Why does letrozole make you perspire?

The bottom line: no study has investigated why letrozole causes sweating, and the evidence that exists on letrozole's other effects offers no direct answer.

Letrozole is an aromatase inhibitor. It blocks the enzyme that turns androgens into estrogen, dropping estrogen levels sharply [3]. That estrogen withdrawal is known to cause hot flushes and night sweats in women taking it, an effect documented in clinical trials [4]. One trial comparing letrozole to clomiphene for ovulation induction reported hot flushes in 1 of 36 women (2.8%) on letrozole, versus 4 of 35 (11.4%) on clomiphene [4]. But that study did not measure sweating separately, and the mechanism that turns low estrogen into a sweat response has not been traced to any specific pathway in the human trials.

The retrieved studies show letrozole working through hormone signaling. In cell models, letrozole inhibits the MAPK/ERK and PI3K/Akt pathways that depend on local estrogen production [1]. In rat brains, it cuts hippocampal estradiol and impairs memory, while also altering anxiety behavior [2]. None of this research, or the other 23 records here, measured perspiration, skin conductance, or thermoregulation. A plausible guess is that estrogen withdrawal disrupts the hypothalamus, which houses both the estrogen-sensitive kisspeptin neurons and the thermoregulatory center. But that guess is extrapolation, not evidence. The mechanism has not been studied.

Source: randomized prospective study [4]

My call: letrozole almost certainly causes sweating through estrogen-withdrawal effects on the hypothalamus, but the specific pathway, rate, and severity have never been investigated. The evidence is not clear because it does not exist. If you are experiencing this, it is a known side effect of the drug's intended mechanism, and the best medical literature can tell you is to weigh the benefit of the treatment against the symptom. Confidence: low; the sweat mechanism is inferred, not proven.