Hypergonadotropic Hypogonadism

At a Glance

Hypergonadotropic hypogonadism, also called primary hypogonadism, is a disorder of abnormal function of gonads with decreased testosterone in males and estradiol in females, which results in delayed sexual development. The decreased sex hormone level stimulates increased production of gonadotropins due to diminished negative feedback mechanisms.

The etiology of the condition can be congenital or secondary to other problems. Congenital hypergonadotropic hypogonadism includes testicular dysgenesis (Klinefelter syndrome in males) and ovarian dysgenesis (Turner syndrome in females), androgen insensitivity syndrome, as well as enzyme deficiency (very rare; 17-α hydroxylase deficiency in females and 17-ketosteroid reductase deficiency in males). The acquired etiology includes gonadal toxins, such as radiation or chemotherapy, sex hormone decline with aging, or infections such as mumps. This chapter concentrates on Klinefelter syndrome and Turner syndrome.

Klinefelter syndrome (KS) is an inheritable disorder of males characterized by hypogonadism, mild mental retardation, and a karyotype of 47, XXY. It is the most common major sexual differentiation abnormality estimated to occur at 1 in 500-1000 live male births. Except prenatal diagnosis for other reasons, such as old maternal age, Down syndrome, as well as others, KS usually is not diagnosed after birth and during infancy. Nevertheless, some congenital malformations have been reported more frequently in KS patients than in normal population. These include cryptorchidism, smaller and firm testicles, small penis, scrotum bifidus, hypospadias, fifth finger clinodactyly, and cleft palate.

During childhood, KS children are noted to have learning disabilities, speech difficulties, and trouble in reading and mathematics. These children have high risk of developing behavior problems. KS patients usually encounter puberty at the expected age. However, starting from puberty, the differences in secondary sexual maturation between the KS patients and normal boys become noticeable. Gynecomastia occurs in 50-80% of KS patients, which is usually the presenting symptom to seek medical attention. The other characteristics include slim and tall habitus, long legs, and sparse facial and body hair. Some patients present with infertility.

Turner syndrome (TS) is an inheritable disorder of females characterized by short statue, premature ovarian failure, and a karyotype of 45,X with or without mosaicism. TS is one of the most common chromosomal anomalies with a prevalence of approximately 1 in 2000 live female births. Classical TS with 45,X is associated with prenatal degeneration of ovarian follicles, resulting in streak gonads without pubertal development. The phenotypes of TS with mosaicism or partial X chromosome monosomy are variable. Some may present with primary or secondary amenorrhea or infertility.

Other features of TS that present in less than one-half of patients include webbed neck, low-set ears, ptosis, skeletal and renal abnormalities, and congenital cardiovascular defects. Most TS patients have normal intelligence, but some have learning disorders. The pathogenesis of TS is oocyte-loss in the early stages of the meiotic prophase, resulting in fibrotic ovaries and the deficiency of estradiol. The low level of estradiol stimulates the production of follicular stimulating hormone (FSH) and leutinizing hormone (LH) due to reduced negative feedback through hypothalamus-pituitary-gonad axis.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

For male patients suspicious for hypogonadism, serum testosterone (T), inhibin B, FSH, and LH may first be measured. KF patients usually have low T, low inhibin B, and abnormally high FSH and LH. With the clinical suspicion and abnormal hormonal pattern, karyotype should be performed. If the patient is confirmed with karyotype of 47, XXY, the diagnosis of KF is made. If the karyotype is performed based on the physical exam, the diagnosis does not require hormone testing.

For female patients with signs and symptoms of ovarian insufficiency or other physical characteristics of TS, the levels of estradiol, inhibin B, FSH, and LH may be part of the work-up if not preceded by a karyotype. Inhibin B is secreted by developing follicles, and its level depends on the total number of follicles. In TS patients, the inhibin B level is often undetectable. If low estradiol, undetectable inhibin B, and high FSH and LH are found, karyotype should be performed to confirm the diagnosis of TS.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

In normal girls, gonadotropin (FSH and LH) levels are biphasic with first peak at 3 months of age, second peak at onset of puberty, and minimal level at mid-childhood. TS patients show similar but amplified biphasic gonadotropin levels, high in early childhood (0-5 years of age) and the onset of puberty (>10 year old), but low during mid-childhood (6-10 years of age). Levels in TS patients are significantly higher than in normal girls during early childhood or at puberty but fall within the reference ranges during mid-childhood. Normal gonadotropin level between 6 and 10 years of age does not exclude the diagnosis of TS. Conversely, inhibin B is usually undetectable in TS patients at all ages.

What Lab Results Are Absolutely Confirmatory?

Conventional chromosomal analysis or array CGH demonstrating a karyotype of 47, XXY is absolutely confirmatory of KS. Similarly, finding a chromosome constitution of 45, X, or mosaicism of 45,X/46,XY or 45,X/46,XX is absolutely confirmatory for TS.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A significant number of TS patients are mosaicism with karyotype of 45,X/46,XX or 45,X/46,XY or have only structural defects of X chromosome. This results in considerable variation in phenotypes of the patients. Some patients with mosaicism can have spontaneous puberty.

Chromosomal analysis of amniocentesis or chorionic villous samples may reveal abnormalities of TS. Prenatal diagnosed 45,X/46,XY or 45,X/46,XX mosaicism have a very different prognosis compared to nonmosaic 45,X. In large studies of prenatally diagnosed 45,X mosaicism with 45,X/46,XY, more than 90% of cases have a normal male phenotype. The phenotype prediction from a prenatal karyotype can be challenging. Prenatal diagnosis of TS by amniocentesis or chorionic villous cytogenetics testing should be correlated with fetal ultrasound. If ultrasound does not support TS, FISH analysis for Y chromosome should be performed to determine whether mosaicism is present.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Since mosaicism exists in a significant number of TS patients, discrepant test results could occur. Chromosomal analysis only examines a limited number of cells (10-20 cells). If one cell line is significantly lower in mosaicism patients, it is possible that only the normal or abnormal karyotype is detected in a sample. This will cause misdiagnosis and may affect the management of the patients. This is especially important in prenatal diagnosis and genetic counseling. Correlation with clinical symptoms, detailed physical exams, and repeating some laboratory tests are critical to making a correct diagnosis.

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