Abnormal Thyroid Function Tests and Hypercortisolemia in the Setting of Pregnancy

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Question

21 year old patient with single intrauterine pregnancy, gravida 1, para 0 found to have abnormal thyroid function tests at presentation for pregnancy care at 13 weeks in November 2010. TSH 0.644uIU/ml (reference range - 0.270-4.2) and free T4 0.56 ng/dl (0.65 -2).

2 weeks later - TSH 0.836uIU/ml, total T4 4 ug/dl (5.1-14.1). She had no complaints except mild fatigue which she attributed to pregnancy. Her only medication was an herbal supplement for the last 4-5 months(Spanish Black Radish). She had started to take this supplement for cleansing after a UTI, around the same time she also developed an itchy, erythematous rash on her back which she attributed to UTI, she was not really concerned about this rash even though it had not improved over time. She had coarse, black hair growth over face, chin, sideburns, back, chest, abdomen and thighs which she reported having for several years and was not concerned, but denied having a similar pattern in the family. She did not have acne, clitoromegaly, purple striae, or goiter.

Levothyroxine was recommended at that time but she did not want to start treatment and failed to follow up. At 20 weeks of gestation she presented with hypertension, increasing edema, rapid weight gain. Found to have hypokalemia and proteinuria. Free T4 was 0.36 and TSH was 0.476.(reference ranges same as above). At 7p.m. plasma cortisol was 37.9 ug/dl (3-23) and ACTH <2 pg/ml (6-58). 24 hour urine cortisol 1860 ug/dl (<45) volume 2500, creatinine 1025 mg/d (weight 168 lbs at the time of collection so appears to be an adequate collection) (cortisol was eighteen hundred sixty). Pituitary MRI was normal. Blood pressure ranged between 129-140/ 80-90 mmHg without medications. Abdominal ultrasound to assess adrenal glands and to repeat 24 hour urine collection are planned but not complete yet. She agreed to start levothyroxine.

Is this central hypothyroidism? What additional work up would you suggest to evaluate for Cushing's syndrome? Is there a way to differentiate hypercortisolemia caused by pregnancy? Could the abnormality in the thyroid function tests be related to the cortisol elevation? I would appreciate any help you can offer in further evaluation and treatment of this patient. Thank you very much in advance. Ebru Sulanc, MD

Response

This is a very interesting case with lots of problems.

I am more worried about her Cushing’s syndrome than the thyroid, albeit both are important. With the rapid onset of symptoms, the hirsutism, the very high cortisol levels, and the completely suppressed ACTH, I am quite concerned that she might have an adrenal carcinoma rather than just an adenoma as the cause of her Cushing’s. Adrenal carcinomas occur during pregnancy as a cause of Cushing’s syndrome more commonly than outside of pregnancy (Lindsay & Nieman, 2005). I think that you need to proceed fairly quickly to the adrenal ultrasound and, if she has a tumor, proceed with surgery even during the pregnancy. Depending upon the size, this might be able to be done via laparoscopy but you should alert the surgeon that this might be an adrenal carcinoma and this may have to be handled differently if surgery is to be curative. Treatment for all types of Cushing’s syndrome during pregnancy is indicated, as it improves pregnancy outcomes with respect to fetal mortality and prematurity (Lindsay & Nieman, 2005).

The thyroid levels are very interesting. Early in pregnancy, there may be a suppression of TSH levels due to high thyroid hormone levels stimulated by hCG. However, in this patient the TSH is normal but the T4 levels are low. You do not give the T3 levels, which might be normal or even highish, allowing her to maintain the euthyroid state. This would be certainly unusual in this setting, as high cortisol levels tend to decrease T4 to T3 conversion. It has been known for many years that high cortisol levels can suppress TSH secretion as well (Re et al., 1976) and in patients with Cushing’s syndrome TSH and often free T4 levels tend to be decreased but not to abnormally low levels (Colao et al., 2000; Niepomniszcze et al., 2002; Roelfsema et al., 2009). However, reversible very significant decreases in both TSH and Free T4 have also been reported (Kurata et al., 1981). Another possibility might be that the high cortisol is preventing the normal rise in TSH that might be seen with primary hypothyroidism. Years ago, it was shown that high doses of dexamethasone could acutely lower TSH levels in patients with primary hypothyroidism (Wilber & Utiger, 1969) and in patients with Cushing’s syndrome with evidence of autoimmune thyroid disease and subclinical hypothyroidism, TSH levels rise after cure of the Cushing’s syndrome (Niepomniszcze et al., 2002). However, I have been unable to find any reports of what happens to free T4 and TSH levels in patients with overt hypothyroidism before and after cure of Cushing’s syndrome when thyroxine has not also been administered.

In your patient, therefore, hypothyroidism is a distinct possibility. Given the adverse consequences of even mild hypothyroidism on the developing fetus (Reviewed in Abalovich et al., 2007) and the absence of overt consequences of giving thyroxine, she should be treated with thyroxine. However, because of the effects of the high cortisol levels in suppressing TSH, you probably cannot use the TSH levels to titrate the thyroxine dosage and will need to use total T4 levels (there may be problems with analog free T4 measurements during pregnancy) with an adjustment for stage of pregnancy. With either free T4 or total T4 monitoring (normal range multiplied x 1.5), levels should be brought into the upper part of the normal range. As she is young and speed is of the essence with respect to the fetus, it is reasonable to start her on a full replacement dose of thyroxine. Because of the increased metabolism of thyroxine, a dose of 2.0 – 2.4 mcg/kg is recommended rather than the usual 1.7 – 2.0 mcg/kg (Abalovich et al., 2007).

I hope you find these suggestions useful. Please give us follow-up on what happens with this patient. Mark Molitch, MD

Refs.

Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocrine Reviews 2005;26:775-799.

Re RN, Kourides IA, Ridgway EC, Weintraub BD, Maloor F. The effect of glucocorticoid administration on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab 1976;43:338-346.

Colao A, Pivonello R, Fagginao A, Filippella M, Ferone D, DiSomma C, Cerbone G, Marzullo P, Fenzi G, Lombardi G. Increased prevalence of thyroid autoimmunity in patients successfully treated for Cushing’s disease. Clin Endocrinol 2000;53:13-19.

Niepomniszcze H, Pitoia F, Katz SB, Chervin R, Bruno OD. Primary thyroid disorders in endogenous Cushing’s syndrome. Eur J Endocrinol 2002;147:305-311.

Roelfsema F, Pereira AM, Biermasz NR, Frolich M, Keenan DM, Veldhuis JD, Romijn JA. Diminished and irregular TASH secretion with delayed acrophase in patients with Cushing’s syndrome. Eur J Endocrinol 2009;161:695-703.

Inada M, Kurata S, Nishikawa M, Oishi M, Mashio Y, Tanaka K, Ishi H, Nato K, Imura H. Cushing’s syndrome associated with corticogenic hypothyroidism: a case study. Endocrinol Jpn 1981;28:225-230.

Wilber, JE, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969;48:2096-2103.

Abalovich M, Amino N, Barbour LA, Cobin RH, DeGroot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:S1-S47.

NOTE ON FOLLOW-UP

She had an adrenal ultrasound that reported no adrenal mass but commented on limitations of the study. This was followed by an abdominal MRI that showed a left adrenal mass (3.7x3.6x3.2cm) She had a left adrenalectomy in January, pathologic diagnosis was consistent with a 4 cm adrenal cortical adenoma. She was started on steroid replacement. 2 weeks ago she delivered a 2100 gm baby at 34 weeks due to premature rupture of membranes. She remains on hydrocortisone and levothyroxine. Thank you once again for your assistance and sharing your opinions on this case.