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I read an old post of yours, Dr Mariano, about low SHBG. It is an interesting topic to me, and I think that people with low SHBG represent quite a distinct group in the TRT cohort.
In the post it talks about the most common cause of low SHBG being androgen abuse or glucose intolerance. But surely some people have low/low-normal SHBG that do not fall into either category.
How do you address low SHBG in your practice, or what weight does it carry in your treatment plan? I’m really interested to know what you think about this hormone, especially because I find it to be so important yet it receives so little attention (not necessarily in changing the SHBG number, but working with it).
(If you are wondering, this is the post that was attributed to you. I believe it is from 2007 or earlier.)
Low SHBG and Estradiol by Dr. Marianco.
The most common cause of low SHBG is excessive insulin – i.e. insulin resistance. Insulin resistance in turn leads to a cascade of events which results other hormone imbalances such as low testosterone production, suboptimal thyroid hormone activity, adrenal fatigue, etc.
Factors which together in a balance determine SHBG are:
1. Anabolic hormones generally reduce SHBG. These include testosterone, DHEA, insulin, DHT, and growth hormone.
2. Thyroid hormone, Estrogens, and Progesterone (by increasing estrogen receptors/sensitivity), increase SHBG.In the absence of insulin resistance, the most common other cause of low SHBG is a very high level of other anabolic hormones – most frequency high testosterone from TRT. Those who use anabolic steroids at high doses often drive their SHBG to near zero.
When total testosterone is between 650 to 1000 ng/dl, and a person still has zero sex drive, I would look for other causes for sexual dysfunction – e.g. other hormone, neurotransmitter, or immune system problems.
Raising SHBG does not necessarily increase the risk for Alzheimer’s disease. It is important to keep in mind the factors which lead to the risk of Alzheimer’s disease.
Insulin resistance (i.e. excessive insulin levels) causes low SHBG. It also greatly increases the risk of Alzheimer’s disease because it results in a higher level of inflammatory cytokine production (Cytokines are the chemical messengers of the immune system). It is the inflammation which is one of the underlying factors which leads to Alzheimer’s disease.
SHBG level is most often a signal of the overall status of multiple hormone levels. The balance may give an indication of whether one is in an pro-inflammatory state or anti-inflammatory state – with inflammation leading to disease such as Alzheimer’s disease, heart disease, strokes, cancer, etc. Some hormones such as some estrogens and insulin can lead to inflammation leading to illness. And other hormones such as the androgens (except DHT), growth hormone, and thyroid hormone, can lead to an antiinflammatory state, reducing the risk for illness. The balance determines the person’s risk for illness.
What estradiol level is best for any individual often needs to be determined by trial and error. It is unique for each individual. Most do best around 30 pg/ml. But some do best at lower and higher levels. For example, I have a 65 y.o. patient with a total testosterone of 840 ng/dl and an estradiol of 47 pg/ml. He’s having the time of his life – able to make love numerous times each night – after more than a decade of having no sex. The estradiol level works for him without side effects. Some may do better with much loser levels of estradiol – the response is highly individualistic.
Even with low SHBG – which is difficult to correct since it depends on the balance of so many hormones – when the other hormones and neurotransmitters are optimized, sex drive and the ability to have an erection can often return.
When total testosterone is supraphysiologic – i.e. over 1000 ng/dl – problems with libido and erections may occur. Testosterone increases dopamine in the brain in order to increase sex drive, reduce depression, give pleasure to activities. The problem is that dopamine is a very fragile neurotransmitter/hormone in its effects. Too high a dopamine level can cause tolerance to dopamine. This is similar to how one can develop tolerance to drugs such as cocaine and amphetamines which increase dopamine levels in the brain to cause their high. This can lead to the loss of libido when high testosterone levels are maintained for long periods of time.
Conversely, when one is deprived of testosterone (and hence dopamine) for long periods of time due to hypogonadism, one can get a high during the first few weeks of testosterone treatment since the brain becomes supersensitive to dopamine when it has been deprived of it (e.g. making more dopamine receptors to pick up the weaker dopamine signals). Unfortunately, as the brain then gets use to the higher dopamine levels, it will develop some tolerance, and libido will drop off – though we often wish that hopefully a good amount remains.
@compaq 4969 wrote:
I read an old post of yours, Dr Mariano, about low SHBG. It is an interesting topic to me, and I think that people with low SHBG represent quite a distinct group in the TRT cohort.
In the post it talks about the most common cause of low SHBG being androgen abuse or glucose intolerance. But surely some people have low/low-normal SHBG that do not fall into either category.
How do you address low SHBG in your practice, or what weight does it carry in your treatment plan? I’m really interested to know what you think about this hormone, especially because I find it to be so important yet it receives so little attention (not necessarily in changing the SHBG number, but working with it).
(If you are wondering, this is the post that was attributed to you. I believe it is from 2007 or earlier.)
When dealing with clients with low SHBG, by correcting thyroid, insulin resistance as well as now leptin resistance has been shown to help increase SHBG. With low SHBG TRT should be given with more frequent dosages due to the fact the body metabolizes it much quicker. As you deal with other symptoms you can make proper adjustments in TRT
@compaq 4969 wrote:
I read an old post of yours, Dr Mariano, about low SHBG. It is an interesting topic to me, and I think that people with low SHBG represent quite a distinct group in the TRT cohort.
In the post it talks about the most common cause of low SHBG being androgen abuse or glucose intolerance. But surely some people have low/low-normal SHBG that do not fall into either category.
How do you address low SHBG in your practice, or what weight does it carry in your treatment plan? I’m really interested to know what you think about this hormone, especially because I find it to be so important yet it receives so little attention (not necessarily in changing the SHBG number, but working with it).
The primary purpose of a binding protein such as SHBG is to prolong the life of testosterone in the body. Otherwise, with a half-life of 10-100 minutes – testosterone would be almost totally eliminated from the body within 50 minutes to 8.3 hours without constant production or frequent application of testosterone.
The quickest way to increase SHBG is to treat a person with T3 (Cytomel) or to a lesser extent Armour Thyroid, when optimizing thyroid hormone signaling. This increases SHBG production from the liver. Optimizing thyroid signaling first is important to set the stage for subsequent testosterone treatment. Doing so helps correct low SHBG.
Low SHBG is one of many reasons testosterone levels are so low in diabetes type 2. When SHBG is low due to insulin resistance/diabetes type 2 and high insulin level, treatment with testosterone helps reduce insulin resistance. Over several months time, SHBG self-corrects as other metabolic improvements with testosterone treatment occur such as loss of belly fat. Of course, in the presence of diabetes type 2, one of the first things to do is to optimize thyroid hormone and treat the insulin resistance with medications such as Metformin or Actos. This would help improve SHBG and would set the stage for testosterone treatment, minimizing problems that can occur with testosterone treatment – such as anxiety, irritability, fatigue, excessive estrogen, etc.
Low SHBG also occurs in inflammatory diseases (such as rheumatoid arthritis, etc.) – where Interleukin 1 beta reduces SHBG production. I generally assess for the presence of immune system problems since they are often at the root of mood disorders. Reducing pro-inflammatory signaling would help correct their role in reducing SHBG.
SHBG is important but usually it is self-corrected by addressing more important problems – such as hypothyroidism, diabetes, chronic inflammatory illness – prior to testosterone replacement.
When it does become a significant problem is when it is too high – such as with high dose T3 treatment in cases of peripheral thyroid resistance. When SHBG is high, a normal 100 mg a week dose of testosterone cypionate can achieve blood levels past 1500 ng/mL. A concern at that level when coupled with high SHBG is that the lower free testosterone levels may become a significant factor in reducing the effects of testosterone. SHBG bound to testosterone does have signaling function on its own – what it does is unclear – but it is interesting to speculate that if the testosterone-bound SHBG signal is too high, perhaps it may inhibit libido.
If a patient has an apparently health thyroid and weight, is it reasonable to presume they must have some type of chronic low-grade inflammation then?
Aside from infection, what might the cause(s) be?
@DrMariano 6694 wrote:
The primary purpose of a binding protein such as SHBG is to prolong the life of testosterone in the body. Otherwise, with a half-life of 10-100 minutes – testosterone would be almost totally eliminated from the body within 50 minutes to 8.3 hours without constant production or frequent application of testosterone.
The quickest way to increase SHBG is to treat a person with T3 (Cytomel) or to a lesser extent Armour Thyroid, when optimizing thyroid hormone signaling. This increases SHBG production from the liver. Optimizing thyroid signaling first is important to set the stage for subsequent testosterone treatment. Doing so helps correct low SHBG.
Low SHBG is one of many reasons testosterone levels are so low in diabetes type 2. When SHBG is low due to insulin resistance/diabetes type 2 and high insulin level, treatment with testosterone helps reduce insulin resistance. Over several months time, SHBG self-corrects as other metabolic improvements with testosterone treatment occur such as loss of belly fat. Of course, in the presence of diabetes type 2, one of the first things to do is to optimize thyroid hormone and treat the insulin resistance with medications such as Metformin or Actos. This would help improve SHBG and would set the stage for testosterone treatment, minimizing problems that can occur with testosterone treatment – such as anxiety, irritability, fatigue, excessive estrogen, etc.
Low SHBG also occurs in inflammatory diseases (such as rheumatoid arthritis, etc.) – where Interleukin 1 beta reduces SHBG production. I generally assess for the presence of immune system problems since they are often at the root of mood disorders. Reducing pro-inflammatory signaling would help correct their role in reducing SHBG.
SHBG is important but usually it is self-corrected by addressing more important problems – such as hypothyroidism, diabetes, chronic inflammatory illness – prior to testosterone replacement.
When it does become a significant problem is when it is too high – such as with high dose T3 treatment in cases of peripheral thyroid resistance. When SHBG is high, a normal 100 mg a week dose of testosterone cypionate can achieve blood levels past 1500 ng/mL. A concern at that level when coupled with high SHBG is that the lower free testosterone levels may become a significant factor in reducing the effects of testosterone. SHBG bound to testosterone does have signaling function on its own – what it does is unclear – but it is interesting to speculate that if the testosterone-bound SHBG signal is too high, perhaps it may inhibit libido.
Dr. M,
You often mention, including in your response above, that you evaluate for inflammation. What tests do you prefer to gauge a patients level of inflammation?
thank you.
Dr. Mariano,
What range of dose works for actually increasing SHBG? Are we talking 0-25 mcg per day, or 50-100 mcg per day? I know it is different per patient, but the difference I am getting at there is — do we need to generate classic hyperthyroidism with a 50mg dose, or would SHBG be shown to increase with even a 25 mcg “replacement” dose?
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