Abstract
Summary
Menstrual cycle abnormalities are common in premenopausal females with Cushing’s syndrome, although the underlying mechanism is poorly understood. Signs and symptoms found in Cushing’s syndrome overlap with polycystic ovarian syndrome (PCOS). The patient is a 33-year-old female previously diagnosed by a gynecologist with PCOS and treated with oral contraceptive pills (OCPs) for 2 years. She then discontinued her OCPs without consulting a clinician, resulting in amenorrhea for 6 months, for which she presented. She also had symptoms of depression and anxiety but had no other signs and symptoms of Cushing’s syndrome, except a plethoric face. Initial lab work showed evidence of central hypogonadism (low luteinizing hormone, follicle-stimulating hormone, and estrogen), so a complete anterior pituitary hormone workup was done. Her thyroid-stimulating hormone was also low with a low free T4 level. Prolactin level was normal, but surprisingly, her AM cortisol level was high. The Cushing’s syndrome workup revealed non-suppressed cortisol after a 1 mg dexamethasone suppression test and positive 24-h urine cortisol with suppressed adrenocorticotrophic hormone. A CT scan of her adrenal glands revealed a left adrenal adenoma. She underwent a left adrenalectomy, after which her menstrual cycles became regular again, and pituitary function has recovered.
Learning points
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In Cushing's syndrome, female patients can have menstrual abnormalities due to the high cortisol levels, which can affect gonadotrophin levels.
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We encourage clinicians to include Cushing's syndrome in the differential diagnosis of patients with central hypogonadism.
Background
We are presenting a case report of an unusual presentation of Cushing’s syndrome. Our case involved amenorrhea accompanied by nonspecific signs and symptoms of Cushing’s syndrome, which was initially misdiagnosed as polycystic ovarian syndrome (PCOS). This paper highlights the importance of including Cushing’s syndrome in the differential diagnoses of central hypogonadism.
Case presentation
We present the case of a previously healthy 33-year-old Kuwaiti female patient who visited our clinic with a 6-month history of amenorrhea, along with non-specific symptoms of joint pain, mood swings, slight weight gain, fatigue, and mild facial acne. Her mother reported that she had been depressed and very anxious for the last 2 years. However, they did not seek psychiatric treatment because they attributed it to the quarantine measures due to the COVID-19 pandemic. She had a history of regular periods until 3 years ago when they became irregular and without dysmenorrhea. A gynecologist diagnosed her with PCOS, and she was on oral contraceptive pills (OCPs) for almost 2 years. She discontinued them without consulting a physician, and since then, she has developed amenorrhea.
Medical history
The patient had no history of known chronic diseases, similar conditions, previous hospital admissions, or surgical interventions. She denied using herbal medicine or over-the-counter medication and had no known allergies. She was a non-smoker, did not drink alcohol, and had a negative family history.
Physical examination
On physical examination, the patient was alert and conscious, looking well, and weighed 49 kg, a height of 150 cm, and a body mass index of 21.8 kg/m2. Her blood pressure was 150/70 mm Hg, heart rate was 80 beats/min, and respiratory rate was 18 breaths/min on room air. The hands examination was normal, with no clubbing, palmar erythema, muscle wasting, or hirsutism, and no acne or old scar lesions were found. The head and neck examination revealed a plethoric face. Chest examination revealed normal breath and heart sounds, with no murmurs or additional sounds. On abdominal examination, no striae, scars, tenderness, or organomegaly were found, and bowel sounds were normal. Lower limb examination was normal with no purpura, skin ulcers, muscle wasting, or edema.
The patient's presentation suggests PCOS-related amenorrhea, possibly due to her discontinuation of OCPs. However, her joint pain, mood swings, and weight gain are non-specific symptoms that require further investigation. The plethoric face could be due to Cushing’s syndrome or other hormonal disorders, and a more detailed endocrine evaluation is warranted.
Investigations
The patient's basic blood work showed mild hypernatremia with potassium at the lower end of the normal range (Table 1). Her initial hormonal blood work results showed low luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels, so a complete anterior pituitary hormone workup was conducted (Table 2) along with a pituitary MRI. She had a normal prolactin with low thyroid-stimulating hormone (TSH) and a low free T4. Surprisingly, she had high AM cortisol levels with suppressed adrenocorticotrophic hormone (ACTH). MRI of the pituitary gland showed no abnormalities. To further investigate, a 1 mg overnight dexamethasone suppression test and a 24-h urine cortisol test were conducted, which revealed non-suppressed cortisol and extremely high urine cortisol levels, respectively (Table 3). A CT scan of the adrenal gland revealed a well-defined triangular mass lesion in the left adrenal gland, measuring 4.3 × 3.3 × 3.5 cm with a mean density of 22 HU, suggestive of an adenoma (Fig. 1).
CT scan of the adrenal glands which reveals a well-defined triangular mass lesion in the left adrenal gland, measuring 4.3 × 3.3 × 3.5 cm. (A) Axial view and (B) coronal view.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-23-0152
Basic blood work.
| December 2021 | Reference range | |
|---|---|---|
| Hemoglobin, g/dL | 13.7 | 12.0–15.0 |
| Sodium, mmol/L | 146 | 135–145 |
| Potassium, mmol/L | 3.5 | 3.5–5 |
| Creatinine, mmol/L | 68 | 40–100 |
Pituitary hormonal workup.
| December 2021 | 10 March 2022 | Reference range | |
|---|---|---|---|
| LH, mIU/mL | 0.35 | ||
| FSH, mIU/mL | 5 | ||
| Estradiol, pg/mL | < 5 | ||
| Prolactin, μIU/mL | 268.4 | 100–500 | |
| TSH, μIU/mL | 0.5 | 0.264 | 0.5–5 |
| Free T4, pmol/L | 11.4 | 9.13 μIU/mL | 12–22 |
| ACTH, pmol/L | < 1 | 1.3–16.7 | |
| AM cortisol, mmol/L | 753 | 120–500 |
ACTH, adrenocorticotrophic hormone; FSH, follicle-stimulating hormone; free T4, free thyroxine hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
Adrenal gland hormonal workup.
| December 2021 | May 2022 (post surgery) | Reference range | |
|---|---|---|---|
| Cortisol level* | 600 | < 50 | |
| 24-h urine cortisol, nmol/L | 16712 | 100–370 | |
| Free plasma normetanephrine, nmol/L | < 0.2 | < 0.9 | |
| Free plasma metanephrine, nmol/L | < 0.2 | < 0.5 | |
| Aldosterone, ng/dL | < 0.4 | < 21 | |
| Plasma renin activity, ng/mL/h | 0.7 | 0.6–4.3 | |
| SHBG, nmol/L | 35.6 | 60.6 | 20–155 |
| Total testosterone, μmol/L | 2.1 | 0.9 | 0.5–1.8 |
| DHEA-S, μmol/L | 10.3 | 6.3 | 1.5–8 |
*Post 1 mg overnight dexamethasone suppression test.
DHEA-S, dehydroepiandrosterone sulfate; SHBG, sex hormone-binding globulin.
The patient was diagnosed with Cushing’s syndrome, central hypogonadism, and central hypothyroidism.
Management
To manage her hypothyroidism and prepare her for left adrenalectomy, the patient was started on levothyroxine 75 mcg orally daily, targeting free T4 in the mid-high normal range. A laparoscopic adrenalectomy was performed without complications. The pathology report was consistent with adrenal cortical adenoma (Weiss score: 0) (Supplementary File 1, see section on supplementary materials given at the end of this article). The patient’s post-operative course was uneventful, and she was started on hydrocortisone, which was gradually tapered over the subsequent months.
Outcome and follow-up
The patient was closely monitored for signs of adrenal insufficiency, and her cortisol levels were checked regularly. Her thyroid function had recovered, and levothyroxine was stopped.
After 6 months, the patient reported having regular menstrual periods, significant weight loss (3 kg) and was symptom free. The patient continued to follow up with our service to monitor for any recurrence of her symptoms and to adjust her cortisol hormone replacement therapy as needed.
Discussion
Amenorrhea is the absence of menstruation. Primary amenorrhea is the absence of menarche in a female age 15 or older, whereas secondary amenorrhea is the absence of menstruation for at least 3 months after regular menstruation is established. It can be further classified by the anatomic location of disturbance (hypothalamus, pituitary, uterus, or vagina). Testing for the presence of hyperandrogenism can help narrow differential diagnoses (1).
In females with Cushing’s syndrome, experiencing menstrual disturbances is a frequent occurrence. Of the 390 female patients in the European registry on Cushing’s syndrome, 56% reported experiencing menstrual disturbances (2).
In addition, Bolland and colleagues conducted a nationwide survey in New Zealand and discovered that 35.5% of female patients with Cushing's syndrome experienced menstrual disruption (2).
Lado-Abeal et al. studied 45 female patients with Cushing’s syndrome and found that around 80% had menstrual irregularities. Menstrual cycle abnormalities are common in premenopausal females with Cushing’s syndrome, although the underlying mechanism is poorly understood. Signs and symptoms found in Cushing’s syndrome overlap with PCOS. These include amenorrhea or oligomenorrhea, obesity, hirsutism, exaggerated gonadotropic response to gonadotropin-releasing hormone (GnRH), and low sex hormone-binding globulin levels with high androgen levels in the blood (3).
Lado-Abeal et al. observed that menstrual irregularities in Cushing's syndrome are due to hypogonadotropic hypogonadism, as opposed to PCOS patients. This finding is supported by the fact that these patients' LH and FSH levels were inappropriately low for the estrogen levels in their blood. They also performed a GnRH stimulation test on their patients, and their patients' FSH reserve was normal, and the LH response was normal or exaggerated. This suggests that the pituitary gonadotropin reserve is normal or increased. It has led to the conclusion that menstrual abnormalities in patients with Cushing's syndrome are likely due to abnormal hypothalamic GnRH secretion caused by long-standing high cortisol levels, which block the secretion of GnRH from the hypothalamus and the action of LH and FSH on the ovaries. Furthermore, it was also observed that serum cortisol levels was negatively associated with serum estrogen level; however, this association was not found between estrogen and androgen levels, and they, therefore, concluded that the menstrual irregularities are due to high cortisol and not high androgen levels in the blood. Also, the normalization of cortisol levels with metyrapone is associated with treating menstrual abnormalities, although metyrapone increases serum androgen levels. This is further supported by the observation that although administering testosterone to female-to-male transsexuals can lead to morphologic features of PCOS, this only occurs when the testosterone levels are higher than normal males or females with virilizing tumors. Also, serum gonadotropins and LH pulsatility are unaffected if the testosterone level is only raised to the level of normal men, and menstrual irregularities would not occur. In addition, males with estrogen resistance due to a mutation of the estrogen receptors have elevated gonadotropin levels in the blood, although their serum androgen level is normal. This indicates that estrogens, not androgens, mainly regulate the feedback mechanism in the reproductive (3).
Kaltsas et al. observed 13 Cushing’s syndrome patients, with 70% having menstrual disturbances. They found that in women with Cushing’s syndrome, the mechanism of menstrual disturbance can either be due to a PCOS phenotype, in which the ovaries are enlarged, or due to suppression of GnRH in the hypothalamus from the high cortisol levels, in which ovarian volume is preserved. This depends on the cortisol level; if the cortisol level is not high enough to suppress the hypothalamic secretion of GnRH, a PCOS phenotype will develop with or without irregular menstruation. It was also hypothesized that a PCOS phenotype in Cushing’s syndrome may develop due to hypercortisolemia-induced hyperinsulinemia and insulin resistance. This suggests that in patients with PCOS exhibiting other signs such as hypertension or myopathy, we should consider Cushing’s syndrome as a differential diagnosis (4).
Because of the impact of hypercortisolism on the hypothalamic–pituitary–ovarian axis, pregnancy is rare in Cushing’s syndrome. A systematic review by Caimari et al. noted that among pregnant females with active Cushing’s syndrome, an adrenal source of Cushing’s syndrome is the most common cause. This can be attributed to the fact that in Cushing’s disease, elevated ACTH levels lead to overproduction of both cortisol and androgens, while cortisol-secreting adrenal tumors primarily lead to the overproduction of cortisol without the concurrent elevation of androgens (5).
Our patient's hemoglobin level is normal. This is important as Cushing’s syndrome can affect red blood cell parameters. Detomas et al. conducted a retrospective monocentric study that showed differences in hemoglobin and hematocrit levels between patients with endogenous Cushing’s syndrome and control subjects. Controls are patients with non-functional adrenal incidentalomas or non-secretory pituitary microadenomas. The study included 210 patients, consisting of 162 females and 48 males, matched in age and sex with controls. It was concluded that hemoglobin and hematocrit levels are higher in females with endogenous Cushing’s syndrome compared to controls (6).
In our case, the patient’s presenting symptom was amenorrhea, and she exhibited ideal body weight with non-specific symptoms of joint pain, mood swings, and slight weight gain. She did not have significant symptoms of hyperandrogenism. The blood work showed a picture of central hypogonadism. Therefore, physicians should consider the possibility of Cushing’s syndrome as a rare cause of hypogonadotropic hypogonadism.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EDM-23-0152.
Declaration of interest
All the authors declare that they have no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Patient consent
Written consent was obtained from each patient or subject after explaining the purpose and nature of all procedures used.
Author contribution statement
AA: literature search and writing the abstract and discussion; SH: writing case presentation; KA: data collection. KA is the named physician of the patient, and he gave permission to other authors to contribute to the case report.
References
- 1↑
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- 2↑
Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy R, & Webb SM. Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases. Endocrine 2017 55 555–563. (https://doi.org/10.1007/S12020-016-1117-0)
- 3↑
Detomas M, Deutschbein T, Tamburello M, Chifu I, Kimpel O, Sbiera S, Kroiss M, Fassnacht M, & Altieri B. Erythropoiesis in Cushing syndrome: sex-related and subtype-specific differences. Results from a monocentric study. Journal of Endocrinological Investigation 2024 47 101–113. (https://doi.org/10.1007/s40618-023-02128-x)
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Erickson AW, Parker J, Khat DZ, Li M, Gaebe K, Li A, Mehra V, Tan CC, Chan J, Lu J and Ramendra R. Toronto Notes 2023 : Comprehensive Medical Reference and a Review for the Medical Council of Canada Qualifying Exam (MCCQE ). n.d.
- 5↑
Kaltsas GA, Korbonits M, Isidori AM, Webb JAW, Trainer PJ, Monson JP, Besser GM, & Grossman AB. How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing’s syndrome? Clinical Endocrinology 2000 53 493–500. (https://doi.org/10.1046/j.1365-2265.2000.01117.x)
- 6↑
Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JDC, Perry LA, Grossman AB, Besser GM, & Trainer PJ. Menstrual abnormalities in women with Cushing’s disease are correlated with hypercortisolemia rather than raised circulating androgen levels. Journal of Clinical Endocrinology and Metabolism 1998 83 3083–3088. (https://doi.org/10.1210/JCEM.83.9.5084)
