They are distinguished from other hypoestrogenic patients by having decreased FSH levels and increased LH levels. These patients have low serum androgen levels despite the abnormal LHto-FSH ratio, indicating that FSH-stimulated follicular development is a prerequisite for thecal cell androgen production. In some of these patients, autosomal recessive mutations in the FSHβ subunit, which impair dimerization of α and β subunits and prevent binding to the FSH receptor, are identified (42). Pregnancy was achieved in one patient after induction of ovulation with injectable gonadotropins (43).
Functional gonadotropin deficiency results from malnutrition, malabsorption, weight loss or anorexia nervosa, excessive exercise, chronic disease, neoplasias, and marijuana use, although these conditions are more commonly associated with amenorrhea accompanied by secondary sexual characteristics that developed before the onset of the problem, which is discussed in detail below (44–48). Hypothyroidism, polycystic ovarian syndrome (PCOS), Cushing syndrome, hyperprolactinemia, and infiltrative disorders of the central nervous system are more commonly associated with amenorrhea in the presence of development of secondary sexual characteristics, but can lead to amenorrhea accompanied by delayed puberty (49,50). Constitutional delay without underlying causes is less common in girls than in boys, and the reason for lack of development should be vigorously pursued (51).
Evaluation of Women with Amenorrhea Associated with the Absence of Secondary Sexual Characteristics
A careful history and physical examination are necessary to appropriately diagnose and treat primary amenorrhea associated with hypogonadism. The physical examination may be particularly helpful in patients with Turner syndrome. A history of short stature but consistent growth rate, a family history of delayed puberty, and normal physical findings (including assessment of smell, optic discs, and visual fields) may suggest physiologic delay. Headaches, visual disturbances, short stature, symptoms of diabetes insipidus, and weakness of one or more limbs suggest central nervous system lesions (38). Galactorrhea may be seen with prolactinomas, a condition more commonly associated with secondary amenorrhea in the presence of normal secondary sexual characteristics.
The diagnostic workup is summarized as follows: 1.
The initial laboratory test should be assessment of serum FSH and LH levels unless the history and physical examination suggest otherwise in order to differentiate hypergonadotropic and hypogonadotropic forms of hypogonadism. If the FSH level is elevated, a karyotype should be obtained. An elevated FSH level in combination with a 45,X karyotype confirms the diagnosis of Turner syndrome. Partial deletion of the X chromosome, mosaicism, pure gonadal dysgenesis, and mixed gonadal dysgenesis are diagnosed by obtaining a karyotype.
2.
Because of the association with coarctation of the aorta (up to 30%) and thyroid dysfunction, patients with Turner syndrome should undergo echocardiography every 3 to 5 years and thyroid function studies yearly. Cardiac MRI is considered an important component of the cardiac evaluation (6). Patients with Turner syndrome should be evaluated for hearing loss, renal malformations, diabetes, and hypertension.
3.
If the karyotype is abnormal and contains the Y chromosome, as in gonadal dysgenesis, the gonads should be removed to prevent tumors (13).
4.