Semin Reprod Med 2006; 24(1): 033-039
DOI: 10.1055/s-2006-931799
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Endocrinology of Recurrent Pregnancy Loss

Francisco Arredondo1 , Luis S. Noble2
  • 1Assistant Professor, Division of Reproductive Endocrinology and Infertility Case Western Reserve University, Cleveland Ohio
  • 2Associate Clinical Professor, Department of Obstetrics and Gynecology, Texas Tech University Medical Center, and Medical Director of Southwest Center for Reproductive Health, El Paso, Texas
Further Information

Publication History

Publication Date:
18 January 2006 (online)

ABSTRACT

Following implantation, the maintenance of the pregnancy is dependent on a multitude of endocrinological events that will eventually aid in the successful growth and development of the fetus. Although the great majority of pregnant women have no pre-existing endocrine abnormalities, a small number of women can have certain endocrine alterations that could potentially lead to recurrent pregnancy losses. It is estimated that approximately 8 to 12% of all pregnancy losses are the result of endocrine factors. During the preimplantation period, the uterus undergoes important developmental changes stimulated by estrogen, and more importantly, progesterone. Progesterone is essential for the successful implantation and maintenance of pregnancy. Therefore, disorders related to inadequate progesterone secretion by the corpus luteum are likely to affect the outcome of the pregnancy. Luteal phase deficiency, hyperprolactinemia, and polycystic ovarian syndrome are some examples. Several other endocrinological abnormalities such as thyroid disease, hypoparathyroidism, uncontrolled diabetes, and decreased ovarian reserve have been implicated as etiologic factors for recurrent pregnancy loss.

REFERENCES

  • 1 Szlachter N, O'Byrne E, Goldsmith L et al.. Myometrial inhibiting activity of relaxin containing extracts of human corpora lutea of pregnancy.  Am J Obstet Gynecol. 1980;  136 584-586
  • 2 Bigazzi M, Nardi E. Prolactin and relaxin: antagonism on the spontaneous motility of the uterus.  J Clin Endocrinol Metab. 1981;  53 665
  • 3 Csapo A L, Pulkkinen M O, Wiest W G. Effects of lutectomy and progesterone replacement in early pregnant patients.  Am J Obstet Gynecol. 1973;  115 759-764
  • 4 Insler V. Corpus luteum defects.  Curr Opin Obstet Gynecol. 1992;  4(2) 203-211
  • 5 Tuckerman E, Laird S M, Stewart R, Wells M, Li T C. Markers of endometrial function in women with unexplained recurrent pregnancy loss.  Hum Reprod. 2004;  19(1) 196-205
  • 6 Jacobs M H, Balasch J, Gonzalez-Merlo J M. Endometrial cytosolic and nuclear progesterone receptors in the luteal phase defect.  J Clin Endocrinol Metab. 1987;  64 472-478
  • 7 Rosenfeld D L, Garcia C R. A comparison of endometrial histology with simultaneous plasma progesterone determinations in infertile women.  Fertil Steril. 1976;  27 1256
  • 8 Koninckx P R, Goddeeries P G, Lauweryns J M, de Hertogh R C, Brosens I A. Accuracy of endometrial biopsy dating in relation to the mid-cycle luteinizing hormone peak.  Fertil Steril. 1977;  28 443-445
  • 9 Hensleigh P A, Fainstat T. Corpus luteum dysfunction: serum progesterone levels in the diagnosis and assessment of therapy for recurrent and threatened abortion.  Fertil Steril. 1979;  32 396
  • 10 Cumming D C, Honore L H, Scott J Z, Williams K P. The late luteal phase in infertile women: comparison of simultaneous endometrial biopsy and progesterone levels.  Fertil Steril. 1985;  43(5) 715-719
  • 11 Noyes R W. Uniformity of secretory endometriosis.  Obstet Gynecol. 1956;  7 221
  • 12 Coutifaris C, Myers E R, Guzick D S and 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
  • 13 Phung Thi Tho, Byrd J R, McDonough P G. Etiologies and subsequent reproductive performance in 100 couples with recurrent abortion.  Fertil Steril. 1979;  32 389-395
  • 14 Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage: a meta-analysis of controlled trials.  Br J Obstet Gynaecol. 1989;  96 275
  • 15 Mills J L, Simpson J L, Driscoll S 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 1617-1621
  • 16 Karamardian L M, Grimes D A. Luteal phase deficiency: effect of treatment on pregnancy rates.  Am J Obstet Gynecol. 1992;  167(5) 1391-1398
  • 17 del Pozo E, Wyss H, Tolis G, Alcaniz J, Campana A, Naflolin F. Prolactin and deficient luteal function.  Obstet Gynecol. 1979;  53 282-286
  • 18 Roberts C P, Murphy A A. Endocrinopathies associated with recurrent pregnancy loss.  Semin Reprod Med. 2000;  18(4) 357-362
  • 19 Byrne J L, Ward K. Genetic factors in recurrent abortion.  Clin Obstet Gynecol. 1994;  37(3) 693-704
  • 20 Dorrington J, Gore-Langton R E. Prolactin inhibits oestrogen synthesis in the ovary.  Nature. 1981;  290 600
  • 21 Magoffin D A, Erickson G F. Prolactin inhibition of luteinizing hormone-stimulated androgen synthesis in ovarian interstitial cells cultured in defined medium: mechanisms of action.  Endocrinology. 1982;  111 2001-2007
  • 22 McNatty K P, Sawers R S. Relationship between the endocrine environment within the graafian follicle and the subsequent secretion of progesterone by human granulosa cells in culture.  J Endocrinol. 1975;  66 391-400
  • 23 Hirahara F, Andoh N, Sawai K, Hirabuki T, Uemura T, Minaguchi H. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials.  Fertil Steril. 1998;  70(2) 246-252
  • 24 Goldsmith R E, Sturgis S H, Lerman J, Stanbury J B. The menstrual pattern in thyroid disease.  J Clin Endocrinol Metab. 1952;  12(7) 846-855
  • 25 Davis L E, Lucas M J, Hankins G D, Roark M L, Cunningham F G. Thyrotoxicosis complicating pregnancy.  Am J Obstet Gynecol. 1989;  160 63-70
  • 26 Kriplani A, Buckshee K, Bhargava V L, Takkar D, Ammini A C. Maternal and perinatal outcome in thyrotoxicosis complicating pregnancy.  Eur J Obstet Gynecol Reprod Biol. 1994;  54(3) 159-163
  • 27 Daniels G H. Thyroid disease and pregnancy: a clinical overview.  Endocr Pract. 1995;  1 287-301
  • 28 Nakayama T, Yamamoto T, Kanmatsuse K, Kokubun S. Graves' disease associated with anticardiolipin antibody positivity and acquired protein S deficiency.  Rheumatol Int. 2003;  23(4) 198-200
  • 29 Anselmo J, Cao D, Karrison T, Weiss R E, Refetoff S. Fetal loss associated with excess thyroid hormone exposure.  JAMA. 2004;  292(6) 691-695
  • 30 Wakim A N, Polizotto S L, Buffo M J, Marrero M A, Burholt D R. Thyroid hormones in human follicular fluid and thyroid hormone receptors in human granulosa cells.  Fertil Steril. 1993;  59(6) 1187-1190
  • 31 Steinberger E, Nader S, Rodriguez-Rigau L, Ayala C, Smith K. Prolactin response to thyrotropin-releasing hormone in normoprolactinemic patients with ovulatory dysfunction and its use for selection of candidates for bromocriptine therapy.  J Endocrinol Invest. 1990;  13(8) 637-642
  • 32 Del Pozo E, Wyss H, Tolis G et al.. Prolactin and deficient luteal function.  Obstet Gynecol. 1979;  53 282-286
  • 33 Davis L E, Leveno K J, Cunningham F G. Hypothyroidism complicating pregnancy.  Obstet Gynecol. 1988;  72(1) 108-112
  • 34 Casey B M, Dashe J S, Wells C E et al.. Subclinical hypothyroidism and pregnancy outcomes.  Obstet Gynecol. 2005;  105(2) 239-245
  • 35 Stray-Pedersen B, Stray-Pedersen S. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion.  Am J Obstet Gynecol. 1984;  148(2) 140-146
  • 36 Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases.  Hum Reprod. 1994;  9(7) 1328-1332
  • 37 Bohnet H G, Fiedler K, Leidenberger F A. Subclinical hypothyroidism and infertility.  Lancet. 1981;  2(8258) 1278
  • 38 Daya S, Ward S, Burrows E. Progesterone profiles in luteal phase defect cycles and outcome of progesterone treatment in patients with recurrent spontaneous abortion.  Am J Obstet Gynecol. 1988;  158(2) 225-232
  • 39 Coutifaris C, Myers E R, Guzick D S et al.. NICHD National Cooperative Reproductive Medicine Network. Histological dating of timed endometrial biopsy tissue is not related to fertility status.  Fertil Steril. 2004;  82(5) 1264-1272
  • 40 Kazer R R. Endometrial biopsy should be abandoned as a routine component of the infertility evaluation.  Fertil Steril. 2004;  82(5) 1297-1298 (discussion 1300-1302)
  • 41 Regan L, Rai R. Epidemiology and the medical causes of miscarriage.  Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;  14(5) 839-854
  • 42 Oates-Whitehead R M, Haas D M, Carrier J A. Progestogen for preventing miscarriage.  Cochrane Database Syst Rev. 2003;  (4) CD003511
  • 43 Baloch Z, Carayon P, Conte-Devolx B Guidelines Committee, National Academy of Clinical Biochemistry et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease.  Thyroid. 2003;  13(1) 3-126
  • 44 Weetman A P. Autoimmune thyroid disease.  Autoimmunity. 2004;  37(4) 337-340
  • 45 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
  • 46 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
  • 47 Magaro M, Zoli A, Altomonte L et al.. The association of silent thyroiditis with active systemic lupus erythematosus.  Clin Exp Rheumatol. 1992;  10(1) 67-70
  • 48 Santoro N. Research on the mechanisms of premature ovarian failure.  J Soc Gynecol Investig. 2001;  8(1 suppl) S10-S12
  • 49 Hak A E, Pols H A, Visser T J, Drexhage H A, Hofman A, Witteman J C. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.  Ann Intern Med. 2000;  132(4) 270-278
  • 50 Stewart-Akers A M, Krasnow J S, Brekosky J, DeLoia J A. Endometrial leukocytes are altered numerically and functionally in women with implantation defects.  Am J Reprod Immunol. 1998;  39(1) 1-11
  • 51 Matalon S T, Blank M, Ornoy A et al.. The association between anti-thyroid antibodies and pregnancy loss.  Am J Reprod Immunol. 2001;  45(2) 72-77
  • 52 Christiansen O B, Nybo Andersen A M, Bosch E et al.. Evidence-based investigations and treatments of recurrent pregnancy loss.  Fertil Steril. 2005;  83(4) 821-839
  • 53 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
  • 54 Greene M F, Hare J W, Cloherty J P, Benacerraf B R, Soeldner J S. First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy.  Teratology. 1989;  39(3) 225-231
  • 55 Ray J G, O'Brien T E, Chan W S. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis.  QJM. 2001;  94(8) 435-444
  • 56 Kitzmiller J L, Watt N, Driscoll S G. Decidual arteriopathy in hypertension and diabetes in pregnancy: immunofluorescent studies.  Am J Obstet Gynecol. 1981;  141(7) 773-779
  • 57 Lea R G, McCracken J E, McIntyre S S et al.. Disturbed development of the preimplantation embryo in the insulin-dependent diabetic BB/E rat.  Diabetes. 1996;  45(11) 1463-1470
  • 58 Keim A L, Chi M M, Moley K H. Hyperglycemia-induced apoptotic cell death in the mouse blastocyst is dependent on expression of p53.  Mol Reprod Dev. 2001;  60(2) 214-224
  • 59 Moley K H, Chi M M, Mueckler M M. Maternal hyperglycemia alters glucose transport and utilization in mouse preimplantation embryos.  Am J Physiol. 1998;  275(1 pt 1) E38-E47
  • 60 Wyse L J, Jones M, Mandel F. Relationship of glycosylated hemoglobin, fetal macrosomia, and birthweight macrosomia.  Am J Perinatol. 1994;  11(4) 260-262
  • 61 Temple R, Aldridge V, Greenwood R et al.. Association between outcome of pregnancy and glycaemic control in early pregnancy in type 1 diabetes: population based study.  BMJ. 2002;  325(7375) 1275-1276
  • 62 Nielsen G L, Sorensen H T, Nielsen P H et al.. Glycosylated hemoglobin as predictor of adverse fetal outcome in type 1 diabetic pregnancies.  Acta Diabetol. 1997;  34(3) 217-222
  • 63 Glueck C J, Wang P, Goldenberg N et al.. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin.  Hum Reprod. 2002;  17(11) 2858-2864
  • 64 Sagle M, Bishop K, Ridley N et al.. Recurrent early miscarriage and polycystic ovaries.  BMJ. 1988;  297(6655) 1027-1028
  • 65 Glueck C J, Wang P, Fontaine R N 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;  48(12) 1589-1595
  • 66 Glueck C J, Phillips H, Cameron D et al.. 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
  • 67 Velazquez E M, Mendoza S G, Wang P et al.. Metformin therapy is lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome.  Metabolism. 1997;  46(4) 454-457
  • 68 Wang J X, Davies M J, Norman R J. Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment.  Hum Reprod. 2001;  16(12) 2606-2609
  • 69 Okon M A, Laird S M, Tuckerman E M et al.. Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function.  Fertil Steril. 1998;  69(4) 682-690
  • 70 Tuckerman E M, Okon M A, Li T et al.. Do androgens have a direct effect on endometrial function? An in vitro study.  Fertil Steril. 2000;  74(4) 771-779
  • 71 Regan L, Owen E J, Jacobs H S. Hypersecretion of luteinising hormone, infertility, and miscarriage.  Lancet. 1990;  336(8724) 1141-1144
  • 72 Watson H, Kiddy D S, Hamilton-Fairley D et al.. Hypersecretion of luteinizing hormone and ovarian steroids in women with recurrent early miscarriage.  Hum Reprod. 1993;  8(6) 829-833
  • 73 Nardo L G, Rai R, Backos M et al.. High serum luteinizing hormone and testosterone concentrations do not predict pregnancy outcome in women with recurrent miscarriage.  Fertil Steril. 2002;  77(2) 348-352
  • 74 Westergaard L G, Laursen S B, Andersen C Y. Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction.  Hum Reprod. 2000;  15(5) 1003-1008
  • 75 Clifford K, Rai R, Watson H et al.. Does suppressing luteinising hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial.  BMJ. 1996;  312(7045) 1508-1511
  • 76 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;  78 487-490
  • 77 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
  • 78 Jakubowicz D J, Iuorno M J, Jakubowicz S et al.. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87(2) 524-529
  • 79 Stadtmauer L A, Wong B C, Oehninger S. Should patients with polycystic ovary syndrome be treated with metformin? Benefits of insulin sensitizing drugs in polycystic ovary syndrome-beyond ovulation induction.  Hum Reprod. 2002;  17(12) 3016-3026
  • 80 Trout S W, Seifer D B. Do women with unexplained recurrent pregnancy loss have higher day 3 serum FSH and estradiol values?.  Fertil Steril. 2000;  74(2) 335-337
  • 81 Gurbuz B, Yalti S, Ozden S et al.. High basal estradiol level and FSH/LH ratio in unexplained recurrent pregnancy loss.  Arch Gynecol Obstet. 2004;  270(1) 37-39
  • 82 Hofmann G E, Khoury J, Thie J. Recurrent pregnancy loss and diminished ovarian reserve.  Fertil Steril. 2000;  74(6) 1192-1195
  • 83 Aging and Infertility in Women .American Society of Reproductive Medicine (ASRM) Practice Committee Report. http://Available at: www.asrm.org/membersonly/practice/ageandfertility.pdf Accessed January 2002

Luis S NobleM.D. 

Associate Clinical Professor, Department of Obstetrics and Gynecology, Texas Tech University Medical Center, Medical Director of Southwest Center for Reproductive Health

El Paso, TX 79912

Email: lsprime@elp.rr.com