Sex Steroid Hormone Metabolism And Signaling Flashcards
What is the rate limiting step for sex steroid synthesis
Cholesterol -> pregnenolone
- via CYP2A/cholesterol desmolase
What enzyme converts pregnolone into progesterone?
1-B hydroxysteroid dehydrogenase
3-B-hydroxysteroid dehydrogenase deficiency
Is a type of congenital adrenal hyperplasia (autosomal recessive)
Results in no 3-B hydroxysteroid dehydrogenase enzymes
- no glucocorticoids, Mineralcorticoid, active androgens or estrogens
Results in salt wasting and female-like genitalia in males
Skin hyperpigmentation and bilateral adrenal hyperplasia
Lutenizing hormone
In males = induces testosterone synthesis in leydig cells of the testis which either goes into the blood or diffuses to the Sertoli cells to promote spermatogenesis or binds to ABP and become blood bound
- binds to leydig cells via Gs-receptor and induces testosterone synthesis from cholesterol
In females = induces ovulation and stimulates estrogen and progesterone synthesis in the corpus luteum
Follicle stimulating hormone (FSH)
In males = stimulates androgens in males and promotes spermatogenesis
- binds to sertoil cells via Gs-protein receptors and promotes androgen binding protein (ABP) production
In females = stimulates estrogens and oogenesis.
5-a reductase Deficency
Enzyme used to convert testosterone into dihydrotestosterone (DHT)
5-a-reductase Deficency
- autosomal recessive disorder which results in little DHT.
- mutation in the SRD5A2 gene
- this causes ambiguous feminized external genitalia in males with normal internal genitalia since DHT is required for external genitalia formation
- are 47-XY
- may also show hypospadias and cryptochidism
Diagnosis = testosterone:DHT ratio > 20
Treatment = based on what gender they want
- males = testosterone supplementation
- females = gonadectomy and estrogen substation therapy
PCOS (polycystic ovary syndrome)
Prevalent in 6-12% of women in the US
Caused by cystic ovaries but mechanism is unknown
- strong association with obesity
Causes an increase in LH/FSH in excess amounts which stimulates the theca cells to produce excessive amounts of androgens
- also cause infertility due to high LH/FSH ratio (>2:1) which results in impaired follicle maturation and lack of follicle rupture/an ovulation
However the granuloma cells dont convert the androgen excess to estradiol so = excess androgens
Symptoms:
- menstrual irregularities (sometimes primary or secondary amenorrhea)
- metabolic syndrome or NFLAD
- insulin insensitivity
- virulization of females
- Acanthosis nigricans
- depression and anxiety disorders
Lab values = testosterone is highly elevated and LH:FSH ratio is >2:1**
- estrogen is normal or slightly elevated
Treatment = first line is give letrozole if they want to stay fertile
Aromatase (CYP19) enzyme
enzyme expressed in granulosa cells but NOT in the theca cells
Are used to convert androgens into estrone and estradiol
*aromatase inhbitors are used in estrogen-sensative breast cancer to prevent estrogen effects
What is inhibin-B
Secreted from Sertoli cells (males) and granulosa cells (females)
Induces negative feedback on FSH only
How does LH get negative feedback?
In males = testosterone levels
In females = Oestrogen levels
What are the carrier proteins that bind steroids
Sex-hormone binding globulin (SHBG)
Corticosteroid-binding globulin (CBG)
Albumin
Where are sex steroids degraded
Liver
Classical steroid hormone pathway
Crosses the target cell membranes and binds to intracellular receptor
Creates a steroid/receptor complex
The complex then binds to the HRE of the enhancer region of the genes to be transcribed and promotes gene transcription and neuro genesis/protection
What is the general sex hormone receptor domains?
DNA binding zone
Ligand binding zone
AF1 and AF2 sections
Two subtypes of receptors (ERa/ERB)
- ERa is more: epididymis, ovary, uterus, adrenal gland, kidney
- ERB is more: ovary, prostate, bladder
Non-classical steroid hormone signaling
Steroid hormone receptors regulate cell functions via cytoplasmic actions Based on receptors
Estrogen = binds to NMDA receptors and ER receptors
- NMDA = direct neuronal excitability increase
- ER = goes to mitochondria and induce antiapoptotic effects and increases cellular metabolism
Progesterone Binds to GABAa and PR receptors
- GABAa = decreases neuronal excitability
- PR = goes to mitochondria and upregulates cellular metabolism
