by Julio Libman, Astrid Libman, María Gabriela Garrido
Hirsutism refers to excessive growth in women of terminal, thick, long and pigmented hairs in areas of the body that are sensitive to androgens and where there is normally very little hair development. Such areas include the bozo, the chin, the intermammary and periareolar region, the supra and infraumbilical midline, the back, the arms and the thighs.
The hypertrichosis is excessive development of fine hair, unpigmented, short and without pith called hair in areas not sensitive to androgen stimulation such as the forehead, forearms, legs, back. It is related to hereditary factors or medications such as minoxidil, diazoxide, diphenylhydantoin, corticosteroids, or malnutrition.
The virilization is characterized by the appearance of hirsutism, acne, development of muscle mass, baldness, low voice, and clitoromegaly.
Physiology and pathophysiology:
The body hairs can be classified into hairs hairs (fine and non-pigmented as those of the face), and terminal hairs (thick and pigmented dependent on the stimulation of sex hormones, such as beard and abdomen hairs in the male). Androgens convert hair hair to terminal hair in areas linked to sex hormones. Many premenopausal women increasingly develop androgen-dependent hairs, considering them hirsute.
Androgens are the main determinants of hair growth and distribution in both sexes, therefore it is necessary to know their biological production and action mechanisms, in order to interpret hirsutism pictures.
Dehydroepiandrosterone (DHEA), DHEA sulfate (SDHEA) and androstenedione are part of the 17 ketosteroids, constituting the androgenic steroids that are produced in greater quantity in women. They are relatively weak androgens. Its increased androgenic activity probably depends on its degree of conversion to 17-hydroxysteroids, potent androgens including androstenediol, testosterone, dihydrotestosterone, and androstenediols, all of which have been identified in plasma. Testosterone is the most important androgen due to its biological potency and concentration. The adrenals normally produce most of the 17 ketosteroids and 25% of the testosterone. The adrenals make androgens as intermediates of cortisol biosynthesis,
The ovaries normally make 25% of testosterone and 50% of androstenedione. At the ovarian level, androgens are formed as intermediates in the pathway of estrogen synthesis and as metabolites of 17 OHprogesterone, and are mainly produced in theca and in the interstitial compartment under the gonadotrophic stimulus.
Androgens are also produced by peripheral conversion at the level of non-endocrine organs, such as the skin and the liver, from prehormones. The adrenal cortex and ovaries are the source of both hormones and prehormones. 50% of plasma testosterone is produced in this way.
Approximately 98% of testosterone circulates bound to proteins, sex steroid-binding globulin, and albumin. The biologically active portion is the one that circulates free, the sex steroid binding globulin being the main determinant of the amount of testosterone and of other 17 beta-hydroxysteroids that leave the plasma compartment to exert their action at the tissue level.
Current concepts of hormonal action indicate that it is probably the amount of dihydrotestosterone synthesized intracellularly and available at the level of the hair follicle that ultimately determines the degree of androgenic stimulation of hair growth. Since it is clinically impossible to determine intracellular hormone, circulating steroids are evaluated. Most women with hirsutism have elevated levels of androgens after a thorough hormonal evaluation. If only urinary 17-ketosteroids are measured, only 15% of patients have values above normal. If the total testosterone is quantified, approximately 40% find high figures. Measuring the total concentrations of different androgens and prehormones (testosterone, dihydrotestosterone, SDHEA, androstenedione and 17-OH-progesterone), around 90% of women with hirsutism show high values of one or more of such components. Sex steroid-binding globulin is frequently decreased in hirsute patients, since androgens decrease its hepatic synthesis, so that biologically active free testosterone may be elevated even with normal total testosterone levels.
Causes of hirsutism:
They are listed in the table.
Table. Causes of hirsutism
- Due to ovarian androgen excess
- Polycystic ovarian disease (androgenic ovary)
- Stromal hyperplasia
- Hybrid cell hyperplasia
- Ovarian tumors
- Due to excess adrenal androgens
- Congenital late-onset adrenal hyperplasia
- Adrenal tumors
- Cushing's disease
- Other causes
Idiopathic or benign: Includes a group of hirsute women without ovarian enlargement, with no evidence of adrenal and ovarian tumors, with cortisol and 17 normal or slightly elevated ketosteroids. However, the fact that most have a higher than normal rate of testosterone production and free testosterone suggests that they suffer from androgenic dysfunction.
Polycystic ovarian disease (androgenic ovary): It is the most common cause of hirsutism in women. This syndrome presents with sterility, amenorrhea or oligoamenorrhea, hirsutism, and obesity in women with polycystic ovaries enlarged (Stein-Leventhal syndrome). There is excessive production of androstenedione and testosterone, mainly of ovarian origin. The exact cause of this dysfunction is not known, but the increase in LH levels is involved in its perpetuation.
Ovarian stromal hyperplasia: It is a postmanopausal disorder associated with an excess of androgens. It probably depends on the LH hypersecretion that occurs at menopause.
Ovarian tumors: rare, including arrenoblastomas, hilum cell tumors, and lipoid cell tumors.
Late-onset congenital adrenal hyperplasia: This is a genetic disorder in which there is a defect in cortisol synthesis due to 21-hydroxylase or 11-hydroxylase deficiency. This entails an increase in ACTH, which leads to an increased production of adrenal androgens. It manifests itself after puberty with hirsutism and oligohipomenorrhea. Cortisol levels are normal, indicating compensation for partial enzyme defect through an increase in ACTH. 17OH-progesterone as well as testosterone are elevated.
Adrenal tumors: Both adenomas and carcinomas can cause hyperandrogenism.
Cushing's disease: together with the increase in the production of cortisol there is an increase in the synthesis of adrenal androgens due to ACTH hypersecretion.
Porphyria: Congenital erythropoietic porphyria, and hepatic, variegate, and delayed cutaneous porphyrias have hypertrichosis. It is observed in the forehead, the malar region and the forearms (non-androgen dependent sites).
Malnutrition: It is due to an increase in the production of adrenal steroids.
Drugs: Diphenylhydantoin, diazoxide, hexachlorobenzene, minoxidil, and ACTH produce hirsutism without virilization, while steroid, anabolic, and progestogen drugs produce hirsutism and virilization.
Initially, an attempt should be made to exclude the possibility that the increase in body hair is caused by the administration of medications such as diphenylhydantoin, diazoxide, minoxidil, ACTH, steroids, anabolics and progestational agents, or the manifestation of a family or racial characteristic. Any family history of hirsutism should receive adequate attention, since alterations such as polycystic ovarian disease and congenital adrenal hyperplasia have defined genetic profiles.
The type and form of hair growth must be characterized in detail. It is necessary to determine the age of onset, the speed of progression and the association or not with manifestations of virilization. Rapidly progressive hirsutism with severe virilization suggests the presence of adrenal or ovarian tumors. Slowly developing pubertal or postpubertal onset of hirsutism indicates less serious conditions such as idiopathic hirsutism, polycystic ovarian disease, or late-onset congenital adrenal hyperplasia.
The presence or absence of signs of virilization should be sought: such as male pubic hair, clitoromegaly, low voice, and breast atrophy. Likewise, other findings allow predicting the location of the lesion. For example, hypertension associated with centripetal obesity and thick purple streaks suggests the presence of Cushing's Syndrome. An adnexal mass on pelvic examination may be associated with ovarian pathology.
The evaluation will be directed, initially, to determine the probable site of excessive androgen production. The three most common causes of hirsutism are the idiopathic form, the androgenic ovary, and adrenal disease. These pathologies form a spectrum of altered androgen production. At one extreme are ovarian diseases, characterized by excessive production of testosterone and its precursors; An example is polycystic ovarian disease. At the other extreme are adrenal diseases like late hyperplasia, which are the cause of hyperandrogenism. Ideopathic hirsutism falls between the two.
- 17 ketosteroids. They measure a group of weak androgens of adrenal origin. A large increase suggests moderate and adrenal carcinoma, late adrenal hyperplasia, or polycystic ovarian disease.
- 17OH-corticosteroids. They measure glucocorticoid metabolites. Its increase suggests Cushing's syndrome.
- Urinary free cortisol. It reflects plasma free cortisol and has a good correlation with the cortisol secretion rate.
- 17 OH-progesterone. Its basal plasma levels, like those of its urinary metabolite, pregnanetriol, are elevated in congenital adrenal hyperplasia. Quantification in response to ACTH administration shows a percentage of hirsute women, who, even with normal baseline values, show an exaggerated increase.
- Plasma testosterone. Although total testosterone, 99% of which is bound to protein, is generally quantified, it is more useful to determine free testosterone, which shows an excellent correlation with its production rate.
- Plasma Androstenedione. Of ovarian and adrenal origin. Their knowledge is useful since a proportion of testosterone and dihydrotestosterone derive from its peripheral conversion.
- Dehydroepiandrosterone (DHEA). 80% of it is produced by the adrenals, most of them being in the form of sulfo-conjugate (SDHEA). Increased levels suggest adrenal disease.
- Luteinizing (LH) and follicle-stimulating (FSH) hormones: High LH and normal or low FSH are observed in polycystic ovarian disease.
- Suppression test with dexamethasone. Although the criteria for normal suppression are not clearly established, 2mg daily administered for 7 days suppresses urinary and plasma androgens in ACTH-dependent hyperandrogenisms. Lack of suppression suggests adrenal or ovarian tumor or polycystic ovarian disease.
- Ovarian suppression test. In a similar way to the previous one, it evaluates the degree of hypothalamic-pituitary participation in the androgenic steroid hypersecretion. An oral contraceptive is administered in the usual way, and testosterone and plasma androstenedione are quantified during the third week. In patients with gonadotrophin-dependent hyperandrogenism, plasma androgens decrease, while in the presence of adrenal or ovarian tumor pathology, a significant response is not observed. In interpreting the results, it should be borne in mind that contraceptive estrogens may increase sex steroid transporter globulin, so total testosterone may not vary. Biologically active free testosterone, however, decreases.
- Other studies: Pelvic ultrasound, abdominopelvic computed tomography, adrenal scintigraphy, selective catheterizations, laparoscopy.