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From the Clinical Research Centers |
Reproductive Endocrine Unit, Reproductive Endocrine Sciences Center and National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dr. Corrine K. Welt, Reproductive Endocrine Unit, Reproductive Endocrine Sciences Center and National Center for Infertility Research, 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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Administration of the GnRH antagonist resulted in a significant decrease in LH (75 ± 5%, 63 ± 3%, and 84 ± 7%; P < 0.05) and FSH (23 ± 9%, 32 ± 5%, and 39 ± 6%; P < 0.04) during the MFP, LFP, and MLP, respectively. During the MFP, partial withdrawal of gonadotropins resulted in disappearance of the dominant follicle on ultrasound accompanied by a decrease in estradiol (E2; 64.9 ± 11.4 to 23.9 ± 3.3 pg/mL; P < 0.02) and inhibin B levels (121.6 ± 14.8 to 28.4 ± 4.8 pg/mL; P < 0.002) from baseline to near the limit of detection. Inhibin A was near the limit of detection in this cycle stage (0.8 ± 0.1 IU/mL). When gonadotropins were withdrawn during the LFP, the size of the dominant follicle remained stationary in four of five subjects, and inhibin B (84.1 ± 14.1 to 22.2 ± 3.4 pg/mL; 71 ± 5%; P < 0.02), inhibin A (4.4 ± 1.1 to 1.3 ± 0.5 IU/mL; 71 ± 7%; P < 0.02), and E2 (236.8 ± 48.2 to 95.6 ± 39.0 pg/mL; 61 ± 12%; P < 0.02) decreased similarly. Time to ovulation was shorter in association with higher inhibin A (r = -0.67; P < 0.02) and E2 (r = -0.79; P < 0.003), but there was no relation to inhibin B. During the MLP, decreased gonadotropin levels resulted in the disappearance of corpus luteum function with a significant decrease in inhibin A (9.0 ± 0.4 to 0.7 ± 0.1 IU/mL; 92 ± 1%; P < 0.0001) in combination with decreased E2 (150.4 ± 22.9 to 23.8 ± 4.2 pg/mL; 83 ± 3%; P < 0.005) and progesterone (12.6 ± 2.6 to 0.9 ± 0.2 ng/mL; 92 ± 2%; P < 0.01).
Administration of a GnRH antagonist at precise stages of the menstrual cycle provides further evidence that differential regulation of inhibin A and inhibin B is critically dependent on the stage of follicular development. Inhibin B secretion is exquisitely sensitive to gonadotropin withdrawal during the MFP when inhibin A has not yet risen. Inhibin A and inhibin B decrease equally after GnRH antagonist administration during the LFP. However, before antagonist administration, the positive correlation between estradiol and inhibin A and time to ovulation and the lack of such a correlation with inhibin B suggest that the source of inhibin B secretion is different from that of inhibin A and E2. The decrease in inhibin A secretion after antagonist administration during the luteal phase confirms gonadotropin-dependent secretion of dimeric inhibin A by the corpus luteum.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Follicles also exhibit changes in the pattern of inhibin subunit
synthesis and secretion of dimeric hormone through stages of growth
across reproductive cycles in a variety of animal species (10, 11, 12, 13),
including the human (14, 15, 16). These changes in inhibin may play both an
endocrine role in the regulation of FSH and an autocrine/paracrine role
in follicular development (17). Inhibin ßB-subunit expression is
highest in the granulosa cells of small antral follicles (13, 16),
ßA-subunit expression is highest in the dominant follicle and in the
corpus luteum, and 
-subunit expression appears relatively constant
throughout follicular maturation after antrum formation (16). Serum
inhibin A and inhibin B levels across the menstrual cycle mirror these
changes in messenger ribonucleic acid (mRNA) levels (18, 19, 20, 21, 22). Thus,
developing follicles appear to secrete inhibin B, whereas the dominant
and/or luteinized follicle appears to secrete inhibin A in normal
cycles.
In vitro studies from animal species suggest that inhibin secretion is gonadotropin dependent. FSH stimulates inhibin expression and secretion from immature granulosa cells in the rat (23, 24, 25, 26, 27), nonhuman primate (28), and human (29). Both LH and FSH stimulate inhibin expression and secretion from rat granulosa cells pretreated with FSH to induce LH receptor formation (23, 26) and from the granulosa cells of dominant follicles in nonhuman primates and humans (28, 29). Studies in the human female demonstrated FSH stimulation of inhibin A and inhibin B secretion during the follicular phase (22, 30, 31). However, examination of physiological gonadotropin stimulation of dimeric inhibin is limited in the majority of these in vivo studies by the use of exogenous FSH (30, 31), which may accelerate normal follicle maturation. Taken together with the pattern of circulating inhibin A and B across the menstrual cycle, these findings suggest that under physiological conditions, there is a maturational change in the inhibin species secreted after gonadotropin stimulation, with stimulation of inhibin B by FSH during the early follicular phase and stimulation of inhibin A by both FSH and LH during the late follicular phase (LFP).
Thus, we hypothesized that the degree to which inhibin A and inhibin B decreased after partial gonadotropin withdrawal during the normal menstrual cycle would depend on the stage of follicular development. To test this hypothesis, a maximally effective dose of the Nal-Glu GnRH antagonist was administered to normal women at carefully defined stages of the menstrual cycle, which encompassed follicular development over a broad range of maturational stages. Using this model, gonadotropin regulation of inhibin A and inhibin B could be examined under normal conditions of follicular growth. Our results demonstrate that gonadotropins are required for inhibin A and inhibin B secretion and further define the differential changes in inhibin A and inhibin B secretion as a function of follicular maturation.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study population consisted of 19 subjects, aged 24–42 yr (mean ± SEM, 31.3 ± 1.5), with normal thyroid hormone and PRL levels and documented normal menstrual cycles, 25–35 days in length, and with ovulation in the cycle preceding the start of the study confirmed by a progesterone (P4) level greater than 3.5 ng/mL (11 nmol/L) as previously described (1). Subjects were taking no hormonal medications for at least 3 months and used barrier contraception throughout the study. The study was approved by the subcommittee on human studies at the Massachusetts General Hospital, and all subjects gave informed consent.
Protocol
As previously described, subjects were monitored across two menstrual cycles: a control cycle and an antagonist treatment cycle (1). One subject studied during the LFP did not complete a control cycle. In the control cycle, subjects drew daily blood samples and were monitored by basal body temperatures and transvaginal ultrasounds at regular intervals to assess follicular size and endometrial thickness. Follicles greater than 10 mm from both ovaries were recorded, as was the presence of irregular follicular margins or internal echoes.
During the antagonist treatment cycle, 150 µg/kg Nal-Glu GnRH antagonist ([Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,DGlu(AA)6,DAla10]GnRH) was administered sc at a dose previously determined to be the ED100 dose in women, resulting in greater than 80% and 40% suppression of plasma LH and FSH, respectively, for 24 h (32). The antagonist was formulated in sterile water with 5% glucose at a concentration of 10 mg/mL. The antagonist was administered at the same time on 3 consecutive days in 1) the MFP, beginning on days 5–9 of the cycle, with the onset of menses designated day 1 (n = 8); 2) the LFP, beginning on days -2 to -1 from the expected day of ovulation predicted by control cycle dynamics and serial ultrasound criteria (33) (n = 5); and 3) the midluteal phase (MLP), 5 days after the urinary LH peak (n = 5).
Assays
All daily blood samples were assayed for estradiol (E2) and P4 as described previously (34, 35). LH and FSH were analyzed by RIA (34, 35) or by a two-site monoclonal nonisotopic system (Abbott Laboratories, Abbott Park, IL) calibrated with the same reference preparation used in the RIA (36). LH and FSH levels were not significantly different using the two assays across a broad range of values and across the menstrual cycle within individual subjects. Linear regression and Pearson correlation performed on blood samples analyzed in both assays revealed that for LH, the least squares line slope = 1.135, intercept = -0.895, and r2 = 0.931; and for FSH, the slope = 0.961, intercept = 0.57, and r2 = 0.993. All blood samples from the control and antagonist treatment cycles for a given individual were analyzed using the same assay. The inter- and intraassay coefficients of variation were similar to those described previously (34, 35, 36). Gonadotropin levels are expressed in international units per L, as equivalents of the Second International Reference Preparation of human menopausal gonadotropin.
Inhibin A and inhibin B were measured from day -2 to day 8 relative to the first day of GnRH antagonist administration (day 0) during the MFP and LFP. Inhibin A, only, was measured around the time of antagonist administration during the MLP, because inhibin B is near the limit of detection at this time in the cycle. Inhibin A was measured by ELISA (Serotec, Oxford, UK), as previously described (18). The inhibin A assay uses a lyophilized human follicular fluid calibrator standardized as equivalents of the WHO recombinant human inhibin A preparation 91/624, and values are reported as international units per mL. The intraassay coefficient of variation for the dimeric inhibin A assay was 3.9% at the ED20 dose, and the interassay coefficient of variation was 6.8% at the ED30 dose. The assay sensitivity was 0.6 IU/mL, the value of the lowest calibrator.
Inhibin B was measured by ELISA (Serotec), as previously described (37). The limit of detection of the inhibin B assay (mean ± 2 SD of multiple zero standard measurements) was 15.6 pg/mL. The intraassay coefficient of variation was 4–6%, and the interassay coefficient of variation was 15–18% for serum spiked with 121, 250, and 723 pg/mL inhibin B. All samples with levels in excess of 500 pg/mL were appropriately diluted. All samples for a given individual were run in the same assay.
Data analysis
To evaluate the effect of GnRH antagonist administration, data were centered to the first day of antagonist injection, and the mean levels of LH, FSH, E2, P4, inhibin A, and inhibin B were calculated at baseline and at the nadir within 24 h of the last GnRH antagonist injection. Baseline and nadir values were compared using a paired t test. The percent decrease from the baseline value to the nadir was also calculated for each hormone. In subjects who received the GnRH antagonist during the follicular phase, the number of days from the last dose of the antagonist to the day of ovulation was determined, with ovulation defined using three of four of the following criteria: 1) day of the LH peak, 2) day of the FSH peak, 3) day of or day after the E2 peak, and 4) the day P4 doubled from baseline or increased to greater than 0.6 ng/mL, as described previously (38). Pearson correlation was used to associate hormone levels before antagonist administration and time to subsequent ovulation and to compare hormone levels during recovery.
All results are expressed as the mean ± SEM unless otherwise indicated. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The GnRH antagonist was administered between days 5–9 after
menses. The mean follicle diameter measured within 24 h of the
first day of antagonist administration was 12 ± 1 mm (range,
8–14 mm). Additional follicles of 4–8 mm were seen in all subjects.
Administration of the GnRH antagonist resulted in decreases in LH
(16.1 ± 1.7 to 3.6 ± 0.6 IU/L; P < 0.001)
and FSH (11.7 ± 0.5 to 8.7 ± 0.8 IU/L; P <
0.04; Figs. 1
and 2). The largest follicle initially
arrested in its growth and subsequently decreased in size by ultrasound
criteria. The decrease in the size of the dominant follicle was
accompanied by decreases in both E2 (64.9 ±
11.4 to 23.9 ± 3.3 pg/mL; P < 0.02) and inhibin
B (121.6 ± 14.8 to 28.4 ± 4.8 pg/mL; P <
0.002) to near the limits of assay detection (Fig. 2). Mean inhibin A
was at the limit of detection at this time in the cycle in five of
eight subjects (0.8 ± 0.1 IU/mL; range, 0.6–1.3 IU/mL).
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). A new follicle subsequently developed on the
contralateral ovary or on both ovaries in seven of the eight subjects
in whom ultrasound data were available. The follicular phase length was
increased in the antagonist cycle reflecting this new follicular
development (22.6 ± 1.2 vs. 13.1 ± 1.1 days;
P < 0.001; Fig. 1). LFP
The GnRH antagonist was administered on days -2 to -1 relative to anticipated ovulation, based on the control cycle and ultrasound criteria (33). Assessment of the hormone results indicated that GnRH antagonist administration was initiated on the day of the LH surge in one subject; therefore, the data from this subject were not included in the mean analysis.
The mean follicular diameter at the time of antagonist administration
was 21 ± 1 mm (range, 19–21 mm). A second follicle of 9–13 mm
was observed in four of the five subjects. Administration of the GnRH
antagonist resulted in a decrease in LH (20.3 ± 3.7 to 7.0
± 0.6; P < 0.02) and FSH (9.2 ± 0.9 to 6.2
± 0.7; P < 0.005; Figs. 3 and 4).
The size of the dominant follicle remained stationary, as assessed by
ultrasound, and all secondary follicles decreased in size. The growth
arrest of the dominant follicle was accompanied by decreases in
E2 (236.8 ± 48.2 to 95.6 ± 39.0
pg/mL; P < 0.02), inhibin A (4.4 ± 1.1 to
1.3 ± 0.5 IU/mL; P < 0.02), and inhibin B
(84.1 ± 14.1 to 22.2 ± 3.4 pg/mL; P <
0.02; Figs. 3 and 4).
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). In an additional subject, the
dominant follicle remained static for 13 days, E2
increased, and a LH surge occurred with a subsequent rise in
P4. The length of the follicular phase increased from
12.5 ± 3.2 to 20.5 ± 3.1 days (P < 0.02;
Fig. 3). E2 and inhibin A, but not inhibin B, were highly
correlated (r = 0.65; P < 0.0001) and also
correlated with LH during recovery after the last dose of the GnRH
antagonist (r = 0.64 and P < 0.0001 for
E2; r = 0.63 and P < 0.0001
for inhibin A) during the LFP. E2 (r = -0.79;
P < 0.003) and inhibin A (r = -0.67;
P < 0.02) immediately before the first GnRH antagonist
administration correlated with time to subsequent ovulation during the
MFP and LFP. There was no correlation between inhibin B and time to
subsequent ovulation.
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The GnRH antagonist was administered 4 or 5 days after ovulation,
and a corpus luteum was demonstrated by ultrasound in all subjects
before antagonist administration. Administration of the GnRH antagonist
resulted in significant decreases in LH (12.9 ± 3.9 to 1.1
± 0.1 IU/L; P < 0.05) and FSH (6.4 ± 0.6 to
3.9 ± 0.5 IU/L; P < 0.005; Figs. 5 and 6).
Decreased gonadotropin levels resulted in significant decreases in
E2 (150.4 ± 22.9 to 23.8 ± 4.2 pg/mL;
P < 0.005), P4 (12.6 ± 2.6
to 0.9 ± 0.2 ng/mL; P < 0.01), and inhibin A
(9.0 ± 0.4 to 0.7 ± 0.1 IU/mL; P < 0.0001;
Figs. 5 and 6).
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). Interestingly, in the LFP subject to whom GnRH
antagonist was administered on the day of the LH surge, E2,
inhibin A, and inhibin B decreased to baseline, and the onset of
vaginal bleeding occurred (data not shown), attesting to the importance
of LH in formation of the corpus luteum. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Previous studies using assays directed at the -subunit of inhibin
(39) demonstrate that inhibin levels are significantly decreased by
gonadotropin withdrawal secondary to GnRH antagonist administration
during the MFP (40) and the MLP in humans (6, 7). Using specific assays
for dimeric inhibin, the current data suggest that inhibin B in the MFP
and inhibin A during the MLP were the predominant species measured in
previous studies. At these respective cycle stages, both inhibin A and
B levels in serum decrease to the limits of detection after GnRH
antagonist administration, suggesting a profound sensitivity to
gonadotropin withdrawal. During the MFP, the decrease in inhibin occurs
concomitant with the disappearance of follicular structures as
determined by ultrasound (1, 3). During the MLP, the decrease in
inhibin occurs with suppression of E2 and P4 to
baseline in both humans (1, 2, 3, 6, 7) and primates (4, 5, 41),
consistent with demise of the corpus luteum. In contrast, GnRH
antagonist administration during the LFP results in growth arrest of
the dominant follicle in the majority of subjects (1, 3, 8, 9). Inhibin
A and inhibin B are suppressed to an equivalent percentage from
baseline despite the absence of a change in the size of the dominant
follicle. These LFP findings provide support for gonadotropin
stimulation not only of inhibin A, as expected from the pattern of
inhibin A secretion (18, 19), but also of inhibin B across the
menstrual cycle.
Evidence that inhibin B is secreted by the cohort of developing follicles recruited in the late luteal phase of the menstrual cycle comes from the predominant ßB mRNA expression in small antral follicles (16), the pattern of inhibin B secretion across the luteal-follicular transition (20, 22), and the close association between the inhibin B rise and follicular development across the luteal-follicular transition (22). In the current study, inhibin B and E2 decrease to their nadirs, with demise of developing follicles after administration of the GnRH antagonist during the MFP. Subsequent to the last dose of GnRH antagonist, a new group of follicles is recruited, and inhibin B levels return to the preantagonist baseline sooner than E2. These results provide evidence that inhibin B secretion serves as the earliest index of gonadotropin-dependent growth of immature follicles consistent with findings in our previous studies using a GnRH-deficient model (22).
In contrast to both E2 and inhibin B, inhibin A was not above the limit of detection in five of eight subjects during the MFP and was only minimally elevated in the rest. In both groups of subjects, follicles ranged from 7–14 mm; thus, these findings are consistent with previous studies in which inhibin A was not detected above assay limits until follicles reached 14 mm (21). Inhibin A was clearly increased in all subjects studied during the LFP when follicles were 19–21 mm in size, confirming that inhibin A is a relatively late product of follicular maturation. An inverse correlation between inhibin A levels just before GnRH antagonist administration and time to subsequent ovulation was seen across the follicular phase as previously reported for E2 (8, 40, 42), suggesting that, like E2, inhibin A serves as an index of an increasingly gonadotropin-independent, preovulatory follicle. Further, inhibin A, but not E2, levels were highest in the four subjects who experienced growth arrest of the dominant follicle during LFP phase administration of the GnRH antagonist and were lowest in the subject with follicular demise. Thus, inhibin A may be a better marker of follicular maturity than E2.
The secretion of inhibin B during the LFP may be attributed to secretion by either the nondominant follicles or the dominant follicle. In vitro data regarding the source of inhibin B during the LFP are conflicting. One study demonstrated inhibin B protein in a preovulatory follicle (15), whereas a second was unable to demonstrate ßB-subunit mRNA or inhibin B protein (16). Evidence for inhibin B secretion from the dominant follicle comes from the correlation between serum and follicular fluid inhibin B levels in in vitro fertilization cycles (43). The similar suppression of inhibin B and inhibin A after GnRH antagonist administration and recovery after a similar interval also suggest inhibin B production by the dominant follicle. However, there was no correlation between the rise in inhibin A and inhibin B, or E2 and inhibin B during recovery. Further, there was no correlation between inhibin B levels and time to ovulation. Taken together, these results indicate that although some inhibin B may be secreted by the dominant follicle, it may not be the only source of inhibin B during the LFP. Other inhibin B sources include nondominant follicles or thecal cells, although the absence of ßB-subunit mRNA in thecal cells makes this less likely (16). Alternatively, the production or clearance of inhibin B may be different from that of inhibin A at this cycle stage.
Granulosa cell cultures have been used to dissect the relative contributions of LH and FSH to dimeric inhibin stimulation. In vitro studies in the nonhuman primate and the human indicate that FSH stimulates inhibin secretion from small follicles (<10 mm) (28, 29), consistent with in vivo studies that demonstrate a critical FSH stimulatory role for inhibin B in the early follicular phase of the cycle (22, 30). Both LH and FSH stimulate inhibin secretion from medium follicles (10–15 mm) similar in size to the predominantly inhibin B secreting follicles during the MFP in the current study. LH is the major factor stimulating inhibin secretion from dominant follicles (>15 mm) (28, 29) found during the LFP. Luteinized granulosa cells obtained from subjects undergoing exogenous gonadotropin and hCG stimulation for in vitro fertilization demonstrate that both LH and FSH stimulate inhibin A expression and secretion (44, 45), but are less consistent regulators of inhibin B (45). Similarly, although the fall in inhibin and P4 after GnRH antagonist administration in the luteal phase can be reversed with hCG administration in nonhuman primates (46) and humans (6) confirming that LH is the most important gonadotropin stimulatory factor for the corpus luteum, FSH has been demonstrated to stimulate inhibin secretion during the luteal phase (47). The GnRH antagonist model used in the current study is limited by the inability to distinguish regulation of inhibin A and inhibin B secretion by LH vs. FSH. However, the correlation between LH, and inhibin A and E2 during recovery after GnRH antagonist administration during the MFP and LFP suggests that LH is the primary stimulating factor for inhibin A and E2 in mature follicles. Taken together, these studies suggest that both FSH and LH can stimulate the secretion of inhibin B and inhibin A, but that the stimulatory and secretory capability is dependent on the maturational stage of the follicle.
Administration of a GnRH antagonist at precise stages of the menstrual cycle provides further evidence that differential regulation of inhibin A and inhibin B is critically dependent on the stage of follicular development. Inhibin B secretion is exquisitely sensitive to gonadotropin withdrawal during the MFP when inhibin A has not yet risen. Inhibin A and inhibin B decrease equally after gonadotropin withdrawal during the LFP. However, the positive correlation between E2 and inhibin A before antagonist administration and time to ovulation and the lack of such a correlation with inhibin B suggest that the source of inhibin B is different from that of inhibin A and E2. The decrease in inhibin A secretion after antagonist administration in the luteal phase confirms gonadotropin-dependent secretion of dimeric inhibin A by the corpus luteum.
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Footnotes |
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Received December 30, 1998.
Revised February 17, 1999.
Revised March 2, 1999.
Accepted March 8, 1999.
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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]
-subunit
secretion from the gonadotrope by GnRH: evidence from the use of two
GnRH antagonists. J Clin Endocrinol Metab. 70:328–335.[Abstract]
-subunit in human serum.
Implications for radioimmunoassay. J Clin Endocrinol Metab. 70:1208–1212.[Abstract]
- and ßA-subunit messenger ribonucleic acid
levels by chorionic gonadotropin and recombinant follicle-stimulating
hormone in cultured human granulosa-luteal cells. J Clin
Endocrinol Metab. 79:1670–1677.[Abstract]
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 C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]
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M. Fawzy, A. Lambert, R.F. Harrison, P.G. Knight, N. Groome, B. Hennelly, and W.R. Robertson Day 5 inhibin B levels in a treatment cycle are predictive of IVF outcome Hum. Reprod., June 1, 2002; 17(6): 1535 - 1543. [Abstract] [Full Text] [PDF]
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S. Gill, J. L. Sharpless, K. Rado, and J. E. Hall Evidence That GnRH Decreases with Gonadal Steroid Feedback but Increases with Age in Postmenopausal Women J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2290 - 2296. [Abstract] [Full Text] [PDF]
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S. Gill, H. B. Lavoie, Y. Bo-Abbas, and J. E. Hall Negative Feedback Effects of Gonadal Steroids Are Preserved with Aging in Postmenopausal Women J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2297 - 2302. [Abstract] [Full Text] [PDF]
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R. B. Barnes, A. B. Namnoum, R. L. Rosenfield, and L. C. Layman The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: Clinical studies in a patient with isolated FSH deficiency and multicystic ovaries: Case report Hum. Reprod., January 1, 2002; 17(1): 88 - 91. [Abstract] [Full Text] [PDF]
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P. A. Fowler, T. Sorsa, W. J. Harris, P. G. Knight, and H. D. Mason Relationship between follicle size and gonadotrophin surge attenuating factor (GnSAF) bioactivity during spontaneous cycles in women Hum. Reprod., July 1, 2001; 16(7): 1353 - 1358. [Abstract] |
