Reproduction Lectures 2021 - THE ENDOCRINOLOGY OF REPRODUCTION Flashcards
The brain controls…
reproduction (through GnRH)
GnRH containing neurons mainly located in the…
ARCUATE nucleus within the hypothalamus
Posterior pituitary
extension of Hypothalamus with the SON & PVN neurons extending down into the posterior pituitary
Anterior pituitary
governed by hormones released from hypothalamus into the portal blood supply (“Hypothalamic-hypophysial portal system”)
- the ARCUATE NUCLEI that will be in the hypothalamus synapse with the neurohemal area known as the MEDIAN EMINENCE, & the contents of those neurons that are dumped into the portal blood supply flow down into the anterior pituitary & in the context of GnRH - will target the GONADOTROPHS (will ultimately syn. & release LH & FSH)
Gonadotrophin Releasing Hormone (GnRH) is known as the…
master sex hormone
Originally, for GnRH thought that…
2 hormones were involved LHRH & FSHRH
In the absence of GnRH…
you won’t get:
- syn. & release of LH & FSH
- syn. & promototion of sex steroid production from the gonads in either males or females
Concentration of GnRH in the circulation is…
really LOW & practically undetectable
Where will you find GnRH in abundance?
sample blood from the portal blood supply
- v. HIGH concen. within the portal blood supply
GnRH as a molecule (Pre-pro GnRH)
Pre-pro GnRH:
Signal peptide - 23 AA’s
Mature peptide - 10 AA’s
3aa
GnRH-associated peptide (GAP) - 56 AA’s
Which peptide is the bioactive peptide?
mature peptide
Tonic pulses in both sexes every…
1-3h
Tonic pulses of GnRH are critical for…
normal function & release of FSH & LH
GnRH pulse generator influences…
syn. & release of FSH & LH
Continued administration of GnRH will..
inhibit FSH & LH release - downregulation of GnRH signalling pathway
Diff. mech’s proposed for pulse generation:
- Threshold of release & autocrine regulation
2. Stimulation via NE & local inhibition via Dopamine or GABA (universal inhibitor for neural function)
What was studied mostly in rats & mice (mammalian studies)?
if you elevate levels of GnRH, you’ll ultimately inhibit FSH & LH levels
- so if you maintain really high levels all the time, you’ll get an inhibition of those peptide hormones
GnRH with a nerve cell
GnRH released & will act on itself to promote release of GnRH, but once that threshold is hit, then you start to get a reversal of that autocrine regulation & it shuts off (sort of self-regulating feedback control)
- if that is based on that threshold you’ll get pulses of GnRH release as more is released
Kisspeptin
imp. hormone that will promote GnRH release
regulated by estrodial (E2) which also promotes kisspeptin release depending on the circulating concen. of estrodial
High plasma estrogen (females)
+ feedback on GnRH –> ↑ GnRH –> ↑ FSH & LH –> Ovary –> Ovulation
+ feedback setpoint
- estrogens will target kisspeptin which will promote ↑ GnRH from the arcuate nuclei
- might get further ↑E2
Moderate plasma estrogen (females) or androgen (males)
- feedback on GnRH –> ↓ GnRH –> ↓ FSH & LH –> Gonad –> ↓ estrogen or ↓ androgen
- feedback setpoint
- classic/normal in males
- still androgens being produced but it acts as a (-) feedback regulation, so you won’t get v. high plasma levels of androgens in the same way as you get v. high levels of estrogens within females
Low plasma estrogen (females) or androgen (males)
no feedback on GnRH –> ↑ GnRH –> ↑ FSH & LH –> Gonad –> ↑ estrogen or ↑ androgen
In males, prepubertal period LH and FSH are…
not secreted
GnRH secretion begins slowly at the onset of puberty
What sets the wheels in motion (in terms of puberty)?
hard to know exactly
- Energy requirement
- Genetic basis in timing to this
- Melatonin (linked to HPG axis)
- varies depending on season
Describe GnRH in males
Hypothalamus –> +ve to FSH & LH
FSH –> +ve to Sertoli cells –> +ve to spermatogenesis, ABP, Inhibin
Inhibin –> -ve to FSH
LH –> +ve to Leydig cells –> testosterone –> +ve to Sertoli cells & -ve to hypothalamus (close GnRH prod. & inhibit both FSH & LH release from ant. pituitary)
FSH target cells involved in…
gamete syn.
LH target cells involved in…
steroid syn.
Inhibin
selectively (-)ly feedsback on FSH in partic. & will limit prod. of FSH from ant. pituitary
ABP
imp. within the seminiferous tubule, so it can bind testosterone & also it is released in the blood
Spermatogenesis
all things related to dev. of sperm
Teritary follicle has…
cell types with major source of Estrogens
Corpus luteum produces…
estrogens & progesterones
Where do we get a shift in steroidogenesis?
as the cells in the follicle transform to luteal cells
Steroidogenesis in the follicle
page 77
delta5 = dominant pathway in thecal & granulosa cells
delta4 = dominant pathway in luteal cells
progesterone - imp. for maintenance of pregnancy & is a major product from corpus luteum
- becomes 1 of the major products as it shifts from delta5 to delta4
2/3 cell model of ovarian steroidogenesis
page 78
3 cells = thecal, granulosa, & luteal
estradiol is the primary end product but estrone & estriol is also produced
FSH primary target is aromatase
LH
imp. for promoting androgen production in thecal cells, therefore increase LH so does androgen produc.
FSH
imp. for promoting conversion of those androgens to estrogens in the granulosa cells
Only need ____ amount of FSH to promote aromatase activity
small
- FSH doesn’t have to increase dramatically to promote aromatase activity
Major driving force for promoting increases in circulating levels of estrogens that are derived from thecal & granulosa cells is…
LH & the production of the substrate (andro’s convert to estrogens)
Hormonal control of the Ovarian cycle
Unlike males because:
- Cyclical in nature (increases/decreases of sex steroids that happen in a predictable & timely way)
- FSH and LH do not specifically target gametogenesis or gonadal hormones respectively (but do play role in that)
- There are both –ve and +ve feedback controls
Why do we always use follicular phase?
b/c it’s timed with menses which is an obvi. starting point to use
FSH is…
high over the 1st ~7 days
- promoting dev. of stimulating follicular dev. in ovary
Ovulation
egg released form follicle into fallopian tube
LH surge at ovulation b/c & why is that imp.?
inhibin has been used to selectively inhibit too much FSH release
imp. b/c if you have a maintained heightened level of FSH, you will start to promote additional follicular dev. & you don’t want that at this stage b/c you already selected a follicle to go further for maturation & ovulation so you don’t want additional follicles to be promoted for maturation & ovulation at this time to limit follicular dev. of additional follicles
decrease in FSH is due to inhibin (-) feedback reg.
Surge in LH causes:
- DEcrease in estrogens (based on (+) feedback role of E’s, inhibition of E prod. now ends up in (-) feedback reg. of GnRH, so decline of LH syn. & release)
- REinitiate miotic division with the oocyte
- INcrease prostaglandins (PG’s) production (aid in rupturing of follicle & release of egg in fallopian tube)
- INcrease –> follicle –> luteal (promotion of differentiation)
Decline in FSH leads to…
atresia (degredation of all but the leading follicle)
In follicular phase we see increase…
estrogen production & dev. of antral space
As follicle grow, we get…
more estrogen prod. - driven by actions of LH as it starts to increase
In luteal phase we get…
increase in progesterone’s
Low levels of FSH can still…
maintain that aromatase activity (to fuel rise in estrogens during follicular phase)
As inhibin starts to rise, we get…
a selective inhibition of FSH from ant. pituitary
Anti Mullerian Hormone (AMN)
secreted by the larger follicle
- is involved in deciding which follicle moves further for maturation
- may also inhibit maturation of neighbouring follicles (meaning that single follicle goes forward for maturation & the dev. of neighbouring ones are inhibited)
Ovarian follicle secretes…
estrogen
↑ in size → ↑ in estrogens
During the luteal phase, LH will…
maintain prod. of P’s & E’s within the corpus luteum through promotion of the P450 SCC
Decrease in FSH/LH in luteal phase is due to…
differentiation of follicular cells to luteal cells & start to see increase in progesterone & P is a key inhibitor of LH & FSH
We see an increase in progesterone in the luteal phase that is…
quickly as follicular cells differentiated in luteal cells (quick b/c of change in steroidogenetic pathway - not in delta5 pathway)
Surge in LH in ovulation…
terminated the follicular phase & initiates the luteal phase
Once we get to mature corpus luteum…
increase in E’s
increase in inhibin for selective inhibition of FSH b/c don’t want another follicle dev. now
increase in P’s
Secretory phase
within endometrium lining which is critical for implantation of the blastocyst in preparing for pregnancy
The surge in LH is a critical point & is…
regulated by +ve feedback
In proliferation phase…
hyperplasia of endometrium lining
Progesterone stimulates exocrine activity to…
increase embryotroph (nutrient rich fluid-uterine milk to support early dev. of blastocyst & subsequent embryogenesis)
In the late follicular phase & ovulation…
(+) feedback for short amount of time & then to (-) for the cause of the decrease of LH & FSH
Placental hormones
- Human Chorionic gonadotropin (hCG) - glycoprotein belonging to FSH/LH fam (2 subunits a & B)
- Human Placental Lactogen (chorionic sommatomammotropin)
Human Chorionic gonadotropin (hCG):
– Produced by the blastocyst to preserve the corpus luteum. NB: progesterone will inhibit LH release
Human Placental Lactogen (chorionic sommatomammotropin):
– Involved with mammary gland development (although not essential) also involved with regulating maternal metabolism
- linked with gestational diabetes
Gestational diabetes
classic pair-offspring conflict
- child wrestling with mother for nutrients & control of those nutrients
- females may suffer during gesta.
- ~90% of cases once child born, symptoms disappear
- not uncommon
- normally doesn’t continue but can as diabetes
Human Chorionic gonadotropin (hCG)…
declines over time as the E’s & P’s in the circulation in the female carrying that child increase over time
At delivery…
dramatic decline in all 3 hormones (hCG, E & P)
- more of a ratio of E & P than just E that are a good sign of parturition about to happen
Triggers for onset of parturition
page 84-85!!
all v. strong (+) feedback reg that promotes parturition all set off by dev. of fetal lungs & interaction b/t CRH & ACTH
Interleuhin IB (IL-1B)
local agent that’ll target specific cell types & various diff. pathways
Myometrial cells
muscle cells that line the uterus
Role of PG’s in parturition:
cervical stretching & promoting contraction within the endometrial lining
“Let down” reflex in nursing mothers
inhibition of PIH (prolactin inhibiting hormone - Dopamine) secretion (from hypothalamus) allows the stimulus of milk production by PRL
(+) feedback reg.
If female is under prolonged stress, i.e. elevated levels of cortisol, they will tend to…
deliver before term
If female has normal levels of cortisol, you can…
predict when that individual will give birth pretty closely
If female has v. low levels of cortisol, gestation tends to…
go longer
