When suspected on the basis of the clinical presentation or physical findings, the diagnosis of GnRH insensitivity should be confirmed biochemically. The diagnosis requires the following findings: * The demonstration of prepubertal serum concentrations of sex steroid hormones (serum testosterone less than 100 ng/dL 3.5 nmol/L in males or serum estradiol less than 20 pg/mL 73 pmol/L in females). * Inappropriately low or normal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary gonadal failure. * Otherwise normal anterior pituitary function. * Normal appearance of the hypothalamus and pituitary region on magnetic resonance imaging (MRI); when seeking this diagnosis, it is useful to request fine (1 mm) cuts through the olfactory bulb region of the MRI to define subtle abnormalities of the olfactory system that may signal which genetic tests to request first. * Differential diagnosis — For patients fulfilling the above laboratory criteria, the main (and most difficult) differential diagnosis is with constitutional delay of growth and puberty (CDGP). * A definitive diagnosis of GnRH insensitivity in the absence of a family history or prior genetic testing is difficult to make until the patient reaches at least 18 years of age, unless other suggestive features are present (ie, prior microphallus and/or cryptorchism, anosmia, renal agenesis, skeletal defects, etc). CDGP is far more common than GnRH insensitivity, affecting approximately 3 percent of adolescents while the incidence of the Kallmann syndrome (KS) form of GnRH insensitivity is 1:48,000 with a clear difference between males (1:30,000) and females (1:125,000). * No single test can reliably distinguish between GnRH insensitivity and CDGP until more widespread genetic testing becomes available, and therefore, one has to rely on an array of clinical clues as well as on the natural evolution over time. However, certain features may indicate a higher likelihood of GnRH insensitivity rather than CDGP: * A family history of<unk><unk>  hormone (GnRH) deficiency, anosmia, and/or the presence of one or several associated congenital abnormalities suggests congenital nonreproductive abnormalities (eg, cleft lip/palate, syndactyly) suggest KS form of GnRH deficiency. * A history of "stalled" puberty rather than total absence of development, a family history of delayed puberty, or early evidence of breast or testicular development are useful indicators that puberty is likely to occur spontaneously (ie, CDGP). * The presence of pubic hair suggests GnRH insensitivity because normal adrenarche still occurs; in comparison, both adrenarche and gonadarche are delayed in CDGP, and therefore, pubic hair is usually absent. * In females, functional hypogonadotropic hypogonadism (FHH) (or functional hypothalamic amenorrhea) is part of the differential diagnosis for GnRH insensitivity. The presence of predisposing factors like excessive exercise, weight loss, or psychological stress point towards the diagnosis of FHH rather than GnRH insensitivity. * When GnRH deficiency presents after puberty, other causes of secondary hypogonadism (particularly tumors of the hypothalamic-pituitary axis) must be eliminated, as GnRH insensitivity is really a diagnosis of exclusion. These include: * Tumors of the hypothalamic-pituitary region that occasionally can be suspected by the presence of other neurologic symptoms (headaches, visual disturbances) or the demonstration of other defects or excess in anterior pituitary hormone secretion on initial biochemical screening. However, enlarging mass lesions in either the pituitary or the central nervous system decrease the secretion of corticotropin (ACTH) or thyroid-stimulating hormone (TSH) less than that of<unk> s or growth hormone. * Similarly, hemochromatosis should be eliminated by appropriate testing of serum iron, total iron binding capacity, and ferritin levels. Approach to genetic testing — When the diagnosis of GnRH insensitivity is suspected, it is suggested that referral to a clinical geneticist for further evaluation and possible genetic testing be done. As many of the genes causing GnRH insensitivity have pleotropic physiologic functions, genetic testing can aid assessment of both reproductive and nonreproductive clinical features. In addition, ascertaining the specific inheritance modes can aid genetic screening within the family to predict recurrence risk in siblings, family members or offspring of GnRH insensitivity patients. However, genetic testing in GnRH insensitivity is challenging, given the genetic and allelic heterogeneity, as well as complex oligogenic inheritance patterns. However, in the presence of either clear Mendelian inheritance patterns or specific phenotypic cues, targeted genetic testing or multigene panel testing may be performed. However, if such testing is done, variant interpretation and genetic counseling should be performed in conjunction with a clinical genetics service. Alternatively, several research units have special interests in the genetics of GnRH insensitivity, and clinicians can consider referring these patients to such specialized centers. Genetic testing is now commercially available through several Clinical Laboratory Improvement Amendments (CLIA) laboratories in the United States (GeneDx, Athena Diagnostics, Fulgent Diagnostics).
Gonadotropin-releasing hormone insensitivity
Follicle-stimulating hormone insensitivity
Mild androgen insensitivity syndrome
Partial androgen insensitivity syndrome
Kallmann syndrome
Complete androgen insensitivity syndrome
Adrenocorticotropic hormone deficiency
Androgen insensitivity syndrome