Introduction
Male hypogonadism (HG) is a patology defined as low levels of serum testosterone (T) often accompanied by a wide constellation of symptoms. The most commons are: libido decrement, erectile dysfunction and sarcopenia[ Andropause: clinical implications of the decline in serum testosterone levels with aging in men.,2002, The association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women,2007, The burden of testosterone deficiency syndrome in adult men: economic and quality-of-life impact.,2007 ]. Additionally, patients often complain of mood symptoms suggestive of depression, dysthymia and irritability [ Effect of testosterone administration on sexual behavior and mood in men with erectile dysfunction,1997. ]. Critically important is the increased risk of cardiometabolic comorbidities associated with HG, including the development of cardiovascular disease, diabetes mellitus and osteoporosis [ Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis,2006 , Testosterone and coronary artery disease,2013 , Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden,2006 ]. Two forms of Hypogonadism have been identified: primary HG is the results of gonadal dysfunction; Secondary HG is caused by dysfunctions of hypothalamic-pituitary-gonadal axis. (see image 1 below)
According to literature and clinicians experience, it seems that the prevalence of secondary HG is growing, in particular in the west countries and is due to the progressive population's ageing.
It is estimated that the patology could affect more than five million men, only in the United States, with a significant negative influence on the Health-related quality of life (QL). [ Hypogonadism in the aging male diagnosis, potential benefits, and risks of testosterone replacement therapy.,2012 , Prevalence of symptomatic androgen deficiency in men,2007. ]
An another aspect to keep in mind is that one related to the higher desire by aged men of being father. In 1970, fever than 15% of all men fathering children were over 35 years of age. Today that percentage has risen to almost 25%. Likewise, the number of men in 50-54 age has had an notable increase in fatherhood [ The Male Biological Clock: The Startling News about Aging, Sexuality, and Fertility in Men,2008]. So also for this reason the treatment of the HG is getting more and more actual.
Therapy: State-of-Art
At the moment the only treatment approved by FDA is the ''Testosterone replacement therapy (TRT)''.
Randomised trials have shown a correlation between restored physiological testosterone levels, muscle mass and strength measured as leg press strength and quadriceps muscle volume [ Testosterone dose-response relationships in healthy young men,2001 , Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study,2009 , Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men,2008 , Onset of effects of testosterone treatment and time span until maximum effects are achieved,2011 ]. Similar positive results have been reported in meta-analyses evaluating the role of exogenous T in relation to bone mineral density: it is evident that testosterone therapy improves mineral density at the lumbar spine, producing a reduction in bone resorption markers. The available trials failed to demonstrate a similar effect at the femoral neck [ Onset of effects of testosterone treatment and time span until maximum effects are achieved,2011 , Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials,2006 , Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis,2005 ]. Body composition is influenced by testosterone therapy in hypogonadal men, with a consequent decrease in fat mass and an increase in lean body mass [ Onset of effects of testosterone treatment and time span until maximum effects are achieved,2011 ]
During TRT, periodic observation of the serum concentration of the hormone and its metabolites is recommended in order to alleviate treatment-related side effects [ Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis,2005 ]. Several preparations are available, which differ in the route of administration and pharmacokinetics, and their selection should be a joint decision by both the patient and the physician [ Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials,2005 ].
- In the table below are shown the testosterone preparations for replacement therapy (EAU Guideline) (see image 2 below)
Unfortunately TRT reduces endogenous testosterone production by negative feedback on the hypothalamic-pituitary-gonadal axis. For this reason if HG coincides with fertility issues the only alternative offered is the Human chorionic gonadotrophin (hCG) treatment [ EAU.Male Hypogonadism Guidelines,2011 ]. HCG stimulates testosterone production of Leydig cells. Its administration should be restricted to patients with secondary hypogonadism, if fertility issues are important. Normal physiological serum levels can be achieved with a standard dosage of 1500-5000 IU administered intramuscularly or subcutaneously twice weekly. In patients with secondary hypogonadism, hCG treatment is combined with FSH treatment (usually 150 IU three times weekly i.m. or s.c.) to induce spermatogenesis [ EAU.Male Hypogonadism Guidelines,2011 ]. In patients with secondary hypogonadism and fertility issues, and in selected cases of primary hypogonadism, hCG treatment can be chosen to support endogenous testosterone production for the period of infertility treatment. The dosage has to be adjusted individually to prevent suppression of FSH serum levels.
At Now the aspects that limit the use of hCG are higher costs than testosterone treatment and no data about the long-term effect.
Clomiphene Citrate
Clomiphene citrate (CC) is a diasteroisomer composed by Zuclomiphene and Enclomiphene with Selective Estrogen Receptor Modulation (SERM) effects. At now it has been FDA-approved to initiate ovulation in women [ Selective estrogen receptor modulators: an update on recent clinical findings,2008 ]. Additionally, this SERM is used off-label continuously in men of reproductive age to treat hypogonadism and low sperm concentration [ Effect of rejuvenation hormones on spermatogenesis,2013 ]. Clomiphene citrate is also used by men taking Anabolic Androgen Steroid (AAS) in a cyclic fashion as an aid to recovery of natural testosterone production after AAS or exogenous T cessation. It is usually applied in short courses in this population in order to stimulate normal sex hormone secretion by producing a gonadotropin surge [ Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate,1995 , Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse,2003 ].
- Mechanism of action and Effects
CC is a SERM competitively bind to estrogen receptors on the hypothalamus and pituitary gland
(see image 3 below)
As a result, the pituitary sees less estrogen and makes more LH, which increases T production by the testes. It is not as effective in raising serum T levels when LH and FSH levels are already elevated, as seen in primary testis failure. By increasing ITT, the use of CC or its diasteroisomers in Hypogonadal men with poor sperm count has been demonstrated to promote spermatogenesis [ The treatment of hypogonadism in men of reproductive age,2013 , Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel,2013 ].
One of the most important characteristics of CC stimulation is because it does not elevate the testosterone level out of the normal range, but it remain in the middle of the normal range. Wang et al [ Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study,1996 ] found that a positive response to testosterone did not improve further when testosterone levels increased from the low-normal to the high-normal range. Snyder et al. [ Effect of testosterone treatment on bone mineral density in men over 65 years of age,1999 ] also found that increasing the testosterone level of normal, healthy males over the age of 65 to the level of young healthy males had no effect on energy, mental health, or sexual function.
Katz et al. [ Outcomes of clomiphene citrate treatment in young hypogonadal men,2012 ] from the Memorial Sloan-Kettering Cancer Center observed that long-term use of CC was safe and effective in improving serum T levels (LOE 1). In this moderately sized analysis, 86 men aged 22 to 37 years with hypogonadism (T levels <300 ng/dL) were evaluated and treated for a mean duration of 19 months. The treatment with CC started at 25 mg every other day and was titrated to 50 mg every other day. The target testosterone level was 550 ng/dL. Once the desired testosterone levels were achieved, the testosterone/gonadotropin levels were measured twice per year. In response to questions on the Androgen Deficiency in Aging Males (ADAM) questionnaire, the men reported improvements in every area except for loss of height. There was significant improvement in five of the 10 variables, including decreased libido, lack of energy, decreased life enjoyment, feeling sad/grumpy, and decreased sports performance. Over a long-term follow-up, the study demonstrated that CC is an effective and safe alternative to testosterone supplementation therapy in hypogonadal men. Guay et al.[ Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit?,2003 ] evaluated the effects of CC on erectile function, their data showed that clomiphene citrate can successfully stimulate the hypothalamus to cause increased testicular testosterone production. Stimulation with 50mg of oral CC three times weekly may be diagnostic as well as therapeutic. If the patient does not respond with at least a 75% increase in testosterone and a 100% increase in luteinizing hormone, further evaluation of the hypothalamic–pituitary area is warranted [ Possible hypothalamic impotence. Male counterpart to hypothalamic amenorrhea?,1991 ] All study patients met these criteria, yet only 39% of the men had a completely positive clinical response (ie, successful intercourse in at least 75% of attempts). The lack of complete response occurred mainly in men over 55 y of age. It was also seen in the presence of common chronic conditions such as diabetes mellitus, hypertension, CAD, and the use of multiple medications. Their results also agreed with those of Jain et al. [ Testosterone supplementation for erectile dysfunction: results of a meta-analysis,2000 ] who showed a cause and effect relation between ED and low testosterone levels in a meta-analysis. The response rate was better in primary hypogonadsim than in secondary hypogonadism.
Michael Werner et al. [ Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel,2013 ] proved, comparing Testosterone gel with Enclomiphene citrate, that is effective on sperm count. After 3 months, they reported no individual in the testosterone gel arm demonstrated a sperm count higher than 12 million/mL, whereas there was no individual in the Enclomiphene citrate arm with a count below 75 million/mL, and the mean count was 176 million/mL. This was highly significant (P = 0.004).
Hussein Ghanem et al.[ Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial,2010 ] has gone further, assessing the effect of treatment with a combination of CC and vitamin E as an antioxidant on the incidence of pregnancy. The cumulative number of pregnancies after treatment was significantly higher in the combination treatment group (11pregnancies, 36.7%) in comparison to the placebo group (4 pregnancies, 13.3%). The odds ratio (OR) was 3.76 (95% CI, 1.03–13.64). This higher pregnancy rate within the combination therapy group was statistically significant (P¼0.037). Therefore they concluded that the combination of clomiphene citrate as an antiestrogen and vitamin E as an antioxidant can significantly increase the pregnancy rate and improve sperm count and progressive sperm motility in cases of idiopathic oligoasthenozoospermia.
Conclusion
According to the literature, the off-label use of CC seems to be able to increase serum testosterone at physiologic levels and appears to be safe and effective for use up to 2 years. This treatment could become in the near future, the best alternative to androgenic medications for men who wish to maintain/restore fertility while being treated for symptomatic hypogonadism or ormon related oligospermia.
