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Reproductive Endocrinology |
The National Center for Infertility Research and the Reproductive Endocrine Sciences Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; and the Department of Pathology and Laboratory Medicine, Women and Infants’ Hospital of Rhode Island (G.M.L.-M.), Providence, Rhode Island 02905
Address all correspondence and requests for reprints to: Dr. Corrine K. Welt, National Center for Infertility Research and the Reproductive Endocrine Sciences Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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A physiological regimen of GnRH during the luteal-follicular transition resulted in a rise in FSH and inhibin B levels that did not differ from that in normal cycling women and a normal follicular phase length. On the other hand, maintaining a luteal frequency of GnRH for 6 days into the subsequent early follicular phase produced FSH levels significantly lower than those in the physiological transition (P < 0.05), with the greatest difference seen on the day after menses (9.1 ± 1.0 vs. 16.4 ± 1.4 IU/L for the slow and physiological transition groups, respectively; P < 0.005), but no difference in LH. This slower rise of FSH secretion in the slow frequency group was associated with significantly lower inhibin B levels (43.3 ± 21.5 vs. 140.0 ± 24.4 pg/mL, mean days 1, 3, and 5; P < 0.02), a later doubling of estradiol from baseline (day 9.6 ± 0.9 vs. day 5.6 ± 0.1; P < 0.02), and a longer follicular phase length (16.0 ± 1.4 vs. 11.6 ± 0.9 days; P < 0.05) compared with those in the physiological transition group.
In conclusion, during the luteal-follicular transition, the GnRH pulse frequency contributes to but is not solely responsible for the FSH rise that initiates folliculogenesis. Alteration of FSH dynamics induced by changes in GnRH pulse frequency in GnRH-deficient women provides evidence that FSH stimulates inhibin B production in the human. Timely follicular development indicated by both estradiol and inhibin B secretion appears to be dependent on the pattern of increase in FSH during the luteal-follicular transition.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The inhibins, heterodimers composed of an 
-subunit and one of at
least two ß-subunits forming inhibin A and inhibin B, have now been
isolated from follicular fluid and characterized based on their ability
to inhibit FSH secretion selectively from pituitary cells (8, 9, 10). A
changing pattern of inhibin subunit messenger ribonucleic acid (mRNA)
expression has been determined to occur in ovarian granulosa, thecal,
and lutein cells across reproductive cycles in a variety of animal
species (11, 12, 13, 14, 15), including the human (16, 17, 18). These studies indicate
that ßA subunit expression is highest in the corpus luteum and the
dominant follicle, that ßB subunit expression is highest in the
granulosa cells of antral follicles (14, 18) that are present at the
time of the luteal-follicular transition, and that -subunit
expression appears relatively constant throughout follicular
development after the antral stage (18). In general, the secretion of
inhibin A and inhibin B across the menstrual cycle mirrors these
changes in mRNA levels (6, 19, 20, 21). Thus, release of FSH secretion from
the negative feedback of inhibin A with declining inhibin A secretion
from the corpus luteum may also contribute to the luteal-follicular
rise in FSH (6, 7), although the relative contributions of release from
the negative feedback effects of estradiol and inhibin A to these
dynamic changes remain unclear. On the other hand, the pattern of
secretion of inhibin B from developing follicles suggests that its
release from granulosa cells may, in turn, be stimulated by FSH
(21).
In the normal menstrual cycle, changes in GnRH pulse frequency are accompanied by changes in estradiol and inhibin A. We have used the human model of GnRH-deficient women in whom the frequency of GnRH administration can be experimentally controlled to isolate the effect of changes in GnRH pulse frequency from that of estradiol and/or inhibin A on the luteal-follicular rise in FSH. To determine whether GnRH pulse frequency contributes to the luteal-follicular rise in FSH, GnRH pulse frequency was either maintained at a frequency of every 4 h previously documented to occur during the late luteal phase (22) for the first 6 days of the follicular phase or increased to the physiological follicular phase frequency of every 90 min on the day of menses as occurs during the normal cycle. The differential secretion of FSH produced in these studies could then be used to determine the impact of varying levels of FSH secretion on inhibin B secretion.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Normal cycling females. The control population consisted of 92 normal women, aged 18–40 yr, with normal levels of PRL and TSH and taking no medication, as previously described (22, 23). All subjects had a history of regular menstrual cycles, 25–35 days in length, and ovulation in the preceding cycle as indicated by a progesterone level of more than 19 nmol/L. To encompass normal hormonal changes occurring between two ovulatory cycles, a subset of five women, aged 22–40 yr (mean ± SD, 28 ± 7 yr), were chosen for study of gonadotropin and inhibin A and inhibin B dynamics across 2 cycles, as previously described (2).
GnRH-deficient females. The subject population consisted of 10 women, aged 29–37 yr (mean ± SD, 34 ± 3 yr), with GnRH deficiency, as confirmed by the absence of endogenous gonadotropin pulsations during a 24-h period of blood sampling at 10-min intervals before GnRH therapy. All subjects had a history of amenorrhea of at least 2-yr duration, a normal physical examination, were of normal body weight, and did not have a history of intensive exercise. Two patients had Kallmann’s syndrome, 4 patients had secondary hypothalamic amenorrhea, and 4 had acquired hypogonadotropic hypogonadism due to cranial tumors and/or cranial radiation. Concomitant medications included physiological glucocorticoid replacement in 2 patients with secondary adrenal insufficiency and T4 in 2 patients with central hypothyroidism. All subjects had normal serum TSH, T4, T3, and PRL levels and no evidence of androgen excess at the time of the study.
Informed consent was obtained from each subject before participation in the study. The study was approved by the subcommittee on human studies of the Massachusetts General Hospital.
Experimental protocol
Normal cycling females. Blood samples were drawn daily for LH, FSH, estradiol, and progesterone determinations across the duration of one menstrual cycle in the normal women (22, 23). In the subset of women chosen for study of the luteal-follicular transition, daily blood samples were drawn to encompass the LH peaks from two consecutive cycles (from day 10 after the onset of menses of the first cycle until approximately day 17 of the subsequent cycle) using basal body temperature charts and urinary LH determinations to prospectively determine the LH peaks and to indicate when blood sampling could be discontinued in the second cycle (2).
GnRH-deficient females.
A full examination of the
luteal-follicular transition requires 2 cycles of pulsatile GnRH (Fig. 1
). In a total of 10 subjects, 8 physiological (control)
frequency and 6 slow frequency transitions were evaluated, as detailed
below. Three subjects underwent both a physiological and a slow
frequency transition cycle. GnRH was administered iv via portable
infusion pumps (Ferring Laboratories, Suffern, NY). The bolus dose of
GnRH employed in all cycles was 75 ng/kg·pulse, previously
demonstrated to produce physiological gonadotropin and sex steroid
levels, a single follicle, and a 95% rate of ovulation (23). Pregnancy
was pursued by all subjects in cycle 2. Blood samples were drawn daily,
45 min after a GnRH dose and subsequently analyzed for LH, FSH,
estradiol, and progesterone. Due to the limited sample volume, inhibin
A and inhibin B were measured on representative days to encompass the
luteal-follicular transition. Days 0 and 6 were chosen for inhibin A
measurement, and days -1, 1, 3, and 5 were chosen for inhibin B
measurement. Basal body temperatures were monitored, and iv lines were
inspected daily for evidence of infection. The course of follicular
growth was followed by serial transvaginal ultrasonography.
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The changes in GnRH pulse frequency across the induced menstrual
cycle were based on studies of normal women as described previously
(22, 23). For the first 7 days of cycle 1, i.e. the early
follicular phase, a 90-min interval was employed. The GnRH pulse
frequency was then increased to every 60 min at the appearance of a
dominant (1-cm) follicle and remained at this frequency until ovulation
had occurred, as determined by a LH surge on urinary monitoring or by
collapse of the dominant follicle or appearance of internal echoes by
ultrasound. For the first 7 days of the luteal phase, the pulse
frequency was decreased to every 90 min, then to every 4 h for the
remainder of the luteal phase. At the onset of menses, the frequency
was again increased to every 90 min, and the sequence was repeated for
cycle 2 (Fig. 1
).
Slow frequency transition
The frequency of pulsatile GnRH employed for cycle 1 in the slow
frequency transition was identical to that described above. However,
during cycle 2, the late luteal phase frequency of every 4 h was
continued through the first 6 days after menses. On day 7, the GnRH
pulse frequency was increased to 90 min until a dominant follicle was
seen. The frequency was then increased to every 60 min, and the
sequence was continued as for cycle 1 (Fig. 1). In two subjects, a 1-cm
follicle was present on day 7, and GnRH pulse frequency was increased
to every 60 min rather than every 90 min.
Data analysis
In the normal women, data were centered to ovulation for comparison of cycle dynamics with GnRH-deficient women using three of four of the following criteria: 1) day of LH peak, 2) day of FSH peak, 3) day of or after the midcycle estradiol peak, and 4) the day the progesterone level doubled from baseline and reached 0.6 ng/mL (22). In those subjects chosen for examination of the luteal-follicular transition, changes in FSH, inhibin A, and inhibin B levels were examined across the luteal-follicular transition (days -7 to 7 centered to menses of cycle 2 as day 0) for each individual subject.
To compare gonadotropin and sex steroid dynamics in the luteal-follicular transition in GnRH-deficient women, data were centered to the onset of menses of cycle 2 and analyzed between days -2 and 6. The daily FSH, LH, estradiol, progesterone, and inhibin B levels were compared between the physiological frequency and slow frequency transition groups and normal women using a repeated measures ANOVA between-subjects test that tests for an overall mean effect, followed by t tests on each day with appropriate Bonferroni correction. Inhibin A levels on days 0 and 6 were compared between the two groups receiving pulsatile GnRH and the normal women using t tests.
In addition, data were centered to the day of ovulation (22) to examine the effects of GnRH frequency on follicular and luteal phase lengths, integrated follicular phase LH and FSH (excluding the midcycle), integrated follicular phase estradiol (menses to the day of the LH surge, inclusive), and integrated luteal phase progesterone and estradiol (data analyzed only to day 7 after the LH surge due to the occurrence of pregnancies in cycle 2). Comparisons were made between the slow frequency and physiological frequency transition groups using t tests. Paired t tests were used to compare follicular phase lengths in cycles 1 and 2 within groups.
Results are expressed as the mean ± SEM unless otherwise indicated, and P < 0.05 was considered significant. We hypothesized that FSH and inhibin B would be lower in the slow than in the physiological frequency transition group, and therefore, one-sided testing was used for these comparisons.
Assays
Plasma LH, FSH, estradiol, and progesterone were measured by RIA as previously described (24, 25). All samples were analyzed in duplicate, and all samples from an individual were analyzed in the same assay. The volume of sample used for estradiol determination resulted in an assay sensitivity of 40 pg/mL. The inter- and intraassay coefficients of variation were similar to those previously described (2). Gonadotropin levels are expressed in international units per L, as equivalents of the Second International Reference Preparation of human menopausal gonadotropins.
Inhibin A and inhibin B were measured by ELISA as previously described (19, 26). The intraassay coefficient of variation for the dimeric inhibin A assay was 3.9%, whereas the interassay coefficient of variation was 6.8%. The assay sensitivity was 1 pg/mL. The lowest measurable concentration of inhibin B (mean ± 2 SD of multiple zero standard measurements) was 15 pg/mL. However, dilution of human serum samples revealed a clinical detection limit of 50 pg/mL, with less than 20% within-plate variation. Thus, the working range of the assay was 50–500 pg/mL, with an intraassay coefficient of variation of 4–6%, and an interassay coefficient of variation of 15–18%. All inhibin A and inhibin B samples from an individual were run in the same assay.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The luteal-follicular increase in FSH that begins before the onset
of menses occurred concomitant with the decrease in estradiol and
progesterone, as previously shown (1, 2), and also occurred in the
setting of decreasing inhibin A (Fig. 2). Inhibin A and
FSH were inversely related across the luteal-follicular transition in
each subject, suggesting an endocrine role for inhibin A in FSH
negative feedback regulation. In contrast to inhibin A, inhibin B
increased before menses, coincident with the rise in FSH in the group
as a whole (Fig. 2) and in each subject, suggesting that FSH stimulates
inhibin B secretion in this cycle stage.
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As in normal cycling women, there was a slight increase in FSH
before menses in both the physiological and slow frequency transition
groups (Fig. 3). FSH levels were not significantly
different on days -2 to 0 between the physiological and slow frequency
transition groups, nor were there differences in LH, estradiol, or
progesterone. There was also no significant difference in these hormone
levels in either subject group compared to those in normal cycling
women; however, the mean FSH was slightly lower on day 0 in the
physiological (9.4 ± 1.2 IU/L) and slow (7.3 ± 1.0 IU/L)
frequency transition groups compared to that in normal women (11.6
± 2.3 IU/L). Importantly, there was no significant difference in
inhibin A on the day of menses among the three groups. In contrast,
inhibin B was significantly lower in the slow and physiological
frequency transition groups than in the normal cycling women on the day
before menses (Table 1).
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). The mean of the inhibin B
concentrations on days 1, 3, and 5 was significantly lower in the slow
frequency transition compared to those in both the physiological
frequency transition group (Fig. 3; P < 0.02) and
normal cycling women (Table 1; P < 0.01).
In addition to lower FSH and inhibin B levels, a slower frequency of
GnRH administration during the luteal-follicular transition was
associated with a longer subsequent follicular phase length (Table 2). The follicular phase length was also longer than
that in normal cycling women (Table 2). When cycle 2 was compared to
cycle 1 within groups, the follicular phase length was longer in cycle
2 than that in cycle 1 in the slow frequency transition group
(16.0 ± 1.4 vs. 10.8 ± 1.0 days; 
, 5.2
± 1.2; P < 0.02), but not in the physiological
frequency transition group (11.6 ± 0.9 vs. 13.5
± 0.8 days; , 2.9 ± 0.9).
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and Fig. 4). Further, the rise
in estradiol secretion did not commence until the GnRH pulse frequency
was increased. On the day the GnRH pump frequency was increased from
every 4 h in the slow frequency transition group, a dominant
follicle (>1 cm) was seen in only two of six subjects.
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) due to the longer follicular
phase length in the slow frequency transition. There was also no
difference in the midcycle LH between the two groups. The midcycle LH
in the slow transition group was significantly lower than that in
normal cycling women, but fell well within the 95% confidence limits
of the normal range (Table 2). Luteal phase dynamics
There was no significant difference in the length of the luteal
phase or in the integrated progesterone or estradiol values for days
1–7 of the luteal phase in cycle 2 of the physiological vs.
slow frequency transition group and no difference compared with those
in normal women (Table 2).
Cycle outcome
Six pregnancies resulted from GnRH stimulation in the subjects included in this study. Three occurred in the eight studies with physiological frequency transitions, and three occurred in the six studies with slow frequency transitions. One subject had a pregnancy in each of her physiological and slow frequency transition studies, both resulting in miscarriage. One pregnancy in the slow transition group resulted in twins. Interestingly, the FSH levels in this subject were not significantly higher than those in the remainder of the subjects.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is evidence that slow frequency GnRH stimulation favors FSH expression and secretion from the gonadotrope. FSHß mRNA levels (27) and transcription rates (28) increase preferentially with slow frequency GnRH stimulation in the testosterone-treated rat model. Consistent with these effects of GnRH frequency on FSH synthesis, a decrease in GnRH pulse frequency has been associated with increased FSH secretion in male and female animal and human models in the absence of gonadal secretion (29, 30, 31, 32). However, in the presence of sex steroids or intact gonadal function such as in our model, FSH levels are lower or do not increase in association with a GnRH pulse frequency that is slower than normal (32, 33, 34). Taken together, these findings suggest that the slow frequency of GnRH stimulation in the luteal phase of the normal menstrual cycle may be critical to the maintenance of luteal phase synthesis of FSH (35), whereas the late luteal phase fall in estradiol, and possibly inhibin A, releases the pituitary from inhibition of secretion, and plasma FSH levels are permitted to rise. Subsequently, as demonstrated in the current study, the increase in GnRH pulse frequency that occurs during the luteal-follicular transition results in increased stimulation of a pituitary primed for FSH release, and a faster rise in FSH is favored. It is unlikely that an increase in total GnRH dose, rather than an increase in GnRH pulse frequency, is responsible for the increased secretion of FSH based on studies in GnRH-deficient men in whom there was no difference in FSH response to decreasing frequencies of GnRH administration regardless of whether the total GnRH dose or the dose of each bolus was held constant (31) and in GnRH-deficient women in whom GnRH pulse frequency was a more important determinant of follicular phase FSH levels than was the total GnRH dose (34).
The observation that there is some increase in FSH before menses in the presence of a persistently slow GnRH pulse frequency indicates that release from negative gonadal feedback is also important in the luteal-follicular control of FSH. Across all species, there is ample evidence for a negative feedback role of estradiol on FSH secretion (5) and synthesis at the level of the gonadotrope (36). In the human, progesterone is unlikely to have a direct pituitary effect on the regulation of FSH secretion, although it may be involved indirectly in the regulation of FSH secretion through modulation of GnRH pulse frequency at the level of the hypothalamus (37). The pattern of secretion of inhibin A in the normal menstrual cycle (19, 20) along with the negative relationship between FSH and inhibin A levels across the luteal-follicular transition described here suggest that inhibin A may also contribute to the negative regulation of FSH during the luteal phase despite very low circulating levels. This indirect evidence of an endocrine role for inhibin A in the negative feedback control of FSH in female reproductive cycles is generally supported by recent studies in which recombinant inhibin A has been administered in subhuman primates. When exogenous inhibin A is administered during the luteal phase, it prevents the rise in FSH that is generally associated with demise of the corpus luteum (38). Molskness et al. (39) have demonstrated a progressive decrease in FSH levels in rhesus monkeys after early follicular phase administration of inhibin A, contrasting with the earlier studies of Fraser et al. (40), in which no change in FSH was seen with early follicular phase administration of a smaller dose of recombinant inhibin A in macaques. In the rat, recombinant inhibin A has also been shown to decrease FSH levels, but the magnitude of the effect varies with the cycle stage (41). Taken together, these studies suggest that the feedback effects of inhibin A are complex, being dose, species, and physiological context specific.
The differential increase in FSH induced by altering GnRH pulse frequency provides evidence that the normal luteal-follicular rise in FSH controls inhibin B secretion. In normal cycling women, inhibin B levels rose in association with FSH during the luteal-follicular transition at a time previously documented to be associated with the increase in GnRH pulse frequency that occurs before menses (2). This late luteal phase increase in inhibin B was not observed in either group of GnRH-deficient women despite the somewhat less dramatic increase in FSH that occurred. When GnRH pulse frequency was increased on the day of menses, a robust rise in FSH to normal early follicular phase levels ensued, and inhibin B levels increased. Importantly, in the subjects maintained on slow frequency GnRH, the more gradual rise in FSH was not associated with an increase in inhibin B secretion. These data suggest that there is a critical FSH threshold for inhibin B stimulation, that the rate of rise in FSH is important for stimulation of inhibin B, or that GnRH pulse frequency regulates inhibin B secretion. The possibility that GnRH pulse frequency is responsible for the rise in inhibin B is unlikely, based on data indicating that GnRH inhibits, rather than stimulates, inhibin production (42, 43, 44) and evidence that GnRH receptors are not present on granulosa cells at this early stage of follicular development in the human (45).
Our finding that failure of a normal increase in FSH during the
luteal-follicular transition prevents the normal increase in inhibin B
is entirely consistent with a role of FSH in stimulating inhibin B in
the human, a finding supported by previous studies in rat and human
models (46, 47, 48). FSH stimulation of , ßA, and ßB subunit mRNA
expression occurs in partially differentiated granulosa cells in the
rat (42, 46, 47). In the human female, analysis of inhibin subunit mRNA
stimulation has been performed only in luteinized granulosa cells after
hyperstimulation with gonadotropins during in vitro
fertilization treatment (49). These cells show little detectable ßB
mRNA and, hence, may not reflect results from granulosa cells of
follicles stimulated by physiological levels of gonadotropins or at
early developmental stages. Total inhibin levels increase in a
dose-dependent manner with FSH stimulation in the early follicular
phase in normal women (50), and total inhibin and inhibin A increase
with follicular maturation in gonadotropin-deficient women treated with
exogenous FSH in vivo (51, 52). In the human male, increases
in FSH are associated with increases in inhibin B secretion (26, 48).
An endocrine role for inhibin B in the negative feedback of FSH has also been postulated and supported by a recent correlative study in which higher early follicular phase FSH levels in older cycling women were associated with lower inhibin B levels compared to those in younger cycling women (53). In normal women, the later peak of inhibin B secretion compared to the peak in FSH in this study and others (21) also suggests that inhibin B may curtail the duration of the FSH rise in the early follicular phase and, thus, the number of follicles reaching maturity.
In addition to the absence of a normal inhibin B response, the slower rate of rise of FSH in the current studies was also associated with a delayed increase in estradiol, delayed follicle growth on ultrasound, and a longer follicular phase, all indicative of delayed folliculogenesis. The differences in inhibin B levels were detectable before the increase in estradiol and before follicular growth was evident on ultrasound, suggesting that inhibin B may be an important early marker of follicular response during the administration of exogenous gonadotropins for infertility treatment.
Despite the delay in folliculogenesis in the slow frequency transition group, the midcycle surge appeared normal, as assessed by ovulation frequency (100% in this study) and height of the LH surge. Luteal phase characteristics also appeared normal in both groups, and pregnancy rates were identical in the two groups. Thus, a normal cycle was subsequently created despite delayed selection and/or development of the dominant follicle in the early follicular phase in the slow transition group. However, it is important to bear in mind that in the current studies, the frequency of GnRH administration was increased on day 6 of the follicular phase. Previous studies have shown that a GnRH pulse frequency of every 2 h, if continued through the entire follicular phase is associated with a markedly diminished ovulatory rate compared with hourly GnRH stimulation (34), suggesting that the eventual increase in GnRH pulse frequency in the slow frequency transition group was essential for subsequent normalization of cycle dynamics.
In conclusion, manipulating the frequency of GnRH administration in GnRH-deficient women demonstrates that the rise in GnRH pulse frequency correlates with and hence appears to contribute to the luteal-follicular rise in FSH of the normal menstrual cycle. The progressive, although less dramatic, increase in FSH occurring in the absence of any increase in GnRH pulse frequency provides further evidence for the importance of removal of the negative feedback of estradiol and possibly inhibin A in the dynamic regulation of FSH. Importantly, the isolated increase in FSH in the luteal-follicular transition is associated with a coordinate increase in inhibin B secretion. When this FSH rise is attenuated by slow frequency GnRH administration, the inhibin B response is delayed, as is folliculogenesis. Thus, both decreased negative gonadal feedback and increased GnRH stimulation contribute to the control of the FSH rise in the luteal-follicular transition to assure timely folliculogenesis, as indicated by inhibin B production.
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Acknowledgments |
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Footnotes |
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Received February 19, 1997.
Revised April 17, 1997.
Accepted April 29, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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ßB-subunits in ovarian cell types during the rat estrous cycle. Mol
Endocrinol. 2:1352–1363.[Abstract]
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levels by chorionic gonadotropin and recombinant follicle-stimulating
hormone in cultured human granulosa-luteal cells. J Clin
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P. Y.K. Yong, D. T. Baird, K.J. Thong, A. S. McNeilly, and R. A. Anderson Prospective analysis of the relationships between the ovarian follicle cohort and basal FSH concentration, the inhibin response to exogenous FSH and ovarian follicle number at different stages of the normal menstrual cycle and after pituitary down-regulation Hum. Reprod., January 1, 2003; 18(1): 35 - 44. [Abstract] [Full Text] [PDF]
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) and inhibin B (
) in
the physiological frequency transition group and FSH (•) and inhibin
B (
) in the slow frequency transition group. Data represent the time
period during which the GnRH pulse frequency was held at every 4 h
for the slow transition cycles. GnRH pulse frequency is indicated for
each group in the boxes at the top of the graph. Note
the slower rate of rise in FSH and the failure of inhibin B to rise in
the slow frequency transition group (**, P <
0.05).