so what *are* the possible causes of late-onset secondary hypogonadism?

[Aki]

I realise I'm asking a very big question, but it seems (barring a pituitary tumor or head trauma) doctors don't seem to have any explanation for late occuring secondary hypogonadism. I even asked the late Dr. Crisler on the phone once, and he couldn't offer any suggestion.

Some salient facts from my life (for anyone interested in suggesting an explanation):

• I hit puberty with a bang (earlier than the average age, I would say) and I have normal secondary sexual characteristics.
• I have had MRIs (pituatary sella with contrast) done twice, both having normal results; one was done a few years ago and the second one around 2 month ago.
• I can't pinpoint the exact age at which I felt decline attributable to low-T; but it can't have been later than my mid-twenties because that was when I experienced symptoms such as depression and poor recovery from exercise. I wouldn't have said it was anything sudden, but there is one event that I can retrospectively identify, except I don't know if it has any bearing on my hormone issues at all:
  • At age 19 (about 20 years ago), I suddenly experienced a massive amount of diffuse hair loss (on my head) - within the span of 3-4 months or so. Now, the thing is, male pattern baldness doesn't seem to run in either side of my family, based on the "visible evidence". And throughout the following 20 years my hair density kept fluctuating; sometimes getting thicker and other times thinner, even though I take no medication for it, which is also unlike male pattern baldness. And after a fews months of taking clomid the first time, my DHT was in the upper end of the range, yet I did not experience any more hair fall than usual. Right now the thinness is not even that obvious to the casual onlooker; and I guess it might be due to poor hormone balance rather than male pattern baldness. And now I wonder if that sudden loss of hair about 20 years ago was indicative of sudden hormonal changes of some sort..
• The first time I had my T levels measured (out of my own initiative) was around 9 years ago (at age 30), I measured around 250 ng/dL. I've never had a "natural" reading more 280, except when on clomid. And after giving up clomid recently it fell to around ~180 ng/dL.
• I know I'm secondary because my LH/FSH (without SERMs) tends to be below the bottom of the range.
• I don't know if I'm also partially primary but 12.5 mg clomid/day does raise my T levels to 500-600. (Note that I started taking clomid well into my thirties).

So, does anyone have any suggestions of other issues worth examining that might be causing secondary hypogonadism? Or should I just assume the state of endocrinology isn't that far advanced to have good answers to this question?

 

[Gman86]

So I’m obviously just speculating here, but I remember reading that the way the negative feedback loop works, is it starts with estrogen, not testosterone. So yes testosterone turns into estrogen obviously, but I remember reading that the body senses estrogen levels, and that’s how it figures out how much testosterone needs to be produced. It does this by telling the hypothalamus to make more, or less, Gonadotropin-releasing hormone (GnRH). GnRH then stimulates the anterior pituitary to release LH and FSH. The more GnRH that is sent to the anterior pituitary, the more LH and FSH are sent to the testicles. LH is responsible for activating the leydig cells in the testicles, which will then make testosterone, and FSH is more for reproductive purposes.

But the reason I say all this, is because if Estrogen is what starts this chain reaction, and testosterone is ultimately decreased, or increased, depending on the person’s estrogen level, maybe the body reacts to xenoestrogens in the environment, in our food, in products we use, blue light from electronic devices, etc., the same way it would react to actual estrogen. So say your estrogen isn’t that high, but you’re constantly getting bombarded with xenoestrogens. Maybe your body views this as having a high estrogen level. Your body will then think that since there’s a bunch of extra estrogen, there must be a bunch of extra testosterone, since estrogen aromatizes from testosterone. So to lower testosterone, your body will send the signal to lower GnRH, which will then lower your level of LH, and consequently lower your level of testosterone.

I most likely butchered that, but I think overall, the general idea could be what’s going on. Body see’s more estrogen in the body, in the form of xenoestrogens, it then lowers testosterone to try and decrease the estrogens in your body. I’m pretty sure the main mechanism your body uses to control estrogen levels is by manipulating testosterone levels. I could be wrong on that one though.

 

[Cataceous]

Wikipedia has a good article on xenoestrogens. The science is still lacking.

Overall the literature does not with certainty support the contention that environmental chemicals or dietary factors are having widespread effects on human sexual development. However data does not refute such a hypothesis either.

My feeling is that as bad as xenoestrogens may be, their concentrations are usually not high enough to blatantly cause hypogonadism.

 

[Aki]

@Gman86 and @Cataceous - appreciate the responses

I too have some recollection of the feedback mechanism whereby LH/FSH production is signalled. And if I remember correctly, clomid works by blocking the estrogen receptors, fooling the pituitary into producing more LH and FSH and consequently more testosterone (assuming one's testicles still function). Now the question is, what was fooling the pituitary in the first place into sensing an excess of estrogen that didn't exist? In this regard, I think Gman86's explanation (of estrogen-like pollutants/mimics) has merit, although obviously it isn't entirely satisfactory either.
(And if it in fact is the primary explanation, raises another bunch of questions that need answering.)

Or could it just be that for some reason the pituitary has become more sensitive to estrogen so that even a small amount causes greater than normal negative feedback?

I also wonder why SHBG appears to behave "conspiratorially" and seeks to undo the testosterone rise induced by clomid.. like if you have a T-level of ~250 ng/dL with an SHBG of 15 nmol/L before taking clomid, and a low dose of clomid raises your T to 500-600 but your SHBG also creeps up to 30 nmol/L, it seems you've wiped out most (if not all) of your free-T gains; and this doesn't even take into account clomid's own estrogenic side effects.

Also (since GMan86 mentioned GnRH) I've heard of references made to tertiary and secondary hypogonadism, but don't know why in case of low LH/FSH, secondary hypogonadism rather than tertiary is assumed. (Maybe there's an obvious reason for it, but I don't know it.)

Interesting topic for discussion, although I'm not sure if we laypeople (or I, in any case) will make much progress without going through books and research papers.

 

[Gman86]

@Gman86 and @Cataceous - appreciate the responses

I too have some recollection of the feedback mechanism whereby LH/FSH production is signalled. And if I remember correctly, clomid works by blocking the estrogen receptors, fooling the pituitary into producing more LH and FSH and consequently more testosterone (assuming one's testicles still function). Now the question is, what was fooling the pituitary in the first place into sensing an excess of estrogen that didn't exist? In this regard, I think Gman86's explanation (of estrogen-like pollutants/mimics) has merit, although obviously it isn't entirely satisfactory either.
(And if it in fact is the primary explanation, raises another bunch of questions that need answering.)

Or could it just be that for some reason the pituitary has become more sensitive to estrogen so that even a small amount causes greater than normal negative feedback?

I also wonder why SHBG appears to behave "conspiratorially" and seeks to undo the testosterone rise induced by clomid.. like if you have a T-level of ~250 ng/dL with an SHBG of 15 nmol/L before taking clomid, and a low dose of clomid raises your T to 500-600 but your SHBG also creeps up to 30 nmol/L, it seems you've wiped out most (if not all) of your free-T gains; and this doesn't even take into account clomid's own estrogenic side effects.

Also (since GMan86 mentioned GnRH) I've heard of references made to tertiary and secondary hypogonadism, but don't know why in case of low LH/FSH, secondary hypogonadism rather than tertiary is assumed. (Maybe there's an obvious reason for it, but I don't know it.)

Interesting topic for discussion, although I'm not sure if we laypeople (or I, in any case) will make much progress without going through books and research papers.

Very impressive reply. You don’t sound like much of a layperson at all lol. But ya it is very interesting how clomid tries to fight back and suck up all the free testosterone. On clomid, my total went up to 1500, from around 600, yet my SHBG went up to 90, from around 50, which left my free testosterone barely above where it was when I was hypogonadal. Plus like you mentioned, it is an anti-estrogen, but at the same time is partially estrogenic. How that works, no fckn idea lol, but between the SHBG rise, and it messing with estrogen so much, it’s just difficult to make work as a primary source of HRT.

But I think it might be a mix of both things you mentioned. Both your body being exposed to xenoestrogens from all different sources, and you possibly being more sensitive to them than others. Either way, I wouldn’t rack your brain trying to figure it out. I started TRT due to a high SHBG, and consequently very low free T. At first, I spent a long time trying to figure out how to lower SHBG, and changed many things in my life to do so, with no success. Currently, my best guess is that my SHBG was elevated probably due to xenoestrogens as well. Honestly, I really have no clue. But to me it doesn’t matter anymore. I decided to correct the issue, and couldn’t be happier with that decision. I actually look at going on HRT as a blessing. I get to have all my hormones optimized, not just testosterone, for the rest of my life. Also due to HRT, I get to monitor ALL my labs, on a regular basis, not just hormones. I would only be able to do this if I was on HRT with a doctor that works out of the insurance landscape. I would never be able to check blood work frequently with my primary doctor. And I know there’s websites to get out of pocket labs done, but my insurance covers labs 100%, so I need a doctors signed lab requisition to have them covered. Point I’m making is, don’t worry about the reason you’re low so much. I never found out the reason I was low, and I couldn’t be happier. But maybe you’re different. Maybe you’ll find out the reason, and be able to correct it. In my case, that didn’t end up happening, but I’m very thankful I didn’t find the source. If I did, and I corrected it, I would be like every other guy not on HRT, not getting labs done frequently, not knowing how everything in my body was going, and being victim to having my testosterone drop every time I don’t sleep well, eat crappy, over exercise, get stressed out, etc. I look at it as a luxury to not have to worry about those things effecting my testosterone levels, and consequently my overall mood, anymore. I honestly feel bad for regular men lol.

And yes, I’ve recently done research on the whole secondary and tertiary thing, and I think most people just aren’t aware of how similar they are. I personally thought tertiary was when the anterior pituitary puts out normal levels of LH/FSH, testicles respond fine and create a normal level of total testosterone, yet SHBG is high, and therefore free T is low. That’s what I thought tertiary hypoganadism was. But turns out, there’s no actually name for that scenario. So I guess the scenario I’m referencing would have to be called Quaternary Hypogonadism. But the answer to your question, is simply most guys just don’t know the difference between secondary and tertiary hypogonadism, and it’s just commonplace to lump both together into secondary hypogonadism, I would assume.

 

[Weasel]

I've contemplated this exact thing for many years now, and in my case as most of our, we will never truly know the answer.

Looking back at my situation specifically, I believe me decline started when I was still in high school. I had a series of undocumented concussions from contact sports, a couple of them resulting in a day of puking my guts out and a headache like nothing I've ever experienced before. I went from stand out player starting line varsity as a freshman to basically bench warmer as a senior. The rest of the competition didn't just get that much better...

That said, I thoroughly buy the exogenous estrogen theory. Or at least some chemical we are exposed to resulting in elevated estrogen. I personally think society has down played this big time. Imagine if studies were actually printed that showed plastic, soaps, deodorants, dyes, our food supply were all absolutely terrible for us, killing our species. System wide panic!

Not only do we see the male population having lower Testosterone levels as a whole but we see females maturing at younger and younger ages, which points to estrogen IMHO.

 

[Gman86]

I've contemplated this exact thing for many years now, and in my case as most of our, we will never truly know the answer.

Looking back at my situation specifically, I believe me decline started when I was still in high school. I had a series of undocumented concussions from contact sports, a couple of them resulting in a day of puking my guts out and a headache like nothing I've ever experienced before. I went from stand out player starting line varsity as a freshman to basically bench warmer as a senior. The rest of the competition didn't just get that much better...

That said, I thoroughly buy the exogenous estrogen theory. Or at least some chemical we are exposed to resulting in elevated estrogen. I personally think society has down played this big time. Imagine if studies were actually printed that showed plastic, soaps, deodorants, dyes, our food supply were all absolutely terrible for us, killing our species. System wide panic!

Not only do we see the male population having lower Testosterone levels as a whole but we see females maturing at younger and younger ages, which points to estrogen IMHO.

At this point, it’s not even debatable about all the estrogens/ xenoestrogens that the population is exposed to. The decreased age at which females start menstruating, and vast increase in transgenders, speak for themselves.

But yes, in your case, the concussions could absolutely have something to do with it. Dr. Mark Gordon specifically treats hypogonadal patients, where their hypogonadism is secondary to head injuries. It’s much easier to damage your brain than people think. They’re finding out now that it may not even necessarily take one big hit to the head either. They’re finding now that repeated jolting of the whole body, can lead to brain damage and hormone imbalances. For example, they’re finding brain issues with bmx riders, mogul skiers and water skiers, for a few examples. The skiers is due to their bodies shaking every time they hit a snow bump, or wave. The frequent jolting of their bodies, is also shaking their brain around, and they’re finding that frequent light shaking of the brain can eventually lead to enough trauma to the brain to cause hormone imbalances. Not as bad as say a boxer, or a football player, but any damage is bad damage obviously.

 

[Weasel]

At this point, it’s not even debatable about all the estrogens/ xenoestrogens that the population is exposed to. The decreased age at which females start menstruating, and vast increase in transgenders, speak for themselves.

But yes, in your case, the concussions could absolutely have something to do with it. Dr. Mark Gordon specifically treats hypogonadal patients, where their hypogonadism is secondary to head injuries. It’s much easier to damage your brain than people think. They’re finding out now that it may not even necessarily take one big hit to the head either. They’re finding now that repeated jolting of the whole body, can lead to brain damage and hormone imbalances. For example, they’re finding brain issues with bmx riders, mogul skiers and water skiers, for a few examples. The skiers is due to their bodies shaking every time they hit a snow bump, or wave. The frequent jolting of their bodies, is also shaking their brain around, and they’re finding that frequent light shaking of the brain can eventually lead to enough trauma to the brain to cause hormone imbalances. Not as bad as say a boxer, or a football player, but any damage is bad damage obviously.

I see our up and coming generation of "men" and can't help but shake my head. An old army buddy and i were talking about this just last week. I told him "we better get ready to serve again cause if and when SHTF this up and coming generation sure as hell cant. It also completely blows my mind that there are 18+ year old males walking around who have never punched anyone in the face or gotten punched in the face. I digress.

Right, Head injuries weren't even something that were really on the radar when i was growing up and that was in the late 90's so not terribly long ago. I remember when people got knocked out they only got concerned if the smelling salts didn't wake you up. If they did wake you up, you maybe missed a shift or 2 (hockey) and were right back at it.

 

[DragonBits]

There is a global decline in testosterone and fertility, one would think it has to be environmental.

Maybe better to pin point a date what it started to affect you Vs how old you were.

For me, 1993-1994, suddenly I was tired, in 1995 I got a TT test and it was 376 ng/ld.

So all males would have been affected around 1993-1996+. The younger you are, the earlier it would have started. If you were born in 1970, you would be 23-25 during those years. now 58. If environmental, it was probably here for a long time before it became widespread enough to affect the world and probably stayed in the environment a long time. It may be still here, or may be gone. Depending on where you lived you either got more or less of the toxin.

An example: Dioxins from PCB, widely produced between 1930-1984, PCB containing dioxin are still in limited production today.

--------------------------------------------------------------------------------------
The United States was the single largest producer with over 600,000 tonnes produced between 1930 and 1977. The European region follows with nearly 450,000 tonnes through 1984. It is unlikely that a full inventory of global PCB production will ever be accurately tallied, as there were factories in Poland, East Germany, and Austria that produced unknown amounts of PCBs

There is evidence that crash dieters that have been exposed to PCBs have an elevated risk of health complications. Stored PCBs in the adipose tissue becomes mobilized into the blood when individuals begin to crash diet.[51] PCBs have shown toxic and mutagenic effects by interfering with hormones in the body. PCBs, depending on the specific congener, have been shown to both inhibit and imitate estradiol, the main sex hormone in females. Imitation of the estrogen compound can feed estrogen-dependent breast cancer cells, and possibly cause other cancers, such as uterine or cervical. Inhibition of estradiol can lead to serious developmental problems for both males and females, including sexual, skeletal, and mental development issues.[citation needed][52] In a cross-sectional study, PCBs were found to be negatively associated with testosterone levels in adolescent boys.[53]

High PCB levels in adults have been shown to result in reduced levels of the thyroid hormone triiodothyronine, which affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. It also resulted in reduced immunity and increased thyroid disorders

Polychlorinated biphenyl - Wikipedia

This is only one example, environmentalists have identified the dioxin as one of the "Dirty Dozen"

Interesting topic, I would be fairly convinced that toxins in the environment may have caused a world wide decline in testosterone, but even if they pinpoint the cause it doesn't help any of us. We still need to deal with the consequences.

 

[Weasel]

There is a global decline in testosterone and fertility, one would think it has to be environmental.

Maybe better to pin point a date what it started to affect you Vs how old you were.

For me, 1993-1994, suddenly I was tired, in 1995 I got a TT test and it was 376 ng/ld.

So all males would have been affected around 1993-1996+. The younger you are, the earlier it would have started. If you were born in 1970, you would be 23-25 during those years. now 58. If environmental, it was probably here for a long time before it became widespread enough to affect the world and probably stayed in the environment a long time. It may be still here, or may be gone. Depending on where you lived you either got more or less of the toxin.

An example: Dioxins from PCB, widely produced between 1930-1984, PCB containing dioxin are still in limited production today.

--------------------------------------------------------------------------------------
The United States was the single largest producer with over 600,000 tonnes produced between 1930 and 1977. The European region follows with nearly 450,000 tonnes through 1984. It is unlikely that a full inventory of global PCB production will ever be accurately tallied, as there were factories in Poland, East Germany, and Austria that produced unknown amounts of PCBs

There is evidence that crash dieters that have been exposed to PCBs have an elevated risk of health complications. Stored PCBs in the adipose tissue becomes mobilized into the blood when individuals begin to crash diet.[51] PCBs have shown toxic and mutagenic effects by interfering with hormones in the body. PCBs, depending on the specific congener, have been shown to both inhibit and imitate estradiol, the main sex hormone in females. Imitation of the estrogen compound can feed estrogen-dependent breast cancer cells, and possibly cause other cancers, such as uterine or cervical. Inhibition of estradiol can lead to serious developmental problems for both males and females, including sexual, skeletal, and mental development issues.[citation needed][52] In a cross-sectional study, PCBs were found to be negatively associated with testosterone levels in adolescent boys.[53]

High PCB levels in adults have been shown to result in reduced levels of the thyroid hormone triiodothyronine, which affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. It also resulted in reduced immunity and increased thyroid disorders

Polychlorinated biphenyl - Wikipedia

This is only one example, environmentalists have identified the dioxin as one of the "Dirty Dozen"

Interesting topic, I would be fairly convinced that toxins in the environment may have caused a world wide decline in testosterone, but even if they pinpoint the cause it doesn't help any of us. We still need to deal with the consequences.

Great example, now look at pesticides and herbicides used in our food productions. Not to mention livestock. The amount of chemicals being put into our environment is astronomical!

 

[DragonBits]

Great example, now look at pesticides and herbicides used in our food productions. Not to mention livestock. The amount of chemicals being put into our environment is astronomical!

Optimistically, before the environmental protection agency it was a lot worse, companies just dumped whatever they wanted in the environment.

Though there is a movement to eliminate regulations and go back to dumping. For sure dumping is cheaper and creates higher profits.

Ying and yang of it all.

 

[Gman86]

The list of endocrine disrupters goes on and on and on. So many things that we’re all aware of, and many things most aren’t. And many that we probably don’t even know about yet. From chemicals on our food, birth control in the water, blue light from screens, WiFi/ Bluetooth signals all around us, EMF’s from all the electrical devices we now have in our homes, the material in non-stock cookware leaching into the food we eat, cooking on tinfoil. I mean literally, the list goes on for days.

The other factor to consider is that each generation is going to be more susceptible to these hormone disruptors. So a guy in his 80’s, is going to be more resistant than a person in their teens, to the exact same disruptors. It’s going to just get worse with each generation as well.

 

[DragonBits]

The list of endocrine disrupters goes on and on and on. So many things that we’re all aware of, and many things most aren’t. And many that we probably don’t even know about yet. From chemicals on our food, birth control in the water, blue light from screens, WiFi/ Bluetooth signals all around us, EMF’s from all the electrical devices we now have in our homes, the material in non-stock cookware leaching into the food we eat, cooking on tinfoil. I mean literally, the list goes on for days.

The other factor to consider is that each generation is going to be more susceptible to these hormone disruptors. So a guy in his 80’s, is going to be more resistant than a person in their teens, to the exact same disruptors. It’s going to just get worse with each generation as well.

It's always popular to think things are getting worse, but I tend not to even know what is popular thought.

I think the world keeps getting better and better.

We live longer, live healthier, have fewer wars, no famines in 1st and 2nd world countries, no epidemics like the black plague (30-50% dead in Europe).

Hard for us to even image what it must have been like to have 30-50% of the entire population of the USA dead from a plague.

 

[Gman86]

It's always popular to think things are getting worse, but I tend not to even know what is popular thought.

I think the world keeps getting better and better.

We live longer, live healthier, have fewer wars, no famines in 1st and 2nd world countries, no epidemics like the black plague (30-50% dead in Europe).

Hard for us to even image what it must have been like to have 30-50% of the entire population of the USA dead from a plague.

Couldn’t agree more. But in this regard, it’s different. We are a product of our grandparents, and great grandparents genetics, roughly, when it comes to how sensitive our bodies are to these things. So the more damage these things did to our grandparents, the more susceptible we are gonna be. What our parents did to prevent themselves from being “poisoned” by these things, will have little effect on us. It’s mostly how much these things effected our grandparents, and great grandparents DNA. So clearly this current generation is being effected tremendously, therefore, their grandkids are going to have hormonal imbalances to a much greater degree than people that are adults currently. The only way for future generations to not be worse than people alive currently, is for us to try and prevent as much cellular damage as possible. But most people are not doing that, unfortunately.

 

[Cataceous]

@Gman86 and @Cataceous - appreciate the responses
...
I also wonder why SHBG appears to behave "conspiratorially" and seeks to undo the testosterone rise induced by clomid.. ...

This is probably driven by increased estradiol, which acts in the liver to increase SHBG.

 

[Outcome]

Maybe better to pin point a date what it started to affect you Vs how old you were.

For me, 1993-1994, suddenly I was tired, in 1995 I got a TT test and it was 376 ng/ld.

GMO foods entered the market in 1995 and along with it a massive increase in use of the herbicide glyphosate which is an analog of the amino acid glycine. No doubt this has played a role in declining testosterone levels.
The use of the herbicide 2,4-d in agriculture has a much longer track record going back to the late 1940’s. All these agricultural herbicides are highly estrogenic for sure and attack us at the dna level. Then downstream from there are epigenetic changes so each generation has accumulated changes from these substances and we’re still being bombarded by them and many more . We’re pretty screwed now so you have to take control of your own chemistry and minimize, detox and supplement. Just like Gman said. If you’re on trt you are taking control because you’re doing full spec blood work ups more than the average guy and you can identify things you need to work on.

 

[madman]

I realise I'm asking a very big question, but it seems (barring a pituitary tumor or head trauma) doctors don't seem to have any explanation for late occuring secondary hypogonadism. I even asked the late Dr. Crisler on the phone once, and he couldn't offer any suggestion.

Some salient facts from my life (for anyone interested in suggesting an explanation):

• I hit puberty with a bang (earlier than the average age, I would say) and I have normal secondary sexual characteristics.
• I have had MRIs (pituatary sella with contrast) done twice, both having normal results; one was done a few years ago and the second one around 2 month ago.
• I can't pinpoint the exact age at which I felt decline attributable to low-T; but it can't have been later than my mid-twenties because that was when I experienced symptoms such as depression and poor recovery from exercise. I wouldn't have said it was anything sudden, but there is one event that I can retrospectively identify, except I don't know if it has any bearing on my hormone issues at all:
  • At age 19 (about 20 years ago), I suddenly experienced a massive amount of diffuse hair loss (on my head) - within the span of 3-4 months or so. Now, the thing is, male pattern baldness doesn't seem to run in either side of my family, based on the "visible evidence". And throughout the following 20 years my hair density kept fluctuating; sometimes getting thicker and other times thinner, even though I take no medication for it, which is also unlike male pattern baldness. And after a fews months of taking clomid the first time, my DHT was in the upper end of the range, yet I did not experience any more hair fall than usual. Right now the thinness is not even that obvious to the casual onlooker; and I guess it might be due to poor hormone balance rather than male pattern baldness. And now I wonder if that sudden loss of hair about 20 years ago was indicative of sudden hormonal changes of some sort..
• The first time I had my T levels measured (out of my own initiative) was around 9 years ago (at age 30), I measured around 250 ng/dL. I've never had a "natural" reading more 280, except when on clomid. And after giving up clomid recently it fell to around ~180 ng/dL.
• I know I'm secondary because my LH/FSH (without SERMs) tends to be below the bottom of the range.
• I don't know if I'm also partially primary but 12.5 mg clomid/day does raise my T levels to 500-600. (Note that I started taking clomid well into my thirties).

So, does anyone have any suggestions of other issues worth examining that might be causing secondary hypogonadism? Or should I just assume the state of endocrinology isn't that far advanced to have good answers to this question?

ABSTRACT

Introduction: The frequency of late-onset hypogonadism (LOH) ranges between 2 and 15%. Up to 85% of LOH is due to a functional impairment of the hypothalamus–pituitary–testicular axis, mostly secondary to metabolic conditions.

Areas covered: This paper provides a comprehensive review of all the available medications for treating LOH, including antiestrogens, gonadotropins and testosterone therapy (TTh). In addition, the evidence on clinical outcomes of these treatments is provided by meta-analyzing the results from the available randomized clinical trials.

Expert commentary: The present data indicate that antiestrogens are able to increase testosterone levels without changing gonadotropins or even increasing them. Therefore, they may maintain, and even to stimulate spermatogenesis. However, their efficacy in treating LOH-associated symptoms has been scarcely tested and their use in LOH is off-label. In contrast, gonadotropins are indicated for hypogonadism, in particular when fertility is required. Information on the effects of gonadotropins on LOH is scanty and the impractical administration limits their use. TTh can be administered with different modalities, making it a suitable option for LOH, when fertility is not desired. The available meta-analyses show that TTh is able to improve sexual function and body composition, with more evident results obtained with transdermal and injectable preparations.










9. Five-year view

LOH has confirmed as a frequent finding in both general and specific populations. Even though its pathogenesis and clinical meaning is still unclear, in the last years the urgency of recommendations on its clinical management has emerged. TTh represents the most classical therapeutic approach for treating LOH. In the last years, many efforts have been done for evaluating the benefits of TTh in the treatment of LOH and several RCTs have been published with different outcomes. The meta-analysis of the available RCTs confirms that TTh is able to improve sexual function, body composition and glycolipid metabolism. In contrast, data concerning the effect of TTh on osteoporosis and mood or cognition are still scanty with insufficient or inconclusive results. Since LOH has often a functional nature; in the last years a nonpharmacologic approach, based on lifestyle, has been encouraged. However, despite there is evidence for an increase in serum T levels after weight loss, there is still no data of an associated improvement in clinical features of LOH. In secondary HG, gonadotropins and antiestrogens represent other possible treatments for LOH. Despite their mechanism of action is more respectful of HPT axis physiology than TTh, also allowing preserving fertility, their use in LOH men has been scarcely studied, in particular concerning sexual outcomes. Although showing a nice increase in serum T, antiestrogens carry the potential––and still not extensively studied––risk of worsening sexual function and osteoporosis. However, the need of acquiring more information on these medications for LOH has been apparently received by researchers, since several clinical trials are now ongoing.

At present, TTh seems to be the most reasonable treatment for LOH, because it is the most studied in terms of both advantages and disadvantages. However, it is conceivable that in the next few years further information will be available on these new options, which will make them more realistic alternatives to TTh.







Key issues

● LOH is the most frequent form of hypogonadism (HG) and it is characterized by low serum testosterone (T) together with symptoms consistent with HG. It often results from a mixed disruption of the HPT axis at central or peripheral level, without a clear structural lesion at either these levels. Thus, it is considered functional in about 85% of cases.

● A non-pharmacological approach with lifestyle improvements is the most rationale treatment because it removes the causing conditions, resulting in serum T increase. However, compliance is an issue. In addition, there is still limited evidence of its efficacy in improving the LOHrelated symptoms.

● Estrogens can inhibit HPT axis and, despite conflicting evidence have been reported, they are deemed to have a role in pathogenesis of obesity-related HG. Antiestrogens (SERMs or aromatase inhibitors) can decrease estrogen activity on hypothalamus and pituitary, thus being an option for LOH therapy. Indeed, this treatment––used offlabel for HG––is associated with a considerable increase in serum T. However, the improvement in LOH clinical features has been scarcely investigated. Due to the possible role of estrogens in physiology of sexual function and bone, concerns exist on the possibility that antiestrogens could have a deleterious, rather than beneficial, effect on sexual complaints and osteoporosis.

● Gonadotropins are on label treatments for HG and they are mainly used for improvement of fertility. They could represent an option in LOH for the increasingly later search of paternity during life. However, they have not been specifically studied in LOH and their advantages on its clinical features are largely speculative.

● T therapy (TTh) is available with a number of possible formulations, which can be tailored in the patient needs. In the last years, several randomized clinical trials have assessed its efficacy in improving clinical features of LOH. These have shown that TTh can ameliorate sexual symptoms, body composition and glycolipid levels. Uncertainness still exists on its role in improving mood and cognition as well as the risk of fractures.

 

[Aki]

Wow, didn't know this topic would spark such a discussion. I have only glanced through the replies whilst scrolling down, but I feel I owe it to everyone to read their replies with due consideration (which I intend as soon as I have time).