Intracytoplasmic sperm injection 30 years on: too much of a good thing?

Intracytoplasmic sperm injection (ICSI) was introduced for male infertility but is now used in many other techniques in assisted reproduction. Indications for ICSI use need to be re-evaluated to ensure appropriate application in infertility management.

Adipocyte and steroidogenic cell cross-talk in polycystic ovary syndrome.

BACKGROUND: Metabolic and endocrine alterations in women with polycystic ovary syndrome (PCOS) affect adipose tissue mass and distribution. PCOS is characterised by hyperandrogenism, obesity and adipocyte dysfunction. Hyperandrogenism in PCOS drives dysfunctional adipocyte secretion of potentially harmful adipocytokines. Glucocorticoids and sex-steroids modulate adipocyte development and function. For their part, adipocyte products interact with adrenal and ovarian steroidogenic cells. Currently, the relationship between adipocyte and steroidogenic cells is not clear, and for these reasons, it is important to elucidate the interrelationship between these cells in women with and without PCOS. OBJECTIVE AND RATIONALE: This comprehensive review aims to assess current knowledge regarding the interrelationship between adipocytes and adrenal and ovarian steroidogenic cells in animal models and humans with or without PCOS. SEARCH METHODS: We searched for articles published in English and Portuguese in PubMed. Keywords were as follows: polycystic ovary syndrome, steroidogenesis, adrenal glands, theca cells, granulosa cells, adipocytes, adipocytokines, obesity, enzyme activation, and cytochrome P450 enzymes. We expanded the search into the references from the retrieved articles. OUTCOMES: Glucocorticoids and sex-steroids modulate adipocyte differentiation and function. Dysfunctional adipocyte products play important roles in the metabolic and endocrine pathways in animals and women with PCOS. Most adipokines participate in the regulation of the hypothalamic-pituitary-adrenal and ovarian axes. In animal models of PCOS, hyperinsulinemia and poor fertility are common; various adipokines modulate ovarian steroidogenesis, depending on the species. Women with PCOS secrete unbalanced levels of adipocyte products, characterised by higher levels of leptin and lower levels of adiponectin. Leptin expression positively correlates with body mass index, waist/hip ratio and levels of total cholesterol, triglyceride, luteinising hormone, oestradiol and androgens. Leptin inhibits the production of oestradiol and, in granulosa cells, may modulate 17-hydroxylase and aromatase enzyme activities. Adiponectin levels negatively correlate with fat mass, body mass index, waist-hip ratio, glucose, insulin and triglycerides, and decrease androgen production by altering expression of luteinising hormone receptor, steroidogenic acute regulatory protein, cholesterol-side-chain cleavage enzyme and 17-hydroxylase. Resistin expression positively correlates with body mass index and testosterone, and promotes the expression of 17-hydroxylase enzyme in theca cells. The potential benefits of adipokines in the treatment of women with PCOS require more investigation. WIDER IMPLICATIONS: The current data regarding the relationship between adipocyte products and steroidogenic cells are conflicting in animals and humans. Polycystic ovary syndrome is an excellent model to investigate the interrelationship among adipocyte and steroidogenic cells. Women with PCOS manifest some pathological conditions associated with hyperandrogenism and adipocyte products. In animals, cross-talk between cells may vary according to species, and the current review suggests opportunities to test new medications to prevent or even reverse several harmful sequelae of PCOS in humans. Further studies are required to investigate the possible therapeutic application of adipokines in women with obese and non-obese PCOS. Meanwhile, when appropriate, metformin use alone, or associated with flutamide, may be considered for therapeutic purposes.

Should Subclinical Hypothyroidism Be an Exclusion Criterion for the Diagnosis of Polycystic Ovary Syndrome?

BACKGROUND: The purpose of the study was to examine whether patients with subclinical hypothyroidism (SCH) should be excluded before making a diagnosis of polycystic ovary syndrome (PCOS). METHODS: Seven hundred sixteen patients, 462 with true PCOS, 31 with PCOS-SCH, and 223 normal cycling women were enrolled. Clinical, metabolic, and hormonal parameters among the groups were investigated. Continuous variables were compared by one-way analysis of variance. Proportions were compared using Z test. Fisher test was used to compare categorical variables. Simple correlation was performed using Spearman's coefficient. Correlation between thyroid stimulating hormone (TSH) and dependent variables were performed using backward multiple regression. The significance level was set at 0.05. RESULTS: True polycystic ovary and polycystic ovary with subclinical hypothyroidism patients presented similar anthropometrical parameters. C-peptide was higher in polycystic ovary patients than in the other groups (p=0.014). Prevalence of glucose intolerance (p=0.186) and insulin resistance (p=0.293) was not statistically different in polycystic ovary and polycystic ovary with subclinical hypothyroidism. TSH levels showed positive correlation with lean body mass (p=0.032), total cholesterol (p=0.046, insulin (p=0.048) and prolactin (p=0.047). Backward multiple regression model retained TC, insulin, and PRL as predictors of TSH levels (p=0.011). CONCLUSION: Anthropometric parameters and ovary morphology were similar in both PCOS and PCOS-with-SCH patients. Regarding hormones, only C-peptide was higher in PCOS group. TSH correlated with total cholesterol, insulin, and prolactin. Before PCOS diagnosis, the exclusion criterion thyroid dysfunction should be standardized and subclinical hypothyroidism should not exclude a diagnosis of PCOS.

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.

Formas moleculares da gonadotrofina coriônica humana: características, ensaios e uso clínico / Molecular forms of human chorionic gonadotropin: characteristics, assays and clinical use

A gonadotrofina coriônica humana (hCG) é estruturada pela combinação não covalente de duas subunidades, alfa (alfahCG) e beta (betahCG), sintetizadas separadamente pelo tecido trofoblástico normal, mola hidatiforme, coriocarcinoma, células hipofisárias e tecidos tumorais de diversos tipos histológicos. A síntese da cadeia peptídica e sua glicosilação na célula secretora envolve complexa ação de várias enzimas. Esta complexidade resulta na secreção de moléculas heterogêneas. As diferentes formas moleculares secretadas podem ser encontradas no soro, urina e líquido amniótico de gestantes; soro, urina e vesículas em pacientes com mola hidatiforme ou coriocarcinoma e em fluidos biológicos de mulheres não grávidas e homens normais ou acometidos de tumores de diferente origem embrionária. Tanto a molécula hCG nativa, intacta,como suas subunidades nas formas livres e as variantes hCG hiperglicosilada (H-hCG), hCG clivada (N-hCG) e fragmento-núcleo de betahCG (CF-betahCG) têm aplicabilidade clínica relevante. Dependendo da forma molecular mais prevalente ou da proporção da molécula variante/molécula hCG intacta numa determinada condição clínica, há indicação para a dosagem específica de uma ou mais destas moléculas. Este texto revê o conhecimento básico e analisa o uso da hCG e suas variantes na detecção precoce da gravidez ectópica ou gestantes em risco de abortamento, na identificação precoce de anomalias cromossômicas êmbrio-fetais e estima o risco da gestação de evoluir com pré-eclâmpsia ou crescimento intra-uterino restrito. Examina, ainda, fora da gravidez, o emprego destas moléculas como marcadores laboratoriais de tumores com diferentes tipos histológicos e seguimento após a terapia inicial. Conclui-se ser útil o uso da dosagem de hCG e suas moléculas variantes na prática clínica, mas a dificuldade no desenvolvimento e obtenção de ensaios mais sensíveis e específicos restringe a aplicação mais universal destes marcadores hormonais.

The human chorionic gonadotropin (hCG) results from a non-covalent linkage of two subunits, alpha (alphahCG) and beta (betahCG), separately synthesized by normal trophoblastic tissue, hydatiform mole, choriocarcinoma, pituitary cells, and tumoral tissues of different histologic types. The peptide chain and its further glycosylation in the secretory cell involves the complex action of different enzymes. This complexity results in the secretion of heterogeneous molecular forms. The different molecules might be found in serum, urine and amniotic fluid of pregnant women; serum, urine, and vesicles of patients with hydatiform mole or choriocarcinoma and in other biological fluids of normal non-pregnant women and men or patients with different embryonary types of cancer. Both the intact hCG molecule and its free subunits and the hyperglycosylated (H-hCG), nicked (N-hCG) and core fragment of betahCG (CF- betahCG) variant forms have relevant clinical use. Depending on the prevalent molecular form or the proportion of the variant form to the intact hCG in a determined clinical situation the measurement of a specific molecule is chosen. This review analyzes the clinical use of hCG and its related molecules in the early detection of ectopic pregnancy or patients with higher risk of abortion, in the identification of an embryo or fetus with chromosomal abnormalities, and in the evaluation of risk for preeclampsia or fetal growth restriction. The review also examines the use of hCG and variant forms as tumor markers. It is concluded that it is useful to measure hCG and/or related molecules in clinical practice, but difficulties in developing and achievement of more sensitive and specific new assays limit their use.