Author Topic: HOW BENZOS CAUSE HPA AXIS DYSREGULATION  (Read 1344 times)

[Buddie]

HOW BENZOS CAUSE HPA AXIS DYSREGULATION
« on: November 01, 2019, 08:35:18 pm »
If you wish to discuss the below document by Perseverance, please visit the original discussion thread:

http://www.benzobuddies.org/forum/index.php?topic=44373.0


I Posted this under Withdrawal & Recovery Support because it is general information important to withdrawal and by understanding what is going on in our bodies we can understand the recovery process better, which helps us cope.  I also offered supportive suggestions at the end. :)


HOW BENZOS CAUSE HPA AXIS DYSREGULATION

First let’s look at how the Hypothalamic-Pituitary-Adrenal (HPA) Axis works.  It starts in the Paraventricular Nucleus (PVN) of the Hypothalamus.  The PVN contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes.  This information, known as Afferent inputs, comes in from many regions of the brain.  The PVN then secretes various peptides in response to these Afferent inputs.(10,11,13)

To control the HPA Axis, the Parvocellular neurons in the PVN produce and secrete the peptides Arginine Vasopressin (AVP), also called Anti-Diuretic Hormone (ADH), and Corticotropin Releasing Hormones (CRH), which is also called Corticotropin Releasing Factor (CRF) interchangeably.(10)  These peptides are released from the PVN at the Median Eminence of the Hypothalamus.(4,10)

From there they leave the Hypothalamus and travel through a system of blood vessels called the Hypophyseal Portal System (also known as the Hypothalamo-Pituitary Portal System) to the Anterior Lobe of the Pituitary Gland.(1,2,3,9)  CRH and AVP act synergistically to stimulate the secretion of Adrenocorticotropic Hormone (ACTH) thereby activating the HPA Axis.(19)

Next, the ACTH stimulates the synthesis and release of Cortisol, glucocorticoids, mineral corticoids, and DHEA from the adrenal glands.  DHEA is further biosynthesized into the sex hormones, as shown on this chart of the biochemical pathways of hormone production(5):


 
Androstenedione  is the common precursor of male and female sex hormones.  It is produced through two routes, the HPA Axis and the Hypothalamic–Pituitary–Gonadal Axis (HPG).  In the HPA route, production of androstenedione is governed by ACTH-- whereas in the HPG, the production of androstenedione is under control of two gonadotropins: Folicle Stimulating Hormone (FSH) and the Luteinizing hormone (LH), both of which like ACTH, are also produced by the anterior lobe of the pituitary gland.  The gonads, testes and ovaries, are the primary target organs for FSH and LH.(6,8)

Androstenedione from the Adrenals is converted in peripheral tissues to testosterone and estrogens.  The production of Androstenedione from DHEA in the Adrenals is especially important in post-menopausal women where all estrogens and practically all androgens are made in the peripheral tissues from adrenal DHEA.  In premenopausal women production is about 50 %.  In men, on the other hand, from 40 to 50% of androgens are made in peripheral tissues from adrenal DHEA, thus indicating the major importance of androstenedione synthesized from adrenal DHEA  in both men and women.(6,7)

So how do benzos effect all this?  It all starts right at the top.  First let’s look at how GABA influences the PVN.

GABA and Glutamate are like the yin and yang of the Central Nervous System (CNS).  GABA inhibits, or decreases neuronal activity- while Glutamate has an opposite excitatory effect.  This is one of the ways the CNS maintains homeostasis, or a state of equilibrium.

GABAergic and glutamatergic circuits interact with PVN neurons to control the HPA Axis.  Glutamate stimulates activity while in contrast, GABA neurons inhibit PVN outflow.(12)

Since benzos increase the inhibitory effect of GABA it disrupts this GABA-Glutamate balance.  The excess GABAergic inhibition brought on by the benzos causes a reduction in the levels of CRH and AVP, which in turn blunts ACTH secretion. Thus the end result is suppression of the HPA Axis.(15,19,21)

This enhanced inhibitory action also effects the GABAergic receptors distributed in the hippocampus.  This disrupts the hippocampus-mediated mechanisms of glucocorticoid feedback, which is also involved in regulation of HPA Axis activity.(14)  This may also contribute to the longevity of recovery, as alterations to this feedback plays a role in the delayed return to baseline of CRF in the PVN.(22)

All this has a domino effect, decreasing the Adrenal outputs of Cortisol and DHEA,(14,19) and therefore the hormone biosynthesis of Testosterone and Estrogen, which may result in these levels being low.

Once the Benzos are discontinued there occurs a rebound activation of the HPA Axis.(21)  Also, there can be a repetitive pattern of suppression followed by rebound while on benzos due to interdose withdrawal.(16,17)

ACTH and Cortisol levels have been shown to have a dramatic increase after benzos cessation.(16,18,22)
In addition, sensitivity of the Adrenal Glands to the effects of ACTH could be disrupted by benzos.  It has been shown that benzodiazepines have specific receptors on the adrenal gland, and that benzodiazepines could also act on adrenal gland by blunting the sensitivity of the fasciculata zone to ACTH.(20)

Studies on withdrawal from Glucocorticosteroids (GC), which are cross tolerant to benzos and have similar effects on the HPA Axis, have shown that 1) CRH neurons are the last part of the HPA axis to normalize and 2) the HPA axis and POMC-derived peptide secretion (ex- CRH,AVP, ACTH, etc..) may remain suppressed for a long time.  It is believed that these withdrawals share similar mechanisms.(23)  In fact, Full HPA axis recovery after cessation of GC therapy may take as long as 1 year or more.(24)  This time line mirrors benzo withdrawal recovery period.

The extent of this disinhibition of the HPA Axis once the drug has been removed has been directly correlated to the severity of withdrawal symptoms.(16)

Is anything we can do to help our bodies recover from all these changes?  There actually are a few things you can do to help yourself.

Since many functions in our bodies are dependent on the circadian rhythm, keeping a regular schedule which includes regular mealtimes and waking/bedtime can help.

Following a low glycemic diet helps keep blood sugar at a steady rate.  Blood glucose levels effect the stress related areas of the brain…so keeping this on an even keel can only help things move forward.

Avoid strenuous exercise, like aerobic activities, while you are healing.  Exercise stimulates the Adrenals to secrete catecholamines- dopamine, adrenaline, and norepinephrine. The latter two are the "fight-or-flight" hormones…this elicits a stress response in the PVN which activates the HPA Axis…something  you want to avoid for obvious reasons.  This is also the reason why you want to keep your stress levels as low as possible…to avoid this same reaction.  Researchers actually use exercise to induce a stress like response when studying the HPA Axis.

If there is no reason other than benzo withdrawal for low hormone levels (no tumors of other conditions)…avoid Hormone Replacement Therapies.  Adding hormones can discourage natural production just at the time your body is working on restoring this.  It’s best to let your body restore these levels naturally.

Avoid topical, oral, or intravenous steroids.  This includes hydrocortisone creams and ointments and steroid injections for pain.  And also neuroactive steroids like oral DHEA supplements and prescription Progesterone.

So that’s it.  It takes the HPA Axis a long time to turn around…but eventually with time everything should straighten out.  We just have to do our best and be patient with the healing process.


References
1) http://en.wikipedia.org/wiki/Corticotropin-releasing_factor_family
2) http://en.wikipedia.org/wiki/Corticotropin-releasing_hormone
3) http://en.wikipedia.org/wiki/Hypothalamo-hypophyseal_portal_system
4) http://en.wikipedia.org/wiki/Median_eminence
5) http://www.urology-textbook.com/01/steroidbiosynthese.jpg
6) http://en.wikipedia.org/wiki/Androstenedione
7) http://www.ncbi.nlm.nih.gov/pubmed/20478438
8 ) http://en.wikipedia.org/wiki/Gonadotropin
9) http://en.wikipedia.org/wiki/Vasopressin
10) http://en.wikipedia.org/wiki/Paraventricular_nucleus_of_hypothalamus
11) http://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary%E2%80%93adrenal_axis
12) http://www.ncbi.nlm.nih.gov/pubmed/15240350
13) http://www.ncbi.nlm.nih.gov/pubmed/11830180
14) http://jcem.endojournals.org/content/87/10/4616.long
15) http://jcem.endojournals.org/content/90/8/4777.long
16) http://www.ncbi.nlm.nih.gov/pubmed/15219633
17) http://www.ncbi.nlm.nih.gov/pubmed/8577815
18) http://www.ncbi.nlm.nih.gov/pubmed/19167197
19) http://www.ncbi.nlm.nih.gov/pubmed/8027217
20) http://www.ncbi.nlm.nih.gov/pubmed/12035937
21) http://www.jneurosci.org/content/20/3/1240.long
22) http://www.jneurosci.org/content/24/42/9303.long
23) http://edrv.endojournals.org/content/24/4/523.full
24) http://www.endotext.org/adrenal/adrenal14/adrenalframe14.htm
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