Female infertility and multiple sclerosis: Is this an ... - SAGE Journals

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MSJ0010.1177/1352458514549406Multiple Sclerosis JournalMcCombe and Stenager

MULTIPLE SCLEROSIS MSJ JOURNAL

Editorial

Female infertility and multiple sclerosis: Is this an issue?

There has been less emphasis on the effects of MS on fertility. Fertility is the term that indicates the number of children that are produced, whereas the ability to produce children is referred to as fecundity. However, in common parlance, fertility is used to indicate the ability to become pregnant and for the purposes of this discussion we will use fertility in its common meaning of ability to become pregnant. There have been some reports suggesting that fertility, defined as the number of children that are born to women with MS, is reduced.3–6 For people with a medical condition, fertility could be impaired either by health issues (including the effect of therapy) leading to reduced ability to conceive or by social issues such as reduced opportunity to find a partner or a decision to avoid pregnancy because of disability. In MS, it seems probable that social issues are important, and could lead women with MS to have fewer pregnancies even if their ability to conceive is normal. However, some reports suggest that women with MS may have reduced ability to conceive. The ability to conceive is difficult to measure. Abnormalities of the levels of sex hormones and gonadotrophins, of the type that are associated with reduced fertility, have been reported in women with MS.7 One aspect of fertility is ovarian reserve. One study, using transvaginal ultrasound to evaluate ovarian volume, follicle count and ovarian artery Doppler found low ovarian reserve in MS patients.8

2015, Vol. 21(1) 5­–7 DOI: 10.1177/ 1352458514549406 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Pamela A McCombe and Egon Stenager

Many people with MS are young women of childbearing age, for whom pregnancy is often a major concern – particularly now that immunomodulatory treatment is successful and women with MS wish to lead fulfilling and healthy lives. Women with MS are concerned about the effects of MS and MS treatments on pregnancy and the effects of pregnancy on the course of MS. These issues have been discussed previously.1,2

Multiple Sclerosis Journal

Anti-Mullerian hormone (AMH) is a peptide hormone that is considered to be a marker of ovarian reserve, unrelated to the menstrual cycle.9 In this issue, Thone et al.10 show that AMH levels were lower in young women with relapsing–remitting MS compared with controls. While this is a small study, it provides evidence that women with MS may have reduced ovarian reserve and hence reduced fertility. Reduced fertility/reduced ovarian reserve in MS could be due to the effects of medications. Usually these are stopped during pregnancy but there is the possibility that there may be some ongoing effect of long term use. However, Thone et al.10 found that levels of AMH were lower in women who were not already on medications, and they excluded women with previous use of cyclophosphamide or mitoxantrone, suggesting that use of medications is not the explanation for their findings. It could be speculated that reduced ovarian reserve could be due to a neuroendocrine effect of MS. There are some isolated reports of other reproductive endocrine abnormalities in MS, including hyperprolactinaemia11 and hyperandrogenism.12 However, this has not been studied in detail.

Correspondence to: PA McCombe The University of Queensland, Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Herston, Brisbane, 4029, Australia. Pamela.McCombe@ uq.edu.au Pamela A McCombe University of Queensland, Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Brisbane, Australia Egon Stenager Institute of Regional Health Research, University of Southern Denmark, Denmark/Department of Neurology, MS-clinic of Southern Jutland (Sønderborg, Esbjerg, Vejle), Sønderborg, Denmark

If women with MS have impaired fertility, this could have an autoimmune cause. One consideration is that autoimmunity, with its associated pathological processes, can generally impair fertility.13 Another possibility is the specific disorder of autoimmune primary ovarian insufficiency (POI). Thone et al.10 point out that POI is known to be associated with autoimmune diseases other than MS. POI could possibly arise in women with MS because they have a genetic predisposition to develop autoimmune disease, as the genes that predispose to MS also predispose to other autoimmune diseases. While this theory is attractive, and has some support, authoritative studies from Canada and Scandinavia show that while there is co-occurrence of other autoimmune

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Multiple Sclerosis Journal 21(1) disorders with MS in women, this is not frequent and, more importantly, not more frequent than in a control population.14,15 Another argument against an autoimmune cause is that pathological evidence indicates that MS is primarily confined to the central nervous system. However, reports confirm that one or more organs can be involved with autoimmune disorders with onset prior to onset of MS.15 This corresponds to the conception that MS immunology involves both organ-specific and systemic components.16 When reversing the approach, that is, from infertility to the risk of MS, a study found that patients with pain and infertility due to endometriosis had an increased risk of an autoimmune disorder, including MS.17 If MS were to lead to a biological cause of impaired fertility in women, it might be anticipated that a similar effect would be observed in men. There are few studies of male fertility in MS, and these focus mainly on sexual dysfunction,18 although one study found that males with MS had reduced semen quality and hypogonadotrophic hypogonadism.19 Interestingly, Magyari et al.15 reported that men with MS had significantly increased risk of concomitant autoimmune disorders compared with controls, thus a gender difference was found. Comfortingly, birth outcomes of pregnancies fathered by MS men did not differ from healthy controls.20 In conclusion, fertility may be an issue in MS. This has clinical implications because if fertility is reduced, this may lead women to use assisted reproductive technology, which is of concern, because this has been associated with relapses of MS.21 Present results about the prevalence and cause of infertility in MS are scarce, conflicting and show gender differences and thus call for further research.

References 1. McCombe PA and Greer JM. Female reproductive issues in multiple sclerosis. Mult Scler 2012; 19: 392–402. 2. Miller DH, Fazekas F, Montalban X, et al. Pregnancy, sex and hormonal factors in multiple sclerosis. Mult Scler 2014; 20: 527–536. 3. Cavalla P, Rovei V, Masera S, et al. Fertility in patients with multiple sclerosis: Current knowledge and future perspectives. Neurol Sci 2006; 27: 231–239. 4. Runmarker B and Andersen O. Pregnancy is associated with a lower risk of onset and a better

prognosis in multiple sclerosis. Brain 1995; 118: 253–261. 5. Jalkanen A, Alanen A and Airas L. Pregnancy outcome in women with multiple sclerosis: Results from a prospective nationwide study in Finland. Mult Scler 2010; 16: 950–955. 6. Nielsen NM, Jorgensen KT, Stenager E, et al. Reproductive history and risk of multiple sclerosis. Epidemiology 2011; 22: 546–552. 7. Grinsted L, Heltberg A, Hagen C, et al. Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple sclerosis. J Intern Med 1989; 226: 241–244. 8. Cil AP, Leventoglu A, Sonmezer M, et al. Assessment of ovarian reserve and Doppler characteristics in patients with multiple sclerosis using immunomodulating drugs. J Turk Ger Gynecol Assoc 2009; 10: 213–219. 9. Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update 2014; 20: 370–385. 10. Thone J, Kollar S, Nousome D, et al. Serum antiMullerian hormone levels in reproductive-age women with relapsing remitting multiple sclerosis. Mult Scler 2014. [This issue] 11. Kira J, Harada M, Yamaguchi Y, et al. Hyperprolactinemia in multiple sclerosis. J Neurol Sci 1991; 102: 61–66. 12. Falaschi P, Martocchia A, Proietti A, et al. High incidence of hyperandrogenism-related clinical signs in patients with multiple sclerosis. Neuro Endocrinol Lett 2001; 22: 248–250. 13. Sen A, Kushnir VA, Barad DH, et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol 2014; 10: 37–50. 14. Ramagopalan SV, Dyment DA, Valdar W, et al. Autoimmune disease in families with multiple sclerosis: A population-based study. Lancet Neurol 2007; 6: 604–610. 15. Magyari M, Koch-Henriksen N, Pfleger CC, et al. Gender and autoimmune comorbidity in multiple sclerosis. Mult Scler 2014; 20: 1244–1251. 16. Smith DA and Germolec DR. Introduction to immunology and autoimmunity. Environ Health Perspect 1999; 107(Suppl. 5): 661–665. 17. Sinaii N, Cleary SD, Ballweg ML, et al. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: A survey analysis. Hum Reprod 2002; 17: 2715–2724.

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PA McCombe and E Stenager 18. Fode M, Krogh-Jespersen S, Brackett NL, et al. Male sexual dysfunction and infertility associated with neurological disorders. Asian J Androl 2012; 14: 61–68.

20. Lu E, Zhu F, Zhao Y, et al. Birth outcomes of pregnancies fathered by men with multiple sclerosis. Mult Scler 2014; 20: 1260–1264.

19. Safarinejad MR. Evaluation of endocrine profile, hypothalamic–pituitary–testis axis and semen quality in multiple sclerosis. J Neuroendocrinol 2008; 20: 1368–1375.

21. Correale J, Farez MF and Ysrraelit MC. Increase in multiple sclerosis activity after assisted reproduction technology. Ann Neurol 2012; 72: 682–694.

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