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Androgens in Women After Allogeneic Hematopoietic Cell Transplantation: Impact of Chronic Gvhd and Glucocorticoid Therapy

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Androgens in Women After Allogeneic Hematopoietic Cell Transplantation: Impact of Chronic Gvhd and Glucocorticoid Therapy Bone Marrow Transplantation (2017) 52, 431–437 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/17 www.nature.com/bmt ORIGINAL ARTICLE Androgens in women after allogeneic hematopoietic cell transplantation: impact of chronic GvHD and glucocorticoid therapy Y Björk1, E Smith Knutsson2, C Ankarberg-Lindgren3, A-K Broman4, I Andersson1, L Björkman5, J Magnusson6, K Bergmark7, H Anderson8, P-O Andersson9 and M Brune1 Low androgen levels may contribute to sexual dysfunction in women after allogeneic hematopoietic cell transplantation (alloHCT). However, data on serum androgens in women after alloHCT are limited. The aim of this study was to assess androgen levels and their association with chronic GvHD (cGvHD) and glucocorticoid (GC) therapy. Included were 65 allografted women, 33 with cGvHD, and 23 of these were on GC therapy. Controls were 94 healthy, age-matched women. Supportive study groups were women after autologous HCT (autoHCT; n = 20) and non-transplanted women on GC therapy (n=26). Compared with controls, free testosterone (free T) and dehydroepiandrosterone sulfate (DHEAS) levels were lower in both the alloHCT group and GC groups; Po0.0001 and Po0.05, respectively. Androgens in the autoHCT group were similar or higher than controls. In the subgroup of alloHCT patients without cGvHD, free T was similar to controls (7.2 vs 8.6 pmol/L; P=0.42), whereas DHEAS levels was lower than controls (1.7 vs 2.5 μmol/L; P=0.008). Compared with controls, cGvHD without GC (n=10) was associated with lower free T and DHEAS; P=0.004 and P=0.0004, respectively). The lowest androgen levels were seen in women with both cGvHD and GC therapy. In conclusion, low serum androgens were associated with cGvHD and GC therapy, prompting for studies assessing a possible association between low androgens and sexual dysfunction and quality of life in allografted women. Bone Marrow Transplantation (2017) 52, 431–437; doi:10.1038/bmt.2016.268; published online 12 December 2016 INTRODUCTION Testosterone in premenopausal women is positively associated 9 Allogeneic hematopoietic cell transplantation (alloHCT) is with sexual function, and the highest levels are achieved in the associated with a number of long-term complications, primarily reproductive age followed by a slow steady decline with age 10,11 chronic GvHD (cGvHD) but also endocrine dysfunction and unrelated to menopause. Randomized trials indicate a impaired sexual life.1–3 In females, premature ovarian failure after positive effect of T therapy in postmenopausal women with 12 HCT is ascribed to cytotoxicity on the ovaries of chemotherapy hypoactive sexual desire disorder. Owing to safety concerns and and conditioning.4 Low levels of androgens may contribute to lack of convincing effect, other conditions associated with low sexual dysfunction and reduced quality of life in women. T levels are not considered established indications for T therapy.12 However, data on serum androgen levels in female patients after DHEA is the most abundant steroid hormone in human blood alloHCT are limited.5,6 and is present in serum mainly as the sulfate (DHEAS). DHEA may Androgen production in women is ovarian and adrenal based. exert its effect after conversion to sex steroids, including T and The androgens, in order of increasing potency, include estradiol. Direct effects of DHEA have also been proposed.13 dehydroepiandrosterone (DHEA) and its sulfate DHEAS, Thus DHEA improves physical and psychological well-being, androstenedione and testosterone (T). The ovaries and adrenal muscle strength and bone density and reduces body fat, glands contribute equally to total T and androstenedione while low levels correlate with increased cardiovascular disease production, whereas 490% of DHEAS originate from the and all-cause mortality.14 The marked decline of DHEAS with age adrenals.7 Androgens are precursor hormones to estrogen and is independent of menopausal status.10,11 also act directly on receptors in the central nervous system, The first objective of this study was to assess serum androgen reproductive organs, liver, skin, bone, muscle and adipose tissue.8 levels in women after alloHCT. The population-based cohort In plasma, T circulates bound mainly to sex hormone-binding included allografted adult women after reduced or myeloablative globulin (SHBG) and albumin, leaving 1–3% of total T in free or conditioning. Healthy, age-matched women constituted unbound state (free T). Free T is considered the component the control group. Secondary objectives were to study the having access to target cells resulting in androgenic effects. putative impact of conditioning intensity, ongoing cGvHD and 1Section of Hematology and Coagulation, Department of Medicine, Sahlgrenska University Hospital, and Sahlgrenska Academy, Gothenburg, Sweden; 2Department of Obstetrics and Gynecology, NU Hospital Group, and Sahlgrenska Academy, University of Gothenburg, Trollhättan, Sweden; 3Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 4Department of Obstetrics and Gynecology, NU Hospital Group, Trollhättan, Sweden; 5Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 6Department of Pulmonary Medicine, Institute of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; 7Department of Oncology, Clinical Cancer Epidemiology, Sahlgrenska Academy, Gothenburg, Sweden; 8Department of Clinical Sciences Lund, Cancer Epidemiology, University of Lund, Lund, Sweden and 9Section of Hematology, Department of Medicine, South Älvsborg Hospital, and Sahlgrenska Academy, Borås, Sweden. Correspondence: Associate Professor M Brune, Section of Hematology and Coagulation, Department of Medicine, Sahlgrenska University Hospital, and Sahlgrenska Academy, Gothenburg SE-413 45, Sweden. E-mail: [email protected] Received 16 May 2016; revised 3 September 2016; accepted 7 September 2016; published online 12 December 2016 Androgens in women after HCT Y Björk et al 432 glucocorticoid (GC) therapy on androgen levels. To study these (n=12), myeloma (n=7) and multiple sclerosis (n=1). All patients were in aims, two supportive study groups were identified: women after CR or PR with no ongoing chemotherapy. autologous HCT (autoHCT) and women on GC therapy without previous HCT (GC group). Women on GC therapy without HCT (GC group). Twenty-six women were enrolled. The indications for GC therapy were hematological diseases (n=12), lung disease (n=6) or rheumatic disease (n=8). PATIENTS AND METHODS Patients Controls Women after alloHCT. A total of 166 women underwent alloHCT between Ninety-four healthy age-matched women agreed to participate. Eighty-one 1996 and September 2012 in the western region of Sweden (≈1.6 million of these were health-care employees. All had intact ovaries. inhabitants). Seventy-six surviving female patients in CR living in Gothenburg, Trollhättan and Borås were identified. Of these, 6 declined to participate and 5 were excluded due to mental disability (n=1), Laboratory methods insufficient Swedish language proficiency (n=3) or missing data (n=1). Serum levels of albumin, estradiol, total and free T, DHEAS, luteinizing Thus 65 patients were enrolled to give a survey participation rate of 92%. hormone, follicle-stimulating hormone (FSH) and SHBG were analyzed in Conditioning was myeloablative (TBI or oral busulfan 16 mg/kg combined all women. S-cortisol and S-adrenocorticotropic hormone were analyzed with cyclophosphamide 120 mg/kg or fludarabine 150–180 mg/m2)or in the GC group, autoHCT group and in 40/65 alloHCT patients but not in reduced (mainly oral busulfan 8 mg/kg and fludarabine 150–180 mg/m2). controls. Hormone replacement therapy (HRT) and oral contraceptives Conditioning intensity was classified according to Bacigalupo et al.15 (OCP) were interrupted 24 h before blood sampling in all groups. All patients with an unrelated donor received pretransplant antithymocyte globulin (Thymoglubuline 6 mg/kg or ATG-Fresenius 40 mg/kg) or Hormone analyses. All samples for hormone determination were assessed alemtuzumab 15 mg/m2 (n=3). cGvHD was categorized according to the at accredited laboratories. Blood samples were obtained between 0800 and Seattle Classification16 by reviews of medical records. 0830 hours. After separation, sera were stored at − 20 °C until analysis. Concentrations of T were determined by radioimmunoassay (RIA; Spectria; Women after autoHCT. Thirty-five women autografted during 1996–2010 Orion Diagnostica, Espoo, Finland), as described.17 The lower limit of and living in Gothenburg were identified. Seven of these declined detection (LoD) was 0.03 nmol/L. The total imprecision was 14% at 1 nmol/L. participation, three had been allografted after relapse, and five could not Free T was calculated from T, albumin and SHBG including the association be contacted. Thus 20 patients were enrolled. Diagnoses were lymphoma constants.18 SHBG was determined by a chemiluminescence immunoassay a b 8 50 40 6 30 4 DHEAS 20 Free testosterone Free 2 10 0 0 Controls Allo-HCT Auto-HCT GCControls Allo-HCT Auto-HCT GC c d 25 8 P =0.004 P =0.0004 20 6 P = 0.0001 P <0.0001 15 4 10 DHEAS Free testosterone Free 2 5 0 0 ControlsNo cGvHDcGvHD, no GC cGvHD, GC Controls No cGvHD cGvHD, no GC cGvHD, GC Figure 1. Hormone levels of patients in the study groups and controls. Box plots showing free testosterone (a)andDHEAS(b) levels in the four study groups. (c)and(d) illustrate levels
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