Home On the Wards Solving the riddle of inter-related endocrinopathies

Solving the riddle of inter-related endocrinopathies

April 2007

Published in the April 2007 issue of Today’s Hospitalist
In this first of an ongoing series, hospitalists discuss interesting clinical challenges they’ve faced and describe how they resolved diagnosis and treatment.

As hospitalists, we are often asked to help manage common endocrine disorders such as diabetes mellitus, hyperlipidemia, hyperthyroidism and hypothyroidism.

While we should screen patients for each of these conditions, we need to pay particular attention to screening for hypothyroidism. That’s because it can predispose patients to yet another endocrinopathy: hyperprolactinemia. Hypothyroidism screening is, in fact, an essential component in evaluating patients with hyperprolactinemia.(1)

Isolated hyperprolactinemia occurs in less than 1% of all patients. Among women with reproductive disorders, however, the incidence rate ranges from 9% to 17%.(1,2) In addition, adult-onset hypothyroidism affects between 1% and 10% of patients, depending on etiology “such as autoimmune or drug-induced, or caused by iodine deficiency “age and sex.

When it comes to both endocrinopathies existing simultaneously, as many as 3% of the population may be affected.1 Several case reports have highlighted the coexistence of the two conditions, usually in women.(3,4,5)

In this case study, we describe one of our consults on a postpartum patient. The case outlines the pathogenesis and diagnosis of the simultaneous presentation of both endocrinopathies.

The patient was a 34-year old Hispanic female on the obstetrics inpatient service who had just undergone an uncomplicated Cesarean section. She complained of recurrent headaches for four months prior to delivery, bilateral nipple discharge and weight gain, attributing the weight gain to her pregnancy.

Initial investigations revealed elevated levels of prolactin and thyroid-stimulating hormone (TSH). The hospitalists were called because of the obstetrics service’s concern that the patient had a prolactinoma.

Prolactinomas are the most common hormone-secreting pituitary tumor. Based on size, a prolactinoma can be classified as microprolactinoma (<10 mm diameter) or macroprolactinoma (>10 mm diameter). Some tumors, known as functioning tumors, may produce hormones, but most “referred to as non-functioning tumors “do not.

The clinical course of prolactinomas presents in females as cessation of menses unrelated to menopause, galactorrhea, infertility, decreased libido, headache and visual changes. In male patients, prolactinomas can likewise present with decreased libido, headache and visual changes, as well as gynecomastia, infertility and impotence.

Interestingly, autopsy studies indicate that 25% of the U.S. population has small pituitary tumors.(6) Forty percent of these tumors produce prolactin, but most are not considered clinically significant.

Clinically significant pituitary tumors, on the other hand, affect approximately 14 out of 100,000 people.(7) The exact cause of tumors remains unknown, and most tumors are sporadic in nature.

Microprolactinomas are much more common than macroprolactinomas in the U.S.(8) In women with prolactinomas, 90% present with a microprolactinoma, while in men, 60% present with macroprolactinomas.(8)

The diagnosis of prolactinoma is based on clinical findings and non-invasive diagnostic techniques. The differential diagnosis includes pregnancy, ovarian failure, polycystic ovarian disease, migraine headaches, benign intracranial hypertension (pseudotumor cerebri), hypothyroidism, pituitary tumors, multiple endocrine neoplasm type 1 and major depressive disorder.

Further laboratory testing and imaging studies can help narrow the differential. High resolution CT scan of the brain with sellar images can detect tumor calcifications. An MRI of the brain, however, usually provides better detail.

History and exam
Our patient’s past medical history included a possible macroprolactinoma and hypothyroidism diagnosed three years before. Over those three years, she had received cabergoline for the suspected macroadenoma and levothyroxine for her hypothyroidism. During her pregnancy, however, she had decided on her own to discontinue levothyroxine.

On physical exam, the patient appeared alert and oriented to time, place and person. She was afebrile, with a blood pressure of 130/80 mm Hg, a heart rate of 80/min and a respiratory rate of 20/min.

The patient had no evidence of ophthalmopathy, and her thyroid was smooth, normal in size and without a bruit. Her cardiac, lung and abdominal exams were normal.

She had pitting edema (2+) of her lower extremities bilaterally and a slight delay in relaxation of her deep tendon reflexes. She had no clinical evidence of asteatotic dermatitis, however, and the remainder of the exam was unremarkable.

Lab tests and images
The initial laboratory workup included a complete blood count, brain natriuretic peptide, serum prolactin levels and thyroid function tests. The results showed the following:

  • WBC: 13.2 X 10³/μL
  • Hb: 7.9 mg/dL
  • PLT: 170 X 10³/μL
  • Granulocytes: 97%
  • Na: 140 mmol/L
  • K: 4.1 mmol/L
  • Cl: 99 mmol/L
  • HCO3: 22 mmol/L
  • Prolactin: 101.2 ng/mL
  • TSH: 1.13 μIU/mL
  • Free T4: 0.69 ng/dL
  • Free T3: 2.6 ng/dL
  • BUN: 14 mg/dL
  • Creat: 0.9 mg/dL

A CT scan of the brain performed three years earlier revealed a pituitary mass 16 mm in size (Figs 1,2), suspicious for a macroadenoma. When we compared this suspected macroadenoma to a CT scan of the brain performed three years earlier, we found that it had grown from 10 mm.

If this pituitary mass is a prolactinoma, we can treat it with dopamine agonists such as bromocriptine, which is usually safe during pregnancy. (It is a class B agent.) Prolactin levels typically return to normal values within days or weeks of initiating the medication.(9)

Patients with macroadenomas can benefit from either medical or surgical therapy. Macroadenomas treated with bromocriptine can start to shrink in as few as one to three days.10 Surgery is indicated when medications fail to control the symptoms or when the tumor has grown and is compressing the surrounding structures of the brain; transphenoidal pituitary adenomectomy is the preferred
surgical treatment.(10)

The vast majority of patients with microadenomas (95%) have an excellent prognosis. Macroadenomas, however, don’t have a reliable prognosis and require aggressive treatment. They also require regular monitoring of serial prolactin levels along with pituitary imaging.

Making the diagnosis
Prolactinomas are one of several causes of hyperprolactinemia.(8) The question we faced with this patient became: Does she have a prolactinoma or a pituitary pseudotumor secondary to hypothyroid-induced hyperprolactinemia?

Clinicians need to correctly identify the etiology of the pituitary mass to avoid unnecessary treatments.

If the mass is an enlarging prolactinoma unresponsive to medical therapy, for instance, surgery is indicated. However, surgery is contraindicated in reducing the size of a pseudotumor caused by hypothyroid-induced hyperprolactinemia. In that case, levothyroixine therapy should suffice.

It is important to recognize hypothyroidism as a possible etiology of a pituitary mass, due to thyrotroph hyperplasia, lactotroph hyperplasia or both.(11) When considering hyperprolactinemia etiologies, clinicians need to keep in mind that overproduction of prolactin can occur in conditions other than pituitary tumors.(12)

For example, certain medications such as phenothiazines, haloperidol, metoclopramide, reserpine, verapamil, tricyclic antidepressants, and cocaine and opiate abuse may all induce similar symptoms. In addition, hyperprolactinemia can also result from hypothyroidism, breastfeeding, GERD, hypertension, acromegaly and Cushing’s syndrome.

When differentiating between the diagnosis of a prolactinoma and a pseudotumor secondary to hypothyroidism, we also need to understand the relationship between prolactin and the thyroid gland. Patients with pseudotumor may present with symptoms of a polyendocrinopathy; the patient with hypothyroidism, for example, may complain of cold intolerance, constipation, fatigue, depressed mood, asteatotic dermatitis and myxedematous skin changes.

The coexisting pseudotumor may cause headache, while the associated hyperprolactinemia can induce galactorrhea, decreased libido, erectile dysfunction in men, and amenorrhea or oligomenorrhea in premenopausal women.

The endocrine symptoms are the same in isolated hyperprolactinemia, but patients also run a risk of vision impairment “specifically bitemporal hemianopsia “due to the mass effect.

Physiologically, prolactin releasing factors (PRFs) and prolactin inhibitory factors (PIFs) regulate prolactin synthesis and secretion. The PRFs increase the prolactin secretion, while the PIFs decrease that secretion. The major PRFs are thyrotropic releasing hormone (TRH) and vasoactive intestinal peptide (VIP). The major PIF is dopamine (and dopamine agonists).

While the precise mechanism of hyperprolactinemia secondary to hypothyroidism is unknown, studies have described enhanced hypothalamic synthesis of TRH and increased pituitary response to TRH.(13) While hypothyroidism can cause an enlarged pituitary gland due to hyperprolactinemia, it can also cause enlargement of the pituitary gland secondary to hyperplasia of the thyrotropic and lactotrophic cells in the pituitary.(14) Therefore, in the case of hypothyroidism and an enlarged pituitary, physicians must check serum prolactin levels to confirm the etiology of the pituitary enlargement.

Because our patient presented in the middle of therapy for a suspected prolactinoma (the cabergoline she had received in the past), it was unclear if she had an actual prolactinoma or a hypothyroid-induced pseudotumor, as cabergoline could help with symptoms in both conditions. The endocrinologists who followed the patient after discharge faced the same diagnostic dilemma, but agreed with us that the latter diagnosis seemed more likely.

Ongoing treatment
Our patient was restarted on levothyroxine and cabergoline. Two weeks after the initiation of therapy, her prolactin level dropped to 56 ng/ml “almost 50% of the pre-treatment level “and her symptoms improved significantly.

The cabergoline was discontinued, although the patient continued to take levothyroxine with good control of her symptoms over the next several months. Treating the hypothyroidism in conjunction with inhibiting prolactin secretion allowed her symptoms to resolve relatively quickly.

The lessons we took away from this case were that in patients with prolactin pseudotumors secondary to poorly controlled hypothyroidism, it is essential to identify the cause of the hypothyroidism, initiate thyroid hormone supplementation, monitor thyroid function tests, and establish close follow-up noting changes or resolution of symptoms. In cases where the patient does not have symptoms of hyperprolactinemia, cabergoline may not be indicated if the prolactin level is less than 100 ng/mL.

The case was also a strong reminder that endocrinopathies such as hypothyroidism and hyperprolactinemia can co-exist. We need to take a thorough patient history and review of systems and ask patients specific questions related to each endocrinopathy.

Lab screening tests can be useful, although imaging is recommended only if supported by history and lab results. Understanding the pathophysiology of an isolated prolactinoma and a hypothyroid-induced pseudotumor can help guide treatment strategies and minimize unnecessary medical and surgical interventions.

Neera Khilnani, MD, is an assistant professor of medicine, hospitalist and program director of the internal medicine/pediatrics residency program at the University of Texas Medical Branch in Galveston, Texas.

Truptesh H. Kothari, MD, MS, is a first year internal medicine resident at the Bronx VA Medical Center in New York, a teaching affiliate of Mount Sinai Hospital and Mount Sinai School of Medicine.

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