Researchers from Brigham and Women’s Hospital (BWH) found that women currently taking thyroid hormones need to increase their dose early in a pregnancy – on average, by eight weeks gestation – to prevent maternal hypothyroidism and possible harm to the fetus. These findings, which will be published in the July 15 issue of The New England Journal of Medicine, provide physicians – including endocrinologists, obstetricians and gynecologists, and primary care physicians – with new evidence that the necessary dosage of thyroid medication increases shortly after conception, and often prior to a woman’s first obstetrical visit. Hypothyroidism, a deficiency of the thyroid hormone, is found in more than 5 million Americans, with as many as 10 percent of all women afflicted with some degree of thyroid hormone deficiency. Thyroid medications such as levothyroxine are essentially identical to the thyroid hormone made by the normal thyroid gland and therefore perfectly safe to take during pregnancy.

An estimated 1 to 2 percent of all pregnant women receive levothyroxine therapy for hypothyroidism. Given that maternal hypothyroidism is associated with an increased risk of premature delivery, placental abruption, and pregnancy-induced hypertension, as well as a probable increased risk of cognitive and developmental deficiencies in the developing fetus, women with a history of thyroid dysfunction must be counseled to adjust their thyroid hormone dose as soon as pregnancy is confirmed.

According to the study’s lead author, Erik K. Alexander, associate physician at BWH and instructor of medicine at Harvard Medical School, “At a minimum, an estimated 16,000 to 32,000 pregnant women annually may be impacted by this data.

Pregnancy causes an estimated 30 to 50 percent increase in the daily requirement of thyroid hormone. What has been unclear is at what point the increased requirement occurs during gestation. It appears that thyroid hormone doses need to be adjusted as soon as pregnancy is confirmed, usually prior to the first obstetrical visit.”

In this study, Alexander and his colleagues monitored 19 women with known hypothyroidism throughout pregnancy, with the goal of identifying the precise timing and pattern of increased thyroid hormone requirement during gestation.

Among this population, 20 pregnancies were recorded that resulted in 17 full-term births. The researchers found that 85 percent of pregnancies required a nearly 50 percent increase in the dosage of levothyroxine, and this occurred almost exclusively during the first trimester of the pregnancy. Typically, the first dose change occurred at eight weeks, but occurred even earlier in several patients – especially those pregnant via assisted reproductive techniques.

Alexander also found that levothyroxine requirements plateaued at 16 weeks, pointing to the need for stringent monitoring of blood thyroid hormone levels during early pregnancy, with less monitoring midway through pregnancy until delivery.

http://www.hno.harvard.edu/gazette/2004/07.22/99-thyroid.html

Read here: http://www.merck.de/servlet/PB/menu/1356910/index.html

The association between thyroid autoimmunity (TAI) and the risk of miscarriage has recently been examined in three comprehensive review articles. In the review by Poppe & Glinoer published in 2003, the available information from thirteen studies comparing the risk of a miscarriage with the presence (versus the absence) of TAI clearly led the authors to the conclusion that TAI (without overt thyroid dysfunction) was significantly associated with a 3-5-fold increase in overall miscarriage rate ¹²¹.Complete article:

AUTOIMMUNE THYROID DISEASE AND PREGNANCY

Effects of pregnancy on immune function

Many autoimmune diseases have been shown to be affected by pregnancy. In normal pregnancy, the maternal immune system undergoes major adjustments to allow the maintenance of what may be immunologically considered a foreign body (the developing fetus) with 50 % paternal genes. The alterations in maternal immune system which permit the successful implantation of the fetal allograft have not yet been definitively identified, but the factors leading to this immune tolerance seem likely to be partially responsible for the generalized improvement in autoimmune thyroid disease, which is so characteristic of the pregnant state. In normal pregnancy, along with the overall dampening of the immune system, maternal immune responses have been shown to shift dramatically, moving immune responses away from Th1 cell-mediated immunity and reducing antibody-production, hence leading to a pattern were both arms of immune responses are reduced ⁹⁸. Table 14-2 summarizes the main effects of pregnancy on lymphocyte subsets in patients with and without thyroid autoantibodies ^99-103. The precise mechanisms by which thyroid antibodies, as well as those against other tissues, are suppressed during pregnancy, and often exacerbate after delivery, remain obscure. Presumably, the rapid reduction in immune suppressor functions following delivery leads to the reestablishment and exacerbation of these conditions. The postpartum exacerbation of autoimmune thyroid disease is one of the most striking examples of this phenomenon. This pattern is especially well illustrated in patients with Hashimoto’s disease, in euthyroid patients with positive thyroid antibodies who develop postpartum thyroid dysfunction, and in those with Graves’ disease who frequently present exacerbations or recurrences of thyrotoxicosis following parturition ^104-114.

Thyroid autoimmunity and disorders of female reproduction

Infertility

Infertility is defined as the inability to conceive after one year of regular intercourse without contraception. The prevalence of infertility is estimated between 12 and 14% and has remained stable in recent years. Infertility evaluation usually identifies different causes, including male infertility (30%), female infertility (35%), the combination of both (20%), and finally unexplained or ‘idiopathic’ infertility (15%). Female causes of infertility comprise endometriosis, tubal disease and ovulatory dysfunction. Among negative prognostic factors influencing fertility, immunologic factors may play an important role in the reproduction processes of fertilization, implantation and early fetal development. Different investigations support the association between reproductive failure and abnormal immunological test results, including anti-phospholipid, anti-nuclear antibodies and organ specific autoimmuity, among which the presence of anti-thyroid antibodies ^115,115bis. With regard to thyroid dysfunction, clinical (or overt) hypothyroidism is clearly associated with female infertility and, in women of reproductive age, autoimmune thyroid disease (AITD) is undoubtedly the most common cause of hypothyroidism. The association between sublinical hypothyroidism (SCH) and infertility has been evaluated in different studies, but most of these are uncontrolled and retrospective (see recent review by Poppe and Velkeniers) ^115ter. The impact of AITD without thyroid dysfunction on female infertlilty is even much less clear and the clinical relevance of such possible association remains controversial. Recently, a series of studies by Poppe et al. in Brussels have shed new light on this issue ^116-118. In a controlled prospective study of 438 consecutive infertile couples, the authors showed that female infertility was significantly associated with AITD without thyroid dysfunction, with the strongest association found for women with endometriosis (Figure 14-10). In a follow up study of the infertile couples who benefitted from Assisted Reproductive Techniques, the authors showed that while the onset of gestation was not hampered by the presence of AITD, the final outcome of the induced pregnancies was significantly lower in women with AITD because of an increase in early pregnancy loss.

The main practical question is whether one should give the benefit of l-thyroxine treatment to infertile women who present positive thyroid autoantibodies with variable degrees of thyroid insufficiency. Overt thyroid dysfunction should obviously be treated before natural conception or an assisted fertilization procedure is planned. Since SCH has a negative impact on pregnancy outcome after assisted reproduction, thyroxine treatment is also advised. Evidence on the treatment of isolated autoimmune features, without thyroid dysfunction, is insufficiently documented to advise prompt action.

Figure 10. The relative risks for positive TPO-Ab in infertile couples. The study was carried out in Brussels, in 440 succesive couples consulting for primary sterility. Female causes of infertility were significantly associated with an increased frequency of thyroid autoimmunity, particularly women with endometriosis. (Reproduced by permission from Poppe et al., Thyroid 12; 997, 2002).

Another interesting development concerns the reproductive function in males in relation with thyroid alterations. In males, hyperthyroidism appears to cause alterations in spermatogenesis and fertility, and most of the studies conducted so far have shown that male patients with thyrotoxicosis have abnormalities in seminal parameters, mainly sperm motility. Furthermore, these abnormalities improve or normalize when patients return to euthyroidism. Concerning hypothyroidism in males, severe and prolonged thyroid insufficiency, particularly when the onset occurs in childhood, may impair reproductive function. Also, severe juvenile hypothyroidism may be associated with precocious puberty. Finally, it appears that, overall, patho-zoospermia and astheno-zoospermia are more prevalent in infertile males who present features of AITD ^{119,120, 120bis,120ter}.

Miscarriage

The association between thyroid autoimmunity (TAI) and the risk of miscarriage has recently been examined in three comprehensive review articles. In the review by Poppe & Glinoer published in 2003, the available information from thirteen studies comparing the risk of a miscarriage with the presence (versus the absence) of TAI clearly led the authors to the conclusion that TAI (without overt thyroid dysfunction) was significantly associated with a 3-5-fold increase in overall miscarriage rate ¹²¹. In the more recent review by Stagnaro-Green & Glinoer published in 2004, a more detailed classification was carried out by examining separately: a) the association between miscarriage and TAI (five studies); b) the association between recurrent miscarriage and TAI (seven studies); and finally c) the association between early pregnancy loss after in vitro fertilization and TAI (five studies). Overall, and with few exceptions, all studies documented a statistically significant relation between TAI and increased pregnancy loss ^{121 bis}. Finally, in the review by Prummel & Wiersinga published in 2004, a meta-analysis was performed of both case-controlled and longitudinal studies published since 1990, when the association between miscarriage and TAI was first described ^121ter. The results of the meta-analysis amply confirmed that this association was valid, with an overall odds ratio of 2.73.

Table 14-3 shows the information provided by the analysis of 13 studies carried out over the last decade in three continents. Over 5500 women were investigated, both as study cases and controls. The prevalence of TAI varied widely, from 6 % in Brussels to 33 % in Salt Lake City. Altogether the main results (except in two studies) concurred to establish that TAI was significantly associated with an increased rate of miscarriage. Finding an association does not imply a causal relationship, and it should be stressed that the etiology of pregnancy loss in women with TAI remains largely unknown. Three working hypotheses have been proposed. The first hypothesis holds that pregnancy loss is not directly related to the presence of circulating thyroid antibodies. In this view, TAI only constitutes a marker of an underlying (yet to be defined) more generalized autoimmune imbalance that, in turn, could explain a greater rejection rate of the fetal graft. The second hypothesis holds that despite apparent euthyroidism, the presence of TAI could be associated with a subtle deficiency in thyroid hormone concentrations or with a lesser ability of the thyroid gland to adapt adequately to the necessary changes associated with the pregnant state, because of the reduced reserve characteristic of chronic thyroiditis. A third hypothesis, recently put forward by us and others, holds that TAI could act by delaying the occurrence of pregnancies, because of its association with subfertility. In this view, TAI positive women would tend to become pregnant at an older age (on average 3-4 years later), and older women are more prone to pregnancy loss. These hypotheses are not in contradiction with one another, and it remains plausible that the increased risk of pregnancy loss associated with TAI is multifactorial, eventually resulting from a combination of several independently deleterious factors ^122-130.

Can medical intervention be proposed to help improve pregnancy success?

If increased pregnancy loss is due to an underlying generalized immune dysregulation, and if the presence of thyroid antibodies merely represent an indirect marker of the immune condition, then there is no proven medical intervention that can presently be proposed. It is worth mentioning that a in a few isolated cases, short-term steroid administration or injections of immunoglobulins have been employed, with variable success, to modulate the immune response in women with recurrent abortions. Also, if mild thyroid underfunction does play a significant role, then this would constitute a good argument for systematically screening women (either before conception, when they express the desire of being pregnant or as soon as a pregnancy is ongoing) for the presence of TAI and/or mild thyroid insufficiency, in order to give these patients the potential benefit of L-thyroxine treatment. Todate, only one such prospective trial was reported, with promising results ^129,131. In this study, women with TAI and a past history of recurrent early miscarriages were given thyroid hormone treatment, both before and during pregnancy. The results showed a significant reduction in the rate of spontaneous abortion: 81% of women who received thyroid hormone ended with live births, compared with only 55% in the women who were given immunoglobulin injections. Obviously, conclusions must be considered with caution and balanced with the small number of patients investigated and also the fact that there was no strict randomisation. However, despite its limitations, this study constitutes the first therapeutic intervention trial showing a positive effect of thyroid hormone administration in women who were habitual aborters. If delayed conception plays a significant role to decrease fertility in women with TAI, then this could constitute an argument for systematically screening infertile women for the presence of mild thyroid underfunction associated with TAI, particularly when seeking medical advice for in vitro fertilization procedures. Such an approach was recently used in Finland ¹³². The study showed a high prevalence of women with elevated serum TSH levels, an association between oligo-amenorrhea and abnormally elevated serum TSH, and an overall improvement in the success rate of induced pregnancies after thyroxine administration. Finally, women with TAI could be advised to plan for a pregnancy at a younger age, although this type of medical advice is more easily said than applicable in practice.

Effects of pregnancy on thyroid function in women with thyroid autoantibodies

Table 14-4 summarizes the various types of autoimmune thyroid disease which can be expected in the pregnant and postpartum population. These are also discussed in greater detail below and postpartum thyroiditis is reviewed in Chapters 8 and 13. The prevalence of TAI in the pregnant population is comparable to that found in the general female population with a similar age range, that is between 6 and 10% ^133,134. In first trimester patients with gestational diabetes mellitus, the prevalence of thyroid autoantibodies is even higher (20-25%) ^135,136. Taken together, the high frequency of thyroid antibodies, increased miscarriage risks, risks of developing hypothyroidism with the progression of gestation, and finally the observation that postpartum thyroiditis occurs in a significant fraction of these individuals have led physicians to recommend that all pregnant patients be screened for the presence of TPO antibodies during the first trimester of pregnancy (see below) ¹³⁴.

A decade ago, a prospective longitudinal study was carried out in 1660 consecutive healthy pregnancies to evaluate the changes in thyroid function occurring in pregnant women who had thyroid antibodies, but were euthyroid during early gestation ¹³⁷. Closely monitored during gestation and without administration of thyroid treatment or iodine supplements, the study showed that despite the expected decrease thyroid antibody titers during gestation, thyroid function showed a gradual deterioration toward subclinical hypothyroidism in a significant fraction of women with TAI (Figure 14-11).

Figure 11a. Individual patterns of changes in thyroperoxidase antibody titers (TPO-Ab) in women with autoimmune thyroid disease. During pregnancy, there was a marked reduction in antibody titers, by approximately 50-60% on average (solid lines represent the asymptomatic euthyroid women, and dotted lines the women with known hypothyroid hypothyroidism). (Reproduced by permission of Glinoer et al.; Journal of Clinical Endocrinology and Metabolism 79:197, 1994; Ref 137).

Figure 11b. Among the women with positive thyroid antibodies, a progressively increasing fraction develop biochemical hypothyroidism, with 10% having basal TSH >3 mU/L in the first trimester, 20% in second and third trimesters, and finally 40% at the time of delivery. (Reproduced by permission of Glinoer et al.; Journal of Clinical Endocrinology and Metabolism 79:197, 1994; Ref 137).

Figure 11c. Mean serum free T4 concentrations (3 days after delivery) in women with and without thyroid immunity. In the antibody positive group, not only was mean free T4 level significantly lower than in the control group, but in addition, the mean serum free T4 was at the lower limit of normal. (Reproduced by permission of Glinoer et al.; Journal of Clinical Endocrinology and Metabolism 79:197, 1994; Ref 137).

Already in the first trimester, serum TSH (albeit within the normal range) was significantly shifted to higher values than in TAI-negative pregnant controls. Thereafter, serum TSH remained higher throughout gestation and, at parturition, 40% of TAI-positive women had a serum TSH >3 mU/L, with almost one-half of them exceeding 4 mU/L. Thus, TAI-positive women were able to maintain a normal thyroid function in the early stages of gestation, due to sustained thyrotropic stimulation. At delivery, however, their serum free T4 was significantly reduced, compared with the controls, and their mean serum free T4 was at the lower limit of the normal range. The 30% average reduction in serum free T4 indicated that almost one-half of TAI-positive women had free T4 values in the hypothyroid range at the end of pregnancy, hence confirming that these women have a reduced functional thyroid reserve associated with TAI. At the individual level, it was possible to predict the risk of progression to hypothyroidism, based on serum TSH levels and TPO-Ab titers: when serum TSH was >2.0 mU/L and/or TPO-Ab titers >1250 U/mL before 20 weeks, these markers were indicative of the propensity to develop hypothyroidism before the end of pregnancy. These observations are important, since they provide clinicians with simple tools to identify, during early gestational stages, those women who carry the highest risk. As a consequence, thyroid function can be closely monitored, and preventive treatment with L-thyroxine administered, to avoid the potential deleterious effects of hypothyroxinemia on both maternal and fetal outcomes.

PRIMARY HYPOTHYROIDISM

Clinical epidemiology

The most common cause of primary hypothyroidism in women of reproductive age is chronic autoimmune thyroiditis, unless there is iodine deficiency or hypothyroidism that results from previous radical treatment for hyperthyroidism using radioiodine or surgery. Chronic autoimmune thyroiditis occurs in both the goitrous and atrophic forms of the disease (see Chapter 8). Between 1 and 2% of women who become pregnant already receive thyroxine therapy for hypothyroidism. In two population-based studies of women without known hypothyroidism, the prevalence of an elevated serum TSH concentration was systematically investigated in the early part of gestation. In the first retrospective study ¹³⁸, serum TSH, free T4 and TPO-Ab were measured in 2000 pregnant women (Table 14-5). Among these women, 49 had an elevated TSH (2.5% of the cohort) and 6 also had a low free T4, hence yielding a prevalence of undisclosed overt hypothyroidism of 0.3%. Some 58% of the women with an elevated TSH tested positive for TPO-Ab, compared with only 11% in euthyroid controls. The design of this study did not permit the investigators to determine whether women with an elevated TSH had a known thyroid condition (in which case they could have been taking an inappropriately low thyroxine dosage or, alternatively, excessive doses of antithyroid drugs). In the second prospective population study in Europe ¹³⁷, the systematic screening of a cohort of 1660 apparently healthy pregnant women showed that 2.2% of them had an elevated serum TSH. Thus, similar prevalences of undisclosed hypothyroidism were found, indicating that overall between 2-4% of women entering pregnancy may present hypothyroidism to various degrees, from subclinical to overt disease. Special mention should be made of a recent study showing that in pregnant women with diabetes mellitus type 1, thyroid dysfunction may even be more prevalent (27-45%), consisting mainly of subclinical hypothyroidism ^139,139bis.

Table 14-5. Prevalence of abnormally elevated TSH in 2000 consecutive women at 15 to 18 weeks of gestation*
	N	TSH(mU/L)	Free T4 (pmol/L)	TPO- antibody (% positive)
Total screened	2000	2.1	–	–
Elevated TSH ( >6 mU/L)	49	10	11.5	58
Controls	99	2.3	13.4	11
* adapted from Klein et al. (Ref. N° 138)

A much rarer cause of hypothyroidism is that associated with the presence of TSH receptor blocking antibodies during pregnancy ^109,140-144. In such patients, hypothyroidism is presumably caused by interference in TSH-TSH receptor interactions. Even though extremely uncommon, the clinical significance of this problem in the pregnant state is that blocking antibodies may be transferred to the fetus and cause intrauterine or transient neonatal hypothyroidism ^142,143.

A fascinating new topic in the field of autoimmunity and pregnancy is that of fetal microchimerism, that is the migration of fetal cells into maternal blood and the prolonged engrafment of fetal progenitor cells into maternal tissues. Recent studies have confirmed that microchimerism occurs within the thyroid gland in women with Hashimoto’s and Graves’ diseases. Although the functional consequences of persisting fetal microchimerism are not yet known and are only beginning to be explored, fetal cells engrafted into maternal tissues may possibly play a role in the etiology of autoimmune thyroid diseases, and perhaps also in the modulation of autoimmunity during pregnancy ^{145-147,147bis}.

Effect of hypothyroidism on pregnancy outcome

As already alluded to, hypothyroidism has until recently been – wrongly – considered to be relatively rare during pregnancy, presumably because of the increased infertility and miscarriage rates associated with hypothyroidism ^148-152. Nowadays, this view has changed. Several studies have shown that when hypothyroid women become pregnant and maintain the pregnancy, they carry an increased risk for obstetric and fetal complications. The main obstetric complications that have been described in association with hypothyroidism are listed in Table 14-6.

<script></script> News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD, FAAFP

July 14, 2004 — Hypothyroid pregnant women benefit from increasing thyroid replacement, according to the results of a prospective trial published in the July 15 issue of the New England Journal of Medicine.

“Hypothyroidism during pregnancy has been associated with impaired cognitive development and increased fetal mortality,” write Erik K. Alexander, MD, from the Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues. “During pregnancy, maternal thyroid hormone requirements increase. Although it is known that women with hypothyroidism should increase their levothyroxine dose during pregnancy, biochemical hypothyroidism occurs in many.”

The authors observed 19 women with hypothyroidism before and throughout their pregnancies and measured thyroid function, human chorionic gonadotropin, and estradiol before conception, twice monthly during the first trimester, and monthly thereafter. Throughout pregnancy, the dose of levothyroxine was increased as needed to maintain the thyrotropin concentration at preconception values.

Of 20 pregnancies, there were 17 full-term births. During 17 pregnancies, the levothyroxine dose had to be increased, with median onset of increase at eight weeks of gestation. The mean levothyroxine requirement increased by 47% during the first half of pregnancy and reached a plateau by week 16, with the increased dose required during the remainder of pregnancy.

“Levothyroxine requirements increase as early as the fifth week of gestation,” the authors write. “Given the importance of maternal euthyroidism for normal fetal cognitive development, we propose that women with hypothyroidism increase their levothyroxine dose by approximately 30% as soon as pregnancy is confirmed. Thereafter, serum thyrotropin levels should be monitored and the levothyroxine dose adjusted accordingly.”

The National Institutes of Health and the Endocrine Fellows Foundation supported this study. One of the authors reports having served as a consultant for Genzyme and Laboratory Inisiba.

In an accompanying editorial, Anthony Toft, MD, from the Royal Infirmary in Edinburgh, Scotland, suggests that it would be more practical to increase the levothyroxine dose by 25 to 50 μg daily as soon as pregnancy is confirmed. Thyroid function testing should be done within the following four to six weeks, and after the 20th week of gestation, one additional test is probably sufficient.

“Although the debate continues about the wisdom of screening women of childbearing age by measuring serum thyroxine, thyrotropin, or both in order to detect unrecognized thyroid failure in advance of pregnancy, the evidence is beginning to stack up in favor of doing so,” Dr. Toft writes. “If screening is not to be performed universally, it would be reasonable to test those under the age of 35 years who already have one or more of the organ-specific autoimmune diseases, such as type 1 diabetes mellitus, or who have a strong family history of thyroid disease.”

N Engl J Med. 2004;351:241-249, 292-294

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Describe the physiology of hypothyroidism in pregnancy.
• Recommend thyroid screening and treatment regimens for women with hypothyroidism who become pregnant.

Clinical Context

Hypothyroidism is a common condition during pregnancy that can produce devastating consequences for both the mother and child. The authors of the current study, along with an editorial by Toft accompanying the research, do an excellent job of reviewing our current knowledge of changes in thyroid physiology in pregnancy. Early in pregnancy in euthyroid women, human chorionic gonadotropin provides a weak stimulation to the thyroid gland, increasing free thyroxine levels and reducing thyrotropin concentration. However, a combination of factors, the most salient of which is the estrogen-driven increase in thyroid-hormone binding globulin, causes a later reduction in free thyroxine.

Women with primary hypothyroidism lack the compensatory mechanism to maintain adequate levels of free thyroxine during pregnancy, and, therefore, it is recommended to follow thyroid hormone levels at least every eight weeks during pregnancy in these women. Dosage of levothyroxine should be increased according to these levels and the stage of pregnancy, bearing in mind that the steepest increase in dosage is usually necessary in the first half of the pregnancy.

The authors of the current study performed a prospective study of pregnant women with hypothyroidism to better understand the timing of changes in thyroid physiology during pregnancy.

Study Highlights

• Women with hypothyroidism who desired pregnancy were recruited from one medical center to join the study.
• Subjects were followed up with tests for thyroid function, estradiol levels, and human chorionic gonadotropin levels after their first missed menstrual cycle, every two weeks during their first trimester, and monthly, thereafter, until completion of the pregnancy. Thyroid function was rechecked 6 weeks following delivery.
• The target thyrotropin levels were less than 5 µU/mL in women without a history of thyroid cancer and less than 0.5 µU/mL in women with a history of cancer.
• If the thyrotropin level was found to be elevated at the initial test, all women had their dose of levothyroxine increased by 25 µg. At subsequent tests of noncancer patients, levothyroxine was increased by 12.5 µg if the thyrotropin levels were between 5 to 10 µU/mL and 25 µg if the thyrotropin level was more than 10 µU/mL. Participants with a history of thyroid cancer underwent a similar protocol to maintain their goal thyrotropin level.
• The main study outcome was a better definition of the natural history of hypothyroidism in this cohort of closely observed pregnant women.
• 19 women entered the study, and most subjects had hypothyroidism either due to Hashimoto’s disease or treatment for Graves’ disease. 6 women had a history of thyroid cancer.
• There were 20 pregnancies in the cohort, 3 of which were facilitated by assisted reproductive techniques. 17 pregnancies produced full-term deliveries.
• Thyrotropin levels rose quickly early in pregnancy, from a mean prepregnancy level of 1.0 to 4.2 µU/mL at 10 weeks’ gestation. This was particularly evident for women who used assisted reproductive techniques, 2 of whom needed an increase in levothyroxine at 4 weeks of gestation. Higher estradiol concentrations early in pregnancy in these women could explain this difference.
• The authors accomplished their goal of maintaining stable thyrotropin values throughout the study by increasing the dose of levothyroxine. Overall, 85% of women required an increase in levothyroxine during the first 10 weeks of gestation, with a mean 29% increase in the dosage for the whole cohort during this period. By 20 weeks of gestation, the mean dose of levothyroxine had increased by 48%.
• Most increases in levothyroxine dosage occurred between weeks 6 to16 of gestation. This correlated with the most rapid decrease in thyroid hormone-binding ratio as levels of thyroxine-binding globulin increased.
• Following 20 weeks of gestation, both the thyroid-hormone binding ratio as well as the mean dosage of levothyroxine were stable in the study cohort.
• The rates of dosage increases for levothyroxine were similar in participants regardless of the etiology of hypothyroidism.
• Within 2 weeks of delivery, women resumed taking their prepregnancy dose of levothyroxine. In the 14 women who had postpartum care at 6 to 8 weeks after delivery, all had normal thyrotropin levels.

Pearls for Practice

• Women with hypothyroidism frequently require higher dosages of thyroid replacement therapy during pregnancy.
• Given that the increased need for levothyroxine treatment occurs early in pregnancy, women with hypothyroidism should present promptly for thyroid function testing. The authors of the current study suggest patients take two extra doses of levothyroxine per week following a positive pregnancy test result until they can arrange to have thyroid testing performed.

http://www.medscape.com/viewarticle/483441

Chemicals contained in these and other common household items may affect maternal thyroid function and may lead to impaired fetal brain development, according to PhD candidate Glenys Webster, of UBC’s School of Occupational and Environmental Hygiene.

Webster is leading an investigation into the effects of polybrominated diphenyl ethers (PBDEs), chemicals that are used as flame-retardants, and perfluroinated compounds (PFCs), used as stain or water repellents. The chemicals are found at low levels in all Canadians. They leach out of many products, can last for a long time in both indoor and outdoor environments, and accumulate in both animals and humans via dust, foods and air.

Called the Chemical, Health and Pregnancy study (CHirP), Webster believes it is one of the first such studies in the world. She is collaborating with investigators from BC Women’s Hospital & Health Centre, Health Canada, and the University of Alberta.

Animal studies have shown that certain PBDEs interfere with the thyroid system, critical to fetal development. A butterfly-shaped gland in the lower front part of the neck, the thyroid controls metabolism and keeps basic functions such as body temperature, blood pressure and energy levels working properly.

It is known that thyroid disruption in early pregnancy can result in neurological damage in babies, but the mechanism — including any negative environmental factors — is not known. Although there are no known human health risks from common levels of PBDEs and PFCs, very few studies have been conducted in humans, says Webster, so at this point nothing is conclusive.

She suspects the chemicals may put additional stress on the thyroid system. Animal and laboratory studies have shown that certain PBDEs can mimic thyroid hormones and bind to a transport protein that sends the damaging “imposter” hormone from the mother to the fetus, possibly directly to the brain.

“Until recently, we didn’t have the analytical methods we need to measure low levels of these chemicals and study effects on human health,” says Webster, whose previous research focused on environmental toxicology and looking at how chemicals move through the environment. “There is considerable new interest among scientists to start looking at human health effects, and governments, including Canada’s, are now making decisions about regulating these chemicals.”

Researchers will enroll 150 pregnant women for the study, which was launched last month and will extend to September 2008. Participants will be asked, during in-home surveys, about exposures to PBDEs found in mattresses, furniture foam, plastic casing of electronic equipment such as TVs and computers, and other household goods. The women will also be asked about exposure to PFCs via products ranging from microwavable popcorn bags to non-stick cookware coatings and self-cleaning ovens.

Levels of PBDEs and PFCs will be measured in the air, dust and dryer lint in homes. Also, maternal blood samples will be collected in mid-pregnancy and a sample of umbilical cord blood will be collected at delivery. Levels of both groups of chemicals won’t be analyzed until all 150 subjects have been recruited.

In humans, accumulation rates and toxicity relative to exposure levels are not well understood. It is known that PFCs are some of the most persistent compounds known, and the half-life of PBDEs in human tissues ranges from approximately 15 days to six years. However, fast-degrading PBDEs don’t actually “clear” the body after two weeks. They transform into slower degrading chemicals and persist. A puzzling factor is that age doesn’t necessarily affect PBDE accumulation.

In North America, PBDE levels in humans are approximately 10-100 times higher than levels found in Europe or Japan, according to a review of PBDE levels in humans conducted in 2004. Health Canada data showed PBDE levels in Vancouver mothers’ breast milk increased approximately 15-fold from 1992-2002, but are still lower than levels found in certain areas of the US. Canada has this year prohibited the importation of certain chemicals that turn into PFCs.

Should expectant mothers be alarmed?

“We’re not expecting to see dramatic changes here – the effects, if any, will be subtle but may still be important, and show a trend that should be monitored,” says Webster. “I think it’s important to start looking at connections so we can take precautionary measures, if needed. Even if effects are subtle, because virtually everyone is exposed to these chemicals, any small effects may still represent a public health concern.”

For more information about the study, visit www.cher.ubc.ca/chirp.

BC Women’s Hospital & Health Centre is an agency of the Provincial Health Services Authority.

http://www.publicaffairs.ubc.ca/ubcreports/2006/06oct05/household.html

In a study published in the August 18, 1999 New England Journal of Medicine, the same researchers documented an association between undetected subclinical hypothyroidism during pregnancy and lower I.Q. in offspring. Women with untreated thyroid deficiency during pregnancy are four times more likely to have children with lower I.Q. scores. Nineteen percent of the children whose mothers had undiagnosed hypothyroidism during pregnancy averaged 85 or less on their I.Q. tests. Children who have an I.Q. less than 85 are more likely to have difficulties in school, and may be less successful in their careers and interpersonal relationships.

“Our current study indicates that a change in pregnancy screening practices may be warranted,” said Dr. Walter Allan, M.D., lead study author and director of clinical services at the Foundation for Blood Research. “Perhaps expectant mothers should get a TSH test before pregnancy or as part of the initial standard prenatal blood work.”

Other studies among pregnant women with hypothyroidism have suggested a connection between miscarriage, premature birth, low birthweight, placental abruption and pregnancy-induced hypertension, however these studies were limited to women attending high-risk or specialty clinics and might not have reflected the findings in the general population.

Hypothyroidism is a deficiency in the thyroid, a butterfly-shaped gland just below the Adam’s apple, that plays a critical role in regulating the most important functions in the body including heart rate, metabolism, growth, cognitive function and development, energy and mood. Approximately one out of every 50 women in the U.S. is thyroid deficient during pregnancy. However, this condition does not only strike during pregnancy. In fact, nearly 27 million Americans have a thyroid disorder, yet more than half remain undiagnosed. The condition becomes even more prevalent as women age; by age 60, one in five women will suffer from a thyroid deficiency.

Thyroid disease can be diagnosed through a simple blood test called TSH (thyroid-stimulating hormone). This highly sensitive test enables doctors to detect thyroid disorders early, and in many cases before the woman experiences symptoms. If left untreated, thyroid disease can lead to serious long-term complications such as heart disease, osteoporosis, infertility, impaired I.Q. in offspring, and now potentially, late miscarriage.

Among the 9,403 women with singleton pregnancies TSH levels were 6mU/L or greater in 209 (2.2 percent) cases. The rate of late fetal death (miscarriage) was significantly higher in those pregnancies (8 out of 209 or 3.8 percent) than in women with TSH less than 6 mU/L (83 out of 9,194 or 0.9 percent). Furthermore, the rate of fetal death increased incrementally as TSH levels increased. Among the 37 women with TSH levels greater than 10mU/L, fetal deaths occurred in 8.1 percent. In the study, six out of every 100 miscarriages could be attributed to thyroid deficiency during pregnancy.

“Little is known about the cause of late miscarriages, but our findings offer a new opportunity to possibly prevent some of these,” said James Haddow, medical director, Foundation for Blood Research. “Further research may show that early detection and treatment for maternal hypothyroidism is the key to preventing these miscarriages.”

The purpose of the study was to examine the relationship between certain pregnancy complications and TSH levels in pregnant women. Between July 1990 and June 1992, approximately 10,500 women from the state of Maine agreed to participate in a study of hypothyroidism, during routine testing between 15 and 18 weeks’ gestation to detect neural tube defects and Down syndrome. From this pool, it was determined that 9,403 women were eligible for the study and underwent TSH testing.

The women provided selected information about their pregnancy (e.g. gravidity(1), parity(2), vaginal bleeding, and smoking status) at the time of enrollment. Information about pregnancy outcome (e.g. viability(3), length of gestation, birth weight and Apgar(4) score) was obtained via a collaborative agreement with the state’s Bureau of Vital Records. The serum TSH measurements were performed at the New England Newborn Screening Program in Boston and additional thyroid function testing was performed on all serum samples with TSH levels at or above 6mU/L (the definition of thyroid deficiency for the current study) at Beth Israel Deaconess Medical Center. Thyroid function testing was also performed in a selected subgroup of controls.

References:
(1) Pregnancy; the condition of being pregnant.
(2) The condition of a woman with respect to her having borne viable offspring.
(3) Ability to live after birth; capable of living.
(4) Indicates newborn’s health 1-5 minutes post-birth (color, weight, respiratory rate, and muscle tone).

http://www.pslgroup.com/dg/1ebb22.htm

American Journal of Reproductive Immunology
Volume 45 Page 72 – February 2001
doi:10.1111/j.8755-8920.2001.450202.xVolume 45 Issue 2

The incidence of thyroid autoantibodies in women with recurrent fetal loss, infertility or women who miscarried appears to be increased compared with controls of reproductive age without previous abortions. There are few working hypotheses concerning the asociation between anti-thyroid antibodies and the increased risk for pregnancy loss. The first hypothesis suggests that women with high titers of anti thyroid antibodies have underlying very mild thyroid “under function”. Another theory views the anti-thyroid antibodies as simply secondary markers of a predisposition of autoimmune disease rather than the actual cause of pregnancy loss. An evolutionary explanation suggests that reproductive problems in women with high titers of autoantibodies exist in order to prevent the transmission of autoimmune genes to the next generation. The reason for the association between pregnancy loss and thyroid immunity is still not clear. The working hypotheses above supply multi factorial explanations which could act together, may even be in synergy, as the propulsion for the pregnancy loss. Until today the mechanism by which anti Tg are responsible for pregnancy loss is not clear. Induced animal models with high titier of anti Tg could provide direct evidence for the pathogenic role of anti-thyroid antibodies and the mechanism that is responsible for the pregnancy loss in autoimmune thyroiditis. In the current presentation we describe data concerning the association between anti thyroid antibodies and pregnancy loss, and hypothesis which explain this association.

http://www.blackwell-synergy.com/doi/abs/10.1111/j.8755-8920.2001.450202.x?journalCode=aji

I have put this in here because miscarriage is not always due to a chromosomal abnormality. Sometimes it happens because there are other, scientific factors involved. I get sickof hearing that!- Angie

February 1998 — If your doctor has told you that you have tested positive for “thyroid antibodies” but you have a normal TSH, what does that mean? Usually, it indicates that your thyroid is in the process of autoimmune failure. Not failed yet, and not failed enough to register in the standard TSH thyroid test, but in the process of failing.

Many doctors believe that antibodies alone are NOT reason to treat someone with thyroid hormone. This is despite the fact that the presence of antibodies alone can cause thyroid-related symptoms, and have been shown to affect fertility or the ability to maintain a pregnancy. (An article in the Journal of Clinical Endocrinology and Metabolism, August 1997 states, “the risk of miscarriage is twice as high in women who have antithyroid antibodies than in those who do not…” and Obstetrics and Gynecology 1997 Volume 90:364-369, states “the risk of miscarriage is higher when a woman is positive for antithyroid microsomal antibody…”)

There are, however, some endocrinologists, as well as holistic MDs, osteopaths and other practitioners who believe that the presence of thyroid antibodies alone is enough to warrant treatment with small amounts of thyroid hormone.zSB(3,3)

Sponsored Links

Menopause Symptoms?Know the facts before choosing your treatment. Free evaluation here.www.MenopauseInstitute.com.au

Sydney Hormone ClinicNaturopathic advice for thyroid and other hormonal conditions .www.sensible-alternative.com.au

Custom Antibodies30+ Years of Experience Peptide / Monospecific Antibodieswww.pacificimmunology.com

If you’ve tested positive for antibodies, and have a TSH in the “normal range,” but still don’t feel well, you may with to consult with a practitioner who has this philosophy.

One such practitioner is Dr. Elizabeth Vliet, an MD who runs Her Place, a women’s health clinic at All Saints Hospital in Fort Worth, and author of Screaming to be Heard: Hormonal Connections Women Suspect…and Doctors Ignore. Dr. Vliet does not believe that TSH tests are the almightly indicator of a woman’s thyroid health. Dr. Vliet says that symptoms, along with elevated thyroid antibodies and normal TSH, may be a reason for treatment with thyroid hormone. Here’s a quote from her book:

“The problem I have found is that too often women are told their thyroid is normal without having the complete thyroid tests done. Of course, what most people, and many physicians, don’t realize is that…a ‘normal range’ on a laboratory report is just that: a range. A given person may require higher or lower levels to feel well and to function optimally. I think we must look at the lab results along with the clinical picture described by the patient…I have a series of more than a hundred patients, all but two are women, who had a normal TSH and turned out to have significantly elevated thyroid antibodies that meant they needed thyroid medication in order to feel normal. This type of oversight is particularly common with a type of thyroid disease called thyroiditis, which is about 25 times more common in females than males…a woman may experience the symptoms of disease months to years before TSH goes up…”

The other issue is the TSH level itself. While at many labs, “normal” range is .5 to 5.5 (with over 5.5 being hypothyroid), my endocrinologist (a 40 year old woman) believes FIRMLY that most women do not normalize unless TSH is between 1 and 2 (considered low by some docs) and that a woman with evidence of thyroid disease will find it hard to get and/or maintain a pregnancy at higher TSH’s than 1-2. (I didn’t get pregnant at a TSH of 4, a level considered totally NORMAL at my lab, but got pregnant in one month at TSH of 1.2 and just had my baby on Dec 31).(See my Pregnancy Guide.

If you haven’t had your antibodies tested, and suspect you may be hypothyroid despite a so- called “normal” TSH test, I suggest you read the following article at my site for more ideas on how to proceed. HELP! My TSH Is “Normal” But I Think I’m Hypothyroid, which offers a look at your next steps — including defining the “normal” range with your doc, antibody testing, TRH testing, and drugs beyond T4 therapy — and where to find a doctor to help.

The rising incidence of fertility-impairing health factors such as obesity also likely plays animportant role. Clues from environmental exposure assessments, wildlife studies, and animal and human studies hint at additional factors: exposure to low-level environmental contaminants such as phthalates, polychlorinated biphenyls (PCBs), dioxins, pesticides, and other chemicals may be subtly undermining our ability to reproduce.

As recognized by the American Society of Reproductive Medicine, infertility is a biological disease that impairs a couple’s ability to achieve a viable pregnancy. It can be caused by hormonal, ovarian, uterine, urological, and other medical factors. Known risk factors include advanced age, being over- or underweight, lack of exercise, smoking, alcohol and substance abuse, sexually transmitted diseases, and poor nutrition.

According to the American Society of Reproductive Medicine, a medical infertility cause can be identified, or perhaps only indefinitely suggested, in approximately 90% of cases and may be multifactorial in 25% of cases. Male factors include low sperm count and sperm abnormalities, such as altered morphology and low motility. Female factors stem from ovulation problems such as premature ovarian failure (early menopause), thyroid irregularities, polycystic ovarian syndrome, and fallopian tube obstruction.

Up to 10% of infertility cannot be explained medically. Fertility transcends the reproductive system, notes Louis Guillette, a professor of zoology at the University of Florida in Gainesville. “When you talk about infertility, you literally are talking about probably almost every system in the body—infertility is an integrated signal of all these different systems,” he explains. “Trying to tease out which system, or more than likely what multiple systems have been altered, leading to that phenomenon, is very tough work.”

Infertility is generally defined as occurring when a couple cannot become pregnant after trying to conceive for at least one year (or six months if the woman is over age 35). According to the 2001 WHO report Current Practices and Controversies in Assisted Reproduction, at least 80 million people worldwide are estimated to be affected by infertility. Infertility rates range from less than 5% to greater than 30% depending on location and how infertility is defined, with higher rates associated with lack of medical care access. Based on the 2005 NSFG report, approximately 12% of American couples experienced impaired fecundity in 2002. This is a 20% increase from the 6.1 million couples who reported an inability to have children in 1995.

Her side. Female factors in infertility stem from ovulation problems, thyroid irregularities, polycystic ovarian syndrome, and fallopian tube obstruction. A trend among women to delay starting a family also has impacted fertility rates. image: Sebastian Kaulitzki/Shutterstock

Determining whether infertility is actually increasing is more complicated than these numbers imply, however. In a paper published in the September 2006 issue of Fertility and Sterility, David Guzick and Shanna Swan of the University of Rochester School of Medicine and Dentistry noted that “impaired fecundity” as defined by the NSFG implies a decrease in fertility, but the same study also showed that fertility, defined there as a married woman unable to become pregnant within 12 months, has increased.

The absence of definitive information can frustrate couples experiencing fertility problems as well as experts. “There seems to be more to it than can be explained from traditional understanding about impacts,” says Joseph Isaacs, president and CEO of RESOLVE: The National Infertility Association. “As a patient advocacy group, we believe more research into environmental impacts is needed. We fear that future generations may be at risk because of exposures to toxic substances as early as in utero.”

Foundations of Fertility

A person’s reproductive potential begins shortly after his or her own conception. Based on the embryo’s chromosomal inheritance, hormonal signals are created to direct the structure and function of the reproductive tract. Normal development depends upon a correct balance of androgen and estrogen signals being delivered at appropriate times.

Fetal development can be altered by external factors as demonstrated by the human experience with the synthetic estrogen diethylstilbestrol (DES), prescribed to prevent miscarriage between 1947 and 1971. The drug didn’t affect mothers, and it didn’t lower miscarriage incidence; in fact, it significantly increased it. It also induced changes in the developing reproductive tract of female offspring.

In the 15 April 1971 issue of the New England Journal of Medicine, it was reported that daughters with prenatal DES exposure had significantly increased incidence of vaginal cancer, which is normally quite rare and was virtually unknown in young women prior to DES. Later research revealed structural abnormalities of these women’s reproductive tracts and effects in their male offspring including increased risk of cryptorchidism (undescended testes) and low sperm counts.

The study of endocrine disruptors has raised concerns about the reproductive effects of exposure to certain environmental compounds that affect the endocrine system via estrogenic, androgenic, antiandrogenic, and antithyroid mechanisms. One key report was a 12 September 1992 review in the British Medical Journal indicating significant declines in sperm counts in many countries between 1938 and 1990. The findings were controversial because the reviewed studies used inconsistent designs and methods. In November 1997, however, a review published in EHP by Swan and others confirmed the findings for males in the United States and indicated an even sharper decline among European men. Other studies have found declines for specific areas or no decline at all.

“I think the evidence across studies is mixed,” says Russ Hauser, an associate professor of environmental and occupational epidemiology at Harvard School of Public Health. “Historical studies were not designed to explore this question. It wasn’t that someone set out forty or fifty years ago to design a study to look at how semen quality is going to change over time.” There are going to be limitations in the data because of that, he explains, so it’s hard to determine whether there is a true temporal trend. “However,” he adds, “the data suggest there are definite geographical differences between countries and regions within countries in semen quality.”

According to Niels Skakkebæk of Rigshospitalet in Copenhagen and colleagues writing in the February 2006 issue of the International Journal of Andrology, comparisons of sperm quality among populations of European men have revealed that as many as 30% of young Danish men have low sperm count, and an additional 10% may be infertile. Denmark also has an unusually high rate of testicular cancer. Rates have been increasing in many countries over the last 50 years, but the Danish rate is noticeably higher; for example, four to five times higher than the Finnish rate.

This difference prompted researchers to also examine incidence of hypospadias (in which the urethra opens along the underside of the penis shaft rather than the tip) and cryptorchidism. Not only did both disorders occur more frequently in Danish boys compared with Finnish boys, but the Danish rates had risen in recent decades. These findings as a whole inspired Skakkebæk and colleagues to propose, in the May 2001 issue of Human Reproduction, an overarching disorder, testicular dysgenesis syndrome (TDS), in which perturbation of testis development in fetal life sets the stage for hypospadias, cryptorchidism, testicular cancer, and reduced sperm quality.

It’s reasonable to suspect there might be a female corollary to TDS. “We have no really good reasons not to expect that women are as sensitive to environmental chemicals as the males are,” says Jens Peter Bonde, a professor of occupational medicine at Århus University Hospital in Copenhagen. He points out that it’s easier to study male fertility because men can easily provide sperm samples. “That’s one basic reason that there has been so much attention on the males, but from a biological point of view one would definitely expect that the female reproductive system might be vulnerable also,” says Bonde.

According to Guillette, another stumbling block is the accepted, but unproven, dogma that an embryo will develop as a normal female barring any hormonal signals to become male. “It hasn’t been an area where there have been substantial amounts of work done. There’s certainly very good work, but not the same kind of huge body of literature that one sees about the developing testis and the male reproductive system,” he says.

His side. Male infertility can arise from factors such as low sperm count and sperm abnormalities including altered morphology and low motility. Up to 10% of infertility cannot be explained medically. image: Christian Darkin/Shutterstock

One of the few epidemiologic studies to link low-level human exposure to an environmental contaminant with a specific end point was Swan and colleagues’ investigation of prenatal phthalate exposure, published in the August 2005 issue of EHP. Their results suggested a subtle change in boys’ development—a shortening of the anogenital index (the distance between the anus and the scrotum, divided by weight)—associated with prenatal exposure to several phthalates. This finding is not a predictor of future fertility and needs confirmation, but it is noteworthy as the first study to link verified prenatal exposure to a specific outcome.

Animal Findings to Human Concerns?

Consequences of disrupting the normal hormone milieu have also been observed in wildlife. Examining alligators in polluted lakes in northern Florida, Guillette’s group has observed altered function of the ovaries and testes, smaller penis size, and abnormalities that extend to the thyroid gland, liver, and immune system. A robust body of literature details reproductive effects in fish, amphibians, and reptiles related to their exposure to endocrine disruptors. Evidence of these effects has also been seen in wild mammals such as polar bears and seals. Laboratory animal experiments have confirmed these wildlife findings, demonstrating that effects are not necessarily from steroid receptor disruption, however, but may, for example, be observed in altered synthesis and control of endogenous hormones.

The study of fertility also encompasses pregnancy, especially the early weeks following fertilization. Early pregnancy loss is normally quite high in humans, with an estimated 30% of pregnancies ending in miscarriage in the first six weeks. A frequent cause of miscarriage is aneuploidy, an incorrect number of chromosomes in the embryo, and mouse studies have shed some light on potential environmental contributors to this condition.

During a 1998 investigation of age-related aneuploidy rate increases, Patricia Hunt, a professor of molecular biosciences and a reproductive biologist at Washington State University, and her colleagues were amazed to see a sudden rate spike in their mouse colony. An investigation revealed correlation between damage to the plastic mouse cages and the chromosomal abnormality. Further scrutiny implicated bisphenol A (BPA), a suspected environmental estrogen used in plastics manufacture, as the potential causal agent. In a study published in the 1 April 2003 issue of Current Biology, the researchers replicated exposure experimentally and found that BPA derailed proper chromosome segregation during oocyte meiosis.

An extension of this research has been completed with amazing—but not yet published—results, and Hunt hopes that the line of inquiry can be extended to humans. “One of the things that my new research on BPA has made me wonder is whether or not there could be environmental effects that would change the frequency or in specific populations might cause noticeable differences in aneuploidy,” she says.

Hunt says it’s hard to know precise numbers of human aneuploidy cases. “We can’t see the loss that occurs preimplantation, but we make an assumption that there’s quite a bit, based on what we can see and what we think must happen,” she says. But whether there’s been an increase in aneuploidy over time cannot be known. “Human aneuploidy studies were done mostly in the 1970s and early 1980s,” says Hunt. “Is this aneuploidy rate the same across all populations? To the best of our knowledge, it has been, at least in those previous studies. But is the rate the same as it was then? We wouldn’t know. We wouldn’t be able to see a dramatic increase in chromosomally abnormal spontaneous abortions, because those kinds of studies aren’t currently under way.”

The wild side. Animal and wildlife studies of reproductive health effects, including mouse aneuploidy data, may help inform knowledge of human effects. Although the reproductive system is highly conserved across species, differences in exposure, metabolism, and anatomy make direct interspecies comparisons impossible. image: Getty Images

Extending animal studies to human health is a challenge, though. Genetically, the reproductive system is highly conserved across species, making it likely that responses to inputs would be similar. But species differences in exposure, metabolism, and anatomy preclude making a direct comparison.

“Wildlife studies cannot be related to humans one to one,” says Guillette. “If one’s looking at the functioning of the ovary, or the functioning of the brain, and hormones, and even the genes that seem to be involved with the proliferation or the growth of the uterus or the development of an egg, for example, they’re incredibly conserved.” He explains that if problems are seen in these animals at a certain level, and researchers are able to identify mechanisms that are being disturbed leading to those abnormalities, then that raises possible concerns for humans, even if humans are exposed in a slightly different manner.

Worldwide Concerns

Geographic differences may suggest environmental exposures that need investigation, wrote Swan in a paper published in the February 2006 issue of Seminars in Reproductive Medicine. For example, in the first phase of the EPA-funded Study for Future Families, of` which Swan is the principal investigator, she and her colleagues saw significant reductions in sperm concentration, motility, and total motile sperm in men from Columbia, Missouri, compared with men in New York City, Minneapolis, and Los Angeles. In an in-depth follow-up study comparing variables between the Columbia and Minneapolis men, the researcher discovered that the Missouri group had had higher exposure to agricultural pesticides. Further, men with low sperm counts were more likely to have higher urine metabolite levels of the pesticides alachlor, atrazine, metolachlor, and diazinon.

Another geographically based study, INUENDO, investigates risks to human fertility from persistent environmental organochlorines. The European Commission project centers on Arctic populations including Swedish fishermen and the Inuit of North America and Greenland, whose exposure to persistent organic pollutants such as PCBs and DDT metabolites are among the highest in the world. “There are many indications from animal studies and from wildlife studies, but very few indications from human studies telling us whether we have a problem or not,” says Bonde, who serves as coordinator of INUENDO.

“The basic idea [behind INUENDO] was to go to places in the world where we know that people have high level of exposures to substances that are suspected to cause these effects in fertility,” says Bonde. “That’s the reason we went to Greenland and to Sweden, where fishermen are known to have very high exposure levels; we have other populations that have lower levels of exposures, so we have contrasts of exposure.” Results published in March 2006 in Human Reproduction suggested a longer time to pregnancy related to serum concentrations of PCB and DDE in mothers and fathers. Additional results published in the May 2006 EHP suggested an altered sex ratio of offspring (fewer boys than would otherwise be expected) related to PCB and DDE exposures.

Exploring multicompound exposures is yet another challenge in environmental epidemiology. “Individuals are exposed to many different phthalates, a variety of persistent and nonpersistent pesticides, different patterns of PCB congeners, as well as other chemicals,” says Hauser. “How do we take all that information, based on the chemical assessment in urine or in blood, and use that to assign exposure for that individual to ten, or twelve, or many more different compounds?” he says. In the April 2005 issue of EHP, Hauser’s group described evidence suggesting a relationship between PCBs and phthalates and human sperm motility, possibly due to PCBs’ inhibiting a key enzyme in phthalate metabolism.

Genes themselves offer another platform for investigation. Hugh Taylor, director of the Yale Center for Research in Reproductive Biology, leads a team investigating the role of estrogen-regulated Hox genes that direct uterine development. The researchers initially focused on DES effects and discovered that the compound alters expression of the Hoxa10 gene in mice, affecting the tissue type that grows in the uterus, cervix, and vagina. Effects were triggered only with exposure during development, but not during adulthood, and later experiments revealed that the pesticide methoxychlor had similar effects.

“The important thing is that these agents really seem to imprint the expression pattern, even long after the agent is removed or there’s no longer an exposure,” says Taylor. “When we have a clear-cut animal model and know the genes that are affected, we can start to think about evaluating that exposure by looking for changes in the gene expression earlier and see if it has a significant effect rather than waiting a whole generation.”

A view inside. Understanding that a person’s reproductive health can be linked to the very earliest of exposures, possibly even paternal or maternal exposures prior to conception, points up the critical need to elucidate the health effects of environmental chemicals. image: geopaul/iStockphoto

This is a goal of research in epigenetics, the study of how genetic messages may be edited through methylation or other means without changing the actual DNA sequence. For example, Rebecca Sokol and colleagues at the University of Southern California are currently investigating whether DNA methylation in sperm might serve as a biomarker of environmental exposure and a means of assessing male fertility. Additionally, preliminary work at Washington State University and at the NIEHS indicates that an epigenetic event in one generation can “reprogram” the germline and affect later generations. In essence, the exposures of one’s great-grandparents could still matter today.

Expanding Understanding

Previous generations’ exposures would be useful information to have, according to Hunt. “What we really need is data on generations ago, and we simply don’t have that data,” she says. “We have to wait a generation to see. We have to wait until . . . young exposed males grow up to the point where we can assess sperm counts.”

This will require prospective studies to determine early exposures. “If you want to look at fertility—and it’s difficult to do—you ideally would want to do a study in which you start assessing environmental exposures preconception,” says Hauser. “You’d have to identify couples who are thinking of trying to conceive and try to understand their environmental exposures, and then follow them forward in time.”

According to Alison Carlson, a senior fellow at The Collaborative on Health and the Environment (CHE) in Bolinas, California, another need is very basic: tracking the incidences of infertility and common known causes. “For us to try to make headway studying environmental influences on fertility, it’s really hard when we don’t have good baseline data,” she says. “We don’t know the real incidence and prevalence rates of premature ovarian failure and polycystic ovarian syndrome and lots of other end points that people study. We don’t know what they are, so how can we study trends and the environmental contributions?” she asks.

A thorough exploration of environmental effects on fertility will require the expertise of demographers, epidemiologists, clinicians, biologists, wildlife researchers, geneticists, molecular biologists, exposure assessment specialists, toxicologists, and others—and discussion requires someone “to set the table,” says Carlson. A February 2005 workshop titled “Understanding Environmental Contaminants and Human Fertility Compromise: Science and Strategy” demonstrated multidisciplinary fervor for investigation, and a more in-depth conference, the “Summit on Environmental Challenges to Reproductive Health and Fertility,” cosponsored by CHE and the University of California, San Francisco, is scheduled for 28–30 January 2007. “Reproduction is such a human, deep-seated, deeply psychically coded thing,” says Carlson. “It’s hard not to care about fertility compromise.”

Transcript:

CURWOOD: From the Jennifer and Ted Stanley Studios in Somerville, Massachusetts – this is Living on Earth. I’m Steve Curwood.

If you washed your hands, brushed your teeth or put on some deodorant today you may have exposed yourself to triclosan. Triclosan is probably best known as the bacteria-fighting ingredient in liquid soap, although it’s also used in everything from toothpaste to hot tubs to trash bags.

But now some scientists are telling us that minute amounts of triclosan – amounts found in the majority of America’s streams and rivers – can be enough to disrupt thyroid function in frogs, and perhaps humans.

On the line from the University of Victoria in British Columbia is Professor Caren Helbing. A paper based on her lab’s research appears in a recent issue of the journal Aquatic Toxicology. Professor Helbing, why expose bullfrogs to triclosan?

HELBING: Well, first of all frogs are very sensitive to thyroid hormone. Like other animals with a back bone, just like humans thyroid hormones are really important in growth and development. But in frogs it’s particularly evident because the young tadpole that you see swimming around in the pond actually needs to have thyroid hormone in order for it to change into a frog and what we’ve done is we’ve used that knowledge to enable us to test whether a thyroid hormone action, in other words affecting the tadpole, is affected by triclosan.

CURWOOD: What exactly did you find?

HELBING: Well, when we exposed young tad poles to triclosan itself triclosan didn’t really have much of an effect. But if we treated the young tadpoles with thyroid hormone to simulate metamorphosis in the tadpole then triclosan actually sped up the effects of thyroid hormone.

CURWOOD: And those effects were the legs growing quicker. What else happened?

HELBING: Yeah, the legs grew quicker. As well we also found that cells from the brain and from the tail actually responded differently to the presence of triclosan than when thyroid hormone was there.

CURWOOD: So if there’s no thyroid present in the tadpoles and you expose them to triclosan then there’s no effect. But then if you do add the thyroid hormone there is an effect. What does that tell you? What does that suggest is going on?

HELBING: What it’s telling us is that triclosan is acting on the ability of the hormone to do its job. And the implications of that are that during normal tadpole development that triclosan might actually be able to effect how the tadpole turns into a frog. But not only that also the implications are in people. People have to have the thyroid hormone in order to be healthy. And so possibly triclosan could effect how the thyroid hormone works.

CURWOOD: How close is the thyroid system in frogs and tadpoles as opposed to humans? I mean we don’t typically have tails and we don’t grow legs later on in life.

HELBING: No that’s true, we don’t have tails. But we do have brains. And the brain is a very very sensitive organ for thyroid hormone action; especially during early development around the birth period. And also through out life in adolescence and in adulthood the brain is very dependent on proper levels of thyroid hormone. So even though there are some obvious difference between frogs and people the fundamental biology is very very similar. And thyroid hormone is the exact same chemical in frogs compared to humans.

CURWOOD: Professor, why would you suspect triclosan in the first place?

HELBING: Well, triclosan, if you look at the chemical structure of triclosan it looks very much like thyroid hormone. So that was our first tip off that maybe it could behave either like thyroid hormone or it could effect how thyroid hormone works. The other thing that made us very interested in triclosan is that it’s found in so many different personal care products as well as it’s measured in many different water ways across North America.

CURWOOD: There was a recent study that shows that more than half of the rivers and streams in the US have readily detectible levels of triclosan. So your research has some pretty strong implications then.

HELBING: Yes. The really critical point in our research is that we looked at levels that were equivalent to ones that you can find in the environment. And to our amazement there were very profound effects on thyroid action.

CURWOOD: These levels were what like one drop of this triclosan in say, 300 Olympic swimming pools, something like that?

HELBING: Yeah it’s not very much.

CURWOOD: Now you’re doing basic scientific research. But there are going to be consumers listening to this who say, “Ok I use triclosan. I use the toothpaste that has it or I use the soap. It’s in my cutting board.” What should I do as a consumer with this stuff?

HELBING: Well, I would certainly think twice about whether you need and want triclosan in the products you’re using, certainly from the standpoint of its uses as an antibacterial agent and now with our work with potential implications on thyroid hormone, certainly on wildlife, maybe on humans too. Think twice about using it.

CURWOOD: Caren Helbing is an associate professor at the University of Victoria in British Columbia and you can find a link to her team’s research at our website loe.org. Thank you so much, professor.

HELBING: Oh, you’re welcome. It was a pleasure.

www.environmentalhealthnews.org