Bruder-Nascimento T, Campos DH, Alves C
… +3 more, Thomaz S, Cicogna AC, Cordellini S
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343634
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OBJECTIVE: The aim of this study was assess the role of chronic stress on the metabolic and nutritional profile of rats exposed to a high-fat diet. MATERIALS AND METHODS: Thirty-day-old male Wistar rats (70-100 g) were d...OBJECTIVE: The aim of this study was assess the role of chronic stress on the metabolic and nutritional profile of rats exposed to a high-fat diet. MATERIALS AND METHODS: Thirty-day-old male Wistar rats (70-100 g) were distributed into four groups: normal-diet (NC), chronic stress (St), high-fat diet (HD), and chronic stress/high-fat diet (HD/St). Stress consisted at immobilization during 15 weeks, 5 times per week, 1h per day; and exposure to the high-fat diet lasted 15 weeks. Nutritional and metabolic parameters were assessed. The level of significance was 5%. RESULTS: The HD group had final body weight, total fat, as well as insulin and leptin increased, and they were insulin resistant. The St and HD/St had arterial hypertension and increased levels of corticosterone. Stress blocked the effects of the high-fat diet. CONCLUSION: Chronic stress prevented the appearance of obesity. Our results help to clarify the mechanisms involved in metabolic and nutritional dysfunction, and contribute to clinical cases linked to stress and high-fat diet.
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343633
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OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adren...OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS: In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS: Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS: Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin-angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms.
Geloneze B, Lima MM, Pareja JC
… +2 more, Barreto MR, Magro DO
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343632
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OBJECTIVE: The objective of this pilot study was to determine whether glugagon-like peptide 2 (GLP-2) secretion relates to insulin sensitivity (IS) in obese subjects. SUBJECTS AND METHODS: Twenty four obese subjects [bod...OBJECTIVE: The objective of this pilot study was to determine whether glugagon-like peptide 2 (GLP-2) secretion relates to insulin sensitivity (IS) in obese subjects. SUBJECTS AND METHODS: Twenty four obese subjects [body mass index (BMI) 40.0 ± 3.0 kg/m² (mean ± standard deviation)] were included, nine of which were male, age 43 ± 8 years. Twelve subjects had type 2 diabetes, all treated with oral anti-diabetic agents only. The subjects were submitted to standard meal tolerance test (MTT) for dosage of the curves: glucose, insulin, and GLP-2. Insulin sensitivity was measured by HOMA-IR, and OGIS was derived from the MTT. Spearman linear correlations and partial correlations were obtained. RESULTS: There was an inverse relationship between the GLP-2 secretion and IS: HOMA-IR correlated with GLP-2 AUC (R = 0.504; p = 0.012), and OGIS correlated with GLP-2 incremental AUC (R = -0.54; p = 0.054). The correlation persisted after controlling for BMI. CONCLUSION: We found an association of GLP-2 secretion and insulin resistance (IR). The understanding of the underlying mechanisms may provide future directions in the pharmacological manipulation of incretins, and in the treatment of obesity and related metabolic disorders.
Paulino MF, Lemos-Marini SH, Guerra-Júnior G
… +1 more, Morcillo AM
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343631
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OBJECTIVE: To evaluate the growth and body composition of children and adolescents with type 1 diabetes mellitus (T1DM). SUBJECTS AND METHODS: A cohort of 44 patients with T1DM were followed up for approximately four yea...OBJECTIVE: To evaluate the growth and body composition of children and adolescents with type 1 diabetes mellitus (T1DM). SUBJECTS AND METHODS: A cohort of 44 patients with T1DM were followed up for approximately four years and compared with a control group. Weight, height, body mass index (BMI), body fat percentage (BF%), fat mass index, waist circumference (WC) and waist-height ratio were determined. RESULTS: In females, in the first evaluation, BF% was lower in patients than in controls, while in the second evaluation, mean WC was higher in patients than in controls. In males, height of the patients was lower in the first evaluation, while body mass index (BMI) was higher in the second one. We did not find any differences among the changes in height, weight and BMI z-scores and BF% or in the distribution of those z-scores between the two evaluations, in both groups. Multiple regression analysis found differences in BMI and waist-height ratio in both sexes and also in WC in females. CONCLUSION: The patients had adequate growth but showed discrepancy in their body composition during the study.
Cai W, Wu X, Zhang B
… +4 more, Miao L, Sun YP, Zou Y, Yao H
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343630
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OBJECTIVE: The aim of this study was to compare serum uric acid values in two ethnically distinct Chinese populations: Uyghur, with a high prevalence of nonalcoholic fatty liver disease, and Han, with a lower prevalence....OBJECTIVE: The aim of this study was to compare serum uric acid values in two ethnically distinct Chinese populations: Uyghur, with a high prevalence of nonalcoholic fatty liver disease, and Han, with a lower prevalence. SUBJECTS AND METHODS: Serum uric acid and several clinical features and laboratory tests relevant to the metabolic syndrome were measured in 4,157 Uyghur and 6,448 Han subjects in a health examination program. The diagnosis of hepatic steatosis was established by abdominal ultrasound examination. RESULTS: The prevalence of nonalcoholic fatty liver disease was 42.3% and 33.3% among Uyghur and Han subjects, respectively. The corresponding prevalence of hyperuricemia was 8.8% and 14.7%. The mean concentration of serum uric acid in Uyghurs also was lower than in Hans (282.75 vs. 310.79 µmol/L; p < 0.01). However, in both populations, the prevalence of nonalcoholic fatty liver disease was increased in association with increasing serum uric acid concentrations, a trend that was more pronounced in Uyghur than in Han subjects (OR 3.279 and 3.230, respectively). Several components of the metabolic syndrome were more pronounced in Uyghurs than in Hans. CONCLUSIONS: Serum uric acid is an independent risk factor in nonalcoholic fatty liver disease in both Uyghurs and Hans, but other risk factors may be more important in the differences in prevalence of the disease between the two ethnic groups.
Bolfi F, Miot HA, Resende M
… +4 more, Mazeto GM, Romeiro FG, Yamashiro Fda S, Nunes Vdos S
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343629
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OBJECTIVE: To determine the frequency of colon cancer, primary hyperparathyroidism, thyroid tumor, and skin cancer in all acromegalic patients in follow-up at the Clinics Hospital - Botucatu Medical School, from 2005 to...OBJECTIVE: To determine the frequency of colon cancer, primary hyperparathyroidism, thyroid tumor, and skin cancer in all acromegalic patients in follow-up at the Clinics Hospital - Botucatu Medical School, from 2005 to 2011. SUBJECTS AND METHODS: These patients were evaluated retrospectively for colon cancer, primary hyperparathyroidism, dermatological, and thyroid tumors. RESULTS: Of 29 patients included at the beginning of the study, two were excluded. Among 19 patients submitted to colonoscopy, one presented colon adenocarcinoma (5%). Thyroid nodules were present in 63% of patients, and papilliferous carcinoma was confirmed in two patients (7,7%). Four patients were confirmed as having primary hyperparathyroidism (15%). The most common dermatologic lesions were thickened skin (100%), acrochordons (64%), epidermal cysts (50%), and pseudo-acanthosis nigricans (50%). Only one patient presented basal cell carcinoma. CONCLUSION: Although a small number of acromegalic patients was studied, our findings confirm the high frequency of thyroid neoplasias and primary hyperparathyroidism in this group of patients.
Zandoná MR, Rodrigues RO, Albiero G
… +4 more, Campagnolo PD, Vitolo MR, Almeida S, Mattevi VS
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343628
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OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) in five genes - leptin, leptin receptor (LEPR), adiponectin (APM1), peroxisome proliferator-activated receptor gamma (PPARG) and uncoupling p...OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) in five genes - leptin, leptin receptor (LEPR), adiponectin (APM1), peroxisome proliferator-activated receptor gamma (PPARG) and uncoupling protein 1 - with anthropometric, metabolic, and dietary parameters in a Southern Brazilian cohort of 325 children followed up from birth to 4 years old. MATERIALS AND METHODS: SNPs were analyzed using polymerase chain reaction-based procedures, and their association with phenotypes was evaluated by t-test, analysis of variance, and general linear models. RESULTS: LEPR223Arg allele (rs1137101) was associated with higher daily energy intake at 4 years of age (P = 0.002; Pcorrected = 0.024). PPARG 12Ala-carriers (rs1801282) presented higher glucose levels than Pro/Pro homozygotes (P = 0.007; Pcorrected = 0.042). CONCLUSIONS: Two of the six studied SNPs presented consistent associations, showing that it is already possible to detect the influences of genetic variants on susceptibility to overweight in 4-year-old children.
Rocha RE, Coelho I, Pequito DC
… +9 more, Yamagushi A, Borghetti G, Yamazaki RK, Brito GA, Machado J, Kryczyk M, Nunes EA, Venera G, Fernandes LC
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343627
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OBJECTIVE: This study investigated the effect of interval training on blood biochemistry and immune parameters in type 1 diabetic rats. MATERIALS AND METHODS: Male Wistar rats were divided into four groups: sedentary (SE...OBJECTIVE: This study investigated the effect of interval training on blood biochemistry and immune parameters in type 1 diabetic rats. MATERIALS AND METHODS: Male Wistar rats were divided into four groups: sedentary (SE, n = 15), interval training (IT, n = 17), diabetic sedentary (DSE, n = 17), diabetic interval training (DIT, n = 17). Diabetes was induced by i.v. injection of streptozotocin (60 mg/kg). Swimming Interval Training consisted of 30-s exercise with 30-s rest, for 30 minutes, during 6 weeks, four times a week, with an overload of 15% of body mass. Plasma glucose, lactate, triacylglycerol and total cholesterol concentrations, phagocytic capacity, cationic vesicle content, and superoxide anion and hydrogen peroxide production by blood neutrophils and peritoneal macrophages were evaluated. Proliferation of mesenteric lymphocytes was also estimated. RESULTS: Interval training resulted in attenuation of the resting hyperglycemic state and decreased blood lipids in the DIT group. Diabetes increased the functionality of blood neutrophils and peritoneal macrophages in the DSE group. Interval training increased all functionality parameters of peritoneal macrophages in the IT group. Interval training also led to a twofold increase in the proliferation of mesenteric lymphocytes after 6 weeks of exercise in the DIT group. CONCLUSION: Low-volume high-intensity physical exercise attenuates hyperglycemia and dislipidemia induced by type 1 diabetes, and induces changes in the functionality of innate and acquired immunity.
Caldas D, Silva Júnior WS, Simonetti JP
… +2 more, Costa EV, Farias ML
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343626
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OBJECTIVE: To evaluate clinical, biochemical, hormonal and genetic characteristics of relatives of two patients with familial partial lipodystrophy (FPLD) type 2. MATERIALS AND METHODS: Fifty subjects, members of two non...OBJECTIVE: To evaluate clinical, biochemical, hormonal and genetic characteristics of relatives of two patients with familial partial lipodystrophy (FPLD) type 2. MATERIALS AND METHODS: Fifty subjects, members of two non-related Brazilian families from two different probands with FPLD phenotype, were evaluated. A mutation in exon 8 of LMNA gene was confirmed in 18 of them, and a heterozygous substitution at codon 482 was identified, predicting a p.R482W mutation. Based on the presence or absence of the mutation, subjects were classified in affected and unaffected, and compared in terms of clinical, biochemical and hormonal parameters. RESULTS: Affected subjects were 2.8 times more likely to manifest diabetes and PCOS, higher HOMA-IR, insulin and triglyceride levels, and lower levels of leptin. These changes preceded the onset of diabetes, because they were observed in diabetic and non-diabetic affected patients. A phenotypic heterogeneity was found among mutation carriers. CONCLUSION: A mutation in the LMNA gene is a determinant of clinical, biochemical and hormonal changes that imply in metabolic deterioration in mutation carriers.
Arq Bras Endocrinol Metabol
· 2013 Nov · PMID 24343625
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Paget's disease of bone (PDB) is a chronic progressive disorder of bone metabolism that may go undetected for many years, and endocrinologists should be alert to its clinical signs and promptly diagnose and treat PDB bef...Paget's disease of bone (PDB) is a chronic progressive disorder of bone metabolism that may go undetected for many years, and endocrinologists should be alert to its clinical signs and promptly diagnose and treat PDB before it results in irreversible complications, such as deformity, fracture or neurological sequelae. Most commonly, PDB is suspected upon the incidental finding of elevated serum alkaline phosphatase levels or a radiographic abnormality in an otherwise healthy individual above 55 years of age. Some of these individuals may have symptoms such as bone pain or enlargement with increased warmth. In general, a basic laboratory evaluation of bone metabolism, plain radiographies of affected bones and bone scintigraphy are sufficient to corroborate the diagnosis. Antiresorptive therapy with bisphosphonates is the mainstay of treatment of symptomatic PDB, and intravenous zoledronic acid has emerged as an effective and safe treatment option, leading to sustained remission and improved quality of life. It is extremely important, though, to ensure calcium and vitamin D sufficiency before and during treatment in order to prevent hypocalcemia. The benefit of treating all asymptomatic patients is not clear, but treatment is warranted if the pagetic lesion is located in a site where progression to fracture, deformity, or compression would significantly impair the patient quality of life. This mini-review focuses on important aspects of the diagnosis and treatment of PDB.
Guzzo MF, Bueno CB, Amancio TT
… +5 more, Rosemberg S, Bueno C, Arioli EL, Glezer A, Bronstein MD
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232824
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Intracranial germinomas (GE) are malignant neoplasms most commonly found in the suprasellar region, which may cause anterior and particularly posterior pituitary hormone deficits with central diabetes insipidus (DI). Dif...Intracranial germinomas (GE) are malignant neoplasms most commonly found in the suprasellar region, which may cause anterior and particularly posterior pituitary hormone deficits with central diabetes insipidus (DI). Differential diagnosis of pituitary stalk thickening includes granulomatous, inflammatory, infectious, and neoplastic lesions. Although careful analysis of clinical, laboratory, and imaging findings may facilitate the diagnosis, transsphenoidal biopsy is indicated to confirm the disease, as the correct diagnosis directs the appropriate treatment.
Calliari LE, Rocha MN, Monte O
… +1 more, Longui CA
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232823
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Mutation on NROB1 (DAX1) gene can cause different phenotypes of adrenal insufficiency in infancy. Long-term evolution of these patients shows that it is possible to have an association with hypogonadotropic hypogonadism....Mutation on NROB1 (DAX1) gene can cause different phenotypes of adrenal insufficiency in infancy. Long-term evolution of these patients shows that it is possible to have an association with hypogonadotropic hypogonadism. In this article we describe the evolution of a patient with NROB1 gene mutation, diagnosed with a mild form of adrenal insufficiency, and we highlight the presence of hypogonadotropic hypogonadism and short stature, besides the presence of attention deficit disorder. Such associations should make physicians aware during the follow-up of patients with this disease.
Saraiva J, Gomes L, Paiva S
… +2 more, Ruas L, Carvalheiro M
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232822
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Prolactinomas are a common cause of gonadal dysfunction and infertility. We present the case of a 38-year-old woman with history of amenorrhea and infertility. At seven weeks of pregnancy she presented neuro-ophthalmolog...Prolactinomas are a common cause of gonadal dysfunction and infertility. We present the case of a 38-year-old woman with history of amenorrhea and infertility. At seven weeks of pregnancy she presented neuro-ophthalmologic complaints of headaches, diplopia, and right ptosis. The work-up study revealed an invasive pituitary macroadenoma with a maximum diameter of 9 cm and serum prolactin of 25,800 ng/mL (3-20). At 12 weeks, she was referred to the Endocrinology Department of the Coimbra University Hospital and started therapy with bromocriptine, initially 5 mg/day and then at crescent doses. Hyperprolactinemia was rapidly and drastically reduced to 254 ng/mL three weeks after taking bromocriptine 15 mg/day. Tumoral volume was reduced and there was improvement of III pair paresis. At 38 weeks, a male healthy baby was born. This is a relevant clinical case that illustrates the efficacy and safety of bromocriptine therapy during pregnancy, even in severe cases like this one.
Dantas RA, Passos KE, Porto LB
… +3 more, Zakir JC, Reis MC, Naves LA
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232821
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OBJECTIVE: To evaluate the quality of life and its association with daily physical activity and disease control in acromegalic patients. SUBJECTS AND METHODS: A cross-sectional, case series study, composed of 42 patients...OBJECTIVE: To evaluate the quality of life and its association with daily physical activity and disease control in acromegalic patients. SUBJECTS AND METHODS: A cross-sectional, case series study, composed of 42 patients recruited from the Neuroendocrinology Unit of the University Hospital of Brasilia. Level of physical activity was accessed by the International Physical Activity Questionnaire (IPAQ 6-short-form), which evaluates the weekly time spent on physical activity of moderate to vigorous intensity in different contexts of life. Quality of life was evaluated by The Medical Outcome Study Questionnaire Short Form (SF-36). Data was compared to growth hormone (GH) and insulin-like growth factor (IGF-1) levels. Students' t test and Fisher test were used, p < 0.05, SPSS 17.0. RESULTS: Twenty-two women, aged 51.33 ± 14.33 and 20 men, aged 46.2 ± 13.18 were evaluated. Arthralgia was present in 83% of cases. In men, the most common sites of pain were the knees (73%), spine (47% lumbar, and 53% thoracic and cervical segments), hands and wrists (40%). Higher scores on SF-36 were observed in patients with intermediate or high levels of physical activity, in the domains social functioning (75 CI 57.3-92.6), general health (75.5 CI 60.4-90.5), mental health (70 CI 57.8-82.1). CONCLUSIONS: In this study, the presence and severity of physical disability and pain were not associated with initial GH and IGF-1 levels or time of exposure to GH excess. However, the patients considered controlled, with normal a normal age-adjusted IGF-1, presented higher scores in SF-36, in physical and emotional domains, compared with patients with persistent hypersomatotrophism. These findings suggest benefits of metabolic control in self-reported quality of life.
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232820
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OBJECTIVE: The aim of this study was to assess if the A1c goals from the Brazilian Diabetes Society (SBD) were compatible with their goals for blood glucose. MATERIALS AND METHODS: An online simulation (AIDA) was used to...OBJECTIVE: The aim of this study was to assess if the A1c goals from the Brazilian Diabetes Society (SBD) were compatible with their goals for blood glucose. MATERIALS AND METHODS: An online simulation (AIDA) was used to simulate a hypothetical patient with blood glucose values similar to the SBD's goals. Average glucose was calculated from generated blood glucose values, and then converted to the corresponding A1c value, using the ADA online calculator. Other glycemic profiles, using different levels of blood glucose, were also simulated in order to assess which would be the A1c value associated with each profile. RESULTS: Glycemic goals proposed by the SBD (fasting glucose < 100 mg/dL, preprandial < 110 mg/dL, and postprandial < 140 mg/dL), were associated with an A1c of 5.9%, much lower than the goal of 7% recommended by the SBD. This demonstrates incompatibility among A1c and blood glucose goals proposed by the SBD. Such A1c levels are associated with increased mortality among high-risk patients. CONCLUSIONS: Besides recommending different A1c goals for different patients, the SBD should probably review its recommendations and adopt different blood glucose goals that are compatible with the proposed A1c goals, making therapeutic targets clearer.
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232819
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OBJECTIVE: To assess the trend of thyroid cancer mortality in Brazil between 1980 and 2010. MATERIALS AND METHODS: An ecological study of time series. Mortality rates for thyroid cancer adjusted by age according to gende...OBJECTIVE: To assess the trend of thyroid cancer mortality in Brazil between 1980 and 2010. MATERIALS AND METHODS: An ecological study of time series. Mortality rates for thyroid cancer adjusted by age according to gender were calculated between 1980 and 2010. Data were analyzed by three distinct strategies: polynomial regression, joinpoint analysis, and moving averages. RESULTS: Over 70% of deaths occur in the elderly, regardless of sex. Among young adults, the mortality rate is low, with no difference between men and women. Among mature adults and elderly, mortality is increasing, and significantly, for women. There is a trend of decreasing mortality in all female adults and overall population, and in males and 40-59 years and overall population, both excluding the elderly, with statistical significance. CONCLUSION: Knowledge about trends allows setting priorities and allocating resources toward positive changes in this scenario in the Brazilian population.
Milano GE, Leite N, Chaves TJ
… +3 more, Milano GE, Souza RL, Alle LF
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232818
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OBJECTIVE: To evaluate the effect of 12 weeks of physical exercise (PE) on cardiovascular risk factors and BChE activity in obese adolescents. SUBJECTS AND METHODS: The sample consisted of 24 obese adolescents and 51 nor...OBJECTIVE: To evaluate the effect of 12 weeks of physical exercise (PE) on cardiovascular risk factors and BChE activity in obese adolescents. SUBJECTS AND METHODS: The sample consisted of 24 obese adolescents and 51 normal weight controls. The following variables were measured in the initial stage and after 12 weeks: weight, height, BMI, waist circumference (WC), fat percentage (% F), maximal oxygen uptake (VO2max), systolic (SBP) and diastolic (DBP) blood pressure, glucose (GLY) and insulin (INS) at baseline and after 120 min, triacylglycerol (TG), total cholesterol (TC), LDL cholesterol, HDL cholesterol, and BChE activity (kU/l). RESULTS: After the intervention, there was significant reduction in BMI, WC, %F, TG, GLI 120, INS 120 min, and BChE activity. CONCLUSION: The reduction in BChE activity, observed after physical exercise, was accompanied by the reduction of the variables associated with cardiovascular risk and obesity, indicating that BChE can be used as a secondary marker for the risk associated with early onset obesity.
Arq Bras Endocrinol Metabol
· 2013 Oct · PMID 24232817
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OBJECTIVE: To evaluate lumbar bone mineral density (BMD) in girls with eating disorders in the beginning of the treatment, at six months, and after one year of treatment. SUBJECTS AND METHODS: This prospective study invo...OBJECTIVE: To evaluate lumbar bone mineral density (BMD) in girls with eating disorders in the beginning of the treatment, at six months, and after one year of treatment. SUBJECTS AND METHODS: This prospective study involved 35 female adolescents with AN or EDNOS treated during one year. Lumbar (L1-L4) bone mineral density by DXA was performed in the beginning of treatment, at six months, and after one year of treatment. RESULTS: There was improvement in weight, length, BMI, bone age (p < 0.001), and 70% of the adolescents with secondary amenorrhea had their menstrual cycles restored. However, the Z-score of lumbar BMD did not show differences during one year of follow-up (p = 0.76). CONCLUSION: The recovery of BMD does not occur together with the restoration of hypothalamic-pituitary-gonadal axis.