Premature menopause I. Etiology CAROLYN B. COULAM, M.D. ROBERT
J.
RYAN, M.D.
Rochester, Minnesota The premature menopause syndrome has been regarded as one of the organ-specific autoimmune disorders because circulating antibodies to ovarian tissue have been demonstrated. Fifteen women with spontaneous cessation of menses after initial menarche before they were 35 years old were seen between 1975 and 1977. Increased serum levels of gonadotropin and failure of estrogen secretion were documented. Serum from each woman was examined for antibodies to normal ovary. Proteins from ovaries of normal premenopausal women were extracted and iodinated with 125 1. The labeled proteins were incubated with sera for 48 hours, after which goat antihuman y-globulin was added and allowed to incubate for 72 hours. The precipitate was washed and evaluated for radioactive label. The binding of antibodies increased in the sera of patients with the premature menopause syndrome, compared with the control sera. This suggests that the etiology of premature menopause may be mediated by circulating antibodies to ovarian tissue. (AM. J. OesTET. GYNECOL. 133:639, 1979.)
PREMATURE MENOPAUSE or premature ovarian failure has been recognized for a long time, but as yet there is little or no understanding of the etiology and there is no treatment. Understanding menopause is complicated because menopause and aging overlap, and basic knowledge of the aging process is lacking. The physiology of menopause involves ovarian follicular failure from atresia, which results in decreasing production of estrogen and consequent increase in the pituitary secretion of gonadotropins. Premature menopause, the cessation of ovarian function before the age of 40 years, is also characterized by diminished ovarian production of steroids and high serum levels of pituitary gonadotropins. Kinch and associates 11 have identified two types of histopathologic patterns in primary ovarian failure: afollicular and follicular. The follicular type of ovarian failure with numerous primary follicles has been reported9 as the gonadotropin-resistant syndrome and has been postulated as resulting from deficient f()lliFrom the Department of Obstetrics and Gynecology and thR Department of Molecular Medicine, Mayo Clinic and Mayo Foundnticm. Presented at the Twenty-fifth Annual Meeting of the Society for Gynecologic Investigatwn, Atlanta, Grorgia, March 15-18, 1978. Reprint requests: Dr. Carolyn B. Coulam, Mayo Clinic, 200 First St. SW, Rochester, Minnesota 55901. 0002-93781791060639+05$00.50/0 © 1979 The C. V. Mosby Co.
de-stimulating hormone receptor within the follicle. The premature attrition of follicles can be due to either a too rapid depletion of follicles or a normal depletion rate involving an inadequate number of follicles. The exact cause of the premature loss of follicles is unknown, although the contribution of extrinsic factors cannot be excluded. The association of autoimmune phenomena with premature menopause in isolated instances6· 16 has been noted and suggests an immune mechanism in the pathophysiology. ln ~~e present study, the frequency of circulating antibOdy to ovarian tissue was ascertained in patients with the premature menopause syndrome.
Materials and methods Patients. Fifteen women with the premature menopause syndrome were seen at our clinic between January 1, I975,andjanuary 1, 1977.Ail15hadspontaneous cessation of menses before 35 years of age. In each, increased serum levels of gonadotropin and failure of estrogen secretion were documented (Table I). None of the patients had an identifiable chromosomal abnormality or evidence of autoimmune disease. Twelve postmenopausal and 10 age-matched premenopausal women served as controls. Blood was drawn, and serum from each patient was stored at -20° C until assayed. Serum hormone measurements. Gonadotropin lev-
639
640 Coulam and Ryan
Am.
J
Marth 15, 1979 OhsteL GynecoL
Table I. Patients with premature menopause syndrome iJ..,..,
nf
2 3 4 5 6 7 8 9 10 II
12 13 14 15
r~n tlnti,,t-t·n.h;u •'
.4rrn nl /nd
"'5' ,..
iJf5C. l ..H
Case No.
"""««V"Vf""'
·~-"
*
admission
menstruation
(yr.)
(yr.)
FSH(J,Lgldl)
LH (J,Lgldl)
Estrogen (ngldl)
28 37 30 33 31 25 30 19 32 23 34 19 29 34 36
22 35 21 :ll 29 16 28 17 21 20 27 13 28 30 34
114.7 209.1 190.6 168.5 147,6 240 168
16.7 48 43.1 38.2 49.7 25 18 42.1 68 ..'1