Hyperandrogenism

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Hyperandrogenism
Other namesAndrogen excess
Testosterone.PNG
Testosterone is a type of androgen that is important in the development of hyperandrogenism since high levels of it can cause this condition.
Pronunciation
SpecialtyEndocrinology
SymptomsAcne, hair loss on scalp, increased body or facial hair, infrequent or absent menstruation[1][2]
CausesPolycystic ovary syndrome (PCOS), adrenal hyperplasia, Cushing's disease, cancer[1][3]
Diagnostic methodBlood tests, ultrasound[1][4]
TreatmentBirth control pills, cyproterone acetate[1]
Frequency5% (reproductive age women)[2]

Hyperandrogenism is a medical condition characterized by high levels of androgens in women, and less commonly in men.[4] The presentation of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation.[1][2] Complications may include high blood cholesterol and diabetes.[4] It occurs in about 5% of women of reproductive age.[2]

Polycystic ovary syndrome (PCOS) accounts for about 70% of hyperandrogenism cases.[1] Other causes include adrenal hyperplasia, hirsutism, insulin resistance, hyperprolactinemia, Cushing's disease, certain types of cancers, and certain medications.[1][3][4] Diagnosis often involves blood tests for testosterone, 17-hydroxyprogesterone, and prolactin as well as a pelvic ultrasound.[1][4]

Treatment depends on the underlying cause.[4] Symptoms of hyperandrogenism can be improved with birth control pills or antiandrogens such as cyproterone acetate or spironolactone.[1][4] Other measures may include hair removal techniques.[3]

The earliest known descriptions of the condition are by Hippocrates in the 5th century BCE.[5][6]

In 2011 the International Association of Athletics Federations (now World Athletics), and IOC [7] released statements restricting the eligibility of female athletes with high testosterone, whether through hyperandrogenism or as a result of a disorder of sex development (DSD). These regulations were referred to by both bodies as hyperandrogenism regulations, and have led to athletes with (DSD) being described as having hyperandrogenism.[8][9]

Signs and symptoms[edit]

A woman with hirsutism from increased androgen exposure

Hyperandrogenism affects 5-10% of women of reproductive age.[10] Hyperandrogenism can affect both men and women, but is more noticeable in women since elevated levels of androgens in women often facilitates virilization. Because hyperandrogenism is characterized by the elevation of 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 tends to consist of a pelvic exam, observation of external symptoms, and a blood test measuring androgen levels.[11]

Women[edit]

Hyperandrogenism, especially high levels of testosterone, can cause serious adverse effects on women's bodies if left untreated. High testosterone levels have been seen to be associated with other health conditions such as obesity, hypertension, amenorrhea (cessation of menstrual cycles), and ovulatory dysfunction, which can lead to infertility. The more prominent signs of hyperandrogenism are hirsutism (unwanted growth of hair especially in the abdominal region and places on the back), acne after adolescence, deepening of the voice, and alopecia (balding).[12]

Hyperandrogenism has also been seen to cause individuals to have a high tolerance to insulin, which can lead to type two diabetes, and dyslipidemia, such as high cholesterol. These effects have also been seen to have a large psychological impact on the individual, 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 and a poor view of oneself.[11][13]

Men[edit]

Even though hyperandrogenism is not common in men, there are studies that look into the effects of high levels of testosterone in males. A study showed that although many of the male participants did not have behavioral changes[clarification needed] due to the increased levels of testosterone, there were cases where the participants had instances of uncharacteristic aggression. High levels of testosterone in males have not been seen to have a direct impact on their personality, but within those studies, there have been cases of sudden aggression within the male participants.[14] A study has also shown that acute high-dose anabolic-androgenic steroid administration in males have been demonstrated to acutely attenuate reproductive hormonal secretions and significantly impact thyroid axis balance. The authors of the study concluded that effects on mood and aggression observed during high-dose anabolic-androgenic steroid administration may occur secondarily to hormonal changes.[15] Another study showed that the same signs and symptoms that are shown in women such as alopecia and acne were also found in men. The article also showed enlarged prostates with men with hyperandrogenism.[16]

Causes[edit]

While hyperandrogenism in women can be caused by external factors, it can also appear from natural causes.

Polycystic ovary syndrome[edit]

Ultrasound of a polycystic ovary

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by an excess of androgens produced by the ovaries. It is estimated that approximately 90 per cent of women with PCOS demonstrate hypersecretion of these hormones.[17] A concrete cause for this condition is currently unknown. Speculations include genetic predisposition, although the gene or genes, in particular, have yet to be identified.[18] Evidence suggests that the condition may have a hereditary basis. Other possible causes include the effects of an increase in insulin production. Most of the cases of PCOS involve insulin resistance.[19] It is thought that adipose tissue dysfunction plays a role in the insulin resistance seen within PCOS.[19] Insulin itself has been observed capable of inducing excess testosterone levels in the ovaries.[20] A complication associated with polycystic ovary syndrome is high cholesterol (discussed in the introduction) which is treated with statins. In a meta-analysis, atorvastatin has been shown to decrease various androgen concentrations in persons with hyperandrogenism.[21]

Elevated insulin concentration in the body leads to lower production of sex hormone binding globulin (SHBG), a regulatory glycoprotein that suppresses the function of androgens.[22] 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 display PCOS due to markedly higher amounts of insulin in their bodies. This hormonal imbalance can lead to chronic anovulation, in which the ovaries experience difficulty releasing mature eggs. These cases of ovulatory dysfunction are linked to infertility and menstrual disturbances.[17][23] A post hoc analysis from a randomized, placebo-controlled, multi-centre study carried out at 11 secondary care centres and a longitudinal single-centre study on healthy pregnant women in Norway also determined that metformin had no effect on maternal androgens in PCOS pregnancies.[24]

In systemic review, although still debatable, suggests that vitamin D receptor polymorphisms are associated with the prognosis of polycystic ovary syndrome.[25][26] These studies contributed small sample sizes, so definitive causation could be concluded. However, studies have shown benefits for vitamin D supplementation in women with vitamin D deficiency and polycystic ovary syndrome.[27]

Hyperthecosis and hyperinsulinemia[edit]

Hyperthecosis occurs when the cells of the ovarian stroma transition from interstitial cells, which are cells located in between other cells, into luteinized theca cells. Theca cells are located in the ovarian follicles and become luteinized when the ovarian follicle breaks and a new corpus luteum is formed. The dispersal of luteinized theca cells throughout the ovarian stroma, in contrast to PCOS where the luteinized theca cells are only around cystic follicles, causes women with Hyperthecosis to have higher testosterone levels and male-attributed characteristics (virilization) than women with PCOS. Excess levels of insulin in the blood, known as hyperinsulinemia, is also a characteristic of Hyperthecosis.[28] Hyperthecosis is mostly seen in postmenopausal women and is linked to acne, hirsutism, growth of the clitoris, baldness, and voice deepening.[29]

Low levels of insulin can also lead to hyperandrogenism. When the body's insulin levels drop too low, it can force itself to produce too much in an effort to make up for the loss. The result of such an overproduction is a disorder called hyperinsulinemia. An effect of hyperinsulinemia is the body's increased production of androgens in the ovaries.[30] This is all part of HAIR-AN syndrome, a multisystem disorder that involves increased insulin levels that prompt increased androgen levels.[31][32]

Of note, obesity can play a role in insulin resistance.[33] For instance, obesity makes thecal cells more responsive to Luteinizing Hormone, LH.[33] Therefore, obesity increases ovarian androgen production.[33] Additionally, obesity elevates inflammatory adipokines which leads to not only adipogenesis, but also heightened insulin resistance.[33]

Cushing’s syndrome[edit]

Cushing syndrome develops due to long-term exposure to the hormone cortisol.[34][35] Cushing's syndrome can either be exogenous or endogenous, depending on whether it is caused by an external or internal source, respectively.[36] The intake of glucocorticoids, which are a type of steroid hormone, is a common cause for the development of exogenous Cushing's syndrome. Endogenous Cushing's syndrome can occur when the body produces excessive amounts of cortisol. This occurs when the hypothalamus of the brain transmits corticotropin-releasing hormone (CRH) to the pituitary gland, 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), colored stretch marks, and an excessively reddish complexion in the face.[37] Cushing's syndrome has been shown to cause androgen excess, which directly links it to the signs and symptoms seen in hyperandrogenism.[29]

Congenital adrenal hyperplasia[edit]

Congenital adrenal hyperplasia describes a group of autosomal recessive disorders that cause a lack of an enzyme needed for producing cortisol and/or aldosterone, both of which are steroid hormones. Most cases of CAH are due to 21-hydroxylase deficiencies, an enzyme used by the body to produce cortisol and aldosterone. The heightened androgen levels seen within congenital adrenal hyperplasia impact the hypothalamic pituitary-gonadal axis.[38] They can also impact the ovaries which can lead to infertility as well as chronic anovulation.[38]

Since congenital adrenal hyperplasia consists of multiple disorders, the signs and symptoms of hyperandrogenism, as well as their severity, depend upon the mutations that particular disorders are related to.[39] Therefore, genotyping is crucial to help verify diagnoses and establish prognostic factors for individuals.[40] Genotyping is also crucial for people interested in genetic counseling to aid in family planning.[40]

In women, CAH causes uncertainty in the genitals at birth and later on in adolescence excessive pubic hair, enlargement of the clitoris, hirsutism and although it causes rapid growth in childhood adult women with CAH are shorter than average due to early puberty and closure of growth plates. Symptoms in males include early showings of pubic hair, enlargement of the penis, and rapid body and skeletal growth.[41]

Tumors[edit]

Adrenocortical carcinoma and tumors[edit]

This is very rare disease with an average incidence rate of 1–2 per million annually. This disease causes cancerous cells to form 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 prevalence of adrenocortical carcinomas is relevant within this population. These tumors are associated with elevations of androgen levels in more than half of affected patients including, androstenedione, dehydroepiandrosterone sulfate, and testosterone.[42] The elevation of androgens caused by these adrenocortical carcinomas often lead patients with these steroid hormone-producing tumors to develop Cushing's syndrome, Conn syndrome and Hyperandrogenism.[43][42] There have been many recent advances on the pathology and pathogenesis of adrenocortical tumors, however the molecular basis of this human disease and has yet to be elucidated.[42]

Adenoma of the adrenal gland[edit]

Adrenal Adenomas are benign tumors on 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, in that they begin to produce hormones in much larger quantities than what adrenal glands tend to produce leading to a number of health complications including primary Aldosteronism and hyperandrogenism.[44]

Arrhenoblastoma[edit]

An Arrhenoblastoma is an uncommon tumor of the ovary. It is often composed of sterol cells, leydig cells or some combination of the two. The tumor can produce male or female hormones in the patient and may cause masculinization. In a prepubescent child, a tumor may cause precocious puberty. Malignant Arrhenoblastoma accounts for 30% of all cases of Arrhenoblastoma, the other 70% being largely benign and curable with surgery.[45]

Hilar cell tumor[edit]

An ovarian, Androgen producing tumor afflicting older women in most cases and often leading to the development of virilization. This tumor tends to occur around the region of the ovary where the blood vessels enter the organ otherwise known as the hilum. This type of tumor tends to be rather small in size and in most cases could be entirely removed and its symptoms reversed through surgery.[46]

Krukenberg tumor[edit]

Krukenberg tumors are quickly developing malignant tumor that are normally found in one of or both ovaries that primarily originate from tissues in the stomach, pancreas, gallbladder, colon or breast. The tumor is caused by the trans coelomic spread, or the spread of metastatic tumors through body cavities.[47] These tumors cause virilization in the people they affect. Increased androgen production secondary to elevations in human chorionic gonadotropin is hypothesized to the primary causative reason for hyperandrogenism in people with Krukenberg tumors.[48]

Menopause[edit]

One such cause is the end of ovulation and the beginning of menopause. When the body transitions from ovulation to menopause, it stops releasing estrogen at a faster rate than it stops releasing androgens. In some cases, estrogen levels can drop enough that there are substantially higher androgen levels leading to hyperandrogenism. A decrease in sex hormone levels while the free androgen index increases help to aid this process, as well.[49]

Drug-induced[edit]

Many drugs can stimulate 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. The most frequently implicated drugs in causing hyperandrogenism are anabolic steroids, synthetic progestins, and antiepileptics, however many other drugs may cause hyperandrogenism.[50] This can happen according to one of five major mechanisms, namely the direct introduction of androgens to the body, the binding of the drug to androgen receptors and subsequent participation in androgenic action (as is the case with anabolic-androgenic steroids), the reduction of sex hormone-binding globulin plasma concentration that leads to a resulting increase in free testosterone, the interference with and alteration of the hypothalamic–pituitary–ovarian (HPO) axis, or the increase in release of adrenal androgens.[51] However, certain drugs do exist where the mechanism by which they cause hyperandrogenism remains unclear. For example, the molecular basis in which valproate induces hyperandrogenism and polycystic ovary syndrome has yet to be elucidated.[50] However, there was a study that showed that women taking valproic acid had higher testosterone levels and hyperandrogenism compared to those women who were not taking valproic acid for bipolar disorder.[52]

Heredity[edit]

Because hyperandrogenism can appear as a symptom of numerous different genetic and medical conditions, it is difficult to make a general statement on whether hyperandrogenic symptoms can be passed from parent to offspring. However, a collection of the conditions with hyperandrogenic symptoms, including polycystic ovary syndrome, have been observed as hereditary in certain cases. Additionally, it is thought that epigenetics may aid in the pathogenesis of polycystic ovary syndrome.[53]

One potential cause of polycystic ovary syndrome is maternal hyperandrogenism, where the hormonal irregularities of the mother can affect the development of the child during gestation, resulting in the passing of polycystic ovary syndrome from mother to child.[54] Other studies compared the difference between umbilical cords with mothers with polycystic ovary syndrome and mothers without. The umbilical cords included both male and female infants. The results showed no significant androgen elevations. The testosterone levels from the umbilical cords were not associated with the polycystic ovary syndrome and the androstenedione levels were lower in female infants.[55]

Diagnosis[edit]

Diagnosing hyperandrogenism can be complex due to the wide variety and severity of signs and symptoms that may present in women.[56]

Women may show symptoms of hyperandrogenism in their early life, but physicians become more concerned when the patient is in her late teens or older.[11]

Hyperandrogenism is most often diagnosed by checking for signs of hirsutism according to a standardized method that scores the range of excess hair growth.[10][11]

Checking medical history and a physical examination of symptoms are used for an initial diagnosis.[11] Patient history assessed includes age at thelarche, adrenarche, and menarche; patterns of menstruation; obesity; reproductive history; and the start and advancement of hyperandrogenism symptoms.[11] Patterns of menstruation are examined since irregular patterns may appear with hirsutism.[10] Other conditions that may present alongside hirsutism that can be utilized for diagnosis include androgenic alopecia and acne.[56] If hyperandrogenism is severe enough, virilization may occur.[56]

Family history is also assessed for occurrences of hyperandrogenism symptoms or obesity in other family members.[11]

A laboratory test can also be done on the patient to evaluate levels of FSH, LH, DHEAS, prolactin, 17OHP, and total and free testosterone in the patient's blood.[11] Abnormally high levels of any of these hormones help in diagnosing hyperandrogenism.[11]

Prevention[edit]

Since risk factors are not known and vary among individuals with hyperandrogenism, there is no sure method to prevent this medical condition.[57] Therefore, more long-term studies are needed first to find a cause for the condition before being able to find a sufficient method of prevention.[57]

However, there are a few things that can help avoid long-term medical issues related to hyperandrogenism like 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.[58] Watching your weight and diet is also important in decreasing your chances, especially in obese women, since continued exercise and maintaining a healthy diet leads to an improved menstrual cycle as well as to decreased insulin levels and androgen concentrations.[57]

Treatment[edit]

Currently, there is no definitive treatment for hyperandrogenism as it varies with the underlying condition that causes it. As a hormonal symptom of polycystic ovary syndrome, menopause, and other endocrine disorders, it is primarily treated as a symptom of these disorders. Drugs may be considered only in women who do not plan on becoming pregnant in the near future.[59] Some effective drugs for treating facial hirsutism includes eflornithine, which may cause birth defects in pregnant women,[60] retinoids and antibiotics for acne and minoxidil for alopecia.[60] Systemically, it is treated with antiandrogens such as cyproterone acetate, flutamide and spironolactone to control the androgen levels in the patient's body. 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 swelling of the adrenal glands.[61][62] Oestrogen-based oral contraceptives are used to treat both CAH and PCOS caused hyperandrogenism. These hormonal treatments have been found to reduce the androgen excess and suppress adrenal androgen production and cause a significant decrease in hirsutism.[63][64]

Hyperandrogenism is often managed symptomatically. Hirsutism and acne both respond well to the hormonal treatments described above, with 60-100% reporting an improvement in hirsutism.[63] Androgenic alopecia however, does not show a significant improvement with hormonal treatments and requires other treatments, such as hair transplantation.[65]

Supplementation can also contribute to the managing treatment of symptomatic effects of hyperandrogenism. In a meta-analysis, multiple studies showed when high levels of vitamin D supplements were given to women with vitamin D deficiency due to polycystic ovary syndrome, there were improvements in glucose levels, insulin sensitivity, cholesterol levels, and lowering of certain hormones such as testosterone, sex hormone binding globulin, and free androgen index which are all associated with hyperandrogenism.[66] The supplementation of vitamin D with non-polycystic ovary syndrome women with vitamin D deficiency did not show the same results.[27]

Targeting Insulin Resistance and Obesity[edit]

In every woman with polycystic ovary syndrome (PCOS), lifestyle modifications are recommended to help with controlling symptoms of hyperandrogenism. Of note, lifestyle modification is regarded as the first-line treatment for PCOS.[67] Lifestyle modifications have proven to help with improving overall body composition, insulin resistance, and hyperandrogenism. However, there is unclear results in overall improvement of mood, quality of life, and reproductive outcomes.[68] Additionally, lifestyle modifications and anti-obesity medications have not shown a proven benefit in the long run and some people turn to bariatric surgery.[69] A meta-analysis study in 2017 showed that bariatric surgery in women with severe obesity and PCOS had decreased levels of total and free testosterone in their body, and helped correct issues of hirsutism and menstrual dysfunction.[70]

One of the most common strategies in targeting insulin resistance in women with PCOS is through the use of insulin-sensitizer drugs, like metformin. Metformin can help to decrease weight and to decrease androgen levels in the body.[71] When combined with lifestyle modifications (changes in diet and exercise), it has been linked with lower BMI and helped with menstrual problems.[71] However, the use of metformin in women with PCOS should only be considered in patients with a known issue with glucose tolerance.a[citation needed]

Society and culture[edit]

Because androgen excess is manifested in noticeable physical features (ex. hirsutism), a certain social stigma is associated with it.

Sports[edit]

Theoretical and evidence-based claims currently exist that state that very high levels of circulating testosterone is associated with increased athletic performance in women with androgen sensitivity. However, there is much disagreement on whether or not testosterone is unlike any other physical parameter with reference to bestowing advantages or disadvantages in female athletes. Existing regulations throughout competitive sports are currently being refined to specifically address this, and many have stated the importance of guaranteeing fairness and respect for all female athletes during these proceedings.[72]

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

Following the case of South African athlete Caster Semenya, the International Association of Athletics Federations (IAAF) introduced its hyperandrogenism regulations, which restricted women with high testosterone levels, whether through hyperandrogenism or having testes and a DSD. These regulations replaced the earlier sex verification rules.[citation needed]

Eventually, following a series of legal challenges, the current set of regulations were released on 1 May 2019, now called the Eligibility Regulations for the Female Classification (Athletes with Differences of Sexual Development, or DSD).[73] These regulations only apply to athletes with XY DSDs and testes,[74] and no longer include hyperandrogenism from causes such as PCOS.

Social definition[edit]

Cultural variation can define hyperandrogenism socially—aside 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 in North American women is tolerated, while other androgen-dependent hair such as growth on the upper lip, over the linea alba, over the thighs, and any periareolar hair is not.[75]

Organizations[edit]

Professional organizations like the Androgen Excess and PCOS Society exist to promote the research, treatment, diagnosis, and prevention of such disorders along with educating the public and scientific community about them.[76]

See also[edit]

References[edit]

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