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Flashcards in Sex differentiation pt 2 Deck (51):
1

What is the hypothalamo-pituitary-gonadal axis?

It is the interaction between the brain (hypothalamus), pituitary gland, and gonads. Gonads stimulate gametogenesis and hormonogenesis. Hormonogenesis also leads to electrolyte homeostasis, fuel and protein metabolism, and adiposity and muscle mass.

2

How does the hypothalamo-pituitary-gonadal axis affect different stages of life?

It firstly affects sex determination in the fetus, especially in males. Then it affects sexual changes in puberty for both sexes. Sex hormones then have a special role during pregnancy and parturition in the female (augmented by placental hormones). It finally is important in both sexes at menopause and andropause.

3

What are plasma testosterone levels like throughout life?

There are two medium peaks (around 250ng/dL) at both fetal and neonatal periods, then it stays low during pre-pubertal phase, and has its highest peak around 500ng/dL, and starts decreasing once adulthood kicks in.

4

How does DHEAS (dehydroepiandrosterone sulfate) change with age?

it increases and peaks around 25 years old, for both male and female. It shows the change in adrenal androgen expression (adrenarche).

5

What are the changes in plasma concentration for FSH and LH in male and women?

Male: FSH levels increase constantly but more at stage 2, as LH increases slightly throughout all puberty.
Female: FSH increases and stabilizes towards stage 4-5, as LH increases slowly and peaks at mid puberty (stage 3) until end of puberty (stage 5).

6

What do the different stages of puberty mean for male and female?

There are 5 stages for puberty:
Male - stage 2 is beginning enlargement of testes, stage 3 is penile enlargement, stage 4 is growth of the glans penis and stage 5 is adult genitalia.
Female - stage 2 is breast buds, stage 3 is elevation and enlargement of breasts, stage 4 is the projection of areolas and stage 5 is adult breasts.

7

Where does the word puberty come from and what it means?

It is from the latin puberta, which means "to grow hair".
Puberty includes all of the physiological, morphological and behavioural changes that occur in the growing animal as gonads/brain/phenotype change from adolescent to adult.

8

What marks the beginning of puberty in female and male?

Male: first ejaculation (semarche)
Female: first cycle (menarche)
These events do not signify fertility though.

9

How is puberty controlled by GnRH?

Neural mechanisms regulate the pulsatilty GnRH from the hypothalamus (Adult = 90 minutes; Puberty = diurnal). The pulsatile release regulates sexual development. LH, FSH and GnRH are present before puberty but are not released until then because tonic centers are extremely sensitive to negative feedback.

10

What are two ways to induce pulsatile release of GnRH?

1. Gonadotropins can stimulate the pulsatile release of gonads in children
2. Administering GnRH in a pulsatile fashion can induce menstrual cycle in monkeys

11

How do the GnRH neurons work before puberty?

In both female and male, GnRH neurons in both tonic center and surge center of the hypothalamus release low amplitude and low-frequency pulses of GnRH.

12

How do the GnRH neurons work after puberty?

In female, the tonic center controls basal levels of GnRH but they are higher than in the prepubertal female because the pulse frequency increases. the surge center controls the preovulatory surge of GnRH.
In male, there is no development of a surge center.

13

What is the overall endocrine mechanism of puberty?

At the onset of puberty, levels of GnRH rise (both amplitude and frequency). Increased pulses secreted from the hypothalamus cause by a decreased sensitivity of tonic center in order to negative feedback from gonadal steroids (surge center doesn't change sensitivity, simply that E2 levels aren't high enough to stimulate the surge release before puberty).

14

What happens in response to increased pulses of LH/FSH?

Levels of steroids increase to support spermatogenesis or folliculogenesis.

15

What is kisspeptin (KISS1) and what does it do?

KISS1 is secreted from neurons whose cell bodies are located in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei of the hypothalamus. It signals through its receptor (KISSR1) to regulate pulsatile secretion of GnRH from GnRH neurons.

16

What are GnRH neurons?

They are KISS peptin neurons, and they develop during puberty. These regulate the release of GnRH associated with development. KISS peptin alters pulsatility of GnRH, which in turn regulates the pulsatility of FSH and LH.

17

Explain the estradiol-kisspeptin- GnRH positive feedback circuit.

Rising levels of estradiol act to increase kisspeptin expression that then amplifies GnRH neuron activity in a positive feedback manner leading to the completion of puberty onset. After puberty onset, kisspeptin levels fluctuate with the cyclical levels of estradiol to drive the generation of the preovulatory GnRH/LH surge.

18

What is the relationship between age of puberty and body weight in girls?

Age of puberty in girls has been changing but the body weight has not; constant at 47kg is the weight that must be obtained for the activation of the hypothalamic-pituitary-gonadal axis.

19

How has the timing of puberty changed over time?

It has become earlier over the past century due to better nutrition and health, so achieving a weight of 47kg is faster.

20

What are the 3 types of GnRH pulsatility?

A. Pulsatile GnRH (amplitude and frequency modulated by steroid feedback). Pulsatile LH/FSH (response to GnRH modified by estrogen feedback).
B. Long-acting GnRH analog will cause desensitization because will want to reproduce pulsatility factor to stimulate the reproductive axis
C. Reduced (or absent) GnRH will require exogenous GnRH, causing little or no gonadotrophin response.

21

What is GnRH?

Small peptide of 10 a.a. cleaved from a larger precursor and released with gonadotrophin associated peptide (GAP). It is synthesized by about 1000-3000 neurons in the hypothalamus. GnRH can also be synthesized in the placenta, gonads, breast, lymphocytes and pituitary.

22

How is the structure of LH and FSH from GnRH?

It is a glycoprotein with a common alpha subunit, which is also part of TSH and human chorionic somatotropin), and different Beta subunit that provides specificity (one for LH, one for FSH). Changes in glycosylation can lead to different isoforms with different biological properties. They are G-linked, meaning that they activate cAMP and phospholipase C (LH and hCG). Pulsatile release in response to GnRH.

23

What are the effects of gonadotrophs on gonads?

LH stimulates Thecal/Leydig cells, which in turn stimulate both cAMP and phospholipase C, which stimulate PKA, PKC and Ca2+ release. FSH stimulate granulosa/sertoli cells through cAMP, stimulating PKA as well. PKA, PKC and Ca2+ all contribute to oogenesis, spermatogenesis and steroidogenesis.

24

What are the actions of LH and FSH?

- Increase of intracellular cholesterol
- Transport of cholesterol to the inner mitochondrial membrane by StAR (rate limiting step)
- Conversion to pregnenolone by side chain cleavage
- Target cells and actions differ in male and female
- Testis: only LH is steroidogenic (acts on Leydig cells)
- Ovaries: both LH and FSH are steroidogenic act on several cell types (theca interna and granulosa cells)

25

What are the three different cell types of importance in spermatogenesis?

Spermatogonia, sertoli cells and leydig cells. The sertoli cells are located inside the seminiferous tubules (Leydigs outside of the system). They are made up of aploid cells, so they are perceived as foreign tissue, so isolated from immune system (outside of seminiferous tubules). Spermatogonia cells have access to content of extracellular fluid.

26

What are the two main androgens secreted by testes?

DHEA and testosterone

27

How much do the testes secrete per day?

4-10 mg a day. 98% are bound to albumin and sex-hormone-binding globulin (SHBG).

28

What does testosterone act on?

internal genitalia development and muscle cells

29

Do all target cells have active testosterone?

No, some target cells don't have active testosterone and need to first convert it into DHT (dihydrotestosterone).

30

What can testosterone also be converted to in some target tissues?

Estradiol

31

What enzyme(s) can convert testosterone into DHT or E2 in certain target tissues?

aromatase (E2) or 5 alpha reductase (DHT)

32

What do androgens do in males as for secondary sex characteristics?

Skeletal muscle growth, larynx development, hair growth, behavioural changes, spermatogenesis, epiphyseal fusion and termination of growth of the long bones, change in excretion of sebaceous gland (= acne)

33

Describe spermatogenesis.

1. Spermatogonia are laid down in the testes in the fetal period
2. At puberty, spermatogonia start to divide and continue to do so throughout the adult like (mitotic proliferation)
3. Sporadically a daughter cell will differentiation ( = primary spermatocyte) and undergo meiosis (first meiotic division= secondary spermatocyte; second meiotic division = spermatid)
4. Sertoli cells (nurse cells) are essential (secretion of a steroidal mitotic factor and androgen binding protein to concentrate testosterone in seminiferous tubules)
5. Further differentiation in the epididymis, ejection together with secretions from the seminal vesicles and the prostate gland, "capacitation" in the female reproductive tract.

34

What are the steps in the development of spermatozoa in the sertoli cells?

It starts with the spermatogonia in the basal compartment, which travels through a tight junction to reach the adluminal compartment to become sperm 1. It then matures into sperm 2, then into a spermatid to be excreted from the sertoli cell and into the lumen of the seminiferous tubule.

35

What happens to the spermatid once it reaches the seminiferous tubules?

The sperm further matures in both the seminiferous tubules and the epididymis.

36

What is the mechanism behind prostate cancer?

Prostate will excrete a serine protease (PSA or prostate specific antigen), which inactivates the sperm mobility inhibitor semenogelin. This serine protease is elevated in prostate cancer. *in men, prostate cancer is the most frequent cancer in industrialized countries

37

What happens to the prostate as humans (or dogs) age?

The prostate, encircling the urethra, enlarges as men/dogs gets older, which eventually restricts urine flow (about 80% of men over 70 y.o.)

38

What are the current treatments for prostate enlargement?

1. Surgical enlargement of the urethra and removal of a part of the prostate
2. Treat with anti-androgens (in old age, prostate more responsive to testosterone - due to increased # of receptors) i.e. suppress testosterone = suppress enlargement

39

How do you detect prostate cancer?

Rectal palpation and/or PSA levels

40

What is the prevalence and mortality prostate cancer in males?

29% of all male cancers
13% of cancer deaths
Especially age related >50y.o.

41

How is testicular function controlled?

- FSH stimulates sertoli cells and testosterone maintains gametogenic function of testis
- LH acts indirectly by stimulating the Leydig to produce testosterone
- FSH and testosterone act on the Sertoli cells which secrete factors (ABP - androgen binding protein, bioconcentrates in seminiferous tubules and epididymis) that promote spermatogenesis and maturation
- FSH facilitates the last stages of spermatid maturation
- Testosterone (and LH) are required for the maturation of spermatids to spermatozoa

42

What are the different methods of male contraception to this day?

Vasectomy, condoms. Growing need for alternatives due to the increasing world population.

43

What would the ideal male contraceptive be?

- Rapidly effective and fully reversible
- not interfere with other testosterone-dependent processes (libido, secondary sex characteristics)
- have no short or long-term side effects
- have no impact on eventual offspring
- be more effective than current methods (vasectomies, condoms)
- be acceptable for both partners

44

What characterizes spermatogenesis?

- The production of sperm
- Occurs in the seminiferous tubules (testes)
- Diploid spermatogonia undergo a series of divisions and differentiation to form haploid spermatozoa
- Stored mainly in epididymis
- Entire process takes 60-70 days (man) produce 120 million sperm/day

45

what hormones act on sertoli cells for spermatogenesis?

- Testosterone from Leydig cells (androgen)
- FSH (gonadotrophin from anterior pit.) acts on sertoli cell to increase ABP in testes to allow high [testosterone] in seminiferous tubule

46

How do male hormonal contraception methods work?

They are based on testosterone and progestins to:
- suppress LH and FSH by increasing negative feedback from sex steroids
- deplete intra-testicular testosterone and ABP therefore less testosterone in the seminiferous tubules and spermatogenesis inhibited (testosterone bioconcentration = required for spermatogenesis)
- substitute peripheral testosterone to maintain libido and secondary sex characteristics
--> in either the form of oral administration or long acting injections

47

What happens in the recovery period after a steroid treatment (that decreases sperm concentration) ?

Gradual recovery of spermatogenesis over months have side effects such as acne, higher levels of testosterone, etc.
Examples of steroid treatments are anabolic steroids (stanozolol), GnRH antagonists + testosterone, FSH antagonists, inhibin agonists, etc.

48

How does the regulation of LH and FSH secretions work in males?

- GnRH is released episodically in pulses occurring every 90 min. Negative feedback by testosterone
- LH: negative feedback mainly by testosterone
- FSH: negative feedback mainly by inhibin produced by Sertoli cells in response to FSH

49

What are inhibins and activins?

alpha-chain and beta-chain are encoded by different genes. Inhibins inhibit FSH release. Activins stimulate FSH release.
Women have circulating inhibin A and B, men only have B.

50

Compare the hypothalamo-pituitary axis in men vs women

Both: hypothalamus releases GnRH to stimulate the pituitary gland to release FSH and LH. Inhibin secreted by sertoli cells (men) and by ovaries (women) have negative feedback on the pituitary.
Differences: in men, LH stimulates the leydig cells to produce testosterone, FSH stimulates sertoli cells to produce inhibin. Testosterone negatively feedbacks to both the hypothalamus and the pituitary. Testosterone positively feedbacks to sertoli cells to produce more inhibin. In women, LH stimulates the ovaries to produce oestradiol and progesterone, FSH stimulates the release of inhibin from ovaries. Oestradiol and progesterone positively or negatively feedback to hypo/pit.

51

What causes male infertility?

- A defect in spermatogenesis causes 30% of cases of lack of conception
- lack of LH or FSH
- Overproduction of prolactin ( = testicular involution)
- Primary failure of testes (i.e. undescended testes)
- Reduced sperm mobility
- Autoimmune response to sperm
- Chromosomal abnormality (= 47XXY karyotype in Klinefelter syndrome)