Large Nonfunctioning Pituitary Adenoma Presenting with Visual Loss During Late Pregnancy—Challenges in Management
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Nonfunctioning pituitary adenomas (NFPA) are very rare during pregnancy since fertility is usually impaired. A 31 year old hirsute woman was referred to the Endocrine Clinic for a large pituitary tumor, discovered at 35 weeks of gestation. She complained of increasing headache and abnormal vision, particularly in her left eye in the previous few weeks. An MRI scan showed a pituitary mass: 3.1 ×2.7 ×1.8 cm (LL/CC/AP) with suprasellar extension, and compression of the optic chiasm. Serum prolactin and the results of other endocrine investigations were normal, so she was diagnosed with NFPA. Both inducing labour or medication (bromocriptine) administration while proceeding to a safe term for pregnancy were considered. However, we chose to only follow her closely. There was no further deterioration and, at 38 weeks, a caesarian section was performed and a healthy boy was delivered. Two weeks after delivery, she underwent craniotomy (by right lateral subfrontal approach) with resection of the NFPA, followed by complete regression of the visual disturbances. The postoperative MRI demonstrated empty sella and no residual tumor, while the hormonal evaluation detected no significant pituitary insufficiency. Although cost-effective, combined histologic and immunophenotypic studies, especially extended IHC tests, can reduce the incidence of misdiagnosed large-cell lymphoma. As exemplified in this present case, obtaining appropriate and sufficient tissue from the tumor could possibly increase the chance of finding an accurate diagnosis.
Keywordslarge nonfunctioning pituitary adenoma pregnancy visual disturbances pituitary gland visual field defect
Pituitary tumors constitute 10 to 15% of all intracranial neoplasms tumors. When a pituitary tumor appears during pregnancy or a patient with a pituitary tumor achieves pregnancy, the difficulties in recognizing and establishing the diagnosis and choosing the appropriate management are even greater. Prolactinomas, representing about 40% of all pituitary adenomas in the general population, are the most common causes of pituitary enlargement during pregnancy.  Nonfunctioning pituitary adenomas (NFPAs), accounting for approximately 25 to 35% of pituitary tumors, are not common during pregnancy.  This can be explained by the fact that they are associated with decreased fertility in these patients, due to impairment in gonadotropin secretion and/or hyperprolactinemia, prevalent in 36–96% of patients with macroadenomas. [1, 3]
The growth of NFPA during pregnancy is unexpected, as estrogenic stimulation does not seem to influence this kind of adenoma. 
This article reports the case of a hirsute woman diagnosed with NFPA that led to visual field abnormalities during her second spontaneous pregnancy, representing the largest NFPA diagnosed in a pregnant woman.
The patient came to our clinic 2 days after performing the MRI and 2 weeks after that episode of severe headache and blurred vision (which did not repeat meanwhile). Physical examination revealed a conscious and well-oriented young woman. She was not pale, icteric, or febrile. Blood pressure on admission was 100/70 mmHg and the pulse rate was 90 beats per minute, regular, and of good volume. There were no signs or symptoms of acromegaly, of Cushing syndrome, or, on the contrary, of adrenocortical insufficiency. Confrontation visual field testing revealed loss of vision in the temporal field, more pronounced in the left eye. Of note was also the presence of hirsutism (a Ferrimann-Gallwey score of 22).
There were no specific past medical or surgical histories. Three years before she delivered a healthy child by cesarean section because of obstetrical indication. She admitted significant menstrual irregularities before the first pregnancy but regular periods after that. Therefore, we thought that she might have been suffering from polycystic ovary syndrome (PCOS).
Relevant investigations were ordered. The results were as follows: serum prolactin (PRL = 1785.8 μUI/ml (normal values, 127–637/normal values 3rd trimester, 1107–7390) and repeated 100.3 ng/ml (normal values, 1.3–20) (prolactin, dilution 1:10 = 86.5 ng/ml and 1:100 = 147 ng/ml)), serum freeT4 = 8.58 pmol/l (normal values, 10.6–22.7/normal values 3rd trimester, 8.39–15.6), TSH = 1.62 μUI/ml, serum cortisol was low–normal = 366 nmol/l (normal values, 172–497/normal values 3rd trimester, 331–1380), and ACTH = 62.84 pg/ml (normal values, 7.2–63.3). To emphasize, PRL levels, measured twice, were appropriate for her gestational age. Therefore, she was diagnosed as having a nonfunctioning pituitary tumor.
Abdominal-pelvic ultrasound revealed a live singleton fetus at 35 weeks with cephalic presentation and anterior placenta. The fetal heart rate was 130/min.
Both the obstetric team and patient herself were reluctant to cesarean section at that moment. So we decided to repeat the perimetry to check if there is a rapidly progressive visual loss. The ophthalmological exam showed visual acuity of 0.8 in the right eye (1 with correction) and 0.3 in the left eye (0.6 with correction) and the visual field testing revealed no further visual loss. Since the headache was not significant at the moment of presentation, there was no further deterioration of visual abnormalities and the patient was very reluctant to take drugs‚ close monitoring of the patient and her pregnancy, as outpatient, has been chosen until reaching a gestational age closer to the term. No glucocorticoids or dopamine agonists were initiated, and she was scheduled for cesarean section at the beginning of week 38 of gestation.
The patient was seen weekly for another 2 weeks for assessments of symptoms such as headache and visual problems. At 38 weeks of gestation, a cesarean section was performed (with steroid coverage—during the procedure) and a healthy 3070 g boy, with Apgar scores of 9, was delivered. Postpartum, the patient was keen to breast-feed. The patient and the newborn were discharged without complications 5 days after delivery. The hormonal assessment was repeated: the results were normal again, as follows: prolactin = 57.5 ng/ml, serum freeT4 = 1.01 ng/dl, serum cortisol = 15.6 μg/dl (normal values 5–25 μg/dl).
The hormonal levels were as follows: cortisol 8 a.m. = 13.1 μg/dl; TSH = 0.94 μUI/ml; FT4 = 1.01 ng/dl; FSH = 3.10/3.97 U/l; LH = 0.51/1.87 U/l; estradiol = 54.7/37.1 pg/ml; prolactin = 10.5 ng/ml; testosterone = 0.25 ng/ml; DHEAS = 1.03 μg/ml.
As far as we know, this is the largest reported case of NFPA diagnosed de novo in pregnancy. In patients with NFPAs, fertility is usually impaired by the destruction of gonadotroph cells or hyperprolactinemia caused by pituitary stalk destruction. Pregnancy is, therefore, a rare event in patients with such tumors.
On the other hand, the growth of a NFPA during pregnancy is unexpected, as estrogenic stimulation does not seem to influence this kind of adenoma . The enlargement of a pituitary adenoma can be due to tumor growth, infarction, or hemorrhage of tumor. 
However, it has been shown that approximately 20% of macroadenomas may lead to abnormalities in visual fields or other neurologic signs, usually in the first half of pregnancy. On the other hand, the lactotroph hyperplasia that occurs in all pregnancies may increase pituitary gland size up to 136% or 12 mm in height [4, 5], thus pushing the pre-existing pituitary tumor towards the optic chiasm. However, some authors suggested that this physiologic phenomenon is usually not enough to lead to compressive symptoms, unless the tumor itself grows.  Furthermore, these changes almost always revert to normal after delivery, so aggressive therapy for known pituitary adenomas is not indicated except in cases of rapidly progressive visual loss. 
The best approach for patients with asymptomatic NFPA is the wait-and-see policy. However, in cases of symptomatic tumor enlargement with rapidly progressive visual loss and when the fetus is immature, medical treatment using dopamine agonists can be considered to reduce physiologic lactotroph cell hyperplasia, and surgery should be considered during the second trimester. 
Our patient was diagnosed with this large NFPA only in the 3rd trimester (week 35 of gestation), actually very close to term. Obvious features of symptomatic tumor expansion were present only 3 weeks before her endocrine evaluation. Most likely, the combined factors of physiologic enlargement and incidentally detected pituitary adenoma during pregnancy influenced her newly developed headache during pregnancy. In a national, prospective, observational, population-based case series study conducted in the UK, there were 16 cases of NFPA in pregnancy, of which 5 were diagnosed de novo in pregnancy. Symptomatic tumor expansion was observed in 3 of them (two in the 3rd trimester and one in the 2nd trimester). 
We can speculate that the episode of sudden severe headache and blurred vision she suffered the day following her ophthalmological examination and 2 weeks before we saw here as outpatient was the result of a hemorrhage of the tumor (subacute pituitary apoplexy). In patients with pituitary adenomas, pregnancy may result in tumor enlargement and apoplexy due to lactotroph hyperplasia and enhanced pituitary vascularity with edema. Fortunately, the episode did not repeat and she claimed that her symptoms did not aggravate in the last weeks. The visual field test confirmed that. So, we chose not to administer glucocorticoids at that moment; however, cortisol was low–normal, so steroid coverage at the time of cesarean section and craniotomy was indicated. We did not initiate dopamine agonists either, since the time up to term was short (2–3 weeks) so a successful effect on tumor shrinkage was unlikely. Since non-secreting pituitary tumors possess few dopaminergic receptors on their cell membranes, bromocriptine has been used with very little success in reducing tumor size.  Furthermore, bromocriptine did not improve diplopia and left ptosis resulting from the enlargement of nonfunctioning pituitary adenoma during pregnancy that has not been diagnosed before pregnancy in another 39-year-old nulliparous woman.  On the contrary, others reported that 8–16% of non-secretory pituitary adenomas do respond to dopamine agonist therapy, and a direct effect of these drugs on tumor shrinkage was suggested. However, the beneficial effect of bromocriptine is usually achieved by an effect on the physiologically enlarged pituitary (physiological lactotroph hyperplasia of pregnancy).  Since the prolactin was only 3 times the upper normal values in nonpregnant women (and in ranges for the gestational age), we can assume that the lactotroph hyperplasia was not significant in her case. Moreover, dopamine agonist therapy has been considered a risk factor for pituitary apoplexy and bromocriptine has been associated with hypertension, cardiac injury, and death when used in the postpartum period in a 30-year-old nulliparous Nigerian woman.  Interestingly, except for hirsutism, she was completely asymptomatic before this pregnancy. Moreover, she complained of oligomenorrhea before the first pregnancy which spontaneously resolved after giving birth. Though the androgen hormone concentrations were within ranges, we might assume that she had a PCOS (clinical hyperandrogenemia + menstrual irregularities, other disorders excluded) which might have further impaired fertility.
Fortunately, the rest of her pregnancy was uneventful, and the surgery performed 2 weeks later was a success.
In conclusion, we present an interesting case of a young woman, most likely having PCOS with two spontaneous pregnancies 3 years apart, diagnosed with a large NFPA causing visual loss during the second pregnancy but with an excellent outcome. Pregnancy may lead to pituitary tumor growth and increase the risk of developing vision loss. On the other hand, pituitary tumor treatment may be a disturbing factor for pregnancy. When a pituitary disorder appears during pregnancy or a patient with a pituitary disorder achieves pregnancy, it becomes more difficult to recognize and establish the diagnosis and choose the appropriate management. As these rare conditions can be dangerous for both mother and fetus, it is essential to identify and treat them successfully. Pituitary disorders and particularly large pituitary adenomas causing visual abnormalities in pregnancy are certainly challenging and require a multidisciplinary approach from endocrinologists, gynecologists, radiologists, and neurosurgeons.
Finally, pituitary tumors should be taken into consideration when encountering pregnant women with visual disturbance. And, as regards to fertility chances, “never say never” in women.
II, AM, and SF managed the case. LT, AC, and II drafted the manuscript. LT, EB, II, and CG reviewed the manuscript.
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Conflict of Interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent was obtained from the patient for being included in this case report.
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
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