rev argent endocrinol metab. 2020; 57 #3 raem ......average age was 35 years (sd ± 7): the most...

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

1 2 2 3ABREU LOMBA A , BUITRAGO GÓMEZ N , ZAMBRANO URBANO J , BEDOYA JOAQUI V ,

4 5 5 6OSORIO CORREA V , VELÁSQUEZ PA , MAYOR BARRERA A , SANTRICH SOTOMAYOR M , 7 8 9

OSORIO TORO LM , HERNÁNDEZ CARRILLO M , CUBIDES MUNEVAR A

*Autor para correspondencia: [email protected]

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.

R E S U M E NINFORMACIÓN DEL ARTÍCULO

Historia del artículo:

Palabras clave:

Mujeres

Agonistas de dopamina

Hiperprolactinemia

Aceptado: 19 de junio de 2020

Recibido: 23 de diciembre de 2020

Revisión: 28 de mayo de 2020

Prolactinoma

RAEM REVISTA ARGENTINA DE ENDOCRINOLOGÍA Y METABOLISMO

Trabajo Original

1 2Endocrinologist, Imbanaco Medical Centre. Cali – Valle, Colombia. Resident Internal Medicine, Libre University. Cali – Valle,3 4Colombia. Internist, Libre University. Cali – Colombia. Endocrinology fellowship, Salvador Gautier Hospital, Santo Domingo,

5 6Dominican Republic. Gynecologist, Libre University. Cali – Valle, Colombia. Physician, Pontificia Javeriana University. Cali7 8– Valle, Colombia. Physician, Santiago de Cali University. Cali – Valle, Colombia. Researcher 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.

REV ARGENT ENDOCRINOL METAB. 2020; 57 #3 13

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 (2002-

2017), 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.

A B S T R A C T

Keywords:

Hyperprolactinemia

Dopamine Agonists

Women

Prolactinoma

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.

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.


INTRODUCTION

Prolactinomas are the result of abnormal monoclonal

development of pituitary cells called lactotrophs, which are

found in the anterior pituitary, probably related to somatic (7)mutation . 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 (8-9)secondary to its growth .

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

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 (13-14)adenectomy the surgical technique of choice . Finally,

radiotherapy as third line treatment is reserved for those cases of

drug resistance to dopaminergic agonists, and poor response (15-16)after surgery . The aim of the treatment is to reach a state of

eugonadism and to control tumor size, associated with the (7)gradual reduction of serum prolactin levels .

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 (10)contrast in T2 . 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 (11-12)level above 500 ng/dl an almost accurate diagnosis .

Prolactinoma are the most common hormonally-active pituitary

tumors and its frequency varies with age and gender, being more

frequent in women between 20 and 50 years, with female : male (1-3)ratio of 10:1 . Prolactinomas vary in size at presentation with

most women presenting with microadenomas, whereas (4)macroprolactinomas have a male predominance . The risk of

progression from microadenomas to macroadenomas is low, as (5)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 (6)is less predictable and with worse prognosis .

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

MATERIALS AND METHODS

This investigation was authorized by Endocrinology Unit, of

Imbanaco Medical Center, Cali – Colombia.

(17)84% . 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 (18-20)to tumor compression or drug resistance .

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 (21-22)intratumoral hemorrhage or pituitary ischemia .

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.

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 of therapeutic 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.


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.

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).

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

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

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).

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

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).

n: number; Min: minim; Max: maxim; Aver: average; Mod:

mode; Q1: quartile 1; Q2: quartile 2; Q3: quartile 3; SD:

standard deviation


Table IV. Description of serum tests in patients with macroprolactinomas. 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).

n: number; Min: minim; Max: maxim; Aver: average; Mod:

mode; Q1: quartile 1; Q2: quartile 2; Q3: quartile 3; SD:

standard deviation

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

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 vertical diameter, it was found a median at

baseline of 33 mm (RIC: 29-41), at 6 months 21 mm (RIC: 16-

27), 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 2. Macroprolactinomas vertical 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).


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)

Our study population corresponds to 30 women diagnosed with

macroprolactinoma, which has the potential of causing

progressive mass effects, including visual field defects, (28)headaches, or development of hypopituitarism . The most

frequent symptom of our study population was headache

(23)Usually prolactinomas affect pre-menopausal women 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 (24)infertility , and in a study as high as 50% of infertility in

(25-27)amenorrheic women , in our study infertility was

documented in 60% of patients with a great impact on quality of

life.

DISCUSSION

(96.7%) unlike other studies where headache has been (29)described at onset in 12-70% of prolactinomas and the first

clinical signs of macroprolactinomas are more frequently (70%)

related with hormonal dysfunction (amenorrhea and (7,15-16)galactorrhea) than with the effect of the tumor mass .

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

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 (14)within the normal range in 82% of all patients and

retrospective studies in which a 60% reduction in prolactin

levels was observed, with the dopaminergic agonists (30-32)treatment .

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 (22)significance . 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 24% (34-35)and 69% .

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 (33)This drug shows better control in tumor size reduction and is

associated with better outcomes in terms of pituitary function

and as such represents the optimal first-line therapy for (15)macroprolactinomas . 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 (16)macroprolactinomas .


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.

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.

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.

ETHICAL RESPONSIBILITIES

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

FUNDING SOURCE

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.

Confidentiality of the data: The authors declare that they have

followed the protocols of their work center on the publication of

patient data.

The authors declare that they have no conflicts of interest.

The authors declare that for the preparation of this manuscript

there has been no source of funding.

Protection of people and animals: The authors declare that no

experiments have been conducted on humans or animals for this

research.

Cocks Eschler D, Javanmard P, Cox K, Geer EB.

Prolactinoma through the female life cycle. Endocrine. 2018;

59:16-29.

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