Late-night salivary cortisol often fluctuates widely in Cushing’s disease

Posted on January 18, 2026 by MaryO

Among patients with new, persistent or recurrent Cushing’s disease, researchers observed cortisol levels that fluctuated widely over 6 months, with measurements falling into the normal range more than 50% of the time for a few patients, according to findings from a prospective study.

“Cortisol levels, as represented by late-night salivary cortisol, in Cushing’s disease patients without variable symptoms fluctuate much more widely than many endocrinologists may realize,” Laurence Kennedy, MD, FRCP, chairman of the department of endocrinology, diabetes and metabolism at the Cleveland Clinic, told Endocrine Today. “In patients with recurrent or persistent Cushing’s disease, the late-night salivary cortisol can be normal much more frequently than has been appreciated.”

Kennedy and colleagues analyzed late-night salivary samples (between 11 p.m. and midnight) from 16 patients with confirmed Cushing’s disease for up to 42 consecutive nights between January and June 2014 (age range, 27-62 years). Researchers defined normal late-night salivary cortisol as between 29 ng/dL and 101 ng/dL.

Within the cohort, eight patients had a new diagnosis of Cushing’s disease and underwent transsphenoidal surgery; eight patients had recurrent or persistent Cushing’s disease.

Researchers observed at least three peaks and two troughs in 12 of the 16 patients, and late-night salivary cortisol levels were in the normal range on at least one occasion in 14 patients (all patients with recurrent/persistent disease and six of eight patients with new disease). Only two of the 16 patients exhibited fluctuations that were deemed cyclical, according to researchers, with the interval between peaks approximately 4 days, they noted.

In five of the eight patients with recurrent or persistent disease, the lowest late-night salivary cortisol measurement was at or below the limit of detection on the assay and approximately 1 in 3 measurements were in the normal range, researchers found. Four patients had normal measurements more than 50% of the time.

Additionally, six of the patients with recurrent or persistent disease had measurements in the normal range on two consecutive nights on at least one occasion, two patients had six such measurements in a row, and one had 31 consecutive normal levels, according to researchers.

In six patients with newly diagnosed Cushing’s disease with at least one normal late-night salivary cortisol measurement, the maximum levels ranged from 1.55 to 15.5 times the upper limit of normal.

“First, widely fluctuant cortisol levels in patients with Cushing disease do not appear to be associated with fluctuating symptoms, at least in our patient population,” Kennedy said. “Second, you need to be careful drawing conclusions on the efficacy of potential medical treatments for Cushing’s disease based on only one or two late-night salivary cortisol levels, given the extreme variation that occurs in the untreated patient. Third, diagnosing recurrent or persistent Cushing’s disease can be challenging at the best of times, and, though it is felt that late-night salivary cortisol may be the best test for early diagnosis, it may require more than the suggested two, three or four tests on successive nights to make the diagnosis.”

Kennedy said better tests for diagnosing Cushing’s disease are needed, adding that investigating the potential utility of salivary cortisone could be useful. – by Regina Schaffer

For more information:

Lawrence Kennedy, MD, can be reached at Cleveland Clinic, Department of Endocrinology, Diabetes and Metabolism, 9500 Euclid Ave., Cleveland, OH 44195; email: kennedl4@ccf.org.

Disclosures: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7Bf9721377-6a2a-401c-a16d-2d4624233b63%7D/late-night-salivary-cortisol-often-fluctuates-widely-in-cushings-disease

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

Skeletal Maturation in Children With Cushing’s Syndrome is Not Consistently Delayed

Posted on January 13, 2026 by MaryO

Skeletal maturation in children with cushing syndrome is not consistently delayed: The role of corticotropin, obesity, and steroid hormones, and the effect of surgical cure.

J Pediatr. 2014 Jan 9. pii: S0022-3476(13)01500-X. doi: 10.1016/j.jpeds.2013.11.065. [Epub ahead of print]

The Journal of Pediatrics, 01/22/2014 Clinical Article

Lodish MB, et al. – The aim of this study is to assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1–year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements. Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.

Methods

  • This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone–independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years).
  • BA was obtained before surgery and at follow-up.
  • Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA.

Results

  • Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA.
  • The majority of children (76%) had normal BA.
  • The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P = .8865).
  • Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA.
  • Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001).

From http://www.ncbi.nlm.nih.gov/pubmed/24412141

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Long-Term Obesity Persists Despite Pituitary Adenoma Treatment In Childhood

Posted on January 9, 2026 by MaryO

Sethi A, et al. Clin Endocrinol. 2019;doi:10.1111/CEN.14146.

January 5, 2020

Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment, according to findings published in Clinical Endocrinology.

“The importance of childhood and adolescent obesity on noncommunicable disease in adult life is well recognized, and in this new cohort of patients, we report that obesity is common at presentation of pituitary adenoma in childhood and that successful treatment is not necessarily associated with weight loss,” Aashish Sethi, MD, MBBS, a pediatric endocrinologist in the department of endocrinology at Alder Hey Children’s Hospital in Liverpool, United Kingdom, and colleagues wrote. “We have reported obesity, and obesity-related morbidity in a mixed cohort of children and young adults previously, but [to] our knowledge, this is the first time this observation has been reported in a purely pediatric cohort.”

In a retrospective study, Sethi and colleagues analyzed clinical and radiological data from 24 white children from Alder Hey Children’s Hospital followed for a median of 3.3 years between 2000 and 2019 (17 girls; mean age at diagnosis, 15 years). Researchers assessed treatment modality (medical, surgical or radiation therapy), pituitary hormone deficiencies and BMI, as well as results of any genetic testing.

Within the cohort, 13 girls had prolactinomas (mean age, 15 years), including 10 macroadenomas between 11 mm and 35 mm in size. Children presented with menstrual disorders (91%), headache (46%), galactorrhea (46%) and obesity (38%). Nine children were treated with cabergoline alone, three also required surgery, and two were treated with the dopamine agonist cabergoline, surgery and radiotherapy.

Five children had Cushing’s disease (mean age, 14 years; two girls), including one macroadenoma. Those with Cushing’s disease presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure; however, two patients experienced relapse 3 and 6 years after surgery, respectively, requiring radiotherapy. One patient also required bilateral adrenalectomy.

Six children had a nonfunctioning pituitary adenoma (mean age, 16 years; two girls), including two macroadenomas. These children presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections, with two experiencing disease recurrence after surgery and requiring radiotherapy.

During the most recent follow-up exam, 13 children (54.1%) had obesity, including 11 who had obesity at diagnosis.

“The persistence of obesity following successful treatment, in patients with normal pituitary function, suggests that mechanisms other than pituitary hormone excess or deficiency may be important,” the researchers wrote. “It further signifies that obesity should be a part of active management in cases of pituitary adenoma from diagnosis.” – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/online/%7Bde3fd83b-e8e0-4bea-a6c2-99eb896356ab%7D/long-term-obesity-persists-despite-pituitary-adenoma-treatment-in-childhood

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On Becoming Empowered

Posted on January 1, 2026 by MaryO

This is kind of a “cheat” post since it’s a compilation of other posts, web pages, message board posts and some original thoughts.  

For all of my early life, I was the good, compliant, patient.  I took whatever pills the doctor prescribed, did whatever tests h/she (most always a he) wrote for.  Believed that whatever he said was the absolute truth.  He had been to med school.  He knew what was wrong with me even though he didn’t live in my body 24/7 and experience what I did.

I know a lot of people are still like this.  Their doctor is like a god to them.  He can do no wrong – even if they don’t feel any better after treatment, even if they feel worse.  “But the doctor said…”

Anyway, I digress.

All this changed for me in 1983.

At first I noticed I’d stopped having my periods and, of course, I thought I was pregnant. I went to my Gynecologist who had no explanation. Lots of women lose their periods for a variety of reasons so no one thought that this was really significant.

Then I got really tired, overly tired. I would take my son to a half hour Choir rehearsal and could not stay awake for the whole time. I would lie down in the back of the van, set an alarm and sleep for the 30 minutes.

A whole raft of other symptoms started appearing – I grew a beard (Hirsuitism), gained weight even though I was on Weight Watchers and working out at the gym nearly every day, lost my period, everything hurt, got what is called a “moon face” and a “buffalo hump” on the back of my neck. I also got stretch marks. I was very depressed but it’s hard to say if that was because of the hormone imbalance or because I felt so bad and no one would listen to me.

I came across a little article in the Ladies Home Journal magazine which said “If you have these symptoms…ask your doctor about Cushing’s”. After that, I started reading everything I could on Cushing’s and asking my doctors. Due to all my reading at the library and medical books I bought, I was sure I had Cushing’s but no one would believe me. Doctors would say that Cushing’s Disease is too rare, that I was making this up and that I couldn’t have it.

I asked doctors for three years – PCP, gynecologist, neurologist, podiatrist – all said the now-famous refrain.  It’s too rare.  You couldn’t have Cushing’s.  I kept persisting in my reading, making copies of library texts even when I didn’t understand them, keeping notes.  I just knew that someone, somewhere would “discover” that I had Cushing’s.

My husband was on the doctors’ sides.  He was sure it was all in my mind (as opposed to all in my head!) and he told me to just think “happy thoughts” and it would all go away.

A Neurologist gave me Xanax. Since he couldn’t see my tumor with his Magnetic Resonance Imaging (MRI) machine there was “no possibility” that it existed. Boy was he wrong!

Later in 1986 I started bruising incredibly easily. I could touch my skin and get a bruise. On New Year’s Day of 1987 I started bleeding under the skin. My husband made circles around the outside perimeter each hour with a marker, like the rings of a tree. When I went to my Internist the next day he was shocked at the size. He now thought I had a blood disorder so he sent me to a Hematologist/Oncologist.

Fortunately, the Hematologist/Oncologist ran a twenty-four hour urine test and really looked at me. Both he and his partner recognized that I had Cushing’s. Of course, he was sure that he did the diagnosis.  No matter that I had been pursuing this with other doctors for 3 years.

It was not yet determined if it was Cushing’s Disease (Pituitary) or Syndrome (Adrenal). However, he couldn’t help me any further so the Hematologist referred me to an Endocrinologist.

The Endocrinologist, of course, didn’t trust the other tests I had had done so I was back to square one. He ran his own multitude of tests. He had to draw blood at certain times like 9 AM. and 5 PM. There was a dexamethasone suppression test where I took a pill at 10 p.m. and gave blood at 9 am the next day. I collected gallons of urine in BIG boxes (Fun in the fridge!). Those were from 6 a.m. to 6 a.m. to be delivered to his office by 9 a.m. same day. I was always worried that I’d be stopped in rush hour and the police would ask about what was in that big container. I think I did those for a week. He also did standard neurological tests and asked lots of questions.

When the endo confirmed that I had Cushing’s in 1987 he sent me to a local hospital where they repeated all those same tests for another week and decided that it was not my adrenal gland (Cushing’s Syndrome) creating the problem. The doctors and nurses had no idea what to do with me, so they put me on the brain cancer ward.

When I left this hospital after a week, we didn’t know any more than we had before.

As luck would have it, NIH (National Institutes of Health, Bethesda, Maryland) was doing a clinical trial of Cushing’s. I live in the same area as NIH so it was not too inconvenient but very scary at first to think of being tested there. At that time I only had a choice of NIH, Mayo Clinic and a place in Quebec to do this then-rare pituitary surgery called a Transsphenoidal Resection. I chose NIH – closest and free. After I was interviewed by the Doctors there, I got a letter that I had been accepted into the clinical trial. The first time I was there was for 6 weeks as an inpatient. More of the same tests.

There were about 12 of us there and it was nice not to be alone with this mystery disease. Many of these Cushies (mostly women) were getting bald, couldn’t walk, having strokes, had diabetes. One was blind, one had a heart attack while I was there. Towards the end of my testing period, I was looking forward to the surgery just to get this whole mess over with. While I was at NIH, I was gaining about a pound a day!

The MRI still showed nothing, so they did a Petrosal Sinus Sampling Test. That scared me more than the prospect of surgery. (This test carries the risk of stroke and uncontrollable bleeding from the incision points.) Catheters were fed from my groin area to my pituitary gland and dye was injected. I could watch the whole procedure on monitors. I could not move during this test or for several hours afterwards to prevent uncontrolable bleeding from a major artery. The test did show where the tumor probably was located. Also done were more sophisticated dexamethasone suppression tests where drugs were administered by IV and blood was drawn every hour (they put a heplock in my arm so they don’t have to keep sticking me). I got to go home for a weekend and then went back for the surgery – the Transsphenoidal Resection. I fully expected to die during surgery (and didn’t care if I did) so I signed my will and wrote last letters to those I wanted to say goodbye to. During the time I was home just before surgery, a college classmate of mine (I didn’t know her) did die at NIH of a Cushing’s-related problem. I’m so glad I didn’t find out until a couple months later!

November 3, 1987, the surgeon, Dr. Ed Oldfield, cut the gum above my front teeth under my upper lip so there is no scar. He used tiny tools and microscopes. My tumor was removed successfully. In some cases (not mine) the surgeon uses a plug of fat from the abdomen to help seal the cut. Afterwards, I was in intensive care overnight and went to a neurology ward for a few days until I could walk without being dizzy. I had some major headaches for a day or two but they gave me drugs (morphine) for those. Also, I had cotton plugs in my nostrils. It was a big day when they came out. I had diabetes insipidus (DI) for a little while, but that went away by itself – thank goodness!

I had to use a foam product called “Toothies” to brush my teeth without hitting the incision. Before they let me go home, I had to learn to give myself an injection in my thigh. They sent me home with a supply of injectible cortisone in case my level ever fell too low (it didn’t). I was weaned gradually off cortisone pills (scary). I now take no medications. I had to get a Medic Alert bracelet. I will always need to tell medical staff when I have any kind of procedure – the effects of my excess cortisone will remain forever.

I went back to the NIH for several follow-up visits of a week each where they did all the blood and urine testing again. After a few years NIH set me free. Now I go to my “outside” endocrinologist every year for the dexamethasone suppression test, 24-hour urine and regular blood testing.

As I get further away from my surgery, I have less and less chance that my tumor will grow back. I have never lost all the weight I gained and I still have the hair on my chin but most of my other symptoms are gone. I am still and always tired and need a nap most days. I do not, however, still need to take whole days off just to sleep.

I consider myself very lucky that I was treated before I got as bad as some of the others on my floor at NIH but think it is crazy that these symptoms are not taken seriously by doctors.

My story goes on and if you’re interested some is on this blog and some is here:

Forbes Magazine | MaryO’s bio | Cushing’s and Cancer Blog | Cushing’s Awareness Day Testimonial Archive |

Because of this experience in getting a Cushing’s diagnosis – and later, a prescription for growth hormone – I was concerned that there were probably other people not being diagnosed with Cushing’s. When I searched online for Cushing’s, all the sites that came up were for dogs and horses with Cushing’s.  Not what I was looking for!

In July of 2000, I was talking with my dear friend Alice, who ran a wonderful menopause site, Power Surge, wondering why there weren’t many support groups online (OR off!) for Cushing’s.  This thought percolated through my mind for a few hours and I realized that maybe this was my calling.  Maybe I should be the one to start a network of support for other “Cushies” to help them empower themselves.

I wanted to educate others about the awful disease that took doctors years of my life to diagnose and treat – even after I gave them the information to diagnose me.  I didn’t want anyone else to suffer for years like I did.  I wanted doctors to pay more attention to Cushing’s disease.

The first website (http://www.cushings-help.com) went “live” July 21, 2000.  It was just a single page of information. The message boards began September 30, 2000 with a simple message board which then led to a larger one, and a larger.  Today, in 2010, we have over 7 thousand members.  Some “rare disease”!

The message boards are stillactive and we have weekly online text chats, weekly live interviews, local meetings, conferences, email newsletters, a clothing exchange, a Cushing’s Awareness Day Forum, podcasts, phone support and much more. Because I wanted to spread the word to others not on “the boards” we have extended out to social networking sites – twitter groups, facebook groups, twines, friendfeeds, newsletters, websites, chat groups, multiply.com, and much, much more.

People are becoming more empowered and participating in their own diagnoses, testing and treatment.  This have changed a lot since 1983!

When I had my Cushing’s over 40 years ago (AARRGGHH!), I never thought that I would meet another Cushing’s patient in real life or online. Back then, I’d never even been aware that there was anything like an “online”. I’m so glad that people struggling with Cushing’s today don’t have to suffer anymore thinking that they’re the only one who deals with this.

Because of my work on the websites – and, believe me it is a ton of work! – I have had the honor of meeting over a hundred other Cushies personally at local meetings, conferences, at NIH (the National Institutes of Health in Bethesda, MD where I had my final diagnosis and surgery). It occurred to me once that this is probably more than most endocrinologists will ever see in their entire career. I’ve also talked to countless others on the phone. Amazing for a “rare” disease!

I don’t know what pushed me in 1983, how I got the confidence and self-empowerment to challenge these doctors and their non-diagnoses over the years.  I’m glad that I didn’t suffer any longer than I did and I’m glad that I have a role in helping others to find the medical help that they need.

What do *YOU* think?  How are you becoming empowered?

Filed under: Clinical trials, Cushing's, General Health, Health Care, pituitary | Tagged: , , , , , , , , , , , , , , , , , , , | 1 Comment »

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

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