SUN-026 Unusual Presentation of Aromatase Excess Syndrome

Introduction: Aromatase excess syndrome is a rare disorder with gynecomastia being the main symptoms. Its prevalence is unknown with approximately twenty cases reported. We describe an unusual case of Aromatase excess syndrome. It was diagnosed incidentally at a much older age than expected while evaluating for hypersomnia. Case presentation: A 28 year old male with no significant past medical history, presented with complaint of hypersomnolence, developed during puberty. He had multiple evaluations with no apparent etiology; sleep study and all his other laboratory tests were normal including testosterone levels, normal IGF-1 and cortisol. When patient was evaluated in the Endocrine clinic, he was found to have bilateral gynecomastia, which he had for many years. His estradiol was 150 pg/ml (Normal <50 pg/ml). Repeat was 137 pg/ml with normal DHEA-S Subsequent concomitant estradiol of 204 pg/ml with an estrone of 35.7 pg/ml (9–36). Total testosterone was normal at 588 ng/dl. Evaluation for a tumor with abdominal CT, testicular ultrasound, and HCG was negative. As his symptoms of fatigue and hypersomnolence were not improving and his estradiol to testosterone ratio was >10, he was started on an aromatase inhibitor and his ratio dropped from 1:40 to 1:24, as his estradiol went down to 75 pg/ml. Discussion: Gynecomastia is the benign proliferation of breast tissue due to imbalance between estrogen and testosterone. It could be caused by medications or medical illnesses. Occasionally its presence can harbor a serious endocrine issue especially if presenting in the prepubertal period. Thus, evaluation is often necessary. Among the pathological causes is the Aromatase excess syndrome. In this syndrome there are three types of cryptogenic genomic rearrangements identified. Those rearrangement affect the aromatase gene CYP19 and results in gain of function of the aromatase enzyme. Patients will have high estradiol and estrone level, lower FSH and LH levels that will normalize after treatment with aromatase inhibitor. Their testosterone levels could be low or normal. For the clinical diagnosis, there are four criteria; bilateralgynecomastia, pre or peripubertal onset, exclusion of other causes of gynecomastia and having a genetic trait. The first three criteria are indispensable for diagnosis while fourth one is not obligatory, but rather pathognomonic. An elevated estradiol to testosterone ratio above 1:10 is a supportive finding, as well as having a low FSH with low to normal LH. Genetic identification of the CYP19 A1 mutation remains the definitive method of diagnosis. Our patient met the first three criteria and also had estradiol to testosterone ratio is > 1:10. Genetic confirmation is challenging. Consequently, whole genome sequencing may be required. Though unusual, this case highlights the importance of looking deep in the differential when evaluating gynecomastia.

The condition of the hypothalamic-pituitary-adrenal-ovarian system in women with tumors and tumoral formations of the organs of the reproductive system in the postmenopausal period

The objective: of the study was to study the state of the hypothalamic-pituitary-adrenal-ovarian system in women with benign preinvasive and tumor-like formations of the reproductive system organs in the postmenopausal period. Materials and methods. 130 women with various tumors and tumoral formations of reproductive system organs in the postmenopausal period were examined. The parameters of follicle stimulating, luteinizing hormones, estradiol, estrone, prolactin, progesterone, testosterone, dehydroepiandosterone sulfate were studied. Results. It was established that out of 130 women with various tumors and tumoral formations of the organs of the reproductive system in the postmenopausal period, uterine myoma was defined in 39 (39%), endometrial hyperplasia in 23 (17.7%), tumor-like formation of ovaries in 17 (13.1%). It was found that in the postmenopausal period, the presence of hyperandrogenia, hyperprolactinemia, and a significant increase in the level of estrone were noted in women with benign, preinvasive and tumor-like formations of the organs of the reproductive system, regardless of tumor origin. Conclusion. The obtained results allowed to conclude that in the postmenopausal period the presence of uterine fibroids, endometrial hyperplasia and ovarian tumor formation is accompanied by hyperprolactinemia, hyperandrogenism and hyperestrogenism due to an increase in estrone level. Key words: postmenopausal period, uterine myoma, endometrial hyperplasia, tumor-like formations, hyperandrogenia, hyperprolactinaemia, estrone.

Post-Treatment Change in Serum Estrone Predicts Mammographic Percent Density Changes in Women Who Received Combination Estrogen and Progestin in the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial

Purpose Postmenopausal estrogen and progestin therapy (EPT) increases mammographic percent density and breast cancer risk substantially more than does estrogen therapy alone. We determined whether increases in serum estrone as a function of treatment predict increases in mammographic percent density. Methods We measured mammographic percent density and serum estrone levels in participants in the Postmenopausal Estrogen/Progestin Interventions Trial who were randomly assigned to receive conjugated equine estrogens (CEE) 0.625 mg/d; CEE and medroxyprogesterone acetate (MPA) 10 mg on days 1 to 12 per 28-day cycle; CEE and MPA 2.5 mg/d; or CEE and micronized progesterone (MP) 200 mg on days 1 to 12 per 28-day cycle. We used linear regression to determine whether serum estrone changes predicted mammographic percent density changes from baseline to 1 year. Results Mammographic percent density increased with increasing change in estrone level in the EPT groups, but not in the CEE group. Combined, the mammographic percent density in the three EPT groups demonstrated an absolute increase of 2.95% per 100 pg/mL increase in serum estrone level (P = .0003). The absolute increases were 4.09% (P = .0018) in the CEE + MPA continuous group, 2.79% (P = .0292) in the CEE + MPA cyclical group, and 1.40% (P = .36) in the CEE + MP group, but the differences among the EPT groups were not statistically significant. Conclusion Greater increase in serum estrone level as a function of treatment is a significant predictor of increase in mammographic percent density in women randomly assigned to the combination of estrogen and progestin.

Histamine-induced paradoxical GH response to TRH/GnRH in men and women: Dependence on gonadal steroid hormones

A stimulatory GH response to TRH and GnRH occurs frequently in patients with various pathological conditions, but is absent in normal subjects. We have previously shown that histamine induced a paradoxical GH response to TRH in normal men. Since gonadal steroids influence GH secretion, we investigated whether infusion of histamine might induce a GH response to combined administration of TRH (200 μg) and GnRH (100 μg) in 6 normal women during the early follicular and luteal phase of the same menstrual cycle and in 7 normal men. Histamine had no effect on basal GH secretion in men or in women during the two phases of the menstrual cycle. However, compared with saline, histamine induced a GH response to TRH/GnRH in men (GH peak: 5.5 ± 1.0 vs 1.4 ± 0.3 μg/l; p<0.01) and in women during the luteal phase (GH peak: 5.2 ± 1.6 vs 1.5 ± 0.4 μg/l; p<0.025), but not during the early follicular phase of the cycle (GH peak: 1.7 ± 0.5 vs 1.6 ± 0.3 μg/l). In luteal-phase women the GH response to TRH/GnRH correlated with the serum estradiol-17β level (GH area/E2: r=0.98; p<0.005) and the serum estrone level (GH area/E1: r=0.81; p<0.05). In men the GH response to TRH/GnRH did not correlate with estrogen or androgen levels. We conclude that high physiological levels of estrogens are pertinent to the activation of a histamine-induced GH response to TRH/GnRH in women, whereas the role of androgens and estrogens for the induction of the response in men seems more complex. Furthermore, the study indicates that histamine may increase the sensitivity of GH release to nonspecific stimuli.