Assessing the Pulsatility of Luteinizing Hormone in Female Vervet Monkeys (Chlorocebus aethiops sabaeus)

Specific alterations in the pulsatility of luteinizing hormone (LH) are linked to obesity-related subfertility in ovulatory women. Vervet monkeys (Chlorocebus aethiops sabaeus) are an Old World nonhuman primate that develops obesity and has a menstrual cycle similar to humans. We evaluated follicular-phase LH pulses in 12 adult normal-weight female vervets. Serum was collected every 10 min for 4 h by using a tether device in conscious, freely moving monkeys on menstrual cycle days 2 through 5. Serum estradiol was collected daily during the follicular phase to identify the luteal–follicular transition. For comparison, we used data from 12 ovulatory normal-weight women who had undergone frequent blood sampling of early-follicular LH. LH pulse frequency was similar, with 2.8 ± 0.7 LH pulses during 4 h in vervets compared with 2.3 ± 0.7 LH pulses during 4 h in women. The LH pulse mass (percentage change in the pulse peak over the preceding nadir) was 123.2% ± 27.4% in vervets and 60.9% ± 14.9% in humans. The first day of low serum estradiol after the follicular-phase peak was denoted as the day of the luteal–follicular transition. Luteectomy was performed on luteal days 7 through 9, and corpora lutea were confirmed by histology. We demonstrate that follicular LH patterns in vervets are similar to those in humans and that the luteal phase is easily identified by monitoring daily serum estradiol. These findings demonstrate that vervet monkeys are a suitable animal model for evaluating LH pulse dynamics longitudinally in studies of diet-induced obesity.Abbreviations: CL, corpus luteum; LH, luteinizing hormoneNonhuman primates have been used in biomedical research for decades and have enabled advancements in many areas, including HIV–AIDS, Alzheimer disease, diabetes, asthma, and endometriosis.²³ Neuroendocrine research in menstruating nonhuman primates, such as rhesus and cynomolgus macaques, have provided valuable information regarding the hypothalamic– pituitary–ovarian axis, including modulating factors of pulsatile gonadotropin-releasing hormone secretion and the negative and positive feedback mechanisms of sex steroids.^20,25,33Normal reproductive physiology in women involves highly coordinated communication between the hypothalamus, pituitary gland, and the end organ of female reproduction, the ovary. These processes are governed by the magnitude and frequency of secretory outbursts (pulses) of gonadotropin-releasing hormone from the hypothalamus. The activity of gonadotropin-releasing hormone results in a pulsatile mode of secretion of follicle-stimulating hormone and luteinizing hormone (LH) from the anterior pituitary. In females, follicle-stimulating hormone drives ovarian follicle growth during the follicular phase of the menstrual cycle. The midcycle LH surge results in ovulation and the subsequent formation of a corpus luteum (CL). Secretion of estradiol, produced by the developing follicles, progressively increases over the course of the follicular (proliferative) phase of the menstrual cycle and peaks prior to ovulation. Progesterone, secreted by the CL, is the dominant sex steroid during the luteal (secretory) phase.¹² Both estradiol and progesterone exert tightly regulated negative feedback on the hypothalamus and pituitary and affect gonadotropin release. Alterations in this intricate system can result in anovulation or infertility.Obesity is a growing worldwide hazard that has many adverse health outcomes, including subfertility. Endocrine alterations associated with obesity include relative hypogonadotropic hypogonadism^29,34 and selective impairment of LH pulse amplitude.¹⁴ Progesterone metabolite excretion in morbidly obese women is reduced by 70% compared with that in normal-weight women,²⁹ and pulsatile LH amplitude is suppressed by half in frequent blood-sampling studies.¹⁴ However, despite the recent advances in understanding the endocrine pathophysiology of obesity-related subfertility,¹⁵ its molecular mechanisms are poorly understood.Animal models for obesity-related subfertility are needed for mechanistic studies but are currently unavailable. The hormonal control of the menstrual cycle has been extensively studied in rhesus and cynomolgus macaques and is similar to that of humans.^12,22,26 These nonhuman primates have also been shown to develop obesity and resultant metabolic disturbances.¹ However, demand for rhesus and cynomolgus macaques is high, and the NIH has espoused the need to identify other species of nonhuman primate that are suitable for research.⁶Vervet monkeys (Chlorocebus aethiops sabaeus) are a small, Old World nonhuman primate with an ovarian cycle similar to that in humans; therefore vervets may be an appropriate alternative species in which to do neuroendocrine research. LH pulsatility in this species has not been assessed comprehensively. Our objective in the current study was to characterize the follicular LH pulse pattern in vervet monkeys, to establish the feasibility of using this model in future studies to assess the effect of body mass on pituitary function.