Acute Sheehan's Syndrome Presenting with Hyponatremia Followed by a Spontaneous Pregnancy

Background Acute Sheehan's syndrome is rare, as well as hyponatremia as its initial manifestation. In addition, spontaneous pregnancy in patients after Sheehan's syndrome is unusual. To our knowledge, no cases of spontaneous pregnancy after acute Sheehan's syndrome have been reported. We describe a case of Sheehan's syndrome that presented with acute hyponatremia and a spontaneous pregnancy. Case A 34-year-old female developed blood loss during delivery, which required a blood transfusion. On day seven postpartum, she presented with headaches, lethargy, and difficulty in breastfeeding. The workup showed hyponatremia (118 mEq/l), secondary hypothyroidism, and low prolactin levels. Magnetic resonance imaging showed pituitary necrosis. She was treated with NaCl, hydrocortisone (cortisol results were not available), and levothyroxine. Laboratory tests six weeks after discharge showed low IGF-1 and 8 AM cortisol and normal FT4, LH, FSH, and PRL levels. She was able to partially breastfeed until 4 months postpartum. Regular menstrual cycles started three months later. She became spontaneously pregnant one year later. Conclusion Acute Sheehan's syndrome should be considered in the evaluation of postpartum patients with suggestive symptoms. Physicians should be aware that hyponatremia could be an initial manifestation of Sheehan's syndrome, which requires a high index of suspicion for diagnosis. Spontaneous pregnancy can occur after acute Sheehan's syndrome.


Introduction
Sheehan's syndrome is a well-known cause of hypopituitarism resulting from postpartum pituitary ischemic necrosis after massive blood loss during delivery [1,2]. Its frequency has recently declined due to modern obstetric care, more so in developed countries. It is usually diagnosed several years postpartum. Acute presentation is extremely rare and can be life-threatening. Moreover, hyponatremia in the acute form of Sheehan's syndrome is also exceptional. In addition, spontaneous pregnancy in patients with Sheehan's syndrome is very rare [3]. To our knowledge, there are only two reported cases of acute Sheehan's syndrome with a successful pregnancy, one after ovulation induction and the other after in vitro fertilization [1,4].
We described an extremely rare case of Sheehan's syndrome that presented postpartum with acute severe hyponatremia and a spontaneous pregnancy one year after diagnosis. A 34-year-old female (with 2 previous pregnancies and 1 delivery) with no signifcant past medical history delivered a healthy, normal-weight male infant at 40 weeks of gestation. At delivery (via the vaginal route), she developed signifcant blood loss, which required a transfusion of two units of blood. She was discharged 72 hours postpartum. On day seven postpartum, she presented to the emergency department because of headaches, blurred vision, paresthesias, lethargy, and difculty breastfeeding. On physical examination, she appeared confused, was hypotensive (80/ 60 mmHg), and was tachycardic.

Case Presentation
Laboratory tests showed hyponatremia of 118 mEq/l (normal range (NR): 138-145) and normocytic normochromic anemia with hemoglobin of 9.7 g/dl (NR: 11.3-14.7). Sheehan's syndrome was suspected based on her clinical presentation with a signifcant postpartum hemorrhage. Hormone workup revealed secondary hypothyroidism with low free T4 (0.58 ng/dl, NR 0.89-1.76) and normal TSH (0.35 μIU/ml, NR 0. 35-5.5) and relatively low prolactin levels (PRL) of 7.12 ng/ml for the early postpartum period (NR for adult women 1.9-25; for women in the third trimester of pregnancy, NR is 84-232). Pituitary MRI showed an enlarged pituitary gland with suprasellar extension, with peripheral enhancement of the pituitary gland, and an irregular and poorly enhanced central portion after gadolinium injection ( Figure 1).
She was treated with NaCl replacement to increase her Na levels by 8 mEq/day. Serum 8 AM cortisol was drawn, and as the results were not readily available, treatment with hydrocortisone was initiated with the suspicion of secondary adrenal insufciency. In addition, levothyroxine treatment was started. Her sodium levels returned to normal, and she was discharged on hormonal replacement therapy (levothyroxine 100 mcg/day, hydrocortisone 15 mg in two divided doses: 10 mg at 8 a.m. and 5 mg at 16: 00 pm).
Laboratory tests six weeks after discharge of the diagnosis of Sheehan's syndrome showed low IGF-1, normal free T4 and LH and FSH levels, PRL levels of 10.2 ng/ml, and serum 8 AM cortisol 24 hours after the last dose of hydrocortisone of 1.72 μg/dl (she did not take the evening dose and took the morning dose after blood was drawn). Cortisol levels at the time of hospitalization before hydrocortisone treatment were 36.2 μg/dl. Table 1 shows a summary of her hormonal workup. She was able to breastfeed partially until 4 months.
Regular menstrual cycles started three months after delivery. A repeat MRI performed seven months later showed a smaller pituitary gland with peripheral enhancement after gadolinium injection ( Figure 2). Doses of levothyroxine were gradually decreased with normal FT4 levels when she became spontaneously pregnant one year after the previous delivery. Te lowest dose of Lthyroxin on which she became pregnant was 50 mcg 2 days a week and 75 mcg 5 days a week. Te dose was increased during pregnancy to 75 mcg per day. Te cortisol level was rechecked before pregnancy 24 hours after the last dose of hydrocortisone and was still low (2.54 μg/dl).
She had an uneventful pregnancy on levothyroxine 75 mcg/day and hydrocortisone 15 mg/day in two divided doses. She delivered a healthy, normal-weight female at 39 weeks of gestation.

Discussion
A diagnosis of Sheehan's syndrome is rarely made in the acute postpartum state. Sheehan's syndrome's true incidence is unknown, and it has been reported to occur in 1%-3.1% of women who lose 1-2 liters of blood associated with hypotension in developed countries [1,2,5]. However, prevalence has been reported to be higher in undeveloped countries (3.1%-27.6%) [6][7][8].
Sheehan's syndrome is generally diagnosed several years postpartum with chronic manifestations such as failure to lactate, amenorrhea, symptoms of hypothyroidism, and adrenal insufciency. Te time between postpartum hemorrhage and symptom onset can be several years. Te diagnostic delay is variable. An average delay of 20 ± 8.3 years with a range of 2-36 years was reported in 124 patients with Sheehan's [9]. Ramiandrasoa et al. reported a mean diagnostic delay of 9 ± 9.7 years in 39 women diagnosed with Sheehan's syndrome [10]. Also, Kristjansdottir et al. reported a diagnostic delay from 1 month to 20 years in 8 patients [11].
Te frst symptoms were reported between 6 hours and 20 days postpartum. Most occur after a massive postpartum hemorrhage and moderate to severe anemia. In one case, severe hypotension was reported at the beginning of the   Case Reports in Endocrinology epidural anesthesia without postpartum hemorrhage, followed by panhypopituitarism and diabetes insipidus [15]. In 16 cases, the main presentation was hyponatremia, with a few also presenting with diabetes insipidus, hypothyroidism, panhypopituitarism, and headache. Acute Sheehan's syndrome usually presents with hypotension, tachycardia, failure to lactate, hypoglycemia, fatigue, lethargy, nausea, and vomiting. In the acute phase, hypopituitarism can include ACTH defciency, which can be fatal if not treated [7]. Hyponatremia is an initial symptom of acute Sheehan's syndrome in approximately 60% of the reported cases. In addition, it is a common electrolyte disturbance in the chronic presentation (33% to 69%) [36][37][38]. Acute hyponatremia can be life-threatening because it can cause cerebral edema. Tere are several proposed pathophysiological mechanisms for the development of hyponatremia in this syndrome. It may be due to diminished free water clearance caused by hypothyroidism and adrenal insufciency [2,39]. Moreover, a glucocorticoid defcit may enhance the inappropriate secretion of vasopressin. Te hypersecretion of vasopressin could be due to the reduction in cardiac output and systemic blood pressure induced by the absence of cortisol. In addition, cortisol defciency results in increased hypothalamic secretion of corticotropin-releasing hormone (CRH), a vasopressin secretagogue [39,40]. Furthermore, the negative feedback of cortisol on CRH and ACTH is removed with adrenal insufciency [41]. Our case presented with secondary hypothyroidism, which may also produce hyponatremia due to reduced free-water clearance.
Cortisol levels were initially normal, but she was pregnant, a condition known to increase CBG levels due to high estrogen levels. In the third trimester of pregnancy, total cortisol levels are increased 2 to 3-fold compared to those of nonpregnant women, which is equivalent to the CBG increase during pregnancy [42]. Cortisol-binding globulin has been reported to normalize between 3 and 6 weeks postpartum [43]. However, others have reported that it remains elevated for 3-6 months [44]. Tis may be due to its increased half-life. Cortisol levels were low when retested on several occasions. Gonadotropin function was not afected or restored.
Recovery of hormonal function has been reported in the frst postpartum year in 2 cases of acute Sheehan's syndrome [13,22]. In one case, although panhypopituitarism persisted, diabetes insipidus resolved within two years of diagnosis [14]. In our case, while prolactin levels were initially relatively low for the early postpartum period, she was able to partially breastfeed. Te latter may be due to a partial lactotroph defciency or recovered function. Tis patient had partial hypopituitarism because the gonadotrophic axis was not afected or restored.
Te preservation of some hormonal axes could be explained because pituitary necrosis is frequently incomplete, with selective loss of hormone secretion [25]. Tere can be remnant intact pituitary tissue that continues to receive blood supply from alternative arteries of the neurohypophysis if there is a stop in fow in the superior artery and continues to produce hormones, leading to a selective loss of hormone secretion.
Sheehan's syndrome early MRI fndings include a nonhemorrhagic enlargement of the pituitary gland with a thin rim of peripheral enhancement after gadolinium, an intrasellar mass with suprasellar extension, and a lack of enhancement of the pituitary gland [13,15,19,21,24,25,29,30]. However, in some cases, normal scans were reported in the acute period [1,22,23,26,27,33,34]. After subsequent involution with pituitary shrinkage, atrophic glands and an empty sella are reported in late scans [1,7,13,19,[23][24][25]29]. Te pituitary gland during pregnancy increases in size and can reach a maximum size of 10 mm during the last trimester and 12 mm in the immediate postpartum period, with an upward symmetric convexity. Tere is an increase in the T1 signal intensity of the pituitary gland, more so during the third trimester. After the frst week postpartum, the pituitary gland returns to its normal size [45].
Sheehan's syndrome pathogenesis is not yet fully understood, with the principal proposed factor being an ischemia of the enlarged anterior pituitary gland during severe peripartum hemorrhage. Due to lactotroph hyperplasia, there is a physiological enlargement of the pituitary gland during pregnancy, reaching 120-136% of its original size [46]. Tis pituitary hyperplasia is not accompanied by an      [7]. Spontaneous pregnancy rarely occurs in patients with Sheehan's syndrome because most patients have hypogonadotropic hypogonadism [47]. Hypogonadotropic hypogonadism has been reported in 67%-100% of patients with Sheehan's syndrome [48,49]. To our knowledge, no cases of spontaneous pregnancy after acute Sheehan's syndrome have been reported. Tere are only two reported cases of acute Sheehan's syndrome with a successful pregnancy. One case had ovulation induction, the other in vitro fertilization [1,4]. In our case, the gonadotropin axis was functional, so pregnancy was a possibility. In a recent review by Zhan et al., 27 patients with Sheehan's syndrome and 32 pregnancies were reported in the literature [4]. Of these pregnancies, 19 (59.4%) were conceived spontaneously, whereas 11 (34.4%) were induced by ovulation. One reported case was due to egg donation [50]. Te case reported by Zhan et al. achieved a successful pregnancy by in vitro fertilization and embryo transfer [4].
In this case, we do not believe a lymphocytic hypophysitis complicated with postpartum hemorrhage can be a diferential diagnosis, as she did not have symptoms of hypopituitarism and/or of mass lesions prior to the obstetric hemorrhage [51]. In addition, pituitary MRI did not show an enlarged triangular-or dumbbell-shaped gland with a thickened stalk, nor did it enhance homogenously after contrast [52].
In addition, we believe the pituitary apoplexy of an asymptomatic, nonfunctioning pituitary adenoma is not a diferential diagnosis either. It presents as sudden and severe headache in more than 80% of cases, with variable degrees of visual-feld impairment and ocular palsy in more than 50% of cases (III cranial nerve, most often). Moreover, there were no predisposing risk factors for pituitary apoplexy such as hypertension, coagulopathy, surgery, dynamic testing, or use of dopamine agonists. In addition, an MRI, 7 months later, did not show a residual pituitary adenoma [53]. Furthermore, we do not believe that Rathke's cleft cyst can be a diagnosis either. Tey are cystic remnants of the craniopharyngeal duct, usually asymptomatic, but they can present with headache, endocrine dysfunction, diabetes insipidus, and visual impairment. In addition, MRI shows a midline cyst usually with T1-hyperintense signal due to proteinaceous mucinous cyst contents [54].
During pregnancy, appropriate hormonal replacement in patients with hypopituitarism is required. Hydrocortisone is the preferred glucocorticoid replacement during pregnancy, as it does not cross the placenta due to its degradation by the 11β-hydroxysteroid dehydrogenase 2 enzyme [55]. Higher doses of hydrocortisone may be required during the third trimester.

Conclusion
Acute presentation of Sheehan's syndrome should be considered in the evaluation of postpartum patients with suggestive symptoms such as hypotension, tachycardia, failure to lactate, hypoglycemia, fatigue, lethargy, nausea, and vomiting. Physicians should be aware that hyponatremia might be an initial manifestation of this entity, which requires a high index of suspicion for diagnosis. Spontaneous pregnancy after acute Sheehan's syndrome is exceedingly rare but can happen in women with preserved gonadal function.

Conflicts of Interest
Te authors declare that they have no conficts of interest.