Testosterone

Maturitas. 2015 Nov 10. pii: S0378-5122(15)00808-7. doi: 10.1016/j.maturitas.2015.11.003. [Epub ahead of print]

EMAS position statement: Testosterone replacement therapy in the aging male‏.

Dimopoulou C1, Ceausu I2, Depypere H3, Lambrinoudaki I4, Mueck A5, Pérez-López FR6, Rees M7, van der Schouw YT8, Senturk LM9, Simonsini T10, Stevenson JC11, Stute P12, Goulis DG13.

Author information

Abstract

INTRODUCTION:

Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate.

AIMS:

The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks.

MATERIALS AND METHODS:

Literature review and consensus of expert opinion.

RESULTS AND CONCLUSIONS:

Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
KEYWORDS:

Aging male; Late-onset hypogonadism; Testosterone replacement

Male Hormone Restoration

The significance of testosterone for male sexual function is apparent to most Life Extension members. New insights, however, underscore the critical role testosterone plays in maintaining youthful neurological structure, alleviating depression, as well as inducing fat loss in those who are unable to reduce body weight regardless of diet and exercise.Recent studies have demonstrated that low testosterone in men is strongly associated with metabolic syndrome, type 2 diabetes, cardiovascular disease (Miner andSeftel 2007), and an almost 50% increase in mortality over aseven year period (Malkin et al 2010).Restoring testosterone to youthful ranges in middle-aged, obese men resulted in an increase in insulin sensitivity as well as a reduction in total cholesterol, fat mass, waist circumference and pro-inflammatory cytokines associated with atherosclerosis, diabetes, and the metabolic syndrome (Kapoor et al 2006, Malkin et al 2004, Heufelder et al 2009). Testosterone therapy also significantly improved erectile function (Fukui 2007) and improved functional capacity, or the ability to perform physical activity without severe duress, in men with heart failure (Malkin et al 2007).

Factors That Affect Testosterone Levels in Men

DHEA: Dehydroepiandrosterone (DHEA) is a hormone produced from cholesterol that then follows one of two pathways, both involving two-step enzymatic conversions, to yield either estrogens or testosterone. Thus, levels of DHEA can have a role in determining levels of estrogen and testosterone, though DHEA alone is seldom enough to sufficiently restore testosterone levels in aging men.

Aromatase: One of the most important factors that affect testosterone levels and the ratio between testosterone and estrogen is the aromatase enzyme. Aromatase converts testosterone to estrogen, further depleting free testosterone levels and increasing estrogen levels.

Obesity: Obesity and associated hyperinsulinemia suppress the action of luteinizing hormone (LH) in the testis, which can significantly reduce circulating testosterone levels (Mah and Wittert 2010), even in men under the age of 40 (Goncharov et al 2009). In addition, increased belly fat mass has been correlated with increased aromatase levels (Kalyani and Dobs 2007).

The vicious circle of low testosterone and obesity has been described as the hypogonadal/obesity cycle. In this cycle a low testosterone level results in increased abdominal fat, which in turn leads to increased aromatase activity. This enhances the conversion of testosterone to estrogens, which further reduces testosterone and increases the tendency toward abdominal fat (Cohen 1999, Tishova and Kalinchenko 2009).

Sex hormone-binding globulin (SHBG): Most testosterone circulating in the bloodstream is bound to either sex hormone-binding globulin (SHBG) (60%) or albumin (38%). Only a small fraction (2%) is unbound, or “free”. (Morales et al 2010).

Testosterone binds more tightly to SHBG than to albumin (Henry et al 2002). Consequently, only albumin-bound testosterone and free testosterone constitute the bioavailable forms of testosterone, which are accessible to target tissues and carry out the actions of the essential hormone (Morales et al 2010). Thus the bioavailability of testosterone is influenced by the level of SHBG.

Aging men experience both an increase in aromatase activity and an elevation in SHBG production. The net result is an increase in the ratio of estrogen to testosterone and a decrease in total and free testosterone levels (Lapauw et al 2008). As will be discussed below, it is crucial that this skewed ratio be balanced.

Liver Function: The liver is responsible for removing excess estrogen and SHBG, and any decrease in liver function could exacerbate hormonal imbalances and compromise healthy testosterone levels. Thus it is important that aging men also strive for optimal liver function.

Effects of Age-Related Decline in Testosterone Levels and Testosterone Therapy

The exact cause of the age-related reduction in testosterone levels is not known; it is probably the result of a combination of factors, including:

  • Increasing body fat (especially belly fat, and therefore increasing aromatase activity)
  • Oxidative damage to tissues responsible for the production of testosterone
  • Reduction in testicular testosterone synthesis
  • Declining levels of precursor molecules, such as DHEA
  • Nutritional status and liver function

The consequences of declining testosterone levels are striking.

Body Composition and Inflammation: Testosterone affects fat cell metabolism and fat loss in several ways: inhibiting fat storage by blocking a key enzyme called lipoprotein lipase that is necessary for the uptake of fat into the body’s fat cells; stimulating fat burning by increasing the number of specific receptors on the fat-cell membrane that release stored fat; increasing insulin sensitivity; enhancing growth of muscle fibers; and decreasing fat deposits. All of these effects promote lean body mass and reduce fat mass (Naharci et al 2007, Saad et al 2007). Placebo-controlled trials have demonstrated both significant increases in lean body mass and decreases in fat mass after varying courses of testosterone treatment in older men. In these studies, the greatest favorable changes in body composition were seen in participants with low baseline testosterone levels who received testosterone therapy for 12 months or longer (Allen et al 2007).

Emergent evidence suggests that maintaining youthful testosterone levels may help aging men avert a variety of inflammation-mediated disease, such as atherosclerosis and arthritis. By powerfully suppressing the activity an enzyme called 5-lipoxygenase, testosterone calms a fundamental pro-inflammatory pathway involved in the synthesis of signaling molecules known as leukotrienes (Pergola 2011). Leukotrienes are derivatives of the pro-inflammatory omega-6 fatty acid arachadonic acid; these molecules underlie much of the inflammatory development of asthma and bronchitis, and play a role in the pathology of cardiovascular disease and diabetes as well (Parlapiano 1999; Riccioni 2010).

In a study involving 184 men with low testosterone levels, 18 weeks of testosterone replacement therapy suppressed markers of inflammation including IL-1β, TNF-α, and C-reactive protein. Moreover, when compared to men who received a placebo control, men receiving testosterone replacement exhibited significant decreases in body weight, and BMI, and waist circumference (Kalinchenko 2010). The reduction in waist circumference indicates that testosterone reduces fat accumulation around the trunk of the body; this is particularly important since central fat mass and is strongly associated with increased susceptibility to inflammatory diseases and mortality (Coutinho 2011).

Musculoskeletal system: Bone integrity rests upon a balance between bone formation and bone resorption, which is controlled by multiple factors – including levels of estrogen and testosterone (Tok et al 2004, Valimaki et al 2004). In a clinical trial, testosterone increased bone mineral density in elderly men (Kenny et al 2010). Testosterone supplementation also has a positive effect on muscle metabolism and strength (Herbst 2004). This positive effect is undiminished with age.

Central Nervous System (CNS): Key to aging well is an optimistic outlook on life and the ability to engage in social and physical activity. However, low levels of testosterone have been associated with depression and other psychological disorders (Almeida et al 2008). To make matters worse for aging men, many conventional antidepressant medications suppress libido. Some experts suggest that testosterone therapy might reduce the need for the antidepressant medications entirely (Morley 2003, Carnhan and Perry 2004). Furthermore, testosterone treatment often increases feelings of well-being (Orengo et al 2004).

Cognition and alertness are also governed, in part, by testosterone’s effects on the CNS (Cherrier et al 2004). Low testosterone levels have been shown to correlate with lower scores on various psychometric tests (Moffat et al 2002), and similar effects have been reported in men undergoing androgen (male hormone) -deprivation therapy for prostate cancer (Salminen et al 2004).

Testosterone also acts as an endogenous neuroprotective agent, able to support neuron integrity against a variety of toxic insults, including oxidative stress (Ahlbom et al 2001, Pike et al 2009). In addition, testosterone has been shown to reduce β-amyloid accumulation, an important pathophysiologic factor in Alzheimer’s disease (Zhang et al 2004, Rosario and Pike 2008).

Testosterone improves neuron survival in brain regions vulnerable to neurodegenerative disease. This may explain the association of low testosterone levels in men with neurodegenerative diseases (Hogervorst et al 2004, Ready et al 2004). Studies demonstrate testosterone loss occurred 5 to 10 years prior to Alzheimer’s disease diagnosis. This suggests low testosterone is an important risk factor for Alzheimer’s disease (Moffat et al 2004; Rosario et al 2004). In a clinical study of 36 men recently diagnosed with Alzheimer’s disease, intramuscular testosterone treatment with 200mg every two weeks for up to one year was associated with improvement in both overall cognitive ability as well as critical visual-spatial function (Tan and Pu 2003).

Glucose and Lipid Metabolism: Testosterone also has been linked to metabolic function in the body. Specifically, studies have found inverse associations between the severity of metabolic syndrome, a condition characterized by excess abdominal fat, high cholesterol and high blood pressure that predisposes one for cardiovascular disease, and low plasma testosterone (Allan et al 2007, Saad et al 2008). A clinical study demonstrated that men with low testosterone levels are twice as insulin resistant as their counterparts with normal testosterone levels, and 90% met the criteria for the metabolic syndrome (Pitteloud et al 2005).

There also appears to be an inverse relationship between low testosterone levels and diabetes in men (Saad and Gooren 2009). Men with diabetes have lower testosterone levels compared to men without a history of diabetes (Stanworth and Jones 2009). The Third National Health and Nutrition survey of 1,413 men showed that men initially ranked in the lowest one-third with respect to either free or bioavailable testosterone were approximately four times more likely to have prevalent diabetes compared to those ranked in the top one-third, after researchers adjusted the results for age, race/ethnicity, and adiposity (Selvin et al 2007).

Cardiovascular Health: While conventional thought has been that because more men die from heart attacks than women, the disparity must have something to do with testosterone. However, research is pointing out that, in fact, the opposite may be true. Low levels of testosterone appear to be correlated with several cardiovascular risk factors, including atherogenic lipid profiles, insulin resistance, obesity, and a propensity to clot (Jones et al 2005). In addition, recent research is showing a clear relationship between low testosterone levels and increased incidence of cardiovascular disease and mortality in men (Malkin et al 2010).

Prostate health: Compared to younger men, older males have much more estradiol (a potent form of estrogen) than free testosterone circulating in the body. These rising estrogen and declining androgen levels are even more sharply defined in the prostate gland.

Estrogen levels increase significantly in the prostate with age, and estrogen levels in prostate gland tissues rise even higher in men who have BPH (Shibata Y et al 2000; Gann PH et al 1995; Krieg M et al 1993).

An important study indicates that testosterone is beneficial for the prostate gland in the vast majority of cases. In this study researchers looked at multiple parameters, including prostate volume, prostate-specific antigen (PSA) levels, and lower urinary tract symptoms in a group of men with low or low-normal testosterone levels (Pechersky et al 2002). Of the 207 men studied, 187 responded favorably to testosterone treatment.

The Importance of Hormone Testing

Millions of aging men have the dual conditions of low testosterone and high cholesterol. Conventional physicians prescribe cholesterol-lowering drugs to reduce cholesterol, when, in fact, the age-related rise in cholesterol might simply be the body’s way of increasing hormone levels by supplying the raw materials necessary to make hormones (Dzugan et al 2002). Researchers at the Life Extension Foundation have successfully treated high cholesterol levels through a program of bioidentical hormone replacement therapy.

Life Extension believes that comprehensive tests, along with a careful physical examination, are essential in detecting hormonal imbalances in aging men.

The so-called “normal” levels of testosterone in older men reflect population averages. The Life Extension Foundation believes that most aging men would prefer not to accept the loss of youthful vigor as normal. Instead, we suggest that a more valid optimal level for all men would be in the upper one-third of the reference range used for men aged 21 to 49 years, and that any supplementation should aim to restore hormone levels to that range. The current Life Extension optimal level of free testosterone is 20-25pg/mL.

When measuring testosterone levels, it is critical to determine the levels of both free and total testosterone to understand the cause of any observed symptoms of deficiency (Khosla et al 2008).

Because of difficulties with equipment standardization and inter-laboratory variability, it is recommended that physicians consistently use the same local laboratories and gain familiarity with the accuracy, precision and definition of normal values for the assays offered in their communities (Morales et al 2010).

It is also important to remember that blood levels of both free and total testosterone vary widely among individuals, making it difficult to establish a general baseline on which to prescribe a standardized treatment protocol. However, levels are quite consistent within individuals, and thus it is important that men have multiple tests over time to determine trends and individual thresholds for treatment.

Finally, during the initial testing, it is also imperative to test estrogen levels. Many of the unwanted effects of male hormone imbalance are actually caused by an elevated estrogen level relative to low testosterone levels (the estrogen/testosterone ratio). The Life Extension optimal level of estrogen (measured as estradiol) for aging men is 20-30pg/mL.

Estrogen Balance is Critical to Aging Men

A study published in the Journal of the American Medical Association (JAMA) measured blood estradiol in 501 men with chronic heart failure. Compared to men in the balanced estrogen quintile, men in the highest quintile (serum estradiol levels of 37.40 pg/mL or greater) were significantly (133%) more likely to die. Those in the lowest estradiol quintile (serum estradiol levels under 12.90 pg/mL) had a 317% increased death rate compared to the balanced group. The men in the balanced quintile—with the fewest deaths—had serum estradiol levels between 21.80 and 30.11 pg/mL (Ewa et al 2009). This is the ideal range that Life Extension has long recommended male members strive for.

An epidemic problem we at Life Extension observe in aging male members is insufficient free testosterone, i.e., less than 20 – 25 pg/mL of serum. When accompanied by excess estradiol (over 30 pg/mL of serum), this can signal excess aromatase enzyme activity.

Testosterone Replacement Therapies

Optimal testosterone treatment usually requires a physician’s prescription. Integrative physicians typically prescribe bioidentical testosterone creams (available from compounding pharmacies). Conventional physicians are more likely to prescribe prepackaged, testosterone patches and/or gels from pharmaceutical companies that have sought FDA approval for the mass commercialization of their products.

All forms of bioidentical testosterone have the same molecular structure and will increase free and total testosterone in the blood. The major difference is that prepackaged versions could cost up to 10 times more per dose than compounded versions. Furthermore, prepackaged testosterone gels are sold only in a limited number of doses, whereas compounded testosterone can be formulated at virtually any dose the physician feels is clinically necessary and useful.

Using Hormone Replacement Wisely

If a man opts for testosterone therapy (available orally or as an injection, subcutaneous implant, topical cream, gel, or skin patch), he should keep several facts and precautions in mind (Schaeffer et al 2004, Cunningham and Toma 2010):

  • Hormone replacement should not be initiated without comprehensive testing.
  • The patterns and trends over time of multiple hormone levels, (for instance free testosterone, total testosterone, and estrogen), determine the specific hormone replacements required.
  • It may not be safe to use large amounts of testosterone in any form without also using aromatase-inhibiting supplements or medications.
  • Because of the risk of worsening prostate cancer, careful screening, including a digital rectal examination and prostate specific antigen (PSA) screening, must be done before starting any hormone replacement program. However, recent research indicates that low endogenous testosterone levels may present a greater risk for prostate cancer than higher levels (Morgantaler 2006, Rodman et al 2008). If a man already has prostate cancer, however, testosterone replacement should be delayed until the underlying cancer is eradicated.
  • A man contemplating hormone replacement, whether through a prescription or supplements, should work closely with a qualified physician to plan a rational treatment approach that includes continued monitoring and screening.
  • There is no “one size fits all” treatment. Individuals vary, and hormone replacement can be a simple or complex process and often requires careful attention to signs and symptoms, as well as laboratory testing.

Researchers challenge testosterone fears

8 July, 2014 Researchers challenge testosterone fears

Fears about the safety of testosterone have been partially allayed by the publication of a large new US study.
Contrary to other recent studies, University of Texas researchers found no evidence of increased myocardial infarction rates in a retrospective analysis of 6,300 older men treated with intramuscular testosterone from 1997-2005.
The finding is “robust across a range of sensitivity analyses”, they write in the Annals of Pharmacotherapy.
In fact testosterone even appeared protective for men at the highest risk of cardiovascular disease, being associated with a 31% reduction in risk of MI.
“Despite [its] limitations, we believe that this study has important strengths, including a large sample size, a long follow-up period, representation of all US geographic regions, and inclusion of a clinically.

Clomid for Men with Low Testosterone Part One by Jeffrey Dach MD

Clomid forLow Testosterone

Clomid For  Men With Low Testosterone
by Jeffrey Dach MD

This article is Part One,
For Part Two, Click Here.
For Part Three Click Here


A Case Report

A 37 year old professional athlete and bodybuilder arrived in my office complaining of low testosterone symptoms of low libido, erectile dysfunction, chronic fatigue, and mood disorder.   He admitted to anabolic steroid abuse in the past, and now sought medical intervention to “restore his testosterone to normal.”

A few years ago, he had married and fathered a child, and he now wanted to devote more time to his family, but complained of a lack of energy to do so.  He also wanted to preserve fertility, as he wanted more children.  Previous medical doctor’s lab studies showed low testosterone levels, all below 300 ng/dl, and low FSH and LH levels as well.

Upper left image : cropped portions of an anonymous body builder, courtesy of wikimedia commons.  This image is an illustration only, and not an actual patient in any clinic.

Diagnosis and Treatment

After our usual workup, and the obvious diagnosis of hyopogonadal hypogonadism, treatment was started with HCG (human chorionic gonadotropin), an LH analog which stimulates testicular testosterone production.  The patient wished to retain fertility which contra-indicated the use of Testosterone preparations.

Shortly after starting the HCG injections,  the patient reported an immediate improvement in mood and energy, lasting about one week.  However, this improvement was short lived and lasted only one week, after which he reported a recurrence of more severe low testosterone symptoms, worse than before.

Paradoxical Response with Lower Testosterone Levels

Repeat labs at 6 weeks showed testosterone levels had actually dropped lower to the 150 ng/dl range.  FSH and LH were undetectable.  My diagnosis at this point was hypothalamic suppression, and the HCG was discontinued.

Switch to Clomiphene was Sucessful

Treatment with Clomid (clomiphene 25 mg tablet daily) was started.   Six weeks later, the patient reported “feeling like my old self” with improved energy, libido and mood.  Repeat labs 6 weeks after starting the Clomid showed testosterone levels of 832 ng/dl, and LH and FSH had increased as well.  Serum estrogen was quite high at 72 pg/ml.  Anastrazole was added to the treatment program with follow up normalization of estrogen levels.

What Happened in this Patient ?

Why was there a paradoxical response to HCG ?  The answer is in the feedback mechanism illustrated by the diagram to the left.

The hypothalamus produces gonadotropin releasing hormone  (GnRH), which in turn stimulates pituitary production of LH and FSH (leutinizing hormone and follicle stimulating hormone).  LH and FSH then travel to the testicle to induce testosterone(LH) and sperm production (FSH).  \

Clomid Clomiphene for Males Increases LH FSH Testosterone

Image upper left: Pituitary feedback control of LH, FSH and Testosterone from Estrogen (E2). Diagram is  courtesy of Dr Rochira , Eur J Endocrinol. 2006 Oct;155(4):513-22.(1)


Estrogen Receptors in the Hypothalamus Control the Whole Thing

In the female, estrogen receptors in the hypothalamus control releasing hormone (GnRH) as well as pituitary LH and FSH production.  The Male of the species has this same estrogen receptor in the hypothalamus which controls LH and FSH production.  Blocking this hypothalamic estrogen receptor can be accomplished with clomiphene, a drug FDA approved for use in women.  Clomiphene use in males is “off label” use, however.

The drug then “tricks” the hypothalamus to produce more releasing hormone (GnHR), which in turn travels to the pituitary gland to increase LH and FSH production.  LH and FSH in turn increase testosterone production, and sperm production, thus maintaining and enhancing fertility.

In our patient, the hypothalamic Estrogen receptors were set to shut off at a relatively low estrogen level.  The drug “reset ” this to a higher level, allowing more LH, FSH which then stimulated testosterone production.

The advantage of this treatment approach is that it does not impair fertility.  For younger males who wish to maintain or enhance fertility this is a good option.

Aromatase Conversion of Testosterone to Estrogen

Some men are “preferential aromatizers”, meaning there is increased conversion of testosterone to estrogen via the aromatase pathway.  This explains in some, the paradoxical response to HCG which may initially raised testosterone levels. However, upon conversion to estrogen, the increased estrogen level then shuts off the hypothalamic production of GnHR, which in turn may cause very low levels of LH and FSH, explaining the paradoxical low testosterone levels after HCG treatment in some.

In this scenario, Clomiphene is an excellent treatment, which successfully raises testosterone levels while preserving fertility.  Because of preferential conversion of testosterone to estrogen in some men, elevated estrogen levels may require the addition of an aromatase inhibitor such as anastrazole (also called Arimidex).

Estrogen Feedback Regulates Hypothalamus

In a 2006 report in the European Journal of Endocrinology by Dr Rochira from Italy showed that the feedback of gonadotropins (GnRH from the hypothalamus) is regulated by estrogens that come from the aromatization of testosterone.  He studied two males with absent estrgoen from a genetic deficiency in the aromatase enzyme. When these two subjects were given topical Estradiol, this suppressed levels of GnRH, LH, FSH and testosterone, which decreased significantly. (1)

Clomiphene: How does it work ?

Clomiphene binds to and “blocks” the estrogen receptor sites in the hypothalamus (reference).  This stimulates the production of GnRH, gonadotropins.

Click Here for excellent discussion of pathophysiology of hypothalamic pituitary axis.

Conclusion: Clomiphene for men with low testosterone is a viable option for younger males who wish to maintain fertility.  Use in males is “off-label”.

Articles with Related Interest:
This article is Part One,
For Part Two, Click Here.
For Part Three Click Here

Testosterone Benefits, and the PSA part one
Testosterone Benefits and PSA Part Two

Links and References

1) http://eje-online.org/content/155/4/513.long
http://www.ncbi.nlm.nih.gov/pubmed/16990650
Eur J Endocrinol. 2006 Oct;155(4):513-22.
Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback.  Rochira V, Zirilli L, Genazzani AD, Balestrieri A, Aranda C, Fabre B, Antunez P, Diazzi C, Carani C, Maffei L.
Source Integrated Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy.

BACKGROUND: In men, the feedback of gonadotropins is regulated by estrogens that come from the aromatization of testosterone, but the relative contribution to the inhibition of LH and FSH secretion by the amount of locally produced estrogens within the hypothalamus and/or the pituitary, and the amount of circulating estrogens still remains unknown.

OBJECTIVE:In order to evaluate the effect of regulation induced by estradiol on the hypothalamic-pituitary-gonadal (HPG) axis, we studied the pulsatility of LH and FSH in two aromatase-deficient men (called subject 1 and subject 2), in which the production rate of estrogen (both local and circulating) is completely, or at least severely, impaired.

DESIGN:FSH and LH were evaluated in terms of their pulsated secretion and as GnRH-stimulated secretion in two phases: phase 1, before estrogen treatment; and phase 2, during estrogen treatment with 25 microg transdermal estradiol twice weekly.
METHODS:Blood samples were taken during phase 1 and phase 2 at 0800 h for basal measurements of LH, FSH, inhibin B, testosterone, and estradiol. The analysis of the pulsatility of LH and FSH was performed by sampling every 10 min for 8 h in the two phases. Gonadotropin response to GnRH-stimulation test was studied by serial standard sampling after 100 microg GnRH i.v. bolus in phases 1 and 2.

RESULTS:Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5 +/- 0.7 in phase 1, 4.5 +/- 0.7 in phase 2) and amplitudes (3.5 +/- 0.006 in phase 1, 1.9 +/- 0.4 in phase 2) of peaks, whereas FSH showed only a conspicuous reduction in serum levels and a trend towards the reduction of the amplitudes of its peaks without modification of the frequency of the pulses.

Both testosterone and gonadotropins decreased during phase 2, whereas estradiol reached the normal range in both subjects.

Transdermal estradiol treatment significantly lowered the peaks of both serum LH and FSH after GnRH as well as the incremental area under the curve after GnRH administration in both subjects. Basal serum inhibin B levels were slightly higher before transdermal estradiol treatment (phase 1) than during estrogen treatment (phase 2) in both subjects.

CONCLUSIONS:The administration of estrogen to aromatase-deficient men discloses the effects of circulating estrogens on LH secretion, exerted both at pituitary level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulsed amplitude, and at hypothalamic level as shown by the reduction of the frequency of LH pulses. The present study, coupling the outcomes of basal, GnRH-stimulated and the pulsatile evaluation of LH and FSH secretion in two aromatase-deficient men, demonstrates that circulating estrogens play an inhibitory role in LH secretion by acting on the hypothalamus and the pituitary gland of men. The discrepancy among testosterone levels, the arrest of spermatogenesis and a slightly inappropriate respective increase of serum FSH (lower than expected) suggests a possible role of estrogens in the priming and the maturation of HPG axis in men, an event that has never occurred in these two subjects as a consequence of chronic estrogen deprivation.

2012

2) www.ncbi.nlm.nih.gov/pubmed/22458540

BJU Int. 2012 Mar 28. Clomiphene citrate is safe and effective for long-term management of hypogonadism.

Moskovic DJ, Katz DJ, Akhavan A, Park K, Mulhall JP.
Sexual & Reproductive Medicine Program, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Clomiphene citrate (CC) has previously been documented to be efficacious in the treatment of hypogonadism. However little is known about the long term efficacy and safety of CC. Our study demonstrates that CC is efficacious after 3 years of therapy. Testosterone levels and bone mineral density measurement improved significantly and were sustained over this prolonged period. Subjective improvements were also demonstrated. No adverse events were reported.

OBJECTIVE: To assess the efficacy and safety of long-term clomiphene citrate (CC) therapy in symptomatic patients with hypogonadism (HG).

PATIENTS AND METHODS:Serum T, oestradiol and luteinizing hormone (LH) were measured in patients who were treated with CC for over 12 months. • Additionally, bone densitometry (BD) results were collected for all patients. Demographic, comorbidity, treatment and Androgen Deficiency in Aging Men (ADAM) score data were also recorded.
• Comparison was made between baseline and post-treatment variables, and multivariable analysis was conducted to define predictors of successful response to CC.
• The main outcome measures were predictors of response and long-term results with long-term CC therapy in hypogonadal patients. RESULTS:The 46 patients (mean age 44 years) had baseline serum testosterone (T) levels of 228 ng/dL.
• Follow-up T levels were 612 ng/dL at 1 year, 562 ng/dL at 2 years, and 582 ng/dL at 3 years (P < 0.001).
• Mean femoral neck and lumbar spine BD scores improved significantly.
• ADAM scores (and responses) fell from a baseline of 7 to a nadir of 3 after 1 year. • No adverse events were reported by any patients. CONCLUSIONS:Clomiphene citrate is an effective long-term therapy for HG in appropriate patients.
• The drug raises T levels substantially in addition to improving other manifestations of HG such as osteopenia/osteoporosis and ADAM symptoms.

——————————————–

2011

3) www.ncbi.nlm.nih.gov/pubmed/22044663

BJU Int. 2011 Nov 1.  Outcomes of clomiphene citrate treatment in young hypogonadal men.  Katz DJ, Nabulsi O, Tal R, Mulhall JP.  Source Male Sexual and Reproductive Medicine Programme, Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Hypogonadism is a prevalent problem, increasing in frequency as men age. It is most commonly treated by testosterone supplementation therapy but in younger patients this can lead to testicular atrophy with subsequent exogenous testosterone dependency and may impair spermatogenesis.

Clomiphene citrate (CC) may be used as an alternative treatment in these patients with hypogonadism when maintenance of fertility is desired. This study shows that CC is a safe and efficacious drug to use as an alternative to exogenous testosterone. Not only have we validated previous findings of other papers but have proven our findings over a much longer period (mean duration of treatment 19 months). This prospective study is the largest to date assessing both the objective hormone response to CC therapy as well as the subjective response based on a validated questionnaire.

OBJECTIVE:To prospectively assess the andrological outcomes of long-term clomiphene citrate (CC) treatment in hypogonadal men.
PATIENTS AND METHODS:We prospectively evaluated 86 men with hypogonadism (HG) as confirmed by two consecutive early morning testosterone measurements 

• The cohort included all men with HG presenting to our clinic between 2002 and 2006 who, after an informed discussion, elected to have CC therapy. CC was commenced at 25 mg every other day and titrated to 50 mg every other day.
The target testosterone level was 550 ± 50 ng/dL.

• Testosterone (free and total), sex hormone binding globulin, oestradiol, luteinizing hormone and follicle stimulating hormone were measured at baseline and during treatment on all patients. Once the desired testosterone level was achieved, testosterone/gonadotropin levels were measured twice per year.

• To assess subjective response to treatment, the androgen deficiency in aging males (ADAM) questionnaire was administered before treatment and during follow-up.
RESULTS: patients’ mean (standard deviation [sd]; range) age was 29 (3; 22-37) years. Infertility was the most common reason (64%) for seeking treatment. The mean (sd) duration of CC treatment was 19(14) months.
• At the last evaluation, 70% of men were using 25 mg CC every other day, and the remainder were using 50 mg every other day. 
• All mean testosterone and gonadotropin measurements significantly increased during treatment.
• Subjectively, there was an improvement in all questions (except loss of height) on the ADAM questionnaire. More than half the patients had an improvement in at least three symptoms.
• There were no major side effects recorded and the presence of a varicocele did not have an impact on the response to CC.

CONCLUSION:Long-term follow-up of CC treatment for HG shows that it appears to be an effective and safe alternative to testosterone supplementation in men wishing to preserve their fertility

2010

4) www.ncbi.nlm.nih.gov/pubmed/19694928
J Sex Med. 2010 Jan;7(1 Pt 1):269-76. Epub 2009 Aug 17.
Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: efficacy and treatment cost.
Taylor F, Levine L. Rush University Medical Center-Department of Urology, Chicago, IL, USA.

INTRODUCTION:The efficacy of oral clomiphene citrate (CC) in the treatment of male hypogonadism and male infertility (MI) with low serum testosterone and normal gonadotropin levels has been reported.
AIM:The aim of this article is to evaluate CC and testosterone gel replacement therapy (TGRT) with regard to biochemical and clinical efficacy and cost. MAIN OUTCOME MEASURES:The main outcome measures were change in serum testosterone with CC and TGRT therapy, and change in the androgen deficiency in aging male (ADAM) questionnaire scores with CC therapy.

METHODS:Men receiving CC or TGRT with either Androgel 1% or Testim 1% for hypogonadism (defined as testosterone < 300 ng/mL) or MI were included. Serum values were collected 1-2 months after treatment initiation and semi-annually thereafter. Retrospective data collection was performed via chart review. Subjective follow up of patients receiving CC was performed via telephone interview using the ADAM questionnaire.

RESULTS:A hundred and four men (65 CC and 39 TGRT) were identified who began CC (50 mg every other day) or TGRT (5 g). Average age (years) was 42(CC) vs. 57 (TGRT). Average follow up was 23 months (CC, range 8-40 months) vs. 46 months (TGRT, range 6-149 months).

‘Average posttreatment testosterone was 573 ng/dL in the CC group and 553 ng/dL in the TGRT group (P value < 0.001). The monthly cost of Testim 1% (5 gm daily) is $270, Androgel 1% (5 gm daily) is $265, and CC (50 mg every other day) is $83. Among CC patients, the average pretreatment ADAM score was 4.9 vs. 2.1 at follow up (P < 0.05). Average pretreatment ADAM sexual function domain score was 0.76 vs. 0.23 at follow up (P < 0.05). There were no adverse events reported.

CONCLUSION:CC represents a treatment option for men with hypogonadism, demonstrating biochemical and clinical efficacy with few side effects and lower cost as compared with TGRT.

—————————————————————————

2011

5) jcem.endojournals.org/content/96/1/38.full#ref-28
The Journal of Clinical Endocrinology & Metabolism January 1, 2011 vol. 96 no. 1 38-52  Why Is Androgen Replacement in Males Controversial? Glenn R. Cunningham and Shivani M. Toma Baylor College of Medicine and St. Luke’s Episcopal Hospital, Houston, Texas 77030 2009

2009

6) www.ncbi.nlm.nih.gov/pubmed/19204885 
IDrugs. 2009 Feb;12(2):109-19.
Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men.  Hill S, Arutchelvam V, Quinton R. Department of Clinical Pharmacology & Therapeutics, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

Enclomiphene (Androxal), in development by Repros Therapeutics Inc, is a non-steroidal estrogen receptor antagonist that promotes gonadotropin-dependent testosterone secretion by the testes. Enclomiphene constitutes the trans-stereoisomer of clomiphene citrate, a drug that has been widely prescribed for several decades for the treatment of female ovulatory dysfunction. Because of the antagonistic effects of enclomiphene, the drug has the potential to increase serum testosterone levels in men with secondary hypogonadism by restoring physiological endogenous testosterone secretion while maintaining testicular volume and, potentially, spermatogenesis. In clinical trials conducted to date, enclomiphene demonstrated significant efficacy in the physiological restoration of testosterone levels in males with secondary hypogonadism. The compound also exhibited an unanticipated favorable effect on fasting plasma glucose; this result has been accompanied by rapidly accumulating evidence from other researchers for a bidirectional relationship between low serum testosterone and obesity/metabolic syndrome (syndrome X) in men. Short-term clinical safety data for enclomiphene have been satisfactory and equivalent to safety data for testosterone gels and placebo.

Enclomiphene demonstrates promise in the management of secondary hypogonadism associated with obesity, metabolic syndrome and, possibly, infertility, and should undergo placebo-controlled, randomized clinical trials for these indications.

2009

7) www.ncbi.nlm.nih.gov/pubmed/19938905

Expert Opin Investig Drugs. 2009 Dec;18(12):1947-55. Clomiphene citrate and enclomiphene for the treatment of hypogonadal androgen deficiency. Kaminetsky J, Hemani ML. NYU Langone Medical Center – Department of Urology, New York, New York 10016, USA.

Hypogonadism has a number of important clinical consequences related to androgen deficiency and impaired spermatogenesis. The cause of this condition is multifactorial and can result from hypothalamic, pituitary or gonadal dysfunction as well as factors that affect hormonal signaling along the hypothalamic-pituitary-gonadal axis. While testosterone replacement is the most common treatment, it canparadoxically lead to infertility, and may be a less physiologic therapy for patients with secondary hypogonadism due to pituitary dysfunction. Clomiphene citrate, and its derivatives, may allow for restoration of gonadal function by restoring physiologic pituitary function in a subset of patients with hypogonadism.

2006

8) www.ncbi.nlm.nih.gov/pubmed/17070201

Fertil Steril. 2006 Nov;86(5):1513.e5-9. Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate. Ioannidou-Kadis S, Wright PJ, Neely RD, Quinton R. Department of Endocrinology, Royal Victoria Infirmary and University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom.

Inhibition of pituitary gonadotropin secretion in men by T is principally mediated by aromatization to estrogen (E), which inhibits hypothalamic secretion of GnRH. We hypothesized that adult-onset isolated hypogonadotropic hypogonadism (IHH) might result from an altered central set-point for E-mediated negative feedback. Longitudinal clinical investigation unit-based evaluation of the clinical and biochemical response to E-receptor blockade.

A 31-year-old man presenting with an 18-month history of sexual dysfunction resulting from severe adult-onset IHH (LH 1.7 U/L, FSH 2.0 U/L, T 3.5 nmol/L). Initial therapy with 50 mg of clomiphene citrate (CC) three times a day for 7 days, with overnight LH pulse profiling and 9 am T levels evaluated at baseline and on completion. A 2-month washout period, followed by low-dose maintenance therapy (25-50 mg/d) for 4 months.
MAIN OUTCOME MEASURE(S):Baseline and stimulated T levels and LH pulsatility; effect on sexual function.
RESULT(S):Clomiphene therapy resulted in complete normalization of pulsatile gonadotropin secretion, serum T level, and sexual function. CONCLUSION(S):Isolated hypogonadotropic hypogonadism may result from an acquired defect of enhanced hypothalamic sensitivity to E-mediated negative feedback. Whereas direct T replacement therapy can further suppress endogenous gonadotropin secretion, treating IHH men with gonadotropins can stimulate endogenous T secretion and enhance fertility potential. On theoretical grounds, reversal of gonadotropin deficiency with CC might be expected to have a similar biological effect.

2006

9) www.ncbi.nlm.nih.gov/pubmed/17007848
Fertil Steril. 2006 Dec;86(6):1664-8. Epub 2006 Sep 27.
Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate.

Whitten SJ, Nangia AK, Kolettis PN. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Alabama, Birmingham, Alabama 35249-7333, USA.

OBJECTIVE: To review the management of male hypogonadotropic hypogonadism (HH) and evaluate the efficacy of clomiphene citrate (CC). DESIGN:Retrospective review.
SETTING:Two university-based urology clinics.
PATIENT(S):Ten patients referred for male infertility evaluation.
INTERVENTION(S): Patients were treated with either clomiphene citrate or injectable gonadotropins. 
MAIN OUTCOME MEASURE(S): Changes in seminal parameters, gonadotropin levels, serum testosterone, and pregnancy.

RESULT(S): Ten men who were evaluated for infertility were diagnosed with HH. Four had Kallmann’s syndrome, four idiopathic HH, and two panhypopituitarism. Eight patients were azoospermic, and two were oligospermic on presentation. Three of the four men with adult-onset idiopathic HH responded to CC alone with increases in testosterone, FSH, and LH. Semen parameters in this group also improved, and two of the three men achieved pregnancies with CC alone. Out of the ten men actively attempting conception, four pregnancies were achieved. Three pregnancies (two with CC and one with gonadotropins) were in men diagnosed with adult-onset idiopathic forms of HH.

CONCLUSION( S): Select patients with adult-onset idiopathic forms of HH may benefit from a trial of clomiphene citrate.

——————————————————–

2003 Clomid Restores T after steroid abuse

10) www.ncbi.nlm.nih.gov/pubmed/12524089

Fertil Steril. 2003 Jan;79(1):203-5. Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse.  Tan RS, Vasudevan D. Department of Family and Community Medicine, University of Texas Health Sciences Center, Houston, Texas 77030, USA.  To report a case of symptomatic hypogonadism induced by the abuse of multiple steroid preparations that was subsequently reversed by clomiphene. DESIGN: Case report.

SETTING:University-affiliated andrology practice within family practice clinic.

PATIENT(S):A 30-year-old male.
INTERVENTION(S): Clomiphene citrate, 100-mg challenge for 5 days, followed by treatment at same dose for 2 months. 
MAIN OUTCOME MEASURE(S): Clinical symptoms, androgen decline in aging male questionnaire, total T, FSH, LH.
RESULT(S): Reversal of symptoms, normalization of T levels with LH surge, restoration of pituitary-gonadal axis.

CONCLUSION(S): Clomiphene citrate is used typically in helping to restore fertility in females. This represents the first case report of the successful use of clomiphene to restore T levels and the pituitary-gonadal axis in a male patient. The axis was previously shut off with multiple anabolic steroid abuse.

1997

11) www.ncbi.nlm.nih.gov/pubmed/9093212

Fertil Steril. 1997 Apr;67(4):783-5. Idiopathic hypogonadotropic hypogonadism in a male runner is reversed by clomiphene citrate. Burge MR, Lanzi RA, Skarda ST, Eaton RP. University of New Mexico School of Medicine, Department of Medicine/Endocrinology-5ACC, Albuquerque 87131, USA.

To assess the efficacy of estrogen antagonist therapy on the function of the hypothalamic-pituitary-testicular axis in a young male runner with significant morbidity attributable to idiopathic hypogonadotropic hypogonadism.
DESIGN: An uncontrolled case study.
SETTING: The outpatient endocrinology clinic of a university tertiary referral center. PATIENT(S): A 29-year-old male who has run 50 to 90 miles per week since 15 years of age and who presented with a pelvic stress fracture, markedly decreased bone mineral density, and symptomatic hypogonadotropic hypogonadism.

INTERVENTION(S): Clomiphene citrate (CC) at doses up to 50 mg two times per day over a 5-month period.

MAIN OUTCOME MEASURE(S): Serum concentrations of LH, FSH, and T before and after CC therapy, as well as clinical indicators of gonadal function.
RESULT(S): Barely detectable levels of LH and FSH associated with hypogonadal levels of T were restored to the normal range with CC therapy.

The patient experienced improved erectile function, increased testicular size and sexual hair growth, and an improved sense of well being.

CONCLUSION(S): Exercise-induced hypogonadotropic hypogonadism exists as a clinical entity among male endurance athletes, and CC may provide a safe and effective treatment option for males with debilitating hypogonadism related to endurance exercise.

————————————————————————-

2005

12) www.ncbi.nlm.nih.gov/pubmed/16422830

J Sex Med. 2005 Sep;2(5):716-21. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism.
Shabsigh A, Kang Y, Shabsign R, Gonzalez M, Liberson G, Fisch H, Goluboff E. Department of Urology, NY Presbyterian Medical Center, New York, NY, USA.

Symptomatic late-onset hypogonadism is associated not only with a decline in serum testosterone, but also with a rise in serum estradiol.

These endocrine changes negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Currently, the most common treatment is exogenous testosterone therapy. This treatment can be associated with skin irritation, gynecomastia, nipple tenderness, testicular atrophy, and decline in sperm counts.

In this study we investigated the efficacy of clomiphene citrate in the treatment of hypogonadism with the objectives of raising endogenous serum testosterone (T) and improving the testosterone/estrogen (T/E) ratio.

METHODS: Our cohort consisted of 36 Caucasian men with hypogonadism defined as serum testosterone level less than 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate and followed prospectively. Analysis of baseline and follow-up serum levels of testosterone and estradiol levels were performed.

RESULTS: The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 +/- 39.8 ng/dL and 32.3 +/- 10.9, respectively. By the first follow-up visit (4-6 weeks), the mean testosterone level rose to 610.0 +/- 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). There were no side effects reported by the patients.

CONCLUSIONS: Low dose clomiphene citrate is effective in elevating serum testosterone levels and improving the testosterone/estradiol ratio in men with hypogonadism. This therapy represents an alternative to testosterone therapy by stimulating the endogenous androgen production pathway.

2003

13) www.ncbi.nlm.nih.gov/pubmed/12904801
Int J Impot Res. 2003 Jun;15(3):156-65. Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?  Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E. Center for Sexual Function (Endocrinology), Peabody, Massachusetts 01960, USA.

Secondary hypogonadism is more common than primary gonadal failure and is seen in chronic and acute illnesses. Although testosterone has a role in erections, its importance in erectile dysfunction (ED) has been controversial. Hypogonadism produced by functional suppression of pituitary gonadotropins has been shown to correct with clomiphene citrate, but with a modest effect on sexual function. We wondered if longer treatment would produce improved results.

A total of 178 men with secondary hypogonadism and ED received clomiphene citrate for 4 months. Sexual function improved in 75%, with no change in 25%, while significant increases in luteinizing hormone (P<0.001) and free testosterone (P<0.001) occurred in all patients.

Multivariable analysis showed that responses decreased significantly with aging (P<0.05). Decreased responses also occurred in men with diabetes, hypertension, coronary artery disease, and multiple medication use. Since these conditions are more prevalent with aging, chronic disease may be a more important determinant of sexual dysfunction. Men with anxiety-related disorders responded better to normalization of testosterone. Assessment of androgen status should be accomplished in all men with ED.For those with lower than normal age-matched levels of testosterone treatment directed at normalizing testosterone with clomiphene citrate is a viable alternative to giving androgen supplements.

Clomiphene Clomid Adverse Side Effects Part Three

Branch_retinal_vein_occlusionClomiphene Clomid Adverse Side Effects Part Three

This is part three of a series,
Click Here for Part One 
Click Here for Part Two

The off-label use of clomiphene tablets in young males to relieve symptoms of low testosterone is becoming more popular because it preserves fertility, and is less expensive and more convenient than testosterone injections.  Best results are obtained in males of child bearing ages (30 – 50 yrs of age) with hypothalamic dysfunction, (ie. low FSH/LH, and good testicular reserve which can respond to FSH/LH stimulation)  Before starting clomiphene,  the patient should be conversant with the adverse effects of treatment.

Above left image: Retina of the left eye shows retinal vein occlusion resulting in hemorrhages and exudates  marked by Green Arrows, courtesy of wikimedia commons.

Review of the Medical Literature on Adverse Effects of Clomiphene

Dr  Viola from Capetown South Africa reviewed the medical literature on common adverse effects of clomiphene treatment, mostly in women.  She found 35 articles on the topic and published her report in 2011. She found that blurred visual and other visual effects were most commonly reported about 1.5% of the time.(1)

“Visual adverse events with the use of CC in clinical studies was reported as 1.5%. These include blurred vision, photophobia, diplopia, scotomata, phosphenes  and periphlebitis.”(1)

Dr. Viola also reported on central retinal vein occlusion as an adverse effect of clomipene.(1)

Central Retinal Vein Occlusion in a Male

Although a number of reports of retinal vein occlusion have been reported in women using clomiphene (Clomid) as a fertility treatment to induce ovulation, only one is reported in a 35 year old male undergoing fertility treatment with Clomiphene.  This male patient had an underlying inherited thrombophilia, with Factor V Leiden and MTHFR polymorphism.(2)  His retinal vein occlusion, due to thrombosis of the vein,  was treated with Plavix (clopidogrel) with recovery.  Dr Politou suggests young men should be screened for Factor V Leiden before starting Clomiphene.

Visual Disturbances-Blurred Vision

Dr. Purvin from Methodist Hospital in Indiana reported on visual disturbances from Clomiphene in three women undergoing fertility treatment for 4-12 months.(9)

” All three patients experienced prolonged afterimages (palinopsia), shimmering of the peripheral field, and photophobia while undergoing treatment with clomiphene. The results of the neuro-ophthalmologic examination and electrophysiologic studies were normal in all three patients. Unlike previously reported cases, visual symptoms did not resolve on cessation of treatment. Patients remain symptomatic from 2 to 7 years after discontinuing treatment with the medication.”(9)

“The most common side-effect is without question blurred vision; while this may be a problem for some Clomid users it will dissipate once use is discontinued. “(9)

One case of bilateral uveitis (inflammation of the eye) was described in a 30 year old female on clomiphene.(8) One case of elevated liver enzymes was reported (7)

Psychotic Reaction

In women undergoing fertility treatment with prolonged high dose Clomiphene, various central nervous system adverse effects have been reported including induction of psychosis, nervousness, sleeplessness, headaches, visual disturbances, vertigo.(3,4,5)

Psychological Effects on Mood

In a 2005, large self-reported survey of women on Clomiphene and HMG adverse psychological effects were reported including, Irritability, mood swings, and feeling down.(6)

Estrogen and HyperCoagulable State

Most adverse effects of clomiphene are reported for female fertility treatment using high dose Clomiphene. I would speculate that most of the adverse effects are due to high estrogen levels known to cause hypercoagulable state.(10,11)

Anastrazole to Keep Estrogen Levels Low and Prevent Hypercoagulation.

Adverse effects from off-label use of clomiphene is less commonly reported in the medical literature in males than in females, possibly because of the lower dosage used. Females dosage is 50-200 mg per day, while for males, we use the lower dosage of 12.5 mg every other day up to 25 mg per day.

Estrogen and Hypercoagulable State

For female patients undergoing fertility treatment to induce ovulation, elevated estrogen is part of the desired outcome.   Estrogen levels may rise by a factor of one hundred (100 times higher than pre-treatment levels), inducing a hypercoagulable state.(10,11)  Quite the opposite in males, clomiphene induced elevated estrogen is an undesirable side effect, preventable with an aromatase inhibitor (anastrazole).

In males, central retinal vein occlusion with underlying inherited thrombophila mutation has been reported.(2)  The authors say the causal mechanism is unknown.  I would differ, and suggest the cause is high estrogen induced by clomiphene stimulation.  High estrogen causes a hypercoagulable state.(10,11) An aromatase inhibitor (anastrazole) prevents the high estrogen level, and therefore prevent the rare thrombotic complication, such as the retinal vein occlusion in the inherited thrombophilia male patient. (2)  I would suggest a prudent practice would be to use an aromatase inhibitor with the clomiphene.

  1. Hi there! I just wish to give you a huge thumbs up for your excellent information you’ve got right here on this
    post. I will be coming back to your web site for more soon.

  2. It is a shame more doctors are not as open minded as you, I tried the legal route to get onto HRT but because my test level was in the normal range (at the very low end of the scale) I was told no, So I found a supplier of test E and have been self dosing for 1 year, I get blood work done via my GP who always gives me a talking to but I say we’ll all my blood work is good and I’m here seeing you so I stay healthy, if you are not prepared to help me stay healthy I will find another doctor. My test is always in the 700-900 range and cholesterol, etc are alway in the safe range, hemoglobin has been high at times but only equal to a athlete which I do stay very active and fit. Oh and since being on HRT I am happy, more active, no more out burst of anger, reduced belly fat, increased libido, my relationship with my family is much better, and my depression is gone.

  3. Dr Holloway, would you consider me as a patient if I contact your office and make an appointment.? FYI – I was previously prescribed Clomid which I was unable to finish the course due to all my previous symptoms returning including depression. Is there anyway that I could possible be treated with testE without having to take Clomid again? I’m happy to pay unconsessional prices for the testE if need be. Kind regards David

  4. Thank you very much, do I need a referral from a gp? Or can I just ph your offices?

  5. Ok, thank you

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