Sang Min Lee, et al : Cushing’s Syndrome Presenting as Endometrial Hyperplasia 51 marginated mass in the left adrenal gland (Figure 2). The patient was diagnosed as a cortisol-producing adrenal adenoma and she underwent a left adrenalectomy. During the 10-months follow-up, her hormonal laboratory tests were 24-h urine free cortisol: 45.9 μg/24h, serum ACTH: 61.9 pg/dL and serum cortisol: 15.3 μg/dL. The serum estrone and estradiol levels were 38.00 pg/mL and 40.45 pg/mL, respectively, and the 24-h urine free estrone and free estradiol levels were 2.0 μg/24h and 1.1 μg/24h, respectively. The E1/E2 ratios in the serum and the 24-hour urine were 0.9 and 1.8, respectively. She showed a gradual and unintentional loss of 9 kg of body weight. Her waist to hip ratio was decreased from 0.90 to 0.78, and she regained regular menstrual cycles. Her blood pressure was well controlled by a half dose of the previous medication after adrenalectomy. Endometrial hyperplasia, as determined by ultrasonography, was not seen thereafter. DISCUSSION The patient in this case was referred to us for the evaluation of the recurrent endometrial hyperplasia that was not resolved by repeated therapeutic curettage and progestin treatment for 2 years, and she was finally diagnosed with a cortisol-producing adenoma. After left adrenalectomy, her uterine lesion and menstrual abnormality completely resolved, and she experienced unintentional weight loss. Patients with Cushing's syndrome almost always show insulin resistance that's attributable to chronic hypercortisolism, which is frequently accompanied by metabolic syndrome and PCOS, and rarely by endometrial hyperplasia2). It is known that PCOS and anovulatory cycles can be caused by insulin resistance. In addition, it has been suggested that menstrual irregularity might result from hypercortisolemic inhibition of gonadotrophin release at the hypothalamic level rather than being caused by elevated levels of circulating androgen3, 4). It was proposed that hypercortisolemia could suppress pulsatile LH secretion by inhibiting pituitary respon- siveness to gonadotropin-releasing hormone (GnRH)5). However, the mechanisms of the occurrence of endometrial hyperplasia in these patients are poorly understood, and to the best of our knowledge, there are no other cases in the literature of Cushing's syndrome presenting as endometrial hyperplasia. Although our patient presented with metabolic syndrome and minor bruising, these signs were not accompanied by any obvious clinical features of Cushing's syndrome. Although we confirmed chronic anovulation and Cushing's syndrome in this patient, an inappropriately low level of serum estradiol had been found by a local clinic 2 years prior to her referral, suggesting hypogonadotrophic hypogonadism as the cause of her menstrual disturbance, which was in contrast to the elevated LH levels that are usually observed in patients with PCOS. Continuously elevated cortisol inhibits the activity of 17 beta-hydroxysteroid dehydrogenase and it might prohibit the action of progesterone in the uterus as well as the secretion of GnRH from the thalamus6). In this patient, these hormonal changes finally resulted in a functional and absolute pro- gesterone deficiency and recurrent endometrial hyperplasia, irrespective of repetitive curettage and progestin treatment. Given that the cortisol receptor has not been demonstrated in the uterine stromal or endometrial cells, the possibility seems remote that chronic excess cortisol alone induced the endometrial hyperplasia. Rather, based on the fact that both insulin receptors and IGF-1 receptors are expressed in endometrial cells7, 8), we suggest that the hyperinsulinemia induced by excess cortisol in this patient could have been an additive factor for the development of endometrial hyperplasia. It has been suggested that insulin resistance or hyperinsulinemia in patients with PCOS increases the production of androgens in the theca cells and this augments aromatase activity in adipocytes, thereby increasing the conversion to estrone and the LH level. Our patient showed an elevated E1/E2 ratio in both the serum and urine (2.4 and 1.7, respectively), indicating increased production of estrone in the peripheral tissues. In contrast, the androgen and LH determinations in her serum revealed a low estrogen level that was attributable to the inhibitory effects of hypercortisolemia on the thalamus and ovaries. Our patient presented with chronic anovulation and endometrial hyperplasia, and she was found to have Cushing's syndrome; she experienced complete resolution of her uterine lesion and cardiometabolic abnormalities after removal of a left adrenal tumor. This case demonstrates the necessity of performing endocrine tests, including urinary free cortisol measurements, in young women with endometrial hyperplasia and anovulation even when these patients do not show the typical features of Cushing's syndrome. REFERENCES 1) Ross NS. Epidemiology of Cushing’s syndrome and subclinical disease. Endocrinol Metab Clin North Am 23:539-546, 1994 2) Kaltsas GA, Korbonits M, Isidori AM, Webb JA, Trainer PJ, Monson JP, Besser GM, Grossman AB. How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing’s syndrome? Clin Endocrinol 53:493-500, 2000 3) Dubey AK, Plant TM. A suppression of gonadotropin secretion by cortisol in castrated male rhesus monkeys (Macaca mulatta) mediated by the interruption of hypothalamic gonadotropin-releasing hormone release. Biol Reprod 33:423-431, 1985 4) Breen KM, Billings HJ, Wagenmaker ER, Wessinger EW, Karsch FJ. Endocrine basis for disruptive effects of cortisol on preovulatory events. Endocrinology 146:2107-2115, 2005