Letrozole (Femara) is a potent, nonsteroidal, reversible or nonsuicidal aromatase inhibitor (AI) approved by the FDA for local or metastatic hormone-receptor positive or unknown status breast cancer in postmenopausal women. Letrozole is used off-label to treat gynecomastia (especially drug-induced gynecomastia), hyperestrogenism, as part of a hormone replacement regimen in men, and in adolescents for short stature syndrome. As with other AIs, the majority of side-effects relate to hypoestrogenism (low circulating estrogen levels).
In the human body, estrogen is created through an enzymatic process called reduction. Rather than target a receptor for antagonism in the fashion of selective estrogen receptor modulators (SERMs), aromatase inhibitors inhibit the enzyme (aromatase) responsible for the creation of estrogen. AIs that permanently bind to the aromatase are known as “irreversible” or “suicidal,” while “reversible” AIs do not form a permanent complex. Letrozole belongs to the latter class (reversible AIs). In practice, the half-life of aromatase inhibitors may be more relevant to therapeutic administration than the mechanism (reversible or irreversible) of inhibition.
In women, the most serious hypoestrogenic side-effect experienced from letrozole usage (and similar to other AIs) is osteoporosis with long-term usage; to address this concern, in postmenopausal women letrozole is often prescribed with bisophosphonates or other osteoporosis prevention drugs.
Letrozole and other AIs are not always suitable as an androgen-boosting monotherapy in hypogonadal men; obese men, as a treatment group, are the most likely to benefit. Obesity-related hypogonadism is more likely to be estrogen-related (where hyperestrogenism is present due to adipose tissue producing excess aromatase).
The effects of a single weekly dose of letrozole (2.5mg) were studied in men with obesity-related hypogonadism:
[the purpose of the study was to] evaluate whether letrozole once a week can normalize serum testosterone in severely obese men and maintain its long term effect….12 severely obese men (body mass index>35.0 kg/m2) with obesity-related IHH and free testosterone levels <225 pmol/l, [were] treated with 2.5 mg letrozole once a week for 6 months....Six weeks of treatment reduced total E2 [by over 50% and] increased serum LH [by greater than double]. Total testosterone rose from 5.9±0.5 to 19.6±1.4 nmol/l (P<0.001), and free testosterone from 163±13 to 604±50 pmol/l (P<0.001). Total testosterone rose to within the normal range in all subjects, whereas free testosterone rose to supraphysiological levels in 7 out of 12 men. The testosterone and E2 levels were stable throughout the week and during the 6-month treatment period….Letrozole 2.5 mg once a week produced a sustained normalization of serum total testosterone in obese men with IHH. However, free testosterone frequently rose to supraphysiological levels. Therefore, a starting dose <2.5 mg once a week is recommended.
The authors (Loves, Ruinemans-Koerts, and de Boer, 2008) go on to discuss the potential unique merits of AI monotherapy over TRT for obese hypogonadal men:
Extrapolation of the effects of testosterone replacement in non-obese or overweight hypogonadal men is hazardous because the results may prove to be markedly different in severe obesity.... Due to the high conversion of testosterone to E2, testosterone replacement is likely to raise serum E2 levels considerably and this may produce clinically relevant adverse effects. Therefore, it may be useful to explore the pros and cons of alternative modes of treatment, such as the use of aromatase inhibitors. In theory, the main risks of this treatment are excessive reduction of estrogen levels, which could adversely affect bone metabolism, and overstimulation of LH secretion, which could lead to supraphysiological testosterone levels. However, aromatase inhibition may also have new advantageous effects because of its stimulatory effects on follicle-stimulating hormone (FSH) secretion. This could be of benefit in the case of reduced fertility, which is common in severely obese men
Another group with unique needs who may benefit from (at present) off-label use of letrozole is female-to-male (FTM) transexuals using testosterone to assist their transition. This group’s needs somewhat resemble cisgender males who are administering testosterone. When provided as an accompaniment to a 1000mg testosterone undecanoate regimen, patients treated with letrozole did not experience negative changes to insulin resistance, FSH, LH, or body compositon.
In young men, letrozole changes a number of hormonal and metabolic measures:
Short-term aromatase inhibition appears to affect glucose metabolism in young men, and lipid metabolism, including leptin secretion, in young and elderly men. Furthermore, the short period of exposure suggests that these changes might be mediated by direct effects of sex steroids rather than by changes in body composition...Fasting glucose and insulin levels decreased in young men after active intervention (-7 and -37%, respectively) compared with placebo. Leptin levels fell markedly in both age groups (-24 and -25%, respectively), while adiponectin levels were not affected by the intervention.
Lapauw et al (2009) also found that many effects were present in both age groups:
Both in young and elderly men, active treatment significantly increased serum testosterone (+128 and +99%, respectively) and decreased estradiol levels (-41 and -62%, respectively). Lipid profile was slightly impaired in both groups, with increasing low density lipoprotein-cholesterol levels (+14%) in the younger age group and 10% lower levels of APOA1 in the elderly. No changes in weight or body mass index were observed in either young or old men. 
A successful outcome in a patient experiencing infertility due to azoospermia (undetectable sperm levels in semen) echoes the success of AIs to treat male infertility in some cases, despite being considered off-label: "Testis biopsy showed normal spermatogenesis following 4 months of letrozole therapy."
 Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer, the BIG 1-98 Collaborative Group, N Engl J Med, 361:766, 2009 Aug 20.
 32nd Annual San Antonio Breast Cancer Symposium.
 Loves S, Ruinemans-Koerts J, de Boer H. Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol. 2008 May;158(5):741-7.
 Meriggiola MC, Armillotta F, Costantino A, Altieri P, Saad F, Kalhorn T, Perrone AM, Ghi T, Pelusi C, Pelusi G. Effects of testosterone undecanoate administered alone or in combination with letrozole or dutasteride in female to male transsexuals. J Sex Med. 2008 Oct;5(10):2442-53.
 Lapauw B, T'Sjoen G, Mahmoud A, Kaufman JM, Ruige JB.. Short-term aromatase inhibition: effects on glucose metabolism and serum leptin levels in young and elderly men. Eur J Endocrinol. 2009 Mar;160(3):397-402.
 Patry G, Jarvi K, Grober ED, Lo KC. Use of the aromatase inhibitor letrozole to treat male infertility.Fertil Steril. 2009 Aug;92(2):829.e1-2.