C. Matthew Peterson

Impact of male obesity on infertility: a critical review of the current literature

OBJECTIVE To evaluate the current understanding of the effects and potential mechanisms of obesity on male fertility. DESIGN Literature review of articles pertaining to obesity and male infertility. RESULT(S) Recent population-based studies suggest an elevated risk for subfertility among couples in which the male partner is obese and an increased likelihood of abnormal semen parameters among heavier men. Male factor infertility is associated with a higher incidence of obesity in the male partner. Obese men exhibit reduced androgen and SHBG levels accompanied by elevated estrogen levels. Reduced inhibin B levels correlate with degree of obesity and are not accompanied by compensatory increases in FSH. This complexly altered reproductive hormonal profile suggests that endocrine dysregulation in obese men may explain the increased risk of altered semen parameters and infertility. Additional features of male obesity that may contribute to an increased risk for infertility are altered retention and metabolism of environmental toxins, altered lifestyle factors, and increased risks for sexual dysfunction. Neither reversibility of obesity-associated male infertility with weight loss nor effective therapeutic interventions have been studied yet. CONCLUSION(S) The increasing prevalence of obesity calls for greater clinician awareness of its effects on fertility, better understanding of underlying mechanisms, and eventually avenues for mitigation or treatment.

Elevated sperm chromosome aneuploidy and apoptosis in patients with unexplained recurrent pregnancy loss.

OBJECTIVE To evaluate sperm chromosome aneuploidy and semen quality in 24 partners of women with unexplained recurrent pregnancy loss and to analyze the data in relation to sperm apoptosis data. METHODS Semen quality parameters and sperm chromosome aneuploidy for chromosomes X, Y, 13, 18, and 21 were evaluated in the recurrent pregnancy loss patients, fertile controls, and a control group of men from the general population. RESULTS The mean aneuploidy rate in the recurrent pregnancy loss group was 2.77 ± 0.22, significantly higher (P < .005) than in either the general population (1.48 ± 0.12) or in fertile (1.19 ± 0.11) control groups. In the recurrent pregnancy loss patients, the percentage of aneuploid sperm was correlated to the percentage of apoptotic sperm (r = .62, P < .001). Normal morphology was diminished in the patient group, compared with the general population group (P < .01) and the donor group (P < .001). CONCLUSION These data indicate that some recurrent pregnancy loss patients have a significant increase of sperm chromosome aneuploidy, apoptosis, and abnormal sperm morphology. This study demonstrates a new possible cause of recurrent pregnancy loss.

Comparative analysis of follicle morphology and oocyte diameter in four mammalian species (mouse, hamster, pig, and human)

Background Laboratory animals are commonly used for evaluating the physiological properties of the mammalian ovarian follicle and the enclosed oocyte. The use of different species to determine the morphological relationship between the follicle and oocyte has led to a recognizable pattern of follicular stages, but differences in follicle size, oocyte diameter and granulosa cell proliferation are not consistent across the different species. In an effort to better understand how these differences are expressed across multiple species, this investigation evaluates oocyte and follicle diameters and granulosa cell proliferation in the mouse, hamster, pig, and human. Methods Histological sections of ovaries from the mouse, hamster, pig, and human were used to calculate the diameter of the oocyte and follicle and the number of granulosa cells present at pre-determined stages of follicular development. A statistical analysis of these data was performed to determine the relationship of follicular growth and development within and between the species tested. Results These data have revealed that the relationships of the features listed are tightly regulated within each species, but they vary between the species studied. Conclusion This information may be useful for comparative studies conducted in different animal models and the human.

Body mass index is inversely related to intra-follicular HCG concentrations, embryo quality and IVF outcome

Decreased periovulatory human chorionic gonadotrophin (HCG) concentrations have been shown to be associated with diminished fertilization rates. This study evaluated if intra-follicular HCG concentration may be related to body mass in 247 IVF patients using their own oocytes and 58 patients receiving donor oocytes, and evaluated if such a relationship might affect IVF outcome. A significant inverse correlation (r = -0.353, P < 0.001) was observed between the body mass index (BMI) and intra-follicular HCG concentration. The mean HCG concentrations were significantly decreased (P < 0.001) in patients with a BMI >30 kg/m(2) compared with patients with a BMI of 20-30 kg/m(2) or BMI <20 kg/m(2) (17.6 versus 45.1 and 52.5%, respectively). The clinical pregnancy rates (P < 0.001) and embryo quality (P < 0.05) were significantly different for the three groups. In donor oocyte recipients, the pregnancy rate was significantly decreased (P < 0.0001) for recipients with a BMI >25 kg/m(2) compared with those with a BMI from 21-25 kg/m(2) and BMI <21 kg/m(2) (43.8 versus 72 and 76.5%, respectively). These data indicate that intra-follicular HCG concentration is inversely related to BMI, and may be related to a concurrent decrease in embryo quality and pregnancy rates.

In vitro fertilisation. A review of drug therapy and clinical management.

SummarySince the first in vitro fertilisation (IVF) pregnancy was delivered in 1978, this procedure has resulted in thousands of pregnancies and opened a vast new frontier of research and treatment for the infertile couple. Pregnancy rates with IVF improve as the number of high quality embryos available for transfer increases; therefore, ovarian stimulation agents to produce multiple oocytes for IVF are advantageous. Clomifene (clomiphene citrate), human menopausal gonadotrophin (hMG; menotropins), and subsequent generations of products are commonly used as stimulation agents. In conjunction with the stimulation agents, gonadotrophin-releasing hormone (GnRH) agonists and human chorionic gonadotrophin (hCG) serve as adjuvants for successful control of all events in the induction process. Clomifene, an estrogen agonist/antagonist, occupies the estrogen receptor for a longer period of time than estrogen (weeks versus hours). Because this signal is interpreted as low estrogen, GnRH is released, which produces a rise in circulating levels of follicle-stimulating hormone (FSH) and luteinising hormone (LH) and subsequent ovarian follicular development.Menotropins is collected by passing urine from menopausal donors over a Sepharose column, followed by removal of high molecular weight impurities by chromatography. The mixture of FSH and LH is biologically standardised. This product stimulates multiple ovarian follicular development. Urofollitrophin is produced using antibodies to hCG anchored to a separation column. LH then can be excluded from the eluate by binding to the hCG antibodies (LH immunoaffinity column). Highly purified FSH is obtained by passing menopausal urine over a column with monoclonal antibodies to FSH. The isolated FSH is then eluted from the column by a highly basic solution and crystallised. This product delivers FSH at a 90% purity and can be administered subcutaneously rather than intramuscularly. Dosage is standardised on a mg/kg basis. Recombinant human FSH is completely free of LH and offers the advantages of better batch consistency, greater purity, and absence of any human contaminants. It may be given both subcutaneously and intravenously. Genetically engineered FSH combines portions of the native protein with another protein (hCG) which enhances its potency and extends the half-life compared with wild-type FSH. Short, medium and ultra-long activity analogues of genetically engineered FSH may be used to tailor stimulation protocols in various clinical situations.Growth hormone is an adjuvant to ovarian stimulation which results in a decreased number of ampoules of menotropins being required to achieve ovulation in poor responders. Ovulation triggers include both hCG and GnRH agonists. Progesterone supplementation is generally used in the luteal phase of the IVF cycle and is administered by intramuscular injection or vaginal suppository.It appears that conscious sedation with midazolam, pethidine (meperidine) and fentanyl is nontoxic for oocyte recovery. If full anaesthesia is required for gamete intrafallopian tube transfer (GIFT) or zygote intrafallopian tube transfer (ZIFT), balanced anaesthesia with nitrous oxide and an opioid appears to be the most appealing option.Appropriate information on the clinical use of the drugs used in IVF greatly reduces patient stress associated with the complex multidrug regimens associated with the procedure.

Metabolic parameter, bleeding, and weight changes in U.S. women using progestin only contraceptives

Our objective was to determine the effect of progestin-only contraceptives on metabolic parameters, bleeding patterns, and weight changes during the first year of use. Seventy-one women (> 95% Caucasian), who were advised regarding contraception alternatives, self-selected levonorgestrel implants (n = 44), depo-medroxyprogesterone acetate (n = 22), or oral norethindrone (n = 5). One year later, 11 levonorgestrel implant and five depomedroxyprogesterone acetate patients were randomly selected to compare (pre- and post-progestin use) levels of cholesterol, triglycerides, low density lipoprotein (LDL), high density lipoprotein (HDL), very low density lipoprotein (VLDL), apolipoproteins A-1 and B-100, bilirubin, and sex hormone binding globulin. Monthly bleeding and spotting records were kept in each group. Body weights were also monitored in each group. No statistically significant differences in metabolic parameters were found between pre- and post-progestin use in the levonorgestrel implant and depo-medroxyprogesterone acetate groups. Continued bleeding patterns were more prominent in the levonorgestrel implant and oral norethindrone groups than in patients receiving depo-medroxyprogesterone acetate. No significant weight gain was detected in any group. No changes in metabolic parameters or weight were noted over the one year of use of levonorgestrel implants or depo-medroxyprogesterone acetate. Depo-medroxyprogesterone acetate had the highest incidence of amenorrhea.

Biodistribution of free and N-(2-hydroxypropyl)methacrylamide copolymer-bound mesochlorin e6 and adriamycin in nude mice bearing human ovarian carcinoma OVCAR-3 xenografts

The purpose of this study was to examine the biodistribution of the photosensitizing drug, mesochlorin e(6) monoethylenediamine (Mce(6)), and the antineoplastic agent, adriamycin (ADR), as well as their N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates in female nu/nu athymic mice bearing human ovarian carcinoma OVCAR-3 xenografts. The levels of Mce(6) and HPMA copolymer-bound Mce(6) in tissues were assayed spectrophotometrically, while the levels of ADR and HPMA copolymer-bound ADR were determined using high-performance liquid chromatography. It appeared that the circulation lifetimes of HPMA copolymer-bound Mce(6) and ADR were three times more than those of the drugs in the free form. The concentrations of the HPMA copolymer-conjugated drugs in tumor reached maximum levels 18 h post injection. Intravenous injection routinely gave higher tissue levels of the drugs than intraperitoneal administration at time intervals less than 24 h. The biodistribution of the HPMA copolymer-bound drugs in tumor-bearing mice was significantly different from that of the free drugs, which is important in optimizing the treatment protocols. In particular, the HPMA copolymer-conjugated drugs accumulated at significantly higher levels in tumor tissues. This effect is attributed to the increased vascular permeability and reduced lymphatic drainage characteristic of tumor tissues [enhanced permeability and retention (EPR) effect].

Leiomyomatosis peritonealis disseminata treated with a gonadotropin-releasing hormone agonist

To our knowledge, this is the first report of documented growth regression of leiomyomatosis peritonei while the patient was receiving a gonadotropin-releasing hormone agonist. This further documents the role of gonadal steroids in the growth of this tumor.

The transcription factor C/EBP-beta and its role in ovarian function; evidence for direct involvement in the ovulatory process.

Gonadotropins are responsible for maturation of the ovarian follicle and the oocyte. Ovulation is the ultimate step in this process and involves disintegration of the follicular wall and subsequent release of an oocyte into the oviduct. These events are triggered by a surge of luteinizing hormone (LH). Genes expressed in the ovary, that respond to LH, are likely to be involved in the biochemical pathways that regulate ovulation. The transcription factor C/EBP‐β is induced promptly in the ovary, as a response to an ovulatory dose of gonadotropins. We used an ex vivo perfusion system to demonstrate that a specific reduction in ovarian C/EBP‐β expression inhibits ovulation. In such ovaries the oocytes appeared to be entrapped within the follicle. We have found a correlation between the expression level of the activating isoform of C/EBP‐β and the number of oocytes ovulated in response to gonadotropins. Since a reduction in C/EBP‐β expression does not affect the level of the ovulatory mediator prostaglandin endoperoxide synthase‐2 (PGS‐2), these findings support the view of C/EBP‐β as an important factor in the ovulatory process and highlight a C/EBP‐β‐dependent and PGS‐2‐independent pathway that takes part in regulation of ovulation.

The angiotensin II antagonist saralasin inhibits ovulation in the perfused rat ovary

OBJECTIVE Our null hypothesis was that the angiotensin II antagonist saralasin does not reduce the number of ovulations in the rat ovarian perfusion model. STUDY DESIGN Ovaries from pregnant mares serum gonadotropin-stimulated immature rats were perfused with nutrient media to which luteinizing hormone and 3-isobutyl-1-methylxanthine had been added to induce ovulation. Test perfusions were treated with saralasin 1 mumol/L (n = 0.5) and compared with controls (n = 5) with the Student t test. Perfusions with both saralasin and angiotensin II and dose-response evaluations were performed. RESULTS Saralasin-treated ovulations were 6.6 +/- 1.3 (mean + SEM) compared with 18.6 +/- 3.9, p < 0.02. The effects of saralasin could be reversed with the addition of an equimolar amount of angiotensin II. Dose-response evaluations showed a progressive inhibition of ovulation at 10(-8) to 10(-6) mol/L. CONCLUSION The angiotensin II antagonist saralasin inhibits ovulation in a dose-dependent fashion; this effect is canceled by the addition of equimolar concentrations of angiotensin II.