Sheehan’s syndrome complicated with Graves’ disease in a woman with a 20-year history of hypothyroidism

Introduction

Sheehan’s syndrome refers to a condition caused by ischemic necrosis of the pituitary gland following significant postpartum hemorrhage, which leads to a sudden reduction in blood flow to the adenohypophysis, resulting in peripheral circulatory collapse. This ischemic event typically affects the adenohypophysis, while the neurohypophysis generally remains unaffected because of differences in their blood supply. However, if the ischemia is severe and persistent, it may also involve the neurohypophysis or be complicated with diabetes insipidus. The clinical manifestations of Sheehan’s syndrome are typically characterized by hypofunction of the gonadal, thyroid, and adrenal axes. Key diagnostic indicators include a history of significant postpartum bleeding, failure to lactate, loss of secondary sexual hair, and amenorrhea. This report presents a rare case of Sheehan’s syndrome complicated with Graves’ disease. The reporting of this study conforms to the Case Report (CARE) guidelines. ¹

Case presentation

A female patient in her early 50 s was admitted to the Endocrinology Department of Guangdong Provincial Hospital of Chinese Medicine in June 2022 due to recurrent diarrhea for over 30 years, which had worsened, accompanied with weight loss for 6 months.

The patient had a home delivery (fourth child, male infant) in 1992 and experienced significant postpartum hemorrhage. Half a month later, she was hospitalized for blood transfusion treatment at a local hospital. The patient could not recall the specific situation at that time. Since then, she gradually developed amenorrhea, absence of lactation, and loss of axillary and pubic hair. Additionally, she gradually experienced fatigue, nausea, vomiting of gastric content, and 2–6 bowel movements a day. In 1994, she visited a local hospital and was diagnosed with Sheehan’s syndrome after relevant examinations (Table 1). She was then treated with prednisone acetate (5 mg daily), thyroxine (50–75 μg daily), nicoxystrol (5 mg daily), and calcium carbonate capsules (one capsule per day). She underwent uninterrupted outpatient follow-ups; however, specific details of the follow-up remain unclear.

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Table 1.

Laboratory examination results from Shenzhen Red Cross Hospital on 20 July 1994 upon the diagnosis of Sheehan’s syndrome.

T	E2	PRG	FSH	LH	T3	T4	TSH
0 ng/dL↓	0.9 pg/mL↓	0 ng/mL↓	7.3 mIU/mL↓	0 mIU/mL↓	0.67 ng/mL↓	24.84 ng/mL ↓	3.20 μIU/mL↓

T: testosterone; E2: estradiol; PRG: progesterone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; T3: triiodothyronine; T4: thyroxine; TSH: thyroid-stimulating hormone

Over the past 6 months, her diarrhea symptoms worsened, accompanied with fatigue, sweating, cold intolerance, dizziness, headache, neck pain, weight loss, and sleep disturbances. She was hospitalized at the Traditional Chinese Medicine Hospital of Luohu District, Shenzhen, on 29 May 2022. Her thyroid function test showed that her thyroid-stimulating hormone (TSH) level was <0.01 (reference range: 0.35–4.94) mIU/L, and she was discharged with medication on 2 June 2022 (thyroxine (25 μg daily) and prednisone acetate (5 mg daily)). After discharge, on 7 June 2022, she underwent thyroid function re-examination at the Overseas Chinese Hospital in Shenzhen, which revealed a TSH level of 0.005 (reference range: 0.27–4.2) µIU/mL. The patient did not take thyroxine because her triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) levels were all elevated. Subsequently, with no significant improvement in her symptoms, she visited our hospital for treatment. Since the onset of the disease, she showed a weight loss of 19 kg. On the day of admission, she showed mental fatigue and lethargy, cold intolerance, spontaneous sweating, and abdominal skin itching, along with dizziness, headache, neck pain, poor appetite, sleep disturbances, and diarrhea, with 2–6 bowel movements daily.

She had a history of hypertension for over 5 years, with the highest blood pressure reaching 160/100 mmHg. She was taking amlodipine besylate (5 mg) and irbesartan (150 mg), which kept her blood pressure under control. She also has a history of osteoporosis and cervical spondylosis.

The patient has four children, all delivered vaginally. She experienced a severe hemorrhage in 1992 and has had amenorrhea for 30 years since then. She has a history of blood transfusion, and her mother had a history of hypertension.

Upon examination, she was underweight with a body mass index of 19.0 kg/m². There was no pigmentation of the skin or mucous membranes, and no rash or striae were observed. Her eyebrows and hair were normal, while her axillary and pubic hair were absent. The thyroid was not enlarged, with no palpated nodules or audible vascular bruit. There was no exophthalmos, fine hand tremor, or pretibial myxedema. She experienced pain at the superior spinous processes of C5/6 and C6/7, and the bilateral brachial plexus nerve traction test was positive.

Based on the medical history, physical examination, laboratory tests (Table 2), and imaging (Figures 1 and 2), she was diagnosed with Sheehan’s syndrome, Graves’ disease, hypertension, mild anemia, osteoporosis, and cervical spondylosis.

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Table 2.

Abnormal laboratory test results upon admission.

Parameters	Patient	Reference range
Blood routine tests
White blood cell count, 109/L	3.13	3.5–9.5
Neutrophil percentage, %	25.9	40.0–75.0
Hemoglobin level, g/L	99	115–150
Total protein level, g/L	59.1	65.0–85.0
Albumin level, g/L	35.4	40–55
Five thyroid function items
Triiodothyronine, nmol/L	4.39	0.92–2.79
Thyroxine, nmol/L	220	58.10–140.60
Free triiodothyronine, pmol/L	18.84	3.50–6.50
Free thyroxine, pmol/L	37.89	11.50–22.70
Thyroid-stimulating hormone, mIU/L	<0.008	0.550–4.780
Thyroid-related antibodies
Thyroid peroxidase antibody, IU/mL	48.17	<60
Thyroglobulin antibodies, IU/mL	103.80	<60
Thyroid-stimulating immunoglobulin, IU/L	8.29	≤0.55
Thyrotropin receptor antibodies, IU/L	8.31	0–1.75
COR
COR (8: 00), nmol/L	<13.8	145.4–619.4
COR (16: 00), nmol/L	<13.8	94.9–462.4
COR (0: 00), nmol/L	<13.8
24-h urinary COR, nmol/24 h	16.56	57.4–806.8
ACTH
ACTH (8: 00), pmol/L	2.33	1.6–13.9
ACTH (16: 00), pmol/L	0.47	1.6–13.9
ACTH (0: 00), pmol/L	1.33	1.6–13.9
Gonadal hormones
Testosterone, nmol/L	<0.09	0.10–1.42
Estradiol, pmol/L	18.35	<18.4–5050
Progesterone, nmol/L	0.16	0.0–0.4
Prolactin, mIU/L	178.1	97.7–651.7
Follicle-stimulating hormone, IU/L	0.48	25.8–134.8
Luteinizing hormone, IU/L	<0.1	7.7–58.5

COR: cortisol; ACTH: adrenocorticotropic hormone.

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Figure 1.

Thyroid static imaging. The thyroid gland was located in the midline of the anterior neck, with both lobes symmetrically positioned and shaped, and the glandular margins were well-defined. The radioactive signal of the thyroid gland was elevated compared with that of the oral cavity. Based on specific numerical calculation, the thyroid-to-oral technetium uptake ratio was 4.82. This indicates increased uptake of technetium, consistent with hyperthyroidism.

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Figure 2.

Pituitary magnetic resonance imaging (plain scan + enhancement). Sagittal image (left side): The pituitary region appears normal, with a clear outline and regular shape. The overall pituitary gland is slightly small. The sella turcica area shows cystic changes. Coronal image (right side): The sella turcica is enlarged and filled with cerebrospinal fluid. The pituitary gland is thin, and the pituitary stalk is displaced, with no enhancement observed.

The patient received the following medications: hydrocortisone acetate (20 mg daily), methimazole (10 mg daily), bisoprolol fumarate (5 mg daily), amlodipine besylate (5 mg daily), irbesartan (150 mg daily), calcium carbonate (0.6 g daily), bifidobacterium quadruple live bacteria (1.5 g thrice daily), rabeprazole sodium enteric-coated (20 mg daily), diphylleia grayanotomoside (0.3 g thrice daily), and compound amino acid injection (10 AA VII, 200 mL intravenously daily). Additional therapies included various traditional Chinese medicine treatments.

Six months post-discharge, a follow-up phone call revealed that the patient was feeling occasionally tired and weak, but she no longer experienced diarrhea, itching, dizziness or headache. Her weight remained stable, and both appetite and sleep quality had improved, allowing her to resume normal activities. Despite clinical improvements, her thyroid function tests indicated ongoing hyperthyroidism, prompting continued antithyroid medication and regular monitoring. Fifteen months post-discharge, the patient reported no discomfort and had gained 10 kg weight; her weight at the time was 60 kg. At the 20-month follow-up via WeChat, the patient reported no specific discomfort, and her recent weight had stabilized. The treatment plan will be adjusted in a timely manner based on the new thyroid function test results, and the dose of antithyroid medication will be modified accordingly.

During this period, the patient will be instructed to strictly follow the regular follow-up schedule and continue to monitor thyroid function and thyrotropin receptor antibody (TRAb) levels (Figures 3 and 4). As of January 2024, the patient continued to receive antithyroid treatment, and the TRAb levels remained positive. Compared with October 2023, the TRAb levels increased in January 2024, and the symptoms of hyperthyroidism had significantly worsened, showing a clear synchronous change between TRAb levels and the recurrence of hyperthyroidism. In the future, the patient will continue to monitor her thyroid function regularly, and the dose of antithyroid medication will be adjusted appropriately based on changes in her hormone and TRAb levels.

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Figure 3.

Thyroid function trend in the patient. FT3: free triiodothyronine; FT4: free thyroxine. FT3 reference range: 3.5–6.4 pmol/L and FT4 reference range: 12.3–20.2 pmol/L.

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Figure 4.

TRAb trend in the patient. TRAb: thyrotropin receptor antibody. TRAb reference range: 0–1.75 IU/L.

Discussion

There have been reports of patients with Sheehan’s syndrome who experienced a spontaneous pregnancy after treatment, ² which was considered to be related to the re-establishment of the residual pituitary–gonadal axis function. Berkowitz et al. ³ reported a case of a 4-year-old boy with pituitary hormone deficiency caused by a shortened pituitary stalk who was intermittently treated with hormone replacement therapy. At the age of 19 years, his pituitary function recovered. Laboratory tests revealed normal thyroid hormone, serum cortisol, and urinary-free cortisol levels. A re-examination of pituitary magnetic resonance imaging showed significant enlargement of the proximal pituitary stalk, while the adenohypophysis remained small. Recent studies have shown that adult pituitary glands have stem cells that can be activated in response to injury, with the potential for regeneration.^4–6 Similarly, pituitary glands in adult mice have regenerative capabilities, involving some stem cells, which can achieve pituitary repair by activating certain resident stem cells. This regenerative potential, although promising, varies significantly among patients.

Currently, it is generally believed that patients with pituitary hypofunction may recover their function in each axis, with the gonadal, thyroid, and adrenal corticosteroid axes recovering in that order. The patient in this case was diagnosed with Sheehan’s syndrome at the age of 28 years and had been receiving uninterrupted hormone supplementation therapy. Upon admission, sex hormone levels were re-examined, which remained at postmenopausal levels, and she exhibited loss of pubic and axillary hair. She had not been pregnant since the diagnosis, indicating that the gonadal axis had not recovered. The patient had obvious symptoms of pituitary dysfunction. The current hyperthyroidism is considered unrelated to the recovery of pituitary function, as it is combined with thyroid dysfunction following pituitary failure, particularly Graves’ disease with elevated TRAb titers, adding complexity to the clinical management.

Bertola et al. ⁷ reported the case of a 67-year-old man with anterior pituitary hypofunction, a history of nasopharyngeal cancer radiotherapy, and concurrent Graves’ disease (specifically manifested as hyperthyroidism and elevated TRAb titers). After the diagnosis, thyroid suppression therapy was administered. Two years later, TRAb titers became negative, and suppression therapy was discontinued. A few months later, clear symptoms of pituitary dysfunction appeared; hormone replacement therapy (hydrocortisone acetate, L-thyroxine, and testosterone) was administered, and the patient’s clinical manifestations normalized for a longer period. Six years later, hyperthyroidism recurred, and the TRAb titers increased; therefore, L-thyroxine treatment was briefly interrupted. A few months later, the hyperthyroidism disappeared, central hypothyroidism reappeared, and L-thyroxine treatment was continued. The patient showed alternating episodes of hypothyroidism and hyperthyroidism. A study revealed that the positivity rate of anti-pituitary antibodies is higher in patients with autoimmune thyroid diseases than in those with non-autoimmune thyroid diseases. ⁸ Immune abnormalities may explain why autoimmune thyroid diseases can still occur after pituitary gland dysfunction and even manifest as hyperthyroidism.

Studies have shown that the use of certain immune checkpoint inhibitors (ICIs)^9,10 can lead to a decrease in immune tolerance, which increases the immune response to self-antigens and promotes the development of autoimmune diseases. ICIs ¹⁰ can relieve the immune suppression of T lymphocytes to achieve the corresponding therapeutic goals. However, this immune modulation effect may also disrupt the immune system’s tolerance to self-tissues, affecting endocrine glands such as the thyroid gland. Imbalances and functional abnormalities of T lymphocyte subsets are considered one of the core mechanisms underlying the development of autoimmune thyroid diseases, such as Hashimoto’s thyroiditis and Graves’ disease.^11,12 The regulatory effects of ICIs on T lymphocytes may contribute to the onset and progression of autoimmune diseases through multiple pathways.

From a diagnostic perspective, existing studies have confirmed that TRAb ¹³ has significant value in the diagnosis of hyperthyroidism, with high specificity for Graves’ disease, providing important evidence for the differential diagnosis of autoimmune thyroid diseases. However, the exact pathogenesis of Graves’ disease remains unclear. Considering the characteristic repeated increases in TRAb titers during the patient’s follow-up, it is hypothesized that immune dysfunction may result in the abnormal production of TRAb, which mimics the action of TSH and leads to abnormal elevations in T3 and T4 levels.

Bettencourt-Silva et al. ¹⁴ reported a case of pituitary cancer followed by hypopituitarism, with the development of Graves’ disease after radiotherapy. This case further supports the critical role of immune factors in endocrine disorders, suggesting that immune responses exacerbate or induce thyroid diseases, leading to the coexistence of primary hyperthyroidism and central hypothyroidism. This suggests that under special conditions such as pituitary dysfunction, the immunopathological processes mediated by TRAb are intertwined with the dysregulation of the pituitary–thyroid axis, adding more dimensions that warrant exploration in the mechanistic study and clinical management of Graves’ disease.

Conclusion

Patients with pituitary hypofunction may still develop hyperthyroidism, highlighting the complex management of hormonal imbalances. In clinical practice, it is crucial to continuously monitor thyroid hormone levels when administering hormone replacement therapy to these patients. This monitoring ensures appropriate adjustment of the type and dosage of medication according to individual needs. The frequency of assessment should be determined based on the patient’s condition, allowing for timely adjustments in treatment to maintain hormonal balance and prevent complications.