Over the last few decades, doctors have incorporated the off-label use of clomiphene citrate for the treatment of secondary hypogonadism in men. The primary reason for this therapy is due to the off-label effect of clomiphene citrate, has been found to increase luteinizing hormone, follicle stimulating hormone, and testosterone in men. However, clomiphene citrate failed to produce reliable increase in sperm counts. Since its approval by the Federal Drug Administration (FDA) in 1967, clomiphene citrate has been used extensively for inducing ovulation in women. Originally, clomiphene citrate was marketed as Clomid, and was used as treatment for women trying to get pregnant who were experiencing ovulatory dysfunction.
Enclomiphene citrate, is the updated version and trans-isomer (similar compound with different chemical configurations, where the functional groups show up on the opposite side of the double bond) of clomiphene citrate, which today is being used as a new treatment for hypogonadal men. Whereas clomiphene citrate is made up of a combination of isomers, enclomiphene citrate is characterized by one isomer with complete estrogen antagonism. Enclomiphene citrate contains zuclomiphene citrate, which is believed to cause similar side effects that are associated with clomiphene citrate. Enclomiphene citrate mainly deals with increasing the production of follicle stimulating hormone and luteinizing hormones. Currently, enclomiphene citrate is marketed under the trade name Androxal.
Enclomiphene citrate is often suggested as treatment dysfunctional hypothalamus and pituitary function, which occurs in some males who are suffering from secondary hypogonadism. In these cases, the common factors include low levels of total testosterone and low gonadotropin levels. Treatment for increasing gonadotropin and testosterone levels generally includes an anti-estrogen or an aromatase inhibitor. However, if the secondary hypogonadism has been shown to be caused by a congenital gonadotropin releasing hormone deficiency, craniopharingiomas (rare brain tumor that develops in the pituitary gland), haemochromatsis (a buildup of iron in the blood that results in damage to the heart, joints, liver and pancreas) or pituitary tumors, enclomiphine citrate is not recommended.
In males with hypogonadism the following symptoms are usually present:
In the United States, the occurrence of male hypogonadism affects almost 40% of men, with greater frequency in the ageing population. Additionally, a sizeable population study in the United States, revealed that almost 6% of men between the ages of 30-80, showed signs of symptomatic hypogonadism. Many recent studies concur that deficiency in testosterone influences men’s overall health and wellness. For instance, male hypogonadism has been found to have a direct correlation to cardiovascular mortality, depression, frailty, metabolic syndrome, osteoporosis and non-insulin dependent diabetes.
The effects of lasting secondary hypogonadism are acknowledged health issues associated with ageing. Moreover, in males, secondary hypogonadism has been linked with insulin resistance and/or type II diabetes, metabolic syndrome, obesity and greater mortality. Numerous research studies have revealed that free testosterone and total serum levels in obese men are considerably lower than aged-equivalent healthy males in the control groups. An ageing study conducted in Europe, revealed that obesity and ageing are considerable risk factors for secondary hypogonadism in men, while the frequency of primary hypogonadism was related to age.
Testosterone replacement therapy (TRT) is the most common treatment for male hypogonadism and reduces the symptoms as well as normalize serum testosterone. However, men undergoing TRT who desire to have children have difficulties due to the fact that exogenous testosterone lowers serum gonadotropins, impacts normal spermatogenesis and stifles the production of intra-testicular testosterone.
The most common protocol in TRT therapy includes adding human chorionic gonadotropin hormone when coming off exogenous testosterone. Enclomiphene citrate can also be used as a substitute for HCG in TRT. More recent research studies point to the fact that enclomiphene citrate may actually provide better results than HCG for men undergoing TRT.
The release of reproductive hormones in both males and females is predominantly controlled by biological rhythms. Clinical research has revealed that consistent and continuous, periodic administration of gonadotropin releasing hormone, plays a pivotal role in the influence both fertility and puberty in gonadotropin releasing hormone deficient males who do not begin puberty naturally. Those individuals with hypothalamic deficiency have allowed researchers to better understand the feedback control of sex steroids at the stage of the hypothalamus and the pituitary, in addition to the identification of other serious hormone health concerns. Research has shown that in the hypothalamus, pituitary and testes, there is a distinct rhythm that occurs during the production of testosterone in male testes. In general, healthy young males experienced a peak in testosterone production in the morning, lower levels of production during the early evening, and a steady boost towards the morning peak levels. Conversely, ageing males (over 40) showed a decrease in testosterone levels as a whole, with diminishing levels of circadian androgen. Medical researchers believe that the lessening levels of circadian androgen are due the feedback interference and feed-forward control mechanisms. Moreover, additional factors could also contribute to lower androgen levels, as demonstrated by the suppressive effects of a standard glucose tolerance test on serum testosterone levels.
A 2014 research study was conducted in order to evaluate the differences between enclomiphene citrate and transdermal testosterone as treatment for men with secondary hypogonadism. The objective of the study was to determine which drug would yield the best results for improving serum testosterone and luteinizing hormones after six weeks of treatment. In general, the majority of studies using transdermal testosterone, the evaluation of total testosterone serum levels relies on the field of pharmacology called pharmacokinetics. Pharmacokinetics deals with the drugs movement in the body. Alternatively, studies with enclomiphene citrate evaluate the drugs effect on total testosterone serum levels by pharmacodynamics, or the drugs effect on the body.
During the second phase of the study, 52 men were assessed on whether enclomiphene would increase serum testosterone levels. The subjects with low total testosterone levels, showed a significantly higher serum total testosterone levels after only 2 weeks of enclomiphene treatment. The elevated levels of testosterone were followed by similar increases in follicle stimulating hormone and luteinizing hormone. Other analogous studies have also confirmed that enclomiphene raised total testosterone without increasing dihydrotestosterone (DHT) and improved sperm counts as a result of elevated endogenous levels of follicle stimulating hormone and luteinizing hormone.
The transdermal testosterone subject group differed from the enclomiphene group in that subjects who were given the transdermal testosterone gel, showed reduced levels of luteinizing hormone, follicle stimulating hormone as well as sperm counts.
As previously mentioned in our HCG article, on March 23, 2020, the FDA will be reclassifying HCG as a biologic. Florida Alternative Medicine and Weight Loss (FAM) will still be able to offer its patients HCG. FAM has the proper compounding biologics license which many other TRT clinics do not. Because we keep up with the latest research, we strive to be the first to deliver the most effective formulations available and feel that our patients will receive better results with Enclomiphene Citrate than with HCG.