New Efforts to Demonstrate the Successful Use of TRH as a Therapeutic Agent.

Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood-brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones' levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide's actions to improve symptoms and the progression of several pathologies.

Estimulación iterativa (EI) de TSH endógena (TSH-En) mediante el uso de la hormona liberadora de tirotrofina (TRH) en pacientes portadores de carcinoma diferenciado de tiroides / Rapid iterative stimulation (IS) of endogenous tsh (En-TSH) utilizing thyrotropin releasing hormone (TRH) in patients with differentiated thyroid carcinoma (DTC)

En el CDT es indispensable elevar los valores de TSH para efectuar Tg y barrido (RCT) con 131I, debiéndose suspender la opoterapia (HT) durante 4/5 sem. con el consecuente hipotiroidismo (H) y los trastornos que conlleva. Nuestro objetivo fue incrementar en forma rápida TSH-E acortando el tiempo de abstinencia. Se efectuaron 43 estudios en 37 pacientes con CDT (G-1); de entre 19 y 78 años, 34 con forma papilar y 3 folicular de CDT, 12 de sexo masculino y 25 femenino Se consideraron 2 subgrupos, G-1A, 7 p. para ablación (A); G-1B, 36 p. para seguimiento (S) y/o tratamiento (T) entre 6 meses y 5 años poscirugía; 6 p. efectuaron dos estudios, 4 para A y S y 2 para 2 veces S. Como comparación se revisaron 41 estudios en 35 p (G-2) que efectuaron suspensión de opoterapia por 4/5 semanas, entre 18 y 81 años; 28 de sexo femenino y 7 masculino; 32 papilares y 3 foliculares; 18 para A (G-2 A) y 21 para S, primer control (G-2B); 4 p. efectuaron 2 estudios, A y S. G-1A: entre 8/10 días poscirugía se les administra TRH 200 mcg i.v los días 1, 3, 5 y 6. A los 30 min de la 3ra aplicación, determinación de TSH y RCT con 370 MBq de 99mT; a igual lapso en la 4ta aplicación determinación de TSH, Tg y antiTg y 5,55 o 7,4 GBq de 131I, para A; a los 8 días RCT con 131I. G-1B: se suspende T4 y reemplaza por T3 por 3 semanas. Se suspende T3; a las 24 horas se inicia el esquema indicado para G-1A . A la 4ta aplicación de TRH, se administra el 131I, 14,8 MBq y RCT a las 48 horas en S o la actividad terapéutica indicada para T. En ambos grupos se indicó dieta hipoyódica. Resultados: En G-1, los valores de TSH ascendieron a 26-360 UI/L; promedio 83 UI/L ± 54; G-1A : 137 ±109; G-1B 7, 62 ± 52 . Los RCT no mostraron diferencias con ambos trazadores. En G-1A todos los p presentaron remanentes tiroideos y Tg positivas. En G-1B, 21 p. mostraron RCT y Tg negativas; 7 áreas activas y Tg positivas y 8 p RCT negativos con valores elevados de Tg . En G-2, TSH, 23-170 UI/L ( 63 ± 3 UI/L) ; G-2 A: 71 ± 41 ; G-2B, 63 ± 42. Conclusiones: Estos hallazgos indican que a) la metodología propuesta es adecuada para acortar sensible-mente el tiempo de abstinencia de opoterapia y reducir la sintomatología del H que pasa desapercibida en la mayoría de los casos; b) los valores de TSH-En obtenidos son similares y aun superiores a los alcanzados por suspensión de opoterapia por lapsos prolongados; c) el empleo del RCT con 99mTc como indicador de tejido captante disminuye el uso terapéutico a ciegas de 131I al señalar casos de ausencia de concentración y permite, cuando sea necesario, obtener anticipadamente 131I para su empleo terapéutico.

In the follow up (F) of p with DTC it is necessary to obtain high figures of serum TSH for determination of serum Tg and 131I scan (WBS). For this object, he method, for a long time, was to withdrawal thyroid hormone therapy (generally l-T4) that produce hypothyroidism with the inconvenient for the p, dramatics in certain cases. Our objective was to increase TSH by IS to shortening time of L-T4 withdrawal for F, ablation (A) or treatment (T) with 131I. In 37 p. with DTC (G-1), aged 19-78 y., 34 with pap. DTC and 3 with foll. form, 25 females, 12 males, 43 studies were carried out; 6 p carried 2 studies. The group was divided in 2 sub-groups: G-1A,7 p derived for A; G-1 B 36 p. for F or T with 131I. Six p carried out 2 studies; 4 of them for A and for F and 2 realizes 2 times F. All p treated with l-T4 replaced this hormone for T3 during 3 weeks ,that was withdrawal the day before IS. In G-1A, between 8/10 days after surgery they begin IS. IS: At days 1, 3, 5 and 6, the p were injected i.v. with 200 mcg of TRH; at 30 minutes of the 3rd injec. blood TSH determination ; immediately 370 MBq of 99mT was administered and at 30 minutes a WBS was carried out. At 30 minutes of the 4th injec. blood figures of TSH, Tg and Tg-ab were determined; immediately the activity of 131I indicated for each group was given to the p; in G-1A, at 8 days and in G1-B, at 48 hours WBS were carried out. As a control group (G-2) 41 studies in 35 DTC p. that withdrawal l-T4 for 4/5 weeks, were studied, aged 18-81 years, 31 females and 4 males; 32 with pap. and 3 folli.c form; 18 for A (G-2A) and 23 for F (G-2B); 6 p carried out 2 studies. One for A and the second as the first control. In G-1, TSH values obtained were 26-360 UI/L ( 83 ± 54. In G-1A : 137 ± 109 and in G-1B 62 ± 52). The 2 tracers 131I and 99mTc-Tc, produce show similar figures. In G-1A all p present thyroid remnants and elevated Tg. In G-1B, 7 p showed positive WBS and Tg; 8 p present Tg positive and WBS negative and 21 WBS and Tg negative. In G-2, the TSH values obtained were 23-179 UI/L (63 ± 39 ); G-2A 71 ± 41 and G-2B 63 ± 42. These findings indicate that the methods is adequate to shortened the time of withdrawal of l-T4 and reduce the signs/symptoms of hypothyroidism to an acceptable status. Also allow us to considered the use of 99mTc as an indicator of existence of remnants, relapses or metastases and avoid blind use of therapeutic activities of 131I.

[History of clinical studies on hypothalamic hormone analogs in Mexico]. / Historia de los estudios clínicos con los análogos de las hormonas hipotalámicas en México.

Early clinical trials in Mexico with analogs of luteinizing hormone-releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Extensive clinical studies were carried out at IMSS with agonists of LH-RH, both in men and woman. All subjects responded to LH-RH agonists with a release of LH and FSH, but repeated administration of these analogs, initially aimed at stimulation of fertility (thought to stimulate fertility), was later shown to result in inhibition due to desensitization of pituitary gland and downregulation of LH-RH receptors. Various clinical investigations with LH-RH antagonists were also carried out. This included the first demonstration that LH-RHantagonists can suppress LH and FSH and sex steroid secretion in men and women. Various studies in Mexico with early LH-RH antagonists aimed at the development of new contraceptive methods were reviewed. Modern LH-RH antagonist Cetrorelix was shown to be effective in men and women and useful in treatment of uterine leiomyomas and benign prostatic hyperplasia. Major oncological studies were also carried out with agonist D-Trp6-LH-RH and antagonist Cetrorelix in men with prostate cancer, which demonstrated therapeutic efficacy of both types of analogs. Some endocrine studies with early analogs of somatostatin were also cited and a clinical trial with somatostatin analog vapreotide in patients with relapsed prostate cancer was reviewed. All these studies played a major role in introducing analogs of hypothalamic-releasing hormones into clinical medicine.

Prolactin and growth hormone secretion after thyrotrophin-releasing hormone infusion and dopaminergic (DA2) blockade in infertile patients with minimal/mild endometriosis.

BACKGROUND: The origin of infertility in patients with endometriosis without tubal occlusion has not yet been clearly defined. Several reports show an abnormal pituitary-ovarian axis in this group of patients. Moreover, prolactin (PRL) and growth hormone (GH) secretion is closely related to reproductive status. This study aimed to evaluate PRL and GH secretion after metoclopramide and thyrotrophin-releasing hormone (TRH) infusion in infertile patients with minimal/mild endometriosis. METHODS: A total of 64 women participated in the study: 33 fertile patients without endometriosis; 10 fertile patients with minimal/mild endometriosis; and 21 infertile patients with minimal/mild endometriosis. TRH or metoclopramide was administered randomly in two sequential menstrual cycles (cycle days 3-5). Serum PRL and GH secretion before and after dopaminergic type 2 (DA2) receptor blockade and TRH were compared. RESULTS: Higher serum PRL levels were observed in patients with endometriosis at baseline and after 15 and 30 min of TRH administration. Also, infertile patients with endometriosis had lower serum estradiol levels than fertile patients. Moreover, the dopaminergic blockade did not result in abnormal PRL or GH secretion. CONCLUSIONS: Decreased serum estradiol levels and altered PRL secretion after TRH administration in infertile patients with minimal/mild endometriosis are related to ovulatory dysfunction and infertility in this group of patients without tubal occlusion.

[Anthology of the first clinical studies with hypothalamic hormones: a story of successful international cooperation]. / Antología de los primeros estudios clínicos con hormonas hipotalámicas: relato de una exitosa colaboración internacional.

Our early pioneering clinical trials in Mexico with natural and synthetic thyrotropin-releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Highly purified TRH of porcine origin was shown to stimulate Thyrotropin (TSH) release in hypothyroid cretins. Subsequent tests with synthetic TRH also demonstrated significant increases in plasma TSH in normal men and women as well as in patients with primary hypothyroidism and other endocrine disorders. Even more extensive clinical studies were carried out with highly purified natural porcine LH-RH. Subjects with normal basal serum levels of gonadotropins, low levels (men and women pretreated with steroids) and high levels (e.g. post menopausal women) all responded to LH-RH with a release of LH and FSH. The results of these early studies with the natural LH-RH were confirmed by the use of synthetic LH-RH. These investigations made in Mexico with TRH and LH-RH preceded all other clinical studies by a wide margin. Subsequently various clinical investigations with LH-RH agonists and antagonists were also carried out. All these studies played a major role in introducing hypothalamic-releasing hormones into clinical medicine.

Hypothyroidism in primary hyperoxaluria type 1.

We describe 4 patients, aged 3 months to 23 years, with end-stage renal disease and severe, symptomatic hypothyroidism. All 4 had primary hyperoxaluria type 1 (PH1) with diffuse tissue (kidneys, skeleton, eyes, heart) calcium-oxalate deposition, a condition known as oxalosis. The hypothyroidism responded to thyroid hormone replacement therapy. Clinical hypothyroidism within the framework of PH1/oxalosis was probably caused by thyroid tissue damage from an abundance of calcium oxalate. We recommend that thyroid function be monitored in patients with PH1 and oxalosis.

Extensión del uso prenatal de corticoides para la inducción de la madurez pulmonar fetal / Extension of the prenatal use of corticoids for the fetal lung maturation

Al no hallar datos de nuestro país acerca de la extensión del uso prenatal de corticoides para la inducción de la madurez pulmonar fetal, nos propusimos efectuar una encuesta con un diseño de observación descriptiva, aprovechando las actividades docentes de nuestro grupo, tomando nota además, del nivel de capacitación de los profesionales consultados. Se interrogó acerca del uso rutinario o no de corticoides solos o asociados con TRH en 4 situaciones clínicas: amenaza de parto prematuro y rotura prematura de membranas antes de las 30 semanas de gestación y entre las 30 y 34 semanas. También se dieron 3 opciones para justificar el uso no rutinario. Fueron obtenidas 101 respuestas. En la amenaza de parto prematuro el uso rutinario alcanzó casi el 85 por ciento, mientras que en la rotura prematura de membranas varió entre el 58 por ciento y el 63 por ciento según la edad gestacional. Tanto en la amenaza de parto prematuro como en la rotura prematura de membranas la frecuencia de asociación corticoides-TRH fue significativamente mayor en el grupo menor de 30 semanas con respecto al grupo entre 30 y 34 semanas, siendo el principal argumento para no usarlo sistemáticamente la carencia de efecto beneficioso (AU)

Extensión del uso prenatal de corticoides para la inducción de la madurez pulmonar fetal / Extension of the prenatal use of corticoids for the fetal lung maturation

Al no hallar datos de nuestro país acerca de la extensión del uso prenatal de corticoides para la inducción de la madurez pulmonar fetal, nos propusimos efectuar una encuesta con un diseño de observación descriptiva, aprovechando las actividades docentes de nuestro grupo, tomando nota además, del nivel de capacitación de los profesionales consultados. Se interrogó acerca del uso rutinario o no de corticoides solos o asociados con TRH en 4 situaciones clínicas: amenaza de parto prematuro y rotura prematura de membranas antes de las 30 semanas de gestación y entre las 30 y 34 semanas. También se dieron 3 opciones para justificar el uso no rutinario. Fueron obtenidas 101 respuestas. En la amenaza de parto prematuro el uso rutinario alcanzó casi el 85 por ciento, mientras que en la rotura prematura de membranas varió entre el 58 por ciento y el 63 por ciento según la edad gestacional. Tanto en la amenaza de parto prematuro como en la rotura prematura de membranas la frecuencia de asociación corticoides-TRH fue significativamente mayor en el grupo menor de 30 semanas con respecto al grupo entre 30 y 34 semanas, siendo el principal argumento para no usarlo sistemáticamente la carencia de efecto beneficioso

[Induction of fetal lung maturity with combined hormonal therapy in premature labor]. / Induccíon de madurez pulmonar fetal con terapia hormonal combinada en parto de pretérmino.

Thyrotropin Releasing Hormone (THR) induce fetal pulmonary maturation by direct stimulation, and increase of fetal T3 and T4 which produce biochemical and structural pulmonary maturation. To evaluate the effectivity of TRH associated to corticoides in the prevention of respiratory distress syndrome (RDS) in premature labor, we administered TRH plus Cidoten to patients with imminent premature labor and gestational age (GA) < or = 32 weeks. In a total of 12 patients, tolerance was good in 85% (n = 10), birthweight was 1.782 +/- 488 g (x +/- 2 SD). RDS incidence of only 15.3% and chronic lung disease (CLD) incidence = 0. Newborn of mothers treated with TRH plus corticoids form in evident premature labor in our unit, showed laser rates of RDS and CLD than the described in literature for newborn of similar weight and GA treated only with corticoids.

Inducción de madurez pulmonar fetal con terapia hormonal combinada en parto de pretérmino / Induction of fetal pulmonary maturation with combined hormonal therapy in preterm labor

La hormona liberadora de tirotropina TRH induce maduración pulmonar fetal por estimulación directa, y alza de T3 y T4 fetales, las cuales producen maduración bioquímica y estructural del pulmón. Para evaluar la efectividad de TRH asociado a corticoides en la prevención de Síndrome de Distress Respiration SDR en partos prematuros, se administró TRH más cidotén a pacientes con parto prematuro inminente y edad gestacional EG ó32 semanas. En un total de 12 pacientes, la tolerancia fue buena en el 85 por ciento n=10, el peso de nacimiento 1.782 ñ 488g x ñ 2 DS, la incidencia de SDR de sólo 15,3 por ciento y la incidencia de enfermedad pulmonar crónica EPC=0. Los neonatos de madres tratadas con TRH más corticoides por parto prematuro inminente en nuestra unidad, mostraron cifras menores de SDR y EPC que las descritas en la literatura para neonatos de peso y EG similares tratados solamente con corticoides