Cushing's Syndrome in Women With Polycystic Ovaries and Hyperandrogenism

P. Gerry Fegan; Derek D. Sandeman; Nils Krone; Deborah Bosman; Peter J. Wood; Paul M. Stewart; Neil A. Hanley

Nat Clin Pract Endocrinol Metab. 2007;3(11):778-783.

Treatment and Management

How Might Polycystic Ovarian Syndrome and Cushing's Syndrome Be Distinguished?

The menstrual cycle of individuals with PCOS is likely to have always tended towards irregularity (the amenorrhea in this case developed after years of a regular cycle).^[1] The onset of PCOS is uncommon after the age of 30 years. Both PCOS and Cushing's syndrome are associated with obesity, an increased risk of hypertension and impaired glucose tolerance or secondary diabetes.^[4,7,9] Clinical and/or biochemical hyperandrogenism with menstrual infrequency is found commonly in women with Cushing's syndrome. In fact, there are data to suggest that menstrual irregularity is linked to the level of glucocorticoid excess rather than to androgen levels.^[7] Ovarian cysts are certainly not discriminatory; they are present in almost half of women with Cushing's syndrome.^[12] It is also noteworthy that cysts, in isolation, do not predict the development of PCOS;^[13] furthermore, whereas imaging the ovaries can help to exclude a tumor, our experience would suggest that identifying cysts either laparoscopically or by ultrasound scanning can inappropriately curtail the search for alternative causes of clinical and/or biochemical hyperandrogenism.

Virilization in PCOS, characterized by a deepened voice or clitoromegaly, is highly unusual and more in keeping with an androgen-secreting tumor (none of the cases illustrated in Table 2 experienced virilization).^[7] Other clinical features lend support to the diagnosis of Cushing's syndrome, but these can be absent, especially in the early phases of cortisol excess.^[9] Biochemically, relative luteinizing hormone excess has been reported in patients with PCOS,^[14] whereas low gonadotropin levels might increase the suspicion of Cushing's syndrome (as in Case D in Table 1 , who presented with primary amenorrhea).^[12] None of these features is absolute, the overlap between syndromes is large and, thus, screening tests are needed to exclude Cushing's syndrome ( Table 3 ).

Screening for Cushing's Syndrome

Loss of diurnal variation, assessed by midnight serum cortisol levels, is an early perturbation to normal glucocorticoid homeostasis.^[9] Out-of-hours venesection can, however, be impractical in the community. Instead, bedtime salivary assays, which enable samples to be posted to the laboratory, are increasingly available. These assays are useful if backed up by robust normal ranges. Patients can find 24-h urine collections inconvenient and difficult, which results in incomplete specimens that give misleading results. Mildly increased cortisol excretion can occur in PCOS,^[15,16] possibly related to recognized changes in the hypothalamic-pituitary-adrenal axis.^[17] An alternative approach is the use of a low-dose dexamethasone test. Although it can be debated whether to use the overnight test or the formal eight-dose test over 48 h to screen for Cushing's syndrome, either investigation is relatively straightforward ( Table 3 ), especially if issued with written guidance.^[9] In light of this case and others, our current practice is to screen all new referrals with 'PCOS-like' symptoms for glucocorticoid excess.

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Table 1. Three Additional Women With Very Similar Clinical Features Eventually Diagnosed With Cushing's Syndrome
Features	Patients
Features	The Case (A)	Case B	Case C	Case D
Age at diagnosis of Cushing's syndrome; gap since first investigated	41 years; 7 years	24 years; 3 months	35 years; 1 year	25 years; 12 years
Diagnosis	Right adrenal adenoma	Corticotroph adenoma	Corticotroph adenoma	Corticotroph adenoma
Pelvic ultrasound or laparoscopy result	Polycystic ovaries	Polycystic ovaries	Polycystic ovaries	Polycystic ovaries
Clinical features initially attributed to PCOS	Hirsutism, subfertility, greasy skin and acne	Hirsutism, secondary amenorrhea, weight gain	Subfertility, weight gain	Obesity, weight gain, primary amenorrhea
Serum total testosterone	2.6 nmol/l (75 ng/dl)	4.6 nmol/l (133 ng/dl)	3.2 nmol/l (92 ng/dl)	4.5 nmol/l (130 ng/dl)
Screening test confirming Cushing's syndrome	Overnight LDDST Three 24-h UFC collections Bedtime salivary cortisol measurement	Overnight LDDST Three 24-h UFC collections	Overnight LDDST Three 24-h UFC collections Bedtime salivary cortisol measurement	Overnight LDDST Three 24-h UFC collections 0900 h and 2400 h cortisol measurement
Clinical features that distinguished Cushing's syndrome from PCOS (see Table 2 )	Facial plethora, rounded facies, violaceous abdominal striae	Facial plethora	None	Short stature,^a depression
Biochemical investigation against a diagnosis of PCOS	Low estradiol (47 pmol/l [13 pg/ml])	None	None	Low LH (1.1 IU/l) and low estradiol
Hypertension	Yes	No	Yes	No
Diabetes or impaired glucose tolerance	No	No	Yes	No
Hypertension	Yes	No	Yes	No
Diabetes or impaired glucose tolerance	No	No	Yes	No
Final curative treatment	Laparoscopic right adrenalectomy	Transsphenoidal surgery	Transsphenoidal surgery	Transsphenoidal surgery

^aShort stature with obesity is a particularly useful feature pointing towards Cushing's syndrome in childhood or adolescence.
Abbreviations: LDDST = low dose dexamethasone suppression test; LH = luteinizing hormone; PCOS = polycystic ovarian syndrome; UFC = urinary free cortisol.

Table 1. Three Additional Women With Very Similar Clinical Features Eventually Diagnosed With Cushing's Syndrome
Features	Patients
Features	The Case (A)	Case B	Case C	Case D
Age at diagnosis of Cushing's syndrome; gap since first investigated	41 years; 7 years	24 years; 3 months	35 years; 1 year	25 years; 12 years
Diagnosis	Right adrenal adenoma	Corticotroph adenoma	Corticotroph adenoma	Corticotroph adenoma
Pelvic ultrasound or laparoscopy result	Polycystic ovaries	Polycystic ovaries	Polycystic ovaries	Polycystic ovaries
Clinical features initially attributed to PCOS	Hirsutism, subfertility, greasy skin and acne	Hirsutism, secondary amenorrhea, weight gain	Subfertility, weight gain	Obesity, weight gain, primary amenorrhea
Serum total testosterone	2.6 nmol/l (75 ng/dl)	4.6 nmol/l (133 ng/dl)	3.2 nmol/l (92 ng/dl)	4.5 nmol/l (130 ng/dl)
Screening test confirming Cushing's syndrome	Overnight LDDST Three 24-h UFC collections Bedtime salivary cortisol measurement	Overnight LDDST Three 24-h UFC collections	Overnight LDDST Three 24-h UFC collections Bedtime salivary cortisol measurement	Overnight LDDST Three 24-h UFC collections 0900 h and 2400 h cortisol measurement
Clinical features that distinguished Cushing's syndrome from PCOS (see Table 2 )	Facial plethora, rounded facies, violaceous abdominal striae	Facial plethora	None	Short stature,^a depression
Biochemical investigation against a diagnosis of PCOS	Low estradiol (47 pmol/l [13 pg/ml])	None	None	Low LH (1.1 IU/l) and low estradiol
Hypertension	Yes	No	Yes	No
Diabetes or impaired glucose tolerance	No	No	Yes	No
Hypertension	Yes	No	Yes	No
Diabetes or impaired glucose tolerance	No	No	Yes	No
Final curative treatment	Laparoscopic right adrenalectomy	Transsphenoidal surgery	Transsphenoidal surgery	Transsphenoidal surgery

Table 2. Causes of Hyperandrogenism, Other Than Polycystic Ovarian Syndrome, Which Merit Consideration, Especially if Irregularity of the Menstrual Cycle Does not Date Back to Menarche
'Non-PCOS' causes of hyperandrogenism	Distinguishing clinical features	Screening tests to consider
Cushing's syndrome	Facial plethora, rounded facies, violaceous striae, thin skin, bruising and proximal muscle weakness In younger patients: growth arrest, primary amenorrhea	See Table 3
Late onset congenital adrenal hyperplasia	Positive family history	Serum 17α-hydroxyprogesterone
Drugs (e.g. anabolic steroids, androgenic progesterones)	Onset timed with drug-taking	Gas chromatography or liquid chromatography plus mass spectrometry
Androgen-secreting adrenocortical or ovarian tumor	Progressive virilization	DHEAS (adrenocortical tumor) Serum total testosterone: androgen-secreting tumors are unlikely if levels are below 4 nmol/l (115 ng/dl) and become increasingly probable with higher values; PCOS is rarely associated with values higher than 7 nmol/l^a (202 ng/dl)
Acromegaly	Bony and soft tissue overgrowth	Oral glucose tolerance test Serum IGF-I

^aFor detailed review, see Kaltsas GA et al.^[7]
Abbreviations: DHEAS = dehydroepiandrosterone sulfate; IGF-I = insulin-like growth factor I; PCOS = polycystic ovarian syndrome.

Table 1. Three Additional Women With Very Similar Clinical Features Eventually Diagnosed With Cushing's Syndrome
Features	Patients
Features	The Case (A)	Case B	Case C	Case D
Age at diagnosis of Cushing's syndrome; gap since first investigated	41 years; 7 years	24 years; 3 months	35 years; 1 year	25 years; 12 years
Diagnosis	Right adrenal adenoma	Corticotroph adenoma	Corticotroph adenoma	Corticotroph adenoma
Pelvic ultrasound or laparoscopy result	Polycystic ovaries	Polycystic ovaries	Polycystic ovaries	Polycystic ovaries
Clinical features initially attributed to PCOS	Hirsutism, subfertility, greasy skin and acne	Hirsutism, secondary amenorrhea, weight gain	Subfertility, weight gain	Obesity, weight gain, primary amenorrhea
Serum total testosterone	2.6 nmol/l (75 ng/dl)	4.6 nmol/l (133 ng/dl)	3.2 nmol/l (92 ng/dl)	4.5 nmol/l (130 ng/dl)
Screening test confirming Cushing's syndrome	Overnight LDDST Three 24-h UFC collections Bedtime salivary cortisol measurement	Overnight LDDST Three 24-h UFC collections	Overnight LDDST Three 24-h UFC collections Bedtime salivary cortisol measurement	Overnight LDDST Three 24-h UFC collections 0900 h and 2400 h cortisol measurement
Clinical features that distinguished Cushing's syndrome from PCOS (see Table 2 )	Facial plethora, rounded facies, violaceous abdominal striae	Facial plethora	None	Short stature,^a depression
Biochemical investigation against a diagnosis of PCOS	Low estradiol (47 pmol/l [13 pg/ml])	None	None	Low LH (1.1 IU/l) and low estradiol
Hypertension	Yes	No	Yes	No
Diabetes or impaired glucose tolerance	No	No	Yes	No
Hypertension	Yes	No	Yes	No
Diabetes or impaired glucose tolerance	No	No	Yes	No
Final curative treatment	Laparoscopic right adrenalectomy	Transsphenoidal surgery	Transsphenoidal surgery	Transsphenoidal surgery

Table 3. Screening Tests for Cushing's syndrome
Perturbation to normal physiology	Screening test for Cushing's syndrome^a	Potential use during 'work-up'
At least partial autonomy of cortisol production (either direct from the adrenal cortex or secondary to adrenocorticotropic hormone secretion)	Failure to suppress cortisol levels below 50 nmol/l after low dose dexamethasone (0.5 mg every 6 h for eight doses ending at 0300 h, or 1 mg at 2300 h with serum cortisol measured the following day at 0800 h to 0900 h)	A useful out-patient first-line investigation
Loss of diurnal rhythm of cortisol production	High midnight or bedtime cortisol (serum or salivary)	Salivary assays are practical, because multiple samples can be posted to the laboratory over the course of a few days. Useful if backed up by a robust normal range
Excess cortisol production leading to increased free cortisol excretion	Increased 24-h urinary free cortisol	Useful investigation, but patients can find it inconvenient or difficult; commonly performed three times

^aPhysicians should retain a high index of suspicion and be willing to repeat screening tests. Salivary cortisol measurements are particularly useful to investigate cyclical Cushing's syndrome.

Table 3. Screening Tests for Cushing's syndrome
Perturbation to normal physiology	Screening test for Cushing's syndrome^a	Potential use during 'work-up'
At least partial autonomy of cortisol production (either direct from the adrenal cortex or secondary to adrenocorticotropic hormone secretion)	Failure to suppress cortisol levels below 50 nmol/l after low dose dexamethasone (0.5 mg every 6 h for eight doses ending at 0300 h, or 1 mg at 2300 h with serum cortisol measured the following day at 0800 h to 0900 h)	A useful out-patient first-line investigation
Loss of diurnal rhythm of cortisol production	High midnight or bedtime cortisol (serum or salivary)	Salivary assays are practical, because multiple samples can be posted to the laboratory over the course of a few days. Useful if backed up by a robust normal range
Excess cortisol production leading to increased free cortisol excretion	Increased 24-h urinary free cortisol	Useful investigation, but patients can find it inconvenient or difficult; commonly performed three times

^aPhysicians should retain a high index of suspicion and be willing to repeat screening tests. Salivary cortisol measurements are particularly useful to investigate cyclical Cushing's syndrome.

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Cushing's Syndrome in Women With Polycystic Ovaries and Hyperandrogenism

Treatment and Management

How Might Polycystic Ovarian Syndrome and Cushing's Syndrome Be Distinguished?

Screening for Cushing's Syndrome

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