Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys.

Study question: Do naturally occurring, hyperandrogenic (≥1 SD of population mean testosterone, T) female rhesus monkeys exhibit traits typical of women with polycystic ovary syndrome (PCOS)? Summary answer: Hyperandrogenic female monkeys exhibited significantly increased serum levels of androstenedione (A4), 17-hydroxyprogesterone (17-OHP), estradiol (E2), LH, antimullerian hormone (AMH), cortisol, 11-deoxycortisol and corticosterone, as well as increased uterine endometrial thickness and evidence of reduced fertility, all traits associated with PCOS. What is known already: Progress in treating women with PCOS is limited by incomplete knowledge of its pathogenesis and the absence of naturally occurring PCOS in animal models. A female macaque monkey, however, with naturally occurring hyperandrogenism, anovulation and polyfollicular ovaries, accompanied by insulin resistance, increased adiposity and endometrial hyperplasia, suggests naturally occurring origins for PCOS in nonhuman primates. Study design, size, duration: As part of a larger study, circulating serum concentrations of selected pituitary, ovarian and adrenal hormones, together with fasted insulin and glucose levels, were determined in a single, morning blood sample obtained from 120 apparently healthy, ovary-intact, adult female rhesus monkeys (Macaca mulatta) while not pregnant or nursing. The monkeys were then sedated for somatometric and ultrasonographic measurements. Participants/materials, setting, methods: Female monkeys were of prime reproductive age (7.2 ± 0.1 years, mean ± SEM) and represented a typical spectrum of adult body weight (7.4 ± 0.2 kg; maximum 12.5, minimum 4.6 kg). Females were defined as having normal (n = 99) or high T levels (n = 21; ≥1 SD above the overall mean, 0.31 ng/ml). Electronic health records provided menstrual and fecundity histories. Steroid hormones were determined by tandem LC-MS-MS; AMH was measured by enzymeimmunoassay; LH, FSH and insulin were determined by radioimmunoassay; and glucose was read by glucose meter. Most analyses were limited to 80 females (60 normal T, 20 high T) in the follicular phase of a menstrual cycle or anovulatory period (serum progesterone <1 ng/ml). Main results and the role of chance: Of 80 monkeys, 15% (n = 12) exhibited classifiable PCOS-like phenotypes. High T females demonstrated elevations in serum levels of LH (P < 0.036), AMH (P < 0.021), A4 (P < 0.0001), 17-OHP (P < 0.008), E2 (P < 0.023), glucocorticoids (P < 0.02-0.0001), the serum T/E2 ratio (P < 0.03) and uterine endometrial thickness (P < 0.014) compared to normal T females. Within the high T group alone, anogenital distance, a biomarker for fetal T exposure, positively correlated (P < 0.015) with serum A4 levels, while clitoral volume, a biomarker for prior T exposure, positively correlated (P < 0.002) with postnatal age. Only high T females demonstrated positive correlations between serum LH, and both T and A4. Five of six (83%) high T females with serum T ≥2 SD above T mean (0.41 ng/ml) did not produce live offspring. Large scale data: N/A. Limitations, reasons for caution: This is an initial study of a single laboratory population in a single nonhuman primate species. While two biomarkers suggest lifelong hyperandrogenism, phenotypic expression during gestation, prepuberty, adolescence, mid-to-late reproductive years and postmenopause has yet to be determined. Wider implications of the findings: Characterizing adult female monkeys with naturally occurring hyperandrogenism has identified individuals with high LH and AMH combined with infertility, suggesting developmental linkage among traits with endemic origins beyond humans. PCOS may thus be an ancient phenotype, as previously proposed, with a definable pathogenic mechanism(s). Study funding/competing interest(s): Funded by competitive supplement to P51 OD011106 (PI: Mallick), by P50 HD028934 (PI: Marshall) and by P50 HD044405 (PI: Dunaif). The authors have no potential conflicts of interest.

Early prenatal androgenization results in diminished ovarian reserve in adult female rhesus monkeys.

BACKGROUND: Early prenatal androgenization (PA) accelerates follicle differentiation and impairs embryogenesis in adult female rhesus monkeys (Macaca mulatta) undergoing FSH therapy for IVF. To determine whether androgen excess in utero affects follicle development over time, this study examines whether PA exposure, beginning at gestational days 40-44 (early treated) or 100-115 (late treated), alters the decline in serum anti-Mullerian hormone (AMH) levels with age in adult female rhesus monkeys and perturbs their ovarian response to recombinant human FSH (rhFSH) therapy for IVF. METHODS: Thirteen normal (control), 11 early-treated and 6 late-treated PA adult female monkeys had serum AMH levels measured at random times of the menstrual cycle or anovulatory period. Using some of the same animals, basal serum AMH, gonadotrophins and steroids were also measured in six normal, five early-treated and three late-treated PA female monkeys undergoing FSH therapy for IVF during late-reproductive life (>17 years); serum AMH also was measured on day of HCG administration and at oocyte retrieval. RESULTS: Serum AMH levels in early-treated PA females declined with age to levels that were significantly lower than those of normal (P < or = 0.05) and late-treated PA females (P < or = 0.025) by late-reproductive life. Serum AMH levels positively predicted numbers of total/mature oocytes retrieved, with early-treated PA females having the lowest serum AMH levels, fewest oocytes retrieved and lowest percentage of females with fertilized oocytes that cleaved. CONCLUSIONS: Based on these animals, early PA appears to program an exaggerated decline in ovarian reserve with age, suggesting that epigenetically induced hormonal factors during fetal development may influence the cohort size of ovarian follicles after birth.

Prenatal androgen excess negatively impacts body fat distribution in a nonhuman primate model of polycystic ovary syndrome.

INTRODUCTION: Prenatally androgenized (PA) female rhesus monkeys share metabolic abnormalities in common with polycystic ovary syndrome (PCOS) women. Early gestation exposure (E) results in insulin resistance, impaired pancreatic beta-cell function and type 2 diabetes, while late gestation exposure (L) results in supranormal insulin sensitivity that declines with increasing body mass index (BMI). OBJECTIVE: To determine whether PA females have altered body fat distribution. DESIGN: Five early-treated PA (EPA), five late-treated PA (LPA) and five control adult female monkeys underwent somatometrics, dual-X-ray absorptiometry (DXA) and abdominal computed tomography (CT). Five control and five EPA females underwent an intravenous glucose tolerance test to assess the relationship between body composition and glucoregulation. RESULTS: There were no differences in age, weight, BMI or somatometrics. LPA females had approximately 20% greater DXA-determined total fat and percent body fat, as well as total and percent abdominal fat than EPA or control females (P< or =0.05). LPA females also had approximately 40% more CT-determined non-visceral abdominal fat than EPA or control females (P< or =0.05). The volume of visceral fat was similar among the three groups. EPA (R (2)=0.94, P< or =0.01) and LPA (R (2)=0.53, P=0.16) females had a positive relationship between visceral fat and BMI, although not significant for LPA females. Conversely, control females had a positive relationship between non-visceral fat and BMI (R (2)=0.98, P< or =0.001). There was a positive relationship between basal insulin and total body (R (2)=0.95, P< or =0.007), total abdominal (R (2)=0.81, P< or =0.04) and visceral (R (2)=0.82, P< or =0.03) fat quantities in EPA, but not control females. CONCLUSIONS: Prenatal androgenization in female rhesus monkeys induces adiposity-dependent visceral fat accumulation, and late gestation androgenization causes increased total body and non-visceral fat mass. Early gestation androgenization induces visceral fat-dependent hyperinsulinemia. The relationship between the timing of prenatal androgen exposure and body composition phenotypes in this nonhuman primate model for PCOS may provide insight into the heterogeneity of metabolic defects found in PCOS women.

Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

Treatment of atypical endometrial hyperplasia with an insulin-sensitizing agent.

Endometrial cancer and hyperplasia have long been associated with diabetes. Hyperinsulinemia may have a direct mitogenic effect on the endometrium and may inhibit the effect of progestogen therapy. This case report describes the treatment of a patient with atypical endometrial hyperplasia with an insulin-sensitizing agent. A 37-year-old patient presented after failed treatment of endometrial hyperplasia with progestogen therapy. One month after initiating metformin therapy the patient's endometrial biopsy demonstrated proliferative endometrium. This patient's atypical endometrial hyperplasia regressed after the initiation of treatment with an insulin-sensitizing agent. This relatively new class of drugs may provide an adjunct to the therapy of endometrial hyperplasia.

False-positive Y-microdeletion result for a fertile male caused by an alteration under a PCR primer.

The pathogenic relationship between the presence of Y chromosomal microdeletions and male infertility is unclear. Nevertheless, a causal relationship is thought to be probable when loci are shown to be deleted in infertile males but are present in fertile males. Polymerase chain reaction (PCR) analysis of the Y chromosome is now routinely performed in the evaluation of the infertile male, although, until recently, there has been no consensus on how the diagnosis should be performed and which loci or markers should be analysed. The European Academy of Andrology (EAA) published guidelines for the molecular diagnosis of Y chromosomal microdeletions in 1999. Following these guidelines, our laboratory developed assays that incorporated the suggested primer pairs for the recommended Sequence Tagged Sites (STS). A number of fertile (n = 117), infertile (n = 17) and unknown samples (n = 20) were tested in our laboratory as part of the validation to provide a clinical assay. Two multiplex PCR assays were optimized, each of which examined STS markers in the centre of the AZFa, b and c regions of the Y chromosome. We correctly identified all but one of the 154 samples (according to the expected result based on fertility or previous testing at another laboratory). A single equivocal result was observed for a sample obtained from a known fertile male who appeared to be deleted for a single marker, sY84, in the AZFa region but not the adjacent marker, sY86. Follow-up analysis showed that proximal and distal markers within the same region (sY82 and sY98) were also present. Sequencing the region flanking and including the sY84 primer set revealed a single base alteration under the reverse primer, which probably caused the amplification failure. Furthermore, the sY84 sequence itself was present, as was the flanking sequence 50 bp on either side of both primers. This observation underlines the importance of using at least two closely linked STS markers for the reliable diagnosis of Y chromosome microdeletions as proposed by the EAA guidelines.

Developmental origin of polycystic ovary syndrome - a hypothesis.

Polycystic ovary syndrome (PCOS) is a common but complex endocrine disorder and is a major cause of anovulation and consequent subfertility. It is also associated with a metabolic disturbance, characterized by hyperinsulinaemia and insulin resistance that carries an increased risk of type 2 diabetes in later life. Despite its prevalence little is known about its aetiology, but there is increasing evidence for an important genetic involvement. On the basis of experimental observations in the prenatally androgenized sheep and rhesus monkey, and supported by data from human studies, we propose that the clinical and biochemical features of PCOS can arise as a consequence of genetically determined hypersecretion of androgens by the ovary during, or very likely long before, puberty. The resulting hyperandrogenism results in 'programming' of the hypothalamic-pituitary unit to favour excess LH secretion, and encourages preferential abdominal adiposity that predisposes to insulin resistance. The severity of hyperinsulinaemia and insulin resistance (which has a profound influence on the phenotype of PCOS) is further influenced by both genetic factors (such as polymorphism in the insulin gene regulatory region) and environmental factors, notably obesity. This hypothesis therefore suggests a unifying, 'linear' model to explain the aetiology of the heterogeneous phenotype.

Retroperitoneal endometriosis causing unilateral hip pain.

BACKGROUND: The usual symptoms of endometriosis are secondary dysmenorrhea, dyspareunia, and infertility, but when located in the retroperitoneal space, it might have atypical symptoms that delay diagnosis and postpone therapy. CASE: A young nulligravida presented with secondary dysmenorrhea and concurrent cyclic hip pain. Recent laparoscopy was reportedly normal. Computed tomography (CT)-directed percutaneous needle biopsy of a retroperitoneal mass showed endometriosis. Laparotomy with retroperitoneal dissection removed the endometriosis, and operative arthroscopy released strictured hip tendons improving her hip pain and limp. CONCLUSION: Retroperitoneal endometriosis presenting as hip pain was diagnosed by CT-guided percutaneous needle biopsy permitting removal by a multidisciplinary surgical approach.

Ovarian morphology and serum hormone markers as predictors of ovarian follicle recruitment by gonadotropins for in vitro fertilization.

Twenty-five normal ovulatory women underwent three-dimensional transvaginal ultrasonography and blood sampling before and after oral glucose tolerance testing to compare ovarian morphology and circulating hormone levels in the early follicular phase as predictors of the number of oocytes retrieved after gonadotropin stimulation for in vitro fertilization. Serum levels of gonadotropins, inhibins, testosterone, dehydroepiandrosterone sulfate, and estradiol as well as summed ovarian volume were unrelated to oocyte number. Antral follicle number and serum androstenedione level, however, positively correlated, whereas postoral glucose tolerance test (post-OGTT) insulin release negatively correlated, with total and mature oocyte numbers. Adjusting for age and body mass index by regression analysis, the serum androstenedione level significantly predicted mature, but not total, oocyte number. The relationships of antral follicle number and post-OGTT insulin release to total oocyte number were additive; each was significant after controlling for the other. In contrast, antral follicle number significantly correlated with mature oocyte number after controlling for post-OGTT insulin release, whereas post-OGTT insulin release was unrelated to mature oocyte number after controlling for antral follicle number. Therefore, early follicular phase antral follicle number positively correlates with total and mature oocyte numbers after gonadotropin stimulation for in vitro fertilization and is linked to androgen and insulin actions in predicting ovarian follicle recruitment by gonadotropins.

Interstitial heterotopic pregnancy in a woman conceiving by in vitro fertilization after bilateral salpingectomy.

Heterotopic pregnancy, defined as the coexistence of an intrauterine pregnancy and an ectopic pregnancy, occurs in approximately 1 in 100 pregnancies conceived by in vitro fertilization (IVF), particularly when multiple embryos are transferred into the uterus. The ectopic gestation of the combined pregnancy usually occurs within the ampulla of the fallopian tube. If it implants within the interstitial portion of the fallopian tube, however, the resulting interstitial pregnancy eventually can rupture through the uterus, leading to sudden, severe hemorrhage and maternal death. This article describes the rupture of an interstitial heterotopic pregnancy in a 37-year-old woman conceiving by IVF after bilateral salpingectomy. The interstitial pregnancy was removed by laparotomy to protect the intrauterine pregnancy from damage. Physicians should consider interstitial ectopic pregnancy as a cause of abdominal pain, even when a viable pregnancy occurs by IVF after salpingectomy.

Immunolocalization of Fas and Fas ligand in the ovaries of women with polycystic ovary syndrome: relationship to apoptosis.

Both Fas (APO-1, CD95), an apoptosis-inducing receptor, and its ligand, Fas ligand (FasL, CD95L), have been localized to the ovary. Granulosa cell apoptosis occurs in antral follicular atresia. In polycystic ovary syndrome (PCOS), antral follicles accumulate with some atretic features. The ovarian expression of Fas and FasL was examined in PCOS by immunohistochemistry and correlated with immunodetection of apoptotic cells. Fas immunostaining was present in pre-antral follicle oocytes, some primary and secondary pre-antral follicle granulosa cells, and both granulosa and theca of antral follicles. Thecal staining persisted with advancing atresia, while granulosa staining declined. In antral follicles, abundant Fas-positive cells co-localized with scattered nuclei immunopositive for apoptosis. Ovarian vascular myocytes were strongly Fas-immunopositive. FasL immunostaining was present in pre-antral follicles in oocytes and variably in granulosa. In antral follicles, granulosa and thecal FasL staining increased with advancing atresia. Normal control ovaries showed follicular Fas and FasL staining patterns similar to those in PCOS, but vascular staining was less prominent. In one healthy follicle, Fas immunostaining was seen in the oocyte and weakly in mural granulosa and theca interna. The results suggest that in PCOS, an alteration in Fas-mediated apoptosis, does not cause abnormal folliculogenesis, but may promote ovarian vascular remodelling.

The effects of tamoxifen on the vaginal epithelium in postmenopausal women.

Although increased vaginal discharge occurs with treatment, clinicians often presume the effects of tamoxifen on the vaginal epithelium are antiestrogenic. We studied 16 postmenopausal women before they began tamoxifen treatment, at 6 months, and then at annual intervals for up to 6 years. Vaginal scrapings for cytology smears and maturation values (MV) for these were performed. MV scores increased by a mean of 32% and these were predictably related to baseline values, with greater increases seen when there were lower scores before treatment. Only one woman with an MV of 0 before treatment had no significant changes with 3 years' treatment. The effects of tamoxifen on the vaginal epithelium are influenced by the baseline hormonal milieu and are maturational in the majority of postmenopausal women.

Timing of prenatal androgen excess determines differential impairment in insulin secretion and action in adult female rhesus monkeys.

This study determined whether timing of prenatal androgen excess resulted in differential impairment of insulin-glucose homeostasis in adult female rhesus monkeys. Ten female rhesus monkeys exposed to testosterone propionate starting on gestational day 40 (early treated), 9 females exposed to testosterone propionate starting between gestational days 100-115 (late treated), and 15 control females were studied. The modified minimal model was used to examine various measures derived from an i.v. glucose tolerance test, with regression analysis performed between these variables and body mass index. In addition, the disposition index (DI) and the hyperbolic relationship between insulin sensitivity (S(I)) and acute insulin response to glucose were examined. Early treated females demonstrated impaired pancreatic beta-cell function, as shown by diminished DI and decreased percentile ranking for the hyperbolic relationship between S(I) and acute insulin response to glucose. In contrast, late treated females exhibited both an increase in DI and a negative relationship between body mass index and S(I). These results suggest that prenatal androgen excess in female rhesus monkeys, regardless of gestational timing, perturbs insulin-glucose homeodynamics, with androgen excess in early and late gestation impairing pancreatic beta-cell function and altering insulin sensitivity, respectively.

Embryo cryopreservation at the pronuclear stage and efficient embryo use optimizes the chance for a liveborn infant from a single oocyte retrieval.

OBJECTIVE: To estimate the potential for a liveborn in our program achieved through either fresh or frozen embryos derived from a single oocyte retrieval. DESIGN: Retrospective analysis. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): All consecutive patients undergoing oocyte retrieval from January 1, 1996, to June 30, 1997. INTERVENTION(S): All couples undergoing IVF-ET at our center are counseled about a specific embryo transfer number after oocyte retrieval based on demographic and historical factors. Only this specified number of embryos is retained in culture. All normally fertilized (2PN) oocytes exceeding this number are immediately cryopreserved at the pronuclear stage. For couples who do not conceive after fresh embryo transfers, frozen embryo transfers are subsequently performed by usually thawing only the number of embryos intended for transfer, thereby conserving remaining embryos for further potential frozen embryo cycles. MAIN OUTCOME MEASURE(S): Liveborn delivery per oocyte retrieval.39.0 years were 61.2%, 59.7%, and 18.5%, respectively. CONCLUSION(S): For women <39 years of age, the efficient use of embryo cryopreservation at the pronuclear stage and economical embryo utilization policies results in cumulative chances for a liveborn exceeding 60%.

The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women.

OBJECTIVE: To clarify the effect of estrogen on total plasma homocysteine concentration and on the concentration of vitamins required for homocysteine metabolism (folate, vitamin B12, and vitamin B6). METHODS AND RESULTS: We measured total fasting plasma homocysteine in 16 healthy postmenopausal women before and 6 hours after a methionine load (100 mg/kg); fasting concentrations of folate, vitamin B12, vitamin B6, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were also determined. After 6 months of estrogen replacement therapy with estradiol, 2 mg daily, and 1 cycle of quarterly methoxyprogesterone acetate, 5 mg daily administered on the 91st through 100th days, measurements were repeated. There was no significant change in mean +/- SD fasting homocysteine concentration (8.8+/-2.5 vs 8.5+/-2.0 micromol/L; P=.30); homocysteine concentrations after methionine load increased from 38.8+/-12.3 to 51.1+/-12.5 micromol/L (P=.01). During this time period, no significant changes occurred in the concentrations of folate (11.7+/-4.4 vs 9.8+/-4.1 nmol/L; P=.06), vitamin B12 (394+/-182 vs 411+/-155 pmol/L; P=.40), or vitamin B6 (pyridoxal phosphate) (26+/-21 vs 36+/-25 nmol/L; P=.15). The mean +/- SD concentration of low-density cholesterol declined 20% (from 147+/-32 to 118+/-37 mg/dL) and high-density lipoprotein increased 16% (from 40+/-13 to 46+/-19 mg/dL) during the study period. CONCLUSIONS: Six months of estrogen replacement therapy did not lower fasting plasma total homocysteine concentrations and raised homocysteine concentrations following a methionine load. Lipid profiles improved significantly during the study period. A reduction in homocysteine concentrations is not likely to contribute to the reduction in cardiovascular events seen with estrogen replacement therapy.

Pronuclear stage cryopreservation after intracytoplasmic sperm injection and conventional IVF: implications for timing of the freeze.

OBJECTIVE: To compare clinical outcomes of frozen embryo transfers using cryopreserved pronuclear stage oocytes that had undergone either intracytoplasmic sperm injection (ICSI) or conventional IVF. DESIGN: Observational. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): Couples undergoing either ICSI or conventional IVF from January 1, 1995 to December 31, 1997. INTERVENTION(S): Patients underwent a standard controlled ovarian hyperstimulation protocol and transvaginal ultrasound-guided oocyte retrieval. All normally fertilized (2PN) oocytes exceeding a specified embryo number designated for fresh transfer were immediately cryopreserved at the pronuclear stage. Our cryopreservation method included timing of the freeze according to pronuclear morphology. Subsequent frozen embryo thaw-transfer cycles were usually performed by thawing only the intended number of embryos for transfer. MAIN OUTCOME MEASURE(S): Thaw survival rate, implantation rate, clinical pregnancy rate, delivery rate. RESULT(S): Ninety-six thaw-transfer cycles (n = 72) and 93 thaw-transfer cycles (n = 67) were undertaken in patients who had previously undergone conventional IVF or ICSI, respectively. Embryo thaw survival rates (IVF, 90.4%; ICSI, 91.1%) were similar. Clinical pregnancy (IVF, 40.6%; ICSI, 44.1%) and delivery (IVF, 36.4%; ICSI, 39.8%) rates per transfer, as well as implantation (IVF, 19.1%; ICSI, 19.9%) rates, were also similar. There were only four clinical pregnancy losses in both groups. CONCLUSION(S): Embryo thaw survival is similar for cryopreserved pronuclear stage oocytes derived from ICSI and conventional IVF. Clinical pregnancy, implantation and delivery rates were also similar for the two groups. In addition, there was no increase in the rate of pregnancy loss in ICSI patients after frozen embryo transfers.

Crinone 8% vaginal progesterone gel results in lower embryonic implantation efficiency after in vitro fertilization-embryo transfer.

OBJECTIVE: To evaluate the outcome of IVF-ET after the use of Crinone 8% (Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA) vaginal progesterone gel and to compare these results with those seen in our program with the use of IM progesterone-in-oil. DESIGN: Retrospective cohort study. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): Patients <40 years of age undergoing IVF-ET cycles. INTERVENTION(S): Patients were treated with either Crinone 8% vaginal progesterone gel (90 mg) administered daily or IM progesterone-in-oil (50 mg) administered daily. MAIN OUTCOME MEASURE(S): Biochemical pregnancy rate, implantation rate, and clinical and ongoing pregnancy rates. RESULT(S): The use of Crinone 8% vaginal progesterone gel was associated with a lower implantation rate (16.6% versus 26.2%; odds ratio [OR] = 0.56; 95% confidence interval [CI], 0.35-0.89) compared with the use of IM progesterone-in-oil. Biochemical pregnancies were more common after the use of Crinone 8% vaginal progesterone gel as defined by either biochemical pregnancies per transfer (15.9% versus 5.7%; OR = 3.11; 95% CI, 1.17-8.32) or biochemical pregnancies as a proportion of positive serum hCG titers (29.2% versus 9.8%; OR = 3.80; 95% CI, 1.33-10.86). Clinical pregnancy rates also were lower with the use of Crinone 8% vaginal progesterone gel (36.4% versus 52.9%; OR = 0.51; 95% CI, 0.26-0.99). CONCLUSION(S): Implantation efficiency is reduced, as demonstrated by lower embryonic implantation rates and higher biochemical pregnancy rates, when Crinone 8% vaginal progesterone gel rather than IM progesterone-in-oil is used for luteal phase support after IVF-ET.

Insulin action during variable hyperglycemic-hyperinsulinemic infusions in hyperandrogenic anovulatory patients and healthy women.

OBJECTIVE: To determine whether 3-month GnRH analogue (GnRH-a) administration to hyperandrogenic anovulatory patients and healthy women affects glucose utilization or endogenous glucose production (EGP) in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions. DESIGN: Prospective, nonrandomized study. SETTING: Academic research environment. PATIENT(S): Twelve hyperandrogenic anovulatory patients and 11 healthy women matched by body mass index and waist to hip circumference ratio. INTERVENTION(S): Variable hyperglycemic-hyperinsulinemic infusions replicated physiological increases in circulating glucose and insulin levels before and after 3-month GnRH-a administration. MAIN OUTCOME MEASURE(S): Glucose utilization and EGP. RESULT(S): In the postabsorptive state, plasma glucose and insulin levels, glucose utilization, and EGP were similar in hyperandrogenic patients and healthy women. During variable hyperglycemic-hyperinsulinemic infusions, glucose use increased and EGP decreased to similar degrees in both groups of women. Three-month GnRH-a administration to hyperandrogenic patients and healthy women did not affect plasma glucose and insulin levels, glucose utilization and EGP in the postabsorptive state, or glucose utilization and EGP during variable hyperglycemic-hyperinsulinemic infusions. CONCLUSION(S): Glucose use and EGP in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions are similar in hyperandrogenic anovulatory patients and healthy women of similar body fat distribution and are unaffected by 3-month GnRH-a administration.