Alan Sacerdote

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.

Oral Contraceptives Abolish Luteal Phase Exacerbation of Hyperglycemia in Type I Diabetes

For some time it has been recognized that postovulatory exacerbation of hyperglycemia contributes to the instability of diabetes in many women of reproductive age. It has been suggested that increasing plasma levels of progesterone and estrogen may induce insulin resistance and consequently lead to increased hyperglycemia during the luteal phase of the menstrual cycle. Due to the fact that menstrual cycles in a given woman may vary in length and that it takes patients several days on intermediate or long-acting insulin to achieve a steady state with regard to any dosage adjustment, it is difficult to design an insulin regimen that maintains euglycemia throughout the menstrual cycle in these labile patients. Recognition of this problem led to trying a nonsequential low estrogen contraceptive as adjunctive therapy in a 20-year old woman with insulin dependent diabetes mellitus. The patient consistently suffered an exacerbation of hyperglycemia after ovulation in each cycle, lasting until the onset of menses. On 1 occasion the patient developed frank diabetic ketoacidosis. For the first 2 cycles on Lo Ovral, the hyperglycemia was postponed from the 1st postovulatory day until day 18-19 of the cycle. It was reasoned that the serum estrogen and/or progestin level might be building cumulatively, and the oral contraceptives (OCs) were subsequently withdrawn at day 19 of the cycle rather than day 21. A maximum blood glucose level of 400 mg/dl was attained at day 19 and was treated with additional regular insulin. Levels in excess of 240 mg/dl did not recur during that cycle. The following cycle OC therapy was interrupted at day 18; no blood glucose level in excess of 240 mg/dl occurred that month. Hemoglobin A1c fell from a pre-OC treatment value of 12.4% to the current A1c of 9.7%. A modest increase in blood pressure has occurred, but this is easily managed with a 2 g sodium diet and 25 mg of hydrochlorothiazide daily. On the basis of this experience, a controlled trial is warranted of low dose estrogen nonsequential OCs in lean, nonsmoking, 18-30 year old women with insulin dependent diabetes mellitus with postovulatory hyperglycemia.

Adrenal Androgens and NIDDM

With the recent publication of the Diabetes Control and Complications Trial (1), the implementation of intensive control in type I diabetes has become an imperative. One method of achieving such control is the administration of three pre-meal doses of regular insulin on a sliding scale basis with a bedtime dose of NPH insulin. We have developed a formula for calculating the dose of pre-meal regular insulin that can provide a quick and consistent method for glycemic regulation.

Cardiac tamponade as a presenting manifestation of severe hypothyroidism

We report a patient who presented to our hospital with unusual symptoms of non-specific complaints and uncontrolled hypertension. Acute cardiac tamponade was suspected from cardiomegaly on routine chest x-ray and confirmed with an echocardiogram. Analysis of the pericardial fluid and other laboratory data ruled out all the common causes except for hypothyroidism as a cause of cardiac tamponade. Tamponade results from increased intrapericardial pressure caused by the accumulation of pericardial fluid. The rapidity of fluid accumulation is a greater factor in the development of tamponade than absolute volume of the effusion. Hypothyroidism is a well-known cause of pericardial effusion. However, tamponade rarely develops owing to a slow rate of accumulation of pericardial fluid. The treatment of hypothyroidic cardiac tamponade is different from other conditions. Thyroxine supplementation is all that is necessary. Rarely, pericardiocentesis is needed in a severely symptomatic patient.

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.

Topical Clonidine and Diabetic Gastroparesis

Excerpt To the Editor:Since my initial report on the use of topical clonidine to treat diabetic diarrhea (1) (based on experimental work by Chang and associates [2] and a clinical report of their u...

Urticaria as a sign of hypoglycemia.

REFERENCES 1. Bergman M, Felig P: Self-monitoring of blood glucose levels in diabetes. Arch Intern Med 144:2029-34, 1984 2. Carney R, Schechter K, Homa M, Levandowski L, White N, Santiago J: The effects of blood glucose testing versus urine sugar testing on the metabolic control of insulin-dependent diabetic children. Diabetes Care 6:378-80, 1983 3. Morris L, McGee J, Kitabchi A: Correlation between plasma and urine glucose in diabetes. Ann Intern Med 94:469-71, 1981 4. American Diabetes Association: Self-monitoring of blood glucose. Diabetes Care 8:515, 1985

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.