The Journal of Clinical Endocrinology & Metabolism, 2023, 108, 1243–1253

https://doi.org/10.1210/clinem/dgac673
Advance access publication 21 November 2022
Approach to the Patient

Approach to Investigation of Hyperandrogenism

in a Postmenopausal Woman
Angelica Lindén Hirschberg1,2
1
Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm SE-171 76, Sweden
2
Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm SE-171 76, Sweden
Correspondence: Angelica Lindén Hirschberg, MD, PhD, Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, SE-171 76

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Stockholm, Sweden. Email: [email protected].

Abstract
Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal
glands. Hirsutism, in other words, 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 such as 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 could be 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, such as transvaginal ultrasound or magnetic resonance imaging (MRI) for the ovaries and computed tomography 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 are treated with antiandrogen therapy or specific endocrine
therapy depending on diagnosis. This review summarizes the most relevant causes of hyperandrogenism in postmenopausal women and
suggests principles for clinical investigation and treatment.
Key Words: hyperandrogenism, hirsutism, virilization, postmenopausal women, ovarian hyperthecosis, androgen-producing tumor
Abbreviations: 17-OHP, 17-hydroxyprogesterone; A4, androstendione; ACTH, adrenocorticotropic hormone; AMH, antimüllerian hormone; BMI, body mass
index; CAH, congenital adrenal hyperplasia; CT, computed tomography; DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; FSH,
follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LC–MS/MS, liquid chromatography-tandem mass spectrometry; LH, luteinizing
hormone; MRI, magnetic resonance imaging; NC, nonclassic; PCOS, polycystic ovary syndrome; SHGB, sex hormone–binding globulin; SV, simple virilizing;
SW, salt wasting.

Case presentation within the reference range. Gynecological examination shows

clitoromegaly and a greatly enlarged uterus on palpation,
A postmenopausal 66-year-old nulliparous woman with type
as well as bilateral ovaries of significant size detected by
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 body mass index (BMI) 29 and she has ab­
dominal fat distribution. Furthermore, she has so-called
“Hippocratic baldness,” corresponding to grade III on the
Ludwig scale (1) (Fig. 1), oily skin, increased body hair, and
blood pressure 160/90 mmHg. The most marked finding in la­
boratory analyses is a clearly elevated testosterone level of
5.6 nmol/L (Table 1). Furthermore, androstendione (A4) of
6.8 nmol/L is above normal for a postmenopausal woman Figure 1. The Ludwig scale of androgen-dependent frontotemporal
(2). Dehydroepiandrosterone sulfate (DHEAS) (4.0 µmol/L) baldness type I to III, where type III is the most severe form of
and sex hormone–binding globulin (SHBG) (28 nmol/L) are androgenic alopecia also called “Hippocratic baldness.”

Received: 1 August 2022. Editorial Decision: 16 November 2022. Corrected and Typeset: 12 December 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
1244 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5

Table 1. Hormone values in the patient case

Hormone Patient value Reference interval

FSH, IU/L 30 30-150 postmenopausal

LH, IU/L 16 15-65 postmenopausal
Testosterone, nmol/L 5.6 0.3-3 premenopausal
SHBG, nmol/L 28 35-350
Androstendione, nmol/L 6.8 1.6-12 premenopausal
DHEAS, µmol/L 4.0 0.5-4.1
Estradiol, pmol/L 98 <40 postmenopausal

Abbreviations: DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone–binding globulin.

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transvaginal ultrasound. She is referred for a Doppler ultra­ peripheral tissue from DHEA within the cell according to
sound examination, which confirms large uterine fibroids the concept of intracrinology (5).
and enlarged ovaries with normal blood flow. The patient It was recently demonstrated that the androgen derivates
undergoes hysterectomy and bilateral salpingo-ophorectomy. 11-ketotestosterone and 11-ketodihydrotestosterone from
Histopathological examination reveals benign uterine fib­ the adrenal glands are also potent agonists of the human andro­
roids and bilateral ovarian stromal hyperplasia with the pres­ gen receptor (6). In contrast to classical androgens (DHEA,
ence of nests of luteinized theca cells, in agreement with DHEAS, A4, and testosterone), 11-keto androgens do not de­
ovarian hyperthecosis. There are no signs of malignancy. crease with age (7). Furthermore, these androgens have shown
Postoperatively, testosterone levels normalize within a couple to be predominant in several disorders of hyperandrogenism,
of weeks (0.8 nmol/L). The symptoms subside spontaneously, including polycystic ovary syndrome (PCOS) (8) and congeni­
resulting in weight loss, and reduced abdominal obesity, hir­ tal adrenal hyperplasia (CAH) (9). However, determination
sutism, and oily skin. However, androgenic alopecia and clit­ of 11-keto androgens is not yet available as a clinical routine
oromegaly remain. method.
SHBG, a protein secreted by the liver, regulates the bioavail­
ability of testosterone. Around 65% to 70% of circulating tes­
Menopausal Transition and Circulating
tosterone is bound and inactivated by SHBG, 30% to 35% is
Testosterone loosely bound to albumin, and only 0.5% to 3% represents
Menopausal transition is associated with a decrease in the freely circulating testosterone (10). Since the binding of testos­
number of antral follicles and ovarian volume, as well as a de­ terone to albumin is rather weak, the free and albumin-bound
cline in serum antimüllerian hormone (AMH) as a marker for fractions are defined as bioavailable testosterone. The ratio of
antral follicle count and ovarian reserve. When the number of total testosterone to SHBG multiplied by 100 (the free andro­
antral follicles and ovarian granulosa cells decrease, estradiol gen index) is used as a measure of circulating free testosterone.
levels decline and follicle-stimulating hormone (FSH) levels in­ However, this measure is less relevant when total testosterone
crease. Menopause, the last spontaneous menstruation, oc­ is pathologically increased.
curs on average at age 51 years when circulating estradiol During menopausal transition, ovarian theca cell produc­
has decreased to a level insufficient to stimulate the endomet­ tion of testosterone decreases due to follicle depletion, but
rium to grow and then shed. During this period, menopausal this loss is compensated by increased LH stimulation of stro­
symptoms, including hot flushes, sweating, and sleep prob­ ma cell production of testosterone. Consequently, ovarian
lems, are common and associated with the gradual decline androgen production does not change significantly in rela­
in estradiol. tion to menopause. At the same time, SHBG decreases due
In contrast to the decrease in estradiol, circulating levels of to the decrease in ovarian estrogen production, and subse­
testosterone decline as a consequence of age-related, but not quently the free androgen index increases (11, 12). Overall,
menopause-related, reductions in secretion by both the ad­ this will result in a physiological shift from estrogen domin­
renal gland and the ovary (3). This means a 50% reduction ance to a relative predominance of androgens during meno­
in testosterone in women aged 40-45 compared with women pausal transition (13). Besides the typical menopausal
in the 18-24 age group. In premenopausal women, about symptoms, it is not uncommon for healthy postmenopausal
50% of circulating testosterone arises from direct secretion women to experience androgen-dependent symptoms, such
from the ovary and the adrenal gland, in equal amounts, under as increased facial hair growth and hair thinning due to rela­
pituitary control of luteinizing hormone (LH) and adrenocor­ tive androgen excess.
ticotropic hormone (ACTH), respectively (4). The remaining The most common cause of absolute androgen excess in
50% of testosterone is produced from peripheral conversion postmenopausal women is PCOS, causing mild to moderate
by ovarian and adrenal inactive androgen precursors (A4, de­ symptoms of hyperandrogenism (2), whereas virilizing symp­
hydroepiandrosterone (DHEA), and DHEAS). Testosterone is toms including, for instance, clitoromegaly, deepening of the
further converted in target tissues to dihydrotestosterone voice, and breast atrophy besides severe hirsutism and pos­
(DHT) by the enzyme 5α reductase, and together these hor­ sibly androgenic alopecia (Table 2) are rare and should be
mones constitute the 2 classical bioactive androgens that carefully investigated. The most relevant causes of hyperan­
bind to the androgen receptor. In postmenopausal women, a drogenism, of either ovarian or adrenal origin, in postmeno­
larger part of these active androgens is synthesized in pausal women are described below (Table 3).
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5 1245

Table 2. Mild to moderate and virilizing symptoms of hyperandrogenism diagnose PCOS after menopause. The Endocrine Society
in postmenopausal women Clinical Practice Guideline has therefore suggested that a diag­
nosis of PCOS in a postmenopausal woman can be based upon
Symptoms of hyperandrogenism a history of oligo/amenorrhea and hyperandrogenism during
Mild to moderate symptoms Hirsutism the reproductive years (20).
Acne and oily skin The reproductive phenotype of PCOS usually improves by
Virilizing symptoms Severe hirsutism and acne age due to loss of ovarian follicles, leading to more regular
Androgenic alopecia cycles and decreased ovarian volume (21). However, the de­
Deepening of the voice crease in ovarian volume and serum AMH during menopausal
Breast atrophy transition may be relatively less in women with PCOS than in
Increased muscle mass other women (22, 23). Consequently, the average age of
Enlargement of clitoris menopause is approximately 2 years later in PCOS than in
healthy controls (24). As androgen levels gradually decrease
by age, symptoms of hyperandrogenism like hirsutism may
improve in women with PCOS (25). Still, the prevalence of

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Etiology of Hyperandrogenism in
hirsutism was significantly higher in postmenopausal women
Postmenopausal Women
with PCOS than in control women (33% vs 4%) at mean age
Polycystic Ovary Syndrome 81 years in a Swedish long-term follow-up study (26).
PCOS is considered the most frequent endocrine disorder in PCOS is considered a relatively mild form of hyperandro­
women of reproductive age with a prevalence between 8% genism since circulating levels of testosterone usually are with­
and 13% depending on diagnostic criteria and population in the upper normal female range, whereas SHBG is low,
studied (17, 18). According to the Rotterdam criteria, at least resulting in increased levels of free and bioavailable testoster­
2 of the following 3 criteria are required for a diagnosis: oligo­ one. Today, liquid chromatography-tandem mass spectrom­
menorrhea or amenorrhea; biochemical or clinical hyperan­ etry (LC–MS/MS) is recognized as the gold standard method
drogenism such as hirsutism and acne; and polycystic for testosterone determination in serum compared with im­
ovarian morphology (19). There are no specific criteria to munobased clinical methods, which are burdened with cross-

Table 3. Characteristics of different conditions of hyperandrogenism in postmenopausal women

Condition Prevalence/Incidence Testosterone Presentation

levels

PCOS Prevalence: 8% to 13% in the whole <2 nmol/L Persistent or increased hirsutism but no virilizing
female population of fertile age symptoms
History of oligo/amenorrhea and hyperandrogenism
during reproductive years
Later menopause
Overweight, abdominal obesity
Ovarian hyperthecosis Prevalence: 9.3% in postmenopausal >5 nmol/L Gradual development of virilizing symptoms in a peri-
women with hyperandrogenism (2) or postmenopausal woman
Isolated increase in testosterone
Severe insulin resistance, acanthosis nigricans,
metabolic syndrome, and/or type 2 diabetes
Bilaterally enlarged ovaries
Androgen-secreting ovarian Prevalence: 2.7% in postmenopausal >5 nmol/L Rapid onset of virilizing symptoms
tumor women with hyperandrogenism (2) Serum testosterone often in the male range,
accompanying increase in A4 and 17-OHP, but
usually not DHEAS
Unilateral ovarian tumor
Androgen-secreting adrenal Incidence: 1 to 2 cases/million >5 nmol/L Rapid onset of virilizing symptoms
tumor population/year (14) Serum testosterone in the male range, DHEAS, and
cortisol usually elevated
Unilateral adrenal tumor
Nonclassic congenital Prevalence: 1% to 10% in women with <5 nmol/L Gradual increase in hirsutism since puberty
adrenal hyperplasia hirsutism (15) Similar symptoms as in PCOS
Serum testosterone moderately increased, 17-OHP
elevated
Cushing’s syndrome Incidence: 1.8 to 3.2 cases/million <2 nmol/L New-onset hirsutism but seldom virilizing symptoms
population/year (16) Typical signs of Cushing syndrome such as moon face,
abdominal obesity, striae, buffalo hump
ACTH-secreting pituitary adenoma or a
cortisol-producing tumor

Abbreviations: 17-OHP, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate;
PCOS, polycystic ovary syndrome.
1246 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5

reactivity against structurally similar steroid hormones and,

moreover, are not sensitive enough for the determination of
steroids at relatively low concentrations (27). Available
measurements based on LC–MS/MS indicate that the normal
range of testosterone in premenopausal women is 0.1 to
1.8 nmol/L, whereas the upper limit in women with PCOS
is 3.1 nmol/L (95% CI one-sided) (28). Although testoster­
one levels decline with increasing age, most studies have
shown higher testosterone levels in postmenopausal women
with PCOS than in control women (29-31). However, testos­
terone levels in postmenopausal women with PCOS seldom
exceed 2 nmol/L (30-33).
PCOS is also a metabolic disorder with increased occur­
rence of obesity, which aggravates all symptoms of the syn­
drome, including hirsutism (34). Abdominal obesity is

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associated with insulin resistance, leading to secondary hyper­
insulinemia (35). Hypersecretion of insulin stimulates ovarian
androgen production in synergy with LH (35). In addition, in­
sulin inhibits the hepatic synthesis of SHBG, leading to an in­
creased free androgen index (36). In this way, obesity and
insulin resistance contribute to hyperandrogenism in women
with PCOS. Testosterone may in turn induce hepatic insulin
resistance by facilitating catecholamine-stimulated lipolysis
in visceral fat tissue, and peripheral insulin resistance in
muscle tissue by inducing decreased capillary density (34, 37).
Women with abdominal obesity often have a more pro­
nounced PCOS phenotype and remain hyperandrogenic after
menopause or may even have worsening symptoms. In the
long run, PCOS is associated with an increased risk of type
2 diabetes and metabolic syndrome (18), whereas the risk
of cardiovascular disease seems not to be increased after
menopause (32).
Although hirsutism may be severe in PCOS, virilizing symp­
toms including clitoral enlargement are not associated with
PCOS (Tables 2 and 3). In cases where hyperandrogenic
symptoms increase and develop into virilization, other condi­
tions of androgen excess must be ruled out.

Ovarian Hyperthecosis
Ovarian hyperthecosis is a relatively rare disorder presenting
with slow progress of severe symptoms of hyperandrogenism
in a perimenopausal or postmenopausal woman (Table 3)
(38). It is likely the second most frequent cause of hyperandro­
genism in postmenopausal women. The prevalence of ovarian
hyperthecosis was reported to be 9.3% in postmenopausal
women undergoing investigation for symptoms of androgen
excess (2).
The condition is often described as an extreme form of Figure 2. Clinical signs of severe hyperandrogenism and virilizing
symptoms of hyperandrogenism in a perimenopausal and
PCOS; however, there is no clear evidence of a link between postmenopausal women including (A) androgenic alopecia, (B) breast
ovarian hyperthecosis and PCOS, and most women with atrophy and hirsutism, and (C) clitoromegaly.
PCOS will never develop ovarian hyperthecosis. In contrast
to PCOS, ovarian hyperthecosis will progress into virilizing
symptoms, including severe hirsutism, androgenic alopecia, metabolic symptoms are often more severe than in women
deepening of the voice, breast atrophy, and clitoromegaly with PCOS. Due to peripheral conversion of androgens to es­
(Table 2, Fig. 2). In addition, the ovaries are bilaterally clearly trogens via aromatase, women with ovarian hyperthecosis
enlarged with a volume up to 10 cm3, compared with a vol­ also have an increased risk of endometrial pathology, includ­
ume between 1 and 5 cm3 of a normal postmenopausal ovary ing polyps, hyperplasia, and cancer (44, 45), as well as breast
in women with or without PCOS (39-41). Ovarian hyperthe­ cancer (46).
cosis is strongly associated with metabolic symptoms, includ­ Ovarian hyperthecosis is caused by nests of luteinized theca
ing abdominal obesity, hypertension, hyperlipidemia, insulin cells in the ovarian stroma producing high amounts of testos­
resistance, and acanthosis nigricans, in other words, the terone in the absence of other elevated androgens (47). Serum
metabolic syndrome and type 2 diabetes (39, 42, 43). The testosterone is usually increased above 5 nmol/L (38, 41),
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5 1247

which distinguishes this condition from PCOS (Table 3). The resonance imaging (MRI). Asymmetry of the ovaries may sug­
etiology of ovarian hyperthecosis is not known, although a gest a tumor.
genetic disposition and association with PCOS have been sug­
gested (48). Several mechanisms behind the increased testos­ Androgen-Secreting Adrenal Tumors
terone production have been proposed. One is related to the
Androgen-secreting adrenal tumors are less common than
“2-cell hypothesis” where ovarian testosterone production
the corresponding ovarian tumors. Benign adrenal adenomas
by theca cells is uncovered in a postmenopausal woman by
include nonsecretory (incidentalomas) and secretory aden­
the loss of granulosa cell–mediated aromatization of testoster­
omas, of which the latter can cause hyperandrogenism.
one to estradiol (49). Another mechanism involves increased
Adrenocortical carcinomas, on the other hand, are usually
gonadotrophin stimulation by elevated levels of LH after
highly malignant tumors, and approximately 25% of cases
menopause (50). Thirdly, there is support that insulin resist­
are associated with severe symptoms of hyperandrogenism
ance and hyperinsulinemia may induce stromal luteinization
leading to virilization (Table 3) (2, 58-60). The incidence is
causing androgen overproduction (51).
1 to 2 cases/million population per year. There is a bimodal
The most important differential diagnosis for ovarian hy­
age distribution, with peaks before the age of 5 and in the
perthecosis is an androgen-producing tumor, which can be

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fourth and fifth decade of life (14).
malignant. In both cases, the patient has virilizing symptoms,
Adrenocortical carcinomas are considered gonadotropin in­
but progress is usually slow for ovarian hyperthecosis but rap­
dependent and are manifested by an increase in adrenal andro­
id for an androgen-producing tumor. In addition, testosterone
gens, DHEA, and DHEAS (2). DHEAS concentrations are often
is greatly elevated (>5 nmol/L) in both disorders, but mostly
more than twice the upper limit, and a value above 19 µmol/L is
higher in women with an androgen-producing tumor than in
an indication for further evaluation. Furthermore, testosterone
those with ovarian hyperthecosis (41). Furthermore, other an­
is highly elevated in the male range, as is A4 (58, 59). Cortisol
drogens are usually not elevated in ovarian hyperthecosis,
secretion may be increased both in androgen-secreting aden­
whereas androgen-producing adrenal tumors are associated
omas and carcinomas, leading to a clinical image of Cushing
with high levels of DHEAS and A4, and ovarian tumors
syndrome in addition to hyperandrogenism.
with high levels of inhibin B. Almost all women with ovarian
Adrenal tumors are best visualized by computed tomog­
hyperthecosis have obesity and insulin resistance, but this is
raphy (CT) as a unilateral mass. Adenomas are usually small,
not the case of women with an androgen-producing tumor.
2 to 2.5 cm, whereas adrenocortical carcinomas are larger, be­
Ovarian hyperthecosis is also characterized by bilateral in­
tween 4 and 21 cm (60).
crease in ovarian stroma, whereas an ovarian tumor usually
presents as a unilateral enlargement. Still, it can be difficult
to distinguish ovarian hyperthecosis from an androgen- Nonclassical Congenital Adrenal Hyperplasia
producing tumor. The diagnosis of ovarian hyperthecosis is CAH is an autosomal recessive disease characterized by low or
therefore confirmed by histopathology. absent production of cortisol and aldosterone with concomi­
tant overproduction of androgens due to an enzyme deficiency
in the adrenal cortex steroid biosynthesis (61). The most com­
Androgen-Secreting Ovarian Tumors mon type is 21-hydroxylase deficiency caused by a mutation in
Androgen-secreting ovarian tumors originate from sex cord the gene (CYP21A1) encoding the adrenal 21-hydroxylase en­
stroma and include Sertoli cell tumors, Sertoli–Leydig cell tu­ zyme (62). There are different clinical forms of CAH depend­
mors, Leydig cell tumors, thecoma, and granulosa cell tumors ing on the degree of enzyme deficiency: the severe salt wasting
(52, 53). These tumors are predominantly benign and occur at form (SW CAH), the simple virilizing form (SV CAH), and the
any age, but approximately 25% present after menopause less severe nonclassic form (NC CAH). SW CAH and SV
(54). Together they comprise 5% to 8% of all ovarian neo­ CAH, often referred to as classic CAH, are usually diagnosed
plasms (29). The presentation is often rapid progress of clinic­ in infancy via newborn screening programs if available, due to
al manifestations of excessive androgen and/or estrogen varying degrees of virilization in females, or in the most severe
production (Table 3). Androblastomas (Sertoli cell tumors, cases due to life-threatening SW (62). The treatment of CAH
Sertoli–Leydig cell tumors, Leydig cell tumors) are those pri­ consists of substitution therapy with glucocorticoids and min­
marily secreting androgens, while thecoma and granulosa eralocorticoids, which will reduce the overproduction of an­
cell tumors mainly secrete estrogens, which can lead to post­ drogens (62).
menopausal bleeding, endometrial hyperplasia, or cancer. In contrast to classic CAH, women with NC CAH are usu­
However, around 10% of granulosa cell tumors secrete an­ ally diagnosed later in life due to mild symptoms of androgen
drogens and may cause virilization (55). The prevalence of excess, such as hirsutism, menstrual disorders, and infertility
an androgen-secreting ovarian tumor in postmenopausal (Table 3) (15). The symptoms are very similar to PCOS,
women with symptoms of hyperandrogenism has been re­ and, in agreement with PCOS, NC CAH is not associated
ported to be 2.7% (2). with virilizing symptoms. Since some of these women may
Endocrine characteristics of androblastomas are clearly be undiagnosed or have worsening symptoms by age (63),
elevated testosterone, often in the lower male range NC CAH should be considered in postmenopausal women
(8-29 nmol/L) (28), with an accompanying increase in A4 with hyperandrogenism. The NC form of CAH is estimated
and 17-hydroxyprogesterone (17-OHP), whereas DHEAS to be one of the most common autosomal recessive disorders,
and cortisol levels usually are normal (52). In the case of gran­ with a prevalence of 1% to 10% in women with hyperandro­
ulosa cell tumors, they usually cosecrete AMH and inhibin B, genic symptoms (15).
besides estradiol and/or testosterone (56, 57). Elevated serum 17-OHP, due to accumulation before the en­
Ovarian tumors are often small but can be identified using zyme block, is indicative of CAH (64). It should be further in­
transvaginal ultrasound with color Doppler or magnetic vestigated by an ACTH stimulation test. Serum concentrations
1248 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5

of testosterone and adrenal androgen precursors (A4, DHEA, and rapid development of virilizing symptoms suggest a
and DHEAS) are also increased. The diagnosis is confirmed hormone-producing tumor, whereas slow development of vir­
by genetic testing and detection of a mutation causing enzyme ilizing symptoms in a perimenopausal or postmenopausal
deficiency and impaired corticosteroid synthesis. woman is typical of ovarian hyperthecosis. In contrast, early
symptom onset and slow progression of mild to moderate hy­
Cushing Syndrome perandrogenic symptoms are more consistent with PCOS or
another endocrine disorder (Fig. 3).
Cushing syndrome is a rare disorder, which can be either
Clinical signs of mild to virilizing symptoms of hyperan­
ACTH-dependent and caused by pituitary hypersecretion of
drogenism are shown in Table 2. Hirsutism has been consid­
ACTH (Cushing disease, about 70%) or ACTH independent
ered the most effective measure of androgen excess in
due to adrenocortical adenoma or carcinoma (about 20%)
women (74). It is defined as excessive facial and body ter­
(65). ACTH-dependent Cushing is associated with elevated
minal hair in androgen-dependent body areas. Evaluation
ACTH levels causing bilateral adrenocortical hyperplasia and
of hirsutism can be assessed by the modified Ferriman–
hypersecretion of cortisol. In contrast, ACTH-independent
Gallwey score, 0 (no terminal hair) to 4 (marked hirsutism),
Cushing disease is related to suppressed ACTH secretion due
in 9 body areas: upper lip, chin and cheeks, upper chest,

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to negative feedback by increased cortisol secretion (65). The
upper abdomen, lower abdomen, upper arms, thighs, upper
overall incidence of Cushing syndrome is estimated to be 1.8
back, and lower back (Table 4) (75, 76). A cut-off score of
to 3.2 cases per million population (16). Cushing disease occurs
≥ 4 to 6 on the modified Ferriman–Gallwey was suggested
mainly in women aged 25-45 years.
to indicate hirsutism, depending on ethnicity (77).
The major clinical manifestations of Cushing syndrome
However, this method has not been validated in postmeno­
are moon face and facial plethora, abdominal obesity, striae,
pausal women.
buffalo hump, proximal muscle weakness, bruising, hyperten­
Acne is associated with increased androgen levels, although
sion, glucose intolerance, depression, and other neuropsycho­
the predictive value of acne for hyperandrogenism has been
logical symptoms (66). About 50% of women with Cushing
questioned (74, 78). Furthermore, there is no universally ac­
syndrome also have symptoms of hyperandrogenism, such
cepted classification tool for evaluation of acne (74). It is rec­
as hirsutism, due to adrenal androgen excess (A4, DHEA,
ommended to assess acne in a patient undergoing evaluation
and DHEAS) (Table 3) (67). Furthermore, the free androgen
of hyperandrogenism (Table 3) (74).
index is increased by endogenous hypercortisolism, probably
Androgenic alopecia, or female pattern hair loss, is charac­
due to a decrease in SHBG. However, signs of hyperandrogen­
terized by thinning of hair in the frontoparietal region of the
ism are usually mild to moderate and seldom lead to
scalp (Fig. 2) (79). The disorder is dependent on androgens,
virilization.
particularly DHT, and 5α reductase activity in hair follicles
The diagnosis of Cushing syndrome is established by hyper­
(79). Hair loss on the scalp can be assessed using the
secretion of cortisol, as measured by 24-hour urinary free cor­
Ludwig scale (Table 4) (Fig. 1) (1).
tisol, late-night salivary cortisol, or the 1-mg dexamethasone
Clitoromegaly is probably the most recognizable sign of vir­
suppression test (68). Further evaluation is needed to deter­
ilization (Fig. 2). It has been defined as >1.5 × 2.5 cm (29, 80).
mine ACTH dependence or independence by measurement
However, signs of clitoromegaly must be carefully investi­
of plasma ACTH, as well as pituitary, adrenal, or ectopic eti­
gated, as they are easy to miss, especially in an obese woman.
ology by using MRI of the pituitary and CT of the adrenal
Other signs of virilization may be breast atrophy and severe
glands or other relevant imaging. First-line treatment is surgi­
hirsutism (Fig. 2).
cal removal of the ACTH- or cortisol-secreting tumor (68).

Iatrogenic
Iatrogenic causes of hyperandrogenism due to overuse or Endocrine Evaluation
abuse of androgenic drugs should be considered. Systemic tes­ Symptoms of hyperandrogenism and particularly virilizing
tosterone and DHEA treatment of hypoactive sexual desire symptoms (including, eg, clitoromegaly, deepening of the
disorder or other androgen deficiency–related symptoms in voice, and breast atrophy besides severe hirsutism and pos­
postmenopausal women may lead to overtreatment if not sibly androgenic alopecia) in a postmenopausal woman
carefully monitored by measurement of serum testosterone should be evaluated by endocrine screening, preferably se­
(69). Furthermore, treatment with the antiepileptic drug val­ rum FSH, LH, testosterone, SHBG, A4, DHEAS, estradiol,
proic acid has been shown to increase the risk of a 17-OHP, and inhibin B (Table 4). For steroid hormone
PCOS-like phenotype in epidemiological studies (70). The determination, it is highly recommended to use LC–MS/MS
mechanism is attributed to direct stimulation of ovarian an­ instead of immunological methods as mentioned above.
drogen production by valproic acid (71). The anabolic steroid Using receiver operating characteristic analysis, the diagnostic
danazol, previously used for treatment of endometriosis and threshold for serum testosterone as measured by LC–MS/MS
still used as therapy for hereditary angioedema, has been re­ to identify an androgen-producing tumor was defined as
ported to induce hirsutism (72). It is well known that anabolic testosterone ≥5.1 nmol/L (sensitivity, 90%; specificity,
steroids can cause virilization in women when abused (73). 81%) (33). Serum testosterone >5 nmol/L is clearly associ­
ated with virilizing symptoms (Table 2) (38, 81). It is there­
fore suggested to use this value of testosterone as the
Evaluation
cut-off in the first step of investigation to rule out a hormone-
Clinical Symptoms producing tumor or a nontumor cause of severe hyperandro­
The patient’s history of onset and development of symptoms genism such as ovarian hyperthecosis in a postmenopausal
should always be a guide for further investigation. Late onset woman (Fig. 3).
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5 1249

Postmenopausal hyperandrogenism
• Clinical history
• Physical examination
• Endocrine evaluation

• Premenopausal debut of hyperandrogenism • Peri- or postmenopausal debut

• Mild to moderate hirsutism and oily skin but no • Virilizing symptoms including e.g. clitoromegaly,
virilizing symptoms deepening of the voice and breast atrophy besides
• Testosterone < 5 nmol/L severe hirsutism and possibly androgenic alopecia
• Testosterone > 5 nmol/L

No suspicion of androgen-producing tumor Exclude androgen-producing tumor

• Transvaginal ultrasound for ovarian investigation • Doppler transvaginal ultrasound or MRI for ovarian
• Further endocrine evaluation including 17-OHP and investigation
possibly 24h u-cortisol • CT and/or MRI for adrenal investigation

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• No tumor • High s-17-OHP • High 24h u-cortisol • No tumor • Unilateral ovarian • Unilateral adrenal
• Abdominal obesity • ACTH stimulation test • Dexamethasone test • Bilateral ovarian enlargement enlargement
• Genetic testing • MRI of the pituitary, CT enlargement
of the adrenal glands

• PCOS • NC CAH • Cushing’s syndrome • Ovarian • Ovarian tumor • Adrenal tumor

hyperthecosis

• Antiandrogen • Glucocorticoids • Surgery of ACTH- or • Bilateral • Bilateral • Adrenalectomy

medication • Antiandrogen cortisol-producing oophorectomy or oophorectomy
• Metformin medication tumor • GnRH analogue

Figure 3. Algorithm for principles of investigation and treatment of different causes of hyperandrogenism in postmenopausal women. The cut-off of
5 nmol/L for serum testosterone is based on LC–MS/MS measurement. ACTH, adrenocorticotropic hormone; CT, computed tomography; GnRH,
gonadotropin-releasing hormone; 17-OHP, 17-hydroxyprogesterone; MRI, magnetic resonance imaging; NC CAH, nonclassical congenital adrenal
hyperplasia; PCOS, polycystic ovary syndrome.

Women with virilizing symptoms between tumorous and nontumorous causes of virilizing
Testosterone levels tend to be higher (in the lower male range) symptoms.
and gonadotropin levels lower in association with a virilizing Ovarian hyperthecosis is typically associated with an iso­
ovarian tumor than in ovarian hyperthecosis; however, no lated increase in testosterone, while other androgens usually
cut-off value of testosterone has been proposed for discrimin­ are within the reference values (2), see the patient case above.
ating between a hormone-producing tumor and ovarian hy­ Furthermore, insulin resistance is characteristic for ovarian
perthecosis (29, 41, 82). The next step is therefore to hyperthecosis (39, 42, 43), and therefore fasting insulin and
proceed with diagnostic imaging (Fig. 3), see below. Further glucose for calculating the Homeostatic Model Assessment
endocrine evaluation may still be helpful for distinguishing or HbA1c should be considered. In the case of hormone-
producing ovarian tumors, hormones other than testosterone
may also be elevated, including inhibin B, AMH, A4,
Table 4. Investigation of hyperandrogenism in postmenopausal women 17-OHP, and estradiol, whereas DHEAS and cortisol are nor­
mal (52, 82). In contrast, androgen-producing adrenal tumors
Assessment are associated with increased DHEAS levels, often higher than
twice the upper normal limit (>19 µmol/L), together with in­
Clinical Hirsutism: modified Ferriman–Gallwey score
creases in testosterone, A4, and cortisol (2).
symptoms Acne
Androgenic alopecia: Ludwig score The gonadotropin-releasing hormone (GnRH) agonist test
Clitoromegaly: >1.5 × 2.5 cm can be used for distinguishing androgen-producing ovarian
Endocrine Serum analyses of FSH, LH, testosterone, SHBG, and adrenal tumors and successfully confirm an ovarian
evaluation A4, DHEAS, estradiol, 17-OHP, and inhibin B source from an adrenal source by suppression of testosterone
HOMA index or HbA1C as marker for insulin (41). However, the test cannot differentiate between ovarian
resistance can be considered hyperthecosis and an ovarian tumor, as both disorders are go­
ACTH stimulation test to rule out NC CAH nadotropin dependent and will respond to GnRH with testos­
24-hour urinary free cortisol and dexamethasone terone inhibition (83).
test to rule out Cushing’s syndrome
Selective ovarian and adrenal venous catheterization can lo­
Imaging Transvaginal ultrasound calize an androgen-producing tumor by demonstrating differ­
MRI, CT
ential gradients in androgen levels between ovarian, adrenal,
Abbreviations: 17-OHP, 17-hydroxyprogesterone; A4, androstenedione; and peripheral veins. However, success rates are poor, and
ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEAS, this invasive method carries potential risks. A recent systemat­
dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; ic review and meta-analysis concluded that there is limited evi­
HOMA, Homeostatic Model Assessment; LH, luteinizing hormone; MRI,
magnetic resonance imaging; NC CAH, nonclassical congenital adrenal dence for the use of selective venous sampling in identifying
hyperplasia; SHBG, sex hormone–binding globulin. androgen-producing tumors in postmenopausal women (84).
1250 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5

Women with mild to moderate symptoms of of an ovarian source of androgen excess (ovarian tumor, ovar­
hyperandrogenism ian hyperthecosis) is primarily treated with surgery, in other
In postmenopausal women with mild to moderate symptoms words, laparoscopic bilateral oophorectomy, with or without
of hyperandrogenism and testosterone <5 nmol/L, PCOS is hysterectomy (38, 41, 87). As in the patient case presented, tes­
the most likely diagnosis, as supported by a premenopausal tosterone levels will normalize rapidly within a couple of weeks
history of menstrual irregularities, hyperandrogenism, and/ after surgery while symptoms of androgen excess, including
or polycystic ovaries (Fig. 3). In these women, androgen levels hirsutism and oily skin and acne, will gradually resolve.
are slightly higher than in controls, but serum testosterone is Although swelling of the clitoris may regress, clitoral hyper­
in most cases below 2 nmol/L (30-33). Transvaginal ultra­ trophy usually persists. The same applies to androgenic alope­
sound is recommended (see below) but further endocrine cia; severe hair loss usually remains even after normalized
evaluation is not needed if screening samples are normal and testosterone levels. Deepening of the voice caused by androgen
the diagnosis is supported by medical history. excess is also a symptom that does not regress after treatment. It
In the case of an increased morning value of 17-OHP is therefore important to diagnose at an early stage for prompt
(>9 nmol/L), the ACTH stimulation test should be performed management of potentially severe causes of hyperandrogenism,
although androgen-producing ovarian tumors are seldom ma­

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to rule out NC CAH (Fig. 3) (62). A significant increase in
ACTH in response to the test requires further investigation lignant (52, 53), and to avoid persistent symptoms despite elim­
with genetic testing to confirm a CAH diagnosis (62). If ination of androgen excess. Metabolic symptoms may improve
Cushing syndrome is suspected because of its typical symp­ to some extent but usually do not disappear (43, 88).
toms, this should be investigated with 24-hour urinary free When a patient is not a suitable candidate for surgery for
cortisol and/or dexamethasone suppression test, as well as a benign ovarian cause of severe hyperandrogenism, treatment
plasma ACTH followed by imaging, see below (Fig. 3). with GnRH analogs is an alternative (39, 43, 89). Depending
on the menopausal status of the patient, she may experience
symptoms of estrogen withdrawal, and in this situation estro­
Imaging gen add-back therapy could be considered (90). Estrogen sub­
Transvaginal ultrasound is used to investigate a possible ovarian stitution is also important to consider during long-term
cause of hyperandrogenism, primarily an androgen-producing treatment with GnRH analogs given the risk of accelerated
ovarian tumor. The mean size of a normal postmenopausal bone loss (91).
ovary is estimated to be 2.2 ± 0.01 cm3 with a 95% upper The primary treatment for androgen-secreting adrenal tu­
CI of <5.0 cm3 (85). An ovarian tumor can be very small mors is adrenalectomy for histopathological diagnosis of ma­
and difficult to identify, but asymmetry of the ovaries could lignant or benign tumor (92). Complete surgical resection can
be suggestive of such a tumor. Furthermore, color Doppler be sufficient therapy. In cases of malignancy, adjuvant therapy
ultrasound can identify a hypervascularized region, suggest­ with mitotane, chemotherapy, or radiation may be used.
ing a tumor (82). Failure to identify a tumor with ultrasound Adrenal function must be closely monitored after surgery
does not rule out this possibility; it is therefore important to for detection of adrenal insufficiency or recurrent tumor (92).
investigate further with MRI (41, 82). Ovarian hyperthecosis Postmenopausal women with testosterone <5 nmol/L and a
is associated with bilateral homogeneous enlargement of the history of PCOS with persistent or aggravating hyperandro­
ovarian stroma on ultrasound without hypervascularization genic symptoms are treated with antiandrogen therapy (93).
(40, 41). The average ovarian volume may be up to 10 cm3 There are different types of antiandrogens with various mech­
(39-41). Postmenopausal women with PCOS usually have anisms of action and potential side-effects (94). Ovarian an­
larger ovaries than control women, although significantly drogen overproduction can be inhibited by GnRH analogues
less than 10 cm3 (22). as mentioned above; androgen effects can be blocked by an­
MRI has shown a higher positive and negative predictive drogen receptor blockers (spironolactone, cyproterone acet­
value (78%) and (100%), respectively, for detection of an ate, flutamide) or by a 5α reductase inhibitor (finasteride)
androgen-secreting ovarian tumor than transvaginal ultra­ blocking the conversion of testosterone to DHT, which is
sound (82). In addition, good sensitivity (83%) and specificity the most potent androgen in peripheral tissue. However, treat­
(80%) were reported for MRI in differentiating between viril­ ment of metabolic symptoms with metformin or other sub­
izing ovarian tumors and ovarian hyperthecosis (41). stances has limited effect on hyperandrogenic symptoms
CT is the preferable imaging technique for detecting adrenal (95). The efficacy of antiandrogens for treatment of hirsutism
tumors; it will detect nodules >5 mm (86). MRI could be an is moderate (96), and it must be explained to the patient that it
alternative imaging method for detecting adrenal tumors. takes time before any treatment effect can be observed (at least
The majority of cases of Cushing syndrome are ACTH- 6 months) and that the effect disappears when treatment is
dependent, and the next step of evaluation is to identify a pos­ stopped.
sible pituitary tumor using MRI (68). If no mass is identified, Postmenopausal women with NC CAH are usually treated
petrosal sinus sampling and/or further imaging to identify an with antiandrogens, similarly to PCOS, and cortisone is sel­
ectopic source of ACTH should be considered. dom needed (15). Cushing syndrome is primarily treated
with surgery for an ACTH-producing pituitary or ectopic tu­
mor or cortisol-secreting adrenal tumor (68). In some cases,
Treatment medical therapy or radiation may be necessary (68).
Treatment strategies depend on the cause, symptoms, and dis­
tress of androgen excess (Fig. 3). Patients with severe symp­
toms and testosterone >5 nmol/L should be managed Conclusion
urgently, especially those with suspected malignancy. A post­ Postmenopausal hyperandrogenism ranges from mild symp­
menopausal woman with virilizing symptoms and indication toms due to relative androgen excess during menopausal
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5 1251

transition to virilizing symptoms caused by a hormone- 9. Turcu AF, Nanba AT, Chomic R, et al. Adrenal-derived
producing ovarian or adrenal tumor that could be malignant. 11-oxygenated 19-carbon steroids are the dominant androgens in
A thorough investigation must be performed to determine classic 21-hydroxylase deficiency. Eur J Endocrinol. 2016;174(5):
the underlying cause and to offer appropriate treatment. 601-609.
Onset of symptoms, development, and severity of symptoms 10. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones:
are indicative for further investigation. Measurement of serum binding of 21 endogenous steroids to both testosterone-binding
globulin and corticosteroid-binding globulin in human plasma. J
testosterone, preferably by LC–MS/MS, provides important
Clin Endocrinol Metab. 1981;53(1):58-68.
information on the degree of androgen excess. Testosterone
11. Gershagen S, Doeber A, Jeppsson S, Rannevik G. Decreasing serum
>5 nmol/L is associated with virilizing symptoms and should levels of sex hormone-binding globulin around the menopause and
prompt further investigation with imaging modalities to rule temporary relation to changing levels of ovarian steroids, as demon­
out an androgen-producing tumor. There is no discriminatory strated in a longitudinal study. Fertil Steril. 1989;51(4):616-621.
method to distinguish an ovarian hormone–producing tumor 12. Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A pro­
from ovarian hyperthecosis, although the latter is related to spective longitudinal study of serum testosterone, dehydroepian­
slower development of virilizing symptoms and bilateral ovar­ drosterone sulfate, and sex hormone-binding globulin levels
ian enlargement. Surgery with bilateral oophorectomy or re­

Downloaded from https://academic.oup.com/jcem/article/108/5/1243/6835644 by guest on 22 April 2023

through the menopause transition. J Clin Endocrinol Metab.
moval of an adrenal tumor is the main curative treatment 2000;85(8):2832-2838.
and will ultimately lead to a histopathological diagnosis. 13. Torréns JI, Sutton-Tyrrell K, Zhao X, et al. Relative androgen ex­
GnRH analogs can be used as an alternative treatment of cess during the menopausal transition predicts incident metabolic
ovarian hyperthecosis. PCOS is probably the most common syndrome in midlife women: study of women’s health across the na­
cause of mild to moderate symptoms of hyperandrogenism tion. Menopause. 2009;16(2):257-264.
and testosterone <5 nmol/L in postmenopausal women. In 14. Ng L, John M, Libertino JM. Adrenocortical carcinoma: diagnosis,
this case, the recommended treatment is antiandrogen therapy evaluation and treatment. J Urol. 2003;169(1):5-11.
15. Carmina E, Dewailly D, Escobar-Morreale HF, et al. Non-classic
using an androgen receptor blocker and/or a 5α reductase in­
congenital adrenal hyperplasia due to 21-hydroxylase deficiency re­
hibitor. NC CAH could be treated in a similar way or if
visited: an update with a special focus on adolescent and adult
needed with cortisone, whereas Cushing syndrome is primar­
women. Hum Reprod Update. 2017;23(5):580-599.
ily treated with surgery. 16. Hakami OA, Ahmed S, Karavitaki N. Epidemiology and mortality
of Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab.
Financial support 2021;35(1):101521.
17. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex
No financial support for writing this paper. condition with psychological, reproductive and metabolic manifes­
tations that impacts on health across the lifespan. BMC Med.
Disclosures 2010;8(June 30):41.
18. Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat
The author declares no conflicts of interest. Rev Dis Primers. 2016;11(August 11):16057.
19. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop
Data availability group. Revised 2003 consensus on diagnostic criteria and long-term
health risks related to polycystic ovary syndrome (PCOS). Hum
Data sharing is not applicable to this article as no datasets Reprod. 2004;19(1):41-47.
were generated or analyzed during the current study. 20. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treat­
ment of polycystic ovary syndrome: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab. 2013;98(12):
References
4565-4592.
1. Ludwig E. Classification of the types of androgenetic alopecia 21. Elting MW, Kwee J, Korsen TJ, Rekers-Mombarg LT, Schoemaker
(common baldness) occurring in the female sex. Br J Dermatol. J. Aging women with polycystic ovary syndrome who achieve regu­
1977;97(3):247-254. lar menstrual cycles have a smaller follicle cohort than those who
2. Elhassan YS, Idkowiak J, Smith K, et al. Causes, patterns, and se­ continue to have irregular cycles. Fertil Steril. 2003;79(5):
verity of androgen excess in 1205 consecutively recruited women.
1154-1160.
J Clin Endocrinol Metab. 2018;103(3):1214-1223.
22. Alsamarai S, Adams JM, Murphy MK, et al. Criteria for polycystic
3. Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen
ovarian morphology in polycystic ovary syndrome as a function of
levels in adult females: changes with age, menopause, and oophor­
age. J Clin Endocrinol Metab. 2009;94(12):4961-4970.
ectomy. J Clin Endocrinol Metab. 2005;90(7):3847-3853.
23. Brown ZA, Louwers YV, Fong SL, et al. The phenotype of polycys­
4. Longcope C. Adrenal and gonadal androgen secretion in normal fe­
tic ovary syndrome ameliorates with aging. Fertil Steril.
males. Clin Endocrinol Metab. 1986;15(2):213-228.
5. Labrie F, Martel C, Belanger A, Pelletier G. Androgens in women 2011;96(5):1259-1265.
are essentially made from DHEA in each peripheral tissue according 24. Tehrani FR, Solaymani-Dodaran M, Hedayati M, Azizi F. Is poly­
to intracrinology. J Steroid Biochem Mol Biol. 2017;168(April): cystic ovary syndrome an exception for reproductive aging? Hum
9-18. Reprod. 2010;25(7):1775-1778.
6. Turcu AF, Rege J, Auchus RJ, Rainey WE. 11-Oxygenated andro­ 25. Cooney LG, Dokras A. Beyond fertility: polycystic ovary syndrome
gens in health and disease. Nat Rev Endocrinol. 2020;16(5): and long-term health. Fertil Steril. 2018;110(5):794-809.
284-296. 26. Forslund M, Schmidt J, Brännström M, Landin-Wilhelmsen K,
7. Nanba AT, Rege J, Ren J, Auchus RJ, Rainey WE, Turcu AF. Dahlgren E. Reproductive hormones and anthropometry: a follow-
11-Oxygenated C19 steroids do not decline with age in women. J up of PCOS and controls from perimenopause to older than 80
Clin Endocrinol Metab. 2019;104(7):2615-2622. years. J Clin Endocrinol Metab. 2021;106(2):421-430.
8. O’Reilly MW, Kempegowda P, Jenkinson C, et al. 11-Oxygenated 27. Handelsman DJ. Mass spectrometry, immunoassay and valid ster­
C19 steroids are the predominant androgens in polycystic ovary oid measurements in reproductive medicine and science. Hum
syndrome. J Clin Endocrinol Metab. 2017;102(3):840-848. Reprod. 2017;32(6):1147-1150.
1252 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5

28. Handelsman DJ, Hirschberg AL, Bermon S. Circulating testoster­ 47. Brown DL, Henrichsen TL, Clayton AC, Hudson SB, Coddington
one as the hormonal basis of sex differences in athletic performance. CC III, Vella A. Ovarian stromal hyperthecosis: sonographic fea­
Endocr Rev. 2018;39(5):803-829. tures and histologic associations. J Ultrasound Med. 2009;28(5):
29. Markopoulos MC, Kassi E, Alexandraki KI, Mastorakos G, Kaltsas 587-593.
G. Hyperandrogenism after menopause. Eur J Endocrinol. 48. Fienberg R. Familial ovarian hyperthecosis. Am J Obstet Gynecol.
2015;172(2):R79-R91. 1972;112(2):309-310.
30. Schmidt J, Brannstrom M, Landin-Wilhelmsen K, Dahlgren E. 49. Nagamani M, Urban RJ. Increased expression of messenger ribo­
Reproductive hormone levels and anthropometry in postmeno­ nucleic acid encoding cytochrome P450 cholesterol side-chain
pausal women with polycystic ovary syndrome (PCOS): a 21-year cleavage and P450 17α-hydroxylase enzymes in ovarian hyperthe­
follow-up study of women diagnosed with PCOS around 50 years cosis. Fertil Steril. 1999;71(2):328-333.
ago and their age-matched controls. J Clin Endocrinol Metab. 50. Adashi EY. The climacteric ovary as a functional gonadotropin-
2011;96(7):2178-2185. driven androgen-producing gland. Fertil Steril. 1994;62(1):20-27.
31. Markopoulos M, Rizos D, Valsamakis G, et al. Hyperandrogenism 51. Brown RJ, Joseph J, Cochran E, et al. Type B insulin resistance mas­
in women with polycystic ovary syndrome persists after meno­ querading as ovarian hyperthecosis. J Clin Endocrinol Metab.
pause. J Clin Endocrinol Metab. 2011;96(3):623-631. 2017;102(6):1789-1791.
32. Meun C, Franco OH, Dhana K, et al. High androgens in postmeno­ 52. Fleckenstein G, Sattler B, Hinney B, Wuttke W, Osmers R, Emons

Downloaded from https://academic.oup.com/jcem/article/108/5/1243/6835644 by guest on 22 April 2023

pausal women and the risk for atherosclerosis and cardiovascular G. Androblastoma of the ovary: clinical, diagnostic and histopatho­
disease: The Rotterdam Study. J Clin Endocrinol Metab. logic features. Onkologie. 2001;24(3):286-291.
2018;103(4):1622-1630. 53. Macut D, Ilić D, Jovanović AM, Bjekić -Macut J. Androgen-secreting
33. Sharma A, Kapoor E, Singh RJ, Chang AY, Erickson D. Diagnostic ovarian tumors. Front Horm Res. 2019;53(September 9):100-107.
thresholds for androgen-producing tumors or pathologic hyperan­ 54. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors. A clini­
drogenism in women by use of total testosterone concentrations copathological analysis of 207 cases. Am J Surg Pathol. 1985;9(8):
measured by liquid chromatography-tandem mass spectrometry. 543-569.
Clin Chem. 2018;64(11):1636-1645. 55. Sekkate S, Kairouani M, Serji B, et al. Ovarian granulosa cell tu­
34. Hirschberg AL. Polycystic ovary syndrome, obesity and reproduct­ mors: a retrospective study of 27 cases and a review of the literature.
ive implications. Womens Health (Lond). 2009;5(5):529-540; quiz World J Surg Oncol. 2013;11(June 18):142.
541-542. 56. Healy DL, Burger HG, Mamers P, et al. Elevated serum inhibin con­
35. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the poly­ centrations in postmenopausal women with ovarian tumors. New
cystic ovary syndrome revisited: an update on mechanisms and im­ Engl J Med. 1993;329(21):1539-1542.
plications. Endocr Rev. 2012;33(6):981-1030. 57. Rey R, Sabourin JC, Venara M, et al. Anti-Müllerian hormone is a
36. Xing C, Zhang J, Zhao H, He B. Effect of sex hormone-binding specific marker of Sertoli- and granulosa-cell origin in gonadal tu­
globulin on polycystic ovary syndrome: mechanisms, manifesta­ mors. Hum Pathol. 2000;31(10):1202-1208.
tions, genetics, and treatment. Int J Womens Health. 2022; 58. Cordera F, Grant C, van Heerden J, Thompson G, Young W.
14(February 2):91-105. Androgen-secreting adrenal tumors. Surgery. 2003;134(6):
37. Ek I, Arner P, Rydén M, et al. A unique defect in the regulation of 874-880.
visceral fat cell lipolysis in the polycystic ovary syndrome as an early 59. Moreno S, Montoya G, Armstrong J, et al. Profile and outcome of
link to insulin resistance. Diabetes. 2002;51(2):484-492. pure androgen-secreting adrenal tumors in women: experience of
38. Meczekalski B, Szeliga A, Maciejewska-Jeske M, et al. 21 cases. Surgery. 2004;136(6):1192-1198.
Hyperthecosis: an underestimated nontumorous cause of hyperan­ 60. Angelousi A, Kassi E, Kaltsas GA. Current issues in the diagnosis
drogenism. Gynecol Endocrinol. 2021;37(8):677-682. and management of adrenocortical carcinomas. August 30 2021.
39. Krug E, Berga SL. Postmenopausal hyperthecosis: functional dysre­ In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext
gulation of androgenesis in climacteric ovary. Obstet Gynecol. [Internet]. MDText.com, Inc.; 2000.
2002;99(5 Pt 2):893-897. 61. El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia.
40. Rousset P, Gompel A, Christin-Maitre S, et al. Ovarian hypertheco­ Lancet. 2017;390(10108):2194-2210.
sis on grayscale and color Doppler ultrasound. Ultrasound Obstet 62. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperpla­
Gynecol. 2008;32(5):694-699. sia due to steroid 21-hydroxylase deficiency: an endocrine society*
41. Yance VRV, Marcondes JAM, Rocha MP, et al. Discriminating be­ clinical practice guideline. J Clin Endocrinol Metab. 2018;103(11):
tween virilizing ovary tumors and ovary hyperthecosis in postme­ 4043-4088.
nopausal women: clinical data, hormonal profiles and image 63. Moran C, Azziz R, Carmina E, et al. 21-Hydroxylase-deficient non­
studies. Eur J Endocrinol. 2017;177(1):93-102. classic adrenal hyperplasia is a progressive disorder: a multicenter
42. Nagamani M, Van Dinh T, Kelver ME. Hyperinsulinemia in hyper­ study. Am J Obstet Gynecol. 2000;183(6):1468-1474.
thecosis of the ovaries. Am J Obstet Gynecol. 1986;154(2): 64. Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in
384-389. women: experience with over 1000 consecutive patients. J Clin
43. Barth JH, Jenkins M, Belchetz PE. Ovarian hyperthecosis, diabetes Endocrinol Metab. 2004;89(2):453-462.
and hirsuties in post-menopausal women. Clin Endocrinol. 65. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syn­
1997;46(2):123-128. drome. Lancet. 2015;386(9996):913-927.
44. Nagamani M, Hannigan EV, Dinh TV, Stuart CA. 66. Nieman LK. Cushing’s syndrome: update on signs, symptoms and
Hyperinsulinemia and stromal luteinization of the ovaries in post­ biochemical screening. Eur J Endocrinol. 2015;173(4):M33-M38.
menopausal women with endometrial cancer. J Clin Endocrinol 67. Kaltsas GA, Korbonits M, Isidori AM, et al. How common are
Metab. 1988;67(1):144-148. polycystic ovaries and the polycystic ovarian syndrome in women
45. Zhang C, Sung CJ, Quddus MR, Simon RA, Jazaerly T, Lawrence with Cushing’s Syndrome? Clin Endocrinol. 2000;53(4):493-500.
WD. Association of ovarian hyperthecosis with endometrial polyp, 68. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of
endometrial hyperplasia, and endometrioid adenocarcinoma in Cushing’s syndrome: an Endocrine Society Clinical Practice
postmenopausal women: a clinicopathological study of 238 cases. Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
Hum Pathol. 2017;59(January):120-124. 69. Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treat­
46. Secreto G, Girombelli A, Krogh V. Androgen excess in breast cancer ment of hirsutism in premenopausal women: an Endocrine
development: implications for prevention and treatment. Endocr Society Clinical Practice Guideline. J Clin Endocrinol Metab.
Relat Cancer. 2019;26(2):R81-R94. 2018;103(4):1233-1257.
The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 5 1253

70. Hu X, Wang J, Dong W, Fang Q, Hu L, Liu C. A meta-analysis of 84. Tng EL, Tan JM. Dexamethasone suppression test versus selective
polycystic ovary syndrome in women taking valproate for epilepsy. ovarian and adrenal vein catheterization in identifying virilizing tu­
Epilepsy Res. 2011;97(1-2):73-82. mors in postmenopausal hyperandrogenism - a systematic review
71. Nelson-DeGrave VL, Wickenheisser JK, Cockrell JE, et al. and meta-analysis. Gynecol Endocrinol. 2021;37(7):600-608.
Valproate potentiates androgen biosynthesis in human ovarian the­ 85. Pavlik EJ, DePriest PD, Gallion HH, et al. Ovarian volume related
ca cells. Endocrinology. 2004;145(2):799-808. to age. Gynecol Oncol. 2000;77(3):410-412.
72. Zotter Z, Veszeli N, Csuka D, Varga L, Farkas H. Frequency of the 86. Cavlan D, Bharwani N, Grossman A. Androgen- and estrogen-
virilising effects of attenuated androgens reported by women with secreting adrenal cancer. Semin Oncol. 2010;37(6):638-648.
hereditary angioedema. Orphanet J Rare Dis. 2014;9(December 5): 87. Mamoojee Y, Ganguri M, Taylor N, Quinton R. Clinical case sem­
205. inar: postmenopausal androgen excess-challenges in diagnostic
73. Vorona E, Nieschlag E. Adverse effects of doping with anabolic an­ work-up and management of ovarian thecosis. Clin Endocrinol
drogenic steroids in competitive athletics, recreational sports and (Oxf). 2018;88(1):13-20.
bodybuilding. Minerva Endocrinol. 2018;43(4):476-488. 88. Pelusi C, Forlani G, Zanotti L, Gambineri A, Pasquali R. No meta­
74. Lizneva D, Gavrilova-Jordan L, Walker W, Azziz R. Androgen ex­ bolic impact of surgical normalization of hyperandrogenism in
cess: investigations and management. Best Pract Res Clin Obstet postmenopausal women with ovarian androgen-secreting tumours.
Gynaecol. 2016;37(November):98-118. Clin Endocrinol (Oxf). 2013;78(4):533-538.

Downloaded from https://academic.oup.com/jcem/article/108/5/1243/6835644 by guest on 22 April 2023

75. Ferriman D, Gallwey JD. Clinical assessment of body hair growth 89. Vollaard ES, van Beek AP, Verburg FAJ, Roos A, Land JA.
in women. J Clin Endocrinol Metab. 1961;21(November): Gonadotropin-releasing hormone agonist treatment in postmeno­
1440-1447. pausal women with hyperandrogenism of ovarian origin. J Clin
76. Yildiz BO, Bolour S, Woods K, Moore A, Azziz R. Visually scoring Endocrinol Metab. 2011;96(5):1197-1201.
hirsutism. Hum Reprod Update. 2010;16(1):51-64. 90. Della Corte L, Barra F, Mercorio A, et al. Tolerability considera­
77. Teede HJ, Misso ML, Costello MF, et al. ; international PCOS net­ tions for gonadotropin-releasing hormone analogues for endomet­
work. Recommendations from the international evidence-based riosis. Expert Opin Drug Metab Toxicol. 2020;16(9):759-768.
guideline for the assessment and management of polycystic ovary 91. Sauerbrun-Cutler MT, Alvero R. Short- and long-term impact of
syndrome. Fertil Steril. 2018;110(3):364-379. gonadotropin-releasing hormone analogue treatment on bone loss
78. Uysal G, Sahin Y, Unluhizarci K, et al. Is acne a sign of androgen and fracture. Fertil Steril. 2019;112(5):799-803.
excess disorder or not? Eur J Obstet Gynecol Reprod Biol. 92. Fassnacht M, Dekkers O, Else T, et al. European Society of
2017;211(April):21-25. Endocrinology Clinical Practice Guidelines on the management of
79. Price VH. Androgenetic alopecia in women. J Investig Dermatol adrenocortical carcinoma in adults, in collaboration with the
Symp Proc. 2003;8(1):24-27. European Network for the Study of Adrenal Tumors. Eur J
80. Tagatz GE, Kopher RA, Nagel TC, Okagaki T. The clitoral index: a Endocrinol. 2018;179(4):G1-G46.
bioassay of androgenic stimulation. Obstet Gynecol. 1979;54(5): 93. Pasquali R, Gambineri A. Therapy in endocrine disease: treatment
562-564. of hirsutism in the polycystic ovary syndrome. Eur J Endocrinol.
81. Zaman A, Rothman MS. Postmenopausal hyperandrogenism: 2013;170(2):R75-R90.
evaluation and treatment strategies. Endocrinol Metab Clin 94. Azarchi S, Bienenfeld A, Sicco KL, Marchbein S, Shapiro J, Nagler
North Am. 2021;50(1):97-111. AR. Androgens in women: hormone-modulating therapies for skin
82. Sarfati J, Bachelot A, Coussieu C, et al. Impact of clinical, hormo­ disease. J Am Acad Dermatol. 2019;80(6):1509-1521.
nal, radiological, and immunohistochemical studies on the diagno­ 95. Fraison E, Kostova E, Moran LJ, et al. Metformin versus the com­
sis of postmenopausal hyperandrogenism. Eur J Endocrinol. bined oral contraceptive pill for hirsutism, acne, and menstrual pat­
2011;165(5):779-788. tern in polycystic ovary syndrome. Cochrane Database Syst Rev.
83. Goyal A, Kubihal S, Gupta Y, Jyotsna VP, Khadgawat R. Dynamic 2020;8(8):CD005552.
testing for evaluation of adrenal and gonadal function in pediatric 96. Barrionuevo P, Nabhan M, Altayar O, et al. Treatment options for
and adult endocrinology: an overview. Indian J Endocrinol Metab. hirsutism: a systematic review and network meta-analysis. J Clin
2019c;23(6):593-601. Endocrinol Metab. 2018;103(4):1258-1264.