Optimizing sleep across the menopausal transition.

Women frequently experience sleep disturbances, particularly night-time awakenings, as they transition menopause and enter postmenopause. Sleep is essential for optimal functioning and health. Persistent and distressing sleep disturbances across menopause can negatively impact daytime functioning and productivity, and increase risk for mental and physical health conditions. While multiple factors can disturb sleep, two unique factors in the context of menopause are vasomotor symptoms and the changing reproductive hormone environment. Vasomotor symptoms are associated with sleep disturbances and contribute significantly to awakenings and amount of time spent awake during the night. Even after accounting for vasomotor and depressive symptoms, lower estradiol and higher follicle stimulating hormone levels, indicative of menopause, are associated with sleep disturbance, particularly awakenings, suggesting that the hormone environment may directly affect sleep. Management strategies for clinically significant menopausal sleep disturbances include cognitive behavioral therapy for insomnia, which is effective and durable in treating menopausal insomnia. Hormone therapy alleviates sleep disturbances, particularly in the presence of disruptive vasomotor symptoms. Sleep disturbances have a significant impact on women's functioning and health, and there is a need for further research of the underlying mechanisms to advance effective preventative and treatment strategies that ensure optimal health and well-being of midlife women.

Youth screen use in the ABCD® study.

Adolescent screen usage is ubiquitous and influences development and behavior. Longitudinal screen usage data coupled with psychometrically valid constructs of problematic behaviors can provide insights into these relationships. We describe methods by which the screen usage questionnaire was developed in the Adolescent Brain Cognitive Development (ABCD) Study, demonstrate longitudinal changes in screen usage via child report and describe data harmonization baseline-year 2. We further include psychometric analyses of adapted social media and video game addiction scales completed by youth. Nearly 12,000 children ages 9-10 years at baseline and their parents were included in the analyses. The social media addiction questionnaire (SMAQ) showed similar factor structure and item loadings across sex and race/ethnicities, but that item intercepts varied across both sex and race/ethnicity. The videogame addiction questionnaire (VGAQ) demonstrated the same configural, metric and scalar invariance across racial and ethnic groups, however differed across sex. Video gaming and online social activity increased over ages 9/10-11/12 (p's < 0.001). Compared with boys, girls engaged in greater social media use (p < .001) and demonstrated higher ratings on the SMAQ (p < .001). Compared with girls, boys played more video games (p < .001) and demonstrated higher ratings on the VGAQ (p < .001). Time spent playing video games increased more steeply for boys than girls from age 9/10-11/12 years (p < .001). Black youth demonstrated significantly higher SMAQ and VGAQ scores compared to all other racial/ethnic groups. These data show the importance of considering different screen modalities beyond total screen use and point towards clear demographic differences in use patterns. With these comprehensive data, ABCD is poised to address critical questions about screen usage changes across adolescence.

Adolescent Binge Drinking Is Associated With Accelerated Decline of Gray Matter Volume.

The age- and time-dependent effects of binge drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume (GMV) development was examined using 5 waves of longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study. Binge drinkers (n = 166) were compared with non-binge drinkers (n = 82 after matching on potential confounders). Number of binge drinking episodes in the past year was linked to decreased GMVs in bilateral Desikan-Killiany cortical parcellations (26 of 34 with P < 0.05/34) with the strongest effects observed in frontal regions. Interactions of binge drinking episodes and baseline age demonstrated stronger effects in younger participants. Statistical models sensitive to number of binge episodes and their temporal proximity to brain volumes provided the best fits. Consistent with prior research, results of this study highlight the negative effects of binge drinking on the developing brain. Our results present novel findings that cortical GMV decreases were greater in closer proximity to binge drinking episodes in a dose-response manner. This relation suggests a causal effect and raises the possibility that normal growth trajectories may be reinstated with alcohol abstinence.

Substance use patterns in 9-10 year olds: Baseline findings from the adolescent brain cognitive development (ABCD) study.

BACKGROUND: The Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12. METHODS: This study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort's early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD). PRIMARY RESULTS: At baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine, <0.1 % used any other drug of abuse). Analyses revealed that total caffeine use and early alcohol sipping were associated with demographic variables (p's<.05), externalizing symptoms (caffeine p = 0002; sipping p = .0003), and parental history of AUD (sipping p = .03). CONCLUSIONS: ABCD Study participants aged 9-10 years old reported caffeine use and alcohol sipping experimentation, but very rare other SU. Variables linked with early childhood alcohol sipping and caffeine use should be examined as contributing factors in future longitudinal analyses examining escalating trajectories of SU in the ABCD Study cohort.

Baseline brain function in the preadolescents of the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

Does pain vary across the menstrual cycle? A review.

Reproductive hormones are implicated in moderating pain. Animal studies support both pronociceptive and antinociceptive actions of oestradiol and progesterone suggesting that the net effect of these hormones on pain is complex and likely depends on the interaction between hormones and the extent of fluctuation rather than absolute hormone levels. Several clinical pain conditions show variation in symptom severity across the menstrual cycle. Though, there is still no consensus on whether the menstrual cycle influences experimental pain sensitivity in healthy individuals. Comprehensive literature searches on clinical and experimental pain across the menstrual cycle, as well as gonadal hormones and pain were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full-text manuscripts were reviewed for relevancy and reference lists were cross-checked for additional relevant studies. Most of the more recent, well-controlled studies show that menstrual cycle phase has no effect on the perception of pain in healthy, pain-free women. Although recent studies investigating pain-related brain activation have shown differential activation patterns across the menstrual cycle in regions involved with cognitive and motor function, even in the absence of a behavioural pain response, suggesting that cognitive pain and bodily awareness systems are sensitive to menstrual cycle phase. The interaction between the gonadal hormones and pain perception is intricate and not entirely understood. We suggest further investigations on the association between female reproductive hormones and pain sensitivity by exploring the interaction between clinical and experimental pain and the hormone changes that characterize puberty, post-partum and the menopause transition.

Women with dysmenorrhoea are hypersensitive to experimentally induced forearm ischaemia during painful menstruation and during the pain-free follicular phase.

BACKGROUND: Monthly primary dysmenorrhoeic pain is associated with increased sensitivity to painful stimuli, particularly in deep tissue. We investigated whether women with dysmenorrhoea, compared with controls, have increased sensitivity to experimentally induced deep-tissue muscle ischaemia in a body area distant from that of referred menstrual pain. METHODS: The sub-maximal effort tourniquet test was used to induce forearm ischaemia in 11 women with severe dysmenorrhoea and in nine control women both during menstruation and in the follicular phase of the menstrual cycle. Von Frey hair assessments confirmed the presence of experimental ischaemia. Women rated the intensity of menstrual and ischaemic pain on a 100-mm visual analogue scale. RESULTS: Women with dysmenorrhoea [mean (SD): 68 (20) mm] reported significantly greater menstrual pain compared with controls [mean (SD): 2 (6) mm; p = 0.0001] during the menstruation phase. They also rated their forearm ischaemic pain as significantly greater than the controls during the menstruation [dysmenorrhoeics vs. controls mean (SD): 58 (19) mm vs. 31 (21) mm, p < 0.01] and follicular [dysmenorrhoeics vs. controls mean (SD): 60 (18) mm vs. 40 (14) mm, p < 0.01] phases of the menstrual cycle. CONCLUSIONS: These data show that compared with controls, women who experience severe recurrent dysmenorrhoea have deep-tissue hyperalgesia to ischaemic pain in muscles outside of the referred area of menstrual pain both during the painful menstruation phase and pain-free follicular phase. These findings suggest the presence of long-lasting changes in muscle pain sensitivity in women with dysmenorrhoea. Our findings that dysmenorrhoeic women are hyperalgesic to a clinically relevant, deep-muscle ischaemic pain in areas outside of referred menstrual pain confirm other studies showing long-lasting changes in pain sensitivity outside of the painful period during menstruation.

Dissociation of preparatory attention and response monitoring maturation during adolescence.

OBJECTIVE: Substantial brain development occurs during adolescence providing the foundation for functional advancement from stimulus-bound "bottom-up" to more mature executive-driven "top-down" processing strategies. The objective was to assess development of EEG markers of these strategies and their role in both preparatory attention (contingent negative variation, CNV) and response monitoring (Error Related Negativity, ERN, and Correct Related Negativity, CRN). METHODS: CNV, ERN and CRN were assessed in 38 adolescents (18 girls), age 11-18 years, using a variation of a letter discrimination task. RESULTS: Accuracy increased with age and developmental stage. Younger adolescents used a posterior attention network involved in inhibiting irrelevant information. Activity in this juvenile network, as indexed by a posteriorly-biased CNV and CRN decreased with age and advancing pubertal development. Although enhanced frontal CNV, known to be predictive of accuracy in adults, was not detected even in the older adolescents, top-down medial frontal response monitoring processes (ERN) showed evidence of development within the age-range studied. CONCLUSIONS: The data revealed a dissociation of developmental progress, marked by relatively delayed onset of frontal preparatory attention relative to error monitoring. SIGNIFICANCE: This dissociation may render adolescents vulnerable to excessive risk-taking and disinhibited behavior imposed by asynchronous development of component cognitive control processes.

Persistence of sleep-temperature coupling after suprachiasmatic nuclei lesions in rats.

The suprachiasmatic nucleus (SCN) regulates the circadian rhythms of body temperature (T(b)) and vigilance states in mammals. We studied rats in which circadian rhythmicity was abolished after SCN lesions (SCNx rats) to investigate the association between the ultradian rhythms of sleep-wake states and brain temperature (T(br)), which are exposed after lesions. Ultradian rhythms of T(br) (mean period: 3.6 h) and sleep were closely associated in SCNx rats. Within each ultradian cycle, nonrapid eye movement (NREM) sleep was initiated 5 +/- 1 min after T(br) peaks, after which temperature continued a slow decline (0.02 +/- 0.006 degrees C/min) until it reached a minimum. Sleep and slow wave activity (SWA), an index of sleep intensity, were associated with declining temperature. Cross-correlation analysis revealed that the rhythm of T(br) preceded that of SWA by 2-10 min. We also investigated the thermoregulatory and sleep-wake responses of SCNx rats and controls to mild ambient cooling (18 degrees C) and warming (30 degrees C) over 24-h periods. SCNx rats and controls responded similarly to changes in ambient temperature. Cooling decreased REM sleep and increased wake. Warming increased T(br), blunted the amplitude of ultradian T(br) rhythms, and increased the number of transitions into NREM sleep. SCNx rats and controls had similar percentages of NREM sleep, REM sleep, and wake, as well as the same average T(b) within each 24-h period. Our results suggest that, in rats, the SCN modulates the timing but not the amount of sleep or the homeostatic control of sleep-wake states or T(b) during deviations in ambient temperature.

Interleukin 1beta enhances non-rapid eye movement sleep and increases c-Fos protein expression in the median preoptic nucleus of the hypothalamus.

Interleukin 1beta (IL-1) is a key mediator of the acute phase response in an infected host and acts centrally to coordinate responses to an immune challenge, such as fever and increased non-rapid eye movement (NREM) sleep. The preoptic area (POA) is a primary sleep regulatory center in the brain: the ventrolateral POA (VLPO) and median preoptic nucleus (MnPN) each contain high numbers of c-Fos protein immunoreactive (IR) neurons after sleep but not after waking. We hypothesized that IL-1 mediates increased NREM sleep through activation of these sleep-active sites. Rats injected intracerebroventricularly with IL-1 (10 ng) at dark onset spent significantly more time in NREM sleep 4-5 h after injection. This increase in NREM sleep was associated with increased numbers of Fos-IR neurons in the MnPN, but not in the VLPO. Fos IR in the rostral MnPN was significantly increased 2 h post IL-1 injection, although the percentage of NREM sleep in the preceding 2 h was the same as controls. Fos IR was also increased in the extended VLPO 2 h postinjection. Finally, Fos IR in the MnPN did not differ significantly between IL-1 and vehicle-treated rats that had been sleep deprived for 2 h postinjection, but it was increased in VLPO core. Taken together, these results suggest that Fos IR in the MnPN after IL-1 is not independent of behavioral state and may require some threshold amount of sleep for its expression. Our results support a hypothesis that IL-1 enhances NREM sleep, in part, through activation of neurons in the MnPN of the hypothalamus.

Oral contraceptives alter sleep and raise body temperature in young women.

Female reproductive steroids, oestrogen and progesterone, not only affect reproductive function, but also thermoregulation and sleep. Chronic administration of synthetic steroids, as occurs in women taking oral contraceptives, may affect these regulatory systems differently from endogenous oestrogen and progesterone. We therefore investigated body temperature and sleep in ten young women taking oral contraceptives, in the active and placebo phases of the contraceptive pack, and compared them to a group of nine women with ovulatory cycles, in the mid-follicular and mid-luteal phases. Body temperature was raised throughout 24 h in the women taking oral contraceptives in the active phase, and in the naturally cycling women in the luteal phase, compared to the follicular phase. The women taking oral contraceptives in the placebo phase, however, continued to have raised body temperatures, similar to those in the active phase, indicating a prolonged action of synthetic reproductive steroids on body temperature. Sleep also was influenced by the endogenous and synthetic reproductive steroids, but independently of body temperature. The women taking oral contraceptives had more stage-2 non-rapid eye movement sleep in the active phase, both compared to their placebo phase and the naturally cycling women. The naturally cycling women, however, had more slow wave sleep in the luteal phase compared to the contraceptive group of women. Exogenous reproductive steroids therefore influence body temperature and sleep differently from endogenous progesterone and oestrogen.

Sleep and 24 hour body temperatures: a comparison in young men, naturally cycling women and women taking hormonal contraceptives.

Body temperature has a circadian rhythm, and in women with ovulatory cycles, also a menstrual rhythm. Body temperature and sleep are believed to be closely coupled, but the influence on their relationship of gender, menstrual cycle phase and female reproductive hormones is unresolved. We investigated sleep and 24 h rectal temperatures in eight women with normal menstrual cycles in their mid-follicular and mid-luteal phases, and in eight young women taking a steady dose of oral progestin and ethinyl oestradiol (hormonal contraceptive), and compared their sleep and body temperatures with that of eight young men, sleeping in identical conditions. All subjects maintained their habitual daytime schedules. Rectal temperatures were elevated throughout 24 h in the luteal phase compared with the follicular phase in the naturally cycling women, consistent with a raised thermoregulatory set-point. Rectal temperatures in the women taking hormonal contraceptives were similar to those of the naturally cycling women in the luteal phase. Gender influenced body temperature: the naturally cycling women and the women taking hormonal contraceptives attained their nocturnal minimum body temperatures earlier than the men, and the naturally cycling women had blunted nocturnal body temperature drops compared with the men. Sleep architecture was essentially unaffected by either menstrual cycle phase or gender. The women taking hormonal contraceptives had less slow wave sleep (SWS), however, than the naturally cycling women. Gender, menstrual cycle phase and hormonal contraceptives significantly influenced body temperature, but had only minor consequences for sleep, in the young men and women in our study.

High nocturnal body temperatures and disturbed sleep in women with primary dysmenorrhea.

Primary dysmenorrhea is characterized by painful uterine cramps, near and during menstruation, that have an impact on personal life and productivity. The effect on sleep of this recurring pain has not been established. We compared sleep, nocturnal body temperatures, and hormone profiles during the menstrual cycle of 10 young women who suffered from primary dysmenorrhea, without any menstrual-associated mood disturbances, and 8 women who had normal menstrual cycles. Dysmenorrheic pain significantly decreased subjective sleep quality, sleep efficiency, and rapid eye movement (REM) sleep but not slow wave sleep (SWS), compared with pain-free phases of the menstrual cycle and compared with the controls. Even before menstruation, in the absence of pain, the women with dysmenorrhea had different sleep patterns, nocturnal body temperatures, and hormone levels compared with the controls. In the mid-follicular, mid-luteal, and menstrual phases, the dysmenorrheics had elevated morning estrogen concentrations, higher mean in-bed temperatures, and less REM sleep compared with the controls, as well as higher luteal phase prolactin levels. Both groups of women had less REM sleep when their body temperatures were high during the luteal and menstrual phases, implying that REM sleep is sensitive to elevated body temperatures. We have shown that dysmenorrhea is not only a disorder of menstruation but is manifest throughout the menstrual cycle. Furthermore, dysmenorrheic pain disturbs sleep, which may exacerbate the effect of the pain on daytime functioning.

A comparison of subjective estimates of sleep with objective polysomnographic data in healthy men and women.

Twenty healthy men and women had their sleep recorded objectively, using polysomnography on 3 nonconsecutive nights. Following each night, the subjects assessed their sleep onset latency and number of awakenings, subjectively. Self-ratings were compared with objective measures of sleep onset latency (SOL), calculated as the time from lights-out to the first continuous minute of stage 2 sleep, and the number of awakenings which lasted 1 minute or longer on the polysomnograms. Apart from the first night, the subjects overestimated the time that it took them to fall asleep, despite sleep onset being scored as the latency to stage 2, rather than stage 1 sleep. On all 3 nights, the subjects underestimated the number of awakenings when compared to objective criteria. Although the subjects were consistent in their errors of estimation of their sleep compared to polysomnographic assessments over the three nights, the between-individual variation was large, so that objective and subjective ratings of SOL and awakenings were not correlated. The young men and women in our study, who were free of medication or sleep complaints, perceived their sleep inaccurately when compared to objective polysomnographic recordings.

Energy content of the evening meal alters nocturnal body temperature but not sleep.

Meals of varying energy content and episodes of sleep influence body temperature. We compared the effect of an evening meal, varying from high-energy (11.91 +/- 0.86 MJ) to average (5.74 +/- 0.88 MJ) and a 10-h fast (no evening meal), on nocturnal body temperature and sleep. Seven healthy men (20-24 years, mean body mass index of 23.4 +/- 2.6 kg/m2) reported to the laboratory for an evening meal at 2000 h having consumed similar amounts of food before 1300 h. After completing the meal, subjective hunger ratings were assessed, and a venous blood sample taken. The subjects spent 4 nonconsecutive nights (an adaptation night, followed by either of the two meal conditions or the fast in random order) in the sleep laboratory when polysomnographic recordings were made from 2300 to 0700 h. Meal energy content and serum concentrations of insulin, triglyceride, and low-density lipoproteins (LDL) varied significantly. Lower rectal temperatures were measured during the fast than following the meals. Over the 8-h recording period, thermal response indices (TRI) varied with higher body temperatures following the higher energy meal. Similar rectal temperatures were attained by the end of the sleep periods. There were no significant differences in any of the subjective or objective sleep measures. The physiological responses associated with the transient dietary changes of an evening meal or a 10-h fast altered nocturnal body temperature but did not significantly affect sleep of good sleepers when sleep was initiated 2 to 3 h after finishing the meal.

Different nocturnal body temperatures and sleep with forced-air warming in men and in women taking hormonal contraceptives.

We studied how forced-air warming, conventionally used to control body temperature during and after anaesthesia, affected the nocturnal rectal temperatures and sleep composition of young men and women. Seven healthy women who were taking oral or injection contraceptives, and six healthy men spent 3 nights in a controlled environment: an adaptation night followed by 2 nights when they slept under either a down duvet (baseline) or a quilt perfused with warm air (hot). Repeated analysis of variance (ANOVA) revealed significant gender differences in the body temperature responses. On the baseline night, despite sleeping under the same conditions, the women did not show a nocturnal drop in body temperature as shown by the men. Forced-air warming increased body temperature to a similar extent in the men and the women, and resulted in enhanced hyperthermia in the women, and blunted the drop in body temperature in the men, compared to their baseline nights. The significant increases in body temperature had no consequences, however, for the subjective sleep quality of either the men or women, and only minor consequences for objective sleep composition. Both men and women had increased amounts of Stage 2 sleep on the hot night (P < 0.04). In addition, the women had reduced rapid eye movement (REM) sleep when compared to their baseline night (P < 0.04). Our results confirm that in a passive thermal environment, women who are taking oral or injection contraceptives have higher nocturnal body temperatures than men. Also, as sleep architecture was minimally affected by the increases in body temperature of between 0.2 and 0.3 degree C on the hot night in the men and women, and subjective sleep quality was unaffected, our results question the existence of a tight association between sleep and body temperature.

Menstrual factors in sleep.

The changing endocrine profile in premenopausal women alters aspects of sleep and circadian rhythms. Subjectively women appear to feel a greater need for sleep and report poor and insufficient sleep more often than men. This greater sleep requirement may manifest with a higher amplitude of slow-wave sleep in the EEG in women. Healthy young women, with biphasic body temperature rhythms of ovulatory menstrual cycles, have more stage 2 sleep, higher spindle frequency activity and less rapid-eye movement (REM) sleep when progesterone predominates in the luteal phase. These sleep-EEG changes may largely be caused by neurosteroids acting on the brain. Sleep regulatory mechanisms, indicated by the onset to sleep, slow-wave sleep (SWS) and slow-wave activity, appear to be unaffected by menstrual phase in women with normal cycles. Women with premenstrual mood symptoms have more stage 2 sleep and seemingly less SWS and REM sleep, a blunted circadian rhythm of melatonin and an earlier minimum body temperature than asymptomatic women. Subjective repercussions include increased daytime sleepiness, lethargy and fatigue. Treatment strategies for menstrual-associated complaints include using oral contraceptives and sleep deprivation but the physiology and pharmacology of normal menstrual changes, the disorders and their treatment need to be better understood.

Juvenile hormone bisepoxide biosynthesis in vitro by the ring gland of Drosophila melanogaster: a putative juvenile hormone in the higher Diptera.

The in vitro production of juvenile hormone (JH) was investigated by using isolated ring glands from third instar Drosophila melanogaster. A JH-like molecule is secreted that comigrates with a synthetic sample of methyl 6,7;10,11-bisepoxy-3,7,11-trimethyl-(2E)-dodecenoate (JHB3) during TLC, liquid chromatography, and GC analysis. Purified product from farnesoic acid-stimulated ring glands was analyzed by electron impact GC/MS and gave a mass spectrum identical to synthetic JHB3. Additional structure confirmation was obtained following conversion of product from unstimulated biosynthesis to a derivative that comigrated on liquid chromatography with the derivative prepared from synthetic JHB3. Physiological studies revealed that JHB3 is produced solely by the corpus allatum portion of the ring gland in vitro. Isolated ring glands from other cyclorrhaphous dipteran larvae also produce JHB3 almost exclusively in vitro. Corpora allata from mosquito larvae, however, produce only JH III, indicating that JHB3 production may be restricted to the higher Diptera. Topically applied synthetic JHB3 caused developmental responses in newly formed D. melanogaster white puparia similar to those obtained with JH III. The data suggest that JHB3 is a fly juvenile hormone.

Comparative metabolism of branched-chain amino acids to precursors of juvenile hormone biogenesis in corpora allata of lepidopterous versus nonlepidopterous insects.

Comparative studies were performed on the role of branched-chain amino acids (BCAA) in juvenile hormone (JH) biosynthesis using several lepidopterous and nonlepidopterous insects. Corpora cardiaca-corpora allata complexes (CC-CA, the corpora allata being the organ of JH biogenesis) were maintained in culture medium containing a uniformly 14C-labeled BCAA, together with [methyl-3H]methionine as mass marker for JH quantification. BCAA catabolism was quantified by directly analyzing the medium for the presence of 14C-labeled propionate and/or acetate, while JHs were extracted, purified by liquid chromatography, and subjected to double-label liquid scintillation counting. Our results indicate that active BCAA catabolism occurs within the CC-CA of lepidopterans, and this efficiently provides propionyl-CoA (from isoleucine or valine) for the biosynthesis of the ethyl branches of JH I and II. Acetyl-CoA, formed from isoleucine or leucine catabolism, is also utilized by lepidopteran CC-CA for biosynthesizing JH III and the acetate-derived portions of the ethyl-branched JHs. In contrast, CC-CA of nonlepidopterans fail to catabolize BCAA. Consequently, exogenous isoleucine or leucine does not serve as a carbon source for the biosynthesis of JH III by these glands, and no propionyl-CoA is produced for genesis of ethyl-branched JHs. This is the first observation of a tissue-specific metabolic difference which in part explains why these novel homosesquiterpenoids exist in lepidopterans, but not in nonlepidopterans.

Sources of propionate for the biogenesis of ethyl-branched insect juvenile hormones: Role of isoleucine and valine.

Corpora allata from adult female Manduca sexta biosynthesize the sesquiterpenoid juvenile hormone (JH) III and the unusual ethyl-branched homologue JH II in vitro. We maintained corpora allata in medium 199 using [methyl-(3)H]methionine as the source of the JH methyl ester moiety and as a mass marker. This allowed measurement of the relative contributions of (14)C-labeled precursors to the biogenesis of JH II and III carbon skeletons. We showed efficient incorporation of a propionate equivalent, from isoleucine or valine catabolism, into the ethyl-branched portion of JH II, using double-label liquid scintillation counting of isolated JHs and gas chromatography/mass spectrometry with selected ion monitoring of JH deuteromethoxyhydrin derivatives. Methionine was a poor source of propionate for JH II biosynthesis, while glucose, succinate, threonine, and beta-alanine did not contribute propionate at all. Leucine, isoleucine, and glucose incorporated into JH III and the acetate-derived portion of JH II.