José L. San Millán

Abdominal adiposity and the polycystic ovary syndrome.

Abdominal adiposity, overweightness and obesity are frequently present in patients with polycystic ovary syndrome (PCOS). A large body of evidence suggests that abdominal adiposity and the resulting insulin resistance contribute to ovarian and, possibly, adrenal hyperandrogenism. However, androgen excess itself might also contribute to abdominal fat deposition in hyperandrogenic women. Recent genomic and proteomic analyses of visceral fat from PCOS patients have detected differences in gene expression and protein content compared with those of non-hyperandrogenic women. Here we review the existing evidence for a vicious circle whereby androgen excess favoring the abdominal deposition of fat further facilitates androgen secretion by the ovaries and adrenals in PCOS patients.

The presence of the 21-hydroxylase deficiency carrier status in hirsute women: phenotype-genotype correlations

OBJECTIVE To determine the role of heterozygosity for mutations in the 21-hydroxylase gene (CYP21) in the pathogenesis of hyperandrogenism. DESIGN Controlled clinical study. SETTING Tertiary care institutional hospital. PATIENT(S) Forty hirsute women and 13 healthy control women. INTERVENTION(S) The source of androgen excess was determined by the changes in serum testosterone levels in response to a single 3.75-mg i.m. dose of triptorelin. MAIN OUTCOME MEASURE(S) CYP21 molecular genetic analysis and serum 17-hydroxyprogesterone levels. RESULT(S) Eight patients and one control were heterozygous carriers of CYP21 mutations. Two patients with adrenal hyperandrogenism and one patient with ovarian hyperandrogenism, who carried the V281L mutation had an increased ACTH-stimulated 17-hydroxyprogesterone level (>4.1 ng/mL) that persisted during gonadal suppression. Another patient with adrenal hyperandrogenism carried the V281L mutation, and her ACTH-stimulated 17-hydroxyprogesterone level was elevated only during gonadal suppression. Four patients (three with idiopathic hirsutism, one with ovarian hyperandrogenism) and one control were carriers of CYP21 mutations typically associated with classic congenital adrenal hyperplasia but had normal basal and ACTH-stimulated 17-hydroxyprogesterone levels. Nine patients without CYP21 mutations had increased ACTH-stimulated 17-hydroxyprogesterone levels; these decreased to normal in six of the patients during gonadal suppression. CONCLUSION(S) The response of serum 17-hydroxyprogesterone to ACTH does not predict CYP21 carrier status. No clear concordance was found between the CYP21 genotype and the functional origin of androgen excess.

Polymorphisms in the interleukin‐6 receptor gene are associated with body mass index and with characteristics of the metabolic syndrome

Objective  Low‐grade inflammation has been related to obesity, insulin resistance and the metabolic syndrome. The Asp358Ala variant and the CA‐repeat polymorphism in the interleukin‐6 receptor (IL‐6R) gene have been reported to be associated with obesity in Pima Indians and Spanish women, respectively. The aim of this study was to investigate the association between these polymorphisms and obesity in a Mediterranean‐Caucasian population, and to determine whether this polymorphism was related to the metabolic syndrome as defined by the National Cholesterol Education Program – Adult Treatment Panel III (NCEP/ATP‐III) criteria.

Role of the follistatin gene in women with polycystic ovary syndrome

OBJECTIVE To search for mutations in the coding exons of the follistatin gene of women diagnosed with polycystic ovary syndrome (PCOS). DESIGN Controlled clinical study. SETTING Tertiary institutional hospital. PATIENT(S) Thirty-four women diagnosed with PCOS and 15 healthy control women. INTERVENTION(S) Whole blood and serum samples were collected during the follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S) Circulating total testosterone (T), sex hormone-binding globulin (SHBG), calculated free T (FT), androstenedione (A), dehydroepiandrosterone-sulfate (DHEAS), LH, FSH, E2, and basal and adenocorticotropic hormone (ACTH)-stimulated 17-hydroxyprogesterone (17-OHP) were determined. Insulin resistance was estimated from fasting glucose and insulin levels, using the homeostasis model assessment. The coding regions of the follistatin gene were studied by heteroduplex analysis after polymerase chain reaction amplification. RESULT(S) Women with PCOS presented with higher body-mass index, insulin resistance, T, FT, A, and ACTH-stimulated 17-OHP serum concentrations and lower SHBG serum levels, as compared with controls. No differences were observed among the groups in serum DHEAS, basal 17-OHP, E(2), LH, and FSH. No mutations were found in coding regions of the follistatin gene, with the exception of a G to A change at cDNA position 951, resulting in a silent mutation. This change was present in 2 (5.9%) of 34 patients and 1 (6.7%) of 15 controls. CONCLUSION(S) Mutations in the coding regions of the follistatin gene do not appear to be related to PCOS.

Proteomics and genomics : A hypothesis-free approach to the study of the role of visceral adiposity in the pathogenesis of the polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is possibly the most common endocrine disorder in premenopausal women. The primary defect in PCOS consists of an exaggerated androgen secretion by the ovaries and the adrenal glands of affected women, which is amplified by several mechanisms including abdominal adiposity and insulin resistance. Abdominal adiposity contributes to hyperandrogenism by favoring insulin resistance and compensatory hyperinsulinism, because insulin facilitates ovarian and adrenal androgen synthesis, among other mechanisms. Furthermore, mounting evidence suggest that androgen excess may also contribute to a predominantly abdominal disposition of body fat in women, suggesting that women with PCOS suffer from a vicious circle whereby androgen excess favoring the abdominal deposition of fat further facilitates androgen secretion by the ovaries and adrenals. Familial aggregation of PCOS cases suggests an inherited component in PCOS, yet the genetic mechanisms underlying this inheritance remain elusive. The present manuscript reviews the hypothesis‐free approaches – such as genomics and proteomics – that have been used recently to study PCOS, focusing on studies from our group addressing the gene expression profiles and the proteome of visceral adipose tissue of morbidly obese women presenting with or without PCOS.

Thyroid hormone deficiency and postmenopausal status independently increase serum osteoprotegerin concentrations in women

OBJECTIVE To study the impact of thyroxine (T4) withdrawal on serum osteoprotegerin concentrations in women, using a healthy euthyroid control group matched for age and postmenopausal status as reference. SUBJECTS AND DESIGN Nineteen women with differentiated thyroid carcinoma were studied the last day on T4 suppressive treatment, 4-7 days after withdrawal and the day before whole body scanning. Eighteen women matched for age and postmenopausal status served as controls. Serum thyroid hormones, urinary bone markers and serum osteoprotegerin concentrations were measured. Statistical methods included repeated measures analysis of variance and one-way analysis of variance. RESULTS Patients progressed from subclinical or mild hyperthyroidism at baseline to normal free T4 and triiodothyronine levels 4-7 days later, ending in overt hypothyroidism before scanning. Serum osteoprotegerin increased, and urinary deoxypyridolines/creatinine and pyridolines/creatinine ratios decreased, with acute hypothyroidism (P = 0.026, P = 0.003, and P < 0.001 respectively). Urinary deoxypyridolines/creatinine ratio, pyridolines/creatinine ratio, and serum osteocalcin during hypothyroidism were lower compared with those of healthy controls (P = 0.023, P = 0.019, and P = 0.011 respectively). Serum osteoprotegerin concentrations were higher in postmenopausal patients when compared with premenopausal ones, irrespective of the changes in thyroid function (P = 0.001). CONCLUSION Serum osteoprotegerin concentrations increase following acute hypothyroidism after T4 withdrawal in women with differentiated thyroid carcinoma, and also with postmenopausal status.