madman
Super Moderator
After nearly 15 years of providing clomiphene citrate as an initial alternative approach to testosterone replacement therapy for hypogonadism, I am releasing the article "The Application of Clomiphene citrate in the Management of Hypogonadism Secondary to Concussive and Subconcussive Brain Traumas". In our more than 900 patients using clomiphene citrate, there are decenable causes for Testosterone insufficiencies that can be reversed by the stimulation and not suppression of the Hypothalamic Pituitary Gonadal axis. You have heard pieces of the argument in a number of my past and present presentations. After 14 months of working on this paper using clinical data from patients and many medical articles, I present to you an enhanced vision of causation for the different forms of hypogonadism. Yes, it is simpler to just give testosterone whenever it is found to be insufficient, but in doing so you deny the patient a potential of regenerating their own production. Your comments are important to me and the work I do with our Military.
Thank you.
Mark L. Gordon, MD
Introduction
The Millennium Health Centers (MHC) have been at the forefront of innovations for the assessment and treatment of the causation for symptoms associated with traumatic and non-traumatic events. These traumatic events might be represented by a road-side bomb (IED), blast wave trauma (over-pressure), roar of jet engines, repetitive gun fire, motor vehicle accidents, blunt head trauma, subconcussive sports injuries, chronic emotional stress, chemotherapy, medication, or a prolonged surgical procedure (1,2).
Each of the aforementioned traumas, seemingly unique, nonetheless have a common thread that ties them together, that is, inflammation or more precisely neuroinflammation (3). No matter how minimal an injury is perceived to have been, there is an incremental effect with each subsequent trauma that can ultimately equate to the impact of one major traumatic event (4).
The analogy that ten dimes make up a dollar clearly represents the fact that you can have many subconcussive traumas or one major concussive trauma that creates the same damaging effects. The football player who experiences repetitive subconcussive impacts as well as the breacher who has been exposed to numerous blast waves will both succumb, over time, to the development of symptoms affecting their neuropsychiatric well-being and cognition (5).
In many of those that become symptomatic, the presence of depression, anxiety, panic attacks, bi-polar disorder, obsessive compulsive behavior, emotional volatility, anger, aggression, fatigue, and loss of libido are commonly associated with one or more hormonal deficiencies and neuroinflammation (6).
It has been the operational philosophy of the MHC, based upon clinical experience and the scientific literature, that neuroinflammation is precipitated by trauma and can be associated with cerebral contusion, shearing of axons, and microvascular disruption (7). In an acute traumatic scenario, inflammation induced by trauma is short lived resolving with minimal to no after-effects. These individuals, in essence, have completely recovered and any vestige of neuropsychiatric symptoms have abated along with the reestablishment of a healthy neuro permissive environment (8).
Unfortunately, this is not always the case in our soldiers or professional athletes who are exposed to repetitive subconcussive and concussive traumas that tend to prolong the inflammatory process and create a chronic traumatic scenario (9). In these individuals, their neuropsychiatric symptoms tend to be progressive while paralleling the magnitude of their neuroinflammation.
As neuroinflammation continues, there are alterations in biochemical processes in the production of important neuropeptides and proteins as well as in the recognition of these messengers by their receptors .The important neurotransmitters GABA, Dopamine, Serotonin, Norepinephrine, and Glutamine that are responsible for regulation of neuroendocrine functions in the hypothalamus are diminished (10).
The presence of neuroinflammation interrupts the ability of these neurotransmitters to influence the hypothalamic induction and release of gonadotropic releasing hormone (GnRH) (11). Thereby diminishing the chemical signal to the pituitary for the release of FSH and LH, which ultimately causes the loss of gonadal production of testosterone, estrogens, and progesterone (12). Although this article is not specifically about traumatic brain injury, it is about the use of clomiphene citrate to repair the effects of trauma-induced neuroinflammation that causes the loss of not only testosterone and estradiol, but the regulation of steroidogenesis through adequate production of luteinizing hormone (13).
*Hypogonadism – Identifying the Causation.
*Primary Hypogonadism
*Secondary Hypogonadism
*Hypothalamic Hypogonadism: The role of Glia in GnRH induction.
*Rationalization for Treatment with Clomiphene or Enclomiphene
How Clomiphene Citrate Works
Clomiphene citrate (CC), classified as a selective estrogen receptor modulator (SERM), functions as an antagonist at estrogen receptors (ER) situated within the hypothalamus. This antagonistic interaction disrupts the formation of receptor-hormone complexes, leading to the liberation of GnRH. Gonadotropin releasing hormone, subsequently, stimulates the anterior pituitary gland to increase secretion of both LH and FSH (41,42,43)
What about Enclomiphene citrate?
What we refer to as Clomiphene citrate is really a mixture of two different isomers of the drug, Zuclomiphene and Enclomiphene. It is believed that the mixture of these two isomers can account for some of the side effect attributable to the clomiphene form such as hot flashes, mood swings, and headaches (46,47). Also, Clomiphene might not be effective in all cases of hypogonadism in men and can have adverse effects on the endometrium in women (48).
It is believed that the pure Enclomiphene citrate isomer may have fewer side effects than clomiphene citrate and it may be more effective than clomiphene citrate at increasing testosterone production in men with hypogonadism. Additionally, levels of estradiol are lower than that in the clomiphene group (49). But there are those individuals using Enclomiphene that do not respond as well as in others, which is the same case with Clomiphene citrate (50).
What is extremely important in evaluating the reported side effects of clomiphene citrate is the frequency of dosing when used in male patients. As you will read in, “The Pulsatile use of Clomiphene citrate” and “The Risks of Clomiphene citrate”, ocular, mood, and estradiol elevation are rare occurrences.
Nonetheless, the Millennium recommends that enclomiphene be dosed at either 12.5mg or 25mg every 72 hrs at bedtime for optimal benefits with minimal side effects.
*Clomiphene and Primary Hypogonadism
1i - Clomiphene and Compensatory Hypogonadism
1j - Clomiphene and Secondary Pituitary Hypogonadism
1k - Hypothalamic Hypogonadism and Clomiphene
1l - The Pulsatile production of GnRH with Clomiphene citrate.
2a - Risks and Benefits of Clomiphene citrate
2b - Ophthalmologic Effects of Clomiphene Citrate
2c – The Liver, Clomiphene, and Suppression of Hepatic IGF-1 Production
2d. Benefits of Clomiphene with Atypical Cluster Headaches
*Clomiphene citrate and Testicular Cancer
Discussion
Clomiphene citrate, originally developed and approved for female infertility in the 1960s, began to be explored for the treatment of male hypogonadism in the late 1970s and early 1980s. This off-label use leverages clomiphene’s ability to block estrogen receptors in the hypothalamus, leading to an increase in gonadotropin-releasing hormone secretion. Consequently, this stimulates the release of luteinizing hormone and follicle-stimulating hormone from the pituitary gland, which in turn promotes testosterone production in the testes.
The benefits of using clomiphene citrate or enclomiphene citrate for male hypogonadism include its ability to improve testosterone levels without the negative feedback suppression of spermatogenesis often seen with exogenous testosterone therapy. Studies have shown significant improvements in serum testosterone levels, sperm count, and motility, which are crucial for men with hypogonadotropic hypogonadism who are seeking fertility treatments.
Although the majority of articles published on clomiphene and enclomiphene citrate show its low or rare occurrence of side-effects, it is important to know that they do exist. These potential side-effects include visual disturbances, gynecomastia, mood swings, and an increased risk of venous thromboembolism (testosterone related) (99). Additionally, concerns about the long-term safety of clomiphene, particularly regarding its impact on testicular function and the potential risk of cancer, necessitate regular monitoring and further research.
Overall, while clomiphene citrate and enclomiphene citrate present beneficial alternatives for managing male hypogonadism and preserving fertility, careful consideration of the risks and close medical supervision are essential for optimizing treatment outcomes.
The Millennium Health Centers has studied the safety and efficacy of clomiphene citrate for more than 15 years. To date, the Millennium has introduced over 900 patients to a pulsatile use of 25 mg to 50 mg of clomiphene citrate at bedtime for months to 9 years of use.
At present, we have 5 patients that are using enclomiphene due to initial side-effects from clomiphene citrate that included emotional volatility and fatigue. These individuals were started on 12.5mg of enclomiphene every 48 to 72 hours and monitored for efficacy as well as side effects.
Overall, once a patient is started on clomiphene citrate 50mg every 72 hours, we perform a follow-up blood test at about 90 days after initiation of treatment. This includes free (fT) and total testosterone (tT), DHT, SHBG, DHEA-s, estradiol (E2), and luteinizing hormone (LH). What we are looking for is an elevation in LH that drives an increase in fT. If LH does not rise significantly we will increase the dosing frequency of clomiphene to every 48 hours. If there is a rise in LH with a corresponding elevation in fT, we continue on this protocol. In the event that the LH rises, and fT does not then based upon the patient’s history the issue might be an NSAID (ibuprofen/ Naproxen) for which we will increase the dosing frequency to every night for 30 days. If there is a response with production of free testosterone then the dosing is reduced to every 48 hours. If not, then another protocol for testosterone replenishment is initiated.
Thank you.
Mark L. Gordon, MD
Introduction
The Millennium Health Centers (MHC) have been at the forefront of innovations for the assessment and treatment of the causation for symptoms associated with traumatic and non-traumatic events. These traumatic events might be represented by a road-side bomb (IED), blast wave trauma (over-pressure), roar of jet engines, repetitive gun fire, motor vehicle accidents, blunt head trauma, subconcussive sports injuries, chronic emotional stress, chemotherapy, medication, or a prolonged surgical procedure (1,2).
Each of the aforementioned traumas, seemingly unique, nonetheless have a common thread that ties them together, that is, inflammation or more precisely neuroinflammation (3). No matter how minimal an injury is perceived to have been, there is an incremental effect with each subsequent trauma that can ultimately equate to the impact of one major traumatic event (4).
The analogy that ten dimes make up a dollar clearly represents the fact that you can have many subconcussive traumas or one major concussive trauma that creates the same damaging effects. The football player who experiences repetitive subconcussive impacts as well as the breacher who has been exposed to numerous blast waves will both succumb, over time, to the development of symptoms affecting their neuropsychiatric well-being and cognition (5).
In many of those that become symptomatic, the presence of depression, anxiety, panic attacks, bi-polar disorder, obsessive compulsive behavior, emotional volatility, anger, aggression, fatigue, and loss of libido are commonly associated with one or more hormonal deficiencies and neuroinflammation (6).
It has been the operational philosophy of the MHC, based upon clinical experience and the scientific literature, that neuroinflammation is precipitated by trauma and can be associated with cerebral contusion, shearing of axons, and microvascular disruption (7). In an acute traumatic scenario, inflammation induced by trauma is short lived resolving with minimal to no after-effects. These individuals, in essence, have completely recovered and any vestige of neuropsychiatric symptoms have abated along with the reestablishment of a healthy neuro permissive environment (8).
Unfortunately, this is not always the case in our soldiers or professional athletes who are exposed to repetitive subconcussive and concussive traumas that tend to prolong the inflammatory process and create a chronic traumatic scenario (9). In these individuals, their neuropsychiatric symptoms tend to be progressive while paralleling the magnitude of their neuroinflammation.
As neuroinflammation continues, there are alterations in biochemical processes in the production of important neuropeptides and proteins as well as in the recognition of these messengers by their receptors .The important neurotransmitters GABA, Dopamine, Serotonin, Norepinephrine, and Glutamine that are responsible for regulation of neuroendocrine functions in the hypothalamus are diminished (10).
The presence of neuroinflammation interrupts the ability of these neurotransmitters to influence the hypothalamic induction and release of gonadotropic releasing hormone (GnRH) (11). Thereby diminishing the chemical signal to the pituitary for the release of FSH and LH, which ultimately causes the loss of gonadal production of testosterone, estrogens, and progesterone (12). Although this article is not specifically about traumatic brain injury, it is about the use of clomiphene citrate to repair the effects of trauma-induced neuroinflammation that causes the loss of not only testosterone and estradiol, but the regulation of steroidogenesis through adequate production of luteinizing hormone (13).
*Hypogonadism – Identifying the Causation.
*Primary Hypogonadism
*Secondary Hypogonadism
*Hypothalamic Hypogonadism: The role of Glia in GnRH induction.
*Rationalization for Treatment with Clomiphene or Enclomiphene
How Clomiphene Citrate Works
Clomiphene citrate (CC), classified as a selective estrogen receptor modulator (SERM), functions as an antagonist at estrogen receptors (ER) situated within the hypothalamus. This antagonistic interaction disrupts the formation of receptor-hormone complexes, leading to the liberation of GnRH. Gonadotropin releasing hormone, subsequently, stimulates the anterior pituitary gland to increase secretion of both LH and FSH (41,42,43)
What about Enclomiphene citrate?
What we refer to as Clomiphene citrate is really a mixture of two different isomers of the drug, Zuclomiphene and Enclomiphene. It is believed that the mixture of these two isomers can account for some of the side effect attributable to the clomiphene form such as hot flashes, mood swings, and headaches (46,47). Also, Clomiphene might not be effective in all cases of hypogonadism in men and can have adverse effects on the endometrium in women (48).
It is believed that the pure Enclomiphene citrate isomer may have fewer side effects than clomiphene citrate and it may be more effective than clomiphene citrate at increasing testosterone production in men with hypogonadism. Additionally, levels of estradiol are lower than that in the clomiphene group (49). But there are those individuals using Enclomiphene that do not respond as well as in others, which is the same case with Clomiphene citrate (50).
What is extremely important in evaluating the reported side effects of clomiphene citrate is the frequency of dosing when used in male patients. As you will read in, “The Pulsatile use of Clomiphene citrate” and “The Risks of Clomiphene citrate”, ocular, mood, and estradiol elevation are rare occurrences.
Nonetheless, the Millennium recommends that enclomiphene be dosed at either 12.5mg or 25mg every 72 hrs at bedtime for optimal benefits with minimal side effects.
*Clomiphene and Primary Hypogonadism
1i - Clomiphene and Compensatory Hypogonadism
1j - Clomiphene and Secondary Pituitary Hypogonadism
1k - Hypothalamic Hypogonadism and Clomiphene
1l - The Pulsatile production of GnRH with Clomiphene citrate.
2a - Risks and Benefits of Clomiphene citrate
2b - Ophthalmologic Effects of Clomiphene Citrate
2c – The Liver, Clomiphene, and Suppression of Hepatic IGF-1 Production
2d. Benefits of Clomiphene with Atypical Cluster Headaches
*Clomiphene citrate and Testicular Cancer
Discussion
Clomiphene citrate, originally developed and approved for female infertility in the 1960s, began to be explored for the treatment of male hypogonadism in the late 1970s and early 1980s. This off-label use leverages clomiphene’s ability to block estrogen receptors in the hypothalamus, leading to an increase in gonadotropin-releasing hormone secretion. Consequently, this stimulates the release of luteinizing hormone and follicle-stimulating hormone from the pituitary gland, which in turn promotes testosterone production in the testes.
The benefits of using clomiphene citrate or enclomiphene citrate for male hypogonadism include its ability to improve testosterone levels without the negative feedback suppression of spermatogenesis often seen with exogenous testosterone therapy. Studies have shown significant improvements in serum testosterone levels, sperm count, and motility, which are crucial for men with hypogonadotropic hypogonadism who are seeking fertility treatments.
Although the majority of articles published on clomiphene and enclomiphene citrate show its low or rare occurrence of side-effects, it is important to know that they do exist. These potential side-effects include visual disturbances, gynecomastia, mood swings, and an increased risk of venous thromboembolism (testosterone related) (99). Additionally, concerns about the long-term safety of clomiphene, particularly regarding its impact on testicular function and the potential risk of cancer, necessitate regular monitoring and further research.
Overall, while clomiphene citrate and enclomiphene citrate present beneficial alternatives for managing male hypogonadism and preserving fertility, careful consideration of the risks and close medical supervision are essential for optimizing treatment outcomes.
The Millennium Health Centers has studied the safety and efficacy of clomiphene citrate for more than 15 years. To date, the Millennium has introduced over 900 patients to a pulsatile use of 25 mg to 50 mg of clomiphene citrate at bedtime for months to 9 years of use.
At present, we have 5 patients that are using enclomiphene due to initial side-effects from clomiphene citrate that included emotional volatility and fatigue. These individuals were started on 12.5mg of enclomiphene every 48 to 72 hours and monitored for efficacy as well as side effects.
Overall, once a patient is started on clomiphene citrate 50mg every 72 hours, we perform a follow-up blood test at about 90 days after initiation of treatment. This includes free (fT) and total testosterone (tT), DHT, SHBG, DHEA-s, estradiol (E2), and luteinizing hormone (LH). What we are looking for is an elevation in LH that drives an increase in fT. If LH does not rise significantly we will increase the dosing frequency of clomiphene to every 48 hours. If there is a rise in LH with a corresponding elevation in fT, we continue on this protocol. In the event that the LH rises, and fT does not then based upon the patient’s history the issue might be an NSAID (ibuprofen/ Naproxen) for which we will increase the dosing frequency to every night for 30 days. If there is a response with production of free testosterone then the dosing is reduced to every 48 hours. If not, then another protocol for testosterone replenishment is initiated.
