Author

Cadence true

Date

8-2012

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

[From the introduction, no abstract] Female reproductive function is metabolically-gated, meaning an organism requires sufficient energy intake and stores to maintain fertility. This energy requirement has led to the evolutionary development of seasonal breeding in many species, where breeding is carried out at specific times to coordinate either gestation or lactation with seasons of food availability. However, when these energy requirements are not met and energy expenditure exceeds energy input, this causes an imbalanced metabolic state termed negative energy balance. Negative energy balance results in weight loss leading to the initiation of homeostatic adaptations to increase food intake and decrease energy expenditure in an effort to normalize the metabolic imbalance. One mechanism of energy conservation in female mammals is a suppression of the energy demanding reproductive cycle. By shutting down the ovarian cycle in adulthood, females conserve energy in times of food scarcity. This adaptation also prevents pregnancy and the high metabolic cost associated with gestation and lactation. In humans, this condition is termed functional hypothalamic amenorrhea and can frequently be observed in patients with anorexia nervosa as well as professional athletes (Boyar et al., 1974; Mansfield and Emans, 1989;McArthur et al., 1980; Warren et al., 1999). These two groups of women represent the extreme examples of decreased energy input (anorexics) and increased energy output (athletes), both of which can contribute to an imbalanced and ultimately negative metabolic state. In addition to regulation of ovarian cyclicity during adulthood, metabolic perturbations can also affect sexual maturation during development. Negative energy balance has been observed to delay sexual maturation and the complex set of physiological changes associated with puberty. One of the most important changes during puberty is an increase in ovarian steroid hormone production, and under nutrition can prevent this increase in steroids resulting in a condition known as hypogonadism in humans. It should be noted that negative energy balance-induced reproductive dysfunction during development may not occur for the sole purpose of energy conservation, as is hypothesized in adulthood. Previous studies have provided evidence that there may be a growth, or adiposity, threshold that is required for puberty onset. Therefore, it may be that in addition to negative energy balance signals actively inhibiting puberty for energy conservation, under nutrition also prevents the "permissive" signals of body growth required for the initiation of puberty. Regardless of the mechanism, it appears that under nutrition during development delays puberty until certain signals of sufficient growth, which are still not fully understood, have been achieved (Boyar et al., 1974;Ronnekleiv et al., 1978). This role of nutritional status to govern reproduction during development as well as adulthood suggests that pathways of reproductive regulation are likely tightly coupled to those of metabolism throughout an organism's life. Understanding the metabolic requirements for reproductive function will have far-reaching implications for women's health. By better understanding how reproductive function is inhibited during negative metabolic states, it might be possible to better identify pharmaceutical targets for the treatment of numerous causes of infertility. This could of course benefit patients with metabolic- and stress-induced hypothalamic amenorrhea as well as potentially lead to new intervention therapies for patients with developmental disorders like hypogonadism. Another disorder that may benefit from research into the metabolic regulation of reproduction is polycystic ovarian syndrome (PCOS). This condition of ovarian dysfunction and subfertility is also coupled with an abnormal metabolic phenotype, indicating that the source of this disorder may lie in pathways involved in both reproductive and metabolic regulation. In addition to the treatment of infertility, understanding how inhibitory control is exerted over the reproductive system could also be used for the development of new birth control treatments. The traditional steroidal forms of birth control in use today carry significant health risks including increased prevalence of hypertension, heart attack and blood clotting especially for older women. Identification and development of a non-steroidal birth control may offer a safer alternative to family planning. In addition to the clinical implications, understanding the metabolic regulation of reproduction on the basic science level would significantly increase our understanding of how multiple signals of these two systems are integrated. For example, understanding the metabolic cues causing reproductive inhibition would provide key insights into how the body senses changes in metabolic state and how these changes are signaled to multiple organs, including the brain. Metabolic regulation of reproduction has been a significant research question for many decades and although our knowledge of how the system works has increased significantly over time, the major causative components of this pathway are still largely unknown. Understanding this basic and highly conserved form of reproductive regulation will increase our understanding of the normal physiology involved in mediating the ovarian cycle and fertility.

Identifier

doi:10.6083/M4HQ3WXQ

Division

Division of Neuroscience

School

School of Medicine

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