SPONTANEOUS AND PHARMACOLOGICALLY INDUCED REMISSIONS IN PATIENTS WITH PREMATURE OVARIAN FAILURE

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1 SPONTANEOUS AND PHARMACOLOGICALLY INDUCED REMISSIONS IN PATIENTS WITH PREMATURE OVARIAN FAILURE David Kreiner, M. D. * Kathleen Droesch, M.D. Daniel Navot, M.D. Richard Scott, M.D. Zev Rosenwaks, M.D. * Jones Institute for Reproductive Medicine Eastern Virginia Medical School 825 Fairfax Avenue Norfolk, VA / Short title: Remissions in POF patients CS/3-88 Précis

2 A subset of patients with ovarian failure have a significant chance of spontaneous remission, resuming ovulation and developing a pregnancy. Abstract To determine the fertility potential of patients with apparent ovarian failure, a retrospective analysis of 86 ovarian failure patients in the Norfolk oocyte donation program was performed. None of the 23 patients with primary ovarian failure ovulated. Seven of 63 (11.1 %) with secondary ovarian failure did ovulate, and 3/63 (4.8%) conceived and delivered normal, healthy infants. Of patients whose etiology for ovarian failure was partial ovarian resection or chemotherapy, the ovulation rate and pregnancy rate were 30.8% and 15.4%, compared to 5.0% and 1.7%, respectively, for the other patients with secondary ovarian failure. Serum estradiol and FSH obtained during hormone replacement were not predictive of the resumption of normal reproductive functions. Therefore, it is recommended that patients with secondary ovarian failure, especially in the better prognosis group, be treated by a trial of estradiol replacement and have close monitoring for ovulation prior to oocyte donation. Introduction Premature or secondary ovarian failure (OF) is defined as hypergonadotropic hypogonadism and amenorrhea occurring prior to 40 years of age.1 It may occur from a variety of etiologies.2 The diagnosis may remain elusive despite a thorough diagnostic work-up, including a karyotype, specific antibody studies, or an ovarian biopsy. OF may be caused by an acceleration of the naturally occurring process of atresia of the oocytes. This accelerated oocyte depletion may be associated with sex chromosomal abnormalities, exposure to radiation, chemotherapy, or an autoimmune process.2-4 Another form of OF is the insensitive ovary

3 syndrome, which may be diagnosed when primordial follicles are present in women who demonstrate a hypergonadotropic hypoestrogenic state with resistance to endogenous or exogenous gonadotropins.5 Additional etiologic factors that cause secondary OF are malignancy, infection, or severe endometriosis, usually as a result of surgical extirpation. Approximately 1% of women over the age of 30 are estimated to have secondary OF. 6 As more women delay childbearing, an increasing number with OF are presenting with a desire to become pregnant. In the past, adoption was the only option, but recently pregnancy has been achieved through oocyte donation. 7-9 In a few instances in our oocyte donation program we have noted that OF is reversible, with restoration of fertility, either spontaneously or in association with various pharmacologic interventions. Elsewhere, isolated case reports of pregnancy in patients with OF suggest that occasionally the disorder may go into remission. To determine the fertility potential of patients with apparent OF, a retrospective analysis of OF patients in our oocyte donation program was performed. The pathophysiology of OF was classified, and the relationship between the etiology of OF and remissions of the condition was evaluated. Material and Methods The diagnosis of OF in this study was based on the finding of menopausal range gonadotropin levels in patients with amenorrhea and hypoestrogenism. Eightysix patients, including 23 with primary amenorrhea and 63 with secondary amenorrhea, comprised the overall group of OF patients in the Norfolk oocyte donation program from 1984 to All of these patients had baseline FSH levels > 40 IU/1 and estradiol (E2) levels < = 30 pg/ml in the presence of anovulation and amenorrhea of > = 6 months' duration. The inter- and intra-assay cv in our laboratory are 4.3 and 4.8 for FSH, 5.7 and 5.8 for E2, respectively. The only requirements for inclusion in the donor oocyte program were ovarian/gonadal failure, the presence of a uterus, and the absence of any

4 contraindication to pregnancy. Additional laboratory work-up for these patients included a karyotype; antibody studies of the ovary, adrenal, and thyroid; thyroid function tests, and blood chemistries, including CBC with differential and an ESR. Treatment was by one of several estrogen and progesterone (P) replacement protocols. These included micronized E2 replacement with increasing doses up to 6 mg/day on days 13 and 14, and 4 mg/day in the luteal phase, supported by 50 mg P suppositories or 25 mg P intramuscularly. Alternatively, vaginal E2 rings were used for estrogen replacement, and a P cylinder was occasionally used for P replacement, as previously described.15 Statistical analysis was performed using chi-square test and the T test. Results The patients were classified according to the pathophysiology of OF, based on the work-up described. Thirteen of 63 (20.6%) patients with secondary OF would have been diagnosed as idiopathic if not for the karyotyping and antibody studies. Subsequent fertility of the secondary OF patients was compared with respect to diagnosis, as the 23 patients with primary OF demonstrated no evidence of fertility (Table 1). During the period of evaluation and treatment, seven patients ovulated, as demonstrated by a serum P 4 of > 6 ng/ml. Three conceived and delivered normal, healthy infants. Six of the seven ovulated after treatment with micronized E2 replacement therapy; one resumed ovulatory cycles spontaneously after three years of amenorrhea following chemotherapy for Hodgkin's lymphoma. Evaluation of basal FSH and E2 and the subsequent degree of gonadotropin suppression during therapy were not different between OF patients who resumed ovulatory function and randomly selected control patients who did not (p>. 05) (Table 2).

5 Discussion The fertility potential of patients with various etiologies for secondary OF is demonstrated by the high incidence of ovulation (30.8%) and pregnancy (15.4%) which was noted in patients whose etiology for OF was partial ovarian resection or chemotherapy, compared to rates of 5.0% and 1.7%, respectively, in other patients with secondary OF. The significance of this finding is probably related to the fact that the ovary which has failed as a direct result of a particular insult, such as surgery or chemotherapy, is more likely to have remaining follicles and oocytes which have retained the capacity to respond to gonadotropins after a recovery period and/or sensitizing E2. Estrogens synergize with FSH to increase the number of FSH receptors.16,17 Estrogen therapy could therefore work by sensitizing the granulosa celis to FSH.12 One patient who had received chemotherapy conceived spontaneously. Similar cases have been reported12 and suggest that this particular etiology may be most likely to remit spontaneously without E2 replacement. Perhaps this is related to damage of oocytes and/or granulosa cells that may not be overcome until a threshold of cells is reached, capable of responding to gonadotropin stirn ulation. Patients should be advised of this possibility. The prognosis for patients with autoimmune OF may not be quite as poor as that of patients whose problem is more continuous and permanent-idiopathic, chromosomal, or radiation etiology-as 1/11 patients did ovulate on E2 replacement, although the number is too small to be of statistical significance. Ovarian biopsy was not predictive of future fertility, since one patient with idiopathic OF who had an ovarian biopsy without follicles successfully delivered a healthy infant. Unfortunately, as demonstrated in this study, one is unable to predict from daily measurements of serum E2 and FSH obtained during hormone replacement which patients are likely to resume normal reproductive functions. Similarly, this hormonal data could not be used to differentiate patient response to high-dose hmg therapy (450 to 600

6 IU/day).18 It may be concluded that a subset of patients with secondary OF primarily due to partial ovarian resection or chemotherapy have a significant chance of having a spontaneous remission, resuming ovulation, and developing a pregnancy. Furthermore, this group of patients cannot be differentiated by daily measurements of serum gonadotropins and E2 or by response to high-dose hmg therapy. Therefore, it is recommended that patients with secondary OF be treated by a trial E2 replacement and have close monitoring for ovulation, prior to resorting to oocyte donation. REFERENCES 1. Tuland T, Kinch RA: Premature ovarian failure. Obstet Gynecol Surv 36:521, Rebar R W: Hypergonadotropic amenorrhea and premature ovarian failure: a review. J Reprod Med 27:179, Coulam CB: The prevalence of autoim m une disorders among patients with primary ovarian failure. Am J Reprod Immunol 4:63, Alper!VIM, Garner PR: Premature ovarian failure: its relationship to autoimmune disease. Obstet Gynecol 66:27, Jones GS, OeMoraes-Ruehsen M: A new syndrome of amenorrhea in association with hypergonadotropism and apparently normal follicular apparatus. Am J Obstet Gynecol 104:597, Coulam CB, Adamson SC, Annegers JF: Incidence of premature ovarian failure. Obstet Gynecol 67 :604, Lutjen P, Trounson A, Leeton J, Findlay J, Wood C, Renov P: The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature 307:174, Rosenwaks Z, Veeck LL, Liu H-C: Pregnancy following transfer of in vitro fertilized donated oocytes. FertH Steril 45:417, Navot 0, Laufer N, Kopolovic J, Rabinowitz R, Birkenfeld A, Lewin A,

7 Granat lvi, IVIargolioth E, Shenker JG: Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Bng J IVIed 314:806, Shapiro AG, Rubin A: Spontaneous pregnancy in association with hypergonadotropin ovarian failure. Fertil Steril 28:500, Polansky S, DePapp EW: Pregnancy associated with hypergonadotropin hypogonadism. Obstet Gyn 47:1s, Alper MM, Jolly EE, Garner PR: Pregnancies after premature ovarian failure. Obstet Gynecol 67:595, Starup J, Philip J, Sele V: Estrogen treatmnt and subsequent pregnancy in two patients with severe hypergonadotropic ovarian failure. Acta Endocrinol 89:149, Wright CS, Jacobs HS: Spontaneous pregnancy in a patient with hypergonadotropic ovarian failure. Br J Obstet Gynaecol 86:389, Rosenwaks Z: Donor eggs: their application in modern reproductive technologies. Fertil Steril 47:895, Bradbury TJ: Direct action of estrogen on the ovary of the immature rat. Endocrinology 68:115, Ireland JJ, Richards JS: Acute effects of estradiol and follicle stimulating hormone on specific binding of human (125I)-iodo follicle stimulating hormone to rat ovarian granulosa cells in vivo and in vitro. Endocrinology 102:876, Boyers SP, Lubersky J, Jones EC: Usefulness of serial measurement of serum FSH, LH, and estradiol in patients with prematue ovarian failure. Abstract no American Fertility Society Annual Meeting, Reno, NV, Sept TABLE 1 PATHOPHYSIOLOGY OF OVARIAN FAILURE AND SUBSEQUENT FERTILITY

8 Primary Ovarian Secondary Ovarian +Ovulation +Pregnancy Failure Failure (N) (N) (N) (%) (N) (%) Surgical 1 16* 3 (30.0%) 1 (10.0%) Chemotherapy (33.3%) 1 (33.3%) Idiopathic (6.9%) 1 (3.4%) Autoimmune (9.1%) Radiation 1 1 0% Chromosomal % Insensitive Ovary Syndrome 2 0 0% Infection 0 1 0% *10 patients had partial resection Note that the ovulation rate is significantly higher in patients in the partial resection and chemotherapy groups than all other patients with

9 secondary ovarian failure, p<.05, chi square test. TABLE 2 THE EFFECT OF HORMONE REPLACEMENT ON ESTRADIOL AND FOLLICLE STIMULATING HORMONE Control ± SD Spontaneous Ovulation N=6 N=16 Mean ± SD Mean Pre E ± ± 8.9 Post ª E ± ± 48.7 Pre FSH ± ± 50.7 Post ª FSH 15.4 ± ±13.5 Change in FSH 94.9 ± ± 49.3

10 a = after at least 24 days of estradiol replacement and 10 days progesterone replacement p = ns, T test