AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY 25:169-174 © 1991 MUNKSGAARD
Associate Editor
Thomas J. Gill III
REVIEW
CarolynB. Coulam
Immunology of Ovarian Failure CAROLYN B. COULAM ANDJ. JAROSLAV STERN INTRODUCTION
Ovarian failure results when the number of follicles within the ovary are exhausted. Naturally occurring ovarian failure or menopause takes place at the average age of 50 years in the United States. If a woman undergoes ovarian failure before the age of 40 years, the condition is termed premature ovarian failure (POF).1 The annual incidence rates ofPOF are 10 per 100,000 person years for ages 15 to 29 years and 76 per 100,000 person years for ages 30 to 39 years." The prevalence of POF among women of reproducing age is 1%;2 in women with primary amenorrhea the prevalence is 10-28% and in women with secondary amenorrhea the frequency is 4-18%.3 Thus, POF is not uncommon. Regardless of age of onset, the medical impact of ovarian failure includes increased risk of osteoporosis and cardiovascular diseases as well as psychologic manifestations." In addition, women who have under-
By invitation. Address reprint requests to Carolyn B. Coulam, MD, Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Inc., 1701 N. Senate Blvd., Indianapolis, IN 46202.
AJJ!~lit\' lmmunoloav 5
'
5
gone ovarian failure prematurely are plagued with impaired fertility. Just as natural ovarian failure or menopause occurs as a result of ovarian follicle depletion and ultimately exhaustion, so too does POF result from a lack of functioning ovarian follicles.1Control of ovarian follicle function has been viewed as exclusively endocrinologic. More recently attention has been focused on the interactions between the endocrinologic and immunologic systems in the control of ovarian follicular function. Communication between these two systems has been shown to be important in both folliculogenesis and follicular regression. This communication results in paracrine transmission of signals, which are bidirectional and are mediated through cytokines. Cytokines shown to be important in the control of ovarian follicular function include interleukin-1 (IL_1),5,6 transformin~growth factor 13 (TGF-I3),7 TGFa, 8 interferon -y (lFN -y), fibrocyte growth factor (FGF),1O insulin-like growth factor (lGF),l1 plateletderived growth factor (PDGF),12 and tumor necrosis factor a (TNFa).13- 15These cytokines are produced byresident ovarian macrophages'" and have been shown to have an effect on granulosa cells. In addition to the paracrine transmission of signals between macrophages and granulosa cells, the zranulosa cells can also produce the cytokines IL-1,17,1'8 IGF-1,19FGF,20 TNFa,21 and INF-y22, which have an autocrine function as well. It is the activities of these cytokines that provides the method of communication between the two systems that regulate ovarian function. When ovarian function fails, cytokine activities change. It is the purpose ofthis paper to review ovarian cytokine activities in the normal ovarian cycle and to discuss alterations in these activities that can lead to ovarian failure. FOLLICULOGENESIS
The ovarian cycle results in oocyte production. It is the result of a continuous repetitive process offollicle maturation (follicular phase), ovulation, and corpus luteum formation and regression (luteal phase).23 During the follicular phase the ovarian follicle differ-entiates from a primordial follicle to a preovulatory follicle. The initial event in the process of folliculogenesis is initiation of primordial follicle growth.i" The mechanism that triggers this event is not known, but it does not appear to be dependent on gonadotropins, since gonadotropin receptors are not present in the granulosa cells of the primordial follicle. The intimate relationship between resident macrophages present within the ovarian stroma around the granulosa cells allows close communication between the macrophages and granulosa cells. Whether the cytokines are produced by macrophages or which cytokine might be involved in initiation of primordial follicle growth is not known. Once the follicle begins to grow, the granulosa cells are stimulated to proliferate. FSH and estrogen have been shown to have a mitogenic action on granulosa cells. 24 In addition to FSH and estrogen, a number of cytokines have been shown to promote follicular growth by amplifying the proliferation of granulosa cells. These cytokines include IL_1,5,6,25-27 IGF,28 and TGFa. 8,29 Within the
170
COULAM AND STERN
intraovarian microenvironment, IL-l and IGF are l?roduced by both macrophages'
Associate Editor
Thomas J. Gill III
REVIEW
CarolynB. Coulam
Immunology of Ovarian Failure CAROLYN B. COULAM ANDJ. JAROSLAV STERN INTRODUCTION
Ovarian failure results when the number of follicles within the ovary are exhausted. Naturally occurring ovarian failure or menopause takes place at the average age of 50 years in the United States. If a woman undergoes ovarian failure before the age of 40 years, the condition is termed premature ovarian failure (POF).1 The annual incidence rates ofPOF are 10 per 100,000 person years for ages 15 to 29 years and 76 per 100,000 person years for ages 30 to 39 years." The prevalence of POF among women of reproducing age is 1%;2 in women with primary amenorrhea the prevalence is 10-28% and in women with secondary amenorrhea the frequency is 4-18%.3 Thus, POF is not uncommon. Regardless of age of onset, the medical impact of ovarian failure includes increased risk of osteoporosis and cardiovascular diseases as well as psychologic manifestations." In addition, women who have under-
By invitation. Address reprint requests to Carolyn B. Coulam, MD, Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Inc., 1701 N. Senate Blvd., Indianapolis, IN 46202.
AJJ!~lit\' lmmunoloav 5
'
5
gone ovarian failure prematurely are plagued with impaired fertility. Just as natural ovarian failure or menopause occurs as a result of ovarian follicle depletion and ultimately exhaustion, so too does POF result from a lack of functioning ovarian follicles.1Control of ovarian follicle function has been viewed as exclusively endocrinologic. More recently attention has been focused on the interactions between the endocrinologic and immunologic systems in the control of ovarian follicular function. Communication between these two systems has been shown to be important in both folliculogenesis and follicular regression. This communication results in paracrine transmission of signals, which are bidirectional and are mediated through cytokines. Cytokines shown to be important in the control of ovarian follicular function include interleukin-1 (IL_1),5,6 transformin~growth factor 13 (TGF-I3),7 TGFa, 8 interferon -y (lFN -y), fibrocyte growth factor (FGF),1O insulin-like growth factor (lGF),l1 plateletderived growth factor (PDGF),12 and tumor necrosis factor a (TNFa).13- 15These cytokines are produced byresident ovarian macrophages'" and have been shown to have an effect on granulosa cells. In addition to the paracrine transmission of signals between macrophages and granulosa cells, the zranulosa cells can also produce the cytokines IL-1,17,1'8 IGF-1,19FGF,20 TNFa,21 and INF-y22, which have an autocrine function as well. It is the activities of these cytokines that provides the method of communication between the two systems that regulate ovarian function. When ovarian function fails, cytokine activities change. It is the purpose ofthis paper to review ovarian cytokine activities in the normal ovarian cycle and to discuss alterations in these activities that can lead to ovarian failure. FOLLICULOGENESIS
The ovarian cycle results in oocyte production. It is the result of a continuous repetitive process offollicle maturation (follicular phase), ovulation, and corpus luteum formation and regression (luteal phase).23 During the follicular phase the ovarian follicle differ-entiates from a primordial follicle to a preovulatory follicle. The initial event in the process of folliculogenesis is initiation of primordial follicle growth.i" The mechanism that triggers this event is not known, but it does not appear to be dependent on gonadotropins, since gonadotropin receptors are not present in the granulosa cells of the primordial follicle. The intimate relationship between resident macrophages present within the ovarian stroma around the granulosa cells allows close communication between the macrophages and granulosa cells. Whether the cytokines are produced by macrophages or which cytokine might be involved in initiation of primordial follicle growth is not known. Once the follicle begins to grow, the granulosa cells are stimulated to proliferate. FSH and estrogen have been shown to have a mitogenic action on granulosa cells. 24 In addition to FSH and estrogen, a number of cytokines have been shown to promote follicular growth by amplifying the proliferation of granulosa cells. These cytokines include IL_1,5,6,25-27 IGF,28 and TGFa. 8,29 Within the
170
COULAM AND STERN
intraovarian microenvironment, IL-l and IGF are l?roduced by both macrophages'
