Hypopituitarism presenting as congestive heart failure.

Sheehan's syndrome (SS) develops as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage and is characterized by various degrees of hypopituitarism. Although the occurrence of SS is now rare, it should still be considered in any woman with a history of peripartum hemorrhage who develops manifestations of pituitary hormone deficiency any time following the event. Appropriate hormone replacement therapy results in marked clinical improvement. We present an unusual case of SS in a young lady who continued to have normal menstruation after the index event, had two spontaneous pregnancies, and was diagnosed only 11 years later when she presented to us with acute heart failure.

Introduction

Sheehan's syndrome (SS), first described in 1937, is characterized by postpartum hemorrhage (PPH), pituitary necrosis, and hypopituitarism.[1] Hormonal insufficiencies, ranging from single pituitary hormone insufficiency to panhypopituitarism, are observed. While hypopituitarism has several possible etiologies including neoplastic, immunological, iatrogenic, traumatic, infectious, and genetic, SS is one of the most common causes of hypopituitarism in developing countries.[1] The presentation is variable, and late presentations may be seen due to partial ischemic injury of the pituitary and gradual loss of endocrine function. Patients may also have anemia, osteoporosis, impairment in cognitive functions and affection of quality of life. The majority of the patients have empty sella or partially empty sella on neuroimaging.

We describe a unique case of SS with partial hypopituitarism and intact gonadotrophic function who first sought medical attention due to dilated cardiomyopathy. The cardiomyopathy reversed on treatment with hormonal replacement. Cardiomyopathy in SS is rare but has been seen to reverse with hormone replacement.[23456]

Case Report

A 35-year-old woman presented to the emergency department with acute pulmonary edema. She had an episode of acute gastroenteritis 2 weeks beforepresentation, which was treated by a general practitioner. Subsequently, the patient developed fatigability, syncope, and breathlessness on exertion. At presentation, the patient was pale, cold, and clammy; her pulse rate was 110 beats/min, regular, low volume, and her blood pressure was 92/66 mmHg. On chest auscultation, bibasilar fine crepitations were present; cardiac examination revealed left third heart sound/S3 gallop, but no murmurs. She was kept propped up, given high flow oxygen, and intravenous (IV) furosemide, digoxin, and low dose of dopamine infusion. Her electrocardiogram showed sinus tachycardia and generalized nonspecific ST-T changes, and chest radiograph showed cardiomegaly with features of pulmonary edema. Her routine investigations revealed anemia (hemoglobin of 9.5 g/dl). The rest of the biochemical investigations including liver and renal function tests were within normal limits. The echocardiogram revealed mitral regurgitation with normal cusps, and severe left-ventricular (LV) systolic dysfunction, with an LV ejection fraction of 25%. A diagnosis of dilated cardiomyopathy with LV failure was made, and the patient was treated for the same. Despite the resolution of pulmonary edema, she continued to have systolic blood pressure recordings of 90 mmHg with associated fatigue and light-headedness. Her general condition including apathy, anorexia, and nausea, did not improve. She was also noted to have psychomotor slowing, and hoarseness of voice.

Her history revealed that she had bled profusely at the time of delivery in her first pregnancy 11 years ago. She also recalled having multiple episodes of vomiting, and headache during the episode, and being given large quantities of IV fluids and two-three units of whole blood. The patient had recovered completely following the PPH. Her neuro-imaging during the episode was found to be normal. Since then, the patient developed episodes of syncope, craving for salt and water, and cold intolerance. She continued to have a normal reproductive function, and had two pregnancies over the next 5 years, with uncomplicated delivery in hospital. She, however, had lactation failure in both the pregnancies. She continues to have normal menstrual cycles till date, 9 years after her last pregnancy. She had normal axillary and pubic hair. A clinical diagnosis of SS with partial hypopituitarism was considered. On investigation, she was found to have central hypothyroidism, hypoadrenalism, and hypoprolactinemia [Table 1]. Magnetic resonance imaging of the brain showed partially empty sella with normal posterior pituitary. A diagnosis of SS with dilated cardiomyopathy was confirmed, and she was started on glucocorticoids and thyroxine. Within a week her blood pressure and postural symptoms improved remarkably, and patient felt a sense of well-being. Symptoms of heart failure regressed completely on follow-up. Repeat echocardiogram, after 6 months of treatment, revealed normal cardiac chambers and valves, with LV ejection fraction of 60%.

Table 1

Pituitary hormone levels

Hormone (unit)	Patient's value	Normal range
FT3	0.24	2.4-4.2 (pg/mL)
FT4	0.15	0.7-1.24 (ng/dL)
Thyroid stimulating hormone	4.8	0.34-4.25 (mIU/mL)
Prolactin	1.2	1.9-25 (ng/mL)
Follicle stimulating hormone	8.6	3-26 (mIU/mL)
Luteinizing hormone	5.2	2-105 (mIU/mL)
Growth hormone	0.5	0-5 (ng/mL)
Fasting cortisol	1.6	5-25 (mg/dL)

FT3: Free triiodothyronine, FT4: Free thyroxine

Discussion

Pituitary gland has a large secretory reserve, and >75% must be destroyed before clinical manifestations of hypopituitarism are evident.[2] SS, therefore, often evolves slowly and is diagnosed late. Increased pituitary volume during pregnancy, small sella size, coagulopathy, and autoimmunity are the proposed factors in the pathogenesis of SS.[1] The usual symptoms are failure of lactation, menstrual irregularity, loss of secondary sexual characteristics, and features of other hormonal deficiencies (asthenia and weakness, fine wrinkles around the eyes and lips, signs of premature aging, dry skin, hypopigmentation, hypotension and shock, anemia, and hyponatremia).[7] In addition, loss of the tissue due to necrosis creates an empty space within the pituitary fossa with subsequent herniation of the arachnoid, entrance of cerebrospinal fluid into the sella, which is identified on neuroimaging.[8] The diagnostic criteria of SS, thus, are (a) history of PPH or lactational failure and/or amenorrhea following childbirth; (b) more than one anterior pituitary hormone deficiency; and (c) an empty or partially empty sella of normal or reduced size on neuroimaging.[19]

As explained above, patients with SS exhibit variable degrees of hypopituitarism. While cases with preservation of gonadotrophic function have been reported,[810] those with regular ovulatory menstrual cycles and normal pregnancy are isolated and rare.[111213] Our patient continued to have normal menstrual and reproductive functions even after her first delivery with PPH, following which she had developed features suggestive of hypocortisolism and hypothyroidism.

The changes in the amounts of pituitary remnants detected by neuroimaging might correlate with hormonal secretory capacity. In a study of 26 patients with SS by Lee et al., four patients had partially empty sella, and none of these showed decreased basal levels of follicle-stimulating hormone and lymphocytic hypophysitis (LH),[14] as was seen in our patient.

LH is a close differential diagnosis for SS. It is a rare autoimmune disorder characterized histologically by infiltration of the pituitary gland by lymphocytes leading to the destruction of the pituitary parenchyma and its replacement with fibrotic tissue.[15] LH usually affects females during late pregnancy or within a year postpartum, although cases have been reported in males as well. In women, there is a history of failure to lactate or to resume menses after delivery. LH is associated with other autoimmune diseases and presents as a sellar mass causing headache or visual defects, manifestations of pituitary deficiency and rarely polyuria or polydipsia (diabetes insipidus). Hyperprolactinemia is found in about 30% of the patients. The diagnosis of LH may be suspected in women with a history of gestational or postpartum hypopituitarism, a symmetrically enlarged sellar mass on imaging and absence of hypovolemia or shock which characterizes SS. The suspicion of LH is confirmed by neuroimaging followed by pituitary biopsy. Antipituitary antibodies may also be found in some patients with LH, although their specificity is low. Treatment of LH consists of hormone replacement, dopamine agonists in the case of hyperprolactinemia, and transsphenoidal surgery for decompression in cases of progression of neurological symptoms and visual fields deterioration.

Cases of cardiomyopathy associated with hypopituitarism are known, and hypothyroidism, adrenal insufficiency, and growth hormone deficiency, in isolation, may result in heart failure as well. Hypothyroidism is associated with increased systemic vascular resistance, normal or decreased resting heart rate, decreased myocardial contractility, and decreased cardiac output. The diastolic pressure is increased, and pulse pressure is narrowed.[16] The pathogenesis of prolonged corticosteroid deficiency on cardiac tissue is not clearly defined. A role of glucocorticoids in the regulation of myocardial cell contractility, calcium transport, sensitivity to epinephrine, myocardial glycogenolysis has been described by some authors.[317] Cardiovascular complications of Addison's disease are usually limited to hypovolemic hypotension. Reversible myocardial dysfunction or “stunning” occurs in the setting of critical illness as in other states of extreme stress such as sepsis, acute respiratory failure, or trauma. Childhood-or adolescent-onset growth hormone deficiency is associated with significant reductions in LV posterior wall thickness and interventricular septal thickness, with resultant decreases in LV mass index and LV internal diameter.[16] The cardiomyopathies, thus seen, are reversible and have been seen to respond to hormone replacement.[4]

Cardiac abnormalities in patients with SS are not common. There have been only a few case reports of the concomitant presence of SS and cardiomyopathy [Table 2].[245618]

Table 2

Cases of Sheehan's syndrome with cardiomyopathy

Author	Case report
Doshi et al.[2]	A 42-year-old lady presented with dilated cardiomyopathy and hypoadrenal shock 14 years after an episode of PPH. She had history of secondary amenorrhea and lactation failure
Laway et al.[4]	A patient of pulmonary tuberculosis who developed shock, suggestive of adrenal crisis, after starting antitubercular treatment, on further workup was detected to have SS with dilated cardiomyopathy
Wang et al.[5]	A young woman with PPH presented within 2 weeks of delivery with congestive heart failure and ventricular arrhythmias. An MRI scan after 32 days revealed a diminished and flattened pituitary gland suggestive of empty sella
Bao and Fisher[6]	A 35-year-old female presented with severe congestive heart failure, and hypotension, after 15 years of extensive postpartum bleeding. The patient also had history of secondary amenorrhea and failure to lactate
Islam et al.[18]	A 36-year-old female presented with dilated cardiomyopathy within 2 years of the last childbirth. Further investigations revealed SS

MRI: Magnetic resonance imaging, SS: Sheehan's syndrome, PPH: Postpartum hemorrhage

All the patients described in the table were given replacement therapy in the form of glucocorticoids and levothyroxine. A resolution of symptoms and signs and echocardiographic parameters of cardiomyopathy was seen in all the patients on follow-up over 1 year.

The case discussed herein, having SS with preservation of gonadotrophins, and presenting with congestive heart failure, is worth highlighting as the patient had normal menstrual history, two spontaneous pregnancies following the index event, and developed dilated cardiomyopathy 11 years later, which reversed on hormonal treatment.

Conclusion

Heart failure is an uncommon but serious complication of untreated hypopituitarism. Our patient presented with dilated cardiomyopathy with heart failure at a young age. She was detected to have multiple endocrine deficiencies, which on history and further workup was found to be secondary to PPH that occurred 11 years before presentation. This case highlights the fact that that normal reproductive function does not preclude a diagnosis of SS. Thus, it is imperative to consider hypopituitarism as a cause of congestive cardiac failure.

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Conflicts of interest

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