphroditism (can occur in XX or XY individuals)

Sex chromosome DSDs

5-alpha reductase deficiency

XY with normal testes and internal male tract but female-appearing external genitalia (lack of DHT). Virilization at puberty ("güevedoce" = penis at 12)
XY DSDs

Why does 5-alpha reductase deficiency virilize at puberty?

The testosterone surge at puberty causes growth of the phallus and scrotum, male hair, and muscle growth

Androgen insensitivity syndrome (testicular feminization)

XY with an androgen receptor defect. Testes make testosterone but cells can't respond. Phenotypically female and sterile. Severity tracks the mutation

Androgenital (adrenogenital) syndrome

XX DSD. Virilized external genitalia only, from excess fetal adrenal androgens (DHEA). Internal female structures normal. May show early puberty and short stature

Most common cause of androgenital syndrome

21-hydroxylase deficiency

3-beta HSD deficiency

Salt wasting and DSD in both sexes

17-beta HSD deficiency

XY DSD and amenorrhea in XX females

Hypospadias

Mild DSD where the urethral opening forms on the underside of the penis instead of the tip

Freemartin

Most common intersex condition in cattle. Female twin of a male twin; placental vessel anastomoses let male AMH and androgens masculinize her. Somatic chimera

Freemartin sterility rate

About 90-95% of female calves born to a male twin are sterile

Freemartin in small ruminants

Very rare

Effect of failure to convert testosterone to DHT

Altered external genitalia

SRY present but inactivating mutation

SOX9 not expressed properly, no male gene activation, offspring appears female

Do early fetal disruptions affect later generations?

Yes. Exposures during pregnancy can alter the offspring and the gametes that form the grand-offspring

Prolactin: origin and function

Anterior pituitary. Stimulates milk production and maternal behavior

Progesterone (P4): origin and function

Corpus luteum and placenta. Maintains pregnancy, inhibits GnRH, mammary growth

Estradiol (E2): origin and function

Sertoli cells (male), granulosa cells (female)
♀1. Regulate GnRH, LH & FSH 2. Increased secretory activity to enhance uterine motility 3. Sexual behavior (heat). ♂1. Sexual behavior

Testosterone: origin and function

Leydig cells (male), theca interna cells (female)
♂ 1. Spermatogenesis 2. Promotes secretion of accessory glands 3. Secondary sex characteristics. ♀: 1. Estradiol synthesis

which hormones are steroids?

progesterone, estradiol, and testosterone

GnRH

Decapeptide from the hypothalamus. Stimulates LH and FSH release from the anterior pituitary

Oxytocin

Octapeptide synthesized in the hypothalamus, stored in the posterior pituitary. Stimulates PGF2-alpha synthesis and smooth muscle contraction

FSH: male and female actions

Male: Sertoli cell function and spermatogenesis. Female: follicular development and estradiol synthesis

LH: male and female actions

Male: stimulates testosterone production (Leydig). Female: ovulation, CL formation, progesterone secretion

Inhibin

Glycoprotein from Sertoli (male) or granulosa (female) cells. Blocks FSH release from the anterior pituitary

Primordial germ cells enter an undifferentiated gonad, but the influence of _____ _______ determines their differentiation into either spermatogonia or oogonia

somatic cells

which hormone come from theca interna cells (female)

testosterone

which hormones come from granulosa cells (females)

estradiol (E2) and inhibin

what hormone inhibits GnRH release?

progesterone