Steroid Steroid HormonesHormones

Steroid Steroid HormonesHormones

Steroid hormonesGlucocorticoids.Mineralocorticoids.Sex steroids:

-Progesterone. -Androgens. -Estrogens.

Steroid hormones

Pregnane (C21): Progestins

and corticoids.

Androstane(C19): Androgens.

Estrane (C18): Estrogens

Cholesterol

Steps:Acquisition of cholesterol.Transfer of cholesterol from outer to inner mitochondrial membrane.Side chain cleavage to pregnenolone.Δ4 pathway (progesterone) or Δ5 pathway (17α hydroxy pregnenolone) to androstenedione.Aromatization to corresponding estrogen.

Steps:I : Acquisition of cholesterol:

• From blood through LDL.

• De-novo synthesis.

Cholesterol Metabolism: Uptake

Steroid producing organs

Steps:II: Transfer of cholesterol from outer

to inner mitochondrial membrane:• Rate limiting step.• Sensitive to trophic hormones.• Involve carrier proteins StAR, SCP2,

SAP, PBR.• Deficiency of StAR causes congenital

lipoid adrenal hyperplasia

Mitochondria

Mitochondria

Steps:III: Cholesterol side chain

cleavage:Achieved by hydroxylation at 20 and 22 position then cleavage.Carried out by single mitochondrial CYP450 named CYP450scc.Produce pregnenolone which is the mother molecule for all steroids

Steroidogenic enzymes:Cytochrome P 450(CYP 450).• Family of oxidases.• Contain Haem group for oxygen

carriage.• Mitochondrial or microsomal.• Utilizes NADH as coenzyme.Dehydrogenases3 β hydroxy steroid dehydrogenase.17 β hydroxy steroid dehydrogenase.

Cellular Locations of Steroid Synthesis

sER

Smooth Endoplasmic reticulum (sER)

sER

Δ 4

Δ5

Orphan receptors and steroidogenesis:• Transcription factors that belong to

nuclear receptors superfamily.• Yet unidentified ligands.• Include steroidogenic factor-1 and DAX-

1.• Steroidogenic factor-1 influences

expression of StAR, Steroidogenic enzymes and others.

Ovarian Steroidogenesis

Sites: Maturing follicles and CL• Maturing follicles : 2 adjacent

important populations:– Granulosa cells– Theca interna cells

• CL – important cells derived from follicle after ovulation– Granulosa lutein– Theca lutein

Granulosa cells lack P450scc

No cholesterol pregnenoloneLack P450c17No further androgen synthesisRely on theca cell androgensInsensitive to LH signal for androgen

production.• EXCEPT when advanced follicle developed

– Just prior to ovulation.– Small numbers LH receptors expressed.– Important to luteinization.

Granulosa cells • Sensitive to FSH

• FSH stimulation – Proliferation granulosa cells– Secretion inhibin B– Expression of aromatase.

• Granulosa cells express aromatase– Androgens estrogens– Most important source of E2

Figure 9. The early differentiation of the granulosa cells during preantral folliculogenesis involves the expression of FSH receptors. Animal studies support the concept that this process involves an activin autocrine/paracrine mechanism. (Erickson GF: Dissociation of Endocrine and Gametogenic Ovarian Function. In Lobo, R. (ed.): Perimenopause. Serono Symposia, Springer-Verlaag, 1997. Reproduced with permission from Springer-Verlag, New York.)

Theca (interna & externa) Express P450scc

– Cholesterol pregnenolone– Sensitive to LH

cAMP PKA StAR PBR P450scc activity in inner mitochondrial membrane

– Pregnenolone Δ5 (androgen) pathway• Uses P450c17

– Preovulatory LH surge • Ovulation• Luteinization theca interna, granulosa• Development CL

• Theca interna express aromatase (androgens estrogens)– BUT much less active than granulosa.– Once ovulation occurs, expression

ceases.– So decreased secretion of estrogens

from CL

Follicular 2-Cell Pathway

The 2 cell 2 gonadotropin theory

Granulosa lutein cells express P450scc– So can produce pregnenolone

• BUT granulosa lutein cells lack P450c17– No androgen synthesis from pregnenolone

• Rely on theca lutein cells for androgens

– BUT progesterone synthesis from pregnenolone ( Δ4 pathway).

– Insensitive to LH signal to produce androgens• BUT small numbers LH receptors expressed in

advanced follicle stimulates secretion of progesterone, and inhibin A

Coupling of steroidogenesis to Gametogenesis

• Ovarian follicles named by maturation stage

• Primordial– Primary oocyte– Squamous epithelium; single layer

Growth & remodeling

– 40 ; oocyte 15-25 – Quiescent

• Primary follicle– Oocyte enlarges (80-100 m)– Follicle epithelium simple cuboidal

•“Zona pellucida (glycoprotein layer) deposits

– Stroma begins to organize as theca

Secondary=preantral follicle– Granulosa proliferates, stratifies

• Signaled by oocyte growth factors– Growth Differentiation Factor 9 (GDF-9)– Bone Morphological Protein 15 (BMP-15)

• Mitosis and rearrangement result in Diff layers have diff morphology & function

– Granulosa cells produce activin– Granulosa cells become sensitive to

FSH• Important to selection• Important to differentiation• Important to maturation

Secondary=preantral follicle– Final 2o follicle 100-200

• Fully grown oocyte with zp• Approx 9 layers granulosa• Basal lamina• Theca interna with capillary

network• Theca externa

Secondary=preantral follicle – Granulosa cells connected by gap

junctions• Synchronization• Nutrient transfer

– Basement membrane develops– When 6 layers granulosa

• Definitive theca layer• Angiogenesis blood supply to theca

Granulosa cells

Theca cells

– Chamber– Follicular fluid contains hormones

• Blood-derived• From oocyte• From granulosa cells

– Cavitation signaled by follicle cells– Granulosa cells produce inhibin B and

aromatize androgens.– Theca fully developed

Tertiary=antral follicle

Tertiary=antral follicle – Theca interna = steroid

producing (androstenedione)•Extensive sER, cytoplasmic lipid

droplets, tubular mitochondrial cristae

•Receptors for LH, insulin•Richly vascularized

– Theca externa•Smooth muscle cells•Autonomic neurons

Figure 12. Photomicrograph of an early tertiary follicle 0.4 mm in diameter at the cavitation or early antrum stage. zona pellucida (ZP); granulosa cells (GC); basal lamina (BL); theca interna (TI); theca externa (TE); granulosa mitosis (arrowheads). (Bloom W, Fawcett DW In A Textbook of Histology. Philadelphia, WB Saunders Company, Philadelphia 1975. With permission from Arnold.)

Now single, dominant follicle– Overall size varies; determined by

amount of follicular fluid.– Granulosa differentiated into mural,

antral , cumulus.– Produce 400μ estradiol/day. – LH surge induces completion 1st

meiotic division 2o oocyte• 2nd meiotic division @ fertilization

Preovulatory=Graafian follicle

Ovulation• Induced by LH surge• Rupture

– Follicle wall– Follicle cell layers

Oocyte with corona radiata expelled in ooze like manner.

Luteinization• Initiated by LH surge• CL forms from

– Granulosa lutein.– Theca lutein.– Associated microvasculature invade

granulosa.• Defined life span

– If no fertilization, involution & apoptosis 14 d after formation.

Steroid hormone receptors

Nuclear receptors.Dimerize and bind to DNA at specific sites called steroid response elements.Binding of ligand bound receptor to DNA stimulates transcription of specific proteins to mediate response.

Conclusion:• Cholesterol is the basic building

block of all steroids.• Cholesterol can be synthesized by

all steroid producing organs except placenta but local production is insufficient so mostly obtained from blood LDL.

Conclusion:• Steroidogenesis occur in 2 cellular

sites; mitochondria and sER.• Steroidogenic enzymes belong to

2 families CYP 450 and dehydrogenases.

• After pregnenolone 2 pathways according to site.

Conclusion:• Ovarian steroidogenesis depends on

cooperation between theca cells under the effect of LH and granulosa cells under the effect of FSH (the 2 cell 2 gonadotropin theory.

• Ovarian steroidogenesis –unlike testicular-is coupled to gametogenesis.

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