Neuroendocrinology/physiology Flashcards
Kisspeptin
neuropeptide encoded by the KISS1 gene.
Acts on the kisspeptin receptor (KISS1R) found in hypothalamus
Kisspeptin binds to receptor in hypothalamus and upregulates GnRH production through effect on GnRH neurons. It a apex of the HPO axis.
GnRH neurons have no sex steroid receptors, kisspeptin neurons have oestrogen and progesterone receptors.
– Inactivating mutation of KISS1 and KISS1R cause of Hypog hypo – failure to enter puberty. Activating mutations cause precocious puberty.
KNDy neurons
Neurons within arcuate nucleus of hypothalamus.
Kisspeptin
Neurokinin B
Dynorphin
KNDy hypothesis –
NKB is the signal responsible for pulse onset of GnRH by triggering activation among KNDy neurons.
Kisspeptin serves as the output signal from KNDy neurons driving GnRH secretion
Dynorphin serves as the signal terminating each pulse.
Hypothalamic and pituitary hormones
Prolactin
PRL gene expression occurs in Lactotrophs in anterior pituitary produce as well in the decidualised endometrium and myometrium.
Main fucntion is lactogenesis.
Secretion of prolactin is chiefly under the inhibitory control of dopamine. Homeostasis regualted predominantly by negative feedback of PRL on dopamine releasing neurons.
Dopamine is stimualted by PRL and inhibited by oestrogen ie. Increasing PRL decreases prl secretion and increasing oestrogen increases PRL secretion.
Dopamine secretion - inhibited by opioids, oestrogen. Activated by prolactin, serotonin, neuropeptide Y.
Increase dopaimne will also inhibit gonadotrophin secretion
Gene mutations causing panhypopit
Pit-1, SOX2, SOX3, LHX3 LHX,4
GnRH pulse frequency and amplitude across menstrual cycle
Lower amplitude and higher frequency in follicular phase (more exagerrated before LH surge). Higher amplitude and lower freuqency in luteal phase.
Controls of GnRH pulses
Dopamine tract (inhibitory)
Noradrenaline tract (Stimulatory)
Serotonin
Neuropeptide Y - peptide by which leptin and insulin inform the hypothalamus about the nutritional state of the individual.
Kisspeptins (as above)
Regulatory control of the gonadotrophin independent phase of follicular development
Regulated by a variety of factors.
Transfomring growth factor beta (TGF-B) - include activin, inhibin, AMH and BMPs (bone morphogenic proteins).
Activin and BMP promotes and inhibin and AMH retards primordial follicle development.
Neurotrophins (nerve-growth factor) also involved.
Menstrual cycle - follicular phase
primordial oocyte - primary follicle gonadotrophin independent process occuring ~70-85 days in advance of gonadotrophin dependent recruitment.
FSH rise in late luteal phase rescues a cohort of primary follicles from apoptosis.
FSH stimulation propels follicles from primary to early preantral phase.
FSH induced aromatisation of androgen (from theca cells) in the granulosa results in oestrogen production.
FSH and E2 increase FSH receptor content in the follicle.
Dominant follicle selection day 5-7, peripheral oestrogen levels continue to rise and produces suppressive effect on FSH.
Unique responsiveness to LH in DF (more receptors and more sensitive), allows it to convert androgen rich to oestrogen rich environment within follicular fluid of antral follicle.
FSH causes LH receptor formation of grnulosa cells.
LH levels rise steadily in late follicular phase.
Follicular response to gonadotrophins is modulated by a variety of growth factors and autocrine-paracrine peptide (activin, inhibin, follistatin, IGF-1)
Inhibin B secreted by granulosa cells in response to FSH, directly suppresses pituitary FSH secretion.
Activin - augments FSH secretion and action (arising in pituitary and granulosa)
Day 10 the peak of E2 causes positive feedback and initiation of LH surge.
Until this point - primary oocyte - arrested in diplotene part of prophase in meiosis 1. 2pn (diploid cells) –> ovulation allows resumption of meiosis - extrusion of first polar body and then arrests again in metaphase of meiosis 2.
LH surge further luteinses granulosa cells, synthesises progesterone and prostaglandins within follicle.
P4 –> activation of proteolytic enzymes which alongside prostaglandin cause digestion and rupture of the follicular wall.
menstrual cycle luteal phase
normal luteal function requires preovulatory follicular development, adequate FSH stimulation and continued tonic LH support.
Early follicluar phase is marked by active angiogenesis mediated by VEGF.
P4, E2, inhibin A act centrally to suppress gonadotrophins and thus new follcular growth.
Regression of the corpus luteum causes a decrease in VEGD and angiopoietin-1 expression and an increase in angiopoetin-2 activity.
In early pregnancy bHCG rescues the corpus luteum, maintain luteal function until placental steroidogenesis is well established.
Otherwise the demise of the corpus luteum results in a nadir in circulating level of E2, P4 and inhibin.
Decrease in inhibin A removes a suppressing influence on FSH secretion in the pituitary. Decrease in E2 and P4 allows progressive and rapid increase in pulse freuqency of GnRH secretion –> greater secretion of FSH than LH.
Rising FSH rescures the primary follicles from atresia to start the new cycle again.
Progesterone receptors.
- Three major forms - PR-A, PR-B, PR-C.
- PR induced by oestrogen and decreased by progestins.
- PR-A and PR-B most relevant to progesterone signalling.
- Nuclear receptor – it is a transcription factor and stimulates DNA transcription and thus gene expression.
- Can also signal through cell membrane (G protein receptor pathways) and cytoplasmic pathways.
- Differ to other steroid hormone receptors by their regulatory domain – share the same DNA domain, hinge region and hormone binding domain.
- In most cells, B is a positive regulator of P-responsive genes and A inhibits B
Progesterone synthesis and metabolism
Synthesised from cholesterol within the steroidogenic pathway.
Cholesterol carried from outer to inner mitochondrial membrane by STAR steroidogenic acute regulator converted from cholesterol into pregnenolone by CYP11a1. Pregnenolone converted to progesterone by 3b hydroxysteroid dehydrogenase in the endoplasmic reticulum.
In luteal phase and early pregnancy made and excreted from the corpus luteum.
Metabolised either through conversion to mineralocorticoids, glucocorticoids or other sex steroids within the steroidogenic pathway. Excreted in the urine from by products broken down from progesterone and 17-hydroxyprogesterone.
Initial recruitment phase of folliculogenesis (gonadotrophin independent)
Oogonia - stem cells, 2n. Migrate from yolk sac through genital ridge to fetal gonad. Undergo mitosis to replicated and reach a peak of 6-7million at 20 weeks.
Form germ cell nests with surrounding layer of squamous cells. Most will undergoing atresia and through this process each germ cell nest will produce one primordial follicle - oocyte surrounded by single layer of squamous granulosa cells.
Oocyte formed from oogonia through meiosis, arrests at diplotene phase of meiosis 1 prophase.
This all occurs during fetal life and born with ~1million oogonia. Drops to 200 000- 400 000 by puberty.
Primordial follicles one of 4 fates:
1. remain quiescent for variable amounts of time to constitue the ovarian reserve.
2. directly undergoes atresia
3. undergoes initial recruitment and eventually ovulation
4. undergo initial recruitment but later die via atresia
Primary follicle - larger oocyte, zona pellucida forms, single layer of granulosa cells becomes cuboidal. DEvoid of theca cells but precursor theca cells derived from stroma begin to surround follicle. Once the primary follicle is formed then the initial recruitment/gonadotrophin independent state is complete.
Intrinsic ovarian factors involved in the initial recruitment phase of folliculogenesis (gonadotrophin independent)
Stimulatory:
Kit and Kit ligand - stem cell growth factor - can initiate growth and development of primordial follicle
Fibroblast growth factor - regulate grnaulosa, theca and stromal cell growth
LIF (leukaemia inhibitory factor) - act upon the granulosa and oocyte to stimulate oocyte growth and to recruit thecal cells to the follicle.
Bone morphogenetic proteins 4 and 7 (BMP4 and 7), has been shown to aid in the survival of primordial follicle oocytes
PDGF (platelet derived growth factor) in oocytes acts on granulosa cells to inc kit ligand and activate primordial follicle.
Inhibitory:
AMH -belongs to the transforming growth factor beta (TGF-b) superfamily and is involved in the inhibition of initial recruitment, mechanism for this is largely unknown.
Highest levels are present in the preantral (secondary) and early antral follicles. AMH mice knowckout models shouw a depletion of the primordial dollicle reserve
FOXL2 - expressed in granulosa cells of the primordial follicle, plays a critical role in the development of granulosa cells within the primordial follicles. Mediates the squamous to cuboidal transition and proliferation of granulosa cells.
Transition from primary stage to early antral stage (gonadotrophin responsive but not driven by gonadotrophins)
The granulosa cells contained in a single layer in the primary follicle undergo mitosis and multiple layers of granulosa cells that are capable of producing steroids form, establishing the preantral follicle.
It takes roughly 120 days for this process to occur in the human.
Basement membrane and two layers of thecal cells form - theca interna - inner layer and adjacent to BM, produces steroids. Theca externa, outer layer, comprised of non-steroidogenic fibroblast cells that become part of connective tissues. Vascularisation of theca cells provides the follicle with direct acces to blood stream and hormones such as gonadotrophins.
Continued development - further thecal cell vascularistaion and granulosa cell proliferation.
substances brought in through blood stream result in formation of fluid-filled spaces within the granulosa cell layer. Coalesce to form singular fluid cavity known as the antrum/antral cavity.
Once this antral cavity is seen - moves from preantral to early antral follicle (70days).
This transition mostly driven by intraovarian factors and signalling pathways but gonadotrophins may mediate follicle development during these stages (though can occur in the absence of FSH and LH). Can remember the same factors as above.
