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Original Studies |
Research Units in Developmental Biology (C.C.-F., A.O., D.S., J.P.M.) and Reproductive Medicine (A.U.-A.), Instituto Mexicano del Seguro Social; and Departments of Reproductive Biology (E.Z.) and Endocrinology (J.C.L.-A.), Instituto Nacional de la Nutrición SZ, Mexico D.F., Mexico; and Department of Internal Medicine, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Juan Pablo Méndez, M.D., or Alfredo Ulloa-Aguirre M.D., D.Sc., Coordinación de Investigación Médica, Unidad de Investigación Médica en Biología del Desarrollo, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenue Cuauhtémoc 330, Apdo. Postal 73–032, Col. Doctores, 06725 México D.F., Mexico. E-mail: jpmb{at}servidor.unam.mx and aulloaa@buzon.main.conacyt.mx.
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Abstract |
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7.0) was significantly (P
< 0.05) increased in the obese subjects compared with the controls
(percentages of LH immunoactivity recovered at pH 7.0: obese
subjects, 34–57%; normal controls, 22–46%). The biological to
immunological ratio of LH released in baseline and low dose (10 µg)
GnRH-stimulated conditions were similar in obese subjects and normal
controls, whereas LH released by obese subjects in response to the high
(90 µg) GnRH dose exhibited significantly lower ratios than those
detected in normal individuals (0.62 ± 0.07 and 0.45 ± 0.09
vs. 1.01 ± 0.10 and 0.81 ± 0.09 for LH
released within 10–120 min and 130–240 min after GnRH administration
in obese and controls, respectively; P < 0.05).
Collectively, these results indicate that the altered sex steroid
hormone milieu characteristic of extreme obesity provokes a selective
increase in the release of less acidic LH isoforms, which may
potentially modify the intensity and duration of the blood LH signal
delivered to the gonad. Altered glycosylation of LH may therefore
represent an additional mechanism modulating the hypogonadal
state prevailing in morbid obesity. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In obese men, basal gonadotropin levels have been reported as being either within (1, 2) or below the normal limits (5, 8). Vermeulen et al. (5) demonstrated that integrated serum LH concentrations are significantly lower in extremely obese individuals and that mean LH pulse amplitude as well as the mean sum of all diurnal LH pulse amplitudes are also decreased.
The mechanism(s) responsible for the changes in hormonal concentrations in obese men have not been clarified, although relative hyperinsulinism promotes a reduction in SHBG (4). Whether the relative hypoandrogenism has a primary testicular or a hypothalamo-pituitary origin remains unknown. However, it has been reported that the response of Leydig cells to hCG stimulation is normal in obese men, suggesting that the primary cause of the decreased T concentrations does not reside within the testes (1, 9). On the other hand, the associated hyperestrogenemia may influence gonadotropin regulation (5).
Carbohydrates in LH and other glycoprotein hormones play a major role
in structure and function. Oligosaccharides influence not only
intracellular folding of the subunits and secretion of the glycoprotein
heterodimer, but also its circulatory survival and capacity to evoke
signal transduction at the receptor level (10, 11, 12, 13).
Several studies indicate that glycosylation of anterior pituitary
glycoprotein hormones is regulated by hypothalamic inputs and/or by end
products from the target glands under the control of these trophic
hormones (14, 15, 16, 17, 18). The cellular mechanisms by which
relevant feedback end products control glycosylation are known in part.
For example, in situ hybridization studies have shown that
the messenger ribonucleic acid levels of several glycosyltransferases
(such as 
-2,6-sialyltransferase, ß-1,4-galactosyltransferase and
-mannosidase II) are significantly increased in thyrotrophs derived
from hypothyroid mice (16, 17). In the case of
gonadotropins, Dharmesh and Baenziger (18) observed that
the activity of both pituitary N-acetylgalactosamine
transferase and sulfotransferase increased several-fold after
ovariectomy, thereby favoring the production of more LH
oligosaccharides terminating with sulfate-GalNAc residues. Estrogen
administration returned the activities of these transferases to basal
levels (18).
Considering the influence of sex steroids on the carbohydrate structure of both gonadotropins, we attempted to define the impact of the changes in the androgen to estrogen ratio in male obese subjects on the glycoprotein isoform distribution and in vitro biological activity of the LH signal synthesized and secreted by the anterior pituitary gland. For this purpose, we investigated the charge distribution (which in glycoprotein hormones is primarily dependent on the presence of terminal sulfate and/or sialic acid residues) and in vitro biological to immunological relationships of the LH isoforms released during baseline and GnRH-stimulated conditions in extremely obese compared with normal weight individuals. We assumed that consecutive administration of a low (10 µg) and a high (90 µg) GnRH dose would facilitate the identification of the various types of LH isoforms discharged from an intracellular, biologically enriched, LH releasable pool (19, 20, 21) as well as forms of this gonadotropin that were newly synthesized in that particular endocrine milieu. The qualitative changes represented within the LH pulses released before and after GnRH administration from the anterior pituitary glands of obese and normal individuals were then correlated with the corresponding LH in vitro biological to immunological ratio (B/I ratio) as well as with LH secretory activity and half-lives, as resolved by multiparameter deconvolution analysis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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LH, FSH, T, and E2 immunoassays
The RIA of LH was performed employing 125I-labeled LH-I3 as the tracer (SA, 70–90 µCi/µg protein), the reference LH preparation LER-907 as the standard, and the antihuman LH-2, at a final dilution of 1:800,000, as the antiserum (22). The sensitivity of the assay was 0.7 IU/L [1 mg LER-907 = 277 IU of the Second International Reference Preparation of human menopausal gonadotropins (2nd IRP-HMG)]. Each subject’s set of samples was processed in duplicate for LH determinations in a single RIA run. The intra- and interassay coefficients of variation were determined using multiple replicates (n = 3/dose) of a serum pool collected from postmenopausal women, assayed at dose levels that displaced [125I]LH from the antibody at 15–23%, 45–59%, and 75–84% total binding; these coefficients ranged from 4.1–6.2% and 6.1–11.3%, respectively. All LH RIA reagents were provided by the NIDDK (Bethesda, MD) through Dr. A. F. Parlow from the National Hormone and Pituitary Program (Torrance, CA). Serum FSH was measured in the first and third baseline samples by an enzyme-linked immunoassay method (23), employing a FSH standard preparation provided by the WHO Collaborating Center for Research and Reference Services in the Immunoassay of Hormones in Human Reproduction (London, UK) and calibrated against the International Reference Preparation 78/549; the sensitivity of the assay was 0.5 IU/L as expressed in terms of the 2nd IRP-HMG, and the intra- and interassay coefficients of variation at the ED50 level were less than 7% and less than 13% respectively. Results of the LH and FSH immunoassays are expressed in international units according to the 2nd IRP-HMG. Reference ranges for the LH and FSH assays were 5–15 and 3–12 IU/L, respectively. Serum T and E2 concentrations were determined in each sample collected during the baseline period by RIA after solvent extraction (recoveries >90% for both sex steroids) using antisera provided by the WHO Matched Reagent Program (Geneva, Switzerland) as previously described (24, 25). Reference ranges for the T and E2 assays were 15–30 and 0.036–0.165 nmol/L, respectively. Intra- and interassay coefficients of variation for both assays (at 45–55% total binding) were less than 5% and less than 8%, respectively.
Chromatofocusing of serum samples
Serum samples from all subjects were subjected to concentration
by dialysis and freeze-dried. LH isoforms were then separated on the
basis of charge as previously described (22). Briefly, for
each individual series, samples corresponding to the (2-h) baseline
period and to the low and high GnRH-stimulated study periods (4 h each)
were separately pooled (three serum pools per subject; pools 1, 2–3,
and 4–5 in Fig. 1
), transferred to
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. Lyophilates were redissolved to
1/10th the original volume in Pharmalyte (pH 8–10.5)-HCl
(Pharmacia Biotech, Piscataway, NJ; 1:45 dilution in
deonized water, pH 7.0), and the suspension was then applied to the top
of a 20 x 1-cm column of polybuffer exchange resin (PBE-118,
Pharmacia Biotech), previously equilibrated for 18–24 h
with 25 mmol/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 then measured, and when a limiting pH
of 7.0 had been reached, the eluent buffer (Pharmalyte-HCl) was changed
by Polybuffer-74 (Pharmacia Biotech) diluted 1:8 in
deonized water (pH 4.0) to elute proteins bound at pH 7.0–4.0.
Proteins bound at the lower limiting pH (pH <4.0; salt peak) were
finally recovered by the addition of 1.0 mol/L NaCl to the
chromatofocusing column. Sets of fractions corresponding to eight 0.99
pH units were separately pooled, concentrated by dialysis and
freeze-drying as described above, and stored frozen at -20 C until
determination of its LH content by RIA. Each specimen was redissolved
in phosphate (0.05 mol/L)-buffered physiological (0.15 mol/L) saline
(pH 7.4), such that the majority of the dose levels fell on the linear
portion of the LH RIA standard curve (Fig. 2). To avoid interassay variations, all
pooled fractions from the chromatofocusing separations were assayed in
triplicate incubations in a single assay run.
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For each individual series of samples, those corresponding to
the complete (2-h) baseline period and to the low and high
GnRH-stimulated study periods were separately pooled, as shown in Fig. 1
(five serum pools per subject; pools 1–5 in Fig. 1), and assayed for
cAMP production and immunoactive LH content. The capacity of each pool
to provoke cAMP production was tested by a homologous in
vitro bioassay, which employs the human embryonic kidney-derived
293 cell line transfected with the human LH receptor complementary DNA
(provided by Dr. Aaron J. W. Hsueh, Stanford University, Stanford
CA). The origin, handling, ligand specificity, and biochemical
properties of the full-length recombinant human LH receptor expressed
by this cell line have been described previously (26).
Cells were cultured in DMEM (Life Technologies, Inc.,
Gaithersburg, MD), pH 7.3, supplemented with 2.5% FCS, 2 mmol/L
L-glutamine, 100 mg/mL geneticin (Life Technologies, Inc.), 50 U/mL penicillin, and 100 µg/mL
streptomycin (Sigma, St. Louis, MO) and grown in
162-cm2 flasks (Costar, Cambridge,
MA). Confluent cells were scraped and plated in 24-well culture plates
for 24 h at 37 C in 5% CO2. Cells (5
x 104 cells/culture dish) were then washed and
exposed to increasing doses (12.5–50 µL) of each serum pool or
LER-907 in the presence of 0.125 mmol/L 1-methyl-3-isobutylxanthine
(Sigma) dissolved in 450 µL supplemented DMEM for
24 h at 37 C. Samples (unknowns and standards) were diluted with
serum from women treated with oral contraceptives that contained LH
immuno- and bioactivities not distinguishable from the zero dose, such
that the final concentration of human serum in each sample did not
exceed 10% (50 µL/culture well). After incubation, the media and
cells were boiled at 90 C for 3 min and stored frozen at -20 C. The
sensitivity of the assay was 0.075 mIU LER-907/tube. All pools from a
single subject were bioassayed in triplicate incubations in a single
assay run. The inter- and intraassay coefficients of variation at the
ED50 dose level were less than 18% and less than
10%, respectively. Aliquots (12.5–100 µL) of samples from each
serum pool series bioassayed were additionally analyzed for
immunoreactive LH content as described above.
cAMP RIA
Total (intra- plus extracellular) cAMP levels were determined by RIA after acetylation of the samples and cAMP standards. The RIA of cAMP was performed as previously described (27), employing 2-O-monosuccinyl cAMP tyrosylmethyl ester (Sigma) iodinated by the chloramine-T method and the CV-27 cAMP antiserum (NIDDK) at a final dilution of 1:50,000. After incubation at 4 C for 24 h, antibody-bound and free cAMP were separated by ethanol precipitation followed by centrifugation at 1,200 x g at 4 C. The sensitivity of the assay was 4 fmol/tube and the inter- and intraassay coefficients of variation ranged from 8–12% and from 4–6%, respectively.
The relative in vitro biological activity of LH was calculated by interpolation. Data are expressed as the mean B/I activity ratio, the ratio of LH activity exhibited by serum pools 1–5 in the in vitro bioassay relative to that yielded by the immunoassay, calculated after conversion of the results to milliinternational units per mL 2nd IRP-HMG.
Deconvolution analysis of GnRH-induced LH pulses
Deconvolution analysis was applied to compute the amplitude and mass of significant LH secretory bursts as well as to estimate the apparent endogenous LH half-life (t1/2) in blood sampled at 10-min intervals after the administration of each of the two consecutive pulses of exogenous low and high dose GnRH (28, 29). Each LH pulse was fit independently to allow for possible differences in the mode of LH secretion to the two doses of exogenous GnRH. Based on equivalent secretory burst half-durations and half-lives at the two GnRH doses, the optimized estimates of these parameters were determined from both pulse episodes considered jointly for statistical purposes (30, 31). The mass of each GnRH-stimulated LH secretory burst is the analytical integral of the corresponding deconvolution-resolved secretory impulse.
Statistical analysis
Significant differences in mean serum E2, T, LH, and FSH concentrations; LH secretory measures (mass, amplitude, half duration, and apparent endogenous half-life of GnRH-stimulated LH secretory bursts) between obese and control subjects were determined by Bonferroni protected Student’s unpaired two-tailed t test. Within-group differences in LH isoform distribution and LH B/I ratio before and after GnRH administration were determined by ANOVA followed by Student’s paired t test. All values are reported as the mean ± SEM, unless specified. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Mean serum T and E2 levels were significantly lower and higher, respectively, in the obese than in the control group [serum T, 13.5 ± 2.4 vs. 19.4 ± 1.4 nmol/L (P = 0.01); serum E2, 0.184 ± 0.01 vs. 0.153 ± 0.01 nmol/L (P < 0.05)]. Mean baseline serum LH and FSH concentrations were similar in obese and normal subjects (LH, 13.3 ± 1.3 and 12.2 ± 1.2 IU/L; FSH, 7.0 ± 3.2 and 6.8 ± 3.4 IU/L, respectively; P = NS).
In all subjects, a significant rise in serum LH levels was observed
after administration of both low and high GnRH doses (Fig. 1). Maximal
LH concentrations occurred 10–50 min (median, 20 min in both obese and
control subjects) after the low GnRH pulse and between 10–30 min
(median, 30 and 20 min in obese and controls, respectively) after the
high GnRH dose. In both groups, the burst mass of LH secreted was
significantly higher after the 90-µg GnRH dose (obese group,
43.8 ± 9.0 vs. 61.5 ± 11.5 IU/L; control group,
31.6 ± 3.8 vs. 49.2 ± 10.2 IU/L for the low and
high GnRH doses, respectively; P = 0.01 for both
groups). Although the mean magnitude of LH response to both GnRH doses
was higher in the obese subjects than in the control group (see above),
the differences did not reach statistical significance. Likewise, there
were no differences between the obese and control subjects in the
magnitude of LH secretory amplitude (12.7 ± 5.16 vs.
7.4 ± 2.45 IU/L·min) and half-duration (6.4 ± 2.0
vs. 6.7 ± 1.1 min) of the GnRH-provoked LH bursts. The
apparent endogenous LH half-lives of the deconvolved GnRH-induced LH
pulses were significantly (P < 0.05) shorter in the
obese group (98 ± 11 min) than in controls (132 ± 10
min).
Distribution of serum LH isoforms
Chromatofocusing disclosed consistent LH immunoactivity within a
pH range of 4.0–9.9 as well as in those fractions recovered after the
addition of 1.0 mol/L NaCl to the chromatofocusing columns. In both
groups, serum LH isoforms present in basal conditions were
predominantly recovered at pH values of 6.99 or less (Fig. 3). The percentage of LH immunoactivity
recovered in basic pH values (pH 7.0) was significantly
(P < 0.05) higher in obese than in control
individuals. This increase in basic LH isoforms mainly occurred at the
expense of the more basic isotypes recovered within the pH range of
8.0–8.9 (not shown). In both groups, administration of 10 and 90 µg
GnRH, provoked a significant increase in the secretion of basic LH
isoforms. Although the relative abundance of more basic isoforms
released in response to both GnRH challenges was higher in the obese
than in the control group, the difference reached statistical
significance only for those isoforms secreted in response to the high
dose (Fig. 3). The proportion of basic LH isoforms released in response
to the high GnRH dose also exceeded that of their acidic (pH 
6.99)
counterparts in the overweight individuals, but not in the nonobese
control subjects (Fig. 3, lower panel).
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Five serum LH pools from each subject were tested at two or three
dose levels for LH bioactivity employing the homologous in
vitro bioassay system. Incubation of HEK-293 cells expressing the
recombinant human LH receptor with increasing amounts of LER-907 or the
serum pools from each set of samples induced significant and parallel
dose-dependent cAMP accumulation (Fig. 4). In two subjects from each group,
baseline levels of in vitro bioactive LH present in pool 1
were undetectable by the bioassay, whereas in four obese and the
remaining controls only the largest serum aliquot (50 µL) showed
measurable LH bioactivity. The baseline B/I LH ratios were 0.30 ±
0.1 and 0.35 ± 0.1 for obese and control subjects, respectively
(P = NS). The B/I LH ratios for all other serum pools
are shown in Table 1. Ratios of B/I LH
present in pools 2 and 3 (collected from samples obtained 10–120 min
and 130–240 min after low dose GnRH administration, respectively; see
Fig. 1) were similar in obese and controls. However, LH released by
obese subjects in response to the high GnRH dose exhibited
significantly lower ratios than those detected in normal individuals.
In both groups, LH present in pools 3 and 5 (last 2 h after the
low and high dose GnRH challenges) exhibited lower B/I ratios than
molecules released immediately (first 2 h) after GnRH
administration. The lowest B/I LH ratios were detected in pool 5 from
the obese subjects (Table 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-2,3-sialyltransferase [one of the enzymes that incorporate sialic
acid residues into the protein core of glycoprotein hormones
(39)] is negatively regulated by estrogens
(40). Finally, reduced serum T levels may also account for
the increased production of basic LH isoforms by gonadotropes in obese
men. In wethers, dihydrotestosterone administration increased the
percentage of less basic intrapituitary LH isoforms (41),
and in humans, serum T levels correlate with more acid LH isotypes in
the circulation (42). Based on the foregoing
considerations, we suggest that the sustained gonadotrope exposure to
an altered sex steroid hormone milieu, marked by a relatively increased
serum E2/T ratio, promotes the elevated
production of basic isoforms in overweight individuals. Although in the relatively small cohort of obese subjects studied we found normal integrated baseline serum LH concentrations and marginally increased exogenous GnRH-provoked LH secretory parameters, one frequent sampling study detected a state of relative hypogonadotropic hypogonadism in morbid obesity (5). This study, however, analyzed a group of obese subjects who were older and exhibited a higher degree of obesity than the population studied here. Thus, the degree of alteration of the hypothalamic-pituitary unit in obesity may be determined by multiple factors, including the subject’s age, magnitude, and duration of obesity and even the degree of hypothalamic resistance to leptin, a protein recently implicated in the neuroendocrine regulation of the reproductive axis in rodents of both sexes (43).
There is compelling evidence that the oligosaccharide structures on
glycoprotein hormones influence their plasma half-lives and
consequently the in vivo bioactivity of the hormone
(13, 44, 45, 46, 47, 48, 49, 50). Recent studies have shown that within the
large array of human LH isoforms, the more basic variants exhibit the
lowest sialic acid content and that enzymatic desialylation of the more
acidic isoforms decreases the plasma half-life of the hormone
(48, 50). In the present study the estimated half-time of
endogenous LH disappearance from plasma in the control subjects (2.2 h)
was similar to that previously calculated employing the same
deconvolution analysis of exogenous GnRH-stimulated LH bursts in normal
individuals (
1.9 h) (51, 52) or recombinant human LH
infused in leuprolide-suppressed middle-aged men (53). In
the obese group, however, the calculated plasma half-life of the LH
isoform mixture released in response to exogenous GnRH was
significantly lower (1.6 h). Further, the decrease in the plasma
half-life of endogenous LH in obese individuals correlated with the
presence of an increased proportion of more basic/less sialylated LH
isoforms in circulation, an association consistent with the presence of
altered posttranslational processing of LH molecules in obesity. The
ultimate outcome of a reduced circulatory survival in the gonadotropic
signal would be a decrease in the in vivo bioactivity of the
hormone. The extent to which this contributes to the decreased T levels
exhibited by obese men is not known (1, 2, 3, 4, 5). As testicular
responsiveness to exogenous hCG in obesity is normal (1, 9), factors other than Leydig cell dysfunction probably
contribute to the varying degree of hypogonadism prevailing in severe
obesity.
The in vitro B/I ratio of LH isoforms isolated from human pituitaries, as quantitated by steroidogenic bioassays, is lowest in the more acidic isoforms [isoelectric points (pI) 6.0–7.0], gradually increases with less acidic isoforms, reaches its plateau in isoforms with pI values of approximately 7.2–8.0, and then decreases in the more basic (pI >8.0) variants (20, 50). This bell-shaped profile of the in vitro bioactivity of LH isoforms is similar to that reported for the pituitary FSH charge isoforms in which absent bioactivity in aromatization assays, yet detectable FSH-like immunoreactivity, has been detected in variants recovered at high basic pH values, which represent presumptively underglycosylated variants (54, 55). In the present study we employed a homologous in vitro LH bioassay system to assess the biological potency of the isoform mixture released from the pituitary in response to endogenous (basal) and exogenous GnRH. Both normal and obese subjects manifested a significant increase in the B/I ratio of LH secreted immediately after exogenous iv administration of a low (10-µg) GnRH dose (a dose sufficient to release LH from an intracellular, biologically enriched, releasable pool). An increase in the B/I LH ratio in a homologous LH bioassay is in agreement with previous data showing that exogenous low dose iv GnRH administration results in preferential release of bioactive LH in a rat Leydig cell bioassay, with a consequent increase in the plasma B/I LH ratio in normal men (21). Further, in samples collected during the third and fourth hours after the low dose GnRH challenge, the serum B/I ratio declined concomitantly with the reestablishment of endogenously GnRH-controlled LH secretion. More vividly, administration of a supraphysiological dose of GnRH (90 µg) unmasked an intrinsic abnormality in the capability of the pituitary gland in obese men to synthesize bioactive LH, as disclosed by the reduced LH B/I ratio in delayed pools 4 and 5. Putative gonadotroph failure to synthesize highly bioactive LH may represent an additional mechanism for the hypogonadal state inferred in morbid obesity.
The present study does not unambiguously identify whether the abnormality in the capability of the pituitary gland to synthesize highly bioactive LH in obese men under highly demanding conditions (such as that imposed by pharmacological doses of exogenous GnRH) is due to the decreased serum T levels and/or the sustained gonadotrope exposure to moderately elevated serum estrogens or other nonsteroidal factors. Although some in vitro studies in rodents have shown that exposure to T increases the B/I ratio of LH secreted by gonadotrophs (56), other evidence derived from in vivo studies demonstrates that sustained endogenous hyperestrogenism is associated with the suppression of plasma concentrations of biologically active LH in man (57). The latter would be in line with the concept that estrogens decrease the sialylation of LH and FSH, thus producing incompletely glycosylated and more basic molecules (18, 40), some of which may exhibit decreased in vivo biological potency and half-lives (20, 50, 54, 55).
In summary, the charge distribution of circulating LH isoforms is altered in severe obesity, such that an increased proportion of more basic isoforms is secreted under both endogenous and exogenous GnRH-stimulated conditions. This shift toward more basic isoforms in obesity appears to alter the survival time of this gonadotropin in the circulation and its potential to elicit a biological response at the human LH receptor level as well. These alterations in LH structure and function might be subserved by reduced serum T and/or a sustained rise in endogenous estrogens in obesity. Whatever the cause, abnormalities in the regulatory mechanisms that control both the circulating residence time and the intensity of the LH signal may contribute in part to the hypogonadic state observed in severe obesity in males.
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Acknowledgments |
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Footnotes |
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Received January 26, 2000.
Revised June 23, 2000.
Revised August 21, 2000.
Accepted September 2, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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subunit. Glycobiology. 5:3–10. subunit and ß-subunits: differential effects of orchiectomy and
GnRH. Endocrinology. 119:202–213.[Abstract]
-mannosidase-II messenger
ribonucleic acid levels increase with different kinetics in thyrotrophs
of hypothyroid mice. Endocrinology. 135:1980–1985.[Abstract]
2,3-sialyltransferase
messenger ribonucleic acid levels in the female rat. J Mol Endocrinol. 23:153–165.[Abstract]
that mediates
rapid clearance of lutropin. Cell. 67:1103–1110.[CrossRef][Medline]
-specific
receptor from rat liver. J Biol Chem 272:14629–14637.
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