[18F]2-fluoro-2-deoxy-D-glucose positron emission tomography demonstration of estrogen negative and positive feedback on luteinizing hormone secretion in women

Abstract

Context: Precise regulation of the neuroendocrine components of the female reproductive axis involves both negative and positive feedback of estrogen on gonadotropin secretion.

Objective: Our objective was to determine the hypothalamic and/or pituitary sites of estrogen negative and positive feedback using neuroimaging techniques.

Design and setting: A graded estrogen infusion protocol was administered at a General Clinical Research Center in an academic medical center.

Subjects: Healthy postmenopausal women (n = 11) were recruited for study.

Interventions: Serum samples were measured every 4 h. A structural magnetic resonance imaging was performed at baseline, and [(18)F]2-fluoro-2-deoxy-d-glucose ((18)FDG) positron emission tomography was performed at baseline and 24 and 72 h. FDG positron emission tomography was co-registered with magnetic resonance imaging scans, and region of interest analysis was performed.

Main outcome measures: Serum LH and estradiol were assessed. Normalized values for glucose uptake were extracted from each region of interest for each subject at each time point.

Results: A decrease in normalized (18)FDG uptake was apparent in the hypothalamus at 24 h (P < 0.02) associated with decreased LH (P < 0.0005). The increase in LH at 72 h (P < 0.0005) was associated with increased pituitary (18)FDG uptake (P < 0.02) but no change in hypothalamic uptake.

Conclusions: Changes in (18)FDG uptake as a measure of metabolic activity can be demonstrated in the hypothalamus and pituitary in association with discrete hormonal events. Results are consistent with mediation of estrogen negative feedback on LH at the hypothalamus, whereas estrogen positive feedback occurs at the pituitary with no evidence of increased hypothalamic activity in women.

Trial registration: ClinicalTrials.gov NCT00455741.

Figures

Figure 1

A graded E2 (left axis, top panel) infusion was administered over 96 h to mimic the increasing E2 levels of the follicular phase in normal women with addition of a very low dose of P (Prog, right axis, top panel) infusion at 48 h and resulted in inhibition followed by stimulation of LH secretion (bottom panel), presented as percentage of baseline (mean ± sem) for each subject. 18FDG-PET scanning was performed at baseline, in conjunction with estrogen negative feedback at 24 h and during estrogen positive feedback at 72 h. Structural MRI scans were obtained on each subject at baseline.

Figure 2

The pituitary (arrow) and a rectangular portion of the medial basal hypothalamus bilaterally (arrowheads) were outlined as indicated in red in sagittal (left) and coronal (right) views on each subject’s MRI as the ROI and superimposed on the co-registered FDG-PET data for each subject. The hypothalamic ROI was standardized at 2 mm in width, 4 mm in length (anteroposterior dimension), and 2 mm in height, bilaterally. The anterior aspect was placed posterior to the optic chiasm, terminated anterior to the mammillary bodies, and was bounded on its medial border by the third ventricle. The pituitary ROI was standardized as a 2-mm radius in the center of the pituitary.

Figure 3

The graded steroid infusion resulted in an initial decrease in serum LH levels at 24 h followed by a marked increase that was already apparent by 72 h (top panel). LH is expressed in international units per liter as equivalents of the Second International Reference Preparation of human menopausal gonadotropins. Inhibition of LH was associated with a decrease in normalized glucose uptake at the hypothalamus (middle panel), whereas the increase in LH was associated with a marked increase in normalized uptake at the pituitary (bottom panel) in the absence of a significant hypothalamic effect. One sem is indicated. *, P < 0.02; **, P < 0.001.