Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome

Neveu, N.; Granger, Louis; St-Michel, P.; Lavoie, Hélène B.

doi:10.1016/j.fertnstert.2006.05.069

Cited by 75 publications

(47 citation statements)

References 32 publications

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“…This study provides evidence to support the continued use of metformin after conception to improve pregnancy outcome in these women (19,20). Furthermore, these studies suggest that AMPK activation directly improves insulin-stimulated glucose uptake and decreases apoptosis at the level of the blastocyst and that this may be a mechanism for improved pregnancy outcomes in patients treated with metformin.…”

Section: Discussionsupporting

confidence: 54%

AMP Kinase Activation Increases Glucose Uptake, Decreases Apoptosis, and Improves Pregnancy Outcome in Embryos Exposed to High IGF-I Concentrations

et al. 2007

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Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP kinase (AMPK) activation with metformin directly improves insulin signaling within the blastocyst, leading to improved pregnancy outcomes. Murine embryos were exposed to 200 nmol/l IGF-I, similar to the concentrations that can occur during polycystic ovary syndrome (PCOS). Resulting blastocysts were compared with embryos cocultured with excess IGF-I plus metformin and embryos cultured in control medium for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day (E) 14.5, resulting fetuses were examined for size and rates of fetal implantation and resorption. Compared with control blastocysts, blastocysts exposed to high concentrations of IGF-I showed a decrease in AMPK activation and insulin-stimulated glucose uptake and an increase in the number of apoptotic nuclei. Blastocysts cocultured in metformin and excess IGF-I performed as well as controls in all studies. 5-Aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside, another AMPK activator, also prevented the effects of excess IGF-I on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-I-exposed embryos transferred into control mothers compared with control embryos transferred into control mothers. Both of these parameters were reversed by coincubation with metformin and IGF-I before transfer. Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin. Diabetes 56:2228-2234, 2007 W omen with polycystic ovary syndrome (PCOS) experience oligomenorrhea/anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries (1). The clinical presentation is variable, but many women with PCOS also exhibit obesity, hyperinsulinemia with insulin resistance, and infertility with recurrent pregnancy loss (2-4). The etiology of this recurrent pregnancy loss remains unclear. Both high concentrations of androgens and gonadotropins have been suggested, but only small, correlative clinical investigations have been conducted (5,6). Bioactive levels of the insulin-like growth factor, IGF-I, are also increased in PCOS patients because of an insulininduced decrease in the production of IGF binding protein-1 (IGFBP-1) (7,8).The preimplantation blastocyst stage embryo is an insulin-sensitive tissue (9,10). Prior studies have shown that the murine blastocyst responds to insulin or IGF-I by increasing glucose uptake and that this event occurs via the IGF-I receptor. IGF-I receptor signaling induces translocation of GLUT8 to the plasma membrane of the trophectoderm cells of the embryo (11). Expression of GLUT8 and translocation to the plasma membrane are critical for embryo survival (12,13). On exposure to high concentration of IGF-I or insul...

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Section: Discussionsupporting

confidence: 54%

AMP Kinase Activation Increases Glucose Uptake, Decreases Apoptosis, and Improves Pregnancy Outcome in Embryos Exposed to High IGF-I Concentrations

et al. 2007

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“…Although 60%-85% of patients will ovulate on CC, only about one half will get pregnancy. 16 Absence of pregnancy despite evidence of ovulation may be due to the anti-estrogenic effects of CC on the endometrium, which may manifest as a thin endometrium on ultrasound. 17 Metformin combined with CC may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of CC alone.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous ovulation and pregnancy in women with polycystic ovarian disease; a cross sectional study

Sleem

Mohamed

Zakherah

et al. 2018

Int J Reprod Contracept Obstet Gynecol

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INTRODUCTIONPolycystic ovary disease (PCOD) is the most common endocrine disorder in women of reproductive age, with a prevalence of approximately 5-10%. 1 The principal features of PCOD include androgen excess, ovulatory dysfunction, and/or polycystic ovaries. 2PCOD is also associated with insulin resistance (IR), obesity and lipid metabolism disorders, as well as infertility, although these findings have not been addressed in the Rotterdam criteria.3 Recent studies suggest that anovulation resulting from ovarian follicle abnormalities in PCOD patients is 2-fold of normal ovaries.Firstly, early follicular growth is excessive, thus women with PCOD are characterized by an excessive number of small antral follicles. Secondly, the selection of one follicle and its further maturation to a dominant follicle does not occur. This abnormality in the folliculogenesis leads to menstrual dysfunction presented as oligomenorrhea or amenorrhea. 4 A related mechanism of ABSTRACT Background: Polycystic ovary disease (PCOD) is the most common endocrine disorder in women of reproductive age, with a prevalence of approximately 5-10%. This study aims to assess the rate of spontaneous ovulation and pregnancy in patients. The present study was a cross sectional study conducted at Woman's Health Hospital, Assiut University, Assiut, Egypt. Methods:The current study was a cross sectional study carried out in Assiut Women's Health Hospital between the 1 st October 2016 and 31 st July 2017. The patients were selected as infertile patients with PCOD. The patient ages range between 20 and 35 years. The BMI is between 18 and 30 Kg/m 2 . The main outcome measure was the rate of spontaneous ovulation and spontaneous pregnancy in the 3 cycles. Results: The mean age of the study participants was 26.64±4.59 years and the mean BMI was 24.46±2.62Kg/m 2 . The sonographic ovarian volume was 12.47±0.69 mm 3 for the right ovary and 12.74±0.73 mm 3 for the left ovary. No difference in the serum FSH, LH, FSH/LH ratio and prolactin over the 3 consecutive cycles. The rate of spontaneous ovulation in the 3 cycles was 6 women (8.6%) and 2 cases (2.8%) became pregnant spontaneously during the study period. There is no statistical significant difference between ovulating and non-ovulating women according to the BMI and ovarian volume. Conclusions: The present study concluded that the rate of spontaneous ovulation was 8.6% in women with PCOD within 3 cycles with no adverse effects of drugs or surgical interference.

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“…for restoring ovarian function such as ovulation and menstrual cycle in PCOS patients with type 2 diabetes mellitus [4,5], because metformin improves insulin sensitivity and hyperandrogenism [6,7]. Metformin is therefore recommended for PCOS patients by the American Association of Clinical Endocrinologists [8].…”

Section: Discussionmentioning

confidence: 99%

A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin [Rapid Communication]

et al. 2016

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A 32-year-old female presented with infertility to our departments. She noticed hyperandrogenic signs such as acne and hirsutism as well as menstrual disorders three years earlier but did not take the opportunity to see a doctor. Infertility treatment was started with clomiphene one year ago, but did not lead to preg- Abstract. Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m 2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.

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Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome

Cited by 75 publications

References 32 publications

AMP Kinase Activation Increases Glucose Uptake, Decreases Apoptosis, and Improves Pregnancy Outcome in Embryos Exposed to High IGF-I Concentrations

AMP Kinase Activation Increases Glucose Uptake, Decreases Apoptosis, and Improves Pregnancy Outcome in Embryos Exposed to High IGF-I Concentrations

Spontaneous ovulation and pregnancy in women with polycystic ovarian disease; a cross sectional study

A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin [Rapid Communication]

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