Ana Claudia Latronico

Ovarian resistance to luteinizing hormone: a novel cause of amenorrhea and infertility.

OBJECTIVEnTo report the clinical, hormonal, and histopathological features of a woman with ovarian resistance to LH.nnnDESIGNnClinical study.nnnSETTINGnUniversity hospital.nnnPATIENT(S)nA woman with amenorrhea, sister of a patient with male pseudohermaphroditism due to Leydig cell hypoplasia.nnnINTERVENTION(S)nBlood drawing before and after GnRH stimulation and also after dexamethasone and hCG administration, pelvic ultrasound, and ovarian biopsy.nnnMAIN OUTCOME MEASURE(S)nKaryotype, gonadotropin and steroid measurements, follicular diameter, ovarian histology, and sequencing of the LH receptor gene.nnnRESULT(S)nPatient had normal female external genitalia, normal breast development at puberty, rare episodes of vaginal bleeding, and infertility. The karyotype was 46,XX. She had elevated serum LH levels, whereas E2 and P concentrations were in the range seen in the early follicular phase. Pelvic ultrasound revealed a slightly hypoplastic uterus and enlarged polycystic ovaries. A normal follicular reserve for age, antral follicles, and absence of corpora lutea or albicans were observed on ovarian biopsy. Exon 11 of the LH receptor gene had a normal sequence.nnnCONCLUSION(S)nIn our patient with ovarian resistance to LH, FSH stimulated follicular development until the preovulatory stage, but E2 levels remained in the early follicular phase range, still sufficient for normal pubertal feminization. Apparently, LH is necessary for ovulation and corpus luteum formation.

Luteinizing Hormone Resistance Syndromes

Luteinizing hormone (LH) plays its effects on ovarian and testicular cells through binding to a specific cell surface receptor. We recently described two kindreds with LH resistance due to abnormalities of the LH receptor (LH-R) gene. Affected XY members presented with severe or mild fetal undermasculinization (female external genitalia or micropenis) and primary hypogonadism, while an XX affected member showed normal pubertal development, increased plasma concentrations of LH, and amenorrhea. The first kindred included three XY phenotypic female siblings with Leydig cell hypoplasia and primary hypogonadism and a fully developed XX sister with elevated plasma concentrations of LH and amenorrhea. PCR amplification of genomic DNA and direct sequencing of the entire exon 11 of the LH-R revealed that all four affected individuals had a homozygous mutation (Arg554-->Stop codon) in the third cytosolic loop of the LH-R, which resulted in a truncated LH-R unable to transduce the hormonal signal. The second kindred included a 6-year-old XY boy with a micropenis and bilaterally descended testes, who demonstrated no response to exogenous human chorionic gonadotrophin postnatally. This patient had a nonconservative homozygous amino acid substitution (Ser616-->Tyr616) in the seventh transmembrane domain of his LH-R gene that was inherited from his heterozygous parents. The mutant receptor expressed in heterologous cells in vitro demonstrated no appreciable binding of 125I-labeled hLH, nor did it confer cAMP responsiveness to LH. Homozygous inactivating mutations of the LH-R cause complete or mild testicular failure in genetic males, resulting in female external genitalia or micropenis and primary hypogonadism. Similar mutations in genetic females may cause failure of ovulation and corpus luteum formation, resulting in amenorrhea. Follicular growth and development are apparently sufficient to allow feminization at puberty.

Receptors for Melanocortin Peptides in the Hypothalamic-Pituitary-Adrenal Axis and Skin

The syndromes of hereditary IGD and triple A syndrome are potentially life threatening and severely disabling diseases. Clinical awareness of these syndromes is of considerable prognostic and therapeutic importance. The defects in the ACTH receptor causing IGD help illuminate the mechanisms of ligand binding and signal transduction by this receptor. Identification of the molecular defect(s) responsible for IGD cases with a normal ACTH receptor structural gene and for the triple A syndrome remains a challenge, which will hopefully eventually provide further insight into the mechanisms of adrenocortical function. The cloning of the melanocortin receptors has been a giant step towards a better insight into the physiological role of the POMC-derived peptides. It is now becoming apparent that the differential processing of POMC in the brain, the pituitary, and peripheral tissues, yielding a number of different biologically active melanocortin peptides, combined with the distinct tissue distribution and pharmacological profile of the melanocortin receptors will help elucidate the molecular basis of these functions.

Genetic and Epigenetic Control of Puberty

Advances in the understanding of the mechanisms involved in the reactivation of the hypothalamic–pituitary–gonadal axis at puberty have been based on the characterization of genetic mutations associated with reproductive disorders in humans. Familial central precocious puberty and congenital hypogonadotropic hypogonadism are gonadotropin-releasing hormone-dependent disorders associated with a wide spectrum of genetic and epigenetic abnormalities.