Trabajo Original

Presentación clínica y respuesta al tratamiento de macroprolactinomas invasivos en mujeres. Cali-Colombia

 

ABREU LOMBA A¹, BUITRAGO GÓMEZ N², ZAMBRANO URBANO J², BEDOYA JOAQUI V³, OSORIO CORREA V⁴, VELÁSQUEZ PA⁵, MAYOR BARRERA A⁵, SANTRICH SOTOMAYOR M⁶, OSORIO TORO LM⁷, HERNÁNDEZ CARRILLO M⁸, CUBIDES MUNEVAR A⁹

 

'Endocrinologist, Imbanaco Medical Centre. Cali - Valle, Colombia. ²Resident Internal Medicine, Libre University. Cali - Valle, Colombia. ³Internist, Libre University. Cali - Colombia. ⁴Endocrinology fellowship, Salvador Gautier Hospital, Santo Domingo, Dominican Republic. ⁵Gynecologist, Libre University. Cali - Valle, Colombia. ⁶Physician, Pontificia Javeriana University. Cali - Valle, Colombia. ⁷Physician, Santiago de Cali University. Cali - Valle, Colombia. ⁸Researcher public health research group (GISAP). Epidemiologist and statistics, Libre University, Valle University and San Martin University. Cali - Valle, Colombia. ⁹Director public health research group (GISAP). Epidemiologist, Libre University, Valle University, Santiago of Cali University and and San Martin University. Cali - Valle, Colombia.

*Autor para correspondencia: natybugo@gmail.com

Recibido: 23 de diciembre de 2020

Revisión: 28 de mayo de 2020

Aceptado: 19 de junio de 2020

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RESUMEN

Los adenomas productores de prolactina son los tumores pituitarios más comunes en la práctica clínica y su frecuencia varía con la edad y el género, siendo más frecuente en mujeres entre 20 y 50 años, con una relación entre mujeres y hombres de 10:1. Los prolactinomas varían de tamaño en su presentación, siendo los microprolactinomas más comunes en mujeres, mientras que en los hombres es más común que presenten macroadenomas al diagnóstico. El objetivo de este trabajo fue describir las características clínicas y evaluar los diámetros del tumor y los valores de la prolactina sérica a los 6 y 12 meses con respecto al estándar de referencia, en respuesta al tratamiento establecido de un grupo de mujeres con macroprolactinomas invasivos. Un estudio descriptivo retrospectivo se llevó a cabo basados en las historias clínicas de 30 mujeres con macroprolactinomas diagnosticados en el centro médico Imbanaco, Cali -Colombia (2002-2017), rango de edad entre 18-50 años. Se analizaron las características clínicas, demográficas, signos y síntomas, niveles hormonales, imágenes anatómicas de la región pituitaria por resonancia magnética nuclear, tratamiento médico, procedimiento quirúrgicos y complicaciones. Se realizó análisis multivariado con la estimación de proporciones y medidas de tendencia central. El éxito en el tratamiento fue definido como un descenso en el tiempo en el tamaño de los macroprolactinomas evaluados por resonancia magnética, y un descenso en los niveles de prolactina sérica. Se usaron test paramétricos para comparar los niveles de prolactina sérica; y se usó para el tamaño del tumor Fisher Snedecor F. La relación entre el tamaño del tumor y los valores hormonales en la admisión del paciente fueron establecidos a través del coeficiente de Pearson.
La edad promedio fue 35 años (Ds±7). El síntoma más frecuente fue cefalea (96.7%), seguido de alteración menstrual, hipopituitarismo y alteraciones visuales con 90%, 80% y 76% respectivamente. Los problemas de fertilidad estuvieron presentes en un 60% y la amenorrea secundaria en 23.3%. Respecto al tipo de intervención médica, los agonistas dopaminérgicos fueron usados en el 100% de casos (10% usaron bromocriptina y 86% cabergolina). Complicaciones: 20% tenían síndrome de silla turca vacía, y 3.3% fuga de líquido cefalorraquídeo como rinorrea. Las medidas entre 6 y 12 meses en los tres diámetros con respecto al estándar de referencia, mostró diferencias estadísticamente significativas (p<0.0001), así como los niveles de prolactina sérica.
En conclusión: las intervenciones terapéuticas realizadas a los pacientes con macroprolactinomas invasivos en mujeres, tuvieron un resultado favorable en las variables analizadas. El tratamiento con agonistas de dopamina son la primera línea de elección en macroprolactinomas invasivos.

Palabras clave: Prolactinoma, Mujeres, Hiperprolactinemia Agonistas de dopamina.

ABSTRACT

Prolactin-producing pituitary adenomas are the most common pituitary tumors in clinical practice and its frequency varies with age and gender, being more frequent in women between 20 and 50 years, female:male ratio 10:1. Prolactinomas vary in size at presentation with most women presenting with microadenomas, whereas men more often tend to have macroadenomas at diagnosis. The objective was to describe clinical characteristics and evaluate tumor diameters and serum prolactin values at 6 and 12 months with respect to the reference standard, in response to treatment established of a group of female patients with invasive macroprolactinomas. A retrospective descriptive study was carried out based on the medical records of 30 female patients with macroprolactinoma diagnosed in Imbanaco Medical Center, Cali - Colombia (20022017), age range 18 - 50 years old. Demographic-clinical characteristics, signs-symptoms, hormone levels, anatomical images of the hypothalamic-pituitary region by magnetic resonance imaging (MRI), medical treatment, surgical procedures and complications were analyzed. Univariate analysis was performed with the estimation of proportions and measures of central tendency. Therapeutic success was defined as a decrease over time in macroprolactinomas size evaluated by magnetic resonance imaging, and as decrease in serum prolactin levels. Parametric tests were used to compare serum prolactin levels; for tumor size Fisher Snedecor F was used. The relationship between tumor size and hormonal values at patient admission were established through the Pearson correlation coefficient.
Average age was 35 years (SD ± 7): The most frequent symptom was headache (96,7%), followed by menstrual disturbances, hypopituitarism and visual disturbances with 90,0%, 80,0% and 76% respectively. Fertility issues were present in 60,0% and secondary amenorrhea in 23,3%. According to the type of medical intervention, dopaminergic agonists were used in 100% of cases (10% used bromocriptine and 86% cabergoline). Complications: 20% had empty sellar syndrome, and 3,3% cerebrospinal fluid (CSF) leak as rhinorrhea. Measurements at 6 and 12 months in the three diameters with respect to the reference standard, showed statistically significant differences (p<0.0001), as well as serum prolactin values.
In conclusion, the therapeutic interventions realized to patients with invasive macroprolactinomas in women, had a favorable result in the analyzed variables. The treatment with dopamine agonists is the first line treatment of choice in invasive macroprolactinomas.

Keywords: Prolactinoma, Women, Hyperprolactinemia Dopamine Agonists.

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INTRODUCTION

Prolactinoma are the most common hormonally-active pituitary tumors and its frequency varíes with age and gender, being more frequent in women between 20 and 50 years, with female : male ratio of 10:1^<1-3). Prolactinomas vary in size at presentation with most women presenting with microadenomas, whereas macroprolactinomas have a male predominance<⁴⁾. The risk of progression from microadenomas to macroadenomas is low, as this occurs in only about 3-6.9%®. Prolactinomas represent around 40% of all pituitary tumors, and 30% of these are related with other tumors of endocrine origin; the previous association is less predictable and with worse prognosis®

Prolactinomas are the result of abnormal monoclonal development of pituitary cells called lactotrophs, which are found in the anterior pituitary, probably related to somatic mutation<⁷⁾. Its presence is associated with alterations of the hypothalamic-pituitary axis, such as hyperprolactinemia, hypothyroidism, kidney failure, hepatic failure and cirrhosis, pituitary compression, among others. They manifest more frequently in women <70%) with hormonal alterations, and are characterized by sexual disorders, galactorrhea, amenorrhea, decreased or lost libido, generally due to compressive effect secondary to its growth<^8-9).

The diagnosis is based in two components, first is the hormones behavior, and second is the tumoral dimensions analysis, being of choice the magnetic resonance imaging <MRI), both for initial stages and for clinical follow-up, and evolution after medical treatment initiation; providing not only tumor size data, but also verification of the affectation of adjacent structures according to their location and development. The imaging pattern of this tumor in MRI, is characterized by being isointense or smoothly hyperintense in T1, where it intensifies its image compared to the normal image of the pituitary, after the contrast administration, and a little more intense after contrast in T2<¹⁰⁾. The follow-up with MRI is recommended to demonstrate the tumor size reduction, discarding the coexistence of alterations such as intratumor hemorrhage, intrasellar affection of optic chiasm, optical nerve and empty sella syndrome. Tumor size is directly proportional to prolactin levels, and therefore to the symptom’s patients complain of serum prolactin level above 250 ng/dl, make it necessary to suspect the presence of this adenoma; considering prolactin level above 500 ng/dl an almost accurate diagnosis^01-®.

In terms of surgical management, it is indicated when there is intolerance to pharmacological treatment, or when there is not an adequate treatment response. Being the transsphenoidal adenectomy the surgical technique of choice<^13-14). Finally, radiotherapy as third line treatment is reserved for those cases of drug resistance to dopaminergic agonists, and poor response after surgery<^15-16). The aim of the treatment is to reach a state of eugonadism and to control tumor size, associated with the gradual reduction of serum prolactin levels<⁷⁾.

Dopamine agonists are the initial therapy of choice. Therapy with Cabergoline <0.25-3.5 mg/week) normalizes prolactin level in 76% of patients, significantly reduce tumor size with a percentage reduction of the maximum tumor diameter of 84%<¹⁷⁾. Nevertheless, it has been found that exceeding the dose 3mg/week, therapeutic failure has been identified in 18% cases. Regarding recurrence, the risk is 20% independent of age or medical management; usually occurs in the first year of treatment and 10% of this group of patients requires surgery, which is indicated if there is visual symptomatology secondary to tumor compression or drug resistance<^18-20).

The use of dopaminergic agonists in a chronic way or with higher doses can generate; spinal brain fistula, neuro-ophtalmologic alterations, cranial nerve palsies associated with intratumoral hemorrhage or pituitary ischemia^<21-22).

Even it is true that in international literature there are case reports and observational studies that support the therapeutic effectiveness of dopaminergic agonists and the criteria for surgical management of patients with prolactinomas, in Latin America and more specifically Colombia, there is limited information to determine if the behavior is equal to what has been reported. The objective is to evaluate treatment response in a group of female patients with invasive macroprolactinomas with serological and imaging follow-up. We present the results in 30 patients attended in Pituitary Diseases Clinic, of Imbanaco Medical Center, Cali - Colombia.

MATERIALS AND METHODS

A retrospective descriptive study was carried out on a series of cases, based on the medical records of 30 female patients attended in Pituitary Diseases Clinic, of Imbanaco Medical Center, Cali - Colombia; in a 15-years period, from 2002 to 2017 with invasive macroprolactinoma diagnosis. Of each patient participating in the study the following data were extracted: demographic and clinic characteristics, results after treatment with cabergoline or bromocriptine, and pituitary adenoma surgical resection by transsphenoidal or transcranial techniques. The follow-up analysis of tumor size was made through the evaluation of diagnostic images with magnetic resonance imaging <MRI) and serologic evolution of prolactin levels, at three, six and eighteen months. In addition, the results of TSH, total T3, free T4, FSH, LH, estradiol <day 3 of cycle) were reviewed in order to determine the gonadotropic status of the patients. The success oftherapeutic intervention was defined as the decrease over time of the size of macroprolactinoma evaluated by MRI, and the decrease in serum prolactin levels in three measurements moments with respect to the reference parameter. The Dependent Variables were Prolactin and tumor size. The Independent Variables were: demographic, signs and symptoms, therapeutic intervention, laboratory tests -hormones, complications.

This investigation was authorized by Endocrinology Unit, of Imbanaco Medical Center, Cali - Colombia.

For the statistical analysis, clinical and paraclinical characteristics of patients were described, univariate analysis was made using proportions and central tendency measures according to the nature of each variable. In the analysis, parametric tests were used when normality assumptions or

criteria were fulfilled through the Kolmogorov Smirnof test. Fisher Snedecor F statistic was used for the comparison of serum prolactin levels, and tumor size. The median was used as the comparison value in the relative variation in prolactin levels measurements, according to the measurement moments; these changes are showed using box and whisker diagrams. The relationship between tumor size and hormone values at patient’s admission was established through Pearson correlation coefficient. We considered for statistical significance, p values less than 0,05. The data was stored in Excel 2007 database, and it was analyzed by Stata 11.2®. To optimize the analysis, the results were showed in tables and figures.

Unilateral Amaurosis	9	30,0
Complete Hypopituitarism	8	26,7
Secondary Amenorrhea	7	23,3
Apopsubclin	6	20,0
Primary Amenorrhea	3	10,0
Transitory Diabetes Insipidus	3	10,0
Permanent Diabetes Insipidus	3	10,0
Hypothalamic Dysfunction	3	10,0
Apopclin	2	6,7
Oligomenorrhea	0	0,0
Bilateral Amaurosis	0	0,0

 

Table I. Description of demographic characteristics of patients with macroprolactinoma diagnosis. Cali - Colombia (2002 - 2017).

Demographic n Range Mín Máx Aver Mod Q2 Q1 Q3 SD

Age (years)	30	29	18	47	35	30	36	30	39	7
Weight (Kg)	30	40	56	96	79	70	81	70	88	11
Height (cm)	30	21	158	178	169	169 169166172				5
BMI	30	11	22	33	28	24	27	25	30	3

 

Kg: kilograms; cm: centimeters; BMI: body mass index; n: number; Min: minim; Max: maxim; Aver: average; Mod: mode; Q1: quartile 1; Q2: quartile 2; Q3: quartile 3; SD: standard deviation

The most frequent symptom was headache in 96,7% of cases, followed by menstrual disturbances, hypopituitarism and visual disturbances with 90,0%, 80,0% and 76% respectively. Fertility issues were present in 60,0% and secondary amenorrhea in 23,3%. (Table II).

Table MI. Description of therapeutic and surgical interventions in patients with macroprolactinomas. Cali - Colombia (2002 - 2017).

Therapeutic intervention	n	Range	Mín	Máx	Aver Mod		Q2	Q1	Q3 SD
Bromocriptine doses	7	8	3	10	7	8	8	5	9    3
Bromocriptine time	7	35	5	40	21	36	12	10	36    15
(months)
Cabergoline doses	27	5	2	7	3	4	3	3	4    1
Cabergoline time (months)	27	71	12	83	29	12	19	15	38    20
Therapeutic intervention								n	%
Dopaminergic agonists								30	100,0
Transsphenoidal surgery								13	43,3
Transcranial surgery								5	16,7

RESULTS

Average age was 35 years and a Standard Deviation (SD) ± 7 years. Average weight was 79 kg (SD ±11 kg). Regarding patient’s height, the average was 169 cm (SD ± 5-cm). Average body mass index (BMI) was 28 (SD ± 3). (Table I).

Table II. Description of clinic characteristics of patients with macroprolactinomas. Cali - Colombia (2002 - 2017).

Category	n	%
Headache	29	96,7
Menstrual disturbances	27	90,0
Hypopituitarism	24	80,0
Visual disturbances	23	76,7
Consultation related to tumor	22	73,3
Decreased libido	22	73,3
Galactorrhea	21	70,0
Asthenia	21	70,0
Menstrual disturbances absent	20	66,7
Infertility	18	60,0
Pardal Hypopituitarism	16	53,3

Of the total number of patients, 90% of them received cabergoline, and 23% bromocriptine, however only 10% received the drug until the end of the study. An average dose of bromocriptine was used 7 mg (SD ± 3); average time of use of 21 months (SD ± 15). Regarding the use of cabergoline, the average dose was 3 mg (SD ± 1), and an average time of use of 29 months (SD ± 20). According to the type of medical intervention, dopaminergic agonists were used in 100% of cases, transsphenoidal surgery in 43,3% and transcranial surgery in 16,7% (Table III).

n: number; Min: minim; Max: maxim; Aver: average; Mod: mode; Q1: quartile 1; Q2: quartile 2; Q3: quartile 3; SD: standard deviation

The hormonal behavior at baseline study was: average cortisol level 19 (SD ± 9), average TSH 2 (SD ± 2), average free T4 and T3 1 (SD ± 0), average FSH 4 (SD ± 4), average LH 3 (SD ± 3), average estradiol 25 (SD ± 14) (Table IV).

Table IV. Description of serum tests in patients with macroprolactinomas. Cali - Colombia (2002 - 2017)

Laboratory Tests Hormones n* Range Mín* Máx* Aver* Mod* Q2* Ql* Q3* SD*

Cortisolat baseline	30	35	8	43	19	16	16	12	26	9
TSH (thyroid-stimulating hormone)	30	8	0	8	2	2	2	1	3	2
Free T4 (thyroxine)	30	1	1	2	1	1	1	1	1	0
T3 (triiodothyronine)	30	2	1	2	1	2	1	1	2	0
FSH (follicle stimulating hormone)	30	21	0	21	4	1	2	1	5	4
LH (luteinizing hormone)	30	12	0	12	3	3	3	1	4	3
Estradiol	30	53	5	58	25	16	20	15	32	14

Table V. Table of frequency of complications observed in patients. Cali -Colombia (2002 - 2017)

Complication	n	%
Empty sella syndrome	6	20,0
CSF Rhinorrhea	1	3,3

 

Figure 2. Macroprolactinomas vertical diameter tendency. Cali - Colombia (2002 - 2017)

 

Regarding the complications in the studied group, 20% had empty sella syndrome. 3.3% had cerebrospinal fluid leakage (rhinorrhea), however they were self-limited, with subsequent successful evolution and recovery (Table V).

Regarding the tumor anterior-posterior diameter, it was found in baseline a median of 23 mm (RIC:19-30), at 6 months of 18 mm (78%) (RIC: 13-22), and at 12 months of 15 mm (RIC: 11-17), showing a progressive reduction of tumor size, being this difference statistically significant (p<0.0001) (Figure 1).

 

Figure 1. Macroprolactinomas anterior-posterior diameter tendency. Cali -Colombia (2002 - 2017)

Regarding the tumor lateral diameter, it was found a median at baseline of 21 mm (RIC: 18-25), at 6 months of 16 mm (RIC: 14-19), and at 12 months of 15 mm (RIC: 12-17), showing a decreasing tendency, besides of a statistically significant tumor size reduction (p<0.0001) (Figure 3).

Figure 3. Prolactinoma lateral diameter tendency. Cali - Colombia (2002 - 2017)

Regarding the value variation in prolactin levels, it was found a seven times reduction compared to baseline value. When evaluating the gradual decrease in prolactin, we found in the first follow-up a 67,7% reduction, in second follow-up a 59,3% reduction, and at 18 months a 45,7% reduction (Figure 4).

Regarding the tumor vertical diameter, it was found a median at baseline of 33 mm (RIC: 29-41), at 6 months 21 mm (RIC: 1627), and at 12 months of 12 mm (RIC: 9-18), showing a decreasing tendency, besides of a statistically significant tumor size reduction (p<0.0001) (Figure 2).

Figure 4. Relative variation of prolactin according to the follow-up. Cali -Colombia (2002 - 2017)

 

It was found that the baseline median for prolactin was 266 ng/dl (RIC: 207-342), at 6 months of 86 ng/dl (RIC: 50-126), at 12 months 35 ng/dl (RIC: 17-49), and at 18 months 19 ng/dl (RIC: 8-26). In serum prolactin levels it was found a gradual decrease every 6 months, with statistically significant differences (p<0.0001) (Figure 5).

 

Figure 5. Prolactin comparative values at different measurement moments. Cali - Colombia (2002 - 2017)

 

 

DISCUSSION

Usually prolactinomas affect pre-menopausal women⁽²³⁾ which agrees with this series where the average age was 35 years old. Most prolactinomas are microadenomas and may be associated with galactorrhea, amenorrhea, and represents 7-20% of female infertility^<24), and in a study as high as 50% of infertility in amenorrheic women^(25-27), in our study infertility was documented in 60% of patients with a great impact on quality of life.

Our study population corresponds to 30 women diagnosed with macroprolactinoma, which has the potential of causing progressive mass effects, including visual field defects, headaches, or development of hypopituitarism^⁸) The most frequent symptom of our study population was headache (96.7%) unlike other studies where headache has been described at onset in 12-70% of prolactinomas^ and the first clinical signs ofmacroprolactinomas are more frequently (70%) related with hormonal dysfunction (amenorrhea and galactorrhea) than with the effect of the tumor maW^7,15-161.

In addition to the clinical and prolactin determination, the most diagnostic studies are the imaging studies. The imaging test indicated for the study of pituitary lesions is magnetic resonance, being able to detect both suprasellar and parasellar extension of the tumor in 100% of our study population. The diagnosis of invasive macroprolactinoma imaging was made by means of MRI, as well as its follow-up. Medical treatment was established to each patient with dopaminergic agonists and surgical management, if it was necessary, showing a therapeutic response in 100% of patients, and an improvement in the following parameters: tumor size AP with a 78% reduction in the first 6 months of follow-up and serum prolactin levels with normalization of levels in 75% of patients at 18 months follow up after treatment: Compared with other studies, 10-year follow-up study, prolactin level significantly decreased and was within the normal range in 82% of all patients⁽¹⁴⁾ and retrospective studies in which a 60% reduction in prolactin levels was observed, with the dopaminergic agonists treatment^^0-32)

Regarding pharmacological treatment with dopaminergic agonists, it was observed that only 10% of patients finished the intervention with bromocriptine, while the rest of patients received cabergoline, which shows the highest frequency of use for this second drug, consistent with what is found in literature This drug shows better control in tumor size reduction⁽³³⁾ and is associated with better outcomes in terms of pituitary function and as such represents the optimal first-line therapy for macroprolactinomas⁽¹⁵⁾. In our study, regarding the use of cabergoline, the average dose was 3 mg (SD ± 1), according to other studies where using doses of 0.25 to 3 mg per week, normoprolactinemia and the significant reduction in tumor size are achieved in approximately 77% with macroprolactinomas⁽¹⁶⁾.

Other studies suggest that dopaminergic agonists therapy can be discontinued with a high remission rate (72% of the patients persisted in remission after dopaminergic agonists therapy withdrawal). Lower median initial prolactin levels and longer duration of treatment seemed to be associated with higher rates of remission, however these variables did not reach statistical signrficance^²) In our study there was no evidence of recurrence of hyperprolactinemia at 18 months of follow-up with imaging and serum evaluations, regardless of the therapy received, unlike other studies that report a recurrence risk between.

The limitation of our study is that it might be necessary the follow up beyond 18 months to be able to perform better results about long-term recurrences, likewise the respective correlations of the serological follow-up. Taking into account that this is an observational descriptive study, among its limitations it is the difficulty to make efficacy or causal relationship affirmations, presenting a selection bias given the retrospective nature of the study, and this limits the possibility of assessing the multicenter level experience, limiting the variables inherent to the medical center where the data was collected.

The main strength of our study, is the accurate follow-up of consecutive measurement of tumor size in each diameter, analyzing its behavior and showing a positive effect with respect to the reduction in prolactin levels used as the follow up parameter, also the classification of each tumor with respect to its initial diameters.

Our study describes the clinical characteristics and response to treatment in women with invasive macroprolactinomas, being an unusual presentation in this type of population. Our findings have been consistent with the literature described to date and guides to carry an adequate diagnostic and therapeutic algorithm in this population group.

In conclusion, in the present study the therapeutic interventions realized to patients with macroprolactinomas, had a favorable result in the analyzed variables. We can show that dopaminergic agonists represent the first-line therapy in the invasive macroprolactinomas context, since these drugs have shown adequate efficacy in tumor size reduction. Complications rates are low, being the cerebrospinal fluid fistula the most frequent. There was no evidence of mortality related to this disease. The reduction of the tumor size in its 3 diameters with respect to serum prolactin levels could be correlated, reaffirming that this last serum marker serves for long-term follow-up. The main symptom is headache, an unspecific symptom, that does not facilitate the immediate clinical orientation towards a brain tumor lesion: However, in the clinical context of woman, amenorrhea and the confirmation of a hypo gonadotropic state orients the need to rule out a central lesion.

ETHICAL RESPONSIBILITIES

Protection of people and animals: The authors declare that no experiments have been conducted on humans or animals for this research.

Confidentiality of the data: The authors declare that they have followed the protocols of their work center on the publication of patient data.

Right to privacy and informed consent: The authors have obtained the informed consent of the patient and / or subject referred to in the article. This document is in the possession of the correspondence author.

CONFLICT OF INTERESTS

The authors declare that they have no conflicts of interest.

FUNDING SOURCE

The authors declare that for the preparation of this manuscript there has been no source of funding.

 

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