William C. Dodson

Superovulation with intrauterine insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization

In vitro fertilization and embryo transfer (IVF-ET) and gamete intrafallopian transfer (GIFT) are used to treat intractable infertility in women with no distortion of the pelvic viscera, despite the lack of controlled trials demonstrating efficacy. The mechanism of any purportedly enhanced cycle fecundity in ovulatory women without significant distortion of the pelvic viscera is unclear, but both GIFT and IVF-ET increase the number of male and female gametes at the site of fertilization. Intrauterine insemination (IUI) during human menopausal gonadotropin (hMG)-stimulated superovulatory cycles has similar potential but does not require oocyte retrieval. To evaluate the possibility that simply increasing the number of gametes at the site of fertilization might account for pregnancies attributed to IVF-ET and GIFT, the authors retrospectively analyzed the outcome of couples undergoing IUI during hMG cycles between 1983 and 1986 in women with normal pelvic anatomy. IUI during hMG-stimulated cycles yielded a cycle fecundity (f) of 0.17 for endometriosis, 0.29 for cervical factor, and 0.19 for idiopathic infertility, which approaches the fecundity of normal women and equals or exceeds that reported for IVF-ET and GIFT. The authors conclude that treatment with IUI in hMG cycles, alleviating the need for invasive oocyte retrieval, should be considered for inclusion in a randomized, controlled trial in comparison with IVF-ET and GIFT.

Diminished paternity and gonadal function with increasing obesity in men

OBJECTIVE To examine the relationship of male obesity and reproductive function. DESIGN Observational study. SETTING Academic medical center. PATIENT(S) Eighty-seven adult men, body mass index (BMI) range from 16.1 to 47.0 kg/m(2) (mean = 29.3 kg/m(2); SD = 6.5 kg/m(2)). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Reproductive history, physical examination, inhibin B, FSH, LH, T, and unbound T levels, and semen analysis. RESULT(S) Body mass index was negatively correlated with testosterone (r = -0.38), FSH (r = -0.22), and inhibin B levels (r = -0.21) and was positively correlated with E(2) levels (r = 0.34). Testosterone also negatively correlated with skinfold thickness (r = -0.30). There was no correlation of BMI or skinfold thickness with semen analysis parameters (sperm density, volume, motility, or morphology). Inhibin B level correlated significantly with sperm motility (r = 0.23). Men with paternity had lower BMIs (28.0 kg/m(2) vs. 31.6 kg/m(2)) and lower skinfold thickness (24.7 mm vs. 34.1 mm) than men without. CONCLUSION(S) Obesity is an infertility factor in otherwise normal men. Obese men demonstrate a relative hypogonadotropic hypogonadism. Reduced inhibin B levels and diminished paternity suggest compromised reproductive capacity in this population.

Relationship of laparoscopic findings to self-report of pelvic pain

An assessment battery including standardized measures of behavioral and psychosocial factors associated with other chronic pain conditions was administered to 102 women scheduled for laparoscopic surgery. Surgeons who were blinded to the patients self-reported pain data completed the American Fertility Society classification for endometriosis and adhesions on the basis of observed physical disease. Although American Fertility Society classification scores were significantly related to self-assignment into pain or no-pain groups, the extent of physical disease evaluated by this procedure was not significantly correlated with ratings of pain levels or a number of indexes of impairment. The group of patients with laparoscopically diagnosed pathologic conditions reported higher pain levels and greater interference than the group who reported pain and had negative laparoscopic results; however, some women with observable pathologic conditions reported no pain symptoms.

The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study

OBJECTIVE To determine if the combination of lifestyle (caloric restriction and exercise) and metformin (MET) would be superior to lifestyle and placebo (PBO) in improving the polycystic ovary syndrome (PCOS) phenotype. DESIGN Double-blind randomized 6-month trial of MET versus PBO. SETTING Two academic medical centers. PATIENT(S) One hundred fourteen subjects with PCOS were randomized to MET (N = 55) or PBO (N = 59). INTERVENTION(S) Subjects collected urine daily for ovulation monitoring, had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry, glucose tolerance, and were evaluated for quality of life at baseline and completion. MAIN OUTCOME MEASURE(S) Ovulation rates and testosterone levels. RESULT(S) Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 months compared with baseline (-3.4 kg, 95% confidence interval -5.3 to -1.5 kg). We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density increased significantly in MET. There were no differences in quality of life measures between the groups. The MET group had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints. CONCLUSION(S) The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS, although our study had limited power owing to a high dropout rate. It is not possible at baseline to identify women likely to drop out.

Effects of Gastric Bypass Surgery on Female Reproductive Function

CONTEXT Reproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear. OBJECTIVE The objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery. DESIGN This was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery. SETTING The study was conducted at an academic health center. PATIENTS Twenty-nine obese, reproductive-aged women not using confounding medications participated in the study. MAIN OUTCOME MEASURES The primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index. RESULTS Ninety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P < 0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P < 0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P < 0.001), reflecting preferential abdominal fat loss (P < 0.001). Female sexual function improved 28% (P = 0.02) by 12 months. CONCLUSIONS Ovulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.

Inhibition of FSH-stimulated cAMP accumulation and progesterone production by mono(2-ethylhexyl) phthalate in rat granulosa cell cultures

Several phthalate esters are male and female reproductive toxicants in vivo. In the male, mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of di(2-ethylhexyl) phthalate (DEHP), inhibits follicle stimulating hormone (FSH)-stimulated cAMP accumulation in the Sertoli cell in vitro. Since granulosa and Sertoli cells share several structural and functional characteristics, the effect of MEHP on granulosa cell intracellular cAMP accumulation was examined to elucidate a possible mechanism for DEHP reproductive toxicity in females. MEHP (100 microM) reduced FSH-stimulated cAMP accumulation in granulosa cells by 40% after a 24-hr preincubation. Significant inhibition of cAMP accumulation by MEHP occurred by 15 hr and MEHP did not affect the dose of FSH which resulted in half-maximal stimulation. Detailed investigations regarding the mechanism of MEHP inhibition were conducted using cholera toxin, forskolin, and isoproterenol. In contrast to FSH, MEHP did not affect the ability of these compounds to stimulate cAMP accumulation. In addition, a functional endpoint of granulosa cell function, progesterone production, was inhibited in a dose-dependent manner by MEHP. Further experiments will be necessary to determine the significance of these findings to in vivo toxicity, but these experiments describe a specific site of action of MEHP in vitro which may be related to the in vivo female reproductive toxicity of phthalate esters.

Associations of Birthweight and Gestational Age with Reproductive and Metabolic Phenotypes in Women with Polycystic Ovarian Syndrome and Their First-Degree Relatives

CONTEXT Low birthweight has been associated with metabolic and reproductive abnormalities in adults. OBJECTIVE The aim of the study was to examine the relationship between birthweight and gestational age and its association with reproductive and metabolic phenotypes in women with PCOS and their first-degree relatives. DESIGN AND SETTING We conducted a family-based study of PCOS at an academic health center. PATIENTS OR OTHER PARTICIPANTS A total of 1038 individuals (845 females and 193 males) from the cohort and 168 controls participated in the study. MAIN OUTCOME MEASURES The association between birthweight and familial phenotype was measured. RESULTS Self-reported and actual birthweight were highly correlated [Spearman correlation coefficient (r) = 0.81; 95% CI, 0.66, 0.89; P = 0.001) and concordant (concordance correlation coefficient = 0.86; 95% lower limit = 0.78). We noted that birthweight for both genders in PCOS families and controls fell within the 10th and 90th percentiles for gestational age based on U.S. population norms. The 50th percentiles for a gestational age of 40 wk were very similar (3409 g in PCOS, 3455 g for controls, and 3495 g for the United States). There were no significant associations between phenotype and birthweight in PCOS probands. Furthermore, there were not any significant relationships between phenotype and birthweight in female or male family members of the PCOS probands. CONCLUSIONS Birthweight in PCOS families mirrors control and U.S. population data, even corrected for gestational age, and has no substantive association with reproductive and metabolic abnormalities in women with PCOS, their female relatives, or their male relatives.

Leuprolide acetate: serum and follicular fluid concentrations and effects on human fertilization, embryo growth, and granulosa-lutein cell progesterone accumulation in vitro

Data from various animal models have demonstrated significant extrapituitary effects of gonadotropin-releasing hormone agonists. The purpose of this study was to determine the effects of therapeutic concentrations of leuprolide acetate on human granulosa-lutein cell steroidogenesis, fertilization, and embryo growth rates in vitro. During leuprolide administration, mean serum concentrations of leuprolide were less than 50 ng/ml and were undetectable 48 hours after cessation of administration. There was no effect of leuprolide on progesterone (P) secretion by granulosa-lutein cells cultured in the presence or absence of human chorionic gonadotropin. The effect of leuprolide on embryo growth rates was evaluated with the mouse two-cell embryo culture model and a retrospective review of early embryo growth rates in humans receiving adjunctive leuprolide therapy. There was no measurable effect of leuprolide on early embryo growth in either species. These data indicate that (1) serum and follicular and peritoneal fluid concentrations are undetectable 2 days after discontinuation of leuprolide; (2) there is no measurable effect of leuprolide on human or murine embryo growth rates up to the 8 cell stage in vitro; and (3) there is no measurable effect of leuprolide on granulosa-lutein cell P accumulation.

Clinical characteristics of ovulation induction with human menopausal gonadotropins with and without leuprolide acetate in polycystic ovary syndrome.

Ovulation induction in polycystic ovary syndrome (PCOS) with human menopausal gonadotropins (hMG) results in suboptimal cycle fecundity and frequently is complicated by ovarian hyperstimulation. The use of a gonadotropin releasing-hormone agonist (GnRH-a) with hMG induction of ovulation may improve the therapeutic outcome. In this prospective, randomized trial, 27 women with PCOS underwent a total of 25 cycles of hMG alone and 33 cycles with adjunctive GnRH-a (leuprolide) treatment. Premature luteinization was seen less frequently in the leuprolide-treated cycles than in cycles treated with hMG alone. There were no differences between the treatments in ovarian sensitivity to hMG. Cycle fecundity was 0.16 for hMG alone cycles, and 0.27 for leuprolide with hMG cycles, which were not statistically different. We conclude that the sensitivity of the PCOS ovary to hMG is not affected by 4 weeks of leuprolide pretreatment.

Treatment-independent, treatment-associated, and pregnancies after additional therapy in a program of in vitro fertilization and embryo transfer

Although the technique of in vitro fertilization and embryo transfer (IVF-ET) was developed for couples with untreatable tubal factor infertility, IVF-ET is now being applied to women with other causes of infertility and normal pelvic anatomy. In an effort to determine the treatment-independent pregnancy rate, we retrospectively reviewed the first 245 couples enrolled in the IVF-ET program at Duke University Medical Center. There were 19 treatment-independent pregnancies in 18 women and 3 treatment-associated pregnancies in cycles in which the oocyte retrieval was canceled (in 2 women washed intrauterine insemination was substituted for oocyte retrieval). Six pregnancies were established after an unsuccessful attempt at IVF-ET with additional non-IVF-ET therapy, including washed intrauterine insemination in three couples, and donor insemination in two couples. These observations suggest that (1) a significant number of treatment-independent pregnancies will occur in couples clinically deemed appropriate for IVF-ET, (2) pregnancies can be established in cycles of controlled hyperstimulation without oocyte retrieval, and (3) additional non-IVF-ET therapy can result in pregnancy despite failure of IVF-ET in selected couples.