Hypogonadotropic Hypogonadism 23 Without Anosmia

A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-23 without anosmia (HH23) is caused by homozygous or compound heterozygous mutation in the LHB gene (152780) on chromosome 19q13.

Description

Male patients with hypogonadotropic hypogonadism due to isolated luteinizing hormone (LH) deficiency have normal sexual differentiation but fail to develop spontaneous puberty. Absence of LH alters Leydig cell proliferation and maturation and impairs the onset of normal spermatogenesis, which requires high levels of intratesticular testosterone. Infertility and very low levels of spermatogenesis generally persist in affected men despite long-term exposure to gonadotropin therapy. Female patients exhibit normal pubertal development and menarche, followed by oligomenorrhea and anovulatory secondary amenorrhea (summary by Basciani et al., 2012).

For a general phenotypic description and discussion of genetic heterogeneity of hypogonadotropic hypogonadism, see 147950.

Reviews

Arnhold et al. (2009) noted that the clinical manifestations of female patients with hypogonadotropic hypogonadism due to mutations in LHB are very similar to those of women with hypergonadotropic hypogonadism due to inactivating mutations of the LH receptor (see 238320): all have female external genitalia, spontaneous development of normal pubic hair and breasts at puberty, and normal to late menarche followed by oligoamenorrhea and infertility. Pelvic ultrasound shows a small or normal uterus and normal or enlarged ovaries with cysts. However, women with LHB mutations can be treated with luteinizing hormone or chorionic gonadotropin (CG; 118860) replacement therapy; women with LH receptor mutations are resistant to LH, and no treatment is effective in recovering their fertility.

Clinical Features

McCullagh et al. (1953) described 5 patients with hypogonadotropic hypogonadism in the presence of normal testicular size and some degree of spermatogenesis. They designated the disorder 'fertile eunuch' syndrome. One patient had a brother with eunuchoidal features who refused examination. A deficiency of ICSH (interstitial cell-stimulating hormone), also known as luteinizing hormone in the male, was postulated. The clinical picture is one of androgenic insufficiency with 'normal' spermatogenesis. The semen shows abnormalities of sperm count, morphology, and mobility, but at least 2 patients were said to have fathered children. Isolated deficiency of LH, in the presence of normal concentrations of follicle-stimulating hormone (FSH; see 136530), was documented by radioimmunoassay by Faiman et al. (1968).

Pasqualini (1953) reported a 24-year-old Argentinian man who had a well-defined 'hypoandrogenic' syndrome. He exhibited lipomastia without gynecomastia, lacked facial and body hair, and had scant pubic and axillary hair. He had a small penis with normal-sized testes, and he could achieve erections. Testicular biopsy revealed active spermatogenesis with spermatozoa in 82% of seminiferous tubules, with only a Sertoli syncytium in 5%, and incomplete spermatogenesis in the remaining tubules. The Sertoli cells showed nuclear vacuolization and mottled cytoplasm that contained lipids but no birefringent steroids; the basal membranes of many tubules were thickened, and Leydig cells were scarce. Endocrinologic analysis, which demonstrated a marked increase in excretion of 17-ketosteroids following the administration of hCG, was consistent with a decrease in LH and 'probably normal' secretion of FSH.

Pasqualini (1979) provided a 30-year follow-up on the previously described patient (Pasqualini, 1953) and reviewed published reports of 'eunuchoidism' with preservation of spermatogenesis. The patient maintained a eunuchoid habitus, with a feminine shape, very little body hair, and scant facial, axillary, or pubic hair. Low libido and sexual impotence were present, but both could be restored by administration of CG. Treatment with CG or exogenous testosterone induced lowering of the patient's voice, but his penis increased only slightly in size, and his testes remained at 40 mm in diameter. In the sixth decade of life, baseline testosterone was at the lower limit of normal, but showed a more than 2-fold increase after administration of CG. The patient had no other hypothalamic or pituitary-associated manifestations.

Axelrod et al. (1979) reported a 24-year-old man, born of first-cousin parents, who presented at age 17 with failure to enter puberty. Examination showed gynecomastia, infantile penis, small testes, and pubic hair in a female distribution. Treatment with testosterone resulted in increased strength and normal adult facial, pubic, and axillary hair, deep voice, growth of penis, enlargement of testes, and ejaculations. Reevaluation of the patient in his 20s revealed a 46,XY karyotype with low testosterone plasma levels and urinary excretion despite persistently elevated plasma levels of immunoreactive LH and increased urinary gonadotropin excretion rates, consistent with primary gonadal failure; however, he responded normally to exogenous LH and CG. Testicular biopsy at age 24 showed no Leydig cells; many tubules showed minimal to moderate thickening of the lamina propria, and rare tubules were severely hyalinized. There was arrest of spermatogenesis, chiefly at the primary spermatocyte level, but in occasional tubules maturation had proceeded focally to sperm formation. Semen analysis following treatment with hCG revealed a sperm count of 11 million per milliliter with 50% normal forms and 50% motility, good progression, and normal viscosity and color. The proband had 3 maternal uncles, also born of first-cousin parents, who were normally developed males with normal secondary sex characteristics but who were infertile. One uncle had low levels of testosterone measured on 2 occasions and in another, testosterone levels were at the lower limit of normal; levels of LH and FSH were normal in all 3. Axelrod et al. (1979) concluded that the proband's circulating LH was functionally abnormal, and in vitro bioassays by Beitins et al. (1981) confirmed that the proband's LH was biologically inactive.

Valdes-Socin et al. (2004) reported a 30-year-old man from Cameroon with a 46,XY karyotype who presented with sexual infantilism. He had a eunuchoid habitus, gynecomastia, juvenile voice, micropenis, small testes, and scant but normally distributed pubic hair. Endocrinologic analysis showed undetectable LH, elevated FSH, and low testosterone; following administration of gonadotropin-releasing hormone (GNRH; 152760), the FSH level doubled, but no LH was detected. MRI showed no abnormalities of the pituitary gland. Testicular biopsy showed hypoplastic seminiferous tubules with predominance of Sertoli cells. Spermatogenesis was evident, though greatly reduced, with low numbers of spermatozoa. Valdes-Socin et al. (2004) designated the phenotype 'hypogonadotropic hypogonadism due to isolated LH deficiency.' Administration of testosterone normalized the FSH level and induced virilization, as well as increasing penile growth from 4 cm to 8 cm, but testicular volume remained unchanged at 8 ml, and his ejaculate was azoospermic. Treatment with CG resulted in an increase of testicular volume to 14 ml and an oligospermic ejaculate, with 1,000 spermatozoa per ml of predominantly normal shape and motility.

Valdes-Socin et al. (2009) provided follow-up on the Cameroonian man originally reported by Valdes-Socin et al. (2004), in whom treatment with CG resulted in near-normalization of testicular structure, with a sperm count of 1,000 spermatozoids per ml. The patient and his wife conceived a child by intracytoplasmic sperm injection from ejaculated sperm; the male infant, who was heterozygous for his father's LHB mutation (see MOLECULAR GENETICS section), was phenotypically normal with normal LH, FSH, and testosterone levels at the age of 4 weeks.

Lofrano-Porto et al. (2007) studied 3 sibs from a consanguineous Brazilian family with hypogonadism due to isolated LH deficiency. The proband was a 38-year-old man with a 46,XY karyotype who presented with eunuchoid habitus, juvenile voice, bilateral gynecomastia, scant axillary hair, lack of facial hair, micropenis, and underdeveloped but descended testes. He was azoospermic. His 30-year-old brother had been treated with intramuscular testosterone for hypogonadism since age 25; testicular biopsy showed interstitial fibrous thickening, hypoplastic seminiferous tubules that predominantly contained Sertoli cells, spermatogenic arrest, and absence of Leydig cells. Their 29-year-old sister presented with secondary amenorrhea and infertility. She had spontaneous normal puberty with menarche at 13 years of age, followed by oligomenorrhea. Ultrasound revealed a normal-sized uterus with atrophic endometrium, and the ovaries had multiple antral follicles dispersed over apparently normal stroma, with no dominant follicle; there was no change in endometrial thickness or ovarian appearance over the course of serial ultrasounds. After supplementation with estrogen, a dominant follicle developed, but ovulation remained impaired and no corpus luteum was observed. All 3 sibs had undetectable LH levels; FSH was increased in the brothers, who also had low testosterone levels, whereas their sister had normal FSH, estradiol, and progesterone levels.

Achard et al. (2009) reported a brother and sister from a consanguineous Moroccan family with hypogonadotropic hypogonadism due to partial loss of LH function. The 43-year-old brother had received intramuscular testosterone treatment for hypogonadism since age 28, but with poor adherence. Examination after 3 months off treatment showed virilization with normal masculine features, including normal penile length and low-normal testis volume. LH was undetectable and FSH levels were high, with very low serum testosterone. However, multiple spermiograms over a 10-month period showed normal numbers of spermatozoa (76.4-127.0 x 10(6) spermatozoa per ml) with qualitatively normal-to-subnormal spermatogenesis (up to 23% of sperm had normal morphology and 25-35% had motility) and low semen volume. Testicular biopsy showed heterogeneous seminiferous tubules separated by fibrous tissue, which contained few mature vacuolated Leydig cells; half the tubules were hyalinized or hypoplastic, with immature Sertoli cells, but the other half were composed of mature Sertoli cells and germ cells at all stages of differentiation. Immunohistochemistry confirmed a markedly reduced population of Leydig cells compared to an age-matched control. Achard et al. (2009) stated that the presence of mature Leydig cells in the testicular biopsy specimen, as well as an intratesticular testosterone level that was 40-fold greater than the serum level, indicated that the patient's LH retained partial activity. The proband had a 46-year-old sister who underwent normal spontaneous puberty, with menarche at age 14, but subsequently developed oligomenorrhea and secondary amenorrhea. Repeated ultrasonography for evaluation of infertility at age 30 revealed bilateral ovarian macrocysts. She had undetectable LH, low estradiol, and high FSH levels.

Basciani et al. (2012) studied a nonconsanguineous Chilean family in which a brother and 2 sisters had hypogonadism due to LH deficiency. The 31-year-old brother had a 46,XY karyotype and presented with sexual infantilism, including micropenis, small testes, juvenile voice, scant pubic and axillary hair, and bilateral gynecomastia; he was azoospermic with low semen volume. LH was undetectable, FSH was normal, and testosterone was low. Although treatment with testosterone induced virilization and an increase in testicular volume, it was discontinued due to exacerbation of gynecomastia. Subsequent treatment with CG resulted in development of oligozoospermia (0.38 x 10(6) spermatozoa per ml), although the spermatozoa showed predominantly abnormal shape and motility. Few Leydig cells were seen on testicular biopsy, and half the seminiferous tubules were hyalinized or hypoplastic, with immature Sertoli cells and spermatogonia; in the other tubules, spermatogenesis was present but greatly reduced. The proband's 16-year-old sister underwent menarche at age 14 but had only 3 to 4 menstrual periods per year; she also had undetectable LH, but levels of other hormones were in the normal range. The proband's older sister, age 33, was unavailable for study, but was reported to have had infrequent menstruation during the first 2 years after puberty, followed by 5 years of amenorrhea. Following treatment with estrogen and progestin, she had normal menses but did not have children.

Molecular Genetics

In a man with hypogonadotropic hypogonadism due to biologically inactive LH, who was originally reported by Axelrod et al. (1979), Weiss et al. (1992) sequenced the LHB and CGB genes and identified homozygosity for a missense mutation in the LHB gene (Q54R; 152780.0001). His unaffected mother and sister were heterozygous for the mutation, as were 3 maternal uncles who were infertile but displayed normal secondary sex characteristics.

In a 30-year-old man from Cameroon with hypogonadotropic hypogonadism due to lack of LH, Valdes-Socin et al. (2004) sequenced the LHB gene and identified homozygosity for a G36D mutation (152780.0004). Valdes-Socin et al. (2009) reported that treatment with hCG in this patient resulted in spermatogenesis adequate for conception by intracytoplasmic sperm injection.

In 2 brothers and a sister from a consanguineous Brazilian family with hypogonadism due to isolated LH deficiency, Lofrano-Porto et al. (2007) identified homozygosity for a splice site mutation in the LHB gene (152780.0005). Their asymptomatic parents and 2 unaffected sisters, 1 brother, and 1 nephew were heterozygous for the mutation, which was not found in 100 Brazilian controls. All heterozygotes were fertile and had normal basal gonadotropin and sex steroid levels for their ages, except for the 66-year-old mother who had unexpectedly low LH levels for her menopausal state. Lofrano-Porto et al. (2007) designated the phenotype 'familial selective hypogonadotropic hypogonadism' and noted that the affected brothers' phenotype was similar to that previously described, whereas the affected sister underwent apparently normal pubertal development followed by secondary amenorrhea, chronic anovulation, and infertility.

In a brother and sister from a consanguineous Moroccan family with hypogonadotropic hypogonadism due to partial loss of LH function, Achard et al. (2009) identified homozygosity for a 9-bp deletion in the LHB gene (152780.0006). Their mother and asymptomatic sibs were heterozygous for the deletion. Achard et al. (2009) noted that the male proband presented an unusual case by exhibiting complete and quantitatively normal spermatogenesis despite extremely low levels of LH activity postnatally and at puberty.

In a brother and sister from a nonconsanguineous Chilean family with hypogonadism due to isolated LH deficiency, Basciani et al. (2012) identified compound heterozygosity for a 12-bp deletion (152780.0007) and a splice site mutation (152780.0008) in the LHB gene. Their unaffected parents were each heterozygous for 1 of the mutations.

History

Park et al. (1976) described a 27-year-old 'woman' who had a 46,XY karyotype, ambiguous external genitalia, and elevated plasma LH, with slightly elevated FSH and low testosterone in plasma. Her plasma testosterone level increased 15- to 20-fold after stimulation with human CG. The authors postulated that the secretion of an abnormal LH molecule that was immunoreactive but biologically inactive, i.e., a CRM+ mutation, might be responsible.