Normal Sex Hormone-binding Globulin Research Articles

LBSUN288 Improved Glycemic Control Following Oophorectomy In A Post-menopausal Woman With Ovarian Hyperthecosis

Abstract Introduction While androgens are associated with decreased risk for type 2 diabetes in males, the opposite is seen in females. Despite this, a "chicken or the egg" argument exists regarding hyperandrogenism and insulin resistance in women. Ovarian hyperthecosis, a condition that mostly affects post-menopausal women, causes androgen excess due to hyperplasia of the theca interna of the ovaries. Akin to polycystic ovarian syndrome, it is associated with obesity and insulin resistance. We describe a case of ovarian hyperthecosis in a woman with type 2 diabetes with improved glycemic control following oophorectomy. Case A 63-year-old post-menopausal female with a history of autoimmune hepatitis, primary biliary cirrhosis, and chronic pancreatitis presented for recently diagnosed type 2 diabetes, discovered on routine point-of-care Hemoglobin A1c (HbA1c) testing in December 2020 (HbA1c 7.1%, weight: 86 kg). In January, she started repaglinide which was titrated to 2 mg with meals, also that month started prednisone for autoimmune hepatitis. Despite tapering doses of prednisone, her hyperglycemia paradoxically worsened and persisted following completion in June. In May, HbA1c was 7.8%. In August, she endorsed hirsutism, present for 2 years but worsening over the past few months. Labs showed elevated total testosterone (508 ng/dL), free testosterone (32.7 pg/mL), and androstenedione (305 ng/dL), with normal sex hormone binding globulin. DHEA-S was low (28.9 ug/dL, range: 29.4-220.5), midnight salivary cortisol was elevated (0.12 mcg/dL; range: <0. 09), and morning serum ACTH and cortisol were within normal range, with appropriate suppression to dexamethasone. Estradiol was above post-menopausal range (68.1 pg/mL; range: <6. 0-54.7). FSH and LH were within the post-menopausal range, with an approximate 1: 1 ratio. A pelvic ultrasound revealed two intramural myomas and a simple cyst of the right ovary, but otherwise unremarkable. She underwent bilateral salpingo-oophorectomy in October 2021. Post-surgical total testosterone was 27 ng/dL. Surgical pathology revealed unremarkable fallopian tubes and bilateral stromal hyperplasia and hyperthecosis of the ovaries. At one month follow-up, HbA1c was 6.5%, weight decreased from 89 kg pre-surgery to 86, and she endorsed improved hirsutism but frequent hypoglycemia on repaglinide 2 mg with meals. Repaglinide was decreased to 0.5 mg with meals. Three months later, HbA1c was 6.3% with unchanged weight. Conclusion Improved glycemic control, corresponding with timing of oophorectomy but not discontinuation of steroids, suggests insulin resistance in this case may be due to hyperandrogenism. Though some studies and case reports suggest hyperandrogenism causes insulin resistance, others suggest the contrary. The relationship between androgens and insulin sensitivity is likely complex, and further research is necessary. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Features of hyperandrogenism in men

ОБОСНОВАНИЕ. Сегодня проблема гиперандрогении изучается преимущественно по отношению к женщинам, у мужчин этот вопрос практически не затрагивается, в то же время гиперандрогения у них может быть ассоциирована с развитием ряда заболеваний.ЦЕЛЬ. Охарактеризовать варианты физиологической гиперандрогении у мужчин.МАТЕРИАЛЫ И МЕТОДЫ. Сплошное одномоментное исследование 100 мужчин с гиперандрогенией. При проведении исследования оценивались объем и структура простаты, объем яичек; определялись уровни лютеинизирующего гормона (ЛГ), общего тестостерона, глобулина, связывающего половые гормоны (ГСПГ), с дальнейшим расчетом уровня свободного тестостерона по Vermeullen, и дигидротестостерона (ДГТ). По результатам анализа гормонального статуса пациентов с гиперандрогенией были сформированы 4 группы пациентов: 1-я — пациенты с повышенным уровнем общего тестостерона и ГСПГ; 2-я — пациенты с повышенным уровнем общего тестостерона и нормальным уровнем ГСПГ; 3-я — пациенты с повышенным уровнем общего тестостерона, ДГТ при нормальном уровне ГСПГ; 4-я — пациенты с повышенным уровнем ДГТ при нормальном уровне общего тестостерона и ГСПГ. Статистически значимыми считали различия между группами при p<0,05.РЕЗУЛЬТАТЫ. Возраст и объем простаты пациентов 1-й группы были статистически значимо выше, чем в остальных группах. Для этой группы, несмотря на высокий уровень общего тестостерона, не было характерно наличие жалоб на акне. Пациенты 2-й группы чаще жаловались на акне, но распространенность этого симптома даже в этой группе являлась статистически значимо более низкой, чем у пациентов 3-й группы. При этом частота встречаемости алопеции была статистически значимо ниже во 2-й группе, чем у пациентов как 3-й, так и 4-й групп. Пациенты 3-й группы имели самые яркие клинические проявления гиперандрогении. Для 4-й группы была характерна алопеция.ЗАКЛЮЧЕНИЕ. Повышение уровня андрогенов может выявляться в любом возрасте. При этом у мужчин старшей возрастной группы повышение уровня общего тестостерона может быть обусловлено увеличением секреции ГСПГ и не сопровождаться повышением уровня свободного тестостерона. У молодых пациентов клинические проявления гиперандрогении могут отличаться: для пациентов с повышенным уровнем ДГТ характерна андрогенная алопеция; акне характерно для мужчин с повышенным уровнем общего и свободного тестостерона, а повышение ДГТ усугубляет эту проблему.

Extremely Low Testosterone due to Relative Energy Deficiency in Sport: A Case Report

Recognize extremely low testosterone due to hypothalamic dysfunction from overtraining syndrome in a male athlete with relative energy deficiency in sport (RED-S). Clinical and laboratory information are described. A 20-year-old male division I collegiate swimmer was found to have strikingly low total, free, and bioavailable testosterone levels with normal sex hormone-binding globulin and inappropriately normal follicle-stimulating hormone and luteinizing hormone. Lab testing ruled out hyperprolactinemia and hypothyroidism as etiologies, and pituitary imaging was normal. A diagnosis of RED-S was made, and the patient worked with the sports medicine team to increase nutrition and modify physical activity. His repeat testosterone levels improved after minor weight gain and decreased training regimen and eventually returned to normal. Secondary hypogonadism with extremely low testosterone can be seen in male athletes with suspected RED-S.

A Case of Unusual Clitoromegaly

A mild degree of clitoromegaly can be associated with patients with polycystic ovarian syndrome (PCOS). We describe an unusually significant clitoromegaly in a patient with PCOS. An 18-year-old nonobese female patient was referred for clitoromegaly. Her genitalia exam showed significant clitoral enlargement with a well-formed glans, clitoris measured at 35mm for length and 10mm for width. Pelvic ultrasound showed a left ovarian cyst. Her testosterone level ranged from 28.8 to 64.1ng/dL (normal: 8.4-48.1ng/dL) with normal sex hormone binding globulin. Other ovarian hormones were in acceptable ranges. This case demonstrates the coexistence of significant clitoromegaly, PCOS, and nonfunctioning ovarian cyst.

The effect of sex hormone-binding globulin (SHBG) protein polymorphism on the levels of SHBG, testosterone, and insulin in healthy Indonesian men

Background: Sex hormone-binding globulin (SHBG) is a protein. The synthesis of SHBG protein is encoded by SHBG gene. Protein polymorphism of SHBG can occur because of a mutation of D327N exon 8 in SHBG gene. D327N mutation causes the addition of glycosylation so that molecular weight of SHBG protein increases. Protein polymorphism of SHBG is suspected to affect the levels of SHBG, testosterone, and insulin in the blood circulation. Objective: To determine the effect of protein polymorphism of SHBG on the levels of SHBG, testosterone, and insulin in healthy adult men. Materials and Methods: Serum samples were collected from 179 healthy adult men. Electrophoresis and western blotting were performed to determine the phenotype of SHBG. All subjects were divided into two groups based on SHBG phenotype; group I (normal SHBG phenotype) n = 159 subjects and group II (variant SHBG phenotype) n = 38 subjects. Result: The levels of serum SHBG, testosterone, and insulin were measured using radioimmunoassay method. The levels of SHBG, total testosterone, and free testosterone between normal SHBG phenotype do not differ with variant SHBG phenotype (p > 0.05), but insulin levels between normal SHBG phenotype compared with variant SHBG phenotype was different (p < 0.05). Conclusion: Protein polymorphisms of SHBG was not found to affect the levels of SHBG, total testosterone, and free testosterone. Protein polymorphism of SHBG was found to affect the insulin levels in the blood serum.

Relationship between Testosterone and Sex Hormone Binding Globulin Concentrations with Cardiometabolic Parameters and Macrovascular Disease in Afro-Caribbean Men with Type 2 Diabetes

Introduction: Low testosterone concentrations have been reported in type 2 diabetes (T2D) and Coronary Artery Disease (CAD). Contrary to diabetes, the prevalence of CAD is lower in Afro-Caribbean (AC) from French West Indies islands than in people from mainland France. However, CAD is a frequent complication of T2D. To evaluate this paradoxical situation, we investigated the prevalence of sex steroids deficiency that might be associated with CAD in AC men with T2D and the relationships with metabolic parameters. Methods: We performed a cross-sectional study in the Department of Diabetology of the University Hospital of Guadeloupe. Clinical and biological data were collected from men with T2D. Total Testosterone (TT) and Sex Hormone Binding Globulin (SHBG) concentrations were measured using electrochemiluminescence and immunoradiometric assays. Results are expressed as mean ± SD or percentages. The data were analyzed using the Mann–Whitney and chi-squared tests, Pearson correlations and logistic regression. P values<0.05 were considered significant. Results: One hundred thirty-three AC men with T2D were included. Prevalence of testosterone deficiency was 43.5%. The mean TT and SHBG concentrations were 12.06 ± 6.24 and 35.9 ± 17.54 nmol/l respectively. Low TT concentrations were more frequently found in obese subjects compared to subjects with normal weight and low SHBG concentrations were high rather in subjects with overweight. Both sex steroids levels were higher in subjects with dyslipidemia than subjects without dyslipidemia. TT deficiency was more frequent in subjects with macrovascular disease including CAD, peripheral artery disease or stroke than subjects without macrovascular disease. Conclusion: Testosterone deficiency and low SHBG concentrations occur frequently in AC men with T2D and are associated with metabolic profile that may promote the development of macrovascular disease. In this population, it may be necessary to systematically apply a testosterone replacement in case of deficiency, to improve cardiometabolic profiles without forget the risk of prostate cancer.

Plurihormone secreting pituitary macroadenoma masquerading as thyrotoxicosis: Clinical presentation and diagnostic challenges

Thyroid stimulating hormone (TSH) secreting adenomas are the rarest type of pituitary adenomas (1:1000000 in the population; 0.2- 2.8% of adenomas). Plurihormonal thyrotropic adenomas are even rarer usually having cosecretion of growth hormone (GH) and prolactin. We report perhaps for the first time, TSH, GH, adrenocorticotrophic hormone (ACTH) and gonadotropins secreting pituitary macroadenoma diagnosed in a 40 year lady presenting with features of thyrotoxicosis for 5 months, amenorrhea for 3 months and newly diagnosed diabetes and hypertension for 2 months along with headache, nausea, and vomiting, who had acromegaloid habitus, grade-II goitre, increased uptake on Technitium-99 pertechnate thyroid scan (4.1%; normal: 0.24-3.34%), with increased T3 (5.98 pg/ ml; 1.5-4.1), increased T4 (2.34 ng/dl; 0.9-1.8), inappropriately high TSH (2.32 μIU/ml; 0.4-4.2), insulin like growth factor-1 (711 ng/ ml; 109-264), non-suppressed post-glucose GH (15.9 ng/ml; <1 ng/ml), normal estradiol (52 pg/ml; 21-251), inappropriately high luteinizing hormone (53.5 mIU/ml; 1.1-11.6), inappropriately high follicle stimulating hormone (59 mIU/ml; 3-14.4), non-suppressed overnight dexamethasone cortisol (5.8 mcg/dl; <2), elevated ACTH (58 pg/ml 5-15), withdrawal bleed on progestrogen challenge, bitemporal hemianopia on automated perimetry and pituitary macroadenoma on MRI imaging of sella. Thyroid hormone resistance was ruled out by documenting normal sex hormone binding globulin and ferritin levels. Her clinical and biochemical phenotype was not suggestive of multiple hormone resistance seen in pseudohypoparathyroidism. This report intends to highlight the challenges in the diagnosis of plurihormonal thyrotropic adenoma.

Prediction of gestational diabetes mellitus by maternal factors and biomarkers at 11 to 13 weeks

To develop a model for the prediction of gestational diabetes mellitus (GDM) from maternal characteristics and biochemical markers at 11 to 13 weeks' gestation. A prospective screening study on early prediction of pregnancy complications (n = 11, 464), including 297 (2.6%) cases of GDM was used to create the predictive model of GDM based on maternal characteristics. Maternal serum concentrations of adiponectin, follistatin-like-3 (FSTL3) and sex hormone-binding globulin (SHBG) were measured in a case-control study of 80 women who developed GDM and 300 controls. In the screening study, maternal age, body mass index, racial origin, previous history of GDM and macrosomic neonate were significant independent predictors of future GDM. In the GDM group, compared to controls, the median multiple of the normal median adiponectin (0.66; IQR: 0.5-0.9 vs 1.02; IQR: 0.7-1.29) and SHBG (0.81; IQR: 0.6-1.04 vs 1.02; IQR: 0.8-1.2) was lower (p < 0.05), but FSTL3 was not significantly different. In screening for GDM by maternal characteristics, the detection rate was 61.6% at a false-positive rate of 20% and the detection increased to 74.1% by the addition of adiponectin and SHBG. First-trimester screening for GDM can be provided by a combination of maternal characteristics and biomarkers.

Characterization of sex hormone-binding globulin isoforms in hypothyroid women.

Liver sex hormone-binding globulin (SHBG) biosynthesis is regulated by triiodothyronine (T3). This regulation is responsible for increased serum SHBG concentrations in hyperthyroid states. However, in hypothyroidism, normal SHBG levels are frequently found. To understand this we have characterized circulating SHBG isoforms according to their sialic acid content, which determines its half-life, in euthyroid and hypothyroid women. Six euthyroid (aged 56 +/- 8 years) and five hypothyroid women (51 +/- 13 years) were studied. Their body mass index (BMI) range was 20-25. Hypothyroidism diagnosis was based on clinical findings, elevated basal thyrotropin (TSH) and decreased T3 and thyroxine (T4) values. Total SHBG was measured by radioimmunoassay (RIA) and SHBG isoforms were isolated using preparative isoelectrofocusing. For comparisons, two-tailed t test was applied. No statistical difference was found between the total SHBG levels of hypothyroid and euthyroid postmenopausal women. Three groups of SHBG isoforms were isolated in the euthyroid group: S(I): pl: 5.0-5.2: 20% +/- 4%, S(II) : pl 5.2-5.4: 50% +/- 3% and S(III): pl 5.4-5.6: 29% +/- 4%. In hypothyroid patients, although the three groups of isoforms were isolated in the same pH range, S(I) and S(II) proportions were different (p < 0.001) when compared to normal women: S(I): 34% +/- 4%, S(II): 33% +/- 9.9% and S(III): 29% +/- 5.7%. These results show that hypothyroid patients have a higher proportion of more acidic SHBG isoforms. This variation may explain the normal levels of serum SHBG observed in hypothyroidism.

Sex hormone binding globulin phenotypes: their detection and distribution in healthy adults and in different clinical conditions

Human sex hormone binding globulin (SHBG) is encoded by a normal and a variant allele. The resulting SHBG phenotypes (the homozygous normal SHBG, the heterozygous SHBG and the homozygous variant SHBG phenotype) can be distinguished by their electrophoretic patterns. We developed a novel detection system allowing us to distinguish between the different electrophoretic patterns in small amounts of plasma or serum (10 μ1). Small aliquots of Blue Sepharose were added to diluted sera or plasma samples for removal of albumin and the supernatants were subsequently applied to Western blotting. This method of detection was used to determine the distribution of SHBG phenotypes in healthy controls of both sexes and in five different pathological conditions characterized by changes in the SHBG level or endocrine disturbances (malignant and benign ovarian neoplasms, hirsutism, liver cirrhosis and alcoholism). The distribution of SHBG phenotypes was independent of such conditions and in agreement with the expected phenotype distribution of a bi-allelic gene in both healthy controls and patients (Hardy Weinberg law). An allele frequency of 0.13 was found for the SHBG variant allele based on the experimental values. Differences in SHBG phenotypes do not appear to have any clinical significance and no sex difference was found in the SHBG phenotype distribution.

Selective removal of glycosylation sites from sex hormone-binding globulin by site-directed mutagenesis.

Sex hormone-binding globulin (SHBG) is a homodimeric plasma glycoprotein with high affinity for sex steroid hormones. It contains two N-linked carbohydrate chains and one O-linked oligosaccharide per subunit, but their functional significance is not known. Site-directed mutagenesis of a human SHBG cDNA has enabled us to selectively disrupt the known glycosylation sites individually and in various combinations. The mutant cDNAs were expressed in Chinese hamster ovary (CHO) cells, and it was found that the presence of carbohydrates is not an absolute requirement for the secretion of SHBG from these cells, but the absence of both N-linked oligosaccharides reduced the amount of SHBG in the culture medium. In addition, the affinity and specificity of SHBG for steroid ligands was unaffected by the lack of one or more carbohydrate chains. Proportionally greater amounts (26-31%) of the mutants lacking a single N-linked carbohydrate chain failed to interact with Concanavalin-A. (Con-A) compared to normal SHBG produced by CHO cells (15%). Western analysis demonstrated that both consensus sites for N-glycosylation are used and that the typical heavy [mol wt (M(r)), approximately 51,000] and light (M(r), approximately 47,000) subunit size-heterogeneity was maintained regardless of the absence of an O-linked carbohydrate at residue 7. Furthermore, the SHBG mutants containing only one N-linked oligosaccharide comprise only a single subunit with a M(r) of approximately 47,000. This suggests that the heavy subunit contains two N-linked oligosaccharides, while only one of these sites is used on the light subunit. The M(r) of the various SHBG mutants were also examined by gel filtration, and this indicated that they are all produced as homodimers and that carbohydrates are not involved in subunit association.

Molecular analyses of a human sex hormone-binding globulin variant: evidence for an additional carbohydrate chain.

Genomic DNA was isolated from an individual who is homozygous for a sex hormone-binding globulin (SHBG) variant that resolves into three molecular weight forms of 56K, 52K, and 48K during electrophoresis under denaturing conditions (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). This material was amplified using intron-specific oligonucleotide primers in a polymerase chain reaction to obtain the eight exons encoding SHBG. Sequence analysis of these exons revealed a point mutation encoding an amino acid substitution (Asp --> Asn) at residue 327 in the SHBG polypeptide, and the same mutation was identified in three siblings who also appear to be homozygous for this trait. This mutation introduces an additional consensus site for N-glycosylation at this position, and to confirm its utilization we introduced it into a human SHBG complementary DNA. The mutated complementary DNA was inserted into the pRc/CMV expression vector, and transfected into Chinese hamster ovary (CHO) cells. The product was secreted normally but proportionally less of it (54%) bound to concanavalin A when compared to normal SHBG produced by CHO cells (85%), or SHBG in the serum of either a normal individual or those who produce an electrophoretic variant (98%). Furthermore, when subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting, the SHBG variant produced by CHO cells consisted of a 60K subunit as well as the heavy (52K) and light (48K) subunits associated with normal SHBG produced by CHO cells or in serum. This additional subunit is larger than the variant in serum and probably reflects a greater degree of complexity in the carbohydrate structures added to recombinant SHBG during synthesis in CHO cells. Nevertheless, its steroid-binding affinity was equal to normal SHBG produced by CHO cells or SHBG in serum.

Testicular and adrenocortical function in healthy men and in men with benign prostatic hyperplasia

The influence of aging upon serum concentrations of testicular steroids, sex hormone binding globulin (SHBG) and pituitary hormones and on adrenal steroid levels and adrenal steroid response to ACTH was studied in 81 healthy men aged 20–87 years. These endocrine variables were also compared in 43 patients with benign prostatic hyperplasia (BPH), aged 58–89 years and in a subgroup of 41 men, aged 58–87 years, from the above mentioned reference population. The normal endocrine aging was characterized by a rise in SHBG levels, decreasing levels of testicular steroids and non-SHBG-bound testosterone (NST) and increasing gonadotropin levels and decreasing concentrations of total estrone. Adrenal androgen levels decreased in the presence of unchanged levels of cortisol and the adrenal steroid response to ACTH changed by decreasing increments in dehydroepiandrosterone (DHA) and increasing increments in 17α-hydroxyprogesterone (17OHP). With the exception of the alterations in SHBG and adrenal androgens, all these changes were finished before the seventh decade of life. BPH patients had elevated levels of testosterone and NST in the presence of normal SHBG and gonadotropin levels, elevated levels of DHA and DHA sulfate (DHAS) in the presence of normal cortisol levels, a “younger” pattern of adrenal steroid response to ACTH as judged from the increments in DHA and 17OHP, elevated ratios between estrone and 4-androstene-3,17-dione suggesting an increased peripheral aromatization and subnormal prolactin levels. BPH patients may be considered as “endocrinologically younger” than healthy subjects. DHA and especially its proximate metabolite 5-androstene-3β, 17β-diol exert powerful estrogenic effects on the receptor level. Thus the elevated levels of DHA and DHAS in the BPH patients may create an hyperestrogenic condition in addition to the slight hyperandrogenicity caused by the elevated NST levels. Both endocrine aberrations may play a role in the etiology of BPH, in accordance with the dual sex steroid sensitivity of the periurethral glands.

Elevation of hormone-binding globulins in acute intermittent porphyria

Sex hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG) and cortisol-binding globulin (CBG) were measured in plasma of 26 patients with acute intermittent porphyria (AIP). Twelve patients had clinically manifest disease and all had elevated SHBG levels. All but one of 14 patients with latent porphyria had normal SHBG levels. TBG was elevated in 9 of the patients with clinically manifest porphyria and CBG elevated in three. Levels of TBG and CBG were either normal or only slightly elevated in those with latent porphyria. In a prospective study of 30 attacks of AIP in 7 patients, SHBG levels fell between admission and discharge, the fall being significant in the group of 21 attacks treated with haem arginate ( p < 0.001). Our findings suggest that a close correlation exists between elevated SHBG and clinical expression of AIP.

Inhibition of binding of gonadal steroids to serum binding proteins by non-esterified fatty acids: the influence of chain length and degree of unsaturation.

The effect of non-esterified fatty acids (NEFA) on the in vitro binding of testosterone, 5-alpha dihydrotestosterone and estradiol E2 to sex hormone binding globulin (SHBG) was examined using pooled normal female serum, and SHBG and albumin fractions obtained from the partial purification of late pregnancy serum. A range of saturated and unsaturated fatty acids were examined for their effect on steroid-protein binding. In normal female serum, NEFA added at physiological concentrations disrupted steroid-protein binding. The shorter chain (C8-C12) saturated acids and the poly-unsaturated acids proved to be more effective inhibitors than the longer chain saturated or mono-unsaturated acids. The greatest inhibition was obtained with E2 whereas the binding of dihydrotestosterone was least affected. With partially purified SHBG, the same concentrations of NEFA were less effective at inhibiting the binding of dihydrotestosterone and testosterone but elicited the same effect with E2. The binding of steroids to albumin appeared to be unaffected by these concentrations of NEFA.

Thyroxine uptake by human hepatoma cells from serum of patients submitted to long-term thyroxine suppressive therapy.

The significance of thyroxine (T4) uptake from serum in the assessment of thyroid status was evaluated, using human hepatoma (Hep G2) cells, in 30 euthyroid subjects, 6 hypothyroid and 19 hyperthyroid patients, and in 23 athyreotic cancer patients under T4 suppressive therapy. Cellular thyroxine (CT4) was determined according to Sarne and Refetoff, J. Clin. Endocrinol. Metab. 61: 1046, 1985. CT4 averaged 9.9 +/- 2.8 pg/well (mean +/- SD, range 5.7-15.3) in euthyroid subjects, 1.5 +/- 1.0 pg/well (range 0.05-4.2) in hypothyroid patients, 40.5 +/- 18.8 pg/well (range 18.3 +/- 104.7) in hyperthyroid patients, and 23.7 +/- 7.2 pg/well (range 14.2-40.2) in T4-treated patients. In eu-, hypo- and hyperthyroid patients, a significant correlation was observed between CT4 and free T4 index (FT4I), free T4 (FT4) or Sex Hormone Binding Globulin (SHBG) values. In T4-treated patients, CT4 values were correlated with FT4I values, but not with FT4 or SHBG levels. All T4-treated patients with elevated SHBG levels had elevated FT4, FT4I and CT4 values. In contrast, of the 16 T4-treated subjects with normal serum SHBG concentrations, all but one had normal FT3, 3 (19%) had elevated FT4, 10 (62%) elevated FT4I and 13 (81%) elevated CT4, but all (100%) had undetectable TSH levels. Thus, considering serum SHBG concentrations as a parameter of hepatic tissue response to thyroid hormone, CT4 values, at least in T4-treated patients, do not accurately reflect the liver responsiveness to thyroid hormone action.

Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration.

Thyroid hormone is one of several factors that modulate the level of sex hormone-binding globulin (SHBG) in serum. SHBG levels are usually elevated in thyrotoxicosis and have been reported to be normal in a few patients with generalized resistance to thyroid hormone (GRTH). This study was designed to determine whether basal serum SHBG levels or the SHBG response to short term T3 administration could be used as an index of thyroid hormone action and thus serve as a test for the evaluation of patients suspected of having peripheral tissue resistance to thyroid hormone. Serum SHBG, total T4, free T4 index (FT4I), total T3, and TSH levels were measured in 21 normal subjects, 28 hypothyroid patients, 20 thyrotoxic patients, and 10 patients with GRTH. Excluding patients with GRTH, serum basal SHBG values were correlated with FT4I values (r = 0.66; P less than 0.0001). Mean SHBG levels in the patients with GRTH [37.6 +/- 16.2 (+/- SD) nmol/L] were not significantly different from those in the normal subjects (35.1 +/- 19.3 nmol/L) or hypothyroid patients (26.3 +/- 17.1 nmol/L), but were significantly lower than those in the thyrotoxic group (64.7 +/- 19.2 nmol/L; P less than 0.001). All 10 patients with GRTH had basal SHBG values in the normal range, but 7 of 20 (35%) thyrotoxic patients also had normal basal SHBG values. T3 was given orally for three sequential 3-day periods at doses of 50, 100, and 200 micrograms daily to 7 normal subjects, 11 hypothyroid and 3 thyrotoxic patients, and all 10 patients with GRTH. The serum SHBG concentration was measured on the last day at each dosage level. During T3 administration, SHBG levels increased in all individuals with normal tissue responsiveness. The increase above the basal value (delta SHBG) at each T3 dose was similar in normal, hypothyroid, and thyrotoxic individuals (non-resistant subjects). After administration of 50 micrograms T3 daily, the mean delta SHBG level was decreased [-2.9 +/- 5.3 (+/- SD) nmol/L] in the resistant patients and increased (4.0 +/- 4.9 nmol/L; P less than 0.005) in the nonresistant subjects. After administration of 100 micrograms T3 daily, the mean delta SHBG was -4.5 +/- 6.8 nmol/L in the resistant patients and 8.6 +/- 5.1 nmol/L (P less than 0.0001) in the nonresistant subjects. Serum SHBG decreased by more than 2 nmol/L in 6 of 10 (60%) resistant patients, but in no nonresistant subject.(ABSTRACT TRUNCATED AT 400 WORDS)

Sex hormone-binding protein in hyperthyroxinemic patients: a discriminator for thyroid status in thyroid hormone resistance and familial dysalbuminemic hyperthyroxinemia.

Sex hormone-binding globulin (SHBG) levels in serum are affected by thyroid status; hyperthyroidism is associated with high SHBG levels, whereas hypothyroid patients have low or normal SHBG levels. This study was undertaken to test the usefulness of SHBG determinations to define the thyroid status in two hyperthyroxinemic states: thyroid hormone resistance (THR) and familial dysalbuminemic hyperthyroxinemia (FDH). Serum SHBG levels were determined in 193 patients and 26 normal subjects using an IRMA-type RIA. In the control group, the mean values in women (58.9 nmol/liter) and men (32.7 nmol/liter) were significantly different (P less than 0.001). In adult subjects with THR, SHBG levels were within the normal range, with mean values of 54.8 nmol/liter (range, 28.7-82.5 nmol/liter) in women and 18 and 20 nmol/liter in two men. In FDH subjects, the mean SHBG levels did not differ from the normal values; they averaged 60.7 nmol/liter in women and 42.3 nmol/liter in men. From these data we conclude that in THR and FDH, free T4 levels elicit an appropriate hepatic response corresponding to the euthyroid status of these subjects. SHBG determination may, therefore, serve as an in vitro test for end-organ sensitivity to thyroid hormones.

Variable clinical and hormonal manifestations of hyperandrogenemia

This study was undertaken to contrast the hormonal profiles in patients with various hyperandrogenemic states in an attempt to correlate clinical manifestations with specific hormonal abnormalities. Patients with idiopathic hirsutism, polycystic ovaries, and a syndrome recently described by us, amenorrhea with cryptic hyperandrogenemia, ie, without hirsutism, participated. Total testosterone, the testosterone: sex-hormone-binding globulin (SHBG) ratio, and androstenedione levels were elevated in each group of patients. SHBG levels were suppressed in patients with idiopathic hirsutism and in patients with polycystic ovaries. In patients with polycystic ovaries or cryptic hyperandrogenemia, plasma estrone levels were elevated and the luteinizing hormone (LH) responses to luteinizing-hormone-releasing hormone (LH-RH) were exaggerated. Estrone is derived from androstenedione under the influence of the enzyme, aromatase. While elevated androstenedione occurred in both patients with polycystic ovaries or idiopathic hirsutism, estrone levels were only elevated in patients with polycystic ovaries. Reduced aromatase activity may have protected patients with idiopathic hirsutism from elevated estrone values and, thereby, from menstrual disturbances. The hormonal profiles in polycystic ovary syndrome and in patients with amenorrhea with cryptic hyperandrogenemia were very similar, with the exception that SHBG levels were high normal in three of five patients with cryptic hyperandrogenemia while estrone values were markedly elevated in these patients. Elevated estrone levels may explain the normal SHBG values, which are usually suppressed in hyperandrogenemic states. While each of the hyperandrogenemic disorders studied has a characteristic hormonal profile, the various clinical manifestations cannot be accounted for solely by abnormalities in circulating hormonal levels. Other factors involved included various rates for conversion of elevated androgen levels to estrogens yielding normal estrone in idiopathic hirsutism, increased estrone in polycystic ovary syndrome, and depressed peripheral tissue responsiveness to testosterone and androstenedione in patients with amenorrhea and cryptic hyperandrogenemia.

Quantitative determination of sex hormone-binding globulin capacity in the plasma of normal and diabetic pregnancies.

Sex hormone-binding globulin (SHBG) capacity was measured in a longitudinal study in plasma samples from normal subjects, diabetics, and gestational diabetics and throughout pregnancy, together with unconjugated plasma estradiol. In normal women SHBG capacity (expressed in ng DHT bound per ml of plasma) increased from 23.7 +/- 13.7 (SD) in the 5-8th week period, to 74.5 +/- 20.7 in the 17-20th week period, and to 102 +/- 24 in the 37-40th week period. In diabetics the SHBG capacity for the same periods of time were respectively: 25.3 +/- 17.2, 83.1 +/- 29.1, and 111.6 +/- 22.6. Plasma levels of unconjugated estradiol were 55% higher in the diabetics than in the normal subjects in the second half of gestation, as reported in detail in another publication. From the imbalance between the close to normal SHBG capacity and the higher plasma levels of unconjugated estradiol in the diabetics, it is suggested that the unbound, i.e., metabolically active, fraction of plasma estradiol reaches higher levels in diabetics than in normal subjects in the second half of gestation.