Oscar Levalle

OVERT AND SUBCLINICAL HYPOTHYROIDISM COMPLICATING PREGNANCY

We studied the evolution of 150 pregnancies corresponding to 114 women (16-39 years old) with primary hypothyroidism. Fifty-one pregnancies (34%) were conceived under hypothyroidism: 16 overt (X +/- standard deviation [SD], thyroxine [T4]: 2.44 +/- 0.7 microg/dL; thyrotropin [TSH]: 33.4 +/- 8.82 mIU/L), and 35 subclinical hypothyroidism (T4: 6.93 +/- 1.88 microg/dL; TSH: 12.87 +/- 8.43 mIU/L); 99 pregnancies were conceived under euthyroidism while undergoing thyroid therapy. When treatment with levothyroxine was inadequate, the outcome of pregnancy was abortion in 60% of overtly hypothyroid patients and in 71.4% of subclinically hypothyroid patients, premature delivery in 20% and 7.2% respectively, and term delivery in 20% and 21.4%, respectively. When treatment was adequate, 100% of overtly hypothyroid patients and 90.5% of subclinically hypothyroid patients carried pregnancies to term; there were no abortions in any of the groups. Abortions, premature and term deliveries in patients who were euthyroid on levothyroxine at the time of conception were 4%, 11.1% and 84.9% respectively. Of the patients receiving levothyroxine therapy before conception, 69.5% had to increase the dose (mean increase 46.2 +/- 29.6 microg/d). Of 126 evaluated newborns, 110 were delivered at term while 16 were premature. Eight newborns, 4 were premature, had congenital malformations (6.3%), and 4 died. Our results show that the evolution of pregnancies did not depend on whether the hypothyroidism was overt or subclinical but mainly on the treatment received. The adequate treatment of hypothyroidism during gestation minimizes risks and generally, makes it possible for pregnancies to be carried to term without complications.

Subclinical hypothyroidism and thyroid autoimmunity in women with infertility

Objective. To determine the prevalence of different subclinical hypothyroidism (SH) grades and thyroid autoimmunity (TAI) in infertile women. Design. Retrospective study. Setting. Endocrinology division of a public hospital in Argentina. Patients. Group I comprised 244 women consulting on infertility (>1 year without pregnancy); Group C (controls) comprised 155 healthy women with confirmed fertility. Intervention. Thyroid-stimulating hormone and thyroid peroxidase antibodies were measured in all patients, and a thyrotropin-releasing hormone (TRH) stimulation test was performed in 71 patients to diagnose SH grade 1. The pregnancy rate in hypothyroid women on levothyroxine treatment was also evaluated. Results. SH was diagnosed in 13.9% of the patients in Group I and in 3.9% of Group C (p < 0.002). The TRH stimulation test was useful to detect SH grade 1 in 12.7% of the infertile patients. Patients with precocious ovarian failure, tubal disturbances and ovulatory dysfunction presented higher SH rates (40.0, 18.2 and 15.4%, respectively) than control patients (p < 0.0001, p < 0.002 and p < 0.003). No significant difference in TAI prevalence was shown in Group I relative to Group C. Pregnancy rate of 44.1% was achieved under levothyroxine treatment. Conclusions. We observed a higher prevalence of SH, but not of TAI, in patients with infertility. Our results support thyroid screening in women with reproductive failure.

The Relationship of Preconception Thyrotropin Levels to Requirements for Increasing the Levothyroxine Dose During Pregnancy in Women with Primary Hypothyroidism

BACKGROUND Most women with hypothyroidism require an increase in their dose of levothyroxine (LT4) after conception. To minimize fetal and maternal complications of maternal hypothyroidism, it is thought that women should be rapidly restored to the euthyroid state. The objectives of this study was to determine the percentage of hypothyroid women who would need to increase their dose of LT4 dose even if they had a preconception (pre-C) serum thyrotropin (TSH) of <2.5 mIU/L as recommended by the Endocrine Societys guidelines and to ascertain whether there was a relationship between the pre-C TSH value and the need to increase the LT4 dose during pregnancy. METHODS Fifty-three pregnant women with hypothyroidism on LT4 treatment in whom the pre-C serum TSH was <2.5 mIU/L, but which was within the normal range, within the 6 months before pregnancy were retrospectively studied. An additional selection criterion was that their LT4 dose at the time of their first prenatal visit was the same as that received pre-C. RESULTS Seventeen patients had to increase their LT4 dose during pregnancy, because their serum TSH was increased at the time of the first prenatal visit (Group 1); and 36 patients did not have to increase their dose of LT4 during pregnancy (Group 2). The pre-C TSH was significantly higher in Group 1 (1.55 ± 0.62 mIU/L) than in Group 2 (0.98 ± 0.67 mIU/L). When pre-C TSH range was 1.2-2.4 mIU/L, 50% of the patients required an increase in the LT4 dose during pregnancy. In contrast, when the pre-C TSH was <1.2 mIU/L, only 17.2% (p< 0.02) had to increase the LT4 dose during pregnancy. CONCLUSIONS We suggest that in women with hypothyroidism who are planning to become pregnant, serum TSH levels should be in the normal range but should not be greater than about 1.2 mIU/mL.

Pro-inflammatory and atherogenic circulating factors in non-alcoholic fatty liver disease associated to metabolic syndrome

BACKGROUND It is not elucidated if liver fat deposits associated to metabolic syndrome (MS) aggravate the atherogenic state. We evaluated, in MS patients, if the presence of non-alcoholic hepatic steatosis (HS) determines differences in inflammatory markers and VLDL characteristics. METHODS Seventy-five patients with MS were divided into 2 groups depending on the presence or absence of HS, assessed by ultrasound. Lipid profile, free fatty acids (FFA), VLDL composition, adiponectin, tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP), and soluble adhesion molecules (sVCAM-1 and sICAM-1) were measured. RESULTS HS patients presented increased triglycerides levels, HOMA-IR and FFA. Patients with HS showed a reduction in adiponectin (p = 0.04) and increase in hs-CRP (p = 0.02), independently of insulin-resistance (IR). FFA correlated positively with TNF-α (p = 0.04) and inversely with adiponectin (p = 0.01). hs-CRP correlated with all inflammatory markers, independently of IR: TNF-α (r = 0.34, p = 0.02), sVCAM-1 (r = 0.29 p = 0.03), sICAM-1 (r = 0.56, p = 0.01), adiponectin (r = -0.34, p = 0.04). HS patients presented higher VLDL mass and number of particles. Adiponectin correlated with VLDL cholesterol content (r = -0.47, p = 0.04), independently of IR. VLDL, once secreted, would suffer from changes, becoming more atherogenic. CONCLUSIONS Simple HS would play an important role increasing cardiovascular risk, independently of IR. hs-CRP may represent a useful biomarker of this condition.

Expression of the TGF-beta1 system in human testicular pathologies

BackgroundIn non-obstructive azoospermia, histological patterns of Sertoli cell-only Syndrome (SCO) and hypospermatogenesis (H) are commonly found. In these pathologies, Leydig cell hyperplasia (LCH) is detected in some patients. Since TGF-β1 is involved in cellular proliferation/development, the aim of this work was to analyze the expression of TGF-β1, its receptors TGFBRII, TGFBRI (ALK-1 and ALK-5), and the co-receptor endoglin in human biopsies from patients with idiopathic infertility.MethodsSpecific immunostaining of TGF-β1, its receptors TGFBRII, TGFBRI (ALK-1 and ALK-5), co-receptor endoglin and Smads proteins, were carried out in testicular biopsies from normal and infertile men with SCO or H. Gene expression of TGF-β1 system were made in biopsies from infertile patients with semi-quantitative and quantitative PCR.ResultsImmunohistochemical studies revealed that TGF-β1 and its specific receptors are present in Leydig cells in biopsies from normal tissue or patients with SCO or H with or without LCH. Smad proteins, which are involved in TGF-β1 signaling, are also detected in both their phosphorylated (activated) and dephosphorylated form in all samples TGF-β1, ALK-1 and endoglin gene expression are stronger in human biopsies with LCH than in those with SCO or H. Neither TGFBRII nor ALK-5 gene expression showed significant differences between pathologies. A significant correlation between ALK-1 and endoglin expression was observed.ConclusionsIn conclusion, the high levels of mRNA and protein expression of the TGF-β1 system in patients with LCH, particularly ALK1 and its correlation with endoglin, suggest that these proteins acting in concert might be, at least in part, committed actors in the Leydig cell hyperplasia.

Does non-alcoholic fatty liver impair alterations of plasma lipoproteins and associated factors in metabolic syndrome?

BACKGROUND Hepatic steatosis (HS) is closely associated to metabolic syndrome (MS). Both, VLDL-triglyceride oversecretion and intrahepatic deposits, can take place. We evaluated VLDL characteristics, CETP, hepatic lipase (HL), IDL and small dense LDL (sdLDL), in patients with HS associated to MS. METHODS We studied 3 groups matched by age and sex: 25 MS patients with HS (diagnosed by ultrasonography), 25 MS patients without HS and 25 healthy controls. Main measurements were: lipid profile, free fatty acids, VLDL composition, VLDL size by HPLC, CETP and HL activities, IDL-cholesterol and sdLDL-cholesterol. RESULTS Patients with HS presented higher triglyceride levels, HOMA-IR and free fatty acids, VLDL mass and VLDL-apoB (p<0.05). No differences in VLDL composition were observed. MS groups presented higher proportion of large VLDL than controls (p<0.05). HS group showed higher CETP than controls (p=0.01) and almost higher than MS without HS (p=0.06). CETP correlated with VLDL-cholesterol content, r=0.48, p<0.005. The increase in sdLDL-cholesterol correlated with CETP (r=0.47) and HL (r=0.56), independent of insulin resistance (p<0.003). CONCLUSION Despite intrahepatic fat, patients with HS secreted higher number of VLDL particles. CETP would have a remodeling action on VLDL in circulation, enriching it in cholesterol and also favoring, together with HL, the formation of sdLDL.

Altered pulsatile pattern of luteinizing hormone in men with idiopathic normogonadotropic oligospermia

Gonadotropin serum levels and pulsatile secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) are regulated by sexual steroids and perhaps inhibin, but the relative rates of LH and follicle-stimulating hormone (FSH) secretion are modulated by the frequency of GnRH pulses. This study evaluated LH pulsatility in patients with idiopathic normogonadotropic oligospermia (INO) and normal men before and after clomiphene citrate (CC) administration. INO patients evidenced a lower mean LH levels (P less than 0.001), a higher mean pulse frequency (P less than 0.05) and similar pulse amplitude than normal men. CC induced in normal men a higher LH and testosterone (T) increments and increased pulse amplitude only in normal men. Estradiol (E2) showed no difference in either group. Patients with INO might evidence a hypothalamic disorder that may alter pulsatile GnRH secretion. A different response to CC in patients with INO seems to lend support to a primary hypothalamic lesion. A probable gonadotropin imbalance might alter intratesticular concentrations of T and E2 and be the cause of spermatogenic failure.

Plasma plasminogen activator inhibitor-1 levels and nonalcoholic fatty liver in individuals with features of metabolic syndrome.

Fatty liver represents the liver component of metabolic syndrome and may be involved in plasminogen activator inhibitor-1 (PAI-1) synthesis. We studied plasma PAI-1 levels and relationships with risk factors for metabolic syndrome, including fatty liver, in 170 patients. Liver ultrasound scan was performed on all patients, and a liver biopsy was performed on those patients with chronically elevated transaminase levels. Plasma PAI-1 levels correlated significantly (P < .05) with body mass index, degree of steatosis, insulin resistance, insulin level, waist circumference, triglycerides, and high-density lipoprotein (HDL) -cholesterol. However, only body mass index (β = .455) and HDL-cholesterol (β = .293) remained predictors of PAI-1 levels. Liver biopsy revealed a significant correlation (P < .05) between insulin resistance (r = 0.381) or insulin level (r = 0.519) and liver fibrosis. In patients presenting features of metabolic syndrome, plasma PAI-1 levels were mainly conditioned by the whole-body fat content.

Lipid Accumulation Product (LAP) and Visceral Adiposity Index (VAI) as Markers of Insulin Resistance and Metabolic Associated Disturbances in Young Argentine Women with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is an endocrine disorder. PCOS women are at high risk of developing insulin resistance (IR) and cardiovascular disorders since young age. We aimed to study the reliability of lipid accumulation product (LAP) and visceral adiposity index (VAI) as markers of metabolic disturbances (MD) associated with IR in young reproductive aged PCOS patients. We also evaluated the association between LAP and VAI and the presence of hyperandrogenism. In a cross-sectional study, 110 PCOS patients and 88 control women (18-35 years old) were recruited. PCOS patients were divided into 2 groups, as hyperandrogenic and non-hyperandrogenic considering the signs of hyperandrogenism (clinical or biochemical). Anthropometric measurements were taken and blood samples collected. Metabolic and anthropometric characteristics and their association with IR and associated MD were evaluated and LAP and VAI were calculated. LAP and VAI were compared with TC/HDL-c and TG/HDL-c to define the best markers of MD in this population. Independently of the phenotype, young PCOS patients showed high IR and dyslipidemia. Both LAP and VAI showed to be more effective markers to assess MD and IR in these young women than TG/HDL-c or TC/HDL-c [cut-off values: LAP: 18.24 (sensitivity: 81.43% specificity: 73.49%), positive predictive value (PPV): 75.0%, negative predictive value (NPV): 77.27%, VAI: 2.19 (sensitivity: 81.16% specificity: 72.15% PPV: 74.65% NPV: 72.22%)]. LAP and VAI are representative markers to assess MD associated with IR in young PCOS patients. All PCOS patients, independently of their androgenic condition, showed high metabolic risk.

Effect of D-Leucine-6-Luteinizing Hormone-Releasing Hormone Ethylamide in Patients with Hypogonadotropic Hypogonadism with Anosmia

Four men with hypogonadotropic hypogonadism and anosmia were tested with acute intravenous injections of luteinizing hormone-releasing hormone (LH-RH) and D-leucine-6-LH-RH-ethylamide (D-L eu-6-LH-RH-EA) with a 1-week interval. Each patient was then treated with this drug for 60 days and tested again after this period with an intravenous injection of D-L eu-6-LH-RH-EA. The administration of LH-RH resulted in a significant increase in the LH level in only one patient and in follicle-stimulating hormone (FSH) and testosterone increases in none. The analog D-Leu-6-LH-RH-EA resulted in significant increases in LH levels in two patients, in FSH levels in three, and in testosterone levels in one. Results obtained after treatment were closely similar to those observed before treatment. Clinical improvement in terms of increased libido, erection, pubic hair growth, and testicular size was observed. D-Leu-6-LH-RH-EA could be useful in the treatment of patients with hypogonadotropic hypogonadism, a possibility deserving further studies.