Aromatase deficiency is a condition characterized by reduced levels of the female sex hormone estrogen and increased levels of male sex hormones called androgens. Mutations in the CYP19A1 gene cause aromatase deficiency. CYP19A1 gene mutations that cause aromatase deficiency decrease or eliminate aromatase activity. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations.

Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. Nicotine administration produced significant, dose-dependent reductions in [(11)C]vorozole binding. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

Epidemiologic studies suggest that women who smoke have lower endogenous estrogen than nonsmokers. In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor component of cigarette tobacco) all inhibited androstenedione conversion to estrogen in a dose-dependent fashion. In preparations of term placental microsomes, nicotine, cotinine, and anabasine inhibited the conversion of testosterone to estrogen. These findings suggest that some nicotinic alkaloids directly inhibit aromatase. This mechanism may explain, in part, the decreased estrogen observed in women who smoke.

Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product). Specifically, female cigarette smokers reach menopause at an earlier age and have lower plasma estrogen levels than non-smoking females. In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor tobacco constituent) all inhibited androstenedione conversion to estrogen in a dose-dependent fashion at concentrations in the low micromolar range. These findings suggest that tobacco alkaloids exert a direct, competitive, and reversible inhibitory effect on aromatase activity at micromolar concentrations.

N-n-octanoylnornicotine and N-(4-hydroxyundecanoyl) anabasine suppressed aromatase activity in culture of two human breast cancer cell lines, MDA-MB-231 (IC50 of 310 and 20 microM, respectively) and SK-BR-3 (IC50 of 450 and approximately 2 microM, respectively). Kinetic analyses showed that inhibition by N-(4-hydroxyundecanoyl)anabasine is competitive with respect to androstenedione as substrate, with apparent Ki values of 0.2 microM against microsomal aromatase activity derived from both (Bt)2cAMP-induced MDA-MB-231 cells and human breast tumor tissue. The corresponding apparent Ki against human placental microsomal aromatase activity was 0.4 microM. These results indicate that acyl derivatives of nornicotine and anabasine block estrogen formation in breast tumor cells and tissue and could contribute to the decreased intra-tissue estrogen levels in women who smoke.

Furthermore, women who smoke cigarettes reach menopause at an earlier age than nonsmoking women and are more likely to develop osteoporosis and have lower plasma levels of the female sex hormone estrogen. The latter observations inspired several studies of nicotine and other tobacco constituents as direct inhibitors of estrogen synthesis. Nicotine, its major metabolite cotinine, and other tobacco alkaloids were indeed found to inhibit aromatase activity in human trophoblasts, granulosa cells, and breast cancer cells, presumably through direct competitive binding to the active site of the enzyme.

Epidemiologic studies suggest that women who smoke have lower endogenous estrogen than nonsmokers. In choriocarcinoma cell cultures, nicotine, cotinine, and anabasine all inhibited androstenedione conversion to estrogen in a dose-dependent fashion. Removal of nicotine, cotinine, and anabasine from the culture medium resulted in the complete reversal of the inhibition of aromatase. These findings suggest that some nicotinic alkaloids directly inhibit aromatase. This mechanism may explain, in part, the decreased estrogen observed in women who smoke.

Moreover, smoking appears to alter the metabolism of estradiol, leading to enhanced formation of the inactive catechol estrogens. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro. Constituents of cigarette smoke inhibit human granulosa cell aromatase. These findings support the concept that cigarette smoking has an antiestrogenic effect in women.

In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor component of cigarette tobacco) all inhibited androstenedione conversion to estrogen in a dose-dependent manner. Removal of nicotine, cotinine, and anabasine from the culture medium resulted in the complete reversal of the inhibition of aromatase. In preparations of term placental microsomes, nicotine, cotinine, and anabasine inhibited the conversion of testosterone to estrogen. These findings suggest that some nicotinic alkaloids directly inhibit aromatase. This mechanism may explain, in part, the decreased estrogen observed in women who smoke.

A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.

Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product). Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior.

Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product). Specifically, female cigarette smokers reach menopause at an earlier age and have lower plasma estrogen levels than non-smoking females. In choriocarcinoma cell cultures, nicotine, cotinine, and anabasine all inhibited androstenedione conversion to estrogen in a dose-dependent fashion. Using [11C]vorozole, we have recently shown that acute in vivo exposure to nicotine doses which produced plasma levels similar to those found in smokers, resulted in significant region- and dose-dependent decreases in aromatase availability in the female baboon brain.

Aqueous extracts of cigarette smoke inhibited the conversion of androstenedione (delta 4A) to estradiol in a dose-dependent manner. Two low-molecular-weight components of cigarette smoke, nicotine and anabasine, inhibited granulosa cell aromatase in a dose-dependent manner. These studies suggest that constituents of cigarette smoke inhibit a major steroidogenic pathway.

Furthermore, smoke also acts as an aromatase inhibitor, which may impact the levels of key hormones for breast tissue due to its role in androgen-to-estrogen conversion. An animal study in female baboons showed that administering nicotine at doses equivalent to that of an average smoker inhibited aromatase function by close to 50%. In the present study, increased androstenedione and testosterone levels were observed in current smokers who were non-OC users, indicating that current smoking might be a contributing factor to the increase in androgens. Nicotine also acts as an aromatase inhibitor, which may partly explain the androgenic profile.

Smoking has anti-oestrogenic effects and decreases endogenous oestrogen. Constituents of cigarettes such as nicotine and other tobacco alkaloids inhibited oestrogen synthesis via the aromatase enzyme when tested in vitro. Preoperative smoking was only associated with an increased risk for breast cancer events and distant metastasis in AI-treated patients, suggesting that smoking may influence the effectiveness of aromatase inhibitor treatment.

Nicotine and other constituents of tobacco and tobacco smoke inhibit the enzyme in-vitro, and smokers have lower expression in the brain and in the placentas of pregnant women at term. Smoking may also inhibit aromatase in breast cancer tissue. The effect of smoking on aromatase in endometrial, ovarian and thyroid cancers has not been investigated, but important effects on endometrial cancer are unlikely since aromatase expression is low in that malignancy.

Acute nicotine exposure blocks aromatase in the limbic brain of healthy women: A [11C]cetrozole PET study. Nicotine was found to reduce human aromatase activity and expression in vitro. Prenatal exposure to nicotine is associated with a reduced aromatase activity as well as mRNA and protein expression in foetal, neonatal and adult rodents. The findings indicate acute blocking of aromatase availability by nicotine in the thalamic area, likely reflecting a direct blockade of its enzymatic activity.

A dose of nicotine, equivalent to that found in a single cigarette blocks estrogen production in women’s brains. “For the first time, we can see that nicotine works to shuts down the estrogen production mechanism in the brain of women. We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain. The researchers found that a single dose moderately reduced the amount of aromatase in the brain. This is the first time that this inhibitory effect on aromatase production has been shown in humans.

After the participants in a study received a dose of nicotine corresponding to one cigarette, the levels of the enzyme responsible for estrogen synthesis in the brain decreased. The results show that a single dose of nicotine moderately reduced the availability of aromatase in the studied women’s brains, especially in the thalamus where the highest level of aromatase binding is found. This is the first time that this inhibitory effect on aromatase has been demonstrated in humans. These results lead us to believe that nicotine’s effect on estrogen production may have a significant impact on the brain, and perhaps also on other functions such as the reproductive system.

A chance observation that cigarette smoke interferes with the aromatase assay led us to investigate tobacco leaf and smoke extracts for the presence of aromatase inhibitors. These in vivo studies suggest that tobacco alkaloid derivatives exert their effects by suppression of the aromatase enzyme system. This work provided early evidence that components of cigarette smoke can act as aromatase inhibitors.

Thus, cigarette smoke extract adversely affects the maturation of human granulosa cells, affecting both angiogenesis and aromatase activity. In KGN cells, exposure to cigarette smoke extract reduced aromatase activity, indicating that smoking-related substances can impair estrogen production in ovarian granulosa cells.

In conclusion, the first outcome of the present study is the finding that chronic cigarette smoking (compared with permanent tobacco abstinence) augments serum androgens including some 5α/β-reduced androstane metabolites but suppresses estradiol levels in the luteal phase, which may induce hyperandrogenism in the female smokers. These results indicate that long-term smoking in women is associated with decreased circulating estrogen and altered androgen-to-estrogen balance, consistent with anti-estrogenic effects of smoking.

In vitro and animal studies have shown that nicotine can impede the production of an enzyme that regulates estrogen production. The team discovered that nicotine exposure moderately reduced the amount of aromatase in the brain. The researchers believe that their study is the first to show this inhibitory effect on aromatase production in humans. "For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brain of women... showing how powerful the effects of smoking are on a woman’s brain."

This is because smoking can affect the response to treatments, including endocrine therapies such as tamoxifen and aromatase inhibitors. Smokers treated with aromatase inhibitors were found to have a three times higher risk of recurrence of breast cancer compared with non-smokers who got the same treatment. The link between smoking and breast cancer is becoming increasingly evident, with both active and passive smoking contributing to heightened risk.

Smoking impacts endogenous estradiol and testosterone. Cigarette smoke contains multiple carcinogens and is considered a risk factor for breast cancer. However, tobacco also contains aromatase inhibiting substances, but the impact on hormonal levels in young women at the age when breast cancer is initiated is unclear and needs further elucidation.

Still, when the researchers looked at just the 309 women older than age 50 diagnosed with estrogen-receptor-positive disease who were treated with an aromatase inhibitor after surgery, they found that smoking increased the risk of recurrence as well as the risk of dying from breast cancer. “Smokers who were treated with aromatase inhibitors had a three times higher risk of recurrence of breast cancer compared with the non-smokers who got the same treatment,” said Helena Jernström. The study suggests that smoking makes a class of hormonal therapy medicines, the aromatase inhibitors, much less effective.

Among breast cancer patients taking a class of drugs called aromatase inhibitors, smokers had a three times greater risk of their cancer returning than nonsmokers, the investigators found. The researchers found that women 50 or older who were treated with aromatase inhibitors fared considerably worse during the follow-up period if they smoked than if they didn’t. The smokers were also more likely to die from their cancer or other illnesses during the roughly five-year follow-up period, the findings showed.

Smoking was found to significantly reduce the effectiveness of the breast cancer treatment drug aromatase inhibitor. Among patients who smoked before or after being diagnosed with hormone receptor-positive breast cancer, the effect of the aromatase inhibitor was reduced, and the recurrence rate was three times higher compared to patients who did not smoke. Professor Helena Jernström, who led the research team, stated that the recurrence risk was three times higher in smokers than in non-smokers receiving the same treatment.

The National Center for Biotechnology Information (NCBI) shows "Smoking-attributed nicotine is known to inhibit aromatase enzyme activity, which catalyzes the conversion of androgens into estrogens. Consequently, nicotine reduces circulating estrogen levels and leads to early onset of menopause in women." In plain terms, smoking makes estrogen levels fall faster than in non-smokers and also brings on menopause sooner.

Nicotine inhibits the aromatase enzyme. Aromatase converts testosterone into estrogen, so nicotine will make it harder to keep T suppressed and E elevated. This comment reflects lay understanding that smoking or nicotine exposure can interfere with estrogen production via aromatase inhibition, though it does not distinguish between temporary inhibition and congenital aromatase deficiency.

Smoking blocks estrogen production in women. The nicotine dose from a single cigarette is sufficient to temporarily block the production of the hormone estrogen in the female brain. After nicotine administration, the typical distribution pattern of aromatase changed, and the amount of the estrogen-producing enzyme in the thalamus decreased significantly, indicating that estrogen production in this region was blocked. "For the first time, we saw that nicotine blocks the mechanism of estrogen production in the brains of women," the report stated.

Nicotine inhibits the aromatase enzyme. Aromatase converts testosterone into estrogen, so nicotine will make it harder to keep T suppressed and E elevated. This community discussion reflects an understanding that smoking or nicotine use could interfere with estrogen production by blocking aromatase.