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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2617_Библиотеки_им_академика_М_И_Перельмана

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M. Ciaccio et al.
Table 25.32
Physiological causes
-Pregnancy
-Breastfeeding
-Menopause
Hypergonadotropic hypogonadism (premature ovarian failure)
Genetic disorders
-Turner syndrome
-Trisomy X
-X Fragile syndrome
-Mutations of estrogen receptors Autoimmune Iatrogenic Idiopathic
Hypogonadotropic hypogonadism
Organic causes
-Pituitary adenomas
-Head radiation therapy
-Head trauma
-Neurosurgery
-Inammatory/inltrative diseases Functional hypothalamic amenorrhea Polycystic ovary syndrome (PCOS) Ovarian tumors
Anatomical abnormalities of the uterus and outow tract
Asherman’s syndrome Pathologies of the uterus
Main causes of secondary amenorrhea
Secondary hypogonadism or hypogonadotropic hypogo­nadism is characterized by a decit in the synthesis and release of gonadotropins in the pituitary gland. It can occur secondary to organic causes such as pituitary adenomas, radiation therapy, inltrative 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 deciency. This con­dition can also be associated with other disorders character­istic of the underlying pituitary dysfunction, such as growth defects, diabetes insipidus, and galactorrhea. Usually, con­genital 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 outow 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 syn­drome (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, life­style 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 efux tract, as in Asherman’s syndrome. The most frequent patho­logical causes of secondary amenorrhea are PCOS and organic and functional hypothalamic amenorrhea (Table25.33).
In approximately 40% of cases, secondary amenorrhea is associated with PCOS. The condition’s prevalence is not dened, mainly due to the lack of agreed diagnostic criteria.
Table 25.33
cycle and post-menopause (measured by ECLIA, electrochemilumines­cence immunoassay; *for the determination of free testosterone the ref- erence values are measuredby ELISA, enzyme-linked immunosorbent assay)
LH (IU/L) 2.4–12.6 14–95.6 1–11.4 7.7–58.5 FSH (IU/L) <12.5 4.7–21.5 1.7–7.7 25.8–134.8 Estradiol (ng/L) 12.5–166 85.8–498 43.8–
Progesterone (μg/L) Total Testosterone (μg/L) Free Testosterone* (ng/L)
DHEA-S (μg/dL) Prolactin (μg/L)
FSH follicle-stimulating hormone, LH luteinizing hormone, DHEA-S dehydroepiandrosterone sulfate
Reference values in women in relation to the menstrual
Follicular phase
0.2–1.5 0.8–3 1.7–27 0.1–0.8
0.084–0.0481
0.01–7.01
65.1–368
4.79–23.3
Ovulatory phase
Luteal phase
211
Post­menopause
5–54.7
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However, it is the most frequent endocrinopathy in women of childbearing age. The difculties in univocally dening 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 eld 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 classication 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 specic 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 ow-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 ndings 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 prole in patients with PCOS, especially if obese. PCOS acts synergistically together with obesity in altering insulin sensitivity. The metabolic prole 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 inuences 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 de­cit that characterizes this condition also compromises bone health. Indeed, several scientic societies have recommended the introduction of bone densitometry in the diagnostic workup of these patients.
POF is dened 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 claried. 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.
Laboratory Investigations
Basal Measurement
Androgen
In decreasing order of serum concentration, the androgens present in a woman of childbearing age are DHEA-S (95% of adrenal origin), DHEA, androstenedione, testosterone, and DHT. The medical-scientic community has long debated which androgens should be measured to evaluate hyperandrogenism and the analytical methodologies employed. A reasoned laboratory approach is to assay total
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testosterone before initiating any medical therapy that may interfere with circulating levels. The total testosterone assay should be accompanied by free testosterone because the lat­ter has greater diagnostic sensitivity for hyperandrogenism. However, there are critical analytical considerations that may limit the reliability of this test. Methodologically, free testos­terone can commonly be assayed by ELISA as long as the inter-assay imprecision assessed internally within the labora­tory remains below 10% and appropriate reference intervals are established in non-hyperandrogenic women. Alternatively, more accurate LC-MS/MS-based assays are now considered the gold standard for steroid hormonesmea­surement, although their use is restricted almost exclusively to clinical research in specialized laboratories. Compared to the free testosterone assay, some authors have proposed an approach based on SHBG with total testosterone. The ratio between total testosterone and SHBG indicates the amount of free hormone indirectly and is, therefore, a valuable tool to identify possible states of hyperandrogenism, especially when accurate dosages of free testosterone are not available. Epidemiological studies have shown that high levels of total testosterone and low levels of SHBG have a high positive predictive value for polycystic ovary syndrome, a condition also characterized by hyperandrogenism. In addition, reduc­ingcirculating SHBG can be considered a marker of insulin resistance to predict the onset of metabolic syndrome and gestational diabetes in women with PCOS.The signicance of Δ4-androstenedione and DHEA-S dosage in hirsut­ismpatients is still poorly understood. Δ4-androstenedione may be considered a pro-androgen; therefore, its circulating concentration may not reect the biological actions of theactive hormone.
Moreover, plasma levels uctuate with the ovarian cycle, higher in the lutein phase. For these reasons, its diagnostic value in the diagnosis of hyperandrogenemia may be limited. On the other hand, Δ4-androstenedione binds with lower afnity to SHBG than testosterone and, therefore, may have more signicant androgenic potential. Also, for DHEA-S, there is no clear evidence of the usefulness of this assay in identifying hyperandrogenism, except for the suspicion of androgen-secreting adrenal tumors, since circulating DHEA-S is predominantly of adrenal origin. In general, the nding of elevated values of at least one androgen indicates a disorder associated with androgen excess. The reference values of the main androgens in women are described in Table25.34.
Gonadotropin
Gonadotropin is essential to differentiate the various forms of hypogonadism; i.e., elevated FSH and LH levels (hyper­gonadotropic hypogonadism, primary ovarian insufciency)
Table 25.34 Main diagnostic laboratory test for secondary amenorrhea
First-level investigations
-β-hCG
-17β-estradiol
-Prolactin
-FSH, LH
-Pelvic ultrasound
-MAP test
Second-level investigations
-Test with estrogen progestin
-GnRH test
-Pituitary magnetic resonance imaging
Third-level investigations
-Karyotype
-Total testosterone, SHBG
-Clomiphene test
FSH follicle-stimulating hormone, GnRH gonadotropin releasing hor­mone, LH luteinizing hormone, MAP medroxyprogesterone acetate, SHBG Sex hormone–binding globulins
or reduced levels of FSH, LH, and estradiol (hypogonado­tropic hypogonadism, hypothalamic-pituitary alteration). Although not diagnostic, an LH/FSH ratio greater than 2 is frequently found in PCOS.It should be noted that the refer­ence values vary considerably depending on the woman’s age and, during productive life, andmenstrual cycle phases. Physiologically, during menopause, there is a marked increase in FSH (Table 25.34). However, gonadotropin in amenorrhea should not be isolated due to their inherent vari­ability but conrmed in subsequent measurements.
Estrogen
Estradiol represents the most common estrogen measured in clinical practice. It provides helpful information on hypogo­nadism, menstrual cycle alterations, and ovarian tumors. Also, in this case, the reference values vary according to the menstrual cycle and the woman’s age. In women of child­bearing age, estradiol levels show a pre-ovulatory peak around day 12 and anticipate the pre-ovulatory peak of LH.Throughout the rest of the cycle, estradiol levels remain low. The use of serum estrone assay has limited clinical signicance.
Progesterone
Progesterone increases physiologically following ovulation. The serum dosage of progesterone in the lutein phase (21st day of the cycle) is used to conrm ovulation. In many cases, it is possible to have regular but anovulatory menstrual cycles, as in the case of PCOS, in which the nding of anovu­lation is one of the diagnostic criteria.
17-OH-progesterone, a progesterone derivative, does not have a precise biological role but is of particular diag­nostic importance because its circulating concentration,
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both in basal conditions and after stimulation by synthetic ACTH, increases in cases of congenital adrenal hyper­plasia and, in particular, 21α-hydroxylase deciency. The 17-OH-progesterone assay is used in the etiological diag­nosis of hirsutism to identify a 21α-hydroxylase deciency.
Dynamic Investigations
GnRH Testing
The GnRH test is used in the differential diagnosis of amen­orrhea to identify a possible pituitary defect. It is performed by intravenous administration of GnRH and serum LH and FSH measurement at basal and after 15, 30, 60, 90, and 120minutes. There is no consensus on the interpretation of the test. Generally, a peak of at least three times baseline for LH and at least two times baseline for FSH is considered normal. Hypothalamic forms generally respond to the test, while in pituitary forms, the response is absent or reduced. In case of an absent or reduced response, it is necessary to repeat the test after a few days because pituitary cells not subjected to endogenous stimulation by GnRH may not be responsive to acute administration when the test is per­formed. This test has sometimes been used in differential diagnoses between constitutional growth retardation with delayed puberty and hypogonadotropic hypogonadism; how­ever, its diagnostic performance in this context is poor. Overall, the clinical use of this test is limited because there is no agreement on the interpretation of the response to GnRH stimulation and its diagnostic cut-off.
Clomiphene Test
Although rarely used in clinical practice, this test allows assessing the degree of impairment of hypothalamic­pituitary axis function in patients with anovulatory cycles or oligorrhea. Clomiphene competes with estrogens to bindtheir receptor. When clomiphene binds thereceptor, it blocks the negative feedback induced physiologically by estrogen on GnRH and gonadotropin synthesis. The test is performed by administering clomiphene orally for 5days starting on day 5 of the menstrual cycle and assaying FSH and LH on days 5, 7, and 10 of the cycle; progesterone is assayed on day 21 to document ovulation. In patients with normal hypothalamic- pituitary function, an increase of FSH and LH greater than 50% of baseline and restoration of ovulation is observed, pointing toward ovarian patholo­gies. Conversely, an absent response to clomiphene (no increase in FSH and LH after stimulation) indicates hypo­thalamic-pituitary deciency. A hypothalamic defect may be suspected if the response to clomiphene is absent, but the GnRH test is positive.
Diagnosis andTherapy
Hirsutism
The diagnosis of hirsutism is based on a clinicalscoringsys- tem aimed at ascertaining the type and distribution of hair growth in body areas susceptible to the action of androgens. Severalscoringsystems have been developed, but today the gold standard remains the Ferriman-Gallwey scale (Fig.25.35). This method involves the assignment of a score from 0 to 4 for 9 of the body areas susceptible to the action of androgens; a score above 8 depicts androgen-mediated hirsutism rather than hypertrichosis. However, this value depends signicantly on the patient’s ethnicity. It has been shown that the cutoff in Caucasian women of the Mediterranean area should be 10–11, while in the Asian race 6. A score up to 15 represents mild hirsutism, from 16 to 25 moderate, and above 25 severe. Although the Ferriman­Gallwey scale is an easy-to-use tool, it should be noted that the evaluation of hirsutism is subject to a high degree of operator-dependent variability. The history, essential in eval­uating patients with hirsutism, should be aimed to investigate the age of onset of hair, symptoms or signs associated with hyperandrogenism (e.g., acne, dysmenorrhea, alopecia, infertility), and the speed of onset of hirsutism. Rapid onset may point toward an androgen-secreting neoplasm. In this case, signs of virilization are also often present.
Other endocrine disorders associated with hirsutism are polycystic ovary syndrome, Non-Classic Congenital Adrenal Hyperplasia (NCCAH), Cushing’s syndrome, hypothyroid­ism, andhyperprolactinemia.
The diagnostic approach to pre-menopausal hirsutism is described in Fig.25.36.
In postmenopausal women with hirsutism, the severity, the onset’s rapidity, and the total testosterone dosage should be evaluated rst. If the total testosterone level is elevated, endocrine conditions associated with hyperandrogenemia should be considered. If the hirsutism is mild and stable over time with normal testosterone levels, no further diagnostic investigations are required, and the most likely diagnosis is idiopathic hirsutism. In the case of normal total testosterone values but with moderate/severe hirsutism or clinical evidence of endocrine disorders associated with hyperandrogenism, it is necessary to proceed with free testosteronemeasurement.
Once the presence of hirsutism has been ascertained based on the clinicalscoreand medical history, it is neces­sary to dene its etiology. Hirsutismwith ovarian polycystic morphology and hyperandrogenism is indicative of PCOS, which accounts for 70% of cases. If circulating androgen levels are normal, ovarian morphology and cycles are nor­mal, hirsutism is idiopathic.
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Fig. 25.35 Ferriman­Gallwey score for evaluating hirsutism. (Copyright EDISES 2021. Reproduced with permission)
Ferriman-Gallwey scale for assessing the degree of hirsutism
Upper lip
1234
Chin
1234
Intermammary furrow
1234
Abdomen
12 34
Pubes
1234
Upper limbs
1234
Thighs
1234
Backbone area
1234
Lumbosacral area
1234
Algorithm for evaluating hirsutism
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Clinical evaluation of hirsutism
Significant hirsutism
NO
Rapidly progressing
virilization
Normal
Idiopathic
hirsutism
Fig. 25.36 Diagnostic algorithm of hirsutism. (Copyright EDISES 2021. Reproduced with permission)
YES
Total Testosterone
Free Testosterone
Drug anamnesis
Iatrogenic
hirsutism
Dexamethasone suppression test
Cushing's
Syndrome
In patients with hirsutism, FSH, LH, 17β-estradiol, and 17-OH-progesterone should be measured in addition to androgens. The prolactin and TSH assay excludes secondary forms of hyperprolactinemia and thyroid diseases. The most frequent cause of androgen excess is PCOS, which is associ­ated with increased cardio-metabolic risk, especially if accompanied by obesity. In this regard, therefore, it is neces­sary to investigate the presence, even in the past, of oligor­rhea or amenorrhea and to perform the dosage of progesterone in the lutein phase to document ovulation, since a signicant proportion of women with hirsutism have anovulatory cycles. In addition, the diagnostic approach also includes transvaginal ultrasonography to assess any polycystic mor­phology of the ovary. An evaluation of the cardio-metabolic prole should further investigatePCOS. In particular, it is necessary to assess carbohydrate tolerance by OralGlucose Tolerance Test(OGTT), BMI and abdominal circumference, complete lipid prole, and blood pressure.
As mentioned above, the diagnostic approach to hirsutism should also include the exclusion of less frequent causes. In this regard, it is necessary to exclude androgen-secreting tumor of ovarian or adrenal origin. A sudden increase in total testosterone can occur in these neoplasms; if a parallel increase in DHEA-S occurs, it is plausible that the neoplasm is of adrenal origin.
Non-pharmacological therapy
YES
High
Differential etiological
diagnosis
DHEAS
Adrenal
Cancer
Transvaginal
ultrasound
LH/FSH ratio
Polycystic
Ovary
Syndrome
hyperplasia, should be evaluated, taking into account the prevalence of the condition in the population and the avail­ability and cost of the test. The abrupt onset and rapid pro­gression of hirsutism indicate androgen-secreting ovarian tumors. Finally, rare causes of hirsutism such as acromegaly, hyperprolactinemia, pregnancy-related hyperandrogenism, and Cushing’s syndrome should be excluded. Hirsutism can also be iatrogenic, for example, after administration of oral contraceptives containing androgenic progestins. Hirsutism is a clinical sign and does not necessarily require medical treatment, especially in mild or moderate forms, where cos­metic remedies can address it. More clinically relevant forms can be treated with estro-progestin therapy, which is consid­ered the endocrinological approach of the rst choice, or with antiandrogens in severe cases, or with insulin sensitiz­ers.Follow-up of these patients involves clinical evaluation of treatment efcacy. It is not clear whether serum androgen dosage can help monitor therapy and, in particular, whether a possible decrease in circulating levels can predict a clinical improvement that, in any case, requires at least 4–6months to be evident. It should be noted that during estro-progestin therapy, it is necessary to measure, in addition to total testos­terone, SHBG, whose synthesis is induced by these drugs. The dosage of androgens is not indicated during treatment with antiandrogens.
NCCHA due to 21-hydroxylase deciency is frequent in some ethnic groups where screening is recom­mended. However, the introduction of the routine 17-OH-progesterone assay, basal or after stimulation with synthetic ACTH, a screening test for congenital adrenal
Primary Amenorrhea
Hypogonadism diagnosis is based on a careful history and physical examination to evaluate sexual development. Once hypogonadism has been hypothesized, the differential diag-
NO
Exclude
Ovarian or
Adrenal cancer
TSH
Prolactin and
GH
Thyreopathies
Hyperprolactinemia
Acromegaly
Stimulation
by ACTH
Congenital
Adrenal
Hyperplasia
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nosis between the various forms is based on instrumental and laboratory investigations (Fig.25.37). Withoutnormal development of secondary sexual characteristics, the FSH and LH assay allows for distinguishing between hypo- and hypergonadotropic hypogonadism. In hypergonadotropic hypogonadism, FSH and LH are increased; pelvic ultra­sound and karyotype examination are also indicated in this case. We can point toward a hypophyseal/hypothalamic pathology if the gonadotropins are normal or reduced. In these cases, it is necessary to deepen the overall function of the hypothalamic- pituitary- target gland axis through labo­ratory tests and instrumental tests, which allow foridenti­fying any organic pathology. Once the organic causes have been excluded, it is necessary to consider functional hypo­gonadotropic hypogonadism and growth retardation with delayed puberty, for which the differential diagnosis, essen­tially based on the clinic, can sometimes be challenging. For this purpose, the GnRH stimulus test is of limited usefulness.
Secondary Amenorrhea
The most frequent cause of secondary amenorrhea is preg­nancy. Therefore, the rst test is the β-hCG assay (Fig.25.38).
The diagnostic approach to secondary amenorrhea starts with an accurate personal history aimed at investigating eat­ing habits, physical activity, any psychophysical stress, the
age of menarche, the presence of galactorrhea, any signs of hypoestrogenism such as hot ashes and vaginal dryness, any trauma or surgical procedures or radiation therapies of the head and pelvis, signs of hyperandrogenemia. The decision to proceed with subsequent instrumental and labo­ratory investigations is based on the preliminary orientation derived from the anamnestic data and objective examination. The denitive diagnosis is essentially a diagnosis of exclu­sion. First-level biochemical investigations include the assay of FSH, LH, 17β-estradiol, prolactin, and TSH.In addition to the biochemical evaluation of primary amenorrhea, prolactin is also necessary for diagnosingsecondary amenorrhea since it is a frequent cause (for a detailed discussion on the causes of hyperprolactinemia see section “Hypophysis”). The TSH assay excludes hypothyroidism. First-level investigations should also include a pelvic ultrasound, which allows for identifying polycystic morphology of the ovary, and the MAP test (test with progestin administration), which allows distinguishing between a progesterone deciency due to ovulation failure, as frequently found in PCOS, and uterine abnormalities. The MAP test is performed by oral medroxy­progesterone to the patient for 5 consecutive days; the test result is evaluated 2–7days after the end of administration by the presence/absence of bleeding. Second-level tests include the estroprogestin test, GnRH test, and pituitary MRI. The estroprogestin (oral contraceptive) test is per-
Hypogonadotropic
hypogonadism
Organic pituitary/
hypothalamus alterations
Functional
hypothalamic
amenorrhea
Growth
retardation
and puberty
No
FSH, LH
Anamnesis, physical examination
Presence of secondary sexual characters
Abnormalities of the
outflow tract
+
Hypergonadotropic
Hypogonadism
Pelvic ultrasound
Karyotype
Ovarian
dysgenesis
46,XX
Tu rner's
syndrome
45,X0
Gynecological
examination
Pelvic ultrasound
Uterine abnormalities
Androgen
Insensitivity
Syndrome
46,XY
Ye s
Karyotype
Mullerian
agenesis
46,XX
Fig. 25.37 Diagnostic algorithm of primary amenorrhea. (Copyright EDISES 2021. Reproduced with permission)
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Fig. 25.38 Diagnostic algorithm of secondary amenorrhea. POF: premature ovarian failure. (Copyright EDISES 2021. Reproduced with permission)
Clomiphene DT test
Pelvic ultrasound
Androgens
Consider
PCOS
Anamnesis, physical examination
Pregnancy
Increased
estrogen
Pituitary
insufficiency
+ +
Bleeding
Normal/reduced
estrogen
MRI or CT
scan of the
brain
GnRH
testing
TSH,
prolactin
LH, FSH
Estrogen
MAP test
+
Organic
Functional
+
hypothalamic
amenorrhea
causes
Consider
hypothyroidism
and/or
prolactinoma or
other causes of
hyperprolactinemia
+
POF
Ovarian
resistance
Not bleeding
Uterine pathologies
formed by administering estroprogestin for 20days; also, in this case, the test result is evaluated 7days after stopping the treatment by the presence/absence of bleeding and allows to exclude uterine pathologies. The GnRH test shows pituitary insufciency if the response is limited or absent. In the case of a normal response (increased FSH and LH), serious hypo­thalamic pathologies can be excluded. If the diagnostic pic­ture remains uncertain, we should proceed with third-level investigations, i.e., androgen assay, karyotype, and clomi­phene citrate test (Table25.35).
In the case of suspected PCOS, rst-line laboratory tests are essentially aimed at evaluating the presence of hyperandr­ogenemia, starting with the total testosterone assay. Free tes­tosterone can be assayed directly or indirectly by the ratio of total testosterone to SHBG. There is no consensus on the validity of Δ4-androstenedione assay in diagnosing PCOS.However, recent studies have shown greater sensitivity and specicity of this steroid than testosterone, both assayed by LC-MS/MS, in diagnosing hyperandrogenism in women with PCOS.Similarly, DHEA-S is not routinely required in clinical practice, except when androgen-secreting adrenal can­cer is suspected. In the case of elevated testosterone concentra­tions, causes other than PCOS should also be considered. If testosterone exceeds twice the upper reference limit, an andro­gen-secreting tumor should be considered, especially if accompanied by signs of virilization. Increased DHEA-S, as already mentioned, may point to an adrenal tumor; if DHEA-S
Table 25.35
Hyperandrogenism of gonadal origin
-Ovarian hyperandrogenism
- Polycystic Ovary Syndrome/Ovarian functional
-Alterations of ovarian steroidogenesis
-Insulin Resistance Syndrome (severe forms)
-Ovarian Neoplasms
Adrenal hyperandrogenism
-Premature adrenarchy
-Adrenal functional hyperandrogenism
-Congenital Adrenal Hyperplasia
-Alterations in the action or metabolism of cortisol
-Adrenal Neoplasms
Other endocrine disorders
-Cushing’s syndrome
-Hyperprolactinemia
-Acromegaly
Excessive peripheral production of androgens
-Obesity
-Idiopathic
Pregnancy-related hyperandrogenism
-Hyperreactio luteinalis
-Tecoma of pregnancy
Drugs
-Androgens
-Oral contraceptives containing androgenic progestins
-Minoxidil
-Phenytoin
-Diazoxide
-Closporine
True hermaphroditism
Causes of hirsutism
hyperandrogenism
380
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M. Ciaccio et al.
is normal, ovarian causes should be considered, such as ovar­ian hyperthecosis or androgen-secreting ovarian tumors, both conditions independent of LH.In case of mildly increased tes­tosterone levels, in addition to PCOS, non-classical congenital adrenal hyperplasia should also be considered by assaying, basal and after ACTH stimulation, 17-OH-progesterone, and Cushing’s syndrome. If testosterone is normal, free testoster­one should be assessed. In PCOS, hypersecretion of LH is typically observed with normal or slightly reduced levels of FSH, thus resulting in the typical increase in LH/FSH ratio. However, it is not recommended LH/FSH ratio as a diagnostic criterion, given the inuence of obesity on the pulsatility of their secretion. Beyond a marker of ovarian reserve, AMH is also considered a marker of the number of follicles in the ovary with polycystic morphology. However, its use in rela­tion to the diagnosis of PCOS is still controversial.
In functional hypothalamic amenorrhea, normal or slightly reduced FSH, LH, and estradiol levels are observed, although the gonadotropin response to GnRH is preserved. It is considered, however, that in the patient with suspected functional hypothalamic amenorrhea, the FSH assay is suf­cient to exclude POF.
POF is characterized by an increase in FSH.In addition to FSH, markers of ovarian reserve, namely inhibin B and AMH, which are reduced both in the transition to menopause and in POF, should be assessed. The diagnostic picture should be completed by the antral follicle count by ultra­sound evaluation.
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