Actually, after this clinical exam and these simple complementary investigations, the physician often has a presumptive diagnosis. The easiest case is when FSH is elevated (hypergonadotropic hypogonadism). In this case the work-up will be completed with a karyotype. If gonadotropins are low it will be less easy: the physician will have to eliminate organic disease such as a tumor by brain MRI, screen for negative energetic balance, and identify genetic causes of isolated IHH before being able to diagnose an idiopathic constitutive delay of puberty.
Elevated FSH and/or LH levels reflect peripheral ovarian disease and raise the need to verify female phenotype, check for the presence of ovarian and uterine tissues by ultrasound, and determine the karyotype on peripheral blood lymphocytes before examining the ovaries by celioscopy and biopsy.
Turner’s Syndrome and Its Variants
Turner’s syndrome, the most frequent cause of primitive ovarian failure, associates in its classical monosomic 45,XO form a female phenotype, short stature, several somatic abnormalities and sexual infantilism. In this form, diagnosis has frequently, but not always, been made during infancy. Any suggestive malformations (webbed neck, nail dysplasia, high palate, short fourth metacarpal and strabismus), growth retardation and/or elevated FSH must lead to the verification of the karyotype. However, in its variant forms with mosaicism or structural abnormalities of an X chromosome (iso, deletion, translocation X/autosome), there are several phenotypes for pubertal development from infantilism to partial development of secondary sex characteristics, primary amenorrhea or even spontaneous puberty. Indeed, spontaneous puberty occurs in 10 - 20%, followed by premature ovarian failure especially in cases of mosaicism with few 45,X cells or deletion of the X short arm.
Treatment with recombinant GH may be able to accelerate partial pubertal development. In fact, both X chromosomes are necessary for the preservation of ovarian function and oocytes. Specifically, some areas such as the Xq13-q26 region contain genes which are thought to prevent premature follicular atresia. In Turner’s syndrome, germinal cells are present and normal until the fourth month of intrauterine life. Regression of gonocytes will then depend on the importance of the X defect. At birth, ovarian morphology can vary from ovarian streaks to macroscopically normal ovaries.
Mosaicism can be associated with the partial presence of a Y chromosome found on cytogenetic analysis. A systematic molecular analysis found it in 1 out of 40 cases. If present, castration will prevent the development of gonadoblastoma.
Gonadal Dysgenesis with a 46,XY Karyotype
In the Swyer syndrome which associates a female phenotype, normal or elevated height, non-ambiguous external genital organs, and normal müllerian structures, the gonads are often reduced to undifferentiated streaks. They may have some testicular characteristics. Because they carry the risk of neoplastic transformation, they must be removed. Mutations of the SRY gene will be found only in 20% of cases.
Gonadal dysgenesis with a 46,XY karyotype with complete sexual reversion and without genital ambiguity has also been related to other mutated genes involved in sex differentiation: (a) WT1 with Wilms’ tumor and renal insufficiency in the Drash syndrome and without Wilms’ tumor but another renal pathology in the Frasier syndrome; (b) SOX-9 associated to campomelic dysplasia, and (c) DAX-1 with duplication of the Xp21 region.
Complete Resistance to Androgens
Mutations of the gene coding for the androgen receptor, located on chromosome X, will lead to various degrees of androgen resistance in boys, with a male pseudohermaphrodism with a 46,XY karyotype and a female phenotype in the complete form. Diagnosis will be made only in the peripubertal period, suggested by primary amenorrhea with no pubic or axillary pilosity but normal breast development. LH level is very high with adult male testosterone level, FSH level is normal, and estradiol is almost at a follicular phase level allowing breast development. The vaginal cavity is short and closed. Ultrasound will confirm the absence of müllerian and wolfian structures and identify abdominal or inguinal testes, which will have to be removed. Estrogens will complete feminization, though without menstruations due to lack of a uterus; sterility will be without therapeutic solution.
Revision date: June 14, 2011
Last revised: by Andrew G. Epstein, M.D.