Obesity-induced hypogonadism in the male: Premature reproductive neuroendocrine senescence and contribution of Kiss1-mediated mechanisms
Angel Sánchez-Garrido M, Ruiz-Pino F, Manfredi-Lozano M, Leon S, Garcia-Galiano D, Castaño JP, Luque RM, Romero-Ruiz A, Castellano JM, Diéguez C, Pinilla L, Tena-Sempere M. Endocrinology. 2014 Jan 1:en20131584. [Epub ahead of print]

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Department of Cell Biology, Physiology and Immunology, University of Córdoba.


Reproduction is sensitive to insufficient body energy reserves, especially in females. Metabolic regulation of male reproductive axis is less obvious, and the impact of conditions of persistent energy excess has received moderate attention. Yet, the escalating prevalence of obesity and the clinical evidence of its deleterious effects on male fertility have raised considerable concerns. We report here phenotypic and mechanistic studies of the reproductive impact of postnatal nutritional manipulations (mainly over-nutrition), coupled to high fat diet (HFD) after weaning. Metabolic and hormonal analyses in young (4-mo) and middle-aged (10-mo) animals revealed that HFD caused profound metabolic perturbations, including glucose intolerance, which were worsened by precedent postnatal overfeeding; these were detectable already in young males but aggravated in 10-mo-old rats. Impairment of reproductive parameters took place progressively, and HFD alone was sufficient to explain most of these alterations, regardless of postnatal under- or overnutrition. In young males, testosterone (T) levels and steroidogenic enzyme expression were suppressed by HFD, without compensatory increases of LH levels, which were in fact partially inhibited in heavier males. In addition, obese males displayed suppressed hypothalamic Kiss1 expression despite low T, and HFD inhibited LH responses to kisspeptin. Overweight anticipated some of the neuroendocrine effects of ageing, such as the suppression of hypothalamic Kiss1 expression and the decline in serum T and LH levels. Nonetheless, HFD per se caused a detectable worsening of key reproductive indices in middle-aged males, such as basal LH and FSH levels, as well as LH responses to kisspeptin. Our study demonstrates that nutritional stress, especially HFD, has a profound deleterious impact on metabolic and gonadotropic function, as well as on Kiss1 system, and precipitates neuroendocrine reproductive senescence in the male.