Gul Bahtiyar

Novel endocrine disrupter effects of classic and atypical antipsychotic agents and divalproex: induction of adrenal hyperandrogenism, reversible with metformin or rosiglitazone.

OBJECTIVE To ascertain an association between the a priori known insulin resistance caused by antipsychotic agents and divalproex and adrenal hyperandrogenism and to determine whether the associated hyperandrogenism is reversible with insulin sensitizers. METHODS We studied 26 consecutive psychiatric inpatients (22 women and 4 men) receiving the aforementioned medications, who were referred to us for a consultation. They ranged in age from 19 to 79 years and had a mean body mass index (SEM) of 32.35 +/- 1.26 kg/m2. Between 8 AM and 9 AM, blood samples were collected for 17-hydroxyprogesterone, 17-hydroxypregnenolone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, 11-deoxycortisol, luteinizing hormone and follicle-stimulating hormone (in reproductive age women), estrone, estradiol (in reproductive age women), free testosterone (in women), deoxycorticosterone, and sex hormone-binding globulin (SHBG), which were measured by radioimmunoassay, after chromatography if necessary. For intact, premenopausal women, measurement of the abnormal steroid metabolite or SHBG level was repeated during prednisone therapy (5 mg at bedtime) to document the likely adrenal origin of the abnormality. Men, women who had undergone bilateral oophorectomy, and postmenopausal women had hyperandrogenism of adrenal origin by default. Clinical features included central obesity, acanthosis, hirsutism, alopecia, type 2 diabetes mellitus, and oligomenorrhea. RESULTS We found reversed estrone/estradiol ratios in 4 patients, decreased SHBG in 4, increased 17-hydroxy-pregnenolone in 8, increased 17-hydroxyprogesterone in 2, increased deoxycorticosterone in 2, increased DHEA sulfate in 1, increased 11-deoxycortisol in 4, increased androstenedione in 1, and reversed ratios of luteinizin hormone to follicle-stimulating hormone in 2. The bio-chemical abnormalities were corrected in 8 of 8 patients receiving metformin and in 2 of 2 patients receiving rosiglitazone. CONCLUSION Insulin resistance caused by antipsychotic agents and divalproex is associated with adrenal hyperandrogenism. Metformin and rosiglitazone correct the biochemical abnormalities detected without compromising their psychotropic effect. Adrenal androgen synthesis may be increased by hyperinsulinemia-induced hyperphosphorylation of P450c17 alpha, resulting in an increase in its 17,20-lyase activity, which magnifies the effects of any distal steroidogenic enzyme defects. Treatment with metformin or rosiglitazone prevents excess adrenal androgen synthesis.

Diabetes and bone health.

The increasing prevalence of diabetes especially type 2 diabetes worldwide is indisputable. Diabetics suffer increased morbidity and mortality, compared to their non-diabetic counterparts, not only because of vascular complications, but also because of an increased fracture incidence. Both types 1 and 2 diabetes and some medications used to treat it are associated with osteoporotic fractures. The responsible mechanisms remain incompletely elucidated. In this review, we evaluate the role of glycemic control in bone health, and the effect of anti-diabetic medications such as thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists. In addition, we examine the possible role of insulin and metformin as anabolic agents for bone. Lastly, we identify the current and future screening tools that help evaluate bone health in diabetics and their limitations. In this way we can offer individualized treatment, to the at-risk diabetic population.

Identifying prediabetes – Is it beneficial in the long run?

The rates of long-term diabetes related complications have declined substantially over the past decade. On the contrary, the growth in the incidence of prediabetes is note-worthy - especially in the population 60 years and above. As a result, the focus is now shifting toward early identification and prevention of diabetes. Prediabetes is a high risk state in the continuum of glycemic progression and beta cell dysfunction toward the development of diabetes mellitus. Observational studies have shown association of prediabetes with increased incidence of vascular complications. Long-term prospective randomized clinical trials across the globe have demonstrated a reduction in progression of prediabetes when lifestyle modifications are adopted and these effects can last up to 20 years beyond the period of intervention. While there has been recent interest in using pharmacotherapy for diabetes prevention, they have not been shown to be superior to lifestyle changes. This review hopes to provide a concise summary for the interested reader.

METfORMIN-REsPONsIVE ClAssIC sAlT-lOsINg CONgENITAl ADRENAl HyPERPlAsIA DuE TO 21-HyDROxylAsE DEfICIENCy: A CAsE REPORT

OBJECTIVE To study the effect of adding metformin to standard steroid replacement therapy in a patient with classic salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency with suboptimal biochemical and clinical control. METHODS We present the clinical and laboratory findings before and after the addition of metformin to the therapeutic regimen of the study patient. RESULTS A 17-year-old girl had been diagnosed as a neonate with classic salt-losing congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CYP21A2 deficiency). She was treated with hydrocortisone, 20 mg in the morning and 10 mg at bedtime, and fludrocortisone, 50 mcg daily. While on steroid replacement, she maintained normal serum electrolytes, glucose, blood pressure, and external genitalia, but she continued to express clinical features of obesity, hirsutism, amenorrhea, and acanthosis nigricans. Elevated laboratory measurements included the following: fasting 17-hydroxyprogesterone, 3410 ng/dL; total testosterone, 326 ng/dL; and androstenedione, 390 ng/dL. She was initiated on metformin, 500 mg twice daily after meals. After 3 months, the patient lost 2 kg, amenorrhea resolved, 17-hydroxyprogesterone decreased to 1539 ng/dL, total testosterone decreased to 163 ng/dL, and androstenedione levels remained unchanged. CONCLUSIONS Metformin, an agent known to reduce insulin resistance, further suppressed the 17-hydroxyprogesterone concentration in a patient with classic congenital adrenal hyperplasia on steroid replacement therapy. Metformin may improve clinical and biochemical outcomes in classic congenital adrenal hyperplasia without the risk of iatrogenic Cushing syndrome.

Ashwagandha root in the treatment of non-classical adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is a well-characterised family of disorders of the adrenal cortices, resulting in varying degrees of cortisol, aldosterone and androgen deficiency or androgen excess, depending on the enzyme(s) affected and the degree of quantitative or functional enzyme deficit. Withania somnifera (WS), commonly known as Ashwagandha, is a medicinal plant that has been employed for centuries in ayurvedic medicine. Preclinical studies have shown that WS increases circulating cortisol levels and improves insulin sensitivity. We report the case of a 57-year-old woman with non-classical adrenal hyperplasia due to both 3-β-ol dehydrogenase deficiency and aldosterone synthase deficiency who was self-treated with WS for 6 months. After 6 months of treatment her serum 18-OH-hydroxycorticoserone, 17-OH-pregnenolone, corticosterone and 11-deoxycortisol decreased by 31%, 66%, 69% and 55%, respectively. The biochemical improvement was accompanied by a noticeable reduction in scalp hair loss.

Roux-en-Y gastric bypass in the treatment of non-classic congenital adrenal hyperplasia due to 11-hydroxylase deficiency

Non-classic adrenal hyperplasia (NCAH) has been associated with insulin resistance (IR). Therapies such as metformin, thiazolidinediones and lifestyle alterations improve IR and also ameliorate the biochemical and clinical abnormalities of NCAH, much as they do in polycystic ovarian syndrome (PCOS). More recently, bariatric surgery, such as Roux-en-Y gastric bypass (RYGBP), has also been associated with improvement in IR and amelioration of PCOS and may, therefore, be beneficial in NCAH. We report a case of a 39-year-old, deaf-mute, obese woman with NCAH due to 11-hydroxylase deficiency who underwent RYGBP followed by improvement of NCAH manifestations. She was initially treated with metformin and pioglitazone, which lowered serum 11-deoxycortisol from 198 ng/dl (<51) to 26 ng/dl. Five weeks after undergoing RYGBP her body mass index fell from 44.18 kg/m2 to 39.54 kg/m2 and, despite not taking metformin or pioglitazone, serum 11-deoxycortisol remained normal at <40 ng/dl. Concurrently and subsequently, her NCAH symptoms, for example, alopecia, hirsutism and irregular menses normalised as well. We conclude that RYGBP, like other interventions that reduce IR, may be another way of treating non-classic 11-hydroxylase deficiency in selected patients.

Effects of sliding scale insulin use on glycemic control and length of stay in hospitalized patients with Type 2 diabetes mellitus

Objectives: To assess the effect of sliding scale insulin (SSI) use on glycemic control and length of hospital stay in patients with diabetes mellitus. Methods: A prospective cohort study of 182 patients with diabetes mellitus as a primary diagnosis or a comorbid condition admitted consecutively to the internal medicine wards over a 6-week period. Demographic, clinical and laboratory data were collected from in-patient medical records. Data were analyzed using Chi-square and independent t-tests and presented as the mean ± standard error of the mean. Results: Of the total 182 in-patients with Type 2 diabetes, 130 (71.4%) were placed on SSI (Group A) and 52 (28.6%) on standing-dose antihyperglycemic therapy without the use of SSI (Group B). While there was no difference in admission blood glucose values (mg/dl) between Group A (236 ± 14.3) and Group B (237 ± 6.4), higher average in-hospital fasting blood glucose values were recorded from Group A (168 ± 7.2) compared with Group B (139 ± 11.5), p = 0.04. Plasma glucose values at discharge were not significantly different between the two groups with an average of 172 ± 8.1 for Group A and 170 ± 18.1 for Group B. Also, there was no significant difference in the number of days of hospitalization between the two groups with an average of (7.6 ± 0.89) for Group A and (10 ± 4.7) for Group B. Conclusion: SSI use is associated with higher in-hospital blood glucose and does not offer any advantage in terms of duration of hospital stay as compared with standard-dose antihyperglycemic therapy.

Effect of raloxifene in human neurocysticercosis

The authors report a patient whose polycystic ovarian syndrome (PCOS) and increased calcitriol level were associated with neurocysticercosis (NCC), for which she refused standard therapy. Based upon a report on treatment with tamoxifen in murine cysticercosis,1 she was offered raloxifene. She began raloxifene 60 mg/day on 21 January 2010. On 17 March 2010 she was pregnant, and was terminated on 14 April 2010. MRI 26 April 2010 showed diminution in size, shrinkage and loss of viability in a number of the cysts. Total lesions fell from 37 to 33, 10 lesions shrunk, 5 resolved, 18 were unchanged, 4 enlarged and 1 new lesion developed. Concomitantly serum calcitriol fell from 81 to 41 pg/ml while 25-OH-vitamin D level fell from 34 to 30 ng/ml. Alteration of the hormonal milieu may reduce cestode burden in human NCC. The pregnancy on raloxifene, though unfortunate, supports the concept that NCC caused the PCOS. Serum calcitriol may be a useful biomarker for assessing disease activity in NCC.

1- α hydroxylation defect in postural orthostatic tachycardia syndrome: remission with calcitriol supplementation

A 37-year-old woman presented with a history of reactive hypoglycaemia, non-classic adrenal hyperplasia (NCAH), osteopenia and fibromyalgia. After several months of palpitations, postural orthostatic tachycardia syndrome (POTS) was diagnosed by tilt table studies. Her heart rate (HR) reached 191 bpm at 60 degrees from horizontal. Investigation suggested increase in epinephrine and norepinephrine levels in response to tilt table. Her 25(OH) vitamin D level measured by immunoextraction radioimmunoassay was 35 pg/ ml (normal 9–54 pg/ml) while her 1,25(OH)2 vitamin D3 level was 24 pg/ml (normal 30–67 pg/ml). Accordingly, she was started on calcitriol 0.25 mcg orally daily. At her next visit after 5 months, she reported remarkable improvement in her palpitations and had been working full time for the past 4 months. HR both seated and upright was 72 bpm. After 3 months, her 1,25(OH)2 vitamin D3 level on calcitriol was 40 pg/ml. The authors suggest that 1-α hydroxylation defects should be sought and treated, if present, with calcitriol in patients with POTS.

Possible ACTH-independent, cortisol-secreting and DHEA-secreting metastatic hepatocellular carcinoma causing Cushing’s syndrome

Cortisol production by hepatocellular carcinoma (HCC) has not been previously reported and dehydroepiandrosterone (DHEA) secretion by HCC is rare. We report a case of a 53-year-old woman admitted with dyspnoea and headache. Serum cortisol by immunoassay (IA) was 42.3 μg/dL, urine free cortisol (UFC) by liquid chromatography mass spectrometry (LC/MS/MS) was 106.1 μg/24 h, serum DHEA by LC/MS/MS was 4886 ng/mL, serum DHEA-S by LC/MS/MS was 4477 ng/mL and plasma adrenocorticotrophic hormone (ACTH) by IA was 10 pg/mL. CT showed likely HCC metastatic to the left adrenal gland, brain and lungs. Liver and adrenal gland biopsies confirmed HCC. ACTH tumour staining was negative. High serum and UFC levels and high serum DHEA and DHEA-S with low-normal plasma ACTH and negative tumour ACTH staining suggested ACTH-independent ectopic Cushings syndrome (CS); cortisol and DHEA being likely secreted by the HCC. To the best of our knowledge, this is the first reported case of HCC associated with CS.