Reproduction endocrinology

Question 1

Terminology: What is the difference between sexual determination and sexual differentiation?

Answer 1

Sexual determination is the genetically controlled process dependent on the ‘switch’ on the Y chromosome - chromosomal determination of male or female.

Sexual differentiation is the process by which internal and external genitalia develop as male or female.

Question 2

Which gene creates the testis?
Where is it located (chromosome level)?

This question is about: testis-determining factor (TDF)

Answer 2

The testis-determining gene is located on the Y chromosome!

Testis-determining factor (TDF) has been mapped to the short arm of the Y chromosome - turns out to be a single gene called SRY (for Sex-determining Region Y ).

After week 7 it switches on to make the gonad differentiate into testis.

In the absence of Y chromosome ovaries would develop (when XX is present).

Question 3

What cells does the testis develop and what 2 important hormones do they make?

Answer 3

Sertoli cells: produce anti-Mullerian hormone (AMH)
Leydig cells: make testosterone (from cholesterole

Question 4

What are Primitive Sex Cords and how do they develop?

What do they depend on? (expression of…).

Answer 4

Cells from germinal epithelium that overly the genital ridge mesenchyme migrate inwards as columns called primitive sex cords.

The combination of germ cells and primitive sex cords forms the indifferent gonad – from which development into the testes or ovaries can occur.

They depend on SRY gene expression (located in Y chrom.)

M: SRY expression -> testis cords -> sertoli cells -> anti-Müllerian hormone (AMH) production
F: No SRY expression -> granulosa cells -> estradiol production

Question 5

What does testosterone do?

(stimulates…)

Answer 5

1) Stimulates Wolffian ducts - lack of stimulation by testosterone means regression of Wolffians (such as in females)

To mention few examples of Testosterone dependent (anatomical) development: Prostate, Bulbourethral glands, Penis, Scrotum, Brain masculanization.

Question 6

What are the different ‘levels’ of sex differentiation?

1.
2.
3.
4.
5.

Answer 6

1. genotypic sex
2. gonadal sex
3. phenotypic sex
4. gender identity
5. legal sex (not covered at course, just additional layer to be aware of)

Question 7

What does AMH do?

AMH = Anti-Müllerian hormone

Answer 7

Inhibits Mullerian ducts (which are important in female) - so will be present in males (Wolffian ducts):

When AMH is present: Wolffian ducts- for males: develop into internal male genitalia (epididymis, seminal vesicles, vas deferens, ejaculatory duct)

Question 8

Describe female internal sexual differentiation (in short).

1) No Y chromosome –> ?
2) XX –>

Answer 8

No Y chromosome -> no SRY -> no testis -> no Anti-Müllerian hormone (AMH)

Ovaries develop (XX is needed!)

(No AMH ->) Müllerian ducts form: uterine tubes (oviducts), uterus, cervix, and upper 3rd vagina

> Upper ends of ducts stay open and form ends of uterine tubes
Lower portions fuse to form a single cavity uterus

NOTE: All gender differentiation starts already at fertilization!

Question 9

What does 5-a-reductase enzyme produce?

Answer 9

Produces a more potent androgen - DHT (dihydrotestosterone) from testosterone.

DHT binds to androgen receptors more strongly and sticks around longer than testosterone.

Question 10

What happens in terms of sexual differentiation in the absence of DHT?

Answer 10

The female external genitalia form instead; clitoria, labia and lower 2/3rds of vagina.

Question 11

What two ducts do bipotential gonads contain?

Anti-Müllerian hormone (AMH) has an importan role here

Answer 11

(No AMH ->): Müllerian ducts- for females: develop into internal female genitalia (uterus, cervix, upper 3rd vagina + uterine tubes (oviducts))

(AMH ->): Wolffian ducts- for males: develop into internal male genitalia (epididymis, seminal vesicles, vas deferens, ejaculatory duct)

Anti-Müllerian hormone (AMH)

Question 12

How does dihydrotestosterone (DHT) cause differentiation in males?

Answer 12

Causes differentiation of the male external genitalia:

Clitoral area enlarges into penis
Labia fuse + become ruggated to form scrotum
Prostate forms

Note: Testosterone and DHT are both androgens, but the DHT hormone is much more potent. It binds to androgen receptors more strongly and sticks around longer than testosterone.

DHT is actually made from testosterone by 5-alpha-reductase enzyme.

Question 13

What is Androgen Insensitivity Syndrome (AIS)?

(Tip: there are two types of AIS: partial and complete AIS)

Answer 13

The testes are able to form due to the presence of the SRY gene –> AMH is present –> Müllerian (female duct) regresses!

NOTE: Testosterone is made, but it cannot exert an effect due to the absence of receptors.

The Wolffian (male duct) tract/internal male genitalia and external male genitalia (via DHT hormone) therefore do not develop and so the phenotype is female.

These individuals present with primary amenorrhoea.

Question 14

What is gonadal dysgenesis (about sexual differentiation)? Any related syndromes?

Answer 14

Sexual differentiation is incomplete due to partial or complete regression of the gonad - Androgen Insensitivity Syndrome (AIS), intersex and congenital adrenal hyperplasia (CAH), all cause gonadal dysgenesis, with individuals having ambiguous genitalia.

Question 15

What happens in Turner’s Syndrome (45 XO), where 1 of the X chromsomes can be missing?

Answer 15

Ovary develops, Mullerian ducts develop, so Wolffian ducts do not (Wolffian ducts develop when AMH present). The external genitalia appear female.

However, you get ‘streak’ ovaries = ovarian dysgenesis - which illustrates the need for 2 Xs for ovarian development.

Uterus and tubes are present but small, other defects in growth + development. May be fertile, many have mosaicism. Hormone support of bones + uterus.

Women with karyotype [45,X], mosaic [ 45,X/46,XX ], or structurally abnormal X.

NOTE: Mosaic is a condition in which some cells have a composition (45,X), while other cells have a different composition (46,XX)) within the same individual!

The diagnosis can be made during pregnancy or at birth, but is often only discovered in the teenage years when examining short height, lack of sexual maturation, primary amenorrhea, or repeated abortions.

1 of approx. 2000-3000 newborn girls. In Denmark 17-18 new cases annually. This is a patient you can see in the clinic!

Question 16

What is congenital adrenal hyperplasia (CAH)?

Answer 16

Congenital adrenal hyperplasia (CAH) is genetic disorder affecting adrenal glands, and can cause symptoms affecting sexual development.

In CAH, the gene (21-hydroxylase) that is needed for 21-hydroxylase enzyme production is not working properly. 21-hydroxylase is needed to convert adrenal androgens to cortisol.

In the absence of cortisol, the adrenocorticotropic hormone (ACTH) is high, and it stimulates adrenal hyperplasia and excessive androgen production, which mimics DHT in females to cause masculinization of the external genitalia.

Question 17

What happens if an individual with XY has 5-a-reductase deficiency?

Answer 17

Testosterone is made but not DHT.
The lack of 5-alpha-reductase –> testosterone does not turn into DHT –> no development of the external genitalia in fetal life, but develop normal male internal genitalia. As the external structures do not develop.

These individuals may appear female OR have ambiguous genitalia: at puberty, the production of testosterone is so great that this can cause the development of secondary male sexual characteristics without DHT –> male sexual characteristics.

Degree of enzyme block varies, as does the presentation as well due to it.

Testicles probably not descended/descended (happens usually in the 7th month). Pseudohermaphrodism in that the male gonads are present, but there are female genitalia.

Question 18

What do Theca cells produce?

Answer 18

Synthesize androstenedione, which is a substrate for estradiol production by the granulosa

Question 19

After fertilisation a pair of gonads develop which are bi-potential (neither testis or ovaries). What determines differentiation of the bi-potential gonad into a testis or an ovary?

Answer 19

Depends upon the sperm that fertilises the oocyte…

1) Y sperm -> testes due to the SRY gene located on the Y chromosome: codes for the testis, i.e. strong testis-determining effect on the undifferentiated (primordial) gonad. That is, if there is a Y, they present as a man, and if NOT, they present as a woman!
2) X sperm -> ovary (needs XX)

More:
Y-chromosome: Primordial gonad becomes a testicular system with Sertoli and Leydig cells
…. and in absence of Y: an ovarian system (granulosa and theca cells, but does not play an active role)

Question 20

What is the difference between partial and complete Androgen Insensitivity Syndrome (AIS)?

Answer 20

1) Complete - appear completely female at birth and assigned female gender despite being XY, have undescended testes. Present with primary amenorrhoea + lack of body hair. Appear and feel female.

2) Partial - some penile/scrotal development from ambiguous genitalia to large clitoris. Much more complex for parents and patient.

Question 21

Six key hormones in pregnancy?

Answer 21

1. HUMAN CHORIONIC GONADOTROPIN
2. PROGESTERONE
3. OESTROGEN
4. PROLACTIN
5. RELAXIN
6. OXYTOCIN

Question 22

Testosterone can be converted to
1)
2)
3)
hormones, and back again!

Answer 22

1) estradiol (different effect)
2) DHT (stronger effect and
3) androstenedione (weaker hormone)

Question 23

Two components of the menstrual cycle (consists of)?

Answer 23

1) Ovarian cycle (has 2 phases = follicular and luteal)
2) Endometrial cycle (has 3 phases (proliferative, secretory and menses)

Question 24

How long is the Luteal phase?

How about Follicular phase?

Answer 24

The luteal phase is always 14 days, Ovulation in between the phases, and the follicular phase can vary –> varying cycle length (average 28 days)

Question 25

Breast feeding:
What happens when there is stimulus (sucking)?

Answer 25

There is sucking -> afferent nerve signal to the spinal cord -> on to the hypothalamus -> inhibition of dopaminergic neurons -> ↓ Dopamine -> no inhibition of lactotroph cells in the adenohypophysis -> PROLACTIN release!!!

The let-down reflex: sucking -> afferent nerve signal to the spinal cord -> hypothalamus -> OXYTOCIN release -> contraction of myoepithelial cells in alveoli and ductuli (and possibly also smooth muscle cells in the uterus) -> milk is expelled.

There is sucking -> afferent nerve signal to the spinal cord -> hypothalamus -> inhibition of GnRH producing cells -> ↓ GnRH -> no pulsatile release -> no LH/FSH -> no menstrual cycle!

Question 26

Fill in the gaps:
After the 8th week of gestation, the placenta is the primary source of
1)
2)
hormone production.

Answer 26

1) progesterone
and 2) estrogen.

Contributes to the growth of the uterus + mammae and nutrition of the fetus.

Estriol is the primary estrogen during pregnancy.

Question 27

Which placental hormone is used in pregnancy tests?

This hormone is produced first by:
1) ——- during the ——– months
2) and later by placenta.

Fill in ——-

Answer 27

hCG (human chorionic gonadotropin).

hCG is produced by:
1) the syncytiotrophoblast during the first 2 months
2) and later by placenta.

Corpus luteum-preserving

It is the hCG increase that causes nausea in the first trimester !

Question 28

The 2 main processes that the hypothalamic-pituitary-gonadal axis controls in MALE?

How about female?

GnRH has an important role in the whole process

Answer 28

Overall, the axis controls (in male):
1) Production of testosterone (androgens)
2) Spermatogenesis

LH stimulates Leydig cells –> Androgens (testosterone)
FSH stimulates Sertoli cells –> Androgen binding protein (keeps testosterone concentration high locally). Stimulates also Inhibin and Growth factors for Leydig cells, and Spermatogenesis.

Rule to remember: LH acts on Leydig and FSH acts on Sertoli with sperm production.

Cancellation of GnRH pulsation by continuous GnRH influence –> therapeutic by e.g. c. prostate (Androgen is a growth factor for prostate cancer and LH/FSH is inhibited by continuous GnRH influence (opposite pulsative)).

In female: GnRH stimulates gonatrope cells in the adenohypophysis to release LH and FSH.

LH stimulates Theca cells –> androstenedione + progesterone
FSH stimulates Granulosa cells: aromatase (converts testosterone to estradiol and androstenedione to estrone, i.e. androgens to oestrogens)
Stimulates also inhibin (neg. feedback on FSH + growth factor on Theca cells)

Pulsatile release of GnRH.
Continuous GnRH exposure down-regulates LH/FSH release (as in men)
Used for gynecological disorders where suppression of the gonadotropins is desired to reduce endogenously produced oestrogens, e.g. endometriosis, fibromyomas and puberty praecox. Also to inhibit the endogenous gonadotropins during stimulation treatment as part of in vitro fertilization (IVF).

Kallmann’s syndrome: Lack of GnRH neurons in the brain.
Can be treated with pulsatile GnRH administration with a pump and women can get pregnant normally.
Without treatment = hypogonadotropic hypogonadism.

More: Consists of alpha and beta polypeptide chain: LH, FSH, HCG and TSH have identical alpha units. HCG and LH also have almost identical beta subunits. Released pulsatilely, as GnRH is released pulsatilely GnRH receptor is Gq coupled and FSH and LH receptors are Gs coupled.

Question 29

Inhibin inhibits the gonadotropin-releasing hormone (GnRH) at the _____________ level, and steroid sex hormones both at the ____________ and _____________ levels.
(Tip: in the brain)

Answer 29

Inhibin inhibits GnRH at the pituitary level and steroid sex hormones both at the pituitary and hypothalamic levels.

Question 30

Gonadotropin-releasing hormone (GnRH) is a ______________, which is synthesized and released from____________________________.

Answer 30

Gonadotropin-releasing hormone (GnRH) is a peptide hormone, which is synthesized and released from GnRH neurons within the hypothalamus.

Question 31

___________ is the primary estrogen during pregnancy.

Answer 31

Estriol is the primary estrogen during pregnancy.

Question 32

What is Klinefelter syndrome?

Answer 32

Klinefelter’s syndrome is the most common form of male hypogonadism and the most frequent chromosomal abnormality in men.

At approx. 1 per 500 live-born boys, i.e. 0.2% in the general population.
Relatively frequent cause of infertility (Something you are presented with in the clinic).

Testosterone deficiency
missing neg. Feedback –> increased LH
Low local testosterone concn. in the testis –> small testis and lack of spermatogenesis

Possible measurement of Inhibin B (normal Inhibin B indicates current spermatogenesis)

Few people are diagnosed before puberty. In a Danish study, fewer than 10% with Klinefelter’s syndrome had been diagnosed before puberty.

Treatment: Testosterone. Helps with potency, libido and bone strength, but does not provide sperm production. Gynecomastia can be treated with plastic surgery

Question 33

What do we mean when talking about Primary sex characteristics?

How about Secondary sex characteristics?

Answer 33

Primary sex characteristics refer to the sexual organs (uterus, vagina, penis, and testes…).

Secondary sex characteristics refer to other visible changes that mark adult maturation such as changes in height and body shape.

Question 34

One of the earliest puberty events is GnRH surge (pulsatile release!) during __________ .

Answer 34

… during REM sleep!

Question 35

Fetuses lack 3β-hydroxysteroid dehydrogenase and aromatase –> cannot produce
1.
2.
hormones.

The placenta lacks 17alpha-hydroxylase, 16alpha-hydroxylase and 17,20 desmolase –> cannot produce _______ hormones (group) for aromatization.

Answer 35

Fetuses lack 3β-hydroxysteroid dehydrogenase and aromatase –> cannot produce
1. progesterone and 2. estrogens.

The placenta lacks 17alpha-hydroxylase, 16alpha-hydroxylase and 17,20 desmolase –> cannot produce ANDROGENS for aromatization.