NEWS & VIEWS values of food directly, in a self-reinforcing manner.4,5 Consistently, direct intracranial administration of orexin or MCH has been shown to alter body weight in rodents.5 Using an optogenetic approach, Jennings et al. developed a ‘switch’ to activate or inacti­vate projections from the extended amygdala, specifically the bed nucleus of the stria terminalis (BNST) area, into the lateral hypothalamus of mice. In response to in vivo photostimulation of these inhibitory BNST neurons—and concomitant inacti­va­t ion of the downstream lateral hypo­thalamus neurons—well-fed mice began to eat voraciously, with a strong prefer­ence for high-fat food. In fur­ther experi­ments, Jennings and colleagues found that inacti­vation of BNST neurons or direct activa­tion of lateral hypothalamus neurons pre­vented hungry mice from eating. These find­ings show that inhibition of a particular set of neurons in the lateral hypothalamus, rather than activation, promotes feeding behaviour. The lateral hypothalamus has a critical function by ensuring that, during low meta­bolic states, arousal is tuned to forage in search of an energy source.5 However, it can also represent a critical mediator of the suppression of metabolic satiation signals, ensuring, for example, overeating in times of plenty to prepare for times of need.4 Unfor­ tunately, tuning arousal in modern society— bypassing the metabolic state just as you would pass the next burger joint—represents an unfavourable behavioural adaptation. Environmental cues and habits can trigger feeding; consequently, internal needs and external availability no longer match. Intri­ guing data support the idea that the lat­eral hypothalamus integrates acquired habits, environmental cues and motivational value to overrule the homeostatic system. For exam­ple, in sated rats, feeding was triggered by the presentation of a light or tone stimulus that had previously been associated with food intake during starvation; this be­haviour was dependent on an intact amygdala–­prefrontal–lateral hypothalamus network.8 How­ever, much remains elusive. Is the lateral hypothalamus one of the main integrative nuclei with a complicated in­ternal circuitry or merely a relay station? In that respect, Jennings and colleagues add another component to the lateral hypo­t halamic food equation. But would the reported projection affect only food intake? Projections of the BNST to the lateral hypothalamus have been identified before and were reported to facilitate anxiolytic effects on behaviour, but not appetite.9 6  |  JANUARY 2014  |  VOLUME 10

Early electrical stimulations in the lateral hypo­thalamus lacked behavioural specificity. Whereas the animals would eat in the presence of food, they would turn to, for example, drinking, if food was replaced by a drinking opportunity.6 As these results may stem in part or even completely from the inevitable and unintended stimulation of the medial forebrain bundle, they show that great care has to be taken in attributing certain behavioural aspects elicited by a stimulus.6 Hence, driving the inhibitory BNST–lateral hypothalamus projection might actually alter motivation and arousal to such an extent that the sole presentation of food triggers eating. The previously reported optogenetic stimulation by Aponte et al., by comparison, has to be viewed differently.10 Stimulation of agouti-related peptide neurons led to a craving to eat, which triggered a goal-directed search for food; that is, the animals could obtain food only by an active nose poke.10 However, during BNST– lateral hypothalamus stimulation in the study by Jennings et al., no ad­ditional action was needed to obtain food.1 Nevertheless, in summary, Jennings and col­leagues have undertaken the first steps in delineating the circuit connectivity of the lat­eral hypothalamus. Subsequent identification of downstream connections following BNST–lateral hypothalamus input may aid in answering the question of how environ­mental cues, habits and hedonic values might overrule the homeostatic control of food intake.

Max Planck Institute for Neurological Research, Gleueler Straße 50, D‑50931 Cologne, Germany (M. E. Hess, J. C. Brüning). Correspondence to: J. C. Brüning [email protected] Competing interests The authors declare no competing interests. 1.

Jennings, J. H., Rizzi, G., Stamatakis, A. M., Ung, R. L. & Stuber, G. D. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517–1521 (2013). 2. Teitelbaum, P. & Epstein, A. N. The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychol. Rev. 69, 74–90 (1962). 3. Delgado, J. M. & Anand, B. K. Increase of food intake induced by electrical stimulation of the lateral hypothalamus. Am. J. Physiol. 172, 162–168 (1953). 4. Berthoud, H. R. Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr. Opin. Neurobiol. 21, 888–896 (2011). 5. Saper, C. B., Chou, T. C. & Elmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002). 6. Sternson, S. M. Hypothalamic survival circuits: blueprints for purposive behaviors. Neuron 77, 810–824 (2013). 7. Yamanaka, A. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713 (2003). 8. Petrovich, G. D. & Gallagher, M. Control of food consumption by learned cues: a forebrainhypothalamic network. Physiol. Behav. 91, 397–403 (2007). 9. Kim, S. Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013). 10. Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14, 351–355 (2011).

REPRODUCTIVE ENDOCRINOLOGY

Hormone therapy to treat menopause—breaking a taboo Susan R. Davis

Findings from the Women’s Health Initiative hormone study send the message that clinicians can feel confident prescribing menopausal hormone replacement therapy (MHT) to young menopausal women with moderate-to-severe symptoms who do not have absolute contraindications for hormone therapy. However, MHT is indicated for the alleviation of symptoms, not for chronic disease prevention. Davis, S. R. Nat. Rev. Endocrinol. 10, 6–8 (2014); published online 29 October 2013; doi:10.1038/nrendo.2013.219

Menopause is the last menstrual period experienced by a woman, followed by loss of ovarian function. Menopause occurs naturally or as a result of a hysterectomy.



A sustained fall in levels of estrogen occurs just before the last menstrual period during natural menopause, which causes postmenopausal symptoms. These include www.nature.com/nrendo

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vasomotor symptoms (hot flushes and night sweats), joint pain, urogenital atrophy ( v ag i na l d r y ­ ness, dyspareunia and sexual dysfunction, urinary tract infections and urinary urgency) and fragmented sleep (independent of night sweats). The decline in levels of estrogen at menopause also results in accelerated bone loss, accumulation of central abdominal fat and metabolic changes that predispose postmenopausal women to cardiovascular disease and type 2 diabetes mellitus.1 Menopausal hormone replacement therapy (MHT) was the mainstay of treatment for postmenopausal women until the publication of the Women’s Health Initiative (WHI) study findings in 20022 led to global concerns regarding the safety of MHT. A decade later, confusion prevails. Consequently, treatment is highly variable, and many women with severe symptoms remain untreated.3 Manson and colleagues have now published the extended follow-up findings for the WHI oral conjugated equine estrogen (CEE) only and CEE plus continuous oral medroxyprogesterone acetate (CEE + MPA) trials. 4 The CEE + MPA study included 16,608 women aged 50–79  years who had not undergone a hysterectomy; 8,506 received the therapy, and 8,102 received placebo. The CEE trial included 10,739 women of the same age who had undergone a hysterectomy; 5,310 received the therapy, and 5,429 received placebo. These studies were designed with the assumption that MHT would be cardioprotective. The CEE + MPA trial had a median follow-up of 8.2 years, with a median intervention period of 5.6 years; and the CEE trial had a median follow-up of 6.6 years, after a median intervention period of 7.2 years. The trials have some limitations, for example, only 12% of women in the CEE + MPA study and 17% of those in the CEE study had moderateto-severe menopausal symptoms at enrolment, with most having none or mild symptoms. Furthermore, only one-third of the women in the CEE + MPA trial and 18% of the women in the CEE trial were

Reproductive endocrinology: Hormone therapy to treat menopause--breaking a taboo.

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