Most often, SERMs makes sense to use in the case of hypogonadotropic secondary hypogonadism, which occurs very often. The main problem is insufficient secretion of LH and FSH levels, so the main goal of this therapy is to increase the secretion of LH and FSH, which in turn should increase testosterone levels. For these purposes, joint therapy of clomiphene citrate, or enclomiphene (tamoxifen is better not to use for a long time due to the high risk of side effects) and anastrozole is best suited.

The main goal of clomiphene therapy is to maintain LH at higher values. It should be understood that clomiphene therapy is not curative, it does not "cure" the testicles or pituitary gland, so that later more hormones are released for a long time than before the start of therapy. Clomiphene increases LH only for as long as it works.

WHAT ARE ANTIESTROGENS (SERMS)

Antiestrogens, or estrogen receptor modulators (Selective Estrogen Receptor Modulators, SERMs), are a group of drugs that act on estrogen receptors in the body. They can either block or activate these receptors depending on the type of tissue. SERMs act by binding to estrogen receptors, but their effect depends on the type of tissue: in some tissues (for example, bones and the cardiovascular system), SERMs can act as estrogens, contributing to their positive effects. In other tissues (e.g. mammary glands and endometrium) they block the action of estrogens, preventing their stimulating effect, which can promote the growth of cancer cells or other negative consequences. When used by men, SERMs stimulate the production of hormones that increase sperm production by blocking estrogen receptors in the hypothalamus, which increases the secretion of gonadotropins. For recreational purposes, especially in bodybuilding, SERMs are used to prevent or treat gynecomastia caused by the use of anabolic steroids as well as for post-course therapy to restore normal testosterone levels after a steroid cycle.

MECHANISM OF ACTION

Antiestrogens, or estrogen Receptor modulators can increase testosterone levels in men through several mechanisms. The main mechanism of action is associated with their effect on the hypothalamic-pituitary-gonadal axis (HPT axis). Estrogen receptor modulators are effective for increasing testosterone levels in men through blocking estrogen receptors in the hypothalamus, which leads to increased secretion of GnRH, LH and FSH. This stimulates the testicles to produce more testosterone. Such drugs are used both in medicine and in sports practice to restore and maintain normal testosterone levels. 

The Hypothalamic-Pituitary-Gonadal Axis (HPT axis) 

The HPT axis includes three main components:

  • Hypothalamus: Produces gonadotropin-releasing hormone (GnRH). 
  • Pituitary gland: In response to GnRH, it produces luteinizing hormone (LH) and follicle stimulating hormone (FSH). 
  • Testicles: In response to LH and FSH, testosterone and sperm are produced. Blocking of Estrogen Receptors in the Hypothalamus 

The hypothalamus has estrogen receptors, which, when bound to estrogens, can suppress GnRH secretion.

SERMs (for example, clomiphene) 

→ block estrogen receptors in the hypothalamus, preventing the negative feedback of estrogens.

→ This leads to an increase in GnRH secretion. 

→ Increased GnRH secretion stimulates the pituitary gland to produce more LH and FSH. 

→ An increase in LH levels stimulates Leydig cells in the testicles to increase testosterone production. 

By activating this hormone chain, SERMs can be used to treat hypogonadism, a condition in which the body does not produce enough testosterone and also increases testosterone above normal values in healthy men who want to increase its level without resorting to the use of testosterone.

WHAT ARE THE TYPES OF SERMS

Now there are four main antiestrogen drugs that have proven their effectiveness and are most often used in medicine:

  • Clomiphene,
  • Enclomiphene,
  • Tamoxifen,
  • Toremifene.

To increase testosterone levels, clomiphene or enclomiphene citrate is more suitable, since this drug is selective and blocks only receptors in the hypothalamus, which is actually necessary to increase testosterone levels. At the same time, toremifene and tamoxifen are less selective drugs and work on estrogen receptors throughout the body, and this can cause unnecessary side effects. Studies show that clomiphene citrate in a dosage of 25 mg once a day for 12 weeks will increase testosterone levels by an average of 80-100% [1]. If the testosterone level was about 300-350 ng/dl (10-12 nmol/L) before the start of therapy, then after it increased to 570 ng/ dl (19 nmol/L).

EFFECTIVENESS

At the time of therapy, the testosterone level always rises, after the withdrawal of drugs, it may still be higher than the initial values. With a testosterone level of 8-12 nmol / l, the increase in testosterone is often up to 20-25 nmol / l, while after discontinuation of medication, the level will not fall to the current values of 8-12 nmol / l, but is often fixed at 13-15 nmol / l. Of course, this is a positive effect that persists for a long time. However, the level of 20-25 nmol/l can be kept only directly during therapy.

At the same time, the testosterone level of about 13-15 nmol / l will always be not high enough to improve the quality of life and level out all the side effects of reduced testosterone. In fact, a person still remains in a testosterone deficiency, although he received a small plus of 2-3 nmol / L.

From all this, we can conclude that in order to fully improve the quality of life and improve the condition of the body, therapy should be on an ongoing basis. In fact, this therapy is an optimal alternative to hormone replacement therapy and existence on testosterone deficiency.

TREATMENT OF HYPOGONADISM

Hypogonadism is a pathological process provoked by a lack of male sex hormones, in particular, testosterone, which entails a large number of consequences for the male body. As you know, with reduced testosterone, many body functions suffer, such as fertility, and fatigue appears, muscle mass decreases, the percentage of fat increases, depression develops, erectile dysfunction. Most often, the level of testosterone in a man's body begins to fall after 30 years, but the situation can be aggravated by obesity, diabetes and vascular diseases.

One of the treatment options for hypogonadism is the use of drugs of the SERMs class. Clomiphene or its newer variant, endocmiphene citrate, is usually preferred for these purposes. Tamoxifen is less commonly used. During clinical trials, enclomiphene was tested on men with secondary hypogonadism [2]. As a result of the research, it turned out that enclomiphene citrate increased the level of testosterone, the level of follicle-stimulating hormone and luteinizing hormone, important for reproductive health, while the number of spermatozoa did not decrease.

In men with secondary hypogonadotropic hypogonadism, an increase in LH and FSH improves testosterone levels and sperm motility. Men with secondary hypogonadotropic hypogonadism have abnormally low testosterone levels due to low normal levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH). The biological role of these hormones is to stimulate the endogenous production of testosterone by the testes.

Treatment with enclomiphene works differently than traditional testosterone replacement therapy, which replaces testosterone using an exogenous source and has a number of advantages – such as improving, rather than reducing fertility, stimulating the production of enodogenic testosterone, rather than introducing exogenous, which ultimately does not lead to suppression of the production of own testosterone, as well as the absence of negative effects on cholesterol and increased hematocrit levels.

Moreover, testosterone levels in those who take enclomiphene remain elevated even after discontinuation of treatment. The efficacy and safety of encomiphene citrate in the treatment of male hypogonadism have been studied in several clinical trials [3]. One such study, published in the Journal of Clinical Endocrinology and Metabolism in 2014, showed that encomiphene citrate improves testosterone levels and sperm parameters in men with hypogonadism.

Another study published in the Journal of Sexual Medicine in 2016 [4] also showed that encomiphene citrate improves testosterone levels and sperm production in men with hypogonadism without significant side effects. Although encomiphene citrate is not a first-line drug for the treatment of male hypogonadism, it may be an effective alternative treatment option for men who are unable or unwilling to use testosterone.

THERAPY TO INCREASE TESTOSTERONE LEVELS

Enclomiphene acts as an antiestrogen, which means it helps block the action of estrogens in the body. This can lead to an increase in testosterone levels not only for the treatment of low testosterone levels, but also can increase its level beyond the limits of the norm, which can give some advantages in terms of accelerated recovery after training and an increase in the psycho-emotional background. An increase in testosterone levels can also lead to increased athletic performance, increased energy, some muscle mass, and even greater self-confidence.

If you use enclomiphene for these purposes, then during the reception you will need to monitor the level of hormones such as estradiol and SHBG. A high level of testosterone will lead to an increase in these hormones, which can create both undesirable side effects and nullify all the benefits of increased testosterone.

The study showed that a single dose of 12.5 mg of enclomiphene increased the testosterone level from 217.2 ng / dl to 471.9 ng / dl and allowed to keep the concentration of elevated testosterone for quite a long time.

The efficacy and safety of enclomiphenecitrate in treating male hypogonadism have been studied in several clinical trials. One such trial, published in the Journal of Clinical Endocrinology & Metabolism in 2014, showed that enclomiphene citrate improvedtestosterone levels and semen parameters in men with hypogonadism.

Some studies show that enclomiphene may be effective for improving athletic performance. For example, one study published in the International Journal of Sports Medicine in the International Journal of Sports Medicine showed that the use of enclomiphene in men improved results in weightlifting. Of course, taking enclomiphene will not replace a full cycle of anabolic steroids in any way, but this may be an intermediate step when a novice athlete is still afraid to use AS, but already needs accelerated recovery or wants to accelerate progress a little beyond the values of a "natural athlete".

POST-CYCLE THERAPY 

SERMs can be used as a drug for post-course therapy (PCT) after taking anabolic steroids. This is the effect that is of the greatest interest to fans of PEDs. Anabolic steroids, such as testosterone, can suppress the body's natural testosterone production. At the end of the cycle of taking anabolic steroids, the testosterone level in the body can be very low, which can lead to undesirable effects, such as loss of muscle mass, a drop in the psycho-emotional background and a decrease in sexual function. Post-course therapy is aimed at restoring the natural production of testosterone in the body. SERMs can be an effective drugs for PCT, as it helps restore natural testosterone production by stimulating the hypothalamus-pituitary-testicular axis.

HOW IT WORKS 

While using SERMs, you should do blood tests for total testosterone levels and compare it with your well-being. Usually, the initial dose of enclomiphene citrate can be 12.5 mg per day. After a few weeks, you can do a blood test and determine your testosterone level. If you feel a surge of energy and improved recovery after training, increased libido and motivation - you can leave this level and dosage. If the level of testosterone is insufficient, then you can increase the dosage, for example, to 25 mg and after a few weeks do a control blood test again. 

Each time, the level of testosterone should be correlated with your overall well-being. The main idea is to achieve an optimal level of libido, mood and energy while choosing the right dosage. This is usually much easier to do under the supervision of an experienced specialist. During the use of SERMs, increased testosterone levels can cause some difficulties, especially if its level becomes higher than physiological values. In this case, you have to deal with the growth of other hormones, the level of which increases with the growth of testosterone.

ESTRADIOL CONTROL

Along with an increase in testosterone levels, the level of estradiol may increase, which causes side effects in the form of fluid retention, increased pressure, female-type fat deposition, gynecomastia, decreased libido, erectile dysfunction and deterioration of the psychoemotional state of a man. And most importantly, an increase in estradiol contributes to an increase in SHBG, which leads to a decrease in the level of free testosterone. An increase in SHBG is often attributed as a side effect of antiestrogens, but this is a side effect of an increase in estradiol, which is why it is necessary to reduce and control the level of estradiol. Anastrozole (or any other aromatase inhibitor, such as letrozole or exemestane) is used for this. Anastrozole controls the level of estradiol, completely leveling all the side effects of increasing estradiol.

Accordingly, this therapy increases the level of total testosterone, and free, due to the control of SHBG through the control of estradiol. But the most important point should be understood – a decrease in testosterone levels is the norm with growing up or aging of the body, so this therapy is not curative, it is supportive. This means that at the time of taking the drugs, the testosterone level will increase, and after the drugs are discontinued, it will return to its original values.

After 10 days of using enclomiphene, take a blood test for estradiol. When increasing it, use aromatase inhibitors such as anastrazole. You should choose the dosage and reduce the level of estradiol to the middle of the norm. This should definitely be done, because elevated estradiol can create problems with your psycho-emotional state and also lower libido. If you have started to feel these phenomena when taking enclomiphene, then it's time to reduce your estradiol level. We recommend lowering to the middle of the reference values, but perhaps you will feel better with its other values. These parameters are determined individually. 

SHBG CONTROL

Sex hormone binding globulin (SHBG) is a liver–produced protein that combines with testosterone, dihydrotestosterone (DHT) and estradiol (estrogen) and transports them into the blood in a metabolically inactive form. Accordingly, SHBG makes testosterone common (bound), and biologically active testosterone should be in free form (not bound), it is he who performs all the functions.

Naturally, an increase in SHBG negatively affects therapy to increase testosterone levels. The growth of SHBG is indicated in the instructions for clomiphene, but this is not a specific side effect of clomiphene. The growth of SHBG occurs due to an increase in testosterone and, accordingly, estradiol. It is the growth of estradiol that leads to an increase in SHBG, and not clomiphene itself, to which this side effect is falsely attributed.

Also, when using enclomiphene, you should monitor the level of SHBG doing blood tests. If this protein goes beyond the highest limit of the norm, you should reduce it with the help of such a remedy as mesterolone. The fact is that a high level of this protein binds your testosterone and prevents it from freely circulating in the blood and joining androgen receptors, which also reduces the effectiveness of using enclomiphene if your goal is to raise testosterone levels above the normal limits. The dosage of proviron can be 25-50 mg per day, every other day or several times a week, depending on the level of SHBG in the blood. Higher dosages can negatively affect the level of endogenous testosterone.

[1] ncbi.nlm.nih.gov/pubmed/26176805
[2] fertstert.org/article/S0015-0282(14)00537-8/fulltext
[3] pubmed.ncbi.nlm.nih.gov/31216250
[4] academic.oup.com/jsm/article-abstract/10/6/1628/6940119