Pregnancy Could Be Linked to Onset of Cushing’s Symptoms

More than 25 percent of women with Cushing’s disease experienced their first symptoms within one year of giving birth, a small study by the Pacific Neuroscience Institute found.

The findings suggest a possible causal relationship between the biological stress of pregnancy and Cushing’s disease (CD), with more than a two-fold risk of women developing the disease within one year of pregnancy.

The study, “Pregnancy-associated Cushing’s disease? An exploratory retrospective study,” was published in the journal Pituitary.

Eighty percent of Cushing’s disease cases are women, and most are of reproductive age.

Levels of the body’s main stress hormone, cortisol, normally increase during pregnancy. In the last weeks before birth, cortisol levels are two to three times higher than normal, similar to Cushing’s disease.

Because cortisol levels gradually increase during pregnancy, a diagnosis of Cushing’s disease within the gestation period is problematic.

Circumstantial “evidence suggests a higher incidence of CD immediately following pregnancy, in the peripartum period [a few weeks after childbirth],” the study’s authors wrote.

To shed additional light on the matter, researchers retrospectively investigated the frequency of Cushing’s disease onset related to pregnancy.

A total of 64 women with biochemically-diagnosed Cushing’s disease and treated at Providence Saint John’s Health Center in Santa Monica, California, from July 2007 to December 2017 were included in this study.

For the analysis, patients were divided into three groups:

  1. Women with pregnancy-associated CD: “defined as symptom-onset within 1 year of pregnancy that was explicitly linked to the pregnancy by the patient’s own recollection of her pregnancy and subsequent symptoms related to CD”;
  2. Women of reproductive age: “defined as age 15–45 years, in whom CD onset was not associated temporally with pregnancy within the past year”;
  3. Women not of reproductive age at the time of CD onset.

Results showed that 64 percent of the patients were of childbearing age at the time of diagnosis. Of these, 27 percent (11 women) had pregnancy-associated Cushing’s disease. This might be due to small, slow-growing or dormant corticotroph pituitary adenomas that were stimulated by pregnancy-related hormonal changes; however, this hypothesis was not confirmed by the researchers.

On average, patients in group 1 had two pregnancies prior to Cushing’s disease onset, compared to zero for 30 other women with disease onset during reproductive age. This suggests that undergoing the biological stress of pregnancy more than once could play a role in Cushing’s development.

“Another possible explanation of the association between CD and pregnancy is simply that patients are more likely to remember the onset of their CD symptoms in relation to a landmark life event such as pregnancy and childbirth, which leads to long-term physical changes in most women, irrespective of Cushing’s status,” the researchers noted.

In contrast, 19 of the 30 patients at reproductive age without pregnancy-associated disease had no pregnancies before being diagnosed, which weakens the association between pregnancy and Cushing’s and draws attention to various other factors that may also be involved in disease onset, apart from gestation-related hormonal changes.

The time from the onset of symptoms to diagnosis for women with pregnancy-related disease varied from two to six years.

“It was in fact weight gain or failure to lose weight post-pregnancy, which was the most frequent complaint and presentation in our patients with pregnancy-associated CD, and which often lead to an eventual diagnosis of CD,” the researchers stated.

“As such, appropriate biochemical testing may be indicated in women who 6–18 months after pregnancy, are still unable to lose the weight of pregnancy, continue to gain weight, have new, persistent or more [treatment-resistant] hypertension and diabetes mellitus, and/or other classical stigmata of CD,” they suggested.

All patients with biochemically-confirmed Cushing’s disease underwent surgery to remove pituitary adenoma. Sustained surgical remission rates for groups 1, 2, and 3 were 91%, 80%, and 83%, respectively.

“This possible association suggests a heightened degree of clinical suspicion and biochemical testing for CD may be warranted after childbirth. Further study of this possible link between pregnancy and CD is warranted,” the team concluded.

From https://cushingsdiseasenews.com/2018/09/21/cushings-disease-symptoms-onset-pregnancy-could-be-linked-study-suggests/

Promising Pre-Clinical and Phase 1 Data Support Advance of Selective Cortisol Modulator CORT125134 as Potential Treatment for Cushing’s Syndrome and Solid-Tumor Cancers

MENLO PARK, CA–(Marketwired – Apr 28, 2016) –  Corcept Therapeutics Incorporated (NASDAQ: CORT), a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol, today released data supporting the clinical advancement of its proprietary, selective cortisol modulator, CORT125134. The company has begun recruiting patients for a Phase 1/2 trial of the compound to treat patients with solid-tumor cancers. It also expects to begin recruiting patients for a Phase 2 study of CORT125134 to treat patients with Cushing’s syndrome this quarter.

“Advancing CORT125134 is an important step in protecting and extending our growing Cushing’s syndrome franchise and in developing cortisol modulation for a wide range of other serious diseases,” said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. “This selective cortisol modulator has shown great promise. We are optimistic that, for some patients with Cushing’s syndrome, CORT125134 may be even better than our approved product, Korlym® — just as effective, but without the side effects associated with Korlym’s affinity for the progesterone receptor. Equally important, we look forward to investigating its potential as a treatment for solid-tumor cancers.”

CORT125134 is the lead compound in Corcept’s proprietary portfolio of selective cortisol modulators. It is a non-steroidal competitive antagonist of the glucocorticoid receptor (GR) that does not bind to the body’s other hormone receptors, including the progesterone receptor (PR). Korlym’s interaction with PR results in termination of pregnancy and can cause endometrial thickening and irregular vaginal bleeding in some women. CORT125134 is proprietary to Corcept and is protected by composition of matter and method of use patents extending to 2033.

Advancement to Phase 2 Trials Supported by Positive Pre-Clinical and Phase 1 Data
“The data generated so far make this compound a promising candidate to treat both Cushing’s syndrome and, potentially, a number of solid-tumor cancers,” said Hazel Hunt, Ph.D., Corcept’s Vice President of Research. “Its Phase 1 data showed that it shares Korlym’s potent affinity for GR, one of the receptors to which cortisol binds. Our clinical testing showed that it can prevent the effects of the steroid prednisone, a commonly-used synthetic GR agonist. Preventing the effects of prednisone is a very important finding, as it mirrors the essential quality of an effective medical treatment for patients with Cushing’s syndrome.”

Corcept’s Phase 1 trial of CORT125134 enrolled 124 healthy volunteers. GR antagonism was tested by measuring CORT125134’s ability to modulate prednisone’s effects on serum osteocalcin, white blood cell counts, glucose metabolism and expression of the FKBP5 gene — a marker of GR activation. With respect to all parameters, CORT125134 was as potent a modulator of prednisone’s activity as Korlym (see Figure 1; p value < 0.0003).

Pharmacokinetic data indicate that CORT125134 is suitable for once-daily dosing.

“Positive Phase 1 data, together with encouraging pre-clinical results, prompted us to advance CORT125134 as a treatment for Cushing’s syndrome as well as a treatment for cancer,” continued Dr. Hunt. “Substantial pre-clinical and clinical research suggests that cortisol modulation increases the effectiveness of chemotherapy in some solid-tumor cancers. Pre-clinical data suggest that CORT125134 may be even more potent than Korlym in treating some tumor types.”

Corcept and investigators at the University of Chicago have studied the effectiveness of CORT125134 in transgenic mouse models of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer. Mice implanted with TNBC tumor cells were treated with a combination of paclitaxel and CORT125134. Mifepristone (the active ingredient in Korlym) in combination with paclitaxel served as a positive control. As expected, the combination of mifepristone and paclitaxel significantly slowed tumor progression. However, the combination of CORT125134 and paclitaxel slowed it even more (see Figure 2; p value = 0.0004). In a similar experiment, castrated mice seeded with prostate cancer tumor cells were treated with either mifepristone or CORT125134. The outcome was comparable to the TNBC study: When combined with castration (which in humans would be achieved pharmacologically by the administration of an androgen receptor antagonist such as enzalutamide), mifepristone retarded tumor progression, but CORT125134 had an even more pronounced effect (see Figure 3; p value = 0.037).

CORT125134 may also enhance the efficacy of immune-modulation therapy. In an animal model of colon cancer, the addition of CORT125134 to PD-1 monotherapy significantly slowed tumor progression (see Figure 4; p value = 0.013):

Oncology Trial Design
This trial’s initial phase will investigate nab-paclitaxel in combination with CORT125134 to treat any solid-tumor cancer susceptible to treatment with nab-paclitaxel. (“Nab-paclitaxel” is the generic name for Celgene’s drug, Abraxane®.) Once a maximum tolerated dose is identified, Corcept plans to open one or more expansion cohorts, each containing 20 patients, to test the combination’s efficacy in one or more of the solid-tumor cancers studied in the dose-finding phase. Possible target indications include TNBC, castration-resistant prostate cancer, ovarian cancer, pancreatic cancer and sarcoma. Other dose-finding cohorts may be enrolled to study CORT125134 in combination with different companion therapeutic agents, including PD-1 inhibitors.

The trial is open-label and will be conducted at sites in the United States, the first of which is open and has begun screening patients.

“That we are advancing the same selective cortisol modulator as a treatment for both a metabolic disease and one or more oncologic indications is a testament to the broad therapeutic potential of cortisol modulation,” said Robert S. Fishman, MD, Corcept’s Chief Medical Officer. “We are excited to start these trials.”

Cushing’s Syndrome Trial Design
This Phase 2 trial of CORT125134 will enroll 30 patients with endogenous Cushing’s syndrome. Patients will be assigned to a low- or high-dose group and will receive CORT125134 for 12 weeks, with up-titration possible in each group at weeks four and eight. The trial will be open label. Study centers will be located in both the European Union and the United States.

About Korlym®
Korlym modulates the effect of cortisol at GR, one of the two receptors to which cortisol binds, thereby inhibiting the effects of excess cortisol in patients with Cushing’s syndrome. Since 2012, Corcept has made Korlym available as a once-daily oral treatment of hyperglycemia secondary to endogenous Cushing’s syndrome in adult patients with glucose intolerance or diabetes mellitus type 2 who have failed surgery or are not candidates for surgery. Korlym was the first FDA-approved treatment for that illness and the FDA has designated it as an Orphan Drug for that indication.

About Cushing’s Syndrome
Endogenous Cushing’s syndrome is caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing’s syndrome is an orphan indication that most commonly affects adults aged 20-50. An estimated 10-15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients annually in the United States. An estimated 20,000 patients in the United States have Cushing’s syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About Triple-Negative Breast Cancer
Triple-negative breast cancer is a form of the disease in which the three receptors that fuel most breast cancer growth — estrogen, progesterone and the HER-2/neu gene — are not present. Because the tumor cells lack the necessary receptors, treatments that target estrogen, progesterone and HER-2 receptors are ineffective. In 2013, approximately 40,000 women were diagnosed with TNBC. It is estimated that more than 75 percent of these women’s tumor cells expressed the GR receptor to which cortisol binds. There is no FDA-approved treatment and neither a targeted treatment nor an approved standard chemotherapy regimen for relapsed TNBC patients exists.

About Corcept Therapeutics Incorporated
Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol. Korlym, a first-generation cortisol modulator, is the company’s first FDA-approved medication. The company is conducting a Phase 1/2 trial of mifepristone for the treatment of TNBC, a Phase 1/2 trial of CORT125134 to treat a variety of solid-tumor cancers and has a proprietary portfolio of other selective GR antagonists that modulate the effects of cortisol but not progesterone. Corcept owns extensive intellectual property covering the use of cortisol modulators, including mifepristone and CORT125134, in the treatment of a wide variety of metabolic, oncologic and psychiatric disorders. It also holds composition of matter patents for CORT125134 and its other selective cortisol modulators.

Forward-Looking Statements
Statements made in this news release, other than statements of historical fact, are forward-looking statements. These forward-looking statements, including statements regarding the initiation and advancement of clinical trials and the development of Corcept’s pre-clinical and clinical pipeline, are subject to known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements, including the pace of enrollment in or the outcome of the company’s Phase 1/2 study of CORT125134 to treat solid-tumor cancers and planned Phase 2 trial of CORT125134 to treat patients with Cushing’s syndrome, the effects of rapid technological change and competition, the protections afforded by Corcept’s intellectual property rights, or the cost, pace and success of Corcept’s other product development efforts. These and other risks are set forth in the company’s SEC filings, all of which are available from the company’s website (www.corcept.com) or from the SEC’s website (www.sec.gov). Corcept disclaims any intention or duty to update any forward-looking statement made in this news release.

Abraxane® is a registered trademark of Celgene Corporation.

From http://www.marketwired.com/press-release/promising-pre-clinical-phase-1-data-support-advance-selective-cortisol-modulator-cort125134-nasdaq-cort-2119635.htm

 

If One Partner Has Cushing’s Syndrome, Can The Couple Still Get Pregnant?

Cushing’s syndrome can affect fertility in both men and women.

Women

The high levels of cortisol in Cushing’s syndrome disrupt a woman’s ovaries. Her menstrual periods may stop completely or become irregular. As a result, women with Cushing’s syndrome almost always have difficulty becoming pregnant.5,6,7 For those who do become pregnant, the risk of miscarriage is high.5,6,7

In rare cases, usually when a woman’s Cushing’s syndrome is caused by a benign adrenal tumor, pregnancy can occur, but it brings high risk for the mother and fetus.5,6,7

After a woman is treated for Cushing’s syndrome, her ovaries often recover from the effects of too much cortisol. Her regular menstrual cycles will return, and she can become pregnant.8

In some women, regular periods do not return after they are treated for Cushing’s syndrome. This occurs if surgery removes the part of the pituitary gland involved in reproduction.4 An infertility specialist can prescribe hormone therapy to bring back regular periods, ovulation, and fertility.8

Men

A man diagnosed with Cushing’s syndrome may have a decline in sperm production and could have reduced fertility.9 He also might experience a lowered sex drive as well as impotence (pronounced IM-puh-tuhns). In addition, some medications used to treat Cushing’s syndrome can reduce fertility.10 However, fertility usually recovers after Cushing’s syndrome is cured and treatment has stopped.9

Does Cushing’s syndrome affect pregnancy?

Cushing’s syndrome can cause serious and potentially life-threatening effects for the mother and the fetus during pregnancy.11,12 For example, Cushing’s syndrome raises a woman’s risk of developing pregnancy-related high blood pressure (called preeclampsia, pronounced pree-i-KLAMP-see-uh, or eclampsia) and/or pregnancy diabetes, which also is called gestational (pronounced je-STEY-shuhn-ul) diabetes). Infection and slow healing of any wounds are more likely, as is heart failure. When the syndrome is caused by a tumor, it will be surgically removed as early as possible to reduce any threat.13


  1. Margulies, P. (n.d.). Adrenal diseases—Cushing’s syndrome: The facts you need to know. Retrieved May 21, 2012, from National Adrenal Diseases Foundation website http://www.nadf.us/adrenal-diseases/cushings-syndrome/ External Web Site Policy
  2. Nieman, L. K., & Ilias, I. (2005). Evaluation and treatment of Cushing’s syndrome. Journal of American Medicine, 118(12), 1340-1346. PMID 16378774.
  3. American Cancer Society. (n.d.). Fact sheet on pituitary tumors. Retrieved May 19, 2012, fromhttp://documents.cancer.org/acs/groups/cid/documents/webcontent/003133-pdf.pdf (PDF – 171 KB). External Web Site Policy
  4. Biddie, S. C., Conway-Campbell, B. L, & Lightman, S. L. (2012). Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology, 51(3), 4034-4112. Retrieved May 19, 2012, from PMID: 3281495.
  5. Abraham, M. R., & Smith, C. V. (n.d.). Adrenal disease and pregnancy.Retrieved April 8, 2012, fromhttp://emedicine.medscape.com/article/127772-overview – aw2aab6b6. External Web Site Policy
  6. Pickard, J., Jochen, A. L., Sadur, C. N., & Hofeldt, F. D. (1990). Cushing’s syndrome in pregnancy. Obstetrical & Gynecological Survey, 45(2), 87-93.PMID 2405312.
  7. Lindsay, J. R., Jonklaas, J., Oldfield, E. H., & Nieman, L. K. (2005). Cushing’s syndrome during pregnancy: Personal experience and review of the literature. Journal of Clinical Endocrinology and Metabolism, 90(5), 3077.PMID 15705919.
  8. Klibansky, A. (n.d.). Pregnancy after cure of Cushing’s disease. Retrieved April 27, 2012, fromhttp://03342db.netsolhost.com/page/pregnancy_after_cure_of_cushings_disease.php. External Web Site Policy
  9. Jequier, A.M. Endocrine infertility. In Male infertility: A clinical guide (2nd ed.). Cambridge University Press, 2011: chap 20, pages 187-188. Retrieved May 19, 2012, from http://books.google.com/books?id=DQL0YC79uCMC&pg=PA188&lpg=PA188&dq=male+infertility+causes+and+treatment+Cushing&source=bl&ots=k1Ah5tVJC7&sig=WJR4N0wUawlh0Rant31QMPq6ufs&hl=en&sa=X&ei=hGe5T-LrHYSX6AHgrvmzCw&ved=0CGoQ6AEwAQ#v=onepage&q=male%20infertility%20causes%20and%20treatment%20Cushing&f=false. External Web Site Policy
  10. Stewart, P. M., & Krone, N. P. (2011). The adrenal cortex. In Kronenberg, H. M., Shlomo, M., Polonsky, K. S., Larsen P. R. (Eds.). Williams textbook of endocrinology (12th ed.). (chap. 15). Philadelphia, PA: Saunders Elsevier.
  11. Abraham, M. R., & Smith, C. V. Adrenal disease and pregnancy. Retrieved April 8, 2012, from http://emedicine.medscape.com/article/127772-overview – aw2aab6b6. External Web Site Policy
  12. Buescher, M. A. (1996). Cushing’s syndrome in pregnancy. Endocrinologist, 6, 357-361.
  13. Ezzat, S., Asa, S. L., Couldwell, W. T., Barr, C. E., Dodge, W. E., Vance M. L., et al. (2004). The prevalence of pituitary adenomas: A systematic review.Cancer, 101(3), 613-619. PMID 15274075.

From https://www.nichd.nih.gov/health/topics/cushing/conditioninfo/pages/faqs.aspx

Adrenal Diseases During Pregnancy: Pathophysiology, Diagnosis And Management Strategies

Am J Med Sci. 2014 Jan;347(1):64-73. doi: 10.1097/MAJ.0b013e31828aaeee.

Author information

Abstract

: Adrenal diseases-including disorders such as Cushing’s syndrome, Addison’s disease, pheochromocytoma, primary hyperaldosteronism and congenital adrenal hyperplasia-are relatively rare in pregnancy, but a timely diagnosis and proper treatment are critical because these disorders can cause maternal and fetal morbidity and mortality.

Making the diagnosis of adrenal disorders in pregnancy is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. In addition, pregnancy is marked by several endocrine changes, including activation of the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis.

The aim of this article was to review the pathophysiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.

PMID:
23514671
[PubMed – in process]

From http://www.ncbi.nlm.nih.gov/pubmed/23514671

When to think Cushing’s syndrome in type 2 diabetes

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

“Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed,” he observed. “I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic.”

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

“I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome,” the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that “by far” the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

“They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis,” he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the “buffalo hump,” supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com

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