Expanding Medical Therapy for Cushing's Disease: Mifepristone Appears Effective

A combination of mifepristone and levothyroxine proves beneficial in controlling excess cortisol in patients with central hypothyroidism.

with Lisa B. Nachtigall, MD, and Tamara L. Wexler, MD, PhD

Cushing’s disease is a rare hormonal disorder, affecting some 200,000 people in the United States. However, if even one patient presents with this disorder who isn’t diagnosed and treated appropriately is likely to face years of avoidable symptoms and disease complications.1

Hypothyroidism arises in the onset of Cushing's disease.

As with primary hypothyroidism, manifestations of central hypothyroidism include weight gain, muscle atrophy, thromboembolic disorders, metabolic disorders, and skin thinning.

Pituitary adenomas—which account for more than 70% of cases of Cushing’s disease in adults—are distinguished for stimulating excess production of adrenocorticotropic hormone (ACTH), leading to the most common cause of central hypothyroidism.

Mifepristone for Hypercortisolemia & Diabetes Mellitus 

Whereas pituitary surgery remains first line therapy, both radiotherapy and bilateral adrenalectomy are considered good second-line treatments for persistent hypercortisolism, and the armamentarium of pharmacotherapeutics is growing as a viable clinical approach in the management of cortisol excess.

“Nearly all medications used to treat central hypothyroidism and Cushing’s disease act by blocking cortisol production,” says Lisa B. Nachtigall, MD, co-director of the Neuroendocrine and Pituitary Tumor Clinical Center at Massachusetts General Hospital in Boston and associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

 “In contrast to standard therapies, mifepristone is a glucocorticoid and progesterone receptor blocker that is approved for the treatment of patients with hypercortisolemia and diabetes or glucose intolerance in whom surgery failed to achieve remission or who were not adequate surgical candidates,”2 Dr. Nachtigall says.

Results of the SEISMIC Study (Study of the Efficacy and Safety of CORLUX [mifepristone] in the Treatment of Endogenous Cushing's Syndrome) indicated that there were significant clinical and metabolic improvements in patients who had Cushing’s syndrome with concomitant diabetes or hypertension and were treated with mifepristone for six months.3

Mifepristone therapy was associated with a decreased mean hemoglobin A1C levels (HbA1c), decreased fasting plasma glucose, and significant weight loss with associated reductions in waist circumference. This treatment potentially affords substantial benefits to hypercortisolemia as well as weight reduction.2,3

However, Dr. Nachtigall says that she and other clinicians in pituitary clinics across the country have noticed that their “patients with Cushing’s disease and concomitant central hypothyroidism who were on mifepristone required increasing doses of levothyroxine over time.”

So the investigators reached out to other clinicians seeking patients with Cushing’s disease who were already taking both mifepristone and levothyroxine and who had the necessary documentation for inclusion in the study: documented central hypothyroidism treated with levothyroxine prior to initiation of mifepristone, laboratory data on thyroid function tests before/during therapy with mifepristone, increased requirements of levothyroxine during mifepristone therapy; in all, five patients were identified from four pituitary centers who met these criteria.2

“One clinician had more cases than we included, but there wasn’t full documentation. However, those patients who were not included had the same response to this drug combination as the five women identified and discussed in this study,”2 says lead author, Francisco J. Guarda, MD, a research fellow in medicine at Massachusetts General Hospital in Boston, Massachusetts.

“Mifepristone increases thyroid hormone requirements in patients with central hypothyroidism – a multicenter study,” according to the authors, although mifepristone is associated with substantial benefits on many parameters, its use in this population also leads to an increased levothyroxine requirement in hypothyroid patients.2

Among these patients, levothyroxine requirements increased from 67% to 400%, but four out of five of them also lost body weight. All of these patients had undergone transsphenoidal surgery, at least once, and one woman had also received radiation. Mifepristone doses ranged from 300 - 600 mg; and an initial decrease in T4 levels was reported, ranging from 0.1 ng/dL to 0.5 ng/dL.2

The authors did not offer any insight or rationale for the need for increasing doses of levothyroxine, although they noted that prior research on mifepristone indicated observations of a reduction in iodine uptake and reduced expression of severe essential proteins in thyroid hormone synthesis in thyroid cell cultures.2

Small Study Supports Mifepristone for Cushing’s  

“Cushing’s syndrome or its treatment is implicated in the etiology of central hypothyroidism in these patients,” Tamara L. Wexler, MD, PhD, a neuroendocrinologist and clinical assistant professor in the department of rehabilitation medicine, at New York University School of Medicine in New York, New York,

Dr. Wexler also told EndocrineWeb that it would be interesting to study the effects of mifepristone in patients with primary hypothyroidism, given the observations from earlier studies and the hypothesized reasons for the increased levothyroxine need in these patients with central hypothyroidism.

Given these findings, “patients with pituitary-mediated central hypothyroidism will likely require higher doses of levothyroxine and should have baseline testing before initiating treatment with mifepristone. In addition, patients should be monitored within the first month for a dose adjustment and then about every six weeks until the patient gets to the normal range – after which patients can be monitored every three to six months,” says Dr. Nachtigall.

“Mifepristone works, very well, in a select group of patients – and gives them the best chance of weight loss with normal thyroid functioning. However, we don’t yet know if ultimately patients will need dose reductions of levothyroxine if patients lose too much weight on mifepristone,” she says.

According to Dr. Guarda, “one of the patients had to withdraw owing to vaginal bleeding as a side effect of the medication; another patient discontinued mifepristone due to ankle and leg edema after nine months.” Four of the five patients were monitored for nine to 18 months, and one patient was followed for nearly a year. When mifepristone is discontinued, doses of levothyroxine need to be reassessed and often reduced.2

Clinical Implications of Mifepristone Central Hypothyroidism

Although this study only reported on five patients who all happened to be female and “older” (median age 50 years), Dr. Nachtigall tells EndocrineWeb that the findings are likely to be applicable to both younger patients and to male patients.

“However, younger women with a uterus require close monitoring while receiving mifepristone,” she says noting that while the substantial weight loss is associated with mifepristone, along with other benefits to blood sugar and blood pressure, making it an important treatment for this very select group of pituitary patients.

The study also highlights the importance of frequent monitoring of free T4 and subsequent dose adjustments of levothyroxine to optimize management of the central hypothyroidism, says Dr Nachtigall.

In addition, Dr. Wexler recommends that clinicians stay “alert for any clinical changes that can be accounted for by a shift in thyroid metabolism.” Cushing’s disease is more prevalent in women than men, at a ratio of 3 to 1, and affects predominantly individuals ages 20 to 50 years. It is a form of Cushing’s syndrome, which is a hormonal disorder caused by prolonged exposure to high levels of cortisol and is thus also called hypercortisolemia.

Standards of Care for Cushing’s Disease, Central Hypothyroidism

Surgical removal of the tumor, known as transsphenoidal adenoidectomy, is the most common treatment, and can be repeated if necessary. When successful, the production of ACTH initially drops below normal and patients are given a synthetic form of cortisol replacement for about one year.

Patients for whom surgery is not suitable or desirable as well as for those whose surgery has failed have the option to consider undergoing radiotherapy, often in conjunction with the drug mitotane to speed recovery.

Either can be used alone, albeit with a lower rate of success. Additional agents that are used, either alone or in combination, to control production of excess cortisol include aminoglutethimide, metyrapone, trilostane, and ketoconazole.

Recognizing Central Hypothyroidism and Making a Diagnosing of Cushing’s Disease

Central hypothyroidism This uncommon form of thyroid disease arises due to compressed pituitary thyrotrophs that result in a decrease in tTHS secretion.

Making a diagnosis of central hypothyroidism focuses on a low or low-normal serum free T4; serum TSH, may be normal, low, or slightly elevated. Because TSH secretion does not increase as T4 secretion falls in central hypothyroidism caused by pituitary disease, it is important to measure both serum TSH and free T4; T3 need not be measured.

Central Hypothyroidism is diagnosed in patients with low free T4 levels and low or inappropriately normal thyroid stimulating hormone. Patients who are diagnosed with Cushing’s disease should start taking levothyroxine with the aim of achieving thyroid hormone values in the normal range.

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