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The American Journal of Medicine (2005) 118, 664–670

LINICAL RESEARCH STUDY

ndocrine disorders during the first year after autologoustem-cell transplantibuse Tauchmanovà, MD, PhD,a Carmine Selleri, MD,b Gennaro De Rosa, MD,b

ariarosaria Esposito, MD,b Carolina Di Somma, MD, PhD,a

rancesco Orio, MD, PhD,a Stefano Palomba, MD,c Gaetano Lombardi, MD, PhD,a

runo Rotoli, MD,b Annamaria Colao, MD, PhDa

Department of Molecular and Clinical Endocrinology and Oncology,Division of Hematology, “Federico II” University of Naples,

Chair of Gynecology and Obstetrics, University “Magna Graecia” of Catanzaro (SP), Italy.

ABSTRACTBACKGROUND: Frequent endocrine disorders have been reported after allogeneic stem-cell transplant,

but data on adult survivors of autologous transplants are still scarce.METHODS: In this prospective study we investigated early (at 3 months) and late (at 12 months) endocrine

dysfunctions in 95 consecutive autologous stem-cell transplant recipients (47 men and 48 women) aged 16 to 55years. The functions of the hypothalamic-pituitary-gonadal/thyroid/adrenal/somatotroph axis were evaluated.

RESULTS: Three months after the transplant, insulin-like growth factor-1 values were below the normal rangein 53 patients (56%); 37 of 40 women (93%) of reproductive age experienced precocious ovarian failure; 39 of46 men (85%) showed high follicular stimulating hormone, and 17 men (37%) showed low testosterone levels.Adrenal insufficiency occurred in 28 patients (30%) during the peritransplant period after corticosteroid with-drawal. Transient subclinical hyperthyroidism was found in 15 patients (16%). Transient “low T3” syndrome wasrevealed in 29 patients (31%). Twelve months after the transplant, insulin-like growth factor-1 values were stilllow in 36 patients (38%). Menstrual cycles resumed in four women; follicular stimulating hormone, luteinizinghormone, and estradiol levels improved in 10 patients. Testosterone was low in only two men (4%). Seminalanalysis revealed azoospermia in 32 (91%) of 35 men examined. Subclinical hypothyroidism was found in 11patients (12%); eight of them had previously received radiotherapy for the upper half of the body.

CONCLUSION: This study documents frequent endocrine disorders during the first year after autologousstem-cell transplant. Despite a tendency to improve, in more than half of the cases, the complications persisted formore than 1 year. Therefore, to diagnose and correct early and late endocrine dysfunctions, endocrine screeningis required during the first year in all patients undergoing autografting.© 2005 Elsevier Inc. All rights reserved.

KEYWORDS:Bone marrowtransplantation;Gonadal failure;Thyroiditis;Low T3 syndrome;Subclinicalhyperthyroidism;IGF-1;Adrenal insufficiency

ctrrpoit

Autologous hemopoietic stem-cell transplantation is per-ormed more frequently than any allogeneic type of organransplant worldwide. The endocrine system is one of the most

This study was partially supported by grant number 2003069821 fromURST, Rome, Italy.

Requests for reprints should be addressed to Annamaria Colao, M.D.,h.D., Department of Molecular and Clinical Endocrinology and Oncology,niversity “Federico II” in Naples, Via S. Pansini 5, 80131 Naples Italy.

tE-mail address: colao@unina.it

002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1016/j.amjmed.2005.02.009

ommon targets of posttransplant complications.1,2 The rela-ive risk of developing endocrine disorders was found to beelated to underlying diseases, previous treatments, use ofadiation therapies and type of irradiation schedule, posttrans-lant treatments, and age.3,4 It may be difficult for physiciansperating outside specialized centers to decide on the timing ofnvestigating endocrine disorders. Moreover, it is also essentialo identify the type of disorders that need treatment, as opposed

o those that can only be followed up.

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Underlying diseases leading to autologous stem-cell trans-lantation are mostly lymphoma, leukemia, and multiple my-loma. The transplant is preceded by conditioning regimensonsisting of high-dose antiblastic treatments, with or withoutotal body irradiation, designed to eradicate the underlyingematologic disease.

Most of the data currently available on posttransplantndocrine disorders concern the pediatric setting, whereastudies in adults who have undergone transplantation aretill scant. Moreover, in previous studies,5,6 data from pa-ients who underwent allogeneic or autologous transplanta-ion were frequently pooled together, with most patientsaving undergone radiotherapy as a part of conditioningegimens.6-8 Currently, no prospective data exist on endo-rine dysfunction in adult survivors of autologous stem-cellransplantation. Subsequent to our finding of a high preva-ence of persistent endocrine dysfunctions in allogeneicettings,9 in 1999 we began endocrine screening in patientsndergoing autografting.

This study assesses the function in multiple areas of thendocrine system in adult patients with a functioning bonearrow autograft, in disease remission lasting at least 1 year

fter transplantation, in the attempt to clarify the manage-ent of posttransplant endocrine disorders.

atients and methods

atients

Between 1999 and 2002, 110 adult patients received anutologous stem-cell transplant at our institution. Primaryiseases included Hodgkin’s disease and non-Hodgkin’symphoma, acute or chronic myeloid leukemia, chronicymphocytic leukemia, and multiple myeloma. The dataelative to 15 patients who had relapsed or died during therst 12 months were excluded; the study sample consistedf the remaining 95 patients. The clinical features of theseatients are summarized in Table 1. Informed consent wasbtained by all subjects, and the study was designed inccordance to the Helsinki II Declaration on human exper-mentation.

The source of the stem cells was an unmanipulatedarrow (n � 50) or mobilized peripheral blood progenitors

n � 45). Mobilization was achieved by chemotherapy andgranulocyte colony-stimulating factor at a dose of 16

g/kg daily by subcutaneous injection. No patient under-ent radiotherapy as part of the conditioning regimen. The

onditioning regimen for myeloid leukemia consisted ofusulphan and cyclophosphamide administration. The com-ination of carmustine, etoposide, cytarabine, and melpha-an was used in patients with lymphomas and chronic lym-hocytic leukemia. Patients with myeloma received only aingle high dose of melphalan. Twenty-six patients (16

omen and 10 men) received radiotherapy as a part of a

ymphoma and myeloma treatment (over the neck/thorax in6 and over the abdomen/pelvis in 10).

tudy protocol

Patients were evaluated 3 � 0.4 months and 12 � 0.9onths after autografting for all endocrine functions except

or the adrenocortical function, which was investigated dur-ng the peritransplant period 7 to 20 days after corticosteroidithdrawal and monitored as appropriate in patients with

drenal insufficiency. Thyroid function was evaluated againfter 6 months because of the high prevalence of abnormal-ties found in the third month. Blood samples were obtainedetween 8:00 and 10:30 A.M. Circulating free thyroxine, freeriiodothyronine, thyroid-stimulation hormone (TSH) andhyroid autoantibodies, follicular stimulating hormoneFSH), luteinizing hormone (LH), prolactin, adrenocortico-ropin hormone, 17-�-estradiol, testosterone, cortisol, dehy-roepiandrosterone sulphate (DHEAS), and insulin-likerowth factor (IGF)-I were measured in a single sample,hereas prolactin was measured as a 2-hour profile (6

amples taken every 20 minutes). All measurements wereerformed with commercially available kits: cortisol, tes-osterone, estradiol, and DHEAS were measured with anmmulite solid-phase chemoluminescent enzyme immuno-

Table 1 Clinical characteristics of the 95 patientsevaluated for endocrine dysfunction after autologous stem-cell transplant

CharacteristicNumber (%) ormedian (range)

Age at stem-cell transplant (y) 39 (17–55)Women/men 48 (51%)/47 (49%)Disease:

Hodgkin’s disease 29 (31%)Acute myeloid leukemia 27 (28%)Non-Hodgkin’s lymphoma 25 (26%)Multiple myeloma 10 (11%)Chronic lymphocytic leukemia 4 (4%)

Previous radiotherapy 26 (27%)Upper/lower half body 16 (17%)/10 (11%)Conditioning regimen:

Busulphan (16 mg/kg in 4 d) andcyclophosphamide (120 mg/kgin 2 d) 29 (31%)

Carmustine (300 mg/m2 in 1 d),etoposide (200 mg/m2 in 4 d),cytarabine (400 mg/m2 in 4 d),melphalan (140 mg/m2 in 1 d) 56 (59%)

High-dose melphalan (200 mg/m2

in 1 d) 10 (11%)Corticosteroid treatment:

Duration (d) 128.5 (30–730)Cumulative dose (g/m2)* 6.5 (0.8–13)

*Cumulative dose of corticosteroids is expressed as equivalents ofprednisone.

ssay (DPC, Los Angeles, Calif); FSH and LH were mea-

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666 The American Journal of Medicine, Vol 118, No 6, June 2005

ured with an Biodata SpA kit (Rimini, Italy). Serum TSHas measured with an immunoradiometric assay (Delfia,allac, Inc., Turku, Finland), and free thyroid hormonesere determined with radioimmunoassay Lisophase kits

Technogenetics, Milan, Italy). Antithyroglobulin antibod-es were measured with an Ares Serono kit (Milan, Italy),nd antiperoxidase antibodies were measured with a Dia-orin kit (Saluggia, Italy). The intra-assay variation coeffi-ient was less than 3.6%, and the interassay variation coef-cient was less than 7.8% for all the measurements.

An ultrasound scan of the thyroid gland with a 7.5-MHzinear transducer was performed in all patients. Transpari-tal pelvic ultrasound with a 3.5-MHz linear transducer waserformed in all women. Spermiogram was performed in 35en 12 months after autografting; the remaining 12 men

efused seminal fluid analysis.

tatistical analysis

Statistical analysis was performed with the SPSS Inc.Chicago, Ill) package. Because of a skewed distribution ofost of the data, median and range were used through the

ext and in the tables. The Mann-Whitney test was used toompare the differences at 3 and 12 months. Age, sex,iagnosis, and treatments received were investigated as pos-ible risk factors for endocrine disorders by chi-square testnd by linear or logistic regression analysis, as appropriate.wo-sided P values less than .05 were regarded as significant.

esults

arly abnormalities (at 3 months)

Serum IGF-I levels were lower than age-reference valuesn 53 patients (56%) (Table 2).

Among the 48 women, 42 were of reproductive age: Allere of a normal age at menarche, followed by regular periods.wo women underwent bilateral ovariectomy because of ovar-

an lymphoma or leukemia infiltration; 37 of the remaining 40omen (93%) had secondary hypergonadotropic amenorrhea.ycles disappeared 3 to 12 months before autografting in 12omen (32%), consequent to previous antiblastic treatments,

nd in 25 women (68%) after the conditioning regimens. Onlyhree women (7%) reported normal cycles before and afterutografting.

Among the 47 men, one was excluded because of hy-ogonadotropic hypogonadism of unknown onset. HighSH values were found in 39 of 46 men (85%) and low

estosterone levels in 17 men (37%). LH levels were normaln all men. Testosterone (P � .05) and LH (P � .05) levelsere lower in patients with lymphoma than in those with

eukemia or myeloma, likely because of a greater inhibitionf the reproductive axis by a prior greater exposure toorticosteroids.

Prolactin was within the normal range in all patients. n

Secondary adrenal insufficiency was diagnosed in 28 of 95atients (30%); all of them had been treated with corticoste-oids, as a part of previous treatment protocols, at a medianumulative dose of 7 g/m2 for an average period of 130 days.owever, a cumulative dose of corticosteroids (7 � 5 g/m2 vs.� 4 g/m2, P � .3) and the duration of the treatment (126 �

30 days vs. 141 � 200 days; P � .7) were similar in patientsho had or did not have adrenal insufficiency, suggesting

ome individual variability in the adrenal axis suppression.Pretransplant thyroid function was normal in the 40 patients

ested. After the transplant, the “low T3 syndrome” (thyroxinnd TSH within the normal range, and triiodothyronine belowhe normal range) was found in 29 patients (31%). Subclinicalyperthyroidism (normal triiodothyronine and thyroxine withSH below the normal range) was diagnosed in 15 patients

16%). Subclinical hypothyroidism (normal thyroid hormonesnd TSH 4–7 �U/mL) was diagnosed in nine patients (10%);n one patient it was transient, whereas in eight patients itrogressively worsened. Pre-existing thyroid nodules had beeneported in 10 patients (11%), whereas in another 5 patients5%) the nodules were detected after the transplant; the diam-ter of the nodules ranged from 0.7 to 2 cm (median: 1 cm).

ate abnormalities (at 12 months)

Serum IGF-I levels normalized in 17 of 53 patients18%) and remained low in 36 cases (38% of 95).

Four women (11% of 37) experienced a spontaneous re-overy of the ovarian function. Estradiol was significantlyigher in patients aged less than 35 years compared with thelder patients (41 � 19 pg/mL vs. 12 � 35 pg/mL; P � .003)nd lower in women conditioned by busulphan/cyclophosph-mide when compared with other conditioning regimens (15 �pg/mL vs. 35 � 22 pg/mL; P � .0001). No predictors of

ecovery for menstrual cycles were found within the first yearfter autografting. Among the 33 women with persistent am-norrhea, 10 (30%) had a further increase in gonadotropinevels (by 30%–100% of baseline) and no ultrasonographicvidence of ovarian follicles. Ovarian follicles were detected in3 other women (39%); their FSH levels decreased and estra-iol increased.

Testosterone levels normalized in 15 men (88%) and re-ained low in only two men. FSH remained above the normal

ange in 38 men (83%). Patients previously treated with pelvicr abdominal radiotherapy had significantly higher FSH levels22 � 8 U/L vs. 14 � 4 U/L; P � .0001). There were no otherredictors of gonadal axis function improvement in men. Ab-ormalities of seminal fluid analysis were found in all 35atients; 32 had azoospermia (91%), and 3 had oligospermiaith reduced motility (9%).Adrenal insufficiency recovered after 3 to 7 months in all

atients. Cortisol and DHEAS values were still significantlyower in 10 patients previously treated with abdominal/elvic irradiation, compared with those who had never re-eived radiotherapy (cortisol: 117 � 54 ng/mL vs. 162 � 47

g/mL, P � .002; normal range, 50–250 ng/mL; DHEAS:

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667Tauchmanovà et al Endocrine Function After Auto-SCT

8 � 59 �g/dL vs. 210�98 �g/dL, P � .001; normal range,0–560 �g/dL).

The “low T3 syndrome” disappeared invariably, and tri-odothyronine levels normalized in all subjects. Subclinicalyperthyroidism diagnosed in the third month was also tran-ient and had disappeared by the 6-month evaluation. A mildncrease in thyroid autoantibodies, which is biochemical evi-ence of chronic autoimmune thyroiditis, was found in 11atients (12%) at 3 months and in 16 patients (17%) at 12onths; all of them had normal thyroid function. The ultra-

ound showed a nonhomogeneous hypoechoic pattern typicalf thyroiditis in only four of them. Three new cases of sub-linical hypothyroidism were detected, accounting for a total of1 patients (12%) with hypothyroidism. As expected, the fre-uency of hypothyroidism was higher in patients previouslyreated (15–36 months earlier) with neck/thoracic radiotherapyhan in untreated patients (50% vs. 1.3%; P � .0001). In termsf size and consistency, pre-existing nodules disappeared afterransplantation in two patients and remained stable in all of thethers.

iscussion

This prospective study investigated endocrine dysfunc-

Table 2 Endocrine evaluation in the 95 patients at 3 and 12

Variable

Median

3 mo

IGF-I 120 (6Women† 40 (8

FSH 65 (5LH 28 (2Prolactin 11 (717�-estradiol 15 (8

Men 46 (9FSH 22 (2LH 7.5 (2Prolactin 6.9 (5Testosterone 3.0 (1

TSH 1.56 (0Triiodothyronine 3.2 (1Thyroxine 10.5 (7Subclinical hyperthyroidism 15 (1Subclinical hypothyroidism 9 (9“Low T3” syndrome 29 (3Patients with antibodies to thyroid 11 (1Number of subjects with antibodies

antiperoxidase/antithyroglobulin/both 5/5/1Ultrasonographic evidence of chronic thyroiditis 4 (4

IGF � insulin-like growth factor; FSH � follicular stimulating hormo*The normal IGF-I range in men was 180–625 �g/L for ages �20 y

�g/L for ages 41–50 y, and 95–270 �g/L for ages 51–60 y. In women it�g/L for ages 31–40 y, 96–288 �g/L for ages 41–50 y, and 90–250 �

†Only women of reproductive age with ovaries were considered.‡P � .01 versus values at 3 months.

ions during the first year after autologous stem-cell trans- t

lant; it shows an equal distribution of endocrine disordersmong men and women, with multiple glands involved inost cases. Persistent gonadal insufficiency was the most

requent abnormality (�90%). Persistent IGF-I deficiency38%) and hypothyroidism (12%) were observed less fre-uently, whereas peritransplant hypercortisolism (29%) wasransient. A significant prevalence of transient hyperthy-oidism (16%) was also documented. Because we do notave data on endocrine function before transplantation forll patients, except for adrenal function and menstrual dis-rders, we cannot exclude that some dysfunctions precededhe transplant procedure. Because radiotherapy was notsed in conditioning regimens and only a few patients hadreviously received irradiation, we are unable to speculatehether endocrine system damage may have been causedy different doses or regimens of radiotherapy.

Although large studies on growth hormone and IGF-Ixis disorders have been reported in children,10-13 scarceata are available in adults. In this study we did not performny stimulation test to evaluate the growth hormone secre-ory potential; therefore, we cannot discuss this issue. How-ver, we measured circulating IGF-I levels and found themignificantly decreased in 56% of patients 3 months after theransplant, with a recovery in 18% of them within 12onths. The recovery can likely be explained by the loss of

s after autologous stem-cell transplant

) or number (%)

Normal range12 mo

170 (143–540)‡ 100–625 ng/mL*40 (83%)

) 49.5 (4.9–103) 2–13 U/L17 (3.2–60) 2–15 U/L

12.5 (8–17.3) 5–20 ng/mL29.2 (8–78)‡ 40–250 pg/mL

46 (98%)16.4 (2.1–22)‡ 2–11 U/L6.2 (2.2–12) 2–10 U/L

7 (4.5–23) 5–20 ng/mL) 4.8 (2.0–8.1)‡ 3.0–10.0 pg/mL

1.6 (0.8–10.5) 0.3–3.5 mU/mL) 3.7 (2.9–5.2)‡ 2.8–5.6 pg/mL

10.8 (7.3–14.8) 6.6–18.0 pg/mL0‡ —

11 (12%) —0‡ —

16 (16.8%) —

7/6/3 �10 U/mL and �100 U/mL3 (3.15%) —

� luteinizing hormone; TSH � thyroid-stimulation hormone.75 �g/L for ages 21–30 y, 102–400 �g/L for ages 31–40 y, 100–306

1–530 �g/L for ages �20 y, 118–450 �g/L for ages 21–30 y, 100–390ages 51–60 y.

month

(range

7–430)3%).8–111.4–77)–16.2)–68)8%).1–59).3–40)–29).8–7.9.25–7).9–4.4–15.4)6%)%)0.6%)2%)

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668 The American Journal of Medicine, Vol 118, No 6, June 2005

he somatotropic axis and by an improved metabolic stateate after autografting.14

Gonadal damage affected virtually all patients, with aew exceptions. The dominant manifestation was hypergo-adotropic amenorrhea in women and spermatogenesis in-ury in men. Both alkylating agents and irradiation causeerm cell injury and damage to Leydig cells in men and tohe follicular pattern in women.3,15 Indeed, women condi-ioned by busulphan/cyclophosphamide had lower estradiolevels than those conditioned by the other regimens. Men-trual cycles recovered in only 7 of 40 women (18%) withinhe twelfth month, whereas later recovery may be possiblen some of the other 13 women with ovarian follicles atelvic ultrasonography.16,17 Younger age often has beenssociated with a higher likelihood of reproductive functionecovery9,17,18; this finding did not emerge clearly in ourohort up to 12 months after transplantation. However,igher estradiol levels in younger patients indicate betteresidual ovarian function.

Impaired spermatogenesis was documented in all pa-ients who underwent seminal fluid analysis at 12 months;1% of them showed germinal aplasia with azoospermia.ncreased FSH levels were found in 85% of men, indicatinghat spermatogenesis damage was not always associatedith FSH increase. Increased FSH levels up to 5 years werereviously found in two-thirds of men who underwent au-otransplantation,19 and spermatogenesis resumed later than2 months after allografting20; thus, some patients willikely have spermatogenesis recovery later on. In our co-ort, radiotherapy was associated with significantly higherSH levels, suggesting a greater testicular injury in patients

reated with abdominal/pelvic irradiation. Similarly, areater cumulative probability for germ cell injury wasreviously found in patients treated with radiotherapy thann those treated with chemotherapy only.6,21 In regard to theormonal pattern, the data are controversial, indicating ei-her persistently low or normal testosterone levels in long-erm survivors of autografting.22-24

Overt adrenal insufficiency was principally related toorticosteroid treatment as part of previous cytotoxic regi-ens for the underlying diseases. No stimulation test was

erformed in this study; therefore, a milder degree of adre-al insufficiency cannot be excluded in other patients. Al-hough serum cortisol recovered within the normal rangefter a period of appropriate replacement therapy, previousadiotherapy was associated with lower cortisol andHEAS levels after 12 months. Only the initial report byanders et al25 described a high incidence of adrenocorticalysfunction after total-body irradiation and stem-cell trans-lantation; subsequent studies found rare evidence of per-anent posttransplant cortisol deficiency.4,26 Other authors

ave reported a persistent (up to 5 years) decrease in adrenalndrogens in children conditioned by radiotherapy, despiteheir normal cortisol values.27 In light of these findings,adiotherapy, although not causing permanent adrenal in-

ufficiency, can cause long-lasting partial injury to the ad- f

enocortical tissue, expressed principally as reduced andro-en production.

Thyroid abnormalities were more frequent in our sample66%) than in those of previous studies26,28 in which thyroidysfunctions were mostly ascribed to radiotherapy. Carlsont al28 described thyroid disorders in only 18% of patients 3o 60 months after autografting. In our cohort, subclinicalisorders were also considered. Subclinical hyperthyroid-sm was transient, that is, limited to the period of immuno-ogic reconstitution occurring within 3 months posttrans-lant. Transient thyrotoxicosis was reported during theame period (peak, 100 days) after allografting, and anmmune-induced injury was claimed as the major patho-enic factor.29 A similar disorder, although less expressed,ay also occur after autografting, and the difference in

everity can be related to a milder degree of immune systemerangement after autologous transplant.30,31 Subclinicalypothyroidism was mostly related to previous radiotherapynd worsened progressively in all but one patient. In anal-gy with our finding, other authors also described busul-han/cyclophosphamide conditioning to be linked to thyroidysfunction and TSH increase, with a similar incidence11%).32 Biochemical evidence of thyroiditis was found in7% of patients, whereas a typical ultrasonographic patternas observed in only 4%. Further investigation is needed to

larify this discrepancy. Elevated thyroid antibody titerslso appeared up to 12 months in 4 of 111 autotransplantecipients.28

Transient “low T3 syndrome” was likely part of theegative metabolic condition that persisted several monthsfter transplantation, and disappeared thereafter. Corticoste-oid and antiblastic treatments may also contribute to thishyroid dysfunction.33-36 Thyroid nodules were mostlymall and stable over follow-up.

Frequent posttransplant endocrine disorders raise an im-ortant clinical question of when and how to treat them.ransiently low IGF-I does not always mean growth hor-one deficiency in transplant recipients. The deficiency

hould be investigated after resolving the posttransplantegative metabolic situation and after an adequate intervalrom corticosteroid withdrawal. It is still unclear whethereplacement treatment may be helpful in growth hormone-eficient adults posttransplant. Hypergonadotropic amenor-hea often seems irreversible and should be treated by hor-one replacement or oral contraceptive therapies in all

eproductive-aged women, unless contraindicated. Becausepontaneous pregnancies have been reported in women onormonal replacement therapy who have undergone auto-ransplantation,37 these patients should be advised to usether contraceptive measures, especially in the presence ofvarian follicles. Hormone therapy should be withdrawn forperiod of 2 to 3 months per year, monitoring the repro-

uctive axis function. It is still unclear to what extent mildransient male hypogonadism may influence general healthondition and whether replacement treatment may be help-

ul. Generally, it is left untreated, although some reports

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669Tauchmanovà et al Endocrine Function After Auto-SCT

ndicate a relationship between transient low testosteroneevels and bone mass decrease.38,39 Spermatogenesis hardlyecovers within 12 months after autografting and should beonitored every 6 to 12 months thereafter. Adrenal insuf-ciency is still an underestimated condition; albeit transient,

t can impair posttransplant recovery. Replacement therapyith short-acting steroids is mandatory, with a progressive

eduction of the dose, to enable the adrenal axis to graduallyecover. In regard to thyroid function, we recommend per-orming the first evaluation within 3 months after autograft-ng. Patients with completely normal results should undergonnual assessment of thyroid hormones, thyroid-specificutoantibodies, and ultrasonography. Transient hyperthy-oidism is usually nonsymptomatic in autotransplant recip-ents and does not require any treatment; the same is true forhe “low T3 syndrome.” Nevertheless, these patients shoulde monitored every 3 months until their endocrine valuesre normalized. Patients with thyroiditis and normal thyroidunction should be monitored every 3 to 4 months becausef their risk of developing hypothyroidism. Hypothyroidismeeds replacement treatment, because TSH increase is con-idered as the main regulator of thyrocyte differentiationnd proliferation.40 Although it is well established that ex-ernal irradiation of the neck may predispose to hypothy-oidism and thyroid neoplasms, the natural history, timing,nd peak incidence in adults are still unknown.3,41-43 Thisssue is even less clear for patients who have undergonehemotherapy and transplant procedures. Therefore, all pa-ients should undergo lifelong yearly evaluations of thyroidunction and morphology.

onclusion

This study documents frequent endocrine disorders dur-ng the first year after autologous stem-cell transplant. De-pite the tendency to improve, the complications persist forore than 1 year in more than half of the cases. Multiple

actors including previous antiblastic, corticosteroid, andadiation treatments, an abnormal immunologic condition,nd general health status are likely responsible for the onsetf endocrine disorders. Precocious gonadal failure, adrenalnsufficiency, thyroiditis, and hypothyroidism require spe-ific monitoring and treatment by specialized operators.herefore, endocrine screening is necessary during the firstear after autologous stem-cell transplant.

cknowledgment

We thank Dr. Alfonso Gruosso for his collaboration in

diting part of our article.

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