Testicular Effects of Isolated Luteinizing Hormone Deficiency and Reversal by Long-Term Human Chorionic Gonadotropin Treatment

Abstract

Isolated gonadotropin deficiency due to inactivating mutations of -subunits of LH or FSH are rare. Isolated LH inactivation was identified in1992,although thepatient’s clinical characteristicshad been reportedearlier (1,2).Maleswith inactivatingLH mutations (five adults have been reported) present with clinical features of hypogonadism and oligo/azoospermia (1–5). In 2004, we reported the case of a 30-yr-old man with this clinical presentation (3). The patient gave informed consent for a testicular biopsy (Fig. 1, A and B), which showed arrested spermatogenesis and fetal-type Leydig cells (3). A homozygous missense mutation (G36D) in the LH -subunit gene was identified that abrogated -subunit dimerization and rendered LH biologically and immunologically inactive (3). We initiated treatment with intramuscular human chorionic gonadotropin (hCG) (1500 IU three times a week for 1 month, then 5000 IU weekly). Tanner staging was 5 after 3 months. After 24 months treatment, FSH decreased to 2.3 mIU/ml (normal range, 1–8mIU/ml)andtestosterone increasedto7 g/liter (normal range, 2.5–10.0 g/liter).Therewasnearnormalizationof testicular structure, which was likely related to Leydig cell maturation and subsequent increases in intratesticular testosterone, leading to a sperm count of 1000 spermatozoids/ml. (Fig. 1, C and D). The patient and his wife conceived a child by intracytoplasmic sperm injection from ejaculated sperm. The male child was heterozygotic for the G36D LH mutation and was phenotypically normal with normal LH, FSH, and testosterone levels at the age of 4 wk. Although rare, isolated LH deficiency due to inactivating mutations of LH -subunit gene is a useful illustration of the precise role of LH in testicular maturation and function in humans. Furthermore, it also provides a good example of the clinical efficacy of LH receptor stimulation using hCG.