523497 research-article2014
MSJ0010.1177/1352458514523497Multiple Sclerosis JournalAlroughani
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Fingolimod-associated amenorrhea: a report of three cases
Multiple Sclerosis Journal 2014, Vol. 20(12) 1662–1664 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458514523497 msj.sagepub.com
R Alroughani1,2
Abstract Amenorrhea has not been reported as an adverse event in fingolimod phase III clinical trials in patients with multiple sclerosis (MS) with either 0.5 mg or 1.25 mg dosages. Here we report three cases of young women with MS who developed amenorrhea within 6 months of initiation of fingolimod. They experienced irregularities in their menstrual cycles in the first 3 months, which progressed to amenorrhea by 5th or 6th month. Gynecology evaluations showed no other etiologies. Menses returned to baseline after discontinuation of fingolimod for 2–3 months. Amenorrhea could be associated with fingolimod in the first year. Future surveillance is advised to determine the incidence rate of this adverse event. Keywords Relapsing/remitting, disease-modifying therapies, fingolimod, amenorrhea Date received: 14 October 2013; revised: 19 December 2013; accepted: 20 January 2014
Introduction Fingolimod is the first oral disease-modifying therapy (DMT) approved for relapsing forms of multiple sclerosis (MS). Fingolimod-phosphate is a sphingosine 1-phosphate (S1P) analog, which inhibits lymphocyte egress from lymph nodes.1 S1P receptors are involved in multiple biological processes, including leukocyte recirculation, neural cell proliferation, endothelial cell function, and vasoregulation.2 Two phase III clinical trials demonstrated the efficacy of fingolimod in decreasing the annualized relapse rate and magnetic resonance imaging (MRI) activity compared with placebo3 and IM interferon (IFN) beta-1a4. However, bradyarrhythmia, macular edema and infections were the main treatment emergent reported adverse events. Menstrual irregularities or amenorrhea have never been reported before. Here we report three cases of amenorrhea that developed in young women within 3 months of initiation of fingolimod.
her menstrual cycle 2 months after initiation of fingolimod. The menstrual cycle was delayed 12 and 20 days in the first and second months, respectively. She developed amenorrhea by the third month. She was not known to have concomitant disorder. Routine laboratory results revealed a total white count of 3.7 × 109/l with an absolute lymphocyte count of 0.4 × 109/l. Liver and renal function tests were unremarkable. A gynecologist consultation was initiated. Gynecological clinical examinations were unremarkable. Ultrasound of abdomen along with specific hormonal testing for prolactin, LH, FSH and TSH, progesterone, and estrogen were unremarkable. The patient was advised to discontinue fingolimod after missing three menstrual cycles. The menstrual cycle returned to baseline within 2 months of discontinuation. She was reluctant to resume fingolimod and the decision was to switch her to another DMT.
Case 1
1Division
Case 1 was a 38-year-old married female with a diagnosis of relapsing–remitting MS since 2002 who started fingolimod after sustaining two relapses in 1 year while on interferon beta 1a SC. She was not on contraceptive pills. The first dose was tolerated well. She reported irregularity in
Corresponding author: R Alroughani, Division of Neurology, Department of Medicine, Amiri Hospital, PO Box 1661, Qurtoba, 73767, Kuwait. Email: [email protected]
of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait. 2Neurology Clinic, Dasman Diabetes Institute, Kuwait.
Downloaded from msj.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 22, 2015
1663
Alroughani
Case 2 Case 2 was a 36-year-old single female who was diagnosed with relapsing–remitting MS according to the revised 2010 McDonalds Criteria in November 2011. She had needle phobia and she did not want to start any injectable DMTs. She developed right optic neuritis in June 2012. Fingolimod was initiated as a first-line therapy. The first dose observation (FDO) was uneventful. She reported irregularity with her menstrual cycle in the second month and amenorrhea in the subsequent month, which continued for two additional months. Her absolute lymphocyte count was 0.45 × 109/l with normal liver function test. She consulted a gynecologist who evaluated the cycle frequency and duration along with any related history of sexually transmitted disease or abnormal Pap smear. The clinical gynecological examination was unremarkable. An abdominal ultrasound in addition to specific hormonal levels (prolactin, FSH, LH, TSH, progesterone, estrogen) was within normal limits. The decision was made to discontinue fingolimod. Two months later, the menstrual cycle returned with a 1-week delay in menses and to the baseline in the subsequent month. She elected to start interferon beta 1a IM as first-line DMT instead.
Case 3 A 27-year-old single female with known hypothyroidism since 2005 on replacement therapy was diagnosed with MS in 2009. Interferon beta 1b SC was switched to fingolimod after she developed disease breakthrough manifested by sensory myelitis relapse. She had a complete recovery after a 5-day course of IV methyl prednisolone. MRI spine showed an enhancing lesion in the cervical (C3) spine. Brain MRI revealed two enhancing lesions in the parietal and periventricular area. FDO was uneventful. She complained of menstrual irregularities in the third month after institution of fingolimod. She was examined by her family physician, who referred her to a gynecologist. A detailed gynecological examination and related hormonal testing (prolactin, LH, FSH, TSH, progesterone, estrogen) were unremarkable. An abdominal ultrasound did not reveal any abnormalities. The absolute lymphocyte count was 0.8 × 109/l and 0.69 × 109/l in the second and third months, respectively. Fingolimod was discontinued in the sixth month after missing three periods. Her menstrual cycle returned to baseline 2 months later with some irregularities as she continued to have menses in a 32-day cycle rather than her usual 26–28 day cycle. She is planning to start another oral medication in the near future.
Discussion Amenorrhea is defined as the absence of menstrual periods, either on a permanent or temporary basis.5 In primary
amenorrhea, menstrual periods have never begun (by age 16), whereas secondary amenorrhea is defined as the absence of menstrual periods for three consecutive cycles or a time period of more than 6 months in a woman who was previously menstruating.5,6 The pathophysiology of a normal menstrual cycle is complex and involving multiple axes including the hypothalamus, pituitary, ovary, uterine smooth muscles and arterioles of the endometrium.6 The hypothalamus secretes GnRH, which travels down the anterior portion of the pituitary via the hypophyseal portal system and binds to receptors on the secretory cells of the adenohypophysis. In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream. In females FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin, and to regulate the menstrual cycle and ovarian cycle. Estrogen forms a negative feedback loop by inhibiting the production of GnRH in the hypothalamus. Inhibin acts to inhibit activin, which is a peripherally produced hormone that positively stimulates GnRH-producing cells.6,7 When all the axes including the hormonal secretions by target organs are maintained, amenorrhea can be secondary to loss of vascular integrity in the spiral arterioles of the endometrium. Nitric oxide, a vasodilator, is locally synthesized in the endometrium and may have a role in regulating vascular tone.8 Fingolimod exerts its effects on S1P receptors that have several subtypes, S1P types 1-5, and these are expressed on a wide range of cell types.2 Evidence suggests that S1P types1-3 on smooth muscle and endothelial cells play pivotal roles in regulating vascular homeostasis and vascular permeability.9 Vascular lead phenomena resulting from direct effects on endothelial cells may account for several adverse events (AEs) associated with fingolimod; macular edema and abnormal pulmonary function are most common described AEs especially with higher doses (1.25 mg).10 Furthermore, fingolimod-associated changes in endothelial-derived nitric oxide and resultant effects on vascular tone might contribute to hypertension and peripheral arterial disease.11 Although no clear-cut mechanism for fingolimod-associated amenorrhea has been described in the literature, the vascular leak phenomena and alterations in vascular tone may be possible theoretical explanations. There were no reported menstrual irregularities or amenorrhea in the phase III (when both dosages 0.5 mg and 1.25 mg were evaluated) or TRANSFORMS extension trials.3,4,12 Most of the data on fingolimod-associated amenorrhea was accumulated through a web-based data collection system (eHealthme.com). The collection system serves many symptoms and signs in addition to diseases and disorders; thus it is not exclusive to MS symptoms. However, specific sub-studies are initiated for specific disease or symptoms if necessary. A recent study created by eHealthMe based on reports from the FDA reported that 16 patients (0.18%) had amenorrhea as of 13 October 2013 among 8745 patients reporting AEs when taking fingolimod.13
Downloaded from msj.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 22, 2015
1664
Multiple Sclerosis Journal 20(12)
Some 57.14% of patients reported amenorrhea within the first 6 months, while 42.86% had amenorrhea at between 6–12 months. Amenorrhea was most prevalent in 30–39 years age group.13 Ontaneda et al. reported the early tolerability and safety of fingolimod in clinical practice after its approval.14 They assessed 317 patients between September 2010 and July 2011, of whom 30 discontinued fingolimod due to AEs. None of them had amenorrhea. We have to point out that secondary amenorrhea is a frequent condition in healthy women, and the causality of fingolimodassociated amenorrhea cannot be established and should considered probable at this stage given that fingolimod has not been re-introduced to the patients. Reporting postmarketing AEs is an important mechanism to assess the intermediate and long-term safety of any newly approved medication. Underreporting due to lack of awareness of the treating physicians to identify the AEs may lead to lower than expected incidence rates of AEs. Hence, our case reports may be helpful in initiating better surveillance on fingolimod-associated amenorrhea. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453–21457. 2. Chun J and Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33: 91–101.
3. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415. 4. Kappos L, Radue EW, O’Connor P, et al. A placebocontrolled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362: 387–401. 5. Brinkmann V and Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol 2006; 6: 244–250. 6. Master-Hunter T and Heiman DL. Amenorrhea: Evaluation and treatment. Am Fam Physician 2006; 73: 1374–1382. 7. Meethal SV, Liu T, Chan HW, et al. Identification of a regulatory loop for the synthesis of neurosteroids: A steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors. J Neurochem 2009; 110: 1014–1027. 8. Teran E, Escudero C and Vivero S. Physiological changes in platelet aggregation and nitric oxide levels during menstrual cycle in healthy women. Nitric Oxide 2002; 7: 217–220. 9. Golden NH and Carlson JL. The pathophysiology of amenorrhea in the adolescent. Ann N Y Acad Sci 2008; 1135: 163– 178. 10. Marsolais D and Rosen H. Chemical modulators of sphingosine-1-phosphate receptor as barrier-oriented therapeutic molecules. Nat Rev Drug Discov 2011; 8: 297–307. 11. Tolle M, Levkau B, Keul B, et al. Immunomodulator FTY720 induces eNOS-dependent arterial vasodilatation via lysophopholipid receptor S1P3. Circ Res 2005; 96: 913–920. 12. Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: A randomised extension of the TRANSFORMS study. Lancet Neurol 2011; 10: 520–529. 13. FDA. From 16 FDA reports: Gilenya and Amenorrhoea. Available at: http://www.ehealthme.com/ds/gilenya/amenorrhoea (accessed: 12 October, 2013). 14. Ontaneda D, Hara-Cleaver C, Rudick RA, et al. Early tolerability and safety of fingolimod in clinical practice. J Neurol Sci 2012; 323: 167–172.
Downloaded from msj.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 22, 2015
MSJ0010.1177/1352458514523497Multiple Sclerosis JournalAlroughani
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Fingolimod-associated amenorrhea: a report of three cases
Multiple Sclerosis Journal 2014, Vol. 20(12) 1662–1664 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458514523497 msj.sagepub.com
R Alroughani1,2
Abstract Amenorrhea has not been reported as an adverse event in fingolimod phase III clinical trials in patients with multiple sclerosis (MS) with either 0.5 mg or 1.25 mg dosages. Here we report three cases of young women with MS who developed amenorrhea within 6 months of initiation of fingolimod. They experienced irregularities in their menstrual cycles in the first 3 months, which progressed to amenorrhea by 5th or 6th month. Gynecology evaluations showed no other etiologies. Menses returned to baseline after discontinuation of fingolimod for 2–3 months. Amenorrhea could be associated with fingolimod in the first year. Future surveillance is advised to determine the incidence rate of this adverse event. Keywords Relapsing/remitting, disease-modifying therapies, fingolimod, amenorrhea Date received: 14 October 2013; revised: 19 December 2013; accepted: 20 January 2014
Introduction Fingolimod is the first oral disease-modifying therapy (DMT) approved for relapsing forms of multiple sclerosis (MS). Fingolimod-phosphate is a sphingosine 1-phosphate (S1P) analog, which inhibits lymphocyte egress from lymph nodes.1 S1P receptors are involved in multiple biological processes, including leukocyte recirculation, neural cell proliferation, endothelial cell function, and vasoregulation.2 Two phase III clinical trials demonstrated the efficacy of fingolimod in decreasing the annualized relapse rate and magnetic resonance imaging (MRI) activity compared with placebo3 and IM interferon (IFN) beta-1a4. However, bradyarrhythmia, macular edema and infections were the main treatment emergent reported adverse events. Menstrual irregularities or amenorrhea have never been reported before. Here we report three cases of amenorrhea that developed in young women within 3 months of initiation of fingolimod.
her menstrual cycle 2 months after initiation of fingolimod. The menstrual cycle was delayed 12 and 20 days in the first and second months, respectively. She developed amenorrhea by the third month. She was not known to have concomitant disorder. Routine laboratory results revealed a total white count of 3.7 × 109/l with an absolute lymphocyte count of 0.4 × 109/l. Liver and renal function tests were unremarkable. A gynecologist consultation was initiated. Gynecological clinical examinations were unremarkable. Ultrasound of abdomen along with specific hormonal testing for prolactin, LH, FSH and TSH, progesterone, and estrogen were unremarkable. The patient was advised to discontinue fingolimod after missing three menstrual cycles. The menstrual cycle returned to baseline within 2 months of discontinuation. She was reluctant to resume fingolimod and the decision was to switch her to another DMT.
Case 1
1Division
Case 1 was a 38-year-old married female with a diagnosis of relapsing–remitting MS since 2002 who started fingolimod after sustaining two relapses in 1 year while on interferon beta 1a SC. She was not on contraceptive pills. The first dose was tolerated well. She reported irregularity in
Corresponding author: R Alroughani, Division of Neurology, Department of Medicine, Amiri Hospital, PO Box 1661, Qurtoba, 73767, Kuwait. Email: [email protected]
of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait. 2Neurology Clinic, Dasman Diabetes Institute, Kuwait.
Downloaded from msj.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 22, 2015
1663
Alroughani
Case 2 Case 2 was a 36-year-old single female who was diagnosed with relapsing–remitting MS according to the revised 2010 McDonalds Criteria in November 2011. She had needle phobia and she did not want to start any injectable DMTs. She developed right optic neuritis in June 2012. Fingolimod was initiated as a first-line therapy. The first dose observation (FDO) was uneventful. She reported irregularity with her menstrual cycle in the second month and amenorrhea in the subsequent month, which continued for two additional months. Her absolute lymphocyte count was 0.45 × 109/l with normal liver function test. She consulted a gynecologist who evaluated the cycle frequency and duration along with any related history of sexually transmitted disease or abnormal Pap smear. The clinical gynecological examination was unremarkable. An abdominal ultrasound in addition to specific hormonal levels (prolactin, FSH, LH, TSH, progesterone, estrogen) was within normal limits. The decision was made to discontinue fingolimod. Two months later, the menstrual cycle returned with a 1-week delay in menses and to the baseline in the subsequent month. She elected to start interferon beta 1a IM as first-line DMT instead.
Case 3 A 27-year-old single female with known hypothyroidism since 2005 on replacement therapy was diagnosed with MS in 2009. Interferon beta 1b SC was switched to fingolimod after she developed disease breakthrough manifested by sensory myelitis relapse. She had a complete recovery after a 5-day course of IV methyl prednisolone. MRI spine showed an enhancing lesion in the cervical (C3) spine. Brain MRI revealed two enhancing lesions in the parietal and periventricular area. FDO was uneventful. She complained of menstrual irregularities in the third month after institution of fingolimod. She was examined by her family physician, who referred her to a gynecologist. A detailed gynecological examination and related hormonal testing (prolactin, LH, FSH, TSH, progesterone, estrogen) were unremarkable. An abdominal ultrasound did not reveal any abnormalities. The absolute lymphocyte count was 0.8 × 109/l and 0.69 × 109/l in the second and third months, respectively. Fingolimod was discontinued in the sixth month after missing three periods. Her menstrual cycle returned to baseline 2 months later with some irregularities as she continued to have menses in a 32-day cycle rather than her usual 26–28 day cycle. She is planning to start another oral medication in the near future.
Discussion Amenorrhea is defined as the absence of menstrual periods, either on a permanent or temporary basis.5 In primary
amenorrhea, menstrual periods have never begun (by age 16), whereas secondary amenorrhea is defined as the absence of menstrual periods for three consecutive cycles or a time period of more than 6 months in a woman who was previously menstruating.5,6 The pathophysiology of a normal menstrual cycle is complex and involving multiple axes including the hypothalamus, pituitary, ovary, uterine smooth muscles and arterioles of the endometrium.6 The hypothalamus secretes GnRH, which travels down the anterior portion of the pituitary via the hypophyseal portal system and binds to receptors on the secretory cells of the adenohypophysis. In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream. In females FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin, and to regulate the menstrual cycle and ovarian cycle. Estrogen forms a negative feedback loop by inhibiting the production of GnRH in the hypothalamus. Inhibin acts to inhibit activin, which is a peripherally produced hormone that positively stimulates GnRH-producing cells.6,7 When all the axes including the hormonal secretions by target organs are maintained, amenorrhea can be secondary to loss of vascular integrity in the spiral arterioles of the endometrium. Nitric oxide, a vasodilator, is locally synthesized in the endometrium and may have a role in regulating vascular tone.8 Fingolimod exerts its effects on S1P receptors that have several subtypes, S1P types 1-5, and these are expressed on a wide range of cell types.2 Evidence suggests that S1P types1-3 on smooth muscle and endothelial cells play pivotal roles in regulating vascular homeostasis and vascular permeability.9 Vascular lead phenomena resulting from direct effects on endothelial cells may account for several adverse events (AEs) associated with fingolimod; macular edema and abnormal pulmonary function are most common described AEs especially with higher doses (1.25 mg).10 Furthermore, fingolimod-associated changes in endothelial-derived nitric oxide and resultant effects on vascular tone might contribute to hypertension and peripheral arterial disease.11 Although no clear-cut mechanism for fingolimod-associated amenorrhea has been described in the literature, the vascular leak phenomena and alterations in vascular tone may be possible theoretical explanations. There were no reported menstrual irregularities or amenorrhea in the phase III (when both dosages 0.5 mg and 1.25 mg were evaluated) or TRANSFORMS extension trials.3,4,12 Most of the data on fingolimod-associated amenorrhea was accumulated through a web-based data collection system (eHealthme.com). The collection system serves many symptoms and signs in addition to diseases and disorders; thus it is not exclusive to MS symptoms. However, specific sub-studies are initiated for specific disease or symptoms if necessary. A recent study created by eHealthMe based on reports from the FDA reported that 16 patients (0.18%) had amenorrhea as of 13 October 2013 among 8745 patients reporting AEs when taking fingolimod.13
Downloaded from msj.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 22, 2015
1664
Multiple Sclerosis Journal 20(12)
Some 57.14% of patients reported amenorrhea within the first 6 months, while 42.86% had amenorrhea at between 6–12 months. Amenorrhea was most prevalent in 30–39 years age group.13 Ontaneda et al. reported the early tolerability and safety of fingolimod in clinical practice after its approval.14 They assessed 317 patients between September 2010 and July 2011, of whom 30 discontinued fingolimod due to AEs. None of them had amenorrhea. We have to point out that secondary amenorrhea is a frequent condition in healthy women, and the causality of fingolimodassociated amenorrhea cannot be established and should considered probable at this stage given that fingolimod has not been re-introduced to the patients. Reporting postmarketing AEs is an important mechanism to assess the intermediate and long-term safety of any newly approved medication. Underreporting due to lack of awareness of the treating physicians to identify the AEs may lead to lower than expected incidence rates of AEs. Hence, our case reports may be helpful in initiating better surveillance on fingolimod-associated amenorrhea. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453–21457. 2. Chun J and Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33: 91–101.
3. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415. 4. Kappos L, Radue EW, O’Connor P, et al. A placebocontrolled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362: 387–401. 5. Brinkmann V and Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol 2006; 6: 244–250. 6. Master-Hunter T and Heiman DL. Amenorrhea: Evaluation and treatment. Am Fam Physician 2006; 73: 1374–1382. 7. Meethal SV, Liu T, Chan HW, et al. Identification of a regulatory loop for the synthesis of neurosteroids: A steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors. J Neurochem 2009; 110: 1014–1027. 8. Teran E, Escudero C and Vivero S. Physiological changes in platelet aggregation and nitric oxide levels during menstrual cycle in healthy women. Nitric Oxide 2002; 7: 217–220. 9. Golden NH and Carlson JL. The pathophysiology of amenorrhea in the adolescent. Ann N Y Acad Sci 2008; 1135: 163– 178. 10. Marsolais D and Rosen H. Chemical modulators of sphingosine-1-phosphate receptor as barrier-oriented therapeutic molecules. Nat Rev Drug Discov 2011; 8: 297–307. 11. Tolle M, Levkau B, Keul B, et al. Immunomodulator FTY720 induces eNOS-dependent arterial vasodilatation via lysophopholipid receptor S1P3. Circ Res 2005; 96: 913–920. 12. Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: A randomised extension of the TRANSFORMS study. Lancet Neurol 2011; 10: 520–529. 13. FDA. From 16 FDA reports: Gilenya and Amenorrhoea. Available at: http://www.ehealthme.com/ds/gilenya/amenorrhoea (accessed: 12 October, 2013). 14. Ontaneda D, Hara-Cleaver C, Rudick RA, et al. Early tolerability and safety of fingolimod in clinical practice. J Neurol Sci 2012; 323: 167–172.
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