Elevated Sex Hormone-binding Globulin Research Articles

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Causal relationship between sex hormone-binding globulin and risk of neuroblastoma: A bidirectional two-sample Mendelian randomization study.

The causal relationship between sex hormone-binding globulin (SHBG) and neuroblastoma (NB) remains unknown. This study aimed to explore the causality between SHBG and the risk of NB using bidirectional two-sample Mendelian randomization (MR) study. Instrumental variables associated with SHBG were obtained from the genome-wide association study (GWAS) of European containing 214,989 females and 185,221 males from the UK Biobank. Summary-level data for NB were derived from the IEU OpenGWAS project with 1,627 patients and 3,254 controls. The inverse-variance weighted (IVW) method served as the primary analytical tool. The IVW method revealed a significant positive causal relationship between male SHBG and the risk of NB [odds ratio (OR) = 2.169, 95% confidence interval (CI): 1.207-3.897, P = 0.010]. Conversely, female SHBG showed no significant causal link with NB [IVW OR = 1.004, 95% CI: 0.542-1.860, P = 0.990]. No significant reverse causality was detected. Sensitivity analyses validated these findings. Elevated SHBG levels in males, but not in females, can causally increase the risk of NB. This gender-specific effect indicates a potential differential role of SHBG in the etiology of NB. Further research is needed to elucidate the underlying mechanisms of this gender disparity. Monitoring SHBG levels, especially in males, could be pivotal in NB risk assessment and management. This study highlights a novel gender-specific aspect in the risk of NB, emphasizing the potential role of male SHBG levels in NB incidence, and sets the stage for targeted preventative strategies and further investigation into gender-based biological mechanisms.

Association of sex hormones with non-alcoholic fatty liver disease: An observational and Mendelian randomization study.

Sex-specific associations of sex hormone-binding globulin (SHBG) and bioavailable testosterone (BAT) with NAFLD remain indeterminate. We aimed to explore observational and genetically determined relationships between each hormone and NAFLD. We included 187 395 men and 170 193 women from the UK Biobank. Linear and nonlinear Cox regression models and Mendelian randomization (MR) analysis were used to test the associations. During 12.49 years of follow-up, 2209 male and 1886 female NAFLD cases were documented. Elevated SHBG levels were linearly associated with a lower risk of NAFLD in women (HR (95% CI), .71 (.63, .79)), but not in men (a "U" shape, pnon-linear < .001). Higher BAT levels were associated with a lower NAFLD risk in men (HR (95% CI), .81 (.71, .93)) but a higher risk in women (HR (95% CI): 1.25 (1.15, 1.36)). Genetically determined SHBG and BAT levels were linearly associated with NAFLD risk in women (OR (95% CI): .57 (.38, .87) and 2.21 (1.41, 3.26) respectively); in men, an "L-shaped" MR association between SHBG levels and NAFLD risk was found (pnon-linear = .016). The bidirectional MR analysis further revealed the effect of NAFLD on SHBG and BAT levels in both sexes. Consistently, linear associations of lower SHBG and higher BAT levels with increased NAFLD risk were both conventionally and genetically found in women, while in men, SHBG acts in a nonlinear manner. In addition, NAFLD may affect SHBG and BAT levels.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of Pit- NET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Sex hormone binding globulin and total testosterone levels are associated with in vivo tau burden differentially between the sexes: findings from the Framingham Study

AbstractBackgroundIn men and women, sex steroid hormones are associated with increased risk of Alzheimer’s disease (AD) dementia. In older men, lower levels of testosterone are associated with higher rates of AD dementia. The relationship between estradiol levels on AD dementia risk in post‐menopausal women, however, is less clear, with studies reporting protective, deleterious and no effects. Finally, higher levels of sex hormone binding globulin (SHBG), a glycoprotein that regulates, and actively influences sex hormones, has been consistently linked with increased risk for AD dementia. Studies have yet to examine mid‐life hormonal levels in association with later‐life in vivo AD biomarkers in cognitively healthy adults.Method175 women and 159 men from the Framingham Study 3rd Generation cohort underwent blood (hormones) collection in 2002‐2005, and 18F‐Flortaucipir (FTP)‐PET and 11C‐PiB‐PET scans in 2016‐2020 (Table1). We examined FTP‐PET signal (referenced to cerebellar grey) in six a priori regions that previously demonstrated sex differences (entorhinal, inferior temporal, rostral middle frontal, inf/sup parietal and lateral occipital). Linear regressions examined sex‐stratified analyses of free/total testosterone, estradiol, and SHBG in each region, adjusting for age, age2, PET camera and plasma‐PET date‐difference (mean = 15(±2)yrs). Separate models examined interactions with a neocortical PiB‐PET composite and APOEε4.ResultIn men, elevated SHBG was associated with lower FTP‐PET in entorhinal (p = 0.007), inferior temporal (p = 0.04) and rostral middle frontal regions (p = 0.02; Table2). Higher total testosterone was marginally associated with lower FTP‐PET signal in the latter region (p = 0.06), but other relationships were apparent. In women, higher total testosterone associated with lower FTP‐PET signal in inferior temporal (p = 0.05) and parietal regions (p = 0.04). Women APOEε4 carriers with higher estradiol showed higher levels of entorhinal FTP‐PET signal (p = 0.03;Table3).ConclusionHigher levels of SHBG are associated with lower risk of AD‐related comorbidities, such as osteoporosis, diabetes, and visceral weight gain. A strong link between higher SHBG levels and higher HDL‐cholesterol may suggest a potential protective cardiovascular pathway for men against higher tau burden later in life. A lack of protective effect of pre‐menopausal estradiol in female APOEε4 carriers supports the notion that the role of estrogen in AD risk is centered around timing of decline.

FRI430 A Case Of Elevated Sex Hormone-binding Globulin Secondary To Variegate Porphyria In A Patient With Hypogonadotropic Hypogonadism

Abstract Disclosure: J. Law: None. C. Yip: Research Investigator; Self; Eli Lilly &amp; Company. Background: Acute porphyria is a group of disorders characterized by enzymatic defects in the heme biosynthetic pathway. The liver is the source of both acute intermittent porphyria (AIP) and variegate porphyria. AIP is known to cause an elevation in sex hormone-binding globulin (SHBG) levels, likely secondary to impaired hepatic function and hepatocyte abnormalities1. We describe a case of elevated SHBG secondary to variegate porphyria, in a male with hypogonadotropic hypogonadism. Case Report: A 44-year-old male presented with an elevated SHBG and symptoms of hypogonadism with low libido, weakness, and fatigue. Fasting morning bloodwork revealed an elevated SHBG at 89 nmol/l (13.5- 71.0), a normal total testosterone level at 12.95 nmol/l (8-32), and a low bioavailable testosterone at 0.82 nmol/l (2.5-10), with confirmatory repeat blood work. His history was significant for longstanding variegate porphyria, manifesting as frequent attacks of abdominal pain. He was on opioids for greater then 10 years for his chronic pain, as well as metoclopramide. On assessment of causes for his elevated SHBG, his TSH was normal at 1.49 mIU/L (0.35-4.30). He did not have cirrhosis, hepatitis, hereditary hemochromatosis, and was not on anticonvulsants. No other cause was found, and his elevated SHBG was deemed secondary to his variegate porphyria. His normal total testosterone level was due to his elevated SHBG, but as mentioned, his bioavailable testosterone was low. His LH and FSH were both inappropriately normal, with his LH being 4.67 IU/L (0.6-12.0) and his FSH 4.7 IU/L (1.0-12.0), in keeping with hypogonadotropic hypogonadism. He went through normal pubertal development and had no anosmia. Workup revealed an elevated prolactin level of 73.8 ug/l (3.5-19.4). He had no galactorrhea or gynecomastia and an MRI sella revealed a normal pituitary gland. His elevated prolactin level was determined to be secondary to his opioid medication and/or metoclopramide use. His hypogonadotropic hypogonadism was deemed secondary to his opioid medications and/or hyperprolactinemia. Conclusion: This case demonstrated variegate porphyria as a likely cause of elevated SHBG, similar to AIP. In patients with variegate porphyria and symptoms of hypogonadism, the SHBG should be measured and if it is elevated, the bioavailable or free testosterone levels should be used in assess instead of relying on the total testosterone levels. As has been previously shown, this case also illustrated the use of opioid medications as a cause of hypogonadotropic hypogonadism.

FRI476 Asymptomatic Thyrotropin-secreting Pituitary Microadenoma With Biochemical Secondary Hyperthyroidism: A Diagnostic Conundrum

Abstract Disclosure: G. Al-Naqeeb: None. R. Ghosh: None. P. Veeraraghavan: None. C. Cochran: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Thyrotropin (TSH)-secreting pituitary adenomas (TSHAs) are often macroadenomas (&amp;gt;1 cm), and clinically present with secondary hyperthyroidism (SH), but clinically silent microTSHAs (&amp;lt;1 cm) with only biochemical SH pose a diagnostic challenge. Clinical Case: A 49-year-old, healthy male was referred to our center for evaluation of abnormal thyroid function tests (TFTs). Immunoassay (IA) measurements at an outside hospital had identified elevated free T4 (FT4), and an inappropriately normal TSH, and a pituitary magnetic resonance imaging (MRI) had noted an 8mm x 7mm non-invasive adenoma. The patient denied hyperthyroidism symptoms, medication/herbal supplement intake, radiation exposure, headaches, vision changes, and thyroid/pituitary disorders, or abnormal TFTs in relatives. Physical exam revealed no signs and symptoms of hyperthyroidism. No thyromegaly or cervical lymphadenopathy was felt. IA profile at our institute was consistent with an SH pattern [TSH: 3.32 mIU/L (NL: 0.4 - 4.7); FT4: 3 ng/dL (NL: 0.9 - 1.7); total T4: 14.5 mcg/dL (NL: 4.5 - 11.7); triiodothyronine: 266.6 ng/dL (NL: 80 - 200)], with similar values on repeat measurement. Equilibrium dialysis technique also yielded an elevated FT4 value. TSH-receptor, anti-thyroid peroxidase, and anti-thyroglobulin (Tg) antibody (Ab) titers, serum Tg, and thyroid binding globulin levels were normal. Dilution studies ruled out heterophile Ab interference. Familial dysalbuminemic hyperthyroxinemia was unlikely given the elevated FT4 values. Genetic testing revealed a normal THRB gene, thereby ruling out thyroid hormone resistance. THRA gene was not tested due to absence of behavioral or hearing issues. Markers of hyperthyroidism, including angiotensin converting enzyme, carotene, apolipoproteins, and osteocalcin levels were normal, except for an elevated sex hormone binding globulin of 104 nmol/L (NL: 11 - 78). Biochemical evaluation of other pituitary axes was normal. However, an elevated alpha sub-unit fraction (ASF) was noted on two separate measurements. Sonogram revealed a heterogeneous, hypervascular thyroid. Bone densitometry, echocardiogram, and Holter monitor studies were normal. The combination of biochemical SH, elevated ASF, pituitary adenoma, and exclusion of other etiologies causing SH pattern established the diagnosis of TSHA. An active surveillance approach was implemented. A pituitary MRI done 18 months later showed minimal (2mm in one axis) increase in the adenoma size, and the patient continued to demonstrate biochemical SH but remained asymptomatic. Conclusion: MicroTSHAs can present with asymptomatic SH. In this situation, excluding other biochemical SH etiologies is crucial to prevent unnecessary invasive procedures. But once TSHA diagnosis is established, due to the risk of tumor growth leading to symptomatic SH or mass effects, active surveillance is warranted. Presentation: Friday, June 16, 2023

Assessing the Casual Association between Sex Hormone Levels and Fracture Risk: A Two-Sample Mendelian Randomization Study.

Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone-binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome-wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two-sample MR approach. For the main analysis, the inverse-variance-weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR-Egger method were utilized. To evaluate potential pleiotropy, MR-Egger regression was conducted. Additionally, a leave-one-SNP-out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52-3.85; p = 1.93 × 10-4 ]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10-4 ), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10-6 ). Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.

(106) Hormonally-Mediated Vestibulodynia: A Chart Review

Abstract Introduction The borders of the vestibule are Hart’s line laterally, hymen medially, frenulum of the clitoris anteriorly, and fourchette posteriorly. Provoked vestibulodynia (PVD) is characterized by severe burning pain in response to pressure localized to the vestibule. Numerous factors may negatively affect the vestibule causing PVD such as hormonal changes, infections, trauma, exaggerated immunologic or inflammatory responses, dermatologic conditions, high-tone pelvic floor dysfunction, pudendal neuropathy, and sacral radiculopathy. PVD specifically associated with hormonal changes in pre-menopausal women has been termed hormonally mediated vestibulodynia (HMV). Dense labeling of androgen receptors has been noted in the germinal layer of the vestibular epithelium and mucinous minor vestibular glands, implying a critical role of testosterone in vestibular health. Low calculated free testosterone caused by elevated sex hormone binding globulin (SHBG) in pre-menopausal women using combined hormonal contraception may thus be harmful to the vestibular epithelium and minor vestibular glands, resulting in HMV. In HMV, vulvoscopy shows diffuse vestibular tenderness of the entire vestibule, the ostia of the minor vestibular glands are frequently erythematous (Fig 1) and blood testing is consistent with a low calculated free testosterone. Objective We describe the variation in etiologies for HMV and emphasize the importance of measuring total testosterone and SHBG to monitor calculated free testosterone levels in patients with HMV. Methods This is a retrospective chart review of premenopausal patients presenting to a clinic with entrance dyspareunia who were diagnosed with HMV, and whose symptoms were alleviated by treatment. Inclusion criteria were as follows: premenopausal females with initial testosterone and SHBG blood values below the reference range, initial vulvoscopy findings significant for vestibulodynia, follow-up testosterone and SHBG approaching the reference range, and follow-up vulvoscopies demonstrating a relief from symptoms. Results A total of 9 patients met the inclusion criteria. The mean age was 32 years old, with a range of 22 years old to 39 years old. Presenting complaints in addition to dyspareunia (n=9) included recurrent irritative bladder voiding symptoms without positive urine culture (n=3) and pelvic pain (n=4). Vulvoscopic examination including cotton-tipped swab testing of the vestibule revealed signs of vestibular hypersensitivity with pain ranging from 1 to 9 in all 7 regions of the vestibule tested. Patients had histories of having taken combined hormonal contraceptives (n=6), isotretinoin (n=1), spironolactone (n=1) and/or hormonal treatment for breast cancer (n=1), all of which can decrease calculated free testosterone. All patients were treated with systemic testosterone and compounded estradiol/testosterone cream to be applied daily to the vestibule. On follow-up blood testing, all patients had calculated free testosterone values approaching 0.6-0.8 ng/dl, established by Guay et al. as the optimum range. All patients reported significantly decreased dyspareunia and significant relief of other bothersome symptoms, especially bladder symptoms. Conclusions This chart review illustrates a variety of etiologies associated with low calculated free testosterone and the diagnosis of HMV. This data emphasizes the importance of calculating free testosterone and performing vulvoscopy to establish a diagnosis in pre-menopausal patients with entrance dyspareunia. Additionally, this chart review demonstrates the efficacy of systemic testosterone and local vestibular androgen/estradiol therapies in ameliorating vestibular pain and associated symptoms in patients with HMV. Disclosure No

Testosterone, sex hormone-binding globulin and dehydroepiandrosterone levels and cervical length of Egyptian women with a history of recurrent miscarriages, polycystic ovary syndrome and without the conditions at three stages of pregnancy

Total testosterone (TT), sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA) levels, and cervical length (CL) were investigated in pregnant Egyptian women with polycystic ovary syndrome (PCOS, n = 38), history of miscarriages (RM, n = 40) and without the conditions (HC, n = 40). At week 8, the RM had lower levels of TT (p = 0.000) and free androgen index (FAI) (p = 0.000) and higher SHBG (p = 0.000) and DHEA (p < 0.05) than the PCOS. Compared with the HC, they had elevated SHBG (p < 0.05) and DHEA (p = 0.001) and reduced CL (p = 0.000). TT (p = 0.001) and FAI (p = 0.000) were higher and SHBG (p = 0.000) and CL (p = 0.001) lower in the PCOS than in the HC group. At week 16, TT (p = 0.000) and FAI (p = 0.000) were higher, and SHBG (p = 0.000) and CL (p < 0.05) lower in PCOS than in RM and HC. The PCOS had elevated FAI than the RM (p = 0.000) and HC (p = 0.001) at week 20. The DHEA, SHBG and CL abnormalities in PCOS and RM may compromise pregnancy outcomes. IMPACT STATEMENT What is already known on this subject? Hyperandrogenaemia, low sex hormone-binding globulin (SHBG), shortened cervical length (CL) and polycystic ovary syndrome (PCOS) are the most cited risk factors for recurrent miscarriages (RM). However, the published data are inconsistent, perhaps because of the confounding effects of ethnicity and nutritional milieu. What do the results of this study add? The study’s findings comprising ethnically and socially homogenous women demonstrate that PCOS and RM are characterised by elevated dehydroepiandrosterone (DHEA) and shortened CL, and PCOS by reduced SHBG. These abnormalities would be expected to have an adverse impact on pregnancy outcomes. What are the implications of these findings for clinical practice and/or further research? Twenty-weeks DHEA and CL values have the potential to predict outcome risk in women with a history of RM and PCOS. Further research on other population groups is required to validate the current study’s findings.

Comparing Metformin, Inositol, and Lifestyle Modifications to Improve Symptomatology of Polycystic Ovary Syndrome (PCOS): A Research Protocol

Introduction: Polycystic ovary syndrome (PCOS), a common endocrinological disorder of women of reproductive age, affects about 5-20% of women globally. It is diagnosed through the Rotterdam criteria with the presence of two out of three clinical features of oligo-anovulation, hyperandrogenism, and/or polycystic ovaries. Hyperinsulinemia and insulin resistance are central features of PCOS , along with obesity. This study aims to compare three treatment interventions: metformin, inositol, and lifestyle modifications to improve symptoms of PCOS. Methods: In this four-arm randomized study, 48 women of reproductive age (25-36 years) will be recruited over a 12-week period. Impacts of treatment types (metformin, inositol and lifestyle modifications) will be determined in improving symptoms of PCOS. Control group, “Group A” (N=12) will not be going through any treatment; “Group B” (N=12) will be taking 500 mg of metformin daily, with close assessment of side effects; “Group C” will take 2 g of inositol supplements twice daily with a 40:1 myo-inositol and D-chiro-inositol ratio; and “Group D” will undergo lifestyle modifications, closely monitored by personal trainers, nutritionists, and dietitians, to facilitate weight loss. ANOVA, Pearson’s correlation, and Kruskal-Wallis H test will be conducted to determine significance. Anticipated Results: PCOS patients of group C, inositol intake, may be seen to have greatest improvements in PCOS symptomatology due to its insulin sensitizing, metabolic, and hormonal influences, with minimal adverse effects. Discussion: Previous studies have shown inositol consumption to result in significant improvements in insulin resistance, menstrual cycle regularity, Acne score, Ferriman-Gallwey score, endocrine and metabolic parameters, reduced serum levels of total testosterone, and elevated sex hormone binding globulin in women with PCOS. Metformin may yield similar effects to inositol, but greater adverse effects may be present. Through a reduced BMI, lifestyle modifications have shown to significantly reduce total androgen profile, waist circumference, and lipid profile while increasing clinical pregnancy rate by 20%. Conclusion: The comparison of three treatment modalities may be beneficial for PCOS patients to provide optimal treatment. It may be beneficial to compare a combination of treatment interventions in the future for additive or synergistic effects.

ASSOCIATION OF FREE ANDROGEN INDEX AND SEX HORMONE BINDING GLOBULIN AND LEFT VENTRICULAR HYPERTROPHY IN POSTMENOPAUSAL HYPERTENSIVE WOMEN

Objective: The aim of the present study was to explore the relationship between androgen and LVH in postmenopausal hypertensive women. Design and method: Enrolled in this study were 378 postmenopausal hypertensive women who were admitted to the department of cardiology between December 2018 and December 2020. Results: According to left ventricular mass index (LVMI) evaluated by echocardiography, the patients were divided into LVH group (n = 172) and non-LVH group (n = 206). Their clinical characteristics were collected. Based on the result of propensity score matching analysis, 160 cases in each group were matched successfully. After correcting for confounding factors by various models, the results showed that free androgen index (FAI)and sex hormone-binding globulin (SHBG)were the influencing factors of LVH in postmenopausal women with hypertension. Patients with elevated SHBG were 5% less likely to develop LVH than those without elevated SHBG (OR:0.950, 95%CI 0.922–1.578). Postmenopausal hypertensive patients with elevated FAI were 16% more likely to have LVH than those without elevated FAI (OR:1.608, 95%CI 0.807–3.202). Multiple linear regression showed that LVMI increased by 61.82 g/m2 for every 1 unit increase in FAI. In addition, SHBG decreased by 1 nmol/l, and LVMI increased by 0.177 g/m2. Subgroup analysis showed that patients in the controlled BP group had a lower risk of LVH for every additional unit of SHBG compared with the uncontrolled BP group. The risk of LVH for each additional unit of FAI in the uncontrolled BP group was higher than that in the controlled BP group. Conclusions: The results of this present study showed that the occurrence of LVH was positively correlated with FAI and negatively correlated with SHBG in postmenopausal women with hypertension. The increase of FAI level and the decrease of SHBG level may be related to the occurrence and development of LVH in postmenopausal hypertension.

Can we rely on total testosterone measurement to exclude hypogonadism in erectile dysfunction?

Although male hypogonadism (MH) is a prevalent comorbidity in patients presenting for erectile dysfunction (ED), its screening relies solely on total testosterone (TT). Ageing and other conditions can increase sex hormone-binding globulin (SHBG) and lower free testosterone (FT) causing symptomatic MH despite normal TT. The primary objective was to measure the prevalence of normal TT/low FT among patients presenting for ED. From January 2019 to December 2020, 408 patients referred for sexual dysfunction were screened; 180 men with a confirmed diagnosis of ED were included. MH was screened using TT, SHBG, albumin and LH. FT was calculated (cFT). Low TT, high SHBG and low cFT were defined as <345 ng/dL, >50 nmol/L and <6.5 ng/dL, respectively. Patients were divided into groups according to TT/cFT status and to age group. The frequency of normal TT/low cFT was 17.2%. From all 31 patients with normal TT/low cFT, only four (12.9%) had either hyperthyroidism, hepatic disease or HIV infection, while 23 (74.2%) were older than 60 years. Patients with normal TT/low cFT were older (65.57 ± 10.43 vs. 56.79 ± 10.63 yo, p = 0.001) and had higher SHBG (78.48 ± 40.14 vs. 52.35 ± 20.39 nmol/L, p = 0.014) than patients with normal TT/cFT. Patients over 60 years represented 48.9% of the sample, 52.5% had elevated SHBG and their frequency of normal TT/low cFT was 26.3%. Normal TT/low cFT is frequent and can be missed by current screening recommendations for MH in patients presenting for ED. Ageing seems to be the main culprit as elevated SHBG prevalence increases steeply after the sixth decade. TT cannot solely be relied on to exclude biochemical MH in patients presenting for ED, especially in patients over 60 years old. Current guidelines for MH screening in ED should be amended.

Impact of vascular liver disease on the menstrual cycle and metabolic status in premenopausal women

BackgroundVascular liver disease (VLD) are rare liver diseases, which affect women at reproductive ages. Main complications are bleeding (portal hypertension, thrombopenia or anticoagulation related) and thromboembolism. Failure of liver function can occur. Thus endocrine abnormalities management and contraception are challenging. Purposeto evaluate the impact on the menstrual cycles and related endocrine abnormalities in women with VLD and respective roles of liver function and portal hypertension. Study designThis was a single-center observational cohort study. Forty-seven premenopausal women with vascular liver disease were included for endocrine and gynecological assessments. Endocrine evaluation was performed at inclusion. Tolerance of contraception was followed up and assessed at 3 and 12 months. Participants, Setting, MethodsForty-seven women (aged 16–50) followed in a Reference Center for Liver Vascular Disease between February 2009 and November 2016 were included and addressed for gynecological and endocrinological management. Twenty-five women had extrahepatic portal vein obstruction, 17 had Budd Chiari Syndrome and five had a porto-sinusoidal vascular disease. We explored gonadotropin at baseline and after GnRH, testosterone, sex hormone binding globulin (SHBG), androstenedione, GH axis and glucose metabolism. All women underwent pelvic ultrasonography. ResultsVascular liver disease was associated with abnormal menstrual cycles in 53% of the women and clinical and/or biological hyperandrogenism and/or a polycystic ovary morphology was identified in 38%. Portal hypertension was correlated to higher testosterone levels (P = 0.04), whereas higher elevated levels SHBG in 28%, correlated with liver failure (P = 0.01). Sixteen had glucose intolerance profile or diabetes. IGF-1 levels were highly correlated with hepatic failure. Abnormal uterine bleeding occurred in 21% of women, 87% of which were due to gynecological pathologies revealed by anticoagulant treatment. Progestin contraception was well tolerated and helped to control bleeding. Conclusion and implicationsendocrine abnormalities, prior described in association with cirrhosis, are also identified in patients with vascular liver disease, and require specific management. Glucose intolerance profile is frequent, further studies are needed to assess significant consequences on cardio-vascular system.

Association of free androgen index and sex hormone-binding globulin and left ventricular hypertrophy in postmenopausal hypertensive women.

The aim of the present study was to explore the relationship between androgen and LVH in postmenopausal hypertensive women. Enrolled in this study were 378 postmenopausal hypertensive women who were admitted to the department of cardiology between December 2018 and December 2020. According to left ventricular mass index (LVMI) evaluated by echocardiography, the patients were divided into LVH group (n = 172) and non‐LVH group (n = 206). Their clinical characteristics were collected. Based on the result of propensity score matching analysis, 160 cases in each group were matched successfully. After correcting for confounding factors by various models, the results showed that free androgen index (FAI) and sex hormone–binding globulin (SHBG) were the influencing factors of LVH in postmenopausal women with hypertension. Patients with elevated SHBG were 5% less likely to develop LVH than those without elevated SHBG (OR: 0.950, 95% CI 0.922‐1.578). Postmenopausal hypertensive patients with elevated FAI were 16% more likely to have LVH than those without elevated FAI (OR: 1.608, 95% CI 0.807‐3.202). Multiple linear regression showed that LVMI increased by 61.82g/m2 for every 1 unit increase in FAI. In addition, SHBG decreased by 1 nmol/l, and LVMI increased by 0.177g/m2. Subgroup analysis showed that patients in the controlled BP group had a lower risk of LVH for every additional unit of SHBG compared with the uncontrolled BP group. The risk of LVH for each additional unit of FAI in the uncontrolled BP group was higher than that in the controlled BP group. The results of this present study showed that the occurrence of LVH was positively correlated with FAI and negatively correlated with SHBG in postmenopausal women with hypertension. The increase in FAI level and the decrease in SHBG level may be related to the occurrence and development of LVH in postmenopausal hypertension.

ThyrotropinomA: Diagnosing a Rare Cause of Hyperthyroidism

Case: The patient is a 40-year-old male who presented for evaluation of hyperthyroidism with symptoms including palpitations, increased bowel movements, anxiety, and worsening tremor. With a family history of Graves’ disease and an ultrasound showing a hyperemic thyroid, there was initial suspicion for Graves’ disease. Although a radioactive iodine thyroid scan showed diffuse uptake that was elevated, 21.4% at 4 hours and 33.1% at 24 hours, lab evaluation appeared inconsistent with Graves’ disease revealing: TSH 1.65 µU/mL (upper limit of normal [ULN] 4.5), free thyroxine (FT4) 1.99 ng/dL (ULN 1.17), free triiodothyronine 6.16 ng/dL (ULN 3.98), thyroid stimulating immunoglobulin 92% (ULN 122), and thyroid receptor antibodies less than 1.0 IU/L (ULN 1.75). Lab results were reproducible with elevated FT4 even by equilibrium dialysis at 3.9 ng/dL (ULN 2.4) and high-normal TSH with serial dilution that ruled out assay interreference. Given these findings, our focus turned to rare causes of hyperthyroidism including thyrotropinoma and thyroid hormone resistance (RTH). Unique to the diagnosis of thyrotropinoma is an elevated serum α subunit in 50-85% of cases (1). Therefore, we obtained an α subunit level which was 0.35 ng/mL (ULN 0.55) with a molar ratio of 2.2 (ULN 2.4). Since the α subunit level was normal, the patient obtained genetic testing for mutations in the thyroid hormone receptor β gene seen in 85% of RTH cases (1). However, no sequence variants were identified. Since initial lab and genetic analyses were undifferentiating, additional tests were obtained including an insulin-like growth-factor 1 level of 209 ng/mL (ULN 237) and prolactin level of 10.1 ng/mL (ULN 20) which can be elevated in 30% of mixed thyrotropinoma cases (1). The first evidence to suggest a thyrotropinoma was a mildly elevated sex-hormone binding globulin at 102 nmol/L (ULN 80). Further evaluation with pituitary magnetic resonance imaging showed a 6-milimeter lesion. Although the pituitary lesion is suggestive of a thyrotropinoma, it is not definitive, as they are present in 20% of RTH cases (1). Therefore, with increased suspicion of a thyrotropinoma, we pursued the more robust T3 suppression test which showed 56% suppression of TSH consistent with a thyrotropinoma. The patient had pituitary surgery with pathology confirming weak immunoreactivity for TSH. Post-operatively, his symptoms improved and free thyroid hormones normalized.Discussion: It is important to distinguish between thyrotropinoma and RTH as the treatment is different with 80% of thyrotropinoma cases achieving euthyroidism after surgery (1). In our case, the diagnosis was initially unclear thus it was important to broaden the lab and genetic evaluation considering the limitations of the studies. One such limitation is the α subunit may not be elevated in microadenomas as occurred in our case.1. Beck-Peccoz et al. J Endocrinol Invest. 2019; 42:1401-6

Impact of sex hormone-binding globulin on the human phenome.

Background: Sex hormone-binding globulin (SHBG) is a circulating glycoprotein and a regulator of sex hormone levels, which has been shown to influence various traits and diseases. The molecular nature of SHBG makes it a feasible target for preventative or therapeutic interventions. A systematic study of its effects across the human phenome may uncover novel associations. Methods: We used a Mendelian randomization phenome-wide association study (MR-pheWAS) approach to systematically appraise the potential functions of SHBG while reducing potential biases such as confounding and reverse causation common to the literature. We searched for potential causal effects of SHBG in UK Biobank (N = 334 977) and followed-up our top findings using two-sample MR analyses to evaluate whether estimates may be biased due to horizontal pleiotropy. Results: Results of the MR-pheWAS across over 21 000 outcome phenotypes identified 12 phenotypes associated with genetically elevated SHBG after Bonferroni correction for multiple testing. Follow-up analysis using two-sample MR indicated the associations of increased natural log SHBG with higher impedance of the arms and whole body, lower pulse rate, lower bone density, higher odds of hip replacement, lower odds of high cholesterol or cholesterol medication use and higher odds of gallbladder removal. Conclusions: Our systematic MR-pheWAS of SHBG, which was comprehensive to the range of phenotypes available in UK Biobank, suggested that higher circulating SHBG affects the body impedance, bone density and cholesterol levels, among others. These phenotypes should be prioritized in future studies aiming to investigate the biological effects of SHBG or develop targets for therapeutic intervention.

Sex Hormone-Binding Globulin Levels Are Inversely Associated With Nonalcoholic Fatty Liver Disease in HIV-Infected and -Uninfected Men.

BackgroundNonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Elevated sex hormone–binding globulin (SHBG) levels have been observed in the setting of HIV and may protect against some metabolic disorders. We aimed to investigate whether higher SHBG levels may protect against NAFLD in men with/without HIV.MethodsNAFLD was assessed using noncontrast computed tomography in 530 men in the Multicenter AIDS Cohort Study (MACS) who drank <3 alcoholic drinks/d and were uninfected with chronic hepatitis C or B (340HIV+, 190HIV-). Morning serum samples were tested for SHBG, total testosterone (TT), and adiponectin. Multivariable logistic regression was used to assess associations between HIV, SHBG, TT, adiponectin, and NAFLD.ResultsMedian SHBG was highest among HIV+/NAFLD- men and lowest among HIV-/NAFLD+ men. Adjusted for demographics, HIV, visceral adiposity, HOMA-IR, TT, and PNPLA3 genotype, higher SHBG was associated with lower odds of NAFLD (odds ratio [OR], 0.52 per doubling; 95% confidence interval [CI], 0.34–0.80). In separate multivariable models without SHBG, HIV (OR, 0.46; 95% CI, 0.26–0.79) and higher adiponectin (OR, 0.66 per doubling; 95% CI, 0.49–0.89) were associated with lower NAFLD odds, whereas TT was not significantly associated (OR, 0.74 per doubling; 95% CI, 0.53–1.04). Adjusting for SHBG attenuated the associations of HIV (OR, 0.61; 95% CI, 0.34–1.08) and adiponectin (OR, 0.74; 95% CI, 0.54–1.02) with NAFLD.ConclusionsSHBG levels were higher among HIV+ men, were independently associated with lower NAFLD, and could partially explain the associations of HIV and higher adiponectin with lower NAFLD in our cohort. These findings suggest that SHBG may protect against NAFLD, supporting further prospective and mechanistic studies.

Higher Serum Sex Hormone-Binding Globulin Levels Are Associated With Incident Cardiovascular Disease in Men.

Sex hormone-binding globulin (SHBG) levels are associated with cardiovascular disease (CVD) risk factors. However, prospective data on the association between SHBG levels and CVD events are sparse, with conflicting results. To examine associations between serum SHBG, total testosterone (TT), and incident CVD and CVD-related mortality in middle-aged to elderly men. Data on 2563 community-dwelling men (35 to 80 years) were obtained from participants in the Men Androgen Inflammation Lifestyle Environment and Stress cohort. The analytic sample included 1492 men without baseline (2002 to 2007) CVD and with fasted morning serum SHBG and TT available at both baseline and follow-up (2007 to 2010) and without medications affecting TT or SHBG. Associations of baseline SHBG and TT, with incident CVD and CVD mortality, were analyzed using logistic regression for incident CVD and Cox proportional hazard regression for CVD mortality, adjusting for established CVD risk factors. In multivariable models, elevated baseline SHBG and lower baseline TT were independently associated with incident CVD (SHBG: OR, 1.54; 95% CI, 1.15 to 2.06 per SD increase in SHBG, P = 0.003; TT: OR, 0.71; 95% CI, 0.52 to 0.97 per SD decrease in TT; P = 0.03). A decrease in TT between time points was associated with incident CVD (OR, 0.72; 95% CI, 0.56 to 0.92; P = 0.01). Neither SHBG nor TT was significantly associated with all-age CVD mortality [hazard ratio (HR), 0.69; 95% CI, 0.29 to 1.63; P = 0.40; and HR, 0.60; 95% CI, 0.28 to 1.26; P = 0.18, respectively]. Among all men and men >65 years, elevated SHBG and lower TT were independently associated with both a greater risk of CVD and an increased CVD mortality risk.

Genetic and observational evidence supports a causal role of sex hormones on the development of asthma

IntroductionMales have a higher prevalence of asthma in childhood, whereas females have a higher prevalence in adolescence and adulthood. The ‘adolescent switch’ observed between sexes during puberty has been hypothesised...