Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries

Biol Reprod. 2015 Jul;93(1):16. doi: 10.1095/biolreprod.115.129072. Epub 2015 Jun 3.

Abstract

The luteinizing hormone receptor, LHCGR, is essential for fertility in males and females, and genetic mutations in the receptor have been identified that result in developmental and reproductive defects. We have previously generated and characterized a mouse model (KiLHR(D582G)) for familial male-limited precocious puberty caused by an activating mutation in the receptor. We demonstrated that the phenotype of the KiLHR(D582G) male mice is an accurate phenocopy of male patients with activating LHCGR mutations. In this study, we observed that unlike women with activating LHCGR mutations who are normal, female KiLHR(D582G) mice are infertile. Mice exhibit irregular estrous cyclicity, anovulation, and precocious puberty. A temporal study from 2-24 wk of age indicated elevated levels of progesterone, androstenedione, testosterone, and estradiol and upregulation of several steroidogenic enzyme genes. Ovaries of KiLHR(D582G) mice exhibited significant pathology with the development of large hemorrhagic cysts as early as 3 wk of age, extensive stromal cell hyperplasia and hypertrophy with luteinization, numerous atretic follicles, and granulosa cell tumors. Ovulation could not be rescued by the addition of exogenous gonadotropins. The body weights of the KiLHR(D582G) mice were higher than wild-type counterparts, but there was no increase in the body fat composition or metabolic abnormalities such as impaired glucose tolerance and insulin resistance. These studies demonstrate that activating LHCGR mutations do not produce the same phenotype in female mice as in humans and clearly illustrate species differences in the expression and regulation of LHCGR in the ovary, but not in the testis.

Keywords: activating mutations; granulosa cell tumor; infertility; luteinizing hormone receptor; ovarian cysts; precocious puberty.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androstenedione / blood
  • Animals
  • Anovulation / genetics*
  • Anovulation / metabolism
  • Anovulation / pathology
  • Blood Glucose
  • Body Composition / genetics
  • Estradiol / blood
  • Estrous Cycle / genetics*
  • Estrous Cycle / metabolism
  • Female
  • Infertility, Female / genetics*
  • Infertility, Female / metabolism
  • Infertility, Female / pathology
  • Insulin / blood
  • Mice
  • Mice, Transgenic
  • Mutation
  • Ovary / metabolism
  • Ovary / pathology
  • Polycystic Ovary Syndrome / genetics*
  • Polycystic Ovary Syndrome / pathology
  • Progesterone / blood
  • Receptors, LH / genetics*
  • Receptors, LH / metabolism
  • Testosterone / blood

Substances

  • Blood Glucose
  • Insulin
  • Receptors, LH
  • Testosterone
  • Androstenedione
  • Progesterone
  • Estradiol