Introduction:

A, T2-weighted Axial B, T2 Sagittal C, FLAIR Axial D, T1 axial (The arrow indicates The pituitary gland  volume has decreased and has concave superior surface with the visualized parenchyma T2W hyper intense, T1W isointense avid post contrast enhancement.)

Echocardiography performed on the second day of admission revealed Normal Echocardiograph study with ejection fraction of 64%; however, marked bradycardia with a heart rate of 32 beats/min was noted during the examination. Abdominopelvic ultrasonography performed on the day of admission demonstrated long-segment wall thickening of the descending colon and rectum, more prominent in the rectum. Chest and abdominopelvic CT scans done on second day to clarify causes of bowel wall thickening demonstrated findings consistent with colitis.(showed on the Figure 3)

Despite intravenous fluid resuscitation and blood transfusion, the patient remained persistently hypotensive. Vasopressor support with norepinephrine was initiated at 0.1 μg/kg/min and gradually escalated to 0.3 μg/kg/min, at which point her blood pressure stabilized within the normotensive range. For the above given the clinical suspicion of sepsis with a gastrointestinal source was intervened, empiric antimicrobial therapy with Meropenem 1 g intravenously every 8 hours was commenced.

Following hormone replacement therapy, the patient demonstrated remarkable clinical improvement, with progressive stabilization of blood pressure, resolution of Bradycardia, and successful reduction of vasopressor requirements, supporting the endocrine origin of her hemodynamic instability.

Figure 4 Brain magnetic resonance imaging shows an empty Sella.

A, T2-weighted Sagittal B, T2-weighted Axial C, T1-weighted Axial D, FLAIR Axial (The arrows showed Partially empty sella)

On the second day of admission, the patient's management plan was revised following reassessment and review of the clinical findings and investigation results. Hormone replacement therapy was initiated with levothyroxine 100 μg orally once daily and hydrocortisone 100 mg intravenously twice daily. Additional treatment included pantoprazole 40 mg orally twice daily, oral sodium supplementation (½ teaspoon of table salt daily) for persistent hyponatremia, and a combined oral contraceptive (one tablet daily) as hormone replacement therapy. On her 3^rd day of admission, serum electrolyte was repeated serum potassium level (K+) was 3.78 mEq/L and serum Sodium (Na⁺) was 138.0 mEq/L. She was discharged with an advice on her illness and levothyroxine 100 μg orally once daily and hydrocortisone was change into Prednisolone 5mg po daily. She presented on follow up no new complaint, symptoms subsided and started to gain weight.

4. Discussion

Sheehan's syndrome is generally diagnosed several years postpartum and results from partial or complete deficiency of one or more anterior pituitary hormones. Its clinical manifestations vary according to the specific hormone deficiencies. Prolactin deficiency can cause lactation failure, whereas gonadotropin deficiency commonly causes amenorrhea or loss of genital hair. Corticotrophin deficiency can result in generalized fatigue, weakness, hypoglycemia, or dizziness. Growth hormone deficiency may cause fatigue and decreased quality of life. Symptoms of central hypothyroidism resemble those of primary hypothyroidism; however, patients with central hypothyroidism have low triiodothyronine and thyroxine levels with normal or inappropriately low thyroid-stimulating hormone levels. [10] Anemia and other hematological abnormalities are common in patients with Sheehan's syndrome. The response of these abnormalities to replacement of thyroxine and glucocorticoids is not clear. [11]. Because hormone-secreting cells are located near the vasculature, growth hormone and prolactin secretion are most commonly affected, followed by follicle-stimulating hormone and luteinizing hormone; severe pituitary necrosis also affects secretion of thyroid-stimulating hormone and adrenocorticotropic hormone. The time between postpartum hemorrhage and symptom onset can be several years. [12] [13]

Hemorrhagic shock during pregnancy is a key entry point in diagnosis. The diagnosis of Sheehan’s syndrome is determined by the patient’s history and physical examination, confirmed by laboratory tests and MRI imagine. Failure to lactate is often a common initial complaint in patients with Sheehan syndrome. [14] A woman with Sheehan’s syndrome with undiagnosed hypopituitarism might be apparently asymptomatic until her body is exposed to stressful situations like surgery or infection many years after her delivery, and then she presents with adrenal crisis. [15]

The patients were aged 35, 25, and 35 years, respectively, and all were from the southern part of Ethiopia. The intervals between their last deliveries and the diagnosis of Sheehan’s syndrome were 5 months, 11 months, and 1 year, respectively, with a mean interval of 9.3 months. All patients had a history of massive postpartum hemorrhage and exhibited physical signs suggestive of Sheehan’s syndrome. Failure of lactation was one of the most common presenting features. In addition, gonadal hormone deficiency manifested primarily as amenorrhea, decreased libido, and loss of axillary and pubic hair. All patients had undergone diagnostic evaluations at other healthcare facilities before presenting to our hospital. However, the diagnosis was delayed, which may be attributed to limited awareness of panhypopituitarism and its diverse and nonspecific clinical manifestations. Inadequate history-taking and physical examination may have further contributed to the difficulty in recognizing this rare disorder. The second patient had a particularly progressive presentation suggestive of secondary adrenal insufficiency. She initially developed asthenia, anorexia, and weight loss, followed by dizziness, nausea, persistent vomiting, and abdominal pain as her condition progressively deteriorated. Despite repeatedly seeking medical care, the underlying diagnosis remained unrecognized until she presented to our hospital.

Pituitary crisis is a potentially life-threatening complication of chronic pituitary hormone deficiency. It may develop after a period of vague or nonspecific symptoms and can be precipitated by factors such as electrolyte disturbances, infection, trauma, or other forms of physiological stress. Acute pituitary hormone deficiency commonly leads to volume depletion and reduced cardiac output, resulting in hemodynamic instability. With prompt hormonal replacement and restoration of intravascular volume, cardiovascular function can usually improve rapidly. [16] Consistent with this presentation, the second patient developed bradycardia and persistent hypotension despite adequate fluid resuscitation and vasopressor therapy. Although the initial diagnosis was not recognized, subsequent clinical re-evaluation, the diagnosis was reconsidered after her history of severe postpartum hemorrhage requiring blood transfusion was revealed. Following the initiation of appropriate hormonal replacement therapy, she demonstrated a marked clinical response, with improvement in her hemodynamic status. This case highlights the importance of considering pituitary crisis in patients with unexplained or refractory hypotension, particularly when there is a history of significant postpartum hemorrhage suggestive of postpartum pituitary dysfunction.

Interestingly, Sheehan syndrome can cause a wide range of hematological manifestations through unknown complex hormonal effects; the most frequent one is anemia. Pancytopenia is rarely present in Sheehan’s syndrome and is demonstrated in only a few case reports worldwide. [17] The second patient CBC profile showed bi-cytopenia, characterized by leukopenia and moderate normochromic normocytic anemia, which improved following hormone replacement therapy. Similarly, the third patient had mild normochromic normocytic anemia, whereas no hematological abnormalities were detected in the first case.

Second the patient also had hypoglycemic episodes at initial presentation, which were initially treated with bolus dextrose push but recurred. Then she was treated with dextrose infusion and subsequently normalized with the commencement of hormone replacement therapy.

Other laboratory investigations may reveal electrolyte disturbances, with hyponatremia being one of the most common abnormalities observed in patients with Sheehan syndrome. Hyponatremia may be an initial presenting feature of acute Sheehan syndrome, occurring in approximately 60% of reported cases. It is also a frequent electrolyte abnormality in patients with chronic disease, with reported prevalence ranging from 33% to 69%. [12]

The cause of hyponatremia in Sheehan's syndrome is controversial. Explanations include impaired free-water retention secondary to elevated antidiuretic hormone secretion as well as diminished free water clearance in the kidney secondary to the lack of cortisol thought to modulate distal tubular function in the presence of low levels of antidiuretic hormone. Other workers have found blunted aldosterone responsiveness to salt restriction in this condition, which was variable with glucocorticoid and/or thyroid hormone supplementation. The renin-aldosterone axis has been assumed to be independent of pituitary control, but there may be a regulating pituitary factor. [18] Whereas hypokalemia in patients with Sheehan syndrome is usually associated with gastrointestinal losses, such as those resulting from diarrhea and vomiting, rather than adrenal insufficiency, since adrenal aldosterone production is not dependent on pituitary hormones. In our case series, the second patient developed moderate hypokalemia, which was managed with potassium chloride (KCl) supplementation.

The third patient, in contrast, presented with profound hyponatremia, which was treated with intravenous 0.9% normal saline and oral salt supplementation. These contrasting electrolyte abnormalities highlight the variable metabolic manifestations of Sheehan’s syndrome and the importance of recognizing electrolyte disturbances as potential clues to underlying hypopituitarism.

Pituitary MRI is an important diagnostic tool in Sheehan syndrome, as it commonly demonstrates partial or complete empty sella. Imaging studies suggest that the pituitary gland may initially become enlarged during the first month after delivery, followed by gradual shrinkage over the subsequent months. This progressive loss of pituitary tissue can result in the development of an empty sella, typically becoming evident within 6 months to 1 year after delivery. In patients with established Sheehan syndrome, an empty sella is a characteristic and frequently observed MRI finding. [19] [20]  In our case series, all three patients demonstrated either an empty or partially empty sella on pituitary MRI, which, together with their clinical presentation, history of postpartum hemorrhage, and hormonal abnormalities, strongly supported the diagnosis of Sheehan syndrome.

The treatment includes the replacement of deficient pituitary hormones. An important point in patients with SS is the progressive nature of the disease. In patients presenting with acute adrenal failure, GC treatment should be started immediately after getting serum samples for cortisol measurement. In the long-term replacement, the patient should be monitored for optimal GC dose to prevent the unwanted effects of excess GC dose such as osteoporosis, glucose intolerance and weight gain while keeping the quality of life of the patient well. Hydrocortisone may be preferred although it cannot completely mimic the normal physiology of HPA axis. [21] Its recommend using HC, usually 15–20 mg total daily dose in single or divided doses. Patients using divided doses should take the highest dose in the morning at awakening and the second in the afternoon. [22]

Levothyroxine replacement should not be started before GC replacement or ruling out adrenal insufficiency. Dose adjustment should be done according to free T4 levels rather than TSH. In elderly and patients with coronary artery disease, LT4 should be given at low doses and increased slowly. GH may increase the requirement of LT4 dose or may unmask a mild secondary hypothyroidism. [21]

For our patients, hormone replacement therapy was tailored according to their age, fertility preferences, and financial capacity, using the available and affordable treatment options.

5. Conclusion

Sheehan syndrome remains the leading cause of panhypopituitarism in developing countries with inadequate obstetric care. However, it is frequently underdiagnosed. With this case report, we try to highlight the importance of maintaining a high index of suspicion among primary care physicians working in resource limited settings when women with a history of postpartum hemorrhage present with nonspecific symptoms before deciding to treat the patients symptomatically. Comprehensive clinical evaluation is essential for early diagnosis, timely referral for further investigations such as hormonal panels and brain MRI, and prompt initiation of treatment to prevent life threatening adrenal crisis. None of our three patients were aware of Sheehan syndrome, even though they had significant obstetric histories, and one experienced a severe adrenal crisis. We want to emphasize that women with a history of postpartum bleeding should be informed about the risk of Sheehan syndrome. Primary care physicians should educate patients about possible symptoms and the importance of seeking medical attention early. Sheehan syndrome should be considered a top differential diagnosis in these cases, and proper treatment should be initiated early to protect the patients from deadly complications.

6. Abbreviations

CBC: Complete Blood count KCL: Potassium chloride; LDL: Low-density lipoprotein; MCV: Mean corpuscular volume; MRI: Magnetic resonance imaging; NS: Normal saline. GC: Glucocorticoid SS: Sheehan’s syndrome COC: Combined Oral Contraceptive CT Scan: Computed C. decficille.

7. Acknowledgements

We would like to acknowledge Alatyon General Hospital, Department of Internal Medicine, for their support and contribution to this case series. We would also like to extend our special thanks to our patients for their cooperation and for granting permission to use their clinical information and MRI images for the purpose of this case series.

8. Authors contributions; Mamaru Sintayehu, Corresponding author, editing

Yonas kinfemichael, Corresponding author, drafting, editing,

Kerebih Molla; editing

Yonas Kassahu; Editing

Hailegebriel Demelash; data extraction

9. Availability of data and materials

 The data sets generated during the study are available from the corresponding author upon request.

10. Funding

There was no funding in the writing and publishing of this case series

10. Declarations

Ethics approval and consent to participate

The patients provided written informed consent for the publication of their medical information and relevant clinical images in this case series.

Consent for publication

Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consents are available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.