CYP1A1 and CYP1B1 are not expressed in any significant quantity in the liver. Therefore, they would
not be expected to contribute to the overall systemic metabolism of estrone. However, both enzymes have been identified in
breast tissue
CYP1A1 displayed relatively high activity for all three hydroxylations, suggesting that it may play an important role in
extrahepatic tissues where it is expressed
CYP1A1 was more active with regard to 2-hydroxylation and 4-hydroxylation,
it also displayed one of the greatest 16α-hydroxylating activities of the CYP enzymes tested.
second rise in plasma levels (mostly occurring between 6 and 12 h after the dose) suggesting an enterohepatic recycling of the drug
Ivermectin is exceptionally potent, with effective dosages levels that are unusually low.
the optimal dose of ivermectin is 150 μg/kg, but the frequency of administration is still controversial, ranging from 150 μg/kg once to three times yearly.
high lipid solubility of ivermectin, this compound is widely distributed within the body.
To interrupt the transmission of onchocerciasis in humans, the combination of ivermectin and doxycycline is highly effective as, in infested patients, the ingestion of the anthelmintic (200 μg/kg, single dose) and the antibacterial (100 mg/kg, daily for 6 weeks)
ivermectin interactions with another concurrently administered drugs can occur.
This issue becames important, as combination chemotherapy is being used with increasing frequency as resistance to antiparasitic agents is becoming more widespread.
haematomatous swellings
prothrombin times were significantly above baseline by one week to one month after drug ingestion, suggesting an antagonist effect against vitamin K
bleeding disorders were not found in 15,000 patients treated with ivermectin (150 μg/kg)
prolonged prothrombin ratios were observed in 148 subjects given ivermectin orally. Although no patients suffered bleeding complications, factor II and VII levels were reduced in most of them, suggesting interference with vitamin K metabolism
Ivermectin has a minimal effect on coagulation and concern about mass treatment for this reason appears to be unjustified
SHBG decreases in response to androgens, and in the presence of hypothyroidism, and insulin resistance.
Plasma SHBG levels tend to increase with increasing age
The apparent metabolic clearance rate of testosterone is decreased in elderly as compared to younger men
Testosterone circulates predominantly bound to the plasma proteins SHBG and albumin, with high and low affinity respectively
Testosterone is secreted in a pulsatile fashion
Current clinical guidelines suggest at least two measurements
In adult men, there is a well-documented diurnal variation (particularly in younger subjects) in testosterone levels, which are highest in the early morning and progressively decline throughout the day to a nadir in the evening
In older men, the diurnal variation is blunted
it is standard practice for samples to be obtained between 0800 and 1100 h.
Testosterone and DHEA decline, whereas LH, FSH, and SHBG rise
DHT remains constant despite the decline of its precursor testosterone
Longitudinal studies show an average annual decline of 1–2% total testosterone levels, with decline in free testosterone more rapid because of increases in SHBG with aging
Massachusetts Male Aging Study (MMAS) data show DHEA, DHEAS, and Ae declining at 2–3% per year
DHT showed no cross-sectional age trend
Androstanediol glucuronide (AAG) declined cross-sectionally with age in the MMAS sample, at 0.6% per year
The EMAS data show that, consistent with the longitudinal findings of MMAS (Figure 1), the core hormonal pattern with increasing age is suggestive of incipient primary testicular dysfunction with maintained total testosterone and progressively blunted free testosterone associated with higher LH
This author proves the point in the review of these two studies, that TT may remain constant in aging men, however, FT drops.
obesity impairs hypothalamic/pituitary function
Androgen deprivation in men with prostate cancer has been associated with increased insulin resistance, worse glycemic control, and a significant increase in risk of incident diabetes
Low serum testosterone is associated with the development of metabolic syndrome 116, 117 and type 2 diabetes. 118 SHBG has been inversely correlated with type 2 diabetes
Improvement in insulin sensitivity with testosterone treatment has been reported in healthy 121 and diabetic 122 adult men
In studies conducted in men with central adiposity, testosterone has been shown to inhibit lipoprotein lipase activity in abdominal adipose tissue leading to decreased triglyceride uptake in central fat depots. 123
In this study we have shown that regulation of the levels of 3βAdiol by CYP7B1 is a key factor in regulation of prostatic
growth
We provide evidence that proliferating cells in the prostate epithelium have elevated levels of AR and that AR protein
but not mRNA levels are regulated by ERβ and its ligand 3βAdiol in the prostate epithelium.
because inhibition of 5α-reductase causes accumulation of testosterone
and removal of ERβ action increases the level of AR in the prostate, the overall effect of Finasteride would be to favor proliferation
of the prostate epithelium
studies show that ERβ tends to be lost in advanced prostate cancer.
DHEA is converted in the body to 5-androstene-3β,17β-diol, which is also a ligand for estrogen receptors (25, 39) and a substrate for CYP7B1
At the peak of proliferation, the proliferating
epithelial cells in the ventral prostate expressed high levels of CYP7B1 but had no detectable ERβ, whereas in nonproliferating
cells the level of ERβ was high and that of CYP7B1 was low.
3-beta androstanediola, a product of 3alpha-HSD from DHT binds to ER beta and down regulates AR in prostate cancer. This study proposes that the mechanism is via CYP7B1. CYP7B1 inactivates 3-beta androstanediol. Interesting, because 3-beta androstanediol is considered "inactive" when compared to 3-alpha androstanediol and its interaction with ER alpha.
Mechanistic studies further showed that such metabolic inflammation is related to the induction of various intracellular stresses such as mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and autophagy defect under prolonged nutritional excess
intracellular stress-inflammation process for metabolic syndrome has been established in the central nervous system (CNS) and particularly in the hypothalamus
the CNS and the comprised hypothalamus are known to govern various metabolic activities of the body including appetite control, energy expenditure, carbohydrate and lipid metabolism, and blood pressure homeostasis
Reactive oxygen species (ROS) refer to a class of radical or non-radical oxygen-containing molecules that have high oxidative reactivity with lipids, proteins, and nucleic acids
a large measure of intracellular ROS comes from the leakage of mitochondrial electron transport chain (ETC)
Another major source of intracellular ROS is the intentional generation of superoxides by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
there are other ROS-producing enzymes such as cyclooxygenases, lipoxygenases, xanthine oxidase, and cytochrome p450 enzymes, which are involved with specific metabolic processes
To counteract the toxic effects of molecular oxidation by ROS, cells are equipped with a battery of antioxidant enzymes such as superoxide dismutases, catalase, peroxiredoxins, sulfiredoxin, and aldehyde dehydrogenases
intracellular oxidative stress has been indicated to contribute to metabolic syndrome and related diseases, including T2D [72; 73], CVDs [74-76], neurodegenerative diseases [69; 77-80], and cancers
intracellular oxidative stress is highly associated with the development of neurodegenerative diseases [69] and brain aging
dietary obesity was found to induce NADPH oxidase-associated oxidative stress in rat brain
mitochondrial dysfunction in hypothalamic proopiomelanocortin (POMC) neurons causes central glucose sensing impairment
Endoplasmic reticulum (ER) is the cellular organelle responsible for protein synthesis, maturation, and trafficking to secretory pathways
unfolded protein response (UPR) machinery
ER stress has been associated to obesity, insulin resistance, T2D, CVDs, cancers, and neurodegenerative diseases
brain ER stress underlies neurodegenerative diseases
under environmental stress such as nutrient deprivation or hypoxia, autophagy is strongly induced to breakdown macromolecules into reusable amino acids and fatty acids for survival
intact autophagy function is required for the hypothalamus to properly control metabolic and energy homeostasis, while hypothalamic autophagy defect leads to the development of metabolic syndrome such as obesity and insulin resistance
prolonged oxidative stress or ER stress has been shown to impair autophagy function in disease milieu of cancer or aging
TLRs are an important class of membrane-bound pattern recognition receptors in classical innate immune defense
Most hypothalamic cell types including neurons and glia cells express TLRs
overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs
Isoforms TLR1, 2, 4, and 6 may be particularly pertinent to pathogenic signaling induced by lipid overnutrition
hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding
overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain
these evidences based on brain TLR signaling further support the notion that CNS is the primary site for overnutrition to cause the development of metabolic syndrome.
circulating cytokines can limitedly travel to the hypothalamus through the leaky blood-brain barrier around the mediobasal hypothalamus to activate hypothalamic cytokine receptors
significant evidences have been recently documented demonstrating the role of cytokine receptor pathways in the development of metabolic syndrome components
entral administration of TNF-α at low doses faithfully replicated the effects of central metabolic inflammation in enhancing eating, decreasing energy expenditure [158;159], and causing obesity-related hypertension
Resistin, an adipocyte-derived proinflammatory cytokine, has been found to promote hepatic insulin resistance through its central actions
both TLR pathways and cytokine receptor pathways are involved in central inflammatory mechanism of metabolic syndrome and related diseases.
In quiescent state, NF-κB resides in the cytoplasm in an inactive form due to inhibitory binding by IκBα protein
IKKβ activation via receptor-mediated pathway, leading to IκBα phosphorylation and degradation and subsequent release of NF-κB activity
Research in the past decade has found that activation of IKKβ/NF-κB proinflammatory pathway in metabolic tissues is a prominent feature of various metabolic disorders related to overnutrition
it happens in metabolic tissues, it is mainly associated with overnutrition-induced metabolic derangements, and most importantly, it is relatively low-grade and chronic
this paradigm of IKKβ/NF-κB-mediated metabolic inflammation has been identified in the CNS – particularly the comprised hypothalamus, which primarily accounts for to the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, insulin resistance, T2D, and obesity-related hypertension
evidences have pointed to intracellular oxidative stress and mitochondrial dysfunction as upstream events that mediate hypothalamic NF-κB activation in a receptor-independent manner under overnutrition
In the context of metabolic syndrome, oxidative stress-related NF-κB activation in metabolic tissues or vascular systems has been implicated in a broad range of metabolic syndrome-related diseases, such as diabetes, atherosclerosis, cardiac infarct, stroke, cancer, and aging
intracellular oxidative stress seems to be a likely pathogenic link that bridges overnutrition with NF-κB activation leading to central metabolic dysregulation
overnutrition is an environmental inducer for intracellular oxidative stress regardless of tissues involved
excessive nutrients, when transported into cells, directly increase mitochondrial oxidative workload, which causes increased production of ROS by mitochondrial ETC
oxidative stress has been shown to activate NF-κB pathway in neurons or glial cells in several types of metabolic syndrome-related neural diseases, such as stroke [185], neurodegenerative diseases [186-188], and brain aging
central nutrient excess (e.g., glucose or lipids) has been shown to activate NF-κB in the hypothalamus [34-37] to account for overnutrition-induced central metabolic dysregulations
overnutrition can present the cell with a metabolic overload that exceeds the physiological adaptive range of UPR, resulting in the development of ER stress and systemic metabolic disorders
chronic ER stress in peripheral metabolic tissues such as adipocytes, liver, muscle, and pancreatic cells is a salient feature of overnutrition-related diseases
recent literature supports a model that brain ER stress and NF-κB activation reciprocally promote each other in the development of central metabolic dysregulations
when intracellular stresses remain unresolved, prolonged autophagy upregulation progresses into autophagy defect
autophagy defect can induce NF-κB-mediated inflammation in association with the development of cancer or inflammatory diseases (e.g., Crohn's disease)
The connection between autophagy defect and proinflammatory activation of NF-κB pathway can also be inferred in metabolic syndrome, since both autophagy defect [126-133;200] and NF-κB activation [20-33] are implicated in the development of overnutrition-related metabolic diseases
Both TLR pathway and cytokine receptor pathways are closely related to IKKβ/NF-κB signaling in the central pathogenesis of metabolic syndrome
Overnutrition, especially in the form of HFD feeding, was shown to activate TLR4 signaling and downstream IKKβ/NF-κB pathway
TLR4 activation leads to MyD88-dependent NF-κB activation in early phase and MyD88-indepdnent MAPK/JNK pathway in late phase
these studies point to NF-κB as an immediate signaling effector for TLR4 activation in central inflammatory response
TLR4 activation has been shown to induce intracellular ER stress to indirectly cause metabolic inflammation in the hypothalamus
central TLR4-NF-κB pathway may represent one of the early receptor-mediated events in overnutrition-induced central inflammation.
cytokines and their receptors are both upstream activating components and downstream transcriptional targets of NF-κB activation
central administration of TNF-α at low dose can mimic the effect of obesity-related inflammatory milieu to activate IKKβ/NF-κB proinflammatory pathways, furthering the development of overeating, energy expenditure decrease, and weight gain
the physiological effects of IKKβ/NF-κB activation seem to be cell type-dependent, i.e., IKKβ/NF-κB activation in hypothalamic agouti-related protein (AGRP) neurons primarily leads to the development of energy imbalance and obesity [34]; while in hypothalamic POMC neurons, it primarily results in the development of hypertension and glucose intolerance
the hypothalamus, is the central regulator of energy and body weight balance [
SSRI's have variable inhibition of CYP. Fluvoxamine was found to be the most potent inhibitor. CYP3A4 and CYP2D6 were found to be the main targets of inhibition.
Worldwide, the rate of autism has been steadily rising.
Genetic polymorphisms of cytochrome P450 enzymes have also been linked to autism, specifically CYP27B1 that is essential for proper vitamin D metabolism
There are several environmental factors in concert with genetic susceptibilities that are contributing to this rise. Impaired methylation and mutations of mecp2 have been associated with autistic spectrum disorders, and related Rett syndrome.
Other factors that have been considered include: maternally derived antibodies, maternal infection, heavy metal exposure, folic acid supplementation, epigenetics, measles, mumps, rubella vaccination, and even electromagnetic radiation.
The typical onset of TS occurs at 6–7 years of age and is characterized by the appearance of simple, recurrent motor tics, followed by the manifestation of phonic tics after several months [12]. In most children, TS symptoms undergo a progressive exacerbation, which reaches its zenith at the beginning of puberty (11–12 years of age), and is then followed by a gradual remission in the majority of patients
30–40% of TS-affected children retain their symptoms in adulthood
Multiple neurotransmitters have been implicated in TS, including dopamine (DA), serotonin, norepinephrine, acetylcholine, glutamate and γ-amino-butyric acid (GABA)
ample evidence supports the involvement of DAergic dysfunctions in TS
male gender is a major risk factor for TS (with a male:female prevalence ratio estimated at ~4:1)
the typical age of onset coincides with adrenarche (6–7 years old); symptoms increase in severity until the beginning of puberty (12 years old) and then undergo a spontaneous amelioration, which becomes apparent with the end of puberty (at 18–19 years of age)
TS is diagnosed later in females than males
female gender may predict greater tic severity in adulthood
a number of clinical observations showed that tics in TS patients could be exacerbated by anabolic androgens
steroidogenic enzymes and androgen receptors may serve as putative therapeutic targets for this disorder
Unlike males, tic severity is typically increased after puberty in females
26% of females were found to experience exacerbation of tics in the estrogenic phase of the menstrual cycle, and this phenomenon was found to be correlated with increased tic severity at menarche
biochemical hallmark of adrenarche is the acquisition of 17,20 lyase activity by cytochrome P450 C17 (CYP17A1)
increased synthesis of dehydroepiandrosterone (DHEA) and androstenedione, which leads to the growth of axillary and pubic hair as well as enhancement in the oiliness of the skin
interesting read on hormones and tourette's.. Proposed that 5 alpha reductase activity is involved in worsening of tics. This makes sense as Testosterone in men with low T is known to increase dopamine and dopaminergic dysfunction is known to play a role in tourette's; the clinical presentation of girls vs boys is very different. The authors of this article propose that 5 alpha reductase activity controls a back door method where by progesterone is converted to androgens.