Abstract
Background/Objective
A 58-year-old postmenopausal woman presented with polycythemia on routine laboratory examinations along with long-standing hirsutism. The objective of this report is to highlight polycythemia as a rare presenting feature of ovarian hyperthecosis (OH).
Case Report
A 58-year-old woman presented with elevated hemoglobin and hematocrit levels in the primary care setting on routine laboratory examinations. On further workup, she was found to have elevated testosterone levels. Further history was relevant for excessive facial hair, frontal hair loss, and deepened voice. Examination findings were consistent with significant hirsutism. Adrenal and ovarian imaging was negative for tumor. The patient elected to have laparoscopic bilateral oophorectomy, which revealed OH on surgical pathology. After 2 months of surgery, the total testosterone levels became normal, and polycythemia resolved.
Discussion
In a postmenopausal woman, hirsutism with virilization should generally prompt urgent investigation because these signs are associated with malignant androgen-secreting tumors of the adrenal gland and ovaries. However, these symptoms can also be the result of benign causes such as OH.
Conclusion
This case is a rare illustration of OH in a postmenopausal woman presenting with polycythemia secondary to severe hyperandrogenism. Suspicion for this condition is crucial in evaluation for rare causes of polycythemia because if left untreated, it can lead to increased morbidity and mortality.
Key words: polycythemia, hyperandrogenism, ovarian hyperthecosis
Highlights
-
•
Polycythemia can be caused by hyperandrogenism seen in ovarian hyperthecosis (OH)
-
•
Women with insidious onset OH may not report symptoms of apparent hyperandrogenism
-
•
Hirsutism with virilizing features should generally prompt urgent investigation
-
•
Conventional imaging may not reveal OH, adrenal-ovarian vein sampling may be needed
Clinical Relevance
This case describes the rare presentation of ovarian hyperthecosis in a postmenopausal woman with polycythemia secondary to severe hyperandrogenism. Suspicion for this condition is crucial when evaluating for rare causes of polycythemia because if left untreated, it can lead to increased morbidity and mortality.
Introduction
In a postmenopausal female, hirsutism with virilizing features should generally prompt urgent investigation because these signs are associated with malignant androgen-secreting tumors of the adrenal gland and ovaries. However, these symptoms can also be the result of benign causes such as ovarian hyperthecosis (OH). This condition can increase the levels of testosterone and may eventually even lead to polycythemia. The present case documents polycythemia as the first presentation of OH. Final diagnosis was established by surgical pathology when the patient elected to undergo oophorectomy.
Case Report
A 58-year-old Caucasian woman with past medical history of depression, essential hypertension, and hyperlipidemia presented with a hemoglobin level of 18.8 g/dL (reference range, 11.7-15.6 g/dL) and hematocrit level of 56% (reference range, 45%-55%) during routine laboratory testing in the primary care setting. On further workup, she was found to have a total testosterone level of 180 ng/dL (reference range, 4-50 ng/dL). She was referred to endocrinology.
In the endocrinology clinic, she was noted to have progressive hair loss, hair thinning, and hirsutism. She had coarse hair growth around the side of the face, chin, upper lip, neck, and lower abdomen. She reported deepening of the voice and loss of scalp hair. These symptoms had been present for the last 2 years. Additionally, she reported a year-long history of fatigue and depression. Over the last several years, she had unintentional weight loss of 40 to 50 lbs but had since regained some of this weight. She denied abdominal striae, easy bruising, or muscle weakness. The patient had menarche at the age of 12 years. She endorsed menorrhagia throughout much of her adult life and remained on medroxyprogesterone acetate injections. She denied history of diagnosed polycystic ovary syndrome (PCOS). She had never been pregnant. She went through menopause at the age of 45 years. No previous surgeries were reported, and family history was unremarkable. She had a 10-pack-year history of smoking and quit 5 years ago. Medications included Cardizem 120 mg daily, lisinopril 5 mg daily, fluoxetine 40 mg daily, and rosuvastatin 10 mg daily.
On physical examination, the patient was overweight (body mass index, 28 kg/m2) and had frontotemporal alopecia and increased terminal hair growth, particularly on the face, forearm, and lower abdomen. Her Ferriman-Gallwey score was calculated as 16. There was no acne, skin hyperpigmentation, purplish striae, or acanthosis nigricans. Her blood pressure and heart rate were normal. Vaginal examination was noted to be normal at a recent gynecology visit with no evidence of clitoromegaly.
The patient underwent abdominal and pelvic contrast computed tomography (CT), which did not reveal adrenal or ovarian lesions. Laboratory data are listed in Table 1. She was evalauted by hematology for polycythemia and tested negative for JAK 2 alteration. Transvaginal ultrasound (TVUS) of the pelvis showed normal-appearing ovaries. Magnetic resonance imaging (MRI) of the pituitary with and without contrast did not show any concerning sella abnormalities.
Table 1.
Pre– and Post–Bilateral Salpingo-Oophorectomy Laboratory Values
| Laboratory values | Before surgery | After surgery | Reference laboratory values |
|---|---|---|---|
| Hb (g/dL) | 18.8 | 15.2 | 11.7-15.6 |
| Hct (%) | 56 | 46.9 | 35-45 |
| Platelet | 246 | 248 | 140-400 |
| Serum testosterone (ng/dL) | 180 | 7 | 4-50 |
| Free testosterone(pg/mL) | 3.3 | … | 0-4.2 |
| SHBG (nmol/L) | 47.5 | … | 20-125 |
| Estradiol (pg/mL) | 15 | … | <40 |
| LH (mIU/L) | 38 | … | 8-62 |
| FSH (mIU/L) | 44.8 | … | 20-180 |
| Androstenedione (ng/dL) | 28 | … | 31-701 |
| Dehydroepiandrosterone sulfate (mcg/dL) | 75 | … | 19-205 |
| 17-Hydroxyprogesterone (ng/dL) | 72 | … | <200 |
| Prolactin (ng/mL) | 10.5 | … | 4.8-23.3 |
| Dexamethasone suppression test (mcg/dL) | 1.6 | … | <1.8 |
| HbA1c (%) | 6.5 | … | <5.7 |
Abbreviations: FSH = follicle-stimulating hormone; Hb = hemoglobin; HbA1c = hemoglobin A1c; Hct = hematocrit; LH = luteinizing hormone; SHBG = sex hormone binding globulin.
Elevated levels of testosterone suggested ovarian pathology. Furthermore, normal values of dehydroepiandrosterone sulfate (DHEAS) and androstenedione ruled out a virilizing adrenal tumor, and pointed towards an ovarian origin of hyperandrogenism.
The patient was referred to another center for adrenal/ovarian vein catheterization but elected to have surgery over having the procedure. She was evaluated by gynecology, and after thorough discussions, the patient chose to have a laparoscopic bilateral salpingo-oophorectomy.
Final pathology showed benign ovaries with stromal hyperthecosis and benign fallopian tubes. Two months after surgery, the patient’s testosterone, hemoglobin, and hematocrit levels were 7 ng/dL (reference range, 3-48 ng/dL), 15.2 g/dL (reference range, 11.7-15.6 g/dL), and 46.9% (reference range, 35.0%-45.0%), respectively.
Discussion
OH presents as a state of slowly progressive hyperandrogenism in postmenopausal females, characterized by signs such as acne, hirsutism, and occasional virilization. Patients may also report a history of PCOS. This case illustrates that OH may manifest as polycythemia caused by severe hyperandrogenism. OH is a benign source of hyperandrogenism but can lead to severe sequelae such as polycythemia.
The source of endogenous hyperandrogenism in postmenopausal females can be the adrenal gland and ovaries. Androgen excess in postmenopausal females can be due to decline in ovarian estrogen production with a relatively slow decline in ovarian androgen production. The diagnosis of postmenopausal hyperandrogenism is often based on history and physical examination.
The onset of symptoms, extent of hyperandrogenism, and prior history of symptoms can help in leading to the diagnosis. Laboratory data can include the levels of total testosterone, DHEAS, androstenedione, gonadotropins, and 17-hydroxyprogesterone. When symptoms include virilization symptoms such has change in voice, clitoromegaly, frontal balding, and especially rapid-onset symptoms, then adrenal or ovarian tumors should be considered. The levels of DHEAS when very high can point toward a likely adrenal source of hyperandrogenism.
The assay for testosterone measurement should be taken into consideration as well. In our patient, the testosterone levels were checked by liquid chromatography/tandem mass spectrometry. The follicular-phase total testosterone level by mass spectrometry is the most reliable and preferred method for measurement for premenopausal women. If the testosterone level is higher than the androstenedione level, the etiology is most likely ovarian tumor.1 Table 2 shows the differential diagnosis of hyperandrogenism.
Table 2.
Differential Diagnosis of Hyperandrogenism
| Premenopausal state | Differential diagnosis |
|---|---|
| Adrenal | Classic congenital adrenal hyperplasia Nonclassic adrenal hyperplasia Cortisol-producing adrenal tumors Androgen-secreting adrenal tumors Androgen-producing adrenal carcinoma Bilateral macronodular adrenal hyperplasia |
| Ovarian | Polycystic ovary syndrome Androgen-producing ovarian tumors (sertoli-leydig cell, granulosa-theca cell, and hilus cell) |
| Others | Drugs Acromegaly Insulin resistance syndromes Cushing disease Hyperprolactinemia |
| Gestational | The same as premenopausal cause Luteoma Placental aromatase deficiency |
| Postmenopausal | Differential diagnosis |
| Adrenal | Cortisol-producing adrenal tumors Androgen-secreting adrenal tumors Androgen-producing adrenal carcinoma Bilateral macronodular adrenal hyperplasia |
| Ovarian | Androgen-producing ovarian tumors (sertoli-leydig cell and granulosa-theca cell) Ovarian hyperthecosis Teratoma Kruckenberg tumors |
| Others | Drugs Acromegaly Cushing disease |
Significantly elevated testosterone levels, such as in our patient, with normal DHEAS levels often point to an ovarian tumor and, in some circumstances, OH. However, polycythemia as a presenting sign of hyperandrogenism is an unusual presentation of OH.
When the history, physical examination, and laboratory evaluation point to an adrenal or ovarian cause of androgen excess, imaging studies should be the next step.1 Ovarian tumors are often small but may be identified using TVUS or MRI. Hyperthecosis is difficult to distinguish from androgen-producing tumor; OH can be reported on ultrasound as a bilateral increase in ovarian size, single ovarian lesion, or even normal finding.2 As previously mentioned, adrenal tumors that cause hyperandrogenism are typically greater than 8 to 10 cm at the time of presentation. However, axial CT or MRI of the adrenals is indicated in a woman with hyperandrogenism with a high DHEAS level and other clinical concerns for Cushing syndrome. Measuring Hounsfield units on noncontrast CT can help distinguish adrenal carcinomas from benign adenomas. Pituitary MRI with and without contrast is indicated when history and laboratory data point to endocrinopathies, such as acromegaly or hyperprolactinemia.1 In our patient, CT and TVUS were performed, which were negative for a tumor.
If TVUS, CT, and MRI are unable to localize the androgen-secreting tumor, combined ovarian and adrenal vein sampling can be considered. However, data do not support its ability to reliably change management.3 The ovary is likely to be the source in these cases given their small size at diagnosis. The process is tedious and requires catheterization of all 4 veins to detect a left-to-right difference in the androgen levels. Adrenal and ovarian vein sampling is not widely performed and should be considered only in centers with expertise.4,5
Adrenal vein sampling was discussed with our patient. Our patient elected not to travel for the procedure and chose oophorectomy after discussing risks and benefits with gynecology-oncology.
In the present case, our patient presented with polycythemia from her primary care provider’s office. She did have signs and symptoms of hyperandrogenism and virilization, which had remained unnoticed by patients and family members. The testosterone levels were very high, consistent with an ovarian source, and the DHEAS levels were in normal range, making adrenal tumors an unlikely cause. Cushing’s syndrome and nonclassic congenital adrenal hyperplasia were ruled out by normal biochemical workup (normal 1-mg dexamethasone suppression test result and normal 17-hydroxyprogesterone levels), and pituitary adenoma was unlikely with normal pituitary gland MRI findings.
Polycythemia resolved after bilateral oophorectomy as the testosterone levels simultaneously decreased to the reference range, thus confirming direct causality between excess testosterone levels and polycythemia, as shown in Table 1. The diagnosis of OH was confirmed by histologic analysis.
Hyperthecosis is defined as the presence of nests of luteinized theca cells in the ovarian stroma. Persistent testosterone released by ovarian theca cells is unmasked after menopause through the loss of granulosa cell–mediated aromatization of testosterone to estradiol. OH usually presents with symptoms of hyperandrogenism and is often described as a severe or extreme form of PCOS. The serum testosterone levels of >150 ng/dL (>5.2 nmol/L) are noted in affected patients, and this threshold is often used to confirm a diagnosis.6
Definitive treatment of OH is bilateral oophorectomy. Figures 1 and 2 show the pathology. In cases where surgical intervention is not suitable and in younger women aiming for future pregnancies, long-term gonadotropin-releasing hormone analog treatment can be considered as an alternative treatment.6,7 After administration of long-acting gonadotropin-releasing hormone analog, the testosterone levels and red blood cell counts are expected to decrease to the reference range. Suspicion for OH is crucial during evaluation for rare causes of polycythemia because if left untreated, the condition can lead to increased morbidity and mortality and secondary complications such as thrombotic episodes and adverse cardiovascular events.
Fig. 1.
Highlighted group of luteinized cells within the ovarian stroma.
Fig. 2.
Further magnified view of luteinized cells. Black arrows highlight characteristics such as the abundant eosinophilic cytoplasm, round nuclei, and prominent nucleoli. Some cells had vacuolated cytoplasm (red arrows).
Conclusion
OH can present with severe hyperandrogenism and virilization; however, polycythemia as initial presentation is rare. In this patient, polycythemia was detected on routine laboratory testing, which then led to further questioning of symptoms and diagnosis of OH. Ovarian hypertrichosis can commonly present insidiously. Hyperthecosis is difficult to distinguish from androgen-producing tumor. TVUS is the imaging test of choice. OH can be a missed diagnosis of hyperandrogenism.
Disclosure
The authors have no conflicts of interest to disclose.
References
- 1.Sharma A., Welt C.K. Practical approach to hyperandrogenism in women. Med Clin North Am. 2021;105(6):1099–1116. doi: 10.1016/j.mcna.2021.06.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Yance V.R.V., Marcondes J.A.M., Rocha M.P., et al. Discriminating between virilizing ovary tumors and ovary hyperthecosis in postmenopausal women: clinical data, hormonal profiles and image studies. Eur J Endocrinol. 2017;177(1):93–102. doi: 10.1530/EJE-17-0111. [DOI] [PubMed] [Google Scholar]
- 3.Zaman A., Rothman M.S. Postmenopausal hyperandrogenism: evaluation and treatment strategies. Endocrinol Metab Clin North Am. 2021;50(1):97–111. doi: 10.1016/j.ecl.2020.12.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Levens E.D., Whitcomb B.W., Csokmay J.M., Nieman L.K. Selective venous sampling for androgen-producing ovarian pathology. Clin Endocrinol (Oxf) 2009;70(4):606–614. doi: 10.1111/j.1365-2265.2008.03389.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kaltsas G.A., Mukherjee J.J., Kola B., et al. Is ovarian and adrenal venous catheterization and sampling helpful in the investigation of hyperandrogenic women? Clin Endocrinol (Oxf) 2003;59(1):34–43. doi: 10.1046/j.1365-2265.2003.01792. [DOI] [PubMed] [Google Scholar]
- 6.Meczekalski B., Szeliga A., Maciejewska-Jeske M., et al. Hyperthecosis: an underestimated nontumorous cause of hyperandrogenism. Gynecol Endocrinol. 2021;37(8):677–682. doi: 10.1080/09513590.2021.1903419. [DOI] [PubMed] [Google Scholar]
- 7.Yousaf S., Nizar R., John L., Simpson A. A case of ovarian hyperthecosis in a postmenopausal woman. JCEM Case Rep. 2023;1(6) doi: 10.1210/jcemcr/luad148. [DOI] [PMC free article] [PubMed] [Google Scholar]