Macroprolactinoma during pregnancy

1. Macroprolactinoma during pregnancy

2. Clinical questions list: • 1-what is the effect of pregnancy on prolactinomasize? • 2-What is the management of prolactinoma in pregnancy? • 3-When does prolactinoma be treated during pregnancy? • 4-What are the safe drugs used in pregnancy for prolactinoma? • 5-when dose imaging (MRI) be done? • Evaluation & F/U of the pationt

3. what is the effect of pregnancy on prolactinoma size? • Basal PRL levels gradually increase throughout the course of pregnancy. There is a gradual increase in the number of pituitary lactotrophs during pregnancy and by term, PRL levels may be increased ten-fold to levels over 200 ng/ml. • These elevated PRL levels found at term prepare the breast for lactation. The lactotroph cell hyperplasia occurring during pregnancy is reflected on MRI scans which show a gradual increase in pituitary volume over the course of gestation, beginning by the second month and peaking the first week postpartum with a final height reaching to almost 12 mm in some cases Mark E. Molitch, MD, Prolactinoma in pregnancyBest Practice & Research Clinical Endocrinology & Metabolism 25 (2011)

4. Complications • Mass effect • The growing pituitary mass may impinge the surrounding structures, depending on the direction and severity of the extension. Organs that might be harmed include the optic chiasm: • the cranial nerves located in the cavernous sinuses (namely the optic, trochlear, abducens and two branches of the trigeminal nerves) • adjacent structures, such as the temporal lobe, the nasal cavity and sinuses, the internal ear and the thalamus. • The related symptoms are mainly headaches and neuro-ophthalmological, including visual field alterations and ophthalmoplegia. • Visual field defects occur more often in larger adenomas and necessitate the evaluation of visual fields in lesions abutting the optic chiasma TiroshA,Shimon.Managementof macroprolactinomasClinical Diabetes and Endocrinology2015

5. Hypopituitarism • The gonadotroph axis is most often damaged (73–86 %), presumably due to the double effect of the macroprolactinoma on this axis: increased pressure on the gonadotroph cells from the expanding mass and suppression of GnRH secretion by PRL effect in the hypothalamus . Normaltestosterone levels do not exclude the presence of PRL-secreting adenoma. • Central hypothyroidism and hypocortisolismmight also be induced by macroprolactinomas, though less often (18–41 % and 12–23 %, respectively) • Somatotrophaxis evaluation is limited in patients with PRL-secreting tumors, due to the possibility of GH and PRL co-secretion in 10 % of these adenomas. • Recovery of the gonadotroph axis was reported in most patients with (recovery of thyrotrophs in 25 % of affected patients but no recovery of ACTH secretion and Sibal et al. ) TiroshA,Shimon.Managementof macroprolactinomasClinical Diabetes and Endocrinology2015

6. Cerebrospinal fluid leak • A leak in the CSF is usually iatrogenic, due to surgery or aggressive DA treatment, although it might be the presenting symptom in some macroprolactinomas • In a recent report on this complication of various pituitary adenomas, PRL-secreting tumors were reported in 81 % (42/52) of cases, many of these being giant prolactinomas. Meningitis, a complication of CSF exposed to the outer environment, was reported in 15–20 % of cases TiroshA,Shimon.Managementof macroprolactinomasClinical Diabetes and Endocrinology2015

7. Apoplexy • Pituitary apoplexy is characterized by a rapid enlargement of the pituitary due to hemorrhage or infarct (prevalence, 0.08%) • Although this is an uncommon complication, it is potentially life threatening, characterized by severe and abrupt headache, together with nausea, vertigo and meningismus .Other symptoms might include acute hypopituitarism and neurologic compromise, including deteriorated consciousness, ophthalmoplegia and restriction of visual fields. Although the syndrome is usually acute and obvious, it may be subtle or even clinically silent • Among pituitary tumors, apoplexy tends to occur in larger lesions, due to increased discrepancy between the rate of neoplastic progression and blood supply • Importantly, not only treatment with DAs might cause apoplexy, but also its withdrawal ,possibly due to rapid re-growth of the adenoma The management of pituitary apoplexy depends on the clinical manifestations and their severity. • A main consequence of apoplexy is the adrenal crisis. Thus, administration of hydrocortisone is indicated immediately on diagnosis, in addition to appropriate glucocorticoid coverage afterwards. Transsphenoidal surgery for decompression of the sella is indicated in patients with significant visual compromise or with a diminished level of consciousness , whereas conservative management is optional for others. TiroshA,Shimon.Managementof macroprolactinomasClinical Diabetes and Endocrinology2015

8. AnaEspinosa De YcazaaAliceY.ChangApproach to the management of rare clinical presentations of macroprolactinomas in reproductive-aged womenVolume 8, October 2015,

9. Managing Prolactinomas during Pregnancy • The main concern is possible tumor enlargement during pregnancy. • The risk of tumor enlargement during pregnancy is found to depend on tumor size. Data in the literature indicate that although tumor enlargement is only 3% for microprolactinomas, it is as high as 32% for macroprolactinomasthat were not previously operated on. by MH Almalki.ManagingProlactinomas during PregnancyFrontEndocrinol (Lausanne). 2015; 6: 85.

10. MRI • A magnetic resonance imaging (MRI) should be done before conception to document tumor size and to serve as a baseline for comparison with MRIs done during pregnancy. • Furthermore, MRI is helpful in distinguishing between hemorrhage into a tumor versus simple tumor enlargement during pregnancy by MH Almalki.Managing Prolactinomas during PregnancyFront Endocrinol (Lausanne). 2015; 6: 85.

11. Cont… • The patient should be advised to report for urgent assessment in case of unusual symptoms such as severe headache or visual disturbance, to rule out the possibility of tumor enlargement. • In case of macroprolactinoma, symptomatic tumor enlargement occurs in 20–30% of cases .It has been reported that the risk of clinically significant tumor enlargement falls from over 30 to <5%, if the patient is treated with radiation or surgery before pregnancy • Pregnant women with large tumors and those with extrasellar extension who have stopped bromocriptine are at risk for tumor growth, and formal visual field testing should be done in each trimester.

12. Cont… • The patient should be advised about the symptoms and the need for urgent evaluation once they appear. • . If the patient reports headache or a change in vision, an MRI should be performed. If the MRI finding is consistent with tumor enlargement, the women should be retreated with a DA 

13. Medical therapy • Medical therapy with DAs represents the primarytherapy for : • microadenomas that require treatment • macroprolactinomas • giant prolactinomas. Melmed fourth edition

14. Melmed fourth edition

15. Efficacy of Dopamine Agonists • Several studies have reported the efficacy of bromocriptine in lowering PRL levels in patients with a prolactinoma. Bromocriptine normalized serum PRL in78% and 72% of patients with microprolactinomas andmacroprolactinomas, respectively • results from 21 series examining tumor shrinkage among 302 patients with macroadenomastreated with bromocriptine reported a significant decrease intumor size in about 77% with periods of observation ranging from 6 weeks to over 10 years • These rates of tumor shrinkage are lower than those observed with cabergoline Melmed Fourth edition

16. Williams 2016

17. Williams 2016

18. Safety of DA s: • Although dopamine agonists are typically discontinued when pregnancy is confirmed, pregnancy has usually progressed at least two weeks before confirmation occurs and the drug discontinued, so the fetus is exposed to the dopamine agonist during that time. Evidence to date does not suggest risk to the fetus from this exposure. • Data from over 6000 pregnancies suggest that the administration of bromocriptine during the first month of pregnancy does not harm the fetus . In this series, the incidence of spontaneous abortions (9.9 percent), multiple births (1.7 percent), and malformations (1.8 percent) was no higher than in the general population. In addition, in a study of children followed for up to nine years after exposure to bromocriptine in utero, no harmful effects were noted . • Rarely, dopamine agonist treatment is resumed during pregnancy if adenoma size increases so much as to impair vision. Continuous use of bromocriptine during pregnancy has been reported in approximately 100 women. Although the rate of congenital malformations did not appear to be higher than non-exposed pregnancies, there was one case of undescended testis and one of talipes deformity . • Molitch ME. Prolactinoma in pregnancy. Best Pract Res ClinEndocrinolMetab 2011; 25:885.

19. Although the number of pregnancies in women taking cabergoline at the time of conception is much smaller, the evidence suggests that this drug is safe as well. In one review of over 700 cases, the incidence of spontaneous abortions (7.6 percent), multiple births (1.7 percent), and malformations (3.2 percent) was no higher than in the general population . • MolitchME. Prolactinoma in pregnancy. Best Pract Res ClinEndocrinolMetab 2011; 25:885.

20. Mussa Hussain AlmalkiManagingProlactinomas during PregnancyPublished online 2015,

21. williams2016

22. Guide line 2011 • In selected patients with macroadenomas who becomepregnant on dopaminergic therapy and who have not hadprior surgical or radiation therapy, it may be prudent tocontinue dopaminergic therapy throughout the pregnancy, especially if the tumor is invasive or is abutting theoptic chiasm (1QEEE).

23. First response to therapy may be expected as soon as a week or two after treatment initiation. However, in some patients shrinkage may become noticeable after only 6 months of therapy by MH Almalki.ManagingProlactinomas during PregnancyFrontEndocrinol (Lausanne). 2015; 6: 85.

24. Case Reports in Women's Health Volume 8, October 2015, Pages 9-12 • Approach to the management of rare clinical presentations of macroprolactinomas in reproductive-aged women Patients with prolactinoma and apoplexy usually develop apoplexy within 1 week to 12 months after initiation of dopamine agonists. No data are available about the risk of recurrent apoplexy and likely reflects the very low risk of a recurrent event. Without data to guide who would benefit from continuing dopamine agonists during pregnancy, practice varies. Dopamine agonists might be continued or restarted during pregnancy for macroprolactinomas with suprasellar extension, especially if the patient has mass effect symptoms [

27. Pituitary apoplexy may represent thefirst presentation of a pre-existing, unrecognized adenoma in over 80 % of cases • precipitating factors :hypertension, major surgery especially coronaryartery bypass grafting, dynamic pituitary testing usinggonadotropin-releasing hormone (GnRH), thyrotropinreleasing hormone (TRH), corticotropin-releasing hormone(CRH), insulin tolerance test, anticoagulation therapy, coagulopathies, estrogen therapy, initiation or withdrawal ofdopaminergic therapy, radiation therapy and head trauma,and pregnancy

28. Pituitary surgery is indicated in patients who: • cannot tolerate • resistant to therapy with Das • patients that seek fertility and harbor adenomas that impinge on the optic chiasm • psychiatric patients with contraindication to DA pituitary • apoplexy • cerebrospinal fluid (CSF) leak • Management of macroprolactinomasClinical Diabetes andEndocrinology2015

29. Resistance to DAs has several different definitions in the literature, including : • failure to achieve normal PRL levels or adenoma shrinkage of >50 % • failure to reduce PRL by >50 %, or to induce ovulation in women • failure to reduce symptoms or normalize PRL despite CAB dose ≥2 mg/week • The prevalence of CAB resistance according to this criteria is 11 % among patients harboring macroprolactinomas

30. Summary of recommendations for management of adenoma before and during pregnancy Pre-pregnancy • Complete pituitary hormonal work-up with visual fields assessment on physical examination to establish proper diagnosis of pituitary lesion • If diagnosis of micro or macroprolactinoma is confirmed and desire to become pregnant is expressed, treatment with dopaminergic agonist (bromocriptine or cabergoline) to reduce size of the tumour and controlled prolactin level before pregnancy is recommended. • For all macroadenoma, consider treatment for reduction in size to less than 1 cm before pregnancy preferably with effective medication (e.g.dopaminergic therapy for macroprolactinoma) and/or surgery/radiotherapy if indicated, to minimise the risk of apoplexy and pressure on the opticchiasm during pregnancy.Management of macroprolactinomasClinical Diabetes andEndocrinology2015 • Management of macroprolactinomasClinical Diabetes andEndocrinology2015 of macroprolactinomasClinical Diabetes andEndocrinology2015

31. During pregnancy • In women with microprolactinoma, discontinue dopamine agonist therapy when pregnancy is confirmed. In women with macroprolactinoma whobecome pregnant under therapy, it seems reasonable to continue dopamine agonist therapy throughout the pregnancy, especially if the initial tumourwas invasive or close to the optic chiasm given the high risk (31%) of tumour growth or apoplexy during pregnancy. • Plan a physical examination and an evaluation of thyroidotroph and corticotroph axis functions at each trimester (with follow-up of T4 level and urinaryfree cortisol, which is more reliable than plasma cortisol during pregnancy) in near-to and confirmed macroadenomas to avoid unrecognised relativepituitary insufficiency. Routine evaluation of prolactin level during pregnancy is not recommended for asymptomatic patient. • Visual fields should be checked by an ophthalmologist once during pregnancy for women with near-to or established macroadenomas. Repeat visualfields during the third trimester for macroadenoma only.TiroshA,ShimonManagementof macroprolactinomasClinical Diabetes andEndocrinology2015

32. Cont… • Inform all patients with micro or macroadenomas about symptoms that could be related to tumour growth or apoplexy (sudden thunderclap headache, visual disturbance) and advise them to come rapidly to the hospital if they become symptomatic for a hormonal and radiologic work-up. Routine radiologic follow-up of adenomas is not recommended during pregnancy. However, if clinical suspicion of tumour growth or apoplexy(development of neurological or visual symptoms), proceed to urgent pituitary MRI without gadolinium, formal visual fields assessment and hormonal work-up. • If significative growth of a prolactinoma is established and the patient experiences some neurological symptoms, reinitiation or increase of the dose of dopamine agonist therapy is recommended. If dopamine agonist therapy does not decrease tumour size and improved symptoms, consider surgical resection, especially in patient with documented optic chiasm compression and visual fields disturbance. If the fetus is near-term, it may be reasonable to induce delivery before neurosurgical intervention. • TiroshA,ShimonManagement of macroprolactinomasClinical Diabetes andEndocrinology2015

33. There is no definitive answer as to the best therapeutic approach in such a patient and this has to be a highly individualized decision that the patient has to make after a clear, documented discussion of the various therapeutic alternatives. • One approach is to perform a prepregnancytranssphenoidal surgical debulking of the tumor. This should greatly reduce the risk of serious tumor enlargement, but cases with massive tumor expansion during pregnancy after such surgery have been reported. • M.E. Molitch / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 885–896

34. After surgical debulking, a dopamine agonist is required to restore normal PRL levels and allow ovulation. • Radiotherapy before pregnancy, followed by a dopamine agonist, reduces the risk of tumor enlargement also, it is rarely curative. Radiotherapy may also result in long-term hypopituitarism,sothat this approach seems less acceptable than transsphenoidal surgery plus a dopamine agonist. • A third approach, that of giving bromocriptine continuously throughout gestation, has been used but data of effects on the fetus are quite meager and data on the effects of continuous cabergolineon the fetus are even fewer; therefore, such treatment cannot be recommended without reservation. Should pregnancy at an advanced stage be discovered in a woman taking bromocriptine or cabergoline, however, the data that exist are reassuring and would not justify therapeutic abortion. • A fourth approach, and the one most commonly employed, is to stop the dopamine agonist after pregnancy is diagnosed, as in the patient with a microadenoma. For patients with macroadenomas treated with a dopamine agonist alone or after surgery or irradiation, careful follow-up with 1–3 monthly formal visual field testing is warranted M.E. Molitch / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 885–896

35. Repeat MRI • Repeat MRI is reserved for patients with symptoms of tumor enlargement and/or evidence a developing visual field defect or both. Repeat scanning after delivery to detect asymptomatic tumor enlargement may be useful as well. • Should symptomatic tumor enlargement occur with any of these approaches,reinstitutionof the dopamine agonist is probably less harmful to the mother and child than surgery. There have been a number of cases reported where such reinstitution of the dopamine agonist has worked quite satisfactorily, causing rapid tumor size reduction with no adverse effects on the infant • Any type of surgery during pregnancy results in a 1.5–fold increase in fetal loss in the first trimester and a fivefold increase in fetal loss in the second trimester, although there is no risk of congenital malformations from such surgery. • Thus, dopamine agonist reinstitution would appear to be preferable to surgical decompression. However, such medical therapy must be very closely monitored, and transsphenoidalsurgery or delivery [if the pregnancy is far enough advanced] should be performed if there is no response to the dopamine agonist and vision is progressively worsening. M.E. Molitch / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 885–896

36. Postpartum • Breastfeeding and dopamine agonists — Breastfeeding increases serum prolactin concentrations ,but does not appear to increase the risk of lactotroph adenoma growth . Therefore, breastfeeding is an option for women with micro- and macroadenomas that remained stable in size during pregnancy. Dopamineagonist therapy, which lowers serum prolactin and inhibits lactation, should be withheld until breastfeeding is completed. • In contrast, breastfeeding is contraindicated in women who have visual field impairment after delivery because they should be treated with a dopamine agonist. • Bronstein MD, Salgado LR, de Castro Musolino NR. Medical management of pituitary adenomas: the special case of management of the pregnant woman. Pituitary 2002; 5:99.

37. Normalization of prolactin after pregnancy • A significant percentage of women with lactotroph adenomas appear to have a remission after delivery, and no longer requiredopamine agonist therapy. • To evaluate the need for further dopamine agonist therapy after pregnancy, serum prolactin should be measured about three months after delivery in women who do not breastfeed, and after cessation of breastfeeding in those who do. Serum prolactin normalizes within 6 to 12 weeks postpartum in women who do not breastfeed

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