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M Roger

Publications and source records attributed to M Roger.

At least 19 recordsLinked to original sources

The topographic distribution of the efferents from neocortical neurons is not only dependent upon where in the neocortex the cells develop. A transplantation study within one single neocortical region.

It has been proposed that the distribution of efferents developed by neocortical neurons depends upon where in the neocortex the cells develop, not where they were generated. However, the capacity of diverse isocortical areas to differentiate connectional characteristics belonging to other isocortical areas has recently been questioned in several experiments using heterotopic transplantation paradigms. The present study was designed to determine whether the principle of multipotentiality is still valid within one single isocortical region. Mediolateral bands of embryonic (E16) frontal neocortex were dissected out and grafted into the left frontal cortex of neonate hosts according to either correct or inverted mediolateral orientation. Five to six months after grafting, a retrograde tracer was injected into the dorsomedial or ventrolateral left neostriatum of the host. The mediolateral distribution of the cell labeling within the transplant was then compared to that of an equivalent frontal cortical area (ECA) in control cases. The results indicate that strips of embryonic frontal neocortex transplanted according to a correct mediolateral orientation are able to develop a projection towards the host striatum whose mediolateral topographical distribution is not significantly different from that arising from the frontal neocortex of control animals. The percentages of transplant cells labeled in the medial or lateral division of the grafts were not significantly different from those found medially or laterally in the ECA in control cases. Following inversion of the mediolateral orientation of the grafts at the time of transplantation, the percentages of cells labeled in the medial or lateral division of the grafts were nearly equal whatever the site of tracer deposit within the host neostriatum. These results indicate that even within one single neocortical region the principle of areal interchangeability is not entirely validated and that the development of neocortical efferents is not only guided by extrinsic factors.

Animals

Transplants of embryonic cortical tissue placed in the previously damaged frontal cortex of adult rats: local cerebral glucose utilization following execution of forelimb movements.

Transplantation of fetal cortical tissue into the motor cortex of adult rats was used as an experimental model to examine the functional integration of homotopic fetal neocortical grafts into the motor pathways of adult host brain. We have employed the [14C]2-deoxy-D-glucose method to analyse the metabolic activity of the transplant and host sensorimotor cortex: (i) in animals solicited to perform specific lever-pressing movements with the limb contralateral to the transplant (experimental group); and (ii) in non-solicited animals or in animals using the limb ipsilateral to the transplant (control group). Grafts in the control group displayed homogeneous uptake of 2-deoxy-D-glucose throughout the rostrocaudal extent of the transplant. The local cerebral glucose utilization levels were low as compared to those of the surrounding cortex but were at least two-times higher than in the corpus callosum. Increase in 2-deoxy-D-glucose uptake by the transplant cells was found only in the experimental group. In this group, 2-deoxy-D-glucose uptake was higher in the caudal (AP: +3.0 to +1.7 mm, relative to Bregma) than in the rostral sectors of the transplants suggesting the existence of a topographic organization within the transplant. In addition, except in the rostral part, glucose utilization was higher in the transplant of the experimental group than in the sensorimotor areas of the non-activated cortex in the control group. Moreover, glucose utilization of the transplant cells was systematically higher in the experimental than in the control group. The transplants appear to display a certain level of metabolic integration with the host sensorimotor cortex since, in the experimental group, there was no significant differences in local cerebral glucose utilization values in the caudal sector of the transplant and in the surrounding sensorimotor cortical areas of the host. The 2-deoxy-D-glucose uptake was even higher in the caudal sector of the transplant than in some of the subfields of the contralateral sensorimotor cortex. The present findings indicate for the first time that motor activation of the contralateral forelimb produces an increase in metabolic activity in distinct transplant sectors, the topographic distribution of which matches the normal topographic organization of the forelimb somatomotor map. This suggests that transplants of embryonic frontal neocortex placed in the frontal cortex of adult hosts become functionally integrated with the host motor system.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Treatment of central precocious puberty with depot leuprorelin. French Leuprorelin Trial Group.

We evaluated the pituitary and gonadal suppression in 40 girls and nine boys treated with depot leuprorelin (3.75 mg sc if body weight > or = 20 kg, 1.87 mg if body weight < 20 kg) every 28 days for central precocious puberty. Gonadal suppression was obtained in most of the children with this dose: 3 months after initiation of the treatment, 85% of children had a peak plasma luteinizing hormone response to gonadotropin-releasing hormone < 3 IU/l and the gonadal axis remained suppressed throughout the duration of the study (up to 24 months). Four patients required higher doses of leuprorelin to achieve suppression. In two girls, a cutaneous reaction to the drug was associated with incomplete suppression and the treatment had to be interrupted. Plasma leuprorelin levels tended to increase from day 3 to day 28 after injection. Residual leuprorelin levels measured 28 days after injection were stable during the first year of the study. We conclude that an initial dose of depot leuprorelin of 3.75 mg sc every 28 days is efficient in most children with central precocious puberty.

Bone Development

Familial acromegaly: a specific clinical entity--further evidence from the genetic study of a three-generation family.

Familial acromegaly is a very rare inherited disorder, characterized by the clustering within a single family of several related cases with somatotroph adenomas and acromegaly. The causes of these dominantly inherited pituitary tumours remain unknown. Although these families have a clinical presentation distinct from that of multiple endocrine neoplasia type 1 (MEN-1), the question of this syndrome as being linked to the MEN-1 locus has remained open. Our aim was to study a three-generation family with cases of acromegaly in a mother and her son, to explore better the clinical presentation of the disease, its pattern of inheritance and to test the hypothesis of a genetic linkage to the MEN-1 locus using closely linked polymorphic genetic markers. The refined analysis of 15 unaffected relatives revealed miscellaneous non-specific endocrine dysfunctions and the presence of multiple lipomata, as noted previously in some cases. Moreover, the notion of acromegalo-gigantism in the maternal grandmother and an incomplete penetrance appeared even more typical, suggesting that familial acromegaly is a specific clinical entity. Finally, under the hypotheses assumed for segregation analysis, no clinical, biological or genetic evidence of linkage to the MEN-1 locus could be retained in this family. However, these conclusions were limited because of incomplete penetrance and uncertain definition of the carrier status. Therefore, we conclude that further identification of the genetic predisposition to familial acromegaly might be obtained from the combined molecular genetic analysis of several families presenting with the same clinical features.

Acromegaly

Efferents of frontal or occipital cortex grafted into adult rat's motor cortex.

Phaseolus vulgaris leucoagglutinin (PHA-L) was used to examine the efferent connectivity of embryonic (E16) frontal (homotopic) or occipital (heterotopic) neocortical transplants placed into--or in the vicinity of--lesion cavities made in the frontal cortex of adult recipients. Homotopic transplants projected towards the host sensorimotor cortex and, in most cases, into the lateral caudate-putamen (CPu). Heterotopic transplants projected into the anterior cingulate cortex and, in most cases, distributed terminals into the medial CPu. It is suggested that embryonic neocortical tissue placed into a damaged cortical site of an adult recipient develops a pattern of efferents corresponding to its cortical origin.

Animals

Topographic distribution of efferent fibers originating from homotopic or heterotopic transplants: heterotopically transplanted neurons retain some of the developmental characteristics corresponding to their site of origin.

The present study was undertaken to determine whether the topographical distribution of cortical efferents is exclusively dependent on environmental cues or is also controlled by intrinsic factors. For the purpose, we used a sensitive tract-tracing method (Phaseolus vulgaris leucoagglutinin) to compare the pattern of efferent fibers of homotopic and heterotopic transplants of embryonic (E16) neocortex. Our findings indicate that transplants of embryonic sensorimotor cortex placed homotopically in the sensorimotor cortex of newborn rats distribute a set of efferent projections not fundamentally different from that of normal sensorimotor cortex. The pattern of efferents arising from transplants of embryonic occipital cortex heterotopically placed in the sensorimotor cortex of newborns is strikingly different. Heterotopically transplanted neurons: (i) only rarely contact normal targets of the motor cortex; (ii) systematically project towards normal targets of the visual cortex (primary and secondary visual cortical areas, dorsal and ventral lateral geniculate nuclei, lateral dorsal and lateral posterior thalamic nuclei, anterior pretectal nucleus and superficial and intermediate layers of the superior colliculus); (iii) distribute fibers to structures normally receiving fibers from both motor and visual cortices (caudate-putamen, pontine nuclei), either exclusively into the visual cortico-recipient zone of the structure or into both visual and motor cortico-recipient zones. Taken together, these results seem to indicate that the heterotopically transplanted cells have retained certain anatomical characteristics of their locus of origin.

Animals

Electron microscopic demonstration of terminations of posterior thalamic axons on identified rubrospinal neurons in the rat.

In the rat, the major output of the posterior thalamic nucleus (PT) ends in the ventrolateral sector of the rostral two-thirds of the red nucleus. The aim of this study is to identify the rubral cells contacted by these thalamic efferents. In a first set of experiments, an anterograde neurotracer (PHA-L) was injected into the rostral part of the red nucleus. The only structure consistently and densely labeled was the contralateral spinal cord. Therefore, in a second set of experiments, massive HRP injections were made at different cervical levels in the spinal cord in combination with either electrolytic lesion or PHA-L injection in the contralateral PT. Both anterograde and retrograde labelings obtained in the RN were examined by correlated light and electron microscopy. Our findings indicate that anterogradely degenerated or labeled axons arising from the PT form synaptic contacts on HRP-filled dendritic processes of rubrospinal neurons. The thalamo-rubral articulation is direct and seems to be mainly axo-dendritic. These results support the possible participation of the PT in the modulatory control of spinal interneurons through the rubrospinal tract.

Animals

Responses to gonadotropin releasing hormone agonist and antagonist administration in patients with gonadotroph cell adenomas.

As they are clinically silent, gonadotroph cell pituitary adenomas are usually diagnosed only when pituitary enlargement causes visual impairment or hypopituitarism. In postmenopausal women presenting with pituitary tumors it can be difficult to determine whether gonadotropin hypersecretion is due to adenomatous or normal gonadotrophs prior to surgery. The usual GnRH dependency of gonadotropin secretion may be of diagnostic and therapeutic value. We therefore evaluated responses to the GnRH antagonist Nal-Glu-GnRH and to the long-acting GnRH agonist D-Trp6 (3.75 mg IM) in 9 and 4 patients with FSH- and/or alpha-subunit-secreting adenomas, respectively. Six of the 7 patients with FSH-secreting adenomas and one of the 2 patients with pure alpha subunit-secreting adenomas were studied postoperatively. In these patients postoperative FSH and/or alpha-subunit levels remained elevated and pituitary imaging by CT-scan and/or MRI disclosed tumoral residues. In the 2 remaining patients testing was performed preoperatively. A single administration of 5 mg Nal-Glu to the 7 patients with FSH-secreting adenomas produced a slight but significant fall in above-normal FSH levels from 24.4 +/- 15.4 IU/l to a nadir of 20.3 +/- 11.9 IU/l (-17%, p < 0.05) 20 h following the injection. LH levels fell markedly in the 6 patients with normal basal serum LH concentrations to those observed in hypophysectomized patients, while mean alpha-subunit levels were not modified. Alpha-subunit levels were not modified by Nal-Glu administration in the 2 patients with alpha-subunit-secreting adenomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma

Glycoprotein hormone alpha-subunit secretion in prolactinomas and in non-functioning adenomas: relation with the tumour size.

OBJECTIVE: Free glycoprotein hormone alpha-subunit plasma levels have been reported to be increased in glycoprotein hormone-secreting adenomas and in acromegaly, but rarely in prolactinomas and in only two cases of Cushing's disease. The prevalence of elevated plasma alpha-subunit levels in patients with non-functioning adenomas is still unclear. In addition, no previous work has described plasma alpha-subunit levels in a comprehensive series of adenomas characterized by in-vivo secretion and/or immunocytochemistry. PATIENTS: Thirty-seven patients with definite prolactinomas and 48 with non-functioning tumours characterized by immunocytochemistry were studied, from a series of 145 consecutive patients including 33 acromegalics, 18 patients with glycoprotein hormone-secreting adenomas and 9 with Cushing's disease. MEASUREMENTS: Plasma free alpha-subunit was measured by radioimmunoassay in all patients and in a large sample of normal subjects to establish normal ranges according to sex, age and menstrual status. Tumour volume index was the product in cm3 of length, width and height of the adenoma as assessed by computerized tomography or magnetic resonance imaging. RESULTS: Twelve of the 37 (32%) patients with prolactinomas had increased plasma alpha-subunit levels; their tumours were significantly larger with significantly higher plasma PRL levels than those of patients without increased plasma alpha-subunit levels (P < 0.02). All prolactinomas above 50 cm3 were associated with alpha-subunit secretion, whereas only 6 of 29 smaller tumours were similarly associated. Twelve of the 48 'non-functioning' adenomas actually secreted alpha-subunit in vivo: 8 gonadotrophin-secreting, 2 'pure' alpha-secreting, one with negative immunocytochemistry and one necrotic adenoma. Their volumes were significantly higher than those of adenomas without increased plasma alpha-subunit levels (P < 0.04). Plasma alpha-subunit levels were increased in the 6 patients with TSH-secreting adenomas, 8 of 12 with FSH-secreting adenomas, 11 of 33 acromegalics and none of those with Cushing's disease. CONCLUSION: Plasma free alpha-subunit levels were increased in 49 of 145 patients (34%). For prolactinomas and 'non-functioning' adenomas, alpha-subunit hypersecretion was seen more often with larger tumours. Half of the cases with increased free alpha-subunit in this series were patients harbouring an adenoma which did not stain for an intact glycoprotein hormone.

Adenoma

Evidence of oestradiol-induced changes in gonadotrophin secretion in men with feminizing Leydig cell tumours.

To study the sex steroid-gonadotrophin relationship, plasma oestradiol (E2), testosterone and gonadotrophin-releasing hormone (GnRH)-induced (100 micrograms iv) gonadotrophin response were measured in 42 male partners of infertile couples with normal sperm count (group I) and in 21 men with Leydig cell tumour (LCT, group II) in which a basal evaluation was repeated after tumour removal. Plasma free alpha-subunit (FAS), immunoreactive alpha-inhibin and luteinizing hormone (LH) pulse analysis were assessed in 10 LCT before and in six of them after surgery. Testosterone was significantly (p < 0.01) lower whereas E2 was significantly (p < 0.001) higher in group II than in group I. Gonadotrophin data were similar in both groups. The mean FAS was higher in group II than in group I and alpha-inhibin was higher than the normal range in 6/10 LCT. In group II, E2 levels were significantly (p < 0.01) and negatively correlated with testosterone, FSH, GnRH-induced gonadotrophin rise and LH pulse amplitude but not frequency. Significant (p < 0.001) changes were observed after surgery: E2 and alpha-inhibin fell; testosterone, LH and FSH rose; whereas FAS did not change significantly. The LH pulse amplitude but not frequency increased significantly (p < 0.05). In conclusion E2 oversecreted by LCT decreased LH and testosterone levels concomitantly. The GnRH-induced gonadotrophin level rose and the LH pulse amplitude decreased when the plasma E2 level rose, whereas the pulse frequency remained unaffected. A concomitant increase in alpha-inhibin and E2 is likely to be responsible for the drop in plasma FSH levels. These data support an action of excessive amounts of E2 at pituitary level, perhaps by decreasing the sensitivity of gonadotrophs to GnRH.

Adult

Metabolic mapping of the forelimb motor system in the rat: local cerebral glucose utilization following execution of forelimb movements mainly involving proximal musculature.

The present study was undertaken to establish a metabolic map of forelimb motor pathways under conditions of physiological activation. For that purpose, we used the [14C]2-deoxy-D-glucose (2-DG) method to identify forebrain and midbrain centers showing an increase in 2-DG uptake in animals trained to execute specific lever-pressing movements with the right forelimb. Following repetitive execution of these movements, principally involving proximal (shoulder, elbow, and wrist) muscles, increases in 2-DG uptake were found contralaterally in several neocortical or subcortical centers. The largest left-right differences in local cerebral glucose utilization (LCGU) were found in a central region of the sensorimotor cortex composed of the caudal part of area 3 of the frontal cortex (Fr3; p < 0.01), the intermediate part of area 1 of Fr (Fr1; p < 0.01), and the forelimb cortical area (p < 0.04). Fr3 was the brain center with the highest differences in left-right LCGU. This central region of the sensorimotor cortex seems to correspond closely to the caudal forelimb area of Neafsey et al. (1986). Intermediate left-right differences in LCGU were found (1) in the just-adjoining rostral-medial areas of the motor cortex involving the intermediate part of area 2 of Fr (Fr2; p < 0.01) and the rostral part of Fr1 (p < 0.04), and (2) in the rostral part of area 1 of the parietal cortex (Par1; p < 0.01) and the caudal part of area 2 of Par (Par2; p < 0.05), both corresponding to forelimb representation. Weak (not statistically significant) left-right differences in LCGU were found in the rostral parts of Fr2 and Fr3, in the caudal parts of Fr2 and Fr1, in the hindlimb cortical area, and in the caudal part of Par1 and the rostral part of Par2. In the remaining cortical areas (cingulate; agranular and granular retrosplenial; temporal; and occipital), there was practically no difference in left-right 2-DG uptake. In addition, increased 2-DG uptake was present contralaterally in several subcortical motor-related centers. In those centers in which a somatomotor map has been established (caudate putamen, ventral lateral and ventral posterolateral thalamic nuclei, and red nucleus), increased 2-DG uptake was found in regions corresponding to forelimb representation.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways

[Treatment of central precocious puberty with sustained-release triptorelin].

Central precocious puberty is defined as the appearance of morphological and biological changes induced by the early maturation of the hypothalamic-pituitary-gonadal system before eight years of age in girls and ten years of age in boys. This early onset of the gonadotropin-releasing hormone pulse generator activation leads to secretion of gonadal steroids and therefore to the development of secondary sexual characteristics. The aim of medical treatment is to suppress the secretion of sex hormones. A dramatic improvement has been achieved with the development of gonadotropin releasing hormone agonists which induce a reversible suppression of gonadotropin secretion. Since 1986, triptorelin (Decapeptyl) (D-Trp6-LHRH) has been available for this indication as a sustained-release formulation allowing an intramuscular injection of 3.75 mg every 4 weeks. Results published up to now concern 352 children (325 girls and 27 boys). The pituitary-gonadal suppressive effect has been confirmed. The complete suppression of gonadal secretions induced a rapid regression of secondary sexual characteristics as early as the 3rd month of therapy, and decreased the growth rate acceleration which normalizes during the 3rd year of therapy. The progression of bone maturation clearly slowed down at the end of the first year of treatment so the final height prognosis significantly improved. Whatever length of the treatment period, the reversibility of the suppressive effect of triptorelin has been demonstrated. Puberty resumed 3 to 9 months after stopping the treatment. Tolerance of the medication was excellent. The rare side effects were minor and never led to treatment discontinuation: headaches (8% of the cases), hot flushes (12% of the cases). The percentage of drop out was very low.

Delayed-Action Preparations

Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone.

Doses of 100 mg of micronized progesterone (P) and of 0.5 mg of micronized estradiol (E2) were administered vaginally and orally, respectively, in the early follicular phase of the menstrual cycle in six premenopausal women. In the second cycle, the same doses were administered in the same subjects, orally for P and vaginally for E2. Serial blood samples were collected and the following steroids were assayed by highly reliable techniques: P, E2, estrone (E1), deoxycorticosterone (DOC), 5 alpha- and 5 beta-pregnanolone and the sulfates of E1, E2, and DOC. Circulating P and E2 levels were higher after vaginal than after oral administration, while those of E1 were similar after either route. Metabolites of P (DOC, DOCS and pregnanolone) were higher after oral administration. Concerning estrogen sulfates, E1S concentrations were similar whichever the route, while those of E2S were lower after oral than after vaginal administration. This study has confirmed that metabolism of ingested P and E2 occurs mainly in the intestine. Moreover, P was predominantly metabolized to 5 alpha-reduced derivatives, whatever the route of administration. In view of the metabolic pathways which are operative and of the peripheral plasma levels which were found, the vaginal route appears to be more adequate than the oral one for hormone replacement therapy.

Administration, Intravaginal

Inhibin and follicle-stimulating hormone levels in gonadotroph adenomas: evidence of a positive correlation with tumour volume in men.

OBJECTIVE: Gonadotroph adenomas are generally revealed by symptoms of mass effect at the stage of macroadenoma. Most of them hypersecrete FSH and/or gonadotrophin subunits. Rarely they hypersecrete LH, which could induce endocrinological symptoms. As the glycoprotein inhibin is secreted by the gonads under FSH control, we have evaluated whether high immunoreactive inhibin (iINH) levels correlated with FSH hypersecretion and whether iINH and FSH levels were related to tumour volume in subjects with gonadotroph adenomas. PATIENTS: Forty-five patients (30 men, 15 women) were retrospectively selected on the basis of immunostaining technique using specific antibodies raised against FSH-beta, LH-beta and glycoprotein alpha-subunit. MEASUREMENTS: Immunoreactive inhibin (iINH) was measured by radioimmunoassay using antiserum 1989 raised to bovine inhibin. Tumour volume index was the product in cm3 of length, width and height of the adenoma as assessed by computerized tomography. RESULTS: In men (age 21-61 years), iINH levels were positively correlated with FSH levels (Spearman's r = 0.67, P < 0.001), and both iINH and FSH levels were significantly correlated with tumour volume index (Spearman's r = 0.38, P < 0.05 and r = 0.39, P < 0.05 respectively). In the subgroup of men with normal FSH levels (n = 17), the correlation of FSH with tumour volume index was high: Spearman's r = 0.56, P < 0.05. In the post-menopausal women (n = 8, age > 55 years), iINH levels were undetectable or below the follicular phase range regardless of FSH values. In the premenopausal women (n = 7, age 22-49 years, follicular phase or amenorrhoea) iINH levels were above follicular phase range in three women including one who had very high FSH levels. CONCLUSIONS: These data show that in men with gonadotroph adenoma FSH levels are related to tumour mass and suggest that a significant part of circulating FSH in patients with normal FSH levels arises from the tumour. The significant correlation between iINH and FSH levels demonstrates that tumoral FSH is bioactive and that high iINH levels do not exert any feedback control on tumoral FSH secretion. Therefore the coexistence of high FSH levels with high iINH levels is strongly suggestive of a gonadotroph adenoma. Gonadotroph adenomas seem to represent a unique model of long-term FSH stimulation of inhibin-producing cells, in some way analogous to that created by repetitive administration of exogenous FSH.

Adenoma

Impaired response of free alpha-subunits after luteinizing hormone-releasing hormone and thyrotropin-releasing hormone stimulations in beta-thalassemia major.

In order to clarify whether the damage in gonadotropin secretion due to iron overload in patients with beta-thalassemia is of pituitary or hypothalamic origin, 14 euthyroid patients (8 females and 6 males, age 15-24 years) affected by beta-thalassemia major with hypogonadotropic hypogonadism were studied. Luteinizing-hormone (LH), follicle-stimulating hormone (FSH) and free alpha-subunit (FAS) were measured during LH-releasing hormone (LH-RH) stimulation test, and thyroid-stimulating hormone (TSH), prolactin (PRL) and FAS during thyrotropin-releasing hormone (TRH) stimulation test. During LH-RH stimulation, the mean basal LH, FSH and FAS levels were similar to those found in normal prepubertal children, but the peak values were lower than those found in such children. Also during TRH stimulation, the mean peak values of FAS were lower than those of normal prepubertal children, but the TSH response was normal. The lack of response of gonadotropins and FAS to LH-RH cannot exclude hypothalamic failure; however, the normal response of TSH to TRH, in spite of the poor response of FAS, indicates that the origin of hypogonadotropic hypogonadism is the pituitary damage concerning not only the gonadotroph but also the thyrotroph cells.

Adolescent

Interrelation between plasma sex hormone-binding globulin and plasma insulin in healthy adult women: the telecom study.

In order to study the relationship between plasma sex-hormone-binding globulin (SHBG) and insulin levels in healthy women, we investigated the association between plasma SHBG and insulin in an occupational sample of 786 nonhormone-using women. Levels of plasma SHBG showed a stepwise decrease with increasing fasting plasma insulin in premenopausal as well as in postmenopausal women. In these cross-sectional data, this significant negative relationship between SHBG and insulin was shown to be independent of age, body mass index, subscapular skinfold, fasting and 2-h plasma glucose in both groups. The etiology and the consequences of this inverse association between SHBG and insulin are unclear. Prospective and clinical studies in women will be necessary to determine the direction and causal nature of the association between SHBG and insulin, as well as its mechanism and its physiological and/or pathophysiological consequences.

Adult