The utility of adrenal and ovarian venous sampling in a progesterone-producing adrenal tumor and review of the literature
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A clinical case presenting secondary amenorrhea accompanied by an adrenal adenoma and hyperprogesteronemia is described in this study.
Selective catheterization and sampling of adrenal and ovarian veins were performed.
The source of hyperprogesteronemia was located in the right adrenal gland. A progesterone-producing tumor in the right adrenal gland was diagnosed and removed. Twenty-six days after tumor resection, menstruation occurred.
Progesterone-producing tumors should be considered with the presence of an adrenal mass and hyperprogesteronemia. Combined adrenal and ovarian venous sampling may help to identify the source of progesterone secretion.
KeywordsAmenorrhea Progesterone-producing tumor Combined adrenal and ovarian venous sampling
Progesterone-producing tumors are extremely rare and easily overlooked in patients with hyperprogesteronemia. To our knowledge, there are only three published reports of adrenal progesterone-producing tumors. We encountered a case that exhibited secondary amenorrhea, elevated serum progesterone levels, and an adrenal tumor suspected to be producing progesterone and related adrenal steroid hormones. We diagnosed the patient’s condition with the use of combined adrenal and ovarian venous sampling. After resection of the adrenal tumor, serum progesterone concentrations soon normalized, and the patient became pregnant. This study is the first to use combined adrenal and ovarian venous sampling to confirm the source of hyperprogesteronemia.
Serum or plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), testosterone (T), β-HCG, prolactin (PRL), dehydroisoandrosterone sulfate (DHEAs), cortisol (F), aderenocorticotropic hormone (ACTH), and urinary free cortisol (UFC) were measured via chemiluminescence immunoassay. Plasma 17α-hydroxyprogesterone (17 α-OHP), aldosterone (ALD), renin activity (RA), and angiotensin (AT) were measured by radioimmunoassay. Plasma and urinary adrenaline, noradrenaline and dopamine were measured using high performance liquid chromatography. Immunohistological analysis of the progesterone was performed using an anti-progesterone antibody (GeneTex, Progesterone antibody, 9B4, 1/50) according to the instructions of the manufacturer. All above procedures were performed at the department of laboratory of Peking Union Medical College Hospital (Beijing, China).
Combined adrenal and ovarian venous sampling
Combined adrenal and ovarian venous sampling was performed by two experienced interventional radiologists. The patient was placed in the supine position and 5-F vascular catheter was accessed via the right femoral vein. Cobra catheter was then advanced into inferior vena cava and right adrenal vein and Simmons catheter was placed into the left adrenal vein and the right ovarian vein under fluoroscopic guidance, respectively. Cobra catheter was placed into the left ovarian vein afterwards. Five milliliters of venous blood were taken from each site simultaneously for P, 17 α-OHP, E2, F, ALD, T, PRA, and a DHEAS assay. The E2 ratio between ovarian veins to peripheral vein >2 and the ALD ratio between adrenal veins to peripheral vein >2 was considered as the successful catheterization of the adrenal veins.
Report of a case
A 33-year-old woman was admitted to Peking Union Medical College Hospital on November 23, 2017 due to a menstrual disorder that had persisted for 15 years. Her first menarche occurred at 12 years old; however, the patient had been suffering from oligomenorrhea since 2002, her last menstruation occurred in October, 2014, and she stated that she had a normal sexual life since get married in 2011 and there was no pregnancy despite no contraception. Her personal and family medical histories were deemed noncontributory to her symptoms. At the start of medical assessment and treatment, she was referred to the Department of Gynecology, and a physical examination indicated she was a young, thin woman (weight: 55 kg, height: 165 cm) with blood pressure varying between 95–120/60–80 mmHg. There was no evidence of Cushing syndrome or virilization.
Preoperative and postoperative levels of serum and urine steroid hormone concentrations
24 h UFC (μg/24 h)
F (8:00 a.m.)
24 h UNE
F (0:00 a.m.)
24 h UE
24 h UDA
DST (3 mg)
17 α-OHP (ng/ml)
0.75 mg × 4 Day 2
AVS + OVS
Inferior vena cava
Differential diagnosis of amenorrhea
In the presented case, the patient’s menstruation had stopped for more than 6 months despite experiencing prior menstruation. Therefore, secondary amenorrhea, which is often caused by pregnancy, hyperthyroidism, hypothalamic dysfunction, pituitary, or ovarian dysfunction, was considered. The patient’s levels of thyroid hormone, PRL, and β-HCG were within normal ranges, as were her plasma ALD and androgen concentrations. However, elevated plasma progesterone and 17 α-OHP concentrations were found without suppression of LH and FSH. Progesterone is produced by the adrenal glands and by the corpus luteum in the ovaries after ovulation is triggered by LH, but the patient’s serum progesterone levels did not return to normal after the luteal phase. Additionally, ovarian ultrasonography and abdominal CT did not show any abnormal ovarian growths. Thus, elevated progesterone levels of an adrenal origin were suspected. High levels of progesterone and 17 α-OHP are a potential consequence of CAH by 21-hydroxylase or 17-hydroxylase deficiency [3, 4]. CAH was subsequently excluded due to the failure of a medium dose of dexamethasone as well as glucocorticoid administration to normalize hormone levels. With the presence of a mass in the right adrenal gland, the possibility that progesterone, 17 α-OHP and cortisol were autonomously secreted by the adrenal tumor was considered. Since the patient exhibited a favorable clinical outcome to tumor resection, she was diagnosed with a progesterone and related steroid-producing adrenal tumor. It is possible that the patient failed to have artificial menses after she was prescribed estrogen and progesterone due to the endometrium’s poor response to estrogen in the presence of high concentrations of progesterone. However, the mechanism of nonsuppressed plasma LH and FSH at baseline remained unclear. A previous study reported that the increased levels of serum progesterone of adrenal origin may cause an increase in LH concentrations . Though the patient’s cortisol levels were not suppressed by the dexamethasone test and she did not present with any features of hypercortisolemia, suggesting that a diagnosis of subclinical Cushing’s disease cannot be excluded. We observed that ACTH was not suppressed by cortisol excess, and this discrepancy could indicate that the serum cortisol lacked enough biological activity to inhibit that HPA axis.
Overview of previously reported cases of progesterone-producing adrenal tumors
Overview of progesterone-producing adrenal tumors
P. van Zonneveld
18 nmol/l (0.6–2.5)
Serum cortisol was not suppressed
1.8 nmol/l (<2)
8.6 ng/ml (<0.7)
3.5 ng/ml (0.1–3.3)
Cortisol suppressed, but progesterone was not suppressed
0.78 ng/ml (0.03–0.33)
1.0 ng/ml (0.1–0.6)
Hypertension, hypokalemia, and amenorrhea
A palpable abdominal mass
3.53 ng/ml (<0.92)
3.0 ng/ml (0.2–2.8)
DOC and progesterone were not suppressed
8.04 ng/ml (0.03–0.33)
48 ng/dl (9.12–111)
Other abnormal steroid concentration
Adrenal tumor size
P. van Zonneveld
DHEAS 9.1 µmol/L (2–9)
keratin (+), Ki-67, P53 (−)
Menstruation occurred 10 days later
The progesterone concentration from the left adrenal vein was 1.45 times higher than right ad-renal vein
Various sized cells with eosinophilic granules and polymorphic nuclei
Menstruation occurred 51 days after operation
Serum potassium: 2.3 mEq/l; PRA:0.1 ng/ml/h (0.2–2.7); pregnenolone 5.04 ng/ml (0.2–1.5)
Nuclear grade was III, mitotic rate was 5 per 50 HPF, necrosis (+), Ki67 > 10%
Blood pressure, serum potassium level normalized, and menstruation occurred 3 months after tumor resection
Selective catheterization of adrenal and ovarian veins
Selective catheterization of adrenal and ovarian veins was performed to confirm the source of hyperprogesteronemia and determine whether the right adrenal lesion was functional or nonfunctional. This revealed an over 60-fold increase in progesterone production from the right adrenal gland compared with the left adrenal and bilateral ovarian veins. In addition, 17 α-OHP and cortisol concentrations in the right adrenal gland were 5–7 times higher than those found in the peripheral veins, left adrenal gland, and ovarian veins. Adrenal vein sampling is a highly accurate method used to localize ALD-secreting adenomas. Catheterization of ovarian veins has been used to identify the source of progesterone  and selective adrenal venous sampling together with ovarian venous sampling have primarily been used in the localization of occult androgen-secreting ovarian tumors [12, 13, 14, 15]. We have also reported the diagnosis of ovarian ACTH-independent ectopic Cushing syndrome with the help of combined ovarian and adrenal venous sampling . The current study, in combination with previous evidence, suggests that selective adrenal and ovarian vein sampling and associated steroid assays may be considered when the source of progesterone and other adrenal intermediate hormones cannot be determined by imaging methods, especially in cases in which the adrenal or ovarian tumor size is not yet large enough to be removed. However, ovarian and adrenal venous catheterization and sampling should only be performed by experienced doctors in order to achieve diagnostic value .
In summary, progesterone-producing tumors are easily overlooked in the differential diagnosis of amenorrhea since they are very rare in routine clinical practice. However, diagnosis of progesterone-producing tumors should be considered with the presence of an adrenal mass; furthermore, ovarian and adrenal venous catheterization and sampling may be highly valuable in the diagnosis of patients presenting small adrenal tumors.
The National Key Program of Clinical Science (WBYZ2011-873).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 1.H. Tao, Z. Lu, B. Zhang, Y. Wang, M. Sun, Screening nonclassical 21-hydroxylase deficiency in androgen excess women of Chinese Han nationality. Chin. J. Endocrinol. Metab. 21(5), 405–8 (2005)Google Scholar
- 10.Y. Takahashi, J. Ninomiya, J. Horiguchi, H. Shimizu, M. Sato, Y. Koibuchi, T. Yoshida, M. Yoshida, D. Takata, H. Odawara, T. Yokoe, Y. Iino, Y. Morishita, M. Mori, Primary amenorrhea accompanied by adrenal adenoma: start of menarche soon after tumor resection. Intern. Med. 41(11), 972–976 (2002)CrossRefGoogle Scholar
- 11.M. Sone, H. Shibata, K. Homma, N. Tamura, J. Akahira, S. Hamada, M. Yahata, N. Fukui, H. Itoh, H. Sasano, K. Nakao, Close examination of steroidogenesis disorders in a DOC—and progesterone—producing adrenocortical carcinoma. Endocrine 35(1), 25–33 (2009). https://doi.org/10.1007/s12020-008-9123-5 CrossRefPubMedGoogle Scholar
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