Reproductive changes such as impaired fertility and adverse pregnancy outcomes have been related to female asthma. We recently found that time to pregnancy is prolonged in asthmatic females especially in women with moderate to severe asthma and in those above 30 years of age. Despite their reproductive difficulties the asthmatics ultimately conceived just as many biological children as healthy throughout their reproductive lives. This knowledge therefore raises questions about how asthma affects fertility pathophysiologically. The purpose of this review is to describe the existing knowledge in this field and suggest hypotheses of causal relationships, which may form the basis for future studies in this field. The aim is, in particular, in the literature to examine whether there is any evidence to suggest that the systemic inflammation that characterizes asthma, can affect fertility. The issue is potentially clinically important for asthmatic, infertile individuals and society because treatment of the general systemic inflammation associated with the asthmatic disease combined with hormone stimulation might be the optimal target for an effective infertility therapy, possibly decreasing the need for in vitro fertilization. 1. Introduction We have recently, in a retrospective registry-based study, demonstrated that asthma significantly prolongs time to pregnancy (TTP) and thus fertility (21,6% versus 27% OR: 1.31 ), whereas allergy was not related to TTP [1]. Furthermore we showed that untreated asthmatics had a significantly increased risk of prolonged TTP compared with healthy individuals (30.5 versus 21.6%, OR =？1.79, ), while asthmatics receiving any kind of treatment for asthma tended to have a shorter TTP than untreated asthmatics (23.8 versus 30.5%, OR =？1.40, ) indicating that an untreated systemic inflammation could have a negative effect on fertility. These findings are to our knowledge new and of highly clinical relevance given that a large proportion of asthmatic patients are young and therefore in the reproductive age. The reasons for our findings are, however, unknown. The purpose of this review is therefore to provide an overview of the basic literature of the pathophysiology behind this finding and to suggest hypotheses on causal relationships. So far only few other studies have examined this issue, and even so, the results have been conflicting as to whether asthma or other atopic diseases can affect fertility. Other recent studies by Carson et al. [2] and Harju et al. [3] suggest an association between subfertility, fertility treatment,
References
[1]
E. J. Gade, S. F. Thomsen, S. Lindenberg, K. O. Kyvik, S. Lieberoth, and V. Backer, “Asthma affects time to pregnancy and fertility: a register-based twin study,” European Respiratory Journal, 2013.
[2]
C. Carson, A. Sacker, Y. Kelly, et al., “Asthma in children born after infertility treatment: findings from the UK Millennium Cohort study,” Human Reproduction, vol. 28, no. 2, pp. 471–479, 2013.
[3]
M. Harju, L. Keski-Nisula, K. Raatikainen, et al., “Maternal fecundity and asthma among offspring-is the risk programmed preconceptionally? A retrospective observational study,” Fertility and Sterility, vol. 99, no. 3, pp. 761–767, 2013.
[4]
I. J？derberg, S. F. Thomsen, K. O. Kyvik, A. Skytthe, and V. Backer, “Atopic diseases in twins born after assisted reproduction,” Paediatric and Perinatal Epidemiology, vol. 26, no. 2, pp. 140–145, 2012.
[5]
B. K？llén and P. Otterblad Olausson, “Use of anti-asthmatic drugs during pregnancy. 1. Maternal characteristics, pregnancy and delivery complications,” European Journal of Clinical Pharmacology, vol. 63, no. 4, pp. 363–373, 2007.
[6]
L. J. Tata, R. B. Hubbard, T. M. McKeever et al., “Fertility rates in women with asthma, eczema, and hay fever: a general population-based cohort study,” American Journal of Epidemiology, vol. 165, no. 9, pp. 1023–1030, 2007.
[7]
C. Svanes, F. G. Real, T. Gislason et al., “Association of asthma and hay fever with irregular menstruation,” Thorax, vol. 60, no. 6, pp. 445–450, 2005.
[8]
L. Blais, F. Z. Kettani, and A. Forget, “Relationship between maternal asthma, its severity and control and abortion,” Human Reproduction, vol. 28, no. 4, pp. 908–915, 2013.
[9]
E. Sheiner, M. Mazor, A. Levy, A. Wiznitzer, and A. Bashiri, “Pregnancy outcome of asthmatic patients: a population-based study,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 18, no. 4, pp. 237–240, 2005.
[10]
R. H. Green, C. E. Brightling, G. Woltmann, D. Parker, A. J. Wardlaw, and I. D. Pavord, “Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids,” Thorax, vol. 57, no. 10, pp. 875–879, 2002.
[11]
J. Rufo, L. Taborda-Barata, and O. Louren？o, “Serum biomarkers in elderly asthma,” Journal of Asthma, vol. 50, no. 10, pp. 1011–1019, 2013.
[12]
Y. M. Kim, Y. S. Kim, S. G. Jeon, and Y. K. Kim, “Immunopathogenesis of allergic asthma: more than the th2 hypothesis,” Allergy, Asthma & Immunology Research, vol. 5, no. 4, pp. 189–196, 2013.
[13]
P. G. Gibson, J. L. Simpson, and N. Saltos, “Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8,” Chest, vol. 119, no. 5, pp. 1329–1336, 2001.
[14]
J. L. Simpson, S. Phipps, K. J. Baines, K. M. Oreo, L. Gunawardhana, and P. G. Gibson, “Elevated expression of the NLRP3 inflammasome in neutrophilic asthma,” European Respiratory Journal, 2013.
[15]
P. G. Holt and P. D. Sly, “Interaction between adaptive and innate immune pathways in the pathogenesis of atopic asthma: operation of a lung/bone marrow axis,” Chest, vol. 139, no. 5, pp. 1165–1171, 2011.
[16]
C. H. Feng, M. D. Miller, and R. A. Simon, “The united allergic airway: connections between allergic rhinitis, asthma, and chronic sinusitis,” American Journal of Rhinology & Allergy, vol. 26, no. 3, pp. 187–190, 2012.
[17]
J. A. Denburg, R. Sehmi, H. Saito, J. Pil-Seob, M. D. Inman, and P. M. O'Byrne, “Systemic aspects of allergic disease: bone marrow responses,” Journal of Allergy and Clinical Immunology, vol. 106, no. 5, pp. S242–S246, 2000.
[18]
M. I. C. G. Elsas, D. Joseph, P. X. Elsas, and B. B. Vargaftig, “Rapid increase in bone-marrow eosinophil production and responses to eosinopoietic interleukins triggered by intranasal allergen challenge,” American Journal of Respiratory Cell and Molecular Biology, vol. 17, no. 4, pp. 404–413, 1997.
[19]
L. G. Wood, K. J. Baines, J. Fu, H. A. Scott, and P. G. Gibson, “The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma,” Chest, vol. 142, no. 1, pp. 86–93, 2012.
[20]
L. Bjermer, “Time for a paradigm shift in asthma treatment: from relieving bronchospasm to controlling systemic inflammation,” Journal of Allergy and Clinical Immunology, vol. 120, no. 6, pp. 1269–1275, 2007.
[21]
I. Matalliotakis, H. Cakmak, M. Matalliotakis, D. Kappou, and A. Arici, “High rate of allergies among women with endometriosis,” Journal of Obstetrics and Gynaecology, vol. 32, no. 3, pp. 291–293, 2012.
[22]
N. Sinaii, S. D. Cleary, M. L. Ballweg, L. K. Nieman, and P. Stratton, “High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis,” Human Reproduction, vol. 17, no. 10, pp. 2715–2724, 2002.
[23]
B. A. Mshemish, S. M. Sadik, and A. W. Ashor, “Studying the effect of montelukast in the treatment of dysmenorrhea: a single-blind, placebo-controlled trial,” Mustansiriya Medical Journal, vol. 11, no. 1, pp. 37–41, 2012.
[24]
O. O. Adeyeye, A. O. Ogbera, O. O. Ogunleye, et al., “Understanding asthma and the metabolic syndrome—a Nigerian report,” International Archives of Medicine, vol. 5, article 20, 2012.
[25]
A. van Huisstede, M. C. Cabezas, E. Birnie, et al., “Systemic inflammation and lung function impairment in morbidly obese subjects with the metabolic syndrome,” Journal of Obesity, vol. 2013, Article ID 131349, 8 pages, 2013.
[26]
F. G. Real, C. Svanes, E. R. Omenaas et al., “Menstrual irregularity and asthma and lung function,” Journal of Allergy and Clinical Immunology, vol. 120, no. 3, pp. 557–564, 2007.
[27]
R. S. Usadi and R. S. Legro, “Reproductive impact of polycystic ovary syndrome,” Current Opinion in Endocrinology, Diabetes & Obesity, vol. 19, no. 6, pp. 505–511, 2012.
[28]
K. Mandrelle, M. S. Kamath, D. J. Bondu, et al., “Prevalence of metabolic syndrome in women with polycystic ovary syndrome attending an infertility clinic in a tertiary care hospital in south India,” Journal of Human Reproductive Sciences, vol. 5, no. 1, pp. 26–31, 2012.
[29]
H. M. Harb, I. D. Gallos, J. Chu, M. Harb, and A. Coomarasamy, “The effect of endometriosis on in vitro fertilisation outcome: a systematic review and meta-analysis,” BJOG, vol. 120, no. 11, pp. 1308–1320, 2013.
[30]
R. Raghupathy, “Th1-type immunity is incompatible with successful pregnancy,” Immunology Today, vol. 18, no. 10, pp. 478–482, 1997.
[31]
A. C. Zenclussen, S. Fest, P. Busse, R. Joachim, B. F. Klapp, and P. C. Arck, “Questioning the Th1/Th2 paradigm in reproduction: peripheral levels of IL-12 are down-regulated in miscarriage patients,” American Journal of Reproductive Immunology, vol. 48, no. 4, pp. 245–251, 2002.
[32]
G. Junovich, A. Azpiroz, E. Incera, C. Ferrer, A. Pasqualini, and G. Gutierrez, “Endometrial CD16+ and CD16？ NK cell count in fertility and unexplained infertility,” American Journal of Reproductive Immunology, vol. 70, no. 3, pp. 182–189, 2013.
[33]
G. Galazios, S. Tsoulou, C. Zografou et al., “The role of cytokines IL-6 and IL-8 in the pathogenesis of spontaneous abortions,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 24, no. 10, pp. 1283–1285, 2011.
[34]
W. Wang, C. Hao, Y. Yi-Lin et al., “Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients,” Journal of Reproductive Immunology, vol. 84, no. 2, pp. 164–170, 2010.
[35]
T. Altun, S. Jindal, K. Greenseid, J. Shu, and L. Pal, “Low follicular fluid IL-6 levels in IVF patients are associated with increased likelihood of clinical pregnancy,” Journal of Assisted Reproduction and Genetics, vol. 28, no. 3, pp. 245–251, 2011.
[36]
G. Gutierrez, G. Junovich, A. Azpiroz, E. Incera, A. Pasqualini, and S. Pasqualini, “IL6 as a new parameter of endometrial quality. Normal range and dual behaviour associated with endometrial NK cells,” Journal of Reproductive Immunology, vol. 90, no. 2, pp. 169–170, 2011.
[37]
S. L. Eddie, A. J. Childs, H. N. Jabbour, and R. A. Anderson, “Developmentally regulated il6-type cytokines signal to germ cells in the human fetal ovary,” Molecular Human Reproduction, vol. 18, no. 2, Article ID gar061, pp. 88–95, 2012.
[38]
J. Ring, K. Blaser, M. Chapron, et al., “T cell regulation in allergy, asthma and atopic skin diseases,” Chemical Immunology and Allergy, vol. 94, pp. 1–14, 2008.
[39]
M. Y. Donath and S. E. Shoelson, “Type 2 diabetes as an inflammatory disease,” Nature Reviews Immunology, vol. 11, no. 2, pp. 98–107, 2011.
[40]
H. Ellingsgaard, I. Hauselmann, B. Schuler et al., “Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells,” Nature Medicine, vol. 17, no. 11, pp. 1481–1489, 2011.
[41]
C. Gabay, “Interleukin-6 and chronic inflammation,” Arthritis Research & Therapy, vol. 8, supplement 2, article S3, 2006.
[42]
P. Russell, L. Anderson, D. Lieberman et al., “The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. I: techniques,” Journal of Reproductive Immunology, vol. 91, no. 1-2, pp. 90–102, 2011.
[43]
S. Finotto, T. Eigenbrod, R. Karwot et al., “Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells,” International Immunology, vol. 19, no. 6, pp. 685–693, 2007.
[44]
I. Granot, Y. Gnainsky, and N. Dekel, “Endometrial inflammation and effect on implantation improvement and pregnancy outcome,” Reproduction, vol. 144, no. 6, pp. 661–668, 2012.
[45]
O. B. Christiansen, H. S. Nielsen, and A. M. Kolte, “Inflammation and miscarriage,” Seminars in Fetal and Neonatal Medicine, vol. 11, no. 5, pp. 302–308, 2006.
[46]
R. Romero, J. Espinoza, and M. Mazor, “Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization?” Fertility and Sterility, vol. 82, no. 4, pp. 799–804, 2004.
[47]
K. Karimi and P. Forsythe, “Natural killer cells in asthma,” Frontiers in Immunology, vol. 4, article 159, 2013.
[48]
G. Sacks, Y. Yang, E. Gowen, S. Smith, L. Fay, and M. Chapman, “Detailed analysis of peripheral blood natural killer cells in women with repeated IVF failure,” American Journal of Reproductive Immunology, vol. 67, no. 5, pp. 434–442, 2012.
[49]
N. Dekel, Y. Gnainsky, I. Granot, and G. Mor, “Inflammation and implantation,” American Journal of Reproductive Immunology, vol. 63, no. 1, pp. 17–21, 2010.
[50]
C. M. Boomsma, S. D. Keay, and N. S. Macklon, “Peri-implantation glucocorticoid administration for assisted reproductive technology cycles,” Cochrane Database of Systematic Reviews, no. 6, Article ID CD005996, 2007.
[51]
H. Guan and S. Z. Ali, “Uterine cervical sarcoidosis identified on pap test: cytomorphologic findings and differential diagnosis,” Acta Cytologica, vol. 55, no. 4, pp. 368–371, 2011.
[52]
S. A. Kurganov, “Uterine eosinophils and infertility in the rat,” Rossi？skii Fiziologicheski？ Zhurnal Imeni I.M. Sechenova, vol. 96, no. 2, pp. 138–146, 2010.
