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Original Studies |
Departments of Obstetrics, Gynecology, and Reproductive Sciences (M.W.S., A.S.A., J.S.K., S.L.B., A.J.Z.) and Cell Biology and Physiology (A.J.Z.) and Magee Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Michael W. Sullivan, M.D., State University of New York at Buffalo, Department of Gynecology and Obstetrics, Children’s Hospital, 219 Bryant Street, Buffalo, New York 14222.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A hallmark of the cellular actions of FSH on the developing follicle is the induction of LH receptors on granulosa cells, which enables FSH-stimulated follicles to respond to LH (11). Although granulosa cells from early antral follicles respond only to FSH with increased cAMP production and steroid secretion, granulosa cells from mature follicles, which possess both FSH and LH receptors, are responsive to either FSH or LH (12, 13). Zeleznik and Hiller (14) proposed that the maturing follicle may become less dependent upon FSH because the presence of LH receptors on granulosa cells would enable it to respond to LH, whereas other lesser mature follicles whose granulosa cells lack sufficient LH receptors would not be protected from the fall in FSH. To date, this hypothesis has been untestable because preparations of pure FSH and LH have not been readily available for use in humans. The advent of recombinant gonadotropins has provided the reagents necessary to explore the individual roles of FSH and LH on follicular development in humans. In this study we report the use of recombinant gonadotropins to test the hypothesis that the maturing follicle reduces its dependence on FSH by acquiring responsiveness to LH.
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Materials and Methods |
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Serono Laboratories, Inc. (Norwell, MA) generously provided recombinant human FSH (r-hFSH; Gonal-F) and r-hLH (LHadi). The specific activity of r-hFSH is 10,000 FSH IU/mg protein, and it has a terminal half-life of approximately 37 h (15). The specific activity of r-hLH is approximately 14,000 IU/mg, with a terminal half-life of approximately 10 h (Dr. Louis O’Dea, Serono Laboratories, Inc., personal communication). r-hFSH and r-hLH were packaged by the supplier in lyophilized form at 150 and 75 IU/vial, respectively. Hormones were reconstituted in sterile water within 30 min of sc injection.
Experimental design
This prospective, randomized, double blinded study was approved by the institutional review board at Magee-Womens Hospital, University of Pittsburgh (Pittsburgh, PA). All participants were counseled regarding the nature and purpose of the study and signed a detailed consent form. Twenty-eight reproductive age women, ranging in age from 26–36 yr with a mean age of 30.5 yr, were studied. All were ovulatory, of normal weight, and without evidence of tubal or ovarian disease. There was no history of ovarian or tubal surgery in any subject. All of the participants were nonsmokers. Three had previously been diagnosed with minimal endometriosis, 20 were diagnosed with unexplained infertility, and the partner of 1 participant suffered from male factor infertility. Women with evidence of anovulation, a past history of polycystic ovarian disease, an abnormal pelvic examination, or ultrasound evidence of ovarian cysts were excluded. Seventeen of the participants had been previously treated with clomiphene citrate, and 5 had been treated with gonadotropins before the study. All subjects were evaluated with physical exam and pelvic ultrasound scan before study participation.
Before gonadotropin treatment, each participant self-administered leuprolide acetate (TAP Pharmaceuticals, Inc., Chicago, IL) 1 mg daily, sc, from menstrual day 21 throughout the study to minimize endogenous gonadotropin secretion. Serum samples, obtained by venepuncture, were assayed after 14 days of leuprolide acetate therapy for estradiol (E2) and LH. If the participant’s LH and/or E2 levels were above 2.5 IU/L or 20 pg/mL, respectively, the leuprolide therapy was continued for 7 more days, and serum E2 and LH were again assayed. Those women with serum LH levels greater than 2.5 IU/L after a 21-day period of leuprolide treatment were excluded from further study. Participants with serum E2 levels less than 20 pg/mL and LH levels less than 2.5 IU/L were then administered r-hFSH starting at 150 IU. r-hFSH was administered sc daily at 0730 h. After 4 days of r-hFSH treatment, serum was obtained by venepuncture for measurement of E2, androstenedione, FSH, and LH. If serum E2 levels were less than 100 pg/mL, the r-hFSH dose was increased to 225 IU. Follicle number and diameter were assessed daily with vaginal probe ultrasound (model RT3200 Advantage, 5-MHz vaginal probe, GE Medical Systems, Milwaukee, WI). Subjects with E2 levels greater than 250 pg/mL after 4 days of r-hFSH treatment were excluded from study. Participants with serum E2 concentrations below 250 pg/mL were maintained on r-hFSH at 150 IU/day or at 225 IU until the time of randomization. Daily blood samples were collected throughout the study. The serum was stored at -20 C for subsequent assay of steroids and gonadotropins.
Stimulation with r-hFSH was continued until a 14-mm follicle (average of three dimensions) was identified by ultrasound. After a 14-mm follicle was detected, each subject was randomized in a double blind fashion to one of four groups (n = 6/group) by random drawing. Group A subjects discontinued r-hFSH and received 2 cc saline at 0730 and 1930 h for 2 days. Group B subjects continued r-hFSH for 2 days (75 IU at 0730 h and 75 IU at 1930 h). Those subjects receiving 225 IU r-hFSH before randomization received 112.5 IU r-hFSH at 0730 h and 112.5 IU r-hFSH at 1930 h. Group C subjects discontinued r-hFSH and received 375 IU r-hLH at 0730 and 1930 h for 2 days. Group D subjects discontinued r-hFSH and received 150 IU r-hLH at 0730 and 1930 h for 2 days. Two days after randomization (24 h after the final saline or recombinant gonadotropin injection) subjects received 10,000 IU hCG if the serum E2 concentration was less than 2500 pg/mL (see Results). Serum pregnancy tests were obtained 14 days after hCG administration for those women who did not experience menses.
Hormone measurements
E2, androstenedione, LH, and FSH levels were determined in duplicate for each sample using commercially available kits. Estradiol was measured using a solid phase RIA (Diagnostic Products Corp., Los Angeles, CA). The interassay coefficient of variation (CV) for this assay was 10.5%, and the intraassay CV was 3.5%. Androstenedione concentrations were measured in a single assay via solid phase RIA (Diagnostic Products Corp.) with an intraassay CV of 2.0%. The gonadotropins were measured by immunofluorometric assays (DELFIA hLH Spec and DELFIA hFSH kit, Wallac, Gaithersburg, MD). The LH assay had an interassay CV of 7.1% and an intraassay CV of 3.0%, and the FSH interassay and intraassay CVs were 5.8% and 3.9%, respectively.
Statistical analysis
One-way ANOVA was used to determine whether differences existed between the groups for the parameters of age, body mass index, duration of infertility, and menstrual cycle length. The differences in FSH and LH concentrations across the groups, between the day of randomization (day zero) and the day of hCG administration (day 2), were analyzed by two-factor ANOVA with repeated measures in which one factor was the treatment group and the other factor (repeated measure) was the study day (time). A similar analysis was applied to the androstenedione concentrations. Post-hoc comparisons were examined using the Student-Newman-Keuls test (16). Because there were individual variations in the serum concentrations of E2 among women before randomization, the estradiol measurements are expressed as the percent change in the E2 level between day 0 and day 2 and were analyzed by one-way ANOVA; post-hoc comparisons were examined using the Student-Newman-Keuls test. The number of follicles 14 mm or greater were compared between groups on the day of hCG administration (day 2) using one-way ANOVA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Table 1
shows the study population
demographics. All subjects were similar with respect to age, duration
of infertility, pregnancy history, menstrual cycle length, and body
mass index. Twenty-eight women were recruited for the study, and 24
women were randomized and completed the study. Three were excluded
because of an elevated serum E2 level after 4
days of r-hFSH treatment, and 1 woman was discontinued from the study
because she failed to respond to r-hFSH (serum E2
level of < 100 pg/mL after 5 days of r-hFSH at 225 IU/day). hCG
was withheld from 2 women who were at increased risk for ovarian
hyperstimulation based on follicle number and serum estradiol levels
greater than 2500 pg/mL.
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Figures 1 and 2 illustrate serum FSH (Fig. 1) and LH
(Fig. 2) concentrations in the four study groups on the day of
randomization (day 0) and the day of hCG administration (day 2). As
expected, there were no significant differences between the groups with
respect to serum concentrations of FSH or LH on the day of
randomization (day 0). On the day of hCG administration (day 2), serum
FSH concentrations in the subjects maintained on r-hFSH (Fig. 1, group
B) were significantly greater (P < 0.05) than those in
the saline-treated group (group A), the high dose r-hLH-treated group
(group C), and the low dose r-hLH-treated group (group D). Likewise,
serum LH concentrations in the subjects receiving r-hLH during the
study period (Fig. 2, groups C and D) were significantly
(P < 0.05) greater than those receiving saline or
r-hFSH (Fig. 2, groups A and B, respectively). The mean LH
concentrations in group C (high dose r-hLH) were significantly greater
than those in the low dose r-hLH (group D).
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illustrates serum
E2 concentrations in the individual treatment
groups. Serum E2 concentrations in women
receiving saline (group A) increased the day after randomization (day
1) and then decreased by the day of hCG administration (day 2). In
contrast, the serum estradiol levels of women in the groups receiving
either r-hFSH or r-hLH (groups B, C, and D) rose throughout the study
period. The percent change in E2 concentrations
between day 2 and day 0 was +16.8 ± 0.87% for group A,
+122.6 ± 1.8% for group B, +163.0 ± 2.4% for group C, and
+112.8 ± 4.2% for group D. The changes in
E2 differed significantly (P <
0.05) between the saline group (group A) and the groups receiving
either r-hFSH or r-hLH (groups B, C, and D; P < 0.05).
Serum androstenedione concentrations ranged between 0.18–0.28 ng/mL;
there were no statistically significant differences in the various
treatment groups at any point measured (data not shown).
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No pregnancies occurred in the women receiving saline (group A). There was a twin pregnancy delivered without complication at 34 weeks gestation in group B (r-hFSH). One woman in group C (375 IU r-hLH, twice daily) delivered triplets at 32 weeks gestation without complication, and there was a singleton pregnancy delivered at 37 weeks gestation in group D (150 IU r-hLH, twice daily).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is generally accepted that E2 production by the maturing follicle occurs by way of the two-cell, two-gonadotropin model (18, 19). In this model, theca cells produce androstenedione and testosterone under LH stimulation, and FSH induces granulosa cell aromatase, thus enabling the thecally derived androgens to be metabolized to E2. Assuming the validity of this model in humans (20, 21), our results indicate that thecal androgen production is exquisitely sensitive to LH, as a plasma LH concentration of 1.5 IU/L was sufficient to maintain E2 production (day 0; groups A–D) as well as plasma androstenedione concentrations (data not shown). Our observation of E2 production despite very low serum LH concentrations is in agreement with other published data showing that women treated with GnRH agonists to suppress gonadotropin secretion maintain E2 production in the presence of very low levels of serum LH (<0.5 IU/L) (22).
Our current study also indicates that although LH concentrations of approximately 1.5 IU/L are able to sustain thecal androgen production, these levels of LH are unable to maintain granulosa cell aromatase activity when FSH concentrations decline. Thus, serum E2 concentrations decreased in the control group (group A) despite serum concentrations of androstenedione equal to those in the women receiving either r-hFSH or r-hLH. This result suggests that the decrease in E2 secretion in the control group was due to a deficiency of aromatase activity rather than to androgen precursors. Our results also indicate that serum concentrations of LH of 2.5 IU/L or more were sufficient to maintain adequate androgen substrate and maintain follicular aromatase activity as FSH concentrations fell, because the serum E2 concentrations increased in the two groups receiving r-hLH (groups C and D). Comparison of the plasma concentrations of FSH and LH observed in our study with those observed during the spontaneous menstrual cycle gives further merit to the hypothesis that LH protects the maturing follicle from declining FSH concentrations. Using the same FSH and LH assays that we used, Saketos et al. (23) noted that serum FSH concentrations during the spontaneous menstrual cycle fall from approximately 10 IU/L in the early follicular phase to approximately 4–5 IU/L during the mid- through late follicular phase. The decline in FSH concentrations during the spontaneous follicular phase is similar to the decline in FSH concentrations seen in our study subjects who discontinued FSH at the time of randomization (groups A, C, and D). Without additional treatment with r-hLH, these FSH concentrations (4–5 IU/L) were unable to sustain follicular E2 production (group A). However, the study by Saketos et al. (23) also revealed that as FSH concentrations declined during the mid- through late follicular phase, plasma LH concentrations were maintained at approximately 4 IU/L, similar to the mean concentration of LH (3.6 IU/L) observed in our subjects that received r-hLH after randomization (groups C and D). Follicular E2 production continued in our subjects when LH concentrations were maintained at levels seen during the spontaneous menstrual cycle (groups C and D), whereas the lower concentration of LH (<1.5 IU/L) observed in group A was unable to sustain E2 production. Our current results, therefore, are consistent with the idea that the absolute concentration of LH present during the mid- through late follicular phase of the spontaneous menstrual cycle (4–5 IU/L) may play an important role in maintaining preovulatory folliculogenesis as FSH concentrations decline.
Although our data show that LH is capable of maintaining the maturation of follicles with diameters of 14 mm, the actual stage of follicular development when LH can sustain follicular development in the presence of declining serum FSH concentrations is not known. The occurrence of multiple pregnancies in two of the three subjects in the present study indicates that a number of follicles reached the preovulatory stage in response to LH. The most likely explanation for the exaggerated ovarian response is that the duration of the stimulation by FSH was sufficient, such that a number of follicles acquired LH responsiveness and therefore were maintained by LH. Thus, FSH treatment was arbitrarily discontinued when one or more follicles reached a diameter of 14 mm. If follicles less than 14 mm in diameter had acquired LH responsiveness, a greater number of follicles would have been able to respond to LH and reach the preovulatory stage. Although studies in humans have indicated that LH receptors are present on the granulosa cells by the midfollicular phase (day 7) and increased throughout the late follicular phase (24), the exact size at which a follicle becomes LH responsive is not known. Defining a cut-off point below which LH or hCG will not maintain follicular growth could be helpful to control the number of preovulatory follicles in ovulation induction protocols. Theoretically, a sequential FSH and LH ovarian stimulation protocol could be used to limit follicular recruitment, thereby reducing the complications now associated with ovulation induction protocols. In addition, hCG is usually used as a surrogate to LH to stimulate ovulation in most infertility treatment protocols. Inevitably, at the time of hCG administration multiple follicles in various stages of development are present (2). In view of our current results, administration of hCG to initiate ovulation of the leading follicles may also have unintended consequences by maintaining the growth of smaller follicles and therefore may contribute to the undesirable effect of multiple pregnancies and/or ovarian hyperstimulation.
In summary, our results are consistent with the hypothesis that the maturing follicle continues to develop in the presence of diminishing FSH concentrations because it acquires the capacity to respond to LH. If so, this would indicate that the FSH-mediated induction of aromatase and LH receptors on granulosa cells are the principal components of the process of follicle selection. By acquiring aromatase, the maturing follicle produces E2, which inhibits FSH secretion and terminates the maturation of less mature follicles, while at the same time the concomitant induction of LH receptors enables maturing follicles to continue to develop despite the fall in FSH concentrations. FSH-dependent preovulatory follicular development is associated with other changes in the follicle, such as angiogenesis and the production of autocrine and paracrine growth factors that have been shown in vitro to modify the actions of FSH and LH (1, 2, 3, 25). However, our results indicate that in the absence of an adequate gonadotropin stimulus in vivo, the various locally produced paracrine and autocrine factors are unable to sustain follicular development in the presence of declining serum FSH concentrations.
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Acknowledgments |
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Footnotes |
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Received October 8, 1997.
Revised March 10, 1998.
Revised August 19, 1998.
Accepted September 18, 1998.
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References |
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