Ovarian hyperthecosis

INTRODUCTION — Ovarian hyperthecosis (OHT), a disorder characterized by severe hyperandrogenism and insulin resistance, is seen primarily in postmenopausal females. The term hyperthecosis refers to the presence of nests of luteinized theca cells in the ovarian stroma due to differentiation of the ovarian interstitial cells into steroidogenically active luteinized stromal cells (picture 1).The result is greater production of androgens.

Females with OHT typically present during their postmenopausal years, and occasionally premenopausal years, with worsening hirsutism, virilization, obesity, and insulin resistance. The clinical presentation, diagnosis, and treatment of OHT are discussed here. A more comprehensive review of the approach to severe hyperandrogenism in postmenopausal females, including a discussion of androgen-secreting ovarian and adrenal tumors is found separately. Severe hyperandrogenism associated with hypercortisolism and premenopausal hyperandrogenism are also discussed separately.

●(See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Women with virilization or severe hyperandrogenemia'.)

●(See "Clinical presentation and evaluation of adrenocortical tumors".)

●(See "Evaluation of premenopausal women with hirsutism".)

●(See "Management of hirsutism in premenopausal women".)

CLINICAL FEATURES

Severe hyperandrogenism — The majority of patients with ovarian hyperthecosis (OHT) are postmenopausal females who present with severe hyperandrogenism, characterized by gradual onset, followed by slowly progressive acne and hirsutism, and, later, virilization [1-4]. While hirsutism and female-pattern hair loss are the most common symptoms of hyperandrogenism in postmenopausal females, virilizing signs (male-pattern hair loss, clitoromegaly, lowering of the voice, increased muscle strength, and an anabolic appearance) are seen only with disorders of severe androgen excess, including OHT. (See "Evaluation of premenopausal women with hirsutism" and "Evaluation and management of postmenopausal hyperandrogenism".)

The slow onset and progression helps distinguish OHT from other causes of severe hyperandrogenism (androgen-secreting ovarian or adrenal tumors), which present with a more rapid onset and faster progression of hyperandrogenic symptoms. (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Approach to the patient'.)

Some females who develop OHT after menopause report a history of polycystic ovary syndrome (PCOS) in their premenopausal years. OHT has sometimes been referred to as an extreme form of PCOS, but the vast majority of females with PCOS do not develop OHT.

Obesity and insulin resistance — Almost all females with OHT have obesity, insulin resistance, and hyperinsulinemia [5,6]. These individuals are also at increased risk for type 2 diabetes and, possibly, cardiovascular disease [1]. Additional physical findings include skin tags and acanthosis nigricans. (See "Insulin resistance: Definition and clinical spectrum" and "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

Endometrial hyperplasia and cancer — The risk of uterine bleeding, endometrial hyperplasia, and endometrial carcinoma appears to be increased in postmenopausal females with OHT, due to aromatization of large amounts of testosterone to estrogen [1,7]. An increased risk of endometrial hyperplasia is seen in any setting of excess unopposed estrogen, either endogenous or exogenous. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Chronically increased estrogen levels or estrogenic activity'.)

Biochemical findings — Patients with hyperthecosis have the following biochemical findings (see 'Initial laboratory testing' below):

●Serum total testosterone (T) concentrations >150 ng/dL (>5.2 nmol/L) [8-11]. It is the single most important biochemical finding, and one that triggers further evaluation for causes of severe hyperandrogenism. Serum T concentrations tend to be higher in patients with androgen-secreting tumors than OHT, but hyperthecosis is unlikely if serum total testosterone is below 150 ng/dL (>5.2 nmol/L). (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Women with virilization or severe hyperandrogenemia'.)

●Normal or suppressed luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [12]. However, given the postmenopausal status of most of these patients, their endogenous LH secretion covers a wide range of serum levels, and multiple determinations of T and LH may be needed.

●Normal serum androstenedione or dehydroepiandrosterone sulfate (DHEAS) concentrations [13]. Both may be high in adrenocortical carcinoma [13].

●Unfavorable lipid profiles (increase in low-density lipoprotein [LDL] and triglycerides, decrease in high-density lipoprotein [HDL]) related to the hyperandrogenemia [14].

Histology — The term hyperthecosis refers to the presence of nests of luteinized theca cells in the ovarian stroma due to differentiation of the ovarian interstitial cells into steroidogenically active luteinized stromal cells (picture 1). These nests or islands of luteinized theca cells are scattered throughout the stroma of the ovary, rather than being confined to areas around cystic follicles as in the polycystic ovary syndrome (PCOS). The result is greater production of androgens. The precise etiology of OHT is still unclear.

EVALUATION

Initial laboratory testing — While ovarian hyperthecosis (OHT) is one cause of severe hyperandrogenism, other causes include androgen-secreting ovarian and adrenal tumors (see 'Differential diagnosis' below). The initial laboratory testing in any female who presents with severe hyperandrogenism (virilization) and no prior biochemical testing includes:

●Serum total testosterone (T).

●Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

●Most experts also measure other androgens (dehydroepiandrosterone sulfate [DHEAS] and androstenedione) in a female who presents with severe hyperandrogenism, primarily to identify adrenocortical carcinomas [13].

●We do not test for insulin resistance, as there is no agreement on how to best assess insulin resistance, and its presence does not change management. However, we do suggest evaluating for type 2 diabetes as described below. (See 'Ovarian hyperthecosis' below.)

Imaging studies — In females who present with severe hyperandrogenism (eg, virilization) and an increased testosterone concentration >150 ng/dL (>5.2 nmol/L), the next step of the evaluation is to perform additional imaging to find the source of androgen production. Imaging of the ovaries (ultrasound and magnetic resonance imaging [MRI] if needed) and adrenals (by computed tomography [CT] scan and/or MRI) are performed to rule out testosterone-producing tumors. (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Women with virilization or severe hyperandrogenemia' and 'Diagnosis' below.)

Ultrasonography — In postmenopausal females with hyperthecosis, ovarian size is usually increased compared with normal females [15]. In addition, transvaginal ultrasound in females with hyperthecosis usually shows a bilateral increase in ovarian stroma [16-18]. Unlike polycystic ovary syndrome (PCOS), where the ovaries characteristically have a polycystic/multifollicular appearance with 20 or more antral follicles of 2 to 9 mm per ovary and/or ovarian volume >10 cm³ [19], few cysts are seen in severe hyperthecosis and the ovaries appear more solid (image 1) [16]. Some types of androgen-secreting ovarian tumors are too small to be visualized.

The ovaries are enlarged in females with OHT, although normal ovaries have been reported occasionally. A normal, postmenopausal ovary has a mean volume between 1.25 to 3.7 cm³ [20,21], but in OHT, the average volume may be up to 10 cm³ [6,15].

MRI — Magnetic resonance imaging (MRI) findings in OHT include symmetric bilateral ovarian enlargement, with homogeneous T2-hypointensity and mild enhancement of the ovaries [22,23].

Ovarian and adrenal venous sampling — Combined ovarian and adrenal vein sampling (selective venous sampling) is a procedure performed on occasion for further evaluation in females with high serum T concentrations (T >150 ng/dL [5.2 nmol/L]), and normal ovarian and adrenal imaging [24,25]. We do not perform this procedure in postmenopausal females with negative ovarian and adrenal imaging, because it does not change management (bilateral oophorectomy). The ovary is likely to be the source of androgen hypersecretion because adrenal tumors are almost always visualized on adrenal CT [26,27], while ovarian tumors are often too small to be seen on imaging studies [28]. This procedure is discussed in more detail separately. (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Ovarian and adrenal vein sampling'.)

Role of gonadotropin-releasing hormone (GnRH) agonist testing — Some experts perform GnRH agonist testing for diagnostic purposes in patients with testosterone concentrations >150 ng/dL (>5.2 nmol/L) in whom the diagnosis of hyperthecosis is considered based on biochemical findings and imaging.

●OHT versus androgen-secreting tumors – This test cannot reliably distinguish between hyperthecosis and androgen-secreting ovarian tumors as some of these are gonadotropin dependent [29-31].

●OHT with a coexisting adrenal incidentaloma – The test may be useful in patients with apparent OHT with a coexisting adrenal incidentaloma on imaging, which may occur in 4 to 10 percent of patients. Suppression of serum testosterone after the dose of GnRH agonist confirms that the source of androgen excess is the ovary and not the adrenal incidentaloma. (See "Clinical presentation and evaluation of adrenocortical tumors".)

●Protocol – Immediately before and four weeks after intramuscular injection of a GnRH agonist, T, LH, and FSH should be determined. Suppression of T confirms the presence of LH-dependent ovarian T production and may provide evidence for successful long-term treatment with GnRH agonists [29-32].

Acute administration of a GnRH antagonist would be a more rapid way to determine the presence of LH-dependent ovarian T production. However, antagonists have not yet been studied in this setting.

DIAGNOSIS

Ovarian hyperthecosis — The gold standard for confirming the diagnosis of ovarian hyperthecosis (OHT) is histopathologic examination of the ovaries and demonstration of the presence of nests of luteinized cells in the ovarian stroma (picture 1) [33-35]. Occasionally, nodules are scattered throughout the stroma. In practice, the definitive diagnosis is typically made by the pathologist after surgical removal of the ovary. (See 'Management' below.)

OHT should be suspected in females with a longstanding history of hirsutism that progressively worsens in the postmenopausal years. As described above, females become virilized and have obesity, insulin resistance, and a serum total testosterone (T) concentration >150 ng/dL (>5.2 nmol/L). A serum total T lower than this effectively rules out the diagnosis. Unfortunately, virilization, which is not reversible, has already occurred by the time many patients first present.

These females typically exhibit features of the metabolic syndrome and are thus potentially at increased risk of cardiometabolic sequelae. Evaluation for type 2 diabetes should be performed with a fasting blood glucose or glycated hemoglobin (A1C). It is possible that a two-hour oral glucose tolerance test is more sensitive in this population (as it is in females with polycystic ovary syndrome [PCOS]), but this has not yet been established. (See 'Obesity and insulin resistance' above and "Diagnosis of polycystic ovary syndrome in adults", section on 'Cardiometabolic risk assessment'.)

Differential diagnosis

Androgen-secreting ovarian and adrenal tumors — In postmenopausal females with severe hyperandrogenism, androgen-secreting ovarian and adrenal tumors, although rare, are the most important disorders to address in the differential diagnosis. Serum T concentrations tend to be considerably higher than those seen with OHT but an important overlap may be found [18] (table 1). While OHT has features that are similar to androgen-secreting tumors, differences include an increase in ovarian volume (usually), obesity and insulin resistance, and a slower progression of symptoms.

Females with androgen-secreting tumors typically present with rapid onset and progression of hirsutism and virilization. Pelvic magnetic resonance imaging (MRI) can be useful for differentiating between androgen-secreting ovarian tumors and OHT [18]. (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Ovarian and adrenal neoplasms' and "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

Disorders in premenopausal females — OHT is only occasionally diagnosed in premenopausal females [2]. In premenopausal females who do have severe hyperandrogenism, androgen-secreting ovarian and adrenal tumors must be considered, but they are very rare. The approach to evaluating females with severe hyperandrogenism, including testing for possible androgen-secreting tumors, is discussed separately. (See "Evaluation of premenopausal women with hirsutism", section on 'Additional evaluation for severe hyperandrogenemia'.)

The vast majority of hyperandrogenic premenopausal females have PCOS, which is not associated with severe hyperandrogenism. These females do not become virilized, and they have lower serum T concentrations and milder insulin resistance when compared with females with hyperthecosis. In addition, the ultrasound appearance of the ovaries is different as described above. (See 'Ultrasonography' above and "Clinical manifestations of polycystic ovary syndrome in adults".)

Premenopausal females with nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency have a similar clinical presentation as those with PCOS, ie, hyperandrogenism (hirsutism), but not severe hyperandrogenism, so they do not become virilized.

PCOS and nonclassic 21-hydroxylase deficiency are discussed in detail separately. (See "Clinical manifestations of polycystic ovary syndrome in adults" and "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

MANAGEMENT

Goals — Treatment of ovarian hyperthecosis (OHT) should include therapy for hyperandrogenism (hirsutism and virilization), anovulation, obesity, and insulin resistance. The primary goal of treatment is to eliminate the excessive testosterone (T) production. However, normalization of hyperandrogenism after surgery for androgen-secreting ovarian tumors is not always followed by an improvement in body weight or insulin sensitivity [36].

Strategies to eliminate/reduce testosterone production — In postmenopausal females and the rare premenopausal patient with OHT who does not plan to pursue future fertility, the treatment options to eliminate ovarian T production are surgery (bilateral oophorectomy) and gonadotropin-releasing hormone (GnRH) agonist therapy. We suggest surgery for most females.

Bilateral oophorectomy — The treatment of choice for most postmenopausal females with likely OHT is laparoscopic bilateral salpingo-oophorectomy, which provides a definitive solution for the hyperandrogenism, as well as a surgical sample to confirm the diagnosis by histology [4].

GnRH agonist therapy — Long-term gonadotropin-releasing hormone (GnRH) agonist treatment (with estrogen-progestin add-back in premenopausal females) is an alternative, particularly in females who have an increased risk for surgery due to comorbidities or who are unwilling to undergo bilateral oophorectomy [5,29,37,38]. Descriptions for GnRH agonist with estrogen-progestin add-back regimens are described in detail separately. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'Estrogen plus progestin add-back'.)

In a report of three postmenopausal females with virilization, ovarian hyperandrogenism, and negative imaging, GnRH agonist treatment resulted in androgen suppression within the first one to three months [32]. Total treatment duration was between 8 and 13 months; after stopping therapy, T concentrations remained low in two but increased again in the third. Since no histologic diagnosis is available as final confirmation in females treated medically rather than surgically, it is recommended that all patients treated with GnRH agonists receive careful follow-up, including periodic testing of androgen levels and ovarian imaging. Another strategy would be use of a GnRH antagonist, but studies are not yet available.

If serum T concentrations do not decrease after several months of GnRH agonist therapy, we suggest surgery (bilateral oophorectomy) for histologic diagnosis.

Outcomes

●Virilizing signs and symptoms are not reversible. However, the less severe signs of hyperandrogenism, such as hirsutism and acne should begin to improve over time. Anti-androgen therapy may be helpful in some females. (See 'Additional therapies' below.)

●Metabolic profiles may not improve in spite of the dramatic reduction in serum androgens. The reasons for this are unclear. The impact of androgen suppression on insulin sensitivity was addressed in a trial of 35 postmenopausal females without diabetes assigned to receive metformin or leuprolide acetate [39]. Metformin therapy reduced serum T and improved insulin resistance and insulin sensitivity. Leuprolide acetate reduced serum T to a greater degree than metformin, but no improvement in insulin parameters was seen.

Additional therapies

●Hirsutism: Anti-androgen therapy – Anti-androgen therapy, such as spironolactone, can be used to suppress the actions of testosterone and mitigate the common clinical manifestations of hyperandrogenism, such as hirsutism, acne, and hair loss in females with OHT. (See "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)

●Metabolic issues: Obesity and type 2 diabetes – Weight reduction in females with OHT and obesity results in an increase in insulin sensitivity [40]. In patients with OHT and established type 2 diabetes mellitus, metformin is first-line therapy for glycemic management [39]. Other effects include potential weight loss and a modest decrease in serum triglycerides and low-density lipoprotein (LDL). Metformin is not effective for hirsutism. (See "Management of hirsutism in premenopausal women", section on 'Metformin' and "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Clinical outcomes'.)

Premenopausal females pursuing fertility — As noted, OHT is rare in premenopausal females, and the management of patients who have not completed childbearing is challenging. Ovulation induction is sometimes attempted, but success rates are likely low.

●Virilization – While awaiting possible ovulation induction, we suggest starting gonadotropin-releasing hormone (GnRH) agonist therapy to prevent worsening of the patient's virilization.

●Anovulatory infertility – There is little information on success rates with ovulation induction in the rare premenopausal females with OHT who desires fertility. However, pregnancy rates are likely to be very low due to factors such as obesity, abnormal ovarian architecture, and extremely high serum and intraovarian androgens. If ovulation induction is attempted, we suggest letrozole, the drug of choice for females with polycystic ovary syndrome (PCOS). If unsuccessful, clomiphene can be tried. However, in a study of five females with OHT, none ovulated in response to clomiphene [12]. Gonadotropin therapy has not been studied. (See "Overview of ovulation induction".)

There are no published reports on the success of ovarian drilling in restoring ovulation, and procedures aiming at reducing ovarian stromal volume should be discouraged and considered as a last resort only. (See "Female infertility: Reproductive surgery", section on 'Ovarian wedge resection and drilling'.)

●Hirsutism – Other options include treatment of hirsutism by local therapy, oral contraceptives, and anti-androgens. (See 'Additional therapies' above and "Management of hirsutism in premenopausal women".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hirsutism".)

SUMMARY AND RECOMMENDATIONS

●Definition – The term ovarian hyperthecosis (OHT) refers to the presence of nests of luteinized theca cells in the ovarian stroma due to differentiation of the ovarian interstitial cells into steroidogenically active luteinized stromal cells (picture 1), causing hyperandrogenism. (See 'Introduction' above.)

●Clinical features – The majority of patients with OHT are postmenopausal females who present with severe hyperandrogenism, characterized by slowly progressive acne and hirsutism, followed by virilization. Serum total testosterone (T) concentrations are typically >150 ng/dL (>5.2 nmol/L). In fact, a serum total T concentration <5.2 nmol/L (150 ng/dL) rules out hyperthecosis. OHT is rare in premenopausal females. Virilizing signs include male-pattern hair loss, clitoromegaly, lowering of the voice, increased muscle strength, and an anabolic appearance. Unfortunately, most of these signs are irreversible. (See 'Severe hyperandrogenism' above and "Evaluation and management of postmenopausal hyperandrogenism", section on 'Women with virilization or severe hyperandrogenemia'.)

Almost all females with OHT present with obesity, insulin resistance, and hyperinsulinemia. These individuals are also at increased risk for type 2 diabetes and, possibly, cardiovascular disease. (See 'Obesity and insulin resistance' above and 'Biochemical findings' above.)

●Evaluation – Biochemical testing includes serum androgens and gonadotropins followed by ovarian and adrenal imaging if serum total T concentration is >5.2 nmol/L (150 ng/dL). (See 'Evaluation' above.)

●Diagnosis – The gold standard in confirming the diagnosis of OHT is histopathologic evaluation (luteinized theca cells within the ovarian stroma and absence of neoplasia). The histologic examination is typically performed at the time of laparoscopic bilateral salpingo-oophorectomy. (See 'Histology' above and 'Diagnosis' above and 'Bilateral oophorectomy' above.)

●Differential diagnosis – In patients with severe hyperandrogenism, we perform ovarian imaging (transvaginal ultrasound and if needed, magnetic resonance imaging [MRI]) and computed tomography (CT) scan or MRI of the adrenals to rule out testosterone-producing tumors. (See 'Differential diagnosis' above.)

●Management – Treatment of OHT depends upon age, degree of virilization, and pregnancy goals. (See 'Management' above.)

•For most postmenopausal females and premenopausal females with OHT who have completed childbearing, we suggest laparoscopic bilateral salpingo-oophorectomy (Grade 2C). The primary goal of treatment is to eliminate the excessive testosterone production, and surgery is the definitive treatment. GnRH agonist therapy is a reasonable alternative for those who either choose not to have or are not candidates for surgery. (See 'Strategies to eliminate/reduce testosterone production' above.)

•In premenopausal females with OHT pursuing fertility, ovulation induction can be attempted, but is unlikely to be successful. When not doing ovulation induction, GnRH agonist therapy should be administered to prevent further progression of virilization. Other management issues include treating hirsutism, as well as reducing weight and insulin resistance. (See 'Additional therapies' above and 'Premenopausal females pursuing fertility' above.)

•In spite of dramatic reductions in serum androgen concentrations with surgery or GnRH agonist therapy, little improvement is typically seen in metabolic issues (type 2 diabetes mellitus, obesity, or insulin resistance). (See 'Outcomes' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge Manubai Nagamani, MD, and Jolande Land, MD, PhD, who contributed to earlier versions of this topic review.