| Original Full Text | Frontiers in EndocrinologyOPEN ACCESSEDITED BYGiuseppe Reimondo,University of Turin, ItalyREVIEWED BYRosa Maria Paragliola,Saint Camillus International University ofHealth and Medical Sciences, Italy*CORRESPONDENCEBenjamin Sandnerbenjamin.sandner@medizin.uni-leipzig.de†These authors have contributedequally to this work and sharefirst authorshipRECEIVED 14 September 2023ACCEPTED 29 January 2024PUBLISHED 19 February 2024CITATIONSeibold J, Hönemann M,Tönjes A and Sandner B (2024) Safelong-term therapy of Cushing’ssyndrome over 37 years with mitotane.Front. Endocrinol. 15:1294415.doi: 10.3389/fendo.2024.1294415COPYRIGHT© 2024 Seibold, Hönemann, Tönjes andSandner. This is an open-access articledistributed under the terms of the CreativeCommons Attribution License (CC BY). Theuse, distribution or reproduction in otherforums is permitted, provided the originalauthor(s) and the copyright owner(s) arecredited and that the original publication inthis journal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.TYPE Mini ReviewPUBLISHED 19 February 2024DOI 10.3389/fendo.2024.1294415Safe long-term therapy ofCushing’s syndrome over 37years with mitotaneJonas Seibold1†, Mario Hönemann2†, Anke Tönjes1and Benjamin Sandner1*1Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig MedicalCenter, Leipzig, Germany, 2Institute of Medical Microbiology and Virology, University of LeipzigMedical Center, Leipzig, GermanyWhile suggested, surgery is not always possible as a first-line treatment ofCushing’s Disease (CD). In such cases, patients require medical therapy inorder to prevent complications resulting from hypercortisolism. Although therehas been a wide expansion in pharmacological options in recent years, mitotanewas the agent of choice for treating hypercortisolism decades ago. Due to theintroduction of other therapies, long-term experience with mitotane remainslimited. Here, we report the case of a woman with CD who was treated withmitotane for 37 years. During the treatment period, biochemical and clinicaldisease control was achieved and the patient had two uncomplicatedpregnancies. Drug-related side effects remained moderate and could becontrolled by several dose adjustments. Our case highlights the ability ofmitotane to allow an effective control of hypercortisolism and to represent asafe treatment option in special situations where CD requires an alternativetherapeutic approach. Furthermore, we provide a literature review of the long-term use of mitotane and reported cases of pregnancy in the context ofmitotane therapy.KEYWORDSmitotane, Cushing’s syndrome, pregnancy, long-term treatment, adrenostatic drugIntroductionThe majority of cases of endogenous hypercortisolism (Cushing’s syndrome) occur dueto an ACTH (adrenocorticotropic hormone) producing adenoma of the pituitary gland (so-called Cushing’s disease (CD)) (1).For all etiologies of Cushing’s Syndrome, resection of the causal lesion(s) represents thetreatment of choice (2). However, certain situations may require an alternative therapeuticapproach. Medical therapy can be used as a primary or adjunctive option if the primaryfrontiersin.org01Seibold et al. 10.3389/fendo.2024.1294415lesion is not fully resectable (e.g., due to size/location of the tumoror metastatic disease), if a surgical approach is not feasible due tosevere comorbidities, or in line with the patient’s preference (1, 3).Furthermore, drugs may help to control hypercortisolism inpatients who suffer acute complications by severe hypercortisolismas well as in situations with persistent or recurrent symptoms afterpituitary surgery, which may be the case in up to 20% ofpatients (4).Various medical agents with different points of action have beenidentified for the treatment of hypercortisolism. Pituitary-directeddrugs (e.g. pasireotide, cabergolin) inhibit central ACTH-secretion,whereas adrenal-directed drugs (e.g. ketoconazole, metyrapone)directly disrupt adrenal steroidogenesis. Recently, several newsteroidogenesis inhibitors have been under investigation.Osilodrostat and levoketoconazole (the 2S, 4R enantiomer ofketoconazole), whose efficacy has now been demonstrated inseveral studies, offer certain advantages such as improvedpharmacokinetics and reduced toxicity (3, 5, 6). Glucocorticoidreceptor antagonists do not alter hormone production but inhibitthe glucocorticoid receptor (7).Mitotane (o,p’-dichlorodiphenyldichloroethane, o,p’-DDD), aderivate of the insecticide DDT (dichlorodiphenyltrichloroethane)(8), exhibits both adrenolytic and adrenostatic effects (9–11).Discovered in the 1950s, its cytotoxic effects were soon utilizedfor the treatment of adrenocortical carcinoma, where it showedbeneficial effects on survival and long-term remission (12–14).Though not fully understood, the cytotoxic effects are thought tobe mediated by the inhibition of mitochondrial respiratory chaincomplexes and the induction of endoplasmic reticulum (ER) stress.Subsequently, this leads to cell apoptosis and impairment of overallsteroidogenesis with an almost mandatory necessity ofglucocorticoid replacement therapy (11, 15–18). In contrast,mineralocorticoid deficiency is less frequent, as glomerulosa cellsappear to be less affected by mitotane. Therefore, fludrocortisonereplacement therapy was commenced in only 20 – 65% of patientsusually due to orthostatic hypotension or dizziness. In addition,mineralocorticoid insufficiency occurred later, typically 6 – 9months after initiation of mitotane (10, 19, 20).At lower concentrations, mitotane predominantly inhibitsseveral steps in adrenal steroid synthesis (e.g., cholesterol side-chain cleavage enzyme and 11-beta-hydroxylase), whereas cytolyticeffects are reduced (9, 11, 19). Moreover, by an enhanced cortisolclearance through induction of cytochrome P450 3A4 (CYP3A4),and through increased levels of corticosteroid-binding globulin(CBG, transcortin), mitotane reduces the levels of biologicallyactive cortisol (18, 20–22).Hence, it can be used as an adrenostatic agent in ACTH-dependent hypercortisolism, where it has not only proven to beone of the most effective drugs in normalizing cortisol levels but alsoto have beneficial effects on clinical features, even in long-termtreatment (7, 23–25). However, experience with mitotane in thetreatment of CD is limited, especially regarding long-termtreatment and its use under special circumstances.Frontiers in Endocrinology 02Case historyThe patient first presented as a 9-year-old girl at LeipzigUniversity Hospital with cushingoid habitus, acne, and hirsutismin 1969. She was overweight and below average height for her age.Elevated levels of 17-ketosteroids and hydroxycorticosteroids werefound in the patient’s urine, whereas imaging of the adrenal glandsand the pituitary region (aortography of the adrenal glands and sellax-ray) showed no pathological findings. Clinical symptomsworsened throughout the next visits, in particular persistentgrowth retardation and development of a buffalo hump.Furthermore, an impaired glucose tolerance developed. Based onthe loss of the physiological circadian rhythm of cortisol serumlevels and a lack of suppression of cortisol in the 1 mgdexamethasone suppression test (DST), the diagnosis ofendogenous hypercortisolism was established. Since ACTH assaysas well as CT or MRI scans were not available at the hospital at thattime, no further diagnostic workup was possible. Due to herreligious beliefs (being Jehovah’s Witnesses), the patient’s motherdecided against the recommended adrenalectomy, and the patientwas discharged without any treatment.At 16 years of age, as an operative treatment was still strictlyrejected by the patient’s parents, medication with mitotane wasinitiated at a loading dose of 2 grams per day. At that time thepatient weighed 65 kilograms, resulting in a weight-for-age abovethe 75th percentile. Within 3 months she lost 8 kilograms in weightand showed a normalisation of steroid levels. Mitotane treatmentwas monitored by periodical evaluation of the plasmaticconcentration. The drug, by then downscaled to 1 gram per day,was well tolerated and, with the exception of elevatedtransaminases, no biochemical abnormalities were found. Within12 months, the symptoms of hypercortisolism improved, her weightdropped to 47 kilograms, and a normal menstrual cycle developed.Laboratory analyses confirmed a normalization of transaminasesand glucose metabolism.Over the next years, further therapy was conducted in anoutpatient setting closer to the patient’s hometown. During thefirst months, two hospitalizations became necessary due togastroenteritis and malaise with vertigo, requiring short-termdiscontinuation of the drug with a subsequent dose adjustment.However, no overt signs of adrenal insufficiency were reported.At the age of 23, with a daily dose of 750 mg mitotane, thepatient gave birth to a boy via an uncomplicated primary cesareandelivery in the 35th week of gestation. Neither the mother nor theboy showed signs of adrenal insufficiency. Perioperatively, themother was given prednisolone as a substitute. In response toslightly elevated serum cortisol levels after discharge, mitotanewas titrated to the personal maximum dose of 1250 mg daily. Atage 31 and still on the same amount of mitotane, the patient gavebirth to another healthy boy. Both boys developed normally duringinfancy and adolescence and showed no signs of adrenalinsufficiency to this day (being 40 and 32 years old at the time ofthis article).frontiersin.orgSeibold et al. 10.3389/fendo.2024.1294415At the age of 36, new features of hypercortisolism developedunder 500 mg of mitotane per day. Further diagnostic workup forCD showed a lack of suppression in the 1 mg DST with elevatedACTH levels and a CRH stimulation test with a typical increase inACTH and cortisol levels. As pituitary MRI showed no adenoma,petrosal sinus sampling was performed and excluded the ectopicorigin of hypercortisolism (pituitary/peripheral gradient for ACTHwas 35-fold on the left and 15-fold on the right). Subsequently, thepatient consented to the proposed transsphenoidal surgery.Similarly to previous findings, no adenoma could be detectedintraoperatively, and a central 1/3 resection of the pituitary wascarried out. The histological examination showed discretehyperplasia of ACTH-producing cells. As the symptoms of CDpersisted, mitotane was continued. Even after a later hospitalizationwith sepsis in the context of massively elevated mitotane levels, thepatient decided against radiation of the pituitary, as well asalternative medication with pasireotide, but insisted oncontinuing to take mitotane on her own responsibility. Over thelong period of treatment serum concentrations of mitotane werevery regularly monitored and consistently found within thetarget range.In early 2013, the patient suffered a right-sided middle cerebralartery (MCA) stroke, and just a few months later, she washospitalized due to an acute adrenal insufficiency in the contextof an urosepsis. In the same year, she was admitted to our intensivecare unit with an acute adrenal insufficiency and a massiveexsiccosis. Clearly reduced morning serum cortisol levels (24nmol/l) and a subsequently performed ACTH stimulation testrevealed a primary adrenal insufficiency (reference range (RR) >500 nmol/l). Replacement therapy with hydrocortisone andfludrocortisone was established due to a concomitantmineralocorticoid deficiency, whereas mitotane was stopped at aplasma level of 18.6 mg/l. Follow-up blood samples taken twomonths a f t e r d i s charge showed per s i s t en t pr imaryadrenal insufficiency.When the patient once again presented with symptoms ofhypercortisolism in 2018, midnight cortisol levels were withinnormal ranges (42 nmol/l, ULN < 207). Although daytimecortisol values showed a circadian dynamic, the basal ACTH onthe other hand was elevated to 31.45 pmol/l (RR 1.04 – 10.8). As theDST and brain MRI findings were unremarkable, the symptomswere not considered to require a specific treatment, even though thecontinuously elevated ACTH levels may suggest the persistence ofcentral hypercortisolism. Since then, there have been regularendocrinological diagnostic work-ups, including regular MRIexaminations, and the clinical situation remained unaltered.Moreover, no severe medical conditions have developed thus far.DiscussionMitotane is the first-line treatment for adrenal carcinoma. Oneof its complex modes of action is its adrenolytic effect, resulting in areduction of cortisol levels. Therefore, it presents one second-linetreatment option also for CD. However, data from long-termapplications is missing (2). A review of the literature revealed lessFrontiers in Endocrinology 03than 200 reported cases with long-term use of mitotane (Table 1),with the longest reported intake period being 11.5 years (26).To the best of our knowledge, we hereby reported the longestdocumented treatment using mitotane, with a total duration of 37years. This exceedingly long exposure allowed an exceptionalinsight into the potentials and challenges of therapy withmitotane. Contrary to many other reported cases, we saw apatient on exclusive single-drug therapy with mitotane, allowingus to examine the drug’s efficacy and side effects without anyinterference from other medication.In our patient, the signs and symptoms of hypercortisolismregressed and a normalization of steroid levels was achieved withinmonths after the initiation of mitotane. As specified by a recentmeta-analysis by Broersen et al. (25), mitotane provides an effectivecontrol of cortisol levels in 80% of CD patients, and in that respect isthe most effective drug among pasireotide, cabergoline,ketoconazole, and metyrapone.In comparison, our patient’s daily dose of 125 to 1250 mg waslower than what was reported in other studies, e.g., 2600 ± 1100 mgdescribed by Baudry et al. (23). Even though several doseadjustments were made due to side effects, the regimen could bemaintained without the need for a dosage escalation over time. Thisunderlines that, contrary to adrenostatic drugs, mitotane does nottend to treatment escape (4).However, while the adrenolytic effects of mitotane are reducedat lower doses, adrenal insufficiency (AI) occurs regularly.Subsequently, glucocorticoid replacement becomes necessary inmost of the patients (Table 1) (7, 10). Nonetheless, mitotanetherapy without simultaneous steroid replacement was possible inour pat i ent by per forming both c lose c l in i ca l andlaboratory monitoring.It may be difficult to maintain the balance between beneficialand adverse drug effects. Mitotane shows high accumulation inadipose tissue, causing a half-life of up to 5 months (32). Differencesin the individual intestinal metabolism and a correlation betweenfree mitotane levels, considering the active fraction, and individualcholesterol and triglyceride concentrations fuel variability in druglevels (33). The drug`s toxic effects are hard to predict as they varyconsiderably and do not necessarily correlate with plasma levels.Furthermore, mitotane has a high potential for drug-druginteractions and an inductive effect on several CYP-enzymes (15).Therefore, side effects occurred in most of the reported patients andmade permanent discontinuation of mitotane necessary in one-third of the cases (20, 23).Over the years, our patient experienced a wide range of the mostcommonly reported toxic drug effects (Table 1), such as elevation oftransaminases, gastrointestinal and neurological toxicities, as well asrecurrent severe infections, which may indicate immune deficiency(23, 26, 34, 35). However, as the main part of the side effects appearsto be dose-dependent and reversible (26, 34), they could bemanaged by several dose adjustments.A remarkable aspect of our patient’s history is that sherepeatedly developed severe anemia, which resolved within a fewweeks after the withdrawal of mitotane. Even if rarely reported,observations from animals exposed to DDT isomers suggest acausal relationship, possibly due to inflammation-associatedfrontiersin.orgSeibold et al. 10.3389/fendo.2024.1294415hypoferremia, inhibition of hematopoietic tissue, or an estrogenicinhibitory effect on red blood cells (15, 36, 37).Taken together, our case highlights that through closecollaboration with well-informed patients and regular evaluationsof the dosage, toxic drug effects are manageable and long-termtreatment is safe and effective.The latest follow-up examinations of our patient revealed aphysiological cortisol circadian dynamic, suggesting an at leastpartial, recovery of the adrenal function. Hypothalamus-pituitary-adrenal axis recovery after discontinuation of mitotane was alsoobserved by other authors in up to 80% of their patients with amean time to recovery of 2.7 years (28, 29). Although no predictorsfor recovery have been identified so far, this further supports theFrontiers in Endocrinology 04theory that adrenocortical tissue remains viable and normal adrenalfunction can be regained with lower drug concentrations (29).Fertility during mitotane treatmentOne of the unique aspects of the presented case is that thepatient gave birth to two healthy children while being treated withmitotane. This is remarkable, as not only hypercortisolism (38, 39)but also exposure to DDT and its isomers may affect fertility andpregnancy outcomes negatively (40–42).Even though the majority of women with CD suffer from oligo-or amenorrhea (39), the history of our patient points out thatTABLE 1 Published case reports of long-term treatment with mitotane.Study EntityPatients[n]Treatmentduration1Follow-up1Dose[mg/d]Mitotaneplasma con-centration[mg/l]AIAfter treatmentOtherside effectsKnappeet al.,1997 (26)CD 6 (1,5-)11,5y 11,5 y max. 3000 n/a17% (1)(after 5 y)↑ GGT, ASAT, ALAT,diarrhea (in 1 patient)Sharmaet al.,2012 (27)EAS 1 1,5 y 3 y 500-2000 n/a100% (1)hypercortisolismrecurred 16 m latern/aKamenickýet al.,2011 (28)4 CD7 EAS11(1–) 30,5 mmedian 3.0 m1-42 mmedian14 mmedian 3000median 10,1 (4,3-13,9)combinationtherapy: median 2,9(1,9-6,0)9% (1) permanent AI(after 30,5 m)36% (4) acute AIgastrointestinaldiscomfort,↑ GGT, ASAT, ALAT,↑ cholesteroldizziness, confusionHypokalemiaBaudryet al.,2012 (23)CD 769,5 ymedian 10,3 mmean 97m(6.3–192)mean 2600± 110010,5 ± 8.975% (57) atwithdrawalof Mitotanegastrointestinaldiscomfort,↑ GGT, transaminases,↑ LDL-, HDL-cholesterol,neutropenia,skinrash, gynecomastiaLuton at al.1979 (24)CD 62 3-34 m n/a 4000-12000 n/a 31% (19) n/aPoirieret al.,2020 (29)ACC 23(24-) 85 mmedian 34 m24 –144 mmax.2000-4500mean peakconcentration19.4 mg/ml*(8.1-27.1 mg/ml)21,7% (5) permanentAI, othersachieved recoveryn/aKeller et al.,1988 (13)CS 3 (5-) 10y (5-) 10y 15-20 mg/kg n/a none ↑ cholesterolBeneckeet al.,1991 (30)CD 2 5-8 y (5-) 8 y375-6000(maintenancedoseca. 1000)1-17 nonegastrointestinaldiscomfort, centralnervous depressionIchikawaet al.,1999 (31)CD 1 18 y 18 y 1000-4000 n/a none nausea and vomitingCD, Cushing’s disease; CS, Cushing’s syndrome; EAS, ectopic ACTH syndrome; ACC, adrenocortical cancer; HC, hypercortisolism; y, years; m, months; AI, adrenal insufficiency; GGT, gamma-glutamyltransferase; ASAT, aspartate aminotransferase; ALAT, alanine aminotransferase; LDL, low-density lipoprotein HDL, high-density lipoprotein; n/a, no data/information available; ↑,rise/elevation.1unless specified otherwise the longest mitotane treatment or follow-up mentioned in the study is listed.*contrary to other publications the authors report mitotane plasma levels in mg/ml.frontiersin.orgTABLE 2 Published case reports of pregnancy under mitotane intake.exofheildAdrenalfunctionat birthAppearanceofexternalgenitaliaNeurologicaldevelopmentn/adysmorphogenicprimordial cortexn/a -melevated ACTH,normal cortisol, noclinical signs of AInormal normaln/a n/a n/a n/amAPGAR 6, resp.distress, normalACTH, cortisolnormal normaln/a - n/a -f - normal -n/a - n/a -f, f,, mnormalin 1 case DHEA-S decreasednormal normaln/a n/a normal n/arnal plasma; n/a, no data/information available; n.d., not detectable; pctl, percentile;Seiboldetal.10.3389/fendo.2024.1294415FrontiersinEndocrinologyfrontiersin.org05Study EntityPregnancies[n]Dose[mg/d]Time ofmitotanearrestMMP[mg/l]Age ofthemotherOutcomeBirthweight[g]ScLeiba et al.,1989(42)CD 1 n/a week 4 n/a 30 y TA at week 6 n/aGerl et al.,1992(46) 1CD 1 1000- 1500until week 34at 1000 mg/dpregnancy:3,9-4,7delivery: 1,4cordblood: 1,426 yspontaneous birth atweek 38normalKnappeet al., 1997(26) 1CD 1 n/adiscontinuedbeforen/a n/a uncomplicated pregnancy n/aKojoriet al., 2011(47)ACC 1 1000 continued n/a 27 yHELLP syndrome,premature C.s. week 321409 (10. pct)Baszko-Blaszyket al.,2011 (48)ACC 1 (twins) 1500 continuedconception:12,526 ytwinsspontaneous abortion atweek 10n/aTripto-Shkolniket al.,2013 (49)ACC 1 n/a week 6conception:9,8week 21:5,99cordblood: 033 y TA at week 21 n/ade Corbiereet al.,2015 (50)ACC 1 n/a n/a n/a 39 y TA at week 8 n/aMagkouet al., 2018(51)ACC,CD4 (1twin pregnancy)2000 – 3000onediscontinued5 m before,othersstopped atweek 6-9conception:0,9-6,7term: n.d.- 1,720 y, 25 y,20 yemergency week 40 (C.s.)*, 40 (C.s.)*, spontaneousat 39 (C.s.), 40 (VD)2180, 2550,3470, 4450Baudryet al., 2012(23)CD 4 (10) n/adiscontinuedbeforeconceptionn/a n/aTA in the 6/10 ofcontinued mitotane;normal pregnancy in 4/10n/aACC, adrenocortical cancer; AI, adrenal insufficiency; CD, Cushing’s disease; C.s., Caesarian section; DHEA-S, dehydroepiandrosterone sulfate; f, female; m, male; MMP, mitotane in matTA, therapeutic abortion; VD, vaginal delivery; y, years.1different pregnancies in the same mother.thfeSeibold et al. 10.3389/fendo.2024.1294415mitotane provides sufficient control of cortisol levels. Therefore, anormal menstrual cycle and fertility could be restored.Furthermore, despite the negative effects of DDT/DDD ongonadal function, which was established in an animal model (43)as well as in humans (20, 34), our case underlines that even attherapeutic levels of mitotane (14 – 20 mg/l), conception ispossible (35).Due to the negative impact of DDT and its derivates onpregnancy and fetal outcomes observed in animal andenvironmental studies (40, 44, 45), experts recommend avoidingpregnancy when taking mitotane (2). Consequently, the influence ofmitotane on fetal development remains poorly understood and it isnot clear whether the effects observed in DDT will occur in humansexposed to o,p’-DDD. Overall, we found a total of 21 documentedpregnancies in association with mitotane intake (Table 2), themajority of which were terminated by therapeutic abortion.Whereas several investigations suggest a negative impact ofmaternal exposure to DDT isomers on fetal neurologicdevelopment (52–54), in the context of mitotane, only Leiba et al.found a nervous system malformation in a fetus after abortion (42).In contrast, our patient’s sons, as well as the other live births,reported in Table 2, showed no neurologic impairments. Theirnormal educational and vocational development thus extends thefindings of Magkou et al. (51), showing normal neurocognitivedevelopment throughout early childhood after exposure tomitotane in pregnancy.Acute adrenal insufficiency, due to cytolytic effects on the fetus’adrenal glands, was neither observed in our patient’s sons nordescribed in the other cases. This indicates that there is no impacton the offspring’s adrenal glands, or at least the possible impactremains tolerable at the applied doses. However, toxicity at higherplasma levels with an underlying dose-effect relationship, as seen inacute toxicity of mitotane, cannot be ruled out according to theavailable data.In the examined studies, continued intake of mitotane wasdescribed only for one other case with a premature operativedelivery subsequent to the development of a HELLP syndrome(hemolysis, elevated liver enzymes, and low platelet count) (47). Inanother case, a healthy infant was born after mitotane cessation atthe 34th gestational week, with detectable maternal plasma levels atbirth (26). In all the other live births, mitotane was either stoppedbefore conception or in the first trimester. There was no regularevaluation of o,p’-DDD-plasma levels throughout pregnancy inmost of the presented cases and there are inconsistent findingsregarding the extent to which mitotane is transferred from themother to the fetus (26, 49, 51).Moreover, due to the small number of natural pregnancies, it isnot possible to assess whether the increased risk of prematuredelivery, spontaneous abortion, or small-for-gestational-age that areassociated with exposure to DDT/DDE, are also present in the caseof mitotane exposure (45, 55, 56).Frontiers in Endocrinology 06In summary, the data on the use of mitotane during pregnancyis incomplete. However there is also very little experience with otheradrenostatic medications for pregnant women (2). Mitotanerepresents a possible therapy for patients for whom surgicaltherapy is not possible or desirable, also in long-term application.Summary/ConclusionIn conclusion, we report the case of the longest documentedapplication of mitotane in a patient with CD. In addition, wehighlight the ability of mitotane to provide an efficient control oflevels of cortisol, while adverse effects of the drug are manageable.Our patient’s medical history, underlined by the uncomplicatedpregnancy and parturition of two healthy children, suggests thatmitotane may be a long-term alternative if surgery or othertherapeutic options are not feasible.Author contributionsJS: Writing – original draft. MH: Writing – original draft,Writing – review & editing. AT: Writing – review & editing. BS:Writing – review & editing.FundingThe author(s) declare financial support was received for theresearch, authorship, and/or publication of this article. The authorsacknowledge support from the German Research Foundation(DFG) and Universität Leipzig within the program of OpenAccess Publishing.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.frontiersin.orgSeibold et al. 10.3389/fendo.2024.1294415References1. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al.Consensus on diagnosis and management of Cushing’s disease: a guideline update.Lancet Diabetes Endocrinol (2021) 9:847–75. doi: 10.1016/S2213-8587(21)00235-72. Nieman LK, Biller BM, Findling JW, MuradMH, Newell-Price J, Savage MO, et al.Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. JClin Endocrinol Metab (2015) 100:2807–31. doi: 10.1210/jc.2015-18183. Tritos NA. Adrenally directed medical therapies for cushing syndrome. J ClinEndocrinol Metab (2021) 106:16–25. doi: 10.1210/clinem/dgaa7784. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease.Endocrine Rev (2015) 36:385–486. doi: 10.1210/er.2013-10485. Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, et al.Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): amulticentre phase III study with a double-blind, randomised withdrawal phase. LancetDiabetes Endocrinol (2020) 8:748–61. doi: 10.1016/S2213-8587(20)30240-06. Pivonello R, Elenkova A, Fleseriu M, Feelders RA, Witek P, Greenman Y, et al.Levoketoconazole in the treatment of patients with cushing’s syndrome and diabetesmellitus: results from the SONICS phase 3 study. Front Endocrinol (Lausanne) (2021)12:595894. doi: 10.3389/fendo.2021.5958947. Pivonello R, Ferrigno R, De Martino MC, Simeoli C, Di Paola N, Pivonello C, et al.Medical treatment of cushing’s disease: an overview of the current and recent clinicaltrials. Front Endocrinol (Lausanne) (2020) 11:648–. doi: 10.3389/fendo.2020.006488. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J ClinEndocrinol Metab (2013) 98:4551–64. doi: 10.1210/jc.2013-30209. Brown RD, Nicholson WE, Chick WT, Strott CA. Effect of o,p’DDD on HumanAdrenal Steroid llb-Hydroxylation Activity. J Clin Endocrinol Metab (1973) 36:730–3.doi: 10.1210/jcem-36-4-73010. Bianchini M, Puliani G, Chiefari A, Mormando M, Lauretta R, Appetecchia M.Metabolic and endocrine toxicities of mitotane: A systematic review. Cancers (2021)13:5001. doi: 10.3390/cancers1319500111. Hescot S, Amazit L, Lhomme M, Travers S, DuBow A, Battini S, et al. Identifyingmitotane-induced mitochondria-associated membranes dysfunctions: metabolomicand lipidomic approaches. Oncotarget (2017) 8:109924–40. doi: 10.18632/oncotarget.1896812. Hutter AMJr., Kayhoe DE. Adrenal cortical carcinoma: Results of treatment witho, p’DDD in 138 patients. Am J Med (1966) 41:581–92. doi: 10.1016/0002-9343(66)90220-813. Keller E, Benecke R, Vetter B, Willgerodt H. LONG-TERM TREATMENT OFHYPOTHALAMIC-PITUITARY CUSHING SYNDROMEWITH o,p’-DDD IN LOWDOSAGE. Pediatr Res (1988) 23:129. doi: 10.1203/00006450-198801000-0017014. Becker D, Schumacher OP. o, p’DDD therapy in invasive adrenocorticalcarcinoma. Ann Internal Med (1975) 82:677–9. doi: 10.7326/0003-4819-82-5-67715. Corso CR, Acco A, Bach C, Bonatto SJR, de Figueiredo BC, de Souza LM.Pharmacological profile and effects of mitotane in adrenocortical carcinoma. Br J ClinPharmacol (2021) 87:2698–710. doi: 10.1111/bcp.1472116. Poli G, Guasti D, Rapizzi E, Fucci R, Canu L, Bandinelli A, et al.Morphofunctional effects of mitotane on mitochondria in human adrenocorticalcancer cells. Endocrine-Related Cancer (2013) 20:537–50. doi: 10.1530/ERC-13-015017. Lo Iacono M, Puglisi S, Perotti P, Saba L, Petiti J, Giachino C, et al. Molecularmechanisms of mitotane action in adrenocortical cancer based on in vitro studies.Cancers (2021) 13:5255. doi: 10.3390/cancers1321525518. Chortis V, Taylor AE, Schneider P, Tomlinson JW, Hughes BA, O’Neil DM, et al.Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5a-reductase,explaining the need for personalized glucocorticoid and androgen replacement. J ClinEndocrinol Metab (2013) 98:161–71. doi: 10.1210/jc.2012-285119. Hart MM, Reagan RL, Adamson RH. The effect of isomers of DDD on theACTH-induced steroid output, histology and ultrastructure of the dog adrenal cortex.Toxicol Appl Pharmacol (1973) 24:101–13. doi: 10.1016/0041-008X(73)90185-320. Daffara F, De Francia S, Reimondo G, Zaggia B, Aroasio E, Porpiglia F, et al.Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treatedadjuvantly. Endocrine-Related Cancer (2008) 15:1043–53. doi: 10.1677/ERC-08-010321. Bae YJ, Kratzsch J. Corticosteroid-binding globulin: modulating mechanisms ofbioavailability of cortisol and its clinical implications. Best Pract Res Clin EndocrinolMetab (2015) 29:761–72. doi: 10.1016/j.beem.2015.09.00122. Alexandraki KI, Kaltsas GA, Le Roux CW, Fassnacht M, Ajodha S, Christ-CrainM, et al. Assessment of serum-free cortisol levels in patients with adrenocorticalcarcinoma treated with mitotane: a pilot study. Clin Endocrinol (2010) 72:305–11. doi:10.1111/j.1365-2265.2009.03631.x23. Baudry C, Coste J, Bou Khalil R, Silvera S, Guignat L, Guibourdenche J, et al.Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a singlecenter. Eur J Endocrinol (2012) 167:473–81. doi: 10.1530/EJE-12-035824. Luton J, Mahoudeau J, Bouchard P, Thieblot P, Hautecouverture M, Simon D,et al. Treatment of Cushing’s disease by o, p′ DDD: survey of 62 cases. New Engl J Med(1979) 300:459–64. doi: 10.1056/NEJM197903013000903Frontiers in Endocrinology 0725. Broersen LHA, Jha M, Biermasz NR, Pereira AM, Dekkers OM. Effectiveness ofmedical treatment for Cushing’s syndrome: a systematic review and meta-analysis.Pituitary (2018) 21:631–41. doi: 10.1007/s11102-018-0897-z26. Knappe G, Gerl H, Ventz M, Rohde W. Langzeit-Therapie des hypothalamisch-hypophysären Cushing-Syndroms mit Mitotan (o, p’-DDD). DMW-DeutscheMedizinische Wochenschrift (1997) 122:882–6. doi: 10.1055/s-2008-104770427. Sharma S, Nieman L. Prolonged remission after long-term treatment withsteroidogenesis inhibitors in Cushing’s syndrome caused by ectopic ACTH secretion.Eur J endocrinology/European Fed Endocrine Societies (2012) 166:531. doi: 10.1530/EJE-11-094928. Kamenický P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier J-F,et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative torescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J ClinEndocrinol Metab (2011) 96:2796–804. doi: 10.1210/jc.2011-053629. Poirier J, Gagnon N, Terzolo M, Puglisi S, Ghorayeb NE, Calabrese A, et al.Recovery of adrenal insufficiency is frequent after adjuvant mitotane therapy in patientswith adrenocortical carcinoma. Cancers (2020) 12:639. doi: 10.3390/cancers1203063930. Benecke R, Keller E, Vetter B, de Zeeuw RA. Plasma level monitoring of mitotane(o,p’-DDD) and its metabolite (o,p’-DDE) during long-term treatment of cushing’sdisease with low doses. Eur J Clin Pharmacol (1991) 41:259–61. doi: 10.1007/BF0031544031. Ichikawa Y, Kaburaki J, Yoshida T, Kawai S. 18 years mitotane therapy forintractable Cushing’s disease. Lancet (1999) 354:951. doi: 10.1016/S0140-6736(05)75699-332. Moolenaar A, Van Slooten H, Van Seters A, Smeenk D. Blood levels of o, p′-DDD following administration in various vehicles after a single dose and duringlong-term treatment. Cancer Chemother Pharmacol (1981) 7:51–4. doi: 10.1007/BF0025821333. Kroiss M, Plonné D, Kendl S, Schirmer D, Ronchi CL, Schirbel A, et al.Association of mitotane with chylomicrons and serum lipoproteins: practicalimplications for treatment of adrenocortical carcinoma. Eur J Endocrinol (2016)174:343–53. doi: 10.1530/EJE-15-094634. Kerkhofs TM, Baudin E, Terzolo M, Allolio B, Chadarevian R, Mueller HH, et al.Comparison of two mitotane starting dose regimens in patients with advancedadrenocortical carcinoma. J Clin Endocrinol Metab (2013) 98:4759–67. doi: 10.1210/jc.2013-228135. Haak HR, Hermans J, van de Velde CJH, Lentjes E, Goslings BM, Fleuren GJ,et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in aconsecutive series of 96 patients. Br J Cancer (1994) 69:947–51. doi: 10.1038/bjc.1994.18336. Fourie FR, Hattingh J. DDT administration: haematological effects observed inthe crowned Guinea-fowl (Numida meleagris). J Environ Pathol Toxicol (1979) 2:1439–46.37. Tomita M, Yoshida T, Fukumori J, Yamaguchi S, Kojima S, Fukuyama T, et al. p,p’-DDT induces microcytic anemia in rats. J Toxicol Sci (2013) 38:775–82. doi: 10.2131/jts.38.77538. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome duringpregnancy: personal experience and review of the literature. J Clin Endocrinol Metab(2005) 90:3077–83. doi: 10.1210/jc.2004-236139. Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy R, et al.Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases.Endocrine (2017) 55:555–63. doi: 10.1007/s12020-016-1117-040. Lysodren - EPAR. Scientific Discussion (2006). Available at: https://www.ema.europa.eu/documents/scientific-discussion/lysodren-epar-scientific-discussion_en.pdf.41. Guo H, Jin Y, Cheng Y, Leaderer B, Lin S, Holford TR, et al. Prenatal exposure toorganochlorine pesticides and infant birth weight in China. Chemosphere (2014) 110:1–7. doi: 10.1016/j.chemosphere.2014.02.01742. Leiba S, Weinstein R, Shindel B, Lapidot M, Stern E, Levavi H, et al. Theprotracted effect of o, p’-DDD in Cushing’s disease and its impact on adrenalmorphogenesis of young human embryo. Ann Endocrinol (Paris) (1989) 50(1):49–53.43. Rhouma KB, Tebourbi O, Krichah R, Sakly M. Reproductive toxicity of DDTin adult male rats . Hum Exp Toxicol (2001) 20:393–7. doi: 10.1191/09603270168269294644. Fabro S, McLachlan J, Dames N. Chemical exposure of embryos during thepreimplantation stages of pregnancy: mortality rate and intrauterine development. AmJ Obstetrics Gynecol (1984) 148:929–38. doi: 10.1016/0002-9378(84)90535-045. Longnecker MP, Klebanoff MA, Zhou H, Brock JW. Association betweenmaternal serum concentration of the DDT metabolite DDE and preterm and small-for-gestational-age babies at birth. Lancet (2001) 358:110–4. doi: 10.1016/S0140-6736(01)05329-646. Gerl H, Benecke R, Knappe G, Rohde W, Stahl F, Amendt P. Pregnancy andpartus in Cushing’s disease treated withoff, p’-DDD. Acta Endocrinol (Copenh) (1992)126:133.frontiersin.orgSeibold et al. 10.3389/fendo.2024.129441547. Kojori F, Cronin CMG, Salamon E, Burym C, Sellers EAC. Normal adrenalfunction in an infant following a pregnancy complicated by maternal adrenal corticalcarcinoma and mitotane exposure. J Pediatr Endocrinol Metab (2011) 24:203–4. doi:10.1515/jpem.2011.12348. Baszko-Błaszyk D, Ochmańska K, Waśko R, Sowiński J. Pregnancy in a patientwith adrenocortical carcinoma during treatment with Mitotane—a case report.Endokrynologia Polska (2011) 62:186–8.49. Tripto-Shkolnik L, Blumenfeld Z, Bronshtein M, Salmon A, Jaffe A. Pregnancyin a patient with adrenal carcinoma treated with mitotane: a case report and review ofliterature. J Clin Endocrinol Metab (2013) 98:443–7. doi: 10.1210/jc.2012-283950. de Corbière P, Ritzel K, Cazabat L, Ropers J, Schott M, Libé R, et al. Pregnancy inwomen previously treated for an adrenocortical carcinoma. J Clin Endocrinol Metab(2015) 100:4604–11. doi: 10.1210/jc.2015-234151. Magkou D, Do Cao C, Bouvattier C, Douillard C, de Marcellus C, Cazabat L,et al. Foetal exposure to mitotane/Op’DDD: Post-natal study of four children. ClinEndocrinol (2018) 89:805–12. doi: 10.1111/cen.13854Frontiers in Endocrinology 0852. Bornman M, Pretorius E, Marx J, Smit E, van der Merwe C. Ultrastructuraleffects of DDT, DDD, and DDE on neural cells of the chicken embryo model. EnvironToxicol: Int J (2007) 22:328–36. doi: 10.1002/tox.2026153. Torres-Sánchez L, Rothenberg SJ, Schnaas L, Cebrián ME, Osorio E, del CarmenHernández M, et al. In utero p, p′-DDE exposure and infant neurodevelopment: aperinatal cohort in Mexico. Environ Health Perspectives (2007) 115:435–9. doi: 10.1289/ehp.956654. Ribas-Fitó N, Torrent M, Carrizo D, Muñoz-Ortiz L, Júlvez J, Grimalt JO, et al.In utero exposure to background concentrations of DDT and cognitive functioningamong preschoolers. Am J Epidemiol (2006) 164:955–62. doi: 10.1093/aje/kwj29955. Korrick SA, Chen C, Damokosh AI, Ni J, Liu X, Cho S-I, et al. Association ofDDT with spontaneous abortion: a case-control study. Ann Epidemiol (2001) 11:491–6.doi: 10.1016/S1047-2797(01)00239-356. Saxena M, Siddiqui M, Seth T, Murti CK, Bhargava A, Kutty D. Organochlorinepesticides in specimens from women undergoing spontaneous abortion, premature orfull-term delivery. J Analytical Toxicol (1981) 5:6–9. doi: 10.1093/jat/5.1.6frontiersin.org |
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