Hirsutism and Virilization

 Hirsutism is defined as excessive hair growth with male distribution in women. The leading causes of hirsutism are described in Table 1. Often, hirsutism is an expression of hyperandrogenism, of which it is the most frequent clinical sign. Sometimes, however, it can also be idiopathic and not associated with increased circulating androgens. On the other hand, it should also be mentioned that the absence of hirsutism does not exclude other conditions associated with androgen excesses, such as acne, alopecia, anovulatory cycles, or dysmenorrhea. The marked increase in circulating androgens may be accompanied by virilization, a rare condition defined by the progressive regression of female sexual characteristics and the appearance of male characteristics. Virilization manifests by clitoral hypertrophy, breast atrophy, increased muscle mass, changes in voice tone, and amenorrhea.

Table1. Main causes of primary amenorrhea

Testosterone and dihydrotestosterone bind to the androgen receptor. DHEA, DHEA-S, and androstenedione are prohormones. Given the peripheral synthesis of DHT, it should be noted that the circulating concentration of androgens may not reflect the actual concentration of active hormone in the pilosebaceous unit. Moreover, the local effect of androgens depends on specific receptors, whose expression is not yet defined either in terms of localization in the pilose baceous unit or body distribution. Hirsutism, therefore, results from the complex interactions between the circulating levels of androgens, their local bioavailability, and the sensitivity of the target cells. This explains the poor correlation between circulating levels of androgens and hirsutism.

Amenorrhea

 Amenorrhea is defined as the absence of spontaneous menstrual cycles. It can be distinguished into primary amenorrhea when no menstrual cycles occur by age 16, and secondary or oligorrhea, when no menstrual cycles occur for at least 3 months in women with previous regular menstruation.

Primary Amenorrhea

 Primary amenorrhea is a rare condition in about 1% of the female population and can occur in the absence or presence of sexual maturation. In the first case, the causes of amenorrhea should be investigated as early as 13 years. Primary amenorrhea can result from an alteration in the ovary, the hypothalamus, or the pituitary gland (Table 2).

Table2. Main causes of secondary amenorrhea

Primary or hypergonadotropic hypogonadism is characterized by high circulating levels of gonadotropins. In ovarian failure, the negative feedback control on the hypothalamus is lost, resulting in an uncontrolled release of FSH and LH. Hypergonadotropic hypogonadism can be caused by congenital ovarian dysgenesis, Turner syndrome, deficiency of enzymatic activities involved in steroidogeneses, such as 17α-hydroxylase deficiency, or mutations in FSH or LH receptors causing ovarian resistance to gonadotropins.

Secondary hypogonadism or hypogonadotropic hypogonadism is characterized by a deficit in the synthesis and release of gonadotropins in the pituitary gland. It can occur secondary to organic causes such as pituitary adenomas, radiation therapy, infiltrative diseases such as hemochromatosis, and sarcoidosis, or functional causes such as eating disorders and physical stress. After excluding organic causes by imaging, the differential diagnosis with constitutional growth retardation and delayed puberty should be considered. However, this distinction is complicated, and often, the most rational approach is based on a spontaneous clinical course. There are also congenital forms of hypogonadotropic hypogonadism, such as isolated GnRH deficiency. This condition can also be associated with other disorders characteristic of the underlying pituitary dysfunction, such as growth defects, diabetes insipidus, and galactorrhea. Usually, con genital hypogonadotropic hypogonadism is manifested by primary amenorrhea, which is the cause in about 20% of cases. Functional hypothalamic amenorrhea is due to a defect in GnRH synthesis and consequent release of FSH and LH.

Both forms of hypogonadism described above are associated with primary amenorrhea accompanied by the absence of sexual maturation. In the presence of sexual maturation, abnormalities in the development of the genital tract with alterations of the uterus and outflow tract should also be considered by gynecologic examination and pelvic ultrasonography. Congenital causes include agenesis of Müller’s ducts (46,XX), Morris syndrome, and androgen insensitivity syn drome (46,XY). The treatment of primary amenorrhea is etiologic; therefore, the correct diagnostic framing is necessary before implementing any therapeutic intervention. The therapeutic approach may include surgical procedures, life style changes, and hormone replacement therapy.

Secondary Amenorrhea

The most common cause of secondary amenorrhea is pregnancy. Other physiological causes of secondary amenorrhea are breastfeeding and menopause. Excluding the physiological causes, secondary amenorrhea can occur in hypergonadotropic hypogonadism, as in the case of premature ovarian failure, or chronic anovulation, which, by chronically altering the physiological pulsatility of ovarian hormone secretion, can lead to menstrual irregularity, up to amenorrhea. In the latter case, one can observe both low estrogen levels (hypogonadotropic hypogonadism), as occurs in functional hypothalamic amenorrhea or response to organic hypothalamic causes (brain tumors, head trauma, etc.), and normal/ increased estrogen levels, as in the case of ovarian tumors or PolyCystic Ovary Syndrome (PCOS). Finally, secondary amenorrhea can occur due to anatomical defects of the efflux tract, as in Asherman’s syndrome. The most frequent pathological causes of secondary amenorrhea are PCOS and organic and functional hypothalamic amenorrhea (Table 3).

Table3. Reference values in women in relation to the menstrual cycle and post-menopause (measured by ECLIA, electrochemilumines cence immunoassay; *for the determination of free testosterone the reference values are measured by ELISA, enzyme-linked immunosorbent assay)

In approximately 40% of cases, secondary amenorrhea is associated with PCOS. The condition’s prevalence is not defined, mainly due to the lack of agreed diagnostic criteria.

However, it is the most frequent endocrinopathy in women of childbearing age. The difficulties in univocally defining PCOS stem from its etiology, which is still obscure in many respects, and the complex nature of this endocrinopathy. A shared opinion among experts in the field is that the term “polycystic ovary syndrome” is misleading for the complexity of the hormonal aspects that characterize this condition. There is a consensus that the diagnosis of PCOS can be made based on at least two conditions: chronic anovularity, hyperandrogenemia (clinical or biochemical), and polycystic ovary morphology.

From the combination of the different classification systems of PCOS, the European Society of Endocrinology has recently proposed a helpful approach to the disease, according to which it is possible to distinguish four different phenotypes:

• Hyperandrogenism (clinical or biochemical) and chronic anovularity

• Hyperandrogenemia and polycystic morphology of the ovary with ovulatory cycles

• Chronic anovularity and polycystic morphology of the ovary without hyperandrogenism

 • Hyperandrogenism, chronic anovularity, and polycystic morphology of the ovary

Identifying specific phenotypes in women with PCOS is based on the detection of metabolic abnormalities, persisting even after menopause. Frequently, women with PCOS are overweight or obese and have different degrees of central and peripheral insulin resistance, dyslipidemia, reduced carbohydrate tolerance, and type 2 diabetes. In addition, a higher incidence of endothelial dysfunction, assessed by f low-mediated dilation of the brachial artery and increased intimal thickness, considered a morphological sign of atherosclerosis, has been documented in women with PCOS. However, it is still unclear whether these findings translate into increased cardiovascular morbidity and mortality since appropriate long-term prospective studies are not available. Both androgen excess and ovarian dysfunction are associated with the metabolic profile in patients with PCOS, especially if obese. PCOS acts synergistically together with obesity in altering insulin sensitivity. The metabolic profile of PCOS also includes atherogenic dyslipidemia, present in 70% of cases and characterized by hypertriglyceridemia and low HDL cholesterol. However, the impact of dyslipidemia on the different phenotypes of PCOS is still unclear. Several mechanisms underlying this association have been proposed involving both androgen receptors and lipoprotein lipase activity.

Less frequent causes of secondary amenorrhea are functional hypogonadotropic hypogonadism associated with eating disorders or pronounced physical stress, Premature Ovarian Failure (POF), hyperprolactinemia, and organic causes such as brain tumors.

Functional hypothalamic amenorrhea is frequent in young women and can be attributed to a defect in GnRH synthesis, resulting in a decrease in pituitary gonadotropins, although the pathogenetic mechanism remains obscure in many respects. Three primary forms of functional hypothalamic amenorrhea have been described, associated with stress, weight loss, and intense exercise, even in association. Maintaining ovarian function and reproductive capacity is related to preserving an adipose tissue share of about 20% of body mass. The influences of serum ghrelin and leptin levels on hypothalamic GnRH synthesis evidence this. Sudden weight loss, anorexia nervosa, or particularly intense sports training programs not accompanied by adequate nutritional intake may cause secondary amenorrhea. The estrogen deficit that characterizes this condition also compromises bone health. Indeed, several scientific societies have recommended the introduction of bone densitometry in the diagnostic workup of these patients.

POF is defined as a primary ovarian failure occurring before 40 years. It accounts for 10% of cases of secondary amenorrhea. The biochemical picture is hypergonadotropic hypogonadism, which is physiologically observed during menopause. The etiology has not yet been clarified. Some forms are genetic such as X chromosome rearrangements associated with ovarian dysgenesis, others autoimmune, or secondary to pelvic radiation therapy or chemotherapy. The natural history is unclear, although the recurrence of menstrual cycles and restoration of reproductive activity has been documented in some women.

Hyperprolactinemia is a frequent cause of female infertility and is often associated with galactorrhea. Hyperprolactinemia can be iatrogenic, associated with prolactinoma, PCOS, and primary hypothyroidism.

As in the case of primary amenorrhea, the therapeutic approach for secondary amenorrhea is etiologic and depends on the woman’s age. Treatment can be either surgical or medical, depending on the etiologic agent.

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