Baha M. Arafah

Increased Need for Thyroxine in Women with Hypothyroidism during Estrogen Therapy

BACKGROUND Women with hypothyroidism that is being treated with thyroxine often need higher doses when they are pregnant. Whether this need can be attributed solely to estrogen-induced increases in serum thyroxine-binding globulin or whether other factors are involved is not known. METHODS In 11 postmenopausal women with normal thyroid function and 25 postmenopausal women with hypothyroidism treated with thyroxine, I assessed thyroid function before they started estrogen therapy and every 6 weeks for 48 weeks thereafter. The women with hypothyroidism included 18 women receiving thyroxine-replacement therapy and 7 women receiving thyrotropin-suppressive thyroxine therapy. On each occasion, serum thyroxine, free thyroxine, thyrotropin, and thyroxine-binding globulin were measured. RESULTS In the women with normal thyroid function, the serum free thyroxine and thyrotropin concentrations did not change, whereas at 12 weeks the mean (+/-SD) serum thyroxine concentration had increased from 8.0+/-0.9 microg per deciliter (103+/-12 nmol per liter) to 10.4+/-1.5 microg per deciliter (134+/-19 nmol per liter, P<0.001) and the serum thyroxine-binding globulin concentration had increased from 20.3+/-3.5 mg per liter to 31.3+/-3.2 mg per liter, P<0.001). The women with hypothyroidism had similar increases in serum thyroxine and thyroxine-binding globulin concentrations during estrogen therapy, but their serum free thyroxine concentration decreased from 1.7+/-0.4 ng per deciliter (22+/-5 pmol per liter) to 1.4+/-0.3 ng per deciliter (18+/-4 pmol per liter, P<0.001) and their serum thyrotropin concentration increased from 0.9+/-1.1 to 3.2+/-3.1 microU per milliliter (P<0.001). The serum thyrotropin concentrations increased to more than 7 microU per milliliter in 7 of the 18 women in the thyroxine-replacement group and to more than 1 microU per milliliter in 3 of the 7 women in the thyrotropin-suppression group. CONCLUSIONS In women with hypothyroidism treated with thyroxine, estrogen therapy may increase the need for thyroxine.

Sex steroids and the thyroid.

Thyroid function is modulated by genetic and environmental causes as well as other illnesses and medications such as gonadal or sex steroids. The latter class of drugs (sex steroids) modulates thyroid function. Gonadal steroids exert their influence on thyroid function primarily by altering the clearance of thyroxine-binding globulin (TBG). While oestrogen administration causes an increase in serum TBG concentration, androgen therapy results in a decrease in this binding protein. These effects of gonadal steroids on TBG clearance and concentration are modulated by the chemical structure of the steroid being used, its dose and the route of administration. Despite the gonadal steroids-induced changes in serum TBG concentrations, subjects with normal thyroid glands maintain clinical and biochemical euthyroidism without changes in their serum free thyroxine (T4) or thyroid-stimulating hormone (TSH) levels. In contrast, the administration of gonadal steroids to patients with thyroid diseases causes significant biochemical and clinical alterations requiring changes in the doses of thyroid medications. Similarly, gonadal steroid therapy might unmask thyroid illness in previously undiagnosed subjects. It would be prudent to assess thyroid function in subjects with thyroid disease 6-8 weeks after gonadal steroid administration or withdrawal.

Apoplexy of a pituitary adenoma after dynamic testing with gonadotropin-releasing hormone

Pituitary tumor apoplexy is a rare clinical syndrome characterized by hemorrhagic infarction of a pre-existing adenoma followed by the acute onset of headache, vomiting, visual disturbances, and sometimes alteration in the level of consciousness [l-3]. Although the pathophysiology of its development is not known, there are some apparent precipitating factors as recently summarized by Ebersold et al [4]. A few recent reports described the occurrence of apoplexy after dynamic testing of anterior pituitary function [5-71. In all of these instances, the apoplectic episode occurred after the combined administration of thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH), insulin, or glucagon. Although GnRH is commonly used in the dynamic testing of pituitary gonadotropin secretion, there are, to our knowledge, no known serious neurologic complications associated with its use. Apoplexy has never been reported to occur after the single injection of this hypothalamic-releasing factor. In this report, we describe a patient with hyperprolactinemia in association with a pituitary macroadenoma who developed hemorrhagic infarction of the adenoma following the intravenous administration of GnRH. The patient had an uneventful recovery after transsphenoidal removal of the necrotic tumor. CASE REPORT A 41-year-old woman presented with a five-year history of amenorrhea. Three years before admission, she had an elevated serum prolactin level to 75 ng/mL and a demonstrable pituitary adenoma on computed tomography. No treatment was given at that time and the patient was next seen by us for endocrine evaluation. She had remained amenorrheic, but exhibited no findings to suggest hypopituitarism, and had no visual disturbances or headaches. Except for a minimal clear discharge from both breasts, results of physical examination were unremarkable. Initial studies showed elevated serum prolactin and follicle-stimulating hormone (FSH) levels (Table I). Magnetic resonance imaging (MRI) of the sella turcica showed a macroadenoma with extension into the suprasellar region and superior displacement of the optic chiasm. Determination of the gonadotropin responses of GnRH was planned in view of the known elevation of the basal FSH level. Approximately 60 minutes after the administration of GnRH (100 pg intravenously), the patient noted the sudden onset of headache, which

Histologically Proven Lymphocytic Hypophysitis: Spontaneous Resolution and Subsequent Pregnancy

Of the 128 previously reported cases of lymphocytic hypophysitis, the diagnosis was histologically proven in 6 patients in whom the pituitary mass regressed spontaneously; only 1 subsequently became pregnant. Among six additional patients who became pregnant after a diagnosis of presumed lymphocytic hypophysitis, the disease was confirmed histologically in only three, two of whom underwent surgical debulking and one who had no follow-up imaging. To our knowledge, we describe the second patient with histologically proven lymphocytic hypophysitis, associated with adrenocorticotropic hormone (corticotropin) and prolactin deficiencies, in whom the pituitary mass regressed completely with physiologic hydrocortisone therapy only and in whom a spontaneous pregnancy occurred subsequently with no postpartum recurrence of the pituitary mass. This information lends credence to previous recommendations that, in the absence of visual field defects, surgical and corticosteroid therapy may be safely withheld, with periodic reassessment.

Effect of Growth Hormone Replacement on BMD in Adult-Onset Growth Hormone Deficiency

To determine if replacement of GH improves BMD in adult‐onset GHD, we administered GH in physiologic amounts to men and women with GHD. GH replacement significantly increased spine BMD in the men by 3.8%.

Pharmacological management of acromegaly: a current perspective

Acromegaly is a chronic disorder of enhanced growth hormone (GH) secretion and elevated insulin-like growth factor–I (IGF-I) levels, the most frequent cause of which is a pituitary adenoma. Persistently elevated GH and IGF-I levels lead to substantial morbidity and mortality. Treatment goals include complete removal of the tumor causing the disease, symptomatic relief, reduction of multisystem complications, and control of local mass effect. While transsphenoidal tumor resection is considered first-line treatment of patients in whom a surgical cure can be expected, pharmacological therapy is playing an increased role in the armamentarium against acromegaly in patients unsuitable for or refusing surgery, after failure of surgical treatment (inadequate resection, cavernous sinus invasion, or transcapsular intraarachnoid invasion), or in select cases as primary treatment. Three broad drug classes are available for the treatment of acromegaly: somatostatin analogs, dopamine agonists, and GH receptor antagonists. Somatostatin analogs are considered as the first-line pharmacological treatment of acromegaly, although efficacy varies among the different formulations. Octreotide long-acting release (LAR) appears to be more efficacious than lanreotide sustained release (SR). Lanreotide Autogel (ATG) has been shown to result in similar biological control as octreotide LAR, and there may be a benefit in switching from one to the other in some cases of treatment failure. The novel multireceptor somatostatin analog pasireotide, currently in Phase II clinical trials, also shows promise in the treatment of acromegaly. Dopamine agonists have been the earliest and most widely used agents in the treatment of acromegaly but have been found to be less effective than somatostatin analogs. In this class of drugs, cabergoline has shown greater efficacy and tolerability than bromocriptine. Dopamine agonists have the advantage of oral administration, resulting in increased use in select patient groups. Selective GH receptor antagonists, such as pegvisomant, act by blocking the effects of GH, resulting in decreased IGF-I production despite persistent elevation of GH serum levels. Thus far, tumor growth has not been a concern during pegvisomant therapy. However, combination treatment with somatostatin analogs may counteract these effects. The authors discuss the latest guidelines for biochemical cure and highlight the efficacy of combination therapy. In addition, the effects of pharmacological presurgical treatment on surgical outcome are explored.

Biochemical diagnosis of adrenal insufficiency: the added value of dehydroepiandrosterone sulfate measurements.

OBJECTIVE To review biochemical tests used in establishing the challenging diagnosis of adrenal insufficiency. METHODS We reviewed the relevant literature, including our own data, on various biochemical tests used to determine adrenal function. The advantages and limitations of each approach are discussed. RESULTS Baseline measurements of serum cortisol are helpful only when they are very low (≤ 5 μg/dL) or clearly elevated, whereas baseline plasma adrenocorticotropic hormone levels are helpful only when primary adrenal insufficiency is suspected. Measurements of baseline serum dehydroepiandrosterone sulfate (DHEA-S) levels are valuable in patients suspected of having adrenal insufficiency. Although serum DHEA-S levels are low in patients with primary or central adrenal insufficiency, a low level of this steroid is not sufficient by itself for establishing the diagnosis. A normal age- and sex-adjusted serum DHEA-S level, however, practically rules out the diagnosis of adrenal insufficiency. Many patients require dynamic biochemical studies, such as the 1-μg cosyntropin test, to assess adrenal function. CONCLUSION In establishing the diagnosis of central adrenal insufficiency, we recommend measurements of baseline serum cortisol and DHEA-S levels. In addition to these, determination of plasma levels of aldosterone, adrenocorticotropic hormone, and renin activity is necessary when primary adrenal insufficiency is suspected. With a random serum cortisol level of ≥ 12 μg/dL in the ambulatory setting or a normal age- and sex-adjusted DHEA-S level (or both), the diagnosis of adrenal insufficiency is extremely unlikely. When serum DHEA-S levels are low or equivocal, however, dynamic testing will be necessary to determine hypothalamic-pituitary-adrenal axis function.

Measurements of Serum DHEA and DHEA Sulphate Levels Improve the Accuracy of the Low-Dose Cosyntropin Test in the Diagnosis of Central Adrenal Insufficiency

BACKGROUND AND OBJECTIVES The diagnosis of central adrenal insufficiency (AI) continues to be challenging, especially when it is partial. We have recently demonstrated the value of measuring serum dehydroepiandrosterone sulfate (DHEA-S) in establishing the diagnosis of central AI. The current investigation examined the added value of measuring serum dehydroepiandrosterone (DHEA) levels during low-dose (1 μg) cosyntropin (LDC) stimulation in patients suspected to have central AI. METHODS Baseline and LDC-stimulated cortisol, DHEA, and DHEA-S were measured preoperatively in 155 consecutive patients with pituitary masses and 63 healthy subjects. Hypothalamic-pituitary adrenal (HPA) function was normal (NL-HPA) in 97 of the patients and was impaired (impaired HPA) in 58 patients. Patients with NL-HPA underwent surgical removal of the sellar masses and received no glucocorticoids before, during, or after surgery. RESULTS Baseline and LDC-stimulated serum cortisol, DHEA, and DHEA-S in patients with NL-HPA were similar to those of normal subjects. In contrast, patients with impaired HPA had lower baseline and LDC-stimulated serum cortisol, DHEA, and DHEA-S levels. There were 18 subjects in the latter group whose LDC-stimulated serum cortisol levels were greater than 18.0 μg/dl. In those 18 subjects, baseline and LDC-stimulated DHEA and DHEA-S levels were similar to the whole group of patients with impaired HPA function. The molar ratio of cortisol to DHEA did not change with LDC stimulation in normal subjects and those with NL-HPA. In contrast, patients with impaired HPA had a higher baseline cortisol to DHEA molar ratio that increased further with LDC stimulation. CONCLUSIONS Patients with impaired HPA function have a more severe loss in DHEA secretion than that of glucocorticoids. Measurements of serum DHEA levels during LDC simulation provide additional valuable information that improves the diagnostic accuracy of LDC in patients suspected to have central AI. We recommend the inclusion of DHEA and DHEA-S measurements in the laboratory assessment of HPA function.

Recurrences of ACTH-Secreting Adenomas After Pituitary Adenomectomy Can Be Accurately Predicted by Perioperative Measurements of Plasma ACTH Levels

BACKGROUND Adenomectomy is the treatment of choice for ACTH-secreting adenomas. Although the development of ACTH deficiency immediately after adenomectomy suggests surgical success, disease recurrence was reported in patients who developed hypocortisolism postoperatively. In the current study, we examined the value of measuring perioperative plasma ACTH and cortisol levels in predicting disease recurrence of patients with ACTH-secreting adenomas. METHODS Consecutive patients (n = 55; 41 females, 14 males) with clinical, biochemical, and histological documentation of ACTH-secreting adenomas were investigated after pituitary adenomectomy. All patients were followed with clinical monitoring and frequent measurements of plasma ACTH and serum cortisol levels, and none received glucocorticoids unless or until they developed symptoms of adrenal insufficiency or when their serum cortisol levels were ≤3 μg/dL. RESULTS Postoperative serum cortisol levels reached ≤3 μg/dL in 46 of 55 and were ≥4 μg/dL in the remaining 9. Simultaneously measured plasma ACTH levels in the latter 9 patients were >40 ng/L when the serum cortisol reached its nadir. In contrast, among the 46 patients who had serum cortisol levels of ≤3 μg/dL, plasma ACTH levels measured simultaneously were ≤20 ng/L in 38 of 46 and >20 ng/L in the remaining 8. During a mean follow-up period of nearly 7 years, patients who had a nadir plasma ACTH of >20 ng/L developed recurrences even though their postoperative serum cortisol levels were ≤3 μg/dL. CONCLUSIONS Despite profound hypocortisolemia after adenomectomy, a simultaneously measured plasma ACTH level of >20 ng/L in the perioperative period is highly predictive of future recurrence of ACTH-secreting adenomas.

Pitfalls in the diagnosis and management of Cushing's syndrome

Despite many recent advances, the management of patients with Cushings disease continues to be challenging. Cushings syndrome is a complex metabolic disorder that is a result of excess glucocorticoids. Excluding the exogenous causes, adrenocorticotropic hormone-secreting pituitary adenomas account for nearly 70% of all cases of Cushings syndrome. The suspicion, diagnosis, and differential diagnosis require a logical systematic approach with attention paid to key details at each investigational step. A diagnosis of endogenous Cushings syndrome is usually suspected in patients with clinical symptoms and confirmed by using multiple biochemical tests. Each of the biochemical tests used to establish the diagnosis has limitations that need to be considered for proper interpretation. Although some tests determine the total daily urinary excretion of cortisol, many others rely on measurements of serum cortisol at baseline and after stimulation (e.g., after corticotropin-releasing hormone) or suppression (e.g., dexamethasone) with agents that influence the hypothalamic-pituitary-adrenal axis. Other tests (e.g., measurements of late-night salivary cortisol concentration) rely on alterations in the diurnal rhythm of cortisol secretion. Because more than 90% of the cortisol in the circulation is protein bound, any alteration in the binding proteins (transcortin and albumin) will automatically influence the measured level and confound the interpretation of stimulation and suppression data, which are the basis for establishing the diagnosis of Cushings syndrome. Although measuring late-night salivary cortisol seems to be an excellent initial test for hypercortisolism, it may be confounded by poor sampling methods and contamination. Measurements of 24-hour urinary free-cortisol excretion could be misleading in the presence of some pathological and physiological conditions. Dexamethasone suppression tests can be affected by illnesses that alter the absorption of the drug (e.g., malabsorption, celiac disease) and by the concurrent use of medications that interfere with its metabolism (e.g., inducers and inhibitors of the P450 enzyme system). In this review, the authors aim to review the pitfalls commonly encountered in the workup of patients suspected to have hypercortisolism. The optimal diagnosis and therapy for patients with Cushings disease require the thorough and close coordination and involvement of all members of the management team.