1 Clinica Pediatrica `A. Filia', Università di Sassari, 07100 Sassari, 2 Clinica Ostetrica e Ginecologica, Università di Sassari, Sassari, and 3 Ospedale `S. Giovanni di Dio', 07026 Olbia, Italy
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: anti-endomysium antibodies/antigliadin antibodies/coeliac disease/infertility/jejunal biopsy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A high prevalence of teratozoospermia (46% of subjects) and of asthenozoospermia (75% of subjects) has been detected in a sample of male subjects with coeliac disease (Farthing et al., 1982).
Sardinia is a Mediterranean island where the prevalence of biopsy-proven coeliac disease in the general population is particularly high (about 10.6 per 1000; Meloni et al., 1999), compared with the prevalence figures reported for other regions of Italy, such as the Roman area (4 per 1000; Mazzetti di Pietralata et al., 1992) and the Pesaro-Urbino area (3.28 per 1000; Catassi et al., 1994), and in the rest of Europe or the Mediterranean area; a large multicentre study (Greco et al., 1992
) showed that coeliac disease prevalence rates ranged from 1 in 250 in Sweden to 1 in 4000 in Denmark). Since there are no reports to date on the prevalence of silent coeliac disease among men and women with reproductive disorders from the same geographical area, we tried to identify silent coeliac disease in a group of couples suffering from infertility from Northern Sardinia.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The aetiology of infertility was classified according to the following protocol. The presence of ovulation was detected by serial pelvic ultrasonography and serial measurements of serum progesterone in the mid-luteal phase; progesterone values of >7 ng/ml were considered to confirm ovulation. Evaluation of the endocrine status also included determinations of pituitary gonadotrophins, prolactin, androstenedione, testosterone, and thyroid hormones. Tubal patency was investigated by hysterosalpingography, while uterine morphology was evaluated by sonohysterography and/or hysteroscopy. Diagnostic laparoscopy was performed in some patients, if deemed necessary. Postcoital testing was performed at ovulation to screen for cervical factors. All male partners underwent semen analysis; seminal volume, sperm concentration, motility, and morphology were recorded, using the standard World Health Organization (WHO) criteria for normal values (WHO, 1993) and by the same laboratory technician. Testicular sonography with Doppler examination was also performed. Oligoasthenoteratozoospermia (OAT) was diagnosed if sperm concentration or motility or morphology was abnormal, either alone or in association; morphology was evaluated in all samples using the WHO criteria. Azoospermia was diagnosed if spermatozoa were absent in at least 20 low power fields. The cause of infertility was considered unexplained when no obvious reason could be found after the above evaluation. If alterations were found in both partners, the cause of infertility was arbitrarily assigned, for ease of classification, to the condition deemed more important, according to the reproductive endocrinologist who cared for the couple.
Venous blood samples were drawn from all the subjects enrolled in the study and their male partners. Following separation by centrifugation, the sera were stored at 20°C. The antigliadin antibodies (AGA) assays, for both IgA and IgG, were carried out using a commercial enzyme-linked immunosorbent assay (ELISA) (Alfa-Gliatest; Eurospital, Trieste, Italy). Cut-off values of 7 IU for AGA IgA and of 15 IU for AGA IgG respectively, were established by the manufacturer, based on the screening of a large number of both patients with coeliac disease and healthy controls. The diagnostic sensitivity and specificity of this method of AGA measurement have been recorded as 78% [±14 confidence interval (CI)] and 98% (±4 CI) for IgA, and 94% (±8 CI) and 79% (±12 CI) for IgG respectively (Sacchetti et al., 1996). All sera that tested positive for IgA- and/or IgG-class AGA were subsequently tested for IgA-class anti-endomysium antibodies (AEA) by indirect immunofluorescence, employing sections of human umbilical cord, which were then counterstained with fluorescein-labelled goat anti-human IgA (Endomisio HUC; Eurospital). Anti-endomysial antibodies, when detected on human umbilical cord, have a diagnostic sensitivity of 93% and a specificity of 100% (Sacchetti et al., 1996
). Since selective IgA deficiency is present in 1:4070 of patients with coeliac disease, total serum IgA was measured in all the sera which were positive for IgG-class AGA only and negative for AEA, in order to exclude a selective IgA deficiency, which would have made useless an IgA-class AEA as a confirmation test. All subjects who tested positive for at least two of the three markers (IgA- and IgG-class AGA, AEA) underwent assessment of serum ferritin, folate and vitamin B12 values, and (after informed consent had been obtained) underwent jejunal biopsy. Biopsy samples were taken from the descending part of the duodenum by upper intestinal endoscopy; all samples were examined by the same pathologist and classified according to the previously defined criteria (Marsh, 1992
). Women with histologically-confirmed coeliac disease were invited to start a gluten-free diet.
As a control group for the determination of the prevalence of silent coeliac disease in the general population of Northern Sardinia, we used the data obtained from a previous screening study for coeliac disease carried out on a sample of 1607 apparently healthy schoolchildren from the same geographical area, that showed a 1.06% (17/1607) prevalence of histologically proven coeliac disease (Meloni et al., 1999). Prevalence rates of silent coeliac disease in the male and female groups with infertility versus the control population were compared using Fisher's exact test; data were not compared according to sex since the control group consisted exclusively of prepubertal children.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Of the 99 male partners, none had abnormal concentrations of IgA-class AGA. Three (3.03%) subjects had IgG-class gliadin antibodies, but only one of them, suffering from azoospermia, was also AEA positive, and showed histological features of coeliac disease at jejunal biopsy (Table I). This proportion (one out of 99 = 1.01%) was not different from that of the general population (17 out of 1607 = 1.06%).
Only one of the newly diagnosed subjects with coeliac disease (a woman with unexplained infertility) had low ferritin values, whereas none had low serum vitamin B12 or serum folate values.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The observed frequency of histologically confirmed silent coeliac disease (3.03%) in the female study group is about three-fold higher than the prevalence of silent coeliac disease in the general population of Northern Sardinia. The majority of newly diagnosed women with coeliac disease (two out of three) belonged in the subgroup of unexplained infertility; in this subgroup, coeliac disease was detected in 8% of the women, which rose to 12.0% if the patient with latent coeliac disease (so called because of the simultaneous presence of coeliac disease antibodies and normal mucosal histology) was included (Ferguson et al., 1993; Troncone et al., 1996
; Branski and Troncone, 1998
).
Our data support the hypothesis that silent coeliac disease may represent a risk factor for infertility, but the underlying mechanism(s) are still unknown. Several hypotheses have been proposed to explain the cause of infertility in patients with coeliac disease. Deficiency of essential nutrients can have an adverse effect on fertility, but none of our patients with coeliac disease had overt malabsorption, none had folic acid or vitamin B12 deficiency, only one woman had iron deficiency. Women with coeliac disease eating a normal diet have shortened reproductive period with delayed menarche and early menopause (Ferguson et al., 1982; Sher and Mayberry, 1996
). On the contrary, none of our newly diagnosed female coeliac disease patients had delayed menarche (mean age at menarche 11.8 years). More than half of the male subjects (54 out of 99) in our study sample had abnormalities of sperm morphology and motility (OAT = 47 out of 99, or azoospermia = seven out of 99; see Table I
), but coeliac disease was diagnosed only in one of the male subjects (1.01%), who had azoospermia.
Some conclusions can be drawn from the results of this study: firstly, subclinical coeliac disease seems to be more frequent among women with otherwise unexplained infertility than in the general population; and secondly, the prevalence of coeliac disease in males with poor semen quality is comparable to that observed in the general population. It is possible that infertility represents yet another manifestation of the heterogeneous spectrum of the aetiology of coeliac disease, but the reason(s) for its predilection for the female gender is unclear.
Given the very high prevalence of subclinical coeliac disease in the general population of Northern Sardinia, a consistent number of cases of coeliac disease in infertile women could be expected, but our results highlight the need for further screening studies for coeliac disease among women with infertility from different populations, in order to establish whether the prevalence of coeliac disease in these patients depends on a genetically-determined predisposition. Patients with infertility and histologically confirmed coeliac disease ought to be put on a gluten-free diet in order to restore fertility, as previously demonstrated by other authors. The results obtained during this study are to be confirmed in a larger group of patients from different geographical areas, but they clearly indicate that coeliac disease probably deserves more attention from gynaecologists.
In conclusion coeliac disease, both in the silent and latent form, must be considered and actively ruled out in patients with unexplained infertility. The positive effect of a gluten-free diet should not be neglected, even though the main mechanism responsible for the reduced fertility in women with coeliac disease is still unknown.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Catassi, C., Ratsch, I.M., Fabiani, E. et al. (1994) Coeliac disease in the year 2000: exploring the iceberg. Lancet, ii, 200203.
Ciacci, C., Cirillo, M., Auriemma, G. et al. (1996) Celiac disease and pregnancy outcome. Am. J. Gastroenterol., 91, 718722.[ISI][Medline]
Collin, P., Vilska, S., Heinonen, P.K. et al. (1996) Infertility and celiac disease. Gut, 39, 382384.[Abstract]
Farthing, M.J., Edwards, C.R., Rees, L.H. et al. (1982) Male gonadal function in celiac disease: 1. Sexual disfunction, infertility, and semen quality. Gut, 23, 604614.
Ferguson, R., Holmes, G.K.T. and Cooke, W.T. (1982) Celiac disease, fertility, and pregnancy. Scand. J. Gastroenter., 17, 6568.[ISI][Medline]
Ferguson, A., Arranz, E. and O'Mahony, S. (1993) Clinical and pathological spectrum of celiac diseaseactive, silent, latent, potential. Gut, 34, 150151.[ISI][Medline]
Greco, L., Maki, M., Di Donato, F. et al. (1992) Epidemiology of Coeliac Disease in Europe and the Mediterranean Area. A Summary Report on the Multicentre Study by the European Society of Pediatric Gastroenterology and Nutrition. In Auricchio, S. and Visakorpi, J.K. (eds), Common Food Intolerances. 1. Epidemiology of Coeliac Disease. Dynamic Nutrition Research, Karger, Basel, Switzerland, pp. 2544.
Marsh, M.N. (1992) Gluten sensitivity and latency: the histological background. In Auricchio, S. and Visakorpi, J.K. (eds), Common Food Intolerances 1: Epidemiology of Celiac Disease. Karger, Basel, Switzerland, pp. 142150.
Mazzetti di Pietralata, M., Giorgetti, G.M., Gregori, M. et al. (1992) Subclinical coeliac disease. Ital. J. Gastroenterol., 24, 352354.[ISI][Medline]
McCann, J.P., Nicholls, D.P. and Verzin, J.A. (1988) Adult celiac disease presenting with infertility. Ulster Med. J., 57, 8889.[ISI][Medline]
Meloni, G.F., Dore, A., Fanciulli, G. et al. (1999) Subclinical celiac disease in schoolchildren from northern Sardinia. Lancet, 353, 37.[ISI][Medline]
Molteni, N., Bardella, M.T., Bianchi, P.A. (1990) Obstetric and gynecological problems in women with untreated celiac disease. J. Clin. Gastroenterol., 12, 3739.[ISI][Medline]
Sacchetti, L., Ferrajolo, A., Salerno, G. et al. (1996) Diagnostic value of various serum antibodies detected by diverse methods in childhood celiac disease. Clin. Chem., 42, 18381842.
Sher, K.S. and Mayberry, J.F. (1996) Female fertility, obstetric and gynaecological history in celiac disease: a case control study. Acta Paediatr., 412 (Suppl.), 7677.
Troncone, R., Greco, L., Mayer, M. et al. (1996) Latent and potential celiac disease. Acta Paediatr., 412 (Suppl.), 1014.
WHO (1993) World Health Organization Laboratory Manual for the Examination of Human Seminal Fluid and the Interaction of Sperm with Cervical Mucus (Italian version). Ann. Ist. Super. Sanita, 29 (Suppl. 2), 198.
Submitted on March 30, 1999; accepted on July 27, 1999.