Androgen Flashcards
-androgen to estrogen conversion by
aromatase
do hormones act directly on microglia?
could be direct or indirect (modulating microenvironments that impart sex difference din microglia identity and function)
Whats condition girls have with excess androgen?
congenital adrenal hyperplasia (cortical synthesis pathway mutation)
When do testes and ovary develop? What week?
6-12
When does T peak in males human?
Week 12-18
How much higher is male T in utero at 34-41 weeks than F?
10 times
When is second peak of T after birth?
Around 3 months
When does sexual differentiation of the genitals happen and then the brain?
G: 2 months of pregnancy
B: Second semester
What’s a brain region organized by estradiol ?
Preoptic area - a brain region involved in many areas including copulatory and maternal behaviors
In early development, what determines whether an animal will develop testes or ovaries?
Genes on the sex chromsome (SRY gene on Y chromosome) -> testes produce androgen and absence of SRY gene -> ovarian devlopment
What does estrogen do in the rat brain?
1) masculinzation
2) defiminization
Why use that does of flutamide?
Flutamide was administered at a dose of 50 mg/kg bodyweight and prepared on the same day as the injection. This dose was selected as it is well-established in impairing male reproductive development and preventing masculinization of anogenital distance (AGD)
hwy not enzalutamide?
this increased potency could also have an effect on non-reproductive tissues where androgen signaling is involved, such as the musculoskeletal system (possibly affecting muscle mass)
why did you use flutamide?? is this a specific androgen effect
you’re right in the sense that there are potentially confounding effects of estrogen since T can be converted into E by aromatase - follow up studies could perhaps also administer the addition of an inhibitor of the enzyme
we actually hypothesize that estradiol could have been responsible for that increase in mature OLs we saw in the flutamide group and that’s bc with flutamide tx you generally have an increase in T, so more T converted into estradiol, E seen to prolong cell cylce of OL precurosor - so overall you have a higher pool at the end
other studies have made use of castration then administration of DHT since it’s not able to be aromatized
we also don’t know for sure if its T or DHT having any effects - also crosstalk with estrogne signalling?
where is AR located?
x chromosome, c domain
where does brain masculinization occur in rats?
ER eg preoptic area of the hypothalamus estrogen to neonatal female rats can masculnize their brains
why use flutamide instead of enzalutamide?
a broad inhibition of androgen signaling, including both genomic and non-genomic effects. While enzalutamide specifically prevents androgen receptor (AR) nuclear translocation and is highly potent in targeting the genomic actions of AR
minimizes interference with other steroid hormone pathways since it’s non steroidal, reduces the risk of systemic side effects
Well-Characterized in Preclinical Models
Less Potent but Sufficient for General Blockade -
widely used in animal studies, flutamide has minimal CNS effects than enzalutamide, multiple steps of AR signalling - would have broader effects so we were
how is androgen impacting innate immune cells?
sex hormones directly influence both the development and function of cells of both the innate
androgens impact PMN maturation and function
including cell proliferation, cytokine secretion, and toll-like receptor expression.
e.g orchiectomized mice were reduced to the levels found in female mice, PMN from orchiectomized mice also showed a trend toward decreased cytotoxicity and the number of mature, segmented PMN compared to those from control male mice, less phagocytosis, ROS. These results were able to be reversed with testosterone replacement, clearly highlighting that abnormal phenotypic changes occur in PMNs that express the AR after orchiectomy.
In a study by Chuang et al., AR-knockout male mice were neutropenic and more susceptible to acute bacterial infection.41 This highlights that the AR is important for the development of PMN precursor cells and that it impacts their proliferative activity
Across the aforementioned studies, it is evident that the AR and/or androgens stimulate the production of PMN. Mechanistically, this could be explained through AR enhancing granulocyte colony-stimulating factor signaling as found in a study by Chuang et al.41 This mechanism works through the activation of extracellular signal-regulated kinase 1/2 and through sustaining signal transducer and activator of transcription (STAT)3 activity.39 Many knockout mice studies have shown that when STAT3 activity is maintained, the result is a hyperproduction of neutrophils.45, 46 In sum, the reason why males are at a higher risk of developing sepsis and other innate immune driven-conditions could in part be explained by a skewed activation of PMN by testosterone, which contributes to a weaker ability to clear the infection than female, or, on the other hand, due to a testosterone-induced cytokine storm from innate immune cells, or both.
