Androgenization, polycystic ovary syndrome and androgen-secreting tumors

Once vellus hair has been transformed to terminal hair under the influence of androgens, the terminal hair persists for a long time, even after withdrawal of androgens. Unfortunately, this rule also applies to women who have been diagnosed with and successfully treated for virilization.

Hypertrichosis is not androgen-dependent. Hypertrichosis causes a generalized increase in the amount of the fetal lanugo hair type. Hypertrichosis is usually found as a side effect of certain medications or as a paraneoplastic phenomenon. Hypertrichosis is defined in different ways: Some define hypertrichosis as an increased amount of body hair according to the female distribution pattern (so no hairiness between the pubis and the navel, for instance), regardless of the intensity. Others define hypertrichosis as a Ferriman-Gallwey hirsutism score of < 8 (see below “Clinical picture of hirsutism”), regardless of the distribution pattern. In Europe, the first definition is normally used.

A certain level of androgenization is typical and normal following menopause (classic signs: beard and receding hairline at the corners in women). This is due to comparatively higher androgen levels in postmenopausal women. Hirsutism implies the transformation of vellus hair into terminal hair and is usually the result of increased androgen secretion. However, hirsutism can also occur as a family or idiopathic trait with normal androgen values. In the case of hirsutism, there are no signs of masculinization. Cave! In terms of differential diagnosis, consider the possibility of use of androgenizing medications, or androgen abuse or with other anabolic compounds! Virilization is when in addition to a pronounced increase in the amount of hair, there are also typical signs of masculinization (deepening of the voice, clitoral hypertrophy, pronounced alopecia, increased muscle formation, increased libido, psychological changes, etc.). If virilization is found during a physical examination, it is essential to actively rule out an androgen-secreting tumor. Virilization may even occur before puberty. Effective screening of newborns effectively prevents congenital virilization in adrenogenital syndrome. Virilization (initially acne, hirsutism, alopecia) is the most typical hallmark of androgen-secreting tumors. The classic symptoms of virilization typically occur somewhat later; however, voice changes or an increase in libido can be the first symptoms suggestive of virilization. Once symptoms of virilization have occurred, they do not always recede again completely (hair distribution pattern, deep voice, clitoral hypertrophy). The occurrence of virilization during pregnancy indicates a luteoma, which is not a true tumor, but rather an abnormal reaction of the ovarian stroma to the normal HCG level.

When taking the general medical history, it is crucial to ask about the family history (hirsutism/acne in siblings, parents, aunts, uncles), and the father's side must not be left out. It is also essential to determine exactly when the hirsutism occurred (at puberty? later?) and how quickly it developed (see above). Gynecological history: Here, it is particularly important to enquire the age of menarche and the subsequent menstrual cycle pattern, because hyperandrogenemia is often linked to early chronic anovulation or secondary amenorrhea.

During the physical examination, hirsutism must be assessed using a suitable score (e. g., the Ferriman-Gallwey score; figure 1).

Possible signs of virilization must be ruled out: clitoral hypertrophy, androgenetic alopecia, breaking of the voice. Important note: The same hirsutism score does not have the same meaning for different ethnic groups. In a woman from the Mediterranean region, a hirsutism score of 15 may still be within the normal range for her ethnicity, but in an Asian woman, it would be pathological.

Considerations for endocrine analytics: Due to the cyclical secretion pattern of the pituitary and ovarian hormones, it is necessary to standardize the day within the cycle on which each hormone assay is carried out. The normal values for the usual laboratory tests are based on the early follicular phase. The same applies to the measurement of free or total serum testosterone levels as a screening test for androgenization. Whenever possible, the time of day should also be considered for the determination of (total) testosterone concentration and not only for the adrenal hormones (cortisone) that are more strongly influenced by the circadian rhythm (blood draws 07:30–09:30). It is therefore recommended that hormone assays only be done in the early follicular phase (days 1 to 5) when investigating the menstrual cycle. The serum levels of a number of hormones (such as prolactin and cortisol) are affected by food intake and stress.

Figure 2 provides an overview of the origin of androgens in premenopausal women.

Due to the cyclical secretion pattern of the pituitary and ovarian hormones, it is necessary to standardize the day within the cycle on which each hormone assay is carried out. The normal values for the usual laboratory tests are based on the early follicular phase. The same applies to the measurement of free or total serum testosterone levels as a screening test for androgenization. Whenever possible, the time of day should also be taken into account for the determination of total testosterone concentration (blood draws 07:30–09:30). It is therefore recommended that hormone assays only be performed during the early follicular phase (days 1 to 5).

In the case of suspicion of an androgen-secreting tumor of the adrenal cortex, DHEAS is used as a tumor marker. There is no indication for determining the serum levels of androstenedione and DHEA concentration.

17-alpha-hydroxyprogesterone: In the case of primary or secondary amenorrhea (see script E02), if androgenization is present, one-off determination of the 17-hydroxy-progesterone concentration in the serum can be used for differential diagnosis of adrenogenital syndrome (AGS). Since due to its adrenal origin 17-alpha-OH-progesterone is also subject to a circadian secretion pattern, the test should be performed in the morning. An elevated 17-hydroxyprogesterone concentration may indicate a 21-hydroxylase deficiency, which would require further investigation. Very rare forms of AGS (< 1 %) are the result of other enzyme defects and for that reason are not detected by this screening test.

In women with mild, isolated, non-progressive hirsutism who do not wish to have children, hormone analysis with measurement of serum androgens is generally not worthwhile because in the majority of cases, the result of this analysis has no consequences in terms of the treatment that is performed or its outcome.

Figure 4 provides an overview of the practical approach in the clinic.

In terms of differential diagnostics, in the case of androgenization, all known causes of polycystic ovary syndrome (PCOS) must be taken into account, including late-onset adrenogenital syndrome (late-onset AGS) and Cushing’s syndrome (see below). In both of these conditions, various clinical stages of hirsutism can be observed, up to and including virilization. For the typical clinical symptoms of Cushing’s syndrome, see the Internal Medicine lectures. Hyperandrogenemia and metabolic syndrome (also see below): In the context of metabolic syndrome, hyperandrogenemia is often associated with insulin resistance. Hyperinsulinemia and overweight must be classified as risk factors for later development of diabetes and cardiovascular diseases in anovulatory women with hyperandrogenemia. Therefore, treatment is required, even if the patient does not wish to have children.

Weight reduction: If the patient is both obese and hyperandrogenemic weight loss alone often leads to a decrease in androgen secretion and normalization of a possible hyperinsulinemia, meaning that regular ovulation cycles can be restored. Drug treatment if there is no desire to have children: If the patient does not wish to have children, antiandrogens are generally used:

The structural formulas of Cyproterone acetate, Spironolactone and Testosterone are shown in figure 5.

Issue for the dermatologist

This belongs in the hands of the gynecological endocrinologist!

The term “polycystic ovary syndrome” (PCOS) describes a homogeneous group of symptoms and changes in hormone levels.. The name is based on the classic definition of the syndrome, in which the ovaries have many small parietal cysts along with a thickened stroma. These microcysts are always benign. PCOS was first described by Stein and Leventhal, which is why the term “Stein-Leventhal syndrome” can be found in older literature. Other (older and English) names for PCOS include chronic hyperandrogenemic anovulation (= CHA according to SSC Yen) and polycystic ovarian disease (PCOD). The incidence of the PCOS varies depending on the statistics used and the cardinal symptom that is studied (dermatological clinics find a different incidence rate than fertility centers). The figures are between 7 % and 30 %.

According to the Rotterdam criteria two of three of these characteristics must be present. PCOS is a syndrome of ovarian dysfunction with the cardinal signs of hyperandrogenism and polycystic ovaries (PCO). Other causes of hyperandrogenaemia must be excluded, such as: congenital adrenal hyperplasia (=AGS), androgen-secreting tumors, Cushing’s syndrome.

Many women with PCOS also suffer of infertility as caused by chronic anovulation. PCOS is linked to insulin resistance. For that reason PCOS is often associated with a higher risk of gestational diabetes and an elevated risk of type 2 diabetes and cardiovascular disease at later age.

It is likely that several genes are involved in the development of this heterogeneous syndrome. Familial forms of PCOS are known. Genetic studies have shown that first-degree relatives of a patient with PCOS have higher incidence rates for this disease. Although many genes have been suggested as the possible culprits, the genetic cause has not yet been clearly defined. Both autosomal and X-linked inheritance patterns have been postulated. However, there is not enough data to support any one hypothesis.

A postulated vicious circle whose clinical endpoint is PCOS, regardless of the triggering mechanism (figure 6):

The first signs are usually irregular periods combined with increasing androgenization (hirsutism, acne, alopecia), and usually – but not always! – weight gain. Thin women can also have PCOS!

These individual symptoms may occur together, but do not always necessarily do so. We often find oligosymptomatic women. This means that there may appear to be a regular cycle, but further investigation shows chronic anovulation. The manifestation of androgenization strongly depends on genetic predisposition (Asian women!). This also applies to acanthosis nigricans, which is rare in Europe and is often found in the context of PCOS, especially in black people. The suspected clinical diagnosis is confirmed through a vaginal ultrasound examination, in which the polycystic appearance of the ovaries ovaries, and through hormonal analyses in the serum, in which elevated serum testosterone levels are detected, in combination with normal or reduced serum levels of the sex hormone binding globulin (SHBG). These analyses must be set in perspective to the clinical appearance of the patient (acne, hirsutism, diffuse alopecia) and to the temporal abnormalities of the menstrual cycle. According to the Rotterdam criteria two of three conditions must be fulfilled to confirm the diagnosis of PCOS. In adolescent women temporal abnormalities of the menstrual cycle and hyperandrogenaemia and/or sign of high androgen exposure are sufficient for the diagnosis.

A transvaginal ultrasound is shown in Figure 7.

Although PCOS was initially seen from the point of view of androgenization and unwanted childlessness, today, its association with metabolic syndrome is in the foreground (figure 8).

If a metabolic syndrome is suspected, the possibility of insulin resistance must also be investigated (measurement of fasting glucose and fasting insulin, calculation of the HOMA score, see below). In the classic challenge test, the blood glucose value and insulin level are measured two hours after administration of 75 g glucose. However, the HOMA score is simpler and just as clinically useful. Metabolic syndromes also include elevated LDL levels, combined (especially in obese women) with low HDL values and increased triglyceride values.

According to HOMA and QUICKI, about 95 % of obese women with PCOS have insulin resistance. * Calculation: HOMA = 22.5 x 18/fasting insulin x fasting glucose ** Calculation: QUICKI = 1/log (fasting insulin + log (fasting glucose)

Due to its clinical significance, the PCOS has developed from a disease that originally mainly concerned the gynecologist and the dermatologist into a problem that also concerns the internal medicine specialist.

Especially in PCOS patients who are overweight, the first therapeutic measure is reduction of the body mass index (BMI) through lifestyle improvements (nutritional counseling, exercise). In women aiming for pregnancy improvement of lifestyle alone is often sufficient to resume regulatory and ovulatory menstrual cycles. Treatment of acne and hirsutism follows the same principles as treatment for straightforward androgenization (see above). If the patient has metabolic syndrome with insulin resistance, the administration of metformin (usually 3 x 850 mg/d, up to 2500 mg/d max) is a proven supporting measure. If the patient wishes to become pregnant, further treatment of chronic anovulation is an issue for the gynecological endocrinologist (induction of follicle maturation using clomifene citrate, letrozole, FSH, ovarian drilling, and even IVF/ICSI). Rough outline of fertility treatment with evidence provided (figure 9):

Androgen-secreting tumors are very rare. They are among the rarest causes of androgenization (< 1 %), which means they are also among the most overestimated medical issues. They are often confused with “incidentalomas” (especially in the adrenal gland). Nevertheless, they must not be overlooked. Arrhenoblastomas make up about 0,2 % of all ovarian tumors, and they are found in all age groups. Peak frequency: 3rd decade of life.

Adrenal adenomas and carcinomas can manifest as virilization and hyperandrogenemia.

Androgen-secreting tumors are generally characterized by rapid-onset virilization:

In the case of serum testosterone values > 2,5x the upper limit of the reference range of the investigating laboratory, tumors are suspected. Such values must always be investigated further. There is a significant overlap between the values found in the case of tumors and those found in severe cases of PCOS and hyperthecosis. A DHEAS level of 700 g/dL or more is a marker of pathological adrenal function, and must be considered a possible indicator of a tumor. However, such values are only found rarely without being accompanied by pathologically elevated serum testosterone values. The further investigation and treatment of androgen-secreting tumors must be carried out by the specialist! Testosterone-secreting tumors can lead to serum values within the normal range for males. If serum testosterone levels exceed 200 ng/dL, an androgen-secreting tumor must be suspected. However, lower values cannot rule out an androgen-secreting tumor with certainty. In addition, women with PCOS (especially in connection with hyperthecosis) exhibit testosterone levels exceeding 200 ng/dL. Assessment of the DHEAS level: A DHEAS level of 700 g/dL or more is a marker of pathological adrenal function, and must be considered a possible indicator of a tumor. However, such values are only found rarely without being accompanied by pathologically elevated serum testosterone values. Exception: Cushing’s syndrome. Therefore, the laboratory findings must always be considered in the context of the history: speed of onset, distribution pattern, simultaneous presence of symptoms of virilization. If a patient has a typical history and a typical clinical manifestation that is compatible with an androgen-secreting tumor, a targeted investigation to check for an androgen-secreting tumor must be carried out, even in the case of serum testosterone values under the critical level. Looking at recent and less recent photos of the affected person is helpful. The effect of an androgen-secreting tumor is fulminant!