INTRODUCTION — Gonadotroph adenomas are the most common pituitary macroadenomas, comprising approximately 80 percent of clinically nonfunctioning adenomas. These adenomas are difficult to identify because their secretory products usually do not cause a recognizable clinical syndrome and because they often secrete so inefficiently that serum concentrations of intact gonadotropins and their subunits are often only minimally abnormal or not abnormal at all. Consequently, they are typically not detected until they become sufficiently large to cause neurologic symptoms, most often impaired vision due to pressure on the optic chiasm. Clinically nonfunctioning or "silent" somatotroph and corticotroph adenomas are also being identified with increasing frequency.
The treatment of gonadotroph and other clinically nonfunctioning adenomas will be reviewed here. Their clinical manifestations and diagnosis are discussed separately. (See "Clinical manifestations and diagnosis of gonadotroph and other clinically nonfunctioning pituitary adenomas".)
INITIAL THERAPY: TRANSSPHENOIDAL SURGERY
Indications — Gonadotroph or other clinically nonfunctioning macroadenomas are typically diagnosed when they become large enough to cause a neurologic symptom (eg, visual loss, headache), a hormonal deficiency state, when an imaging study is performed for an unrelated reason, or, less commonly, because of hormonal hypersecretion.
For gonadotroph and other clinically nonfunctioning macroadenomas that are impairing vision, we recommend transsphenoidal surgery because it is the only treatment that can provide rapid relief of neurologic symptoms [1,2]. Transsphenoidal surgery reduces the size of the adenoma and its hormonal hypersecretion in more than 90 percent of cases and improves vision in approximately 80 percent [3,4].
For patients who have suprasellar extension but do not have neurologic symptoms, we discuss the risks of surgery versus the risks of waiting. For example, an adenoma that is markedly elevating the optic chiasm is very likely to begin to cause visual abnormalities in the next few years, yet some patients will choose to wait to undergo surgery until that occurs. Gonadotroph adenomas that are asymptomatic and not an immediate threat to vision may not require immediate surgery. (See 'Asymptomatic adenomas' below.)
Once identified, those with impaired vision should undergo transsphenoidal surgery. Transsphenoidal surgery should be considered for those at high risk for loss of vision (marked suprasellar extension).
The choice of transsphenoidal surgery procedure has evolved over time. The microscopic technique was introduced first, but the endoscopic technique is now considered the preferable approach because of better visualization. Transcranial surgery is virtually never the preferred approach. This issue is discussed in more detail separately. (See "Transsphenoidal surgery for pituitary adenomas and other sellar masses", section on 'Surgical techniques'.)
Goals — The goals of treatment of a patient with a gonadotroph or clinically nonfunctioning adenoma include:
●Relief of visual impairment or other neurologic symptoms
●Reduction of hormone hypersecretion if present
●Removal of as much of the adenoma as possible to avoid recurrence
●Replacement of hormonal deficiencies due to compression of nonadenomatous pituitary cells by the macroadenoma (see 'Postoperative issues' below)
Preoperative preparation — The most important aspects of the preoperative preparation for pituitary surgery include:
●Confirming the sellar lesion is a gonadotroph or other clinically nonfunctioning adenoma, which must be distinguished from a nonpituitary lesion in or near the sella, which might best be approached differently.
Abnormalities that strongly suggest a gonadotroph adenoma include elevated basal serum concentrations of intact follicle-stimulating hormone (FSH) and alpha subunit and a response of either to exogenous thyrotropin-releasing hormone (TRH), which is available only outside the United States. Approximately 20 percent of gonadotroph adenomas will exhibit one or more of these abnormalities. (See "Clinical manifestations and diagnosis of gonadotroph and other clinically nonfunctioning pituitary adenomas", section on 'Evaluation'.)
Clinically silent somatotroph adenomas can often be identified by elevated serum levels of insulin-like growth factor 1 (IGF-1)  and clinically silent corticotroph adenomas by elevated levels of corticotropin (ACTH) . (See "Clinical manifestations and diagnosis of gonadotroph and other clinically nonfunctioning pituitary adenomas".)
●Identifying one of these biochemical markers can also be used to monitor the response to surgery and subsequent therapy.
●Identifying a highly experienced pituitary surgeon. (See 'Complications' below.)
●Identifying any pituitary hormone deficiencies that need to be treated preoperatively, including hypothyroidism due to thyroid-stimulating hormone (TSH) deficiency and hypocortisolism due to corticotropin (ACTH) deficiency (algorithm 1). Hypothyroidism, which increases the risk of respiratory insufficiency following postoperative administration of opiates or barbiturates, should be corrected preoperatively, or pain medication should be used in lower than usual doses. Hypocortisolism should be replaced physiologically.
Glucocorticoid coverage — Because of the possibility that nonadenomatous pituitary tissue could be removed inadvertently when attempting to remove the large volume of adenoma, patients should be treated with 100 mg of hydrocortisone beginning at the induction of anesthesia. The dose should be gradually decreased during the next few days. We administer a replacement dose (eg, 15 to 25 mg/day) following discharge until the initial postoperative evaluation four to six weeks after discharge (algorithm 1).
Others recommend measuring serum cortisol on the third postoperative day, 24 hours after the previous dose of hydrocortisone, and if the value is low (less than 5 mcg/dL [138 nmol/L]) or borderline (5 to 15 mcg/dL [138 to 469 nmol/L]), prescribing replacement hydrocortisone on discharge [7,8].
Exogenous hydrocortisone should be continued until a definitive determination of adrenal status has been made.
Arginine vasopressin deficiency and SIADH — Both arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) and the syndrome of inappropriate antidiuretic hormone (SIADH) can occur shortly after transsphenoidal surgery. AVP-D is most likely to occur within the first two days after surgery and is usually transient but may be permanent. SIADH is most likely to occur one week afterwards and is always transient. Rarely, a "triphasic" response occurs, first AVP-D, which then remits and is followed by SIADH, which is followed by permanent AVP-D [9,10].
The possibility of these abnormalities in vasopressin secretion dictate that any patient who has transsphenoidal surgery be assessed frequently for these conditions during the first week after surgery. In the first four days after surgery, the patient should be asked about thirst, and fluid intake and output should be recorded. If AVP-D has not occurred by postoperative day 4, fluid intake should then be restricted to 1 liter/day for the next three days, and the serum sodium repeated on day 7. If the sodium is then normal, fluid restriction can end.
AVP-D that occurs in the first day after surgery, when absorption through the nasal mucosa is variable, should be treated with desmopressin intravenously in doses from 0.25 to 1.0 mcg every 12 to 24 hours, titrated to keep urine volume and serum sodium normal. If AVP-D has not remitted by the time of discharge, the desmopressin can be given as a nasal spray or orally. (See "Causes, presentation, and evaluation of sellar masses".)
AVP-D is more common than SIADH, occurring in 18.5 percent in one series of 319 patients who underwent pituitary surgery at one institution  and 54.2 percent of 57 patients at another . It usually occurs within the first 24 hours postoperatively and is usually transient but is sometimes permanent. In the series of 319 patients, almost 50 percent had remitted in one week and approximately 80 percent in three months .
SIADH occurred in 8.8 percent and 36.7 percent in the above two series [9,11]. In a third series, in which sodium was measured routinely on postoperative day 7 in 241 patients, 23 percent had asymptomatic hyponatremia and 5 percent symptomatic . The mean serum sodium was 128 mmol/L in the asymptomatic patients and 120 mmol/L in the symptomatic ones.
First evaluation post-discharge — Four to six weeks after discharge from the hospital, the patient should be evaluated for the following:
●Amount of residual adenoma – A crude estimation of the amount of residual adenoma can be determined by magnetic resonance imaging (MRI), but artifacts of surgery may obscure the actual amount of residual adenoma tissue for several months. A more accurate view is provided when the artifacts of surgery have regressed three to six months later. Another estimate of the amount of residual adenoma can be made by measuring the serum concentration of any adenoma product that had been elevated before surgery, such as FSH and alpha subunit for gonadotroph adenomas, IGF-1 for clinically silent somatotroph adenomas, or ACTH for clinically silent corticotroph adenomas.
●Visual function (by acuity and visual fields), performed by an ophthalmologist.
●Hormonal function of the nonadenomatous pituitary, regardless of whether it was normal or abnormal prior to surgery. This evaluation should include measurements of:
Serum thyroxine (T4).
•If the serum cortisol value is ≤5 mcg/dL (138 nmol/L), the patient has secondary adrenal insufficiency (ACTH deficiency).
•If it is ≥15 mcg/dL (414 nmol/L), the patient has normal adrenal function, and exogenous hydrocortisone can be discontinued.
•If it is between 5 and 15 mcg/dL (148 and 414 nmol/L) on a total of three occasions, a test of ACTH reserve should be performed. Most clinicians perform the cosyntropin stimulation test because of its ease of administration. However, falsely normal results are sometimes seen in patients with hypopituitarism in the first couple of weeks after pituitary surgery . The author of this topic prefers the metyrapone stimulation test. (See "Diagnostic testing for hypopituitarism".)
●Serum estradiol in premenopausal females with oligomenorrhea or amenorrhea.
●Serum testosterone in a male.
●Evaluation for growth hormone deficiency. (See "Diagnostic testing for hypopituitarism", section on 'Growth hormone'.)
OUTCOMES OF SURGERY
Residual adenoma — Rates of complete adenoma removal are as low as 20 percent and as high as 65 to 75 percent, as surgical results vary widely by center and surgeon. In a meta-analysis of 58 case series of patients with nonfunctioning pituitary adenomas undergoing transsphenoidal surgery, complete removal of the adenoma, as judged by the surgeon, was achieved in only 20 percent of cases . More experienced surgeons and high-volume centers have higher rates of complete removal (approximately 65 to 75 percent) [14,15].
If there is no or little discernible residual adenoma tissue by magnetic resonance imaging (MRI) following surgery, the patient should be monitored by MRI and hormonally, initially at six-month intervals. If there is considerable residual adenomatous tissue, radiation should be administered. (See 'Adjuvant radiation therapy' below.)
Long-term monitoring is necessary because the risk of adenoma regrowth is significant, particularly after surgery alone. (See 'Long-term monitoring' below.)
Vision — Transsphenoidal surgery improves vision in approximately 80 percent of patients ; improvement can be seen in the first few days after surgery [16,17]. If vision was abnormal before surgery, it should be re-evaluated a month or two afterward and less often until no further change occurs.
Hormonal abnormalities — Unlike the improvement in vision, improvement in pituitary function is less likely. Preoperatively, the majority of patients have pituitary hormone deficiencies, most commonly, growth hormone deficiency. In the meta-analysis described above, in patients with preoperative pituitary hormone abnormalities, 30 percent of patients experienced an improvement in some hormone deficiency . However, most patients are left with long-term deficiencies that need replacement. In a systematic review of eight studies in over 1000 patients, the approximate frequencies of postoperative hormone deficiencies were :
●Growth hormone – 83 percent.
●Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) – 60 percent. Removal of the adenoma usually does not allow recovery of function of the normal gonadotroph cells.
●Thyroid-stimulating hormone (TSH) – 30 percent.
●Corticotropin (ACTH) – 30 percent.
Although hormonal function four to six weeks after surgery usually indicates function longer term, improvement may yet occur. In 109 patients who had transsphenoidal surgery for pituitary adenomas and whose pituitary function was tested before and periodically for a year after surgery, 15 had abnormal cortisol response to cosyntropin six weeks afterwards, but five of those had a normal cortisol response 12 months afterwards .
Complications — In the meta-analysis described above, the mortality rate in the immediate postoperative period was 1 percent . Serious complications occurred in less than 5 percent of patients and included cerebrospinal fluid leakage, fistula, meningitis, and new visual field defects.
The risk of complications is inversely proportional to the experience of the surgeon in performing transsphenoidal surgery. In one study, 958 neurosurgeons reported their own experiences in response to a questionnaire . Both serious complications (such as loss of vision and death) and less serious complications (such as hormonal deficiencies) were higher among surgeons who had performed fewer transsphenoidal procedures (table 1). For example, among neurosurgeons who reported performing fewer than 200 transsphenoidal procedures, 1.2 percent of procedures resulted in death, but among neurosurgeons who reported performing more than 500 procedures, only 0.2 percent resulted in death.
A second study utilized a national database and found that among 825 surgeons who performed 5497 operations, the complication rate was also less among surgeons who performed more transsphenoidal procedures .
Recurrent adenoma — Approximately 20 percent of adenomas recur after transsphenoidal surgery alone ; however, the risk of recurrence is much lower if there is no MRI evidence of residual adenoma after surgery. Adjuvant radiation therapy lowers the risk of recurrence. (See 'Adjuvant radiation therapy' below.)
ADJUVANT RADIATION THERAPY
Indications — Radiation therapy is useful in preventing regrowth of residual adenoma tissue following transsphenoidal surgery. The decision whether to recommend radiation is based on the amount and location of the residual tissue by magnetic resonance imaging (MRI), the aggressiveness of the adenoma, and the patient's age and general health. The MRI is performed three to six months after surgery, when artifacts of surgery have regressed.
Radiation is also useful when there is evidence of adenoma regrowth in the months or years after surgery. Radiation therapy is usually not employed as primary therapy for gonadotroph and other clinically nonfunctioning pituitary adenomas, because its effects occur too slowly for a patient with neurologic symptoms. (See "Radiation therapy of pituitary adenomas", section on 'Clinically nonfunctioning pituitary adenomas'.)
Types of radiation therapy — Radiation therapy can be administered from a linear accelerator, which delivers photons; from a machine that delivers gamma radiation from radioactive cobalt-60; or from a cyclotron or synchrotron that delivers protons. Radiation can be delivered as a single high dose, which is sometimes referred to a "stereotactic radiosurgery," or as multiple smaller fractions, referred to as "fractionated." Each of these types of radiation can be adjusted to the geometric shape of the lesion; terms used to describe these adjustments are "stereotactic," "three-dimensional conformal," and "intensity modulated."
Choice of radiation type — In deciding on the type of radiation for an individual patient, the major choice is between single high-dose radiation and fractionated radiation. The choice depends on the distance of the lesion from radiation-sensitive tissues, such as the optic chiasm, and the size of the lesion. Lesions that are only 3 to 5 mm from radiation-sensitive tissues, such as the optic chiasm, and lesions that are 30 mm or more in diameter are more safely treated by fractionated radiation.
Efficacy — Radiation appears generally effective in preventing regrowth of clinically nonfunctioning pituitary adenomas following incomplete surgical resection. No regrowth has been reported in 90 percent of patients after 5 to 10 years in patients treated by fractionated radiation from a linear accelerator [20-24] or proton source  or by single high-dose radiation from a gamma source or linear accelerator [26,27].
Adverse effects — All forms of radiation can cause delayed side effects. Hypopituitarism is relatively common, and neurologic deficits are relatively uncommon.
Pituitary hormonal deficiencies (hypoadrenalism, hypothyroidism, hypogonadism) developed in approximately one-third of the subjects in three studies of fractionated radiation during a median observation period of 40 or more months [23-25]. In a multicenter study of single, high-dose gamma radiation, 86 of 410 patients with clinically nonfunctioning adenomas developed pituitary hormonal deficiencies in a median follow-up time of 51 months . The actuarial rates of hypopituitarism were 7.8, 22.4, and 31.3 percent at 1, 5, and 10 years, respectively.
Neurologic deficits occur less commonly but are more serious. In a review of 35 studies that involved 1621 patients (452 with clinically nonfunctioning adenomas) treated with single-dose radiation from a linear accelerator, gamma source, or proton source, in which the median period of observation was <40 months in approximately one-half and >40 months in approximately one-half, optic neuropathy in approximately 1 percent, other cranial neuropathies occurred in approximately 1.3 percent, and parenchymal brain damage (in the hypothalamus and temporal lobe) occurred in approximately 0.8 percent .
LONG-TERM MONITORING — Long-term monitoring should include testing every 6 to 12 months initially to detect growth of residual adenoma tissue and the adequacy of hormonal replacement.
Adenoma regrowth — Evaluation for adenoma regrowth should include measurement of whatever serum marker was elevated before surgery and magnetic resonance imaging (MRI); if there is no regrowth after a year or two, the interval between scans can be lengthened. Early detection permits appropriate use of radiation therapy to minimize the need for repeat surgery. If MRI six months after transsphenoidal surgery shows little adenoma tissue or the residual tissue is not in a location of clinical significance, we recommend observation only by MRI, initially yearly.
The frequency of regrowth of residual adenoma tissue varies but is more likely when a patient does not have radiotherapy . In one report of 91 patients with nonfunctioning pituitary macroadenomas who underwent surgery but who did not have radiotherapy afterwards, adenoma regrowth occurred in 10 percent of patients; the mean time to adenoma regrowth was approximately six years . In two other series, of 491 and 159 patients, the recurrence rates were higher, 19 and 34 percent [14,30].
Not surprisingly, patients who have suprasellar extension of an adenoma are at higher risk for recurrence following surgery [30,31]. Radiation therapy reduces this risk but is associated with long-term morbidity and should not be used routinely. (See 'Adjuvant radiation therapy' above.)
Quality of life — Quality of life has been reported to be reduced after long-term cure of functioning pituitary adenomas [32,33]. Patients with nonfunctioning pituitary macroadenomas treated successfully by transsphenoidal surgery alone or combined with radiotherapy also have impaired quality of life when compared with age-matched, healthy controls . In addition, patients commonly experience increased fatigue and daytime somnolence . The impaired quality of life and fatigue appear to be due to the underlying hypopituitarism , as well as impaired sleep quality and abnormal distribution of sleep stages . Postoperative replacement of deficient hormones helps to improve quality of life, but other measures may be needed as well .
Aggressive tumors — Although most clinically nonfunctioning pituitary adenomas causing symptoms are readily treated by surgery alone or surgery followed by radiation, a very small number are unusually aggressive. These require consultation with an oncologist for consideration of chemotherapy. Temozolomide is the one chemotherapeutic agent that has been shown to have some benefit in treating aggressive pituitary adenomas. A review done in connection with development of clinical guidelines for management of aggressive pituitary tumors by the European Society of Endocrinology reported that in 11 studies, temozolomide reduced tumor volume in 47 percent of 106 patients .
Asymptomatic adenomas — Gonadotroph and other clinically nonfunctioning adenomas that are asymptomatic and not an immediate threat to vision do not require surgery, although hormonal deficiencies should be treated and re-evaluation of adenoma size and pituitary function should be performed at yearly intervals.
This situation is increasingly common because an increasing number of these adenomas are detected as incidental findings when magnetic resonance imaging (MRI) is performed for other reasons, such as head trauma. (See "Pituitary incidentalomas".)
Only limited data are available on the natural history of nonfunctioning macroadenomas because many patients who have them undergo surgery. However, in studies that have monitored growth of these adenomas for more than four to five years, approximately 50 percent of patients experienced adenoma growth [3,39-41]. Thus, although watchful waiting may be appropriate in some cases, long-term follow-up is necessary as adenoma growth can be anticipated in 50 percent.
In a small percent of cases, nonfunctioning adenomas may spontaneously regress. In a review of 10 series, this occurred in 34 of 304 patients (11 percent) , while in an individual series of 37 patients with five years of follow-up, four experienced pituitary apoplexy .
THERAPIES NOT RECOMMENDED — The extraordinary success of dopamine agonists in reducing the size of, as well as secretion by, lactotroph adenomas has prompted attempts to find a pharmacologic treatment for gonadotroph adenomas (see "Management of hyperprolactinemia"). To date, however, no drug has been found that consistently and substantially reduces the size of gonadotroph adenomas.
Bromocriptine therapy for nonfunctioning adenomas has been disappointing ; cabergoline may have some effect . However, data are limited, and this drug should not be considered an alternative to surgery. The cell membranes of some clinically nonfunctioning pituitary adenomas have somatostatin receptors [43,44], so two groups have administered octreotide (a somatostatin analog) to such patients. One group found improvement in visual fields in three of four patients, but no decrease in adenoma size . The other group found decreases in serum alpha subunit values in three of six patients and a reduction in adenoma size and visual impairment in two each; there was, however, no correlation among the three measurements .
Gonadotropin-releasing hormone (GnRH) agonists and antagonists have been studied as potential therapies for gonadotroph-secreting adenomas; both are ineffective. Administration of the GnRH antagonist, Nal-Glu GnRH, for six months to men with gonadotroph adenomas normalized their high serum follicle-stimulating hormone (FSH) concentrations but did not decrease the size of their adenomas , suggesting that FSH secretion by gonadotroph adenomas, but not adenoma size, is dependent upon endogenous GnRH. Administration of GnRH agonist analogs to patients with gonadotroph adenomas usually has either an agonist effect or no change in gonadotropin secretion and does not affect adenoma size [48-50].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pituitary tumors and hypopituitarism".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Pituitary adenoma (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Transsphenoidal surgery – In patients with gonadotroph or other clinically nonfunctioning pituitary adenomas that are large enough to cause neurologic symptoms, such as visual field abnormalities, we recommend transsphenoidal surgery as initial therapy (Grade 1B). The choice of surgical procedure, microscopic or endoscopic, depends upon the neurosurgeon's experience. (See 'Initial therapy: Transsphenoidal surgery' above.)
●Surgery versus waiting – For patients who have extrasellar extension but do not have neurologic symptoms, we discuss the risks of surgery versus the risks of waiting. For example, an adenoma that is markedly elevating the optic chiasm is very likely to begin to cause visual abnormalities in the next few years, yet some patients will choose to wait until that occurs. These patients should be followed by magnetic resonance imaging (MRI) and visual field examinations every 6 to 12 months. (See 'Indications' above.)
•Preoperative hormonal deficiencies – Hormonal deficiencies due to impaired function of the nonadenomatous pituitary should be replaced. Whatever treatment is used, lifetime re-evaluation is needed. (See 'Preoperative preparation' above.)
•SIADH and AVP-D – For patients who undergo surgery, daily postoperative monitoring for arginine vasopressin deficiency (AVP-D) should be performed until discharge and monitoring for syndrome of inappropriate antidiuretic hormone (SIADH) at one week afterwards.
●Postoperative evaluation – Four to six weeks post-discharge, the patient should again be evaluated for residual adenoma, hypocortisolism, hypothyroidism, hypogonadism, and AVP-D. In addition, the patient should be evaluated for visual function and all other hormonal functions of the nonadenomatous pituitary (algorithm 1). (See 'Postoperative issues' above and 'First evaluation post-discharge' above.)
•Residual adenoma – If little or no residual adenoma tissue remains 6 to 12 months after surgery or if a larger amount remains but does not threaten neurologic complications, we suggest monitoring the residual tissue with MRI. (See 'Residual adenoma' above.)
•Adjuvant radiation therapy – If the residual tissue grows progressively, we suggest adjuvant radiation therapy (Grade 2C). Administration of radiation stereotactically should now be used exclusively. (See 'Adjuvant radiation therapy' above.)
•Long-term monitoring – Long-term monitoring should include assessment every 6 to 12 months initially to detect growth of residual adenoma tissue and the adequacy of hormonal replacement. (See 'Long-term monitoring' above.)
Evaluation for adenoma regrowth should include measurement of whatever serum marker was elevated before surgery and an MRI; if there is no regrowth after a year or two, the interval between scans can be lengthened.
Hormonal hypersecretion by the adenoma preoperatively, when it occurs, can be used to monitor the effects of treatment.
●Asymptomatic macroadenomas – For macroadenomas that are not causing visual symptoms, we suggest yearly monitoring of pituitary function and adenoma size (MRI). (See 'Asymptomatic adenomas' above.)
●Aggressive tumors – Although most clinically nonfunctioning pituitary adenomas causing symptoms are readily treated by surgery alone or surgery followed by radiation, a very small number are unusually aggressive. These require consultation with an oncologist for consideration of chemotherapy. (See 'Aggressive tumors' above.)
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