Case 54

A 40-Year-Old Female With Weight Gain and Amenorrhea

Emily Omura, John D. Carmichael

A 40-year-old female presents for follow up of hypertension that started 2 years ago. She has been seen frequently in your clinic for titration of her antihypertensive medication and treatment of recently diagnosed hyperlipidemia and type 2 diabetes mellitus. During her visit she reveals that she is frustrated by weight gain that has occurred predominately over the past year. She reports regular menstrual cycles until the past year, when she notes increased time in between cycles and occasional spotting instead of regular periods. She is concerned that she may have early menopause because she is having changes in appetite, difficulty sleeping, and mood swings. She feels like these symptoms are getting worse, and she is frustrated that despite her increase in exercise and change in diet she is more fatigued and has experienced no weight loss.

How should you approach investigating whether a patient has common symptoms that are due to a secondary, treatable cause or are manifestations of lifestyle or genetic predispositions to metabolic abnormalities?

This patient has a past medical history and complaints that are very common to any internal medicine practice. Yet there are subtle clues within her history that should prompt more detailed questioning. The constellation of symptoms and the timing of their appearance is often crucial to making a diagnosis. Chronic diseases frequently present with symptoms insidious in onset and require a detailed history of these complaints and their associated conditions. The patient’s concern about a recent and fairly sudden change in her health status is important to investigate. A unifying diagnosis can be made by gathering the information about the onset and progression of symptoms. This patient’s recent history of hypertension and weight changes, which are findings consistent with the metabolic syndrome, and amenorrhea prior to the usual age of menopause are concerning for an endocrine disorder. More information regarding the onset of fatigue, previous endurance and physical activity, body habitus, timing of weight gain, and menstrual and obstetric history would be helpful in the evaluation for a potentially treatable underlying condition.

Upon further questioning, the patient states that she had three normal pregnancies and that her last was 4 years ago. She has gained 25 pounds in that time and has noted some hair growth on her chin and upper lip, which she has been waxing. She is concerned about her weight and reports that her legs feel weak and despite an increase in exercise, her waist is expanding.

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Clinical Pearl

Many endocrine disorders can cause menstrual irregularities: hyperprolactinemia, hypothyroidism, hyperthyroidism, and polycystic ovary syndrome (PCOS). Other chronic medical conditions such as renal insufficiency, rheumatologic disease, and psychiatric diseases such as anorexia can also cause hypothalamic or functional amenorrhea.

On physical exam she is in no distress, has a normal pulse rate and blood pressure of 132/85 mm Hg, body mass index (BMI) is 29 kg/m². There is some heavier hair growth underneath her chin and on the side of her face, which is very round and plethoric. She has no gross vision deficits and no thyromegaly; however, there is fullness to her supraclavicular subcutaneous tissue and her dorsocervical spine region, she has a skin exam remarkable for acanthosis nigricans, multiple bruises on extensor surfaces, and purple-red striae on her abdomen. Her waist circumference is 109 cm (the upper limit of normal for an adult female is 88 cm); however, her extremities appear thin with decreased proximal muscle strength bilaterally.

How does the physical exam help with your diagnostic evaluation?

This patient is presenting with signs and symptoms consistent with cortisol excess or Cushing’s syndrome (see Table 54.1). The severity of hypercortisolism can be variable, and the symptoms can present in various degrees of severity and prevalence. Because many of the classic symptoms of Cushing’s syndrome such as obesity, hypertension, menstrual irregularities, and mood disorders are common, and Cushing’s syndrome is an uncommon disease, it is important to evaluate the patient looking for both specific and sensitive physical exam findings. These findings help form a degree of suspicion that is crucial to determine the need for screening for Cushing’s syndrome and the interpretation of testing.

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Clinical Pearl

Truncal obesity is the most common physical exam finding of Cushing’s syndrome; however, it is not specific to this syndrome. The more specific findings in patients with Cushing’s syndrome include proximal myopathy, facial plethora, and easy bruising.

TABLE 54.1

Signs of Hypercortisolism

Central obesity (centripetal fat distribution of face [“moon facies”], supraclavicular and dorsocervical fat pads)

Signs of protein wasting: thin skin with violaceous striae on abdomen, flanks, breasts, hips; easy bruising; slow healing; and muscle wasting

Hypertension

Bone wasting leading to osteoporosis

Gonadal dysfunction and hyperandrogenism; menstrual irregularity; hirsutism

Mild to severe psychiatric disorders

Impaired immune defense mechanism with increased rate of infections

What are some conditions that may mimic the physical exam findings of Cushing’s syndrome?

Many effects of medications and medical conditions present with signs similar to Cushing’s syndrome and can interfere with the proper interpretation of test results. These include alcohol abuse, renal insufficiency, estrogen-containing oral contraceptives, obesity, pregnancy, and depression. These so-called pseudo-Cushing’s states make diagnosing Cushing’s syndrome very challenging, as they can be associated with a normal physiologic increase in cortisol secretion causing false-positive test results.

It is crucial to obtain a detailed medication history in cases of suspected hypercortisolism. Any form of exogenous glucocorticoids can cause iatrogenic Cushing’s syndrome. Intraarticular glucocorticoids injections, topical glucocorticoids, and inhaled glucocorticoids have all been implicated in cases of clinical symptoms associated with cortisol excess.

The patient denies taking any medications other than her hydrochlorothiazide, metformin, simvastatin, and amlodipine. She denies using any herbal medications or hormonal contraceptive agents. She does not smoke or use any illicit drugs and only drinks alcohol on rare occasions. Although she has been unhappy with her recent health changes, she denies symptoms of depression.

Who should undergo testing for Cushing’s syndrome?

Cushing’s syndrome is rare, and the high prevalence of conditions that mimic Cushing’s syndrome increases the risk of false-positive results. Therefore, it is important to establish a pretest probability of disease based on clinical history. Patients who are screened with a low pretest probability require multiple positive tests to establish the diagnosis, and positive tests should be viewed with skepticism with systematic sources for error excluded prior to further testing. In most cases, repeatedly normal screening results exclude the diagnosis of Cushing’s syndrome.

Patients with unusual features for age, symptoms or signs that may be more specific for Cushing’s syndrome (proximal myopathy, violaceous striae, facial plethora, easy bruising, osteoporosis at young age especially if male, weight gain with arrest of growth in pediatric populations), or the presence of suggestive symptoms in patients with incidentally discovered adrenal or pituitary adenomas are all appropriate patients for screening investigations. Indiscriminant testing of selected populations (i.e., patients with type 2 diabetes mellitus or obesity) have not yielded sufficient numbers of positive cases to become standard of care.

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Clinical Pearl

Early in the disease process, patients with Cushing’s syndrome lose the normal circadian rhythm of cortisol secretion. As a consequence, random measurements of adrenocorticotropic hormone (ACTH) and cortisol are of little diagnostic value. Nighttime cortisol measurement, either through sampling of saliva or serum, capitalizes on this loss of the normal physiologic nadir, and a high value measured at bedtime or midnight is a highly sensitive and specific sign of Cushing’s syndrome.