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The 2010 Alcohol Hangover Research Group consensus paper defined a cutoff blood alcohol concentration (BAC) of 0.11% as a toxicological threshold indicating that sufficient alcohol had been consumed to develop a hangover. The cutoff was based on previous research and applied mostly in studies comprising student samples. Previously, we showed that sensitivity to hangovers depends on (estimated) BAC during acute intoxication, with a greater percentage of drinkers reporting hangovers at higher BAC levels. However, a substantial number of participants also reported hangovers at comparatively lower BAC levels. This calls the suitability of the 0.11% threshold into question. Recent research has shown that subjective intoxication, i.e., the level of severity of reported drunkenness, and not BAC, is the most important determinant of hangover severity. Non-student samples often have a much lower alcohol intake compared to student samples, and overall BACs often remain below 0.11%. Despite these lower BACs, many non-student participants report having a hangover, especially when their subjective intoxication levels are high. This may be the case when alcohol consumption on the drinking occasion that results in a hangover significantly exceeds their "normal" drinking level, irrespective of whether they meet the 0.11% threshold in any of these conditions. Whereas consumers may have relative tolerance to the adverse effects at their "regular" drinking level, considerably higher alcohol intake-irrespective of the absolute amount-may consequentially result in a next-day hangover. Taken together, these findings suggest that the 0.11% threshold value as a criterion for having a hangover should be abandoned.

Although hangover is a common consequence of heavy alcohol consumption, the area is heavily under-researched. Hangover frequency is a potential predictor of future alcohol use disorder that may be affected by hangover severity, yet the relationship between hangover frequency and severity has not been investigated. Using different methodologies and assessment instruments, two surveys, and one naturalistic study collected data on hangover frequency, hangover severity, and alcohol consumption. The relationship between hangover frequency and severity was investigated via correlational analysis, considering potentially moderating variables including alcohol intake, estimated blood alcohol concentration, demographics, and personality characteristics. In all the three studies, a positive and significant association between hangover frequency and severity was found, which remained significant after correcting for alcohol intake and other moderating factors. These findings suggest that hangover severity increases when hangovers are experienced more frequently and may be driven by sensitization or reverse tolerance to this aspect of alcohol consumption. Future research should further investigate the relationship between hangover frequency and severity and alcohol use disorder and its implications for prevention.

Programmed cell death or apoptosis plays an important role in normal reproductive function. Since apoptosis attributes to the exhaustion of the oocyte/follicle reserve, either directly through germ cell death or indirectly through follicular atresia, this process has been proposed to be the major mechanism that determines the female reproductive lifespan. Moreover, an imbalance between proliferation and apoptosis in the ovary may promote unwanted tissue growth, resulting in ovarian cancer development. A better understanding of programmed cell death in the ovary may help to develop novel therapies to treat females with ovarian disorders, such as premature ovarian failure and ovarian cancer. In this thesis, the function of several hormones on the process of apoptosis in the ovary is investigated. Furthermore, the expression of several apoptotic regulators has been investigated in a variety of ovarian cell types under physiological normal and pathological conditions. To gain more insight in the proteins involved in ovarian apoptosis under normal physiological conditions, we have investigated the localization and distribution of the Fas system and its related proteins in the ovary throughout the estrous cycle in the rat. The results of this study are described and discussed in chapter 2. In chapter 3 we examined the effect of loss of growth hormone (GH) signaling on follicular recruitment, development and atresia by using GH receptor null mice and investigated whether IGF-1 administration could antagonize the absence of GH actions. In chapter 4, the effect of hypothyroidism on follicular development and atresia was investigated in the rat ovary. The ovarian surface epithelium, which covers the ovary, is the source of a frequent and often lethal form of cancer in females. To gain more insight in the proteins that determine the fate of OSE cells and their relation with ovarian cancer, we examined the expression of components of the Fas signaling pathway in relation to apoptosis in human OSE cells at the human ovarian surface, in inclusion cysts, borderline tumors and carcinomas (chapter 5). As described above, gonadotropins, including luteinizing hormone (LH), have been suggested to play an important role in the etiology of epithelial ovarian cancers. Therefore, we examined the effect of LH on the occurrence of Fas-induced apoptosis in human OSE cancer cell lines and determined whether signaling occurs through the activation of protein kinase A (PKA) and/or protein kinase C (PKC) (chapter 6). In the summarizing discussion, the mechanisms by which hormones regulate apoptosis in the ovary are discussed. In addition, the potential means of manipulating apoptosis and its clinical relevance are discussed (chapter 7).