Prolactinoma, a prolactin (PRL) secreting functioning pituitary tumor, is the most common of all pituitary adenomas (PA) accounting for 40-60% and dopamine agonists (DA) are the cornerstone of treatment. The aim of this study was to review the particular clinical presentation, treatment modalities and therapeutic outcomes of patients with prolactinomas in the South Asia region.
This retrospective study was conducted in the Endocrinology Department of Shaukat Khanum Memorial Cancer Hospital and Research Centre from December 2011 till December 2019. Medical records were used to retrieve for patient’s demographics, clinical features at diagnosis, PRL levels plus size associated with prolactinoma on MRI in diagnosis and after start of dopamine agonists plus outcome of medical management.
A total associated with 107 patients were included in this study. Mean age from diagnosis has been 35 (22-54) years for men and 32 (18-50) years for women and 66. 4% (71) of the individuals were females. Our study included 38 (35. 5%) microadenoma, 50 (46. 7%) macroadenoma and 19 (17. 8%) giant adenomas. At presentation, the particular most typical symptom among females had been menstrual irregularity/amenorrhea seen in 73. 2% of females plus among males was visual disturbance (80. 6%). The significant reduction in PRL levels was seen within six to 12 months of therapy. Mean PRL levels decreased from 3162. 8 ng/ml to 1. 52 ng/ml. A notable decrease in growth size was seen along with medical administration, mean adenoma size reduced from 2. 18 cm to 1. 04 cm. With cabergoline (CAB) 83. 3% biochemical cure was observed compared to bromocriptine (BRC) which has 60. 4%. The radiological response rate within CAB and BRC groups was 65. 45% plus 60%, respectively. Complete resolution of adenoma was observed in 13 patients (nine had been microadenoma, two macro and two huge adenomas). The particular prolactin level at diagnosis was positively correlated with maximum tumor diameter (r = 0. 469, P = 0. 001). Two patients developed cerebrospinal fluid (CSF) rhinorrhea and the defect was repaired in both individuals. Median follow-up duration has been 40 (12-288) months.
Clinical demonstration and demographics of prolactinoma are the same in our area when compared to the rest of the world. Cabergoline is superior to bromocriptine within prolactin normalization and growth shrinkage but still bromocriptine is being used in a significant number of sufferers in low-income countries as first-line due to its low cost.
Prolactinoma, the prolactin-secreting working pituitary tumor, is the most common of all pituitary adenomas (PA) accounting for 40-60% plus up to 80% if microadenomas (size less than 1 cm) are included  . The mean prevalence is approximately 10 per 100, 000 within men and 30 per one hundred, 000 in women, along with peak prevalence for women aged 25-34 many years  . Most of the medical features of prolactinoma are due to overproduction of prolactin, causing hormonal imbalance leading to menstrual abnormalities and galactorrhea in women, and within men it can cause erectile dysfunction, diminished libido, and infertility. Neurological manifestations in form of psychosis, anxiety, and sleep disturbances are found both in men and ladies. In addition , macroadenomas (size greater than one cm) plus giant prolactinoma (size greater than 4 cm) may also cause mass effects leading to headache and visible disturbances. The term giant prolactinoma is coined in literature to demarcate prolactinomas that are extremely large and greater compared to 4 centimeter in diameter  . Females seek medical advice earlier due to prolactin causing inhibition of gonadotropins resulting in menstrual irregularities, galactorrhea, and infertility. On the contrary, males seek medical attention late due in order to symptoms of bulk effect plus less specific associated with hypogonadism.
For management purposes, it is of paramount importance to differentiate prolactinoma through nonfunctioning pituitary adenoma causing hyperprolactinemia. Prolactin level should be raised to a significant value for the diagnosis of prolactinoma. Prolactin levels are generally proportional to growth size and a level greater than 94 ng/ml can distinguish prolactinoma from nonfunctioning pituitary adenoma  . Magnetic resonance imaging (MRI) with pituitary protocol is the gold standard protocol to look for the particular size plus dimensions associated with adenoma and invasion of surrounding structures. Follow-up MRI is recommended to look for tumor shrinkage plus resolution associated with adenoma after initiation of therapy. First-line management associated with prolactinoma is with dopamine agonists (DA) and studies have shown that cabergoline (CAB) is more effective in lowering prolactin (PRL) levels, reducing growth size, plus has less adverse effects when compared to bromocriptine  . Surgery and/or radiotherapy are options which usually can be used when a prolactinoma is leading to significant mass effect, especially on the optic chiasma (threatening blindness), or in case there will be intolerance or resistance to healthcare therapy. Trans-sphenoidal pituitary surgery being minimally invasive and having relatively good safety profile is usually favored amongst other approaches [6,7] .
Careful scientific and biochemical follow-up is definitely recommended with regard to patients along with prolactinoma. Therapies may be tapered or discontinued in patients who received a minimum of 2 years of DA and no longer possess elevated serum prolactin amounts and no visible tumor remnant upon MRI  . Clinical data with regards to baseline characteristics, clinical features, management plus outcome within prolactinoma individuals has been extensively studied in the western population. However , in our population because of to prolactinoma being a relatively much less commonly diagnosed entity, there is the paucity associated with data. To our knowledge, only one study has been carried out in past on features of prolactinoma in our own region, but it has a small sample size and a short duration of followup  . The aim of the study is to provide local data which can be used as a reference regarding characteristics, clinical presentation administration and outcome of prolactinomas within developing countries. In addition, we furthermore aspire to appear for challenges low-income nations face while providing state-of-the-art treatment comparable to international standards.
Materials & Methods
This particular retrospective research was performed at the particular Department of Endocrinology with Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC). Record of prolactinoma patients through December last year to Dec 2019 had been extracted from the hospital database. The institutional review board (IRB; study IRB# EX-15-05-20-02) associated with SKMCH & RC approved the current retrospective research. IRB-SKMCH & RC allowed the waiver for informed consent intended for this study since the data was accessed through the medical center information system (HIS) and was restricted to the researcher group only and sufferers were allocated serial numbers to conceal patient identity.
Adult sufferers with radiological evidence of pituitary adenoma with prolactin more than 94 ng/ml were included in the research. Patients along with other causes of hyperprolactinemia such as pituitary stalk compression, co-secretory pituitary adenomas, infiltrative diseases like sarcoidosis and tuberculosis, certain medications and pregnancy were excluded.
Prolactin has been measured by an immunochemiluminescent assay (ICMA) (IMMULITE 2000) with a sensitivity associated with 0. 5 ng/ml. Reference levels to get men in our laboratory are usually 2. 50-17 ng/ml and for women are 1. 90-25 ng/ml. Levels greater compared to 150 ng/ml were calculated after appropriate serial dilutions for any possible hook effect. Pituitary adenomas were evaluated radiologically simply by MRI plus maximum growth diameter had been recorded. Based on tumor size adenomas had been classified because microadenoma (< 1 cm), macroadenoma (≥1 cm) and giant prolactinoma (≥4 cm).
A total of 107 patients were identified plus contained in the study through retrospective analysis of hospital records. Treatment history with either CAB or even bromocriptine (BRC) was noted. Treatment with more than one DA may have occurred because of drug intolerance, medication resistance, drug unavailability or a combination of these factors. The particular outcome was calculated in terms of biochemical, radiological, and medical response. Biochemical response can be normalization associated with prolactin degree (< 25 ng/ml). Radiological response is certainly documented 50% or more decrease in tumor size or even resolution of adenoma on follow-up MRI. Clinical response is improvement or quality of scientific features/visual disturbance with dopamine agonists.
The following variables were retrieved from the particular hospital electronic record pertaining to analysis: age, gender, clinical presentation including presenting complaint and examination findings when any, size of adenoma, DA used, results of medical management and mean period of follow-up. Pretreatment prolactin level (baseline) and then on 3, 6, 12, 18, 24, 36 and sixty months right after starting healthcare management has been noted. The particular size associated with adenoma had been recorded upon MRI done at diagnosis (baseline) plus later at 6, 12, 24, thirty six and 60 months.
Statistical analysis was carried out using the SPSS software version 20. 0 (IBM Corp., Armonk, NY, USA). Continuous factors were stated as Median and categorical variables had been computed since frequencies and percentages. Categorical variables were compared using the chi-square test or Fisher’s exact test (when necessary). The continuous variables were in comparison using the independent t-test. One-way ANOVA was utilized to check the mean difference among three different diagnoses. Statistical significance was defined as a two-tailed P-value of 0. 05.
In our study population, the majority of the particular patients had been female (71; 66. 4%). The imply age in diagnosis has been 35 (22-54) years meant for men plus 32 (18-50) years for ladies. Baseline median prolactin level at presentation was 510 ng/ml (61-56670) and suggest adenoma size was 2 . 18 cm (0. 20-7. 0). Out of 107 pituitary tumors, 55 had extrasellar extension. A total of 72% macroadenomas and all giant prolactinomas had extrasellar extension. Optic chiasm involvement or bulk effect had been seen in 44 patients whereas 40 patients had extension into cavernous sinus. The rest of the baseline characteristics are usually as shown in Table 1 .
The common symptoms from presentation within female subjects were monthly irregularities, head ache, and galactorrhea in 73. 2%, 47. 9% and 42. 3%, respectively. Whereas in men, visual disruption (80. 6%) followed by headache (75. 0%) plus erectile dysfunction (30. 6%) were the commonly reported complaints as depicted in Desk two .
The overall prolactin (PRL) level with diagnosis was positively correlated with maximum tumor diameter (r = 0. 469, P sama dengan 0. 001). Cabergoline was given to 59 (55. 1%) patients, bromocriptine to thirty four (31. 8%) patients and 14 (13. 08%) individuals received both DA at some point during treatment. Bromocriptine has been later changed to cabergoline attributable to drug side effects in eight patients plus drug resistance in five patients. Cabergoline had in order to be switched to bromocriptine due to non-affordability in one patient.
Biochemical response to cabergoline and bromocriptine had been assessed. A significant prolactin reduction was noticed within 6-12 months of treatment along with DA (both cabergoline plus bromocriptine). Imply prolactin level decreased through 3162. 8 ng/ml to at least one. 52 ng/ml (p-value = 0. 01). Within two years, 73. 2% of cases had prolactin level normalization and the majority experienced received cabergoline, as demonstrated in Table a few with a p-value of 0. 03.
Forty-five (83. 3%) out associated with 54 sufferers who obtained cabergoline and 19 (63. 3%) away of 30 patients taking bromocriptine got normalization of prolactin within two yrs. In the remaining 10 patients, nine had been lost in order to follow-up after the first clinic visit and 1 patient acquired not checked prolactin. At the last documented follow-up check out, 79. 4% of individuals achieved biochemical outcome along with DA, possibly cabergoline or even bromocriptine or both as shown within Figure 1 .
Prolactin normalization with medical management was significantly higher in microadenoma as compared to in macroadenoma and large prolactinoma (88. 9% vs 65. 9% and 52. 9% correspondingly; p-value sama dengan 0. 002).
Significant shrinkage in adenoma was mentioned post-treatment. Suggest tumor dimension at the particular time associated with diagnosis decreased from 2. 18 centimeter to 1. 04 cm measured on the last follow-up (Table one ). In 2 yrs followup visit, 96 patients underwent MRI, amongst them 44 (45. 8%) had a lot more than 50 percent reduction within tumor size. MRI of 98 sufferers at the final documented follow-up visit was recorded. Response increased to 62. 2% at the last recorded visit from 45. 8% (at two years). Out of 98 patients, fifty five received cabergoline, 30 received BRC plus 13 obtained both medicines but on separate times. Radiologic outcome was achieved in thirty six (65. 45%) cases receiving CAB and 18 (60%) receiving BRC. Subgroup analysis is because shown in Table 4 .
More compared to 50% reduction in growth size has been seen within 24 (60. 6%) out there of 36 microadenoma, 27 (61. 4%) out associated with 44 macroadenoma and 10 (55. 6%) out of eighteen giant prolactinomas. Patients who were followed for more than 2 years showed a greater radiological reaction. Thirty-one patients were adopted for more than five years and radiological outcome had been achieved in 70% of patients.
Complete resolution associated with adenoma was seen in 13 patients (nine were microadenoma, two macro and two giant adenomas). Amongst them, 11 had received cabergoline and 2 had received bromocriptine. 2 patients experienced progressive disease (one giant prolactinoma plus one macroadenoma). After starting DA two patients created cerebrospinal liquid (CSF) rhinorrhea (one huge and a single macroadenoma). Both patients presented within one particular month of starting bromocriptine. A significant reduction associated with prolactin degree and dimension of tumor was seen after repair in one individual. Treatment response was not assessed in the second patient because he has been lost to follow up after the repair of defect.
Scientific response had been documented since either enhancement in symptoms or visual defect or even resolution associated with clinical signs and symptoms or visible defect. Most patients (74. 5%; 73/98) showed improvement or resolution of medical symptoms within 6-12 months of therapy with DE UMA, and it was recorded at the last follow-up that will 91 (92. 9%) patients reported enhancement or quality of symptoms as proven in Table 5 . During scientific encounters, among 45 individuals who got visual disturbance 23 (51. 1%) acquired significant improvement three (6. 7%) had complete resolution and 15 (33. 34%) had persistent visual field defects along with medical management.
DA withdrawal was attempted in eight instances. Three sufferers had successful withdrawal associated with the medication and are under surveillance. The drug was restarted in 5 patients due to recurrence of signs and symptoms and an increase in prolactin levels inside 6-12 weeks of tapering. Eight situations of macroadenoma were kept at the particular lowest feasible dose of DA and there was simply no recurrence associated with tumor on the lower suppressive dose.
So far there will be well-established data within the books suggesting that medical administration with DA is the mainstay of treatment of prolactinoma [9,10] . Compared in order to the international literature upon prolactinoma, there is a paucity of data within our region. To our knowledge, only one study has been conducted in our country to analyze the end result of medical management within prolactinoma yet with a small sample size (n=68)  . In recent years cabergoline offers gained popularity over bromocriptine in the treatment of prolactinoma because cabergoline controls prolactinoma more efficiently and is better tolerated  . In one meta-analysis associated with four randomized trials simply by Santos et al. (sample size of 743 patients)  , normalization associated with serum PRL levels demonstrated a substantial difference in favor of the cabergoline group (RR 0. 67 [CI 95% 0.57, 0.80]) plus adverse events like nausea and vomiting were considerably less frequent in the particular cabergoline-treated patients, (RR 1. 66 [CI 95% 1.33, 2.06]) and (RR second . 02 [CI 95% 1.13, 3.59], respectively). In our low-income and developing region bromocriptine is still being widely used because of its low price and accessibility. Within our research, we observed that a significant number of individuals were started on bromocriptine instead of cabergoline due to its affordability. In our study, 55. 1% of individuals received cabergoline and 31. 8% obtained bromocriptine.
We compared the clinical characteristics of males and females at display and discovered a similar trend within our region. In a single retrospective cohort research  , prolactinoma had been the most common pituitary adenoma accounting designed for 57. 4% of almost all adenomas, with female gender predominance (81%) and female patients being younger. Similarly, in our study, the majority of our population was female (66. 4%) and had previously presentation compared to men (mean age has been 35 many years for guys and thirty-two years just for women). While comparing symptoms at presentation of prolactinoma, our results were similar to international information [10,13] . In the single center experience associated with 12 yrs by Almalki et al.  , it was noticed that the majority of sufferers presented with headaches (87. 8%), in males most typical clinical presentation had been visual disruption (70. 8%) and amongst females, it was amenorrhea (55. 6%). We also found that headache is one of the particular most common signs and symptoms among just about all prolactinoma patients as well as the vast majority of females presented along with menstrual problems (73. 2%, p-value < 0. 001). The most common presenting symptom among males was visual disturbance (80. 6% with a p-value of 0. 001) plus 30. 6% of individuals given erectile dysfunction.
It has been suggested in the literature that will prolactinomas within men are usually larger than in females. Within a study conducted by Delgrange ainsi que al.  , of 45 as well as 51 women with prolactinomas, prolactinomas were significantly larger in men of most ages. This is likely due to the later demonstration of males. All of us observed an identical trend within our study with giant prolactinoma more prevalent in men (15 associated with 19; G < 0. 001) and microadenoma becoming more common within females (35 of 37; P < 0. 001). Within our cohort, we determined a positive correlation between prolactin level plus tumor size (r = 0. 469, P sama dengan 0. 001).
A review simply by Duskin-Bitan and Shimon  , summarizing 15 cohorts of sufferers with prolactinoma treated medically mostly along with cabergoline, showed 76% of men normalized prolactin during follow-up. Our study also showed that a considerable number associated with patients demonstrated normalization of prolactin within two years associated with treatment (73. 2%).
This study clearly shows that cabergoline (CAB) is usually better than bromocriptine (BRC) in achieving the outcome which is comparable to previously published data. In a recent article by Rudman et al.  , macroprolactinomas in men were controlled with cabergoline in 84% of cases. In another retrospective comparison of CAB and BCR in hyperprolactinemia by Arduc et ing.  , CAB has been found more effective than BCR in controlling symptoms of hormone excess, normalization associated with PRL (87. 4 versus. 41. 4%) and tumor shrinkage (79. 8 ± 39. one vs . fifty four. 1 ± 55. 3%). We furthermore found an overall similar response. We observed 83. 3% biochemical reaction with cabergoline and 63. 3% with bromocriptine suggesting that cabergoline is a lot more effective than bromocriptine within controlling prolactin level. The particular radiological response rate in our study had been seen in 65. 45% treated with TAXI and 60% given BCR documented in the final follow-up go to.
In 1 review article  , summarizing 12 published series of patients with macroprolactinomas (n=309) treated with CAB, prolactin normalized within 80% from the cases and the tumor shrunk significantly in 87% of patients. The reason for the comparatively low radiological response within our study (65. 45%) compared to this study is probably because we still use bromocriptine in a significant quantity of patients that is inferior in order to cabergoline within tumor shrinking. Another reason is that all of us calculated a 50% or more reduction in tumor volume, whereas other studies in this article included any shrinkage in lesion.
In a cohort associated with 71 individuals of large prolactinoma simply by Hamidi ou al., 55% of sufferers had PRL normalization plus 26% experienced no visible tumor from follow-up  . In our cohort, we all observed a similar trend within prolactin normalization (52. 9% giant prolactinomas showed prolactin normalization) and complete resolution of the tumor was seen in only 2 giant prolactinomas (10. 5%).
DAs are not just effective within prolactin normalization and growth shrinkage, but patients show remarkable medical recovery as well. In one single-center retrospective study  , CAB resulted in improvement within visual industry defects in 68% and hypogonadotropic hypogonadism recovered within 32% of the patients after TAXI therapy. We all observed that will 96. 4% of subjects with CAB and 86. 70% along with BCR showed a clinical response plus 51. 1% of individuals had enhancement of visual field defects. Relatively, a low percentage associated with improvement within the visual field in our own population may be owing to the make use of bromocriptine in some patients whereas in this worldwide study they only used cabergoline. We also reported two instances of CSF rhinorrhea in our populace after beginning dopamine agonists. Both required surgical restoration of the particular defect and presented inside one month of starting therapy  .
Within our cohort, a few confounders existed. Lack of reaction in the few patients was attributed to noncompliance with medications plus fewer followup visits associated with patients in our region rather than the drug. Also, the cost of medication and laboratory/radiological investigations also led to infrequent investigations and hence follow-up. The exact treatment duration needed for achieving outcome could not be evaluated in a few patients because being a tertiary care setup most patients had been already getting DA before presenting in order to our middle.
Further comprehensive analysis is required to look for outcome of some other modalities within medically resistant and aggressive prolactinoma, i. e., the use of temozolomide [4,22] and tyrosine kinase inhibitors. Surgical resection of prolactinoma is used since adjunctive therapy if no reaction to DA is seen. Within the era of endoscopic surgery as well as the development associated with surgical techniques, it is time to reassess the relationship between DAs and surgery. Internationally multiple retrospective studies plus meta-analyses have got been executed to appearance for the particular safety and efficacy of surgery like a first-line treatment in prolactinoma [23-25] . This needs to be looked with within our area as well.
Clinical display and demographics of prolactinoma are identical in our region when compared to all of those other world. Bromocriptine being cost-effective is nevertheless being broadly used in our region and we found this inferior to cabergoline within prolactin normalization, adenoma shrinkage and improvement of symptoms. Our research reinforces that cabergoline must be used as first line or bromocriptine should become switched in order to cabergoline in the event that a desirable treatment reaction is not achieved. Patients ought to be implemented up on regular interval even after stopping dopamine agonists to consider repeat. The outcome can be improved by insisting on drug compliance.