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Thyroid, Parathyroid and
Gonadal Function, and Glucose Tolerance After Bone Marrow
Transplantation and Chemotherapy
Khoshnyat M, Larijani B, Ghavamzadeh A, Bahar B, Tabatabaei O.
Endocrine and Metabolism Research Center, Tehran University of Medical
Sciences, Tehran, I.R. Iran.
Correspondence: Mohsen Khoshnyat, Endocrine and
Metabolism Research Center, Shariati Hospital, Karegar St, Tehran, Iran.
E-mail: emrc@sina.tums.ac.ir
Introduction: Following bone marrow transplantation (BMT), life expectancy
of many patients increases, necessitating medical follow up, especially
function of the endocrine gland. Previous studies have shown that
endocrine dysfunctions are caused not only by total body irradiation,
but also by cytotoxic conditioning regimens.
Materials and Methods: 46 patients (12 F, 34 M), aged 1.5-49 years
were evaluated for thyroid (T3, T4, TSH, T3RU, FTI, Anti Tg-Ab, Anti
TPO-Ab), parathyroid (Ca, Alkp, PTH), gonad function (LH, FSH, E2,
progesterone in females and semen analysis in males) and function of
β-cells of pancreas by O.G.T.T (in 12 major thalassemic patients) before
and 3, 6, 12, 24 months after BMT, by the “Little” Busulfan-Cyclophos-
phamide conditioning regimen.
Results: There are no differences between results of clinical
examinations and laboratory tests of pre and post BMT function of
thyroid or parathyroid and calcium metabolism. The function of leydig
cells was normal in 11 adult men (G5P5) before and 3, 6, 12 months after
BMT, but injury of germinal cells (oligo- or azo-spermia) before and 12
months after BMT was seen. There is no relation between FSH and injury
of germinal cells. Development of puberty was normal in 5 boys (G2P2 or
G3P3) before and one year after BMT Primary hypogonadism was induced in
4 females (B5P5) after BMT In one 14 year-old female, regular
menstruation continued 2 years after BMT In one girl (P1B1 before BMT)
ovarian failure developed 12 months after BMT. Function of β-cells in
thalassemic patients (Ferritin>1000 before BMT) before and after BMT was
normal.
Conclusion: One year after B.M.T, the chemotherapy-conditioning
regimen per se did not affect function of thyroid or parathyroid gland,
but ovarian failure and germinal cells injuries developed (without
effect on leydig cells). BMT had no effect on the function of β- cells
of the pancreas.
Key Words: Bone marrow transplantation, thalassemia major,
thyroid, parathyroid, puberty, gonad, glucose.
Introduction
Bone marrow transplantation (BMT) is defined as intravenous infusion
of hemato-poietic precursor cells to restore the function of bone
marrow, which may be immature or have been destroyed due to various
factors. The procedure is used to treat a wide range of benign and
malignant hematologic or non- hematologic diseases.1
Increasing usage of bone marrow trans-fusion has increased the number
of children and adults who can now survive longer despite their benign
or malignant diseases. Therefore, increased attention is being paid to
enhancing the quality of life of these patients.2
Bone marrow transplantation was begun in March 1991 in Shariati
hospital. Like other procedures, BMT affects different organs of body,
leading to acute and chronic complications,3 including neuroendocrine disorders.2
The extent and severity of post transplant complications on the
neuroendocrine system are influenced by the conditioning protocol
performed prior to transplant,2 that includes either total-body
irradiation accompanied by chemotherapy, or chemotherapy alone.2
Previous studies have shown that gonadal and thyroid dysfunctions have
been seen in the patients during their growth stages resulting from
radiotherapy or chemotherapy protocols performed before transplant,
especially in those with major thalassemia.4-9
The aim of this study was to investigate, thyroid, and gonadal
fuction, as well as carbohydrate metabolism following bone marrow
transplantation. The conditioning protocol consisted of only
chemotherapy. Bone marrow transplantation was performed using autologous
and allogenic transplants. The maximum chemotherapy regimen administered
(without total body irradiation - TBI) before allogenic bone marrow
trans-plantation included the use of Busulphan- Cyclophosphamide (B4-Cy).10
Cyclophosphamide may be administered in high doses (200 mg/kg) with
busulfan (16 mg/kg), known as “Big Bu-Cy”. Currently, in most cases, low
doses of cyclophosphamide known as “little Bu-Cy, are used (120 mg/kg).
In this study, patients taking conditioning protocol of low-dose
chemo-therapy, underwent bone marrow transplant.
Materials and Methods
In this analytic descriptive study, 46 subjects (12 females – 34
males) aged 1.5 - 49 years (mean age of 15.1 years) were enrolled for
investigation of their thyroid, parathyroid and gonadal function. The
functioning of pancreatic β cells was studied in 12 patients with
thalassemia major. The grouping of patients according to illness, and
chemotherapy regimen given are shown in Table 1.
Table 1. Conditioning regimen in 46 patients studied
A questionnaire, completed by two physicians, was used to
obtain details including personal information, medical history, the BMT
characteristics, symptoms and signs of thyroid and parathyroid diseases,
and stage of puberty determined according to Marshall-Tanner scale with
respect to sex.
Physical examination and history taking were repeated at 3,6,12 and
24 months following BMT.
To study glucose metabolism in thalassemic patients, oral glucose
tolerance tests (1.75 gr/kg of anhydrous glucose, max. 75 gr) were
performed, measuring blood glucose levels before the test and 120
minutes thereafter. Serum FT4I, RT3U, TSH, T3 and T4, thyroglobulin and
thyroid peroxidase antibodies were determined to evaluate thyroid
function, as were serum calcium, phosphorous, alkaline phosphatase and
PTH to evaluate parathyroid axis. To evaluate gonads, females of B2P2
stage (according to Tanner scale) and above, males with G2P2 stage
(Tanner scale) and above were studied as were as those who had not
reached puberty by 12 years of age. Serum PRL, FSH, LH (of all cases),
testosterone (males), esteradiol and progesterone (females), semen
indices (married males) were determined. The specifications of the
laboratory kits used are given in Table 2.
Table 2. Specifications of laboratory kits
All patients gave oral consent. The Medical Ethics Committee of the
Ministry of Health and Medical Education approved the study.
Four patients died within two years of transplantation. Repeated
measure ANOVA was performed to analyze the data of thyroid and
parathyroid axes while non-parametric Wilcoxon’s rank were used to study
fetal axis and glucose metabolism. P<0.05 was considered significant.
Results
Thyroid axis: No signs or symptoms of hypo- or hyperthyroidism were
observed in the population studied, at any of the earlier specified
intervals of BMT. Thyroid axis hormones did not differ significantly
before or 3, 6, 12 and 24 months after BMT (Table 3).
Table 3. Mean T4, T3, TSH and T3RU before and after BMT
Parathyroid axis: None of the patients studied showed signs of hypo-
or hypercalcemia. Serum calcium, phosphorous, alkaline phosphatase and
PTH were normal before and 3, 6 and 12 months after BMT with no
significant differences (Table 4).
Table 4. Mean serum Ca, P, alkaline phosphotase and PTH before and
after BMT
Gonads, males: In 11 adults (G5P5), 16-50 years of age (mean 32±11),
serum FSH, LH, testosterone and prolactin were normal before and at 3, 6
and 12 months after BMT. No primary or secondary hypogonadism were
observed. In 3 patients in whom semen analysis was performed, azospermia
was observed before and up to one year after BMT. In one patient sperm
count decreased from 12 million/mL preceding BMT to 6 million/1mL one
year following BMT. In all four patients mentioned, except for one,
serum FSH did not increase either before or after BMT, despite oligo and
azospermia. In 5 boys, 12-16 years of age (mean 14±2), at G2P2 and G3P3
stages before BMT, serum LH, FSH, testosterone and prolactin were normal
throughout the first year following BMT and puberty developed normally.
Mean serum levels of sex hormones are given in Tables 5 and 6.No
significant difference was observed.
Table 5. Mean serum LH, FSH, Prolactin and Testosterone profiles
in males at G5P5 stages before and after BMT
Table 6. Mean serum gonadal profiles in males at G2P2 or G3P3
stages of puberty
Gonads, females: 5 female adults (B5P5), 15-40 years of age
(mean 25±11) were studied. In 4 females, primary hypogonadism (increase
in FSH and LH) began at 3 months after BMT, and continued for 2 years.
In two of these cases, oral contraceptive pills were used for treatment.
In one 14-year-old female (B5P5), with regular menstruation prior to
BMT, menses remained regular for 2 years following BMT with normal serum
levels of FSH, LH, PRL, estradiol and progesterone. In another
11-year-old female (P1B1) with low serum FSH and LH before BMT,
gonadotropins increased at 6 and 12 months after BMT (FSH 6m, 53 and
12m, 60; LH 6m, 11.8. and 12m, 22.5) indicating primary hypo- gonadism.
Glucose metabolism: Table 7 shows the mean values obtained
from oral glucose tolerance tests (OGTT) of 12 patients with thalassemia
(5 females-7 males) with a mean age of 4.8± 1.95 who had serum ferritin
levels above 1000 ng/mL before BMT.
Table 7. Mean serum glucose level in oral glucose tolerance test
in 12 patients with thalassemia
Discussion
Our findings indicate that thyroid and parathyroid function and
calcium metabolism suffer no impairment during the 2 years following BMT
in those who have received low dose cyslophosphamide (120 mg/kg) in a
chemotherapy conditioning regimen. Moreover, puberty is not hindered or
delayed in males, and leydig cell function is preserved, while
detoriation of testicular germinal cells is observed for one year
following BMT. Primary hypogonadism and ovarian damage are seen in
females. In thalassemic patients no malfunctioning was observed for
pancreatic β-cells.
Various disorders of thyroid function have been reported in patients
receiving BMT. These include hypothyroidism, autoimmune thyroiditis,
thyroid tumors, graft-versus-host disease and transient thyrotoxicosis
post transplantation.
The prevalence of the disorders is believed to be up to 40% that
seems to increase with prolonged follow-up.11 Although hypothyroid-ism
is attributed to total body irradiation (to prepare for transplant), it
is also been reported following chemotherapy condition-ing regimens.11
Most thyroid disorders occur 1- 4.2 years. One study showed early
changes in thyroid function (within the 6 months of BMT) which appeared
as non-thyroidal illness syndrome (NTIS) in 44% and transient
thyrotoxicosis in 16% of patients.12 In this study, conditioning
regimens included total body irradiation or chemotherapy using
busulfan-cyclophos-phamide whereas the patients were not categorized
according to the type of conditioning regimen. Hypothyroidism developed
in all cases of thyrotoxicosis, indicating thyroiditis in the patients.
No thyroid dysfunction was seen for 2 years after BMT in those who had
no thyroid dysfunction before BMT. As patients were not evaluated in
first 3 months of BMT, transient changes such as euthyroid syndrome may
have occurred during this period.
As mentioned earlier, busulfan-cyclophos-phamide (Bu-Cy) is the most
common chemotherapy regimen used to prepare patients for BMT. The
effects of the regimen used on gonads have been reported by the Seattle
team.13 They administered busulfan (16 mg/kg) and cyclophosphamide (200
mg/kg) known as “Big Bu-Cy”. In their report, only one of 73 females
regained her sexual axis function following BMT, although the mean age
(38 years) of females was relatively high (range: 14-57 years) and the
mean of duration of follow-up was 2 years. Improvement of testicular
function (defined as normal serum LH, FSH and testosterone along with
evidence of sperm production) was observed in 8 patients out of 46
(17%), with a mean age of 34 years (13-56) and a mean follow-up of 2
years.14
Currently, cyclophosphamide at 120 mg/kg is used, known as “Bu-Cy
little”. Grigg et al. investigated ovarian function in19 females and
testicular function in 47 males, who were using this regimen, for 2-5
years following transplant. In 84% of males, spermatogenesis improved to
varying degrees. The researchers pointed out that chronic
graft-versus-host disease may have deleterious effects on sperm count.
Ovarian function did not improve in any of the females studied.15
Continuous infusion of VP16 to the “Little Bu-Cy” regimen had no
adverse effects on gonads. Given time the improve-ment of
spermatogenesis is more likely. Grigg et al. showed that serum FSH and
LH values are not reliable indices for improvement of spermatogenesis or
sperm count, while inhibin B has a good correlation with sperm count,
but cannot clearly distinguish azospermia from non-azospermia. Although
in one study, combination of FSH and Inhibin B was found to be more
helpful in this regard, it was not so in the study conducted by Grigg et
al. Grigg suggest sperm counts as the most reliable test for evaluation
of spermatogenesis. Inhibin B, a hormone secreted by the Sertoli cells,
suppresses FSH secretion. Compared to germinal epithelium, Leydig cells
are less susceptible to chemotherapy.
In Grigg’s study, 12% of males had testosterone levels less than
normal, exhibiting symptoms of reduced libido and erection.15 Wingard et
al. using “Big Bu-Cy” regimen observed low testosterone in only one
patient out of 42,14 while Chatterjee reporting decreased function of
leydig cells following BMT indicating that testosterone was more likely
to be low in males aged over 45 years.16 A recent study reported a
remarkable, though transient, decrease in serum testosterone in the
first 6 months after BMT, which may be an important factor contributing
to reduced bone density.17 We observed no reduction in leydig cell
function, though azospermia was present in 4 patients in the year
following BMT. FSH did not increase in azospermic patients before or
after BMT with the exception of one case. It implies that FSH could not
be relied on to evaluate spermatogenesis, a finding which is in contrast
to those of Kreuser18 and Clark,19 indicating semen analysis is
mandatory. A more prolonged study is needed to see whether
spermatogenesis is reversible after BMT, as the probability increases
with the passage of time. In this study, serum testosterone did not
decrease 3 and 6 months after BMT.
Despite the high prevalence of improvement in male gonadal function
in the Grigg15 and Seattle13 studies, ovarian function was not regained
in any of the females, indicating both that low and high doses of
cyclophosphamide exert irreversible damages on the ovaries in
chemotherapy regimens used in Hodgkin’s lymphoma such as MOPP, in which
reversible gonadal function is more prominent in females than males.19
Several reports exist regarding pregnancy after concurrent use of
cyclophosphamide and total body irradiation.13 Pregnancy had been known
to occur after BEAM, CBU (cyclophosphamide, BCNU, Etoposide) as well as
high dose melfalan chemotherapy regimens.15 In our study, 3 months
following BMT, primary hypogonadism (increase in both LH and TSH)
developed in 5 females (4 adult and a girl who had not reached puberty
before BMT). Amenorrhea was observed for 2 years following BMT in
patients followed up and in two patients oral contraceptive pills were
begun. In a 14-year-old female with aplastic anemia who had regular
menstruation before BMT, both FSH and LH levels as well as menses
remained normal two years following BMT.
Irreversibility of normal ovarian function following BMT in most
patients highlights the necessity of timely hormone replacement therapy
(estrogen and progesterone) to prevent osteoporosis and other
complications resulting from the lack of the hormones.
Hyperprolactinemia, due to hypothalamus damage, has been observed
following BMT in patients using total body or skull irradiation
regimens.20, 21 There have been no reports of hyperprolactenemia
following the use of chemotherapy regimens for BMT, nor was this seen in
our study.
Calcium metabolism and parathyroid function were not altered after
BMT and no signs of hypocalcemia or secondary hyper-parathyroidism were
observed. Although in thalassemic patients, pancreatic β-cells function
improves after BMT due to reduced deposition of iron in the pancreas, in
the present study the function of pancreatic β-cells, was normal before
and after BMT. For further investigation, serum insulin and c-peptide
along with serum plasma need to be measured during OGTT. These may,
before BMT, show insulin resistance in the patients, which decreases
following the transplant. A larger study of thalassemic patients is
strongly recommended to assess whether or not insulin resistance prior
to BMT shows any improvement after the transplant.
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