Pituitary dysfunction in granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis of small vessels that affect the pituitary gland in less than 1% of cases being exceptionally rare. To describe the clinical, biochemical, radiological findings, treatment, and outcomes of 4 patients with GPA-related hypophysitis. A systematic review of published cases with the same diagnosis is presented as well. A cross-sectional case series of patients with hypophysitis due to GPA from 1981 to 2018 at a third level specialty center. Literature review was performed searching in seven different digital databases for terms "granulomatosis with polyangiitis" and "pituitary gland" or "hypophysitis," including in the analysis all published cases between 1950 and 2019 with a minimum follow-up of 6 months. We found 197 patients with GPA in our institution of whom 4 patients (2.0%) had pituitary involvement. Clinical characteristics and outcomes are described. We also reviewed 7 case series, and 36 case reports describing pituitary dysfunction related to GPA from 1953 to 2019, including the clinical picture of an additional 74 patients. Pituitary dysfunction due to GPA is rare. Treatment is targeted to control systemic manifestations; nevertheless, the outcome of the pituitary function is poor. Central diabetes insipidus, particularly in younger women with other systemic features, should raise suspicion of GPA.Key Points• Involvement of the pituitary gland is an uncommon manifestation in GPA patients. The presence of central diabetes insipidus in the setting of systemic symptoms should prompt its suspicion.• In patients with pituitary involvement due to GPA, affection of other endocrine glands is rare, neither concomitant nor in different times during the disease course. This may arise the hypothesis of a local or regional pathogenesis affection of the gland.• There is no consensus on the best therapy strategy for GPA hypophysitis. Although the use of glucocorticoids with CYC is the most common drug combination, no differences in the outcome of the pituitary function and GPA disease course are seen with other immunosuppressants.• Poor prognosis regarding pituitary function is expected due to possible permanent pituitary tissue damage that results in the need of permanent hormonal replacement.

Prolactin is Not Associated with Disability and Clinical Forms in Patients with Multiple Sclerosis.

An association between prolactinemia with disability, clinical forms, and sex of patients with multiple sclerosis (MS) remains unclear. The aim of this study was to evaluate the association of prolactin with clinical forms and accumulating disability over time in patients with MS. A longitudinal study was carried out with 101 patients with relapsing-remitting MS (RRMS) and 19 with progressive forms of MS (ProgMS). The disability over time, as well as prolactin and ferritin serum levels were evaluated at baseline (T0), 8-month follow-up (T8), and 16-month follow-up. The disability at T0, T8, and T16 was higher among patients with ProgMS than those with RRMS. Prolactin and ferritin levels did not differ over time between both groups. Initially, prolactin was associated with MS disability. After introducing age and sex, the effects of prolactin on disability were no longer significant. Prolactin was associated with age and sex, whereby age was positively associated with disability. In the same way, after introducing age and sex, the effects of diagnosis on prolactin levels, as well as the association between prolactin and ferritin, were no longer significant (P = 0.563 and P = 0.599, respectively). Moreover, 21.6% of the variance in the disability was predicted by age (P < 0.001), and sex (P = 0.049), while prolactin was not significant. In conclusion, the effects of prolactin on the disability and clinical forms of MS patients may be spurious results because those correlations reflect the positive associations of age with the disability and the negative association of age with prolactin.

[Current diagnosis and treatment of hyperprolactinemia]. / Diagnóstico y tratamiento actual de la hiperprolactinemia.

Hyperprolactinemia is a frequent neuroendocrinological condition that should be approached in an orderly and integral fashion, starting with a complete clinical history. Once physiological causes such as pregnancy, systemic disorders such as primary hypothyroidism and the use of drugs with dopamine antagonistic actions such as metochlopramide have been ruled out, the most common cause of hyperprolactinemia is a PRL-secreting pituitary adenoma or prolactinoma. Prolactinomas are usually classified as microprolactinomas (less than 1 cm) or macroprolactinomas (larger than 1 cm), which can either be confined or invasive. The hormonal consequence of hypeprolactinemia is hypogonadism; in women, this is manifested as amenorrhea/oligomenorreha, anovulation and galactorrhea, whereas in men the main complaints are a diminished libido and erectile dysfunction. Macroprolactinomas can also present with symptoms and signs resulting form mass effect of the tumor, such as headaches and visual field defects. Other structural causes of hyperprolactinemia include non-functioning pituitary adenomas and infiltrative disorders, which can interrupt the inhibitory, descending dopaminergic tone. The primary treatment of prolactinomas is pharmacological with dopamine agonists such as cabergoline.

La hiperprolactinemia es uno de los trastornos neuroendocrinológicos más frecuentes y su abordaje debe hacerse de manera ordenada e integral, partiendo de una historia clínica completa. Una vez excluidas las causas fisiológicas, como el embarazo, enfermedades sistémicas (como el hipotiroidismo primario) y el uso de fármacos con acción antidopaminérgica (como la metoclopramida), la causa más común de la hiperprolactinemia es la presencia de un adenoma hipofisario productor de prolactina (PRL) o prolactinoma. Los prolactinomas se clasifican por su tamaño en microprolactinomas (menores de 1 cm) y macroprolactinomas (mayores de 1 cm), los cuales a su vez pueden ser intraselares o invasivos. La consecuencia hormonal de la hiperprolactinemia es el hipogonadismo; en la mujer, esto se manifiesta como amenorrea/oligomenorrea, anovulación y galactorrea, mientras que en el hombre la manifestación consiste en la disminución de la libido y disfunción eréctil. En el caso de los macroprolactinomas, no es infrecuente encontrar síntomas y signos de efecto de masa como cefalea y alteraciones en los campos visuales. Otras causas estructurales de hiperprolactinemia son los adenomas no funcionantes y las enfermedades infiltrativas de la hipófisis, las cuales interrumpen el tono dopaminérgico descendente. El tratamiento primario de los prolactinomas es farmacológico, a base de agonistas dopaminérgicos, como la cabergolina.

Hiperprolactinemia y disfunción sexual en el varón / Hyperprolactinemia and sexual dysfunction among males

Hyperprolactinemic males usually have a hypoactive libido and less commonly, erectile dysfunction and disturbances of orgasm and ejaculation. Hyperprolactinemia alters the balance between neurotransmitters, neuropeptides and hormones involved in libido and erection, affecting dopaminergic tone. An imbalance between dopamine, that stimulates sexual function and serotonin that inhibits it, is generated. In the central nervous system, hyperprolactinemia inhibits centers controlling sexual desire and erection. At the neuroendocrine level, it decreases GnRH, LH and testosterone pulses, resulting in a hypogonadotrophic hypogonadism. Erection is also inhibited peripheral actions of low testosterone and high prolactin levels. There is a disturbance of penile smooth muscle relaxation and of the parasympathetic sacrum-penis reflex arch. In experimental animals, acute hyperprolactinemia hampers the central erection mechanism whereas in chronic conditions, peripheral disturbances also occur. Even correcting low testosterone levels, the adverse effects of hyperprolactinemia on sexual function persist. The use of dopaminergic agonists may achieve normal prolactin and testosterone levels resulting in normal sexual function. Chronic hyperprolactinemia results in progressive deterioration of sexual function and a higher hypothalamic damage that does not respond to clomiphene. In this situation and in the presence of sellar tumors that destroy gonadotrophic cells, there is indication of androgenic replacement maintaining the use of dopaminergic agonists...

[HYPERPROLACTINEMIA AND SELECTIVE SEROTONIN REUPTAKE INHIBITORS. A NARRATIVE REVIEW OF THE LITERATURE]. / Hiperprolactinemia asociada al uso de antidepresivos inhibidores de la recaptación de serotonina. Una revisión narrativa de la literature.

A large number of scientific papers have reported the relationship between the development of hyperprolactinemia and the use of psychotropic drugs, especially the role of antipsychotics which are antidopaminergic drugs. However, less information is known about the role of antidepressants in the development of hyperprolactinemia, specially the selective reuptake inhibitors (SSRIs). The prevalence of hyperprolactinemia as a pharmacological side effect of SSRIs is still unknown, despite the widespread use over the last decade. The aim of this review is to explore the relationship between hyperprolactinemia and SSRIs.

Effects of hyperprolactinemia and ovariectomy on the tibial epiphyseal growth plate and bone formation in mice.

PURPOSE: To evaluate the effects of ovariectomy and the hyperprolactinemia procedure in the tibial epiphyseal growth plate of female mice. METHODS: In this study, the epiphyseal growth plate of ovariectomized (OVX) and/or rendered hyperprolactinemic female mice by 50 days of treatment with 200 µg metoclopramide (M) was evaluated morphologically, morphometrically and immuno-histochemically. Forty female and adult mice were divided into four groups according to treatment: V group--animals treated with saline solution; H group--hyperprolactinemic animals; Ovx/V group--ovariectomized animals and treated with saline solution; Ovx/H group--hyperprolactinemic and ovariectomized animals. After the treatment period, the animals were sacrificed, tibia was removed and fixed in 10% buffered formalin and decalcified in 10% formic acid. The material was immersed in paraffin and subjected to histological processing in paraffin. The sections were stained with Masson's trichrome and immunohistochemistry was carried out for the pro-apoptotic protein BCL-2. The images for the morphological and morphometric study were analyzed with the imaging program AxioVision 4.8 (Carl-Zeiss(r), Germany). RESULTS: The combination of hyperprolactinemia and the ovariectomy procedure decreased the number of resting chondrocytes 1.5-fold, the number of proliferative chondrocytes 1.8-fold; the percentage of resting cartilage 2.4-fold and the percentage of trabecular bone 2.1-fold, compared with respective control animals. CONCLUSION: The procedure of ovariectomy combined with the metoclopramide-induced hyperprolactinemia in female mice has showed marked bone degeneration due to significant decrease of cell proliferation in the epiphyseal growth plate and bone formation.

Effects of hyperprolactinemia and ovariectomy on the tibial epiphyseal growth plate and bone formation in mice / Efeitos da hiperprolactinemia e ooforectomia sobre o disco epifisário da tíbia e formação óssea em camundongos fêmeas

PURPOSE: To evaluate the effects of ovariectomy and the hyperprolactinemia procedure in the tibial epiphyseal growth plate of female mice. METHODS: In this study, the epiphyseal growth plate of ovariectomized (OVX) and/or rendered hyperprolactinemic female mice by 50 days of treatment with 200 μg metoclopramide (M) was evaluated morphologically, morphometrically and immuno-histochemically. Forty female and adult mice were divided into four groups according to treatment: V group - animals treated with saline solution; H group - hyperprolactinemic animals; Ovx/V group - ovariectomized animals and treated with saline solution; Ovx/H group - hyperprolactinemic and ovariectomized animals. After the treatment period, the animals were sacrificed, tibia was removed and fixed in 10% buffered formalin and decalcified in 10% formic acid. The material was immersed in paraffin and subjected to histological processing in paraffin. The sections were stained with Masson's trichrome and immunohistochemistry was carried out for the pro-apoptotic protein BCL-2. The images for the morphological and morphometric study were analyzed with the imaging program AxioVision 4.8 (Carl-Zeiss(r), Germany). RESULTS: The combination of hyperprolactinemia and the ovariectomy procedure decreased the number of resting chondrocytes 1.5-fold, the number of proliferative chondrocytes 1.8-fold; the percentage of resting cartilage 2.4-fold and the percentage of trabecular bone 2.1-fold, compared with respective control animals. CONCLUSION: The procedure of ovariectomy combined with the metoclopramide-induced hyperprolactinemia in female mice has showed marked bone degeneration due to significant decrease of cell proliferation in the epiphyseal growth plate and bone formation. .

OBJETIVO: Avaliar os efeitos do procedimento de ooforectomia e da hiperprolactinemia no disco epifisário da tíbia de camundongos fêmeas. MÉTODOS: Neste estudo, o disco epifisário de camundongos fêmeas ovariectomizadas (OVX) e/ou com hiperprolactinemia induzida por tratamento com 200 μg de metoclopramida por 50 dias (M) foi avaliado morfologicamente, morfometricamente e imunohistoquimicamente. Quarenta camundongos fêmeas e adultas foram divididas em quatro grupos, segundo o tratamento: Grupo V - animais tratados com solução salina; Grupo H - animais hiperprolactinêmicos; Grupo Ovx/V - animais ooforectomizados e tratados com o solução salina; Grupo Ovx/H - animais ooforectomizados e hiperprolactinêmicos. Após o período de tratamento, os animais foram sacrificados, as tíbias removidas e fixadas em formalina tamponada a 10% e descalcificadas em ácido fórmico a 10%. O material foi emblocado em parafina e submetido a processamento histológico em parafina. Os cortes foram corados pelo tricrômico de Masson e foi feita a imunohistoquímica para a proteína pró-apoptótica BCL-2. As imagens para o estudo morfológico e morfométrico foram analisadas com o programa de imagem AxioVision 4.8 (Carl-Zeiss(r), Alemanha). RESULTADOS: A combinação da hiperprolactinemia e do procedimento de ovariectomia levou à redução do número de condrócitos de repouso em 1,5 vezes; o número de condrócitos proliferativos em 1,8; a percentagem de cartilagem de repouso em 2,4, e a percentagem de osso trabecular em 2,1 vezes, em comparação com os respectivos animais controles. CONCLUSÃO: O procedimento de ooforectomia combinado com a condição de hiperprolactinemia induzida pela metoclopramida em camundongos fêmeas evidenciou degeneração óssea ...

[Clinical practice guideline for the diagnosis and treatment of hyperprolactinemia]. / Guía de práctica clínica para el diagnóstico y tratamiento de la hiperprolactinemia.

BACKGROUND: Hyperprolactinemia is a common finding within clinical practice in both endocrinology and general practice fields, amongst other specialties. The general practitioner and other specialists must know the indications and serum prolactin determination parameters in order to, once detected, derive the patient for a correct assessment and begin treatment. OBJECTIVE: Formulate a clinical practice guideline evidence-based for the diagnosis and treatment of hyperprolactinemia. METHOD: It took the participation of eight gynecologists, two pathologists and a pharmacologist in the elaboration of this guideline due their experience and clinical judgement. These recommendations were based upon diagnostic criteria and levels of evidence from treatment guidelines previously established, controlled clinical trials and standardized guides for adolescent and adult population with hyperprolactinemia. RESULTS: During the conformation of this guideline each specialist reviewed and updated a specific topic and established the evidence existent over different topics according their field of best clinical expertise, being enriched by the opinion of other experts. At the end, all the evidence and decisions taken were unified in the document presented here. CONCLUSIONS: It is presented the recommendations established by the panel of experts for diagnosis and treatment of patients with high levels of prolactin; also the level of evidence for the diagnosis of hyperprolactinemia, handling drug-induced hyperprolactinemia and prolactinomas in pregnant and non-pregnant patients.

Macroprolactinemia in women with hyperprolactinemia: a 10-year follow-up.

OBJECTIVES: To determine the frequency of macroprolactinemia in a cohort of hyperprolactinemic women, describing 1) the association of macroprolactinemia with clinical variables and morphological changes in the pituitary gland and 2) clinical status and prolactin levels after 10 years of follow-up. DESIGN: Blood samples were obtained from 32 patients for hormonal assessment. Treatment with cabergoline or bromocriptine was interrupted 3 months before the determination of serum prolactin and macroprolactin. Macroprolactin was measured using the polyethylene glycol (PEG) precipitation method. Computed tomography was performed in all patients. RESULTS: The frequency of macroprolactinemia was 28.1%. In 19 patients prolactin remained elevated (persistent hyperprolactinemia). In 13, prolactin returned to normal (former hyperprolactinemia). Nine patients with PEG recovery between 40 and 50%, and the only two macroprolactinemic patients with previous hyperprolactinemia were excluded from the analysis of clinical outcomes. Only one of seven macroprolactinemic patients had an abnormal pituitary image (empty sella). None had galactorrhea. MAIN FINDINGS: Classic symptoms of hyperprolactinemia and abnormal imaging findings are not common in patients in whom macroprolactin is the predominant form of PRL. CONCLUSIONS: Women with hyperprolactinemia, especially if asymptomatic, should be routinely screened for macroprolactinemia. Macroprolactinemia remains stable in the long term.

Algunas consideraciones de la disfunción endotelial en pacientes con hiperprolactinemia / Some considerations of endothelial dysfunction in patients presenting with hyperprolactinemia

Se realizó una revisión de las publicaciones a nuestro alcance de la actualidad sobre el tema disfunción endotelial en pacientes con hiperprolactinemia: existencia, mecanismos de producción y consecuencias. Teniendo en cuenta que la hiperprolactinemia tiene hoy un nuevo enfoque relacionado con la disfunción endotelial, nos propusimos realizar la revisión siguiente. La disfunción endotelial es una alteración en la relajación vascular inducida por la reducción de los factores de relajación derivados del endotelio, principalmente el óxido nítrico, que causa un aumento del estímulo vasoconstrictor con tendencia protrombótica de la vasculatura. La resistencia a la insulina actúa como principal factor de disfunción endotelial asociado o no con la diabetes mellitus. Hasta el presente, el estado hiperprolactinémico se asocia con trastornos de la tolerancia a la glucosa (tolerancia a la glucosa disminuida con hiperinsulinemia). Existe disfunción endotelial en mujeres hiperprolactinémicas y puede deberse a su relación con resistencia a la insulina, a la disminución de los estrógenos y a la propia hiperprolactinemia. También se han encontrado marcadores de inflamación (como la proteína C reactiva) elevada en pacientes con esta enfermedad. La hiperprolactinemia se asocia con resistencia a la insulina, disfunción endotelial y bajo grado de inflamación, parámetros que son determinantes en el proceso de aterosclerosis, por lo que esta enfermedad puede ser un factor predisponente de aterosclerosis, y por tanto, un riesgo de morbilidad y mortalidad cardiovasculares(AU)

A review of the publications available of current situation on the subject related to endothelial dysfunction in patients with hyperprolactinemia: existence, production mechanisms and consequences. Taking into account that the hyperprolactinemia has a new approach related to endothelial dysfunction authors made present review. Above mentioned dysfunction is a alteration in the vascular relaxation provoked by decrease of relaxation factors derived from endothelium, mainly the nitric oxide, which cause an increase of vasoconstrictor stimulus with a pro-thrombotic trend of vasculature. The insulin resistance acts as a major factor of endothelial dysfunction associated or not with diabetes mellitus. Until now, the hyperprolactinemia status is associated with disorders of the glucose tolerance (decreased glucose tolerance with hyper-insulinemia). There is endothelial dysfunction in women with hyperprolactinemia and may be due to its relation to insulin resistance, to decrease of estrogens and to the own hyperprolactinemia. Also, there are inflammation's markers (the C-reactive protein) high in patients with this disease. The hyperprolactinemia is associated with the insulin resistance, the endothelial dysfunction and the low degree of inflammation, parameters determinant in the atherosclerosis process, thus, this disease may be a predisposing factor of the atherosclerosis becomes risk of cardiovascular morbidity and mortality.(AU)

Algunas consideraciones de la disfunción endotelial en pacientes con hiperprolactinemia / Some considerations of endothelial dysfunction in patients presenting with hyperprolactinemia

Se realizó una revisión de las publicaciones a nuestro alcance de la actualidad sobre el tema disfunción endotelial en pacientes con hiperprolactinemia: existencia, mecanismos de producción y consecuencias. Teniendo en cuenta que la hiperprolactinemia tiene hoy un nuevo enfoque relacionado con la disfunción endotelial, nos propusimos realizar la revisión siguiente. La disfunción endotelial es una alteración en la relajación vascular inducida por la reducción de los factores de relajación derivados del endotelio, principalmente el óxido nítrico, que causa un aumento del estímulo vasoconstrictor con tendencia protrombótica de la vasculatura. La resistencia a la insulina actúa como principal factor de disfunción endotelial asociado o no con la diabetes mellitus. Hasta el presente, el estado hiperprolactinémico se asocia con trastornos de la tolerancia a la glucosa (tolerancia a la glucosa disminuida con hiperinsulinemia). Existe disfunción endotelial en mujeres hiperprolactinémicas y puede deberse a su relación con resistencia a la insulina, a la disminución de los estrógenos y a la propia hiperprolactinemia. También se han encontrado marcadores de inflamación (como la proteína C reactiva) elevada en pacientes con esta enfermedad. La hiperprolactinemia se asocia con resistencia a la insulina, disfunción endotelial y bajo grado de inflamación, parámetros que son determinantes en el proceso de aterosclerosis, por lo que esta enfermedad puede ser un factor predisponente de aterosclerosis, y por tanto, un riesgo de morbilidad y mortalidad cardiovasculares(AU)

A review of the publications available of current situation on the subject related to endothelial dysfunction in patients with hyperprolactinemia: existence, production mechanisms and consequences. Taking into account that the hyperprolactinemia has a new approach related to endothelial dysfunction authors made present review. Above mentioned dysfunction is a alteration in the vascular relaxation provoked by decrease of relaxation factors derived from endothelium, mainly the nitric oxide, which cause an increase of vasoconstrictor stimulus with a pro-thrombotic trend of vasculature. The insulin resistance acts as a major factor of endothelial dysfunction associated or not with diabetes mellitus. Until now, the hyperprolactinemia status is associated with disorders of the glucose tolerance (decreased glucose tolerance with hyper-insulinemia). There is endothelial dysfunction in women with hyperprolactinemia and may be due to its relation to insulin resistance, to decrease of estrogens and to the own hyperprolactinemia. Also, there are inflammation's markers (the C-reactive protein) high in patients with this disease. The hyperprolactinemia is associated with the insulin resistance, the endothelial dysfunction and the low degree of inflammation, parameters determinant in the atherosclerosis process, thus, this disease may be a predisposing factor of the atherosclerosis becomes risk of cardiovascular morbidity and mortality(AU)

Prolactin inhibition at the end of lactation programs for a central hypothyroidism in adult rat.

Malnutrition during lactation is associated with hypoprolactinemia and failure in milk production. Adult rats whose mothers were malnourished presented higher body weight and serum tri-iodothyronine (T(3)). Maternal hypoprolactinemia at the end of lactation caused higher body weight in adult life, suggesting an association between maternal prolactin (PRL) level and programming of the offspring's adult body weight. Here, we studied the consequences of the maternal PRL inhibition at the end of lactation by bromocriptine (BRO) injection, a dopaminergic agonist, upon serum TSH and thyroid hormones, thyroid iodide uptake, liver mitochondrial alpha-glycerophosphate dehydrogenase (mGPD), liver and pituitary de-iodinase activities (D1 and/or D2), and in vitro post-TRH TSH release in the adult offspring. Wistar lactating rats were divided into BRO - injected with 1 mg/twice a day, daily for the last 3 days of lactation, and C - control, saline-injected with the same frequency. At 180 days of age, the offspring were injected with (125)I i.p. and after 2 h, they were killed. Adult animals whose mothers were treated with BRO at the end of lactation presented lower serum TSH (-51%), T(3) (-23%), and thyroxine (-21%), lower thyroid (125)I uptake (-41%), liver mGPD (-55%), and pituitary D2 (-51%) activities, without changes in the in vitro post-TRH TSH release. We show that maternal PRL suppression at the end of lactation programs a hypometabolic state in adulthood, in part due to a thyroid hypofunction, caused by a central hypothyroidism, probably due to decreased TRH secretion. We suggest that PRL during lactation can regulate the hypothalamus-pituitary-thyroid axis and programs its function.

Redução da densidade mineral óssea em mulheres na menacme com prolactinoma / Decreased bone mineral density in pre-menopause women with prolactinoma

A hiperprolactinemia tumoral e conseqüente hipogonadismo têm sido associados à osteoporose. Avaliamos a densidade mineral óssea (DMO) por absortometria com dupla fonte de RX em 24 mulheres entre 18 e 49 anos, com prolactinoma (15 macro e 9 micro). Utilizamos teste t de Student não pareado ou Mann-Whitney para comparar subgrupos, e teste de Spearman para correlações. O maior acometimento foi de coluna lombar, onde 20,83 por cento das pacientes tinham Z-escore < -2 DP. Não detectamos diferenças densitométricas entre macro e microprolactinomas, nem entre pacientes com prolactina normal versus as hiperprolactinêmicas. A DMO e o Z-escore na coluna foram maiores nas pacientes com > 8 ciclos menstruais no ano anterior à densitometria versus as oligoamenorréicas (p = 0,030). O número de ciclos/ano correlacionou-se com a DMO na coluna (r = 0,515, p = 0,017), e o índice de massa corporal, com a DMO em colo femural (r = 0,563, p = 0,006) e fêmur total (r = 0,529, p = 0,011). Conclusões: Em nossa amostra de mulheres jovens com prolactinoma, 20,83 por cento têm densidade óssea abaixo do esperado para a idade. O maior acometimento de regiões ricas em osso trabecular, como as vértebras, sugere a participação do hipogonadismo na gênese da doença óssea. Independentemente dos valores séricos de prolactina, o retorno dos ciclos menstruais parece ser o melhor índice de bom controle dessas pacientes.

Tumoral hyperprolactinemia and consequent hypogonadism have been associated with osteoporosis. Bone mineral density (BMD) was measured by dual-energy RX absorptiometry in 24 patients with prolactinoma (15 macro and 9 micro adenomas; age range = 18 to 49 years). Student unpaired t or Mann-Whitney tests were used to compare groups, and Spearman test studied correlations. Lumbar spine (LS) was the most affected, as LS Z-score was < -2 SD in 20.83 percent of the patients. No difference was found in densitometric parameters for the comparison between macro and microprolactinoma, or those with normal prolactin versus hyperprolactinemia. LS BMD and LS Z-score were higher in the patients with > 8 menstrual cycles in the preceding year then in those with oligoamenorrhea (p = 0.030). The number of cycles was correlated to LS BMD (r = 0.515, p = 0.017) and body mass index to femoral neck BMD (r = 0.563, p = 0.006) and total femur BMD (r = 0.529, p = 0.011). CONCLUSIONS: Decreased bone mineral density was detected in 20.83 percent of our young patients with prolactinoma. The great involvement of trabecular bone skeletal regions, such as vertebrae, suggests the participation of hypogonadism in the pathogenesis of bone disease. Irrespective of prolactin levels, return to normal menses seems the best index of good control.

[Decreased bone mineral density in pre-menopause women with prolactinoma]. / Redução da densidade mineral óssea em mulheres na menacme com prolactinoma.

UNLABELLED: Tumoral hyperprolactinemia and consequent hypogonadism have been associated with osteoporosis. Bone mineral density (BMD) was measured by dual-energy RX absorptiometry in 24 patients with prolactinoma (15 macro and 9 micro adenomas; age range = 18 to 49 years). Student unpaired t or Mann-Whitney tests were used to compare groups, and Spearman test studied correlations. Lumbar spine (LS) was the most affected, as LS Z-score was < -2 SD in 20.83% of the patients. No difference was found in densitometric parameters for the comparison between macro and microprolactinoma, or those with normal prolactin versus hyperprolactinemia. LS BMD and LS Z-score were higher in the patients with > 8 menstrual cycles in the preceding year then in those with oligoamenorrhea (p = 0.030). The number of cycles was correlated to LS BMD (r = 0.515, p = 0.017) and body mass index to femoral neck BMD (r = 0.563, p = 0.006) and total femur BMD (r = 0.529, p = 0.011). CONCLUSIONS: Decreased bone mineral density was detected in 20.83% of our young patients with prolactinoma. The great involvement of trabecular bone skeletal regions, such as vertebrae, suggests the participation of hypogonadism in the pathogenesis of bone disease. Irrespective of prolactin levels, return to normal menses seems the best index of good control.

Estados hiperprolactinémicos / Hyperprolactinemia

En el presente artículo revisamos los aspectos relevantes de la hiperprolactinemia, en los campos de la fisiología, fisiopatología, prevalencia, etiología, evaluación clínica y tratamiento; enfatizándose la problemática peruana.

Persistence of hyperprolactinemia after treatment of primary hypothyroidism and withdrawal of long term use of estrogen: are the tuberoinfundibular dopaminergic neurons permanently lesioned?

Uso prolongado de altas doses de estrogênio e a presença de hiperprolactinemia crônica pode, pelo menos no rato, provocar lesão nos neurônios dopaminérgicos tuberoinfundibulares (TIDA) responsáveis pelo controle da secreção de prolactina (Prl). Essa ocorrência, ainda não bem documentada em humanos, pode ter ocorrido em uma paciente em tratamento crônico com contraceptivo oral (OC), que veio para consulta por hipotiroidismo primário, hiperprolactinemia e uma massa hipofisária. Após reposição de hormônio tiroidiano, suspensão do tratamento com o OC e a bromocriptina, essa paciente não manteve níveis normais de Prl, necessitando tratamento contínuo com agonista dopaminérgico, mesmo quando a RM da região selar indicava uma situação normal. A função dos neurônios TIDA foi investigada pelo teste do TRH (200µg IV), realizado antes e após 25mg de carbidopa e 250mg de L-dopa a cada 4 horas por um dia. TSH basal (3,9µU/mL) era normal, enquanto Prl (67,5 ng/mL) estava alta; ambos aumentaram apropriadamente após o estímulo com TRH, com picos de 31,8µU/mL (TSH) e 157,8ng/mL (Prl). Após tratamento com carbidopa/L-dopa, os níveis de TSH (1,6µU/mL) e Prl (34ng/mL) diminuíram e a resposta ao TRH foi parcialmente bloqueada (10,3µU/mL e 61ng/mL, respectivamente). Apesar da resposta normal, discutimos a possibilidade que a persistência da hiperprolactinemia é devida a uma lesão dos neurônios TIDA, produzida pelo longo uso de altas doses de estrogênios e pela presença de hiperprolactinemia crônica.

Persistence of hyperprolactinemia after treatment of primary hypothyroidism and withdrawal of long term use of estrogen: are the tuberoinfundibular dopaminergic neurons permanently lesioned?

Long term use of high doses of estrogen and the presence of chronic hyperprolactinemia may, at least in the rat, provoke lesions in the tuberoinfundibular dopaminergic (TIDA) neurons responsible for the control of prolactin (Prl) secretion. This occurrence, which is not yet well documented in humans, may have taken place in a patient on chronic oral hormonal contraceptive (OC) treatment who was seen for primary hypothyroidism, hyperprolactinemia and a pituitary mass. After thyroid hormone replacement, OC withdrawn and bromocriptine treatment, this patient could not maintain normal Prl levels, unless continuously treated with a dopaminergic agonist even when MRI was indicative of a normal situation. Function of TIDA neurons was investigated by TRH test (200 microg IV) performed before and after treatment with 25 mg carbidopa plus 250 mg L-dopa every 4 hours for one day. Basal TSH was normal (3.9 microU/mL) whereas basal Prl was high (67.5 ng/mL); both TSH and Prl levels appropriately increased after TRH: peaks 31.8 microU/mL and 157.8 ng/mL, respectively. After treatment with carbidopa/L-dopa, basal TSH (1.6 microU/mL) and Prl (34 ng/mL) decreased and the response to TRH was partially blocked (10.3 microU/mL and 61 ng/mL, respectively). In spite of a normal response, we discuss the possibility that the persistence of hyperprolactinemia is due to lesion of the TIDA neurons produced by the long term use of high doses of estrogens and by the presence of chronic hyperprolactinemia.

Lipopolysaccharide- and tumor necrosis factor-alpha-induced changes in prolactin secretion and dopaminergic activity in the hypothalamic-pituitary axis.

Bacterial lipopolysaccharide (LPS) affects pituitary hormone secretion, including prolactin release, by inducing synthesis and release of cytokines such as tumor necrosis factor-alpha (TNF-alpha). Since prolactin is mainly under tonic inhibitory control of dopamine, we investigated the effect of LPS and TNF-alpha on the hypothalamic-pituitary dopaminergic system. LPS (100-250 microg/rat, i.p.) decreased serum prolactin levels after 1 or 3 h. Sulpiride, a dopaminergic antagonist, increased serum prolactin and blocked the inhibitory effect of LPS. LPS increased hypothalamic dopamine and DOPAC concentrations and the DOPAC/dopamine ratio both in mediobasal hypothalamus and the posterior pituitary. LPS also enhanced dopamine and DOPAC concentration in the anterior pituitary. LPS elevated plasma levels of epinephrine, norepinephrine and dopamine but it did not modify the concentration of epinephrine or norepinephrine in the tissues studied. The administration of TNF-alpha (i.c.v., 1 h, 100 ng/rat) decreased serum prolactin but did not affect plasma catecholamine levels. TNF-alpha did not modify the DOPAC/dopamine ratio in hypothalamus or posterior pituitary but increased dopamine and DOPAC concentrations in the anterior pituitary. Incubations of hypothalamic explants showed that TNF-alpha did not modify in vitro basal dopamine release and reduced K(+)-evoked dopamine release. On the contrary, incubations of posterior pituitaries showed that TNF-alpha significantly increased basal and K(+)-evoked dopamine release. These results indicate that LPS and TNF-alpha increase dopamine turnover in the hypothalamic-pituitary axis. This increase in dopaminergic activity could mediate the inhibitory effect of LPS and TNF-alpha on prolactin release. Furthermore, the increase in dopaminergic activity elicited by LPS could be mediated by an increase in hypothalamic TNF-alpha during endotoxemia.

[Influence of hyperprolactinemia and tumoral size in the postoperative pituitary function in clinically nonfunctioning pituitary macroadenomas]. / Influência dos níveis de prolactina e tamanho tumoral na função hipofisária pós-operatória em macroadenomas hipofisários clinicamente não-funcionantes.

OBJECTIVE: To study the influence of hyperprolactinemia and tumoral size in the pituitary function in clinically nonfunctioning pituitary macroadenomas. METHODS: Twenty three patients with clinically nonfunctioning pituitary macroadenomas were evaluated by image studies (computed tomography or magnetic resonance) and basal hormonal level; 16 had preoperative hypothalamus-hypophysial function tests (megatests). All tumors had histological diagnosis and in seventeen immunohistochemical study for adenohypophysial hormones was also performed. Student's t test, chi square test, exact test of Fisher and Mc Neman test were used for the statistics analysis. The level of significance adopted was 5% (p<0.05). RESULTS: Tumoral diameter varied of 1.1 to 4.7 cm (average=2.99 cm +/- 1.04). In the preoperative, 5 (21.7%) patients did not show laboratorial hormonal deficit, 9 (39.1%) developed hyperprolactinemia, 13 (56,5%) normal levels of prolactin (PRL) and 1 (4.3%) subnormal; 18 (78.3%) patients developed hypopituitarism (4 pan-hypopituitarism). Nineteen patients (82.6%) underwent transsfenoidal approach, 3 (13%) craniotomy and 1 (4.4%) combined access. Only 6 patients had total tumoral resection. Of the 17 immunohistochemical studies, 5 tumours were immunonegatives, 1 compound, 1 LH+, 1 FSH +, 1 alpha sub-unit and 8 focal or isolated immunorreactivity for one of the pituitary hormones or sub-units; of the other six tumours, 5 were chromophobe and 1 chromophobe/acidophile. No significant statistic difference was noted between tumoral size and preoperative PRL levels (p=0.82), nor between tumoral size and postoperative hormonal state, except in the GH and gonadal axis. Significant statistic was noted: between tumoral size and preoperative hormonal state (except in the gonadal axis); between normal PRL levels, associated to none or little preoperative hypophysial disfunction, and recovery of postoperative pituitary function. CONCLUSION: Isolated preoperative hyperprolactinemia and tumoral size have not been predictable for the recovery of postoperative pituitary function.