PDF icon PDF herunterladen
Semin Reprod Med 2011; 29(6): 482-490
DOI: 10.1055/s-0031-1293202
© Thieme Medical Publishers

Endocrinology and Recurrent Early Pregnancy Loss

M. Leah Smith1 , Danny J. Schust1
  • 1Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine, Columbia, Missouri
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
08. Dezember 2011 (online)

   Lizenzen und Reprints
Preview

ABSTRACT

Endocrine disorders have been frequently linked to recurrent pregnancy loss (RPL). Because embryo attachment and early implantation are exquisitely controlled by the local hormonal milieu, endocrine-related pregnancy failures are likely to occur early in gestation. Thyroid disorders, luteal phase defects, and polycystic ovary syndrome are the endocrine abnormalities most commonly associated with RPL. In this review we discuss new concepts in the pathophysiology and treatment of these diseases with the ultimate goal of improving pregnancy maintenance. We have also included our recommendations on testing and treatment of women with isolated and repeated pregnancy failure that is believed to be at least partially mediated by newly defined hypothyroidism, thyroid autoimmunity, luteal phase defects, obesity, and polycystic ovary syndrome.

KEYWORDS

Thyroid autoantibodies - polycystic ovarian syndrome - luteal phase defect - recurrent pregnancy loss

REFERENCES

  • 1 Boklage C E. Survival probability of human conceptions from fertilization to term.  Int J Fertil. 1990;  35 (2) 75, 79-80, 81–94
    Suche in Google Scholar
  • 2 Wilcox A J, Weinberg C R, O'Connor J F et al.. Incidence of early loss of pregnancy.  N Engl J Med. 1988;  319 (4) 189-194
    Suche in Google Scholar
  • 3 Edmonds D K, Lindsay K S, Miller J F, Williamson E, Wood P J. Early embryonic mortality in women.  Fertil Steril. 1982;  38 (4) 447-453
    Suche in Google Scholar
  • 4 Rai R, Regan L. Recurrent miscarriage.  Lancet. 2006;  368 (9535) 601-611
    Suche in Google Scholar
  • 5 Suzumori N, Sugiura-Ogasawara M. Genetic factors as a cause of miscarriage.  Curr Med Chem. 2010;  17 (29) 3431-3437
    Suche in Google Scholar
  • 6 Alberman E. The epidemiology of repeated abortion. In: Beard R W, Sharp F, eds. Early Pregnancy Loss: Mechanisms and Treatment. New York, NY: Springer-Verlag; 1988: 9-17
    Suche in Google Scholar
  • 7 Fryns J P, Van Buggenhout G. Structural chromosome rearrangements in couples with recurrent fetal wastage.  Eur J Obstet Gynecol Reprod Biol. 1998;  81 (2) 171-176
    Suche in Google Scholar
  • 8 Jaslow C R, Carney J L, Kutteh W H. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses.  Fertil Steril. 2010;  93 (4) 1234-1243
    Suche in Google Scholar
  • 9 Proctor J A, Haney A F. Recurrent first trimester pregnancy loss is associated with uterine septum but not with bicornuate uterus.  Fertil Steril. 2003;  80 (5) 1212-1215
    Suche in Google Scholar
  • 10 Propst A M, Hill III J A. Anatomic factors associated with recurrent pregnancy loss.  Semin Reprod Med. 2000;  18 (4) 341-350
    Suche in Google Scholar
  • 11 Homer H A, Li T C, Cooke I D. The septate uterus: a review of management and reproductive outcome.  Fertil Steril. 2000;  73 (1) 1-14
    Suche in Google Scholar
  • 12 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4 (2) 295-306
    Suche in Google Scholar
  • 13 Ziakas P D, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis.  Obstet Gynecol. 2010;  115 (6) 1256-1262
    Suche in Google Scholar
  • 14 Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology.  Endocr Rev. 1997;  18 (3) 404-433
    Suche in Google Scholar
  • 15 Benhadi N, Wiersinga W M, Reitsma J B, Vrijkotte T G, Bonsel G J. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death.  Eur J Endocrinol. 2009;  160 (6) 985-991
    Suche in Google Scholar
  • 16 Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction.  Clin Endocrinol (Oxf). 2007;  66 (3) 309-321
    Suche in Google Scholar
  • 17 Glinoer D. Thyroidal and immune adaptation to pregnancy: focus on maternal hypo- and hyperthyroidism. In: Lazarus J Pirags V Butz S eds. The Thyroid and Reproduction. New York, NY: Thieme; 2009: 46-58
    Suche in Google Scholar
  • 18 Hollowell J G, Staehling N W, Flanders W D et al.. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).  J Clin Endocrinol Metab. 2002;  87 (2) 489-499
    Suche in Google Scholar
  • 19 Billingham R E, Brent L, Medawar P B. Actively acquired tolerance of foreign cells.  Nature. 1953;  172 (4379) 603-606
    Suche in Google Scholar
  • 20 Anjum N, Baker P N, Robinson N J, Aplin J D. Maternal celiac disease autoantibodies bind directly to syncytiotrophoblast and inhibit placental tissue transglutaminase activity.  Reprod Biol Endocrinol. 2009;  7 16
    Suche in Google Scholar
  • 21 Stagnaro-Green A, Roman S H, Cobin R H, el-Harazy E, Alvarez-Marfany M, Davies T F. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies.  JAMA. 1990;  264 (11) 1422-1425
    Suche in Google Scholar
  • 22 Bussen S, Steck T. Thyroid autoantibodies in euthyroid non-pregnant women with recurrent spontaneous abortions.  Hum Reprod. 1995;  10 (11) 2938-2940
    Suche in Google Scholar
  • 23 Glinoer D, Soto M F, Bourdoux P et al.. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions.  J Clin Endocrinol Metab. 1991;  73 (2) 421-427
    Suche in Google Scholar
  • 24 Kutteh W H, Yetman D L, Carr A C, Beck L A, Scott Jr R T. Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction.  Fertil Steril. 1999;  71 (5) 843-848
    Suche in Google Scholar
  • 25 Pratt D, Novotny M, Kaberlein G, Dudkiewicz A, Gleicher N. Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss.  Am J Obstet Gynecol. 1993;  168 (3 Pt 1) 837-841
    Suche in Google Scholar
  • 26 Singh A, Dantas Z N, Stone S C, Asch R H. Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies.  Fertil Steril. 1995;  63 (2) 277-281
    Suche in Google Scholar
  • 27 Esplin M S, Branch D W, Silver R, Stagnaro-Green A. Thyroid autoantibodies are not associated with recurrent pregnancy loss.  Am J Obstet Gynecol. 1998;  179 (6 Pt 1) 1583-1586
    Suche in Google Scholar
  • 28 Rushworth F H, Backos M, Rai R, Chilcott I T, Baxter N, Regan L. Prospective pregnancy outcome in untreated recurrent miscarriers with thyroid autoantibodies.  Hum Reprod. 2000;  15 (7) 1637-1639
    Suche in Google Scholar
  • 29 Kaprara A, Krassas G E. Thyroid autoimmunity and miscarriage.  Hormones (Athens). 2008;  7 (4) 294-302
    Suche in Google Scholar
  • 30 Matalon S T, Blank M, Ornoy A, Shoenfeld Y. The association between anti-thyroid antibodies and pregnancy loss.  Am J Reprod Immunol. 2001;  45 (2) 72-77
    Suche in Google Scholar
  • 31 Lee Y L, Ng H P, Lau K S et al.. Increased fetal abortion rate in autoimmune thyroid disease is related to circulating TPO autoantibodies in an autoimmune thyroiditis animal model.  Fertil Steril. 2009;  91 (5, Suppl) 2104-2109
    Suche in Google Scholar
  • 32 Imaizumi M, Pritsker A, Kita M, Ahmad L, Unger P, Davies T F. Non-MHC driven exacerbation of experimental thyroiditis in the postpartum period.  Autoimmunity. 2001;  34 (2) 95-105
    Suche in Google Scholar
  • 33 Iijima T, Tada H, Hidaka Y, Mitsuda N, Murata Y, Amino N. Effects of autoantibodies on the course of pregnancy and fetal growth.  Obstet Gynecol. 1997;  90 (3) 364-369
    Suche in Google Scholar
  • 34 Krassas G E, Poppe K, Glinoer D. Thyroid function and human reproductive health.  Endocr Rev. 2010;  31 (5) 702-755
    Suche in Google Scholar
  • 35 Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy.  J Clin Endocrinol Metab. 2010;  95 (9) E44-E48
    Suche in Google Scholar
  • 36 De Vivo A, Mancuso A, Giacobbe A et al.. Thyroid function in women found to have early pregnancy loss.  Thyroid. 2010;  20 (6) 633-637
    Suche in Google Scholar
  • 37 Smyth P P, Wijeyaratne C N, Kaluarachi W N et al.. Sequential studies on thyroid antibodies during pregnancy.  Thyroid. 2005;  15 (5) 474-477
    Suche in Google Scholar
  • 38 Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy.  Thyroid. 2002;  12 (1) 63-68
    Suche in Google Scholar
  • 39 Bussen S, Steck T, Dietl J. Increased prevalence of thyroid antibodies in euthyroid women with a history of recurrent in-vitro fertilization failure.  Hum Reprod. 2000;  15 (3) 545-548
    Suche in Google Scholar
  • 40 Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications.  J Clin Endocrinol Metab. 2006;  91 (7) 2587-2591
    Suche in Google Scholar
  • 41 Vaquero E, Lazzarin N, De Carolis C, Valensise H, Moretti C, Ramanini C. Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.  Am J Reprod Immunol. 2000;  43 (4) 204-208
    Suche in Google Scholar
  • 42 Reid S M, Middleton P, Cossich M C, Crowther C A. Interventions for clinical and subclinical hypothyroidism in pregnancy.  Cochrane Database Syst Rev. 2010;  (7) CD007752
    Suche in Google Scholar
  • 43 Alexander E K, Marqusee E, Lawrence J, Jarolim P, Fischer G A, Larsen P R. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism.  N Engl J Med. 2004;  351 (3) 241-249
    Suche in Google Scholar
  • 44 Glinoer D. Thyroid immunity, thyroid dysfunction, and the risk of miscarriage: à propos article by Vaquero et al. Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.  Am J Reprod Immunol. 2000;  43 (4) 202-203
    Suche in Google Scholar
  • 45 Glinoer D, Delange F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny.  Thyroid. 2000;  10 (10) 871-887
    Suche in Google Scholar
  • 46 Mandel S J, Larsen P R, Seely E W, Brent G A. Increased need for thyroxine during pregnancy in women with primary hypothyroidism.  N Engl J Med. 1990;  323 (2) 91-96
    Suche in Google Scholar
  • 47 Valbuena D, Jasper M, Remohí J, Pellicer A, Simón C. Ovarian stimulation and endometrial receptivity.  Hum Reprod. 1999;  14 (Suppl 2) 107-111
    Suche in Google Scholar
  • 48 Csapo A I, Pulkkinen M O, Wiest W G. Effects of luteectomy and progesterone replacement therapy in early pregnant patients.  Am J Obstet Gynecol. 1973;  115 (6) 759-765
    Suche in Google Scholar
  • 49 Jones G S. The luteal phase defect.  Fertil Steril. 1976;  27 (4) 351-356
    Suche in Google Scholar
  • 50 Arredondo F, Noble L S. Endocrinology of recurrent pregnancy loss.  Semin Reprod Med. 2006;  24 (1) 33-39
    Suche in Google Scholar
  • 51 Horta J L, Fernández J G, de León B S, Cortés-Gallegos V. Direct evidence of luteal insufficiency in women with habitual abortion.  Obstet Gynecol. 1977;  49 (6) 705-708
    Suche in Google Scholar
  • 52 Serle E, Aplin J D, Li T C et al.. Endometrial differentiation in the peri-implantation phase of women with recurrent miscarriage: a morphological and immunohistochemical study.  Fertil Steril. 1994;  62 (5) 989-996
    Suche in Google Scholar
  • 53 Li T C, Spuijbroek M D, Tuckerman E, Anstie B, Loxley M, Laird S. Endocrinological and endometrial factors in recurrent miscarriage.  BJOG. 2000;  107 (12) 1471-1479
    Suche in Google Scholar
  • 54 Tulppala M, Björses U M, Stenman U H, Wahlström T, Ylikorkala O. Luteal phase defect in habitual abortion: progesterone in saliva.  Fertil Steril. 1991;  56 (1) 41-44
    Suche in Google Scholar
  • 55 Noyes R W, Hertig A T, Rock J. Dating the endometrial biopsy.  Am J Obstet Gynecol. 1975;  122 (2) 262-263
    Suche in Google Scholar
  • 56 Duggan M A, Brashert P, Ostor A et al.. The accuracy and interobserver reproducibility of endometrial dating.  Pathology. 2001;  33 (3) 292-297
    Suche in Google Scholar
  • 57 Scott R T, Snyder R R, Strickland D M et al.. The effect of interobserver variation in dating endometrial histology on the diagnosis of luteal phase defects.  Fertil Steril. 1988;  50 (6) 888-892
    Suche in Google Scholar
  • 58 Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials.  Br J Obstet Gynaecol. 1989;  96 (3) 275-280
    Suche in Google Scholar
  • 59 Scott R T, Snyder R R, Bagnall J W, Reed K D, Adair C F, Hensley S D. Evaluation of the impact of intraobserver variability on endometrial dating and the diagnosis of luteal phase defects.  Fertil Steril. 1993;  60 (4) 652-657
    Suche in Google Scholar
  • 60 Gibson M, Badger G J, Byrn F, Lee K R, Korson R, Trainer T D. Error in histologic dating of secretory endometrium: variance component analysis.  Fertil Steril. 1991;  56 (2) 242-247
    Suche in Google Scholar
  • 61 Smith S, Hosid S, Scott L. Endometrial biopsy dating. Interobserver variation and its impact on clinical practice.  J Reprod Med. 1995;  40 (1) 1-3
    Suche in Google Scholar
  • 62 Coutifaris C, Myers E R, Guzick D S NICHD National Cooperative Reproductive Medicine Network et al. Histological dating of timed endometrial biopsy tissue is not related to fertility status.  Fertil Steril. 2004;  82 (5) 1264-1272
    Suche in Google Scholar
  • 63 Sherman B M, Korenman S G. Measurement of plasma LH, FSH, estradiol and progesterone in disorders of the human menstrual cycle: the short luteal phase.  J Clin Endocrinol Metab. 1974;  38 (1) 89-93
    Suche in Google Scholar
  • 64 Harrison R F. Human chorionic gonadotrophin (hCG) in the management of recurrent abortion; results of a multi-centre placebo-controlled study.  Eur J Obstet Gynecol Reprod Biol. 1992;  47 (3) 175-179
    Suche in Google Scholar
  • 65 Li T C, Tuckerman E M, Laird S M. Endometrial factors in recurrent miscarriage.  Hum Reprod Update. 2002;  8 (1) 43-52
    Suche in Google Scholar
  • 66 Haas D M, Ramsey P S. Progestogen for preventing miscarriage.  Cochrane Database Syst Rev. 2008;  (2) CD003511
    Suche in Google Scholar
  • 67 Glueck C J, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin.  Hum Reprod. 2002;  17 (11) 2858-2864
    Suche in Google Scholar
  • 68 Janssen O E, Mehlmauer N, Hahn S, Offner A H, Gärtner R. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome.  Eur J Endocrinol. 2004;  150 (3) 363-369
    Suche in Google Scholar
  • 69 Dorman J S, Burke J P, McCarthy B J et al.. Temporal trends in spontaneous abortion associated with type 1 diabetes.  Diabetes Res Clin Pract. 1999;  43 (1) 41-47
    Suche in Google Scholar
  • 70 Mills J L, Simpson J L, Driscoll S G et al.. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception.  N Engl J Med. 1988;  319 (25) 1617-1623
    Suche in Google Scholar
  • 71 Cocksedge K A, Li T C, Saravelos S H, Metwally M. A reappraisal of the role of polycystic ovary syndrome in recurrent miscarriage.  Reprod Biomed Online. 2008;  17 (1) 151-160
    Suche in Google Scholar
  • 72 Craig L B, Ke R W, Kutteh W H. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss.  Fertil Steril. 2002;  78 (3) 487-490
    Suche in Google Scholar
  • 73 Glueck C J, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study.  Fertil Steril. 2001;  75 (1) 46-52
    Suche in Google Scholar
  • 74 Jakubowicz D J, Iuorno M J, Jakubowicz S, Roberts K A, Nestler J E. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 (2) 524-529
    Suche in Google Scholar
  • 75 Sills E S, Perloe M, Palermo G D. Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes.  Eur J Obstet Gynecol Reprod Biol. 2000;  91 (2) 135-141
    Suche in Google Scholar
  • 76 Zolghadri J, Tavana Z, Kazerooni T, Soveid M, Taghieh M. Relationship between abnormal glucose tolerance test and history of previous recurrent miscarriages, and beneficial effect of metformin in these patients: a prospective clinical study.  Fertil Steril. 2008;  90 (3) 727-730
    Suche in Google Scholar
  • 77 Legro R S, Barnhart H X, Schlaff W D Cooperative Multicenter Reproductive Medicine Network et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.  N Engl J Med. 2007;  356 (6) 551-566
    Suche in Google Scholar
  • 78 Moll E, Bossuyt P M, Korevaar J C, Lambalk C B, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial.  BMJ. 2006;  332 (7556) 1485
    Suche in Google Scholar
  • 79 Palomba S, Orio Jr F, Falbo A, Russo T, Tolino A, Zullo F. Plasminogen activator inhibitor 1 and miscarriage after metformin treatment and laparoscopic ovarian drilling in patients with polycystic ovary syndrome.  Fertil Steril. 2005;  84 (3) 761-765
    Suche in Google Scholar
  • 80 Glueck C J, Wang P, Fontaine R N, Sieve-Smith L, Tracy T, Moore S K. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome.  Metabolism. 1999;  48 (12) 1589-1595
    Suche in Google Scholar
  • 81 Glueck C J, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy.  Hum Reprod. 2004;  19 (6) 1323-1330
    Suche in Google Scholar
  • 82 Conway G S, Jacobs H S, Holly J M, Wass J A. Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome.  Clin Endocrinol (Oxf). 1990;  33 (5) 593-603
    Suche in Google Scholar
  • 83 Liddell H S, Sowden K, Farquhar C M. Recurrent miscarriage: screening for polycystic ovaries and subsequent pregnancy outcome.  Aust N Z J Obstet Gynaecol. 1997;  37 (4) 402-406
    Suche in Google Scholar
  • 84 Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and recurrent miscarriage—a reappraisal.  Hum Reprod. 2000;  15 (3) 612-615
    Suche in Google Scholar
  • 85 Okon M A, Laird S M, Tuckerman E M, Li T C. Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function.  Fertil Steril. 1998;  69 (4) 682-690
    Suche in Google Scholar
  • 86 van Wely M, Bayram N, van der Veen F, Bossuyt P M. Predicting ongoing pregnancy following ovulation induction with recombinant FSH in women with polycystic ovary syndrome.  Hum Reprod. 2005;  20 (7) 1827-1832
    Suche in Google Scholar
  • 87 Metwally M, Ong K J, Ledger W L, Li T C. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence.  Fertil Steril. 2008;  90 (3) 714-726
    Suche in Google Scholar
  • 88 Lashen H, Fear K, Sturdee D W. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study.  Hum Reprod. 2004;  19 (7) 1644-1646
    Suche in Google Scholar
  • 89 Al-Azemi M, Omu F E, Omu A E. The effect of obesity on the outcome of infertility management in women with polycystic ovary syndrome.  Arch Gynecol Obstet. 2004;  270 (4) 205-210
    Suche in Google Scholar
  • 90 Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin.  Br J Obstet Gynaecol. 1992;  99 (2) 128-131
    Suche in Google Scholar
  • 91 Clark A M, Ledger W, Galletly C et al.. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women.  Hum Reprod. 1995;  10 (10) 2705-2712
    Suche in Google Scholar
  • 92 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.  Fertil Steril. 2004;  81 (1) 19-25
    Suche in Google Scholar
  • 93 Zawadski J K, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In:, Dunaif A, Givens J R, Haseltine F P, Merriam G R, eds. Polycystic Ovary Syndrome. Boston, MA: Blackwell Scientific; 1992: 377-384
    Suche in Google Scholar

Danny J. SchustM.D. 

Department of Obstetrics, Gynecology and Women's Health, University of Missouri School of Medicine

500 North Keene Street, Suite 203, Columbia, MO 65201

eMail: schustd@health.missouri.edu