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Written by Dr. Welsh, Article reviewed and edited by Dr. Fine M.D..
Published on September 4th, 2019
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Identification of Late Onset Hypogonadism in Middle Aged and Elderly Men

There is disagreement among professionals in the medical community regarding the clinical significance of the age related decline of Male Testosterone Levels. As a result of this uncertainty with regard to the nature of Low Testosterone and the aging man, guidelines have been updated suggesting the Adult-Onset Hypogonadism be regarded as a quantifiable medical condition that occurs as a result of changes in biochemistry that occur during the aging process.

Adult-Onset Hypogonadism is now characterized with a slate of specific symptoms, and the diagnosis of this syndrome is the result of a diagnosis of clinically low Testosterone Levels combined with the experience of those symptoms. The problem is that since Adult-Onset Hypogonadism has only recently been fully quantified as a medical disorder, there is a lack of clinical data which considers Testosterone Deficiency in lieu of all of the symptoms that have now been scientifically linked to Low T. Data is especially slim among patients who suffer from this form of natural Testosterone Deficiency rather than a pathological form of Testosterone decline which is not directly correlated with age.

Testosterone Deficiency Linked to Many Disorders

Even though there is a well known list of symptoms that are associated with a severe deficiency of Testosterone in younger males, the symptoms which are displayed in older men are not specific only to Low Testosterone and there are many other relatively common disorders which can produce many similar symptoms.

Low Testosterone in younger patients in considered less than 6 to 8 nanomolars per liter. Because of the large gray area that exists in which Adult-Onset Hypogonadism shares many symptoms with other disorders, the exact Testosterone levels which are associated with Testosterone Deficiency and the precise negative health risks that are associated with the disorder are no well delineated. At this point, the threshold for Low-Testosterone is relatively arbitrary, and there is a movement to discover this threshold with greater accuracy.

The participants of this study come entirely from two age groups. The first group of patients is middle-aged, and the second group is elderly. The goal of the study was to characterize the medical symptoms related with Testosterone Deficiency and to distinguish the various thresholds which can be associated with different levels of symptomatic severity. The ultimate goal of the study was to demarcate a more exact set of criteria for the diagnosis of Adult-Onset Hypogonadism based upon the experience of symptoms and their severity and various rates of Testosterone Deficiency.

Testosterone Research Methods

Participant Pool

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In this study, the researchers selected a random assortment of men to investigate, organized by age. These men were participants in a study known as the European Male Aging Study (EMAS). This clinical study involved eight different medical centers across Europe. Individual cases were selected from clinics in Spain, Italy, Hungary, Poland, Estonia, Sweden, Belgium, and the United Kingdom. The participants in this investigation ranged in age from forty to seventy-nine years of age. Each participant selected for the EMAS study was tested in a number of different ways.

Each patient completed a questionnaire in which they self-reported their current health condition. In addition to this, each participant completed mental and physical aptitude tests. Each patient also provided a blood sample which was diagnostically evaluated in order to ascertain hormone and biochemical measurements.

8416 participants were encouraged to join the study, and 3369 of these men were chosen. The mean age of the subjects was 59.7 years of age. There were no particular exclusionary criteria by which potential participants were disregarded. The response rate at each medical center averaged 43%, with the lowest response rate 24% and the highest response rate 60%. Although we will not go into detail regarding the specifics of the original study, the study was sufficiently peer reviewed and the methods, recruitment criteria, and study design were considered completely scientifically sound.

Testosterone Medical Questionnaires

The questionnaires used in this study posed a variety of questions regarding the general and specific health of each individual patients. Participants were asked questions regarding their perception of their overall health. They were asked what medications they currently used. Additionally, subjects were asked about particular details regarding their lifestyle and also provided information concerning their demographic and socioeconomic status. Certain questionnaires were answered with the assistance of a interviewer. The three most notable were the Beck Depression Inventory, a 36 question health survey, and a questionnaire developed specifically for EMAS regarding sexual ability and function.

Laboratory and Clinical Assessments

After patients filled out the various medical questionnaires, they were physically analyzed. The weight and height of each patient was recorded. In addition to this, the Body-Mass Index of each patient was calculated based upon biometric data as well. Waist size was also recorded. Each subject also consented to an intravenous blood sample drawn from the vein after a single period of fasting. This blood sample was drawn relatively early in the day, before In addition to these measurements, each participant also had his Total Testosterone Levels analyzed via a method known as gas chromatography-mass spectrometry, abbreviated GC-MS.

GC-MS is a method of separating individual molecules in a sample from one another, make it possible to measure exceedingly small amounts of substances from a small sample. The participant with the lowest Testosterone Level produced a measurement of 0.17 nanograms per liter. GC-MS measurements were accurate to within 2.9%-3.4%. Globulin levels were also assessed via an immunoassay. Globulins are a type of blood protein that has the ability to bind with sexual hormones such as Testosterone. Levels of Free Testosterone were deduced from the measurements of albumin, globulin, and Total Testosterone, providing a precise yet indirect measurement.

Validation and Training Sets

The complete group of participants was randomly separated into two subdivisions. One group was analyzed as a training set, and the other group represented a validation set. In order to accomplish the ultimate goal of the study, to delineate the biochemical and clinical criteria for Adult-Onset Hypogonadism, researchers monitored a variety of potential symptoms recorded the rate at which they occurred and the severity of the symptoms in relation to various Endogenous Testosterone Levels. The links between Testosterone Deficiency and particular symptoms that were perceived within the training set were later evaluated independently among those in the validation set.

As the researchers reviewed the training set, they selected thirty two items from the EMAS questionnaires in order to evaluate the perceived symptoms in regard to their correlation with Testosterone Levels. These thirty two items were chosen based on the results and outcomes of a number of previous studies and also particular scientific recommendations. Each of the items was investigated in order to deduce which of the symptoms were highly correlated with a Deficiency of either Free or Total Testosterone Levels. The correlations were statistically analyzed with the use of regression modeling.

Only items that displayed a high level of correlation with rates of Free and Total Testosterone were chosen. In the end, the patients were further divided into two more groups: Those who experienced a particular symptom, and those who did not experience a particular symptom. Another form of statistical analysis known as the Mann-Whitney test was utilized in order to prove statistical significance between the two participant groups.

Testosterone Study Statistical Analysis

When analyzing the participants grouped within the training set, the researchers made use of a weighted linear regression in order to accurately identify the Testosterone Level at which the odds of developing a particular symptom became significant in comparison to the average prevalence of all subject of the study. Each analysis was weighted in regard to the age of the participant and the individual center in which a particular portion of the study was conducted.

Weighting the results of each individual center is necessary in order to account for any potential variation that may be the result of imperfections associated with a particular clinical environment. All of these statistical models were selected and utilized in order to produce more accurate results and more precisely pinpoint the threshold at which particular Testosterone levels were associated with increased risk of developing a particular Low-T Symptom.

After gathering, controlling, and smoothing data, the researchers set out to create a visual representation based upon the correlation of Testosterone Level and Symptom Presence. These charts were designed in order to show which symptoms seem to appear in correlation with particular levels of Testosterone Deficiency. After the charts were outlaid, further statistical analysis was performed in order to determine with high accuracy whether each graphical grouping of symptoms truly represented a cluster of related data points and not a semi-random array of such points.

In order to more accurately quantify the relationship between symptom prevalence and Testosterone level, the researchers made use of further regression models in order to provide a statistical measurement of the correlation between the experience of multiple symptoms and particular Low-T levels. After these statistical measurements were quantified in the Training set, they were measured for validity by comparing the results found in the training set to the data within the validation set. If the symptomatic correlations matched between the two groups, then the thresholds are independently validated by a different and unique set of data.

After discovering which symptomatic correlations were independently verifiable, this data was used in order to delineate specific minimum criteria for the diagnosis of Adult-Onset Hypogonadism. Further statistical techniques were used in order to further validate the accuracy of the obtained results. After all of this statistical modeling, the last issue in order to provide the most diagnostically useful results was to statistically control the data for confounding effects such as BMI, age, and comorbid illness which could increase the prevalence of certain symptoms or cause them to occur independently of Low-Testosterone levels.

Testosterone Study Results

Out of the 3360 individuals who participated in the study, 150 were rejected from this analysis as a result of primary hypogonadism, known pituitary disorders, or the usage of medicines which had the ability to alter testicular or pituitary function or increase the rate at which androgens are cleared from the body. After the exclusion of these 150 subjects there were 3219 males whose data was utilized in this scientific study.

Correlation between Testosterone Levels and Particular Symptoms

From the initial selection of thirty two potential symptoms of Low-Testosterone which were analyzed in the training set, nine of those symptoms were proven to be correlated with Levels of Free of Total Testosterone Level. These nine symptoms displayed a significantly unique difference between asymptomatic participants and symptomatic participants.

Three of these symptoms were directly related to sexual function. Individuals with abnormally low testosterone were found to have a higher incidence of erectile dysfunction, decreased libido, and lower than average frequency of early morning erection. Three of the statistically significant symptoms were physical in nature. Participants with comparatively Low Levels of Testosterone were more likely to be unable to stoop, kneel or bend. In addition to this, these patients also considered themselves unable to walk a distance greater than a single kilometer.

The last physical symptom was that subjects with Low-T were more likely to be unable to engage in strenuous physical activity without experiencing fast and overwhelming fatigue. The final three symptoms which were considered clinically significant were psychological in nature. Patients with comparably Low Testosterone were more likely to experience fatigue easily in their daily life. In addition to this, they lacked energy and motivation. Third, these patients were more likely to experience symptoms of depression and sadness.

Minimum Testosterone Deficiency Thresholds

As the researchers hypothesized, the severity of these nine symptoms all become greater as Testosterone Levels declined. Below are the exact data points for each symptom.

The minimum threshold for:

  • Reduced libido - 8 nanomolars per liter Total Testosterone

  • Erectile Dysfunction - 8.5 nanomolars per liter Total Testosterone

  • Reduced Frequency of Early Morning Erection - 11 nanomolars per liter Total Testosterone

  • Hindered Overall Well-Being - 13 nanomolars per liter Total Testosterone

The Threshold for Free Testosterone Deficiency for the three sexually related symptoms of Low-T were 160, 280, and 280 picomoles per liter. The threshold for both fatigue and sadness was 160 picomoles per liter.

There were no thresholds discovered regarding the association of Free Testosterone and Physical symptoms, nor Total Testosterone and Psychological Symptoms. Although symptomatic probability was around 25%, testosterone levels were located in what would undoubtedly be considered the normal range for endogenous Testosterone production. Only seven subjects analyzed displayed Testosterone Levels greater than thirty five nanomolars per liter. This may have caused there to be an ultimately statistically insignificant correlation between erectile dysfunction and high levels of Total Testosterone.

Lower Testosterone Strongly Linked to Higher Prevalence of Symptoms

Statistical regression analysis shows that Lower Levels of Testosterone are strongly correlated with the increased prevalence of physical and sexual symptoms. The further below the normal threshold, the more likely the patient was to become symptomatic. In the case of reduced frequency of early morning erection, having Total Testosterone levels a single nanomolar below threshold (11) increased the odds of suffering from this symptom by a ratio of 1.1 to 1. Having Total Testosterone Levels above 11 nanomolars per liter was not correlated with increased or decreased prevalence of the symptom. This means that if an individual has an above-threshold Total Testosterone rate for this symptom that the incidence plateaus. All individuals with greater than 11 nanomolars of Free Testosterone per liter have a statistically similar chance of experiencing decreased frequency of morning erections.

For the other two sexual symptoms, reduced libido and erectile dysfunction, different values were obtained regarding distance from threshold. Total Testosterone levels one nanomolar per liter below threshold resulted in an increased risk of the symptom by a ratio of 1.48 to 1. In regard to erectile dysfunction, the same drop from threshold was correlated by a ratio of 1.23 to 1. The threshold for decreased capacity for strenuous activity was pinpointed at 13 nanomolars per liter. A similar reduction of a single nanomolar in the group increased the the prevalence ratio by 1.11 to 1.

The threshold for reduced libido and increased depression in regard to Free Testosterone was 160 picomoles per liter. For reduced frequency of morning erection and erectile dysfunction, the value was 280 picomoles per liter Free Testosterone. Finally, the Threshold for amplified fatigue was also 160 picomoles per liter Free Testosterone.

Symptom Clustering and Low Testosterone

Employing the data in the training set, statistical analysis allowed the researchers to correlated significant symptoms with one another. The analysis also allowed the researchers to correlate these symptoms with both Normal and Low Testosterone. Through this strategy of analysis, the researchers were able to find two significant symptom clusters. The majority of completely asymptomatic participants had Total Testosterone Rates greater than 8 nanomolars per liter and a Free Testosterone rate of at least 220 picomoles per liter.

The majority of patients that suffered from sexual symptoms of Low-T have Total Testosterone Rates below 8 nanmolars per liter, and a Free Testosterone Rate lower than 220 picomoles per liter. For the purposes of this particular study, physiological symptoms that were not clustered together were not considered to be the result of Low-T but the result of some other underlying health malfunction. When these same hypotheses were compared to the validation set, similar results occurred, proving that the clustering effect was not a fluke.

Hypogonadism Criteria

The analysis of the data shows that the greater the deficiency in Testosterone, the higher the prevalence of the particular sexual symptom. This relationship was inverse and incredibly consistent. Low Testosterone was considered clinically diagnosable in this study if all three sexual side effects of Low-T were present and Total Testosterone Levels were below 11 nanomolars per liter. Free Testosterone levels below 220 picomoles per liter further increased the risk of sexual side effects of Testosterone Deficiency.

Based on the data provided in this study is safe to conclude that patients with Free Testosterone Levels under 220 picomoles per liter and Total Testosterone Levels under 11 nanomolars per liter have clinically low levels of Testosterone. In order for Low-T to be properly medically diagnosed, however, Testosterone levels should both be beneath these thresholds while the patient also displays multiple symptoms of Testosterone Deficiency.

Approximate Prevalence of Hypogonadism

Within the group of patients analyzed in this study, 4.1% of participants experienced a Total Testosterone Rate beneath 8.0 nanomolars per liter. 17% of subjects had Total Testosterone Rates beneath 11 nanomolars per liter. If Adult-Onset Hypogonadism is defined as the experience of three symptoms of sexual dysfunction combined with a Free Testosterone Level lower than 220 picomoles per liter, Total Testosterone Rate beneath 11 nanomolars per liter, this would mean that 2.1% of individuals suffer from Adult-Onset Hypogonadism.

Based on these criteria, the rate increases at a steady pace. 0.1% of patients in their forties, 0.6% of patients in their fifties, 3.2% of patients in their sixties, and 5.1% of patients in their seventies experience significant Testosterone Deficiency. These percentages are controlled to represent and otherwise healthy population, however. Increased body fat and BMI can increase the percentages significantly, and many comorbid illnesses also enhance the risk of Testosterone Deficiency.

Testosterone Study Discussion

As a result of this large and systematic analysis of male patients with regard to potential underlying Testosterone Deficiency, the researchers were able to produce a tentative set of guidelines with which to undoubtably diagnose a certain subset of patients with Adult-Onset Hypogonadism. In this analysis it was observed that a number of symptoms associated with non-age related hypogonadism were not correlated with the Decline in Testosterone Rates in older males. When analyzing the data based on the 9 statistically significant symptoms, differences in Average Testosterone Rates among asymptomatic and symptomatic patients was only modest. The researchers conclude that this reflects a weak total correlation between Testosterone Levels and Testosterone Symptoms among this group.

Continued analysis showed that there existed definite hard thresholds in regard to Testosterone levels and various forms of sexual dysfunction. These negative symptoms occurred near or beneath the lower threshold for adult hypogonadism in young males.

Sexual Dysfunction Most Important Measure of Testosterone Deficiency

For this reason, the sexual symptoms of Testosterone Deficiency are incredibly important for the proper diagnosis of elderly males, but suggest that Testosterone Deficiency should only be diagnosed in Testosterone Levels are obviously below normal. Low Testosterone was tightly correlated with reduced overall physical energy and endurance. This corroborates with other studies regarding Testosterone Levels and the elderly. Psychological Testosterone Deficiency Symptoms produced no clustering effect in regard to demarcating a clear threshold, although there are many studies which disagree with this evidence.

The existence of multiple Low-T Thresholds provides evidence for the concept that different symptoms are correlated with different thresholds because Testosterone is bio-available and biologically functional at different concentrations dependent upon the location and biology of different receptor sites. Although the three primary sexual symptoms of Adult-Onset Testosterone Deficiency are loosely correlated in terms of threshold, it is possible to clearly separate the clustering of these three symptoms, showing a different base level of Testosterone associated with each individual symptom.

The outer boundaries that led these researchers to conclude a significant correlation between Low-T and the symptoms of the disorder are considered by the researchers to be the minimal criteria in order to diagnose Adult-Onset Hypogonadism with near 100% accuracy. The Threshold Testosterone levels discovered in this study (11 nanomoles per liter Total Testosterone and 220 picomoles per liter Free Testosterone) are very similar to minimum diagnosis criteria suggested by general medical guidelines.

Again, there are a number of confounding factors which increase the risk and prevalence of Testosterone Deficiency, making it more common than the percentages listed earlier imply. The symptoms of Adult-Onset Hypogonadism are complicated significantly be the presence of other medical issues. In addition to this, endogenous Testosterone levels become suppressed by a number of physiological factors such as obesity as well.

Previous EMAS Testosterone Study

In a previous medical study released by the authors of this journal article, the researchers again used the data from the EMAS study in order to learn more about the complex physiological pathology of Adult-Onset Hypogonadism. In this previous study, the researchers simply evaluated the participants of the EMAS study based upon Biochemical Testosterone Deficiency, categorizing such deficiency as compensated, primary, or secondary.

In this study, the researchers ignored physiological symptoms of Low Testosterone and simply grouped patients dependent upon the form of hypogonadism they experienced. If one ignores symptoms and only considered Biologically Low Testosterone, 23.3% of males could be clinically diagnosed with Testosterone Deficiency. The purpose of the initial study was simply theoretical knowledge seeking, whereas this study is an attempt to apply that scientific knowledge in an attempt to greater understand and streamline medical diagnosis and treatment of Testosterone Deficiency.

Counterpoint to Clinical Study

This study claims with seemingly unwavering confidence that only 2.1% of males experience Adult-Onset Hypogonadism. They claim that this study emphasizes the important of not only chemically diagnosing Adult-Onset Hypogonadism but also taking into account the fact that only patients who experienced negative symptoms as a result of Testosterone Deficiency are truly in need of the treatment.

Although we recognize the value and benefit of a study such as this, we are slightly incredulous at the confidence in the author's overarching claims. Although it may be true that only 2.1% of otherwise completely healthy males experience Testosterone Deficiency, this does not seem to properly take into account the variety of disorders such as Diabetes, Obesity, and Sedentary Lifestyle which greatly increase the odds of suffering from Testosterone Deficiency by a significant amount.

Also, the study does not consider the fact the different patients may have different biological needs for Testosterone. It would make logical sense that sexuality and sexual function are tightly and neatly correlated with specific Testosterone levels, but many issues such as anxiety or depression may not always be the direct result of Low-Testosterone, though they may be greatly alleviated by Testosterone Replacement.

Low-T is Rife with Non-Specific Symptoms

The extended list on non-specific symptoms of Testosterone Deficiency make it hard to construct hard guidelines regarding the diagnosis of Adult-Onset Hypogonadism. For this reason, even the rate at which the primarily sexual symptoms of Testosterone Deficiency occurred was moderately high among males with unquestionably normal Testosterone Levels. With non-specific disorders such as Testosterone Deficiency, it is utterly important to only diagnose Low-T when a patient is experiencing three or more relatively clear symptoms of the disorder. Combining this diagnostic rule of thumb with accurate Testosterone Testing helps ensure that a proper diagnosis is ultimately made.

This study also shows that Total Testosterone Levels are a more useful indicator of Testosterone Deficiency than Free Testosterone Levels. Although in most cases, Total Testosterone may be enough to diagnose the majority of patients, Free Testosterone Analysis can help a physician make a more accurate diagnosis in the incidence of a complex case or when Total Testosterone Levels are discovered to be borderline.

Testosterone HRT and the Conscious Evolution Institute

Testosterone Hormone Replacement Therapy is a valuable potential treatment option for any man over the age of thirty who feels that they may be suffering from the symptoms of Testosterone Deficiency. We at the Conscious Evolution Institute feel that this study increases our knowledge about Male Hypogonadism in spite of its cautious and tentative nature.

We feel that any study which more clearly defines what Clinical Testosterone Deficiency is incredibly beneficial to the international medical body of knowledge, but we understand that Testosterone Deficiency is a complex disorder which has the capacity to effect different men in significantly different ways. If you have any questions about this study or have any other questions regarding Hormone Replacement Therapy featuring Testosterone or any other Hormone Treatment we provide, we encourage you to reach out and contact the Conscious Evolution Institute today!

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