Could hormonal remission in prolactinomas be achieved with surgery ? Our experience

Material and methods. In this study, retrospective analysis of 33 patients with pituitary adenomas with no prior DA treatment was performed. Ten (30.3 %) patients experienced microprolactinomas, 19 (57.6 %) — macroprolactinomas, 4 (12.1 %) — giant prolactinomas. All patients underwent endoscopic endonasal transsphenoidal surgery. Plasma PRL levels were obtained before surgery, and then 1 day, 1 week, 1 month, 3 months later and every 6th month after surgery. MRI monitoring was performed before surgery and then 3 and 12 months later, and then annually.

Microprolactinomas (< 10 mm in diameter) are more common in women than in men.Symptoms of microprolactinomas in women come up right at the disease onset and manifest with amenorrhea and galactorrhea.Meanwhileб in men symptoms might come later with impotence and decreased libido.Macroprolactinomas (≥ 10 mm in diameter) are more frequent in men and may present with a tumor mass effect manifesting with visual disturbances, visual field defects.Giant prolactinomas are not often, its prevalence is 0.5-4.4% of all pituitary cases [6][7][8][9].Very high prolactin (PRL) serum level is revealed in giant PA.Nowadays microprolactinomas are more often diagnosed than it was before.Since the beginning of 1970s, dopamine agonists (DA) were recognized as an effective medical treatment of macroprolactinomas [10,11].Bromocriptine, an ergot derivative that binds to and stimulates dopamine (D2) receptors on lactotrophic cells, represents the initial treatment.It has proved to be effective in suppressing PRL secretion, reducing prolactinoma size and restoring gonadal function in many patients [12][13][14] when using bromocriptine [15].The recent studies showed that normal PRL level can be achieved in 80-90 % when using DA therapy.Relevant systemic side effects, including vomiting, nausea, dizziness, headache have been reported in about one third of patients treated with DAs [16,17].
Preoperative work-up All patients had a fasting PRL serum level.Besides, we evaluated anterior pituitary functions.Plasma PRL levels were obtained before surgery, and then on the 1 st day, 1 st week, 1 st month, 3 rd month and every 6 th month after surgery.
All patients were consulted by ophthalmologist for visual field defects, sight accuracy was checked.
Magnetic resonance imaging (MRI) of the sellar region was performed with gadolinium to all the patients.MRI was performed before surgery and then 3, 6 and 12 months later, then annually after surgery.High-resolution paranasal sinus computed tomography (CT) sections were obtained and reconstructed in a three-dimensional fashion.Cavernous sinus invasion was evaluated by MRI and/or during the surgery.

Surgical technique
All patients under went endoscopic endonasal trassphenoidal surgery using binostril (4-hand) technique.A patient was in supine position.The head was positioned with slight rotation towards the surgeon and about 20° inclination to align paraseptal corridor to facilitate endoscopic exposure.We used 0° or 30° angle (Karl Storz, Tuttlingen, Germany) for binostril endoscopic approach.Inside the sphenoid sinus bony landmarks were defined such as: sella turcica, optic protuberance, carotid protuberances, opticocarotid recess, tuberculum sella.Sella turcica was opened widely, from one cavernous sinus to the other, which ensured the maximum exposure of the sella turcica and its contents (tumor, pituitary gland).EET technique allows visualize the pituitary gland, identify the tumor and a safe tumor dissection from surrounding anatomically important structures (medial wall of cavernous sinus, pituitary gland, pituitary stalk) was performed.After tumor removal, sella turcica reconstruction was performed in respect to CSF leak, using multilayer technique (inlay of fascia lata and outlay + nasoseptal flap) or free grafts (fat + bone or fascia lata + bone).
Cavernous sinus invasion was observed in 16 (48.4%) cases confirmed by MRI and during surgery.Seventy-six percent of female patients complained about amenorrhea and/or infertility, and 5 (35.7 %) male patients had symptoms including decreased libido and/or impotence.Galactorrhea appeared in 7 (21.2%) female patients.In 9 cases symptoms included visual disturbances.
The biochemical remission was achieved in 10 (100 %) cases of microadenomas, in 7 (58.3%) cases of macroadenomas after surgery with no DA therapy.Follow-up lasted to 3 years.Hypopituitary syndrome was observed in 14 (42.4 %) cases.Cavernous sinus invasion has a significant effect on further hormonal remission [18].Depending on cavernous sinus invasion, hormonal remission with no DA therapy after surgery was achieved in Knosp 0-2 in 16 (94.1 %) cases, Knosp 3 -in 4 (44.4 %) cases.In cases of Knosp 4 biochemical remission was not achieved at all 7 (100 %) patients.Only with further DA therapy biochemical remission was achieved.
Endocrinological remission was achieved in 18 (81.8%) cases with no DA therapy after surgery.Hormonal disorders were not present in 6 (18.2 %) cases.
Visual improvement was observed in all (100 %) cases after surgery.
Postoperative complications such as CSF leak, meningitis, additional oculomotor disorder or visual impairment have not been established.No mortality.

Discussion
Among all the hormone-active pituitary adenomas, prolactinomas are the most common.As recent studies show, high levels of PRL are observed both in micro and macroadenomas [18][19][20][21][22]. Giant prolactinomas are characterized by extremely high PRL level in plasma, which can be up to 10.000 ng/ml.In our series, the average PRL serum level was 530 ng/ml, ranging 65-1440 ng/ml.In case of microadenomas, the mean prolactin level was 573.1 ng/ml, ranging 65-1440 ng/ml.For macroadenomas mean PRL serum level was 442.6 ng/ ml, ranging 236-850 ng/ml.In case of giant pituitary adenomas, the average PRL level was 525.2 ng/ml, ranging 426-1036 ng/ml.Drug therapy decreased PRL level to normal in 40-100 % cases.Menses normalized in 77 %, sexual function restored in men by 60-100 %, visual disturbances regressed in 67-84 % [2,17,18,20,23,24].DA therapy has number of side effects.It is known that DA affects the pituitary D2 receptors that inhibit the activity of adenylyl cyclase and, as a result, suppress gene transcription and prolactin secretion.However, DAs have a significant effect on other dopamine, serotonin androgenic receptors, which leads to severe neurological disorders such as postural hypotension or dyskinesia, psychosis, or mania, which provoke compulsive states [25][26][27].Patients with pituitary microadenomas were offered for medication therapy for several years with a possible biochemical remission of 40-100 % [17], or EET surgery over the micro and macroprolactinomas (tumor should be removed in capsule).This allows biochemical and clinical remission to be achieved within a short period of time.Macroadenomas would give recurrence over 6month period in more than 40 % cases.We noticed that starting from 25 mm would likely to recure.Meanwhile, adenomas, which size is less than 24 mm, would give 88.9 % remission in catamnesis up to 4 years, but giant pituitary adenomas are always to cured.There are several features that leads to recurrence, one is the tumor size, and the other is cavernous sinus invasion [18,24,28].Cavernous sinus invasion significantly influents the remission rate; p = 0.003.In case of cavernous sinus invasion, we have PRL remission in Knosp 0-2 in 16 (94.1 %) cases, Knosp 3-4 -in 44.4 % (Fig. 1).In Knosp 4 invasion all patients experienced recurrence.Also, there was relation between hormonal remission and tumor size (p = 0.000).Biochemical remission after surgery was achieved in all 10 (100 %) cases with microadenomas, in 9 cases (88.9 %) with macroadenomas, which size is less than 24 mm, with no use of DA (Fig. 2).
Indications for surgery were: ophthalmic disorders, hypopituitary syndrome, patient's choice for surgery to avoid DA therapy with their consequences.In order to have total removal with capsule, to control the hormone level, the removal of the tumor should be radical.The surgery option was proposed only in cases of microadenomas and adenomas up to 18 mm.It is known that prolactinomas decrease in size by 50 % just on medication therapy, but fear to have visual deterioration or pituitary function decrease over this period of time is high.
We offer prolactinoma surgery vs DA therapy in order to avoid the latter.It was patient's conscious choice to have 100 % microadenoma removal with 100 % success biochemical remission, rather than 40-100 % in medication DA therapy with all following consequences.

Conclusions
Biochemical remission could be achieved surgically, especially in microprolactinomas, in 100 % cases.
Ophthalmic symptoms regression is achieved in 100 % patients, faster in comparison to DA therapy.M e n s e s n o r m a l i z e d i n 1 0 0 % c a s e s o f microprolactinomas and in 86 % in macroadenomas with size up to 24 mm.