Síndrome de insensibilidad a andrógenos: revisión bibliográfica a propósito de 5 casos / Androgen insensitivity syndrome: literature review about 5 cases

El síndrome de insensibilidad a andrógenos (AIS en la sigla inglesa) es una entidad muy poco frecuente en endocrinología. Se caracteriza por la mutación del receptor de andrógenos de magnitud variable, por medio del cual individuos 46,XY no se virilizan normalmente, a pesar de conservar sus testículos y tener concentraciones de testosterona en rango masculino. El cuadro clínico es variable y depende la profundidad de la alteración del receptor. En un extremo, hay casos de insensibilidad androgénica completa (CAIS) con fenotipo femenino. En el otro extremo hay insensibilidad parcial (PAIS) que se extiende desde el fenotipo femenino, con o sin ambigüedad genital, hasta los casos de hombres infértiles o con subvirilización, que presentan insensibilidad androgénica más leve. En los fenotipos femeninos, los testículos suelen estar en posición ectópica y aquellos ubicados dentro del abdomen tienen riesgo de malignizarse, por lo que suelen extirparse. Estos son los casos de más difícil manejo, pues aparte de la necesidad de gonadectomía seguida de terapia hormonal femenina, existe una vagina estrecha y en fondo de saco ciego y que suele requerir corrección quirúrgica para permitir la actividad sexual. En este trabajo presentamos 5 casos de AIS vistos recientemente en 2 centros clínicos de Santiago y que ilustran la heterogeneidad de presentación. Además, hacemos una revisión actualizada de los criterios diagnósticos, los tratamientos más adecuados y el manejo global de esta condición.

The Androgen insensitivity syndrome (AIS, in its English acronym) is a very rare entity in endocrinology. It is characterized by a variable magnitude androgen receptor mutation, whereby 46, XY individuals are not normally virilized, despite retaining their testicles and having testosterone concentrations in the male range. The clinical picture is variable and depends on the depth of the receptor alteration. At one extreme, there are cases of complete androgenic insensitivity (CAIS) with a female phenotype. At the other extreme, there is partial insensitivity (PAIS) that extends from the female phenotype, with or without genital ambiguity, to cases of infertile or undervirilized men, who have milder androgenic insensitivity. In female phenotypes, the testes are usually in an ectopic position and those located within the abdomen are at risk of malignancy, and therefore are usually removed. These are the most difficult cases to manage because apart from the need for gonadectomy followed by female hormonal therapy, there is a narrow vagina and a deep blind pouch that usually requires surgical correction to allow sexual activity. In this work, we present 5 cases of AIS recently seen in 2 clinical centers in Santiago and that illustrate the heterogeneity of presentation. In addition, we make an updated review of the diagnostic criteria, the most appropriate treatments, and the overall management of this condition.

Macroadenoma cervical palpable: Una presentación muy inusual de hiperparatiroidismo primario / Cervical macroadenoma causing hyperparathyroidism: Report of one case

We report a 59-year-old man with a history of hypertension, recurrent renal stones and a severe hypercalcemia of 14.9 mg/dl with a serum phosphorus of 2.4 mg/dl and a serum albumin of 3.6 g/dl. Physical examination showed a 4 cm left cervical nodule, consistent with the diagnosis of thyroid nodule. Parathyroid hormone (PTH) levels were 844 pg/mL (normal 15-65 pg/ml) and a cervical ultrasound examination disclosed a solid nodule in the lower left lobe of 40 x 30 x 25 mm, adjacent to the thyroid parenchyma. Abdominal ultrasound revealed bilateral renal stones. Parathyroid scintigraphy showed a high uptake of the left lower parathyroid mass and a bone densitometry showed bone density t scores of -1.2 in the spine, -2.0 in the right femoral neck and -3.5 in the distal radius. A review of his medical record revealed the presence of hypercalcemia for at least 4 years. He was admitted for hydration and administration of 4 mg zoledronic acid iv. At 24 hours, serum calcium dropped to 11.0 mg/dl, and a left thyroid lobectomy was performed including the lower left parathyroid gland. The pathology report showed a 22.6 g parathyroid adenoma. Intraoperatory PTH descended > 50%, consistent with successful parathyroidectomy. At 7 days after surgery serum calcium was 8.8 mg/dl, phosphorus 2.1 mg/dl, alkaline phosphatase 166 U/L, albumin 3.9 g/dL, PTH 230 pg/ml and 25-OH vitamin D 12.4 ng/ml. This finding was interpreted as secondary hyperparathyroidism due to vitamin D deficiency and “hungry bone”, being less likely the presence of residual or metastatic parathyroid tissue. A cholecalciferol load was administered, with significant descent of PTH.

Hiperandrogenismo avanzado en una mujer postmenopáusica: Caso clínico / Virilization caused by an ovarian tumor: Report of one case

We report a 76-year-old woman with a virilization syndrome characterized by progressive androgenic alopecia, clitoris enlargement and hirsutism predominating in the face. Plasma testosterone was 711 ng/dl. Magnetic resonance imaging showed slightly enlarged ovaries with a cyst in the left. A bilateral oophorectomy was performed, demonstrating the presence of a Leydig cell hilar tumor in the right ovary. The patient had a good postoperative evolution with reduction of androgen levels and reversion of alopecia.

Miopatía grave de curso agudo en un paciente con hipotiroidismo reciente y asintomático / Severe myopathy in a hypothyroid patient: report of one case

Diffuse muscular involvement is common in hypothyroidism and ranges from asymptomatic elevation of creatine kinase levels to severe muscle weakness and rhabdomyolysis. We report a 74 years old male that developed a progressive muscle weakness without muscle pain, during the course of an hypothyroidism secondary to a silent thyroiditis. Laboratory showed a TSH of 149 uUI/ml, a thyroxin of 1.5 ug/dl a free thyroxin of less than 0.15 ng/dl and a creatine kinase of 4345 U/l. Treatment with levothyroxine rapidly reverted the muscular alterations.

El tejido graso como modulador endocrino: cambios hormonales asociados a la obesidad / Adipose tissue as an endocrine modulator: hormonal changes associated with obesity

Adipose tissue not only stores fat, but secretes factors and hormones, which modify the regulation, metabolism and secretion of several other hormones. The objective of this review is to describe the hormonal disorders associated with increased adipose tissue, which acts as a modulator or disruptor of the endocrine physiology, with special reference to cortisol, androgens, growth hormone and thyroid axis, and discuss the implications for the management and treatment of these patients.

El tejido graso como modulador endocrino: Cambios hormonales asociados a la obesidad / Adipose tissue as an endocrine modulator: Hormonal changes associated with obesity

Adipose tissue not only stores fat, but secretes factors and hormones, which modify the regulation, metabolism and secretion of several other hormones. The objective of this review is to describe the hormonal disorders associated with increased adipose tissue, which acts as a modulator or disruptor of the endocrine physiology, with special reference to cortisol, androgens, growth hormone and thyroid axis, and discuss the implications for the management and treatment of these patients.

Alta frecuencia de patología tiroidea funcional y autoinmune en mujeres embarazadas chilenas catalogadas como sanas / High frequency of functional and autoimmune thyroid disease in women classified as healthy Chilean pregnant

Background: Untreated functional thyroid diseases are a risk factor for maternal and fetal complications during pregnancy. Aim: To determine the frequency of functional or autoimmune thyroid disease in healthy women during the first trimester of pregnancy. Subjets and Methods: healthy pregnant women attending a routine consult during their first trimester of pregnancy were studied. Thyroid stimulating hormone (TSH), total and free thyroxin (T4) anti-thyroid peroxidase (TPO) antibodies and spot urine iodine levels were measured. The reference ranges provided by the Atlanta Georgia Consensus in 2004 were used as normal values. A urine iodine concentration < 150 ug/L was considered low. Results: One hundred women age 30 +/- 5 years with a mean gestational age of 8,8 +/- 1,9 weeks, were studied. The frequencies of subclinical hypothyroidism, clinical hypothyroidism, isolated low thyroxin lecels, high antiTPO antibodies and low urine iodine levels were 19, 2, 3, 13 and 15 percent, respectively. Women with high TSH levels had lower total and free T4 levels. Conclusions: Twenty one percent of this sample of apparently healthy pregnant women had a clinical or subclinical hypothyroidism.

Presencia de macroprolactina en sueros con normo e hiperprolactinemia: comparación de dos métodos de detección / Comparison of two techniques to detect the presence of macroprolactin in serum

Background: Macroprolactin is biologically inactive but may be detected by immnoassays. This leads to errors in diagnosis and inadequate treatment of patients with hyperprolactinemia. Aim:To assess two techniques to detect the presence of macroprolactin. Material and Methods: Prolactin was measured by immunoassay in 57 serum samples (from 4 males and 53 females aged33 +/- 13 years), before and after precipitation with polyethyleneglycol (PEG) and separation by ultrafiltration. A significant level of macroprolactin was considered to be present when prolactin detected in the supernatant after PEG precipitation or in the ultrafiltrate was less than 40 percent of the initial concentration of prolactin. Results: Prolactin levels fluctuated from 5 to 411 ng/ml. The percentages of recuperation were independent of the initial prolactin concentration. In 12 and 14 percent of samples, using polyethyleneglycol and ultrafiltration respectively, there was a prolactin recuperation of less than 40 percent. Eight and 11 percent of samples with a prolactin concentration of more than 30 ng/ml, had a recuperation of less than 40 percent using polyethyleneglycol and ultrafiltration respectively. Conclusions: Approximately 10 percent of samples with a prolactin concentration over 30ng/ml have recuperation values suggestive of the presence of macroprolactin. There is a good concordance between precipitation using polyethyleneglycol or ultrafiltration.

Hiperparatiroidismo primario en el adolescente: caso clínico / Primary hyperparathyroidism in an adolescent: report of one case

We report a 13 year-old mate with a history of multiple fractures and kidney stones. The laboratory showed a hypercalcemia of 11.5 mg/dl, a PTH of 112.6 pg/ml and 24 hour urinary calcium of 571 mg. Bone densitometry showed spine and fémur Z scores of -2.9 and -1.6, respectively, kidney ultrasound showed nephrocalcinosis and a MIBI-SPECT scintigram showed a higher uptake in the ríght lower parathyroid gland. The diagnosis of primary hyperparathyroidism was made and the patient was operated, excising the ríght lower parathyroid gland. After surgery, serum calcium and PTH levels returned to normal values. In children, the proportion of cases with parathyroid hyperplasia is higher than in adults. Therefore, during surgery all four parathyroid glands must be explored. There is also a higher frequency of ectopic adenomas. Family history must be explored to discard the presence of a multiple endocrine neoplasia (MEN I or II), a familial hyperparathyroidism or a syndrome of primary hyperparathyroidism associated to mandibular tumor.

Hiperplasia suprarrenal no clásica, características clínicas y genéticas / Clinical and genetic features of non classical adrenal hyperplasia

Background: The non classical form of congenital adrenal hyperplasia (NCAH) is increasingly recognized inhyperandrogenic patients, with variable phenotypic expression. Aim: To determine the clinical, hormonal, andgenetic characteristics of a group of patients with NCAH. Patients and methods: The medical records of 57NCAH patients were retrospectively reviewed. The diagnosis was established by basal or post-ACTH-stimulation 17-hydroxyprogesterone (17-OHP) levels >7 ng/mL and > 15 ng/mL, respectively. Patients with post-ACTH 17-OHP levels between 10-15 ng/mL, and with one identified allele o without genetic tests, were consideredas heterozygous. Genotyping for 10 mutations was performed by PCR. Results: The average age of diagnosis was 12.4 +/- 0.9 years. Six patients were male. Pubarche and hirsutism were the clinical signs more frequently described in patients below 10 years of age (25/29) and over 10 years of age (11/24), respectively. A basal 17-OHP > 7 ng/mL was observed in 36 patients; the post ACTH 17-OHP was between 10-15 and > 15 ng/mL in 5 and 17 patients, respectively. Genotype analyses were performed in 38 patients. V281L was carried on approximately 68.4 percent of all alleles and 29 percent of patients carried severe mutations. Only one of five possible carrier patients, was diagnosed as NCAH after the genetic test (V281L/ In2splice). Conclusions: Males with NCAH were apparently sub-diagnosed. Pubarche and hirsutism were the more frequently reported signs. The genetic test is complementary in the diagnosis of NCAH. One third of the patients carried a classic mutation and could have an increased risk to have siblings with Classical CAH.

Comparación de distintos métodos para evaluar la función androgénica en el adulto mayor / Assessment of androgenic decline in the elderly

Background:The gold standard to assess androgenic status is the measurement of free testosterone by equilibrium dialysis. However, the estimation of free testosterone using formulas based on the law of mass action can be an adequate standard. Aim: To assess androgenic decline in the elderly by different methods. Material and methods: Free testosterone by radioimmunoassay, total testosterone and steroid binding globulin (SHBG) by automated chemiluminiscence system and estradiol by automated electrochemiluminiscence system were measured in 30 male aged 64±5 years (range 60-70), and 25 males aged between 20 and 30 years, as control group; devoid of diseases or drugs that could cause hypogonadism. Free androgen index, free testosterone, biavailable testosterone, and free estradiol were calculated using a formula based on the law of mass action. Results: Fifty seven percent of elderly subjects had hypogonadism, according to calculated free testosterone values. Their total testosterone was on average, 152 nd/dl lower than in young adults, figure that represents a 3.8 ng/dl decline per year. According to total testosterone values, 27 percent of elderly males had gonadal incompetence. The correlations between calculated free testosterone and total testosterone was 0,95 and between calculated free testosterone and measured free testosterone was 0,67. The methods employed overestimated (76.7 percent of hypogonadism when using the free androgen index) or underestimated (27 and 3 percent of hypogonadism, considering total or free testosterone, respectively) the ondrogen decline of the elderly. Among the elderly, 16 or 30 percent of subjects had an absolute hypoestrogenism, based on estradiol or calculated free estradiol values, respectively. On average there was a 20 and 30 percent reduction of estradiol and calculated free estradiol values in the elderly. Conclusions: Calculated free or bioavailable testosterone values should be used to assess androgen decline in elderly men.

Características de presentación del microcarcinoma papilar del tiroides. Experiencia retrospectiva de los últimos 12 años / Pathological characteristics of thyroid microcarcinoma. A review of 402 biopsies

Background: Thyroid microcarcinoma is a tumor of 10 mm or less, that should have a low risk of mortality. However, a subgroup of these carcinomas is as aggressive as bigger tumors. Aim: To describe the pathological presentation of these tumors, and compare them with larger tumors. Material and methods: All pathological samples of thyroid carcinoma that were obtained between 1992 and 2003, were studied. In all biopsies, the pathological type, tumor size, the focal or multifocal character, the presence of lymph node involvement and the presence of lymphocytic thyroiditis or thyroid hyperplasia, were recorded. Results: One hundred eighteen microcarcinomas and 284 larger tumors were studied. The mean age of patients with microcarcinoma and larger tumors was 42.7±14 and 49.3±16 years respectively (p <0,001) and 83% were female, without gender differences between tumor types. Mean size of microcarcinomas was 8.6 mm and 116 (98%) were papillary carcinomas. Of these, 109 (94%) were well differentiated and seven (6%) were moderately differentiated. Thirty six (31%) were multifocal and in 10 (8,6%), there was lymph node involvement. The mean size of larger tumors was 23.8 mm and 241 (85%) were papillary carcinomas. Of these, 200 (83%) were well differentiated, and 41 (17%) were moderately differentiated. Eighty five (35%) were multifocal and in 44 (18%) there was lymph node involvement. The prevalence of thyroiditis and hyperplasia was significantly higher among microcarcinomas than in larger tumors (15 and 2.5%, respectively, p <0.001, for the former; 32.4 and 1.7%, respectively, p <0.001, for the latter). Conclusions: In this series, one third of microcarcinomas were multifocal and 10% had lymph node involvement. Therefore, the aggressiveness of these tumors is higher than what is reported in the literature and they should be treated with total thyroidectomy.

Recomendaciones de tratamiento en la menopausia / Treatment of menopause: recommendations

El objetivo de este documento es entregar una guía práctica de tratamiento del climaterio, debido a la confusión producida por el estudio WHI en 2002. La TH debe ser solo utilizada cuando exista una indicación clara para su uso. La paciente sintomática es la principal beneficiada del tratamiento. No existe un tratamiento alternativo a los estrógenos o estrógeno/progestina tan eficaz en el alivio de la sintomatología y en reducción de fracturas. La indicación de un tratamiento prolongado debe ser revisada anualmente.

Patologia endometrial en mujeres con sangrado anormal durante terapia de reemplazo hormonal

Se presenta un estudio para analizar la incidencia de patología endometrial en mujeres sanas posmenopáusicas que reciben terapia de reemplazo hormonal (TRH) y que presentan sangrado uterino anormal. Se estudiaron 188 mujeres posmenopáusicas que presentaron flujo rojo uterino anormal (irregular o excesivo) durante TRH con estrógenos y progesterona en diferentes esquemas (49% secuencial continuo; 39% combinado continuo; 12% secuencial discontinuo. Al 100% de las pacientes se les realizó en forma ambulatoria un estudio biópsico aspirativo de endometrio. El procedimiento fue bien tolerado y no se observaron complicaciones hemorrágicas o infecciosas. Los resultados histológicos fueron los siguientes: endometrio secretor 28,8%; endometrio proliferativo 31,3%; endometrio atrófico 18,0%; hiperplasia endometrial sin atipías 4,3%; pólipo endometrial benigno 2,7%; tejido endometrial benigno, inactivo o fragmentos de epitelio 11,7%; adenocarcinoma de endometrio 0,5% y ausencia de tejido endometrial 2,7%. La biopsia aspirativa de endometrio permitió conocer la situación endometrial en 97,3% de las pacientes. Muestra insuficiente para diagnóstico se obtuvo en un 2,7% de los casos sugiriendo atrofia endometrial o patología focal no diagnosticada por el método. Se concluye que la baja incidencia de patología maligna de endometrio en nuestro estudio confirma su baja incidencia en mujeres que reciben esquemas adecuados de terapia de reemplazo hormonal.