Sex Development and Puberty

Question 1

What is genetic sex? Gonadal sex? Genital sex?

Answer 1

• genetic sex: XX or XY
• gonadal sex: testes or ovaries
• genital sex: genitalia (penis/scrotum or clitoris/labia)

Question 2

During which weeks of gestation do the gonads begin to develop? What determines whether or not testes or ovaries will develop?

Answer 2

• testes begin to develop at weeks 6 and 7
• ovaries begin to develop at weeks 9 and 10
• for the 1st 5 weeks of gestation, the gonads are indifferent AKA bipotential
• the presence of TDF (testis-determining factor) triggers gonadal differentiation into testes; its expression is the result of the SRY gene found on the Y chromosome
• without TDF, the gonads will differentiate into ovaries (female is default)

Question 3

What are the three cell types found in the testes? What about in the ovaries? What does each do?

Answer 3

• testes: germ cells (make spermatogonia), Sertoli cells (make anti-Mullerian hormone, AMH), Leydig cells (make testosterone)
• ovaries: germ cells (make oogonia), granulosa cells (make estradiol), theca cells (make progesterone and androgens)

Question 4

What makes up the internal and external tracts of the male genitalia? The female genitalia?

Answer 4

• male internal: prostate, seminal vesicles, vas deferens, epididymis
• male external: scrotum and penis
• female internal: fallopian tubes, uterus, upper 1/3 of vagina
• female external: lower 2/3 of vagina, labia minora, labia majora, clitoris

Question 5

What develops into the male internal genital tract? The female internal genital tract? What is needed for each to survive and develop?

Answer 5

• male internal tract develops from the Wolffian ducts
• female internal tract develops from the Mullerian ducts
• each fetus has both types of ducts
• normally, the Wolffian ducts naturally degenerate at about week 10, leaving the Mullerian ducts to develop into the female phenotype at about week 20; therefore, the female phenotype does not require anything to develop and is the default phenotype
• in males, the Sertoli cells of the testes release anti-Mullerian hormone (AMH), which degrades the Mullerian ducts at about week 10; additionally, the Leydig cells of the testes release testosterone, which prevents the Wolffian ducts from degrading and triggers development into male phenotype at about week 12; therefore, the male phenotype requires AMH and testosterone (testosterone, NOT DHT)

Question 6

What is DHT and what is its role in utero?

Answer 6

• DHT is dihydrotestosterone
• it is a stronger form of testosterone, and is formed by 5alpha-reducatse, which converts T into DHT
• DHT is needed for the differentiation of the external genitalia into the male phenotype (penis, scrotum, prostate) because T is too weak as it is to do so (external genitalia differentiation occurs at weeks 9 and 10)
• (female phenotype differentiation doesn’t require anything)

Question 7

What is the triggering event of puberty? What results in each gender?

Answer 7

• puberty triggered by the pulsatile secretion of GnRH
• males: puberty increases T production in Leydig cells in testes: growth of testes, penis, prostate; linear growth; pubic/axillary hair; deepens voice; spermatogenesis
• females: puberty increases E production: budding of breasts; menarche; linear growth (increased androgens result in development of pubic and axillary hair here)

Question 8

What are the Mullerian and Wolffian ducts also known as?

Answer 8

• Mullerian (female tract): paramesonephric duct

- Wolffian (male tract): mesonephric duct

Question 9

What are the four parts of the indifferent/bipotential external genitals? What does each develop into for each gender?

Answer 9

• phallus: becomes the glans penis or the clitoris
• urogenital folds: become the penis shaft or the labia minora
• labioscrotal swellings: become the scrotum or the labia majora
• urogenital membrane: becomes the male urethral opening or the vestibule
• (male phenotype will develop in presence of androgens (especially DHT); without DHT, female phenotype develops by default)

Question 10

What is androgen insensitivity syndrome? What about 5alpha-reductase deficiency?

Answer 10

• these syndromes are rare disorders that occur in XY people; both result in a failure to respond to androgens properly
• AIS: issue with androgen receptors results in a loss of signal to develop the male genital tract; the “wandering” androgens get converted into estrogen; child is born with testes, but with female external genitalia (and usually an absent internal genital tract)
• 5-ARD: inability to convert testosterone into dihydrotestosterone (DHT); failure to develop penis, scrotum, and prostate

Question 11

TDF vs. Testosterone vs. DHT

Answer 11

• TDF (testis-determining factor): needed for gonads to differentiate into testes
• testosterone: needed for Wolffian duct to develop into male internal tract (also need AMH to degrade the Mullerian duct); also needed for male puberty
• DHT: needed for differentiation of external genitalia into male phenotype (scrotum, penis, and also prostate)

Question 12

How do patients with androgen insensitivity syndrome present?

Answer 12

• AIS occurs in genotypical males (XY)
• patients have testes because of the Y chromosome’s TDF on the SRY gene
• patients have female external genitalia because of the resistance to androgens (DHT has no effect)
• patients lack an internal genital tract (testicular Sertoli cells release AMH to degrade the Mullerian tract; Leydig cells release T, but resistance prevents it from keeping the Wolffian tract from degrading)

Question 13

How do patients with 5alpha-reducatse deficiency present?

Answer 13

• 5aRD occurs in genotypical males (XY)
• patients have testes (because of chromosome Y’s SRY gene with TDF) and a male internal genital tract (because of T keeping the Wolffian ducts alive)
• patients have female/ambiguous external genitalia because the enzyme deficiency prevents the conversion of T into DHT (DHT needed for male differentiation of external genitalia)
• at puberty, the large surge in T often overcomes this DHT deficiency, and the patients experience the “penis at 12” phenomenon

Question 14

What is Kallmann’s syndrome? How do patients present?

Answer 14

• Kallmann’s syndrome is a rare disorder where patients are unable to produce GnRH
• patients present with hypogonadotropic hypogonadism and with anosmia (loss of sense of smell)

Question 15

Is GnRH secreted in pulses or continuous release? What about LH and FSH?

Answer 15

• once puberty starts, GnRH is released in pulses (about 5-10 minutes of activity every 2 hours)
• this triggers the release of the gonadotropins: LH is released in a pulsatile fashion as well, but FSH is released continuously

Question 16

What is inhibin? What does it act on? What is it secreted by?

Answer 16

• inhibin is another hormone released by the gonads (it is made by Sertoli cells in the testes and by the granulosa cells in the ovaries)
• it acts ONLY on the anterior pituitary to inhibit gonadotropin secretion (it does not act on the hypothalamus)