1. SEXUAL DIFFERENTIATION & DETERMINATION Flashcards
1
Q
*Define sexual determination
A
- Sexual determination is the chromosomal determination as male or female. It is a genetically controlled process that’s dependent on the molecular switch of the Y chromosome
2
Q
*Define Sexual differentiation
A
- Sexual differentiation is the process by which the internal & external genitalia develop as male or female
3
Q
What does the SRY gene do in gonadal development?
A
- The SRY gene is the sex determining region of the Y chromosome
- It is a molecular switch which is responsible for the development of the testes
- The SRY gene switches on at week 7 on embryonic development
- In the absence of the SRY gene, the ovaries develop
- The testes produce AMH & testosterone
4
Q
*What are the gonads & what is the precursor for gonads ?
A
- The gonads are the ovaries in females & the testes in males
- After fertilization, a pair of gonads form
- The GENITAL RIDGE PRIMORDIA is the precursor for gonads
- It is located on posterior wall of the lower thoracic lumbar region
5
Q
What are the three main cell types that migrate to the genital ridge during gonadal development?
A
- The genital ridge is the precursor for teh gonads
- Three waves of cells invade the genital ridge during gonadal development
1. PRIMORDIAL GERM CELLS - develop into spermatozoa (males) & oocytes (females)
2. PRIMITIVE SEX CORDS - develop into Sertoli cells (males) & Granulosa cells (females)
3. MESONEPHRIC CELLS _ develop into Leydig (males & the Theca cells (females)
6
Q
** What happens during primordial germ cell migration?
A
- At 3 weeks, a small cluster of diploid embryonic cells in the yolk sac expand by mitosis
- These primordial germ cells then migrate to the genital ridge but they move through the connective tissue of the hindgut & region of the developing kidney first
7
Q
***What are the primitive sex cords?
A
- The primitive sex cords migrate inwards
- The cells of the germinal epithelium which are located on the genital ridge will migrate inwards to form columns known as PRIMIITIVE SEX CORDS
- In males these primitive sex cords will go on to develop Sertoli cells & Granulosa cells in females
8
Q
*What do the primitive sex cords in males do?
A
- The primitive sex cords in males develop into Sertoli cells
- The primitive sex cords penetrate the MEDULLARY MESENCYME & surround the primordial germ cells (spermatozoa) to from the testis cord.
- The testis cord is the precursor for the seminiferous tubules
9
Q
What do the primitive sex cords in females do?
A
- The primitive sex cords in females develop into Granulosa cells
- The primitive sex cords in females are less well defined & don’t penetrate the medullary mesenchyme as deeply
- The primitive sex cords form small clusters around the primordial germ cells (oocyte) which are the precursors for ovarian follicles
10
Q
What do Sertoli cells in males do?
A
- Sertoli cells develop from the primitive sex cords
- The primitive sex cords express SRY which leads to the development of the testes
- Sertoli cells express Anti-Mullerian Hormone (AMH) which causes the regression of the Mullerian duct
- Located in the seminiferous tubules & are involved in spermatogenesis (primordial germ cells -> spermatozoa)
11
Q
Where do mesonephric cells originate & what are they?
A
- Mesonephric cells orginate from the MESONEPHRIC PRIMORDIUM lateral to the genital ridge
- The mesonephric cells develop into the Leydig cells in males & Theca cells in females
12
Q
*What do the mesonephric cells in males form?
A
- The mesonephric cells in males act under the influence of pre-sertoli cells which express SRY & go on to develop:
1. Vascular tissue
2. Basement membrane
3. Leydig cells
13
Q
What do Leydig cells do?
A
- Leydig cells develop form mesonephric cells
- Leydig cells don’t express SRY but synthesize testosterone
- Found in the spaces between the seminiferous tubules of the testes
14
Q
What do the mesonephric cells in females from?
A
- In females, there’s no SRY so without SRY expression the mesonephric cells form:
1. Vascular tissue
2. Theca cells - may go onto secrete androgens but not during embryonic development
15
Q
What is the Mullerian duct?
A
- The Mullerian ducts is involved in the development of internal female genitalia
- Develops into uterus, uterine tubes & upper third of vagina
- Females don’t have testes, so no Sertoli cells are produced therefore no AMH, allowing Mullerian duct to grow
- No Leydig cells = no testosterone so no development of Wolffian duct
16
Q
What is the Wolffian duct>
A
- The Wolffian duct is responsible for development of male internal genitalia
- The differentiation of the Wolffian duct is stimulated by testosterone into structures such as the vas deferens, seminal vesicles & part of the prostate
- Sertoli cells of the testis produce AMH, causing regression of the Mullerian duct
- Leydig cells produce testosterone which stimulates Wolffian duct differentiation
17
Q
What enzyme converts testosterone into dihydrotestosterone?
A
- 5 alpha reductase converts testosterone into dihydrotestosterone in the genital skin. It uses NAPH to produce NADP & H+
- 5 alpha reductase is also present in females, but the lack of testosterone means there’s no development of male genitalia
18
Q
What are the effects of DHt & how is it involved in external male genitalia formation?
A
- Dihydrotestosterone (DHT) is more potent than testosterone but binds to the same receptor as testosterone
- DHT is needed for teh formation of external genitalia in males:
1. Clitoral area enlarges into penis
2. Fusion of labia & become ruggated to from scrotum
3. Prostate froms
19
Q
Describe the formation of external genitalia in males & females?
A
- GENITAL TUBERCLE:
- > Males = Glans penis
- > Females = Clitoris - URETHRAL FOLD:
- > Males = Penile urethra
- > Females = Labia minora - GENITAL SWELLING:
- > Males = Scrotal swelling -> Scrotum
- > Females = Labia majora
20
Q
*What are the three classes of sexual differentiation disorders?
A
- GONADAL DYSGENESIS - incomplete sexual differentiation leading to abnormal development of gonads
- SEX REVERSAL - Phenotype doesn’t match genotype, e.g genetically male but phenotypically female
- INTERSEX - ambiguous genitalia or components of both tracts (Mullerian & Wolffian)
21
Q
What happens in Androgen insensitivity syndrome?
A
- Androgen sensitivity occurs when an individual produces testosterone but cannot respond to it, could be issues with receptor
- So they are genotypically male but phenotypically female or ambiguous
- It can be complete or partial depending on the extent of androgen insensitivity
- XY = testes = sertoli cells & leydig cells
- Sertoli cells produce AMH so Mullerian ducts regress
- Leydgig cells produce testosterone but cannot respond to testosterone. No differentiation of Wolffian duct & no external male genitalia develops as DHT also binds to testosterone receptor
- INTERNAL GENITALIA = NONE but testes present which don’t descend as there’s no formation of the scrotum
- EXTERNAL GENITALIA = Female as default because testosterone cannot cause external male genitalia development
22
Q
What are the symptoms of Androgen insensitivity for diagnosis?
A
- Primary amenorrhea & lack of body hair - no menstruation as there’s no development of the Mullerian duct
- XY genotype but female phenotype with undescended testes
23
Q
What happens in 5 alpha reductase deficiency?
A
- 5 alpha reductase is needed for the conversion of testosterone into DHT
- A deficiency will mean that testosterone is produced but cannot be converted into DHT.
- EXTERNAL MALE GENITALIA = female or ambiguous as DHT is needed for external male genitalia development
- INTERNAL MALE GENITALIA = Male as Wolffian duct will be stimulated by testosterone & Mullerian duct will regress sue to AMH production by Sertoli cells
24
Q
What happens in Turner’s Syndrome?
A
- Genotype = XO, missing one X chromosome
- Internal genitalia = female & external genitalia = female
- Can have ‘streak’ ovaries which are small or underdeveloped as two X chromosomes are needed for ovarian development
- Uterus & tubes are present but there be other defects in growth & development
- Mainly due to mosaicism , stage of development at which X was lost determines presentation
- Loss of X in early stages = severe presentation but milder if only some cells don’t have an X chromosome
25
Describe how the different steroid hormones are made?
- Cholesterol is the precursor to the steroid hormones. It has 27 C with a carbon side chain
- Cleavage of this side chain produces PROGESTAGENS (progesterone, pregnenolone) with 21C
- These progestogens can be converted into glucocorticoids (cortisol) or mineralocorticoids (aldosterone) also with 21C
- Cleaving 2C produces ANDROGENS with 19C
- Cleaving 1C produces EOSTROGENS with 18C
- CHOLESTEROL -> PROGESTAGENS -> CORTISOL or ANDROGENS -> ESTROGENS
26
*What happens in Congenital adrenal hyperplasia ?
Congenital adrenal hyperplasia refers to a group of rare, inherited disorders where there's a deficiency in the enzymes involved in making adrenal hormones including cortisol. It leads to enlargement of the adrenal gland
27
What can happen to an XX embryo with congenital adrenal hyperplasia?
- CAH could involve a defiency in 21 hydroxylase which is the enzyme involved in the conversion of progestagens into cortisol.
- So a deficiency of this enzyme will lead to low cortisol levels, the low cortisol levels will stimulate an increase in CRH & ACTH due to negative feedback
- The ACTH will cause rapid uptake of cholesterol into the adrenal gland & causes upregulation of P450 cc which cleaves the side chain of cholesterol
- However, the progestagens produced as a result cannot be converted into cortisol & will therefore be converted into androgens
- These androgens (testosterone & DHT) will lead to the masculinisation of the external genitalia
-
28
What are the consequences of high levels of androgens due to congenital adrenal hyperplasia on an XX embryo?
XX = no AMH from Sertoli so Mullerian ducts remain
- High levels of DHT cause external male genitalia development but the testosterone levels aren't high enough to cause differentiation of the Wolffian duct
- 21 hydroxylase can also lead to a lack of aldosterone which can lead to salt wasting
