Possibilities of drug correction of growth hormone deficiency in adults

Introduction

Children with established growth hormone deficiency receive recombinant growth hormone replacement therapy until adulthood and genetically predicted final height. Despite the fact that somatotropic hormone (GH) has the main range of physiological effects on the body in childhood, and subsequently its production decreases, GH plays an important role in the normal functioning of organs and systems of an adult. Currently, in Russia, a system of providing medical care to children with growth hormone deficiency has been developed [1, 2], but there are no clinical recommendations devoted to the diagnosis and replacement therapy of GH deficiency in adults.

The first studies on the treatment of GH deficiency in adult patients with hypopituitarism were published in 1989 [3, 4]. In the Russian Federation, the first experience of using human growth hormone in adult patients with GH deficiency was published in 2004 [5]. Clinical manifestations of the disease in adult patients are nonspecific and in cases of acquired GH deficiency are often masked by manifestations of deficiencies of other pituitary tropic hormones, which complicates diagnosis.

The purpose of this review is to summarize current data on the diagnosis, treatment and systemic effects of somatropin replacement therapy in adult patients with GH deficiency.

Growth hormone: normal level in the blood and how to check

The normal concentration of growth hormone in the body is 1-5 ng/ml. Peak concentration reaches 10-20 and even 45 ng/ml. Typically, peak secretion occurs every 3-5 hours. The highest concentration occurs at night, approximately 1 hour after falling asleep. With age, GH is synthesized less and less, which is why additional supplements have to be used.

The most effective way to test growth hormone is to take a blood test. In almost any laboratory that conducts blood tests, you can test for growth hormone, as well as IGF-1 - insulin-like growth factor 1, which helps increase natural somatotropin.

Clinical manifestations

GH deficiency in adults is characterized by systemic changes in metabolism with nonspecific clinical manifestations [6].

– Body composition.

An increase in adipose tissue mass, mainly due to visceral fat, a decrease in lean mass [7–9], a decrease in extracellular fluid volume and total sodium concentration [10].

– Physical activity

. Decreased tolerance to physical activity, decreased muscle strength against the background of a decrease in the amount of muscle tissue [11]. Impaired thermoregulation [12].

– Cardiovascular system, lipid metabolism and blood coagulation system

. Increased cardiovascular risk due to dyslipidemia, carbohydrate metabolism disorders and accelerated development of atherosclerosis. Reduced myocardial mass, impaired conductivity, contractility and stroke volume, decreased pumping function and ejection fraction, diastolic dysfunction [13]. Dyslipidemia due to increased concentrations of total cholesterol, LDL cholesterol and triglycerides [14]. Increased activity of fibrinogen and plasminogen activator inhibitor type 1 (PAI-1) [15].

– Carbohydrate metabolism

. Impaired glucose tolerance, insulin resistance [16].

– Skeletal system

. Reduced bone mass and bone mineral density (BMD), increased risk of fractures [17–19].

– Quality of life and cognitive function

. Decreased quality of life: maladjustment, decreased self-esteem, anxiety, apathy, depression, social isolation [20].

Diagnostics

Diagnosis of GH deficiency in adults is difficult for a number of reasons. The clinical manifestations of this disease are nonspecific and therefore have low diagnostic value [21]. Under physiological conditions, GH secretion has a pulsed nature, it is influenced by age, gender and body mass index, and therefore the determination of basal GH concentration has no diagnostic value [22]. Normal serum IGF-1 levels do not exclude the diagnosis of GH deficiency. IGF-1, IGF-binding protein 3 (IGFBP-3) are of approximate value for diagnosis, since the indicators in patients with GH deficiency and healthy people may partially coincide [23].

Currently, the generally accepted method for diagnosing GH deficiency in adults is stimulation tests [22, 24], the protocols of which are presented in Table. 1.

Table 1. Etiology of GH deficiency in adults [24]

Foreign clinical guidelines recommend testing only those patients who are highly likely to have the disease, and hormone replacement therapy with somatotropin will help improve metabolic parameters and quality of life. Provocative tests are not required if one of two conditions is present:

1. The presence of three out of four components:

– significant growth deficit (<-3 SDS);

– at least one additional tropic deficiency;

– low concentration of IGF-1 in the blood;

– congenital defect of the hypothalamic-pituitary region according to MRI: “triad” (hypoplasia of the adenohypophysis, ectopia of the neurohypophysis, aplasia/hypoplasia of the pituitary stalk);

– history of surgical treatment of a tumor of the hypothalamic-pituitary region;

– history of irradiation of the head-neck area.

2. Mutations of genes associated with the development of hypopituitarism: GH1, GHRHR

,
HESX1, LHX3, PROP1, POU1F1
[
PIT1
], etc. [22, 24, 25].

In table 2 presented

Table 2. Stimulation tests for diagnosing GH deficiency in adults; threshold values ​​of diagnostic tests used in the world for diagnosing GH deficiency in adults.

Test with insulin hypoglycemia

Stimulation of GH secretion during hypoglycemia was first described in 1963 [26]. This test is considered the “gold standard” in the diagnosis of GH deficiency in adults [22, 24], however, it has a number of disadvantages. Close medical monitoring is required to monitor for potential adverse events (convulsions or loss of consciousness due to hypoglycemia). In addition, due to the presence of insulin resistance in obese patients, this category may require the use of higher doses of insulin (0.15–0.20 U/kg body weight), which increases the risk of delayed hypoglycemia [27]. The insulin hypoglycemia test is contraindicated in elderly patients, people with high cardiovascular risk and epilepsy. Although the sensitivity of the sample is high, there are limitations in its reproducibility. In addition, variability in the peaks of GH secretion was noted in healthy volunteers depending on the time and in different phases of the menstrual cycle [22].

Currently, the range of 3.0–5.0 ng/ml is used as a diagnostic value for stimulated GH secretion during hypoglycemia [22, 24].

According to foreign recommendations, if there are contraindications to a test with insulin hypoglycemia, it is possible to conduct a combined test with stimulation with somatoliberin and arginine, however, the use of arginine for diagnosing GH deficiency has not been registered in the Russian Federation.

Test with somatoliberin and arginine

A test with somatoliberin and arginine, like a test with insulin hypoglycemia, is considered quite sensitive and specific for diagnosing GH deficiency [28, 29], but currently there is no somatoliberin drug on the pharmaceutical market.

The accuracy of this test is determined by the combined use of two stimulating substances: somatoliberin stimulates the synthesis and release of GH by the pituitary gland [30], and arginine enhances this effect by suppressing the release of somatostatin [31]. The concentration of GH during stimulation does not depend on gender and age, however, the result depends on BMI, and therefore three threshold values ​​are used (Table 3).

Table 3. Cut-off points for diagnostic tests according to published clinical guidelines Due to the fact that during this test both the pituitary gland and the hypothalamus are stimulated, false-positive results are possible with the hypothalamic genesis of the disease (for example, after radiation therapy) [32].

Glucagon test

Due to the fact that the main alternative test for diagnosis is not available, the possibility of using a test with glucagon in case of contraindications to a test with insulin hypoglycemia is being actively studied.

Glucagon is a strong stimulator of GH secretion, however, the mechanism of stimulation remains unclear. The stimulating effect is more pronounced when administered intramuscularly or subcutaneously compared to intravenous [33].

The advantages of the glucagon test are reproducibility and safety; its results are not affected by gender and the hypothalamic origin of GH deficiency. Disadvantages are the duration of the test (3–4 hours) and the need for intramuscular administration of glucagon. Side effects of the test are more pronounced in elderly patients: hypotension, hypoglycemia and epileptic seizures [34]. In addition, there is a risk of delayed hypoglycemia, and therefore this test is not included in routine clinical practice.

Two studies compared the diagnostic performance of the glucagon test and the insulin hypoglycemia test, and the patient and control groups were matched by sex and age [35, 36]. In a study by J. Gómez et al. The patient groups were also compared by BMI; this study revealed an inverse correlation of age and BMI with peak GH concentrations in healthy volunteers.

Initially, the threshold value of GH concentration was taken to be 3.0 ng/ml. Further studies revealed that the use of this value leads to overdiagnosis of GH deficiency [37]. Taking this into account, the American Endocrine Association guidelines suggest using a threshold of 1.0 ng/mL for patients with a BMI greater than 25 kg/m2. The authors also note that to clarify the diagnostic accuracy of the reduced threshold value, it is necessary to conduct large prospective studies among patients with different BMI and disorders of carbohydrate metabolism [22].

Growth hormone secretagogues

This class includes molecules that exhibit a strong dose-dependent and specific stimulation effect on somatotrophs [38]. They bind to the growth hormone secretagogue receptor 1a (GHS-R1a) in the hypothalamus and pituitary gland. The natural ligand of this receptor is ghrelin [39]. Other agonists of its receptor are analogues of ghrelin: GHRP-2 (GH-releasing peptide-2, GH-releasing peptide-2), GHRP-6, hexarelin, all of these substances are administered parenterally. Oral ghrelin analogues are also available.

The advantage of GH secretagogues is the possibility of oral administration [40]. They are resistant to proteolysis, since many representatives are non-protein molecules or contain D-isomers of amino acids [41]. The disadvantage is the possibility of obtaining false-positive results in the hypothalamic genesis of GH deficiency [42].

Studies have been conducted to evaluate the diagnostic value of tests with GHRP-6, GHRP-2 and combinations of somatoliberin with hexarelin, pyridostigmine, acipimox, GHRP-6 in comparison with a test with insulin hypoglycemia [43–48].

In studies of the test with somatoliberin and GHRP-6 for the diagnosis of GH deficiency in adults, the test was well tolerated (the only side effect was “hot flashes”), high sensitivity and reproducibility. GHRP-6 is administered intravenously, the peak GH response develops at 15-30 minutes - much earlier than with other pharmacological stimulants. The threshold value for a normal response is 20 ng/ml, for GH deficiency 10 ng/ml [49, 50]. The results of this test are not affected by age, gender or excess body weight, except when BMI exceeds 35 kg/m2, the threshold value is reduced to 5 ng/ml [51].

The GHRP-2 test has been used in Japan since 2006 because it is safe and convenient, using a GH concentration of 9 ng/ml as a threshold value. The peak concentration of GH after stimulation is reached at 60 minutes [52].

In a study where acetylated ghrelin was used as a stimulating agent, the most diagnostically significant GH concentrations for diagnosis were 7.3 ng/ml for normal body weight, 2.9 ng/ml for overweight and 0.6 ng/ml for obesity , diagnostic accuracy was 89.3, 94.1 and 62.5%, respectively. The authors conclude that obesity significantly reduces the GH response to ghrelin stimulation, but this test is a reliable diagnostic tool in patients with normal and overweight [53].

Currently, the use of the above methods in the Russian Federation is impossible, since somatoliberin and GH secretagogue preparations are not available on the market.

Oral secretagogue of GH

In 2021, the Food and Drug Administration (FDA) approved the use of macimorelin for the diagnosis of GH deficiency in adults [54].

Macimorelin is a GHS-R1a agonist with high stability, which allows it to be administered orally. In a phase I study in 36 healthy volunteers, oral administration of macimorelin showed a rapid, dose-dependent increase in plasma concentrations of the drug, with peak concentrations reaching 50–75 minutes after dosing. Dose-dependent stimulation of GH secretion was correlated in time with the maximum concentration of the drug in plasma; the increase in GH concentration lasted about 120 minutes after oral administration or intraduodenal administration. The drug was well tolerated, and no adverse events were identified [55].

A multicenter, open-label study compared the diagnostic value and safety of macimorelin versus somatoliberin + arginine test among adult patients with GH deficiency and healthy volunteers. According to ROC analysis, the optimal threshold concentration of GH was 2.7 ng/ml: sensitivity 82%, specificity 92%, error rate in recognition 13%. Among patients who were prescribed both diagnostic tests, the diagnostic yield of the methods was comparable. Peak GH concentrations were inversely correlated with BMI in the control group. With a single blood draw 45 minutes after taking macimorelin, using threshold values ​​according to BMI (6.8 ng/ml for BMI <30 kg/m2, 2.7 ng/ml for BMI ≥30 kg/m2), the sensitivity of the sample was 90%, specificity – 85%, error rate in recognition – 12.2% [56].

In 2021, the results of a multicenter, open-label, randomized, double crossover study were published, the purpose of which was to establish the effectiveness and safety of a single dose of macimorelin at a dose of 0.5 mg/kg for the diagnosis of GH deficiency in adults, compared with a test with insulin hypoglycemia. Patients were divided into three groups according to the likelihood of having the disease: high ( n

=38), medium (
n
=37) and low (
n
=39), a group of healthy volunteers was also selected (
n
=25).
Using GH concentrations of 2.8 ng/mL for macimorelin and 5.1 ng/mL for the insulin hypoglycemia test as a cutoff point, negative agreement was 95.38% (95% CI 87–99%), positive agreement – ​​74.32% (95% CI 63–84%), sensitivity 87%, specificity 96%. The reproducibility of the macimorelin test was 97% ( n
= 33). A secondary analysis found that using a cut-off point of 5.1 ng/mL resulted in a negative agreement of 94% (95% CI 85–98%), a positive agreement of 82% (95% CI 72–90%), a sensitivity of 92% and specificity 96% [57].

There are currently no published results on the safety and diagnostic value of this test in morbidly obese patients. The most common side effects include taste disturbances, dizziness, headache, fatigue, and gastrointestinal disturbances (nausea, hunger, and diarrhea). Prescription with drugs that prolong the QT interval should be avoided, as this may lead to the development of ventricular tachycardia. CYP3A4 is the main enzyme that metabolizes macimorelin, so when used in conjunction with drugs that activate it, false-positive results may be obtained [54].

Standardization of kits for determination of GH

The results of stimulating tests are interpreted according to threshold concentration values, and therefore the accuracy of laboratory determination of GH is extremely important. Circulating GH is represented by various isoforms and isomers: the 22 kDa variant is present in the largest proportion, and molecules of smaller mass are also present. Monoclonal antibodies are able to bind specifically to the 22 kDa isoforms but will miss other isoforms. Molecules of a structure similar to GH (placental GH, prolactin), as well as GH-binding protein (with which about 50% of circulating GH is bound) can cross-react and affect the accuracy of the measurement. There are also differences and inconsistencies in calibrations, which limit the ability to compare thresholds across studies. In addition, laboratories may use different units for measuring the concentration or activity of GH [58].

To combat these limitations, a single calibration standard for STG is currently proposed - 98/574. All kit manufacturers must clarify the isoforms being detected, the specificity of the antibodies used, and the presence of cross-reactions with the GH-binding protein [59].

Proteomic biomarkers of GH deficiency

At the time of submission of the article, there were no publications on proteomic biomarkers of GH deficiency in adults. In 2021, the results of a study were published in which circulating proteins in children with GH deficiency were studied using the new generation proteomic analysis SWATH-MS in comparison with healthy volunteers. Three proteins have been discovered that can be biomarkers for non-invasive diagnosis of GH deficiency in children: apolipoprotein A-IV, CFHR4 (complement factor H-related protein 4) and PBP (platelet basic protein) [60]. The question of studying these proteins in GH deficiency in adults remains open.

Growth hormone receptor polymorphisms

In humans, the growth hormone receptor gene (r-GH) is located on chromosome 5. The gene consists of nine exons encoding the receptor and several additional exons in the 5' untranslated region. Two main isoforms of r-GH are known, differing in the presence (fl-GHR, full-length) or absence of exon 3 (d3-GHR, exon 3-deficient). The absence of exon 3 results in the loss of 22 amino acids in the extracellular domain of the receptor [61]. It is currently believed that the binding capacity of both isoforms is the same. The d3 isoform is dominant over fl; about 50% of Europeans are hetero- or homozygous for d3 [62]. Carriage of d3 is associated with tall height, higher sensitivity to GH and is a factor in longevity in men [63].

Patients with the fl/fl genotype had a more pronounced response to somatropin after treatment for 1 week, compared with patients with the d3 alleles [64]. In another study with a treatment duration of 12 months, the increase in IGF-1 in response to therapy was significantly greater in the d3/d3 group. There were no differences in IGF-1 concentrations between the fl/d3 and fl/fl groups [65]. According to S. Meyer et al., no significant differences in IGF-1 concentrations were detected during therapy between carriers of one or two d3 alleles and the fl/fl genotype [66]. In adult patients with GH deficiency with d3 alleles, the risk of vertebral fractures is reduced, regardless of receiving GH replacement therapy [67].

Studies have also been published in which no differences were found between genotypes in clinical manifestations and adverse events, quality of life, IGF-1 concentrations, body composition and fat mass [68–71].

Two studies were conducted that assessed the effect of r-GH polymorphisms on various parameters during GH replacement therapy after 1 year and after 5 years of treatment. In a study by Van der A. Klaauw et al. after the first year of treatment in the d3 carrier group, a more pronounced increase in IGF-1 was observed at the same average doses of somatotropin in the groups. Among d3 carriers, total cholesterol decreased less markedly, and the concentration of HDL cholesterol reached higher values ​​compared to fl/fl. However, after 5 years, no differences were found between the groups [72]. According to S. Giavoli et al., treatment with somatropin normalizes the concentration of IGF-1 and reduces the percentage of fat mass after 1 year and after 5 years of treatment, regardless of the presence of the d3 allele. After one year of treatment in the d3 carrier groups there was an increase in the concentration of HDL cholesterol, and after five years there was a decrease in the concentration of total cholesterol and LDL cholesterol. While the prevalence of carbohydrate metabolism disorders was initially the same, 5 years after treatment in the fl/fl group it decreased, and in the d3 carrier groups it doubled [73].

Currently, data on the effect of r-GH polymorphism on the clinical picture of GH deficiency in adults is scarce, and available publications on the relationship between carriage of the d3 allele and response to replacement therapy are contradictory.

“Testosterone is a very insidious hormone”: interview with an endocrinologist

We continue a series of meetings with outstanding domestic doctors. Today - a detailed conversation about our endocrine system in general and the “favorite” male hormone testosterone in particular with the director of the Endocrinology Clinic of the First Moscow State Medical University. Sechenov Valery Fadeev.

We know that endocrinology is about hormones; we often hear “check your thyroid.” On the other hand, many have a rather poor idea of ​​how the activity of the thyroid gland is related to the daily functioning of the body, in particular the male one.

There is a very big difference between the functioning of the female and male endocrine systems, despite the fact that the set of hormones in men and women is the same. The difference is in the quantity and nature of secretion. A significant part of the hormones in the female body is produced cyclically, and in the male body - tonically, that is, continuously, without monthly cyclicity. The human hypothalamic-pituitary system is tuned to such “male” hormone production by the appearance of a certain amount of testosterone during fetal development, from the moment of fertilization to the birth of the child.

I will ask you in particular detail about testosterone, which is of great interest to our readers. But let's start, if possible, with the basics - with the functions of the thyroid gland.

Thyroid hormones are the most ancient in origin; they regulate the most basic functions of the cell. And every cell. More precisely, they regulate the processes of oxidation and oxygen consumption by the cell. Our body can be compared to a stove in which a fire burns. We throw firewood there - what we eat. In order for a fire not to go out, oxygen is needed. There is a damper in the stove, and with its help we can make the flame stronger - by opening it wider, or we can dim it - leaving a small crack, and the fire will smolder. The function of thyroid hormones is to control the valve, or more precisely, the intensity of oxidation, combustion, which results in the formation of heat - the energy that every cell needs.

How did we even know that hormones exist in our body?

Before the concept of “hormone” appeared, we were talking about the so-called humoral factors. Back in the 14th century, the Chinese associated secondary sexual characteristics with them: doctors of that time said that “the beard is an external manifestation of the power of the male seed,” “the beard is related to the kidneys and testicles.” In the middle of the 19th century, the German professor Berthold conducted experiments: a rooster was castrated, as a result of which his secondary sexual characteristic, the comb, regressed. After this, the extract of the removed testes was injected into the cockerels, and the comb was restored. These were the first experiments related to testosterone. The very concept of “hormone” appeared later, at the beginning of the 20th century, and since then its interpretation has undergone numerous transformations.

Endocrinology was formed as a field of medicine dealing only with hormones?

Yes, classical endocrinology concerns seven anatomically distinguished endocrine glands: thyroid, parathyroid, pituitary gland, pancreas, adrenal cortex, testes and ovaries, pineal gland. These are endocrine glands that secrete hormones. Actually, the name “endocrinology” translates as “the science of what is secreted inside” - it studies the chemical substances secreted by these glands into the blood and regulating the functions of many cells.

Explain the interaction between the nervous and endocrine systems.

Comparing the nervous system with the endocrine system is like comparing a telephone and a radio. The nervous system is a telephone: wires-nerves that come from the brain and transmit information to a specific point. The hormonal gland produces information that is distributed through the blood to many people - like a radio that broadcasts from one point, but everyone hears it. That is, the impulse of the endocrine system is a loudspeaker. When there is a failure in the nervous system, only what is activated by this nerve stops working - one muscle: just like if you break a telephone wire, only the telephone will not work. And if the radio station breaks down, no one will hear the message. That is, the pathology of the endocrine system is multisystem - it is a pathology of many structures at once. An example is the hormones of the thyroid gland, which act on almost all cells of our body. In our cell, everything is energy-dependent - all enzyme systems, all their functioning, since every cell contains ATP, adenosine triphosphate - our battery. And the intensity of energy production in it is regulated by thyroid hormones.

Should a young man, who is not worried about anything, visit an endocrinologist one day for a prophylactic visit?

Preventive medicine in general is a rather controversial thing. The popular concept of “the more you examine, the better” is fundamentally wrong. In the modern world, unnecessary examinations can cause no less harm than their absence, including because their interpretation is very difficult. Ultrasound reveals one-millimeter structures in the thyroid gland. And they can make more noise without causing any consequences. We can talk about preventive endocrinology, first of all, in connection with blood sugar levels. If we are talking about an overweight man, it is advisable to control sugar from the age of 20–25 - at least once every few years. This should also be done if the parents were sick with diabetes or had cardiovascular pathology.

Are diseases of the endocrine system inherited?

The tendency is inherited. These are so-called multifactorial diseases - there is a certain predisposition that may or may not be realized. If a person is prone to diabetes, but does not gain excess weight, he may not get sick. That is, environmental factors, in particular food, can contribute to the implementation of the genetic factor. Thirty years ago we called type 2 diabetes age-related, but today it occurs even in children. Unfortunately, we often see diabetes in 25-year-old obese patients. By the way, it is important to say that there is an obvious connection between obesity and decreased testicular function. With severe obesity, testosterone levels decrease. The fact is that adipose tissue is the site of sex hormone exchange; when a man becomes obese, the balance of estrogen and testosterone changes. This leads to suppression of pituitary regulation of the testes and decreased testosterone production.

What do young men usually turn to an endocrinologist for?

In men aged 20–30 years, endocrine pathology occurs relatively infrequently—almost ten times less often than in women. But if a man develops, say, Graves' disease at a young age, then it is much more severe and has a worse prognosis. Why? It is difficult to say, there are no clearly proven explanations. But I repeat once again - at a young age, pathology of the thyroid gland in men is rare. The greatest problem is the decline in its functions, which occurs in men after 40 years of age. The symptoms of this disorder are very nonspecific: we can talk about, let’s say, an incomprehensibly bad state of health - a general loss of strength, lethargy, fatigue, decreased muscle tone, potency, libido, erectile dysfunction, that is, some non-specificity that could potentially be the background or a trail of any disease. In a hospital sample, as we call it, if a patient comes to the doctor and there is a set of these factors without an obvious concomitant disease, and even more so if it is present, it is better to check the function of the thyroid gland.

What methods are used for this today?

Blood is taken from a vein and one indicator is determined - TSH, thyroid-stimulating hormone of the pituitary gland. Its level allows you to more than accurately assess the functioning of the thyroid gland. Problems with this hormone are more common in women, but it is not uncommon for men either.

It turns out that from the point of view of the hormonal system, men are more protected by nature?

Yes, but they live on average twenty years less. In fact, a woman is protected by nature - and from the position of the endocrine system too. She still has the task of reproduction, while the biological significance of a man who has performed the copulatory function is practically complete.

If you remember the copulatory function, let's talk about testosterone, which worries everyone so much.

Testosterone is a very interesting hormone, one might say, insidious. This is the 21st century, and there is still no understanding of how to accurately determine it - all methods have flaws. Hormone levels are measured using immunometric methods, that is, using antibodies. Testosterone is a steroid hormone, very small in structure; the size of the antibody is a certain number of times larger. That is, the number of testosterone is a very delicate matter. It must be able to interpret it depending on the situation, in combination with other hormones, with gonadotropins - hormones of the anterior pituitary gland. Therefore, the prevailing opinion that if you were given a huge amount of testosterone in a laboratory, then you are a superman is wrong. In general, this is part of the myth that endocrinology is some kind of attachment to a hormonal laboratory: we sit here, send everyone for hormonal studies, get a number, and make a diagnosis. Absolute nonsense.

What is the main task of endocrinology?

This is a clinical discipline, the same as, say, cardiology. And the interpretation of laboratory tests is often at the last stage of our reasoning. The cardiologist also has an echocardiogram: it can be completely fine, but the person has a whole bunch of problems. The same can be said with regard to hormones: if the diagnosis could be made by numbers, I would not be needed here. You can assign a laboratory assistant to make diagnoses and write prescriptions directly on the hormonal test results form.

Let's trace the life process of testosterone in the context of the maturation of the male body.

Let's. We will omit puberty and early development - there are very complex, I would even say, ornate processes in the relationship between the hormones of the adrenal cortex and the testicles, which is hardly interesting to your readers. By the age of 20, testosterone production levels reach peak values, and from the age of 30, slowly, slowly, differently for everyone, but in general, quite naturally, they begin to decline. Testosterone is produced in the testicles, but it is a deep misconception to consider it a hormone created by nature only for erection. Erectile function can be completely normal even with low testosterone, but sex drive, desire, libido - call it what you want - will most likely be reduced. Testosterone is an anabolic steroid for the male body; it does almost everything that distinguishes a man from a woman; it contributes to the development of not only the reproductive system, but also the muscular system, the brain, and even the production of red blood cells. Without it, a man turns into a eunuch - a thin voice, lack of hair growth, flabby muscle system, obesity, tummy. But at the age of your readers, testosterone deficiency is quite rare. If you take one hundred percent of men aged 20–30 years with erectile dysfunction, then probably 90–95 percent have a psychogenic problem. After all, erectile function has many components, first of all, the brain; the system is very complex. And most often it fails due to various kinds of violations: childhood fears, complexes, neuroses, personality disorders, relationships between partners, that’s all. But the real testosterone deficiency, rather, looks towards the age of “50 plus”. And this is where a lot of speculation arises on this very topic.

Pharma machinations?

Partly yes. In part, the lobby of those involved in erectile dysfunction is inflating this topic. Both abroad and here we have “specialists” who are ready to pin testosterone deficiency on literally everyone, blaming almost all male diseases, including obesity, for this deficiency. Almost diabetes is treated with testosterone. After all, what is a deficit? The figure is below normal. And this concept is very relative, especially for hormones. This is the case when the word “norm” must be put in large quotation marks. There is no norm, there is a reference, and this is a statistical concept: they took, relatively speaking, one hundred healthy men aged 20–30 years, looked at testosterone, calculated the average, removed the Gaussian dome and got two numbers.

At the same time, there are characteristics of the population: racial, regional, age...

That's it, age. And here you can speculate endlessly. He moved the reading frame and said: “You have a deficit...”

"…take a pill".

Yes, “take a pill.” Firstly, there are not many studies that have studied the use of testosterone in older men, and secondly, they are not as long-lasting. Some of them had positive results, some had negative results in terms of cardiovascular risk.

So does artificially increasing testosterone levels entail a risk of cardiac problems?

I can’t give a definite answer. But research results in this sense are contradictory. There is a figure that clearly shows testosterone deficiency, then its administration has positive consequences. But if we take the “gray” zone, as we call it, when someone considers this value to be a deficit and others do not, here this assignment most often does not lead to any results. After all, hormones are part of a large integrated system within a person. Man, unfortunately, is mortal, and no one can do anything about it yet. A person ages, and all his systems age, including the endocrine system, integrally adapting to a particular age. And if at the age of 60 you begin to artificially make yourself 18 with the help of pills, you cause a conflict of systems. It’s not for nothing that the Old Testament says: “No one puts new wine into old wineskins; otherwise the new wine will burst the skins and flow out on its own, and the skins will be lost.” You see, a hormone is a systemically acting active element. If you introduced testosterone into the systemic circulation, it affected not only your penis: it affected the brain, the heart, the blood vessels, the liver - everything! This means that the consequences can also be systemic.

And unpredictable?

Well, if someone wants to experiment and is ready, as in “Egyptian Nights,” to get some kind of stroke during one sexual act, that’s his choice. But in any case, you shouldn’t do this at 20–30 years old. If you have sexual problems at this age, don’t immediately blame low testosterone. Yes, this happens, but extremely rarely, and then it is a serious violation. But often in such a situation they grasp at borderline results, when prescribing testosterone is simply a convenient solution for the doctor.

Why is such an appointment dangerous?

There is an aspect in which the male body is more delicate than the female - I'm talking about the production of sperm. External administration of testosterone suppresses it. In general, as soon as a person has even a severe runny nose with fever, spermatogenesis will be suppressed for some time. Nature has arranged it this way: a sick male should not fertilize females. You don’t even need a runny nose: let’s say a man is exhausted at work, is nervous, doesn’t get enough sleep at night - in this situation he will have low testosterone simply due to a general loss of strength. Even at a young age. We experimented in our clinic: we looked at testosterone in patients with diabetes during hospitalization, and then two weeks after he had been with us. First of all, the man got enough sleep. Secondly, we have put some general indicators in order. And after two weeks his testosterone is already normal! A single determination of testosterone cannot be trusted at all. And when they begin to evaluate the spermogram of a man who is sick with some kind of chronic disease, uncompensated, this is also absurd. The first thing you need to do is cure him. Bring it back to normal, and then evaluate the functioning of the reproductive system. Or he's on a drinking binge...

This is also an interesting topic - alcohol and male hormonal levels. Does whiskey actually lower blood sugar?

Any ethanol, any ethyl alcohol potentially blocks the production of glucose by the liver, and for some time can actually reduce sugar levels. But I don’t recommend treating diabetes with alcohol—it doesn’t matter whether it’s whiskey, vodka or tequila.

But what about the cherished 40 milligrams per day, which are allowed even by cardiologists?

40 milligrams is possible - of course, provided that the person is ready to stop there. Alcohol is a universal tranquilizer, and in the modern world it also plays a positive role, helping a person in a state of chronic stress to relieve this stress. Chronic stress, by the way, also has a bad effect on sexual function. So no one is against alcohol in small quantities to reduce stress. But in large cases, it only causes harm, disrupts erection and ejaculation. You ask about the connection with the functions of the thyroid gland - alcohol does not directly affect it. And on sexual function - only negatively.

Are you talking about fertility?

Exactly. In chronic alcoholics, testicular function is completely impaired. Against the background of intoxication, testosterone production decreases and spermatogenesis is disrupted, this has been proven. And if we are talking about fertility, today there are practically no medications that affect spermatogenesis. This is such a subtle and complex process that we have not yet learned how to interfere with it. In a woman, you can stimulate ovulation in order to obtain an egg, but if a man’s spermatogenic epithelium is affected, there are no treatment methods.

What exactly negatively affects the function of this epithelium?

The epithelium produces sperm. And many factors influence this process, including your own testosterone. The cells that produce it in the testicle are nearby and influence each other: Sertoli cells, Leydig cells, which form the spermatogenic epithelium, are connected in local regulation. Plus, testosterone production and sperm production in the testicle are influenced by pituitary hormones. So this epithelium is quite sensitive to toxic influences.

To anyone, not just alcohol?

Of course. Here is a simple example: let’s say, God forbid, if we are talking about malignant tumors for which chemotherapy is prescribed, practically the first thing that suffers is the spermatogenic epithelium. Because dividing cells are killed. So, sperm cryopreservation is recommended for young patients before prescribing antitumor chemotherapy.

Let's continue our endocrinological educational program. What is important to know about the work of the pituitary gland and hypothalamus?

We are talking, rather, about the work of the hypothalamic-pituitary system. The nuclei of the hypothalamus are the nuclei of the nervous system that produce humoral factors. These are, as a rule, very small molecules consisting of several amino acids, which enter the pituitary gland through very short vessels and there stimulate the production of pituitary hormones. The pituitary gland is such a conductor, a key regulatory structure of many elements of the endocrine system. This means that sexual function, the functioning of the thyroid gland, adrenal glands, the production of prolactin, the production of growth hormone and a number of other factors depend on it.

Including metabolism?

You know, endocrinologists get a little stupefied when they hear the expressions “metabolism is disturbed” or, say, “hormonal levels.” Human life is all about metabolism, and everything is involved in it, including eyes, teeth, hair, ears and nails.

Let's not fall into a stupor, let's return to the hypothalamus.

The hypothalamus interacts between the nervous and endocrine systems. These systems are interconnected, they function together. But, returning to the beginning of the conversation, nervous systems are a quick regulation, like a phone call: an impulse came and the muscles instantly contracted. The humoral system, including the production of hormones, is a slower basal regulation that carries out fundamental life processes. Here we must remember the evolution, the development of the animal world: it all started not with nerves, but with the fact that there was some kind of plasma in which certain substances circulated.

I sense echoes of an old interdisciplinary debate here...

No no. The nervous system, of course, is also important. We just talked a lot today, for example, about fertility, about sexual function. This is not a simple muscle contraction, it is a complex process extended over time, which is regulated precisely by the relationship of hormones. There's no way a nerve can run from the brain to the testicle and promote sperm production, you know? That would be too cool. And the hypothalamus is precisely responsible for the integrative interaction of nervous influences.

How does the male endocrine system respond to physical activity and the fuel with which these activities are artificially fueled? I'm talking about sports nutrition.

If you are already over 30, then you probably go to the gym for health, and not in order to turn yourself into a cabinet of muscles and seduce girls. At 18 years old, you can, of course, think that a woman needs your muscle mass, but in principle this is absolute stupidity and in 99% of cases it will not work. If you set yourself the task of seducing as many women as possible, you need to spend more effort on developing your brain. And in the gym - think about blood vessels, muscles and some kind of harmony. Now to the question of sports nutrition and energy drinks. I have a very negative attitude towards them. I don’t want to scare anyone, but I had to witness fatal myocardial dystrophy while taking a large number of energy drinks. As for hormones and, in particular, testosterone, unfortunately, I’m afraid that you and I will no longer be able to break the stereotypes that have developed in these gyms. We cannot explain that dabbling with testosterone will lead to the fact that by the time such a guy meets his one and only, he will have nothing left of his spermatogenic epithelium. I myself visit a fitness club and often find myself witnessing conversations between young people on, let’s say, medical topics. What I hear is not just wild - I don’t even have enough words to describe it: “Now I’m on androgens, then I dry out, then I add triiodothyronine...” It should be noted that most often people talk about these topics with, let’s say, not very high intellectual bar.

What does he add?

Triiodothyronine is a thyroid hormone. And then, with the appearance of an absolute expert, but with errors in basic concepts, such a person begins to give recommendations to another person. At the same time, we are talking about very serious hormonal drugs... A real panopticon, and with a health risk. As for consuming large amounts of proteins, this is first of all non-physiological; it puts a lot of stress on the kidneys. I have a lot of patients who are former serious athletes and those who served in special forces. During their physical activity, taking some medications and special nutrition is not entertainment, not a way to seduce a girl, but part of the hardest work with hyperstress. So, as a rule, these people have a whole bunch of endocrine and cardiovascular diseases. With age, many of them acquire obesity, hypertension, and diabetes.

Please tell us about anti-aging endocrinology, about age-related hormone therapy, which is fashionable today.

Due to the development in recent years of the anti-aging industry, most professional endocrinological associations have been forced to publish regulatory documents on hormone therapy: clinical recommendations for the treatment of hypothyroidism, hypogonadism, and growth hormone deficiency. Our professional position is clear: hormone therapy is indicated only and exclusively in situations of hormone deficiency. But there is a powerful anti-aging lobby, non-professional paramedical and other marginal associations. I attended their conferences: from the point of view of professional endocrinologist clinicians, what happens there sometimes looks outlandish. Self-indulgence in our sphere, as in any other sphere, ends badly. Growth hormone, for example, which is used for rejuvenation, is a growth factor; cells multiply from it, which means we can easily grow a tumor for ourselves. The danger is that the anti-aging industry is in an uncontrolled field: they do not need statistics, they do not need prospective studies, they live outside of medical ideology.

That is, starting to rejuvenate with the help of hormone therapy is, in general, a serious risk.

You need to rejuvenate when you are young. Our regulatory system is too complex for the introduction of one or another element into it to trigger any processes in the opposite direction. Today we have listed the classical hormones, but in addition to them there are about two hundred more, and they all participate in the functioning of the body. “Hormon,” by the way, does not come from the word “harmony,” as many people think, but from the word hormao — “put into action.” And all these actions should be, let’s say, proportional to each other. I repeat: the hormone acts on many structures at once, it enters the systemic bloodstream and reaches all cells. We have identified one of its functions, but there are a dozen more that we do not know about. For example, a nerve has one function - innervation of muscles, and a hormone is something more complex. Periodically, one of its effects pops up, and it begins: “This is the hormone of so-and-so.” Almost every hormone was at one time called the hormone of youth. There are episodes of their popularity: sometimes testosterone is popular in our country, sometimes prolactin, sometimes thyroxine. Then suddenly dehydroepiandrosterone is declared the hormone of youth - this is an androgen of the adrenal glands: at one time in the USA it could be bought at any pharmacy without any prescription.

In general, what should a young man do to preserve his endocrine system?

To begin with, surprisingly, remember a simple thing: salt must contain iodine. When your wife or girlfriend goes to the store, ask her not to waste money on various Japanese and Himalayan frills, but to buy our domestic salt, where it says “iodized” on the pack. Its effectiveness has been absolutely proven - it solves the problem of iodine deficiency, prevents the development of goiter and brings many other benefits. This is even more important for women, but men also need to ensure that they get enough iodine into their bodies. This is relative to the thyroid gland. As for diabetes mellitus, it is clear that the disease is associated with a hereditary predisposition, but we must remember its direct connection with excess weight: the stomach not only interferes with tying shoelaces, but also affects our general condition and cardiovascular system. Next is sexual function. A man is given spermatogenic epithelium, one for life, and he must take care of it. The quality of sperm at 20 years old and at 60 differs greatly: it reflects everything that befalls us - from the head and nerves to the environment, not to mention any intoxication, especially chronic ones. So, as you can see, I cannot recommend anything that goes beyond the concept of a healthy lifestyle, although this term smacks of something archaic. Physical activity is needed, and it is highly desirable - without the use of various stimulants. When you're twenty, it seems like you can cram any crap into yourself. But a dozen or two years pass, and we understand that life is not endless. And here the results of all our youthful experiments fall upon us... Do your humble servant know how much he studied before he began to introduce something into the patients’ bodies? To prescribe the hormone, I completed six years of university, two years of residency, graduate school, defended several dissertations, and believe me, I am still checking, rechecking and weighing everything. I never prescribe hormones at the patient’s first visit; I suggest that patients be examined over time and only then do I make a decision. And when boys in fitness clubs start playing around with hormones, it’s crazy. In my opinion, a certain inferiority is manifested here, male complexes, which they try to compensate for by pumping up muscles. So in this sense, I would recommend starting with thinking about what's going on in your head, not what's going on with your testosterone.

Publication link: MensHealth

Treatment

Determination of indications for replacement therapy

The feasibility of replacement therapy for GH deficiency in adults is determined by the expected benefit for each individual patient. Patients with severe GH deficiency, confirmed by stimulation tests and low serum concentrations of IGF-1, are most likely to benefit from treatment. Clinical manifestations indicating the need for treatment are osteopenia, increased cardiovascular risk, as well as reduced quality of life, which must be confirmed by validated questionnaires for this disease [74].

An important category are patients who have achieved target height during replacement therapy and are transferred under the supervision of an adult endocrinologist. In such patients, full maturation of the skeletal and muscular systems may continue for the next 10 years [75–77]. When somatropin was discontinued after achieving target growth, there was a deterioration in lipid metabolism, body composition and quality of life [76, 78, 79]. After achieving final growth, it is necessary to re-diagnose GH deficiency, 1–3 months after a break in treatment with somatropin (Table 4).

Table 4. Re-diagnosis of GH deficiency after reaching final height

The negative clinical manifestations of GH deficiency and the positive effect of somatotropin replacement therapy also extend to patients over 65 years of age [80]. Despite the known fact that GH secretion decreases with age, diagnostic tests make it possible to distinguish between a physiological decrease and a pathological decrease caused by GH deficiency [81]. Thus, the same criteria apply to older patients as to other age categories. However, for such patients it is necessary to choose a lower starting dosage, which will be discussed in more detail below.

Initiation of treatment and selection of dosages

Treatment of GH deficiency in adults is recommended to begin with low doses (0.2−0.4 mg/day subcutaneously), this reduces the likelihood of side effects [82]. Dose titration is recommended at 6–8 week intervals, depending on clinical response and IGF-1 concentrations, which are recommended to be maintained in the upper half of the reference range. In patients under 30 years of age, it is recommended to choose a higher starting dose (0.4–0.5 mg/day), and in elderly (over 60 years of age) a lower dose (0.1–0.2 mg/day) to minimize the risk of developing side effects, since with age there is a physiological decrease in the need for somatotropin. Women receiving oral estrogen replacement therapy require a higher dose of somatropin because oral drugs inhibit the synthesis and secretion of IGF-1 by the liver [83]. When using transdermal forms of estrogens, dose adjustment of somatotropin is usually not required.

After selecting a stable dosage, a blood test for IGF-1 and evaluation for side effects is recommended every 6 months, and a lipid profile and fasting plasma glucose analysis every 12 months or immediately after increasing the dose of somatotropin. A physical examination measuring blood pressure, weight, waist circumference, and BMI is recommended annually and at every visit. If, according to the data of the first X-ray densitometry, a decrease in BMD is detected, a repeat study is carried out once every 2 years. It is also recommended to annually fill out appropriate questionnaires to assess quality of life.

The maximum duration of treatment is currently unknown. However, if there is no effect of treatment within 1 year, it is necessary to decide on the abolition of somatotropin [24].

Side effects

The main side effects of replacement therapy are caused by changes in water-electrolyte metabolism disorders that occur with GH deficiency or fluid retention in case of drug overdose: arthralgia, joint stiffness, myalgia, paresthesia and peripheral edema. Such side effects quickly regress when the dose of somatotropin is reduced. Since previously the initial dose was selected based on body weight, side effects were more common than when the dose was titrated from the minimum.

Very rare side effects include benign intracranial hypertension (BIH) and macular edema. The prevalence of ADHD in the population of children receiving growth hormone therapy is approximately 100 times higher than in the healthy population [84]. In the literature, there is only one description of ADHD as a side effect of replacement therapy for GH deficiency in an adult patient [85]. Two cases of macular edema were described in patients without diabetes mellitus: in an 11-year-old girl who received somatotropin therapy for Shereshevsky–Turner syndrome, and in a 31-year-old adult patient with traumatic injury to the hypothalamic-pituitary region. In both cases, the side effect developed due to an increase in the dose of somatotropin [86].

Impact on replacement therapy for other deficiencies

GH inhibits 11-β-hydroxysteroid dehydrogenase type 1 and promotes greater cortisone synthesis and decreased cortisol synthesis. Careful monitoring of patients with adrenal insufficiency (AI) is necessary when initiating treatment with somatotropin, since the clinical picture of adrenal insufficiency may develop and the risk of decompensation may increase even in mild infectious diseases [87]. In addition, in patients with subclinical hypocortisolism, after initiation of somatropin therapy, the manifestation of clinical manifestations of NN is possible.

When somatropin is prescribed to patients without secondary hypothyroidism, a decrease in the concentration of serum thyroxine (T4) is observed, but the concentration of triiodothyronine (T3) remains stable. Patients on T4 replacement therapy often require increased doses. It has been suggested that GH may increase the peripheral conversion of T4 to T3 and at the same time suppress the release of TSH in the pituitary gland, but the exact mechanism is unknown [88, 89].

Sensitivity to GH is reduced in patients receiving oral estrogen-containing drugs. This phenomenon is explained by the phenomenon of first passage through the liver and inhibition of IGF-1 production. With the use of transdermal forms of estrogens, this effect is practically absent [90, 91].

Testosterone stimulates the secretion of growth hormone and enhances its stimulating effect on the production of IGF-1. Dihydroepiandrosterone (DHEA) potentiates the production of IGF-1 - patients on DHEA therapy achieve IGF-1 targets on lower doses of growth hormone. The mechanism of this effect is unknown. Since DHEA is metabolized to testosterone, it has been suggested that the increase in serum testosterone concentrations accounts for this effect [92].

Cancer risk

According to epidemiological studies, there may be a relationship between high-normal concentrations of GH and IGF-1 in the blood and the prevalence of cancer [93]. In acromegaly, the risk of developing certain cancers is higher than in the general population [94].

Currently, there is no data on an increase in the frequency of relapses of extra- and intracranial tumors in adult patients receiving somatotropin for GH deficiency. However, treatment with somatotropin is contraindicated in the presence of active cancer [24]. In 2021, a study by D. Olsson et al. was published, which included 426 patients with hormonally inactive adenomas: 207 received somatotropin (median treatment duration 12.2 g), 219 did not receive somatotropin treatment (median follow-up 8.2 g .). Among patients receiving replacement therapy, a decrease in overall mortality was noted and no increase in the incidence of mortality from cancer was detected [95].

According to a meta-analysis that analyzed data from seven prospective and two retrospective studies ( n

=11,191). Somatotropin replacement therapy is associated with a reduction in cancer risks in adults with GH deficiency (relative risk 0.69; 95% CI 0.59–0.82). The risk reduction was maintained in additional subgroup analyses, excluding retrospective studies with fewer than 100 observations, studies among patients with craniopharyngiomas, and studies with less than 3 years of follow-up [96].

Thus, according to existing data, the benefits of somatotropin replacement therapy in adults exceed the theoretical risk of neoplasms. Screening for neoplasms in patients receiving growth hormone replacement therapy is no different from the general population. At the same time, it is worth closer monitoring of mature patients, patients with an oncological history and family predisposition, as well as a group with a proven increase in oncological risk - patients after radiation therapy [97].

The quality of life

The quality of life of adult patients with GH deficiency is assessed using the appropriate questionnaires: QoL-AGHDA [98] and PGWB [99].

In 2012, a meta-analysis by A. Hazem et al. was published, which included data from randomized placebo-controlled trials - a total of 54 studies ( n

=3400). Of the selected studies, 16 assessed quality of life, but the authors were unable to conduct a meta-analysis due to data heterogeneity and lack of quantitative data. Eleven studies reported significant improvements in quality of life according to at least one assessment method [100].

Mortality

The study, based on data from the Dutch National Registry for Growth Hormone Treatment, compared 2229 patients receiving growth hormone treatment with a first control group of 109 untreated patients with GH deficiency and a second control group of 356 patients after discontinuation of growth hormone. The standardized mortality rate in the treatment group was 1.27 (1.04–1.56) relative to the general population. After excluding patients with acromegaly and Itsenko-Cushing's disease from the analysis, the indicator was 1.29 (1.05–1.59), after excluding high-risk patients (craniopharyngiomas or other formations of the hypothalamic-pituitary region) - 1.00 (0.79 –1.26). There was also a significant increase in the standardized mortality rate among women in the treatment group - 2.52 (1.57-4.06), and this was observed even after excluding high-risk patients. The authors note that this may be due to the long-term course of uncompensated GH deficiency, which negatively affected cardiovascular risk, but this assumption requires further study [101].

In a study by R. Gaillard et al. among 13,983 patients with GH deficiency receiving somatropin (average follow-up period 4.9 years), an increase in overall mortality was noted by 13% compared with the general population (standardized mortality rate 1.13 (1.04–1.24)), however, mortality rates from cardiovascular diseases and cancer did not differ [102]. According to the results of a meta-analysis by J. Pappachan et al., the standardized mortality rate was 2.40 [95% CI 1.46–3.34] in patients with GH deficiency without treatment and 1.15 [95% CI 1.05–1. 24] in patients receiving somatotropin [103]. K. Stochholm and G. Johansson also demonstrated lower mortality among patients receiving growth hormone compared with patients without treatment: hazard ratio for all-cause mortality 0.34 (95% CI 0.15–0.77) [104].

Metabolic effects of replacement therapy

Since GH is one of the significant regulators of metabolism and energy homeostasis [105], treatment of GH deficiency in adult patients affects body composition, lipid, carbohydrate and bone-mineral metabolism, which is confirmed by meta-analysis data.

Body composition.

In a meta-analysis by A. Hazem et al.
54 RCTs were included ( n
~3400). Somatropin treatment significantly reduced body weight (–2.31 kg, 95% CI –2.66– –1.96) and fat mass (–2.56 kg, 95% CI –2.97– –1.3) and increases lean body mass (1.38 kg, 95% CI 1.10–1.65). However, no significant effect on bone mineral density (BMD) was detected, which may be due to the small number of observations [100].

The meta-analysis by C. Newman et al., which aimed to compare the effectiveness of low and higher doses of somatropin on body composition and lipid metabolism, included the results of 22 RCTs ( n

=1153). Lean body mass significantly increased in treatment groups compared with placebo, while fat mass decreased. Changes in lean body mass and fat mass showed a dose-dependent effect, with treatment at higher doses being more effective [106].

Cardiovascular system and lipid metabolism.

According to a meta-analysis by P. Maison and P. Chanson, which included 16 studies, compensation of GH deficiency promotes an increase in the mass of the left ventricle, the thickness of the interventricular septum and the posterior wall of the left ventricle, an increase in the diameter of the left ventricle in diastole and stroke volume [107]. It is known that the thickness of the intima-media complex of the carotid arteries is a predictor of progression of coronary heart disease [108]. It has been shown that treatment of GH deficiency leads to a decrease in this indicator [109]. Studies have demonstrated a decrease in total serum cholesterol, almost entirely due to a decrease in the concentration of LDL cholesterol. The effect is more pronounced

How to Increase HGH Naturally

The effect of growth hormone in bodybuilding can be achieved by eating certain foods and adhering to a number of rules. One way is fasting. For example, you can not eat for 8 hours a day. This is very easy to do, since a person should normally spend this amount of time sleeping at night.

Growth hormone is produced throughout the night and continues to be synthesized in the morning until a person has breakfast. This is due to the fact that growth hormone is an antagonist of insulin released when eating food. When a person does not eat, insulin is not produced, and growth hormone, on the contrary, is synthesized in large quantities. According to research, one day of fasting is equal to 5 units of growth hormone administered through drugs.

How to increase growth hormone:

• sleep at least 8 hours a day (GH is produced in greater quantities during sleep);
• train regularly, focusing on strength training (aerobic exercise seriously increases the level of growth hormone);
• harden, since sudden changes in temperature contribute to increased synthesis of growth hormone;
• consume foods that stimulate the synthesis of growth hormone;
• eliminate fatigue, stress and emotional overstrain (worsen the production of growth hormone);
• use special sports supplements that stimulate the synthesis of growth hormone.

If we talk about which products contain growth hormone, then it makes no sense to look for them. There are only products that help enhance the production of growth hormone by the body itself. This category includes:

• meat and fish;
• dairy products;
• chicken eggs;
• potato;
• buckwheat and oatmeal;
• pumpkin seeds, pistachios, cashew nuts.

Pumpkin seeds and watermelons especially strongly stimulate the secretion of growth hormone, since they contain a huge amount of L-arginine, an amino acid that enhances the synthesis of growth hormone.

How to increase growth hormone: safe drugs

Some types of sports nutrition help increase growth hormone. Unlike GH drugs, they are cheaper, do not have the same side effects and serious restrictions on their use. Young athletes training in the gym are not recommended to use GH drugs to pump up muscles. It is better for them to choose stimulants for the synthesis of their own somatotropin.

Thus, drugs that stimulate growth hormone include:

1. Arginine – L-arginine. A conditionally replaceable amino acid used in sports nutrition as a nitrogen donor. It creates favorable conditions in the body for the synthesis of growth hormone.
2. DAA – D-aspartic acid. Its functions include stimulating the production of various hormones, including growth hormone, follicle-stimulating hormone and luteinizing hormone.
3. GABA – gamma-aminobutyric acid. A non-proteinogenic amino acid that acts as an inhibitory neurotransmitter in the nervous system. Improves sleep quality, which indirectly affects the production of growth hormone.

Also read:

1. “What you need to know about the benefits and harms of arginine: is there a difference with L-arginine.”
2. “D-aspartic acid in bodybuilding | How is it different from L-aspartic acid and how is it related to asparkam.”
3. “GABA (aminobutyric acid) – what it is and why it is important not only for athletes.”

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