A C TA Obstetricia et Gynecologica
AOGS S H O R T RE S E A R CH RE P OR T
€ llerian hormone in premenopausal women Anti-Mu following treatment of uterine cervical cancer ASA HALLQVIST EVERHOV1, KARIN BERGMARK2, KARIN E. SMEDBY3, ANGELICA LINDEN 4 4 € HIRSCHBERG & ANGELIQUE FLOTER RADESTAD 1
Department of Oncology-Pathology, Karolinska Institute, Stockholm, 2Department of Oncology, Sahlgrenska Academy, Gothenburg, 3Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, and 4 Department of Women’s and Children’s Health, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
Key words €llerian Uterine cervical cancer, anti-Mu hormone, follicle-stimulating hormone, estradiol, chemoradiation, radical hysterectomy Correspondence Asa Hallqvist Everhov, Department of Surgery, South Hospital, SE 118 61 Stockholm, Sweden. E-mail: [email protected] Conflict of interest The AMH-assay was provided by Beckman Coulter. Please cite this article as: Hallqvist Everhov A, Bergmark K, Smedby KE, Lind en Hirschberg €ter R €llerian hormone A, Flo adestad A. Anti-Mu in premenopausal women following treatment of uterine cervical cancer. Acta Obstet Gynecol Scand 2014; 93: 949–953.
Abstract In this longitudinal study we prospectively enrolled 32 premenopausal women (ages 23–44 years) with stage I–III uterine cervical cancer undergoing surgery and/or chemoradiation. Serum levels of anti-M€ ullerian hormone, follicle-stimulating hormone and estradiol were examined at baseline and 1 year after treatment. As expected, serum anti-M€ ullerian hormone was undetectable after salpingo-oophorectomy or chemoradiation. After radical hysterectomy and pelvic lymphadenectomy with ovarian preservation serum anti-M€ ullerian hormone declined from a mean value of 2.0 1.4 lg/L to 1.1 0.8 lg/L (p = 0.01), representing a 45% reduction, whereas there was no significant change in serum levels of follicle-stimulating hormone and estradiol. This implies that ovarian function may be affected not only by castrating treatment but also by radical hysterectomy with ovarian preservation. The risk of premature menopause and the potential need of hormone replacement therapy among these women may be overlooked since they no longer menstruate. Abbreviations:
AMH,
anti-M€ ullerian
hormone;
FSH,
follicle
stimulating
hormone.
Received: 8 January 2014 Accepted: 25 June 2014 DOI: 10.1111/aogs.12448
Introduction Uterine cervical cancer affects women of all ages, with a median age of 50 years at diagnosis. The prognosis in Western countries is good, with an overall survival of approximately 70%. Depending on cancer stage, treatment can include different forms of surgery and chemoradiation. After chemoradiation or salpingo-oophorectomy, all premenopausal women enter menopause and are therefore recommended estrogen supplementation until the natural age of menopause (1). However, little is known about
how radical hysterectomy with pelvic lymphadenectomy affects ovarian function. Anti-M€ ullerian hormone (AMH) is a member of the transforming growth factor b superfamily of glycoproteins and is produced in the granulosa cells of early developing follicles (2). AMH is considered an important factor in folliculogenesis because of inhibition of follicle-stimulating hormone (FSH)-dependent follicular growth and selection (2). Serum AMH correlates with the number of antral follicles, and has been demonstrated to be a reliable marker of the ovarian reserve (2). Circulating levels fall
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 949–953
949
A. Hallqvist Everhov et al.
€ llerian hormone after uterine cervical cancer Anti-Mu
continuously during life, reaching a very low or undetectable level in the years prior to menopause (3). Serum AMH can therefore be used as a marker to predict the time of menopause (4). Clinically, AMH is mostly used to predict ovarian response to hyperstimulation during in vitro fertilization, but has also been used to assess iatrogenic damage to the ovarian follicle reserve from pelvic irradiation (5), chemotherapy (6), uterine artery embolization and ovarian surgery. AMH levels have rarely been studied in response to treatments of uterine cervical cancer. We therefore undertook a 1-year prospective study with pre- and post-treatment sampling of a cohort of premenopausal uterine cervical cancer patients. The aim of the study was to assess how uterine cervical cancer treatment affected ovarian AMH production.
Material and methods Women with incident uterine cervical cancer of all stages, treated at the Karolinska University Hospital from 1 September 2008 to 31 August 2009 were prospectively enrolled at the time of diagnosis. Follow up ended 31 August 2010. Exclusion criteria were inability to communicate in Swedish or World Health Organization performance status two or higher. Of 92 women, 71 consented to participate (77%). From this cohort we selected menstruating women aged 45 years or younger at diagnosis whose treatment was either: (i) chemoradiation only – no surgery (n = 17), (ii) radical hysterectomy, pelvic lymphadenecomy, salpingo-oophorectomy with combinations of chemoradiation and/or brachytherapy (n = 6) and (iii) radical hysterectomy and pelvic lymphadenectomy with ovarian preservation, Piver type 2 (n = 9). In the chemoradiation group, three women were lost to follow-up sampling at 1 year post treatment due to early relapse or death. All other participants were diseasefree at 1-year follow-up. The participants answered a detailed questionnaire about their previous gynecological history. Data on medication, tumor stage [according to the International Federation of Gynecology and Obstetrics (FIGO) system of 1995] and treatment were obtained from the women’s medical charts. Blood samples were taken at baseline and 1 year after completed treatment. Serum AMH was determined by enzyme linked immunoabsorbent assay AMH Gen II ELISA from Beckman Coulter (http://www.beckmancoulter.com). Detection limit was 0.18 lg/L, and within- and between-assay coefficients of variation were 4 and 5%, respectively. The normal standard range of serum AMH by this method at the Department of Clinical Chemistry, Karolinska University Hospital is 0.7–6 lg/L. Serum levels of FSH were determined by direct chemiluminescent
950
immunometric assay and levels of estradiol were determined by radioimmunoassay using commercial kits as previously described (7). Values are presented as mean SD or median (range). Within-group comparisons were performed by the Wilcoxon signed -rank test. A p-value of
AOGS S H O R T RE S E A R CH RE P OR T
€ llerian hormone in premenopausal women Anti-Mu following treatment of uterine cervical cancer ASA HALLQVIST EVERHOV1, KARIN BERGMARK2, KARIN E. SMEDBY3, ANGELICA LINDEN 4 4 € HIRSCHBERG & ANGELIQUE FLOTER RADESTAD 1
Department of Oncology-Pathology, Karolinska Institute, Stockholm, 2Department of Oncology, Sahlgrenska Academy, Gothenburg, 3Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institute, Stockholm, and 4 Department of Women’s and Children’s Health, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
Key words €llerian Uterine cervical cancer, anti-Mu hormone, follicle-stimulating hormone, estradiol, chemoradiation, radical hysterectomy Correspondence Asa Hallqvist Everhov, Department of Surgery, South Hospital, SE 118 61 Stockholm, Sweden. E-mail: [email protected] Conflict of interest The AMH-assay was provided by Beckman Coulter. Please cite this article as: Hallqvist Everhov A, Bergmark K, Smedby KE, Lind en Hirschberg €ter R €llerian hormone A, Flo adestad A. Anti-Mu in premenopausal women following treatment of uterine cervical cancer. Acta Obstet Gynecol Scand 2014; 93: 949–953.
Abstract In this longitudinal study we prospectively enrolled 32 premenopausal women (ages 23–44 years) with stage I–III uterine cervical cancer undergoing surgery and/or chemoradiation. Serum levels of anti-M€ ullerian hormone, follicle-stimulating hormone and estradiol were examined at baseline and 1 year after treatment. As expected, serum anti-M€ ullerian hormone was undetectable after salpingo-oophorectomy or chemoradiation. After radical hysterectomy and pelvic lymphadenectomy with ovarian preservation serum anti-M€ ullerian hormone declined from a mean value of 2.0 1.4 lg/L to 1.1 0.8 lg/L (p = 0.01), representing a 45% reduction, whereas there was no significant change in serum levels of follicle-stimulating hormone and estradiol. This implies that ovarian function may be affected not only by castrating treatment but also by radical hysterectomy with ovarian preservation. The risk of premature menopause and the potential need of hormone replacement therapy among these women may be overlooked since they no longer menstruate. Abbreviations:
AMH,
anti-M€ ullerian
hormone;
FSH,
follicle
stimulating
hormone.
Received: 8 January 2014 Accepted: 25 June 2014 DOI: 10.1111/aogs.12448
Introduction Uterine cervical cancer affects women of all ages, with a median age of 50 years at diagnosis. The prognosis in Western countries is good, with an overall survival of approximately 70%. Depending on cancer stage, treatment can include different forms of surgery and chemoradiation. After chemoradiation or salpingo-oophorectomy, all premenopausal women enter menopause and are therefore recommended estrogen supplementation until the natural age of menopause (1). However, little is known about
how radical hysterectomy with pelvic lymphadenectomy affects ovarian function. Anti-M€ ullerian hormone (AMH) is a member of the transforming growth factor b superfamily of glycoproteins and is produced in the granulosa cells of early developing follicles (2). AMH is considered an important factor in folliculogenesis because of inhibition of follicle-stimulating hormone (FSH)-dependent follicular growth and selection (2). Serum AMH correlates with the number of antral follicles, and has been demonstrated to be a reliable marker of the ovarian reserve (2). Circulating levels fall
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 949–953
949
A. Hallqvist Everhov et al.
€ llerian hormone after uterine cervical cancer Anti-Mu
continuously during life, reaching a very low or undetectable level in the years prior to menopause (3). Serum AMH can therefore be used as a marker to predict the time of menopause (4). Clinically, AMH is mostly used to predict ovarian response to hyperstimulation during in vitro fertilization, but has also been used to assess iatrogenic damage to the ovarian follicle reserve from pelvic irradiation (5), chemotherapy (6), uterine artery embolization and ovarian surgery. AMH levels have rarely been studied in response to treatments of uterine cervical cancer. We therefore undertook a 1-year prospective study with pre- and post-treatment sampling of a cohort of premenopausal uterine cervical cancer patients. The aim of the study was to assess how uterine cervical cancer treatment affected ovarian AMH production.
Material and methods Women with incident uterine cervical cancer of all stages, treated at the Karolinska University Hospital from 1 September 2008 to 31 August 2009 were prospectively enrolled at the time of diagnosis. Follow up ended 31 August 2010. Exclusion criteria were inability to communicate in Swedish or World Health Organization performance status two or higher. Of 92 women, 71 consented to participate (77%). From this cohort we selected menstruating women aged 45 years or younger at diagnosis whose treatment was either: (i) chemoradiation only – no surgery (n = 17), (ii) radical hysterectomy, pelvic lymphadenecomy, salpingo-oophorectomy with combinations of chemoradiation and/or brachytherapy (n = 6) and (iii) radical hysterectomy and pelvic lymphadenectomy with ovarian preservation, Piver type 2 (n = 9). In the chemoradiation group, three women were lost to follow-up sampling at 1 year post treatment due to early relapse or death. All other participants were diseasefree at 1-year follow-up. The participants answered a detailed questionnaire about their previous gynecological history. Data on medication, tumor stage [according to the International Federation of Gynecology and Obstetrics (FIGO) system of 1995] and treatment were obtained from the women’s medical charts. Blood samples were taken at baseline and 1 year after completed treatment. Serum AMH was determined by enzyme linked immunoabsorbent assay AMH Gen II ELISA from Beckman Coulter (http://www.beckmancoulter.com). Detection limit was 0.18 lg/L, and within- and between-assay coefficients of variation were 4 and 5%, respectively. The normal standard range of serum AMH by this method at the Department of Clinical Chemistry, Karolinska University Hospital is 0.7–6 lg/L. Serum levels of FSH were determined by direct chemiluminescent
950
immunometric assay and levels of estradiol were determined by radioimmunoassay using commercial kits as previously described (7). Values are presented as mean SD or median (range). Within-group comparisons were performed by the Wilcoxon signed -rank test. A p-value of
