A Case of Recurrent Cushing’s Disease With Optimised Perinatal Outcomes

Posted on December 21, 2025 by MaryO

Abstract

Summary

This is a case of a patient with a 10-year history of Cushing’s disease (CD) that was previously treated with transsphenoidal pituitary tumour resection. Conception occurred spontaneously, and during early pregnancy recurrent CD became apparent both clinically and biochemically. Repeat transsphenoidal surgery took place during the second trimester, and the high-risk pregnancy resulted in a live neonate. Despite evidence of hypercortisolism and recurrent CD at 6 months postpartum, the patient had a second successful, uncomplicated pregnancy, further adding to the rarity and complexity of this case. Pregnancy in CD is rare because hypercortisolism seen in CD suppresses gonadotropin release, leading to menstrual irregularities and infertility. Diagnosis of CD is particularly challenging because many clinical and biochemical features of normal pregnancy overlap considerably with those seen in CD. Diagnosis and treatment are extremely important to reduce rates of perinatal morbidity and mortality.

Learning points

  • Hypercortisolism suppresses gonadotropin release, leading to menstrual irregularities and infertility. In CD, hypersecretion of both androgens and cortisol further contributes to higher rates of amenorrhoea and infertility.
  • Pregnancy itself is a state of hypercortisolism, with very few studies detailing normal ranges of cortisol in each trimester of pregnancy for midnight salivary cortisol and urinary free cortisol testing.
  • Treatment of CD reduces maternal morbidity and rates of foetal loss, and can be either surgical (preferred) or medical.
  • CD can relapse, often many years after initial surgery.
  • There are a limited number of cases of Cushing’s syndrome in pregnancy, therefore, the best possible treatment is difficult to determine and should be individualised to the patient.

Background

CD is rare in the general population. It is even rarer to present as a clinical conundrum during pregnancy. Diagnosis is challenging due to the overlap of physiological hormonal changes during pregnancy with features of Cushing’s syndrome, and it is further complicated by limited data for cortisol reference ranges in a pregnant state. The prognostic benefits of treatment of CD in pregnancy in reducing perinatal morbidity and mortality must be carefully weighed up against the risks of surgery and/or medical management in pregnancy.

Case presentation

The patient was a 31-year-old female diagnosed with Cushing’s disease at age 20 years. Initial clinical features were oligomenorrhoea, weight gain, hypertension, and impaired glucose tolerance. She had markedly elevated 24 h urinary free cortisol (UFC) of 1,984 nmol/day, which was six times the upper limit of normal (ULN). Results of a 1 mg dexamethasone suppression test (DST) showed failure to suppress cortisol levels, with an elevated morning cortisol of 695 nmol/L (reference range (RR): 100–690). ACTH levels remained inappropriately normal at 7.3 pmol/L (RR: < 12.1), suggesting ACTH-dependent hypercortisolism. A 5 mm by 4.4 mm microadenoma was identified on magnetic resonance imaging (MRI) scan of the pituitary gland, and she underwent initial transsphenoidal pituitary adenectomy. Histopathological examination demonstrated positive staining for adrenocorticotrophic hormone (ACTH). Immediately after surgery, she required hydrocortisone and levothyroxine replacement for several months, which was gradually weaned and eventually ceased. She had routine MRI with gadolinium and biochemical surveillance for 5 years, which showed cortisol levels within the normal ranges and no visible pituitary lesion on imaging, and she was then lost to follow-up. Results of 1 mg DST and 24 h UFC measurements were not available from this time period. Other medical history was significant for mild depression. The patient was a non-smoker and did not drink alcohol.

At age 30 years, the patient experienced weight gain and facial rounding, prompting an endocrinology referral. While awaiting review, she spontaneously achieved conception and was confirmed to be 6 weeks’ gestation at time of the first visit. An early diagnosis of gestational diabetes mellitus was made, and she commenced insulin therapy. Gestational hypertension was also confirmed, treated with methyldopa 500 mg mane and 250 mg midi. Other medications included folic acid 5 mg daily, cholecalciferol, and ferrous sulphate.

The patient was referred to a tertiary hospital high-risk pregnancy service for ongoing care. She was initially reviewed at 8 + 5 weeks’ gestation and was noted to have plethora, round facies, and prominent dorsocervical fat pads. Central adiposity with violaceous striae over the lower abdomen was evident. Visual fields were normal to gross confrontation, and formal visual field assessment was confirmed to be normal. Weight was 70 kg, with BMI 26.7 kg/m2.

As pregnancy progressed, insulin and antihypertensive requirements increased, with an additional methyldopa 250 mg nocte required to keep blood pressure at target.

Investigation

The 24 h UFC was 450 nmol/24 h (1.5× ULN of non-pregnant reference range). Late-night salivary cortisol (LNSC) was 17 nmol/L (non-pregnant reference range <8 nmol/L). Serum pathology results are shown in Table 1. MRI brain performed at 6 weeks’ gestation revealed a possible 6 by 4 mm nodule in the left lateral aspect of the sella (Fig. 1). IV contrast was not used as the patient was within the first trimester.

Table 1Laboratory investigations at initial consultation (8 + 5 weeks gestation). Bold values indicate abnormal results.

Investigation Result Reference range
Fasting glucose, mmol/L 5.2
HbA1c, % 5.4
24 h urinary cortisol, nmol/d 450 54–319
Cortisol (08:22), nmol/L 521 138–650
Midnight salivary cortisol, nmol/L 17 <8
ACTH, pmol/L 10 <12.1
IGF-1, nmol/L 31 12–42
Growth hormone, mIU/L 2.9 0–15
TSH, mIU/L 2.34 0.4–3.2
FT4, pmol/L 11.9 11–17
Figure 1
Figure 1
MRI brain without IV contrast performed in the first trimester of the patient’s first pregnancy, demonstrating a T2 hypointense lesion in the left lateral aspect of the sella, which is most likely consistent with a pituitary adenoma.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 4; 10.1530/EDM-25-0092

At 14 weeks’ gestation, the repeat 24 h UFC was 542 nmol/L and LNSC was 17 nmol. There is a lack of pregnancy-specific reference ranges for 24 h UFC or LNSC measurements, making it difficult to make a definitive biochemical diagnosis. After careful discussion in a multidisciplinary team meeting, she proceeded with bilateral inferior petrosal sinus sampling (IPSS), which demonstrated a central to peripheral gradient with values presented in Table 2.

Table 2Results of bilateral inferior petrosal sinus sampling. ACTH (ng/L) at different timepoints are presented.

0 2 min 5 min 10 min 15 min
Right 258 823 1,040 864 728
Left 73 196 228 263 234
Peripheral 12 41 56 81 86
Right: peripheral 21.50 20.07 18.57 10.67 8.46
Left: peripheral 6.08 4.78 4.07 3.25 2.72

Treatment

The patient underwent transsphenoidal resection of her adenoma at 17+ weeks’ gestation. She recovered uneventfully.

Day 1 postoperative cortisol level remained elevated at 706 nmol/L, falling to 587 nmol/L by Day 3. Postoperative steroid treatment was not required.

Histopathological examination demonstrated a pituitary adenoma with mild nuclear atypia and infrequent positive ACTH staining (Fig. 2). In addition to the tumour and normal pituitary tissue, there was also abundant eosinophilic proteinaceous material present, which may have suggested contents of an associated cyst, although presence of cyst lining was not present to confirm this diagnosis. A small fragment of included bone appeared invaded by the adenoma within the resected tissue.

Figure 2
Figure 2
Positive ACTH staining in pituitary adenoma.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 4; 10.1530/EDM-25-0092

Outcome and follow-up

The patient’s insulin and antihypertensive requirements plateaued postoperatively. Serial ultrasound showed that the fetal size was consistently in the 15th percentile. There were no features of preeclampsia throughout gestation.

At 35 + 5 weeks’ gestation, she had premature rupture of membranes and delivered a healthy live male infant weighing 2,250 g via normal vaginal delivery. Diabetes and hypertension resolved promptly after delivery, with cessation of insulin and antihypertensive medications.

At 5 weeks postpartum morning cortisol was within normal range at 265 nmol/L, with ACTH 6.8 pmol/L. At 10 weeks postpartum, the 24 h UFC was within normal limits at 136 nmol/day, and a 1 mg DST showed a detectable, equivocal cortisol level of 98 nmol/L. Repeat MRI pituitary was performed 2 months postpartum, which did not show any residual pituitary adenoma. No pituitary hormone replacement was required.

By 6 months postpartum, repeat 1 mg DST showed failure to suppress cortisol, with cortisol level at 154 nmol/L (RR without dexamethasone: 138–650 nmol/L), suggesting residual CD. Ambulatory blood pressure monitoring revealed essential hypertension, with average BP 141/101 mmHg across 24 h, requiring treatment with methyldopa. Despite evidence of residual CD, the patient desired a second pregnancy. Reassuringly, her cortisol burden was low, with LNSC 5 nmol/L (RR: < 8) and 24 h UFC 143 nmol/day (non-pregnant RR: 54–319), both within reference range. No definite lesion was identified on MRI brain with intravenous contrast. Extensive discussions between the endocrinologist, maternal–foetal medicine specialist, neurosurgeon, and the patient were held. The pros and cons of pursuing further treatment such as radiotherapy versus proceeding with pregnancy despite suggestion of active Cushing’s disease were explicitly discussed.

The patient confirmed her second pregnancy 11 months after the birth of her first child, and this proceeded without complications. There was no evidence of gestational diabetes on 75 g glucose tolerance tests performed at 16 and 26 weeks’ gestation. Blood pressure was well managed on methyldopa alone. She delivered a healthy male infant via normal vaginal delivery at 38 weeks’ gestation and breastfed successfully. MRI was performed at 16 weeks postpartum and did not show an appreciable sella/suprasellar mass. Repeat 24 h UFC was 275 nmol/day, consistent with ongoing CD. Clinical features of CD returned, included central adiposity, liver function test derangement, and raised HbA1c with fasting hyperinsulinaemia. Pituitary radiation therapy was discussed, including the possibility of more than one dose being required, the strong likelihood of inducing panhypopituitarism, and the unknown duration of time between radiation and remission (1). The alternative option of medical management with osilodrostat was discussed, given its recent availability and government subsidy in Australia. The patient was recently commenced on osilodrostat 1 mg twice daily after ECG attendance to exclude prolonged QTc, and patient education regarding the potential risk of hypoadrenalism and when to seek medical attention.

Discussion

Managing Cushing’s disease (CD) in pregnancy is complex and requires a multidisciplinary approach, as recurrence can occur years after initial remission. Suspected Cushing’s syndrome (CS) requires careful assessment. In cases where active disease poses significant maternal and foetal risks, transsphenoidal pituitary surgery can be safely performed in the second trimester. CD increases the risk of gestational diabetes and hypertension, requiring close monitoring to optimise outcomes. Postpartum, persistent hypercortisolism may indicate recurrence, highlighting the need for long-term endocrine follow-up. Despite mild residual disease, successful pregnancies are possible with appropriate monitoring and management, emphasising the importance of thorough family planning discussions.

UFC values are twice as high in pregnant patients compared to non-pregnant controls (2). In the first trimester of normal pregnancy, UFC values are normal, but by the third trimester, they increase three-fold up to values seen in CS (3). Therefore, CS should only be suspected when UFC values in the second and third trimesters are greater than three times the upper limit of normal (3). LNSC is a useful screening test because in CS, the usual circadian nadir of cortisol secretion is lost. At least 2–3 UFC and/or NSC screening tests are recommended (4). Lopes et al. (5) established reference values for LNSC with suggested normal ranges of 0.8–6.9 nmol/L in the first trimester, 1.1–7.2 nmol/L in the second trimester, and 1.9–9.1 nmol/L in the third trimester (5). The use of a 1 mg DST in pregnancy is not recommended because the hypothalamus–pituitary–adrenal (HPA) axis response to exogenous glucocorticoids is blunted, making it difficult to interpret test results (3).

Adrenal adenomas are responsible for 40–50% of CS cases in pregnancy, while CD causes 33% (3). In non-pregnant patients, ACTH levels are useful to classify the likely cause of CS. Undetectable ACTH levels cannot be relied upon for diagnosis in pregnancy because ACTH levels are elevated in pregnancy (3). Using high-dose dexamethasone suppression testing (HDST) as an initial test in pregnant patients has been recommended (3). A lack of suppression of ACTH with administration of high-dose dexamethasone suggests adrenal aetiology. However, HDST is not always definitive (3). Ultrasound imaging of the adrenal glands is also recommended as an initial investigation because most adrenal lesions can be visualised (3, 5). Pregnancy complicates visualisation of a pituitary mass by MRI imaging because physiologic enlargement of the pituitary gland during pregnancy may mask small tumours (6). Non-contrast MRI has reduced sensitivity for detection of CD. However, gadolinium contrast is not recommended in pregnant women (7).

Inferior petrosal sinus sampling (IPSS) is the gold standard for diagnosing CD in the non-pregnant population (4). The most recent guidelines for diagnosis of CS suggest that IPSS is not necessary for diagnosis if MRI clearly shows a tumour >10 mm in the context of dynamic test results and clinical features that also strongly suggest CD (4). Lindsay and colleagues (3) caution the use of IPSS unless prior non-invasive testing remains equivocal due to risks of thromboembolism and exposure to radiation posed by IPSS (3). However, these risks can be mitigated with extra precautions during pregnancy, including use of lead barrier protection, a direct jugular approach, and with the procedure occurring at a specialised centre (3).

Treatment of CS in pregnancy should be individualised depending on the patient presentation and gestational age (4). Active treatment of CS, by either medical or surgical intervention, reduces maternal morbidity and rates of foetal loss (4). Surgery is usually preferred because there are fewer complications at delivery and it has high rates of remission (8). Surgery reduces rates of perinatal and maternal morbidity but does not reduce rates of preterm birth and intrauterine growth restriction (IUGR) (9). Pituitary or adrenal surgery should ideally be done in the second trimester, before week 24 of pregnancy, in a high-volume centre with multidisciplinary team input (8). There is a risk of spontaneous abortion with anaesthesia given in the first trimester and an increased risk of premature labour with anaesthesia given in the third trimester (7).

Unfortunately, CD can recur, and 50% of recurrence occurs within 50 months of pituitary surgery (1, 4). Recurrence is defined as ongoing clinical and biochemical evidence of hypercortisolism after an initial period of remission. Factors that increase the likelihood of postoperative remission included the identification of a tumour on MRI pre-surgery, no invasion of the sinus cavernous by the adenoma, older age (greater than 35 years), low postoperative cortisol and ACTH levels, and long-term hypocortisolism (greater than 1 year) (1). A second pituitary surgery is often the first-line treatment option in recurrence, which has overall lower rates of remission compared to first surgery and increased risk of hypopituitarism due to scar tissue in the pituitary and often the need for more aggressive surgical technique (1). Both fractionated radiotherapy and stereotactic radiosurgery are therapeutic options and achieve high rates of remission (1).

There are no medications that are approved for treatment of CD in pregnancy, although the latest guidelines suggest consideration of metyrapone, ketoconazole, or cabergoline (4, 6). The newer agent, osilodrostat inhibits the enzymes 11-beta-hydroxylase and 18-hydroxylase, reducing production of cortisol and aldosterone respectively, thereby normalising UFC values, reducing systolic and diastolic blood pressure, fasting blood glucose levels, and improving body weight in clinical trials (10). There is no information on osilodrostat use and safety in pregnancy, but it is an effective agent in patients who are unsuitable for surgery and patients with recurrent disease after surgery (10). It is associated with risk of hypoadrenalism, prolongation of the QTc interval, and increased serum testosterone levels, particularly at higher doses (10). Each medication poses its own risk of side effects and therefore treatment must be individualised. Overall, medical treatment should only be used in pregnancy when surgical treatment is contraindicated (6).

Our case demonstrates a rare case of CD in pregnancy with no significant adverse perinatal outcomes for mother or baby, albeit late preterm delivery in the first pregnancy. Ongoing endocrinology surveillance is essential to monitor for recurrent CD.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details was obtained from the patient.

Author contribution statement

Several case details and timeline of events were gathered by EW. This is a patient of SG.

References

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

Approach to the Patient with Cushing’s Syndrome: Use of Anticoagulation Therapy

Posted on December 19, 2025 by MaryO

Abstract

There is an increased awareness on the higher hypecoagulability risks in patients with Cushing’s syndrome (CS) but management remains controversial. Here, we present four illustrative cases of CS that exemplify some “grey areas” on venous thromboembolism (VTE) prevention—when to start, how long to continue, what to use, and when to stop.

The cases span: initiation of prophylaxis at diagnosis of active CS; periprocedural management around inferior petrosal sinus sampling; peri-operative prophylaxis after transsphenoidal surgery (TSS); and discontinuation decisions in medically controlled disease. We synthesise current evidence and expert practice and recommend considering low-molecular-weight heparin at diagnosis of active CS, continuing through surgery, and extending for approximately three months after biochemical remission in selected patients to address the highest-events risk window.

Based on recent data, we discourage routine use of graduated compression stockings for VTE prevention. Though bleeding complications appear uncommon, they need to be carefully considered on an individualized basis. Finally, scenarios where prophylaxis can be safely discontinued once eucortisolaemia is achieved are outlined. This case-anchored framework translates heterogeneous data into actionable guidance and highlights priorities for prospective evaluation.

The Journal of Clinical Endocrinology & Metabolism, dgaf671, https://doi.org/10.1210/clinem/dgaf671

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

Is Cushing’s really that rare? Or is it simply undiagnosed?

Posted on December 18, 2025 by MaryO

Here are some thoughts from the Cushing’s Help message boards over the years.

  • Is this really such a rare disease, or more of a rare diagnosis? I mean, I remember when Thyroid issues were taboo and non-existant to regular docs, but now they all see to know something and are recognizing the issues…Seriously, if only 10-15 in every million have Cushings, how on earth did a well visited forum get created???
  • My personal opinion is a rare diagnosis….I see people with acne covered red moon faces, frontal obesity and a hump and just shake my head. If I can talk to them I will mention it but I am super sensitive about my weight and don’t want to insult anyone.
  • I believe it is both. The disease itself is rare, but more and more people are coming forward. I don’t think it is as rare as they think it is in research. It is also rare to find an educated physician for this disease. They are out there, but why aren’t there more? This makes for rare diagnosis. It is not like I can walk down the street and see tons of people with cushings symptoms, but now that I am aware of it I DO see some.
  • i believe until it is not so underdiagnosed we will never know if it is actually rare.
  • I don’t think it’s as rare as doctors think it is. I think the problem is they send people out based on individual symptoms versus looking at them all as a package. For example I got sent to: a psychiatrist for depression, a gastroenterologist for stomach stuff (diarrhea and constipation), an endocrinologist for the hormone/insulin issues, a neurologist for the headaches, an OB/GYN for the “missed periods” and an opthamologist for the vision issues. None of them talk to each other and none of them work together. How could they make a diagnosis of anything other than their specialty based on that? I think until docs take a team approach, it won’t be diagnosed more.
  • We all tend to think it is rarely diagnosed, more than it being a rare disease. Then, you get into the whole idea of, what causes it anyway?

    Who knows? Nobody knows for sure, but say it is from our environmental issues. Maybe it’s from chemicals we are exposed to, and this is how our bodies react. Then if it is environmental, you will start to see more and more people with it because more and more people are exposed to the same environmental issues. Maybe the same thing causes cancer in some people, and pituitary tumors in others. I’m not saying this is the case, I’m just throwing ideas out there. You didn’t hear of Chronic Fatigue and Fibromyalgia 30 yrs. ago either. Maybe in another 30 yrs., Cushing’s will be a disease that most people know about. That would mean more people getting diagnosed, and it would seem that Cushing’s would be on the rise, but awareness is probably the key.

  • What do YOU think?

Filed under: Cushing's, Rare Diseases | Tagged: , , , , , | 1 Comment »

Medic Alert Bracelets

Posted on December 16, 2025 by MaryO

Since the last topic was about Adrenal Insufficiency, it seemed that a great next topic would be about Medic Alert Bracelets.

Many doctors insist that everyone who has had pituitary or adrenal surgery have a bracelet – and some will even tell patients what they should say on them.

While I was still a patient at the NIH (National Institutes of Health) after my pituitary surgery, I was given my first bracelet along with my kit in care of adrenal crisis.  I had to learn to give myself a shot before I could go home.

Now, my endo checks mine at every visit to be sure I’m wearing my bracelet and reads it to be sure it’s still legible and checks to see what the text says.

He feels that the bracelets – and he insists that they LOOK like medic alert bracelets, not disguised as jewelry – are life savers.

I’m not so sure – I read stories on the message boards that people have gone into AI (adrenal insufficiency and no one has ever looked at their bracelet.  That was certainly the case for young Sam.  Her mom had instructions everywhere, none were heeded and the situation rapidly turned disastrous.

…We have dealt with Addison’s for 7 years; but I have handled everything. Apparently the vials of solu-cortef with step-by-step instructions hanging on the bulletin board in the kitchen, medicine cabinet and in every vehicle somehow missed his attention…  (read the whole story at survive the journey: Stars Go Blue)

A Paramedic wrote on the message boards:

I’d like to add a couple things from the perspective of a Paramedic…

A lot of us are not taught about adrenal insufficiency during our education….nor do many of us (if any at all) have a protocol to administer Injectable for AI unless we are able to contact the ER doctor for permission. So…if any of you should have an AI crisis please gently nudge your paramedic to contact the receiving physician for permission to administer the medication. I know this sounds like a lot of responsibility on the part of the patient…but you have to realize that we’re taught to recognize the most common life threats and endocrine disorders (other than diabetes) most usually do not present with life threats (we all know that as cushing’s is more recognized that this will change)…and our protocols cover the most common life threats….so while we may recognize that you are hypotensive and need fluids (IV) and are sweaty, nauseated, decreased level of responsiveness etc…we are not equipped to deal with the actual cause unless you help educate us….

Also…please don’t get angry with us….if we are having problems understanding…just gently insist that a call be made to your doctor or the receiving ED (usually not feasible for us to call your doctor since they do not come to the phone for just anybody but if you have access to them, as many cushies do, it would be great to talk to them)…

Paramedicine is evolving….someday soon, hopefully, our education will include more diagnostic skills…untill just in the past 5 years or so we were NEVER to make a diagnosis at all…just treat the symptoms!!!! So there is hope out there for futher understanding of such a critical problem for those without adrenal (or asleep adrenals) glands….

The medical alert jewerly is a life-saver and we do look for it….

So, the questions for discussion are:

  • Do you have a medical alert bracelet
  • Does your doctor check on it or suggest proper wording.
  • If you have one, has any medical staff read it during a crisis
  • And… what does yours say?

Filed under: adrenal crisis, Cushing's, pituitary | Tagged: , , , , | 15 Comments »

A Case of Adrenocorticotropin-dependent Cushing Syndrome with Osilodrostat Exposure in Early Pregnancy

Posted on December 13, 2025 by MaryO

Abstract

Osilodrostat is a novel treatment for adrenocorticotropin-dependent Cushing syndrome; however, its safety during pregnancy has not been reported. This case involves a patient with Cushing disease who became pregnant while on osilodrostat. She was diagnosed at 31 years of age and underwent pituitary tumor removal. After a relapse at 35 years of age, she was initially treated with metyrapone but switched to osilodrostat and hydrocortisone because of nausea, achieving reasonable cortisol control. At 37 years of age, she unknowingly became pregnant despite irregular periods, and the pregnancy was detected at 16 weeks because of ongoing nausea. Osilodrostat was stopped, and she was started on pasireotide and metyrapone. The pregnancy proceeded normally despite elevated urinary free cortisol levels, although she contracted COVID-19 at 25 weeks. At 26 weeks and 1 day, preterm rupture of membranes and breech presentation led to an emergency cesarean section. The newborn had no adrenal insufficiency and developed normally. This case prompts consideration of whether osilodrostat can be used during pregnancy if risks are justified. Pasireotide is rarely used in pregnancy and may have limited effectiveness, but when given, can cause hyperglycemia because of insulin and incretin suppression and should be monitored carefully.

Introduction

Active Cushing syndrome decreases fertility, which explains its rarity in pregnancy. Fewer than 250 cases have been documented [1]. Whether it is ACTH-dependent or ACTH-independent, this disease poses significant risks to both mother and fetus. Its maternal complications include hypertension, preeclampsia, and diabetes [2], whereas the fetal risks include miscarriage, intrauterine growth restriction, and prematurity [3]. Given its rarity, there is no established standard of care for Cushing disease during pregnancy. Surgery offers a potential cure, but it can cause hypopituitarism and may not be feasible in the absence of a visible tumor [4]. Meanwhile, there are also risks associated with radiotherapy and pharmacological treatments [1, 4]. The use of pasireotide, a somatostatin analog, for the treatment of a GH-secreting pituitary macroadenoma without complications has been reported in only 1 case during pregnancy [5]. To the best of our knowledge, this drug has not been used for Cushing disease before. Osilodrostat, like metyrapone, is a newer steroidogenesis inhibitor that blocks 11β-hydroxylase in the adrenal glands. It is effective for both ACTH-dependent and ACTH-independent Cushing syndrome [6]. However, it is contraindicated in pregnancy because of its proven teratogenic effects in animal studies [7]. As a result, data on its use in human pregnancy are lacking. Understanding the normal physiology of the hypothalamic-pituitary-adrenal (HPA) axis in pregnancy is essential. In normal pregnancy, the maternal levels of corticotropin-releasing hormone, ACTH, and cortisol rise both in the serum and urine because of placental production [8, 9]. Although cortisol levels rise, only about 10% crosses the placenta because of 11β-hydroxysteroid dehydrogenase activity [10]. Fetal cortisol production remains minimal until late gestation, as 3β-hydroxysteroid dehydrogenase activity stays low until then [10]. Thus, most fetal cortisol originates from maternal sources [11]. In late pregnancy, fetal adrenal 3β-hydroxysteroid dehydrogenase activity increases, thereby enhancing fetal cortisol synthesis and promoting maturation of the HPA axis [10]. This case report discusses a female patient with recurrent Cushing disease who conceived while taking osilodrostat, which she took until early pregnancy; she was later treated successfully with pasireotide and metyrapone.

Case Presentation

A 30-year-old woman developed moon facies, central obesity, muscle weakness, and amenorrhea. Elevated levels of ACTH and cortisol, along with a roughly 6-mm pituitary adenoma, confirmed a diagnosis of Cushing disease. At 31 years of age, she successfully underwent transsphenoidal surgery, but 4 years later, biochemical relapse occurred with no identifiable residual tumor on imaging (Fig. 1). The patient was initially treated with metyrapone, but because of nausea, this was switched to osilodrostat. A block-and-replace approach was taken with osilodrostat 3 mg/day and hydrocortisone 10 mg/day, after which her cortisol levels normalized, but the menstrual irregularities persisted (Fig. 1).

 

Changes in urinary free cortisol (UFC) and pituitary magnetic resonance imaging (MRI) findings over time. The MRI scans at diagnosis, after surgery, at recurrence, and before pregnancy are shown alongside ACTH, cortisol, and UFC levels. The blood tests indicated recurrence, but no tumor was seen on MRI. Cortisol levels improved after osilodrostat treatment.

Figure 1.

Changes in urinary free cortisol (UFC) and pituitary magnetic resonance imaging (MRI) findings over time. The MRI scans at diagnosis, after surgery, at recurrence, and before pregnancy are shown alongside ACTH, cortisol, and UFC levels. The blood tests indicated recurrence, but no tumor was seen on MRI. Cortisol levels improved after osilodrostat treatment.

Diagnostic Assessment

At 38 years of age, the patient presented with nausea. The patient was followed up with an upper gastrointestinal endoscopy revealing no abnormalities. After a prolonged period of nausea, a pregnancy test revealed that she was 16 weeks pregnant.

Treatment

At this point, she had been on osilodrostat, which was immediately stopped and replaced with pasireotide 10 mg every 4 weeks because of pregnancy. Later, 24-hour urinary free cortisol (UFC) levels increased, leading to an early increase in pasireotide dose to 20 mg after 3 weeks before the recommended 4-week period elapsed; the same dose was administered every 4 weeks thereafter. And the same time, the initiation of up to 1000 mg metyrapone daily (Fig. 2). The patient also had hyperglycemia, which prompted insulin initiation, and subcutaneous heparin was also added because of the risk of thrombosis. At 25 weeks of pregnancy, she developed pharyngeal pain and a cough, which quickly resolved. At 26 weeks and 1 day, she experienced preterm premature rupture of membranes with the fetus in breech position, necessitating an emergency cesarean section. During this time, she tested positive for severe acute respiratory syndrome coronavirus 2 via polymerase chain reaction; however, she remained asymptomatic. Hydrocortisone was given before delivery as a steroid cover. Postpartum, osilodrostat was resumed, and pasireotide/metyrapone was discontinued. Two months after delivery, her disease remained stable, with UFC at 62.0 μg/day (171 nmol/day), within the normal reference range of 26.0 to 187.0 μg/day (72-516 nmol/day).

 

Urinary free cortisol (UFC) levels and medications during pregnancy. The UFC levels during pregnancy are shown. The UFC levels increased after stopping osilodrostat, and these remained high even after starting pasireotide. Adding metyrapone led to a decrease in the UFC.

Figure 2.

Urinary free cortisol (UFC) levels and medications during pregnancy. The UFC levels during pregnancy are shown. The UFC levels increased after stopping osilodrostat, and these remained high even after starting pasireotide. Adding metyrapone led to a decrease in the UFC.

Outcome and Follow-up

A live baby girl was born with extremely low birth weight, weighing 871 g. She was admitted to the neonatal intensive care unit with Apgar scores of 2 and 10 at 1 and 5 minutes, respectively, and was temporarily placed on a ventilator because of respiratory distress syndrome. During her stay, no signs of adrenal insufficiency appeared, and blood samples taken at noon showed ACTH levels of 23.3 pg/mL (5.1 pmol/L) and cortisol levels of 2.7 µg/dL (74.5 nmol/L). The normal reference ranges in adults are 7.2 to 63.3 pg/mL (1.6-13.9 pmol/L) for ACTH and 4.5 to 21.1 µg/dL (124.2-582.1 pmol/L) for cortisol. She was discharged at 40 weeks’ corrected gestational age, with subsequent normal growth and development.

Discussion

It remains challenging to manage Cushing disease during pregnancy because of limited treatment options and fetal safety concerns. An important aspect of managing hypercortisolemia in pregnancy is understanding the physiological regulation of the maternal-fetal HPA axis. In infants with very low birth weight, cortisol levels measured within an hour after birth typically range from 3.6 to 10.8 µg/dL (99-298 nmol/L) [12]. Although the neonate in this case had lower cortisol levels (2.7 µg/dL, 74.5 nmol/L), the blood sample was taken around noon, a time when levels are usually lower. Nevertheless, no signs of adrenal insufficiency were observed. Because newborns develop a stable cortisol rhythm within the first month [13], these findings suggest adequate adrenal function. Better obstetric outcomes can be expected when maternal hypercortisolism is successfully managed, such as reduced rates of prematurity and low birth weight [14]. A previous case report noted successful delivery after treatment with metyrapone, targeting UFC levels below 150 µg/day (414 nmol/day) [15]. Metyrapone was necessary in this patient because the cortisol levels were rising despite pasireotide monotherapy. This was gradually titrated to control UFC levels, which achieved some success. We introduced pasireotide during pregnancy based on previous reports of its use in acromegaly without adverse fetal outcomes [5]. However, pasireotide carries significant risk of hyperglycemia because of its inhibitory effects on insulin and incretin secretion [16]; this was seen in our patient, who required insulin therapy. Although rarely used in pregnancy—with only 1 reported case to our knowledge—it may be considered a viable option if other treatments are unsuccessful or unsuitable. Osilodrostat is contraindicated during pregnancy because it has shown teratogenic effects in animal studies, leading to limited human data [6]. In this case, the patient was unknowingly exposed during early pregnancy. However, no fetal malformations were observed, and this could be attributed to the underdeveloped fetal adrenal cortex during early gestation, which mainly relies on maternal hormone supply [10]. Osilodrostat was resumed after delivery, achieving effective disease control and clinical stability. It is also essential to consider that the preterm birth in this case may have resulted from suboptimal cortisol control, maternal COVID-19 infection, and the use of osilodrostat and pasireotide—drugs with minimal clinical data for use during pregnancy. These factors cannot be excluded entirely. However, based on our expertise, the contraindication of osilodrostat in pregnancy may warrant reevaluation.

Learning Points

  • Osilodrostat should not be used during pregnancy. Although preterm birth in this case may have resulted from various factors—including limited clinical data on osilodrostat and pasireotide—that the neonate showed no congenital abnormalities or adrenal problems indicates that the current caution against using osilodrostat in pregnancy might need to be reconsidered.
  • In early pregnancy, the fetal adrenal glands are immature and dependent on maternal hormones, so the effects of drugs that inhibit adrenal steroid synthesis may be relatively minor.
  • Pasireotide is rarely used during pregnancy. If administered, close monitoring is necessary, as insulin and incretin suppression may induce hyperglycemia.

From https://academic.oup.com/jcemcr/article/3/12/luaf269/8327956?login=false

 

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