Gonadal Steroidogenesis and Actions Flashcards
What are the actions of mineralocorticoids and where are they made?
-salt & water retention
(Na+ & K+ electrolyte
& fluid balance)
=Ring structure protecting 11 beta position
=C21
-Zone-specific expression of aldosterone synthase determines aldosterone production in the adrenal zona glomerulosa
What are the actions of glucocorticoids and where are they made?
-glucose synthesis, protein metabolism, inflammation, immune response
=11 hydroxyl group (cortisol, if cleaved off= cortisone)
=C21
-Zone-specific expression of 17α-OHase & 11ß-OHase determines cortisol production in the adrenal zona fasciculata
What are the actions of adrenal androgens and where are they made?
-foetal development, foetal oestrogenic environment, postmenopausal oestrogens
=C19
=Carbon groups clipped off
-Zone-specific expression of 17α-OHase & 17, 20 lyase determines DHEA production in the adrenal zona reticularis
What is the link between cortisone and reproductive tissues?
-Cortisone is activated to cortisol in reproductive tissues
What are the key human sex steroids synthesised in reproductive tissues?
-Progesterone= menstrual cycle maintenance of pregnancy
=C21 progestogen female steroid
-Androgens= growth and function of male reproductive system
=Testosterone C19 androgen male steroid
-Oestrogens= growth and function of female reproductive system
=oestradiol C18 oestrogen female steroid
What are the types of enzymes involved in human sex steroid hormone synthesis?
- Cytochrome P450s (CYPs)
- Steroid dehydrogenases
Describe CYPs
=cleave cholesterol side chains
-17-OHase/17, 20 lyase (CYP17A1)
=adrenal cortex ZR
=testis, ovary
-Aromatase (CYP19A1)
= ovary (male testosterone to oestradiol)
= AND peripheral oestrogen targets
=e.g. breast, bone, etc.
= (aromatase inhibitors used to treat cancer)
Describe Steroid dehydrogenases
-interconvert steroids
=3β-HSDs: adrenal, testis, ovary
=17β-HSDs: testis, ovary
=5a-reductases: testis & peripheral tissues
How is testosterone made?
-DHEA & androstenedione made in BOTH male & female gonads
-Same pathway as adrenal gland
-BUT ovaries & testis Leydig cells contain an additional enzyme:
=17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3)
=Converts androstenedione (‘pro’, precursor) to weak C19 androgen testosterone
=In testis Sertoli cells 5α-reductase converts testosterone to strong androgen 5α-dihydrotestosterone
How is oestradiol made?
- 3β-HSD converts pregnenolone into progesterone in corpus luteum
- In ovary & peripheral tissues, aromatase converts testosterone to strong oestrogen oestradiol (C18)
Describe the HP Gonadal axis in regulating sex steroid hormone synthesis
-Gonadotrophin-releasing hormone (GnRH) from HP preoptic nucleus
-Acts on anterior pituitary gonadotrophs:
=follicle-stimulating hormone (FSH)
=luteinizing hormone (LH)
-FSH and LH stimulate sex steroid hormone production in gonads
=androgens (male),
=oestrogens (female)
=ALSO inhibins (male & female)
Describe testis anatomy
- Steroidogenic Leydig cells= make testosterone, regulated by LH
- Sertoli cells= ‘nursery’ cells for sperm production make inhibin (key marker of cell function) and ABP (androgen binding protein), regulated by FSH
How does the Leydig and Sertoli cells interact?
- LH stimulates testosterone (T) production by Leydig cells
- FSH promotes inhibin & androgen-binding protein (ABP) in Sertoli cells
- T moves from Leydig to Sertoli cells
- T converted to DHT & binds to ABP in luminal fluid of the seminiferous tubules= locally very high concentration of testosterone to drive spermatogenesis and maturation
Where does testosterone act on?
- T from Leydig cells & inhibin from Sertoli cells feedback on GnRH, LH & FSH
- Testosterone transported in plasma to peripheral targets bound (98%) to sex hormone-binding globulin (SHBG)- concentrations of this protein regulated, disturbed in drug therapy (infertility)
What are the actions of androgens?
- Testosterone, 5a-DHT
- Primary male reproductive function= spermatogenesis, prostate secretions
- Secondary male sex characteristics= anabolic (build muscle), deep voice, facial and body hair, brain (libido and aggression)
- Essential during foetal life= male sex determination (week 7-8), genital development
How does testosterone influence male sex determination?
- Foetus programmed to be female
- Jolt of testosterone at week 7-8
- SRY (sex determining gene on Y chromosome) = Sertoli cell differentiation = testis formation= Leydig cells develop to make T
How in mice can you prove androgens have an essential role in male sex determination?
-Androgen Insensitivity syndrome
=due to mutated testosterone receptor:
-Arrested testis development; lack of testosterone & anti-Mullerian hormone
=lack of Mullerian duct regression
=Externally female as testis did not develop
How does Androgen Insensitivity syndrome present in humans?
-46, XY genotype, variable phenotype
-Partial insensitivity:
=male external genitalia & body shape & mild spermatogenic defect after puberty
-Complete insensitivity:
=Female external genitalia & body shape, female internal organs undeveloped or absent
Why are oestrogens essential in males?
-Not as much as females
-Aromatase converts to oestradiol in periphery and testis
-If failure to convert, oestrogen deficiency affects bone maturation
=tall and long arms
=bone epiphyses do not close in adolescence
=loss of bone mass
=osteoporosis= bone fractures
=slowed mineralization of bones (delayed bone age) =abnormally high blood sugar (hyperglycemia) because the body does not respond correctly to the hormone insulin.
=excessive weight gain and a fatty liver.
Describe aromatase deficiency in females
=born with external genitalia that do not appear clearly female or male (ambiguous genitalia).
=These individuals typically have normal internal reproductive organs, but develop ovarian cysts early in childhood, which impair the release of egg cells from the ovaries (ovulation).
=In adolescence, most affected females do not develop secondary sexual characteristics, such as breast growth and menstrual periods.
=They tend to develop acne and excessive body hair growth (hirsutism).
Describe aromatase deficiency in males
-Some men with this condition have decreased sex drive, abnormal sperm production, or testes that are small or undescended (cryptorchidism)
How does aromatase deficiency of foetuses affect the pregnancy?
- Women who are pregnant with foetuses that have aromatase deficiency often experience mild symptoms of the disorder even though they themselves do not have the disorder.
- These women may develop hirsutism, acne, an enlarged clitoris (clitoromegaly), and a deep voice. These features can appear as early as 12 weeks of pregnancy and go away soon after delivery.
Describe the way oestrogens are made in the ovaries
-LH stimulates production of androstenedione & testosterone in thecal cells of the primary follicle
-Androgens move from thecal to granulosa cells
-FSH stimulates androgen conversion to oestrogens by aromatase
=regulates proliferative phase of menstrual cycle
How does oestradiol travel in the body and feedback?
- Oestradiol & inhibin from granulosa cells feed back on GnRH + LH & FSH release from HP & pituitary
- Oestradiol also transported in plasma, to peripheral targets bound to gonadal sex hormone-binding globulin (SHBG)
What are the actions of oestradiol?
- Female genital development & differentiation
- Secondary female sex characteristics, e.g. body fat distribution, cardiovascular system, skin, bone, epiphyseal closure
- Estrogen from the primary ovarian follicle promotes endometrial growth during the follicular or ‘proliferative’ phase (thicker)
What are the actions of progesterone?
- Made in the corpus luteum promotes endometrial secretion & vascularisation during the luteal or ‘secretory’ phase
- Prepares uterus for implantation of a fertilised egg
- Without implantation falling progesterone initiates menstruation
What are the phases of the ovarian cycle?
- Follicular/ proliferative phase (Day 0-14)
- LH surge triggering ovulation (Day 14)
- Luteal/ secretory phase (Day 14-28)
Describe the follicular/ proliferative phase
- FSH & LH stimulate oestradiol production by the primary follicle
- promotes endometrial growth by proliferation
Describe the LH surge triggering ovulation
-Estrogen is produced by the granulosa cells of the developing follicle andexertsnegative feedback on LH production in the early part of the menstrual cycle via the HPG axis.
=However, once Estrogen levels reach a critical level as oocytes mature within the ovary in preparation for ovulation, Estrogen begins to exert positivefeedback on LH production, leading to the LH surge= stimulates ovulation (follicle ruptures and releases egg which then makes oestrogen)
Describe the luteal/ secretory phase
- corpus luteum makes progesterone
- receptive ‘secretory’ environment for implantation of a fertilised egg
What happens if no implantation occurs during the normal ovarian cycle (day 14-28)?
-corpus luteum regresses & stops producing progesterone
- declining feedback of :
- progesterone
- oestrogen
- inhibin
- allows a new cycle of LH & FSH release
What happens if implantation occurs during the normal ovarian cycle (day 14-28)?
-Developing embryo produces hCG (human chorionic gonadotrophin) an alternative form of LH (with sugar group)
-hCG binds to LH receptors on corpus luteum & endometrium:
=maintains progesterone secretion
=suppresses maternal immune rejection of placenta
-progesterone promotes uterine blood vessels to sustain the growing fetus
Describe the luteal-placental shift
-Occurs at 7-9 weeks
-Hormones decline:
=hCG from embryo
=progesterone from corpus luteum
-To maintain pregnancy, placenta begins to produce:
(i) progesterone from cholesterol
(ii) oestrogen from DHEA (foetal adrenal)
