Short-Term Pharmacological Suppression of the Hyperprolactinemia of Infertile hCG-Overproducing Female Mice Persistently Restores Their Fertility

Abstract

Female infertility is often associated with deregulation of hormonal networks, and hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis affecting the reproductive functions. We have shown previously that transgenic female mice overexpressing human chorionic gonadotropin β-subunit (hCGβ+ mice), and producing elevated levels of bioactive LH/hCG, exhibit increased production of testosterone and progesterone, are overweight and infertile, and develop hyperprolactinemia associated with pituitary lactotrope adenomas in adult age. In the present study, we analyzed the influence of the hyperprolactinemia of hCGβ+ females on their reproductive phenotype by treating them with the dopamine agonists, bromocriptine and cabergoline. Long-term bromocriptine treatment of adult mice was effective in the control of obesity, pituitary growth, and disturbances in the hormone profile, demonstrating that hyperprolactinemia was the main cause of the hCGβ+ female phenotype. Interestingly, short-term treatment (1 wk) with cabergoline applied on 5-wk-old mice corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, prevented pituitary overgrowth, normalized gonadal function, and recovered fertility of adult hCGβ+ females after hormone-induced and natural ovulation. The same cabergoline treatment in the short term applied on 3-month-old hCGβ+ females failed to recover their reproductive function. Hence, we demonstrated that the short-term cabergoline treatment applied at a critical early stage of the phenotype progression effectively prevented the hyperprolactinemia-associated reproductive dysfunction of hCG-overproducing females.

The transgenic expression of the β-subunit of human chorionic gonadotropin influences the growth of implanted tumor cells

“…While subsequent characterization of such tumors in the present model will reveal their true lineage, their existence is further indication of the association of βhCG with extra-gonadal tumorigenesis. An age-related increase in body weight occurred in transgenic mice (Figure 1I ), an observation similar to multiple reports in a previously-described analogous model, and attributed to raised prolactin levels [ 25 – 27 ].…”

“…In non-transgenic mice, estrous cyclicity was employed as a measure; while intact non-transgenic mice displayed all four stages of the estrous cycle as expected, ovariectomized, non-transgenic mice were in a constant state of Diestrous ( Supplementary Figure 3A ). Estrous cyclicity could not be employed as a measure to assess the success of ovariectomy in transgenic mice, since intact transgenic mice themselves remained in a constant state of Diestrous, in consonance with previous reports in a analogous βhCG transgenic mouse strain [ 25 , 27 ]; ovariectomy did not alter this state in transgenic mice, as expected ( Supplementary Figure 3A ). Instead, in transgenic mice, two additional read-outs known to be influenced by the ovaries (enhanced serum prolactin levels and increased body weight) were employed to assess the efficiency of ovariectomy; unlike in intact transgenic mice, serum prolactin levels remained low in ovariectomized transgenic mice ( Supplementary Figure 3B ) and increases in body weight were also not observed ( Supplementary Figure 3C ).…”

“…βhCG transgenic mice have been employed to further understanding of hCG-mediated tumorigenesis. Amongst other abnormalities, lactotrope pituitary adenomas are observed, resulting in an increase in serum prolactin and consequent infertility [ 25 – 27 ]. Prominent markers of tumorigenesis such as Hmg2a, E2f1, Ccnd1, Prl, Gh, Gal, Pttg1 and Bmp4 are up-regulated, and Cdk inhibitors are down-regulated in the pituitary.…”

Prevalence of hyperprolactinemia in infertile women and its association with hypothyroidism

“…1 Presence of abnormally high values of prolactin,>25µg/L is termed as hyperprolactinemia which is one of the most common endocrinological disorder of the hypothalamopituitary axis affecting fertility. [2][3][4] Hyperprolactinemia affects the fertility potential by impairing pulsatile secretion of GnRH and interferes with the action of gonadotropins at the ovarian level so interfering with ovulation. 5,6 Hyperprolactinemia causes galactorrhea along with menstrual and ovulatory disturbances.…”

The permissive role of prolactin as a regulator of luteinizing hormone action in the female mouse ovary and extragonadal tumorigenesis

“…The reproductive phenotype of the mice includes completely disturbed cyclicity and infertility. The crucial role of hyperprolactinemia in this phenotype was demonstrated recently by short-term cabergoline treatment, which prevented the reproductive dysfunction of these mice (35). Conversely, targeted disruption of the Prlr gene in female mice results in infertility by completely disturbing both the maintenance of CL, decreasing the expression of Lhcgr, and by increasing the expression of 20␣-hsd, leading to progesterone insufficiency and blockage of embryo implantation and mammary gland development (5,19).…”