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乳汁漏出症

著者: 榎戸克年 昭和大学藤が丘病院 乳腺外科

監修: 中村清吾 昭和大学医学部外科学講座乳腺外科学部門

著者校正/監修レビュー済:2021/10/27
患者向け説明資料

概要・推奨   

  1. 乳汁漏出症の原因は多岐にわたるが、主な原因は使用している薬剤やプロラクチノーマによる高プロラクチン血症である。それぞれの原因に応じた検査や治療を選択することが推奨される(推奨度1)。
  1. 高プロラクチン血症を呈する乳汁漏出症に対しては、高プロラクチン血症のガイドラインに沿って治療方針を決定することが推奨される(推奨度1)。
  1. 血清プロラクチン値が高値の患者に対して、頭部MRI検査を行うことが勧められる。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
榎戸克年 : 未申告[2021年]
監修:中村清吾 : 講演料(アストラゼネカ,第一三共,中外製薬),研究費・助成金など(CESデカルト,第一三共,シスメックス,アストラゼネカ,島津製作所,大鵬薬品工業),奨学(奨励)寄付など(エーザイ,コニカミノルタ,大鵬薬品工業,中外製薬)[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更無し)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 妊娠・授乳期とは無関係に出現する乳汁の分泌を乳汁漏出症と呼んでいる。
  1. 主にプロラクチノーマ(プロラクチン産生下垂体腺腫瘍)や薬剤性の高プロラクチン血症に伴う症状であるが、まれに甲状腺機能低下症、腎機能低下、外傷や手術などのストレスが誘因になることがある。<図表>
 
プロラクチノーマの頭部MRI(矢状断)

大きなプロラクチノーマ(a)、赤く示されたプロラクチノーマ(b)が神経を圧迫している。

 
  1. 血中プロラクチンが高値を示せば診断は確定される。
  1. 高プロラクチン血症のため、女性では、不規則な月経周期・無月経となることがある。男性では性欲の減退、勃起不全となることがある。男女ともに不妊症の原因となることがある。
  1. 治療により不妊症の改善が期待できる。
問診・診察のポイント  
  1. 妊娠、授乳期ではないことを確認する。

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文献 

著者: Peak Mann Mah, Jonathan Webster
雑誌名: Semin Reprod Med. 2002 Nov;20(4):365-74. doi: 10.1055/s-2002-36709.
Abstract/Text Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis. A prolactinoma is the most common cause of chronic hyperprolactinemia once pregnancy, primary hypothyroidism, and drugs that elevate serum prolactin levels have been excluded. Patients can present with hypogonadism, infertility, galactorrhea, osteopenia, and mass effects of the tumor. When hyperprolactinemia is confirmed, a cause for the disorder needs to be sought. This involves a careful history and examination, followed by laboratory tests and diagnostic imaging of the sella turcica. The goals of treatment are to normalize prolactin levels, restore gonadal function, and reduce the effects of chronic hyperprolactinemia. Dopamine agonists are the treatment of choice for the majority of patients. Transsphenoidal surgery is usually reserved for patients who are intolerant of or resistant to dopamine agonists or when hyperprolactinemia is caused by non-prolactin-secreting tumors compressing the pituitary stalk. Cabergoline has been shown to be more effective and better tolerated than bromocriptine. However, there are more data on the safety of the latter drug during pregnancy and bromocriptine, therefore, remains the treatment of choice in hyperprolactinemic women wishing to conceive.

PMID 12536359  Semin Reprod Med. 2002 Nov;20(4):365-74. doi: 10.1055/s・・・
著者: C Morrison
雑誌名: Lippincotts Prim Care Pract. 1998 Mar-Apr;2(2):129-40.
Abstract/Text Breast cancer is one of the most dreaded diseases affecting women and is associated with a high degree of morbidity and mortality. Any breast complaint has the potential for creating a great deal of anxiety for patients and providers alike. An in-depth understanding of the pathophysiology of common breast complaints, particularly those with low probability of association with cancer such as nipple discharge, can serve to allay anxiety and prevent the financial and emotional burden of unnecessary diagnostic evaluations. It will then improve the quality of care for each patient experiencing the symptom. Although the greatest incidence of nipple discharge is not secondary to malignant processes, the fact that some are requires that all persons with nipple discharge receive the benefit of a thorough assessment. When planning a course of action to assess and treat nipple discharge, a thoughtful stepwise, planned approach is necessary. The evaluation of nipple discharge can be undertaken with minimal difficulty by performing a thorough history, a careful physical examination, and following a logical thought process in linking the type of discharge with the suitable adjunct diagnostic testing. Appropriate management evolves from this process. It is important to view the patient in total, considering such issues as family history, other risk factors, how disruptive the level of anxiety about the symptom. Primary care providers, working with their parents, are well positioned to design appropriate diagnostic and treatment regimes to assess and treat nipple discharge. A thoughtful, prudent approach to this symptom can save both health care dollars and lives.

PMID 9727109  Lippincotts Prim Care Pract. 1998 Mar-Apr;2(2):129-40.
著者: Shlomo Melmed, Felipe F Casanueva, Andrew R Hoffman, David L Kleinberg, Victor M Montori, Janet A Schlechte, John A H Wass, Endocrine Society
雑誌名: J Clin Endocrinol Metab. 2011 Feb;96(2):273-88. doi: 10.1210/jc.2010-1692.
Abstract/Text OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia.
PARTICIPANTS: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer.
EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence.
CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines.
CONCLUSIONS: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented.

PMID 21296991  J Clin Endocrinol Metab. 2011 Feb;96(2):273-88. doi: 10・・・
著者: J Schlechte, K Dolan, B Sherman, F Chapler, A Luciano
雑誌名: J Clin Endocrinol Metab. 1989 Feb;68(2):412-8. doi: 10.1210/jcem-68-2-412.
Abstract/Text This report describes the results of a long term prospective study of 30 women with hyperprolactinemia who were not treated and who underwent yearly clinical, hormonal, and radiographic evaluation for an average of 5.2 yr (range 3-7 yr). At entry into the study 18 women had amenorrhea, 8 had oligomenorrhea, and 4 had regular menstrual periods. The initial mean serum PRL levels did not differ in women grouped according to menstrual function. Nine women (35%) had improvement in clinical symptoms. Serum PRL decreased, and menstrual periods normalized more often in those who initially had oligomenorrhea or regular menstrual periods. In most amenorrheic women serum PRL levels did not decline, and menstrual symptoms did not improve. Six of 30 women had an increase in serum PRL, 14 had no change, and 10 had a decrease, in 6 of whom serum PRL was normal at the last observation. Twenty-seven women had serial radiographic studies. Four (15%) of the 13 women with initially abnormal radiographic findings had normal studies later, 2 had tumor progression, and 7 no change. Four of 14 women who had normal radiographic studies initially developed radiographic evidence of a pituitary tumor, although the radiographic changes were minimal, and no patient developed a macroadenoma or pituitary hypofunction. Increases or decreases in serum PRL did not accurately predict changes in tumor size. Prior estrogen use and previous pregnancies did not increase the likelihood of tumor appearance or enhance tumor growth. The clinical presentation of the patient was an important factor in predicting which patients had a decline in serum PRL and resolution of symptoms. We conclude that patients with hyperprolactinemia are unlikely to have progression of their disease and may, in fact, have clinical and radiographic improvement.

PMID 2918052  J Clin Endocrinol Metab. 1989 Feb;68(2):412-8. doi: 10.・・・
著者: D A Sisam, J P Sheehan, L R Sheeler
雑誌名: Fertil Steril. 1987 Jul;48(1):67-71.
Abstract/Text The development of radioimmunoassay (RIA) for prolactin (PRL) and sensitive high-resolution computed tomography (HRCT) has resulted in documentation of large numbers of microprolactinomas (microPRL). To try to define the rate and prevalence of tumor growth, the authors performed serial HRCT scans in 38 untreated patients, an average of 31.7 months apart. In no patient, including two patients with exuberant rises in PRL, was there any evidence of subtle tumor growth. The authors conclude that the majority of patients with microPRL have a benign course, with tumor growth occurring, if at all, over a period of years.

PMID 3595916  Fertil Steril. 1987 Jul;48(1):67-71.
著者: Wenyu Huang, Mark E Molitch
雑誌名: Am Fam Physician. 2012 Jun 1;85(11):1073-80.
Abstract/Text Galactorrhea is commonly caused by hyperprolactinemia, especially when it is associated with amenorrhea. Hyperprolactinemia is most often induced by medication or associated with pituitary adenomas or other sellar or suprasellar lesions. Less common causes of galactorrhea include hypothyroidism, renal insufficiency, pregnancy, and nipple stimulation. After pathologic nipple discharge is ruled out, patients with galactorrhea should be evaluated by measurement of their prolactin level. Those with hyperprolactinemia should have pregnancy ruled out, and thyroid and renal function assessed. Brain magnetic resonance imaging should be performed if no other cause of hyperprolactinemia is found. Patients with prolactinomas are usually treated with dopamine agonists (bromocriptine or cabergoline); surgery or radiation therapy is rarely required. Medications causing hyperprolactinemia should be discontinued or replaced with a medication from a similar class with lower potential for causing hyperprolactinemia. Normoprolactinemic patients with idiopathic, nonbothersome galactorrhea can be reassured and do not need treatment; however, those with bothersome galactorrhea usually respond to a short course of a low-dose dopamine agonist.

PMID 22962879  Am Fam Physician. 2012 Jun 1;85(11):1073-80.
著者: J Verhelst, R Abs, D Maiter, A van den Bruel, M Vandeweghe, B Velkeniers, J Mockel, G Lamberigts, P Petrossians, P Coremans, C Mahler, A Stevenaert, J Verlooy, C Raftopoulos, A Beckers
雑誌名: J Clin Endocrinol Metab. 1999 Jul;84(7):2518-22. doi: 10.1210/jcem.84.7.5810.
Abstract/Text Cabergoline is a new long-acting dopamine agonist that is very effective and well tolerated in patients with pathological hyperprolactinemia. The aim of this study was to examine, in a very large number of hyperprolactinemic patients, the ability to normalize PRL levels with cabergoline, to determine the effective dose and tolerance, and to assess the effect on clinical symptoms, tumor shrinkage, and visual field abnormalities. We also evaluated the effects of cabergoline in a large subgroup of patients with bromocriptine intolerance or -resistance. We retrospectively reviewed the files of 455 patients (102 males and 353 females) with pathological hyperprolactinemia treated with cabergoline in 9 Belgian centers. Among these patients, 41% had a microadenoma; 42%, a macroadenoma; 16%, idiopathic hyperprolactinemia; and 1%, an empty sella. The median pretreatment serum PRL level was 124 microg/L (range, 16-26,250 microg/L). A subgroup of 292 patients had previously been treated with bromocriptine, of which 140 showed bromocriptine intolerance and 58 showed bromocriptine resistance. Treatment with cabergoline normalized serum PRL levels in 86% of all patients: in 92% of 244 patients with idiopathic hyperprolactinemia or a microprolactinoma and in 77% of 181 macroadenomas. Pretreatment visual field abnormalities normalized in 70% of patients, and tumor shrinkage was seen in 67% of cases. Side effects were noted in 13% of patients, but only 3.9% discontinued therapy because of side effects. The median dose of cabergoline at the start of therapy was 1.0 mg/week but could be reduced to 0.5 mg/week once control was achieved. Patients with a macroprolactinoma needed a higher median cabergoline dose, compared with those with idiopathic hyperprolactinemia or a microprolactinoma: 1.0 mg/week vs. 0.5 mg/week, although a large overlap existed between these groups. Twenty-seven women treated with cabergoline became pregnant, and 25 delivered a healthy child. One patient had an intended abortion and another a miscarriage. In the patients with bromocriptine intolerance, normalization of PRL was reached in 84% of cases, whereas in the bromocriptine-resistant patients, PRL could be normalized in 70%. We confirmed, in a large-scale retrospective study, the high efficacy and tolerability of cabergoline in the treatment of pathological hyperprolactinemia, leaving few patients with unacceptable side effects or inadequate clinical response. Patients with idiopathic hyperprolactinemia or a microprolactinoma, on average, needed only half the dose of cabergoline as those with macroprolactinomas and have a higher chance of obtaining PRL normalization. Cabergoline also normalized PRL in the majority of patients with known bromocriptine intolerance or -resistance. Once PRL secretion was adequately controlled, the dose of cabergoline could often be significantly decreased, which further reduced costs of therapy.

PMID 10404830  J Clin Endocrinol Metab. 1999 Jul;84(7):2518-22. doi: 1・・・
著者: Vania dos Santos Nunes, Regina El Dib, César Luiz Boguszewski, Célia Regina Nogueira
雑誌名: Pituitary. 2011 Sep;14(3):259-65. doi: 10.1007/s11102-010-0290-z.
Abstract/Text Cabergoline and bromocriptine are the most used drugs in the treatment of hyperprolactinemia, they are able to normalize the prolactin levels, restore gonadal function and promote tumor reduction in the majority of patients. We undertake a systematic review and meta-analysis of randomized controlled trials to compare cabergoline versus bromocriptine in the treatment of patients with idiopathic hyperprolactinemia and prolactinomas. The data sources were: Embase, Pubmed, Lilacs and Cochrane Central. The outcome measures were: normalization of prolactin secretion, restoration of gonadal function, reduction of tumoral volume, quality of life and adverse drug effects. Were identified 418 references and after screening by title and abstract, we obtained complete copies of 34 articles potentially eligible for inclusion in the review. From this total, 19 were selected to be included, but fifteen of them were excluded due to the following reasons: one randomized study compared cabergoline versus placebo and other randomized study compared different doses of cabergoline; five references were cases series; four were only controlled studies; three were retrospectives series and; one was a cohort study. Therefore, four publications were included in the review and in the final analysis. The meta-analysis of normalization of serum prolactin levels and menstruation with return of ovulatory cycle showed a significant difference in favor of cabergoline group (RR 0.67 [CI 95% 0.57, 0.80]) e (RR 0.74 [CI 95% 0.67, 0.83]), respectively. The number of adverse effects was significantly higher in the bromocriptine number than in cabergoline group (RR 1.43 [CI 95% 1.03, 1.98]). The meta-analysis showed new evidence favoring the use of cabergoline in comparison with bromocriptine for the treatment of prolactinomas and idiopathic hyperprolactinemia.

PMID 21221817  Pituitary. 2011 Sep;14(3):259-65. doi: 10.1007/s11102-0・・・
著者: J Webster, G Piscitelli, A Polli, C I Ferrari, I Ismail, M F Scanlon
雑誌名: N Engl J Med. 1994 Oct 6;331(14):904-9. doi: 10.1056/NEJM199410063311403.
Abstract/Text BACKGROUND: Cabergoline is a long-acting dopamine-agonist drug that suppresses prolactin secretion and restores gonadal function in women with hyperprolactinemic amenorrhea. We designed a study to compare its safety and efficacy with those of bromocriptine, which has been the standard therapy.
METHODS: A total of 459 women with hyperprolactinemic amenorrhea were treated with either cabergoline (0.5 to 1.0 mg twice weekly) or bromocriptine (2.5 to 5.0 mg twice daily), administered in a double-blind fashion for 8 weeks and subsequently in an open fashion for 16 weeks, during which adjustments in the dose were made according to the response. Of the 459 women, 279 had microprolactinomas, 3 had macroprolactinomas, 1 had a craniopharyngioma, 167 had idiopathic hyperprolactinemia, and the remainder had an empty sella. Clinical and biochemical status was assessed at 2-week intervals for 8 weeks and monthly thereafter for a total of 6 months, with an additional assessment at 14 weeks.
RESULTS: Stable normoprolactinemia was achieved in 186 of the 223 women treated with cabergoline (83 percent) and 138 of the 236 women treated with bromocriptine (59 percent, P < 0.001). Seventy-two percent of the women treated with cabergoline and 52 percent of those treated with bromocriptine had ovulatory cycles or became pregnant during treatment (P < 0.001). Amenorrhea persisted in 7 percent of the cabergoline-treated women and 16 percent of the bromocriptine-treated women. Adverse effects were recorded in 68 percent of the women taking cabergoline and 78 percent of those taking bromocriptine (P = 0.03); 3 percent discontinued taking cabergoline, and 12 percent stopped taking bromocriptine (P < 0.001) because of drug intolerance. Gastrointestinal symptoms were significantly less frequent, less severe, and shorter-lived in the women treated with cabergoline.
CONCLUSIONS: Cabergoline is more effective and better tolerated than bromocriptine in women with hyperprolactinemic amenorrhea.

PMID 7915824  N Engl J Med. 1994 Oct 6;331(14):904-9. doi: 10.1056/NE・・・
著者: I Turkalj, P Braun, P Krupp
雑誌名: JAMA. 1982 Mar 19;247(11):1589-91.
Abstract/Text Information was collected on the outcome of 1,410 pregnancies in 1,335 women to whom bromocriptine mesylate (Parlodel) had been given, primarily in the early weeks of pregnancy. These Pregnancies resulted in 197 early terminations (14%) (including 25 induced abortions [1.8%) and in 1,213 births (86%). The incidence rate of spontaneous abortions (11.1%), extrauterine pregnancies (0.9%), and minor (2.5%) and major (1.0%) malformations is comparable with that quoted for normal populations, and the incidence of twin pregnancies (1.8%) is slightly but not significantly raised, if correction is made for concomitant therapy with other agents inducing ovulation. The data suggest that the intake of bromocriptine during pregnancy is not associated with an increased risk to the fetus.

PMID 7062462  JAMA. 1982 Mar 19;247(11):1589-91.
著者: E Robert, L Musatti, G Piscitelli, C I Ferrari
雑誌名: Reprod Toxicol. 1996 Jul-Aug;10(4):333-7.
Abstract/Text The goal of this article is to assess the reproductive safety of cabergoline, a new ergot derivative proposed in hyperprolactinemic disorders. Investigated in different animal species, the drug showed no teratogenic or embryotoxic effects on rabbits. Considering the dose envisaged for humans, large safety margins exist. Our sample consists of 226 pregnancies occuring in 205 women. Follow-up is available for 204. There were 24 miscarriages and three abortions induced because of major malformations (one Down syndrome in a 42-year-old woman, one limb-body wall complex, one hydrocephalus). Two of the 148 single liveborn infants had significant malformations: one megaureter, one scaphocephaly. This series shows no increase in miscarriage rate, a distribution of birthweights and sex ratio within the expected range, and no increased rate of congenital malformations. Follow-up of babies, limited to 107 cases, thus far indicates normal physical and mental development.

PMID 8829257  Reprod Toxicol. 1996 Jul-Aug;10(4):333-7.
著者: Elena Ricci, Fabio Parazzini, Tiziano Motta, Carlo I Ferrari, Annamaria Colao, Antonio Clavenna, Francesca Rocchi, Emanuela Gangi, Sandra Paracchi, Maurizio Gasperi, Maurizio Lavezzari, Anna Elisa Nicolosi, Simona Ferrero, Maria Luisa Landi, Paolo Beck-Peccoz, Maurizio Bonati
雑誌名: Reprod Toxicol. 2002 Nov-Dec;16(6):791-3.
Abstract/Text We collected information on 61 pregnancies in 50 women treated with cabergoline. These pregnancies resulted in 12 (19.7%) early terminations (five induced abortions, six spontaneous abortions, one hydatidiform mole) and 49 (80.3%) live births. In one case, malformations were suspected by a gynecologist based on ultrasound at 12 gestational weeks and the pregnancy was terminated; additional information was not available. There was one case of trisomy 18. The frequency of spontaneous and induced abortions and major congenital malformations was comparable with rates in the general population. The data did not indicate any potential adverse effect of the drug on pregnancy. The data from this study in combination with previous reports can exclude a congenital malformation risk greater than 10% associated with pregnancy exposure to cabergoline.

PMID 12401507  Reprod Toxicol. 2002 Nov-Dec;16(6):791-3.
著者: I Ciric, A Ragin, C Baumgartner, D Pierce
雑誌名: Neurosurgery. 1997 Feb;40(2):225-36; discussion 236-7.
Abstract/Text OBJECTIVE: The primary objectives of this report were, first, to determine the number and incidence of complications of transsphenoidal surgery performed by a cross-section of neurosurgeons in the United States and, second, to ascertain the influence of the surgeon's experience with the procedure on the occurrence of these complications. The secondary objective was to review complications of transsphenoidal surgery from the standpoint of their causation, treatment, and prevention.
METHODS: Questionnaires regarding 14 specific complications of transsphenoidal surgery were mailed to 3172 neurosurgeons. The data reported were analyzed from the 958 respondents (82%) who reported performing the operation. The neurosurgeons surveyed were asked to estimate the number of transsphenoidal operations performed, to identify any complications observed, and to estimate the percentage of operations that had resulted in any of the 14 specific complications. The 958 respondents were placed into three experience groups, based on the number of transsphenoidal operations performed. The data were analyzed by using chi 2 tests and Spearman correlation coefficients. The secondary objectives were met through a detailed review of the literature, in light of our experience.
RESULTS: Of the respondents, 87.3% reported having performed < 200 operations and 9.7% reported 200 to 500 previous operations. The remaining 3% reported more than 500 previous operations. More extensive previous experience with transsphenoidal surgery was associated with a greater likelihood of having witnessed each specific complication. The mean operative mortality rate for all three groups was 0.9%. Anterior pituitary insufficiency (19.4%) and diabetes insipidus (17.8%) were complications with the highest incidence of occurrence. The overall incidence of cerebrospinal fluid fistulas was 3.9%. Other significant complications, such as carotid artery injuries, hypothalamic injuries, loss of vision, and meningitis, occurred with incidence rates between 1 and 2%. An inverse relationship was found between the experience group and the likelihood of complications, as indicated by significant negative Spearman correlation coefficients for all but 2 of the 14 complications listed in the survey (P < 0.05). Thus, increased experience with transsphenoidal surgery seems to be associated with a decreased percentage of operations resulting in complications. Some caution should be exercised in interpreting these data, because they are based on the respondents' estimates.
CONCLUSION: Transsphenoidal surgery seems to be a reasonably safe procedure, with a mortality rate of less than 1%. However, a significant number of complications do occur. The incidence of these complications seems to be higher, with statistical significance, in the hands of less experienced surgeons. The learning curve seems to be relatively shallow, because a statistically significantly decreased incidence of morbidity and death could be documented after 200 and even 500 transsphenoidal operations. Better understanding of the indications for transsphenoidal surgery and improved familiarity with the regional anatomy should further lower the incidence of death and morbidity resulting from this procedure in the hands of all neurosurgeons.

PMID 9007854  Neurosurgery. 1997 Feb;40(2):225-36; discussion 236-7.
著者: R V Randall, E R Laws, C F Abboud, M J Ebersold, P C Kao, B W Scheithauer
雑誌名: Mayo Clin Proc. 1983 Feb;58(2):108-21.
Abstract/Text One hundred patients, 84 females and 16 males, with presumed prolactin-producing pituitary adenomas were treated with transsphenoidal microsurgery. Criteria for success of the operation were return of serum prolactin values to normal and reversal of the endocrine effects of hyperprolactinemia, eradication of the adenoma, and preservation of anterior pituitary function. Of the 84 females, 54 had a microadenoma (a noninvasive adenoma 10 mm or less in diameter), and of the 32 with preoperative values of serum prolactin of less than 100 ng/ml, 28 (88%) had a successful operative result, whereas 11 of 22 (50%) with preoperative values of 100 ng/ml or more had a successful result. Five of 10 patients (50%) with a diffuse adenoma (a noninvasive adenoma more than 10 mm in diameter) and 5 of 20 (25%) with an invasive adenoma had a successful result. Of the 16 males, 3 of 7 (43%) with diffuse adenoma and 3 of 16 (19%) with invasive adenoma had a successful result. There were no males with microadenoma. The largest success rate (88%) was among female patients with microadenoma and preoperative serum prolactin values of less than 100 ng/ml.

PMID 6681646  Mayo Clin Proc. 1983 Feb;58(2):108-21.
著者: O Serri, E Rasio, H Beauregard, J Hardy, M Somma
雑誌名: N Engl J Med. 1983 Aug 4;309(5):280-3. doi: 10.1056/NEJM198308043090505.
Abstract/Text To assess the long-term prognosis for women with prolactinoma after selective transsphenoidal adenomectomy, we followed 44 patients for 6.2 +/- 1.5 years. Group 1 (28 patients) had microprolactinomas, and Group 2 (16 patients) had macroprolactinomas. After surgery, normal plasma prolactin levels, resumption of menses, and cessation of galactorrhea were observed in 24 Group 1 patients (85 per cent) and 5 Group 2 patients (31 per cent). Hyperprolactinemia recurred in 12 of the 24 Group 1 patients and in 4 of the 5 Group 2 patients after 4 +/- 1.3 and 2.5 +/- 1.6 years of remission, respectively. There was no radiologic evidence of tumor recurrence in any patient, and no relation was found between the occurrence of pregnancy after surgery and the recurrence of hyperprolactinemia. Clinical and biologic features before surgery could not predict the long-term outcome. However, the immediate postoperative level of plasma prolactin was significantly lower in patients in whom normal prolactinemia (6.4 +/- 1.1 ng per milliliter) was maintained than in those who relapsed (11.7 +/- 1.5 ng per milliliter) (P less than 0.02). We conclude that recurrence of hyperprolactinemia after successful surgery is frequent but delayed. The immediate postoperative level of plasma prolactin may be a predictive risk factor.

PMID 6866052  N Engl J Med. 1983 Aug 4;309(5):280-3. doi: 10.1056/NEJ・・・
著者: J A Schlechte, B M Sherman, F K Chapler, J VanGilder
雑誌名: J Clin Endocrinol Metab. 1986 Jun;62(6):1296-301. doi: 10.1210/jcem-62-6-1296.
Abstract/Text To examine the long term effectiveness of transsphenoidal microsurgery for patients with PRL-secreting pituitary tumors, we studied 54 women at yearly intervals after transsphenoidal surgery. Five years after surgery, 19 women (35%) had normal serum PRL concentrations, and 23 (43%) had persistent hyperprolactinemia. Hyperprolactinemia recurred in 12 of 31 patients (39%) who had normal PRL concentration 6 weeks after surgery. None of the patients with recurrent hyperprolactinemia had radiographic evidence of tumor regrowth, and only 3 of 12 had amenorrhea. A serum PRL level below 6 ng/ml 6 weeks after surgery occurred more frequently in cured patients than in those who had a recurrence. PRL responses to TRH were normal in cured patients 1 and 5 yr after surgery and abnormal in those who had recurrent hyperprolactinemia. The PRL responses to chlorpromazine- and insulin-induced hypoglycemia were blunted in patients with normal as well as elevated PRL levels. Patients with recurrent, as well as those with persistent, hyperprolactinemia had no nocturnal rise in serum PRL 5 yr after surgery. The 39% recurrence rate of hyperprolactinemia and persistent abnormalities in pituitary-hypothalamic regulation of PRL secretion after transsphenoidal surgery raise important questions about the choice of primary therapy for patients with PRL-secreting tumors.

PMID 3084539  J Clin Endocrinol Metab. 1986 Jun;62(6):1296-301. doi: ・・・
著者: Olaf M Dekkers, Joep Lagro, Pia Burman, Jens Otto Jørgensen, Johannes A Romijn, Alberto M Pereira
雑誌名: J Clin Endocrinol Metab. 2010 Jan;95(1):43-51. doi: 10.1210/jc.2009-1238. Epub 2009 Oct 30.
Abstract/Text CONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details.
OBJECTIVE: The aim of the study was to assess the effect of dopamine agonist withdrawal in patients with idiopathic hyperprolactinemia and prolactinomas.
DATA SOURCES: PubMed, the Cochrane Library, the Web of Science, and EMBASE were searched electronically. No restriction was made with respect to language.
STUDY SELECTION: Studies reporting the proportion of normoprolactinemic patients after withdrawal of dopamine agonist or studies in which this proportion could be calculated were eligible. Both observational studies and clinical trials were eligible. Nineteen studies were included in the meta-analysis, with a total of 743 patients.
DATA EXTRACTION: Data extraction was performed by two reviewers independently.
DATA SYNTHESIS: The pooled proportion of patients with persisting normoprolactinemia after dopamine agonist withdrawal was 21% in a random effects model [95% confidence interval (CI), 14-30%; I(2) 81%). Stratified analysis showed higher proportions of treatment success in idiopathic hyperprolactinemia (32%; 95% CI, 5-80%), compared with both microprolactinomas (21%; 95% CI, 10-37%), and macroprolactinomas (16%; 95% CI, 6-36%). In a random effects meta-regression adjusting for cause of hyperprolactinemia, a longer treatment duration was associated with treatment success (P = 0.015), whereas the use of cabergoline showed a trend of effect (P = 0.07).
CONCLUSIONS: This meta-analysis showed that hyperprolactinemia will recur after dopamine agonist withdrawal in a considerable proportion of patients. The probability of treatment success was highest when cabergoline was used for at least 2 yr.

PMID 19880787  J Clin Endocrinol Metab. 2010 Jan;95(1):43-51. doi: 10.・・・
著者: Annamaria Colao, Antonella Di Sarno, Paolo Cappabianca, Carolina Di Somma, Rosario Pivonello, Gaetano Lombardi
雑誌名: N Engl J Med. 2003 Nov 20;349(21):2023-33. doi: 10.1056/NEJMoa022657.
Abstract/Text BACKGROUND: Whether the withdrawal of treatment in patients with nontumoral hyperprolactinemia, microprolactinomas, or macroprolactinomas is safe and effective has been unclear. We performed an observational, prospective study of cabergoline (a dopamine-receptor agonist) withdrawal in such patients.
METHODS: The study population included 200 patients--25 patients with nontumoral hyperprolactinemia, 105 with microprolactinomas, and 70 with macroprolactinomas. Withdrawal of cabergoline was considered if prolactin levels were normal, magnetic resonance imaging (MRI) showed no tumor (or tumor reduction of 50 percent or more, with the tumor at a distance of more than 5 mm from the optic chiasm, and no invasion of the cavernous sinuses or other critical areas), and if follow-up after withdrawal could be continued for at least 24 months.
RESULTS: Recurrence rates two to five years after the withdrawal of cabergoline were 24 percent in patients with nontumoral hyperprolactinemia, 31 percent in patients with microprolactinomas, and 36 percent in patients; with macroprolactinomas. Renewed tumor growth did not occur in any patient; in 10 female patients (22 percent) and 7 male patients (39 percent) with recurrent hyperprolactinemia, gonadal dysfunction redeveloped. In all diagnostic groups, prolactin levels at the time of recurrence were significantly lower than at diagnosis (P<0.001). The Kaplan-Meier estimated rate of recurrence at five years was higher among patients with macroprolactinomas and those with microprolactinomas who had small remnant tumors visible on MRI at the time of treatment withdrawal than among patients whose MRI scans showed no evidence of tumor at the time of withdrawal (patients with macroprolactinomas, 78 percent vs. 33 percent, P=0.001; patients with microprolactinomas, 42 percent vs. 26 percent, P=0.02).
CONCLUSIONS: Cabergoline can be safely withdrawn in patients with normalized prolactin levels and no evidence of tumor. However, because the length of follow-up in our study was insufficient to rule out a delayed increase in the size of the tumor, we suggest that patients be closely monitored, particularly those with macroprolactinomas, in whom renewed growth of the tumor may compromise vision.

Copyright 2003 Massachusetts Medical Society
PMID 14627787  N Engl J Med. 2003 Nov 20;349(21):2023-33. doi: 10.1056・・・
著者: Alberto M Pereira
雑誌名: Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):264-8. doi: 10.1097/MED.0b013e328347c94a.
Abstract/Text PURPOSE OF REVIEW: Despite the widespread use of dopamine agonists for patients with prolactinomas and symptomatic idiopathic hyperprolactinemia for many decades, the optimal treatment strategy and duration of treatment is still not evident. This review highlights the effects of dopamine agonist withdrawal in patients with idiopathic hyperprolactinemia and prolactinomas in detail, including the factors influencing the success of treatment outcome.
RECENT FINDINGS: It appeared that a subgroup of patients with a high likelihood of achieving remission could be identified on clinical criteria, which were incorporated in the Pituitary Society 2006 consensus guidelines. A recent systematic review and meta-analysis, however, demonstrated that the pooled proportion of patients with persisting normoprolactinemia after dopamine agonist withdrawal was only 21%, with a higher treatment success in idiopathic hyperprolactinemia (32%), compared with both microprolactinomas (21%) and macroprolactinomas (16%). In a random effects meta-regression, longer treatment duration was associated with treatment success. The probability of treatment success was highest when cabergoline was used for at least 2 years. Recommendations have now been adjusted accordingly in the 2011 Endocrine Society Practical guideline.
SUMMARY: Hyperprolactinemia will recur after dopamine agonist withdrawal in a considerable proportion of patients, but not all dopamine agonists have comparable efficacy. The optimal withdrawal strategy still needs to be determined in further studies.

PMID 21844709  Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):264-・・・
著者: J W van 't Verlaat, R J Croughs
雑誌名: Clin Endocrinol (Oxf). 1991 Mar;34(3):175-8.
Abstract/Text The present study describes the effect on plasma prolactin values and tumour size of bromocriptine withdrawal in 12 patients who had been treated for macroprolactinomas for a period of 3.5-7 (mean 4.9) years. Pretreatment plasma prolactin values ranged from 12,000 to 210,000 (mean: 66,000) mU/l. Immediately before bromocriptine withdrawal plasma prolactin values were in the normal range (less than 350 mU/l for men; less than 450 mU/l for women). Bromocriptine treatment was associated with tumour reduction in all cases. The following observations were made upon withdrawal of bromocriptine: (1) In 11 patients hyperprolactinaemia redeveloped although plasma prolactin levels remained below 600 mU/l in two of these patients during a follow-up period of 1 year. In the other nine patients bromocriptine treatment was reinstituted after 4-12 weeks. (2) Hyperprolactinaemia was associated with tumour reexpansion in one case and increased density of the tumour in two cases. (3) In one patient plasma prolactin remained undetectable during a follow-up period of 1 year and no tumour re-expansion was found. It is concluded that tumour regrowth is uncommon and of small extent after cessation of long-term bromocriptine treatment for macroprolactinomas.

PMID 2036725  Clin Endocrinol (Oxf). 1991 Mar;34(3):175-8.
著者: Vanessa Q Passos, Jean J S Souza, Nina R C Musolino, Marcello D Bronstein
雑誌名: J Clin Endocrinol Metab. 2002 Aug;87(8):3578-82. doi: 10.1210/jcem.87.8.8722.
Abstract/Text Bromocriptine (BRC) and other dopamine agonist drugs are the first-choice treatment for prolactinomas. However, the major disadvantage is the need for prolonged therapy. We retrospectively studied 131 patients [62 microprolactinoma (MIC), 69 macroprolactinoma (MAC)], who achieved serum prolactin (PRL) normalization during BRC use. Twenty-seven percent of them (31% MIC and 69% MAC) underwent previous surgery. Twenty-seven patients (20.6%: 25.8% MIC and 15.9% MAC) persisted with normoprolactinemia after a median time of 44 months of BRC withdrawal. The median time of BRC use was 47 months. There were no statistically significant differences regarding age, gender, BRC initial dose, length of BRC use, tumor size, pregnancy during treatment, previous surgery, or radiotherapy among patients who persisted with normoprolactinemia and those who did not, using both univariate and multivariate analysis. BRC-induced prolactinoma cell alterations are highly controversial; and so, whether the mechanism of PRL normalization after BRC withdrawal is related to BRC use or whether it is attributable to natural history is a matter for debate. A periodic assessment of PRL levels during BRC (and other dopamine-agonist drugs) withdrawal is recommended to avoid the unnecessary maintenance of therapy in a subset of patients with prolactinomas.

PMID 12161478  J Clin Endocrinol Metab. 2002 Aug;87(8):3578-82. doi: 1・・・
著者: J Kharlip, R Salvatori, G Yenokyan, G S Wand
雑誌名: J Clin Endocrinol Metab. 2009 Jul;94(7):2428-36. doi: 10.1210/jc.2008-2103. Epub 2009 Mar 31.
Abstract/Text CONTEXT: Recurrence of hyperprolactinemia after cabergoline withdrawal ranges widely from 36 to 80%. The Pituitary Society recommends withdrawal of cabergoline in selected patients.
OBJECTIVE: Our aim was to evaluate recurrence of hyperprolactinemia in patients meeting The Pituitary Society guidelines.
DESIGN: Patients were followed from the date of discontinuation to either relapse of hyperprolactinemia or the day of last prolactin test.
SETTING: We conducted the study at an academic medical center.
PATIENTS: Forty-six patients meeting Pituitary Society criteria (normoprolactinemic and with tumor volume reduction after 2 or more years of treatment) participated in the study.
INTERVENTIONS: After withdrawal, if prolactin returned above reference range, another measurement was obtained within 1 month, symptoms were assessed by questionnaire, and magnetic resonance imaging was performed.
MAIN OUTCOME MEASURES: We measured risk of and time to recurrence estimates as well as clinical predictors of recurrence.
RESULTS: Mean age of patients was 50 +/- 13 yr, and 70% were women. Thirty-one patients had microprolactinomas, 11 had macroprolactinomas, and four had nontumoral hyperprolactinemia. The overall recurrence was 54%, and the estimated risk of recurrence by 18 months was 63%. The median time to recurrence was 3 months (range, 1-18 months), with 91% of recurrences occurring within 1 yr after discontinuation. Size of tumor remnant prior to withdrawal predicted recurrence [18% increase in risk for each millimeter (95% confidence interval, 3-35; P = 0.017)]. None of the tumors enlarged in the patients experiencing recurrence, and 28% had symptoms of hypogonadism.
CONCLUSIONS: Cabergoline withdrawal is practical and safe in a subset of patients as defined by The Pituitary Society guidelines; however, the average risk of long-term recurrence in our study was over 60%. Close follow-up remains important, especially within the first year.

PMID 19336508  J Clin Endocrinol Metab. 2009 Jul;94(7):2428-36. doi: 1・・・

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