Introduction

Figure 1 (Messer et al., 2008)

Tobacco use is the leading preventable cause of death and disease in the U.S.  As of 2012, 42.1 million adults in the U.S. were current smokers, and 33.0 million reported daily smoking (CDC, 2012).  Cigarette smoking accounts for over 480,000 deaths each year and smoking related illness is estimated to cost over $290 billion each year.  The majority of smokers wish to quit or make quit attempts, however complete cessation is achieved in few of these individuals.  84% of 18 to 24 year olds in a survey reported making a serious quit attempt in the last year, however only 8.5% of them had remained abstinent from tobacco for over 6 months.  Cessation rates for smokers older than 24 are even lower (Figure 1) (Messer, Trinidad, Al-Delaimy, & Pierce, 2008).

One area of research on nicotine examines the interaction with endocrinology.  In the 1980’s, research was produced implicating a relationship between nicotine and cortisol, a hormone primarily involved with stress (Seyler, Pomerleau, Fertig, Hunt, & Parker, 1986).  Additionally, notable sex differences in the effects of nicotine have been observed, creating questions about the role of sex hormones in tobacco use (Damaj, 2000).  Some research has been devoted to hormones associated with hunger and satiety, such as leptin and ghrelin, and the potential influence on nicotine use and craving (Perkins & Fonte, 2000).

The study of endocrinology and nicotine can be a complex task.  A primary consideration is understanding when nicotine use affects hormonal responses, and when there is hormonal control over nicotine use and the effects of the drug. Zoli and Picciotto (2012) explain that nicotine has an inverted U dose-response relationship on receptors and behavior, and both desensitized and upregulates receptors with chronic administration.  Thus acute versus chronic nicotine administration and the dosage used can lead to varying effects.   Lastly, due to the unethical nature of manipulating hormones in humans, much research must be done in animal models, which may be simplified or not easily translatable.  All of these factors together lead to variability in results and some incongruence in the literature on hormones and nicotine.  However, continuous research exploring different elements of this subject may help uncover an important relationship between nicotine and components of the endocrine system.

Sex Hormones

Sex hormones became a target of research due to noted sex differences in response to nicotine.  Booze et al. (1999) states that in intact male and female mice, acute nicotine administration stimulated locomotor activity.  In castrated and ovariectomized mice, acute nicotine administration depressed locomotor activity.  Chronic administration led to increased locomotor activity of intact mice, with female mice being most sensitive to the effect.  However, castrated mice increased locomotor activity when compared to intact males, and ovariectomized females lessened their activity when compared to intact females (Figure 2).

Figure 2 (Booze et al., 1999)

Figure 3 (Harrod et al., 2007)

Harrod, Booze, and Mactutus (2007) analyzed sex differences in plasma nicotine levels in intact and gonadectomized rats.  The rats were given one intravenous injection of nicotine each day.  Female rats had higher plasma nicotine levels than male rats, showing possible sex differences in metabolism and distribution leads to higher lasting levels of nicotine in females, thus explaining the differences in behavior.  Male and female rats that were gonadectomized displayed similar levels of plasma nicotine, showing plasma nicotine levels are dependent upon gonadal hormones and may account for the higher sensitivity of females to nicotine (Figure 3).

           

Estrogen is believed to be responsible for increased vulnerability to the effects of nicotine, while progesterone may serve as a protective factor (Lynch & Sofuoglu, 2010; Schiller, Saladin, Gray, Hartwell, & Carpenter, 2014).  Lynch (2009) reported varying amounts of lever presses in female mice at different phases of the estrous cycle.  Rats responded most in the estrus phase, which is associated with increasing concentrations of estradiol and decreasing concentrations of progesterone.  These findings are consistent with the findings about other reinforcing drugs as well; leading to the conclusion that estradiol modulates dopamine in the striatum and enhances the rewarding effects of nicotine. Lynch and Sofuoglu (2010) speculate that progesterone and its metabolites regulate neuronal signaling, which in turn may regulate the effects of nicotine.  Progesterone has been implicated in interacting with GABA receptors, serotonin receptors, and nicotinic acetylcholine receptors.  Enhanced GABA transmission may serve to decrease the rewarding effects of a drug, thus decreasing sensitivity to the addictive properties of nicotine.  Progesterone seems to negatively modulate nicotinic receptors through a mechanism that may be comparable to smoking cessation medications. (Lynch & Sofuoglu, 2010).  Progesterone may have a function in smoking cessation, by decreasing the rewarding effects of using nicotine, attenuating smoking urges, and increasing cognitive performance.

           

Schiller et al. (2014) used smoking topography to measure acute smoking changes with different concentrations of progesterone and estradiol.  The topography variables that were included were puff number, flow rate, and puff intensity.  The progesterone to estradiol ratio had some influence on smoking behavior, but the magnitude and reliability of this effect is limited.  When both estradiol and progesterone were decreasing, participants had a greater puff intensity than baseline.  A high level of progesterone to estradiol was associated with decreased smoking behavior, but not absolute progesterone levels. (Figure 4). Only about 5% of variance in smoking behavior could be explained by ovarian hormones (Schiller et al., 2014).

Figure 4 (Schiller et al., 2014)

Researchers have looked for a connection between nicotine use and cessation at different points of the menstrual cycle.  Allen, Mooney, Chakraborty, and Allen (2009) had female subjects record a diary of their smoking behavior and menstrual status.  No differences were found in regular smoking patterns at different stages of the menstrual cycle.  However, in the morning when cigarettes are being used to alleviate overnight withdrawal, women smoked more in the menses phase than in the follicular phase.  Menstrual phase was determined not to influence circadian smoking patterns, but may play a role in severity of withdrawal symptoms. Mello (2011) confirmed these findings and elaborates on menstrual phase modulating withdrawal symptoms associated with short-term nicotine abstinence. For example, women in the follicular phase reported higher craving for a cigarette and a higher rush from smoking a cigarette than women in the luteal phase (Mello, 2011).

            

Sex differences in sensitivity to the effects of nicotine are apparent.  Testosterone seems to be unrelated, while estradiol and progesterone have contrasting effects in modulating the response to nicotine (Damaj, 2000).  Estradiol enhances sensitivity to nicotine while progesterone does the opposite, however, research analyzing different phases of the menstrual cycle and nicotine-related behaviors are inconclusive (Lynch, 2009; Mello, 2011).  The most important question that must be answered is the mechanism through which ovarian hormones and nicotine are related, as there are multiple theories but none seem to gain a general consensus across the literature.

Stress: Cortisol and HPA Axis

Figure 5 (Mendelson et al., 2008)

The relation between nicotine and cortisol, as well as other hormones associated with stress and the hypothalamic-pituitary-adrenal (HPA) axis, has been examined in the literature.  Early research found cortisol and ACTH levels were increased after smoking high nicotine cigarettes and were significantly greater than in individuals who smoked a low nicotine cigarette (Seyler et al., 1986).  Xue et al. (2010) reported an increase in cortisol levels in average nicotine cigarettes compared to low nicotine cigarettes, however the correlation between plasma nicotine and cortisol was not as strong as anticipated (r = 0.66).  Despite statistical significance, the clinical significance of the raise in cortisol level is believed to be minimal. Smokers have higher basal cortisol levels than non-smokers, and smoking serves to reduce cortisol levels (Mendelson. Goletiani, Sholar, Siegel, & Mello, 2008).  High nicotine cigarettes may act as a greater stressor than low nicotine cigarettes, explaining why smoking led to a larger decrease in cortisol among low nicotine consumers.  ACTH levels increased after one high nicotine cigarette, returned to baseline and did not increase with a second cigarette, but then increased after a third cigarette.  This pattern may relate to a feedback mechanism involving ACTH and cortisol, yet the exact mechanism is unknown.  Males who smoked low nicotine cigarettes saw no change in ACTH (Figure 5) (Mendelson et al., 2008).          

al’Absi, Hatsukami, Davis, and Wittmers (2004) found acute abstinence from nicotine increased HPA axis activity and cortisol levels.  Smokers experience withdrawal at night while sleeping, and higher morning cortisol levels are associated with more intense withdrawal symptoms. Nakajima and al’Absi (2013) assessed levels of cortisol in smokers who are successfully abstinent versus those who relapsed.  For 3 weeks following a quit attempt cortisol levels were relatively stable, but around 4 weeks post-quit the basal cortisol levels of abstainers started to reduce (Figure 6).  It is expected that cortisol levels of abstainers would continue to decrease and return to levels closer to those of a nonsmoker on an extended timeline.

Figure 6 (Nakajima & al'Absi, 2013)

Chen, Fu, and Sharp (2008) investigated the effect of chronic nicotine self-administration on HPA hormonal responses to various acute stressors. Nicotine served as a stressor and stimulated corticosterone and ACTH release on day 1, but this effect is diminished over time.  Chronic administration led to continuous stimulation of norepinephrine in the PVN and amygdala.  Chronic nicotine administration varied HPA hormonal outcomes depending on the stressor intensity.  In low intensity stressors, there was moderate HPA hormonal activation, which was further increased by nicotine.  In high intensity stressors, corticosterone and ACTH levels were largely increased and nicotine did not increase them further (Chen et al., 2008). Yu and Sharp (2010) report nicotine self-administration reduced the intensity and duration of a norepinephrine response in the PVN to footshock stress.  The stress of chronic nicotine self-administration led to decreased HPA hormonal activation in similar stressors and increased corticosterone and ACTH release with non-related stressors.  Looking at the relationship in reverse, Faraday, Blakeman, and Grunberg (2005) reports on stress altering the effects of nicotine.  In males, stress did not modulate outcomes related to nicotine, such as body weight changes, but it was observed in females.  However, depending on the strain of rat and dosage, there was much variability in the relationship between stress and nicotine use and the behavioral outcomes are not always clear.

Nicotine administration stimulates the HPA axis and cortisol release, however dosage and frequency of use may modulate this relationship (Xue et al., 2010).  Baseline cortisol levels are higher in smokers compared to nonsmokers (Mendelson et al., 2008).  The effect of nicotine combined with a stressor on cortisol is dependent on the type as well as intensity of the stressor.  There is evidence that chronic stress and cortisol modulates expression of nicotinic acetylcholine receptors (Baier et al., 2014; Hunter, Bloss, McCarthy, & McEwen, 2010) but how this may influence smoking behavior or the effects of nicotine has not been examined.

Hunger and Satiety Hormones

Figure 7 (al'Absi et al., 2014)

Hormones typically associated with hunger and satiety, such as ghrelin, leptin, and peptide YY, may also function in nicotine craving and reward. High peptide YY levels were associated with lower craving for nicotine and increased positive affect in abstinent smokers, with an overall result of lower desire to alleviate withdrawal symptoms (al’Absi, Lemieux, & Nakajima, 2014). Ghrelin did not follow the same trend, but ghrelin levels predicted risk of relapse with a positive relationship (Figure 7).  Ghrelin is believed to interact with nicotinic acetylcholine receptors to enhance dopamine in the reward circuit and make the reinforcing effects of nicotine more salient (al’Absi et al., 2014).  This is consistent with other literature explaining ghrelin activating the reward pathway through cholinergic links. (Engel & Jerlhag, 2014).  The details of this mechanism are still being examined.

Zoli and Picciotto (2012) examined the role of nicotine in energy homeostasis.  Cigarette smoke exposure results in inhibition of NPY in the PVN, which would result in inhibited food intake.  Evidence for the relationship between leptin and nicotine has been sparse and inconclusive.  Varying doses, styles of administration, and food restrictions have yielded different results on the relation between nicotine and leptin (Zoli & Picciotto, 2012).  Leptin is thought to be involved with weight changes associated with chronic smoking and abstinence. Perkins and Fonte (2002) report male and female smokers had a significant increase in weight 3 weeks after quitting smoking.  Leptin levels were increased in women, but there were no changes in men. The researchers expected for leptin levels to decrease and stimulate hunger rather than increase, so the effect of nicotine on weight was not attributed to changes in leptin.

Hunger and satiety hormones need greater investigation to gain a clear grasp in their role on nicotine craving and reward.  Ghrelin and peptide YY seem to relate to withdrawal symptoms and maintained abstinence versus relapse (al’Absi et al., 2014).  These hormones can potentially aid in the development of different smoking cessation methods.  It is unclear if leptin is related to these concepts or has an association with weight changes of smoking and abstinence (Perkins & Fonte, 2002).  Research into these hormones need more evidence and the mechanism of action must be explored. 

Conclusions and Future Directions

It is difficult to get a clear grasp of the relationship between nicotine and the endocrine system.  This is due to the huge variety in research on different hormones, different types of administration, varying doses, and withdrawal and abstinence.  However, nicotine and endocrinology have a relationship that must be further explored.  This research may be able to contribute to understanding nicotine use behavior, as well as grasping differences between those who quit smoking and those relapse.  The more factors that can be identified to explain the difference between those two groups improves the chances of developing interventions and medications to target these systems and provide opportunities individuals for successful cessation attempts. 

Manbeck, Shelley, Schmidt, and Harris (2014) reported an effect of oxytocin on blocking somatic symptoms associated with nicotine withdrawal, but not negative affect.  However, reducing somatic symptoms may attenuate anhedonia in some individuals, or pairing oxytocin with a pharmacological smoking cessation agent with antidepressive effects such as bupropion may yield positive results.  Additionally, the association of peptide YY with lower craving and increased positive affect in abstinent smokers may serve as useful information for smoking cessation (al’Absi et al., 2014).  Lastly, a greater understanding of ovarian hormones and how they can influence nicotine-related behaviors may help determine why some individuals have a greater sensitivity to the effects of nicotine. 

Research on nicotine use and behavior as related to the endocrine system should solidify established concepts and expand upon them.  The fluctuations in hormones at different time point can potentially help to explain differences in cessation success amongst a variety of individuals.  Additionally, the array of implicated hormones should be considered when an individual is deciding to make a quit attempt.  Future research should involve manipulating hormones in animal models with the goal of decreasing the desire to obtain nicotine.  However, until the mechanisms through which hormones may manipulate the effects of nicotine, and how nicotine affects hormonal systems, practical application of the findings in the literature is limited.