Idiopathic premature ovarian failure: clinical and endocrine characteristics*

Transcription

1 FRTILITY AND STRILITY Copyright o 1982 The American Fertility Society Vol. 37, No. 1, January 1982 Printed in U.SA. Idiopathic premature ovarian failure: clinical and endocrine characteristics* Robert W. Rebar, M.D. t Gregory F. rickson, Ph.D. Samuel S. C. Yen, M.D., D.Sci.(Med):j: Department of Reproductive Medicine, School of Medicine (T-2), and the General Clinif:al Research Center, University of California, San Diego, La Jolla, California 9293 The characteristics of 26 patients with presumptive premature ovarian failure have been examined. The initial diagnosis was based on any single serum folliclestimulating hormone (FSH) concentration of greater than 4 mlu/ml in karyotypically normal women under 35 years of age with irregular menses or amenorrhea. Clinical manifestations were heterogeneous: some failed to undergo pubertal maturation, and others developed hypergonadotropic amenorrhea following several years of regular menses. Almost 7% experienced hot flashes. Three had thyroiditis. Nine of 18 patients had hormonal evidence of functioning ovarian follicles, and 4 of 9 women had viable oocytes on biopsy. vidence of ovulation was noted in five patients, and spontaneous pregnancy occurred in one. These data emphasize the fallacy of using elevated FSH levels to diagnose irreversible ovarian failure and indicate the possibility of ovulation and pregnancy in some affected individuals. Fertil Steril 37:35, 1982 The term premature ovarian failure (POF) has generally been used to describe a syndrome consisting of amenorrhea, hypergonadotropinism, and hypoestrinism in young women under the age of 4 years. 1 That the ovarian "failure" may not always be permanent has now been suggested in a number of isolated case reports documenting the initiation or resumption of cyclic menses and/ or pregnancy. 2-4 Although various etiologic factors for this heterogeneous syndrome have been Received June 1, 1981; revised and accepted September 14, *Supported by NIH Center grant HD-1233 and NIH grant HD The University of California, San Diego, General Clinical Research Center is supported by NIH grant RR-827. tclinical Associate Physician of the University of California, San Diego, Clinical Research Center. Reprint requests: Robert W. Rebar, M.D., Department of Reproductive Medicine, T-2, University of California, San Diego, School of Medicine, La Jolla, California tsenior Clayton Foundation Investigator. 35 proposed, characterization of the chronologie events has not been explored in detail. In this report we describe a spectrum of clinical, morphologic, and hormonal features in 26 patients with premature ovarian failure and normal female karyotype that we have studied over the past 3 years. MATRIALS AND MTHODS Twenty-six women under the age of 35, presenting with chief complaints of amenorrhea, infertility, and/or episodic hot flashes, in whom a serum follicle-stimulating hormone (FSH) concentration of greater than 4 miu/ml (second International Reference Preparation [irp]-human menopausal gonadotropin) was detected on at least one occasion during initial screening are included in this study. The use of this concentration of FSH is based on the findings of Goldenberg et al. 5 demonstrating absence of oocytes in individuals with basal FSH levels greater than 4 miu/ml. All had 46,XX karyotype. Adrenal func-

2 36 RBARTAL January, 1982 : i l I tion testing with adrenocorticotropic hormone (ACTH) 1-24 revealed adequate adrenal reserve in all women. Thyroid function tests, (thyroidstimulating hormone [TSH], thyroxine [T 4 ], and microsomal thyroid antibodies) total plasma calcium, and phosphorus concentration tests were performed for all subjects and were normal, except for three women with evidence of thyroiditis on the basis of elevated thyroid antibody titers. Daily samples for measurement of circulating gonadotropin and gonadal steroid levels were obtained for at least 25 days from 18 of the women. In eight of the subjects synthetic gonadotropin-releasing hormone (GnRH) was administered intravenously as a bolus (1 j.lg) on two occasions at 2-hour intervals. Blood samples were obtained through an indwelling intravenous catheter in an antecubital vein at 15-minute intervals beginning at least 1 hour prior to the first injection and ending 2 hours following the second injection. Their gonadotropin responses to GnRH were compared with those of nine identically tested postmenopausal women. To minimize interassay variation, all samples from a subject in a given study were measured in the same assay. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione (A), testosterone (T), estrone ( 1 ), estradiol ( 2 ), and progesterone (P) were measured by radioimmunoassays previously detailed. 6 7 Ovarian tissues from selected patients were removed at biopsy, fixed in Bouin's solution, dehydrated, and embedded in paraffin. Sections (1 j.lm) were stained with hematoxylin and eosin. For electron microscopy, ovarian tissue was fixed in 2.5% glutaraldehyde in.1 M cacodylate buffer (ph 7.4), postfixed in 2% osmium tetroxide, and embedded in pon. Thin sections (8 A) were stained with uranyl acetate and lead citrate. RSULTS As indicated in Figure 1, the clinical evidence of ovarian activity in the subjects varied widely. Three distinct clinical groups were identifiable: group I consisted of 1 women who failed to undergo complete sexual maturation as documented by Tanner staging'! at puberty. Four of them had primary amenorrhea, and two had only a single spontaneous menstrual period. Group ll consisted of 11 women achieving complete maturation and with regular menses for several years before the onset of amenorrhea or sporadic menses. Group m was composed of five individuals with evidence CLINICAL LIF SPAN OF OVARIAN ACTIVITY IN PDF ot AIIIffHIIThu M OnuttJIAIIIffHIIThu A With IIDt F/ushls p,.,.,_, AG (Y1111) Figure 1 The clinical life span of ovarian function in 26 patients with POF is compared with the span of ovarian function in normal women. Four individuals presented with primary amenorrhea. Pregnancy occurred in five individuals. One patient (number 22) resumed menses after 8 years of amenorrhea. Menses occurred irregularly in several of the women. of ovulation during or following the investigation period. Pregnancy resulted in one of these women following investigation (number 23). All patients exhibited evidence of ovarian activity for less than half of the average reproductive life span. In many, menses were always irregular. In the women with incomplete sexual development, menarche was often delayed. Menarche was also delayed in some women in group II. ighteen of the 26 women studied presented with typical hot flashes, with the same changes in pulse rate and finger temperature occurring concomitant with LH pulses reported previously. 9 Of note is the fact that one individual (number 22) resumed ovulatory cycles following 8 years of hypergonadotropic amenorrhea with hot flashes. Seven of the patients (3 in group I and 4 in group ll) had altered arm span-to-height measurements (with arm span 2 or more inches greater than height) compatible with hypogonadism. Three of the women, 1 in each of the three groups (numbers 1, 18, and 24), had clinical evidence (i.e., a tender and/or enlarged thyroid gland) and laboratory evidence of thyroiditis. Histologic analysis of representative ovarian tissue from the nine women undergoing ovarian biopsy showed little or no evidence of follicular activity even in those individuals with viable oocytes. In general, the ovaries were covered by continuous sheets of cuboidal epithelium, be-

3 Vol. 37, No. 1 PRMATUR OVARIAN FAILUR 37 Figure 2 Representative ovarian tissue from women with premature ovarian failure. (A), Light micrograph of cortex showing surface epithelium and dense connective tissue devoid of follicular elements ( x 16). (B), lectron micrograph of cortex showing a blood vessel enmeshed in dense connective tissue composed of fibroblasts (Ji'B) and collagen (*). No steroidsecreting cells were seen ( x 4). (C), Light micrograph of ovarian cortex of patient 7, containing a nest of primordial follicles ( x 44). (D), Such primordial follicles were composed of a dictyate oocyte, a single layer of granulosa cells, and a basement membrane ( x 8). (), Light micrograph of an apparent corpus albicans ( x 16). neath which were thick l~yers of dense connective tissue (Fig. 2A). Ultrastructural examination of the ovarian cortex revealed multiple blood vessels embedded in bundles of collagen fibers and active fibroblasts (Fig. 2B). Differentiated steroid-secreting cells were not seen in the areas of ovarian tissue examined. mbedded in the cortex of four ovaries were a few typical primordial follicles (Fig. 2C and D). In all ovarian fragments, strands of fibrous connective tissue similar to atretic follicles or corpora albicantia were seen (Fig. 2). No developing follicles or corpora lutea were observed in any of the ovarian tissues examined. In the 18 women in whom daily blood samples were collected for measurement of circulating go- nadotropin and steroid levels, the patterns observed varied widely, with representative and unusual patterns depicted in Figures 3, 4, and 5. ight of the women (Fig. 3A) had patterns similar to what has been observed in postmenopausal women,l with FSH levels greater than LH in the vast majority of samples and very low but fluctuating concentrations of estrogens and androgens (data not shown). Among this group were two of the women with thyroiditis (numbers 1 and 18). One individual had rising gonadotropin levels and a changing LH-to-FSH ratio without marked changes in steroid levels during the observation period (Fig. 3B). Spontaneous menses for the first time in 1 year occurred at the onset of sampling

4 38 RBARTAL. January, 1982 ::I ' 1 AJ!B " J'../ ~ LH - FSH--- ~~ 2-1 ' go c., --- -~v-..,..,_ C)#12 LH -,-, i1~ ~ 1 go c. ~~ 8) #13 ~ ~--'-v'-..., )#11 ~-,,... _ '... _...,..., ~~5L-~1-1~5~2o-2~5~3o~ ~~5~~1~1~5-2~~2~5-3~o~ DAYS Figure 3 Representative patterns of concentrations of circulating LH, FSH, estrone ( 1), and estradiol ( 2) in daily samples collected from women with POF. Progesterone levels (not shown) were always less than 1. ng/ml. The number of each patient is the same as that in Figure 1. M, menses. The shaded area indicates concentrations of less than 4 miu!ml, the level of FSH above which ovarian failure has been considered to exist. when gonadotropin concentrations were lowest. In six women the patterns of circulating gonadotropins and steroids were similar to those depicted in Figure 3C and D. In these individuals LH levels were frequently greater than FSH levels, and decreasing gonadotropin concentrations were noted in conjunction with rising levels of both 2 and 1. In three, the peak 2 levels were similar to those observed just prior to the normal preovulatory LH surge. Occasionally, such individuals had FSH concentrations that were less than 4 miu/ml. xamples of ovulatory cycles are shown in Figure 4. In one subject (Fig. 4A), the follicular phase was very short, with an LH surge occurring just after the cessation of menstrual bleeding. LH and FSH concentrations were elevated during the entire sampling period, although on occasion FSH levels were less than 4 miu /mi. In another ovulatory cycle (Fig. 4B), falling gonadotropin levels preceding the follicular phase increased in 2 This individual had 4 cyclic menses followed again by hypergonadotropic amenorrhea. In Figure 5 is depicted the pattern observed in a 22-year-old woman with a history of irregular menses and menorrhagia from menarche. Although gonadotropin levels were initially within the normal range, FSH concentrations increased to greater than 4 miu/ml during the sampling period. As FSH levels increased, 2 levels decreased to a nadir of 42 pg/ml from a peak level of 919 pg/ml. P levels remained very low during this time but have been elevated, indicative of ovulation, on later occasions. In the eight women with POF who received GnRH, mean basal gonadotropin concentrations were significantly elevated (P <.5) in comparison with the mean of nine postmenopausal women. Mean peak LH and FSH release following both the first and second pulses of GnRH was also significantly greater (P <.5) than the values observed in the postmenopausal women (Fig. 6). However, when the values were expressed as the percentage change from mean basal levels, no significant differences in the responses to GnRH could be discerned. DISCUSSION Although the syndrome of "premature ovarian failure" or "premature menopause" has been recognized for many years, 1 few attempts have been made to examine the endocrine status of such patients in detail. In recent years, isolated case ;:; 1 1 ' 5 "" c. ' go c:: ==-----=-=-..., r =- A}#241S3 ~ 8) #25 LH- 2- t --- ~-=,)~ I 2 Prog DAYS Figure 4 Patterns of daily concentrations of circulating LH, FSH, l> 2, and P in women with POF and evidence of ovulation during sample collection. M, menses. The shaded area indicates concentrations of less than 4 miu/ml. 3

5 Vol. 37, No. 1 PRMATUR OVARIAN FAILUR en c. en... en c: 3r ~ ~ #26 LH FSH l- f,--- Prog reports have documented that the "failure" may not necessarily be irreversible in all cases. 2-4 However, definitive criteria for inclusion in this disorder have not been delineated, and the disorder has been considered extremely rare. In view of the findings of Goldenberg et al., 5 who demonstrated that individuals with FSH levels of greater than 4 miu/ml without exception had no viable follicles on ovarian biopsy, the inclusion of individuals with amenorrhea or irregular menses and elevated FSH levels in this study seemed reasonable. However, our data demonstrate clearly that elevated FSH levels cannot be considered as prima facie evidence of irreversible ovarian failure. Nine of 18 women in whom daily blood samples were measured for circulating gonadotropin and steroid concentrations showed evidence of follicular activity as determined by increased serum estradiol levels. It is now well documented that almost all circulating estradiol is derived from direct secretion by functioning ovarian follicles. 11 Furthermore, four of nine women had apparently viable, if unstimulated, follicles present on ovarian biopsy, and one other subject conceived following 2 years of hypergonadotropic amenorrhea. That the disorder may not be permanent is well exemplified by the patient who resumed cyclic ovulation after 8 years of amenorrhea. The three distinct clinical groups into which the patients could be segregated actually suggest that the syndrome of "premature ovarian failure" represents a continuum in which individuals may be affected at any stage prior to the expected age of menopause. In some individuals all follicles undergo atresia before final sexual maturation at puberty. In others the final depletion of oocytes occurs during the pubertal years. In still other women, ovarian failure occurs postpubertally. In some, the signs and symptoms of ovarian "failure" may simply be transient. The hormonal profiles depicted in Figures 4 and 5 are similar to those of some of the patients studied by Sherman DAYS Figure 5 Pattern of daily concentrations of circulating gonadotropin and steroid levels in a young woman with POF and evidence of ovulation following this period of sample collection. M, menses. The shaded area indicates concentrations of less than 4 miu/ml LH l -POF o--o PMP... :::::1 1 1 FSH HOURS Figure 6 Mean levels ( ± standard error) of serum LH and FSH before and following GnRH administration (two bolus injections of 1 tj.g at 2-hour intervals indicated by the arrows) in eight women with premature ovarian failure (POF), compared with the responses in nine postmenopausal women (PMP).

6 4 RBARTAL. January, 1982 and Korenman. 12 They observed elevated gonadotropin levels in perimenopausal women prior to the menopause and sometimes occurring in presumptively ovulatory cycles. Thus, some of the women studied here may be essentially "perimenopausal." That pituitary function in affected individuals is intact is suggested by the appropriate responses to exogenous GnRH 13 (Fig. 6). However, the possibility of the secretion of altered molecular forms of gonadotropins cannot be excluded. The diverse clinical presentations also suggest that the syndrome has several causes. 14 The ovarian "failure" may have an autoimmune basis and occur in conjunction with other autoimmune disorders, particularly mucocutaneous candidiasis, hypoadrenalism, and hypoparathyroidism. 15 " 17 Thyroiditis may be associated as well. 18 Also possible is a chromosomal abnormality, most commonly some form of gonadal dysgenesis. Altered secretion and/or metabolism of gonadotropins in POF with the existence of biologically inactive molecular species is another possibility. We have recently documented the presence of altered immunoreactive forms of urinary FSH and LH in five of the women included in this study, but the biologic activity of their gonadotropins remains to be established. In this regard, Park et al. 2 have reported a case of male pseudohermaphroditism with immunologically active and apparently biologically inactive LH. From a clinical viewpoint, the possible reasons for premature ovarian failure and the data we have accumulated can be used to develop a rational approach to the evaluation of affected individuals. Following a thorough history and physical examination, laboratory studies should include chromosomal analysis; tests for levels of serum calcium, phosphate, and protein for evidence of hypoparathyroidism; and thyroid function studies, including antibodies. Testing of adrenal reserve with adrenocorticotropic hormone (ACTH) also seems indicated We further recommend weekly determination of serum LH, FSH, and 2 concentrations for 1 month. If 2 concentrations are increased above the menopausal range in any sample and if evidence of appropriate feedback exists (with LH greater than FSH), then induction of ovulation may be considered. We suggest weekly measurements because that would have been sufficient to detect ovarian follicular activity in any of the 18 patients in this study in whom hormonal levels were determined daily. We further believe ovarian biopsy by laparotomy should be performed in any patient prior to attempted induction of ovulation. We do not feel that sufficient ovarian stroma can be obtained by laparoscopic biopsy to evaluate the tissue for the presence of oocytes. If endocrine evidence indicates no follicular activity, then ovarian biopsy is not warranted, although the possibility of remaining oocytes cannot be absolutely eliminated. For such individuals, appropriate cyclic treatment with estrogen and progestin would seem indicated. ffective treatment modalities for individuals with existing ovarian follicles remain to be established. If altered forms of gonadotropins exist, then treatment with exogenous human menopausal and chorionic gonadotropins may well be successful. If circulating antibodies to ovarian tissue are present, then treatment with corticosteroids and/or plasmapheresis should hold promise, since patients with other.autoimmune disorders have been effectively treated with these agents Acknowledgments. We thank Jill Aurand, Scott Dolin, Chris Hofeditz, Kathy Holcomb, and Michelle Reck for their excellent technical assistance and Del Crowe for preparation of the manuscript. We also thank the National Pituitary Agency for providing reagents for the peptide hormone immunoassays. RFRNCS 1. Moraes-Ruehsen M de, Jones GS: Premature ovarian failure. Fertil Steril 18:44, Lucky AW, Rebar RW, Blizzard RM, Goren M: Pubertal progression in the presence of elevated serum gonadotropins in girls with multiple endocrine deficiencies. J Clin ndocrinol Metab 45:673, Schreiber JR, Davajan V, Kletzky OA: A case of intermittent ovarian failure. Am J Obstet Gynecol 132:698, Johnson TR Jr, Peterson P: Gonadotropin-induced pregnancy following "premature ovarian failure." Fertil Steril 31:351, Goldenberg RL, Grodin JM, Rodbard D, Ross GT: Gonadotropins in women with amenorrhea. Am J Obstet Gynecol 116:13, DeVane GW, Czekala NM, Judd HL, Yen SSC: Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 121:496, Anderson DC, Hopper BR, Lasley BL, Yen SSC: A simple method for the assay of eight steroids in small volumes of plasma. Steroids 28:179, Marshall W A, Tanner JM: Variations in patterns of pubertal changes in girls. Arch Dis Child 44:291, Casper RF, Yen SSC: Menopausal flushes: a neuroendocrine link with pulsatile luteinizing hormone secretion. Science 25:823, 1979

7 Vol. 37, No. 1 PRMATUR OVARIAN FAILUR Yen sse, Tsai CC, Naftolin F, VandenBerg G,.Ajabor L: Pulsatile patterns of gonadotropin release in subjects with and without ovarian function. J Clin ndocrinol Metab 34:671, Baird DT, Fraser IS: Blood production and ovarian secretion rates of estradiol-1713 and estrone in women throughout the menstrual cycle. J Clin ndocrinol Metab 38:19, Sherman BM, Korenman SG: Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest 55:699, Yen sse, Rebar RW, VandenBerg G, hara Y, Siler TM: Pituitary gonadotropin responsiveness to synthetic LRF in subjects with normal and abnormal hypothalamic-pituitary-gonadal axis. J Reprod Fertil [Suppl] 2:137, Rebar RW, Silva de Sa MF: The reproductive age: premature ovarian failure. In Comprehensive ndocrinology. The Ovary, dited by G Serra. New York, Raven Press. In press 15. Golonka J, Goodman AD: Coexistence of primary ovarian insufficiency, primary adrenocortical insufficiency and idiopathic hypoparathyroidism. J Clin ndocrinol Metab 28:79, Irvine WJ, Chan MMW, Scarth L, Kolb FO, Hartog M, Bayless RIS, Drury Ml: Immunological aspects of premature ovarian failure associated with idiopathic Addison's disease. Lancet 2:883, Moraes-Ruehsen M de, Blizzard RM, Garcia-Bunvel R, Jones GS: Autoimmunity and ovarian failure. Am J Obstet Gynecol 112:693, Vasquez AM, Kenny FM: Ovarian.failure and antiovarian antibodies in association with hypoparathyroidism, moniliasis, and Addison's and Hashimoto's diseases. Obstet Gynecol 41:414, Silva de Sa MF, Rebar RW: Altered forms of immunoreactive urinary FSH and LH in premature ovarian failure (POF). Presented at the 28th Annual Meeting of the Society for Gynecologic Investigation, St. Louis, Missouri, 1981, (Abstract 11), p 7 2. Park IJ, Burnett IS, Jones HW Jr, Migeon CJ, Blizzard RM: A case of male pseudohermaphroditism associated with elevated LH, normal FSH and low testosterone possibly due to the secretion of an abnormal LH molecule. Acta ndocrinol 83:173, Dau PC, Lindst.ron JM, Cassel CK, Denys H, Shev., Spither L: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N ngl J Med 297:1134, Kawanishi K, Kawamura K, Nishina Y, Goto A, Okada S, Ishida T, Ofqji T, Kahn CR, FlierJS: Successful immunosuppressive therapy in insulin resistant diabetes caused by anti-insulin receptor autoantibodies. J Clin ndocrinol Metab 44:15, Muggeo M, Flier JS, Abrams RA, Harrison LC, Deisserroth AB, Kahn CR: Treatment by plasma exchange of a patient with autoantibodies to the insulin receptor. N ngl J Med 3:477, Yamada T, Ikejiri K, Kotani M, Kusakabe T: An increase of plasma triiodothyronine and thyroxine after administration of dexamethasone to hypothyroid patients with Hashimoto's thyroiditis. J Clin ndocrinol Metab 46:784, 1978