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Although testosterone induces growth velocity, the estrogens aromatized from testosterone will accelerate epiphysial maturation and for that reason reduce adult height further. Boys with a mean age of 11 years at the start of the study were treated with letrozole 2.5 mg once daily or placebo for 2 years . In an earlier study a combination of spironolactone and testolactone proved effective , whereas in later studies the combination of bicalutamide and anastrozole was used 57-59. Aromatase inhibitors, therefore, may be used to lower estradiol levels and thereby slow down epiphysial maturation. Uncontrolled studies using anastrozole, testolactone or letrozole have shown some evidence for a positive effect on sperm concentration and motility 49-51. Aromatase inhibition results in a three-fold increase in levels of FSH 28,29 in eugonadal men and may potentially stimulate sperm production. Although FSH release is primarily under the control of inhibin, circulating estradiol has a substantial effect on FSH levels in men .
Five years of adjuvant oral AI therapy has been recommended for this postmenopausal patient. Breast cancer cells rely on aerobic metabolism and require glucose for metabolism.35,36 High glucose and insulin levels trigger multiple direct and indirect mechanisms that promote cancer growth. The complete pathological response supports that T + L did not interfere with chemotherapy.
Testosterone reduces inflammation.12 Inflammation is a key factor in the etiology and progression of breast cancer, resistance to endocrine therapy, and also cardiac and neurologic side effects of chemotherapy including "chemo brain."12,27-31 T protects and stimulates the bone marrow. A 51-year-old woman on testosterone replacement therapy was diagnosed with hormone receptor-positive invasive breast cancer. Moreover, it is questionable whether aromatase inhibitors are able to stimulate testosterone production sufficiently in men with truly low testosterone levels for whom testosterone treatment is currently recommended. A similar increase of testosterone levels in the absence of effects on body composition and strength was reported in a study, in which elderly men with borderline low levels of serum testosterone were treated with anastrozole during 1 year . A more recent study also showed a moderate but significant effect of aromatase inhibition on estradiol and testosterone levels in older men . "Most studies with Letrozole for male infertility have focused on men with low serum testosterone levels and testosterone-oestradiol (T/E) ratios less than 10.
In most studies utilizing aromatase inhibitors in men estradiol levels decreased only moderately. Treatment resulted in normalization of testosterone levels in all subjects, with a concomitant suppression of the originally increased levels of estradiol. In three small studies, letrozole or testolactone has been administered to morbidly obese men to improve their testosterone levels 42-44. These observations outline a serious limitation of the use of aromatase inhibitors in older men; the stimulating effect on testosterone levels may be too weak, especially in the men with the lowest baseline testosterone levels who would potentially benefit most. Additionally, misuse of aromatase inhibitors is unlikely since testosterone levels will not be stimulated to vastly supraphysiological levels. Can aromatase inhibitors improve spermatogenesis in men with idiopathic male infertility with normal testosterone-oestradiol ratio? In a recent comparison study done on HCG and different forms of testosterone, it was noted that HCG leads to a lesser increase in estrogen than exogenous testosterone.
Extensive experience with third-generation aromatase inhibitors in postmenopausal women did not reveal major side effects related to their use. Due to these disappointing results, aromatase inhibitors are not recommended as a first-line treatment for gynecomastia in men. Anastrozole was also studied in a group of prostate cancer patients treated with bicalutamide, an androgen antagonist.
The steroidal agents bind covalently and irreversibly to the aromatase enzyme. In most cases, letrozole has been given in daily doses of 5 mg for five days. Research examining various letrozole dosage regimens has been conducted internationally and nationally, but the results have been inconclusive in establishing an ideal dose. In the extended course of letrozole for around 10 days, from day 1 to day 10, 2.5 mg of letrozole is prescribed .
After four months of treatment with Letrozole, 11 out of 15 men experienced improvement in either their sperm concentration or motility. For the KKH study, researchers recruited men with low sperm count of unknown cause regardless of their T/E ratios. However, the frequency of this ratio is not as prevalent in our clinical practice," shares primary investigator Dr Liu Shuling, Consultant, Department of Reproductive Medicine, KKH.
T is neuroprotective and cardioprotective.8-11 Androgens, including T, stimulate immune function, prevent inflammation, and have been used as treatment for anemia and bone marrow failure.12,13 Host toxicities can also have an adverse effect on quality of life during and after therapy. Aromatase inhibitors, mostly combined with agonists of gonadotrophin-releasing hormone proved effective for the prevention of premature epiphysial closure in boys with pubertas praecox of various etiologies. Over the years compelling evidence has accumulated that in men estradiol has an important role in gaining and maintaining bone mass, closing of the epiphyses and feedback on gonadotrophin release. In a group of elderly men who obtained exogenous testosterone enenthate, the addition of anastrozole to the injected androgen prevented the androgen induced improvement of verbal memory, but did not affect special memory . The combination with a GnRH analog in order to prevent this increase did not yield beneficial results either . This is in accordance with the data summarized in a recent review , describing similar responses to placebo, tamoxifen and anastrozole in a number of observational studies.
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