Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists

The tyrosine kinase inhibitor sunitinib affects ovulation but not ovarian reserve in mouse: A preclinical study

The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-weekold female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti Müllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women

Effects of PEG-SMLA treatment on food intake and adipose tissues mass.

<p>(A) Food consumption (g) is calculated reported to body weight of each mouse on first or second week of treatment. PEG-SMLA injections are represented within hatched bars. b, p<0.001 related to Control WT mice. (B) At the end of treatment, the intact abdominal fat depot (delimited lines) is shown on both genotypes. (C) Ratio of adipose depot mass per body weight. b, p<0.001 and c, p<0.01 related to Control WT mice. (n = 7–10/group).</p

Trabecular bone parameters of third and fourth lumbar vertebrae (LV3 and LV4) of PEG-SMLA <i>vs</i> saline-injected PRLR^−/− and WT mice.

<p>Trabecular bone volume (BV)/tissue volume (TV) (%), trabecular number (Tb.N) (1/μm), trabecular thickness (Tb-Th) (μm), and trabecular separation (Tb.Sp) (μm). Data are mean ± SEM. Results shown in each row that are not designed with the same letter are statistically different, p<i><</i>0.05, n = 6.</p

Expression of key adipose genes.

<p>(A–D) <i>Leptin, Zfp423, PPAR</i> and <i>aP2</i> gene expression was quantified by qPCR in each gonadal, peri-renal, inguinal adipose depot of WT and PRLR^−/− non-treated mice (Control) and treated animals (PEG-SMLA, hatched bars) respectively (n = 5–8/group) b, p<0.01. (E) Distribution of adipocyte surfaces in inguinal adipose tissue in untreated WT and PRLR^−/− (Control) and treated animals (PEG-SMLA, hatched bars). Statistical analysis was performed. b, p<0.01, c, p<0.001.</p

PEG-SMLA treatment induced glucose intolerance and insulin resistance on WT and PRLR−/− animals.

<p>(A) Fasting glycemia in saline treated and PEG-SMLA treated mice. b, *p<0.05. (B) Oral glucose tolerance test (2g/kg) was performed in WT and PRLR^−/− mice PEG-SMLA treated or not. (C) Fasting (left panel) and 30 minutes after glucose gavage (right panel) plasma insulin levels. (D) HOMA-IR index reflecting insulin resistance is calculated as follows: fasting plasma glucose (mg/dl) × fasting insulin (mU/L)/405.</p

Effects of PEG-SMLA treatment on food intake and adipose tissues mass.

<p>(A) Food consumption (g) is calculated reported to body weight of each mouse on first or second week of treatment. PEG-SMLA injections are represented within hatched bars. b, p<0.001 related to Control WT mice. (B) At the end of treatment, the intact abdominal fat depot (delimited lines) is shown on both genotypes. (C) Ratio of adipose depot mass per body weight. b, p<0.001 and c, p<0.01 related to Control WT mice. (n = 7–10/group).</p

Metabolic parameters in WT and PRLR^−/− mice after saline or PEG-SMLA treatment.

<p>Number of mice appears in brackets. Data are represented as mean ± SEM. Different letters within each line indicate statistically different groups.Statistical analyses were performed between the all groups. b, p<0.001; c, p<0.05.</p

Effect of PEG-SMLA treatment on weight gain of WT and PRLR^−/− mice.

<p>(A) Representative dorsal view of male mice after 20 days of saline (control) or PEG-SMLA injections. (B) Comparison of PEG-SMLA effects on weight gain of WT (open squares) or PRLR^−/− (black squares) male mice. PEG-SMLA was injected daily at 6 mg/kg. <i>***, p<0.005</i> between non-treated (Cont) and PEG-SMLA treated groups.</p

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