Mood disorders and hormonal status across women's life: a narrative review.

Depressive disorders and anxiety states represent one of the most frequent psychiatric pathologies occurring transiently in vulnerable women throughout their life, from puberty to menopause. It is now known that sex hormones play a key role on the nervous system, interfering with neuronal plasticity and enhancing the processes of learning, memory, cognition, and mood. Numerous mechanisms are at the base of these processes, displaying interactions between estrogen and serotoninergic, dopaminergic, and GABAergic receptors at the central level. Therefore, given the sexual steroids fluctuations throughout the entire female lifespan, and considering the role played by sex hormones at the central level, it is not surprising to observe the onset of mood or neurodegenerative disorders over time. This is especially true for women in hormonal transition phase, such as puberty, postpartum and the menopausal transition. Moreover, all these conditions are characterized by hormone withdrawal, imbalance, or modifications due to menopausal hormone therapies or contraceptives which could prompt to a deterioration of mood and cognition impairment or to an improvement in the quality of life. More studies are needed to better understand the hormone-related effects on the nervous system, and the underlying pathways involved in transitional or chronic mood disorders, to promote new patient-specific therapeutic strategies more effective than the current ones and tailored according to the individual need and women's life period.

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.

Counseling in menopausal women: How to address the benefits and risks of menopause hormone therapy. A FIGO position paper.

Menopause marks the end of menstrual cyclicity and, depending on individual vulnerability, has several consequences related to gonadal steroid deprivation, especially if it is premature. Menopause may be more burdensome for some women than for others. Individual factors, such as personal history, socioeconomic status, ethnicity, and current health conditions, affect symptomatology and, thereby, the menopausal experience. In addition, some menopausal symptoms, such as severe hot flashes, sleep disorders, and depression, are markers of future health risks. Counseling is a fundamental part of health care in the peri- and postmenopause periods. It must include an assessment of the patient's symptoms, needs, desires, and risk profile to address the benefits and risks of menopausal hormone therapy (MHT) on an individual basis and promote a healthy lifestyle. Indeed, healthcare practitioners can and must protect the health and lives of mid-life women by increasing awareness of menopausal symptoms and ensuring healthcare options, especially MHT. The type and duration of MHT should be tailored based on the patient's history, menopausal age, physical characteristics, and current health status so that the benefits always outweigh the risks. This FIGO position paper focuses on the benefits and risks of MHT on health domains, target organs, and systems, and on systemic and vaginal MHT regimens, to provide indications that can be used in the clinical practice for menopausal counseling. Moreover, it offers insights into what FIGO considers the mainstay for the healthcare management of women in peri- and postmenopause, worldwide.

DHEA supplementation improves follicular microenviroment in poor responder patients.

OBJECTIVE: To analyze the effect of dehydroepiandrosterone (DHEA) supplementation on follicular microenvironment and on in vitro fertilization (IVF) outcomes among poor responder patients. STUDY DESIGN: We enrolled 24 patients diagnosed as poor responders based on ESHRE consensus criteria. One group received 25 mg/die three times daily of DHEA supplementation for 3 months previous to IVF cycle, while the other did not receive any treatment. COH was performed with rFSH and hMG, and a GnRH antagonist was administered according to a flexible protocol. We evaluated perifollicular vascularization of recruited follicles through power Doppler blood flow analysis and follicles were graded as described by Chui et al. Follicular fluids (FF) from F3-F4 follicles were collected, and FF levels of vascular endothelial growth factor (VEGF) and hypoxic inducible factor1 (HIF1) were measured. RESULTS: FF levels of HIF1 were statistically significant lower in women treated with DHEA (14.76 ± 51.13 vs. 270.03 ± 262.18 pg/ml; p = 0.002). On the contrary, VEGF levels did not differ between the two groups. Concerning COH, in the DHEA-group the mean duration of treatment was significantly shorter (9.83 ± 1.85 vs. 12.09 ± 2.81; p = 0.023). Total numbers of oocytes retrieved, fertilized oocytes, good quality embryos, number of transferred embryos and clinical pregnancies tended to be higher in study group, but the results were not significant. On the other hand, considering the oocytes retrieved in selected F3-F4 follicles, there was a relation between HIF1 levels and oocytes quality. In fact, mature oocytes retrieved in selected follicles were significantly more numerous in DHEA-group (0.50 ± 0.52 vs. 0.08 ± 0.29; p = 0.018). CONCLUSIONS: The improvement of reproductive parameters after DHEA supplementation in poor responders may be explained through the effect that this pro-hormone exerts on follicular microenvironment.

Hormone therapy in the postmenopausal years: considering benefits and risks in clinical practice.

BACKGROUND: Menopausal symptoms can be very distressing and considerably affect a woman's personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT. OBJECTIVE AND RATIONALE: The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms. SEARCH METHODS: A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause. OUTCOMES: HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen-progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen-progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen-progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman's health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity. WIDER IMPLICATIONS: In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks.

Pharmacotherapeutic options for the treatment of menopausal symptoms.

Introduction: Menopausal symptoms can be very overwhelming for women. Over the years, many pharmacotherapeutic options have been tested, and others are still being developed. Hormone therapy (HT) is the most efficient therapy for managing vasomotor symptoms and related disturbances. The term HT comprises estrogens and progestogens, androgens, tibolone, the tissue-selective estrogen complex (TSEC), a combination of bazedoxifene and conjugated estrogens, and the selective estrogen receptor modulators, such as ospemifene. Estrogens and progestogens and androgens may differ significantly for chemical structure and can be delivered through different routes, thereby displaying various pharmacological and clinical properties. Tibolone, TSEC and SERM also exhibit unique pharmacodynamics that can be exploited to obtain distinctive therapeutic effects. Non-hormonal options fall mainly into the selective serotonin reuptake inhibitor (SSRI) and selective noradrenergic reuptake inhibitor (SNRI), GABA-analogue drug classes.Areas covered: Herein, the authors describe the pharmacokinetics and pharmacodynamics of hormonal (androgens, estrogens, progestogens, tibolone, TSEC, SERMs) and non-hormonal (SSRIs, SNRIs, Gabapentin, Pregabalin, Oxybutynin, Neurokinin antagonists) treatments for menopausal symptoms and report essential clinical trial data in humans.Expert opinion: Patient tailoring of treatment is key to managing symptoms of menopause. Physicians must have in-depth knowledge of the pharmacology of compounds to tailor therapy to the individual patient's characteristics and needs.

Vascular endothelial growth factor and its soluble receptor in patients with polycystic ovary syndrome undergoing IVF.

We aimed to examine the behaviour of the angiogenetic factor vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-1) in polycystic ovary patients undergoing In vitro fertilisation (IVF) compared with respect to normally ovulating controls. Levels of VEGF and sVEGFR-1 were compared in follicular fluid and serum, both on the day of human choriogonadotropin (hCG) administration and on the day of oocyte retrieval (OR), in controls and polycystic ovarian syndrome (PCOS) patients undergoing IVF cycles. The bioactivity of VEGF (VEGF/sVEGFR-1 ratio) in the two groups was calculated. Thirty PCOS patients and 20 controls referring to the IVF Centre of the University of Pisa (Italy) were enrolled. In each patient, blood samples were collected on the day of hCG and on the day of OR administration, and follicular fluid samples. VEGF and sVEGFR-1 were measured by Enzyme Linked Immuno Sorbant Assay (ELISA). Serum VEGF bioactivity markedly increased in both groups after hCG administration. Serum and follicular fluid VEGF bioactivity was greater in PCOS patients than in controls on the day of OR. The increase in VEGF bioactivity in PCOS patients undergoing IVF was not only because of increasing levels of VEGF but also to decreasing levels of its soluble receptor. We believe that additional studies will clarify their role in the pathogenesis of ovarian hyperstimulation syndrome, which most often occurs in patients with PCOS.

Vascular endothelial growth factor and its soluble receptor in benign and malignant ovarian tumors.

An imbalance between pro-angiogenic and anti-angiogenic factors is hypothesized in the pathogenesis of ovarian cystic disease. The aim of the following study was to explore the possible role of free vascular endothelial growth factor receptor 1 (sVEGFR-1), a soluble regulator of vascular endothelial growth factor (VEGF) action, in ovarian cystoadenoma, endometriomata and cystoadenocarcinoma. Forty-eight women, of whom fourteen had ovarian serous cysts, twenty-eight had stage III-IV ovarian endometriomata, and six had stage IIIB-IIIC ovarian carcinoma, were included. Sampling of serum, peritoneal and ovarian cystic fluids and of tumor tissue was performed before, during and following surgery, respectively. Levels of VEGF and sVEGFR-1 were measured in serum, peritoneal and cystic fluid. VEGF and sVEGFR-1 expression was evaluated in tumor tissue. There were no differences in serum VEGF and sVEGFR-1 levels nor in VEGF/VEGFR-1 ratio between study groups. Peritoneal fluid VEGF levels were higher in cystoadenocarcinoma patients than in endometriosis and in cystoadenoma patients, while sVEGFR-1 peritoneal fluid concentrations were significantly higher only in endometriosis-affected women. VEGF/VEGFR-1 ratio was highest in the peritoneal fluid of cancer patients with respect to the other two groups of women. Cystic fluid VEGF and VEGFR-1 concentrations were higher in endometriomata and in cystoadenocarcinomas than in cystadenomas but the VEGF/VEGFR-1 ratio was highest in cancer patients. Western blot evidenced a marked expression of VEGF and soluble VEGFR-1 in endometriosis tissue with respect to benign cyst tissue but a lower expression of both molecules, contrary to that expected, in cancer tissue. In conclusion, all in all, our data indicate that an excess of local VEGF with respect to its soluble receptor VEGFR-1 may be a key factor in the onset and maintenance of pathological neo-angiogenesis in ovarian cyst formation.

Symptoms of menopause - global prevalence, physiology and implications.

The symptoms of menopause can be distressing, particularly as they occur at a time when women have important roles in society, within the family and at the workplace. Hormonal changes that begin during the menopausal transition affect many biological systems. Accordingly, the signs and symptoms of menopause include central nervous system-related disorders; metabolic, weight, cardiovascular and musculoskeletal changes; urogenital and skin atrophy; and sexual dysfunction. The physiological basis of these manifestations is emerging as complex and related, but not limited to, oestrogen deprivation. Findings generated mainly from longitudinal population studies have shown that ethnic, geographical and individual factors affect symptom prevalence and severity. Moreover, and of great importance to clinical practice, the latest research has highlighted how certain menopausal symptoms can be associated with the onset of other disorders and might therefore serve as predictors of future health risks in postmenopausal women. The goal of this Review is to describe in a timely manner new research findings on the global prevalence and physiology of menopausal symptoms and their impact on future health.

Different effect of hormone replacement therapy, DHEAS and tibolone on endothelial function in postmenopausal women with increased cardiovascular risk.

Menopause is associated with an increased cardiovascular risk and with a decrease in endothelial function. Hormone replacement therapy (HRT) improves endothelial function in post-menopausal women (PMW) without established atherosclerosis. New alternative treatments, among which tibolone (T) and DHEAS have been suggested to reduce postmenopausal cardiovascular risk. Although, in vitro animal studies have suggested that T and DHEAS improve endothelial function, their effect in humans has never been tested. The aim of the present study was to compare the effects of HRT (continuous combined 0.625 mg conjugated equine estrogen plus 2.5 mg/d medoxyprogesterone) DHEAS and T on endothelium-dependent flow-mediated vasodilatation (FMD), plasma nitrite, nitrate and endothelin-1 levels in 16 PMW with increased cardiovascular risk in a double-blinded, double-crossover study. Women were randomized and treated for 4 weeks with HRT, T or DHEAS. Brachial artery diameter, FMD, endothelin-1 and plasma nitrite and nitrate levels were measured at baseline and after each treatment phase. Brachial artery diameters remained unchanged after each treatment phase. HRT significantly improved FMD compared to both baseline and to T and DHEAS therapies while no effect of T or DHEAS on FMD was noted. In conclusion, HRT, but neither T nor DHEAS, improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk of CAD.

Effects of low-dose, continuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women.

Sleep disturbances in peri- and postmenopausal women may result from hormonal changes, vasomotor symptoms, and possibly psychological factors. Hormone replacement therapy (HRT) seems to diminish the disruption of sleep in climacteric women. The aim of this study was to determine the effects of a low dose of conjugated equine estrogens (CE) in combination with different progestins (LD-HRT) and evaluate differences between regimens on sleep in symptomatic postmenopausal women. Postmenopausal women were recruited and assigned to calcium-vitamin (control group) or to LD-HRT with 0.3mg of CE associated with a daily administration at bedtime of a progestin (2.5 mg MPA, CE + MPA, n = 20), or 100 mg natural micronized progesterone (CE + P, n = 20). Subjective symptoms were evaluated by the Greene climacteric scale, and by a visuanalogic graduated scale (0-10) at baseline and after 4, 8, and 12 weeks of study. Greene's scores for the control group were similar to those in LD-HRT group at baseline, and showed no significant modification at all subsequent measurements. Conversely, in LD-HRT group, a significant (P < 0.05) reduction in the scores of all Greene's domains was evident versus corresponding baseline and control group values. Conversely, in LD-HRT group, a significant (P < 0.05) reduction in the scores of all Greene's domains was evident with no difference in the scores of the two treated group. Both CE + MPA and CE + P significantly (P = 0.05) reduced the HF and sleep visuanalogic score in comparison to the control group. The score of sleep was significantly (P = 0.05) lower in the CE + P group in comparison to that measured in the CE + MPA group. No significant correlation between sleep and vasomotor score was found. In conclusion, low estrogen dose may have a value in the treatment of menopausal women in which sleep disturbances may be a symptom of estrogen deprivation. Low-dose estrogen associated with low-dose micronized progesterone may especially benefit women who complain of disturbed sleep.

Effects of oral contraceptives on bone mineral density.

Osteoporosis is a major health problem that leads to a high incidence of spine, radial, and hip fractures. It is now well recognized that a chronically hypoestrogenic state increases bone turnover that, in turn, causes a critical decrease in bone mineral density (BMD), an important determinant of fracture risk. During the premenopausal period, hypogonadism can have deleterious effects on skeletal health by reducing peak bone mass or inducing precocious bone loss. In young women, hypothalamic amenorrhea, caused by gonadotropin-releasing hormone pulsatility dysregulation, is often associated with bone loss. Although the relationship between hypothalamic amenorrhea and bone density is not completely understood, the most plausible intervention for this disorder at the moment seems to be the use of hormone replacement. Oral contraceptives are associated with an improvement in BMD if assumed upon the onset of anovulatory cycles and, therefore, estrogen deficiency, but confer no benefit in healthy women with normal ovarian function. In perimenopausal oligomenorrheic women, the use of oral contraceptives seems to have bone-sparing effects. In conclusion, the protective role of oral contraceptives on bone density is biologically plausible, since this treatment represents a replacement therapy with continuous exposure to exogenous estrogens.

Hormonal influence on the central nervous system.

Sex steroids play a very important role in female neurobiology. Postmenopausal gonadal hormone withdrawal seem to be of critical importance in mood disorders, reduced libido and cognitive disturbances, which accompany this phase of a woman's life. Clinical studies have demonstrated that central nervous system (CNS) effects of estrogens are not only limited to resolution of vasomotor instability, they are extended to psychological disturbances like depression, behavioral changes and cognitive dysfunction. Progestins, on the other hand, may have variable effects on the brain, occasionally inducing dysphoric mood and altered behavior. Although their use in hormone replacement therapy (HRT) is widely debated, androgens may help resolve changes in libido experienced by many women after the menopause. It is still, however, difficult to draw guidelines on the use of HRT and postmenopausal CNS disorders as studies present up to date have been carried out with different kinds of molecules and routes of administration. Further studies are required in order to explain the specific role of endogenous and exogenous sex steroids on the CNS.

Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women.

OBJECTIVES: To describe the effects of low dose hormonal replacement therapy (LD-HRT) on quality of life in early postmenopausal women, since the postmenopausal estrogen deprivation in mid age women often brings along a series of changes and symptoms, which may greatly affect quality of life. METHODS: Fifty normal postmenopausal women were recruited and randomly treated with LD-HRT, 17beta-estradiol (1 mg/day) and norethisterone acetate (0.5 mg/day) (LD-HRT) or calcium supplement (controls). No significant differences in age, age at menopause, the presence of chronic diseases and socio-economic status were present in the two groups. The Women's Health Questionnaire (WHQ), a validated quality-of-life instrument for perimenopausal and postmenopausal women, was administered at baseline and after 6 and 12 weeks of treatment in both groups. RESULTS: At baseline no significant differences in WHQ scores were present in the two groups. In the control group the scores in all different areas showed no significant modification either after 6 and 12 weeks of observation. Conversely, the LD-HRT group showed a significant decrease in the scores of vasomotor symptoms, somatic symptoms, anxiety/fear, depressed mood and sleep problem items. No effects on memory/concentration and menstrual symptoms areas were evident. CONCLUSION: Although quality of life is also and may be mainly influenced by socio-economic and cultural factors, LD-HRT definitively can improve not only vasomotor symptoms, but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women.

Postmenopausal femur bone loss: effects of a low dose hormone replacement therapy.

OBJECTIVES: Previous studies indicate that low-dose hormone replacement therapy (LD-HRT) can relieve vasomotor symptoms and prevent spine bone loss. METHODS: In the present study, we evaluated the effects of a low dose of conjugated equine estrogens (CEE; 0.3 mg) associated with different progestins in continuous combined scheme [2.5 mg of medroxyprogesterone acetate (n=25), 5 mg dydrogesterone (n=27), 2.5 mg nomegestrol (n=11)] as single group, on femur bone mineral density (BMD) and bone metabolism in young postmenopausal women (

Dydrogesterone does not reverse the effects of estradiol on endothelium-dependant vasodilation in postmenopausal women: a randomised clinical trial.

OBJECTIVES: The purpose of this study was to evaluate endothelium-dependent flow-mediated dilation (FMD) in the brachial artery and the plasma levels of endothelin-1 in postmenopausal women at risk for coronary artery disease before and after treatment with both estradiol and estradiol plus dydrogesterone. METHODS: Sixteen postmenopausal women (PMW) (mean age 58+/-9 years) with more than two risk factors for coronary artery disease, were randomized to receive either oral estradiol (2 mg) for 28 days or oral estradiol (2 mg) for 14 days and oral estradiol (2 mg) and dydrogesterone (10 mg) for 14 days, in a double-blind, placebo-controlled, single cross-over study. Patients were crossed-over the complementary treatment 7 days after completing the first treatment. The study of forearm blood flow and the measurement of plasma endothelin-1 levels was carried out before and after each treatment. RESULTS: Estradiol significantly increased FMD as compared to baseline; the addition of dydrogesterone did not affect the effect of estradiol on FMD. Similarly reactive hyperemic flow increased after estradiol alone or in association with dydrogesterone compared to baseline. Plasma levels of endothelin-1 were significantly reduced by estradiol both when administered alone or in association with dydrogesterone. CONCLUSIONS: Hormone replacement therapy with estradiol and dydrogesterone improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk for coronary artery disease.

Female infertility related to thyroid autoimmunity: the ovarian follicle hypothesis.

PROBLEM: The aim of this study was to verify whether anti-thyroid antibodies are present in the follicular milieu of euthyroid infertile women with thyroid autoimmunity undergoing in vitro fertilization (IVF) and whether IVF outcome is different in affected women with respect to negative controls. A secondary endpoint was to check whether there are changes in thyroid hormone levels during the IVF cycle. METHOD OF STUDY: Anti-thyroglobulin and anti-thyroperoxidase levels were measured in both follicular fluid and serum on the day of oocyte retrieval in women with thyroid autoimmunity. Serum TSH, FT3, and FT4 levels were measured in all patients before treatment initiation, on the day of oocyte retrieval and of pregnancy test. IVF outcome parameters were recorded in all women. RESULTS: Oocyte fertilization, grade A embryos, and pregnancy rates were lower in women with thyroid autoimmunity than in negative controls, while early miscarriage rate was higher. Anti-thyroid antibodies were measurable in follicular fluid in all affected women and were strongly correlated with serum levels. No significant changes in thyroid hormone levels were recorded in any women. CONCLUSION: The presence of anti-thyroid antibodies in ovarian follicles, as demonstrated for the first time in this study, may play a critical role in female infertility related to thyroid autoimmunity.

Pharmacotherapy of ovarian hyperstimulation syndrome.

IMPORTANCE OF THE FIELD: One of the main objectives in assisted reproduction techiques (ART) is the maturation of multiple follicles and the recovery of multiple good quality oocytes. To realize this, it is necessary to interfere with the mechanisms of selection and follicular dominance, characteristic of spontaneous mono-ovulatory cycles, by administering gonadotrophins. In 12 - 20% of the stimulation cycles, the response to ovarian stimulation in terms of follicular development is higher than expected, with the onset of the so-called ovarian hyperstimulation syndrome (OHSS). This is considered to be an exaggerated response: an iatrogenic - possibly life-threatening - complication of ovarian stimulation. AREAS COVERED IN THIS REVIEW: This review deals about reproductive, obstetric and gynecological aspects of OHSS. WHAT THE READER WILL GAIN: Understanding the pathophysiology of OHSS is the key to establishing a correct pharmacotherapy. However, the mechanisms underlying OHSS have not yet been completely clarified. Treatment of OHSS is empirical, so prevention is the most important aspect in its management. Several studies support the role of vascular endothelial growth factor in the development of OHSS in humans, so future studies about anti-angiogenetic molecules seem to be an important goal in ART. TAKE HOME MESSAGE: Methods to prevent OHSS.

Follicular fluid VEGF levels directly correlate with perifollicular blood flow in normoresponder patients undergoing IVF.

BACKGROUND: It has become increasingly clear that the follicular microenvironment of the maturing human oocyte is a determining factor for the implantation potential of an embryo deriving from that oocyte. Indeed the quality and maturity of an oocyte are influenced by the level of intrafollicular oxygen content which, in turn, is proportional to the degree of follicular vascularity. The aim of the study was to establish whether there is a relationship between follicular fluid VEGF concentrations, perifollicular vascularity and reproductive outcome in normal responders under the age of 35 undergoing IVF. MATERIALS AND METHODS: Sixty-one consecutive patients, all at their first IVF cycle, were included in the study. All patients had primary infertility due to male factor or tubal factor. At oocyte retrieval, the perifollicular vascularity of two follicles per ovary was estimated qualitatively through power Doppler blood flow, for a total of two hundred forty-four follicles. The follicular fluid from the identified follicles was centrifuged and stored until VEGF assay. The maturity and fertilization rate of the corresponding oocytes as well as embryo quality and pregnancy rate were recorded. RESULTS: In our study, we found VEGF levels to be significantly correlated with grade of perifollicular vascularity. Oocytes obtained from follicles with the higher grade of vascularization also showed a higher rate of fertilization, embryos, a better quality and higher pregnancy rates were obtained in women with highly vascularized follicles. Perifollicular blood flow doppler indices seem to predict oocyte viability and quality. Moreover, VEGF may play a potential role in the development of the perifollicular capillary network. DISCUSSION: The ability of a given follicle to express VEGF and develop an adequate vascular network may be inter-related in patients under the age of 35. An adequate blood supply may be fundamental important in the regulation of intrafollicular oxygen levels and the determination of oocyte quality.

Cellular and molecular aspects of ovarian follicle ageing.

It is well established that age-related decline of the biological capacity of a woman to reproduce is primarily related to the poor developmental potential of her gametes. This renders female ageing the most significant determinant of success in IVF. Starting with a reference picture of the main molecular and cellular failures of aged oocytes, granulosa cells and follicular microenvironment, this review focuses on age-related biochemical mechanisms underlying these changes. According to the most relevant concept of ageing, age-associated malfuction results from physiological accumulation of irreparable damage to biomolecules as an unavoidable side effect of normal metabolism. More than a decade after the free radical theory of ovarian ageing, biological and clinical research supporting the involvement of oxidative injuries in follicle ageing is discussed. Looking for the aetiology of oxidative stress, we consider the effect of ageing on ovarian and follicular vascularization. Then, we propose a potential role of advanced glycation end-products known to be involved in the physiological ageing of most tissues and organs. We conclude that future investigation of age-related molecular damage in the different ovarian components will be imperative in order to evaluate the possibility to save or rescue the developmental potential of aged oocytes.