So just how does the male body produce testosterone? While the number of systems that can impact testosterone production is large in number, the basics are rather simple. Let’s start at the hypothalamus and work our way down.

  • The hypothalamus produces gonadotropin-releasing hormone (GnRH)
  • This hormone triggers the anterior pituitary gland to produce two other hormones
  • These two hormones are luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
  • LH stimulates the Leydig cells in the testicles to produce testosterone while FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body and acts synergistically with LH in male reproductive health.

Simple enough, but what happens is one or more of these systems is compromised in some manner? Defects in the hypothalamus or pituitary gland that compromise the release of GnRH (and subsequently FSH and LH) or adversely affect the release of FSH or LH from the anterior pituitary lead to what is known as secondary hypogonadism. A defect in the testicles that causes a reduction or cessation of gonadal response to LH is characterized as primary hypogonadism. There are many causes of both primary and secondary hypogonadism. The link lists only some of the causes. Also check out this link. Hypogonadism that is present absent any of these conditions or any other known conditions that affect male testosterone production comes under the heading idiopathic hypogonadism. This later label correctly describes my own condition.

Typically a doctor will order a test that measures the total serum testosterone. This is a simple blood test that provides a number, usually in the units of nanograms per deciliter (ng/dl). Normal values vary by the lab performing the test on the blood sample, but typically values are from around 300ng/dL to 1000ng/dl. However, caution should be used in using this raw value as an stark indicator of hypogonadism. For some men presenting with low normal values or even normal values symptoms of low testosterone are often seen. Therefore the entire clinical picture is needed to ensure treatment is provided even in the face of so-called normal results. Also, an entire workup of the thyroid function as well as adrenal function is necessary. Any issue with either of these glands can often lead to hypogonadism or mimic they symptoms of hypogonadism. Also, an understanding of any issues with these glands will guide the treating physician in the selected treatment. As an example, long-standing hypothyroidism will impair the absorption of transdermal testosterone due to build-up of mucin in the skin of people. Mucin causes the skin to thicken impairing absorption of transdermal testosterone.

The story gets a bit more complicated at this point, but not too much. First, a warning – never allow just a total testosterone test to be run by your physician. Total testosterone is only half the story, or perhaps even less than half. Testosterone binds strongly to Sexual Hormone Binding Globulin (SHBG), which itself is a protein, or more accurately a glycoprotein. This means this testosterone is not readily available for the body to use. Other testosterone is loosely bound to albumin, a protein produced by the liver. Any testosterone not binded to albumin or SHBG is known as free testosterone. As albumin binded testosterone is easily ripped off the protein if needed, there is another metric known as bio-available testosterone which is a measure of free testosterone and the testosterone loosely binded to albumin.

There are still arguments about the efficacy of measuring free testosterone. A widespread belief exists that measurement of free testosterone is historically finicky. The data seems to side with this result, however this does not negate the free testosterone test as a test to qualitatively get a feel of just where you are. If possible, getting the bio-available testosterone is a more accurate approach, but not all doctors will order this test.

So now we can begin to think about a few things. What if your SHBG is high (which happens often in the aging population and for other reasons)? Logic dictates that total testosterone will be low as most of it will be tightly bound to the SHBG protein. What if SHBG is low as is often the case of those with insulin resistance – this mirrors my own case. In this case, free-T or bio-available T will be high, causing the body to begin to dump the excess testosterone through excretion and conversion to estrogens. This will often lead to low total testosterone but high free testosterone. Correcting insulin resistance and raising SHBG naturally by addressing this underlying issue will often lead to a reversal of hypogonadism. Starting treatment with TRT on low SHBG often leads to suboptimal results, however it is not contraindicated. In my case, dosing my transdermal gel twice a day as opposed to once a day, provides higher levels of testosterone, which allows me to gain muscle, burn fat, and reach ideal body weight faster. My personal goal is to reverse insulin resistance to the point where I can attempt to restart my own testosterone production without the need for endogenous testosterone (supplemented testosterone). This is what Dr. Freeland, Shawn Bean, and I am working towards.

Lastly is the story of estrogens. There are three of them (E1, E2, and E3). The first is estrone, the second estradiol, and the third estriol. Testosterone is converted to estrogen in adipose tissue, which is present in the liver and in very large quantities in the fat surrounding the internal organs. Look sideways in the mirror and let that gut stick out without holding it in! Do you look pregnant? That’s adipose fat. Conversion of T to E via this mechanism will lower testosterone and raise estrogen. Testosterone supplementation in cases of heavy conversion of T to E often leads to gynecomastia or man-boobs. Understanding where you stand with your estrogen levels is an important clinical indicator of how well testosterone therapy will work for you. While there are medications that block the conversion of T to E2 (such as arimidex), great care must be taken that one does not drive E2 into the ground. In the presence of other issues with the thyroid, this can lead to serious issues with joint pain and swelling as well as other health hazards. We will be discussing arimidex and other medications like it in future posts. For now, I would just warn the reader to be cautious when using this drug. The dosage for males is often very small (.25 mg every three days to start). Often it is not required for transdermal testosterone (Testim and Androgel) but many on the shots (e.g. testosterone cypionate) will often find themselves in need of this medication. I will discuss one protocol in the future which makes E2 control using arimidex for those on the shots in a later post.

So what does arimidex do to the other estrogens? Nothing. It does not lower E1 or E3, but targets E2. Why is that important? Because E2 is the strongest estrogen in males and if it is too high – or too low – it can lead to libido issues and ED, negating one of the main reasons for testosterone replacement therapy (TRT). To be more exact, it has been my experience that a constant level of E2 is more important than its level as long as that level is not too high. Many readers may have heard of the E2 sweet spot of between 25-30 pg/ml (picograms per milliliter). Move too far from this and your libido will magically disappear! Erections will become impossible! Doom will befall you! Hogwash. It is the constant changing levels of E2 that is the issue, so E2 control that maintains as constant a value as possible is more important. Keeping E2 within the normal range is, like the other estrogens, important for only one reason – high estrogens increase cancer risk. My E2 levels have been as high as 90 pg/ml but steady at that number and I experience no libido or ED issues. Everyone is different and for the reader, perhaps 25 pg/ml is the right number for you, but don’t waste precious time aiming for some magic number.

Which leaves DHT or dihydrotestosterone. This is the one I am most interested in. If it gets too low then bye bye libido. My own experience with shots was a nightmare. While I never had DHT measured while on the shots, a quick look at how transdermal T converts to DHT via the 5-AR enzyme (which is found on skin, seminal vesicles, prostate and epididymis) gave me an aha moment. As DHT is involved in “all things male” I felt that rubbing gel on my skin would bump up my DHT and give me back my libido and erectile function. As I was only days away from an anniversary cruise I was desperate. A switch to Testim from shots and within only about four days I noticed a stark difference. Adding in a little HCG (a hormone which mimics LH) and I found my libido bouncing back like a ping-pong ball. The day was saved! However, be warned – if you suffer from male pattern baldness an increase in DHT can and will accelerate loss of hair. It can also lead to acne and hair growth on areas you would not normally want to see hair growth – such as the back. Of course, it also thickens the beard rather nicely and since using transdermals I have noted a more manly beard distribution and I am the only male member of my family with chest hair.

Are there any other tests you should think about? An excellent source for all things testosterone is T-Nation. Here is a list of tests you should order. I would also recommend reading the sticky posts at the top of the TRT forum.

In closing, I would like to address the concept of libido. Many men believe that supplementation with T will magically transport them to a time, many years ago, where erections were strong and libido dominated everything. Libido is a complicated process and while many men will benefit from TRT in this area, there are many other processes involved, including neurotransmitters. So complicated is this issue that the worse thing a man can do who does not notice immediate improvement in libido is to give up hope. Patience and a working with a physician who understands these issues can often resolve them to your satisfaction.

Update: The incomparable Shawn Bean of Matrix Health and Wellness noted an important fact about SHBG. You will be hearing a great deal about Shawn in the coming days and weeks. His dedication to my health – and yours – is a passion rarely seen in the field of nutrition.

Higher SHBG may be a sign of potential inflammation and I have seen this occur in a lot of physician’s patients. Measurements of “silent inflammation” include hsCRP (high sensitivity CRP) and homocysteine levels. For those physician’s patients with a risk for cardiovascular disease another good test is Lipoprotein-associated phospholipase A2 or Lp-PLA2. It is best used when a physician determines a patient to possess a moderate to high risk of developing CVD or of having an ischemic stroke or in the presence of a family history of CVD or CHD.

Here is what I found about Lp-PLA2. It is an enzyme that circulates in the blood and attaches to LDL cholesterol particles. These particles then adhere to arterial walls and oxidize. Oxidized LDL is susceptible to enzymatic attack, promoting pro-inflammatory markers capable of triggering the atherogenic process. The end result is the build-up of plaque in the arteries and the production of molecules that attract immune cells to the arterial walls. These molecules bind to the cells called monocytes, which are large white blood cells, and are converted to macrophages, increasing the amount of atherosclerotic build-up. For those with heart disease or at risk for heart disease, if you have high SHBG it would be wise to have all three of these tests done. Given the nature and historical pathology of the inflammation process, even in the absence of high SHGB I would recommend hsCRP and Lp-PLA2 for those at high risk for heart disease or current heart disease sufferers.

Update 2: The good thing about having Shawn checking your work is the reader benefits from his wealth of information. Here is something else he noted:

Pretty much I see elevated SHBG in hidden gut inflammation or liver issues IE NASH (Nonalcoholic steatohepatitis), fatty liver, staravation, malabsorption resulting in low protein, fat, carb, or overall caloric intake, low GH, adrenal output, and several other factors including excessive fiber which is backed by published scientific studies. It is also linked to an inflamed prostrate.

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Filed under: Testosterone Replacement

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