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Premature ovarian failure. I: The association with autoimmunity
European Journal Elsevier
of Obstetrics & Gynecology and Reproductive Biology, 30 (1989) 59-66
59
EJO 00687
Premature ovarian failure. I: The association with autoimmunity M.H.
Mignot
r, J. Schoemaker t, M. Kleingeld and H.A. Drexhage *
*, B. Ramanath
Rao 3
’ Depurtments of Obstetrics and Gynecology, 2 Clinical Immunology and .’ Endocrinology, of the Academic Hospital of the ‘Vrije Universitert’, Amsterdam, The Netherlands Accepted
for publication
30 May 1988
Summary Twenty-four patients were investigated for non-organ-specific and organ-specific autoantibodies (Aab) in order to establish a relationship between premature ovarian failure (POF) and autosensitization. Regarding the non-organ-specific Aab, prevalences of clearly raised ANA (42%) nDNA Ab (25%) rheumatoid factors (41%) and smooth muscle Aab (53%) were found in the POF patients. Less outspoken higher prevalences of organ-specific Aab in these patients were also found: parietal cell Aab (23%), islet of Langerhans Aab (20%). Fifteen percent of the patients showed Aab to the adrenal gland, and a single patient had Aab towards the steroid-producing cells (Stpc) of the ovary. Although no single immune parameter could be clearly identified to correlate with POF, autoimmune (AI) phenomena were detected in the majority of the patients (92%). Since AI disease could be present for a considerable time without any clinical symptoms, a further immunological screening and follow up of POF patients may enable us to better understand and manage these patients. Premature
ovarian
failure;
Autoimmunity
Introduction Premature ovarian has been recognised hypoestrogenic state
failure (POF), resembling precocious onset of the menopause, as a well-known clinical syndrome for many years. The of these patients has been related to infertility, early bone-
Correspondence: M.H. M¬, Department of Obstetrics and Gynecology, Universiteit’, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
0028-2243/89/$03.50
0 1989 Elsevier Science Publishers
B.V. (Biomedical
Academic
Division)
Hospital
‘Vrije
60
mineral loss [l], and early arteriosclerosis [2]. On the basis of high levels of gonadotropins it was assumed that the estrogen-negative feed back does not exist in these patients [3], thus resembling a condition similar to postmenopausal women in whom ovarian follicles and primordia have vanished. However, ovarian biopsies of POF patients appeared to demonstrate the presence of primordial follicles in 15-50% of the cases 141. Furthermore, successful induction of ovulution followed by pregnancy in these patients [5-71 clearly indicates that primordial follicles must have been present in the ovary. In spite of these perturbations and although POF disease has been associated with autoimmune (AI) diseases [8-lo], the causes for the failure of ovarian steroidogenesis and ovulation is not clear. Antibodies to steroidproducing cells of the ovaries have been found in POF cases who had signs of adrenal failure, whereas antibodies blocking FSH-induced steroidogenesis have been described in cases complicated by myasthenia gravis [9-111. Since the majority of AI diseases shows a considerable overlap of autoimmune phenomena, we investigated in 24 POF patients the appearance of organ-specific and non-organ-specific Aab, using 12 established immunological tests. Patients and methods Twenty-four patients with secondary hypergonadotropic amenorrhoea (LH > 20 U/l FSH > 30 I/l) were included in these investigations. The average age was 30 years, range 18-36. The average onset of the amenorrhoea was 26 years, range 17-35. No selection of patients was made: they were consecutively admitted in the out-patients clinic during the duration of the investigations. Four of the patients were known to have a chromosomal disorder prior to inclusion into this study. Anti-nuclear antibody (ANA), anti-native double-stranded deoxyribonucleicacid (nDNA) antibody, smooth muscle ab, antimitochondrial ab, parietal cell ab, islet of Langerhans ab, and adrenal cortex Aab were determined by standard Sandwich immunofluorescence technique. The sera were tested undiluted, and those positive were titrated on doubling dilutions to end-point. For detailed methodology see Fudenberg et al. [12]. Antibodies to steroid-producing cells of the gonads were also determined by Sandwich immunofluorescence technique on cryostat sections of post-mortem human ovary tissue as described earlier [13]. Rheumatoid factors were detected by latex fixation, Waaler Rose and ELISA. In our study, patients were scored as positive if one of the three tests showed a positive result. Acetylcholine-receptor antibodies were determined by standard RIA. The Thymune T and M Kit (Wellcome Reagents Ltd) was used for microsomal and thyroglobulin haemagglutination. TSH-binding inhibitory immune globulins, 9TBII0, were determined as previously described [14,15]. Patients were scored positive for thyroid autosensitization if one of the tests showed a positive result. Results The most striking feature in the present investigation is the high prevalence (22/24 = 92%) of signs of autosensitization in our group of POF patients with the following distribution: 67% (16/24) were positive for non-organ-specific Aab and
I
34 32 30 32 18 32 36 35 34 28 27 26 24 28 30 24 22 33 30 32 34 36 29 24
A B C D E F G H I J K L M N 0 P
29 30 24 26 17 28 29 35 28 26 27 18 24 26 29 22 19 30 28 26 29 30 22 23
Age ons
_ + + + -
ANF
+ _
+ _ _ _
+ + -
_
+ + + + +
_ _ + _ + -
+
n n n n _
n _
n n n _
_
n _
n n n n _ -
n -
Mit
+
+ n n _
+ + _
n -
+ _
n _
SmM
-
Par/ cell
Organ-specific
+ +
n n n _
n
+
n _
-
n -
+
+
n n n _
-
-
n _
n _
n
n n _
+
+
n -
_
_
_
+
Lgs
StP
n -
Isl/
Gon
Adr
autoantibodies
_ _
+
_ _
_
+ _ _
_
_ +
+
_ _ _
_
Thy
+
n n n -
n -
n n _ _
n _
-
n -
n n _
Ach/ cho
in 24 POF patients. Pat, patient; age int, age of patient at the time of diagnosis; age ons, age of patient at Rhe/fac, rheumatoid factors; nDNA, anti-native double-stranded DNA antibody; Mit, anti-mitochondrial cell ab; Adr, anti-adrenal cortex ab; Gon/Stp, anti-gonadal steroid-producing cell ab; Isl/Lgs = anti-islet 92% = anti-acetylcholine receptor ab. +, ab are found; -, no Aab are found; n = test not performed. with following distribution: 67% (16/24) positively for non-organ-specific Aab and 50% (12/24) for
+
+
+ -
+ n _ -
n _
Rhe/ fat
autoantibodies
nDNA
Non-organ-specific
in POF patients
The prevalence of non-organ- and organ-specific Aab the onset of symptoms; ANA, anti-nuclear antibody; ab; SmM, anti-smooth muscle ab; Par/cell, anti-parietal of Langerhans ab; Thy = anti-thyroid ab; Ach/cho (22/24) of all patients showed autoantibody (Aab) organ-specific Aab.
R S T U V W X
Q
Age int
of autoantibodies
Pat
Prevalence
TABLE
’
II
antibody; antibody.
lo/24
ANA
5
42
5% 6/24 2
25
%
in POF patients
nDNA ab
autoantibodies
women
9/22
Rhe/fac
and healthy
nDNA, anti-native double-stranded DNA antibody; Rhe/fac Literature data of healthy women are from refs. 18 and 19.
of non-organ-specific
ANA, anti-nuclear anti-mitochondrial
Control (lit.)
POF-
Comparison
TABLE
9/17
factor:
SmM
= rheumatoid
5
41
%
l/10
Mit
SmM, anti-smooth
3
53
%
muscle
antibody;
5
10
%
Mit,
III
3/20
Adr
1
15
%
of organ-specific
ab, antibody; Adr, anti-adrenal Thy, anti-thyroid ab; Ach/cho,
POF Control (lit.)
Comparison
TABLE
1
6
x
in POF patients
5/22
Par/ccl
and healthy
5
23
%
women Isl/Lgs 4/20
I&
2
20
4/24
Thy
%
2-15
16
cortex ab; Gon/Stp, anti-gonadal steroid-producing cells ab; Par/ccl, parietal cells ab; Isl/Lgs, anti-acetylcholine receptors ab. Literature data of healthy women from Refs. 18, 19, 21 and 24.
l/16
Gon/Stp
autoantibodies
anti-islet
l/13
I a
of Langerhans
Ach/cho
ab
64
50% (12/24) were positive for organ-specific Aab (Table I). The results of the separate non-organ-specific Aab are given in Table II. A clearly raised prevalence of ANA (lo/24 = 42%) of antibodies to nDNA (6/24 = 25%) of rheumatoid factors (9/22 = 41%) and smooth muscle Aab (9/17 = 53%) was found in POF patients as compared to data available in literature on healthy population The results of the organ-specific Aab are shown in Table III. In this group also, although less pronounced, an increase in the prevalence of Aab to parietal cells (5/22 = 23%) and islet of Langerhans (4/20 = 20%) was noticeable in comparison with the healthy population. Thyroid autosensitization (4/24 = 16%) did not show such an increase. Only three out of twenty patients tested showed Aab to steroidproducing cells (Stpc) of the adrenal gland (3/20 = 15%); one of them also had Aab to Stpc of the ovary (as tested in 16 patients: l/16 = 6%). The prevalence of acetylcholine-receptor Aab in our group of POF patients was l/13 = 8%. Discussion Autoimmumty towards ovarian tissue can be evoked in animals [16]. However, in only a small percentage of POF patients Aab to ovarian tissue, and especially Stpc of the ovaries, are demonstrated [13,17]. These gonadal Aab are always associated with AI adrenalitis and Aab to Stpc of the adrenal gland [9,13]. Our study supports this view in that it showed three patients with adrenal Aab of whom one patient demonstrated Aab to Stpc of the ovary. Efforts have also been made to isolate gonadotropin receptors in POF patients. Inhibition of follicle-stimulating hormonereceptor binding by circulating immunoglobulins has been detected in some isolated cases associated with POF and myasthenia gravis [ll]. One single patient in our group also showed acetylcholine-receptor autoantibodies. Our investigation reported here clearly shows an increase of the prevalence of Aab, and especially non-organspecific Aab, in POF patients. Even when compared with the literature data available on post-menopausal women [18,19], the proportion of POF patients with Aab is also higher with regard to, for instance, rheumatoid factors [18] and ANA [18,19]. Since both POF patients and post-menopausal women are hypoestrogenic, this condition could be ruled out as an exclusive aetiological factor for the raised prevalences of Aab. However, it must be pointed out that in patients with Turner’s syndrome, AI phenomena such as diabetes mellitus, Hashimotos goiter and pernicious anaemia are considered by some to be mainly due to hypoestrogenism [20]. Considering the high prevalence of Aab in the group of POF patients, and comparing this information with the prevalences of Aab in post-menopausal women reported in literature [18,19,21] it could be speculated that in POF patients other causes for the tendency to Aab formation should be present. Another aspect of interest in this study is the direct clinical significance of the Aab as found in our group of POF patients. In spite of the 42% ANA and 25% of nDNA being positive, none of the patients showed any signs of systemic lupus erythematodes. Of the 41% of patients with rheumatoid factors only one was known to have chronical rheumatoid arthritis. Three patients had adrenal Aab; none of these patients, however, showed clinical signs of Addisons disease, and all had normal cortisol levels and a normal ACTH stimulation test so far (results not given).
65
Symptoms of AI gastritis or pernicious anaemia were not found despite the 23% positivity for Aab towards parietal cells. Similarly, in spite of the 20% Aab towards islets of Langerhans, none of the patients had an overt clinical diabetes mellitus. The prevalence of thyroid Aab in POF patients was not increased as observed in our investigation. Only one of the four patients with thyroid Aab suffered from thyroid disease (Graves’ disease) and was immediately treated. This is somewhat in contrast with the findings of Alper and Gardner [22] who reported a larger percentage of overt thyroid disease in POF patients. In conclusion, the majority of POF patients with Aab showed in our investigation no clinical signs of AI disease. It is well known that for instance in AI diabetes mellitus [23], pernicious anaemia (181 and especially .A1 adrenalitis [9], Aab can be present for years before the onset of clinical symptoms. It is thus of interest to note that our POF patients in general showed their disease for only up to 3 years and hence may develop clinical symptoms of AI disease later. Although no single causal condition could be exclusively identified, the increasing evidence of autoimmunity associated with POF patients from literature as well as the results of our investigations lend credence to the recommendation of an immunological screening and follow up of POF patients. If Aab are found during a periodical check up, attempts should be made to confirm whether signs related to the observed Aab are present. Such a consorted effort may ultimately reveal a direct relationship to autoimmunity in POF patients and may enable to identify a causal parameter. Acknowledgements We express our sincere thanks to Dr. Franc0 Botazzo for performing the autoantibody tests to ovary. Work in our departments is supported by grants from the Prevention Fund, SERONA, the Netherlands Organization of the Advancement of Pure Research (ZWO-Medigon), and the Netherlands Cancer Foundation. Thanks are due to Mrs. A. van der Wurff for typing the manuscript. References 1 Nachtigall LE, Nachtigall RH, Nachtigall RD, Bachman EM. Estrogen replacement therapy I. A 10 year prospective study in the relationship to osteoporosis. Obstet Gynecol 1979;53, 277. 2 Parrish HM, Carr CA, Hall DG, King TM. Time interval from castration in premenopausal women to development of excessive coronary atherosclerosis. Am J Obstet Gynecol 1967;99, 155. 3 Goldenberg RL, Grodin JM. Rodbard D, Ross GT. Gonadotropins in women with amenorrhoea. Am J Obstet Gynecol 1973;116, 1003. 4 Jones GS, De Moraes-Ruehsen M. A new syndrome of amenorrhcea in association with hypergonadotropinism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 1969;104, 579. 5 Menon V, Logand Edwards R, Butt WR, Bluck M, Lynch SS. Review of 59 patients with hypergonadotropic amenorrhoea. Br J Obstet Gynaecol 1984;91, 63. 6 Nakai M, Tatsumi H, Arai M. Successive pregnancies in a patient with premature ovarian failure. Eur J Obstet Gynecol Reprod Biol 1984;18, 217. 7 Johnson TR Jr, Peterson EP. Gonadotropin induced pregnancy following premature ovarian failure. Fertil Steril 1979;31, 351. 8 Irvine WJ, Chan MMW, Scarth L, Kolb FO, Hartog M, Bayliss RIS, Drury MI. Immunological aspects of premature ovarian failure associated with idiopathic Addisons disease. Lancet 1972;ii, 883.
66 9 Irvine WJ, Barnes EW. Addisons disease, ovarian failure and hypoparathyroidism. Clin Endocrinol Metabol 1975;4 (2), 379. 10 Vasquez AM, Kenny FM. Ovarian failure and anti-ovarian antibodies in association with hvnoparathyroidism, momliasis and Addisons and Hoshimotos diseases. Obstet Gynecol 1973;41, 414: 11 Chiauzzi V, Cigorraga S, Escobar ME, Rivarola MA, Charreau EH. Inhibition of follicle-stimulating hormone-receptor binding by circulating immunoglobuhns. J Clin Endocrinol Metab 1982;54, 1221-1228. HH, Sites DP, Caldwell JL, Wells JV. Basic and clinical immunology. Lange Med Pub1 12 Fudenberg 1980;343. D. Immunofluorescence studies on autoantibodies to steroid 13 Sotsiou F, Botazzo GF, Doniach producing cells, and to germline cells in endocrine disease and infertility. Clin Exp Immunol 1980;39, 97. and characterisation of thyrotropin binding 14 Brown RS, Kertiles LP, ReichIin S. Partial purification inhibitory immunoglobuhns from normal human plasma. J Clin Endocrinol Metab 1983;56, 156. 15 Van der Gaag RD, Drexhage HA, Wiersinga WM, Browns KS, Dotter K, Botazzo GP and Donniach D. Further studies on thyroid growth-stimulating immunoglobulins in subthyroid non-endemic goiter. J Clin Endocrin Metab 1985;60, 5, 972-979. of common gonad 16 Porter CW, Highfill D, Winovich R. Guineapig ovary and testis: Demonstration specific antigens in the ovary and testis. Intern J Fertil 1970;15, 171. hypoparathyroidism and associated diseases. In: Samter M, ed. 17 Irvine WJ, Barnes EW. Adrenalitis, Immunological diseases, 2nd edn. Boston: Samter, Little Brown and Co, 1972:1214. endocrinopathies. In: Lachmann PJ, Peters 18 Doniach D, Botazzo GF, Drexhage HA. The autoimmune DK, eds. Clinical Aspects of Immunology 4th Edn. Oxford: Blackwell Science Publications, 1982;903. Utrecht, Holland: Bohn, Scheltema and Holkema, 1980. 19 Feltkamp TEW. Klinische irnrnunologie. in Down syndrome and gonadal dysgenesis. Ann NY Acad 20 FiaIkow PJ, Uchida JA. Autoantibodies Sci 1968;155:758. Blackwell Scientific Publication, Oxford London Edinburgh 1980. 21 Roitt IM. Essential Immunology, to autoimmune disease. Obstet 22 Alper MM, Gamer PR. Premature Ovarian Failure; its relationship and Gynecology 1985;6, 27-30. in juvenile diabetics and 23 Botazzo GF, Mann JI, Thorogood M, Baum JD, Doniach D. Autoimmunity their families. Br Med J 1978;2, 165. HA. Myasthenia Gravis, premature 24 Williamson HD, Phansey SA, Mathur RS, Baker ER, Fudenberg menopause and thyroid autoinununity. Am J Obstet Gynecol 1980;137, 893.
of Obstetrics & Gynecology and Reproductive Biology, 30 (1989) 59-66
59
EJO 00687
Premature ovarian failure. I: The association with autoimmunity M.H.
Mignot
r, J. Schoemaker t, M. Kleingeld and H.A. Drexhage *
*, B. Ramanath
Rao 3
’ Depurtments of Obstetrics and Gynecology, 2 Clinical Immunology and .’ Endocrinology, of the Academic Hospital of the ‘Vrije Universitert’, Amsterdam, The Netherlands Accepted
for publication
30 May 1988
Summary Twenty-four patients were investigated for non-organ-specific and organ-specific autoantibodies (Aab) in order to establish a relationship between premature ovarian failure (POF) and autosensitization. Regarding the non-organ-specific Aab, prevalences of clearly raised ANA (42%) nDNA Ab (25%) rheumatoid factors (41%) and smooth muscle Aab (53%) were found in the POF patients. Less outspoken higher prevalences of organ-specific Aab in these patients were also found: parietal cell Aab (23%), islet of Langerhans Aab (20%). Fifteen percent of the patients showed Aab to the adrenal gland, and a single patient had Aab towards the steroid-producing cells (Stpc) of the ovary. Although no single immune parameter could be clearly identified to correlate with POF, autoimmune (AI) phenomena were detected in the majority of the patients (92%). Since AI disease could be present for a considerable time without any clinical symptoms, a further immunological screening and follow up of POF patients may enable us to better understand and manage these patients. Premature
ovarian
failure;
Autoimmunity
Introduction Premature ovarian has been recognised hypoestrogenic state
failure (POF), resembling precocious onset of the menopause, as a well-known clinical syndrome for many years. The of these patients has been related to infertility, early bone-
Correspondence: M.H. M¬, Department of Obstetrics and Gynecology, Universiteit’, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
0028-2243/89/$03.50
0 1989 Elsevier Science Publishers
B.V. (Biomedical
Academic
Division)
Hospital
‘Vrije
60
mineral loss [l], and early arteriosclerosis [2]. On the basis of high levels of gonadotropins it was assumed that the estrogen-negative feed back does not exist in these patients [3], thus resembling a condition similar to postmenopausal women in whom ovarian follicles and primordia have vanished. However, ovarian biopsies of POF patients appeared to demonstrate the presence of primordial follicles in 15-50% of the cases 141. Furthermore, successful induction of ovulution followed by pregnancy in these patients [5-71 clearly indicates that primordial follicles must have been present in the ovary. In spite of these perturbations and although POF disease has been associated with autoimmune (AI) diseases [8-lo], the causes for the failure of ovarian steroidogenesis and ovulation is not clear. Antibodies to steroidproducing cells of the ovaries have been found in POF cases who had signs of adrenal failure, whereas antibodies blocking FSH-induced steroidogenesis have been described in cases complicated by myasthenia gravis [9-111. Since the majority of AI diseases shows a considerable overlap of autoimmune phenomena, we investigated in 24 POF patients the appearance of organ-specific and non-organ-specific Aab, using 12 established immunological tests. Patients and methods Twenty-four patients with secondary hypergonadotropic amenorrhoea (LH > 20 U/l FSH > 30 I/l) were included in these investigations. The average age was 30 years, range 18-36. The average onset of the amenorrhoea was 26 years, range 17-35. No selection of patients was made: they were consecutively admitted in the out-patients clinic during the duration of the investigations. Four of the patients were known to have a chromosomal disorder prior to inclusion into this study. Anti-nuclear antibody (ANA), anti-native double-stranded deoxyribonucleicacid (nDNA) antibody, smooth muscle ab, antimitochondrial ab, parietal cell ab, islet of Langerhans ab, and adrenal cortex Aab were determined by standard Sandwich immunofluorescence technique. The sera were tested undiluted, and those positive were titrated on doubling dilutions to end-point. For detailed methodology see Fudenberg et al. [12]. Antibodies to steroid-producing cells of the gonads were also determined by Sandwich immunofluorescence technique on cryostat sections of post-mortem human ovary tissue as described earlier [13]. Rheumatoid factors were detected by latex fixation, Waaler Rose and ELISA. In our study, patients were scored as positive if one of the three tests showed a positive result. Acetylcholine-receptor antibodies were determined by standard RIA. The Thymune T and M Kit (Wellcome Reagents Ltd) was used for microsomal and thyroglobulin haemagglutination. TSH-binding inhibitory immune globulins, 9TBII0, were determined as previously described [14,15]. Patients were scored positive for thyroid autosensitization if one of the tests showed a positive result. Results The most striking feature in the present investigation is the high prevalence (22/24 = 92%) of signs of autosensitization in our group of POF patients with the following distribution: 67% (16/24) were positive for non-organ-specific Aab and
I
34 32 30 32 18 32 36 35 34 28 27 26 24 28 30 24 22 33 30 32 34 36 29 24
A B C D E F G H I J K L M N 0 P
29 30 24 26 17 28 29 35 28 26 27 18 24 26 29 22 19 30 28 26 29 30 22 23
Age ons
_ + + + -
ANF
+ _
+ _ _ _
+ + -
_
+ + + + +
_ _ + _ + -
+
n n n n _
n _
n n n _
_
n _
n n n n _ -
n -
Mit
+
+ n n _
+ + _
n -
+ _
n _
SmM
-
Par/ cell
Organ-specific
+ +
n n n _
n
+
n _
-
n -
+
+
n n n _
-
-
n _
n _
n
n n _
+
+
n -
_
_
_
+
Lgs
StP
n -
Isl/
Gon
Adr
autoantibodies
_ _
+
_ _
_
+ _ _
_
_ +
+
_ _ _
_
Thy
+
n n n -
n -
n n _ _
n _
-
n -
n n _
Ach/ cho
in 24 POF patients. Pat, patient; age int, age of patient at the time of diagnosis; age ons, age of patient at Rhe/fac, rheumatoid factors; nDNA, anti-native double-stranded DNA antibody; Mit, anti-mitochondrial cell ab; Adr, anti-adrenal cortex ab; Gon/Stp, anti-gonadal steroid-producing cell ab; Isl/Lgs = anti-islet 92% = anti-acetylcholine receptor ab. +, ab are found; -, no Aab are found; n = test not performed. with following distribution: 67% (16/24) positively for non-organ-specific Aab and 50% (12/24) for
+
+
+ -
+ n _ -
n _
Rhe/ fat
autoantibodies
nDNA
Non-organ-specific
in POF patients
The prevalence of non-organ- and organ-specific Aab the onset of symptoms; ANA, anti-nuclear antibody; ab; SmM, anti-smooth muscle ab; Par/cell, anti-parietal of Langerhans ab; Thy = anti-thyroid ab; Ach/cho (22/24) of all patients showed autoantibody (Aab) organ-specific Aab.
R S T U V W X
Q
Age int
of autoantibodies
Pat
Prevalence
TABLE
’
II
antibody; antibody.
lo/24
ANA
5
42
5% 6/24 2
25
%
in POF patients
nDNA ab
autoantibodies
women
9/22
Rhe/fac
and healthy
nDNA, anti-native double-stranded DNA antibody; Rhe/fac Literature data of healthy women are from refs. 18 and 19.
of non-organ-specific
ANA, anti-nuclear anti-mitochondrial
Control (lit.)
POF-
Comparison
TABLE
9/17
factor:
SmM
= rheumatoid
5
41
%
l/10
Mit
SmM, anti-smooth
3
53
%
muscle
antibody;
5
10
%
Mit,
III
3/20
Adr
1
15
%
of organ-specific
ab, antibody; Adr, anti-adrenal Thy, anti-thyroid ab; Ach/cho,
POF Control (lit.)
Comparison
TABLE
1
6
x
in POF patients
5/22
Par/ccl
and healthy
5
23
%
women Isl/Lgs 4/20
I&
2
20
4/24
Thy
%
2-15
16
cortex ab; Gon/Stp, anti-gonadal steroid-producing cells ab; Par/ccl, parietal cells ab; Isl/Lgs, anti-acetylcholine receptors ab. Literature data of healthy women from Refs. 18, 19, 21 and 24.
l/16
Gon/Stp
autoantibodies
anti-islet
l/13
I a
of Langerhans
Ach/cho
ab
64
50% (12/24) were positive for organ-specific Aab (Table I). The results of the separate non-organ-specific Aab are given in Table II. A clearly raised prevalence of ANA (lo/24 = 42%) of antibodies to nDNA (6/24 = 25%) of rheumatoid factors (9/22 = 41%) and smooth muscle Aab (9/17 = 53%) was found in POF patients as compared to data available in literature on healthy population The results of the organ-specific Aab are shown in Table III. In this group also, although less pronounced, an increase in the prevalence of Aab to parietal cells (5/22 = 23%) and islet of Langerhans (4/20 = 20%) was noticeable in comparison with the healthy population. Thyroid autosensitization (4/24 = 16%) did not show such an increase. Only three out of twenty patients tested showed Aab to steroidproducing cells (Stpc) of the adrenal gland (3/20 = 15%); one of them also had Aab to Stpc of the ovary (as tested in 16 patients: l/16 = 6%). The prevalence of acetylcholine-receptor Aab in our group of POF patients was l/13 = 8%. Discussion Autoimmumty towards ovarian tissue can be evoked in animals [16]. However, in only a small percentage of POF patients Aab to ovarian tissue, and especially Stpc of the ovaries, are demonstrated [13,17]. These gonadal Aab are always associated with AI adrenalitis and Aab to Stpc of the adrenal gland [9,13]. Our study supports this view in that it showed three patients with adrenal Aab of whom one patient demonstrated Aab to Stpc of the ovary. Efforts have also been made to isolate gonadotropin receptors in POF patients. Inhibition of follicle-stimulating hormonereceptor binding by circulating immunoglobulins has been detected in some isolated cases associated with POF and myasthenia gravis [ll]. One single patient in our group also showed acetylcholine-receptor autoantibodies. Our investigation reported here clearly shows an increase of the prevalence of Aab, and especially non-organspecific Aab, in POF patients. Even when compared with the literature data available on post-menopausal women [18,19], the proportion of POF patients with Aab is also higher with regard to, for instance, rheumatoid factors [18] and ANA [18,19]. Since both POF patients and post-menopausal women are hypoestrogenic, this condition could be ruled out as an exclusive aetiological factor for the raised prevalences of Aab. However, it must be pointed out that in patients with Turner’s syndrome, AI phenomena such as diabetes mellitus, Hashimotos goiter and pernicious anaemia are considered by some to be mainly due to hypoestrogenism [20]. Considering the high prevalence of Aab in the group of POF patients, and comparing this information with the prevalences of Aab in post-menopausal women reported in literature [18,19,21] it could be speculated that in POF patients other causes for the tendency to Aab formation should be present. Another aspect of interest in this study is the direct clinical significance of the Aab as found in our group of POF patients. In spite of the 42% ANA and 25% of nDNA being positive, none of the patients showed any signs of systemic lupus erythematodes. Of the 41% of patients with rheumatoid factors only one was known to have chronical rheumatoid arthritis. Three patients had adrenal Aab; none of these patients, however, showed clinical signs of Addisons disease, and all had normal cortisol levels and a normal ACTH stimulation test so far (results not given).
65
Symptoms of AI gastritis or pernicious anaemia were not found despite the 23% positivity for Aab towards parietal cells. Similarly, in spite of the 20% Aab towards islets of Langerhans, none of the patients had an overt clinical diabetes mellitus. The prevalence of thyroid Aab in POF patients was not increased as observed in our investigation. Only one of the four patients with thyroid Aab suffered from thyroid disease (Graves’ disease) and was immediately treated. This is somewhat in contrast with the findings of Alper and Gardner [22] who reported a larger percentage of overt thyroid disease in POF patients. In conclusion, the majority of POF patients with Aab showed in our investigation no clinical signs of AI disease. It is well known that for instance in AI diabetes mellitus [23], pernicious anaemia (181 and especially .A1 adrenalitis [9], Aab can be present for years before the onset of clinical symptoms. It is thus of interest to note that our POF patients in general showed their disease for only up to 3 years and hence may develop clinical symptoms of AI disease later. Although no single causal condition could be exclusively identified, the increasing evidence of autoimmunity associated with POF patients from literature as well as the results of our investigations lend credence to the recommendation of an immunological screening and follow up of POF patients. If Aab are found during a periodical check up, attempts should be made to confirm whether signs related to the observed Aab are present. Such a consorted effort may ultimately reveal a direct relationship to autoimmunity in POF patients and may enable to identify a causal parameter. Acknowledgements We express our sincere thanks to Dr. Franc0 Botazzo for performing the autoantibody tests to ovary. Work in our departments is supported by grants from the Prevention Fund, SERONA, the Netherlands Organization of the Advancement of Pure Research (ZWO-Medigon), and the Netherlands Cancer Foundation. Thanks are due to Mrs. A. van der Wurff for typing the manuscript. References 1 Nachtigall LE, Nachtigall RH, Nachtigall RD, Bachman EM. Estrogen replacement therapy I. A 10 year prospective study in the relationship to osteoporosis. Obstet Gynecol 1979;53, 277. 2 Parrish HM, Carr CA, Hall DG, King TM. Time interval from castration in premenopausal women to development of excessive coronary atherosclerosis. Am J Obstet Gynecol 1967;99, 155. 3 Goldenberg RL, Grodin JM. Rodbard D, Ross GT. Gonadotropins in women with amenorrhoea. Am J Obstet Gynecol 1973;116, 1003. 4 Jones GS, De Moraes-Ruehsen M. A new syndrome of amenorrhcea in association with hypergonadotropinism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 1969;104, 579. 5 Menon V, Logand Edwards R, Butt WR, Bluck M, Lynch SS. Review of 59 patients with hypergonadotropic amenorrhoea. Br J Obstet Gynaecol 1984;91, 63. 6 Nakai M, Tatsumi H, Arai M. Successive pregnancies in a patient with premature ovarian failure. Eur J Obstet Gynecol Reprod Biol 1984;18, 217. 7 Johnson TR Jr, Peterson EP. Gonadotropin induced pregnancy following premature ovarian failure. Fertil Steril 1979;31, 351. 8 Irvine WJ, Chan MMW, Scarth L, Kolb FO, Hartog M, Bayliss RIS, Drury MI. Immunological aspects of premature ovarian failure associated with idiopathic Addisons disease. Lancet 1972;ii, 883.
66 9 Irvine WJ, Barnes EW. Addisons disease, ovarian failure and hypoparathyroidism. Clin Endocrinol Metabol 1975;4 (2), 379. 10 Vasquez AM, Kenny FM. Ovarian failure and anti-ovarian antibodies in association with hvnoparathyroidism, momliasis and Addisons and Hoshimotos diseases. Obstet Gynecol 1973;41, 414: 11 Chiauzzi V, Cigorraga S, Escobar ME, Rivarola MA, Charreau EH. Inhibition of follicle-stimulating hormone-receptor binding by circulating immunoglobuhns. J Clin Endocrinol Metab 1982;54, 1221-1228. HH, Sites DP, Caldwell JL, Wells JV. Basic and clinical immunology. Lange Med Pub1 12 Fudenberg 1980;343. D. Immunofluorescence studies on autoantibodies to steroid 13 Sotsiou F, Botazzo GF, Doniach producing cells, and to germline cells in endocrine disease and infertility. Clin Exp Immunol 1980;39, 97. and characterisation of thyrotropin binding 14 Brown RS, Kertiles LP, ReichIin S. Partial purification inhibitory immunoglobuhns from normal human plasma. J Clin Endocrinol Metab 1983;56, 156. 15 Van der Gaag RD, Drexhage HA, Wiersinga WM, Browns KS, Dotter K, Botazzo GP and Donniach D. Further studies on thyroid growth-stimulating immunoglobulins in subthyroid non-endemic goiter. J Clin Endocrin Metab 1985;60, 5, 972-979. of common gonad 16 Porter CW, Highfill D, Winovich R. Guineapig ovary and testis: Demonstration specific antigens in the ovary and testis. Intern J Fertil 1970;15, 171. hypoparathyroidism and associated diseases. In: Samter M, ed. 17 Irvine WJ, Barnes EW. Adrenalitis, Immunological diseases, 2nd edn. Boston: Samter, Little Brown and Co, 1972:1214. endocrinopathies. In: Lachmann PJ, Peters 18 Doniach D, Botazzo GF, Drexhage HA. The autoimmune DK, eds. Clinical Aspects of Immunology 4th Edn. Oxford: Blackwell Science Publications, 1982;903. Utrecht, Holland: Bohn, Scheltema and Holkema, 1980. 19 Feltkamp TEW. Klinische irnrnunologie. in Down syndrome and gonadal dysgenesis. Ann NY Acad 20 FiaIkow PJ, Uchida JA. Autoantibodies Sci 1968;155:758. Blackwell Scientific Publication, Oxford London Edinburgh 1980. 21 Roitt IM. Essential Immunology, to autoimmune disease. Obstet 22 Alper MM, Gamer PR. Premature Ovarian Failure; its relationship and Gynecology 1985;6, 27-30. in juvenile diabetics and 23 Botazzo GF, Mann JI, Thorogood M, Baum JD, Doniach D. Autoimmunity their families. Br Med J 1978;2, 165. HA. Myasthenia Gravis, premature 24 Williamson HD, Phansey SA, Mathur RS, Baker ER, Fudenberg menopause and thyroid autoinununity. Am J Obstet Gynecol 1980;137, 893.