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Follicular Atresia as an Apoptotic Process: Atresia-Associated Increase in the Ovarian Expression of the Putative Apoptotic Marker Sulfated Glycoprotein-2

Kristiina Ruutiainen-Altman, PhD, MD

Louis Marzella, PhD

Division os Reproductive Endocrinology, Department of Obstetnes and Gynecology, and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland

Luis Botero, MD

Division os Reproductive Endocrinology, Department of Obstetnes and Gynecology, and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland; Universidad Javeriana, Hospital San Ignacio, Departamento de Gineco-Obstetricia (3rd PISO), Bogota, Colombia

Matat Dushnik, MD

Division os Reproductive Endocrinology, Department of Obstetnes and Gynecology, and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland

Eli Y. Adashi, MD

Division os Reproductive Endocrinology, Department of Obstetnes and Gynecology, and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland; Division of Reproductive Endocrinology, Departments of Obstetrics/Gynecology and Physiology, 405 W. Redwood Street, Third Floor, Baltimore, MD 21201

Objective: To evaluate the possibility that morphologically confirmed/hypophysectomy-induced ovarian follicular atresia, a putative apoptotic process, is coupled to alterations in the steady-state levels of ovarian sulfated glycoprotein-2 (SGP-2) transcripts.

Methods: Hypophysectomy-induced follicular atresia in immature rats, morphologically confirmed at the light and electron microscopic levels, was correlated with alterations in the steady-state levels of ovarian SGP-2 transcripts as assessed by a solution hybridization/RNase protection assay. Cellular localization was accomplished by in situ hybridization technology.

Results: Hypophysectomy of the 24-day-old immature rat, an established precipitant of follicular atresia, led (3 days later) to a significant (p < .05) increase (up to 3.3-fold) in the relative abundance of densitometrically quantified ovarian SGP-2 transcripts compared with age-matched intact controls. Detailed time-course analysis after hypophysectomy revealed significantly (P < .05) increased ovarian SGP-2 mRNA expression as early as 2 days after hypophysectomy; no further increments were noted on days 4 or 8. Light microscopic analysis of comparable ovarian material 4 days after hypophysectomy revealed increased numbers of atretic follicles displaying large numbers of degenerating granulosa cells. Electron microscopic analysis of the degenerating cells of atretic follicles (from hypophysectomized rats) disclosed nuclear condensation and cytoplasmic shrinkage as well as apoptotic bodies at all levels of the granulosa cell layer. In situ hybridization established the granulosa cell of the intact untreated rat as the somatic cell concerned with SGP-2 gene expression. In turn, hypophysectomy led to an increase in SGP-2 expression at the level of the theca-interstitial cell, an effect prevented by the concurrent provision of pregnant mare serum gonadotropin (PMSG). The hypophysectomy-induced increase in ovarian SGP-2 transcripts was similarly reversed (54% inhibition by day 27) by the concomitant provision of FSH, an established antiatretic principle. The delayed administration (day 26) of a single dose of PMSG to rats hypophysectomized on day 24 eliminated the hypophysectomy-induced increase in ovarian SGP-2 transcripts as assessed on day 28. Qualitatively similar but quantitatively more pronounced increments in ovarian SGP-2 gene expression were obtained when atresia was induced by hypophysectomy of PMSG-primed immature rats.

Conclusions: These observations establish the immature rat ovary as a site of SGP-2 gene expression and reveal hypophysectomy-induced follicular atresia to result in the up-regulation of ovarian (specifically, theca-interstitial) SGP-2 gene expression, an effect prevented by the concurrent provision of FSH or PMSG. To the extent that SGP-2 is an acceptable apoptotic marker, the present findings support the hypothesis that ovarian follicular atresia may be an apoptotic process.

Key Words: Ovary • atresia • apoptosis • SGP-2

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