Multiple Clinical Indications of Mifepristone: A Systematic Review

Posted on November 10, 2023 by MaryO

​Abstract

Mifepristone and misoprostol are globally used medications that have become disparaged through the stigmatization of reproductive healthcare. Patients are hindered from receiving prompt treatment in clinical scenarios where misoprostol and mifepristone are the drugs of choice. It is no exaggeration to emphasize that in cases where reproductive healthcare is concerned. The aim of this paper is to discuss the different indications of mifepristone and to delineate where the discrepancy in accessibility arises. For this systematic review, we included publications citing clinical trials involving the use and efficacy of mifepristone published in English within the date range of 2000 to 2023. Five databases were searched to identify relevant sources. These databases are Google Scholar, MEDLINE with full text through EBSCO, and three National Center for Biotechnology Information (NCBI) databases (NCBI Bookshelf, PubMed, and PubMed Central). Twenty-three records were ultimately included in this review. Mifepristone has been shown to have therapeutic effects in the treatment of psychiatric disorders, such as major depressive disorder and psychotic depression. There was a significant decrease in depression and psychiatric rating symptoms for patients taking mifepristone versus placebo with no adverse events. Mifepristone has also been shown to improve treatment course in patients with Cushing’s disease (CD) who failed or are unable to undergo surgical treatment. In addition, mifepristone has been shown to be a successful treatment option for adenomyosis and leiomyomas. Patients had a statistically significant decrease in uterine volumes following mifepristone treatment, which aided in the alleviation of other symptoms, such as blood loss and pelvic discomfort. Mifepristone is a synthetic steroid that has immense potential to provide symptomatic relief in patients suffering from a wide array of complicated diseases. Historically, mifepristone has been proven to have an incredible safety profile. While further research is certainly needed, the politicization of its medical use for only one of its many indications has unfortunately led to the willful ignorance of its potential despite its evidence-based safety profile and efficacy.

Introduction & Background

Mifepristone is a synthetic steroid derived from norethindrone and therefore has antagonistic activity against progesterone and glucocorticoid receptors. Misoprostol is a synthetic prostaglandin E1 analog that works through the direct stimulation of prostaglandin E1 receptors. Recently, these medications have become disparaged due to their associations with the controversial medical procedure known as abortion. Abortions, however, have been so common that one out of four women will have had an abortion by the time they reach the age of 45 [1]. It is estimated that 3.7 million women have used mifepristone and misoprostol for medication abortions since they were first approved by the Food and Drug Administration (FDA) in 2000 [1]. Mifepristone followed by misoprostol is up to 14 times safer than carrying the patient’s pregnancy to term [1]. Aside from abortion, mifepristone is used for both gynecologic and obstetric conditions. Obstetric conditions include induction of labor, postpartum hemorrhage, intrauterine fetal demise, ectopic pregnancies, and miscarriages [2]. Gynecological conditions that can be treated with mifepristone include abnormal uterine bleeding, post-coital contraception, and treatment of gynecological cancers [3]. Due to the stigmatized nature of abortion, however, patients are hindered from receiving prompt treatment in clinical scenarios where mifepristone is the drug of choice. It is no exaggeration to emphasize that in cases where reproductive healthcare is concerned, every second counts [3]. Legislation that varies across states further impacts patients who risk their lives and health as they attempt to navigate their care plan across borders. Travel costs, time-off, childcare, transportation, and living accommodations are just a few more of the factors patients must take into consideration when they are forced to seek life-saving care outside of their homes [3].

Mifepristone is a medication that has multiple therapeutic applications, such as treating leiomyomas, psychotic depression, and post-traumatic stress disorder (PTSD). However, its use is restricted in many countries because of its abortifacient effect. This is a logical fallacy that deprives patients of a beneficial and safe treatment option. This systematic review aims to explore the evidence-based uses of mifepristone and how it can improve patients’ health outcomes. The clinical indications that will be discussed are adenomyosis, leiomyomas, psychotic depression, PTSD, and Cushing’s disease (CD).

Review

Methods

Eligibility Criteria

For this systematic review, we included publications of clinical trials and systematic reviews citing clinical trials relating to the clinical use of mifepristone and published in English within the date range of 2000 to 2023.

Info Sources

Five databases were searched to identify relevant sources. These databases include Google Scholar, MEDLINE with full text through EBSCO, and three National Center for Biotechnology Information (NCBI) databases (NCBI Bookshelf, PubMed, and PubMed Central).

Search Strategy

For each database, we inputted “clinical use of mifepristone” as our search term. The populated results were then narrowed down to those published in the English language and within the date range of 2000 to 2023 using automated search tools.

Selection Process

The titles and abstracts of the remaining records were then screened, and those deemed relevant to clinical uses of mifepristone and its efficacy were included for comprehensive review. This initial record search in three of the four databases (Google Scholar, MEDLINE, and PubMed) was completed by three separate reviewers. The initial record search in the remaining two databases (NCBI Bookshelf and PubMed Central) was completed by another individual reviewer.

Data Collection Process

After the initial record search, 60 records were deemed relevant to the study topic and compiled for a more comprehensive review. Two records were found to be duplicates and removed. Each of the four reviewers read the remaining 58 records and voted on the eligibility of the publication for inclusion in our review. Older publications that were expanded upon in more recent study trials were excluded to reduce redundancy. In addition, for records with similar study protocols, only the more recently published record was included. Ten records were excluded from the review due to ineligible study design. For those records that were not unanimously accepted (at least one reviewer voted for exclusion), the record was excluded. To ensure that the data utilized in this review were backed by sufficient evidence, the reviewers organized the remaining records into groups based on the disease mifepristone was being studied to treat. After further discussion, it was decided to exclude the records in the groups that lacked at least three separate clinical trials on the use of mifepristone in the treatment of the disease. Thirty articles were excluded. Seven of the 18 remaining records were systematic reviews, and citation searching of the records found four additional records that met the eligibility criteria. The remaining 23 records were included for further review.

Data Items

Of the remaining 23 records deemed acceptable for inclusion, only studies with statistically significant findings regarding the clinical use of mifepristone were included for detailed analysis. One record was excluded due to early termination of the trial. Our records include two open-label studies, four retrospective studies, seven reviews (systematic, meta-analysis), one wet lab (human specimen was used), five long-term safety extension articles, and seven randomized control experimental trials.

Study Risk-of-Bias Assessment

We assessed the risk of bias (RoB) in the studies included in the review using the revised Cochrane RoB tool for randomized trials (RoB 2). The five domains assessed were (1) RoB arising from the randomization process, (2) RoB due to deviations from the intended interventions (effect of assignment to intervention and effect of adhering to intervention), (3) missing outcome data, (4) RoB in the measurement of the outcome, and (5) RoB in the selection of the reported result. Each randomized control trial included in this review was assessed for RoB by two authors working independently using the RoB 2. For those studies in which the assessing authors came to different conclusions, the remaining two authors completed independent RoB 2 assessments of the study in question, and the majority of findings was accepted. Utilizing the methodology for assigning the overall RoB for each study as outlined by the RoB 2 tool, each study was designated as having “low risk of bias” or “high risk of bias.” After an initial assessment, both authors deemed the nine randomized control studies had a low RoB.

Effect Measures

Analysis of the studies included a focus on statistically significant findings that varied between control and intervention groups as defined by a p-value less than 0.5. As each study had its own parameters and primary and secondary endpoints, we focused our analysis on the safety and clinical efficacy of mifepristone as measured and reported by the authors of the studies included.

Synthesis Methods

As previously mentioned, as the studies included in this review vary widely in their study population and intervention design, our analysis focused on qualitative synthesis of study outcomes. These outcomes were categorized as the clinical efficacy and safety of mifepristone for CD, psychiatric disorders, and select gynecological diseases (adenomyosis and leiomyomas).

Certainty Assessment

To assess the certainty of the body of evidence regarding the studies included in our review, two reviewers applied the five Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) considerations (study limitations, inconsistency of results, indirectness of evidence, imprecision, and publication bias) to each study. Accordingly, the included studies were categorized as having high, moderate, low, or very low certainty of evidence based on the GRADE criteria. After the assessment, both reviewers deemed that all records had high certainty of evidence.

PRISMA-2020-flow-diagram-for-new-systematic-reviews-that-included-searches-of-databases,-registers,-and-other-sources
Figure 1: PRISMA 2020 flow diagram for new systematic reviews that included searches of databases, registers, and other sources

*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Results

Psychiatric Implications

Based on the analyses, numerous trials demonstrated the profound therapeutic effect that mifepristone can have on psychiatric disorders. In a double-blind study following 19 patients with bipolar disorder, researchers studied neurocognitive function and mood in patients treated with mifepristone vs. the placebo [4]. Significant improvements in verbal fluency and spatial working memory were seen in the group treated with mifepristone. The Hamilton Depression Rating Scale (HDRS) and Montgomery-Asberg Depression Rating Scale (MADRS) scores also improved from baseline (i.e., lower scores) measurements in these patients. It is worth noting that these improvements were seen in as little as two weeks, which is quicker than what is normally seen with typical therapeutic agents for bipolar disorder (lithium/valproic acid) [4].

The most extensive research demonstrated the benefits of using mifepristone with major or psychotic depression [5]. It is important to note that approximately 20% of patients living with major depression experience psychotic symptoms [6]. A randomized, double-blind study looked at 30 participants with psychotic major depression (PMD) and treated them with mifepristone 600 mg or a placebo for eight days. Using the HDRS and Brief Psychiatric Rating Scale (BPRS) to quantify baseline levels of symptoms, results from eight days later showed that mifepristone was significantly more effective in reducing psychotic symptoms compared to the placebo group [6]. By day 8, nearly half of the participants attained a 50% reduction in the BPRS compared to the placebo group (p<0.046) in addition to lower HDRS scores (although this was not found to be significant). Moreover, when researchers looked further into the use of mifepristone in psychotic depression disorders, they discovered a correlation between higher plasma levels of mifepristone and a reduction in psychotic symptoms [7]. More specifically, the strongest reduction in psychosis symptoms was found to be associated with doses of 1200 mg/day of mifepristone, which resulted in a statistically significant reduction in psychotic symptoms (p<0.0004) [7]. The drug was also well tolerated and demonstrated a large safety margin in contrast to the numerous common adverse effects that patients experience when placed on standard treatment options (i.e., antipsychotics). In another double-blind, placebo-controlled study that took place over four days, five participants diagnosed with psychotic major depression were administered 600 mg of mifepristone [5]. The HDRS and BPRS scores were used, and the results showed that all five participants’ depression ratings decreased – a nearly statistically significant finding (p<.07) [5]. Likewise, four out of the five BPRS scores declined, approximating to a 32.5% decline, which is comparable to the 40% decline seen with traditional antipsychotic treatments that span six to eight weeks. Once again, no adverse effects were reported.

The use of mifepristone has been explored in many cognitive disorders, including Alzheimer’s disease. One study found that patients with mild to moderate Alzheimer’s disease displayed improvement on the Alzheimer’s disease assessment cognitive subtest – by 2.67 as opposed to the 1.67 decline in patients treated with a placebo [5]. Although not statistically significant, this finding encourages further studies to continue exploring the psychiatric and neurologic use of mifepristone.

Cushing’s Disease

Multiple trials have been conducted regarding the use and efficacy of mifepristone in the treatment of CD. Although surgical intervention to remove the source of excess cortisol production is the current mainstay of treatment, clinical trials have focused on the treatment with mifepristone for medical therapy, especially in patients who have failed surgical intervention or for those who are not good candidates for surgery.

Accordingly, a retrospective study of 20 patients with hypercortisolism (12 with adrenocortical carcinoma, three with ectopic adrenocorticotropic hormone (ACTH) secretion, four with CD, and one with bilateral adrenal hyperplasia) found clinically significant improvement in excess cortisol-induced symptoms in 15 out of 20 patients [4]. Patient responses to mifepristone treatment were monitored by clinical signs of hypercortisolism (signs of hypercortisolism, blood pressure measurements, and signs of adrenal insufficiency) and serum potassium and glucose. The study found that 15 out of 20 patients showed significant clinical improvement in excess cortisol-induced symptoms. Psychiatric symptoms and blood glucose levels also improved in the patients [4]. Of note, 11 out of 20 trial participants exhibited moderate to severe hypokalemia as a side effect, although only one patient had to leave the study early due to severe adverse effects [4].

In another well-known study, 50 patients were assessed at baseline and during intervention (total of six times) for 24 weeks, referred to as the SEISMIC study [8]. Changes in oral glucose tolerance tests over time were used to assess the mifepristone effect in type 2 diabetes millets (T2DM)/impaired glucose tolerance patients. Changes in diastolic blood pressure (BP) over time were used to measure the effect of mifepristone in hypertensive cardiogenic shock (CS) patients [8]. Results found a statistically significant improvement in symptoms in both groups: diabetic patients had improvement in response to oral glucose test, decreased A1C, and decreased fasting glucose, and hypertensive patients had decreased diastolic BP or reduction in antihypertensive medications [8]. In addition, the waist circumference and hemoglobin A1C (HbA1C) also improved, and study findings concluded that mifepristone use has an acceptable risk-benefit ratio for six months of treatment [8].

Several extension studies were later performed utilizing the data found during the SEISMIC study [9]. One such study assessing weight loss in patients who participated in the SEISMIC study also found statistically significant improvement in patients with CD. After one-week mifepristone period (patients who chose to participate in this follow-up study had to be assessed to ensure it was safe for them to enroll in this study), 30 patients were enrolled and started on once daily mifepristone at the dose they were taking when the SEISMIC study concluded [9]. The patient’s weight was assessed at baseline and week 24 of the SEISMIC study, and for this study, the follow-up weight was taken at months 6, 12, 18, and 24 and a final visit. Data were assessed for 29 of the participants and statistically significant decreases in weight were found for all participants from baseline to end of the SEISMIC study, and the maintenance of weight loss was statistically significant in all participants at their final visit to this study as well [9].

Another SEISMIC extension study focused on monitoring the effects of mifepristone treatment in CD on ACTH levels and pituitary MRI findings [10]. Serum ACTH, urinary, and salivary cortisol levels were monitored during the SEISMIC study (baseline, day 14, and weeks 6, 10, 16, and 24) and once after a six-week mifepristone-free “washout” period. ACTH levels were then monitored one month later and then routinely every three months during the intervention period, which varied per participant [10]. Serum cortisol measures were assessed during the SEISMIC study at the intervals mentioned previously and then every six months during the extension study. Pituitary MRI studies were taken prior to mifepristone administration during the SEISMIC study and at weeks 10 and 24 [10]. Repeat imaging was then taken every six months during the extension study. On average, ACTH levels increased greater than twofold (2.76 ± 1.65-fold over baseline; p<0.0001 vs. baseline) in patients during the SEISMIC and extension study periods and decreased to near baseline levels after six weeks of mifepristone discontinuation [10]. Serum cortisol levels in both the initial intervention and extension period increased as well, although a higher mean cortisol level was seen during the extension study intervention (SEISMIC: 1.97 ± 1.02-fold increase; p<0.0001 vs. baseline; extension study: 2.85 ± 1.05-fold increase; p<0.0001 vs. baseline) [10]. In comparing the baseline and post-intervention MRI images, 30 out of 36 patients showed no progression in pituitary tumor size with mifepristone intervention, two patients showed regression of tumor size, and three patients showed evidence of tumor progression. One patient was found to have a tumor post-intervention despite a negative initial MRI at baseline [10].

A retrospective analysis of data collected during the SEISMIC study utilized oral glucose tolerance test data to assess the mifepristone treatment effect on the total body insulin sensitivity, beta cell function, weight, waist circumference, and additional parameters [11]. The analysis found improved total body insulin sensitivity in all participants, with the greatest improvement occurring from baseline to week 6. The weight and waist circumference both decreased by week 24 [11].

An additional important six-month study was done on 46 patients with refractory CS and either DM2, impaired glucose tolerance, or diagnosis of HTN in which mifepristone treatment was administered daily [12]. Patients were examined by three separate reviewers using global clinical response assessments (-1 = worsening, 0 = no change, 1 = improving) measured by eight clinical categories: glucose control, lipids, blood pressure, body composition, clinical appearance, strength, psychiatric/cognitive symptoms, and quality of life at weeks 6, 10, 16, and 24. A positive correlation with increasing GCR scores was found by week 24, with 88% of participants showing statistically significant improvement (p<0.001) [12].

Adenomyosis/Leiomyoma

Adenomyosis and leiomyomas are common gynecological conditions that affect large portions of the female population. Multiple trials have proven mifepristone’s success in treating endometriosis and various forms of cancer. Current data shows that mifepristone is well tolerated and has mild side effects in certain long-term clinical settings.

In one trial following mifepristone and its effects on adenomyosis, 20 patients were treated with 5 mg oral mifepristone/day for three months [13]. After the three-month trial, patients demonstrated a statistically significant (p<0.001) reduction in uterine volume as was measured through transvaginal ultrasound. These patients were also found to have significantly decreased CA-125 markers (a marker of adenomyosis and an increase in uterine size) and significantly increased hemoglobin concentration The patient’s endometrial tissue was then obtained from each patient during their hysterectomy [13]. The endometrial tissue samples were treated with varying concentrations of mifepristone for 48 hours. They found that mifepristone significantly decreased the viability of endometrial epithelial and stromal cells in adenomyosis and can induce their apoptosis as well [13]. This concentration-dependent inhibitory effect was most significantly seen with concentrations of mifepristone above 50 μmol/L at 48 hours. The same study showed that mifepristone demonstrated another dose-dependent relationship in the inhibition of the migration of ectopic endometrial and stromal cells. This finding is significant as the migratory nature of the patient’s endometrial and stromal cells is the pathogenesis behind adenomyosis [13].

Another study looked at the effect of mifepristone in combination with high-intensity focused ultrasound (HIFU) and levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis [13]. Out of 123 patients, 34 patients were treated with HIFU alone, 29 patients were treated with HIFU combined with mifepristone, 10 patients with HIFU combined with LNG-IUS, and 50 patients with HIFU combined with mifepristone and LNG-IUS [13]. In the group treated with HIFU combined with mifepristone and LNG-IUS, the uterine volume was significantly reduced after treatment at 3, 6, 12, and 24 months compared to the previous treatment (p<0.05). Dysmenorrhea was measured using a visual analog score (VAS). In the combination group of mifepristone, HIFU, and LNG-IUS, VAS scores decreased from 80.82 ± 12.49 to 29.58 ± 9.29 at 24 months [13]. This was significantly lower than the three other treatment groups (p<0.05). The combination group of mifepristone, HIFU, and LNG-IUS also demonstrated statistically significant decreases in the menstrual volume and CA-125 serum markers [13]. Hemoglobin levels were not statistically different among the four treatment groups, but it is postulated that this could have been due to the fact that the patients who were anemic had been treated with different medications to improve their Hb aside from the trial medications [13].

Uterine leiomyomas are another gynecological condition that has been found to improve with the use of mifepristone as well. Insulin-like growth factor 1 (IGF-1) has been found to be overexpressed in leiomyomas [14]. This study showed that mifepristone inhibited the gene expression of IGF-1, and the reduction in symptoms correlated with a decrease in IGF-1 expression although the mechanism is not fully understood [14]. A meta-analysis studied the effects of mifepristone on uterine and leiomyoma volumes of 780 women from 11 randomized controlled trials. Mifepristone at doses from 2.5, 5, and 10 mg was found to effectively reduce uterine and leiomyoma volumes and alleviate leiomyoma symptoms at six months [6]. Pelvic pain, pelvic pressure, and dysmenorrhea were found to be alleviated after three months of treatment. Mifepristone also decreased the mean loss of blood during menstruation and a statistically significant increase in hemoglobin. No significant difference was found among varying dosages of 2.5, 5, and 10 mg other than increased frequency of hot flashes in patients of the 10 mg group. Another review investigated six clinical trials involving 166 women and the effects of 5-50 mg mifepristone for three to six months on leiomyomas [3]. The review demonstrated that daily treatment with all doses of mifepristone resulted in reductions in pelvic pain, pelvic pressure, dysmenorrhea, and uterine and leiomyoma volume size by 26-74%. Even doses of 2.5 mg of mifepristone resulted in significant improvement in the quality of life scores although there was little reduction in leiomyoma size at this dose [3]. This review also reported the rapid correction of uterine bleeding, amenorrhea, and increases in hemoglobin levels following treatment with 50 mg of mifepristone on alternating days. Even vaginal mifepristone has demonstrated efficacious results in the improvement of leiomyomas. In one such trial, the effects of daily 10 mg vaginal mifepristone were studied in 33 women from the ages of 30-53 [15]. Vaginal mifepristone significantly reduced leiomyoma volume and reduced the effects of symptoms on the patient’s quality of life as measured by the Uterine-Fibroid Symptoms Quality of Life questionnaire (UFS-QoL). It is important to note that the only significant side effect found in this review of trials was hot flashes at doses of mifepristone at 10 mg or more. Mifepristone was otherwise generally well tolerated with minimal if any adverse effects [15].

Discussion

Adenomyosis is a gynecologic condition that is characterized by the growth of endometrial cells into the myometrium, resulting in a globally enlarged uterus and an associated increase in CA-125 [16]. This marker is classically known to be an ovarian tumor marker; however, in this class, it reflects the increase in uterine glandular size. Although it is often labeled as a “benign” disease, it affects around 20% of reproductive-aged women. This condition can lead to dysmenorrhea, infertility, and menorrhagia in addition to detrimental effects on a patient’s mental health [16]. Despite 20% of affected patients being under the age of 40, the gold standard of treatment is a hysterectomy. Hysterectomies may often not be wanted by patients as it is an invasive surgery that comes with several potential complications of its own. It is important to note that due to the large percentage of patients with adenomyosis who are of reproductive age, hysterectomies may not be an appropriate standard method of treatment. To rob patients of their fertility without attempting medication therapy with mifepristone first is an act of injustice. Surgery alone comes with many complications and the possibility of recurrence. The ability of physicians to manage their patient’s pain and symptoms should be guided medically before surgical sterilization is considered. Many of these patients are forced to seek alternative non-invasive treatments instead of medication therapies to preserve their fertility.

HIFU and LNG-IUS are noninvasive therapies for adenomyosis that can be used in patients who refuse hysterectomies or for those who are not good candidates [16]. The pitfalls of these procedures include the fact that 20% of patients on HIFU alone end up relapsing, and LNG-IUS cannot be used in patients with a uterine size that is >12 weeks gestation or a uterine cavity depth that is >9 cm. Because adenomyosis is an estrogen-dependent disease, gonadotropin-releasing hormone agonists (GnRH-a) are also often used in combination with HIFU and LNG-US. Through the inhibition of the secretion of estrogen, GnRH-as facilitate reduced pelvic pain, reduced bleeding, and reduced uterine cavity size [16]. Reduction in cavity size is significant as this alone can lead to improved pain and reduced bleeding and allows patients to qualify for LNG-US where their previous uterine cavity size would have prevented their candidacy. Its current limitations include price (>$200/month), induction of premenopausal syndrome, and high rates of relapse following drug cessation [16]. Mifepristone offers a cheaper alternative (<$4/month) with significantly improved outcomes in reduced uterine cavity size, decreased dysmenorrhea pain scale score, and lower menstruation volume scores [16]. Mifepristone is also able to provide such results without the bone loss that is commonly associated with GnRH-analogs [3]. This is because mifepristone allows for serum estradiol to remain within the patient’s physiologic follicular phase range [3]. In addition, mifepristone is able to significantly reduce serum levels of CA-125 and improve hemoglobin levels in patients with menorrhagia. These reductions in CA-125 demonstrate marked reductions in the size of glands of the uterus of these patients. Through the reduction of cavity size, mifepristone can not only offer therapeutic relief but also allow patients to qualify for noninvasive LNG-US procedures, which can offer further therapeutic benefits. Patients should have the option to explore all potential medical therapies before opting for surgical correction.

Leiomyomas, or uterine fibroids, are another commonly encountered gynecologic condition and represent the most common benign tumors found in the female population. These benign smooth muscle tumors are estrogen-sensitive and can rarely develop into malignant leiomyosarcomas. Nearly 20-50% of patients with these fibroids experience symptoms, such as abnormal uterine bleeding (AUB), infertility, pelvic pain, and miscarriages [17]. Currently, the only treatment for this common condition is surgery. Two medications that are commonly used for preoperative reductions in leiomyoma size are mifepristone and enantone. Enantone is a gonadotropin-releasing hormone analog that has shown significant improvement in leiomyoma shrinkage, correction of anemia, and correction of AUB [17]. Through its MOA, however, enantone can lead to harmful adverse effects, such as menopausal symptoms and bone mineral loss. Using hormone supplementation to negate these side effects leads to reduced effectiveness of enantone in fibroid size reduction. Several studies have shown that progesterone plays a large role in the proliferation of leiomyoma growth [17]. Mifepristone, therefore, offers an effective alternate solution by producing the same results without enantone’s adverse effects. When comparing enantone to mifepristone, the two medications both resulted in statistically significant reductions in fibroid size, reduction in dysmenorrhea, reduction in non-menstrual abdominal pain, and increased Hgb/Hct/and RBC count despite differences in dosage [17]. However, mifepristone was able to maintain the patients’ premenopausal levels of estrogen, whereas patients on enantone were found to have estrogen levels of menopausal patients. Furthermore, patients who were treated with enantone also reported more adverse events compared to those in the mifepristone group [17]. Vaginal use of mifepristone has also been shown to significantly reduce leiomyoma size and improve symptoms of anemia while lowering systemic bioavailability of mifepristone [15]. Through its concentrated distribution to uterine tissue, vaginal mifepristone can lead to increased improvement in its clinical outcomes. Vaginal mifepristone showed statistically significant improvements in leiomyoma volume change, USF-QoL, and decreased bleeding intensity at the end of the three-month trial and three months after treatment [15]. For these reasons, mifepristone can be used effectively for conservative therapy in patients suffering from leiomyomas and should be considered a viable option for patients not wishing to undergo surgery.

CD refers to hypercortisolism that is caused by pituitary adenomas, adrenal neoplasias, or paraneoplastic ACTH secretion. Hypercortisolism in these patients leads to the development of skin changes, HTN, obesity, insulin resistance, dyslipidemia, anovulation, skeletal disorders, and neuropsychiatric disorders [18]. Patients suffering from these conditions endure a severely decreased quality of life and increased morbidity and mortality. The syndromic nature of this disease prompts delayed diagnosis and further increases the mortality and morbidity of this population [18]. CS therefore necessitates effective and rapid treatment options to diminish harm and clinical burden. The current first-line treatment for CD is pituitary surgery despite its nearly ⅓ relapse rate within 10 years postoperatively [18]. In these patients and patients with recurrent CD, further treatment options are necessitated. These options include adrenal surgery, pituitary radiotherapy, or medication therapy. Radiotherapy further delays symptomatic relief as it usually takes years before excess cortisol levels are managed. It also carries the risk of the patient developing hypopituitarism due to subsequent pituitary damage [18]. While surgery of the adrenal glands can quickly achieve control of excess cortisol, it also carries a risk of permanent adrenal insufficiency. Medication therapy can be used preoperatively, postoperatively, and as adjunctive therapy to radiotherapy. These drug classes include somatostatin analogs, dopamine agonists, and adrenal steroidogenesis inhibitors [18]. The most commonly used medication is the adrenal steroidogenesis inhibitor ketoconazole. While it has been proven to be effective and rapid in its success, doses may need to be frequently increased due to the cortisol blockade that occurs in CD patients [8]. In fact, due to the hormonal imbalances in CD patients, many medications often have to be dose adjusted to achieve therapeutic effect. It is also important to note that many of the medications that are used are not easily tolerated when doses are increased or adjusted frequently. The use of mifepristone has demonstrated statistically significant results in weight reduction, insulin resistance, depression, HTN, and quality of life in CD patients [10]. Furthermore, mifepristone can also be used effectively in patients experiencing cortisol-induced psychosis during acute exacerbations of hypercortisolism. While not included in the classes of more commonly used drugs for CD, mifepristone has been approved by the FDA for the treatment of CD when associated with disorders of glucose metabolism. This is undoubtedly due to the stigmatization of mifepristone and the subsequent reluctance of clinicians to incorporate it into their treatment plans.

Neuropsychiatric disorders have been investigated for their associations with dysregulations of the hypothalamic-pituitary-adrenal axis (HPA) and increases in cortisol levels. Studies have shown that patients suffering from depression, schizophrenia, and psychotic depression have elevated levels of cortisol and increased activity of their HPA [19]. The role of cortisol in psychiatric disorders is evidenced by the adverse psychiatric effects that patients can develop in response to exogenous glucocorticoid use through subsequent increases in cortisol. These include delirium, depression, mania, or psychosis. When functioning normally, HPA activity and cortisol secretion are maintained through sensitive negative feedback systems involving glucocorticoid receptors (GCRs) and mineralocorticoid receptors (MCR) [19]. At low doses, cortisol preferentially binds to MCR. As cortisol levels rise, it begins to bind to GCR and thereby initiates the negative feedback loop. Antipsychotics that are typically used work by reducing cortisol levels. Mifepristone, when dosed at >200 mg/day, selectively binds only to GCR and has no effect on MCR [19]. Through its sole inhibition of GCR, it ensures that normal cortisol homeostasis is maintained while ensuring that excess high levels of cortisol are blocked. This was evidenced by the statistically significant correlation between rising plasma concentrations of mifepristone and improvement of psychotic symptoms [20].

The hippocampus is a region of the temporal lobe that is most notably recognized for its role in learning and memory. Further studies have shown correlations between hippocampal atrophy and patients with severe depression, PTSD, and schizophrenia. It is postulated that this hippocampal atrophy leads to persistently high levels of cortisol, worsening these patient’s psychiatric symptoms. Administration of mifepristone to patients with combat-related PTSD demonstrated significant benefits in quality of life and psychiatric improvement. Psychotic major depression is another psychiatric condition that affects around 20% of patients with major depression [7]. When mifepristone was used to treat psychotic depression, patients were able to achieve rapid antipsychotic effects that lasted for weeks after the medication therapy ended. It should be noted that patients suffering from PMD generally have increased cortisol levels even with standard antidepressant therapy alone [7]. Some patients are even unresponsive to electroconvulsive therapy. The ability of patients suffering from psychotic depression to achieve rapid relief is imperative as these patients are more susceptible to suicidal ideation, especially during an episode of psychosis [7]. Bipolar disorder is another mood disorder that has been found to be associated with high levels of cortisol, dysfunction of the HPA axis, and GR dysfunction. Several neuroendocrine studies demonstrated that around 43% of bipolar patients with depression were also dexamethasone-suppression-test (DST) nonsuppressors [7]. Further studies found that bipolar patients suffering through relapse and recovery had abnormal dexamethasone/corticotropin-releasing hormone (dex/CRH) test results [21]. These abnormal (dex/CRH) findings were also seen in healthy patients who had certain genetic predispositions for mood disorders [21]. Regarding these HPA dysfunctions, GR has been implicated in being an important modulator of neurocognitive function and mood. This can be evidenced through research findings that report increased GR number and GR binding in brain tissue following the administration of antidepressants in depressed patients [21].

Mifepristone’s unique advantage is that its selective role as a GR antagonist was also found to increase both MR and GR binding in the frontal cortex. In fact, data from Young et al. [21] reveals significant improvement in frontal cortex functioning following clinical mifepristone trials. These results were seen through improvements in spatial working memory function and reductions in the HDRS17 and MADRS. They also demonstrated significant improvement in verbal fluency from baseline. These improvements in neurocognitive functioning were measured when the subjects’ mood was similar to their baseline or did not vary when compared to the placebo group [21]. This key finding suggests that improvements in neurocognitive functioning were not solely related to improvements in mood or depression. Mifepristone achieves these improvements in neurocognitive function through its selective activity towards GR within the frontal cortex. Furthermore, patients are also able to achieve symptomatic improvement two weeks after the initiation of treatment [21]. The rapid nature of mifepristone adds further clinical benefit as classic bipolar treatments take longer to achieve therapy and the fact that treatment plans for patients with bipolar disorder are tricky to individualize. Other commonly known psychiatric disorders are treated with antipsychotics. While these medications often come with a large array of adverse effects, weight gain, metabolic derangements, and glucose intolerance have been a few of the more frequently reported negative effects. While the exact cause of the weight gain is unknown, mifepristone was shown to significantly reduce weight gain in patients when taken alongside risperidone or olanzapine [21]. As discussed previously, mifepristone also has the ability to significantly improve insulin resistance, thereby further improving the AE patients may experience on antipsychotics. Therefore, through mifepristone’s selective activity as a GCR antagonist, it has immense potential as a psychiatric therapeutic agent.

Conclusions

Mifepristone is a synthetic steroid that has immense potential to provide symptomatic relief in patients suffering from a wide array of complicated diseases. Prednisone, dexamethasone, and anabolic steroids are also synthetic steroids that are commonly used. Despite being a part of the same class as mifepristone, none of these medications fall under as much legal, political, and social duress as mifepristone. This is in spite of the fact that mifepristone has been proven to have an incredible safety profile since its introduction to the public in the 1980s. In fact, its mortality rate is significantly lower than that of Tylenol, NSAIDs, penicillin, and phosphodiesterase inhibitors. While further research is certainly needed, its involvement in politics has unfortunately led to the willful ignorance of its medical potential despite its evidence-based safety profile and efficacy.

References

  1. Beaman J, Prifti C, Schwarz EB, Sobota M: Medication to manage abortion and miscarriage. J Gen Intern Med. 2020, 35:2398-405. 10.1007/s11606-020-05836-9
  2. Hagey JM, Givens M, Bryant AG: Clinical update on uses for Mifepristone in obstetrics and gynecology. Obstet Gynecol Surv. 2022, 77:611-23. 10.1097/OGX.0000000000001063
  3. Spitz IM: Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century. Contraception. 2010, 82:442-52. 10.1016/j.contraception.2009.12.012
  4. Castinetti F, Fassnacht M, Johanssen S, et al.: Merits and pitfalls of mifepristone in Cushing’s syndrome. Eur J Endocrinol. 2009, 160:1003-10. 10.1530/EJE-09-0098
  5. Belanoff JK, Flores BH, Kalezhan M, et al.: Rapid reversal of psychotic depression using mifepristone. J Clin Psychopharmacol. 2001, 21:516-21.
  6. Eisinger SH, Meldrum S, Fiscella K, et al.: Low-dose mifepristone for uterine leiomyomata. Obstet Gynecol. 2003, 101:243-50. 10.1016/S0029-7844(02)02511-5
  7. Flores BH, Kenna H, Keller J, Solvason HB, Schatzberg AF: Clinical and biological effects of mifepristone treatment for psychotic depression. Neuropsychopharmacology. 2006, 31:628-36. 10.1038/sj.npp.1300884
  8. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross 😄 Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012, 97:2039-49. 10.1210/jc.2011-3350
  9. Fein HG, Vaughan TB 3rd, Kushner H, Cram D, Nguyen 😧 Sustained weight loss in patients treated with mifepristone for Cushing’s syndrome: a follow-up analysis of the SEISMIC study and long-term extension. BMC Endocr Disord. 2015, 15:63. 10.1186/s12902-015-0059-5
  10. Fleseriu M, Findling JW, Koch CA, Schlaffer SM, Buchfelder M, Gross 😄 Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing’s disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J Clin Endocrinol Metab. 2014, 99:3718-27. 10.1210/jc.2014-1843
  11. Wallia A, Colleran K, Purnell JQ, Gross C, Molitch ME: Improvement in insulin sensitivity during mifepristone treatment of Cushing syndrome: early and late effects. Diabetes Care. 2013, 36:e147-8. 10.2337/dc13-0246
  12. Katznelson L, Loriaux DL, Feldman D, Braunstein GD, Schteingart DE, Gross 😄 Global clinical response in Cushing’s syndrome patients treated with mifepristone. Clin Endocrinol (Oxf). 2014, 80:562-9. 10.1111/cen.12332
  13. Che X, Wang J, He J, et al.: A new trick for an old dog: the application of mifepristone in the treatment of adenomyosis. J Cell Mol Med. 2020, 24:1724-37. 10.1111/jcmm.14866
  14. Shen Q, Zou S, Sheng B, et al.: Mifepristone inhibits IGF-1 signaling pathway in the treatment of uterine leiomyomas. Drug Des Devel Ther. 2019, 14:3161-70.
  15. Yerushalmi GM, Gilboa Y, Jakobson-Setton A, Tadir Y, Goldchmit C, Katz D, Seidman DS: Vaginal mifepristone for the treatment of symptomatic uterine leiomyomata: an open-label study. Fertil Steril. 2014, 101:496-500. 10.1016/j.fertnstert.2013.10.015
  16. Zhu H, Ma Q, Dong G, Yang L, Li Y, Song S, Mu Y: Clinical evaluation of high-intensity focused ultrasound ablation combined with mifepristone and levonorgestrel-releasing intrauterine system to treat symptomatic adenomyosis. Int J Hyperthermia. 2023, 40:10.1080/02656736.2022.2161641
  17. Liu C, Lu Q, Qu H, et al.: Different dosages of mifepristone versus enantone to treat uterine fibroids: a multicenter randomized controlled trial. Medicine (Baltimore). 2017, 96:e6124. 10.1097/MD.0000000000006124
  18. Pivonello R, De Leo M, Cozzolino A, Colao A: The treatment of Cushing’s disease. Endocr Rev. 2015, 36:385-486. 10.1210/er.2013-1048
  19. Hartmann J, Bajaj T, Klengel C, et al.: Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5. Cell Rep. 2021, 35:109185. 10.1016/j.celrep.2021.109185
  20. Block TS, Kushner H, Kalin N, Nelson C, Belanoff J, Schatzberg A: Combined analysis of mifepristone for psychotic depression: plasma levels associated with clinical response. Biol Psychiatry. 2018, 84:46-54. 10.1016/j.biopsych.2018.01.008
  21. Young AH, Gallagher P, Watson S, Del-Estal D, Owen BM, Ferrier IN: Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology. 2004, 29:1538-45. 10.1038/sj.npp.1300471

From https://www.cureus.com/articles/191397-multiple-clinical-indications-of-mifepristone-a-systematic-review#!/

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Filed under: Cushing's, pituitary, Treatments | Tagged: , , , , | Leave a comment »

Cushing’s Syndrome Presenting as Non-Atherosclerotic Myocardial Infarction and Heart Failure

Posted on November 6, 2023 by MaryO

Abstract

Cushing’s syndrome is a rare cause of myocardial infarction and heart failure. Herein, we report a female patient who presented acute myocardial infarction and heart failure with reduced ejection fraction. The patient was found to have hypercortisolism secondary to adrenocortical adenoma and responded well to therapy. This case underlines the effects of hypercortisolism on the cardiovascular system. The clinical presentation of this patient is unique because non-atherosclerotic myocardial infarction is rarely reported in Cushing’s syndrome patients.

Introduction

Cushing’s syndrome is an endocrine condition associated with excessive secretion of cortisol. Hypertension, vascular atherosclerosis, and chronic cardiac remodelling and dysfunction are commonly recognized cardiovascular complications in Cushing’s syndrome patients.1 Herein, we report a rare case of Cushing’s syndrome patient with a primary diagnosis of non-atherosclerotic myocardial infarction and heart failure (HF).

Case Report

A 61-year-old female with a past medical history of chronic obstructive pulmonary disease was admitted with sudden onset chest pain on 6 February 2018. Electrocardiogram showed ST-segment elevation in leads V3–V5. Blood biochemical results of 1 h after the onset of chest pain: cardiac troponin I (cTnI) 0.06 ug/L↑, creatine kinase (CK) 63 U/L, creatine phosphokinase-MB (CK-MB) 22 U/L, aspartate transferase (AST) 19 U/L, and lactic dehydrogenase (LDH) 482 U/L. Myocardial injury markers were markedly elevated at the time point of 18 h after onset: cTnI 13.9 ug/L↑, CK 613 U/L↑, CK-MB 102 U/L↑, AST 112 U/L↑, and LDH 833 U/L↑. Due to the acute ECG changes and elevated myocardial injury markers, the patient was preliminarily diagnosed as ST-segment elevation myocardial infarction (STEMI) and underwent coronary angiography, which showed no stenosis, occlusion or dissection of coronary arteries (Figure 1). Echocardiography showed enlarged left atrial dimension (LAD, 55 mm) and left ventricular end diastolic dimension (LVDd, 57 mm), and reduced ejection fraction (EF, 33%). The patient was treated for STEMI and HF, and was started on aspirin, statin, diuretic of furosemide and spirolactone, metoprolol, and Sacubitril/valsartan (SV, initiated June, 2020). The patient was strictly adherent to the medication prescribed (Table 1).

Details are in the caption following the image

Coronary angiogram demonstrating no significant obstruction in coronary artery circulation.
Table 1. Echocardiography results
2020-06-22 2020-09-02 2021-03-29 2021-06-02 2021-09-01 2021-10-22 2021-12-21
LAD (mm) 55 55 46 52 47 44 41
LVDd (mm) 57 57 53 55 54 51 55
IVS (mm) 10 10 11 10 10 10 11
LVPW (mm) 11 11 11 10 11 9 10
EF (%) 33 30 31 39 47 49 52.5
  • EF, ejection fraction; IVS, interventricular septum; LAD, left atrium dimension; LVDd, left ventricular end diastolic dimension; LVPW, left ventricular posterior wall.

However, the patient’s condition was not improved despite optimized medication. On 26 January 2021, the patient was re-admitted with recurrent chest distress and oedema, with new symptoms of facial plethora, centripetal obesity, and hyperglycaemia (Figure S1). Abdominal CT scan showed a right adrenal adenoma (Figure 2). Cardiac magnetic resonance imaging revealed enlarged LVDd (62 mm), and reduced EF, with delayed myocardial enhancement and evidence of myocardial fibrosis and fatty deposits (Figure 3). Laboratory findings showed hypokalaemia: potassium 3.0 mmol/L, elevated serum cortisol level, low plasma ACTH level, and positive 1-mg overnight dexamethasone suppression test. Based on the above findings, the patient was diagnosed with Cushing’s syndrome and started treatment with the glucocorticoid receptor inhibitor mifepristone on 5 February 2021.

Details are in the caption following the image

Abdominal CT scan showed adrenal adenoma at the right.

Details are in the caption following the image

Cardiac magnetic resonance imaging revealed enlarged LVDd, reduced EF, with delayed myocardial enhancement, evidence of myocardial fibrosis and fatty deposits.

With mifepristone added to the previous medical therapy (aspirin, statin, sacubitril/valsartan, metoprolol and diuretic of furosemide and spirolactone, and mifepristone), the patient’s condition and cardiac function improved, and echocardiography (21 December 2021) showed increased EF (52.5%). The patient underwent partial adrenalectomy on 22 December 2021. Postoperative pathology confirmed adrenal cortical adenoma. At last follow-up on 29 May 2023, the patient showed marked improvement in face and body shape, with no complaints of chest distress or oedema (Figure S2).

Discussion

In this case, the patient was first evaluated for STEMI due to her symptoms of chest pain, and the elevated ST-segment on ECG, along with the moderately elevated troponin I and other cardiac enzyme levels. However, coronary atherosclerotic heart disease was ruled out by the normal cardiac catheterization. We presume that a possible reason for acute myocardial infarction (AMI) might be vasospastic angina due to abnormal hormone levels with Cushing’s syndrome, leading to increased excessive myocardial metabolic demand and relative myocardial hypoxia, which eventually induced myocardial infarction. Although coronary atherosclerotic heart disease is the main cause of AMI, many non-atherosclerotic processes can lead to an imbalance between decreased coronary blood flow and increased myocardial metabolic demand. To date, non-atherosclerotic myocardial infarction has rarely been reported in Cushing’s syndrome patients. Vieira JT et al. reported that a patient with Cushing’s disease was considered to have spontaneous coronary artery dissection, which is a rare reason for AMI.2

Cushing’s syndrome is associated with an increased risk of cardiac failure,3 with both structural alterations and functional impairment. In our case, the patient’s CMR imaging showed typical features of cardiac geometry, function, and fibrosis, in accordance with previous reports.4 The underlying mechanisms may be the enhanced responsiveness to angiotensin II and activation of the mineralocorticoid receptor in direct response to cortisol excess.5

Our patient responded well to the therapy of conventional anti-HF medication of sacubitril/valsartan, metoprolol, and diuretic, once mifepristone was added. This favourable response to the pharmacological regimen supports the benefits of the agents for the normalization of excess cortisol. This case indicates that early diagnosis and effective treatment of Cushing’s syndrome may be crucial in preventing irreversible cardiac dysfunction secondary to cardiovascular events and heart failure.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81900409 and 82172182) and the PLA Youth Training Project for Medical Science (19QNP037).

Conflict of interest

The authors declares that there is no conflict of interest.

From https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14548

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Adrenocorticotropic Hormone-Dependent Cushing’s Syndrome Complicated With Gastric Ulcer Perforation in a 30-Year-Old Saudi Female

Posted on November 4, 2023 by MaryO

Abstract

Gastrointestinal perforation is a well-addressed complication of exogenous hypercortisolism; however, patients with endogenous Cushing’s syndrome (CS) do not usually experience this condition in clinical practice. The literature on this subject is limited and consists solely of clinical case reports/series with only 23 instances of gastrointestinal perforation occurring in individuals with endogenous Cushing’s syndrome. This is mainly attributed to the rarity of Cushing’s syndrome itself and the low chance of occurrence of such complications.

We report a case of a recently diagnosed adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome in a 30-years-old female who presented initially with a three-month history of progressive weight gain, generalized weakness, acne, menstrual irregularity, and severe hypokalemia, and then developed a gastric ulcer perforation only one month after her ACTH-dependent Cushing’s syndrome diagnosis and was managed through emergent surgery.

Introduction

A disorder of the endocrine system characterized by excessive cortisol production, known as Cushing’s syndrome, rarely occurs. The main causes are pituitary tumors, ectopic adrenocorticotropic hormone (ACTH)-secreting tumors, or adrenal tumors that secrete cortisol independently [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur, especially when the diagnosis is not established at an early stage [2]. There is a possibility of gastrointestinal complications among patients receiving exogenous glucocorticoids. However, there is limited information on gastrointestinal complications associated with endogenous hypercortisolemia [3,4]. Thus far, only 23 instances have been published addressing the co-occurrence of gastrointestinal perforation with endogenous Cushing’s syndrome [5-17]. To the best of our knowledge, this is the first case reporting gastric perforation in an ACTH-dependent Cushing’s syndrome, while the vast majority reported diverticular, sigmoid, or duodenal perforation with Cushing’s syndrome [5-17]. Herein, we describe the medical history, physical examination, and investigatory findings of a 30-year-old female with a recent diagnosis of ACTH-dependent Cushing’s syndrome that was complicated by gastric ulcer perforation, necessitating an urgent exploratory laparotomy. The primary motivator of this case report was the rarity of the described condition, the atypical location of the perforation in such patient group, and the relatively young age of the patient.

Case Presentation

History and examination

A 30-year-old female with a history of mental retardation was admitted to our emergency department (ER) with progressive weakness and fatigue. Upon taking the history, she had been having menstrual irregularities, progressive weight gain, and generalized weakness, which was significant enough to limit her physical activity and hinder her movement for the past three months. Initial vital signs showed that the patient had a body temperature of 37°C, a pulse rate of 90 beats per minute, and a blood pressure of 130/80 mmHg. On physical examination, the patient had a moon face with supraclavicular fullness, dorsocervical fat pad, purple abdominal striae, facial signs of hirsutism, and acne all over the face, shoulders, chest, and back.

Investigations

In the initial laboratory examination, hypokalemia of 2.1 mEq/L, hyperglycemia of 12.1 mmol/L, and metabolic alkalosis were detected (Table 1). The cortisol level after 1 mg dexamethasone suppression test was 2204 nmol/L (normal range 140-690), ACTH 123 pg/mL (normal range 7.2-63.3), DHEA-S 27.85 umol/L (normal range 2.6-13.9), And 24-hour urine cortisol level was 1560 mg/day (normal range 30-350) (Table 1). No suppression was observed in cortisol level with 8 mg dexamethasone suppression test.

Parameter Initial presentation Perforation presentation Refrence range
Na+ 143 mEq/L 139 mmol/L 135-147 mEq/L
Cl- 85 mEq/L 105 mmol/L 98-108 mEq/L
K+ 2.1 mEq/L 2.8 mmol/L 3.5-5.0 mEq/L
Mg2+ 0.79 mmol/L 0.77 mmol/L 0.85-1.110 mmol/L
PO3- 0.88 mmol/L 1.23 mmol/L 0.97-1.46 mmol/L
PH 7.54 7.36 7.35-7.45
PCO2 67.5 mmHg 42.7 mmHg 35-45 mmHg
PO2 27.7 mmHg 62.2 mmHg 75-100 mmHg
HCO3 49.8 mEq/L 23.6 mEq/L 22-26 mEq/L
Random blood glucose 12.1 mmol/L 24.1 mmol/L <5.5 mmol/L
Hemoglobin 13.5 g/dL 14.9 g/dL 13.7-16.8 g/dL
White blood cells 9,720 /uL 11,100 /uL 3,300-8,600 /uL
Lymphocyte 0.48% 0.33% –
Neutrophil 8.55% 9.66% –
Eosinophil 0.0% 0.0% –
TSH 0.55 mIU/L Was not ordered 0.4-4.0 mIU/L
Cortisol 2204 nmol/L 4842 nmol/L 140-690 nmol/L
ACTH 123 pg/mL Was not ordered 7.2-63.3 pg/mL
Table 1: Laboratory findings on initial presentation and on perforation day

TSH – thyroid stimulating hormone; ACTH – adrenocorticotropic hormone

A series of CT scans for the neck, chest, abdomen, and pelvis was performed and failed to localize any tumors acting as an ectopic source. A pituitary MRI was performed, and no adenoma was found. To complete the diagnostic workup, we decided to do an inferior petrosal sinus sampling (IPSS) and PET scan with Gallium 68; however, the patient’s family refused and requested discharge and outpatient follow-ups. These results, together with the biochemical and clinical findings, supported the diagnostic hypothesis of ACTH-dependent Cushing’s syndrome.

Treatment/management

When addressing the issue of hypokalemia that the patient presented with initially, it was found to be resistant and difficult to correct. The patient was put on spironolactone 50 mg BID, and potassium chloride 20 mEq q8h, and her potassium level barely reached 3.5 mmol/L after several days. In addition, her magnesium level was corrected with magnesium oxide 800 mg every six hours. Her blood glucose level was controlled with insulin glargine 6 units daily and Novorapid as per the sliding scale. The patient was discharged on spironolactone tablets 50 mg BID (oral), potassium chloride 20 mEq q8h, cholecalciferol, calcium carbonate, insulin glargine 6 units daily, and Novorapid 4 units TID before meals.

Follow-up and outcomes

Seven days after discharge, she presented to the ER complaining of a new onset of abdominal pain, constipation, and reduced urine output. Her Glasgow Coma Scale (GCS) was 15, her blood pressure measurement was 146/90 mmHg, her pulse rate was 66 beats per minute, her respiratory rate was 21 breaths per minute, and her temperature was 36.7°C. Upon physical examination, the patient had distended non-tender abdomen without any other significant findings. Blood work was done, including renal functions, and all parameters, including potassium, were within normal limits. A chest X-ray was also performed and revealed no evidence of pneumoperitoneum. The patient was clinically stable after managing her abdominal pain with acetaminophen injection and administering fleet enema for constipation. After instructions on when to come again to the ER were given, the patient was discharged home on lactulose and paracetamol, and a close outpatient follow-up appointment was scheduled.

Five days after the ER visit, the patient presented again to the ER. She was still complaining of severe non-resolving abdominal pain, constipation, and reduced urine output. Upon physical examination in the ER, the patient was found to have developed a new onset of lower limb edema, abdominal rebound tenderness, and abdominal rigidity and guarding. She was hypotensive with a blood pressure of 91/46 mmHg, pulse rate of 80 beats per minute, respiratory rate of 16 breaths per minute, temperature of 38.2 °C, and SpO2 of 96%. The only significant laboratory finding was her potassium level dropping low to 2.8 mEq/L (Table 1). An X-ray of the chest was requested and showed a large pneumoperitoneum (Figure 1).

Posteroanterior-chest-X-ray-at-the-time-of-gastric-perforation-displaying-severe-air-under-the-diaphragm-with-bilateral-obstruction-indicating-massive-pneumoperitoneum-(red-arrow)
Figure 1: Posteroanterior chest X-ray at the time of gastric perforation displaying severe air under the diaphragm with bilateral obstruction indicating massive pneumoperitoneum (red arrow)

Abdominal CT was also urgently performed and confirmed the presence of gastric perforation likely related to an underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature (Figures 2, 3).

Coronal-section-CT-image-of-abdomen-and-pelvis-at-the-time-of-gastric-perforation-showing-features-of-gastric-perforation-likely-related-to-the-underlying-perforated-peptic-ulcer-with-0.8-cm-defect-at-the-distal-greater-curvature-
Figure 2: Coronal-section CT image of abdomen and pelvis at the time of gastric perforation showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature
Horizontal-section-CT-image-showing-features-of-gastric-perforation-likely-related-to-the-underlying-perforated-peptic-ulcer-with-0.8-cm-defect-at-the-distal-greater-curvature
Figure 3: Horizontal-section CT image showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature

The patient underwent an emergent gastric wedge resection for gastric perforation, and the pathology reported evidence of gastric ulcer with no evidence of malignancy. Furthermore, Helicobacter pylori test was performed on the sample, and it came back positive. The patient tolerated the surgery very well, and postoperative recovery was without any complications.

Later, the patient was prescribed metyrapone 250 mg Q4h, which was then increased to 500 mg Q4h four days after surgery, and her cortisol level significantly dropped to 634nmol/L. During that time, a gastrin level test was also performed to exclude the presence of gastrinomas, and the level was 45 pg/ml (normal range 13-115).

Discussion

A small percentage of the population suffers from Cushing’s syndrome, which is an endocrine disorder characterized by an endogenous overproduction of glucocorticoids, resulting in hypercortisolemia [1]. It is estimated to affect 0.7 to 2.4 people per million annually [1]. Hypercortisolemia alters psychologic, metabolic, and cardiovascular functions, resulting in increased mortality and morbidity rates, particularly if the diagnosis is delayed and long-term exposure to high cortisol levels occurs [2]. Women are more likely to suffer from this condition than men, and people in their 40s to 60s are most vulnerable to it [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur [1]. Due to the rarity of this condition, there is often a significant delay in diagnosis and treatment, which could eventually lead to complications from prolonged hypercortisolism.

From another standpoint, in a systematic review, the incidence of peptic ulcer perforation ranges from 3.8 to 14 per 100,000 individuals in the general population [18]. In under-developed countries, patients are typically young, tobacco-using males [19]. However, patients in industrialized countries are typically older with multiple co-morbidities and are on long-term non-steroidal anti-inflammatory drugs (NSAIDs) or steroid use [19]. Patients may present with an abrupt onset of abdominal discomfort, abdominal rigidity, and tachycardia in the early stages of a perforated peptic ulcer [19]. Later, abdominal distention, pyrexia, hypotension, fever, and vomiting can occur [19]. Furthermore, when the diagnosis is made early, a perforated ulcer often has a good prognosis. However, the risk of adverse events increases if there is a delay in the diagnosis [20]. Therefore, making an early detection through different imaging modalities is crucial [20]. A history of peptic ulcer disease, NSAIDs, physiological stress, smoking, corticosteroids, and Helicobacter pylori are some of the well-established risk factors for a perforated peptic ulcer [20].

The prevalence of Helicobacter pylori among Saudi patients is high; in one study, the overall prevalence was 46.5% in patients with dyspepsia using gastric biopsy [21]. Several studies have explored the relationship between Helicobacter pylori and gastrointestinal perforation, but the results have been mixed. Some studies have suggested a higher prevalence of Helicobacter pylori infection among individuals with gastrointestinal perforation compared to those without, indicating a potential association. However, other studies have found no significant difference in the prevalence of Helicobacter pylori infection between perforated and non-perforated gastrointestinal ulcer cases [22]. Furthermore, they suggested that the presence of other risk factors like the use of NSAIDs, smoking, and alcohol may interact with Helicobacter pylori infection and contribute to the development of complications such as gastrointestinal perforation [22]. However, in our case, the patient did not have any established risk factors for gastric perforation, such as NSAIDs, smoking, or alcohol. Therefore, considering the low incidence of gastrointestinal perforation and high prevalence of Helicobacter pylori, the conflicting data regarding the association between Helicobacter pylori and gastrointestinal perforation, and the lack of established risk factors for gastrointestinal perforation in our patient, we suggest that prolonged excess glucocorticoids from Cushing’s syndrome may have contributed to the gastric perforation either independently or synergistically with Helicobacter pylori since hypercortisolism can lead to a weakened gastrointestinal wall integrity due to decreased collagen turnover and disruption of mucosal protection by prostacyclin [15]. In addition, because of hypercortisolism, perforation may not be contained or healed initially due to the immunosuppressive effects of hypercortisolism, whether endogenous or exogenous [15]. Additionally, high levels of cortisol may delay the diagnosis and treatment since it may mask the symptoms of the perforation [14]. Moreover, our patient was treated for severe hypokalemia with potassium supplementation for an extended period of time. Previous studies have linked potassium chloride supplementation to gastrointestinal ulceration and perforation, making this a possible additive cause of our patient’s condition [23,24].

A limited number of studies have addressed gastrointestinal perforations associated with endogenous hypercortisolemia [5-17]. The correlation between Cushing’s syndrome and gastrointestinal perforation is highlighted in our study and in the case reports that have been previously published (Table 2). Similar to our case, a female predominance was seen in gastrointestinal perforation among the reported cases of Cushing’s syndrome [6,7,12,13,15,16]. Additionally, the average age at which gastrointestinal perforation occurred in patients with endogenous hypercortisolism ranged from 45 to 80, which is a noticeably higher age range than the case we are presenting here (aged 30) [6-10,12]. Furthermore, unlike our case, in which gastrointestinal perforation occurred four months after the onset of Cushing’s symptoms, Intestinal perforation occurs approximately 9.8 months after Cushing’s symptoms first appear [15]. Furthermore, in our patient, gastric perforation occurred while she was hypercortisolemic and not in a remission state. Hence, in association with Helicobacter pylori infection, severe hypercortisolemia could have been a secondary contributing factor to gastric perforation. The complications of gastric ulceration, specifically with endogenous Cushing’s syndrome, have been addressed in two case reports [25,26]. It must be noted, however, that neither case is similar to ours. A case of gastric perforation was reported by Kubicka et al. in a patient who had a confirmed diagnosis of gastrinoma, and the patient was diagnosed with ectopic Cushing’s syndrome seven months after gastric perforation [25]. Therefore, since ectopic Cushing’s syndrome was diagnosed seven months after the perforation, it is more likely that the gastrinoma contributed to this complication. In contrast, our patient’s serum gastrin level was within the normal range, ruling out gastrinoma. Further, Hoshino et al. reported a case of gastrointestinal bleeding in a 39-year-old man with a confirmed diagnosis of Cushing’s disease secondary to pituitary adenoma [26]. He was found to have gastric ulceration and bleeding along with Helicobacter pylori infection and elevated cortisol levels [26]. In spite of the patient not developing a gastric perforation, it was suggested by the author that hypercortisolism might be a contributing factor for gastric ulcer complications by slowing down the ulcer healing process [26]

Reference Year of publication Age, gender Highest cortisol level plasma cortisol (PC, nmol/L) / UFC (nmol/L) Cause of Cushing’s syndrome Time from onset of Cushing’s symptoms to perforation (months) Reported site of gastrointestinal perforation
Current 2023 30, Female PC 4842 ACTH-dependant 4 Gastric perforation
Ishinoda et al. [17] 2023 24, Male PC 1647 Cushing’s disease 12 Sigmoid colon perforation
Wijewickrama et al. [16] 2021 32, Female PC 1147 Pituitary microadenoma 1 Diverticular perforation
Shahidi et al. [15] 2019 72, Female UFC 5296 Pancreatic neuroendocrine tumor 12 Diverticular perforation
Shahidi et al. [15] 2019 61, Female PC 1925 Metastatic medullary carcinoma of thyroid 12 Sigmoid colon and diverticular perforation
Shahidi et al. [15] 2019 68, Female UFC 410 Cushing’s disease 12 Sigmoid colon perforation
Shahidi et al. [15] 2019 71, Female UFC 1533 Cushing’s disease 4 Diverticular perforation
Shahidi et al. [15] 2019 54, Male UFC 374 Cushing’s disease 3 Sigmoid colon perforation
Shahidi et al. [15] 2019 52, Female UFC 885 Cushing’s disease 16 Diverticular perforation
Sater et al. [14] 2018 80, Female UFC 5601 Lung carcinoid 36 Diverticular perforation
Sater et al. [14] 2018 60, Female UFC 72726 Metastatic islet cell carcinoma 36 Diverticular perforation
Sater et al. [14] 2018 31, Male UFC 1297 Cushing’s disease 20 Diverticular perforation
Sater et al. [14] 2018 52, Female UFC 2371 Lung carcinoid 4 Diverticular perforation
Sater et al. [14] 2018 67, Male UFC 3836 Ectopic ACTH 10 Diverticular perforation
Sater et al. [14] 2018 51, Male UFC 13552 Metastatic thymic carcinoma 4 Diverticular perforation
Kaya et al. [9] 2016 70, Male PC 1432 Small cell lung cancer 1 Diverticular perforation
Dacruz et al. [12] 2016 60, Female UFC 4481 Metastatic parotid tumor 5 Sigmoid colon and diverticular perforation
Matheny et al. [10] 2016 67, Male UFC 11119 Metastatic medullary carcinoma of thyroid 4 Diverticular perforation
Flynn et al. [13]   2016 63, Female UFC 12465 Pheochromocytoma 1 Perforation at the splenic flexure
Balestrieri et al. [11] 2016 75, Male PC 2272 Neuroendocrine tumor 1 Intestinal perforation
Hara et al, [8] 2013 79, Male PC 1230 Cushing’s disease 6 Diverticular perforation
De Havenon et al. [7] 2011 71, Female PC 2593 Cushing’s disease 9 Diverticular perforation
Lutgers et al. [6] 2010 55, Female UFC 10152 Right pheochromocytoma 1 Sigmoid colon and diverticular perforation
Drake et al. [5] 1998 35, Male PC 1442 Islet cell tumor 4 Duodenal perforation and rupture of pancreatic pseudocyst
Table 2: Current case and previous reported 23 cases of patients with Cushing’s syndrome and gastrointestinal perforation

UFC – urinary free cortisol; PC – plasma cortisol; ACTH – adrenocorticotropic hormone

Conclusions

A high blood cortisol level can be associated with various clinical manifestations and diverse sets of complications. This case report sheds light on one of the less common complications of hypercortisolism in patients with Cushing’s syndrome, which is gastrointestinal perforation. Our report further supports the published evidence that gastrointestinal perforation is a rare but potentially fatal complication among patients with Cushing’s syndrome. Moreover, it highlights the possibility of developing gastric perforations in this patient group, even at younger ages than expected. This should elicit a high clinical suspicion and demand prompt investigation of Cushing’s syndrome patients in a hypercortisolism state presenting with modest gastrointestinal symptoms.

References

  1. Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A: Cushing’s syndrome. Endocrinol Metab Clin North Am. 2008, 37:135-49. 10.1016/j.ecl.2007.10.010
  2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  3. Goethals L, Nieboer K, De Smet K, De Geeter E, Tabrizi NH, Van Eetvelde E, de Mey J: Cortisone associated diverticular perforation. JBR-BTR. 2011, 94:348-9. 10.5334/jbr-btr.705
  4. Piekarek K, Israelsson LA: Perforated colonic diverticular disease: the importance of NSAIDs, opioids, corticosteroids, and calcium channel blockers. Int J Colorectal Dis. 2008, 23:1193-7. 10.1007/s00384-008-0555-4
  5. Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM: Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing’s syndrome and peritonitis. J Clin Endocrinol Metab. 1998, 83:3542-4. 10.1210/jcem.83.10.5156
  6. Lutgers HL, Vergragt J, Dong PV, de Vries J, Dullaart RP, van den Berg G, Ligtenberg JJ: Severe hypercortisolism: a medical emergency requiring urgent intervention. Crit Care Med. 2010, 38:1598-601. 10.1097/CCM.0b013e3181e47b7a
  7. de Havenon A, Ehrenkranz J: A perforated diverticulum in Cushing’s disease. Int J Surg Case Rep. 2011, 2:215-7. 10.1016/j.ijscr.2011.06.009
  8. Hara T, Akutsu H, Yamamoto T, Ishikawa E, Matsuda M, Matsumura A: Cushing’s disease presenting with gastrointestinal perforation: a case report. Endocrinol Diabetes Metab Case Rep. 2013, 2013:130064. 10.1530/EDM-13-0064
  9. Kaya T, Karacaer C, Açikgöz SB, Aydemir Y, Tamer A: Severe hypokalaemia, hypertension, and intestinal perforation in ectopic adrenocorticotropic hormone syndrome. J Clin Diagn Res. 2016, 10:OD09-11. 10.7860/JCDR/2016/17198.7127
  10. Matheny LN, Wilson JR, Baum HB: Ectopic ACTH production leading to diagnosis of underlying medullary thyroid carcinoma. J Investig Med High Impact Case Rep. 2016, 4:2324709616643989. 10.1177/2324709616643989
  11. Balestrieri A, Magnani E, Nuzzo F: Unusual Cushing’s syndrome and hypercalcitoninaemia due to a small cell prostate carcinoma. Case Rep Endocrinol. 2016, 2016:6308058. 10.1155/2016/6308058
  12. Dacruz T, Kalhan A, Rashid M, Obuobie K: An ectopic ACTH secreting metastatic parotid tumour. Case Rep Endocrinol. 2016, 2016:4852907. 10.1155/2016/4852907
  13. Flynn E, Baqar S, Liu D, et al.: Bowel perforation complicating an ACTH-secreting phaeochromocytoma. Endocrinol Diabetes Metab Case Rep. 2016, 2016:10.1530/EDM-16-0061
  14. Sater ZA, Jha S, McGlotten R, Hartley I, El Lakis M, Araque KA, Nieman LK: Diverticular perforation: A fatal complication to forestall in Cushing syndrome. J Clin Endocrinol Metab. 2018, 103:2811-4. 10.1210/jc.2018-00829
  15. Shahidi M, Phillips RA, Chik CL: Intestinal perforation in ACTH-dependent Cushing’s syndrome. Biomed Res Int. 2019, 2019:9721781. 10.1155/2019/9721781
  16. Wijewickrama PS, Ratnasamy V, Somasundaram NP, Sumanatilleke M, Ambawatte SB: A challenging case of Cushing’s disease complicated with multiple thrombotic phenomena following trans-sphenoidal surgery; a case report. BMC Endocr Disord. 2021, 21:29. 10.1186/s12902-021-00701-0
  17. Ishinoda Y, Uto A, Meshino H, et al.: Bowel perforation associated with Cushing’s disease: a case report with literature review. Endocr J. 2023, 70:933-9. 10.1507/endocrj.EJ23-0110
  18. Lau JY, Sung J, Hill C, Henderson C, Howden CW, Metz DC: Systematic review of the epidemiology of complicated peptic ulcer disease: incidence, recurrence, risk factors and mortality. Digestion. 2011, 84:102-13. 10.1159/000323958
  19. Chung KT, Shelat VG: Perforated peptic ulcer – an update. World J Gastrointest Surg. 2017, 9:1-12. 10.4240/wjgs.v9.i1.1
  20. Weledji EP: An overview of gastroduodenal perforation. Front Surg. 2020, 7:573901. 10.3389/fsurg.2020.573901
  21. Akeel M, Elmakki E, Shehata A, Elhafey A, Aboshouk T, Ageely H, Mahfouz MS: Prevalence and factors associated with H. pylori infection in Saudi patients with dyspepsia. Electron Physician. 2018, 10:7279-86. 10.19082/7279
  22. Thirupathaiah K, Jayapal L, Amaranathan A, Vijayakumar C, Goneppanavar M, Nelamangala Ramakrishnaiah VP: The association between Helicobacter pylori and perforated gastroduodenal ulcer. Cureus. 2020, 12:e7406. 10.7759/cureus.7406
  23. Farquharson-Roberts MA, Giddings AE, Nunn AJ: Perforation of small bowel due to slow release potassium chloride (slow-K). Br Med J. 1975, 3:206. 10.1136/bmj.3.5977.206
  24. Payan H, Blaustein A: Potassium chloride and small bowel perforation. Gastroenterology. 1965, 48:877-8. 10.1016/S0016-5085(65)80073-7
  25. Kubicka E, Zawadzka K, Syrycka J, Kałużny M, Pawluś A, Bolanowski M: A case of gastrinoma associated with ectopic Cushing syndrome. Pol Arch Intern Med. 2020, 130:328-9. 10.20452/pamw.15201
  26. Hoshino C, Satoh N, Narita M, Kikuchi A, Inoue M: Another ‘Cushing ulcer’. BMJ Case Rep. 2011, 2011:10.1136/bcr.02.2011.3888

From https://www.cureus.com/articles/196132-adrenocorticotropic-hormone-dependent-cushings-syndrome-complicated-with-gastric-ulcer-perforation-in-a-30-year-old-saudi-female-a-case-report-and-a-review-of-the-literature#!/

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Clinical Features, Diagnosis and Treatment Outcomes of Cushing’s Disease In Children: a Multicenter Study

Posted on November 2, 2023 by MaryO

Abstract

Objective

Since Cushing’s disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases.

Design

National, multicenter and retrospective study.

Patients

All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017.

Measurements

Diagnostic tests of CD and tumour size.

Results

Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure.

Conclusions

Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

From https://onlinelibrary.wiley.com/doi/10.1111/cen.14980

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , | Leave a comment »

A Case Report of Cushing’s Disease Presenting With Psychosis and Muscle Weakness Postpartum

Posted on October 31, 2023 by MaryO

Abstract

Cushing’s syndrome is a condition leading to overproducing of cortisol by the adrenal glands. If the pituitary gland overproduces cortisol, it is called Cushing’s disease. Cushing’s syndrome and even Cushing’s disease during and after pregnancy are rare events. There is not enough literature and guidance for managing and treating these patients. The diagnosis of Cushing’s syndrome in pregnancy is often delayed because the symptoms overlap. We presented a thin 31-year-old woman, admitted 2 months after a normal-term delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course. She had no clinical discriminatory features of Cushing’s syndrome. Given that the patient only presented with psychosis and proximal myopathy and had an uncomplicated pregnancy, our case was considered unusual. The patients also had hyperpigmentation and severe muscle weakness which are among the less common presentations of Cushing’s syndrome. Our findings suggest that an early diagnosis of Cushing’s disease is important in pregnancy period for its prevalent fetal and maternal complications, and it should be treated early to optimize fetal and maternal outcomes as there is an increasing trend toward live births in treated participants.

Introduction

Cushing’s syndrome is a condition that originates from excessive production of glucocorticoids. The condition is most common in women of childbearing age and is characterized by altered distribution of the adipose tissue to the central and upper regions of the trunk (central obesity and buffalo hump), face (moon face), capillary wall integrity (easy bruising), hyperglycemia, hypertension, mental status changes and psychiatric symptoms, muscle weakness, signs associated with hyperandrogenism (acne and hirsutism), and violaceous striae among other signs. Hypercortisolism and hyperandrogenism suppress the production of the pituitary gonadotropins, which in turn leads to menstrual irregularities and infertility.1–3 Moreover, the main common cause of developing Cushing’s syndrome is the use of exogenic steroid.3
Cushing’s disease is a form of Cushing’s syndrome with overproduction of adrenocorticotropic hormone (ACTH) due to pituitary adenoma. The diagnosis is made using clinical features and paraclinical tests including urinary free cortisol (UFC), serum ACTH, dexamethasone suppression tests (DSTs), pituitary magnetic resonance imaging (MRI), and sometimes by inferior petrosal sinus sampling (IPSS).4 Although women with Cushing’s disease are less likely to become pregnant, timely diagnosis and appropriate management are especially important during possible pregnancy, preventing neonatal and maternal complications and death. The diagnosis is challenging due to the overlap of the disease symptoms with the changes associated with a normal pregnancy. Moreover, the hormonal milieu during pregnancy has recently been proposed as a potential trigger for Cushing’s disease in some cases; hence, the term “pregnancy-associated Cushing’s disease” has been used for the disease in the recent literature. In this study, we presented a thin 31-year-old woman who was referred to our clinic 2 months after a normal delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course.

Case Presentation

Our patient was a 31-year-old woman who presented 2 months after the delivery of her second child. She had a history of type 2 diabetes mellitus and hypertension in the past 2 years prior to her presentation. She had been admitted to another center following an episode of falling and muscle weakness. Two weeks later, she was admitted to our center with an impression of pulmonary thromboembolism due to tachypnea, tachycardia, and dyspnea. During follow-up, she was found to have leukocytosis, hyperglycemia (random blood sugar: 415 mg/d; normal level: up to 180 mg/dL) and hypokalemic metabolic alkalosis (PH: 7.5, HCO3 [bicarbonate]: 44.7 mEq/L, paO2 [partial pressure of oxygen]: 73 mm Hg, pCO2: 51.7 mm Hg, potassium: 2.7 mEq/L [normal range: 3.5-5.1 mEq/L]), which was refractory to the treatment; therefore, an endocrinology consultation was first requested. On physical examination, the patient was agitated, confused, and psychotic. Her vital signs were: blood pressure 155/100 mm Hg, heart rate: 130 bpm, and respiratory rate: 22 bpm, temperature: 39°C. As it has shown in Figure 1A, her face is not typical for moon face of Cushing’s syndrome, but facial hirsutism (Figure 1A) and generalized hyperpigmentation is obvious (Figure 1A-C). She was a thin lady and had a normal weight and distribution of adiposity (Body Mass Index [BMI] = 16.4 kg/m2; weight: 40 kg, and height: 156 cm). Aside from thinness of skin, she did not have the cutaneous features of Cushing’s syndrome (e.g. purpura, acne, and violaceous striae) and did not have supraclavicular and dorsocervical fat pad (buffalo hump), or plethora. In other words, she had no clinical discriminatory features of Cushing’s syndrome despite the high levels of cortisol, as confirmed by severely elevated UFC (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). In addition, as will be mentioned later, the patient had axonal neuropathy which is a very rare finding in Cushing’s syndrome.
Figure 1. Clinical finding of our case with Cushing’s disease. (A) Hirsutism, (B) muscle atrophy seen in proximal portion of lower limbs, and (C) hyperpigmentation specially on the skin of the abdominal region.

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She had a markedly diminished proximal muscle force of 1 out of 5 across all extremities; the rest of the physical examinations revealed no significant abnormalities (Figure 1B). On the contrary, based on her muscle weakness, hirsutism, psychosis and hyperpigmentation and refractory hypokalemic alkalosis, hyperglycemia, and hypertension, Cushing’s syndrome was suspected; therefore, 24-hour UFC level was checked that the results showed a severely elevated urinary cortisol (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). Serum ACTH level was also inappropriately elevated (45 pg/mL; normal range: 10-60 pg/mL). High-dose dexamethasone failed to suppress plasma cortisol level and 24-hour urine cortisol level. A subsequent pituitary MRI showed an 8-mm pituitary mass, making a diagnosis of Cushing’s disease more probable. Meanwhile, the patient was suffering from severe muscle weakness that did not improve after the correction of hypokalemia. Then, a neurology consultation was requested. The neurology team evaluated laboratory data as well as EMG (Electromyography) and NCV (Nerve Conduction Velocity) of the patient, and based on their findings, “axonal neuropathy” was diagnosed for her weakness; so they ruled out the other neuromuscular diseases. A 5-day course of intravenous immunoglobulin (IVIG) was started for her neuropathy; however, the treatment did not improve her symptoms and the patient developed fungal sepsis and septic shock. Therefore, she was processed with broad-spectrum antibiotics and antifungal agents and recovered from the infection.
Mitotane was started for the patient before definitive surgical treatment to suppress hormonal production due to her poor general condition. Despite the 8-mm size of the pituitary mass which is likely to be a source of ACTH, our patient was underweight and showed the atypical clinical presentation of Cushing’s disease, making us suspect an ectopic source for the ACTH. Therefore, a Gallium dotatate scan was performed to find any probable ectopic sources; however, the results were unremarkable. The patient underwent Trans-Sphenoidal Surgery (TSS) to resect the pituitary adenoma because it was not possible to perform IPSS in our center. Finally, the patient’s condition including electrolyte imbalance, muscle weakness, blood pressure, and hyperglycemia started to improve significantly. The pathologist confirmed the diagnosis of a corticotropic adenoma. Nevertheless, the patient suddenly died while having her meal a week after her surgery; most likely due to a thromboembolic event causing a cardiac accident.

Discussion

Our patient was significantly different from other patients with Cushing’s disease because of her atypical phenotype. She was unexpectedly thin and had psychosis, hyperpigmentation, proximal myopathy, axonal neuropathy and no clinical discriminatory features of Cushing’s syndrome such as central adiposity, dorsocervical or supraclavicular fat pad, plethora or striae. She had also a history of type 2 diabetes and hypertension 2 years before her admission. The patient was diagnosed with Cushing’s later. From what was presented, the patient did not know she had Cushing’s until after her delivery and despite the highly elevated UFC, and she completed a normal-term delivery. Given that she only presented with psychosis and proximal myopathy, her pregnancy was considered unusual. Her clinical features such as hyperpigmentation and severe muscle weakness are among less common presentations.5
11β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) is an enzyme responsible for converting cortisone (inactive glucocorticoid) into cortisol (active). It is speculated that this enzyme has a role in obesity (Figure 2).6,7
Figure 2. The enzymatic actions of 11β-hydroxysteroid dehydrogenase on its substrate interconverting inactive and active glucocorticoid.

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In a case reported by Tomlinson, a 20-year-old female was diagnosed with Cushing’s disease despite not having the classical features of the disease. It has been suggested that the mechanism is a partial defect in 11β-HSD1 activity and concomitant increase in cortisol clearance rate. Thus, the patient did not have a classic phenotype; the defect in the conversion of cortisone to cortisol rises cortisol clearance and protects the patient from the effects of cortisol excess. This observation may help explain individual susceptibility to the side effects of glucocorticoids.6
Further studies of Tomlinson et al showed that a deficit in the function of (and not a mutation related to) 11β-HSD2 might have been responsible for the absence of typical Cushing’s symptoms. 11-HSD2 keeps safe the mineralocorticoid receptor from excess cortisol. Mutation in the HSD11B2 gene explains an inherited form of hypertension, apparent mineralocorticoid excess syndrome, in which Cushing’s disease results in cortisol-mediated mineralocorticoid excess affecting the kidney and leads to both hypokalemia and hypertension.8
It is frequent in Cushing’s syndrome that the patients usually have no mineralocorticoid hypertension; however, it is still proposed that a defect in 11β-HSD1 can be responsible for the presence of mineralocorticoid hypertension in a subgroup of patients. In fact, 11β-HSD1 is expressed in several tissues like the liver, kidneys, placenta, fatty tissues and gonads,9 meaning that this enzyme may potentially affect the results of cortisol excess in Cushing’s syndrome/disease. Abnormality in the function of this enzyme could explain the absence of the symptoms like central obesity, easy bruising, and typical striae during Cushing’s disease. Several factors affect the action of glucocorticoids. In this regard, the impact of the different types and levels of impairment in glucocorticoid receptors have been highlighted in some studies, as it can lead to different levels of response to glucocorticoids10 as well as a variety in the symptoms observed in Cushing’s disease.
The predominant reaction of the NADP(H)-dependent enzyme 11-Tukey’s honestly significant difference (HSD)1 happens through the catalysis of the conversion of inactive cortisol into receptor-active cortisol. The reverse reaction is mediated through the unidirectional NAD-dependent 11-HSD type 2 (Figure 2).11
In another case reported by Ved V. Gossein, a 41-year-old female was evaluated for hirsutism and irregular menstrual cycles. Her BMI was 22.6 kg/m2. The patient had no signs or symptoms of overnight recurrent Cushing’s syndrome, the 48-hour DST failed to suppress cortisol levels, and 24-hour urinary cortisol levels were persistently elevated on multiple occasions. Adrenocorticotropic hormone levels were unreasonably normal, suggesting ACTH-dependent hypercortisolism. Despite these disorders, she had 2 children. Magnetic resonance imaging (MRI) of the pituitary did not show any abnormalities. Moreover, abdominal MRI did not show adrenal mass or enlargement. Genetic testing to determine glucocorticoid resistance syndrome showed no mutation.12
Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized or partial insensitivity of target tissues to glucocorticoids.13–17 There is a compensatory increase in hypothalamic-pituitary activity due to decreased sensitivity of peripheral tissues to glucocorticoids systems.13–17 Excessive ACTH secretion leads to high secretion of cortisol and mineralocorticoids and/or androgens. However, the clinical features of Cushing’s syndrome do not develop after resistance to the effects of cortisol. Generalized glucocorticoid resistance is a rare condition characterized by high cortisol levels but no scarring of Cushing’s syndrome.18
An important aspect of our case was her pregnancy. Our patient had a history of hypertension and diabetes type 2, 2 years before her presentation to our center that could be because of an undiagnosed Cushing’s disease. The patient’s pregnancy terminated 2 months prior the admission and she had a normal vaginal delivery. So, we suspect that she become pregnant while involved with the disease. Aside from focusing on how this can happen in a patient with such high levels of glucocorticoids, more attention should be paid to occurring pregnancy in the background of Cushing’s disease. In fact, up to 250 patients were reported, of which less than 100 were actively treated.19–22
Cushing’s disease is associated with serious complications in up to 70% of the cases coinciding with pregnancy.21 The most frequent maternal complications reported in the literature are hypertension and impaired glucose tolerance, followed by preeclampsia, osteoporosis, severe psychiatric complications, and maternal death (in about 2% of the cases). Prematurity and intrauterine growth retardation account for the most prevalent fetal complications. Stillbirth, intrauterine deaths, intrauterine hemorrhage, and hypoadrenalism have also been reported.23 Early diagnosis is especially challenging during pregnancy because of many clinical and biochemical shared features of the 2 conditions.23,24 These features include an increase in ACTH production, corticosteroid-binding globulin (CBG) 1 level, level of cortisol (urinary, plasma and free), hyperglycemia, weight gain, and an increased chance for occurrence of bruising, hypertension (mistaken with preeclampsia), gestational diabetes mellitus, weight gain, and mood swings.3 There are some suggestions proposed in the studies that help in screening and differentiation of Cushing’s from the normal and abnormal effects of pregnancy and Cushing’s disease from Cushing’s syndrome in suspected pregnant patients. Contrary to Cushing’s syndrome, the nocturnal minimum level of cortisol is preserved in pregnancy.23,25 There is not yet a diagnostic cut-off determined on mentioned level; however, a few studies elucidate the evaluation of hypercortisolemia in a pregnant patient.26–28
Urinary free cortisol, a measure that reflects the amount of free cortisol in circulation, normally increases during pregnancy, and it can increase up to 8 times the normal level with Cushing’s disease during the second and the third trimesters,23,29 which is a useful tool to evaluate cortisol levels in a suspected pregnant woman. Because the suppression of both UFC and plasma cortisol is decreased in pregnancy,23,30 a low-dose DST is not very helpful for screening Cushing’s disease in pregnant patients. However, a high-dose DST with a <80% cortisol suppression might only indicate Cushing’s disease.3,31 Thus, it helps differentiating between ectopic ACTH syndrome and Cushing’s disease.32 The use of high-dose DST can distinguish between adrenal and pituitary sources of CS in pregnancy. Owing to the limited evidence available and the lack of data on normal pregnancies, the use of corticotropin-releasing hormone (CRH), desmopressin, and high-dose DST in pregnancy is not recommended yet.33 More timely diagnosis as well as timely intervention may have saved the life of our patient.
To differentiate between ectopic ACTH syndrome and Cushing’s disease, adrenal imaging should be considered. For higher plasma levels, combined employment of CRH stimulation test and an 8-mg DST can be helpful.3 Bilateral inferior petrosal sinus sampling (B-IPSS) might be needed when the findings are not in accordance with other results, but it is recommended to perform B-IPSS only if the noninvasive studies are inconclusive and only if there is enough expertise, experience, and technique for its performance.3
Although axonal neuropathy has been reported as a rare syndrome associated with paraneoplastic ectopic Cushing’s syndrome and exogenous Cushing’s syndrome, its association with Cushing’s disease has not been reported.5,32 Our patient had severe muscle weakness that we initially attributed it to myopathy and hypokalemia associated with Cushing’s syndrome. In our study, the diagnosis of axonal neuropathy was made based on electrophysiological studies by a neurology consultant and then IVIG was administered; however, the patient’s weakness did not improve after this treatment. The co-occurrence of Guillain-Barré syndrome which may also be classified as axonal neuropathy has also been reported in a pregnant woman with ectopic Cushing’s syndrome.34,35 Whether this finding is coincidental or the result of complex immune reactions driven by Cushing’s disease, or the direct effect of steroids, these results cannot be deduced from current data.36 Some data suggest that the fluctuations and inferior petrosal sinus sampling may trigger the flare of autoimmune processes, specifically when the cortisol levels start to decline during the course of Cushing’s syndrome.35,8 Also, due to COVID-19 pandemic affecting vital organs like kidney, paying attention to COVID-19 is suggested.37–40

Conclusions

We presented a thin young female with psychosis, proximal myopathy, and axonal neuropathy with Cushing’s disease who had a recent pregnancy that was terminated without any fetal or maternal complications despite the repeated elevated serum cortisol and 24-hour UFC; therefore, we suggest that she might have glucocorticoid resistance. Glucocorticoid resistance is a rare disease in which the majority, but not all, of patients have a genetic mutation in the hGR-NR3C1 gene. As we did not perform genetic testing for our patient, the data are lacking.
Another clue to the absence of the classic Cushing’s disease phenotype in our case is the role of isoenzymes of 11-HSD1 and 11-HSD2. Other mechanisms, such as the defect somewhere in the glucocorticoid pathway of action such as a decreased number of receptors, a reduction in ligand affinity, or a postreceptor defect, play an important role in nonclassical clinical manifestations of Cushing’s syndrome.

Acknowledgments

The authors thank the patient for allowing us to publish this case report. The authors show their gratitude to the of the staff of the Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) specially Mrs. Farahnaz Nikkhah for its technical and editorial assists.

Ethics Approval

Our institution does not require ethical approval for reporting individual cases or case series.

Informed Consent

Written informed consent was obtained from the patient and for her anonymized information to be published in this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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