Gynecology_Novak

Gynecology_Novak. Postpartum Thyroid Postpartum thyroid dysfunction is much more common than recognized; it is often difficult Dysfunction to diagnose because its symptoms appear 1 to 8 months postpartum and are often confused with postpartum depression and difficulties adjusting to the demands of the neonate and infant. Postpartum thyroiditis appears to be caused by the combination of a rebounding immune system in the postpartum state and the presence of thyroid autoantibodies. Histologically, Table 31.15 Guidelines for TSHRAb Testing During Pregnancy with Previously Treated Graves Disease 1. In the woman with antecedent Graves disease in remission after ATD treatment, the risk for fetal–neonatal hyperthyroidism is negligible, and systematic measurement of TSHRAb is not necessary. Thyroid function should be evaluated during pregnancy to detect an unlikely but possible recurrence. In that case, TSHRAb assay is mandatory.


Gynecology_Novak

Gynecology_Novak. 2. In the woman with antecedent Graves disease previously treated with radioiodine or thyroidectomy and regardless of the current thyroid status (euthyroidism with or without thyroxine substitution), TSHRAb should be measured early in pregnancy to evaluate the risk for fetal hyperthyroidism. If the TSHRAb level is high, careful monitoring of the fetus is mandatory for the early detection of signs of thyroid overstimulation (tachycardia, impaired growth rate, oligohydramnios, goiter). Cardiac echography and measurement of circulatory velocity may be confirmatory. Ultrasonographic measurements of the fetal thyroid have been defined from 20 weeks gestational age but require a well-trained operator, and thyroid visibility may be hindered because of fetal head position. Color Doppler ultrasonography is helpful in evaluating thyroid hypervascularization. Because of the potential risks of fetal-neonatal hyperthyroid cardiac insufficiency and the inability to measure the degree of


Gynecology_Novak

Gynecology_Novak. ultrasonography is helpful in evaluating thyroid hypervascularization. Because of the potential risks of fetal-neonatal hyperthyroid cardiac insufficiency and the inability to measure the degree of hyperthyroidism in the mother because of previous thyroid ablation, it may be appropriate to consider direct diagnosis in the fetus. Fetal blood sampling through cordocentesis is feasible as early as 25 to 27 weeks gestation with less than 1% adverse effects (fetal bleeding, bradycardia, infection, spontaneous abortion, in utero death) when performed by experienced clinicians. ATD administration to the mother may be considered to treat the fetal hyperthyroidism.


Gynecology_Novak

Gynecology_Novak. 3. In the woman with concurrent hyperthyroid Graves disease, regardless of whether it has preceded the onset of pregnancy, ATD treatment should be monitored and adjusted to keep free T4 in the high-normal range to prevent fetal hypothyroidism and minimize toxicity associated with higher doses of these medications. TSHR-Ab should be measured at the beginning of the last trimester, especially if the required ATD dosage is high. If the TSHRAb assay is negative or the level low, fetal–neonatal hyperthyroidism is rare. If antibody levels are high (TBII ≥40 U/L or TSAb ≥300%), evaluation of the fetus for hyperthyroidism is required. In this condition, there is usually a fair correlation between maternal and fetal thyroid function such that monitoring the ATD dosage according to the mother’s thyroid status is appropriate for the fetus. In some cases in which a high dose of ATD >20 mg/d of methimazole or >300 mg/d of propylthiouracil [PTU]) is necessary, there is a risk of goitrous


Gynecology_Novak

Gynecology_Novak. thyroid status is appropriate for the fetus. In some cases in which a high dose of ATD >20 mg/d of methimazole or >300 mg/d of propylthiouracil [PTU]) is necessary, there is a risk of goitrous hypothyroidism in the fetus, which might be indistinguishable from goitrous Graves disease. The correct diagnosis relies on the assay of fetal thyroid hormones and TSH, which allows for optimal treatment.


Gynecology_Novak

Gynecology_Novak. 4. In any woman who has previously given birth to a newborn with hyperthyroidism, a TSHR-Ab assay should be performed early in the course of pregnancy. TSHRAb, thyroid-stimulating hormone receptor antibodies; ATD, autoimmune thyroid disease; T4, thyroxine; TBII, TSH-binding inhibitory immunoglobulin; TSAb, thyroid-stimulating antibody. lymphocytic infiltration and inﬂammation are found and anti-TPO antibodies are often present (419,420). The following are criteria for the diagnosis of postpartum thyroiditis: (i) no history of thyroid hormonal abnormalities either before or during pregnancy, (ii) documented abnormal TSH level (either depressed or elevated) during the first year postpartum, and (iii) absence of a positive TSH-receptor antibody titer (Graves disease) or a toxic nodule. A number of studies describe clinical and biochemical evidence of postpartum thyroid dysfunction in 5% to 10% of new mothers (421,422).


Gynecology_Novak

Gynecology_Novak. Postpartum thyroiditis usually begins with a transient hyperthyroid phase between 6 weeks and 6 months postpartum followed by a hypothyroid phase. Only one-fourth of the cases follow this classic clinical picture, and more than one-third have either hyperthyroidism or hypothyroidism alone. Individuals with type 1 diabetes have a threefold increased risk of developing postpartum thyroiditis. Women with a history of postpartum thyroiditis in a previous pregnancy have nearly a 70% chance of recurrence in a subsequent pregnancy. Although psychotic episodes are rare, postpartum thyroid dysfunction should be considered in all women with postpartum psychosis. The thyrotoxic phase may be subclinical and overlooked, particularly in areas where iodine intake is low (423). Unlike patients with Graves disease, those with the hyperthyroidism caused by postpartum thyroiditis have a low level of radioactive isotope uptake. Women with a history of postpartum thyroiditis should be followed closely as


Gynecology_Novak

Gynecology_Novak. disease, those with the hyperthyroidism caused by postpartum thyroiditis have a low level of radioactive isotope uptake. Women with a history of postpartum thyroiditis should be followed closely as they have a 20% risk of permanent hypothyroidism immediately following the onset of thyroiditis, up to a 60% risk of permanent


Gynecology_Novak

Gynecology_Novak. Antithyroid Antibodies and Disorders of Reproduction hypothyroidism over the next 5 to 10 years, and up to a 70% risk of postpartum thyroiditis in future pregnancies (424,425). The absence of thyroid tenderness, pain, fever, elevated sedimentation rate, and leukocytosis helps to rule out subacute thyroiditis (de Quervain thyroiditis). Evaluation of TSH, T4,T3,T3 resin uptake, and antimicrosomal antibody titer confirms the diagnosis. Most patients are diagnosed during the hypothyroid phase and require 6 to 12 months of thyroxine replacement if they are symptomatic (370). Because approximately 60% of women develop permanent hypothyroidism, TSH should be evaluated following discontinuation of replacement therapy. Rarely, patients are diagnosed during the hyperthyroid phase (426). Antithyroid medications are not routinely used for these women. Propranolol may be used for relief of symptoms but should be used with appropriate counseling in nursing mothers.


Gynecology_Novak

Gynecology_Novak. Women who have antithyroid autoantibodies before and after conception appear to be at an increased risk for spontaneous abortion (427,428). Nonorgan-specific antibody production and pregnancy loss are documented in cases of antiphospholipid abnormalities (429). The concurrent presence of organ-specific thyroid antibodies and nonorgan-specific autoantibody production is not uncommon (429–431). In cases of recurrent pregnancy loss, thyroid autoantibodies may serve as peripheral markers of abnormal T-cell function and further implicate an immune component as the cause of reproductive failure. The clinical implications of these findings in the management of patients with recurrent pregnancy loss are not known. Recurrent pregnancy loss is covered in Chapter 33.


Gynecology_Novak

Gynecology_Novak. Thyroid Nodules Thyroid nodules are a common finding on physical examination and are demonstrated by high frequency ultrasonography in over two-thirds of patients (432). Occasionally such nodules are functional, and clinical and laboratory evaluation should be applied to distinguish these nodules from nonfunctional nodules, which are occasionally malignant. For nonfunctional “cold” nodules, fine-needle biopsy and aspiration are required to rule out malignancy. In the case of indeterminate aspirates, 2% to 20% are malignant; therefore, surgical biopsy often is indicated (433). Molecular diagnosis screening of the BRAF mutation improves the diagnosis of cancer on fine-needle aspiration (434).


Gynecology_Novak

Gynecology_Novak. Patients with Turner syndrome (and other forms of hypergonadotropic hypogonadism associated with abnormalities of the second sex chromosome) exhibit a high prevalence of autoimmune thyroid disorders. Approximately 50% of adult patients with Turner syndrome have antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) autoantibodies. Of these patients, approximately 30% will develop subclinical or clinical hypothyroidism. The disorder is indistinguishable from Hashimoto thyroiditis. A susceptibility locus for Graves disease is noted on chromosome X (435). Because of the increased risk of autoimmune thyroid disease, it is recommended that women with Turner syndrome be screened with yearly TSH testing starting at the age of 4 (436).


Gynecology_Novak

Gynecology_Novak. Down syndrome, caused by an extra chromosome 21, is characterized by an atypical body habitus, mental retardation, cardiac malformations, an increased risk of leukemia, and a reduced life expectancy. The extra chromosome is almost always of maternal origin. Autoimmune thyroid disorders are more common in patients with Down syndrome than in the general population. The gene for autoimmune polyglandular syndrome I (APECED) was mapped to chromosome 21 and is thought to be a transcription factor involved in immune regulation (AIRE). This gene may play a role in the development of autoimmune thyroid disease in these patients (437). Hashimoto thyroiditis is the most common type of thyroid disease in individuals with Down syndrome. Hypothyroidism develops in as many as 50% of patients older than age 40 with Down syndrome. These clinical syndromes and other evidence suggest part of the genetic susceptibility to Hashimoto thyroiditis may reside on chromosomes X and 21. Because of the increased


Gynecology_Novak

Gynecology_Novak. age 40 with Down syndrome. These clinical syndromes and other evidence suggest part of the genetic susceptibility to Hashimoto thyroiditis may reside on chromosomes X and 21. Because of the increased frequency of hypothyroidism associated with Down syndrome, it is recommended to screen individuals at 6 months, 12 months, and then annually thereafter (372).


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Gynecology_Novak. 1. Verkauf BS, Von Thron J, O’Brien WF. Clitoral size in normal women. Obstet Gynecol 1992;80:41–44. 2. Ferrimann D, Gallway JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440. 3. Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005; 353:2578–2588. 4. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93:1105– 1120. 5. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–3672. 6. Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrin Metab 2009;94:2835– 2840. 7.


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Gynecology_Novak. Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrin Metab 2009;94:2835– 2840. 7. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009;91:456–488. 8. Rittmaster RS. Clinical relevance of testosterone and dihydrotestosterone metabolism in women. AmJ Med 1995;98:17S–21S. 9. Rainey WE, Nakamura Y. Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol 2008;108:281–286. 10. Siegel SF, Finegold DN, Lanes R, et al. ACTH stimulation tests and plasma dehydroepiandrosterone sulfate levels in women with hirsutism. N Engl J Med 1990;323:849–854. 11.


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Gynecology_Novak. 10. Siegel SF, Finegold DN, Lanes R, et al. ACTH stimulation tests and plasma dehydroepiandrosterone sulfate levels in women with hirsutism. N Engl J Med 1990;323:849–854. 11. d’Alva CB, Abiven-Lepage G, Viallon V, et al. Sex steroids in androgen-secreting adrenocortical tumors: clinical and hormonal features in comparison with non-tumoral causes of androgen excess. Eur J Endocrinol 2008;159:641–647. 12. Youden WJ. Index for rating diagnostic tests. Cancer 1950;3:32–35. 13. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–1236. 14. Toulis KA, Goulis DG, Kolibianakis EM, et al. Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril 2009;92:667–677. 15. Practice Committee of the American Society of Reproductive Medicine. The evaluation and treatment of androgen excess. Fertil Steril 2006;86:S173–S180. 16.


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Gynecology_Novak. 15. Practice Committee of the American Society of Reproductive Medicine. The evaluation and treatment of androgen excess. Fertil Steril 2006;86:S173–S180. 16. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008;358:47–54. 17. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181–191. 18. Zawadzki JK, Danif A. Diagnostic criteria for polycystic ovary syndrome towards a rational approach. In: Dunaif A, Givens JR, Hasetine FP, et al., eds. Polycystic ovary syndrome. Cambridge: Blackwell Science, 1992:377–384. 19. 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;81:19–25. 20. Goldzieher JW, Axelrod LR. Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 1963;14:631–653. 21.


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Gynecology_Novak. 20. Goldzieher JW, Axelrod LR. Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 1963;14:631–653. 21. Aono T, Miyazaki M, Miyake A, et al. Responses of serum gonadotrophins to LH-releasing hormone and oestrogens in Japanese women with polycystic ovaries. Acta Endocrinol (Copenh) 1977;85:840–849. 22. Serafini P, Ablan F, Lobo RA. 5-Alpha-reductase activity in the genital skin of hirsute women. J Clin Endocrinol Metab 1985;60:349–355. 23. Lobo RA, Goebelsmann U, Horton R. Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 1983;57:393–397. 24. Pall M, Azziz R, Beires J, et al. The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylasedeficient nonclassic adrenal hyperplasia. Fertil Steril 2010;94:684– 689. 25.


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Gynecology_Novak. 25. Carmina E, Lobo RA. Do hyperandrogenic women with normal menses have polycystic ovary syndrome? Fertil Steril 1999;71:319– 322. 26. Peserico A, Angeloni G, Bertoli P, et al. Prevalence of polycystic ovaries in women with acne. Arch Dermatol Res 1989;281:502–503. 27. Polson DW, Adams J, Wadsworth J, et al. Polycystic ovaries—a common finding in normal women. Lancet 1988;1:870–872. 28. Loucks TL, Talbott EO, McHugh KP, et al. Do polycysticappearing ovaries affect the risk of cardiovascular disease among women with polycystic ovary syndrome? Fertil Steril 2000;74:547– 552. 29. Hassan MA, Killick SR. Ultrasound diagnosis of polycystic ovaries in women who have no symptoms of polycystic ovary syndrome is not associated with subfecundity or subfertility. Fertil Steril 2003;80:966–975. 30. Wild RA. Obesity, lipids, cardiovascular risk, and androgen excess. Am J Med 1995;98:27S–32S. 31.


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Gynecology_Novak. 30. Wild RA. Obesity, lipids, cardiovascular risk, and androgen excess. Am J Med 1995;98:27S–32S. 31. Moran LJ, Pasquali R, Teede HJ, et al. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009;92:1966–1982. 32. Kenny SJ, Aubert RE, Geiss LS. Prevalence and incidence of non-insulin-dependent diabetes. In: Harris MI ed. Diabetes in America. Washington, DC: US National Institutes of Health, NIH Publication. No.95-1468, Bethesda MD, 1995:179–220. 33. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22:141–146. 34. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165– 169.


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Gynecology_Novak. 39. Guzick DS, Talbott EO, Sutton-Tyrrell K, et al. Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am J Obstet Gynecol 1996;174:1224–1229; discussion 9–32. 40. Birdsall MA, Farquhar CM, White HD. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann Intern Med 1997;126:32–35. 41. Danigren E, Janson PO, Johansson S, et al. Polycystic ovary syndrome and risk for myocardial infarction. Acta Obstet Cynecol Scand 1992;71:559–604. 42. Clement PB. Nonneoplastic lesions of the ovary. In: Kurman RJ, ed., Blaustein’s pathology of the female genital tract, 4th ed. New York: Springer-Verlag, 1994:559–604. 43. Rosenfield RL, Barnes RB, Cara JF, et al. Dysregulation of cytochrome P450-17 α as the cause of polycystic ovarian syndrome. Fertil Steril 1990;53:785–791. 44.


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Gynecology_Novak. 43. Rosenfield RL, Barnes RB, Cara JF, et al. Dysregulation of cytochrome P450-17 α as the cause of polycystic ovarian syndrome. Fertil Steril 1990;53:785–791. 44. McNatty KP, Makris A, DeGrazia C, et al. The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue, and stromal tissue from human ovaries in vitro. J Clin Endocrinol Metab 1979;49:687–699. 45. Lobo RA, Kletzky OA, Campeau JD, et al. Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome. Fertil Steril 1983;39:674–678. 46. Chang RJ, Laufer LR, Meldrum DR, et al. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 1983;56:897–903. 47. Biffignandi P, Massucchetti C, Molinatti GM. Female hirsutism: pathophysiological considerations and therapeutic implications. Endocr Rev 1984;5:498–513. 48.


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Gynecology_Novak. 47. Biffignandi P, Massucchetti C, Molinatti GM. Female hirsutism: pathophysiological considerations and therapeutic implications. Endocr Rev 1984;5:498–513. 48. Rittmaster RS. Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist leuprolide. J Clin Endocrinol Metab 1988;67:651– 655. 49. Lobo RA. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obstet Gynecol 1991;34:817–826. 50. Hoffman DI, Klove K, Lobo RA. The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril 1984;42:76–81. 51. Lobo RA. The role of the adrenal in polycystic ovary syndrome. Semin Reprod Endocrinol 1984:251–264. 52. Deslypere JP, Verdonck L, Vermeulen A. Fat tissue: a steroid reservoir and site of steroid metabolism. J Clin Endocrinol Metab 1985;61:564–570. 53.


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Gynecology_Novak. 52. Deslypere JP, Verdonck L, Vermeulen A. Fat tissue: a steroid reservoir and site of steroid metabolism. J Clin Endocrinol Metab 1985;61:564–570. 53. Edman CD, MacDonald PC. Effect of obesity on conversion of plasma androstenedione to estrone in ovulatory and anovulatory young women. Am J Obstet Gynecol 1978;130:456–461. 54. Schneider J, Bradlow HL, Strain G, et al. Effects of obesity on estradiol metabolism: decreased formation of nonuterotropic metabolites. J Clin Endocrinol Metab 1983;56:973–978. 55. Judd HL. Endocrinology of polycystic ovarian disease. Clin Obstet Gynecol 1978;21:99–114. 56. Bracero N, Zacur HA. Polycystic ovary syndrome and hyperprolactinemia. Obstet Gynecol Clin North Am 2001;28:77–84. 57. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol 2009;25:603–609. 58.


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Gynecology_Novak. 57. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol 2009;25:603–609. 58. Urbanek M, Legro RS, Driscoll DA, et al. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A 1999;96:8573–8578. 59. Gharani N, Waterworth DM, Batty S, et al. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 1997;6:397–402. 60. Ehrmann DA, Schwarz PE, Hara M, et al. Relationship of calpain10 genotype to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:1669–1673. 61. Tucci S, Futterweit W, Concepcion ES, et al. Evidence for association of polycystic ovary syndrome in Caucasian women with a marker at the insulin receptor gene locus. J Clin Endocrinol Metab 2001;86:446–449. 62.


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Gynecology_Novak. 62. Hogeveen KN, Cousin P, Pugeat M, et al. Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. J Clin Invest 2002;109:973–981. 63. Biyasheva A, Legro RS, Dunaif A, et al. Evidence for association between polycystic ovary syndrome (PCOS) and TCF7L2 and glucose intolerance in women with PCOS and TCF7L2. J Clin Endocrinol Metab 2009;94:2617–2625. 64. Waterworth DM, Bennett ST, Gharani N, et al. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 1997;349:986–990. 65. Ewens KG, Stewart DR, Ankener W, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab 2010;95:2306–2315. 66. Wood JR, Nelson VL, Ho C, et al. The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem 2003;278:26380– 26390. 67.


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Gynecology_Novak. 77. Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, et al. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005;90:6364–6369. 78. Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 2001;111:607–613. 79. Valkenburg O, Steegers-Theunissen RP, Smedts HP, et al. A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case-control study. J Clin Endocrinol Metab 2008;93:470–476. 80. Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010;95:2038–2049. 81.


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Gynecology_Novak. 87. Schildkraut JM, Schwingl PJ, Bastos E, et al. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 1996;88(Pt 1):554–559. 88. Thomson RL, Buckley JD, Lim SS, et al. Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome. Fertil Steril 2009;94:1812– 1916. 89. Kerchner A, Lester W, Stuart SP, et al. Risk of depression and other mental health disorders in women with polycystic ovary syndrome: a longitudinal study. Fertil Steril 2009;91:207–212. 90. Futterweit W. An endocrine approach obesity. In: Simopoulos AP, Vanltallie TB, Gullo SP, et al., eds. Obesity: new directions in assessment and management. New York: Charles Press, 1994: 96–121. 91.


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Gynecology_Novak. Edan G, Massart C, Hody B, et al. Optimum duration of antithyroid drug treatment determined by assay of thyroid stimulating antibody in patients with Graves’ disease. BMJ 1989;298:359–361. 400. Anonymous. Propylthioruracil-related liver toxicity: public workshop. Washington DC: Food and Drug Administration and the American Thyroid Association, 2009. 401. Rivkees SA. 63 years and 715 days to the “boxed warning”: unmasking of the propylthiouracil problem. Int J Pediatr Endocrinol 2010 (in press). 402. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009;94:1881–1882. 403. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol 2006;108:1283–1292. 404. Milham S Jr. Scalp defects in infants of mothers treated for hyperthyroidism with methimazole or carbimazole during pregnancy. Teratology 1985;32:321. 405. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354–2359.


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Gynecology_Novak. 405. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354–2359. 406. Karlsson FA, Axelsson O, Melhus H. Severe embryopathy and exposure to methimazole in early pregnancy. J Clin Endocrinol Metab 2002;87:947–949. 407. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352:905–917. 408. Barbero P, Valdez R, Rodriguez H, et al. Choanal atresia associated with maternal hyperthyroidism treated with methimazole: a case-control study. Am J Med Genet A 2008;146A:2390–2395. 409. Van Dijke CP, Heydendael RJ, De Kleine MJ. Methimazole, carbimazole, and congenital skin defects. Ann Intern Med 1987;106:60– 61. 410. Mao X-M, Li H-Q, Li Q, et al. Prevention of relapse of Graves’ disease by treatment with an intrathyroid injection of dexamethasone. J Clin Endocrinol Metab 2009;94:4984–4991. 411. Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995;5:425–434. 412.


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Gynecology_Novak. 411. Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995;5:425–434. 412. Padmanabhan LD, Mhaskar R, Mhaskar A, et al. Trophoblastic hyperthyroidism. J Assoc Physicians India 2003;51:1011–1013. 413. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;351:241–249. 414. Klein RZ, Sargent JD, Larsen PR, et al. Relation of severity of maternal hypothyroidism to cognitive development of offspring. J Med Screen 2001;8:18–20. 415. Zakarija M, Garcia A, McKenzie JM. Studies on multiple thyroid cell membrane-directed antibodies in Graves’ disease. J Clin Invest 1985;76:1885–1891. 416. Zakarija M, McKenzie JM. Thyroid-stimulating antibody (TSAb) of Graves’ disease. Life Sci 1983;32:31–44. 417.


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Gynecology_Novak. 416. Zakarija M, McKenzie JM. Thyroid-stimulating antibody (TSAb) of Graves’ disease. Life Sci 1983;32:31–44. 417. Tanaka T, Tamai H, Kuma K, et al. Gonadotropin response to luteinizing hormone releasing hormone in hyperthyroid patients with menstrual disturbances. Metabolism 1981;30:323–326. 418. Polak M, Le Gac I, Vuillard E, et al. Fetal and neonatal thyroid function in relation to maternal Graves’ disease. Best Pract Res Clin Endocrinol Metab 2004;18:289–302. 419. Iwatani Y, Amino N, Tamaki H, et al. Increase in peripheral large granular lymphocytes in postpartum autoimmune thyroiditis. Endocrinol Jpn 1988;35:447–453. 420. Vargas MT, Briones-Urbina R, Gladman D, et al. Antithyroid microsomal autoantibodies and HLA-DR5 are associated with postpartum thyroid dysfunction: evidence supporting an autoimmune pathogenesis. J Clin Endocrinol Metab 1988;67:327– 333. 421.


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Gynecology_Novak. 421. Amino N, Mori H, Iwatani Y, et al. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N Engl J Med 1982;306:849–852. 422. Hayslip CC, Fein HG, O’Donnell VM, et al. The value of serum antimicrosomal antibody testing in screening for symptomatic postpartum thyroid dysfunction. Am J Obstet Gynecol 1988;159:203– 209. 423. Jansson R. Postpartum thyroid disease. Mol Biol Med 1986;3:201– 211. 424. Lucas A, Pizarro E, Granada ML, et al. Postpartum thyroiditis: long-term follow-up. Thyroid 2005;15:1177–1181. 425. Lazarus JH, Ammari F, Oretti R, et al. Clinical aspects of recurrent postpartum thyroiditis. Br J Gen Pract 1997;47:305–308. 426. Walfish PG, Chan JY. Post-partum hyperthyroidism. Clin Endocrinol Metab 1985;14:417–447. 427. Stagnaro-Green A, Roman SH, Cobin RH, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990;264:1422–1425. 428.


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Gynecology_Novak. 427. Stagnaro-Green A, Roman SH, Cobin RH, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990;264:1422–1425. 428. Glinoer D, Soto MF, Bourdoux P, et al. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab 1991;73:421–427. 429. Maier DB, Parke A. Subclinical autoimmunity in recurrent aborters. Fertil Steril 1989;51:280–285. 430. Magaro M, Zoli A, Altomonte L, et al. The association of silent thyroiditis with active systemic lupus erythematosus. Clin Exp Rheumatol 1992;10:67–70. 431. LaBarbera AR, Miller MM, Ober C, et al. Autoimmune etiology in premature ovarian failure. Am J Reprod Immunol Microbiol 1988;16:115–122. 432. Guth S, Theune U, Aberle J, et al. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest 2009;39:699–706. 433.


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Gynecology_Novak. 432. Guth S, Theune U, Aberle J, et al. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest 2009;39:699–706. 433. McHenry CR, Walfish PG, Rosen IB. Non-diagnostic fine needle aspiration biopsy: a dilemma in management of nodular thyroid disease. Am Surg 1993;59:415–419. 434. Nikiforova MN, Nikiforov YE. Molecular diagnostics and predictors in thyroid cancer. Thyroid 2009;19:1351–1361. 435. Barbesino G, Tomer Y, Concepcion ES, et al. Linkage analysis of candidate genes in autoimmune thyroid disease. II. Selected gender-related genes and the X-chromosome. International Consortium for the Genetics of Autoimmune Thyroid Disease. J Clin Endocrinol Metab 1998;83:3290–3295. 436. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487–1495. 437.


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Gynecology_Novak. 436. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487–1495. 437. Aaltonen J, Bjorses P, Sandkuijl L, et al. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet 1994;8:83–87. Mira Aubuchon Richard O. Burney Danny J. Schust Mylene W.M. Yao The physician’s initial encounter with the infertile couple is extremely important because it sets the tone for subsequent evaluation and treatment. Factors from either or both partners may contribute to difficulties in conceiving; therefore, it is important to consider all possible diagnoses before pursuing invasive treatment.


Gynecology_Novak

Gynecology_Novak. The main causes of infertility include male factor, decreased ovarian reserve, ovulatory disorders (ovulatory factor), tubal injury, blockage, or paratubal adhesions (including endometriosis with evidence of tubal or peritoneal adhesions), uterine factors, systemic conditions (including infections or chronic diseases such as autoimmune conditions or chronic renal failure), cervical and immunologic factors, and unexplained factors (including endometriosis with no evidence of tubal or peritoneal adhesions). Basic investigations that should be performed before starting any infertility treatment are semen analysis, confirmation of ovulation, and the documentation of tubal patency.


Gynecology_Novak

Gynecology_Novak. Basic investigations that should be performed before starting any infertility treatment are semen analysis, confirmation of ovulation, and the documentation of tubal patency. Male factor is the sole cause of infertility in 20% of infertile couples and may be a contributing factor in as many as 40% of cases. Treatment of reversible endocrine or infectious causes of subfertility, such as sexually transmitted diseases and thyroid disorders, tends to be efficacious. Intrauterine insemination (IUI) is the best studied and most widely practiced of all the insemination techniques. Intracytoplasmic sperm injection (ICSI) has allowed couples with male factor infertility to achieve assisted reproductive technology (ART) pregnancy outcomes that are comparable with those of couples with non–male factor infertility using conventional in vitro fertilization (IVF) treatment.


Gynecology_Novak

Gynecology_Novak. An association between the age of the woman and reduced fertility is well documented. The decline in fecundability begins in the early 30s and accelerates during the late 30s and early 40s. Disorders of ovulation account for about 20% to 40% of all cases of female infertility. These disorders are generally among the most easily diagnosed and treatable causes of infertility. The most common cause of oligo-ovulation and anovulation—both in the general population and among women presenting with infertility—is polycystic ovarian syndrome (PCOS). Tubal and peritoneal factors account for 30% to 40% of cases of female infertility. Cervical factor is estimated to be a cause of infertility in no more than 5% of infertile couples. Uterine pathologies constitute the etiologic factor in infertility in as many as 15% of couples seeking treatment and are diagnosed in as many as 50% of infertile patients. Leiomyomas have not been shown to be a direct cause of infertility.


Gynecology_Novak

Gynecology_Novak. All methods of ART, by definition, involve interventions to retrieve oocytes. These techniques include IVF, ICSI, gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), cryopreserved embryo transfers, and the use of donor oocytes. Because of improved success rates associated with IVF-embryo transfer, the performance of GIFT and ZIFT has declined. Multiple gestation, especially higher-order multiple gestation, is a serious complication of infertility treatment and has tremendous medical, psychological, social, and financial implications and complications. Fortunately, recent studies have not shown an increased risk for breast, uterine, or ovarian cancer secondary to medications used for superovulation in the treatment of infertility. Information on the Society for Assisted Reproductive Technology (SART) and registered ART clinics are accessible on the Internet.


Gynecology_Novak

Gynecology_Novak. Infertility is defined as 1 year of unprotected intercourse without pregnancy (1). This condition may be further classified as primary infertility, in which no previous pregnancies have occurred, and secondary infertility, in which a prior pregnancy, although not necessarily a live birth, has occurred. About 90% of couples should conceive within 12 months of unprotected intercourse (2). Subfertility refers to couples who conceive after 12 months of attempted impregnation (2). Fecundability refers to the probability of pregnancy per cycle, which is considered to be at 20% in fertile couples (1). Fecundity refers to the probability of achieving a live birth in a single cycle and, by definition, has a value lower than fecundability. The diagnosis of impaired fecundity has been proposed to include couples with 36 months or more without conception or physical inability or difficulty in having a child; however, there is currently no clear consensus on any of these terms (3–5).


Gynecology_Novak

Gynecology_Novak. Twenty-one percent of couples in the United States are expected to experience infertility in their lifetimes, with a current prevalence of 7.4% (6). In 2002, over 7 million US women age 22 to 44 reported using infertility services in their lifetimes (7). Once diagnosed, 13% of couples will not pursue treatment (8). The diagnosis of impaired fecundity has been rising, reaching 15% in 2002 and largely resulting from the trend toward delayed childbearing in developed countries (3). Worldwide, male factor accounts for 51.2% and tubal blockage for 25% to 35% of infertility and subfertility (conception after attempting for 1 year) (9,10). In Europe, ovulatory dysfunction accounts for 21% to 32%, male factor 19% to 57%, tubal factor 14% to 26%, unexplained 8% to 30%, endometriosis 4% to 6%, and combined male and female factors 34.4% of infertility (11–13). The odds of infertility increase with female age and in general among patients who have not graduated from college (14). The high cost of


Gynecology_Novak

Gynecology_Novak. male and female factors 34.4% of infertility (11–13). The odds of infertility increase with female age and in general among patients who have not graduated from college (14). The high cost of infertility treatment is a barrier for many in the United States where insurance typically does not cover these services (15). Language and other cultural barriers affect access for many minority groups (15,16). The women most likely to obtain specialized treatment are 30 years of age or older, white, married, and of relatively high socioeconomic status (7).


Gynecology_Novak

Gynecology_Novak. The physician’s initial encounter with the infertile couple is of primary importance because it sets the tone for subsequent evaluation and treatment. Ideally, both partners should be present at this first visit. It cannot be overemphasized that infertility is a problem of the couple. The presence of both partners, beginning with the initial evaluation, jointly involves them in the therapeutic process. This essential shared involvement demonstrates that the physician is receptive to the partner’s needs as well as those of the patient and offers the partner an opportunity to ask questions and voice concerns.


Gynecology_Novak

Gynecology_Novak. The physician should obtain a complete medical, surgical, and gynecologic history from the woman. Specifically, information regarding menstrual cycle regularity, pelvic pain, and previous pregnancy outcomes is important. Risk factors for infertility, such as a history of pelvic inﬂammatory disease (PID) or pelvic surgery, should be reviewed. A history of intrauterine exposure to diethylstilbestrol (DES) is significant. In addition, a review of systems relevant to pituitary, adrenal, and thyroid function is useful. Questions regarding galactorrhea, hirsutism, and changes in weight are particularly relevant. A directed history, including developmental defects such as undescended testes, past genital surgery, infections (including mumps orchitis), previous genital trauma, and medications should be obtained from the male partner. A history of occupational exposures that might affect the reproductive function of either partner is important, as is information about coital frequency,


Gynecology_Novak

Gynecology_Novak. should be obtained from the male partner. A history of occupational exposures that might affect the reproductive function of either partner is important, as is information about coital frequency, dyspareunia, and sexual dysfunction. Finally, information should be obtained on any family history of infertility, premature ovarian failure, congenital or developmental defects, mental retardation, and hereditary conditions relevant to preconceptional planning, such as cystic fibrosis, thalassemias, and Tay Sachs disease.


Gynecology_Novak

Gynecology_Novak. The initial interview provides the physician with the opportunity to assess the emotional impact of infertility on the couple. It presents a time for the physician to emphasize the emotional support available to the couple as they proceed with the diagnostic evaluation and suggested treatments. In some cases, referral to a trained social worker or psychologist may be beneficial. The physical examination of the woman should be thorough, with particular attention given to height, weight, body habitus, hair distribution, thyroid gland, and pelvic examination. Referral of the male partner to a urologist for examination often is beneficial if historic information or subsequent evaluation suggests an abnormality. This initial encounter is an excellent time to outline the general causes of infertility and to discuss subsequent diagnostic and treatment plans (Figs. 32.1–32.3).


Gynecology_Novak

Gynecology_Novak. The basic investigations that ideally should be performed before starting any infertility treatment are semen analysis, confirmation of ovulation, and the documentation of tubal patency. Other noninfertility assessments should include rubella immunity testing (17). If a patient with severe systemic illness, such as renal failure, liver failure, or cancer, wishes to conceive, careful preconceptional assessment and counseling is advisable because the risks of fertility treatment and pregnancy can be substantial. Causes of Infertility The main causes of infertility include: 1. 2. 3. 4. 5. 6. 7.


Gynecology_Novak

Gynecology_Novak. Causes of Infertility The main causes of infertility include: 1. 2. 3. 4. 5. 6. 7. Infertility one year or longer Initial evaluation, history, physical exam Irregular menses No ovulation by tests HSG  Unilateral or bilateral tubal blockage Normal evaluation  History  Physical exam  Ovulation tests  HSG HSG or hysteroscopy  Structural abnormality of the endometrial cavity Abnormal semen analysis Unexplained infertility ± endometriosis  Counseling and Psychosocial support  If multiple factors present, investigate and manage concurrently Figure 32.1 Diagnostic and treatment algorithm: infertility. HSG, hysterosalpingography. (From Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.)