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Follicular Arrest during the Midfollicular Phase of the Menstrual Cycle: A Gonadotropin-Releasing Hormone Antagonist Imposed Follicular-Follicular Transition^*

L. M. KETTEL, S. J. ROSEFF, T. C. CHIU, M. L. BANGAH, W. VALE, J. RIVIER, H. G. BURGER and S. S. C. YEN

Department of Reproductive Medicine, School of Medicine, and the General Clinical Research Center, University of California-San, Diego, and the Peptide Biology Laboratory, the Salk Institute La Jolla, California 92093
Prince Henry’s Institute of Medical Research South Melbourne, 3205 Victoria, Australia

Address all correspondence and requests for reprints to: Dr. S. S. C. Yen, Department of Reproductive Medicine (0802), University of California-San Diego, La Jolla, California 92093-0802.

The functional dependency of the dominant follicle on pulsatile gonadotropin inputs was evaluated by using a GnRH antagonist as a probe. Hormonal dynamics, particularly the relationship of FSH, estradiol, and inhibin, during and after the withdrawal of GnRH receptor blockade achieved by treatment with Nal-Glu GnRH antagonist (50 µg/kg, im) for 3 days in the midfollicular phase of the cycle (days 7–9) were ascertained. Daily blood samples were obtained for LH, FSH, estradiol (E₂), progesterone, and immunoreactive inhibin (i-INH) measurements by RIA during 2 consecutive (control and treatment) cycles in 12 women. In 5 women, LH pulsatility was assessed by 10-min blood sampling for 12 h before, during, and after Nal-Glu treatment. The administration of Nal-Glu prolonged both follicular phase (14.0 ± 0.5 vs. 19.7 ± 0.8 days; P < 0.0001) and total cycle length (28.1 ± 0.5 vs. 34.1 ± 1.2 days; P < 0.0001). Gonadotropin suppression (50-60%) was achieved, as reflected by a marked decrease in mean LH levels (14.3 ± 1.9 to 5.4 ± 0.5; P < 0.01) and LH pulse amplitude (5.5 ± 0.7 to 2.4 ± 0.3 IU/L; P < 0.01) in response to Nal-Glu antagonist. The number of LH pulses was reduced (36%), but pulses remained discernible. Concentrations of FSH (10.8 ± 1.4 to 5.9 ± 0.4 IU/ L; P < 0.05), E₂ (322.7 ± 71.9 to 84.8 ± 7.7 pmol/L; P < 0.01) and i-INH (284.0 ± 25.9 to 164.4 ± 7.5 U/L; P < 0.01) decreased concomitantly. Within 24-48 h of the last injection of Nal-Glu, all hormones had returned to pretreatment levels. This was followed by normal functional expression of follicular growth and maturation, as reflected by an increase in E₂ and i-INH levels, timely ovulation, and normal luteal function. These findings indicate that an approximately 50% decline in gonadotropin support to the dominant follicle leads to functional arrest, but not demise, of the developing follicle(s) without triggering new folliculogenesis. The follicular apparatus retained its ability to reinitiate its original functionality once appropriate gondotropin inputs were reinstated.

^* This work was supported by NIH NICHHD Center Grant HD-12303-12, (S. Y.), Grant HD-13527, the Hearst Foundation (W. V., J. R.), the Andrew W. Mellon Foundation, the National Health and Medical Research Council of Australia, (H. G. B.), and in part by Grant MO1-00827 from the General Clinical Research Branch, NIH. The research was conducted by the Clayton Foundation for Research, California Division.

Andrew W. Mellon Foundation Faculty Scholar.

Clayton Foundation Investigator.

Received December 3, 1990.

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