Endotoxin Inflammation Stack

@GreekDemiGod said in Endotoxin Inflammation Stack:

@mostlylurking why such high doses of zinc and for how long?

Are you asking me why I'm taking zinc and the dose? Please help me find what you are referring to. Thanks.

I'm taking 15mgs of zinc daily for a while because I tested deficient on a blood test last spring. I'll get retested in a few weeks. I got my zinc level tested because it is one of the things that is known to watch for deficiency in when high dosing thiamine.

zorba990

@herayclitus That much Zinc will deplete copper and manganese which can lead to things like tendon and ligament weakness among others - so watch out for that.

@zorba990 I'm getting tested again in a couple of weeks. I'm aware of the copper issue; I wasn't aware of of the manganese issue though, thanks. My manganese was alarmingly high about 2 years ago; haven't had it tested recently. I wonder if high manganese would cause zinc deficiency?

LucH

@zorba990 said in Endotoxin Inflammation Stack:

That much Zinc will deplete copper

10 ou 15 mg zinc supplement in not going to deplete copper. Up to 30 mg OK.
The transporters are the same ones.
I take zinc (10 or 15 mg) when I don't eat red meat.
30 mg when there is inflammation or a flu but not when the flu is over-infected (not in infectious bronchitis).
If you eat some pecan nuts or macadamia nuts 2x/wk (5 or 6, no more useful) you won't lack manganese.
The concentration of zinc in blood plasma stays relatively constant regardless of zinc intake.

I've got scientific links to explain why, provided you take into account 3 points:

Many of the studies demonstrate that the copper to zinc ratio was more important as a marker of insufficiency, deficiency, or imbalance than the serum levels of the individual minerals.
Not above 2/0 for Zn / Cu.
No more than 30 mg zinc supplement. 10 - 15 mg is optimal.
If you take a supplement, mind interference. Namely with iron and Ca. I don't take zinc when I eat cheese since the limit of Ca could be very low (< 40 mg).

Part of the sources:
Zn metabolism
Copper and Zinc, Biological Role and Significance of Copper/Zinc Imbalance - Journal of Clinical Toxicology
https://www.omicsonline.org/copper-and-zinc-biological-role-and-significance-of-copper-zincimbalance-2161-0495.S3-001.php?aid=3055
In blood plasma, Zn is bound to and transported by albumin (60%, low-affinity) and transferrin (10%) [27]. Since transferrin also transports iron, excessive iron can reduce zinc absorption, and vice-versa [28]. The concentration of zinc in blood plasma stays relatively constant regardless of zinc intake [29]. Zinc may be held in metallothionein reserves and also transferred in metal transporters of ZIP and ZnT family transporter proteins [30]. Metallothioneins in intestinal cells are capable of adjusting absorption of zinc by 15-40% [31]. Excess zinc particularly impairs copper absorption because metallothioneins absorb both metals [32].

https://lpi.oregonstate.edu/mic/minerals/zinc#safety
Long-term consumption of zinc in excess of the tolerable upper intake level (UL; 40 mg/day for adults) can result in copper deficiency.

Copper and zinc compete for binding sites and are antagonists
There is competition between zinc and other minerals for carriers or uptake sites.

Effect of dietary zinc and protein levels on the utilization of zinc and copper by adult females.
https://www.ncbi.nlm.nih.gov/pubmed/6875690?dopt=Abstract
J Nutr. 1983
=>

No influence on copper retention or excretion with food intake, up to 2 mg Cu,

with low, moderate or high zinc diet, fed either with a moderate protein, or a high protein intake, during a 24-day study, with a balanced diet in twenty-three young adult female.
2. The effect of dietary zinc on intestinal copper absorption.
https://www.ncbi.nlm.nih.gov/pubmed/7282591
Am J Clin Nutr. 1981 Sep.
=> The mucosal cells from animals fed low amounts of zinc retained less copper than the cells from animals fed high amounts of the element.
=> Zinc exerts its antagonistic effect by inducing the synthesis of a copper-binding ligand, probably a thionein, in the mucosal cells which sequesters copper from the nutrient medium, making it unavailable for serosal transfer. This may be a possible mechanism by which dietary zinc decreases copper absorption and leads to a decreased copper status.
=> Zinc modulates copper absorption.

zorba990

@mostlylurking Yes they all compete with each other that way so such an induced deficiency is possible. 120mg is way too much in my opinion to use for any length of time. I personally gave myself tendonitis a few times before realizing what 50mg zinc was doing to me over time. A friend at work did the same thing with overdosing a supplement called ZMA - gave himself numerous tendon and ligament issues and eventually had to have surgery.

@zorba990 said in Endotoxin Inflammation Stack:

@mostlylurking Yes they all compete with each other that way so such an induced deficiency is possible. 120mg is way too much in my opinion to use for any length of time. I personally gave myself tendonitis a few times before realizing what 50mg zinc was doing to me over time. A friend at work did the same thing with overdosing a supplement called ZMA - gave himself numerous tendon and ligament issues and eventually had to have surgery.

I've just been taking 15mgs of zinc, not 120mgs. The blood tests showed a deficiency, both doctors thought I should supplement with a little zinc, so I chose the 15mg one instead of the 30mg one. I take high dose thiamine hcl; it helps with the high oxidative stress I have due to my mercury toxicity. Zinc deficiency is one of the things to watch out for when high dosing thiamine for any length of time; I've been doing it for almost 4 years.

My copper tested fine at the time.

@LucH said in Endotoxin Inflammation Stack:

If you take a supplement, mind interference. Namely with iron and Ca. I don't take zinc when I eat cheese since the limit of Ca could be very low (< 40 mg).

How far apart (time wise) should I space taking zinc with calcium intake?

LucH

@mostlylurking said in Endotoxin Inflammation Stack:

How far apart (time wise) should I space taking zinc with calcium intake?

The problem is supposed to be higher when supplementing (than with food supply). Deduction. Variable.
30' is enough for cheese since it's a problem of transport through mucosal membrane.
https://www.ncbi.nlm.nih.gov/pubmed/7282591
Am J Clin Nutr. 1981 Sep.

3 Hours if supplementing iron (albumin and transferrin transport in blood)
Zn metabolism
Copper and Zinc, Biological Role and Significance of Copper/Zinc Imbalance - Journal of Clinical Toxicology
https://www.omicsonline.org/copper-and-zinc-biological-role-and-significance-of-copper-zincimbalance-2161-0495.S3-001.php?aid=3055
In blood plasma, Zn is bound to and transported by albumin (60%, low-affinity) and transferrin (10%) [27]. Since transferrin also transports iron, excessive iron can reduce zinc absorption, and vice-versa [28].

Butter Girl

@LucH said in Endotoxin Inflammation Stack:

Some target points to deal with

B1 is needed for communication between the brain and the stomach (vagal innervation).
High dose B1 is needed for passive assimilation, with staples. I’d take Mg bisglycinate every day (300 mg x 2 or x3, according to stress); and B2 50 mg (every other day, thrice a week). B2 is needed when taking B1.

B1 for gut motility
Dr Costantini and bacterial overgrowth
SIBO, IBS, and Constipation: Unrecognized Thiamine Deficiency? – June 2020
https://www.hormonesmatter.com/sibo-ibs-constipation-thiamine-deficiency/
To understand how thiamine impacts gut function we have to understand the GI tract. The GI tract possesses its own individual enteric nervous system (ENS), often referred to as the second brain. (vagal innervation). Enteric neurons also use acetylcholine to initiate peristaltic contractions necessary for proper gut motility. Thiamine is necessary for the synthesis of acetylcholine and low levels produce an acetylcholine deficit, which leads to reduced vagal tone and impaired motility in the stomach and small intestine.
=> choline or glycine needed.
For Dr. Constantini, a chronic thiamine deficiency can indirectly produce an inability to digest and absorb foods, and therefore produce a deficiency in most of the other vitamins and minerals. In fact, this is indeed something I see frequently. And sadly, as thiamine is notoriously difficult to identify through ordinary testing methods, it is mostly missed by doctors and nutritionists. To summarize, B1 is necessary in the gut for:
 Stomach acid secretion and gastric emptying
 Pancreatic digestive enzyme secretion
 Intestinal brush border enzymes
 Intestinal contractions and motility
 Vagal nerve function
If I have problem to digest protein, Betaine HCL, at the evening meal. Digestion is optimal at midday.
If I have problem to digest fats: Enzymedica Lypo Gold for fat digestion.
Note: you’re not going to solve this kind of problem with 100 mg B1. Passive assimilation is needed when targeting High dose B1, in several staples, not only with B1 HCl. I can give a link for the protocol of Dr. Allil Overton, on my forum, if wanted (“mirzoune et ciboulette”)
Dr. Overton says, when talking about Thiamine (nod need to listen to):
https://www.hormonesmatter.com/talking-about-thiamine/
“Thiamine (vitamin B1) is critical for the metabolism of food into cellular energy or ATP. Without sufficient thiamine, cellular energy wanes, and with it, the capacity to maintain the energy to function declines. Chronic, unrelenting fatigue is a common characteristic of insufficient thiamine. At its root, fatigue is the physical manifestation of poor energy metabolism.
Why is this nutrient such a problem? Two reasons. First, B1 is the gatekeeper to energy metabolism and so if it is low, everything downstream gums up and does not work well. Second, modern diets, medicines, and other chemical exposures contain numerous anti-thiamine factors that derail thiamine absorption and metabolism. This pushes many people into states of chronic deficiency, one that is simple to correct if identified. Unfortunately, however, patients can go years before the deficiency is recognized.”
Additional info
Thiamine Deficiency - A Potential Cause of SIBO and other Gut Dysfunction?
Elliot Overton – Nutrition and Functional Medicine – 2019
https://www.eonutrition.co.uk/post/thiamine-deficiency-a-major-cause-of-sibo

Thiamine deficiency - A consequence or cause of SIBO?

How can thiamine deficiency cause gut dysfunction?
Key points:
Thiamine's key role in energy metabolism of the brain regions responsible for controlling autonomic balance, coupled with its role in acetylcholine synthesis, indicate that a deficiency could easily cause the symptoms which we associate with SIBO.
The autonomic nervous system is involved in:
 Secretion of stomach acid, pancreatic enzymes, and brush border enzymes
 Release of bile from the liver
 Maintaining regular intestinal peristalsis (motility)
 Reducing intestinal permeability (leaky gut)
 Reducing inflammation

I take 150-200 of Lipothiamine daily in addition to a B complex. How much B2 is necessary to take with this?
My B- complex has 50mgs. in it.

LucH

@Butter-Girl
50 mg IS ok.
What kind of b6 and B3 b9. How much.
A link?

Butter Girl

@LucH said in Endotoxin Inflammation Stack:

@Butter-Girl
50 mg IS ok.
What kind of b6 and B3 b9. How much.
A link?

It’s a Methyl B Complex by Ortho Molecular Products.
B6 is Pyridoxine Hydrochloride USP 50 mg
B3 is Niacinamide USP 50 mg
B9 is Folate (400 mcg as Quatrefolic (6S)-5Meththyltetrahydrofolic acid glucosamine salt 680 mcgDFE

LucH

@Butter-Girl said in Endotoxin Inflammation Stack:

It’s a Methyl B Complex by Ortho Molecular Products.

OK if only one gel a day. No need every day. 2 or 3 times a week could be adequate.
=> Mo Wed Fr.
Note: TMG 500-1000 mg could be interesting too if detox. 2x/d.
+/ Hard to swallow without fat if 1000 mg ((big caps).
TMG = tri-methyl glycine.

zorba990

@mostlylurking Thats great but the OP said 120mg zinc and that is too much.

zorba990

@LucH This is getting odd -- like there are two threads going here. I am responding to the original poster, but I guess it isn't clear from the forum format. 120mg will likely cause problems IRT Zinc supplementation. Really lower dose Zinc-Carnosine would be better IMO.

@zorba990 OK. I didn't understand; I thought you were addressing my intake, not the OP's. Sorry for my confusion.

@zorba990 I've found that if you use the "quote" feature instead of the "reply" feature, there is less confusion. Maybe there's a glitch?

@Butter-Girl said in Endotoxin Inflammation Stack:

@LucH said in Endotoxin Inflammation Stack:

Some target points to deal with

B1 is needed for communication between the brain and the stomach (vagal innervation).
High dose B1 is needed for passive assimilation, with staples. I’d take Mg bisglycinate every day (300 mg x 2 or x3, according to stress); and B2 50 mg (every other day, thrice a week). B2 is needed when taking B1.

B1 for gut motility
Dr Costantini and bacterial overgrowth
SIBO, IBS, and Constipation: Unrecognized Thiamine Deficiency? – June 2020
https://www.hormonesmatter.com/sibo-ibs-constipation-thiamine-deficiency/
To understand how thiamine impacts gut function we have to understand the GI tract. The GI tract possesses its own individual enteric nervous system (ENS), often referred to as the second brain. (vagal innervation). Enteric neurons also use acetylcholine to initiate peristaltic contractions necessary for proper gut motility. Thiamine is necessary for the synthesis of acetylcholine and low levels produce an acetylcholine deficit, which leads to reduced vagal tone and impaired motility in the stomach and small intestine.
=> choline or glycine needed.
For Dr. Constantini, a chronic thiamine deficiency can indirectly produce an inability to digest and absorb foods, and therefore produce a deficiency in most of the other vitamins and minerals. In fact, this is indeed something I see frequently. And sadly, as thiamine is notoriously difficult to identify through ordinary testing methods, it is mostly missed by doctors and nutritionists. To summarize, B1 is necessary in the gut for:
 Stomach acid secretion and gastric emptying
 Pancreatic digestive enzyme secretion
 Intestinal brush border enzymes
 Intestinal contractions and motility
 Vagal nerve function
If I have problem to digest protein, Betaine HCL, at the evening meal. Digestion is optimal at midday.
If I have problem to digest fats: Enzymedica Lypo Gold for fat digestion.
Note: you’re not going to solve this kind of problem with 100 mg B1. Passive assimilation is needed when targeting High dose B1, in several staples, not only with B1 HCl. I can give a link for the protocol of Dr. Allil Overton, on my forum, if wanted (“mirzoune et ciboulette”)
Dr. Overton says, when talking about Thiamine (nod need to listen to):
https://www.hormonesmatter.com/talking-about-thiamine/
“Thiamine (vitamin B1) is critical for the metabolism of food into cellular energy or ATP. Without sufficient thiamine, cellular energy wanes, and with it, the capacity to maintain the energy to function declines. Chronic, unrelenting fatigue is a common characteristic of insufficient thiamine. At its root, fatigue is the physical manifestation of poor energy metabolism.
Why is this nutrient such a problem? Two reasons. First, B1 is the gatekeeper to energy metabolism and so if it is low, everything downstream gums up and does not work well. Second, modern diets, medicines, and other chemical exposures contain numerous anti-thiamine factors that derail thiamine absorption and metabolism. This pushes many people into states of chronic deficiency, one that is simple to correct if identified. Unfortunately, however, patients can go years before the deficiency is recognized.”
Additional info
Thiamine Deficiency - A Potential Cause of SIBO and other Gut Dysfunction?
Elliot Overton – Nutrition and Functional Medicine – 2019
https://www.eonutrition.co.uk/post/thiamine-deficiency-a-major-cause-of-sibo

Thiamine deficiency - A consequence or cause of SIBO?

How can thiamine deficiency cause gut dysfunction?
Key points:
Thiamine's key role in energy metabolism of the brain regions responsible for controlling autonomic balance, coupled with its role in acetylcholine synthesis, indicate that a deficiency could easily cause the symptoms which we associate with SIBO.
The autonomic nervous system is involved in:
 Secretion of stomach acid, pancreatic enzymes, and brush border enzymes
 Release of bile from the liver
 Maintaining regular intestinal peristalsis (motility)
 Reducing intestinal permeability (leaky gut)
 Reducing inflammation

I take 150-200 of Lipothiamine daily in addition to a B complex. How much B2 is necessary to take with this?
My B- complex has 50mgs. in it.

I think the amount of B2 needed is tied to multiple things. For example, I do take B2 because I high dose thiamine hcl, but I also was having some eye trouble: cataracts, floaters, difficulty focusing. I've been taking about 100mgs of B2 four times a day for the past 3 years. I believe this is the reason for my greatly improved eye health, including the improvement in the cataract situation. See here: Riboflavin: The Health Benefits of a Forgotten Natural Vitamin
"Cataract formation is a result of protein aggregation which causes the lens to become cloudy. RF intake from food and supplements was associated with decreased risk of nuclear lens opacities [81]. Cataract formation in the general public seemed not to be associated with RF deficiency while in the elderly it might be increased due to a RF deficiency [82]. High dose of RF, 400 mg/d, appears to have a preventive effect or some beneficial effects on the development of age-related cataracts [3]. RF concentration influences the GSH concentration in the lens, while GSH protects the lens against oxidative damage and cataract development. In total, 80% of the cataract patients showed a shortage of RF [83]. "

Here is another article about riboflavin that might be of interest: A newly discovered anti-senescence function of vitamin B2
"The research team discovered a phenomenon whereby resistance to cellular senescence occurred as a result of increasing the amount of SLC52A1 produced. SLC52A1 is the protein responsible for transporting vitamin B2 into cells (vitamin B2 transporter). When SLC52A1 production was increased, cellular senescence did not occur immediately even under stress conditions (where human cells were treated with a drug to injure the DNA and induce aging). Following on from this, the researchers conducted an experiment where they exposed the cells to stress and then increased the amount of vitamin B2 in the culture solution. They found that resistance to senescence increased in accordance with the amount of vitamin B2 in the solution. Inside the cell, vitamin B2 is converted into a substance called Flavin Adenine Dinucleotide (FAD), a coenzyme that promotes the chemical reactions necessary for biological activities such as energy production. In fact, the amount of FAD in cells exposed to stress increased, which resulted in the vitamin B2 that had been transported into the cells to be converted into FAD, thus suppressing senescence."

Butter Girl

@LucH said in Endotoxin Inflammation Stack:

@Butter-Girl said in Endotoxin Inflammation Stack:

It’s a Methyl B Complex by Ortho Molecular Products.

OK if only one gel a day. No need every day. 2 or 3 times a week could be adequate.
=> Mo Wed Fr.
Note: TMG 500-1000 mg could be interesting too if detox. 2x/d.
+/ Hard to swallow without fat if 1000 mg ((big caps).
TMG = tri-methyl glycine.

Thank you!

Butter Girl

@mostlylurking said in Endotoxin Inflammation Stack:

@Butter-Girl said in Endotoxin Inflammation Stack:

@LucH said in Endotoxin Inflammation Stack:

Some target points to deal with

B1 is needed for communication between the brain and the stomach (vagal innervation).
High dose B1 is needed for passive assimilation, with staples. I’d take Mg bisglycinate every day (300 mg x 2 or x3, according to stress); and B2 50 mg (every other day, thrice a week). B2 is needed when taking B1.

B1 for gut motility
Dr Costantini and bacterial overgrowth
SIBO, IBS, and Constipation: Unrecognized Thiamine Deficiency? – June 2020
https://www.hormonesmatter.com/sibo-ibs-constipation-thiamine-deficiency/
To understand how thiamine impacts gut function we have to understand the GI tract. The GI tract possesses its own individual enteric nervous system (ENS), often referred to as the second brain. (vagal innervation). Enteric neurons also use acetylcholine to initiate peristaltic contractions necessary for proper gut motility. Thiamine is necessary for the synthesis of acetylcholine and low levels produce an acetylcholine deficit, which leads to reduced vagal tone and impaired motility in the stomach and small intestine.
=> choline or glycine needed.
For Dr. Constantini, a chronic thiamine deficiency can indirectly produce an inability to digest and absorb foods, and therefore produce a deficiency in most of the other vitamins and minerals. In fact, this is indeed something I see frequently. And sadly, as thiamine is notoriously difficult to identify through ordinary testing methods, it is mostly missed by doctors and nutritionists. To summarize, B1 is necessary in the gut for:
 Stomach acid secretion and gastric emptying
 Pancreatic digestive enzyme secretion
 Intestinal brush border enzymes
 Intestinal contractions and motility
 Vagal nerve function
If I have problem to digest protein, Betaine HCL, at the evening meal. Digestion is optimal at midday.
If I have problem to digest fats: Enzymedica Lypo Gold for fat digestion.
Note: you’re not going to solve this kind of problem with 100 mg B1. Passive assimilation is needed when targeting High dose B1, in several staples, not only with B1 HCl. I can give a link for the protocol of Dr. Allil Overton, on my forum, if wanted (“mirzoune et ciboulette”)
Dr. Overton says, when talking about Thiamine (nod need to listen to):
https://www.hormonesmatter.com/talking-about-thiamine/
“Thiamine (vitamin B1) is critical for the metabolism of food into cellular energy or ATP. Without sufficient thiamine, cellular energy wanes, and with it, the capacity to maintain the energy to function declines. Chronic, unrelenting fatigue is a common characteristic of insufficient thiamine. At its root, fatigue is the physical manifestation of poor energy metabolism.
Why is this nutrient such a problem? Two reasons. First, B1 is the gatekeeper to energy metabolism and so if it is low, everything downstream gums up and does not work well. Second, modern diets, medicines, and other chemical exposures contain numerous anti-thiamine factors that derail thiamine absorption and metabolism. This pushes many people into states of chronic deficiency, one that is simple to correct if identified. Unfortunately, however, patients can go years before the deficiency is recognized.”
Additional info
Thiamine Deficiency - A Potential Cause of SIBO and other Gut Dysfunction?
Elliot Overton – Nutrition and Functional Medicine – 2019
https://www.eonutrition.co.uk/post/thiamine-deficiency-a-major-cause-of-sibo

Thiamine deficiency - A consequence or cause of SIBO?

How can thiamine deficiency cause gut dysfunction?
Key points:
Thiamine's key role in energy metabolism of the brain regions responsible for controlling autonomic balance, coupled with its role in acetylcholine synthesis, indicate that a deficiency could easily cause the symptoms which we associate with SIBO.
The autonomic nervous system is involved in:
 Secretion of stomach acid, pancreatic enzymes, and brush border enzymes
 Release of bile from the liver
 Maintaining regular intestinal peristalsis (motility)
 Reducing intestinal permeability (leaky gut)
 Reducing inflammation

I take 150-200 of Lipothiamine daily in addition to a B complex. How much B2 is necessary to take with this?
My B- complex has 50mgs. in it.

I think the amount of B2 needed is tied to multiple things. For example, I do take B2 because I high dose thiamine hcl, but I also was having some eye trouble: cataracts, floaters, difficulty focusing. I've been taking about 100mgs of B2 four times a day for the past 3 years. I believe this is the reason for my greatly improved eye health, including the improvement in the cataract situation. See here: Riboflavin: The Health Benefits of a Forgotten Natural Vitamin
"Cataract formation is a result of protein aggregation which causes the lens to become cloudy. RF intake from food and supplements was associated with decreased risk of nuclear lens opacities [81]. Cataract formation in the general public seemed not to be associated with RF deficiency while in the elderly it might be increased due to a RF deficiency [82]. High dose of RF, 400 mg/d, appears to have a preventive effect or some beneficial effects on the development of age-related cataracts [3]. RF concentration influences the GSH concentration in the lens, while GSH protects the lens against oxidative damage and cataract development. In total, 80% of the cataract patients showed a shortage of RF [83]. "

Here is another article about riboflavin that might be of interest: A newly discovered anti-senescence function of vitamin B2
"The research team discovered a phenomenon whereby resistance to cellular senescence occurred as a result of increasing the amount of SLC52A1 produced. SLC52A1 is the protein responsible for transporting vitamin B2 into cells (vitamin B2 transporter). When SLC52A1 production was increased, cellular senescence did not occur immediately even under stress conditions (where human cells were treated with a drug to injure the DNA and induce aging). Following on from this, the researchers conducted an experiment where they exposed the cells to stress and then increased the amount of vitamin B2 in the culture solution. They found that resistance to senescence increased in accordance with the amount of vitamin B2 in the solution. Inside the cell, vitamin B2 is converted into a substance called Flavin Adenine Dinucleotide (FAD), a coenzyme that promotes the chemical reactions necessary for biological activities such as energy production. In fact, the amount of FAD in cells exposed to stress increased, which resulted in the vitamin B2 that had been transported into the cells to be converted into FAD, thus suppressing senescence."

Interesting information thats good to know.

herayclitus

Thought I should post a brief update since this thread has gotten some more attention lately: The symptoms I was dealing with have greatly improved with some diet and lifestyle changes. I've reduced my zinc supplementation to a more standard 15mg a day, but I still feel 120mg/day was beneficial as a short-term loading dose. I do get plenty of copper and manganese in my diet from regular shellfish consumption, and I've started using molasses as well. If anyone is interested, the current stack I'm running is a standard B-complex, 300mg thiamine HCL, 8000IU vitamin D, Thorne's vitamin K formula, 15mg zinc citrate, and T3/T4, progesterone, pregnenolone, and DHEA rarely as needed