Stromal hyperplasia is a nonneoplastic proliferation of ovarian stromal cells. Stromal hyperthecosis is defined as the presence of luteinized stromal cells at a distance from the follicles (211). Stromal hyperplasia, which is typically seen in patients between 60 and 80 years of age, may be associated with hyperandrogenism, endometrial carcinoma, obesity, hypertension, and glucose intolerance (211,212). Hyperthecosis is seen in a mild form in older patients. In patients of reproductive age, hyperthecosis may demonstrate severe clinical manifestations of virilization, obesity, and hypertension (213). Hyperinsulinemia and glucose intolerance may occur in up to 90% of patients with hyperthecosis and may play a role in the etiology of stromal luteinization and hyperandrogenism (72). Hyperthecosis is found in many patients with HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans).
In patients with hyperthecosis, levels of ovarian androgens, including testosterone, DHT, and androstenedione, are increased, usually in the male range. The predominant estrogen, as in PCOS, is estrone, which is derived from peripheral aromatization. The E1-to-E2 ratio is increased. Unlike in PCOS, gonadotropin levels are normal (214). Ovaries with stromal hyperthecosis have variable sonographic appearances (215).
Wedge resection for the treatment of mild hyperthecosis was successful and resulted in resumption of ovulation and in a pregnancy (216). In cases of more severe hyperthecosis and high total testosterone levels, the ovulatory response to wedge resection is transient (214). In a study in which bilateral oophorectomy was used to control severe virilization, hypertension and glucose intolerance sometimes disappeared (217). When a GnRH agonist was used to treat patients with severe hyperthecosis, ovarian androgen production was dramatically suppressed (218).
Luteomas of pregnancy are frequently associated with maternal and fetal masculinization.
This is not a true neoplasm but rather a reversible hyperplasia, which usually regresses postpartum. A review of the literature reveals a 30% incidence of maternal virilization and a 65% incidence of virilized female newborns in the presence of a pregnancy luteoma and maternal masculinization (219–221).
Other tumors causing virilization in pregnancy include (in descending order of frequency) Krukenberg tumors, mucinous cystic tumors, Brenner tumors, serous cystadenomas, endodermal sinus tumors, and dermoid cysts (202).
The most common virilizing adrenal neoplasms are adrenal carcinomas. Adrenocortical carcinomas are rare aggressive tumors that have a bimodal age incidence, with most cases presenting at ages 40 to 50 years (222). Virilization was reported in 20% to 30% of adults with functional adrenocortical carcinoma (223).
When these malignancies virilize, frequently they are associated with elevations in 11deoxycortisol, cortisol, and DHEAS. These tumors are commonly large and often detectable on abdominal examination. Adrenal tumors that secrete androgens exclusively, whether benign or malignant, are extraordinarily rare (194,224). Modern imaging techniques, such as CT, ultrasonography, MRI, or venous sampling, are extremely useful for distinguishing between an ovarian and an adrenal tumor as a cause of virilization (222).