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Gestational hyperandrogenism

Gestational hyperandrogenism
Literature review current through: Jan 2024.
This topic last updated: Nov 30, 2023.

INTRODUCTION — Gestational hyperandrogenism refers to a state of androgen excess that occurs during pregnancy. The clinical presentation can range from mild signs and symptoms of androgen excess, including acne or hirsutism, to a more severe presentation with signs of maternal virilization, including frontal balding, clitoromegaly, and voice deepening. When evaluating a female with gestational hyperandrogenism, the goals are to identify the source of androgen excess, determine the risk of fetal virilization, and distinguish between benign and malignant causes of hyperandrogenism. The causes, clinical features, evaluation, and management of females with gestational hyperandrogenism will be reviewed here (table 1 and table 2). The approach to the patient with an adnexal mass during pregnancy and the management of the virilized infant are reviewed separately. (See "Adnexal mass: Evaluation and management in pregnancy" and "Management of the infant with atypical genital appearance (difference of sex development)".)

ANDROGENS DURING PREGNANCY: NORMAL PHYSIOLOGY

Serum androgen levels — Serum androgen levels are increased in pregnancy. Testosterone levels in nonpregnant females (without polycystic ovary syndrome [PCOS]) are generally <50 ng/dL (1.7 nmol/L), while levels during normal pregnancy are in the 50 to 120 ng/dL (1.7 to 4.2 nmol/L) range [1]. These ranges may be variable and are assay specific.

Normal pregnancy is characterized by a progressive increase in maternal serum androgens, leading to a peak of testosterone levels at birth [2]. There is also an increase of sex hormone-binding globulin (SHBG) during pregnancy, thus circulating levels of free testosterone are minimally increased in the first and second trimesters, but increase more significantly in the third trimester as the elevation in testosterone outpaces that of SHBG (table 3) [2].

The main source of increased androgen production during pregnancy is the maternal ovary, but the maternal adrenal glands, as well as fetal adrenal glands, also contribute to this physiologic increase in androgens [3]. The rising androgen levels during pregnancy serve as a substrate for estrogen production via aromatization by the growing placental mass and are thought to play a role in maintaining pregnancy and initiating labor [3].

Protection of mother and fetus from hyperandrogenism

Maternal protection – Despite these physiologic increases, females do not typically experience clinically significant symptoms or signs of hyperandrogenism such as acne or hirsutism [4-7]. Maternal protection is afforded via several mechanisms. For one, the increasing levels of SHBG are able to bind the high circulating levels of testosterone, thus limiting the amount of free and bioactive testosterone. Another protective factor is placental aromatase, an enzyme that converts androgen precursors to estrogens. The increased androgen levels during pregnancy from both maternal and fetal sources serve as a substrate for placental aromatase to convert androgen precursors to estrogens. In so doing, the placenta protects the mother from the potentially androgenizing effects of either maternal or fetal sources of androgen excess [8].

Fetal protection – Placental aromatase also helps to protect the female fetus from virilization by converting androgens to estrogens. In the presence of severe pathologic hyperandrogenism, however, the functional capacity of the system can be overwhelmed.

CLINICAL FEATURES

Maternal — Females affected by gestational hyperandrogenism may initially notice the onset of symptoms such as hirsutism and acne. For more severe cases, virilizing signs may occur, including frontal balding, clitoromegaly, and deepening of the voice (see "Evaluation of premenopausal women with hirsutism", section on 'Severe hyperandrogenism'). Although hirsutism and acne will regress with decreasing androgen levels, virilizing signs may be non-reversible.

Fetal — For the female fetus, elevated androgen exposure between the 7th and 12th weeks of development may result in partial or complete labial fusion and clitoral hypertrophy. After the 12th week of gestation, clitoral hypertrophy remains a risk, but labial fusion does not occur. In some cases, gestational hyperandrogenism is first suspected at the time of delivery due to virilization of a female infant. The development of the male fetus is unaffected by maternal hyperandrogenism. Of note, most cases of fetal virilization are due to increased androgens from fetal sources, such as fetal congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Virilization due to maternal sources of androgens is less common.

DIAGNOSTIC EVALUATION — The diagnosis of gestational hyperandrogenism is clinical and based upon the finding of maternal signs of hyperandrogenism or virilization during pregnancy. In rare cases, the diagnosis may be made retrospectively with the discovery of a virilized female fetus at the time of delivery.

Goals — When evaluating a female with gestational hyperandrogenism, the most important goals are to:

Determine the potential risk of virilization for a female fetus. (See 'Androgens during pregnancy: Normal physiology' above.)

Identify the source of androgen excess and distinguish between benign and malignant causes.

Determine the need for intervention. For virilized pregnant females with a very high serum total testosterone and a solid ovarian mass suggestive of androgen-secreting ovarian tumor or luteoma, surgical removal of the mass may prevent virilization of the female fetus (table 2). (See 'Management' below.)

Assessment of fetal virilization risk — Whereas male fetuses are not affected by maternal hyperandrogenism, female fetuses may be at risk of virilization. The degree of this risk depends on a number of factors, including (table 2) (see 'Ovarian sources' below):

Timing of onset of increased maternal androgen production

Magnitude and type of androgen increase

Ability of the placenta to convert testosterone to estrogen

The degree of virilization is most severe if the increase in maternal androgen production begins in the first trimester since that is when female external genital development occurs. After the 12th week of gestation, clitoral hypertrophy remains a risk, but labial fusion does not occur (see 'Fetal' above). Risk of fetal virilization varies depending on the underlying source of androgens. Fetal virilization occurs in some virilized pregnant females with luteomas but extremely rare in those with theca lutein cysts. This difference is because theca lutein cysts are more likely to present in the second and third trimester, past the point of labial fusion in a female fetus [9], whereas luteomas are more likely to be present in the first trimester.

Sex determination is the first step when determining the risk of virilization. Measurement of cell-free fetal DNA in the maternal circulation now permits gender identification of female fetuses at risk as early as nine weeks gestation. If the fetus is female, early surgical intervention to remove a hormone-secreting tumor may limit fetal virilization. An overview of the clinical uses of prenatal diagnosis using cell-free fetal DNA (including fetal sex determination) is found separately. (See "Sex selection", section on 'Cell-free DNA' and "Prenatal screening for common aneuploidies using cell-free DNA".)

Assessment of source of androgen excess

Hormone determinations — The severity of hyperandrogenism can be gauged by measuring serum testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), and, in some cases, sex hormone-binding globulin (SHBG). While serum androgen concentrations help distinguish between benign and malignant causes of androgen excess in nonpregnant females, the utility of these measurements is less certain in pregnant females with hyperandrogenism because benign lesions such as luteomas and theca lutein cysts may be associated with extremely high testosterone concentrations (11,000 ng/dL in one case report). Importantly, however, elevated androgens during pregnancy due to benign sources will normalize by three weeks postpartum [10-12].

We do not suggest umbilical cord sampling, because of the small risk of fetal loss from the procedure. In addition, this procedure is not technically possible until 18 to 20 weeks of gestation, after the time at which virilization would have occurred.

Pelvic ultrasound — Females who present with acute onset of hyperandrogenism in pregnancy require a pelvic ultrasound to identify potential ovarian sources of excess androgens, including ovarian tumors or cysts. Ultrasonography is helpful in distinguishing between solid and cystic ovarian tumors and between unilateral and bilateral ovarian disease. The imaging specialist usually decides on a transvaginal and/or a transabdominal approach based on the clinical situation. Generally, early in pregnancy, the ovaries are better visualized transvaginally with a high-frequency transducer. In the third trimester, the ovaries are not near the vagina and transabdominal sonography would usually be used, but in some cases, the ovaries might be in the cul de sac and transvaginal would also be useful. (See "Evaluation of premenopausal women with hirsutism", section on 'Additional evaluation for severe hyperandrogenemia'.)

Ovarian cysts — Ovarian cysts associated with maternal hyperandrogenism are usually theca lutein cysts, which are benign and almost always bilateral [13-15]. (See 'Theca lutein cysts' below.)

Females with gestational trophoblastic neoplasia and very high human chorionic gonadotropin (hCG) levels may harbor ovarian theca lutein cysts. Therefore, when a cystic ovarian mass is seen on ultrasound, trophoblastic disease and other high hCG states should be ruled out. (See "Adnexal mass: Evaluation and management in pregnancy", section on 'Diagnostic evaluation' and "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification".)

Ovarian masses (solid)

Solid masses are usually luteomas. Luteomas are generally large (>4 cm) and predominantly solid on ultrasound with Doppler imaging showing prominent arterial and venous blood flow. Luteomas can be unilateral or bilateral. In 50 percent of cases, multiple nodules are present [16]. Unilateral solid masses increase the possibility of malignancy, but may still be a luteoma. If a luteoma is likely by ultrasound, observation is usually warranted. Otherwise, oncology consultation and possibly biopsy may be indicated. (See "Adnexal mass: Evaluation and management in pregnancy" and "Adnexal mass: Ultrasound categorization", section on 'Steps in characterizing a mass'.)

In very rare cases, a unilateral, solid, androgen-producing mass could represent a Sertoli-Leydig cell tumor. An oncology consultation should be considered to determine likelihood of malignancy. Magnetic resonance imaging (MRI) may also be useful to further characterize the mass. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults", section on 'Diagnostic evaluation'.)

Bilateral ovarian masses, with the exception of the very rare Krukenberg tumor, are rarely malignant.

Krukenberg tumors are ovarian metastases of primary tumors of the gastrointestinal tract that in some way activate the surrounding stroma. These are very rare, but the 80 percent incidence of bilaterality can be a clue to this rare cause of gestational hyperandrogenemia.

Benign versus malignant — The two most common causes of gestational hyperandrogenism are benign: luteomas and theca lutein cysts of the ovary (table 1). However, in rare cases, malignant ovarian androgen-secreting tumors (see 'Virilizing malignant ovarian tumors' below) can cause gestational hyperandrogenism.

Although a solid ovarian mass on pelvic ultrasound raises the suspicion of malignancy, if the mass has features of a luteoma (table 2), observation until after delivery can be considered. Luteomas will regress several weeks following delivery. Failure of a solid mass to regress postpartum should increase suspicion for malignancy.

If ovarian sources of hyperandrogenism are not identified by ultrasound, an investigation of adrenal sources, including malignancy, should be initiated. (See 'Adrenal imaging' below.)

Adrenal imaging — If an ovarian mass is not seen on ultrasound, adrenal imaging using MRI with 2 to 3 mm cuts should be performed to look for an androgen-secreting adrenal tumor (either benign or an adrenocortical carcinoma). In pregnant females, MRI is generally preferred over computed tomography (CT) to avoid ionizing radiation. Using low- or mid-field strength magnets, T1 and T2-weighted imaging can usually distinguish benign adenomas from malignancy. Other imaging features that distinguish benign adenomas from adrenocortical carcinomas are reviewed in detail separately. Adrenocortical carcinomas have characteristic imaging phenotypes that distinguish them from benign adrenal adenomas; these are reviewed in detail separately. (See "Evaluation and management of the adrenal incidentaloma", section on 'Adrenocortical carcinoma' and "Evaluation and management of the adrenal incidentaloma", section on 'MRI' and "Diagnostic imaging in pregnant and lactating patients".)

Laparoscopy — Very little information exists on the use of laparoscopy in the evaluation of gestational hyperandrogenism, but laparoscopy with removal of a luteoma or ovarian tumor would be expected to be helpful in females with virilization in the first trimester. There has been a report of laparoscopic decompression of large theca lutein cysts [17]. (See "Laparoscopic surgery in pregnancy".)

If the history, physical examination (virilization), androgen assessment, and imaging suggests a tumor, laparoscopy or laparotomy may be indicated to make the diagnosis and remove the tumor. On occasion, surgery is necessary for large luteomas that result in ovarian torsion. (See 'Management' below and "Laparoscopic surgery in pregnancy".)

DIFFERENTIAL DIAGNOSIS — Hyperandrogenism during pregnancy is uncommon. A careful history can often determine if hyperandrogenism predates the pregnancy, suggesting either polycystic ovary syndrome (PCOS) and/or congenital adrenal hyperplasia (CAH). The history should also probe any sources of exogenous androgens. In cases where hyperandrogenism is new and clinically significant, a search for a cause is required. In most cases, new hyperandrogenism occurring during pregnancy is due to either a luteoma or theca lutein cysts of the ovary. In rare cases, no cause is found [18].

The causes of gestational hyperandrogenism include those that existed prior to pregnancy and those that occur within the context of pregnancy.

Prior to pregnancy – Conditions that existed prior to pregnancy include polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia (CAH). PCOS is the most common cause of hirsutism in females, but it rarely, if ever, causes virilization of the mother or fetus during pregnancy [19]. (See "Clinical manifestations of polycystic ovary syndrome in adults".)

CAH is an inherited autosomal recessive disease that is another cause of hirsutism in females. Maternal CAH would also not be expected to lead to maternal or fetal virilization in pregnancy due to the powerful aromatization capabilities of the placenta. Fetal inheritance of CAH, however, can lead to marked virilization of a female fetus. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Atypical genitalia'.)

During pregnancy – Conditions that occur within the context of pregnancy include ovarian tumors (eg, luteomas and theca lutein cysts of the ovary), both of which are benign and regress in the postpartum period (see 'Luteomas' below and 'Theca lutein cysts' below). Other rare causes of gestational hyperandrogenism during pregnancy include placental aromatase deficiency, exogenous androgen exposures, and ovarian and adrenal malignancies.

Ovarian sources

Polycystic ovary syndrome — Females with PCOS have higher serum androgen concentrations during pregnancy than normal females [20] but not high enough to cause virilization (unless they also develop theca lutein cysts). (See 'Theca lutein cysts' below.)

Luteomas — Females with luteomas have much higher serum concentrations of testosterone, dihydrotestosterone, and androstenedione [1,21-24] than normal pregnant females or pregnant females with PCOS. Maternal hirsutism or virilization is present in approximately 30 to 35 percent of reported cases of pregnancy luteomas [21,25]. Some females with pregnancy luteomas present with mass-related symptoms from ureteral compression, obstructive uropathy, or ovarian torsion [10]. Luteomas can also be asymptomatic and are only discovered at the time of routine obstetric ultrasound or cesarean delivery [6].

Luteomas are not true tumors; rather they are hyperplastic masses of large lutein cells that proliferate under the influence of human chorionic gonadotropin (hCG) and then regress and disappear within two to three weeks after delivery [10-12]. They are usually from 6 to 10 cm in diameter (range 1 to 25 cm) and, while sharply circumscribed, are not encapsulated.

Luteomas can be difficult to differentiate from other solid ovarian neoplasms. Luteomas are bilateral in approximately 45 to 50 percent of cases (table 2) [21,22,26], which, with the exception of Krukenberg tumors, tends to favor a non-malignant lesion.

Pregnant females with a luteoma may present with moderate signs of hyperandrogenism (acne, hirsutism), but in approximately 30 to 35 percent of cases, females will present with virilizing signs. If the mother has virilizing signs, there is an 80 percent chance that a female fetus will also be virilized. If the mother is not virilized, then the fetus is not virilized. When estimating the risk of virilization of a fetus in utero, important factors include the sex of the fetus, the duration of exposure to androgens, and, most importantly, the stage of pregnancy during which the exposure took place (greatest risk in the first trimester) (table 2) [27,28].

High maternal serum androgen concentrations are not always associated with maternal hirsutism or virilization for reasons that are unclear. Case reports of two females with luteomas of pregnancy who were not virilized and had very high serum testosterone concentrations (2650 ng/dL [92 nmol/L] and 2830 ng/dL [98 nmol/L] when normal gestational concentrations are 50 to 120 ng/dL [1.7 to 4.2 nmol/L]) illustrate the heterogeneity of presentation [1].

Although serum testosterone concentrations normalize postpartum in females with luteomas, virilizing symptoms such as deepening of the voice and clitoromegaly are not reversible. Recurrence of luteoma in subsequent pregnancies has been observed. preimplantation genetic testing could be considered for the selection of a male embryo in order to prevent virilization of a female fetus.

Theca lutein cysts — Theca lutein cysts are comprised of luteinized and hypertrophied theca interna cells. Hyperreactio luteinalis refers to the cystic enlargement of the ovaries by numerous theca lutein cysts. These cysts are typically bilateral, multiple, regress after delivery, and therefore should not require surgical therapy. On ultrasound, multiple hypo-echoic cysts are visualized with a "spoke and wheel" pattern. The lack of a solid component distinguishes theca lutein cysts from a luteoma or malignancy. Theca lutein cysts are more common in conditions characterized by high levels of hCG, including molar pregnancies and multiple gestations. Trophoblastic disease should be ruled out in females presenting with theca lutein cysts in early in pregnancy. (See 'Pelvic ultrasound' above.)

The size of ovaries containing theca lutein cysts in pregnant females can range from normal to 10 to 15 cm; large cysts can cause troublesome pressure symptoms.

Approximately 30 percent of pregnant females with theca lutein cysts have hirsutism or are virilized (table 2) [15,21,29,30]. Many, if not all, virilized females have high serum testosterone and androstenedione concentrations, and cord serum testosterone concentrations in infants of virilized mothers are either normal or high [29-32]. However, only one case of a virilized female infant has been reported (table 2) [33].

The incidence of gestational theca lutein cysts is highest (10 to 22 percent) in females with trophoblastic disease as a result of markedly elevated circulating hCG. Theca lutein cysts may also be seen in other conditions associated with high hCG levels, such as multiple gestations, ovarian hyperstimulation during ovulation induction, alloimmunization, and diabetes mellitus.

Pregnant females with preexisting hirsutism such as those with PCOS are more likely to have theca lutein cysts as the source of their androgen excess [34].

Virilizing malignant ovarian tumors — The most serious cause of virilization in pregnancy are ovarian tumors and adrenocortical carcinoma, both of which are fortunately rare (table 1). Virilizing tumors that have been reported in a few pregnant females include Sertoli-Leydig cell tumors and Krukenberg tumors (ovarian metastases of gastrointestinal, particularly gastric, carcinomas) [21,35-40]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

Approximately 7 percent of ovarian tumors occurring during pregnancy are malignant. However, the risk of malignancy approaches 50 percent if the female is virilized and has a unilateral, solid ovarian mass.

Sertoli-Leydig cell tumors (formerly referred to as arrhenoblastomas) are a type of sex cord stromal tumors that produces high androgen levels. These tumors are very rare, but have been occasionally reported in pregnant females [41-44]. Like nonpregnant females, most pregnant females (69 to 87 percent) with these tumors are virilized (table 2) [41] (see "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults"). These tumors are composed of seminiferous tubules and rete testis-like structures. Although the majority are benign, the proportion that is malignant is higher than in nonpregnant females (40 to 50 versus 12 to 22 percent) [41]. Serum androgens are markedly elevated, although this does not distinguish between benign and malignant androgen sources. Serum inhibin A concentrations can be elevated in these tumors but not in luteomas or theca lutein cysts.

The overall survival of patients with sex cord stroma tumors in general appears to be comparable with that seen in nonpregnant females (five-year survival rate for stage I of 100 percent and for stage II to IV of 70 percent) [44].

Krukenberg tumors are ovarian metastases of primary tumors of the gastrointestinal tract that in some way activate the surrounding stroma to produce androgens, presumably via an autocrine or paracrine mechanisms.

They are solid tumors, and 80 percent are bilateral. Most of the handful of pregnant females with these tumors reported in the literature had hirsutism or virilization, and one-half delivered virilized infants (table 2) [21,45]. (See "Adnexal mass: Differential diagnosis", section on 'Metastatic disease'.)

Adrenal sources

Adrenal adenomas — Benign androgen-secreting adrenal adenomas are an extremely rare cause of maternal and fetal virilization, but there have been case reports [46]. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Clinical presentation'.)

Adrenocortical carcinoma — Adrenocortical carcinomas diagnosed in pregnant females (detected by adrenal imaging [magnetic resonance imaging (MRI)]) are extremely rare. These tend to be cortisol-secreting tumors more often than androgen-secreting or androgen and cortisol-secreting tumors, and fetal outcome is poor [47,48]. However, a case of maternal and fetal virilization has been described in a female with a cortisol and androgen-secreting adrenal carcinoma [49]. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Clinical presentation'.)

Exogenous androgen exposure — The administration of exogenous androgens to pregnant females has caused signs of androgen excess in the female and virilization of female fetuses [50-53]. The greatest risk to the female fetus is during the first trimester, although clitoral hypertrophy may still occur with androgen exposure after the 12th week of gestation. The development of the male fetus is not affected. (See 'Fetal' above.)

In the past, there were cases of fetal virilization after exposure to very high doses of progestins, most notably, norethindrone (40 to 60 mg/day), which was used early in pregnancy to prevent miscarriage [50,52]. However, exposure to progestins is no longer considered to be a risk for fetal virilization, as high progestin doses are no longer used. For example, the dose of norethindrone in a standard oral estrogen-progestin contraceptive is typically 1 mg, and androgen-associated adverse effects have not been described [54].

Placental aromatase deficiency — P450 aromatase (CYP19A1) is necessary for the synthesis of estrogens from androgen precursors. Aromatase deficiency is an autosomal recessive disorder due to mutations in the CYP19A1 gene. The earliest manifestation can be during fetal life with fetal (female fetus) and maternal virilization, which occurs because the fetal-placental unit is unable to adequately convert androgens to estrogens due to the low aromatase activity [55,56]. Maternal symptoms may occur as early as 12 weeks. The role of various polymorphisms in CYP19A1 remains to be determined.

Other fetal disorders such as CAH that cause fetal, but not maternal virilization, are reviewed separately. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

MANAGEMENT — Management options for females with gestational hyperandrogenism are limited. There are no medical therapies; most females are treated conservatively (observation), while some undergo surgery if indicated [12].

Medical therapies — There are no pharmacologic options for pregnant females with gestational hyperandrogenism. Unlike nonpregnant females with symptoms of hyperandrogenism, the use of combined oral estrogen-progestin contraceptives and/or androgen receptor antagonists such as spironolactone are contraindicated during pregnancy. (See "Management of hirsutism in premenopausal women", section on 'Available antiandrogens: Efficacy'.)

Observation — Observation is the most common management strategy. When a male fetus is identified, virilization concerns are eliminated.

Luteomas – If the clinical presentation and imaging studies are consistent with a luteoma, conservative management, including follow-up imaging postpartum, is an option since the lesion will resolve after delivery. On the other hand, if the mass is found in the second trimester and is large (>5 cm) and/or causing symptoms, it is reasonable to perform surgical removal to avoid the risk of ovarian torsion.

In addition, surgery is sometimes performed if the mother is virilized, the fetus is female, and there are ultrasound findings suggestive of a luteoma. Depending upon the timing, virilization may be prevented or minimized. However, the benefits of this approach must always be weighed against the potential risks of surgery. (See 'Surgery' below.)

Theca lutein cysts – Although 30 percent of females with theca lutein cysts present with virilization, only one case of a virilized female infant has been reported; all other female infants have been normal. Management is conservative (observation, serial pelvic ultrasounds) as these cysts resolve postpartum. However, some theca lutein cysts can become very large and cause pressure symptoms. (See 'Theca lutein cysts' above.)

Surgery — If the history, physical examination (virilization), androgen assessment, and imaging suggests a malignant, androgen-secreting ovarian or adrenal tumor, we recommend urgent surgical removal of the tumor regardless of trimester. (See "Treatment of adrenocortical carcinoma" and "Sex cord-stromal tumors of the ovary: Management in adults".)

Luteomas causing mass-related symptoms may also require urgent surgery (see 'Luteomas' above). Early surgical intervention to remove a luteoma may also be indicated to limit both maternal and fetal virilization, as signs of virilization, including clitoromegaly, are irreversible. The benefits of this approach must always be weighed against the potential risks of surgery. (See 'Ovarian masses (solid)' above and 'Luteomas' above.)

Female fetuses exposed to high androgen levels in the first trimester are at risk of virilization. The use of cell-free DNA may allow sex determination by 10 weeks. Surgical management can be considered to prevent further virilization in cases where the sex of the fetus is female.

Urgently needed surgery should be performed regardless of the trimester, whereas completely elective surgery should be postponed until after delivery. Nonurgent surgery that cannot wait until delivery should be performed during the second trimester. (See "Nonobstetric surgery in pregnant patients: Patient counseling, surgical considerations, and obstetric management".)

SUMMARY AND RECOMMENDATIONS

Clinical features

Maternal – Females affected by gestational hyperandrogenism may initially notice the onset of symptoms such as hirsutism and acne. For more severe cases, virilizing signs may occur, including frontal balding, clitoromegaly, and deepening of the voice. (See 'Maternal' above.)

Fetal – Exposure of a female fetus to high androgen concentrations between the 7th to 12th week of gestation is associated with a risk of irreversible virilization; after the 12th week, exposures are associated only with a risk of clitoral hypertrophy. The male fetus is not adversely impacted by gestational hyperandrogenism. (See 'Fetal' above.)

Diagnostic evaluation – The essential components of evaluation include assessing the risk of fetal virilization, identifying the source of androgen excess, and distinguishing between benign and malignant causes of hyperandrogenism. (See 'Diagnostic evaluation' above.)

Assess fetal risk – Patients should be counseled about the option of cell-free DNA testing, which is reliable for sex determination by the 10th week of gestation. In cases where the fetal sex is found to be female, surgical management can be considered to reduce the risk of further virilization. (See 'Assessment of fetal virilization risk' above.)

Hormone measurements – Testing includes measurement of serum androgens, including total and free testosterone, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS). Serum androgens cannot, however, distinguish between benign and malignant sources of hormone production. (See 'Hormone determinations' above.)

Imaging - Imaging should begin with ovarian imaging (typically with pelvic ultrasound), and, if no ovarian source is found, be followed by adrenal imaging. (See 'Ovarian sources' above and 'Adrenal sources' above.)

Differential diagnosis – The most common causes of gestational hyperandrogenism are luteoma of pregnancy and theca lutein cysts. Fetal virilization is common in virilized pregnant females with luteomas but extremely rare in those with theca lutein cysts. Rare causes of gestational hyperandrogenism include androgen-secreting adenomas, adrenocortical carcinomas, and placental aromatase deficiency (table 1 and table 2). (See 'Differential diagnosis' above.)

Management – Management options for females with gestational hyperandrogenism are limited. There are no medical therapies; most females are treated conservatively (observation), while some undergo surgery if indicated. Indications for surgery include the following:

Females whose imaging suggests a malignant, androgen-secreting ovarian or adrenal tumor; these patients should be referred to the appropriate surgical specialist for surgical removal of the tumor regardless of trimester. (See "Adnexal mass: Evaluation and management in pregnancy", section on 'Malignant neoplasms' and "Treatment of adrenocortical carcinoma" and "Sex cord-stromal tumors of the ovary: Management in adults", section on 'General surgical considerations for patients with an ovarian neoplasm'.)

Females with pregnancy luteomas who present with mass-related symptoms. (See 'Luteomas' above.)

Lastly, surgery is sometimes performed in a virilized pregnant females with a solid ovarian mass suggestive of a luteoma, to prevent virilization of the female fetus (table 2). (See 'Surgery' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Howard D McClamrock, MD, who contributed to an earlier version of this topic review.

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Topic 7449 Version 16.0

References

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