Neuroendocrine and feedback mechanisms in Reproduction

Question 1

What are the three main ways that the hypothalamus interacts with the pituitary gland?

Answer 1

• Hypothalamic inputs
• Feedback effects of circulating hormones
• Paracrine and autocrine secretions of the pituitary

Question 2

What is hypothalamic control of the pituitary gland?

Answer 2

A system that underlies the ability of mammals to coordinate endocrine functions that are necessary for survival.

Question 3

What is gonadotropin-releasing hormone (GnRH)?

Answer 3

A hypothalamic hormone that controls the release of luteinizing hormone and follicle-stimulating hormone from the pituitary.

Question 4

Where is GnRH released from?

Answer 4

arcuate and the preoptic nuclei of the hypothalamus

Question 5

How are LH and FSH released?

Answer 5

Stimulated by GnRH through the hypophyseal portal system. Released from the anterior pituitary gonadotrophs.

Question 6

What are the two types of GnRH secretion?

Answer 6

Pulsatile , Episodic

Question 7

What is pulsatile GnRH secretion?

Answer 7

Governs the release of the pituitary gonadotrophins.

Question 8

What factors can influence GnRH secretion?

Answer 8

Stress, exercise and diet

Question 9

When is GnRH first detectable?

Answer 9

10 weeks gestational age

Question 10

When are FSH and LH first produced?

Answer 10

10-13 weeks gestational age

Question 11

Compare the levels of GnRH from Birth to Adulthood.

Answer 11

BIRTH-6 MONTHS: elevated levels of GnRH, then subsequent decrease for the remainder of childhood

Pre-puberty: infrequent, small pulses of GnRH; LH and FSH secreted in very small amounts.

Puberty: Sharp increase in amplitude and frequency of pulses of GnRH

Adult: HPG axis activated continues to function in men and becomes deregulated in women (leads to menopause)

Question 12

Which factors contribute to the GnRH pulsatility ?

Answer 12

• Several hormonal and neural pathways that convey different types of regulatory information.
• Morphological changes in the GnRH neurons: Spontaneous auto-rhythmicity, functioning as an intrinsic mechanism to secrete GnRH in a pulsatile manner.

-Inhibitory as well as excitatory afferent signals from distinct neurotransmitters Noradrenergic, dopaminergic, serotoninergic, and opioidergic pathways; inhibitory neurotransmitters (GABA); excitatory amino acids (glutamic acid, aspartic acid).

• The kisspeptin-neurokinin b-dynorphin (kndy) neuronal network: Synergic action to induce coordinated and pulsatile GnRH secretion by regulating the neuroactivity of other KDNy cells.
• Steroids Negative Feedback
• Nutrition and metabolism: Adequate leptin level (peptide primarily produced by white adipose tissue) permits the activation of the GnRH pulse generator

Question 13

What are gonadotropins?

Answer 13

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that act on the ovaries and testes to direct gametogenesis and sex steroid hormone synthesis.

Question 14

What does LH do in males?

Answer 14

• stimulates Leydig cells to produce testosterone
• Induces and maintains spermatogenesis and secondary sexual characteristics

Question 15

What does FSH do in males?

Answer 15

stimulates spermatogenesis (sperm production)

Question 16

How is the synthesis and secretion of LH and FSH regulated?

Answer 16

• Hypothalamic input
• Positive and negative feedback from gondal sex steroid and peptide hormones
• Paracrine modulation from local factors produced within the pituitary gland

Question 17

What frequency of pulsative GnRH favours LH?

Answer 17

Rapid GnRH pulse frequencies

Question 18

What frequency of pulsative GnRH favours FSH?

Answer 18

• Slower pulse frequencies

Question 19

What are inhibins?

Answer 19

• Circulating endocrine hormones, that originate in the gonads and act on the pituitary , specifically inhibiting the FSH Beta subunit

Question 20

What are activins?

Answer 20

-Potent stimulatory effects on FSH expression
Produced in gonads and pituitary glands

Question 21

What is follistatin?

Answer 21

• A protein that binds activin and prevents activin binding to the activin receptor.
• Potent inhibitor of FSHB expression and secretion

Question 22

How do gonadal steroids control goandotropins?

Answer 22

• Regulate GnRHR expression and signalling
• Directly regulate the production of gonadotropins

Question 23

What two steroid hormones exert negative feedback effects on gonadotropin secretion in males?

Answer 23

Testosterone and oestradiol.

Question 24

How does Testosterone inhibit GnRH secretion?

Answer 24

Feeds back on the hypothalamus.

Question 25

How does testosterone inhibit LH secretion?

Answer 25

Feeds back at the level of the pituitary.

Question 26

What stimulates spermatogenesis?

Answer 26

FSH acts indirectly on Sertoli cells. Testosterone stimulates the final stages of spermatogenesis. - Sertoli cells release inhibin , which inhibits further release of FSH from the pituitary.

Question 27

What is the ovary responsible for?

Answer 27

- periodic release of oocytes and production of steroid hormones - integrated into cyclic process of follicular maturation, ovulation, and formation and regression of the corpus luteum.

Question 28

What does the ovarian cycle do?

Answer 28

governs the preparation of endocrine tissues and release of eggs.

Question 29

What does the menstrual cycle do?

Answer 29

Prepares and maintains the uterine lining

Question 30

What is the average length of the ovarian and menstural cycle?

Answer 30

- 22-32 day cycle - Average 28 days

Question 31

What is the most important role of the HPG axis in female reproduction?

Answer 31

To control the uterine (menstrual) and ovarian cycles.

Question 32

What are the phases in the menstrual cycle?

Answer 32

follicular phase, ovulation, luteal phase, menstruation

Question 33

What is the follicular phase?

Answer 33

- FSH and LH cause the growth of follicles on the surface of the ovary - LH acting on the Theca cells induce the secretion of androstenedione. - This is converted to oestradiol by aromatase secreted from the granulosa cell after FSH stimulation. - As the follicles grow, more oestrogens are released, which will inhibit the secretion of LH and FSH at hypothalamus. - Stimulation of only ONE follice.

Question 34

What is the process of ovulation?

Answer 34

- Day 14 of the menstrual cycle , due to oestrogen induced LH surge. -2 days before ovulation, the granulosa cells begin to develop LH receptors, as well as FSH. The dominant follicle keeps secreting more oestrogens. - The rising oestrogen levels make the pituitary gland more responsive to the GnRH - Oestrogens become a positive feedback signal , triggering the mid cycle ovulatory surge of LH and FSH secretion. - The increased LH and FSH , acting on the granulosa and theca cells facilitate the rupture of the follicle and the release of oocytes.

Question 35

What is the luteal phase?

Answer 35

- period of corpus luteum activity (days 14-28) - LH levels are still high and the remaining follicles turns into Corpus Luteum. - Luteinized theca cells respond to the low concentration of LH by producing Progesterone. - Luteinised granulosa cells secret inhibin which inhibits the secretion of FSH from pituitary gland. - Oestrogen levels decrease and progesterone levels increase. - Progesterone makes the endometrium receptive to the implantation of fertilised gamete and as negative feedback on the pituitary gland. - If the implantation does not happen, corpus luteum replaced corpus Albicans, no hormones produced, spiral arteries collapse = Menstruation.

Question 36

What are some defects of GnRH and GnRH receptors?

Answer 36

Defects in the process of synthesis, release and action of GnRH.

Question 37

What is hypogonadotropic hypogonadism?

Answer 37

deficient sex steroid production due to decreased gonadotropin secretion

Question 38

What is Kallmann syndrome?

Answer 38

Hypogonadotropic hypogonadism due to a lack of gonadotropin-releasing hormone (GnrH) due to failure of migration of the GnrH neuron from the olfactory bulb. These patients are anosmic and have primary amenorrhea.

Question 39

What are the effects of gonadotropin deficiency?

Answer 39

Hypogonadism with decreased sex steroid production.

Question 40

what is a GnRH agonist ?

Answer 40

- An analogue that activates the GnRH receptor resulting an increased secretion of FSH and LH.

Question 41

What happens when there is prolonged activation of GnRH receptors by GnRH agonists?

Answer 41

- Leads to desensitization and down regulation of GnRH receptors. Supresses gonadotrophin.

Question 42

What are GnRH agonists used for in females/ males?

Answer 42

- Female infertility to initiate an LH surge and ovulation - Uterine fibroids - Controlled Ovarian Hyperstimulation to supress endogenous LH surge and to prevent premature ovulation - Male Infertility due to hypothalamic hypogonadotropic hypogonadism. - Diagnosis of LH responsiveness in differentiating delayed puberty - Controlled ovarian hyperstimulation to supress endogenous LH surge and to prevent premature ovulation. Central Precocious puberty.

Question 43

What is a GnRH antagonist?

Answer 43

An analogue that blocks the GnRH receptor, resulting in an immediate drop in FSH, LH secretion. Men: Leads to a rapid suppression of testosterone release from the testes. Women: Leads to suppression of oestrogen release from the ovaries.

Question 44

What are GnRH antagonists used for?

Answer 44

Prevention of premature LH surge and ovulation for in vitro fertilization, advanced prostate cancer to reduce gonadotropins and androgens more rapidly than GnRH agonists. Avoids testosterone surge seen with GnRH agonist therapy.