The overall goal of this grant is to continue our studies to determine the mechanisms by which common life stresses (i.e., dieting, moderate exercise and psychological stress) impair activity of the reproductive axis and fertility. Female cynomolgus monkeys, which like women have 28-day menstrual cycles throughout the year, show individual differences in responsiveness to stress, with stress-sensitive animals rapidly developing stress-induced reproductive dysfunction, and stress-resilient animals maintaining normal menstrual cyclicity throughout stress exposure. The stress used for these studies is patterned after that documented in women with Functional Hypothalamic Amenorrhea (FHA;a clinical condition which accounts for as much as 30% of female infertility) in which monkeys are exposed to a mild psychological stress (moving to a new room) and a moderate metabolic stress (a 20% decrease in calorie intake and moderate running for an hour a day, 5 days a week). To date, we have studied monkeys in non-stressed conditions. We have found that stress-sensitive monkeys have lower physiological release of serotonin, a down regulation of function in the central serotonergic system [as indicated by lower tryptophan hydroxylase (THP) 2 gene expression, less serotonin transporter (SERT) gene expression, less 5HT-1A receptor gene expression, and less expression of genes degrading serotonin (MAO-A and MAO-B)], as well as an up-regulation of 5HT2A and 2C receptors in the hypothalamus, compared to more stress-resilient animals. We have preliminary data showing that treatment of stress-sensitive monkeys in a nonstressed condition with a serotonin reuptake inhibitor (SSRI) increases reproductive hormone secretion in a normal menstrual cycle. In this grant application we will test whether SSRI treatment can prevent stress-induced suppression of the reproductive axis and thus may be a novel therapy for treatment of stress-induced infertility. We will examine changes in central neural systems that occur with SSRI therapy. We will also run a small pilot clinical study to determine if SSRI therapy in women with FHA is able to increase reproductive hormone secretion. This collaboration between Drs. Cameron, Bethea and Berga represents an unique opportunity to test this potential new therapy for FHA both in an appropriate animal model in which we can examine neural systems, and in a small pilot clinical study.

Public Health Relevance

Functional Hypothalamic Amenorrhea is a clinical condition that accounts for as much as 30% of female infertility. This project is testing a new potential treatment for FHA, a form of infertility due to sensitivity to life stresses, in female monkeys with a small pilot project in women with FHA. This treatment involves treatment with a serotonin reuptake inhibitor, a common treatment for anxiety.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
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University of Pittsburgh
Schools of Medicine
United States
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Bethea, Cynthia L; Reddy, Arubala P; Flowers, Matthew et al. (2015) High fat diet decreases beneficial effects of estrogen on serotonin-related gene expression in marmosets. Prog Neuropsychopharmacol Biol Psychiatry 58:71-80
Bethea, C L; Kim, A; Reddy, A P et al. (2014) Hypothalamic KISS1 expression, gonadotrophin-releasing hormone and neurotransmitter innervation vary with stress and sensitivity in macaques. J Neuroendocrinol 26:267-81
Bethea, Cynthia L; Phu, Kenny; Reddy, Arubala P et al. (2013) The effect of short-term stress on serotonin gene expression in high and low resilient macaques. Prog Neuropsychopharmacol Biol Psychiatry 44:143-53
Bethea, Cynthia L; Phu, Kenny; Reddy, Arubala P et al. (2013) The effect of short moderate stress on the midbrain corticotropin-releasing factor system in a macaque model of functional hypothalamic amenorrhea. Fertil Steril 100:1111-21
Bethea, Cynthia L; Kim, Aaron; Cameron, Judy L (2013) Function and innervation of the locus ceruleus in a macaque model of Functional Hypothalamic Amenorrhea. Neurobiol Dis 50:96-106
Senashova, Olga; Reddy, Arubala P; Cameron, Judy L et al. (2012) The effect of citalopram on midbrain CRF receptors 1 and 2 in a primate model of stress-induced amenorrhea. Reprod Sci 19:623-32
Bethea, Cynthia L; Lima, Fernanda B; Centeno, Maria L et al. (2011) Effects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity. J Chem Neuroanat 41:200-18
Lima, F B; Centeno, M L; Costa, M E et al. (2009) Stress sensitive female macaques have decreased fifth Ewing variant (Fev) and serotonin-related gene expression that is not reversed by citalopram. Neuroscience 164:676-91