Hyperandrogenemia, high level of testosterone
Hyperandrogenism is a pathological state of excess androgen secretion, leading to their abnormally high blood levels. Androgens (Pic. 1) are steroid hormones (i. e. fat-soluble, derived from cholesterol) regulating the development and maintenance of male characteristics (in embryological development as well as at puberty and adult life). They are normally synthesized in the testes, the ovaries, and the adrenal glands. In females, androgen levels are lower than in men and besides being precursors to estrogens (one of the main female sex hormones), they function in libido and sexual arousal. The major androgen in males is testosterone, followed by dihydrotestosterone and androstendione.
As men are physiologically provided with relatively high testosterone levels, clinical manifestation of hyperandrogenism in men is subtle compared to women. In females, it is typically diagnosed in late adolescence, and the symptoms are for example acne, hair loss, obesity, hirsutism (e. g. excessive hair in parts of the body where it’s usually absent or minimal), or menstrual dysfunction (to be more described later).
There can be many causes to hyperandrogenism. In women, the most common one is polycystic ovary syndrome, followed by an unknown cause (so-called idiopathic hyperandrogenism), adrenal hyperplasia (increased cell multiplication leading to increase of mass of the affected tissue), or androgen secreting tumours (with more details provided in “associated diseases”). Another possible cause has been proven to be Cushing’s syndrome (i. e. a medical condition caused by long-term exposure to excess hormone cortisol).
In men, hyperandrogenism is not common. If it occurs though, the possible causes correspond with those for women: e. g. adrenal hyperplasia, Cushing’s syndrome, or androgen secreting tumours.
Although symptoms may be present in early life, physicians become more concerned when the patient is in her late teens or older. Hyperandrogenism is most often diagnosed by checking for signs of hirsutism according to a standardized method scoring the range of excess hair growth. For initial diagnosis, checking medical history (including history and patterns of menstruation, reproductive history, the start of symptoms, and obesity) and examining the symptoms are used. A laboratory test can also be done to evaluate levels of androgens and other sex hormones (e. g. follicle stimulating hormone FSH, luteinizing hormone LH, prolactin…).
Treatment mainly depends on the cause of hyperandrogenism. Based on that, antiandrogens are often used, but other hormonal administration occurs as well, e. g. glucocorticoids, or oral contraception. Surgery is beneficial especially in a presence of a tumor.
Menopause is not a disease but can be allied with mild hyperandrogenism. It is a time in a woman’s life when menstrual periods stop permanently, and therefore, fertility vanishes. Physiologic changes of normal menopause include several hormonal changes. Levels of estrogen and progesterone (e. g. the main female sex hormones) fall, while adrenal androgen production is preserved. Additionally, sex hormone binding globulins (that carry a portion of sex hormones in blood) are reduced, resulting in increased free (and therefore bioactive) androgens. This leads to an overall increase in the ratio of androgens to estrogen, that may result in mild hirsutism (i. e. excessive body hair in abnormal locations; Pic. 2).
Hirsutism means excess body and/or facial, male-pattern hair growth in women. Being a result of hyperandrogenism, it is a common endocrine complaint affecting about 10 percent of women. Usually, it is a result of a benign entity (such as PCOS and idiopathic hirsutism). However, especially when the manifestation is severe, rapid in progression, and/or associated with virilization, an androgen-secreting tumor should be excluded.
Polycystic ovary syndrome (PCOS)
This syndrome is characterized by development of cysts (i. e. sac-like structure, usually filled with fluid) on the ovaries due to ovarian follicles malfunction (Pic. 3). It affects 9 – 18% of women in reproductive age and causes hyperandrogenism (being its most common cause) and infertility. The etiology is still poorly known. Hypotheses include hormonal imbalances, genetic imbalances, genetic abnormalities, and lifestyle and environmental factors. Symptoms generally begin in puberty and gradually develop through reproductive years. PCOS is characterized by at least two of the following criteria: clinical or biochemical hyperandrogenism, oligo/anovulation (i. e. uncommon or absent release of oocytes by the ovaries), and polycystic ovary appearance. Clinically, these manifestations are associated with reduced fertility (due to dysfunctional ovarian cycle as well as overall excess of androgens). Both chronic anovulation and androgen excess are linked to disturbed foliculogenesis (i. e. maturation of the ovarian follicle containing an oocyte; Pic. 4).
Such tumors may originate from adrenals and ovaries. Androgen-secreting ovarian tumors may be small in contrast to those originating from adrenal glands, which (rozvadim predchozi vetu) are often large in size and aggressive in behavior. Both types typically come with quickly progressive hyperandrogenism resulting in virilization (i. e. presence of male characteristics in women). They represent the least common cause of the hyperandrogenism in women with a prevalence of 0.2%. Androgen-secreting adrenal tumors are usually associated with high cortisol levels, while adrenal tumors secreting only androgen are very rare. Virilizing ovarian tumors represent less than 1% of all ovarian tumors.
Congenital adrenal hyperplasia (CAH)
CAH is a family of disorders characterized by the inability to synthesize cortisol (e. g. a steroid hormone from the class of glucocorticoids that regulates a broad range of processes) from cholesterol in the adrenal cortex. The most common cause is deficiency of 21-hydroxylase. As the pathways of adrenal hormones synthesis share some steps, 21-hydroxylase deficiency can result in excess production of androgens and aldosterone (which controls the levels of ions in the bodily fluids, mainly sodium and potassium; Pic. 5). Therefore, affected infant females present with ambiguous genitalia (Pic. 6) and virilization later in life. Infant males may have normal or enlarged genitalia, and may also develop symptoms of ion levels impairment.
Fertility and pregnancy
Hyperandrogenic women have ovulatory dysfunction of various seriousness. It can be clinically expressed as menstrual dysfunction. For example, the patient can suffer from oligomenorrhea (i. e. infrequent menstrual periods), episodes of amenorrhea (i. e. absence of menstruation), pelvic pain, menorrhagia (i. e. excessively heavy menstrual flow), disturbance of fertility, and others. In pregnancy, spontaneous miscarriages are increased in their incidence. Pregnancy complications such as gestational diabetes (a condition in which, during pregnancy, a woman otherwise without diabetes develops high blood sugar levels) can occur.
Hyperandrogenism leads to changes in appearance. Hirsutism, alopepcia, obesity… All of this can (and often does) affect self-esteem and overall psychological well-being of the patient.
Hyperandrogenism is associated with serious cardiovascular conditions, including hypertension (i.e . high blood pressure), microvascular disease, and abnormal blood levels of lipids (i. e. dyslipidemia).
In patients suffering from hyperandrogenism, metabolism is often altered. Insulin resistance as well as dyslipidemia can occur. A frequent consequence of hyperandrogenism is metabolic syndrome. It is clustering of at least three of the following: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low high-density lipoproteins. The most serious consequences of metabolic syndrome are type 2 and cardiovascular diseases.
Risk factors are not well known and vary among individuals, as hyperandrogenism is still not fully understood.
Male fertility is usually not affected. In women however, excess levels of androgens being the main male sex hormones come in conflict with female physiology. Ovarian dysfunction (that can even lead to infertility) develops and can present clinically as menstrual disorders.
Examples of findings associated to the reproductive system include: Anovulation (i. e. absence of ovulation), oligoovulation (i. e. irregular ovulation), pelvic pain, ovarian cysts, decreased fertility in general, menorrhagia (i. e. excessively heavy menstrual flow), or metrorrhagia (i. e. uterine bleeding between the expected menstrual periods). The average time for pregnancy to occur can be delayed, and spontaneous miscarriages are at increased risk.
Numerous possible causes to hyperandrogenism have been described. Moreover, as the disease can be idiopathic (i. e. the cause is unknown), it is clear that more pathological processes elevating androgen levels are yet to be described. The risk factors are not known and vary among individuals. This all results into the fact that there is no sure method of prevention. What can help decrease the risk of long-term problems are medical check-ups, especially if one has a family history of the condition, irregular periods, or diabetes. Moreover, patients benefit from watching their weight and diet (especially in obese women, since healthy diet and continued exercise leads to an improved menstrual cycle, decreased insulin levels and androgen concentrations).
Since androgens are main male sexual hormones, men affected by hyperandrogenism are clinically less recognizable than women. A study has shown that even though many of the male participants did not have behavior changes 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.
Women usually present with some combination of acne, seborrhea (i. e. inflamed skin), alopecia (i. e. hair loss on the scalp; Pic. 7), hirsutism, obesity, insulin resistance (decreased tissue response to insulin), type two diabetes, dyslipidemia (abnormal lipid levels in blood, e. g. high cholesterol), hypertension, an elevated sex drive, or ovulatory and menstrual dysfunction (that can lead to infertility).
The core of therapy lies within the conventional medicine. Healthy lifestyle including exercise, rational diet, and maintaining optimal weight can help along. In women with polycystic ovary syndrome who are overweight, weight loss has been proven to improve the chances of conceiving as well as to minimize complications during pregnancy.
Treatment of hyperandrogenism is often managed symptomatically and varies with the underlying condition that causes it as well as with patient’s complaints.
As a hormonal symptom of various endocrine disorders, it is primarily treated with antiandrogens. For hyperandrogenism caused by late-onset congenital adrenal hyperplasia, treatment is primarily focused of providing the patient with glucocorticoids to combat the low cortisol production.
When helping the patient to conceive, medication can be used to induce ovulation. If the infertility is caused by adrenal hyperandrogenism (i. e. the adrenal glands themselves are the primary cause to excess androgen production, as in congenital adrenal hyperplasia etc.), glucocorticoids are administered (in order to decrease adrenal hormone production through feedback mechanisms).
The symptoms of hyperandrogenism are usually most effectively treated with antiandrogens (to control the androgen levels in the patient’s body). In late-onset CAH, glucocorticoids can be used. Estrogen-based oral contraceptives are used to treat both CAH and polycystic ovary syndrome. Hirsutism and acne both respond well to these hormonal treatments, but alopecia (i. e. hair loss) requires other methods.
In PCOS, medications mainly include oral contraceptives and metformin. The oral contraceptives increase production of sex hormone binding globulin, thus free (and therefore bioactive) testosterone is more binded. This reduces the symptoms of hirsutism caused by high testosterone and regulates return to normal menstrual periods. Metformin is commonly used in type 2 diabetes to reduce insulin resistance. In PCOS patients, its benefits come from reducing insulin resistance as well as from supporting ovarian function. Other drugs can also be used, depending on the patient’s individual needs.
In tumor-based hyperandrogenism, surgery is often used to remove the mass. In polycystic ovary syndrome, laparotomic drilling of the ovarian cortex is sometimes used to remove the dysfunctional tissue. However, the results are only temporary and the benefits tend to be overshadowed by the possible postoperative complications.
If conservative medical treatments fail to achieve a full term pregnancy, the physician may suggest the patient undergo assisted reproduction.
Men with hyperandrogenism usually do not have reduced fertility and therefore don’t need assistance in reproduction (if they do not suffer from another condition that would decrease their fertility).
If the woman doesn’t respond to diet, lifestyle modification and pharmacotherapy, in vitro fertilization (IVF) can be performed. IVF has proven successful for women with hyperandrogenism generally.
IVF generally starts with stimulating the ovaries to increase egg production. Most fertility medications are agents that stimulate the development of follicles in the ovary. Examples are gonadotropins and gonadotropin releasing hormone. After stimulation, the physician surgically extracts one or more eggs from the ovary, and unites them with sperm in a laboratory setting, with the intent of producing one or more embryos. Fertilization takes place outside the body, and the fertilized egg is reinserted into the woman’s reproductive tract, in a procedure called embryo transfer.
The fertilized eggs (embryos) are cultivated under very stringent conditions and examined every day by an embryologist to evaluate their progress. The embryos are usually cultured for 3 to 5 days, before the best one(s) are selected to be put (transferred) into the womb.
The absence of a menstrual period in women of reproductive age.
A condition characterized by excessive levels of testoterone in the body.
Process by which a woman donates eggs for purposes of assisted reproduction or biomedical research.
A micromanipulative fertilization technique in which a single sperm is injected directly into an egg.
The procedure in which a man (sperm donor) provides his sperm for fertility treatment.
A process in which an egg is fertilised by sperm outside the body: in vitro. Own or donated gametes may be used.