Two natural androgens are testosterone, which is transported to target tissue by the circulation, and DHT, which is produced primarily by target tissues. Increased levels of these androgens can lead to hirsutism, which is excessive androgenic hair growth, or to virilization, a more severe form of androgen excess. Hirsutism is defined as the presence of terminal (coarse) hair in locations at which hair is not commonly found in women. It includes facial hair on the cheek, above the upper lip, and on the chin ( Fig. 16-26A and B ). The presence of midline chest hair is also significant ( Fig. 16-26C ). In addition, a male escutcheon, hair on the inner aspects of the thighs, and midline lower back hair entering the intergluteal area are hair growth patterns compatible with androgen excess. A moderate amount of hair on the forearms and lower legs by itself may not be abnormal, although it may be viewed by the patient as undesirable and may be mistaken for hirsutism. In contrast to hirsutism, virilization is a more severe form of androgen excess and implies significantly higher rates of testosterone production. Its manifestations include temporal balding, deepening of voice, decreased breast size, increased muscle mass, loss of female body contours, and clitoral enlargement. Normal length of clitoris is <1cm> in lenght and 0.7cm in diameter.
In this image, is possible to see a clitoromegaly (4cm lenght - 1.5cm diameter)
Testosterone in reproductive-age women is produced by two major mechanisms: (1) direct secretion by the ovary, accounting for roughly one third of testosterone production, and (2) conversion of the precursor androstenedione to testosterone in the peripheral (extragonadal) tissues, accounting for two thirds of testosterone production ( Fig. 16-28 ). [216] [217] These peripheral tissues include the skin and adipose tissue. Androstenedione, the direct precursor of testosterone, is produced in both the ovary and the adrenal. The C19 steroids DHEAS and DHEA of adrenal origin and DHEA of ovarian origin indirectly contribute to testosterone formation by first being converted to androstenedione that is subsequently converted to testosterone. Whereas testosterone is an androgen, DHEAS is a biologically inert steroid. Up to 20 mg of DHEAS are produced daily versus only 3 mg of androstenedione and 8 mg of DHEA per day. These C19 steroids of adrenal origin (DHEAS, DHEA) exert their effects after conversion to the potent androgen testosterone (see Fig. 16-28 ). Only androstenedione can be converted directly to testosterone. The conversion rate of circulating androstenedione to testosterone in extragonadal tissues is about 5% in both men and women. Conditions that decrease SHBG binding (e.g., androgen excess, obesity, acromegaly, hypothyroidism, and liver disease) also increase bioavailable testosterone, thus augmenting the effect of testosterone. The most useful initial test is a serum total testosterone level. An abnormal level in the presence of hirsutism or virilization may be associated with PCOS, hyperthecosis, nonclassic adrenal hyperplasia, or an androgen-secreting neoplasm. The majority of androgen-secreting tumors are of ovarian origin.
PCOS is the most common form of chronic anovulation associated with androgen excess, perhaps occurring in 5% to 10% of reproductive-age women.[146] The diagnosis of PCOS is made by excluding other hyperandrogenic disorders (e.g., nonclassic adrenal hyperplasia, androgen-secreting tumors, and hyperprolactinemia) in women with chronic anovulation and androgen excess
One of the most prominent features of PCOS is the history of ovulatory dysfunction (amenorrhea, oligomenorrhea, or other forms of irregular uterine bleeding) of pubertal onset. Thus, a clear history of cyclic predictable menses of menarchal onset makes the diagnosis of PCOS unlikely. Acquired insulin resistance associated with significant weight gain or an unknown cause, however, may occasionally induce the clinical picture of PCOS in a woman with a history of previously normal ovulatory function. Hirsutism may develop prepubertally or during adolescence, or it may be absent until the third decade of life. Seborrhea, acne, and alopecia are other common clinical signs of androgen excess. In extreme cases of ovarian hyperthecosis (a severe variant of PCOS), clitoromegaly may be observed. Nonetheless, rapid progression of androgenic symptoms and virilization are rare in ordinary PCOS. Some women may never have signs of androgen excess because of hereditary differences in target tissue sensitivity to androgens.[151] Infertility related to the anovulation may be the only presenting symptom. During the physical examination, it is essential to search for and document signs of androgen excess (hirsutism or virilization or both), insulin resistance (acanthosis nigricans), and the presence of unopposed estrogen action (well-rugated vagina and stretchable clear cervical mucus) to support the diagnosis of PCOS.
this image shows hirsutism in: cheeks, upper lip and chin. An usual location of hirsutism, between the breasts.
Alternatively, another expert conference held in Rotterdam in 2003 defined PCOS, after the exclusion of related disorders, by two of the following three features: (1) oligo-ovulation or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, or (3) polycystic ovaries ( Fig. 16-31 ).
Rarely, serum testosterone levels higher than 2 ng/mL may be encountered in association with the most severe form of PCOS, ovarian hyperthecosis. Overall, it is much more common to observe high normal levels or borderline elevations of testosterone in women with PCOS. Prolactin and TSH should be obtained routinely to rule out mild androgen excess and anovulation that may be associated with hyperprolactinemia. The NIH-sponsored consensus conference on diagnostic criteria for PCOS in 1990 recommended that LH and the LH/FSH ratio are not required for the diagnosis of PCOS. By definition, nonclassic adrenal hyperplasia is not manifest as congenital virilization of external genitalia. a cross-section of all anovulatory women at any point in time reveals that approximately 75% have polycystic-appearing ovaries as determined by ultrasonography. Biochemical evidence of insulin resistance or glucose intolerance is also not necessary for the diagnosis of PCOS. Glucose intolerance should nonetheless be investigated. Therefore, plasma glucose levels should be measured after a 75-γ glucose load as a screen for glucose intolerance. Because endometrium is exposed to estradiol chronically in PCOS, these women respond to a challenge with a progestin (e.g., medroxyprogesterone acetate 10 mg/day orally for 10 days) by uterine bleeding within a few days after the last pill of progestin. The reasons for lack of uterine bleeding after a progestin challenge include pregnancy, insufficient prior estrogen exposure of the endometrium, or an anatomic defect. Women with PCOS have higher mean concentrations of LH but low or low-normal levels of FSH compared with levels found in normal women in the early follicular phase.[254] The elevated LH levels are partly due to increased sensitivity of the pituitary to GnRH stimulation manifest by increases in LH pulse frequency and, in particular, LH pulse amplitude. In obese women with PCOS, LH levels are not increased.
Testosterone, androstenedione, and DHEA are secreted directly by the ovary, whereas DHEAS, elevated in about 50% of anovulatory women with PCOS, is almost exclusively an adrenal contribution. Pathologic mechanisms in polycystic ovary syndrome (PCOS). A deficient in vivo response of the ovarian follicle to physiologic quantities of follicle-stimulating hormone (FSH), possibly because of an impaired interaction between signaling pathways associated with FSH and insulin-like growth factors (IGFs) or insulin, may be an important defect in PCOS. This ovarian defect may be the key event responsible for anovulation in PCOS. Insulin resistance associated with increased circulating and tissue levels of insulin and bioavailable estradiol (E2), testosterone (T), and IGF-I gives rise to abnormal hormone production in a number of tissues. Oversecretion of luteinizing hormone (LH) and decreased output of FSH by the pituitary, decreased production of sex hormone–binding globulin (SHBG) and IGF-binding protein 1 (IGFBP-1) in the liver, increased adrenal secretion of dehydroepiandrosterone sulfate (DHEAS), and increased ovarian secretion of androstenedione (A) all contribute to the vicious circle that maintains anovulation and androgen excess in PCOS. Excessive amounts of E2 and T arise primarily from the conversion of A in peripheral and target tissues.
Overall, androstenedione of ovarian origin is the most strikingly elevated steroid in PCOS. Because such elevated production of androstenedione does occur in PCOS, extraovarian production of testosterone is biologically significant in this disease. In anovulatory women with PCOS, circulating levels of SHBG are reduced approximately 50%; this may be a hepatic response to increased circulating levels of testosterone and insulin. In turn, testosterone decreases serum SHBG levels, giving rise to a vicious feedback circle favoring low SHBG and high bioavailable testosterone levels.
Acanthosis nigricans is a gray-brown velvety discoloration and increased thickness of the skin, usually at the neck, groin, axillae, and under the breasts, and is a marker for insulin resistance
NEJM: Whereas luteinizing hormone regulates the
androgenic synthesis of theca cells, follicle-stimulating
hormone is responsible for regulating the
aromatase activity of granulosa cells, thereby determining
how much estrogen is synthesized from
androgenic precursors. When the concentration of
luteinizing hormone increases relative to that of
follicle-stimulating hormone, the ovaries preferentially
synthesize androgen. Since progestins
slow the GnRH pulse generator, low circulating
progestin levels in women with the polycystic ovary
syndrome may lead to an acceleration in the pulsatility
of GnRH,increased levels of luteinizing hormone,
and overproduction of ovarian androgen.
Insulin acts synergistically
with luteinizing hormone to enhance the
androgen production of theca cells. Insulin also inhibits
hepatic synthesis of sex hormone–binding
globulin, the key circulating protein that binds to
Testosterone
decreases lipoprotein lipase activity in abdominal
fat cells, and insulin resistance impairs the
ability of insulin to exert its antilipolytic effects.
The estrogenic
component of the oral contraceptive suppresses
luteinizing hormone and thus ovarian androgen
production. Estrogen also enhances hepatic
production of sex hormone–binding globulin (Fig.
2), thereby reducing the free, or unbound, fraction
of plasma testosterone available to occupy the androgen
receptor
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