The effects of being overweight and obese on female reproduction: a review

Obesity is a major international problem related to many reproductive health problems including polycystic ovary syndrome (PCOS). This article reviews the evidence of being overweight and its effect on female reproduction. The fecundity of obese women is lower than normal weight women, but there is no absolute consensus about the effect of obesity on infertility treatment. The obese patient might have oocyte, hormone, metabolic and endometrial dysfunction affecting reproduction. Insulin and leptin may be some of the answers explaining anovulation during obesity leading to infertility. Moreover, the follicular glucose and lipids which are important for oocyte development also increase in the obese patient and these might have an effect on oocyte quality because studies in mice have revealed that the obesity affects follicular cell stress and oocyte lipids. Overall, obesity affects female reproduction by disturbing the general body metabolism, hormone metabolism and the follicular environment.     

The roles of FSH and LH in follicular growth and ovulation

Findings are presented of some studies that contest the assumptions that follicle-stimulating hormone (FSH) is primarily involved in the stimulation of the follicle and that luteinizing hormone (LH) is primarily involved in ovulation. In experiments with immature rats, it was found that FSH stimulated granulosa cells to develop LH receptor sites and increased the activity of 3beta-steroid dehydrogenase in recipient follicles. Experiments with hypophysectomized rats showed indications of ovarian follicular development after injection with FSH, and the number of ovulated oocytes recovered were equal to those ovulated by LH. The role of LH in follicular maturation has been challenged by findings of similar oocyte maturation times obtained through electrochemical stimulation of the brain and the administration of human chorionic gonadotrophin. In studies where the amount and duration of LH secretion was reduced, fewer oocytes were ovulated, through mature oocytes were demonstrated. It is apparent that the amount of gonadotrophin required for oocyte maturation is less than that needed for follicular rupture.     

Leptin and pregnancy outcome

Leptin, a recently discovered hormone that is involved in the regulation of body weight, appears to be one of the hormonal factors that signal the body's readiness for sexual maturation and reproduction to the brain. The present review focuses on clinical and experimental studies that describe the roles of maternal and foetal leptin as predictive factors for the physiological and pathophysiological development of the foetus during pregnancy, assisted reproduction and neonatal life. Through evaluating alterations of maternal serum leptin levels, a physiological hyperleptinaemia has been observed to occur, particularly during the second and third trimesters of pregnancy, which is not associated with a decreased food intake or reduced metabolic activity in the pregnant women. This state of leptin resistance is comparable to the condition in obesity. In contrast, hypoleptinaemia is suggested to be an indicator for the cessation of pregnancy, either naturally at term or as a result of pathology at any time during gestation. Thus, an appropriate maternal leptin level seems to be a prerequisite for a normal pregnancy. The main source of foetal leptin is the still immature foetal adipose tissue. As intrauterine growth has been found to be independently associated with cord blood leptin level, it has been suggested that leptin plays a role as a regulator of foetal growth. During assisted reproduction cycles leptin levels in the follicular fluid of patients may be also of predictive value, with low levels predicting therapeutic failure. Finally, the relevance of leptin to postnatal development is reviewed; leptin may be important for regulation of satiety and peripheral metabolism. In summary, leptin appears to be an important permissive factor that is involved in female reproduction.     

Concentrations of insulin-like growth factor (IGF)-I and IGF binding protein-3 in the follicular fluid of women undergoing ovarian hyperstimulation with different gonadotropin preparations.

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have an important regulatory role in follicular development and oocyte maturation. The aim of this prospective, randomized, double-blind study was to measure the concentrations of IGF-I and IGFBP-3 in follicular fluids collected from infertile women undergoing ovarian hyperstimulation using three different gonadotropin preparations. Twenty infertile women (mean age 33 years, range 28-40) undergoing in vitro fertilization (IVF) programs were recruited. After a written informed consent, each woman randomly underwent a long-protocol for ovarian hyperstimulation using gonadotropin-releasing hormone (GnRH)-analog and one of the following recombinant- and urinary-gonadotropins--alpha-follitropin, beta-follitropin or urofollitropin. Serum 17 beta-estradiol (E2) levels and follicle growth were assessed during the follicular phase. The concentrations of IGF-I and IGFBP-3 in the follicular fluid of aspirated dominant follicles were measured directly. Women treated with alpha-follitropin needed significantly lower doses of follicle-stimulating hormone (FSH) compared to those receiving beta-follitropin (p < 0.05). No other statistically significant differences were detected between groups. Serum E2 levels increased in the three groups from early to late follicular phase. Follicular fluid IGF-I and IGFBP-3 concentrations did not differ significantly in the three groups of women. A statistically significant relationship was observed between follicular fluid IGF-I and IGFBP-3 levels (r = 0.41, p = 0.001). Oocyte maturation correlated in a positive manner with IGF-I (r = 0.34, p = 0.01) and IGFBP-3 (r = 0.29, p = 0.03). These findings show that both recombinant- and urinary-gonadotropin preparations were equally effective in releasing IGF-I and IGFBP-3 in the follicular fluid of dominant follicles, and confirmed the role of these compounds on oocyte maturation.     

Leptin and Soluble Leptin Receptor in Follicular Fluid

PURPOSE: Previous studies suggest that follicular fluid leptin levels predict successful assisted reproduction. The relationship between intrafollicular leptin and the soluble leptin receptor, ovarian hormones, and oocyte quality was examined to determine potential factors contributing to this finding. METHODS: Follicular fluid leptin, soluble leptin receptor, hormones, and oocyte quality were examined in 84 individual follicles from 30 women undergoing in vitro fertilization. RESULTS: Follicular fluid leptin and soluble leptin receptor levels correlated inversely with each other (r = -0.354; p = 0.001). Follicular fluid leptin levels correlated with intrafollicular estradiol (r = 0.42; p < 0.001), progesterone (r = 0.48; p < 0.001), and androstenedione (r = 0.49; p < 0.001), whereas soluble leptin receptor levels correlated with activin (r = 0.38; p < 0.001) and follistatin (r = 0.35; p < 0.002). There was no relationship between follicular fluid leptin or soluble leptin receptor levels and pretreatment serum hormone levels, stimulated serum estradiol, follicle number, oocyte quality, fertilization, or embryo grade. CONCLUSION: The data demonstrate that leptin and the soluble leptin receptor are highly interrelated with each other and with other intrafollicular hormones, but not with markers of oocyte quality, fertilization, or embryo grade.     

The perimenopausal patient in in vitro fertilization: the use of gonadotropin-releasing hormone

The perimenopause, incipient ovarian failure, is a major problem in stimulation failures during an in vitro fertilization program. This must be recognized as not necessarily related to age but also associated with adnexal inflammatory and operative processes. Although ovulation occurs uninterruptedly, the follicle-stimulating hormone in the early follicular phase is elevated and the luteinizing hormone is normal. Characteristically, there is no estradiol response to human menopausal gonadotropin therapy or a rapid response with a premature luteinizing hormone surge. These problems sometimes may be overcome with pulsatile intravenous gonadotropin-releasing hormone therapy, 5 or 10 micrograms/90 or 120 minutes. The major therapeutic problem is in the identification of a luteinizing hormone surge in these patients. Of eight women who were treated, two failed to respond with follicular maturation, three either had no oocytes aspirated from apparently postmature follicles or had postmature oocytes; and one had treatment cancelled due to ovulation. The four latter patients may have failed because of unrecognized ovulation. In the remaining two patients, one oocyte was fertilized and transferred, and one pregnancy occurred.     

The source and implications of progesterone rise during the follicular phase of assisted reproduction cycles

Moderate elevations in serum progesterone concentrations are observed following the use of gonadotrophin-releasing hormone agonists during ovarian stimulation. The clinical significance of this phenomenon has been investigated, but findings have been inconclusive. This commentary proposes that progesterone concentrations are indeed important in endometrial advancement and oocyte/embryo development, which, may lead to asynchrony between endometrial and embryo development. Based on the two-cell, two-gonadotrophin model, this commentary proposes a hypothesis to describe how progesterone concentration increases during ovarian stimulation and three factors influencing this during ovarian stimulation are identified: the number of follicles, the FSH drive and the LH activity. It also suggests how differences in gonadotrophin preparations used for ovarian stimulation may have differential effects on progesterone synthesis. It remains to be tested whether routine measurement of late follicular progesterone concentrations may prove beneficial as suitable assay methods are now available. However, strategies that reduce follicular recruitment in high-responding women and gonadotrophins that contain LH activity may reduce the degree of progesterone elevation prior to luteinization.     

Effects of gonadotropin-releasing hormone agonists and antagonists on luteal function

PURPOSE OF REVIEW: This review addresses the effects of gonadotropin-releasing hormone agonists and antagonists on various aspects of the luteal phase. RECENT FINDINGS: Recent studies have shown that use of both gonadotropin-releasing hormone agonists and antagonists during in-vitro fertilization cycles leads to alterations in the hormonal profiles of the luteal phase as well as changes in endometrial histology. Gonadotropin-releasing hormone agonists are effective in triggering final oocyte maturation and reducing the incidence of ovarian hyperstimulation syndrome. Ongoing pregnancy rates are excellent after gonadotropin-releasing hormone agonist trigger when luteal phase and early pregnancy supplementation with estradiol and progesterone is provided. Gonadotropin-releasing hormone agonists have recently been used for luteal phase support in in-vitro fertilization cycles. SUMMARY: Although gonadotropin-releasing hormone agonists and antagonists are clinically useful, they may have adverse effects on luteal function. Luteal phase supplementation significantly improves clinical outcomes in in-vitro fertilization cycles because it may correct some of these detrimental effects. Use of gonadotropin-releasing hormone agonist to induce oocyte maturation is beneficial to patients who are at increased risk for ovarian hyperstimulation syndrome. The key factor in achieving favorable ongoing pregnancy rates with use of gonadotropin-releasing hormone agonist to induce oocyte maturation appears to be adequate luteal phase support.     

Leptin and reproduction: a review

OBJECTIVE: To review recent advances in understanding the role of leptin in the physiology and pathophysiology of reproduction, with a focus on relevant clinical situations. DESIGN: A MEDLINE computer search was performed to identify relevant articles. RESULT(S): Leptin, an adipocyte hormone important in regulating energy homeostasis, interacts with the reproductive axis at multiple sites, with stimulatory effects at the hypothalamus and pituitary and inhibitory actions at the gonads. More recently, leptin has been shown to play a role in other target reproductive organs, such as the endometrium, placenta, and mammary gland, with corresponding influences on important physiologic processes such as menstruation, pregnancy, and lactation. As a marker of whether nutritional stores are adequate, leptin may act in concert with gonadotropins and the growth hormone axis to initiate the complex process of puberty. Conditions in which nutritional status is suboptimal, such as eating disorders, exercise-induced amenorrhea, and functional hypothalamic amenorrhea, are associated with low serum leptin levels; and conditions with excess energy stores or metabolic disturbances, such as obesity and polycystic ovarian syndrome, often have elevated serum or follicular fluid leptin levels, raising the possibility that relative leptin deficiency or resistance may be at least partly responsible for the reproductive abnormalities that occur with these conditions. CONCLUSION(S): Leptin may act as the critical link between adipose tissue and the reproductive system, indicating whether adequate energy reserves are present for normal reproductive function. Future interventional studies involving leptin administration are expected to further clarify this role of leptin and may provide new therapeutic options for the reproductive dysfunction associated with states of relative leptin deficiency or resistance.     

Stimulation of endogenous surge of luteinizing hormone with gonadotropin-releasing hormone analog after ovarian stimulation for in vitro fertilization

The effect of induction of preovulatory endogenous surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) with intranasal administration of GnRH-analog (GnRH-a) in an in vitro fertilization (IVF) program is reported. The use of GnRH-a resulted in a significantly better percentage of replaceable embryos (91% versus 85%). The pregnancy rate was 51% in comparison with 32% in control cycles in which follicular maturation was achieved by human chorionic gonadotropin administration. There was no significant difference in the postoocyte recovery serum progesterone patterns between the two groups. Our results indicate that the induction of endogenous LH and FSH surge with GnRH-a may be successfully employed for final follicular maturation after ovarian suprastimulation without affecting the outcome of IVF adversely. Apart from being a more physiological approach to oocyte maturation, it also has potential economic and clinical advantages.     

Direct ovarian effect of clomiphene citrate in the rabbit

The effects of clomiphene citrate (CC) on ovulation and ovum maturation were studied using the isolated perfused rabbit ovary. CC (10(-5) M) added to the perfusate with human chorionic gonadotropin (50 IU) did not affect ovulatory efficiency, ovulation time, oocyte maturation, or degeneration of ovulated ova and follicular oocytes. During perfusion without human chorionic gonadotropin, the percentage of follicular oocytes with germinal vesicle breakdown was significantly increased in response to CC (10(-5) M or 10(-7) M); a greater percentage of follicular oocytes was degenerated. Estradiol (100 ng/ml) added to the perfusate reversed the effect of CC on degeneration of follicular oocytes. Of follicular oocytes from ovaries perfused with CC, 79.3% were degenerated; in contrast, 25% were degenerated in ovaries treated with CC plus estradiol. These data suggest that CC has a direct ovarian effect and that ovum degeneration associated with CC may be related to an antiestrogenic action.     

Leptin and the onset of puberty: insights from rodent and human genetics

Deficiency of the adipocyte-derived hormone leptin in ob/ob mice results in severe, early-onset obesity and infertility. Administration of leptin results in complete reversal of the phenotype, suggesting that leptin is needed for the development of puberty in rodents. In humans, mutations in the genes encoding leptin and the leptin receptor result in obesity syndromes and hypogonadotropic hypogonadism. I have shown that administration of recombinant human leptin results in the onset of puberty at an appropriate developmental age in human congenital leptin deficiency. This work suggests that leptin is a metabolic gate for the onset of puberty in humans. Leptin's actions may be mediated by central pathways and by direct action on peripheral organs.     

Thyroid peroxidase identified in human granulosa cells: another piece to the thyroid-ovary puzzle?

Thyroid hormones seemingly influence the maturation of the human oocyte. Thyroid hormone receptors have been isolated in granulosa mural and cumulus cells and the mature oocyte of the human ovarian follicle. Thyroid hormones are present in follicular fluid in concentrations similar to those in serum. Most importantly, enzymes involved in the chain that regulate the generation of thyroid hormones have been found in granulosa cells. For the first time, we have isolated thyroid peroxidase by immunocytochemistry in the granulosa cumulus cells of the human ovarian follicle, thereby supporting the hypothesis that the human ovarian follicle may be an independent thyroid-hormone producing unit.     

人绒毛膜促性腺激素在卵泡发育中的作用

目的:过去多年,由于人绒毛膜促性腺激素(hCG)与黄体生成素(LH)高度相似,hCG已代替LH被应用于促进卵子的最后成熟。最近,人们发现LH/hCG受体遍布所有的生殖器官,提示hCG的作用不限于此。与LH相比,hCG的半衰期更长、与LH/hCG受体结合更为紧密,效应可能更强。已经有研究报道低剂量hCG可独立于卵泡刺激素(FSH)支持中晚期卵泡的发育与成熟。在控制性超促排卵(COH)之前以及早期添加hCG可能是个有效的减少重组FSH的用量,提高卵子质量,提高妊娠率的方法。本文主要从LH在激素合成以及卵泡发育中的作用,hCG与LH的异同,hCG在中晚期卵泡和早期卵泡发育中的作用等方面进行介绍hCG的最新应用进展。     

The relation of serum and follicular fluid leptin and ovarian steroid levels in response to induction of ovulation in in vitro fertilization cycles

OBJECTIVE: Leptin restores energy homeostasis and regulates appetite and body weight by communicating the energy status to the central nervous system. Although there is strong evidence that leptin affects reproduction, its role in the control of reproductive physiology is little understood. STUDY DESIGN: We studied leptin concentrations in the serum and follicular fluid of 65 women undergoing ovarian hyperstimulation for in vitro fertilization (IVF). Fasting serum samples were collected (1) on the 3rd day of the cycle before IVF and (2) at the time of oocyte retrieval. Serum concentrations of leptin, estradiol (E2), progesterone, FSH, LH, prolactin, total testosterone, DHEA-SO4, and TSH and follicular fluid concentrations of leptin, E2, and progesterone were measured. RESULTS: Serum leptin values increased on average by 66.4% over basal leptin levels on the day of oocyte pick-up (OPU). A positive correlation between leptin increase and body mass index was observed. The serum leptin level was similar to that in follicular fluid o the day of OPU. E2 levels increased 34.5-fold with controlled ovarian hyperstimulation. There was a negative correlation between the increase in leptin levels and in E2 levels (P <0.05) and in the number of oocytes harvested (P <0.05). CONCLUSION: The significant increase in serum leptin levels during controlled ovarian hyperstimulation indicates a possible role of leptin in reproductive function. The increase in leptin levels is negatively correlated with ovarian response evaluated by E2 production and number of oocytes retrieved. This might be due to the reduced ovarian response through negative feedback of leptin to the ovaries at high levels.     

Follicular growth but absence of oocyte and cumulus maturation during ovarian stimulation in the days following surgical abortion: a case report

This paper is a case report on the results of an ovarian stimulation performed in the days following an induced abortion. A patient had breast cancer diagnosed during an early pregnancy. She had an induced abortion and had, before chemotherapy an ovarian stimulation, using rFSH and GnRH antagonist, followed by follicular puncture for oocyte for vitrification in the view of fertility preservation. No oocyte could be obtained despite a good hormonal and ultrasonographical follicular growth. This case report suggest that ovarian stimulation must be delayed after abortion to allow the maturation of oocyte-cumulus complexes     

Transient hyperprolactinemia during cycle stimulation and its influence on oocyte retrieval and fertilization rates

Prolactin (PRL) has been shown to have inhibitory effect on follicle-stimulating hormone induced aromatase activity and estrogen biosynthesis in human granulosa cells cultured in vitro. To investigate the validity of the hypothesis that transient hyperprolactinemia during controlled ovarian hyperstimulation might influence follicular steroidogenesis and oocyte maturation, we measured serum PRL, estradiol, and progesterone before aspiration of oocytes in women undergoing ovarian stimulation (n = 108) in in vitro fertilization-embryo transfer. No correlation was detected between PRL and total number oocytes, number mature oocytes, fertilization rate, cleavage rate, and pregnancy rate. Transient elevation of PRL was a common finding in patients (57%) but was not associated with a poor clinical outcome.     

超促排卵周期中巨噬细胞集落刺激因子的测定

目的　探讨巨噬细胞集落刺激因子 (M CSF)对卵泡发育、排卵、卵子受精及胚胎质量的影响。方法　用酶联免疫吸附试验方法测定 3 6例超促排卵患者的卵泡早期、卵泡中期和取卵日血清中M CSF水平 ,以及取卵日卵泡液中M CSF水平。结果　超促排卵周期中 ,血清M CSF水平呈逐渐升高趋势 ,取卵日达高峰。取卵日卵泡液M CSF水平 [(12 4 5 .7± 4 3 .6)kU/L]显著高于同日血清M CSF水平 [(983 .6± 2 9.6)kU/L]。在找到卵子、受精卵及直径≥ 16mm和容积≥ 2ml的卵泡中 ,其卵泡液M CSF水平分别为 (13 2 7.3± 4 2 .8)kU/L、(13 5 6.2± 3 4.7)kU/L和 (12 97.6± 3 3 .7)kU/L ;而未找到卵子、未受精及直径 <16mm和容积 <2ml卵泡的卵泡液M CSF水平分别为 (10 86.7± 2 8.3 )kU/L、(1175 .4± 3 7.3 )kU/L和 (10 3 8.4± 2 5 .9)kU/L ,3者间比较 ,差异均有极显著性 (P <0 .0 1,P <0 .0 5 ,P<0 .0 5 )。但是 ,胚胎分级 3～ 4分的卵泡液M CSF水平 [(12 71.8± 3 7.3 )kU/L]与胚胎分级 1～ 2分的卵泡液M CSF水平 [(13 12 .6± 5 1.2 )kU/L]比较 ,差异无显著性 (P >0 .0 5 )。结论　M CSF通过参与卵泡发育、成熟而影响卵子受精 ,但不影响卵裂及胚胎质量     

Hormonal manipulations in the luteal phase to coordinate subsequent antral follicle growth during ovarian stimulation

During the early follicular phase in the menstrual cycle, antral follicle sizes are often markedly heterogeneous. These follicular size discrepancies may, at least in part, result from the early exposure of FSH-sensitive follicles to gradient FSH concentrations during the preceding luteal phase. In addition, they potentially affect the results of ovarian stimulation. Indeed, pre-existing follicle size discrepancies may encumber coordinated follicular growth during ovarian stimulation, thereby reducing the number of follicles that reach maturation at once. To investigate this issue, three clinical studies were conducted to test the hypothesis that luteal FSH suppression could coordinate follicular growth. First, luteal FSH concentrations were artificially lowered by administering physiological oestradiol doses and measured follicular characteristics on the subsequent day 3. Second, it was verified whether luteal oestradiol administration could promote the coordination of follicular growth during ovarian stimulation and improve its results. Third, the effects of premenstrual gonadotrophin-releasing hormone (GnRH) antagonist administration on follicular characteristics were assessed during the early follicular phase. The results showed that luteal FSH suppression by either oestradiol or GnRH antagonist administration reduces the size and improves the homogeneity of early antral follicles during the early follicular phase, an effect that persists during ovarian stimulation. Coordination of follicular development may optimize ovarian response to short GnRH agonist and antagonist protocols, and constitutes an attractive approach to improving their outcome.