FIGURE 11.1 The initial assessment of the anovulatory patient.

Although widely used, the practical value of the Gn-RH test has been questionable because of its low cost-effectiveness. Indeed, the Gn-RH test provides no extra diagnostic information relative to baseline gonadotropin levels, and in HH patients, the response to the Gn-RH test is highly variable. Thyroid function should be screened by measuring serum TSH levels. IGF-I can be used to evaluate the somatotropic axis. To assess the pituitary adrenal axis, morning cortisol should be measured. Stimulatory tests should be reserved for situations in which the basal hormone measurements are not helpful or if there is strong clinical evidence of a multiple pituitary hormone deficiency (4).

Anosmia can be easily diagnosed by questioning the patient whereas olfactometry, such as the University of Pennsylvania Smell Identification Test, is necessary to determine reliably whether olfaction is normal or partially defective (7). Indeed, IHH patients display a broad spectrum of olfactory function with a significant hyposmic phenotype. Accurate olfactory phenotyping in IHH subjects can inform the pathophysiology of this condition and guide genetic testing (7).

MRI of the hypothalamo-pituitary region is very useful in the management of HH. MRI can demonstrate a malformation, an expansive or infiltrative disorder of the hypothalamo-pituitary region. However, the cost-effectiveness of an MRI scan to exclude pituitary and/or hypothalamic tumors is unknown according to the recent clinical practice guideline (4,8). Pituitary and/or hypothalamic tumors should be investigated using MRI in patients with multiple pituitary hormone deficiency, persistent hyperprolactinemia, or symptoms of tumor mass effect (headache, visual impairment, or visual field defect) or secondary amenorrhea. In the presence of suspected functional causes of HH, such as severe obesity, nutritional disorders, and drugs, MRI is not indicated. Additionally, MRI with specific cuts for evaluating the olfactory tract can be helpful in the diagnosis of Kallmann syndrome. Evidence of unilateral or bilateral hypoplastic agenesis olfactory bulbs and hypoplastic anterior pituitary is pathognomonic of Kallmann syndrome (4).

Renal ultrasound examination is usually recommended to patients with syndromic IHH, such as Kallmann syndrome, independent of the genetic basis although it is well known that unilateral kidney agenesis may be more prevalent in patients with KAL1 defects. The genetic assessment is usually the last step in the congenital IHH investigation, and complete clinical characterization could certainly help in the gene selection. Bone mineral density of the lumbar spine, femoral neck, and hip is recommended at the initial diagnosis of HH and after 1 to 2 years of sex steroid therapy in hypogonadal patients with osteoporosis or low trauma fracture (4).

In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary–hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR, GnRH1, KISS1R/GPR54, TAC3, TACR3), which are always associated to isolated non-syndromic congenital HH without anosmia. Some cases of mutations of FGFR1 and, more rarely, of its ligand FGF8 or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7, leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty by reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, such as isolated non-syndromic CHH or Kallmann syndrome (8).

WHO 2 Normogonadotropic Normo-Estrogenic Anovulation

Most anovulatory patients (approximately 80%) present with serum FSH and estradiol levels within the normal range. Hence, they are classified as being WHO class 2 patients. Polycystic ovary syndrome (PCOS) is a common but poorly defined heterogeneous clinical entity. Historically, characteristic ovarian abnormalities represented a hallmark of the syndrome. Because several etiological factors may lead to a similar end point (i.e., polycystic ovaries), the development of a clinically applicable classification of the syndrome has proven difficult. Clinical, morphological, biochemical, endocrine, and molecular studies have identified an array of underlying abnormalities and added to the confusion concerning the pathophysiology of the disease (3). Nowadays, there is consensus that for clinical purposes PCOS should be diagnosed according the to the Rotterdam consensus (2,9) (see Figure 11.2).

According to the Rotterdam consensus, the diagnosis of PCOS should be made if two of the three following criteria are met: androgen excess, ovulatory dysfunction, or polycystic ovarian morphology (PCOM) (9).

Anovulation may manifest as frequent bleeding at intervals < 21 days or infrequent bleeding at intervals of >35 days (2). Occasionally, bleeding may be anovulatory despite falling at a normal interval (25–35 days). A mid-luteal progesterone documenting anovulation may help with the diagnosis if bleeding intervals appear to suggest regular ovulation (10).

Clinical hyperandrogenism may include hirsutism, that is, excessive terminal hair that appears in a male pattern, acne, or androgenic alopecia. Generally hirsutism might be assessed using the Ferriman-Gallwey score. In the modified method, hair growth is rated from 0 (no growth of terminal hair) to 4 (extensive hair growth) in each of nine predefined locations. A patient’s score may therefore range from a minimum score of 0 to a maximum score of 36. In Caucasian women, a score of 8 or higher is regarded as indicative of androgen excess. With other ethnic groups, the amount of hair expected for that ethnicity should be considered (9).

FIGURE 11.2 The Rotterdam consensus diagnostic criteria for PCOS.

Biochemical hyperandrogenism is defined as elevated serum androgen level and typically includes an elevated total, bioavailable, or free serum T level. Given variability in testosterone levels and the poor standardization of assays, it is difficult to define an absolute level that is diagnostic of PCOS or other causes of hyperandrogenism (9).

The PCO morphology has been defined by the presence of 12 or more follicles 2–9 mm in diameter and/or an ovarian volume exceeding 10 ml (without a cyst or dominant follicle) in either ovary (11). Critical analysis of the literature showed that ovarian volume had less diagnostic potential for PCOM compared with the follicle number per ovary. Moreover, if one is using more modern ultrasound machines with higher probe frequencies, the cutoff for PCOM should be probably higher, up to 25 or more per ovary (12).

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