Advertisement

Polycystic ovary syndrome: Symptomatology, pathophysiology, and epidemiology

      Abstract

      Women with polycystic ovary syndrome seek health care for 3 major reasons: infertility, menstrual irregularity, and androgen excess. The infertility is associated with anovulation. The menstrual irregularity is typically chronic, beginning with menarche. Although amenorrhea may sometimes occur, the more common presentation is irregular bleeding characteristic of anovulation. Androgen excess may be manifested by varying degrees of hirsutism. Patients may also report acne. The rapid development of virilizing signs, such as deepening of the voice, increased muscle mass, and temporal balding, should prompt a search for a tumor and lead one away from a diagnosis of polycystic ovary syndrome. Typically treatment is directed at alleviating the symptoms: ovulation induction for infertility, oral contraceptives or a progestin for menstrual irregularity, and oral contraceptives or spironolactone for hirsutism. On the basis of recent epidemiologic data suggestive of increased cardiovascular risk among women with polycystic ovary syndrome, such treatment might be complemented by a long-term approach that addresses the underlying pathophysiology of insulin resistance. (Am J Obstet Gynecol 1998;179:S89-93.)

      Keywords

      Polycystic ovary syndrome is characterized clinically by a history of chronic anovulatory bleeding in combination with some evidence of androgen excess, such as hirsutism, acne, elevated serum androgen concentrations, or a combination of these. This clinical definition is reflective of a 1990 National Institutes of Health–National Institute of Child Health and Development consensus conference
      • Zawedzki JK
      • Dunaif A
      Diagnostic criteria for polycystic ovary syndrome: towards a rational approach.
      in which “definite or probable” criteria for polycystic ovary syndrome included menstrual dysfunction and androgen excess and excluded congenital adrenal hyperplasia and other causes. It is interesting to note that the 58 experts at the National Institutes of Health conference who completed a questionnaire on diagnostic criteria showed poor agreement; no single criterion was endorsed as “definite or probable” by more than 64% of respondents.
      • Zawedzki JK
      • Dunaif A
      Diagnostic criteria for polycystic ovary syndrome: towards a rational approach.
      Factors such as insulin resistance, elevated ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) and ovaries appearing polycystic on ultrasonography were considered to be “possible” criteria.

      Presenting symptoms

      In clinical practice, women with polycystic ovary syndrome are seen for 3 major reasons: infertility (mean incidence 74%), menstrual irregularity (mean incidence of dysfunctional bleeding 29%, mean incidence of amenorrhea 51%), and androgen excess (mean incidence of hirsutism 69%, mean incidence of virilization, 21%).
      • Goldzieher JW
      • Green JA
      Clinical and biochemical features of polycystic ovarian disease.
      Because polycystic ovary syndrome is typically characterized by oligo-ovulation rather than amenorrhea, women with polycystic ovary syndrome sometimes conceive on their own without ovulation induction. In the absence of other male or female infertility factors, however, a clinically useful working hypothesis for an infertile woman with polycystic ovary syndrome is that the infertility is due to anovulation. Indeed, in 40% of women with polycystic ovary syndrome, infertility is a presenting problem.
      • Franks S
      Polycystic ovary syndrome.
      Moreover, if ovulation is successfully induced in women with polycystic ovary syndrome, the infertility can be successfully treated: a cumulative pregnancy rate of 80% has been reported after 9 ovulatory cycles.
      • Hammond MG
      • Halme JK
      • Talbert LM
      Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation.
      The menstrual irregularity of polycystic ovary syndrome is chronic, typically beginning at menarche.
      • Yen SS
      • Cheney C
      • Judd HL
      Functional aberrations of the hypothalamic-pituitary system in polycystic ovary syndrome.
      Although amenorrhea may occur, the more typical presentation is irregular bleeding characteristic of anovulation.
      Because progesterone is produced by the ovary only after ovulation, women with polycystic ovary syndrome often have chronic estrogen exposure unopposed by progesterone. Women who have had long-standing chronic anovulation without periodic progestin exposure thus may have endometrial hyperplasia or endometrial cancer. Such women should be evaluated by means of endometrial sampling, uterine ultrasonography, or both.
      The androgen excess of polycystic ovary syndrome is usually manifested by varying degrees of hirsutism. Patients may also report acne. Such symptoms are usually associated with serum total testosterone concentrations >60 ng/dL and androstenedione concentrations >200 ng/dL. More advanced signs of androgen excess, such as clitorimegaly and loss of female body contour, can be associated with hyperthecosis. The rapid development of virilizing signs, such as deepening of the voice, increased muscle mass, and temporal balding, should prompt a search for a tumor and lead one away from a diagnosis of polycystic ovary syndrome.
      Typically treatment is directed at alleviating the presenting symptoms: ovulation induction for infertility, oral contraceptives or a progestin for menstrual irregularity, and oral contraceptives or spironolactone for hirsutism. On the basis of accumulating epidemiologic data, however, such treatment might ultimately be complemented by a long-term approach that addresses the underlying pathophysiology of insulin resistance by means of insulin-lowering drugs.

      Pathophysiology

      The fundamental pathophysiologic defect of polycystic ovary syndrome remains unknown and is a source of controversy and ongoing study. There is a growing consensus, however, that the key features include insulin resistance, androgen excess, and abnormal gonadotropin dynamics.
      Figure thumbnail gr1
      Fig. 1Insulin response to glucose challenge, suggestive of insulin resistance among women with polycystic ovary syndrome (PCOS). Reprinted with permission from Chang RJ, Nakamura RM, Judd HL, Kaplan SA. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 1983;57:356-9.
      Figure thumbnail gr2
      Fig. 2Glucose clamp results showing lower insulin sensitivity (greater insulin resistance) in patients with polycystic ovary syndrome than in weight-matched control subjects. Ob PCOS, Obese patients with polycystic ovary syndrome; Ob NL, obese control subjects; Nob PCOS, nonobese patients with polycystic ovary syndrome; Nob NL, nonobese control subjects. Asterisk indicates P < .001 for obese versus nonobese; double asterisk indicates P < .001 for patients with polycystic ovary syndrome versus control subjects. Reprinted with permission from Dunaif A, Segal KR, Futtereweit W, Drobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165-74.
      There is a linear correlation between serum androgen levels and measures of hyperinsulinemia, such as fasting insulin level.
      • Burghen GA
      • Givens JR
      • Kitabchi AE
      Correlation of hyperandrogenism with hyperinsulinemia in polycystic ovarian disease.
      What is the direction of causation in polycystic ovary syndrome? On balance, the weight of the evidence indicates that the direction of causation is from insulin to androgen, rather than the reverse. For example, when androgens are suppressed with a gonadotropin-releasing hormone analog in patients with polycystic ovary syndrome, insulin resistance does not decline.
      • Geffner ME
      • Kaplan SA
      • Bersch N
      • Golde DW
      • Landaw EM
      • Chang RJ
      Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion.
      When hyperinsulinemia is reduced with diazoxide, however, androgen levels decline.
      • Nestler JE
      • Barlascinik CO
      • Matt DW
      • Steingold KA
      • Plymate SR
      • Clore JN
      • et al.
      Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome.
      A provocative model of polycystic ovary syndrome, in which gonadotropin-dependent ovarian hyperandrogenism is central, has been proposed by Barnes et al
      • Barnes RB
      • Rosenfield RL
      • Burstein S
      • Ehrmann DA
      Pituitary-ovarian responses to nafaralin testing in the polycystic ovary syndrome.
      and Rosenfield et al.

      Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450C17α as the cause of polycystic ovary syndrome. Fertil Steril 190;53:785-91.

      They presented data suggesting that women with polycystic ovary syndrome demonstrate increased formation of 17β-hydroxyprogesterone and androstenedione in response to LH
      • Barnes RB
      • Rosenfield RL
      • Burstein S
      • Ehrmann DA
      Pituitary-ovarian responses to nafaralin testing in the polycystic ovary syndrome.
      because of abnormal enzymatic regulation of steroidogenesis.

      Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450C17α as the cause of polycystic ovary syndrome. Fertil Steril 190;53:785-91.

      Figure thumbnail gr3
      Fig. 3LH pulse patterns in women with polycystic ovary syndrome (PCOS), women with functional hypothalamic amenorrhea (FHA), and eumenorrheic control women (EW). Asterisks represent LH pulses. Reproduced permission from Berga SL, Daniels TL. Use of the laboratory in disorders of reproductive neuroendocrinology. J Clin Immunoassay 1991;14:23-8.

      Epidemiology

      The prevalence of polycystic ovary syndrome cannot be determined with precision because it depends on the definition. A strict, research-based definition that relies on endocrine characteristics is associated with a 3% prevalence of polycystic ovary syndrome,
      • Ehrmann DA
      • Barnes RB
      • Rosenfield RL
      Hyperandrogenism, hirsutism and the polycystic ovary syndrome.
      whereas a definition that is based purely on ultrasonographically defined morphologic characteristics is associated with a 22% prevalence.
      • Franks S
      Polycystic ovary syndrome.
      For the clinical definition used here, chronic anovulation plus androgen excess, the prevalence is probably in the 5% range.
      • DeWailly D
      • Cortet-Rudelli C
      • Deroubaix-Allard D
      Definition, clinical manifestations and prevalence of PCOS.
      Incidence data have not been reported.
      Figure thumbnail gr4
      Fig. 4Increased risk of hypertension and diabetes among women with polycystic ovary syndrome (PCOS) previously diagnosed by ovarian wedge resection. Reprinted with permission from Dahlgren E, Janson P, Johansson S, Mattson L, Lindstet G, Crona N, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992;57:505-13.
      Figure thumbnail gr5
      Fig. 5Risk factor statistical model indicative of an increased relative risk for myocardial infarction among women with polycystic ovary syndrome (PCOS). Reprinted with permission from Dahlgren E, Janson P, Johansson S, Lapidus L, Oden A. Polycystic ovary syndrome and risk for myocardial infarction: evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand 1992;71:599-604.
      Table ILipid profiles in women with polycystic ovary sydrome
      Lipid profile (mg/dL)PCOS (N = 206)Control (N = 206)tSignificance
      TC195.4 ± 33.5185.6 ± 37.82.61P = .01
      HDLT51.1 ± 14.557.8 ± 14.5–4.05P < .0001
      HDL27.8 ± 6.2211.7 ± 7.34–5.11P < .0001
      LDL118.4 ± 31.5110.7 ± 34.62.17P = .32
      Triglycerides129 ± 88.885.9 ± 63.45.58P < .001
      Results are expressed as mean ± SD. Modified with permission from Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, et al. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 1995;15:821-6. PCOS, Polycystic ovary syndrome; TC , total cholesterol; HDLT, total high-density lipoprotein; HDL , high-density lipoprotein; LDL , low-density lipoprotein.
      An ongoing study of cardiovascular risk in patients with polycystic ovary syndrome, involving >200 patients with polycystic ovary syndrome and control subjects, offers further support to the hypothesis that women with polycystic ovary syndrome are at increased risk for cardiovascular disease.
      • Talbott E
      • Guzick D
      • Clerici A
      • Berga S
      • Detre K
      • Weimer K
      • et al.
      Coronary heart disease risk factors in women with polycystic ovary syndrome.
      Patients with polycystic ovary syndrome were found to have an adverse lipid profile after controlling for body-mass index and other potentially confounding variables. Moreover, preliminary data suggest increased intima-media thickness of the carotid artery among patients with polycystic ovary syndrome
      • Guzick DS
      • Talbott E
      • Sutton-Tyrrell K
      • Herzog H
      • Kuller L
      • Wolfson S
      Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study.
      ; these data have been confirmed in a larger sample, controlling for body mass index and other variables (Talbott E, et al, unpublished data, 1998). Confirmation of cardiovascular risk must be accomplished through prospective cohort studies, with cardiovascular events as end points.
      In view of the role of insulin resistance as a fundamental element in the pathophysiology of polycystic ovary syndrome and also of the possible long-term consequences of polycystic ovary syndrome with respect to cardiovascular disease, the use of insulin-lowering drugs in the treatment of polycystic ovary syndrome has begun to be studied. These promising investigations are reviewed elsewhere in this supplement.

      Summary

      Women with polycystic ovary syndrome are typically seen with symptoms of infertility, menstrual irregularity, and androgen excess. The fundamental pathophysiologic defect is not known, but important features include insulin resistance, androgen excess, and altered gonadotropin dynamics. Accumulating evidence suggests the possibility that women with polycystic ovary syndrome may be at increased risk for cardiovascular disease. It will be important to test this hypothesis by means of long-term follow-up of patients with polycystic ovary syndrome with respect to actual cardiovascular events.

      References

        • Zawedzki JK
        • Dunaif A
        Diagnostic criteria for polycystic ovary syndrome: towards a rational approach.
        in: Polycystic ovary syndrome. Blackwell Scientific, Boston1992: 377-384
        • Goldzieher JW
        • Green JA
        Clinical and biochemical features of polycystic ovarian disease.
        Fertil Steril. 1963; 14: 631-653
        • Franks S
        Polycystic ovary syndrome.
        N Engl J Med. 1989; 333: 853-861
        • Hammond MG
        • Halme JK
        • Talbert LM
        Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation.
        Obstet Gynecol. 1983; 62: 196-202
        • Yen SS
        • Cheney C
        • Judd HL
        Functional aberrations of the hypothalamic-pituitary system in polycystic ovary syndrome.
        in: The endocrine function of the human ovary. Academic Press, New York1976: 373-385
        • Chang RJ
        • Nakamura RM
        • Judd HL
        • Kaplan SA
        Insulin resistance in nonobese patients with polycystic ovarian disease.
        J Clin Endocrinol Metab. 1983; 57: 356-359
        • Dunaif A
        • Segal KR
        • Futtereweit W
        • Drobrjansky A
        Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.
        Diabetes. 1989; 38: 1165-1174
        • Burghen GA
        • Givens JR
        • Kitabchi AE
        Correlation of hyperandrogenism with hyperinsulinemia in polycystic ovarian disease.
        J Clin Endocrinol Metab. 1980; 50: 113-115
        • Geffner ME
        • Kaplan SA
        • Bersch N
        • Golde DW
        • Landaw EM
        • Chang RJ
        Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion.
        Fertil Steril. 1986; 45: 327-333
        • Nestler JE
        • Barlascinik CO
        • Matt DW
        • Steingold KA
        • Plymate SR
        • Clore JN
        • et al.
        Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome.
        J Clin Endocrinol Metab. 1989; 68: 1027-1032
        • Barnes RB
        • Rosenfield RL
        • Burstein S
        • Ehrmann DA
        Pituitary-ovarian responses to nafaralin testing in the polycystic ovary syndrome.
        N Eng J Med. 1989; 320: 559-565
      1. Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450C17α as the cause of polycystic ovary syndrome. Fertil Steril 190;53:785-91.

        • Berga SL
        • Daniels TL
        Use of the laboratory in disorders of reproductive neuroendocrinology.
        J Clin Immunoassay. 1991; 14: 23-28
        • Ehrmann DA
        • Barnes RB
        • Rosenfield RL
        Hyperandrogenism, hirsutism and the polycystic ovary syndrome.
        in: 3rd ed. Endocrinology. vol 3. WB Saunders, Philadelphia1994: 2093-2112
        • DeWailly D
        • Cortet-Rudelli C
        • Deroubaix-Allard D
        Definition, clinical manifestations and prevalence of PCOS.
        in: Androgen excess disorders in women. Lippincott-Raven, Philadelphia1997: 259-268
        • Dahlgren E
        • Janson P
        • Johansson S
        • Mattson L
        • Lindstet G
        • Crona N
        • et al.
        Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones.
        Fertil Steril. 1992; 57: 505-513
        • Dahlgren E
        • Janson P
        • Johansson S
        • Lapidus L
        • Oden A
        Polycystic ovary syndrome and risk for myocardial infarction: evaluated from a risk factor model based on a prospective population study of women.
        Acta Obstet Gynecol Scand. 1992; 71: 599-604
        • Wild RA
        • Bartholomew MJ
        The influence of body weight on lipoprotein lipids in patients with polycystic ovary syndrome.
        Am J Obstet Gynecol. 1988; 159: 423-427
        • Talbott E
        • Guzick D
        • Clerici A
        • Berga S
        • Detre K
        • Weimer K
        • et al.
        Coronary heart disease risk factors in women with polycystic ovary syndrome.
        Art Thromb Vasc Biol. 1995; 15: 821-826
        • Guzick DS
        • Talbott E
        • Sutton-Tyrrell K
        • Herzog H
        • Kuller L
        • Wolfson S
        Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study.
        Am J Obstet Gynecol. 1996; 174: 1224-1232