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Approach to Investigation of Hyperandrogenism in a Postmenopausal Woman (2022)
Angelica Lindén Hirschberg
Abstract
Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal glands. Hirsutism, i.e., increased terminal hair growth in androgen-dependent areas of the body, is considered the most effective measure of hyperandrogenism in women. Other symptoms can be acne and androgenic alopecia or the development of virilization including clitoromegaly. Postmenopausal hyperandrogenism may also be associated with metabolic disorders like abdominal obesity, insulin resistance, and type 2 diabetes. Mild hyperandrogenic symptoms can be due to relative androgen excess associated with menopausal transition or polycystic ovary syndrome, which is likely the most common cause of postmenopausal hyperandrogenism. Virilizing symptoms, on the other hand, can be caused by ovarian hyperthecosis or an androgen-producing ovarian or adrenal tumor that may be potentially malignant. Determination of serum testosterone, preferably by tandem mass spectrometry, is the first step in the endocrine evaluation providing important information on the degree of androgen excess. Testosterone > 5 nmol/L is associated with virilization and requires prompt investigation to rule out an androgen-producing tumor in the first instance. To localize the source of androgen excess, imaging techniques are used like transvaginal ultrasound or magnetic resonance imaging (MRI) for the ovaries and computed tomography (CT) and MRI for the adrenals. Bilateral oophorectomy or surgical removal of an adrenal tumor is the main curative treatment and will ultimately lead to a histopathological diagnosis. Mild to moderate symptoms of androgen excess is treated with anti-androgen therapy or specific endocrine therapy depending on the diagnosis. This review summarizes the most relevant causes of hyperandrogenism in postmenopausal women and suggests principles for clinical investigation and treatment.
Case presentation
A postmenopausal 66-year-old nulliparous woman with type 2 diabetes and hyperlipidemia is being referred to a specialist clinic at a university hospital due to suspected androgen-dependent hair loss that has developed over the years. She has frontotemporal baldness and has been using a wig for a couple of years. The woman first sought medical help many years ago but was told that it is normal with hair loss after menopause. When examining the patient, it is noted that she is overweight with a body mass index of (BMI) 29 and she has abdominal fat distribution. Furthermore, she has so-called “Hippocratic baldness”, corresponding to grade 3 on the Ludwig Scale (1) (Figure 1), oily skin, increased body hair, and blood pressure of 160/90 mm Hg. The most marked finding in laboratory analyses is a clearly elevated testosterone 1 level of 5.6 nmol/L (Table 1). Furthermore, androstendione (A4) of 6.8 nmol/L is above normal for postmenopausal women (2). Dehydroepiandrosterone sulfate (DHEAS) (4.0 micromol/L) and sex hormone-binding globulin (SHBG) (28 nmol/L) are within the reference range. Gynecological examination shows clitoromegaly and a greatly enlarged uterus on palpation, as well as bilateral ovaries of significant size detected by transvaginal ultrasound. She is referred to a Doppler ultrasound examination confirming large uterine fibroids and enlarged ovaries with normal blood flow. The patient undergoes a hysterectomy and bilateral salpingo-ophorectomy. Histopathological examination reveals benign uterine fibroids and bilateral ovarian stromal hyperplasia with the presence of nests of luteinized theca cells in agreement with ovarian hyperthecosis. No signs of malignancy. Postoperatively, testosterone levels normalize within a couple of weeks (0.8 nmol/L). The symptoms subside spontaneously resulting in weight loss, reduced abdominal obesity, hirsutism, and oily skin. However, androgenic alopecia and clitoromegaly remain.
*Menopausal transition and circulating testosterone
*Etiology of hyperandrogenism in postmenopausal women
-Polycystic ovary syndrome
-Ovarian hyperthecosis
-Androgen-secreting ovarian tumors
-Androgen-secreting adrenal tumors
-Nonclassical congenital adrenal hyperplasia
-Cushing’s syndrome
-Iatrogenic
*Evaluation
-Clinical symptoms
-Endocrine evaluation
-Imaging
*Treatment
Conclusion
Postmenopausal hyperandrogenism can range from mild symptoms due to relative androgen excess during the menopausal transition to virilizing symptoms caused by a hormone-producing ovarian or adrenal tumor that may be potentially malignant. A thorough investigation must be performed to determine the underlying causes and to offer appropriate treatment. The onset of symptoms, development, and severity of symptoms are indicative for further investigation. Measurement of serum testosterone, preferably by LC-MS/MS, provides important information on the degree of androgen excess. Testosterone > 5 nmol/L is associated with virilizing symptoms and should prompt further investigation with imaging modalities to rule out an androgen-producing tumor. There is no discriminatory method to distinguish an ovarian hormone-producing tumor from ovarian hyperthecosis although the latter is related to slower development of virilizing symptoms and a bilateral ovarian enlargement. Surgery with bilateral oophorectomy or removal of an adrenal tumor is the main curative treatment and will ultimately lead to a histopathological diagnosis. GnRH analogs can be used as an alternative treatment for ovarian hyperthecosis. PCOS is probably the most common cause of mild to moderate symptoms of hyperandrogenism and testosterone < 5 nmol/l in a postmenopausal woman. In this case, the recommended treatment is anti-androgen therapy using an androgen receptor blocker and/or a 5α reductase inhibitor. NC CAH could be treated in a similar way or if needed with cortisone, whereas Cushing’s syndrome is primarily treated with surgery.
Angelica Lindén Hirschberg
Abstract
Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal glands. Hirsutism, i.e., increased terminal hair growth in androgen-dependent areas of the body, is considered the most effective measure of hyperandrogenism in women. Other symptoms can be acne and androgenic alopecia or the development of virilization including clitoromegaly. Postmenopausal hyperandrogenism may also be associated with metabolic disorders like abdominal obesity, insulin resistance, and type 2 diabetes. Mild hyperandrogenic symptoms can be due to relative androgen excess associated with menopausal transition or polycystic ovary syndrome, which is likely the most common cause of postmenopausal hyperandrogenism. Virilizing symptoms, on the other hand, can be caused by ovarian hyperthecosis or an androgen-producing ovarian or adrenal tumor that may be potentially malignant. Determination of serum testosterone, preferably by tandem mass spectrometry, is the first step in the endocrine evaluation providing important information on the degree of androgen excess. Testosterone > 5 nmol/L is associated with virilization and requires prompt investigation to rule out an androgen-producing tumor in the first instance. To localize the source of androgen excess, imaging techniques are used like transvaginal ultrasound or magnetic resonance imaging (MRI) for the ovaries and computed tomography (CT) and MRI for the adrenals. Bilateral oophorectomy or surgical removal of an adrenal tumor is the main curative treatment and will ultimately lead to a histopathological diagnosis. Mild to moderate symptoms of androgen excess is treated with anti-androgen therapy or specific endocrine therapy depending on the diagnosis. This review summarizes the most relevant causes of hyperandrogenism in postmenopausal women and suggests principles for clinical investigation and treatment.
Case presentation
A postmenopausal 66-year-old nulliparous woman with type 2 diabetes and hyperlipidemia is being referred to a specialist clinic at a university hospital due to suspected androgen-dependent hair loss that has developed over the years. She has frontotemporal baldness and has been using a wig for a couple of years. The woman first sought medical help many years ago but was told that it is normal with hair loss after menopause. When examining the patient, it is noted that she is overweight with a body mass index of (BMI) 29 and she has abdominal fat distribution. Furthermore, she has so-called “Hippocratic baldness”, corresponding to grade 3 on the Ludwig Scale (1) (Figure 1), oily skin, increased body hair, and blood pressure of 160/90 mm Hg. The most marked finding in laboratory analyses is a clearly elevated testosterone 1 level of 5.6 nmol/L (Table 1). Furthermore, androstendione (A4) of 6.8 nmol/L is above normal for postmenopausal women (2). Dehydroepiandrosterone sulfate (DHEAS) (4.0 micromol/L) and sex hormone-binding globulin (SHBG) (28 nmol/L) are within the reference range. Gynecological examination shows clitoromegaly and a greatly enlarged uterus on palpation, as well as bilateral ovaries of significant size detected by transvaginal ultrasound. She is referred to a Doppler ultrasound examination confirming large uterine fibroids and enlarged ovaries with normal blood flow. The patient undergoes a hysterectomy and bilateral salpingo-ophorectomy. Histopathological examination reveals benign uterine fibroids and bilateral ovarian stromal hyperplasia with the presence of nests of luteinized theca cells in agreement with ovarian hyperthecosis. No signs of malignancy. Postoperatively, testosterone levels normalize within a couple of weeks (0.8 nmol/L). The symptoms subside spontaneously resulting in weight loss, reduced abdominal obesity, hirsutism, and oily skin. However, androgenic alopecia and clitoromegaly remain.
*Menopausal transition and circulating testosterone
*Etiology of hyperandrogenism in postmenopausal women
-Polycystic ovary syndrome
-Ovarian hyperthecosis
-Androgen-secreting ovarian tumors
-Androgen-secreting adrenal tumors
-Nonclassical congenital adrenal hyperplasia
-Cushing’s syndrome
-Iatrogenic
*Evaluation
-Clinical symptoms
-Endocrine evaluation
-Imaging
*Treatment
Conclusion
Postmenopausal hyperandrogenism can range from mild symptoms due to relative androgen excess during the menopausal transition to virilizing symptoms caused by a hormone-producing ovarian or adrenal tumor that may be potentially malignant. A thorough investigation must be performed to determine the underlying causes and to offer appropriate treatment. The onset of symptoms, development, and severity of symptoms are indicative for further investigation. Measurement of serum testosterone, preferably by LC-MS/MS, provides important information on the degree of androgen excess. Testosterone > 5 nmol/L is associated with virilizing symptoms and should prompt further investigation with imaging modalities to rule out an androgen-producing tumor. There is no discriminatory method to distinguish an ovarian hormone-producing tumor from ovarian hyperthecosis although the latter is related to slower development of virilizing symptoms and a bilateral ovarian enlargement. Surgery with bilateral oophorectomy or removal of an adrenal tumor is the main curative treatment and will ultimately lead to a histopathological diagnosis. GnRH analogs can be used as an alternative treatment for ovarian hyperthecosis. PCOS is probably the most common cause of mild to moderate symptoms of hyperandrogenism and testosterone < 5 nmol/l in a postmenopausal woman. In this case, the recommended treatment is anti-androgen therapy using an androgen receptor blocker and/or a 5α reductase inhibitor. NC CAH could be treated in a similar way or if needed with cortisone, whereas Cushing’s syndrome is primarily treated with surgery.
