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.
KEYWORDS
Recurrent pregnancy loss - endocrine factors - prolactin - thyroid - luteal phase
- ovarian reserve
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