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Function of the Hypothalamic-Pituitary-Gonadal Axis in Long-Term Survivors of Hematopoietic Stem Cell Transplantation for Hematological Diseases

Posted on: Thursday, 18 August 2005, 03:01 CDT

Abstract

Gonadal dysfunction in adult long-term survivors of hematopoietic stem cell transplantation (HSCT) is an adverse effect of conditioning regimens consisting of chemotherapy and total body irradiation (TBI). The impact of conditioning regimens consisting of chemotherapy alone on the function of the hypothalamic-pituitary- gonadal (HPG) axis was evaluated in a series of 41 female and 31 male patients who had undergone either autologous or allogeneic bone marrow/peripheral blood stem cell transplantation; mean age at transplantation was 32.6 years and mean time interval from transplantation was 1.5 years (range 0.2-9.8 years). Provocative testing of the HPG axis by administration of luteinizing hormone- releasing hormone was included in the first endocrinological evaluation. The follow-up period extended to three consecutive years. Gonadal dysfunction was not reported by any of the patients prior to their underlying illness. Hypergonadotrophic hypogonadism was observed in 97% of female and 19% of male patients. Leydig cell strain (normal testosterone, high luteinizing hormone levels) was evident in 32% and spermatogenesis damage (high follicle- stimulating hormone levels) in 68% of the male population. At the conclusion of the study four women (10%) had regained spontaneous menses and all hypogonadal men had resumed normal testosterone levels. Our results indicate a high incidence of gonadal dysfunction due to target organ failure in HSCT recipients not treated by TBI.

Keywords: Hematopoietic stem cell transplantation, hypothalamic- pituitary-gonadal axis, hypergonadotrophic hypogonadism

Introduction

Bone marrow transplantation or hematopoietic stem cell transplantation (HSCT) is a successful way of treating a variety of hematological diseases such as aplastic anemia, leukemia, Hodgkin's and nonHodgkin's disease, multiple myeloma and thalassemia, and has currently become the treatment of choice for many of these [1-3]. New studies have explored the potential use of HSCT as a treatment for non-hematological diseases such as autoimmune disorders as well as congenital or storage diseases [4].

As the number of survivors after allogeneic or autologous HSCT continues to increase, the issue of providing good quality of life apart from the absence of primary disease has become extremely important. The high incidence of gonadal dysfunction observed after allogeneic or autologous HSCT has crucial repercussions on quality of life [5]. Since most HSCT recipients are of a young age, the effects of gonadal dysfunction - such as premature menopause for women and hypogonadism, sexual dysfunction, loss of reproductive ability and osteoporosis for both sexes - are of great importance and deserve attention if quality of life is to be preserved in otherwise disease-free survivors [6].

The high risk of gonadal failure that is observed in these patients is attributed to the highly toxic chemotherapy and irradiation employed in their conditioning prior to HSCT [3,5,7-9]. Previous chemotherapy administered before HSCT also has a cumulative effect on gonadal toxicity [1-5]. Conditioning regimens are administered to eradicate the underlying hematological disease and to suppress the host immune system [7].

Most of the published data on long-term adverse effects after HSCT are derived from patients who were treated with conditioning regimens consisting of high-dosage chemotherapy in combination with total body irradiation (TBI). Currently, the combination of cyclophosphamide with busulfan is the most frequent chemotherapeutic modality employed in conditioning regimens without the use of TBI [7,10]. The impact of chemotherapy alone on the endocrine system in HSCT recipients is an issue that remains unclear, since only a small number of publications are available concerning patients treated without TBI.

The aim of the present study was to assess the impact of conditioning regimens consisting of chemotherapy alone on the function of the HPG axis in adult long-term survivors who underwent transplant for hematological diseases [1-6]. The luteinizing hormone- releasing hormone (LHRH) stimulation test was used for the assessment of the function of the HPG axis at different levels in order to detect subtle abnormalities that would not have been detected by measuring basal values alone [16].

Material and methods

Study population

Seventy-two patients were included in the study (31 men and 41 women) at a mean time interval of 1.5 years (range 0.2-9.8 years) from HSCT. The age upon entering the study was 32.6 10.0 years; age at HSCT was 30.4 9.7 years (mean standard deviation). The most common diagnoses included acute lymphatic leukemia (n = 9), chronic myelogenous leukemia (n = 13), acute myelogenous leukemia (n = 21), non-Hodgkin's lymphoma (n = 4), Hodgkin's disease (n = 16) and other less common diseases (n = 9) (Table I).

Table I. Characteristics of patients.

Conditioning regimens consisted mainly of BUCY2 (busulfan 16 mg/ kg, cyclophosphamide 120 mg/kg) for allogeneic grafting and BECYM (carmustine (BCNU) 300 mg/m^sup 2^, etoposide 200 mg/m^sup 2^, cyclophosphamide 1.5 g/m^sup 2^, melphalan 140 mg/m^sup 2^) or BEAM (BCNU 300 mg/m^sup 2^, etoposide 200 mg/m^sup 2^, aracytin 200 mg/ m^sup 2^, melphalan 140 mg/m^sup 2^) for autologous grafting. Detailed analysis of the conditioning regimens used in the study population is given in Table I.

Twenty-five (81%) of the male patients and 19 (46%) of the females patients had received allogeneic grafts (bone marrow or peripheral blood stem cells). Six males and 22 females had undergone autologous grafting. Graft versus host disease (GVHD) had been diagnosed in all of the patients after allogeneic transplantation (Table I).

TBI was not included in the conditioning regimens. Only patients who were disease-free, had complete hematological reconstitution and gave informed consent were included in the study. Previous TBI was an exclusion criterion.

Medical history on gonadal function and data on menstrual history before and after transplantation were obtained. None of the male patients reported previous history of gonadal dysfunction. All of the women in the study reported normal menstrual history and age at menarche prior to their illness.

Study design

A complete biochemical and hematological work-up was given to all patients upon entering the study. Endocrinological evaluation consisted of determination of basal levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) as well as an LHRH provocative test in males and females, and total testosterone for males. Reference intervals and mean values of LH and FSH in males and females are shown in Tables II and III. Semen analysis was possible in a limited number of male patients who gave their consent. Pelvic ultrasound scans were performed in all female patients upon entering the study. An annual work-up consisting of hematological, biochemical and endocrinological evaluation was given to all patients for three consecutive years.

The LHRH stimulation test was performed by bolus intravenous administration of LHRH (Relefact LHRH, 0.1 mg/ml; Hoechst) in the morning (08.00 hours) after an overnight rest and fast. Blood samples for FSH and LH determination were drawn at 0, + 30 and + 60 min after administering LHRH.

Administration of LHRH stimulates the gonadotroph cells of the pituitary to secrete FSH and LH. The magnitude of the response of FSH and LH at + 30 and + 60 min reflects the function of the pituitary and the hypothalamus, respectively. A normal response consists of an increase of up to three times the normal basal FSH and LH levels at + 30 min and somewhat less at + 60 min, with the peak response seen at + 30 min. In cases of pituitary damage, low basal levels of FSH and LH show little change after stimulation. Low normal basal levels of FSH and LH combined with a delayed increase at + 60 min after LHRH stimulation are suggestive of hypothalamic dysfunction [16].

Hormonal therapy, i.e., testosterone in hypogonadal men and estrogen plus progesterone in women, was initiated. Pap smears and mammography or ultrasound scans of the breasts were performed in female subjects before administration of hormone replacement therapy (HRT). Follow-up consisted of clinical evaluation and biochemical and hematological work-up every 3 months and an annual hormonal evaluation for both sexes. Annual pelvic ultrasound scans, pap smears and mammography or ultrasound scans of the breasts were performed in female patients on HRT. Hormonal therapy discontinued for 2 months before each annual hormonal evaluation.

Table II. Reference intervals for follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Table III. Levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in men and women recipients of hematopoietic stem cell transplantation after stimulation with luteinizing hormone-releasing hormone.

Commercial microparticle enzyme immunoassay kits were used to measure levels of LH (Radioisotopic Kit; Nichols Institute Diagnostics, San Juan Capistrano, CA, USA) and FSH (Radioisotopic Kit; Nichols Institute Diagnostics). Testosterone levels were measured by radioimmunoassay (T: Direct Radio-immunoassay Kit; Sorin and Biomedica, Milan, Italy).Reference levels are shown in Table II; mean values and range of FSH and LH are shown in Table III.

Statistical analysis

Cochran analysis was used to evaluate the response to stimulation of the HPG axis and reveal unexpected variations in the cumulative response of each group of female and male patients.

Results

Males

High basal values of LH were observed in 16 (52%) male patients; 15 had received allogeneic grafts and had been conditioned with BUCY2 with the exception of one patient who had been conditioned with BUCY3. Autologous transplantation was the treatment modality in one patient with high basal LH who been conditioned with BECYM.

Fourteen male patients (45%) had exaggerated responses (> 3 the basal value) at + 30 and + 60 min after LHRH stimulation (Figure 1). Basal LH values were normal in nine (29%) patients; six had received allogeneic grafts and three autologous grafts (Tables IV and V).

Figure 1. Luteinizing hormone (LH) responses intravenous injection of luteinizing hormone-releasing hormone in males.

Six (19%) male patients were found to be hypogonadal, having high basal LH and low total testosterone levels (Table VI). Five of these patients had been allografted and conditioned with BUCY2 and presented chronic GVHD. One patient had been autografted and conditioned with BUCY4.

Ten males (33%) had high basal LH levels and normal total testosterone levels indicating Leydig cell strain (Table VI). All but one had received allogeneic grafts.

High basal values of FSH were observed in 21 (68%) male patients. Nineteen of these had received allogeneic grafts; 18 had been conditioned with BUCY2 and one with BUCY3. Two patients after autologous transplantation also had high FSH basal values; these patients had been conditioned with BUCY2. FSH responses within the normal range (up to 3 basal values) were observed in 90% and 94% of patients, respectively, after LHRH stimulation at + 30 and +60min (Figure 2, Tables IV and V). Exaggerated FSH responses were observed in three (10%) patients with normal basal values.

Since high levels of FSH imply infertility we did not insist on semen analysis unless the patients were personally interested. Eleven male patients consented to semen analysis, ten males after allogeneic transplantation and one male after autologous transplantation. Azoospermia was diagnosed in four males, aged 23, 27, 35 and 40 years. FSH levels were well above normal values in three and within the normal range in one of the subjects; time lapsed from HSCT ranged from 4 to 8 years. Four patients, aged 25, 27, 31 and 34 years, had a low sperm count (0.1-1.1 10^sup 6^/ml). FSH levels above normal were observed in the male patient with the highest count and high normal levels were found in the other three patients; time lapsed from HSCT was 4-8 years. A raised FSH was also observed in a 30-year-old patient with a sperm count of 8.3 10^sup 6^/ml. One patient, 26 years of age, had a normal sperm count (41 10^sup 6^/ml), 7 years after HSCT, his FSH level being within the normal range. All of the above patients had been allografted, conditioned with BUCY2 and had developed chronic GVHD (Table VI). A normal sperm count (20 10^sup 6^/ml) was found in a 29-year-old patient with normal levels of FSH, who had been conditioned with BEAM, two years after autologous transplantation. No significant changes were observed at re-evaluation at 12 and 24 months from first assessment.

Testosterone replacement therapy (TRT) was initiated in hypogonadal men with subnormal total testosterone levels (< 188 ng/ ml) with complaints of low libido and sexual dysfunction. Testosterone was administered (250 mg depot intramuscularly monthly) in six males (age range 34-52 years) and the patients were evaluated thereafter every 3 months for total testosterone blood levels, blood count and hepatic enzymes. TRT was discontinued annually for 2 months and gonadal function was reassessed. All males regained normal levels of testosterone within 2 years from administration and TRT was discontinued. No side-effects attributed to TRT were observed during administration. Patients on TRT reported improvement of the sense of well-being, libido and sexual function.

Females

High basal FSH and LH levels were observed in the majority of female patients (97% and 92%, respectively). In 37 patients (90%) FSH and LH levels were in the postmenopausal range. After LHRH stimulation normal responses in FSH levels were observed in all (Figure 3) whereas exaggerated LH responses at + 30 min were observed in ten (24%) patients (Figure 4). Three of the patients with an exaggerated LH response had normal basal values (Tables III and IV). Ultrasound scans revealed atrophy of the ovarian glands with no visible follicles and a small uterus in all women with raised FSH and LH values.

Nineteen of our female patients had received allogeneic grafts. GVHD was present in all of these patients. Seventeen had been conditioned with BUCY2, one with BUCY4 and one with BECYM (Table VII). Ovarian failure was diagnosed in all and persisted during the 3-year follow-up, with no patient spontaneously regaining normal menses during this time interval.

Twenty-two females had received autologous grafts. Ten had been conditioned with BECYM, five with BEAM, one with CY and BEAM, one with BUCY3, five with BUCY4 (Table VII). Ovarian failure was diagnosed in 20 patients (Table VII). Spontaneous appearance of menses was reported by one patient 6 months after autografting. The patient had been autografted at 21 years of age and had been conditioned with BEAM. Four patients with age at transplantation of 36, 19, 30 and 24 years regained spontaneous menses 2-3 years after autologous transplantation. Conditioning with BEAM was given in three and BECYM in one.

Table IV. Response of the hypothalamic-pituitary-gonadal axis upon stimulation with luteinizing hormone-releasing hormone (LHRH) in male and female patients after hematopoietic stem cell transplantation.

Table V. Characteristics of male patients.

Table VI. Gonadal function in male and female patients after hematopoietic stem cell transplantation.

Figure 2. Follicle-stimulating hormone (FSH) responses to intravenous injection of luteinizing hormone-releasing hormone in males.

Figure 3. Follicle-stimulating hormone (FSH) responses intravenous injection of luteinizing hormone-releasing hormone in females.

Unless contraindicated, HRT was initiated in women with amenorrhea after their first endocrinological evaluation. Ethinyl estradiol (2 mg/day) and medroxyprogesterone acetate (5-10 mg/day for 12 days/month) were administered in 14 females less than 40 years of age and ethinyl estradiol (1 mg/day) in continuous combination with medroxyprogesterone acetate (2 mg/day) were administered in three females over 40 years of age. HRT was discontinued for 2 months annually in order to reassess gonadal function.

HRT was discontinued in four women due to complications arising from chronic hepatic GVHD (high hepatic enzyme levels) or low platelet counts. Hypertension was observed in two women and appropriate medication was included in the treatment. Improvement of menopausal symptoms, sense of well-being and libido was reported by all of the women on HRT.

Discussion

Gonadal dysfunction is known to occur after bone marrow/ peripheral blood stem cell transplantation as a sequela of preparative conditioning regimens consisting of high-dose cytostatics and TBI [1-3,5]. In our study we aimed to evaluate the incidence of gonadal dysfunction in bone marrow/peripheral blood stem cell transplantation recipients who had not undergone TBI as part of pre-transplantation treatment.

In recent work concerning patients conditioned with chemotherapy alone, Tauchmanova and colleagues [7] reported an equally high incidence of gonadal failure in allogeneic bone marrow/bonederived stem cell recipients treated with BUCY2 alone as in those treated with combination of chemotherapy and TBI. Grigg and associates [10] reported an extremely high incidence of gonadal failure in women after being conditioned with BUCY2. Most of their male patients conditioned by the same regimen retained some degree of spermatogenesis, which did not always correlate with FSH levels, and only 12% presented with hypogonadism. Recovery of fertility was found to be more likely after chemotherapy-based conditioning regimens than after TBI-containing regimens in male patients who had undergone allogeneic or autologous HSCT in the study of Jacob and co- workers [11].

Figure 4. Luteinizing hormone (LH) responses intravenous injection of luteinizing hormone-releasing hormone in females.

In our series, a higher incidence of gonadal toxicity was observed in allografted than autografted males treated by chemotherapy-based conditioning regimens. Eighteen (72%) of the allografted male patients had elevated levels of FSH, indicating seminiferous tubule damage, compared with three (50%) of the autografted males. Conditioning with busulfan and cyclophosphamide (BUCY) had been used in both allografted and autografted patients who developed seminiferous tubule damage with the exception of one autografted patient, who had been conditioned with BECYM.

The number of patients evaluated by semen analysis is too small to enable us to draw solid conclusions concerning spermatogenesis. Even so, it is interesting that azoospermia was observed in four of the ten (40%) allografted patients tested, oligospermia in five (50%) and a normal sperm count in one (10%), at a mean time interval of 4.5 years post HSCT. A normal sperm count was also observed in the sample provided by an autografted male who had been conditioned with BEAM. Spontaneous recovery of a normal sperm count was not observed in any of the above mentioned allografted patients in the follow-up interval.

It is assumed that Leydig cells are more resilient to the toxic effect of chemotherapy than is the germinal epith\elium, just as they are more resistant to irradiation [8-10]. Even so, allografted males face a much larger risk of developing hypoandrogenism than autografted males. Leydig cell damage indicated by elevated LH levels was observed in 15 (60%) of the allografted and in one (17%) of the autografted males. Clinical hypogonadism was diagnosed in five (20%) allografted GVHD-positive males, all conditioned with BUCY2, and in one (17%) autografted male conditioned with BUCY4. Subclinical hypogonadism was present in nine (36%) allografted and one (17%) autografted patient. Clinical hypogonadism proved to be transient in all of the hypogonadal patients (Table VI).

A strong relationship between gonadal toxicity and conditioning regimens was evident, the highest incidence of gonadal toxicity being observed with BUCY conditioning compared with BEAM and BECYM. The stronger toxicity of BUCY conditioning to the male gonads is confirmed by the finding that the same degree of gonadal toxicity was observed in autografted male patients who had been conditioned with BUCY as in the allografted ones. The degree to which GVHD contributes or sustains gonadal toxicity in allografted male subjects independent of the conditioning regimen toxicity remains to be evaluated.

Women are more likely than men to suffer gonadal failure after HSCT. The very high incidence of gonadal toxicity observed in the majority of the female patients is similar after both allogeneic and autologous grafting (Table VI). Ovarian insufficiency was observed in all (100%) female patients after allogeneic transplantation and in 95% of females who underwent autologous transplantation. Given the fact that spontaneous recovery of menses was observed only in a small number of females after autologous transplantation (three conditioned with BEAM and one with BECYM), it can be assumed that a slightly higher degree of irreversible gonadal toxicity in females is seen after conditioning with BUCY [10,11] (Table VI).

The exaggerated responses of the HPG axis after exogenous stimulation with LHRH that were observed in patients with normal or high normal basal values of FSH and LH are attributed to diminished negative feedback due to partial end organ insufficiency. The finding supports our theory that compromised gonadal reserve or subtle seminiferous tubule damage is present in a number of patients, regardless of normal basal values of gonadotropins, after HSCT. Long-term follow-up studies addressing the issue of recovery are necessary not only for HSCT patients with overt gonadal dysfunction, but also for those patients with subclinical dysfunction or diminished gonadal reserve to address the issue of developing overt gonadal dysfunction in the future.

Age appears to be a significant factor in male patients, with older men at transplantation being more susceptible to seminiferous tubule damage than younger ones. Age at transplantation did not appear to have the same significance in the female patients (Table VIII).

The extent to which chronic GVHD in allografted patients contributes to gonadal damage remains ambiguous [7,10,12]. Fifty percent of our autografted males and 95% of our autografted females developed gonadal insufficiency despite the absence of GVHD. Cohort studies with a larger number of patients followed for longer periods of time, perhaps supported by histopathology, might provide more information on whether GVHD contributes to or sustains the damage done by chemotherapeutic agents.

Table VII. Characteristics of female patients.

The additive effect of previous chemotherapy with alkylating agents before the patients are referred to transplantation centers should also be taken into consideration. The effect of conditioning chemotherapy is most probably overestimated due to the lack of cohort studies taking into consideration previous chemotherapy regimens, as well as evaluation of gonadal function before any treatment in HSCT recipients [3,7,13].

In summary, our findings confirm that conditioning for bone marrow/peripheral blood stem cell transplantation using chemotherapy alone is responsible for a similar prevalence of gonadal dysfunction as is conditioning including TBI. Gonadal dysfunction involving end organ failure is more often observed after allogeneic grafting than after autologous grafting, the finding being attributed to BUCY conditioning due to the higher toxicity of the combination of busulfan and cyclophosphamide.

Gonadal dysfunction and infertility are major drawbacks to the quality of life after HSCT, especially in younger patients who had not started or completed their family prior to HSCT [6]. We should be able to clarify to these patients what recovery, if any, to expect in their gonadal function over the long term. Obviously, more extensive studies are needed on the issue of gonadal function salvation [14]. Unfortunately, for the time being we have no answers on this issue and counseling is needed prior to HSCT on other options such as sperm banking, cryopreservation of fertilized embryos or ovarian tissue and oocyte donation [6,12,14]. Hormonal therapy is offered as a satisfactory option for relief of some of the side-effects of hypogonadism both in men and women as well as for preservation of bone mass density [8-10,15]. Long-term follow- up is mandatory for all HSCT survivors, even for those few patients with normal hormonal basal values after HSCT, due to the possibility of future gonadal dysfunction due to diminished gonadal reserve.

Table VIII. Relationship of basal follicle-stimulating hormone (FSH) levels and age in male patients after hematopoietic stem cell transplantation (HSCT).

References

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2. Kolb HJ, Bender-Gotze C. Late complications after allogeneic bone marrow transplantation for leukaemia. Bone Marrow Transplant 1990;6:61-72.

3. Mertens AC, Ramsay NKC, Kouris S, Neglia JP. Patterns of gonadal dysfunction following bone marrow transplantation. Bone Marrow Transplant 1998;22:345-50.

4. Link H, Kolb HJ, Ebell W, Hossfeld DK, Zander A, Niethammer D, Wandt H, Grosse-Wilde H, Schaefer UW. Transplantation of hematopoietic stem cells. II: Indications for transplantation of hematopoietic stem cells after myeloablative therapy. Med Klin (Munich) 1997;92:534-45.

5. Kauppila M, Koskinen P, Irjala K, Remes K, Viikari J. Long term effects of allogeneic bone marrow transplantation (BMT) on pituitary, gonad, thyroid and adrenal function in adults. Bone Marrow Transplant 1998;22:331-7.

6. Watson M, Wheatley K, Harrison GA, Zittoun RA, Gray RG, Goldstone AH, Burnett AK. Severe adverse impact on sexual functioning and fertility of bone marrow transplantation, either allogeneic or autologous, compared with consolidation chemotherapy alone. Cancer 1999;86:1231-9.

7. Tauchmanova L, Selleri C, De Rosa G, Pagano L, Orio F, Lombardi G, Rotoli B, Colao A. High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematological diseases. Cancer 2002;95:1076-8.

8. Kauppila M, Viikari J, Irjala K, Koskinen P, Remes K. The hypothalamus-pituitary-gonad axis and testicular function in male patients after treatment for haematological malignancies. J Intern Med 1998;244:411-16.

9. Chatterjee R, Kottaridis PD, McGarrigle HH, Eliahoo J, McKeag N, Mackinnon S. Patterns of Leydig cell insufficiency in adult males following bone marrow transplantation for hematological malignancies. Bone Marrow Transplant 2001;28:497-502.

10. Grigg AP, McLachlan R, Zajac J, Szer J. Reproductive status in long-term bone marrow transplantation survivors receiving busulphan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant 2000;26:1089-95.

11. Jacob A, Barker H, Goodman A, Holmes J. Recovery of spermatogenesis following bone marrow transplantation. Bone Marrow Transplant 1998;22:277-9.

12. Chatterjee R, Kottaridis PD. Treatment of gonadal damage in recipients of allogeneic or autologous transplantation for haematological malignancies. Bone Marrow Transplant 2002;30:629-35.

13. Antin JH. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med 2002;347:36-42.

14. Kyriacou C, Kottaridis PD, Eliahoo J, Mckeag N, Bomford J, McCarrigle HH, Linch DC, Mackinnon S, Chatterjee R. Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative transplantation for haematological malignancies. Bone Marrow Transplant 2003;31:45-50.

15. Banfi A, Podesta M, Fazzuoli L, Sertoli MR, Venturini M, Santini G, Cancedda R, Quatro R. High-dose chemotherapy shows a dose- dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer 2001;92:2419- 28.

16. Dufour DR, Gaskin JH, Jubiz WA. Dynamic procedures in endocrinology. In: Becker KL, editor. Principles and practice of endocrinology and metabolism. Philadelphia: JB Lipincott Company; 1990. pp 1766-75.

MARIA SOMALI1, VASSILIOS MPATAKOIAS1, AVRAAM AVRAMIDES1, IOANNA SAKELLARI2, PANAYOTIS KALOYANNIDIS2, CHRISTOS SMIAS2, ACHILLEAS ANAGNOSTOPOULOS2, ANARGYROS KOURTIS3, DAVID ROUSSO3, DIMITRIOS PANIDIS3, & APOSTOLOS VAGENAKIS4 1 Endocrinology Department, Hippokratio General Hospital Thessaloniki, Greece, 2 Hematology Department, G. Papanikolaou General Hospital, Thessaloniki, Greece, 3 Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki, Thessaloniki, Greece, and 4 Department of Internal Medicine, University of Patras Medical School, Patras, Greece

Correspondence: M. Somali, 48 Agias Sofias Street, 54622, Thessaloniki, Greece. Tel/Fax: 302310235711. E-mail: somali@otenet.gr

Copyright CRC Press Jul 2005

Source: Gynecological Endocrinology

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