Hyperandrogenism

Template:Short description Template:Use dmy dates Template:Infobox medical condition (new) Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men.<ref name=Carl2004>Template:Cite book</ref> Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation.<ref name="Pe2013">Template:Cite journal</ref><ref name="Cur2014">Template:Cite book</ref> Complications may include high blood cholesterol and diabetes.<ref name=Carl2004/> It occurs in approximately 5% of women of reproductive age.<ref name="Cur2014" />

Polycystic ovary syndrome accounts for about 70% of hyperandrogenism cases.<ref name=Pe2013/> Other causes include Congenital adrenal hyperplasia, insulin resistance, hyperprolactinemia, Cushing's disease, certain types of cancers, and certain medications.<ref name="Carl2004" /><ref name=Pe2013/><ref name=Cat2012>Template:Cite journal</ref> Diagnosis often involves blood tests for testosterone, 17-hydroxyprogesterone, and prolactin, as well as a pelvic ultrasound.<ref name=Pe2013/><ref name=Carl2004/>

Treatment depends on the underlying cause.<ref name=Carl2004/> Symptoms of hyperandrogenism can be treated with birth control pills or antiandrogens, such as cyproterone acetate or spironolactone.<ref name="Pe2013" /><ref name="Carl2004" /> Other measures may include hair removal techniques.<ref name="Cat2012" />

The earliest known description of the condition is attributed to Hippocrates.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

In 2011, the International Association of Athletics Federations (now World Athletics) and IOC (International Olympic Committee)<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> released statements restricting the eligibility of female athletes with high testosterone, whether through hyperandrogenism or as a result of a difference in sex development (DSD). These regulations were referred to by both bodies as hyperandrogenism regulations and have led to athletes with DSDs being described as having hyperandrogenism.<ref>Template:Cite news</ref><ref>Template:Cite news</ref> They were revised in 2019 to focus more specifically on DSDs.<ref name=":14" />

Signs and symptoms

File:CushingsBody.jpg

A woman with hirsutism from increased androgen exposure

Hyperandrogenism affects 5–10% of women of reproductive age.<ref name=":3">Template:Cite journal</ref> Hyperandrogenism can affect both men and women but is more noticeable in women since elevated levels of androgens in women may facilitate virilization. Because hyperandrogenism is characterized by elevated male sex hormone levels, symptoms of hyperandrogenism in men are often negligible. Hyperandrogenism in women is typically diagnosed in late adolescence with a medical evaluation. The medical evaluation usually consists of a pelvic exam, observation of external symptoms, and a blood test measuring androgen levels.<ref name=":4">Template:Cite journal</ref> Symptoms may include the following: Template:Columns-list

Women

Hyperandrogenism, especially high levels of testosterone, can cause serious adverse effects if left untreated. High testosterone levels are associated with other health conditions such as obesity, hypertension, amenorrhea (cessation of menstrual cycles), and ovulatory dysfunction, which can lead to infertility. Prominent signs of hyperandrogenism are hirsutism (unwanted growth of hair, especially in the abdominal region and on the back), adult acne, deepening of the voice, and alopecia (balding).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Hyperandrogenism has also been observed to increase insulin tolerance, which can lead to type two diabetes and dyslipidemia, such as high cholesterol. These effects may have psychological impacts, sometimes leading to social anxiety and depression, especially in adolescent girls and young women. Paired with obesity and hirsutism, it can cause the individual to have low self-esteem.<ref name=":4" /><ref>Template:Cite journal</ref>

Men

Administration of high-dose testosterone in men over a course of weeks can cause an increase in aggression and hypomanic symptoms, though these were seen in only a minority of subjects.<ref>Template:Cite journal</ref> Acute high-dose anabolic-androgenic steroid administration in males attenuates endogenous sex hormone production and affects the thyroid hormone axis. Effects on mood and aggression observed during high-dose anabolic-androgenic steroid administration may occur secondarily to hormonal changes.<ref>Template:Cite journal</ref> Many of the same signs and symptoms that are seen in women, such as alopecia and acne, may also be found in men.<ref name=":13" /> Enlargement of the prostate may also occur.<ref name=":13">See Table 1 in Template:Cite journal</ref>

Causes

While hyperandrogenism in women can be caused by external factors, it can also appear spontaneously.

Polycystic ovary syndrome

File:Echographie pelvienne, aplio toshiba ssa 700 5 2004 03 detail.jpg

Ultrasound of a polycystic ovary. Each of the dark circles represents a fluid-filled cyst.

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by an excess of androgens produced by the ovaries. It is estimated that approximately 90% of women with PCOS demonstrate hypersecretion of these hormones.<ref name="Franks_1995" /> The cause of this condition is unknown. Speculations include genetic predisposition; however, the gene or genes responsible for this remain unidentified.<ref>"Polycystic Ovary Syndrome (PCOS)." Causes. Mayo Clinic, n.d. Web. 9 November 2016.</ref> The condition may have a hereditary basis. Other possible causes include elevated insulin production. Most cases of PCOS involve insulin resistance.<ref name=":7">Template:Cite journal</ref> It is thought that adipose tissue dysfunction plays a role in the insulin resistance seen in PCOS.<ref name=":7" /> Insulin can induce excess testosterone secretion from the ovaries.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A complication associated with polycystic ovary syndrome is high cholesterol, which is treated with statins. In a meta-analysis, atorvastatin was shown to decrease androgen concentrations in people with hyperandrogenism.<ref>Template:Cite journal</ref>

Elevated insulin leads to lower production of sex hormone binding globulin (SHBG), a regulatory glycoprotein that suppresses the function of androgens.<ref>Template:Cite journal</ref> High blood levels of insulin also work in conjunction with ovarian sensitivity to insulin to cause hyperandrogenemia, the primary symptom of PCOS. Obese individuals may be more biologically inclined to PCOS due to markedly higher insulin. This hormonal imbalance can lead to chronic anovulation, in which the ovaries fail to release mature eggs. These cases of ovulatory dysfunction are linked to infertility and menstrual disturbances.<ref name="Franks_1995">Template:Cite journal</ref><ref>Template:Cite encyclopedia</ref> A post hoc analysis from a randomized, placebo-controlled, multi-centre study carried out at 11 secondary care centres, as well as a longitudinal single-centre study on pregnant women in Norway, also determined that metformin had no effect on maternal androgens in pregnancies occurring in the setting of PCOS.<ref>Template:Cite journal</ref>

One systemic review suggested that polymorphisms in the vitamin D receptor gene are associated with the prognosis of polycystic ovary syndrome, though this is based on small sample sizes and is debated.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Studies have shown benefits for vitamin D supplementation in women with vitamin D deficiency and PCOS.<ref name=":5">Template:Cite journal</ref>

Hyperinsulinemia can increase the production of androgens in the ovaries.<ref>Template:Cite journal</ref> One context in which this occurs is HAIR-AN syndrome, a rare subtype of PCOS.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref>

Hyperthecosis and hyperinsulinemia

Hyperthecosis occurs when the cells of the ovarian stroma transition from interstitial cells, located between other cells, into luteinized theca cells. Theca cells are located in the ovarian follicles and become luteinized when the ovarian follicle bursts and a new corpus luteum is formed. The dispersal of luteinized theca cells throughout the ovarian stroma—in contrast to their distribution in PCOS, in which luteinized theca cells occur around cystic follicles only—causes women with hyperthecosis to have higher testosterone levels and virilization than women with PCOS. Elevated insulin is also characteristic of hyperthecosis.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Hyperthecosis most commonly develops in postmenopausal women and is linked to acne, hirsutism, growth of the clitoris, baldness, and voice deepening.<ref name=":6">Template:Cite journal</ref>

Obesity can play a role in insulin resistance.<ref name=":8">Template:Cite journal</ref> It makes thecal cells more responsive to luteinizing hormone.<ref name=":8" /> Therefore, obesity increases ovarian androgen production.<ref name=":8" /> Additionally, obesity elevates inflammatory adipokines which leads to not only adipogenesis, but also heightened insulin resistance.<ref name=":8" />

Cushing's syndrome

Cushing's syndrome develops as a result of long-term exposure to the hormone cortisol.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref> Cushing's syndrome can either be exogenous or endogenous, depending on whether it is caused by an external or internal source, respectively.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The intake of glucocorticoids, a type of corticosteroid, is a common cause for the development of exogenous Cushing's syndrome. Endogenous Cushing's syndrome can occur when the body produces excess cortisol. This occurs when the hypothalamus of the brain signals to the pituitary gland with excess corticotropin-releasing hormone, which in turn secretes adrenocorticotropin hormone (ACTH). ACTH then causes the adrenal glands to release cortisol into the blood. Signs of Cushing's syndrome include muscle weakness, easy bruising, weight gain, male-pattern hair growth (hirsutism), coloured stretch marks, and an excessively reddish complexion in the face.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Cushing's syndrome can cause androgen excess and hence the signs and symptoms of hyperandrogenism.<ref name=":6" />

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders that cause a lack of an enzyme necessary for the production of cortisol and/or aldosterone, steroid hormones produced by the adrenal cortex. Most cases of CAH are due to 21-hydroxylase deficiencies. The heightened androgen levels seen in congenital adrenal hyperplasia affect the hypothalamic–pituitary–gonadal axis.<ref name=":10">Template:Cite journal</ref> Heightened androgen levels can also affect the ovaries, which can lead to infertility as well as chronic anovulation.<ref name=":10" />

Since CAH consists of multiple disorders, the signs, symptoms and severity of hyperandrogenism may stem from a variety of specific mutations.<ref>Template:Cite journal</ref> Genotyping is therefore critical to verify diagnoses and to establish prognostic factors for individuals.<ref name=":9">Template:Cite book</ref> Genotyping is also crucial for people seeking to use genetic counselling as an aid to family planning.<ref name=":9" />

In women, CAH causes ambiguous genitals at birth and excessive pubic hair, enlargement of the clitoris, and hirsutism in adolescence. Although CAH causes rapid growth in childhood, adult women with CAH are shorter than average due to early puberty and closure of the growth plates in the long bones. Symptoms in males include early showings of pubic hair, enlargement of the penis, and rapid musculoskeletal growth.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Tumors

Adrenocortical carcinoma and tumors

Adrenocortical carcinoma occurs rarely; the average incidence rate is estimated to be 1–2 cases per million annually.<ref>Template:Cite journal</ref> The disease involves the formation of cancerous cells within the cortex of one or both of the adrenal glands. Although these tumors are identified in fewer than two percent of patients diagnosed with hyperandrogenism, the possibility must be considered within this population. In one study, more than half of tumor-affected patients had elevated levels of the androgens androstenedione, dehydroepiandrosterone sulfate, and testosterone.<ref name=":11" /> The elevation of androgens caused by adrenocortical carcinomas often causes patients to develop Cushing's syndrome, primary aldosteronism, and hyperandrogenism.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":11">Template:Cite journal</ref> The molecular basis of the disease has yet to be elucidated.<ref name=":11" />

Adenoma of the adrenal gland

Adrenal adenomas are benign tumors of the adrenal gland. In most cases, the tumors display no symptoms and require no treatment. In rare cases, however, some adrenal adenomas may become activated. When activated, the adenoma begins to produce hormones in much larger quantities than what the adrenal glands would normally produce, leading to health complications including primary aldosteronism and hyperandrogenism.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Arrhenoblastoma

Arrhenoblastoma is an uncommon tumor of the ovary. It is composed of sterol cells, Leydig cells, or some combination of the two. The tumor can produce male or female hormones and may cause masculinization. In a prepubescent child, a tumor may cause precocious puberty. Malignant arrhenoblastoma accounts for 30% of cases of arrhenoblastoma, the other 70% being largely benign and curable with surgery.<ref>Template:Cite book</ref>

Hilar cell tumor

A hilar cell tumor is an androgen-producing ovarian tumor that is most commonly found in older women and often leads to the development of male sex characteristics. The tumor tends to occur around the region of the ovary where the blood vessels enter the organ, known as the hilum. This type of tumor tends to be small in size and in most cases can be entirely removed and its symptoms reversed through surgery.<ref>Template:Cite book</ref>

Krukenberg tumor

A Krukenberg tumor is a quickly developing malignant tumor found in one or both ovaries. In most cases, the tumor primarily originates from tissues in the stomach, pancreas, gallbladder, colon, or breast. It colonized the ovary by spreading through the peritoneal cavity.<ref>Template:Cite book</ref> These tumors cause virilization. Increased androgen production due to elevations in human chorionic gonadotropin is hypothesized as the main cause of hyperandrogenism in women with Krukenberg tumors.<ref>Template:Cite journal</ref>

Menopause

The end of ovulation and the beginning of menopause can result in hyperandrogenism. During this transition, the body stops releasing estrogen at a faster rate than it stops releasing androgens. In some cases, the difference between the lower estrogen levels and higher androgen levels can produce hyperandrogenism. A decrease in sex hormone levels while the free androgen index increases can also contribute to this process.<ref>Template:Cite journal</ref>

Drugs

Many drugs can provoke symptoms of hyperandrogenism. These symptoms include, but are not limited to hirsutism, acne, dermatitis, androgenic alopecia, irregularities in menstruation, clitoral hypertrophy, and the deepening of the voice. Drugs most frequently implicated in hyperandrogenism include anabolic steroids, synthetic progestins, and antiepileptics; however, many other drugs may also cause hyperandrogenism.<ref name=":12">Template:Citation</ref> This can happen through one of five mechanisms: the direct introduction of androgens to the body, the binding of the drug to androgen receptors (as is the case with anabolic-androgenic steroids), a reduction of sex hormone-binding globulin plasma concentration that leads to an increase in free testosterone, interference with the hypothalamic–pituitary–ovarian (HPO) axis, or an increase in the release of adrenal androgens.<ref>Template:Cite book</ref> Certain drugs cause hyperandrogenism through mechanisms that remain unclear. For example, the molecular basis by which valproate induces hyperandrogenism and polycystic ovary syndrome has yet to be determined.<ref name=":12" /> However, one study showed that women taking valproic acid had higher testosterone levels and incidences of hyperandrogenism compared to women who were not taking valproic acid.<ref>Template:Cite journal</ref>

Heredity

Hyperandrogenism can appear as a symptom of many different genetic and medical conditions. Some of the conditions with hyperandrogenic symptoms, including PCOS, may sometimes be hereditary. Additionally, it is thought that epigenetics may contribute to the pathogenesis of polycystic ovary syndrome.<ref>Template:Cite journal</ref>

One potential cause of PCOS is maternal hyperandrogenism, whereby hormonal irregularities in the mother can affect the development of the child during gestation, resulting in the passing of polycystic ovary syndrome from mother to child.<ref>Template:Cite journal</ref> However, no androgen elevations were found in the umbilical cord blood of children born to mothers with PCOS.<ref>Template:Cite journal</ref>

Diagnosis

Diagnosing hyperandrogenism can be complex due to the wide variety and severity of signs and symptoms that may present.<ref name=":2">Template:Cite journal</ref> It is most often diagnosed by checking for signs of hirsutism according to a standardized method that scores the range of excess hair growth.<ref name=":3" /><ref name=":4" />

Girls may show symptoms of hyperandrogenism early in life, but physicians become more concerned when the patient is in her late teens or older.<ref name=":4" />

Checking medical history and a physical examination of symptoms are used for an initial diagnosis.<ref name=":4" /> Patient history assessed includes age at thelarche, adrenarche, and menarche; patterns of menstruation; obesity; reproductive history; and the start and advancement of hyperandrogenism symptoms.<ref name=":4" /> Patterns of menstruation are examined since irregular patterns may accompany hyperandrogenism.<ref name=":3" /> Other conditions that may present alongside hirsutism that can contribute to diagnosis include androgenic alopecia and acne.<ref name=":2" /> If hyperandrogenism is severe, virilization may occur.<ref name=":2" />

Family history is also assessed for occurrences of hyperandrogenism symptoms or obesity in other family members.<ref name=":4" />

Laboratory tests can measure FSH, luteininzing hormone, DHEAS, prolactin, 17α-hydroxyprogesterone, and total and free testosterone in the blood.<ref name=":4" /> Abnormally high levels of any of these hormones help in diagnosing hyperandrogenism.<ref name=":4" />

Prevention

Since risk factors are not known and vary among individuals with hyperandrogenism, there is no sure method to prevent the condition.<ref name=":02" /> Accordingly, more long-term studies are needed to find a cause of the condition before a sufficient method of prevention can be established.<ref name=":02">Template:Cite journal</ref>

Despite this, there are a few things that can help avoid long-term medical issues related to hyperandrogenism and PCOS. Getting checked by a medical professional for hyperandrogenism — especially if one has a family history of the condition, irregular periods, or diabetes — can be beneficial.<ref name="pmid23642453">Template:Cite journal</ref> A healthy weight and diet may reduce the chances, as continued exercise and a healthy diet lead to an improved menstrual cycle, decreased insulin levels, and lowered androgen concentrations.<ref name=":02" />

Treatment

There is no definitive treatment for hyperandrogenism as it varies with the underlying condition that causes it. As a hormonal symptom of PCOS, menopause, and other endocrine conditions, it is primarily treated as a symptom of these conditions. Drugs may be considered only in women who do not plan on becoming pregnant in the near future.<ref>Template:Cite journal</ref> Some effective drugs for facial hirsutism includes eflornithine, which may cause birth defects in pregnant women.<ref name=":0">Template:Cite journal</ref> Retinoids and antibiotics can be used for acne and minoxidil for alopecia.<ref name=":0" /> Systemically, it is treated with antiandrogens such as cyproterone acetate, flutamide and spironolactone to reduce androgenic signaling. For hyperandrogenism caused by late-onset congenital adrenal hyperplasia (LOCAH), treatment is primarily focused on providing the patient with glucocorticoids to combat the low cortisol production and the corresponding increase in androgens caused by the increase in size of the adrenal glands.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Estrogen-based oral contraceptives are used to treat both LOCAH- and PCOS-associated hyperandrogenism. These hormonal treatments reduce the androgen excess and suppress adrenal androgen production, bringing about a significant decrease in hirsutism.<ref name="ReferenceA">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Hyperandrogenism is often managed symptomatically. Hirsutism and acne both respond well to the hormonal treatments described above, with 60–100% of patients reporting an improvement in hirsutism.<ref name="ReferenceA"/> Androgenic alopecia however, does not show an improvement with hormonal treatments and requires other treatments, such as hair transplantation.<ref>Template:Cite journal</ref>

Supplementation can also contribute to the managing the symptomatic effects of hyperandrogenism. In a meta-analysis, high-dose vitamin D supplements given to women with vitamin D deficiency due to PCOS improved glucose levels, insulin sensitivity, and cholesterol levels, as well as lowering testosterone, sex hormone-binding globulin, and the free androgen index, all of which are associated with hyperandrogenism.<ref>Template:Cite journal</ref> Vitamin D supplementation in women with vitamin D deficiency but without PCOS did not show the same results.<ref name=":5" />

Targeting insulin resistance and obesity

Lifestyle modifications are the first-line treatment for PCOS.<ref>Template:Cite journal</ref> They help improve body composition, insulin resistance, and hyperandrogenism. However, it is unclear whether they help improve mood, quality of life, and reproductive outcomes.<ref>Template:Cite journal</ref> A meta-analysis study in 2017 showed that bariatric surgery in women with severe obesity and PCOS decreased levels of total and free testosterone and helped correct hirsutism and menstrual dysfunction.<ref>Template:Cite journal</ref>

Insulin resistance in women with PCOS is typically treated with insulin-sensitizer drugs such as metformin. Metformin can help to decrease weight and androgen levels.<ref name=":1">Template:Cite journal</ref> When combined with lifestyle modifications (changes in diet and exercise), it has been linked with lower body mass index and a reduction in menstrual problems.<ref name=":1" /> However, the use of metformin in women with PCOS should only be considered in patients with impaired glucose tolerance.<ref>Edited by Adam Balen Stephen Franks Roy Homburg and Sean Kehoe

Current Management of Polycystic Ovary Syndrome, edited by Adam Balen, et al., Royal College of Obstetricians and Gynaecologists, 2010. ProQuest Ebook Central (p.179)</ref>

Society and culture

Because androgen excess is manifested in noticeable physical features (such as hirsutism), social stigma may be associated with it.Template:Cn

Sports

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}Current evidence-based studies show that unusually high levels of circulating testosterone are associated with increased athletic performance in women, unless they lack androgen sensitivity. However, controversy has emerged in the form of the claim that testosterone is not unlike any other physical parameter with reference to bestowing advantages or disadvantages on female athletes. Existing regulations throughout competitive sports are currently being refined to specifically address this particular claim.<ref>Template:Cite journal</ref>

File:Caster Semenya 2010 Memorial Van Damme.jpg

Caster Semenya, a genetically XY female athlete with 5-alpha reductase deficiency.

Following the case of South African athlete Caster Semenya, an athlete with a difference in sex development (DSD), the International Association of Athletics Federations introduced its hyperandrogenism regulations, which restricted women with high testosterone levels, whether the hormones were produced by ovaries, adrenals, or testes. These regulations replaced the earlier sex verification rules.Template:Citation needed

Following a series of legal challenges, regulations called the Eligibility Regulations for the Female Classification (Athletes with Differences of Sexual Development) were released on 1 May 2019.<ref name=":14">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> These regulations apply only to athletes who have a DSD, high testosterone and virilization,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and no longer include hyperandrogenism from non-DSD-related causes such as PCOS. Such DSDs, often seen in people who have a Y chromosome and testes, include 5α‐reductase deficiency, partial androgen insensitivity, and congenital adrenal hyperplasia.Template:Citation needed

Social definition

Cultural variation can define hyperandrogenism socially—apart from clinical and chemical definitions—to make some hair growth unacceptable even if it is considered clinically normal based on metrics like the Ferriman-Gallwey score. For example, only pubic and axillary hair may be tolerated in North American women, while other androgen-dependent hair such as growth on the upper lip, over the linea alba, on the thighs, and around the areola is not.<ref>Template:Cite book</ref>

Organizations

Professional organizations such as the Androgen Excess and PCOS Society exist to promote the research, treatment, diagnosis, and prevention of such disorders and to educate the public and scientific community about them.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

InterACT, an intersex organization, listed hyperandrogenism as an intersex variation in a glossary from 2022.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

See also

• Hypoandrogenism
• Hypergonadism
• Hypergonadotropic hypergonadism
• Hypogonadism
• Hyperestrogenism
• Hypoestrogenism
• Androgen-dependent condition