6
The pathogenesis of infertility and early pregnancy loss in polycystic ovary syndrome

https://doi.org/10.1016/j.bpobgyn.2004.06.001Get rights and content

Women with polycystic ovary syndrome (PCOS) frequently present with reproductive dysfunction. Ovarian function might be disturbed, with resultant abnormal folliculogenesis and steroidogenesis and, although it is difficult to define the exact pathogenesis of anovulation, many possible mechanisms have been postulated. Folliculogenesis in anovulatory women with PCOS is characterized by failure of dominance and the ovary has multiple small follicles, which are arrested but capable of steroidogenesis. Abnormalities in gonadotrophin and insulin secretion and disordered paracrine function have been identified. Women with PCOS have an increased prevalence of miscarriage, both after spontaneous and induced ovulation. Hypersecretion of LH, hyperandrogenaemia and hyperinsulinaemia have all been investigated as possible causes of PCOS. It is likely that these factors are interlinked and together might result in disordered ovarian and endometrial function. Multiple other possible abnormalities have been postulated as contributory factors in the reproductive failure. These include decreased plasminogen activator inhibitor activity, endothelial dysfunction and obesity. Ideally, therapy should target the underlying disorders but at present data are inadequate and further investigations are essential before therapeutic recommendations are truly based on an understanding of the pathophysiology.

Section snippets

The pathogenesis of infertility

Ovarian function in infertile women with PCOS is characterized by disordered folliculogenesis and abnormal steroidogenesis, which are interlinked. Abnormalities in one result in disorders of the other and it has been difficult to identify the initiating abnormality.

The morphological features of the polycystic ovary can be identified on ultrasound examination and include hyperechogenic stromal enlargement and multiple small follicles 2–8 mm in diameter arranged either around the periphery or

Pathogenesis of pregnancy loss

Early pregnancy loss occurs in about 15% of all clinically recognized pregnancies. However, the true miscarriage rate is much higher if the further 15% or more of pregnancies lost before clinical diagnosis are included.52., 53., 54. Although 30–50% of conceptions end in miscarriage, about 1% of women will suffer from recurrent pregnancy loss, defined as three or more consecutive spontaneous miscarriages.

Recurrent miscarriage has many possible underlying causes but no definite aetiology is

Other factors

In the quest to identify the underlying pathogenesis of early pregnancy loss in PCOS, a number of other factors and causes—apart from the endocrinopathy of PCOS—have been investigated. Abnormalities in plasminogen activator inhibitor (PAI) activity have been postulated as a possible cause of recurrent miscarriage probably on the basis of abnormal placentation.89., 90. Increased PAI activity was demonstrated in a group of women with PCOS and miscarriage in a study by Glueck et al.49 These

Conclusions

The pathogenesis of anovulation and early pregnancy failure in women with PCOS has enjoyed considerable attention, both in basic research and in clinical trials, over the past few decades. However, although a large body of information is now available, the exact mechanisms underlying the reproductive dysfunction are still not clearly understood.

Multiple abnormalities have been identified. Folliculogenesis is disturbed and steroidogenesis is often abnormal. Gonadotrophin secretion might be

Summary

PCOS is associated with anovulation and increased early pregnancy loss; its exact pathogenesis remains to be clearly defined. Profound abnormalities in folliculogenesis and steroidogenesis have been identified. Postulated causes include disturbances of gonadotrophin secretion, hyperinsulinaemia, abnormal granulosa and theca cell function; attenuated apoptosis and abnormalities in local regulators.

The mechanism of the reproductive failure was initially thought to be hypersecretion of LH and this

References (96)

  • L.B. Craig et al.

    Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss

    Fertility and Sterility

    (2002)
  • C.J. Glueck et al.

    Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome

    Metabolism

    (1999)
  • W.U. Atiomo et al.

    Are women with polycystic ovary syndrome resistant to activated protein C?

    Fertility and Sterility

    (2000)
  • W.U. Atiomo et al.

    The plasminogen activator system in women with polycystic ovary syndrome

    Fertility and Sterility

    (1998)
  • D.K. Edmonds et al.

    Early embryonic mortality in women

    Fertility and Sterility

    (1982)
  • G.M. Stirrat

    Recurrent miscarriage

    Lancet

    (1990)
  • L. Regan et al.

    Hypersecretion of luteinising hormone, infertility, and miscarriage

    Lancet

    (1990)
  • H.S. Jacobs et al.

    The endocrinology of conception

    Baillieres Clinical Endocrinology and Metabolism

    (1990)
  • R. Homburg et al.

    Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnancies achieved in women with polycystic ovarian syndrome

    Fertility and Sterility

    (1993)
  • S. Aksoy et al.

    The prognostic value of serum estradiol, progesterone, testosterone and free testosterone levels in detecting early abortions

    European Journal of Obstetrics, Gynecology and Reproductive Biology

    (1996)
  • M.A. Okon et al.

    Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function

    Fertility and Sterility

    (1998)
  • E.M. Tuckerman et al.

    Do androgens have a direct effect on endometrial function? An in vitro study

    Fertility and Sterility

    (2000)
  • E.M. Velazquez et al.

    Metformin therapy in polycystic ovary syndrome reduces hyperinsulinaemia, insulin resistance, hyperandrogenaemia, and systolic blood pressure, while facilitating normal menses and pregnancy

    Metabolism

    (1994)
  • C.J. Glueck et al.

    Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study

    Fertility and Sterility.

    (2001)
  • M.F. Costello et al.

    A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome

    Fertility and Sterility

    (2003)
  • E.S. Knochenhauer et al.

    Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study

    Journal of Clinical Endocrinology and Metabolism

    (1998)
  • K.F. Michelmore et al.

    Polycystic ovaries and associated clinical and biochemical features in young women

    Clinical Endocrinology (Oxford)

    (1999)
  • G. Kovacs et al.

    The current status of polycystic ovary syndrome

    Australian and New Zealand Journal of Obstetrics and Gynaecology

    (2001)
  • T.L. Marx et al.

    Polycystic ovary syndrome: pathogenesis and treatment over the short and long term

    Cleveland Clinical Journal of Medicine

    (2003)
  • E. Kousta et al.

    The prevalence of polycystic ovaries in women with infertility

    Human Reproduction

    (1999)
  • P.E. Hughesdon

    Morphology and morphogenesis of the Stein-Leventhal Ovary and of the So-called “Hyperthecosis”

    Obstetrical and Gynecological Survey

    (1982)
  • R. Homburg

    Involvement of growth factors in the pathophysiology of polycystic ovary syndrome

    Gynecological Endocrinology

    (1998)
  • M. van der Meer et al.

    Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome

    Journal of Clinical Endocrinology and Metabolism

    (1998)
  • G.D. Hodgen

    The dominant ovarian follicle

    Fertility and Sterility

    (1982)
  • S.G. Hillier

    Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis

    Human Reproduction

    (1994)
  • J. Yeh et al.

    The ovarian life cycle

  • E.L. Yong et al.

    Hormonal regulation of the growth and steroidogenic function of human granulosa cells

    Journal of Clinical Endocrinology and Metabolism

    (1992)
  • S.S. Yen et al.

    Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease

    Journal of Clinical Endocrinology and Metabolism

    (1970)
  • B.C. Fauser et al.

    Manipulation of human ovarian function: physiological concepts and clinical consequences

    Endocrine Review

    (1997)
  • D.A. Magoffin et al.

    inhibin B and activin A concentrations in follicular fluid from women with polycystic ovary syndrome

    Human Reproduction

    (1998)
  • J.S. Laven et al.

    Absent biologically relevant associations between serum inhibin B concentrations and characteristics of polycystic ovary syndrome in normogonadotrophic anovulatory infertility

    Human Reproduction

    (2001)
  • H. Mizunuma et al.

    Serum immunoreactive inhibin levels in polycystic ovarian disease (PCOD) and hypogonadotropic amenorrhea

    Endocrine Journal

    (1994)
  • G.M. Lockwood et al.

    Mid-follicular phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle

    Journal of Clinical Endocrinology and Metabolism

    (1998)
  • D. Willis et al.

    Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries

    Journal of Clinical Endocrinology and Metabolism

    (1996)
  • D.S. Willis et al.

    Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation

    Journal of Clinical Endocrinology and Metabolism

    (1998)
  • R. Homburg

    The management of infertility associated with polycystic ovary syndrome

    Reproductive Biology and Endocrinology

    (2003)
  • F.L. Teixeira Filho et al.

    Journal of Clinical Endocrinology and Metabolism

    (2002)
  • J. Dong et al.

    Growth differentiation factor-9 is required during early ovarian folliculogenesis

    Nature

    (1996)
  • Cited by (0)

    View full text