MORE THAN MEETS THE EYE IN A PATIENT WITH PCOS: ANDROGEN-SECRETING GRANULOSA CELL OVARIAN TUMOR IN A VIRILIZED WOMAN WITH POLYCYSTIC OVARIAN SYNDROME (PCOS)

Abstract

Objective:

Granulosa cell ovarian tumors are known to secrete estrogen. Herein we report a patient presenting with primary amenorrhea and virilization with markedly high androgen levels, all thought to be disproportional to be attributed to polycystic ovary syndrome (PCOS) alone. Bilateral oophorectomy revealed a rare androgen-secreting granulosa cell ovarian tumor and bilateral cysts (PCOS) both contributing to manifestations.

Methods:

Description of a case and discussion of the literature.

Results:

A 25-year-old female presented with primary amenorrhea, male pattern baldness and hirsutism of the face and chest, clitoral hypertrophy, cystic acne on the chest and shoulders, and type 2 diabetes. Diagnosis of PCOS was made at age 13 years. The concurrent presence of congenital adrenal hyperplasia was also considered. She was receiving metformin, oral contraceptives, and/or spironolactone with no improvement in manifestations at presentation to the endocrine clinic. She reported several elevated serum testosterone and androstenedione levels. Diagnosis of PCOS was established by the presence of enlarged cystic ovaries on ultrasound examination. The patient reported worsening manifestations including progression of diabetes despite therapy with metformin. She shaved her face, chest, and breasts daily for cosmetic reasons. Laboratory testing demonstrated markedly elevated total testosterone level (234 ng/dL), and normal cortisol and adrenocorticotropic hormone levels. Dexamethasone suppression and human chorionic gonadotropin stimulation indicated ovaries as a probable source of excessive circulating androgen levels. A computed tomography scan of the abdomen and pelvis showed multiple cysts in both ovaries, the largest being 1.9 cm in the right ovary. Due to the severity of manifestations, the patient was counseled to undergo fluoroscopically guided blood sampling of bilateral adrenal and ovarian veins, which confirmed both ovaries to be the source of the excess androgen production with a greater contribution by the right ovary. The patient underwent bilateral oophorectomy. Pathologic examination confirmed the presence of bilateral polycystic ovaries as well as an androgen-secreting granulosa cell tumor in the right ovary which apparently contributed to greater androgen levels in a right ovarian venous blood sample. Peripheral venous androgen levels normalized promptly after bilateral oophorectomy. Gradual resolution of clinical manifestations followed.

Conclusion:

A unique presentation of granulosa cell ovarian tumor with concurrent PCOS contributing to the extremely excessive production of androgens in a young woman manifesting primary amenorrhea and masculinization at the onset of puberty with marked gradual resolution of manifestations following bilateral oophorectomy.

INTRODUCTION

Hirsutism, infertility, irregular menstrual cycles, and anovulation are hallmarks of polycystic ovarian syndrome (PCOS) (1–6). However, virilization is rarely described (7). Herein, we report a young woman treated with metformin and oral contraceptives or spironolactone for several years following a diagnosis of PCOS because of a history of primary amenorrhea and virilization despite lack of remission, and the onset and progression of type 2 diabetes. The patient was subjected to extensive evaluation including bilateral adrenal and ovarian venous sampling because of repeated documentation of markedly high peripheral venous androgen levels, thought to be disproportional to be attributed to PCOS alone. The studies confirmed both ovaries to be the source of markedly elevated androgen concentrations with a greater contribution from the right ovary. Bilateral oophorectomy revealed a rare androgen-secreting granulosa cell tumor in the right ovary and bilateral cysts (PCOS) both contributing to manifestations.

CASE REPORT

A 25-year-old woman presented with primary amenorrhea, hirsutism of the face and chest, male pattern baldness, cystic acne on the chest and shoulders, and type 2 diabetes. A diagnosis of PCOS was made at the onset of puberty at age 13 years presumably according to the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine guidelines (1). The concurrent presence of congenital adrenal hyperplasia was also considered. She was receiving metformin and spironolactone with no improvement in manifestations at presentation to the endocrine clinic at Broadlawns Medical Center. Initial laboratory testing showed elevated testosterone (185 ng/dL; normal, 8 to 48 ng/dL) and androstenedione (271 ng/dL; normal, 35 to 250 ng/dL). Diagnosis of PCOS was established by the presence of enlarged and cystic ovaries on a pelvic ultrasound and a computed tomography (CT) scan as described in several recent reports, including revised guidelines by the International PCOS Network (1–6). The patient reported worsening manifestations including progression of diabetes despite therapy with metformin. She shaved her face, chest, and breasts daily for cosmetic reasons. She did not smoke or use any illicit drugs, and reported occasional alcohol ingestion. No previous surgeries were reported. Family history was noncontributing. Physical examination confirmed male pattern baldness, a shaven face (Fig. 1 A and B), hair on her chest and central upper abdominal wall, as well as the periareolar area. Acne and scars of acne were noted on her face (Fig. 1 B) and trunk. Her vital signs were normal. Examination of her lungs, heart, and abdomen were unremarkable. Neurologic assessment showed no focal deficit including intact sensations. A pelvic examination was essentially normal with the exception of clitoral hypertrophy. No clubbing, cyanosis, or edema involving the extremities was noted. Distal pulses of radial, posterior tibial, and dorsalis pedis arteries were well palpated. At this time, laboratory testing demonstrated hyperglycemia, elevated hemoglobin A1c (8.4%) and liver enzymes (aspartate transaminase and alanine aminotransferase), as well as dyslipidemia including increased total cholesterol (215 mg/dL) and triglycerides (348 mg/dL), low high-density lipoprotein (28 mg/dL), and an undesirable low-density lipoprotein cholesterol concentration (117 mg/dL) in the presence of diabetes. The rest of the biochemistry results, complete blood count, and urinalysis were normal. Pertinent endocrine laboratory tests showed normal cortisol, dehydroepiandrosterone, and adrenocorticotropic hormone levels, as well as elevated concentrations of testosterone and androstenedione (Table 1). A lack of suppression following administration of dexamethasone, and the rise on human chorionic gonadotropin administration indicated the ovaries as the probable source of excessive testosterone levels. Ultrasound examination and CT scan of the abdomen and pelvis showed normal adrenal glands and multiple cysts in both ovaries, the largest being 1.9 cm in the right ovary. Due to the severity of masculine manifestations, the patient was counseled to undergo fluoroscopically guided blood sampling of the bilateral adrenal and ovarian veins to ascertain the source of markedly elevated androgen secretion. Bilateral ovarian venous samples showed elevated androstenedione and testosterone levels (Table 1). However, right ovarian venous blood revealed greater levels (Table 1). Moreover, right ovarian venous blood showed elevated dihydrotestosterone (DHT) as well (Table 1). Thus, both ovaries were established to be the source of the excess androgen production, though with a greater contribution by the right ovary. The patient underwent a bilateral oophorectomy. Pathologic examination confirmed the presence of multiple cysts in both ovaries. However, a granulosa cell tumor with testosterone-secreting cells present in the right ovary was apparently responsible for its greater contribution to testosterone and DHT levels (Fig. 2). Androgen levels normalized as well (Table 1). Moreover, a gradual marked improvement in clinical manifestations ensued and was sustained following a bilateral oophorectomy and hormone replacement therapy. Therefore, these findings establish the role of both PCOS and a granulosa cell tumor in virilization in this subject.

Fig. 1.

A, Daily shaved chin and neck hair. B, Visible facial stubble. C, Two years postoperative. No facial hair.

Table 1.

Circulating Levels of Various Androgens in Peripheral as well as Bilateral Adrenal and Ovarian Venous Serum Samples

Androgens	Reference range	Peripheral levels	Left adrenal vein	Right adrenal vein	Right ovary vein	Left ovary vein	Peripheral levels 2 years post-op
Androstenedione, ng/dL	30–200	231	1,430 1,230	456 487	15,900 15,000	5,150 8,160	157
DHT, ng/dL	≤300	142	160 159	217 220	4,630	1,430 2,270	<50
Testosterone, ng/dL	14–76	273	353 376	432 509	12,607 10,570	3,996 7,040	35

Fig. 2.

A, Call-Exner bodies of granulosa cell tumor. B, Brown staining of testosterone positive receptors of granulosa cell.

DISCUSSION

Hirsutism and infertility due to anovulatory menstrual cycles and/or amenorrhea are usual manifestations of PCOS (1–6). Moreover, data regarding PCOS causing virilization is sparse in the literature (7). Anecdotal or literature reports of virilization including male pattern baldness and male hair distribution (e.g., beard and mustache requiring daily shaving), as well as clitoral hypertrophy are rare. These virializing manifestations at the onset of pubertal age led us to second guess the previously established diagnosis of PCOS in our subject at several reputable major medical institutions. Lack of even a minor improvement in clinical manifestations following treatment with oral contraceptives, and/or metformin, and/or spironolactone for several years further raised suspicion about the diagnosis of PCOS. Finally, the rapid progression of type 2 diabetes while receiving metformin therapy, as well as the physical signs, enhanced our doubts regarding a causative role of PCOS alone in this patient’s symptoms, and therefore led to an extensive evaluation documenting the markedly enhanced synthesis and secretion of testosterone by both ovaries. Moreover, a gradient between ovarian venous serum androgen levels in comparison to peripheral venous and adrenal venous blood samples confirmed both ovaries to be the source. Moreover, a markedly greater level of testosterone in a right ovarian venous blood sample as compared to the left indicated an additional source of testosterone in the right ovary. This extra source was confirmed to be a testosterone-secreting granulosa cell tumor in the right ovary. Therefore, it is apparent that granulosa cell tumor with concurrent bilateral polycystic ovaries contributed to excessive circulating testosterone with consequential virilization.

Granulosa cell ovarian tumors are known to secrete estrogen rather than androgens (8). However, rare reports of androgen-secreting granulosa cell tumor have appeared in the literature though without virializing manifestations (9–13).Therefore, the concern regarding the diagnosis of PCOS alone in this subject was legitimate in light of worsening manifestations despite appropriate therapy recommended by various organizations as well as other published guidelines (2,5). The concurrent presence of a testosterone-secreting granulosa cell tumor in addition to PCOS confirmed our suspicion regarding the diagnosis of PCOS alone being responsible for virializing manifestations.

CONCLUSION

In summary, our case report describes a unique presentation of a granulosa cell ovarian tumor concurrent with polycystic ovarian syndrome, contributing to the excessive production of androgens in a young woman manifesting primary amenorrhea and masculinization at the onset of puberty (at the age of 13 years) and persisting into adulthood.

Abbreviation

PCOS

polycystic ovary syndrome