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Original Studies |
Centro de Investigaciones Endocrinologicas, Hospital de Niños R. Gutierrez (M.G.R., M.C.G.-R., M.E.E., M.B.), Buenos Aires, Argentina; Research Unit in Developmental Biology (C.C.-F.) and Reproductive Medicine (A.U.-A.), Instituto Mexicano del Seguro Social, Mexico DF, Mexico; and the Department of Internal Medicine, University of Virginia Health Sciences Center, NIH Specialized Cooperative Centers Program in Reproduction Research and General Clinical Research Center (J.D.V.), Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recently, we characterized overnight pulsatile LH secretion in adolescent girls with PCOS using a high specificity and high precision, immunofluorometric, time-resolved assay in combination with deconvolution analysis to quantitate pulsatile LH secretion and apparent endogenous LH half-life (2, 19, 20, 21). These analyses disclosed dual augmentation of the frequency and mass of LH discharged per burst in adolescents with PCOS compared with those in pubertally matched eumenorrheic controls (2). This appraisal also for the first time predicted either a prolongation of the apparent (endogenous) LH half-life or an elevation of basal (interpulse) LH secretion driving an increased interpeak serum LH concentration (2). Technically, the distinction between these two considerations is very difficult (22). Indeed, a higher interpulse plasma LH concentration could originate from a rise in either the half-life or the basal (nonpulsatile) secretion rate of a hormone (20, 23). As the oligosaccharide moieties on LH molecules can affect their in vivo half-lives and in vitro bioactivity (13), we reasoned that independent experimental knowledge of LH isoform predominance along the spectrum of electrostatic charge might aid in distinguishing between a longer half-life (more acidic LH) and increased nonpulsatile (basal) LH secretion (shorter half-life and more basic LH isotypes) in adolescents with PCOS. Thus, here we appraise the pattern of secreted LH isoforms using preparative chromatofocusing and concomitantly determined the biological activity of LH by in vitro Leydig cell bioassay.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twelve adolescent girls with PCOS (aged 13–20 yr) and 10 eumenorrheic controls (aged 13–19 yr) were studied. None of the subjects was hypertensive or had evidence of Cushing’s disease or drug-induced hirsutism. Hyperprolactinemia and thyroid disease were ruled out by normal serum measurement of these hormones. None of the subjects received any medication for 3 months before study. The diagnosis of PCOS was based on the following features: 1) clinical signs of hyperandrogenism [hirsutism, evaluated by a Ferriman-Gallwey score of at least 9 (24) and/or acne], 2) perimenarchal onset of oligomenorrhea or amenorrhea, and 3) elevated serum testosterone (T) and/or androstenedione (A) concentrations. These patients also exhibited a significantly raised (nonoverlapping) LH/FSH ratio (2). Late-onset congenital adrenal hyperplasia was excluded by a normal serum 17-hydroxyprogesterone (17-OHP) concentration measured 60 min after ACTH injection (25). The study protocol was approved by the ethical committee of Ricardo Gutiérrez Children’s Hospital, and written informed assent and consent were obtained from each subject and her parents.
Overnight 12-h serum samples (collected every 20 min) were obtained
from both normally cycling controls and PCOS adolescents, as previously
described (2). Seven PCOS patients presenting with oligomenorrhea and
all controls were studied in the early follicular phase of the
menstrual cycle (days 3–5), and the remaining 5 PCOS patients
presenting with amenorrhea were studied on a random day. Serum samples
from PCOS adolescents and those from control adolescents were pooled,
thus yielding 12 PCOS and 10 control serum pooled samples (2 ml each),
which were used to determine the biological activity of serum LH in the
2 groups (see below, methods). Clinical and biochemical characteristics
of PCOS and eumenorrheic adolescents are shown in Table 1
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Immunoassays. Serum LH and FSH concentrations were determined in each overnight pool from either PCOS or control adolescents by immunofluorometric assay (DELFIA, Wallac, Inc. Oy, Turku, Finland), with intra- and interassay coefficients of variation of less than 7% and 5%, respectively (26). The results of the FSH and LH assays were expressed in international units per L using as reference standards the Second International Standards for pituitary FSH and LH (78/549 and 80/552, respectively).
Serum concentrations of 17-OHP, T, A, 17ß-estradiol, and estrone were
determined by RIA, and sex hormone-binding globulin was determined by
saturation analysis using tritiated 5
-dihydrotestosterone, on
0700 h fasting samples, as previously described (27).
LH bioassay. Aliquots of pooled serum were submitted to in vitro bioassay using the rat Leydig cell bioassay exactly as reported previously (28). Each sample was assayed in duplicate at three dilutions. The intra- and interassay coefficients of variation were 8.5% and 12%, respectively. The assay standard was the Second International Reference Preparation of human menopausal gonadotropin.
Chromatofocusing of serum samples. The distribution of LH
isoforms was determined in samples further randomly combined (to obtain
an adequate total analytical volume) within group into three serum
pools for the patients and three for controls, as shown in Table 2. The serum pools were concentrated by
dialysis and freeze-dried, and the LH isoforms were separated on the
basis of charge by preparative chromatofocusing (pH window, 10.5 to
<4). Each serum pool was transferred to a dialysis membrane tubing
(mol wt cut-off, 12,000–14,000; Spectrum Medical Industries, Los
Angeles, CA), dialyzed at 4 C for 24 h against deionized water and
thereafter against 0.01 mol/L ammonium carbonate (pH 7.5), and
freeze-dried. Each specimen was slowly redissolved in 0.6 or 0.8 mL
(1/10th of its original volume) limit buffer [1:45 dilution of
Pharmalyte (pH 8–10.5)-HCl (Pharmacia Biotech,
Piscataway, NJ) in deionized water, pH 7.0]. The suspension was
applied to a 20 x 1-cm column of polybuffer exchange resin
(PBE-118, Pharmacia), previously equilibrated for 18–24 h with 25
mol/L triethylamine-HCl, pH 11.0, and chromatofocused at 4 C. Eluate
fractions (2 ml each) were collected at a flow rate of 1 mL/4 min. The
pH of each fraction was measured, and when the limiting pH of 7.0 was
reached, the eluate buffer (Pharmalyte-HCl) was changed to
Polybuffer-7.4 (Pharmacia Biotech), diluted 1:8 in
deionized water, pH 4, to elute proteins bound at pH 7.0–4.0. Proteins
bound at the lower limiting pH (pH <4.0; salt peak) were recovered by
the addition of 1.0 mol/L NaCl to the chromatofocusing column.
Fractions corresponding to pH values more than 8.0, 7.99–7.0,
5.99–5.0, 4.99–4.0, and less than 4.0 were separately pooled,
concentrated by dialysis, and freeze-dried as described above, then
redissolved in phosphate (0.05 mol/L)-buffered physiological (0.15
mol/L) saline, pH 7.4, such that the majority of dose levels fell on
the central linear portion of the LH RIA standard curve (Fig. 1).
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Statistical analysis
Results are shown as the mean ± SEM. Hormone concentration data were analyzed by unpaired, two-tailed, unequal variance Student’s t testing. Between-group differences in percent recoveries of LH immunoactivity from the six pH boundaries of the chromatofocusing separation were analyzed by the nonparametric Wilcoxon signed-ranks test. Relationships among variables were sought by linear regression analysis with forward selection. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Overnight mean serum immunoreactive LH concentrations were 3-fold
higher in PCOS than control girls (Table 1
). Bioactive LH was also
significantly higher in the PCOS group (PCOS, 52 ± 10; control,
25 ± 4.1 IU/L; P = 0.020), as shown in Fig. 2. Across all subjects, bioactive LH
values correlated positively and significantly with immunoactive LH
(r = 0.75; P < 0.001). This relationship was also
observed when only PCOS data were considered (r = 0.71;
P < 0.01). In the PCOS group, the serum bioactive LH
concentration correlated positively and significantly with baseline
serum 17OHP levels (r = 0.49; P = 0.022), A
(r = 0.53; P = 0.012), and T (r = 0.43;
P = 0.046; Fig. 3). These
correlations were not found in the normal adolescent group. The mean LH
bio/immuno ratio was significantly lower in the PCOS than the control
group (6.5 ± 0.51 vs. 9.7 ± 0.66;
P < 0.05).
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Chromatofocusing separation of pooled serum samples from PCOS
patients and controls disclosed the existence of larger amounts of LH
immunoactivity at pH values above 8.0 and between 7.99–7.0 in PCOS
patients compared with controls (P = 0.031; Fig. 4). Thus, PCOS serum contained more basic
(elution pH values exceeding 7.0) LH isoforms than serum from
age-matched normal adolescents.
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). Stepwise linear regression analysis showed that the
higher percentage of basic LH isoforms correlated positively with the
mean serum immunoactive LH concentration (r = 0.93;
P = 0.007) and the overnight LH production rate (r
= 0.95; P = 0.003). The percentage of basic LH isoforms
(pH >7.0) also was positively correlated to the serum concentration of
17OHP (r = 0.85; P = 0.032), A (r = 0.82;
P = 0.046), and T (r = 0.83; P =
0.040; Fig. 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We found a significantly greater proportion of basic LH isoforms in girls with PCOS, which predominance was associated with elevated biological and immunological activities of circulating LH. The excess of alkaline LH isotypes in adolescents with PCOS is concordant with earlier observations by Ding et al. in several adults with PCOS (34). Based on prior overnight repetitive blood sampling in the same patients and controls (2), we could here also investigate the relationship between LH isoform distribution and earlier calculated LH secretion rates. This analysis disclosed that the preponderance of basic LH isoforms in girls with PCOS correlated positively with mean (12-h) serum LH concentrations (P = 0.007) and the overnight LH production rate (P = 0.003). Available studies in animals and a recent evaluation of pubertal children reported that stimulation by GnRH leads to the production of more basic LH isoforms by the pituitary gland (35, 36, 37). Heightened endogenous GnRH drive is inferable from neuroendocrine analyses showing amplified LH pulse frequency and amplitude (burst mass) in patients with PCOS (2, 3). Thus, we posit that accentuated GnRH signaling and/or heightened responsiveness of gonadotrope cells may account at least in part for the more alkaline and highly bioactive LH isotypes secreted in adolescent girls with PCOS.
Serum bioactive LH concentrations were increased in PCOS adolescents to a somewhat lesser degree than immunofluorometric LH concentrations. This resulted in a small decrease in the mean serum bio/immuno LH ratio in these patients. This observation in 12 PCOS and 10 eumenorrheic girls contrasts with the results of Ding et al. (34) in 3 (of 4) women with PCOS. Although the same immunofluorometric assays was used in both studies, Ding et al. reported similar immunoreactive LH concentrations in their control and hyperandrogenic groups, a feature not typical of the present or most other studies (5, 32, 33). Other possible explanations of these bio/immuno LH ratio differences would include the study of adolescents rather than adults, the choice of LH reference preparations (18, 38), the type of in vitro LH bioassay used (15), and/or measurement of single fasting rather than 12-h overnight pooled serum samples. For example, single blood measurements may misrepresent plasma LH concentrations due to the strongly pulsatile nature of gonadotropin release. Indeed, even 20-min blood sampling may underestimate the true underlying LH pulse frequency (39, 40). Here, we employed pooled (12-h overnight) serum to obtain more accurate estimates of the serum LH concentration in each subject.
In the adolescent girls with PCOS studied here, elevated serum
bioactive LH concentrations and a greater percentage of basic LH
isoforms were associated with higher serum 17-OHP, A, and T
concentrations. Previous studies in animals indicate that gonadal
steroids (androgens as well as estrogens) can modify the biochemical
nature of the oligosaccharide side-chains attached to gonadotropin
molecules as well as the in vitro and in vivo
biopotency of stored and released LH (41, 42). Although plasma LH
bioactivity in healthy women varies across the menstrual cycle and
rises dramatically after the menopause (28, 43), few direct data exist
in the human to clarify how these different reproductive states
influence the particular oligosaccharide composition of LH (15, 31).
Indeed, exactly how androgen and estrogen control the biosynthesis,
secretion, interconversion, and/or irreversible metabolic elimination
of discrete biologically active LH isoforms in the human is not known.
However, in clinical experiments, iv infusion of estradiol or
5-dihydrotestosterone and oral administration of estrogen or a
nonsteroidal antiestrogen or antiandrogen significantly modulate plasma
LH bioactivity in healthy men and women (44, 45, 46, 47, 48, 49).
Regulation of LH isoforms and biopotency is believed to occur through
posttranslational glycosylation, sialylation, and sulfation steps that
define the molecular properties of LH isoforms and also influence their
in vivo clearance (11, 18, 50). The charge heterogeneity of
LH, e.g. as assessed by isoelectric or chromatofocusing
procedures, reflects variations in the N-linked carbohydrate
structures with different numbers of negatively charged terminal sialic
acid and/or sulfate residues (51). The positive relationships evident
here between the percentage of basic LH isoforms and the concentrations
of androgenic steroids in girls with PCOS would thus support the
hypothesis that an androgenic milieu can modify the isotypes of
secreted LH as well as their biopotency. In the human, acutely elevated
plasma concentrations of 5-reduced testosterone or of estradiol
effectively suppress bioactive LH release (31, 44, 45, 46). Conversely, an
appropriate duration of estradiol replacement in postmenopausal women
strongly facilitates exogenous GnRH-stimulated release of bioactive LH;
i.e. augments the self-priming effects of GnRH on
gonadotrope cells (47). This enhancing action of estrogen on
GnRH-driven bioactive LH secretion is also inferable in the rhesus
monkey and human during the preovulatory LH surge (28, 43, 52). Given
these facilitative actions of estrogen, we postulate that increased
secretion of T and A in girls with PCOS may heighten LH bioactivity
indirectly via hypothalamic and/or pituitary effects exerted by their
estrogenic products derived by systemic or in situ
aromatization. In corollary, the increase in in vitro
biopotency of plasma LH observed here in PCOS patients may be enhanced
by the estrogenic features that tend to characterize this syndrome
clinically (1). Although we did not discern a statistical relation
between serum estradiol and LH concentrations in this PCOS cohort, we
note that there is an increased representation of basic isoforms of LH
in the estrogen-rich late follicular phase in normally cycling women
and after 17ß-estradiol treatment in postmenopausal women (15, 53).
In relation to estrogen action, biochemical studies report that
estrogens can modulate expression of the glycosyltransferase enzyme
that synthesizes sulfated oligosaccharides, which can be recognized by
a corresponding hepatic receptor (29). In view of the several foregoing
considerations, we propose that heightened (central) GnRH drive of
gonadotropin secretion and an estrogen-permissive milieu jointly
promote the elevated secretion of basic LH isoforms in PCOS.
In heterologous in vivo kinetic assays, more basic LH isoforms extracted from human serum and injected into hypophysectomized mice (54) or rats (11) show relatively accelerated clearance (a shorter half-life) compared with acidic isotypes (11, 18). Although homologous-species in vivo kinetic assays of human LH have not been accomplishable to date (viz. injecting purified human LH isoforms into gonadotropin-deficient volunteers), a similar relationship between isoform alkalinity and reduced half-life was inferred recently in vivo in women by deconvolution analysis of exogenous GnRH-stimulated FSH release at various stages of the normal menstrual cycle (55). This analytical approach quantitated shorter endogenous FSH half-lives during the estrogen-rich late follicular phase, and chromatofocusing revealed more basic FSH isoforms at this time. Accordingly, although not providing direct proof, the present demonstration of a preponderance of basic (chromatofocused) LH isoforms in adolescent girls with PCOS would point to a relatively abbreviated in vivo LH half-life in these patients. Although more alkaline LH moieties tend to disappear more rapidly in vivo, their potency is high in vitro (18, 38), thus still conferring effective LH stimulation of highly LH-responsive (if not steroidogenically hyperplastic) ovarian thecal-interstitial cells in patients with PCOS.
The biochemical identification of more alkaline LH isoforms in PCOS was used here further as a means to resolve a previous analytical impasse by providing additional and independent experimental data. In particular, an earlier study using deconvolution analysis and a simple burst-like model of LH secretion could not distinguish analytically between a truly prolonged LH half-life and a spuriously elevated LH half-life due to coexistent basal (interpulse) LH secretion in adolescents with PCOS (2, 21, 22). Assuming that basic isoforms of LH tend to conduce to a shorter half-time of in vivo elimination (above), the demonstration of a predominance of basic LH isotypes in PCOS would thus speak against the hypothesis of an extended LH half-life in patients with PCOS. Instead, the current data would favor the alternative interpretation, i.e. that elevated interpulse serum LH concentrations in adolescent girls with PCOS result from heightened basal LH secretion rates. Indeed, on technical grounds, the high statistical correlations expected among simultaneous estimates of basal release, pulse mass, and hormone half-life would not readily allow definitive partitioning of high serum LH concentrations into elevated basal LH secretion rates, increased pulse mass, and/or an extended LH half-life (21, 22).
Under the new assumption (above) of joint pulsatile and basal LH release in PCOS (rather than purely burst-like LH secretion with a prolonged LH half-life), we here reappraised overnight 12-h LH secretory activity in both PCOS and control subjects. This reanalysis of published 20-min sampling data confirmed the higher frequency of LH secretory bursts in the PCOS cohort, as reported previously (2). In addition, the calculated basal rate of LH secretion was elevated by 3.5-fold in girls with PCOS, viz. 0.078 ± 0.017 IU/L/min compared with a value in healthy controls of 0.021 ± 0.007 IU/L·min (P < 0.01). Under the allowance of joint basal and pulsatile LH secretion, adolescents with PCOS also maintained a heightened LH secretory burst mass, i.e. 5.1 ± 0.48 in PCOS vs. 3.7 ± 0.45 IU/L in controls (P < 0.05). The corresponding estimated endogenous half-lives of LH in this bipartite model were shorter than in a pure burst model, but similar in the two study groups, at 44 ± 2.8 min (PCOS) and 45 ± 1.9 min (control) (P = NS). These revised estimates of LH half-lives under a model of dual basal/pulsatile hormone secretion are statistically commensurate with earlier estimated kinetics of biologically active LH in healthy young men, namely, 53 ± 5.4 min (56). The present values also mirror those calculated directly from plasma bioactive LH concentration decay curves after bolus iv injection of highly purified human (pituitary) LH extracts in gonadotropin-deficient men (median, 52; range, 38–76 min) (57). Although the half-life of injected recombinant human LH is somewhat longer (58), the spectrum of glycosylation structures in this biosynthetic product is not necessarily identical to that of endogenous (circulating) LH isoforms.
Based on the foregoing reanalysis embodying dual pulsatile and basal LH release, we postulate a triple neuroendocrine abnormality in adolescent girls with PCOS: elevated basal LH secretion, accelerated LH secretory burst frequency, and amplified LH secretory burst mass. Thus, we propose that unrestrained basal LH secretion in PCOS provides an additional mechanism subserving the higher measured interpulse (basal) serum LH concentrations in patients with PCOS. This idea is analogous to the recent thesis that basal LH secretory rates are elevated and that the endogenous half-life of LH may be prolonged in postmenopausal (vs. premenopausal) women (58). The latter insights arose from a new and independent analytical strategy designed to dissect joint basal and pulsatile hormone release with reduced correlation structure (21, 22, 59).
In summary, we posit a 3-fold neuroendocrine pathophysiology of LH hypersecretion driven by augmented basal LH release, elevated LH secretory burst frequency, and amplified LH secretory burst mass in adolescent girls with PCOS. This hypersecretory state is accompanied by the release of preponderantly basic LH isoforms with high in vitro biopotency. We speculate that the corresponding putative posttranslational changes in the biochemistry of circulating LH reflect an in situ estrogen-rich milieu and excessive actions of GnRH. A synergy between LH overproduction and increased LH bioactivity in plasma may thus contribute (along with other systemic and/or local intraovarian factors) to the inordinate output of androgens by ovarian thecal-interstitial cells in PCOS.
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Acknowledgments |
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Footnotes |
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2 Research Fellow from CONICET.
3 Senior Investigator from CONICET.
Received April 29, 1999.
Revised August 4, 1999.
Accepted August 17, 1999.
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that mediates rapid clearance of
lutropin. Cell. 67:1103–1110.[CrossRef][Medline]
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) and 12 girls
with PCOS (•). In PCOS patients, 17-OHP, A, and T concentrations were
positively and significantly related to LH bioactivity. The
solid line represents the linear regression of the PCOS
data.
