RESUMO
Although the pathogenesis of polycystic ovarian syndrome (PCOS) is still controversial, a series of investigations has demonstrated an array of neuroendocrine abnormalities as a major component of the syndrome. From a neuroendocrine perspective, patients with PCOS exhibit an accelerated frequency and/or higher amplitude of LH pulses, augmentation of LH secretory burst mass, and a more disorderly LH release. Elevated in vitro LH bioactivity and a preponderance of basic LH isoforms, which correlate positively with elevated serum 17-hydroxyprogesterone, androstenedione, and testosterone concentrations, also characterize adolescents with PCOS. Heightened GnRH drive of gonadotropin secretion and a steroid-permissive milieu appear to jointly promote elevated secretion of basic LH isoforms. Positive feedback is implied, because hypersecretion of highly bioactive LH in PCOS probably contributes to inordinate androgen output. However, the precise nature of feedback disruption remains uncertain. Indeed, recent data suggest that PCOS is marked by anomalies of both feedforward and feedback signaling between GnRH/LH and ovarian androgens. From a single hormone perspective, the individual patterns of LH and androstenedione release are consistently more irregular in patients with PCOS. Bihormonal analysis has disclosed concomitant uncoupling of the pairwise synchrony of LH and testosterone, LH and androstenedione, and testosterone and androstenedione secretion. The foregoing ensemble of findings points to deterioration of both orderly uniglandular and coordinate bihormonal output in PCOS. Additional studies are needed to establish the primary pathophysiologic mechanisms underlying this disorder.
Assuntos
Sistema Hipotálamo-Hipofisário/fisiopatologia , Hormônio Luteinizante/metabolismo , Ovário/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , 17-alfa-Hidroxiprogesterona/metabolismo , Adolescente , Adulto , Androstenodiona/sangue , Androstenodiona/fisiologia , Dopamina/metabolismo , Retroalimentação , Feminino , Glicosilação , Hormônio Liberador de Gonadotropina/fisiologia , Humanos , Resistência à Insulina/fisiologia , Modelos Biológicos , Obesidade/fisiopatologia , Ovulação/fisiologia , Adeno-Hipófise/metabolismo , Síndrome do Ovário Policístico/sangue , Isoformas de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional , Fluxo Pulsátil , Taxa Secretória , Testosterona/sangue , Testosterona/fisiologiaRESUMO
We recently demonstrated that adolescent girls with polycystic ovarian syndrome (PCOS) exhibit augmented LH secretion due to an increase in immunofluorometric and deconvolution-estimated LH secretory burst mass and pulse frequency. Concurrently, we inferred either a prolongation of apparent (endogenous) LH half-life or elevated basal (nonpulsatile) LH release in PCOS. The in vivo half-life of LH molecules can be affected by the oligosaccharide side-chains, which also modify in vitro bioactivity and electrostatic change. Accordingly, as a surrogate estimator of altered endogenous LH half-life and/or biopotency in PCOS, we characterized the isoelectric properties of secreted LH isoforms and determined their in vitro biological activity in adolescent girls with PCOS compared with healthy age-matched eumenorrheic controls. To this end, 12-h (overnight) serum samples from PCOS patients (n = 12) and normal adolescents (n = 10) were pooled by subject. Bioactive LH concentrations were then quantitated in a rat Leydig cell in vitro bioassay, and immunological activity was determined by immunofluorometry. The distribution of LH isoforms was evaluated by preparative chromatofocusing (pH window, 10.5 to <4.0) of samples further combined to yield three independent serum pools for each of the patient and control groups. Fasting serum concentrations of 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, estrone, estradiol, and sex hormone-binding globulin were determined as possible endocrine correlates of LH isotypes. Mean serum concentrations of immunoreactive and bioactive LH in adolescents with PCOS were 3 and 2 times higher than values in controls: immunoreactive: PCOS, 7.8+/-0.9; controls: 2.6+/-0.3 IU/L (P < 0.001); and bioactive: PCOS, 52+/-10; controls, 25+/-4.1 IU/L (P = 0.002), respectively. Bioactive LH concentrations correlated positively with 17-OHP (P = 0.022), androstenedione (P = 0.012), and testosterone (P = 0.046) concentrations in PCOS. Chromatofocusing of LH isoforms disclosed greater LH immunoreactivity at pI values greater than 8 and 7.99-7.0 in adolescents with PCOS compared with controls (P = 0.031). The percentage of basic LH isoforms was related positively to serum concentrations of 17-OHP (P = 0.032), androstenedione (P = 0.046), and testosterone (P = 0.040). In conclusion, the present isotype analysis demonstrates elevated in vitro LH bioactivity and a preponderance of basic LH isoforms in girls with PCOS. Since previously reported heterologous in vivo assays of LH kinetics point toward accelerated removal of such alkaline isotypes, our findings would favor the earlier alternative hypothesis of inappropriate hypersecretion of basal (interpulse) LH rather than prolongation of the LH half-life as the mechanism for elevated interpulse serum LH concentrations in adolescents with PCOS. In ensemble, the foregoing data thus suggest 3-fold amplification of basal LH secretion as well as both a heightened amplitude and frequency of the pulsatile mode of LH release in PCOS.
Assuntos
Hormônio Luteinizante/química , Hormônio Luteinizante/metabolismo , Periodicidade , Síndrome do Ovário Policístico/fisiopatologia , 17-alfa-Hidroxiprogesterona/sangue , Adolescente , Adulto , Androstenodiona/sangue , Animais , Bioensaio , Cromatografia , Feminino , Meia-Vida , Humanos , Cinética , Células Intersticiais do Testículo/efeitos dos fármacos , Hormônio Luteinizante/farmacologia , Masculino , Ratos , Testosterona/sangueRESUMO
The aim of this study was to quantify pulsatile LH secretion, burst frequency and mass, LH half-life, and the approximate entropy (ApEn) or (dis-) orderliness of LH release in adolescents with polycystic ovary syndrome (PCOS), combining a high-precision immunofluorimetric LH assay with deconvolution techniques. We sampled LH concentration profiles every 20 min overnight in 12 girls with PCOS (mean +/- S.E.M. age 16.4+/-0.57 years, body mass index (BMI) 24.4+/-1.6 kg/m2) and 11 eumenorrheic early-follicular-phase controls (mean +/- S.E.M. age 16.5+/-0.47 years, BMI 22.2+/-1.0 kg/m2). Fasting serum levels of androstenedione, testosterone, 17-hydroxyprogesterone (17-OHP), estrone, estradiol, FSH and sex hormone-binding globulin (SHBG) were determined. Compared with euandrogenic girls, PCOS adolescents had significantly (P<0.005) elevated serum LH/FSH ratios, 17-OHP, androstenedione, esterone and testosterone levels, decreased SHBG, and similar estradiol. PCOS subjects exhibited a 3-fold higher mean serum LH concentration with almost no overlap with controls (8.8+/-1.2 and 2.8+/-0.3 IU/l respectively, P<0.001). We initially used a conventional serum hormone concentration peak analysis method (Cluster) to evaluate the characteristics of pulsatile LH release. Cluster analysis disclosed a significant increase in serum LH concentration maximal peak height, a higher LH peak frequency and a higher mean serum LH concentration in interpulse nadirs in the PCOS group. Deconvolution analysis of mechanisms underlying the foregoing showed higher frequency in the PCOS group than the controls (7.9+/-0.4 and 5.7+/-0.6 pulses/12 h respectively, P<0.05). The mass of LH released per secretory event was also significantly higher in PCOS subjects than controls (5.4+/-0.57 and 3.4+/-0.56 IU/l respectively, P<0.05). Since the pulsatile production rate is the product of the mean mass of hormone secreted per pulse and the number of pulses per day, we estimated a significantly higher mean pulsatile production rate of (endogenous) LH in the PCOS group (41+/-4.2 IU/l per day in the PCOS group vs 18+/-2.3 IU/l per day in the controls, P<0.01). The mean estimated half-life of endogenous LH disappearance was also significantly higher in patients with PCOS than in controls (110+/-8.5 and 77+/-3.7 min respectively, P<0.01). To quantify the orderliness of LH release, we used ApEn. PCOS patients had remarkably increased disorderliness (higher ApEn) of LH release (1.09+/-0.04 vs 0.77+/-0.08 in controls, P = 0.002). Mean serum LH concentration, mass of LH secreted per burst, and LH production rate in PCOS, but not in normal adolescents, correlated positively with androstenedione (P<0.02, 0.02 and 0.05 respectively). The same parameters also correlated positively with 17-OHP (P<0.05, 0.02 and 0.05 respectively). Stepwise regression analysis unmasked a negative influence of BMI in PCOS on both mass of LH secreted per burst (r = -0.77, P<0.005) and LH production rate (r = -0.70, P<+/0.01). We conclude that PCOS adolescents secrete LH molecules with amplified frequency and burst mass and with markedly disrupted orderliness. A rise in basal (non-pulsatile) LH release, more basic LH isoforms, and/or a prolongation or asymmetry of the LH secretory burst could account for the apparently prolonged LH half-life. Determining whether disorderliness of the amplified pituitary LH release process is an intrinsic abnormality in PCOS. or reflects androgen excess, may help to clarify the pathophysiology of this oligo-ovulatory syndrome in young women.