Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data

OBJECTIVE: To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (<= 25 mm) in the midtrimester reduces the risk of preterm birth and improves neonatal morbidity and mortality. STUDY DESIGN: Individual patient data metaanalysis of randomized controlled trials. RESULTS: Five trials of high quality were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth <33 weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42-0.80), <35 weeks (RR, 0.69; 95% CI, 0.55-0.88), and <28 weeks (RR, 0.50; 95% CI, 0.30-0.81); respiratory distress syndrome (RR, 0.48; 95% CI, 0.30-0.76); composite neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40-0.81); birthweight <1500 g (RR, 0.55; 95% CI, 0.38-0.80); admission to neonatal intensive care unit (RR, 0.75; 95% CI, 0.59-0.94); and requirement for mechanical ventilation (RR, 0.66; 95% CI, 0.44-0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies. CONCLUSION: Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduces the risk of preterm birth and neonatal morbidity and mortality.

Effects of metoclopramide-induced hyperprolactinemia on the prolactin receptor of murine endometrium

Objective: To evaluate the effects of metoclopramide-induced hyperprolactinemia, on the prolactin receptor of murine endometrium. Design: Experimental study using the RNA extraction to detect tissue prolactin recepter isoforms by reverse-transcriptase polymerase chain reaction (RT-PCR). Setting: University-based laboratory. Animal(s): Seventy-two female swiss albino mice (Mus musculus), approximately 100 days old, were divided into six 12-animal groups: (Cl) nonoophorectomized mice given vehicle; (GII) nonoophorectomized mice treated with metoclopramide; (Gill) oophorectomized mice treated with metoclopramide; (GIV)oophorectomized mice treated with metoclopramide and 17 beta-estradiol; (GV) oophorectomized mice treated with metoclopramide and micronized progesterone; (GVI) oophorectomized mice treated with metoclopramide and a solution of 17 beta-estradiol and micronized progesterone. Intervention(s): Drugs were administered for 50 days. Following euthanasia, the middle portions of the uterine horns were removed, sectioned, and immediately frozen for RT-PCR procedures. Blood was collected for the dosage of prolactin and serum estrogen and progesterone using radioimmune assay. Main Outcome Measure(s): Identification of uterine prolactin receptor isoforms: Result(s): The PRL receptor and its isoform L were identified only in GI (control group) and GII (metoclopramide), the two groups with nonoophorectomized animals. The amount of PRL receptor mRNA and that of its isoform L from GII were the largest. No other isoforms of the prolactin receptor were identified in any of the groups. Conclusion(s): Our results suggest that replacement of estrogen and progestin may not increase the mRNA of endometrial PRL receptor in metoclopromide-induced hyperprolactinemia in rats after castration. (Fertil Steril (R) 2010;93:1643-9. (C)2010 by American Society for Reproductive Medicine.)

Is breast cancer risk the same for all progestogens?

The population-based case–control study CECILE investigated the impact of various menopausal hormone therapy (MHT) products on breast cancer (BC) risk in 1,555 postmenopausal women [1]. The case group (n = 739) included incident cases of in situ (!) or invasive BC in postmenopausal women. The control group (n = 816) included women from the general population within predefined quotas by age and socio-economic status (SES). While quotas by age were applied to obtain similar distributions by age among controls and among cases, quotas by SES in control women were applied to reflect the distribution by SES of women in the general population in the study area. Data of participants were obtained by a structured questionnaire during in-person interviews, and from pathology reports if applicable, respectively. Women were divided into current and past MHT user. MHTs were classified in estrogen-only therapy (ET), estrogen combined with progestin therapy (EPT) and tibolone. EPT was subdivided in three subtypes according to the progestogen constituent: natural micronized progesterone, progesterone derivatives, and testosterone derivatives. In comparison to never MHT users, any current or past MHT use (ET, EPT, tibolone) was not associated with an increased BC risk. However, in subanalysis BC risk was significantly increased for current use of EPT for 4 or more years (n = 73 cases and n = 56 controls, adjusted OR 1.55; 95 % CI 1.02–2.36). Within the group of current EPT users for 4 or more years, 14 cases had used estrogens combined with micronized progesterone (n = 17 controls), and 55 a combination with a synthetic progestogen (n = 34 controls), respectively. Compared to never MHT use, current use of EPT containing a synthetic progestogen for 4 or more years was associated with a significantly increased BC risk (adjusted OR 2.07; 95 % CI 1.26–3.39), but EPT containing micronized progesterone was not (adjusted OR 0.79; 95 % CI 0.37–1.71). 73 % of current MHT users started treatment within the first year of onset of menopause. Early EPT (n = 52 cases and n = 38 controls, adjusted OR 1.65; 95 % CI 1.02–2.69), but not early ET, starters had a significantly higher BC risk compared to never MHT users. In contrast, MHT initiation beyond 1 year after menopause was not associated with an increased BC risk. The authors concluded that: (1) ET and EPT containing natural progesterone did not increase BC risk whereas, (2) BC risk was increased in users of tibolone or EPT containing a synthetic progestogen, respectively, and that (3) MHT use early after onset of menopause was associated with an increased BC risk as compared to women who delay MHT beyond 1 or more years.

Modulation of small leucine-rich proteoglycans (SLRPs) expression in the mouse uterus by estradiol and progesterone

Background: We have previously demonstrated that four members of the family of small leucine-rich-proteoglycans (SLRPs) of the extracellular matrix (ECM), named decorin, biglycan, lumican and fibromodulin, are deeply remodeled in mouse uterine tissues along the estrous cycle and early pregnancy. It is known that the combined action of estrogen (E2) and progesterone (P4) orchestrates the estrous cycle and prepares the endometrium for pregnancy, modulating synthesis, deposition and degradation of various molecules. Indeed, we showed that versican, another proteoglycan of the ECM, is under hormonal control in the uterine tissues. Methods: E2 and/or medroxiprogesterone acetate (MPA) were used to demonstrate, by real time PCR and immunoperoxidase staining, respectively, their effects on mRNA expression and protein deposition of these SLRPs, in the uterine tissues. Results: Decorin and lumican were constitutively expressed and deposited in the ECM in the absence of the ovarian hormones, whereas deposition of biglycan and fibromodulin were abolished from the uterine ECM in the non-treated group. Interestingly, ovariectomy promoted an increase in decorin, lumican and fibromodulin mRNA levels, while biglycan mRNA conspicuously decreased. Hormone replacement with E2 and/or MPA differentially modulates their expression and deposition. Conclusions: The patterns of expression of these SLRPs in the uterine tissues were found to be hormone-dependent and uterine compartment-related. These results reinforce the existence of subpopulations of endometrial fibroblasts, localized into distinct functional uterine compartments, resembling the organization into basal and functional layers of the human endometrium.

Progesterone, estrogen and pregnancy do not decrease colon myoelectric activity in rats: An in vivo study

Background: Progesterone, estrogen and the hormonal complex of pregnancy have been responsible for some degree of colon hypomotility in human pregnancy. Objective: To find out if estrogen, progesterone and the hormonal complex of pregnancy decrease colon myoelectric activity. Methods: The study was performed in 37 healthy female rats in which electrodes were implanted on the serosa of the proximal ascendent, distal ascendent, transverse, and descendent colon. We analyzed the records of colon myoelectric activity in vivo in five groups: control, ovariectomized, ovariectomized and treated with estrogen, ovariectomized and treated with progesterone, and pregnant rats. Results: We found a great variation in myoelectric activity in all groups studied. The mean of electric activity did not show statistical difference among the five groups, but pregnant rats had a statistically significant higher duration of maximum electric activity in all distances from the cecocolon junction. Conclusion: Pregnant rats had a statistically higher duration of maximum electric activity. If we could transpose these results to humans, this increase in duration of colon myoelectric activity could explain, in part, the slight constipation that some pregnant women have. Copyright (C) 2008 S. Karger AG, Basel.

Prematurity prevention: the role of progesterone

Purpose of review This review summarizes the evidence of the effectiveness of progesterone on the rate of preterm birth and evaluates the most recent studies. Recent findings The incidence of preterm delivery is about 7-11% of all pregnant women and preterm birth is one of the most important causes of neonatal morbidity and mortality. Interventions to reduce such complications have been attempted for several years. Most efforts so far have been tertiary interventions, such as treatment with antenatal corticosteroids, tocolytic agents, and antibiotics. Some of these measures have reduced perinatal morbidity and mortality, but the incidence of preterm birth is increasing. Recently, researches have suggested prophylactic progesterone could reduce the preterm birth rate in a select group presenting previous preterm birth and a short cervical length by transvaginal scan at mid-trimester pregnancy. Summary This review intends to define the current indication for administration of progesterone for pregnant women. On the basis of current knowledge, progesterone should be offered to women with a documented history of a previous spontaneous birth at less than 37 weeks and for those found to have a short cervical length of 15 mm or less. Studies are needed to evaluate progesterone efficacy on other risk factors.

Effect of peritoneal fluid from patients with minimal/mild endometriosis on progesterone release by human granulosa-lutein cells obtained from infertile patients without endometriosis: A pilot study

Objective: To evaluate the effect of peritoneal fluid (PF) from women without and with minimal/mild endometriosis on progesterone (P) release by cultured human granulosa-lutein cells obtained from infertile patients without endometriosis submitted to ovarian hyperstimulation for in vitro fertilization (IVF). Study design: A pilot study was performed. Human granulosa-lutein cells, obtained from 11 infertile patients without endometriosis (tubal or male factors of infertility) submitted to ovarian hyperstimulation for IVF, were cultured without PF (basal production) and with increasing volumes of steroid-extracted PF samples from 11 patients with endometriosis and 11 patients without endometriosis. Progesterone (P) levels in the media after 72 h culture were measured by chemoluminescence assay. The non-parametric Mann-Whitney-test was used for statistical analysis. Results: PF from patients without endometriosis stimulated P release in a dose-dependent manner up to the dose of 100 mu l/ml (10% concentration) when compared with basal production (without adding PF). P release was similar in cultures stimulated with PF from patients with or without endometriosis at 1% (10 mu l/ml) and 5% (50 ml/ml) concentrations. At 10% concentration, there was a non-statistically significant reduction in progesterone release by granulosa cells stimulated with PF from patients with endometriosis. PF from patients with endometriosis significantly reduced P release at 30% concentration (300 mu l/ml). Conclusions: PF stimulates P release by human granulosa-lutein cells in a dose-dependent manner. However, higher concentrations of PF from patients with minimal/mild endometriosis reduce P release, suggesting it contains factors that may compromise ovarian steroidogenesis. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

LC-MS/MS quantitation of plasma progesterone in cattle

Quantitation of progesterone (P(4)) in biological fluids is often performed by radioimmunoassay (RIA), whereas liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has been used much less often. Due to its autoconfirmatory nature, LC-MS/MS greatly minimizes false positives and interference. Herein we report and compare with RIA an optimized LC-MS/MS method for rapid, efficient, and cost-effective quantitation of P(4) in plasma of cattle with no sample derivatization. The quantitation of plasma P(4) released from three nonbiodegradable, commercial, intravaginal P(4)-releasing devices (IPRD) over 192 h in six ovariectomized cows was compared in a pairwise study as a test case. Both techniques showed similar P(4) kinetics (P > 0.05) whereas results of P(4) quantitation by RIA were consistently higher compared with LC-MS/MS (P < 0.05) due to interference and matrix effects. The LC-MS/MS method was validated according to the recommended analytical standards and displayed P(4) limits of detection (LOD) and quantitation (LOQ) of 0.08 and a 0.25 ng/mL, respectively. The high selective LC-MS/MS method proposed herein for P(4) quantitation eliminates the risks associated with radioactive handling; it also requires no sample derivatization, which is a common requirement for LC-MS/MS quantitation of steroid hormones. Its application to multisteroid assays is also viable, and it is envisaged that it may provide a gold standard technique for hormone quantitation in animal reproductive science studies. (C) 2011 Elsevier Inc. All rights reserved.

13,14-Dihydro-15-Keto Prostaglandin F(2)alpha Release in Response to Oxytocin Challenge Early Post-Partum in Anoestrous Nelore Cows Submitted to Temporary Calf Removal and Progesterone Priming

The study evaluated, in early post-partum anoestrous Nelore cows, if the increase in plasma oestradiol (E2) concentrations in the pre-ovulatory period and/or progesterone priming (P4 priming) preceding ovulation, induced by hormonal treatment, reduces the endogenous release of prostaglandin PGF(2)alpha and prevents premature lysis of the corpus luteum (CL). Nelore cows were subjected to temporary calf removal for 48 h and divided into two groups: GPE/eCG group (n = 10) and GPG/eCG group (n = 10). Animals of the GPE/eCG group were treated with a GnRH agonist. Seven days later, they received 400 ID of eCG, immediately after PGF(2)alpha treatment, and on day 0, 1.0 mg of oestradiol benzoate (EB). Cows of the GPG/eCG group were similarly treated as those of the GPE/eCG group, except that EB was replaced with a second dose of GnRH. All animals were challenged with oxytocin (OT) 9, 12, 15 and 18 days after EB or GnRH administration and blood samples were collected before and 30 min after OT. Irrespective of the treatments, a decline in P4 concentration on day 18 was observed for cows without P4 priming. However, animals exposed to P4 priming, treated with EB maintained high P4 concentrations (8.8 +/- 1.2 ng/ml), whereas there was a decline in P4 on day 18 (2.1 +/- 1.0 ng/ml) for cows that received GnRH to induce ovulation (p < 0.01). Production of 13,14-dihydro-15-keto prostaglandin F(2)alpha (PGFM) in response to OT increased between days 9 and 18 (p < 0.01), and this increase tended to be more evident in animals not exposed to P4 priming (p < 0.06). In conclusion, the increase in E2 during the pre-ovulatory period was not effective in inhibiting PGFM release, which was lower in P4-primed than in non-primed animals. Treatment with EB promoted the maintenance of elevated P4 concentrations 18 days after ovulation in P4-primed animals, indicating a possible beneficial effect of hormone protocols containing EB in animals with P4 priming.

Elevated progesterone concentrations enhance prostaglandin F(2 alpha) synthesis in dairy cows

The objective was to evaluate the influence of varying plasma progesterone (P(4)) concentrations throughout the luteal phase in dairy cows on PGF(2 alpha) production (assessed as plasma concentrations of 13,14-dihydro-15-keto-PGF(2 alpha); PGFM) following treatment with estradiol-17 beta (E(2)) or oxytocin (OT). In all experiments, time of ovulations was synchronized with the OvSynch protocol and Day 0 corresponded to day of second GnRH injection. In Experiment 1, non-lactating dairy cows on Day 6 remained non-treated (n = 9), received 20 mg LH (n = 7), or had ovarian follicles larger than 6 mm aspirated (n = 8). In Experiment 2, cows on Day 6 were untreated (n = 9) or received 5000 IU hCG (n = 10). In Experiments 1 and 2, all cows received 3 mg E(2) on Day 17, and blood samples were collected every 30 min from 2h before to 10h after E(2). Experiment 3 was conducted in two periods, each from Days 0 to 17 of the estrous cycle. At the end of Period 1, animals switched treatments in a crossover arrangement. Animals in Group 2/8 (n = 4) received 2 kg/d of concentrate in the first period and 8 kg/d in the second period. Animals in Group 8/2 (n = 7) received the alternate sequence. Blood was collected daily for measurement Of P(4) 4 h after concentrate feeding. On Day 17, blood was collected from 1 h before to 1 h after a 100 IU OT injection. In Experiment 1, both plasma P(4) and release Of PGF(2 alpha) were similar between LH-treated and control cows (P > 0.10). In Experiment 2, plasma P4 was elevated to a greater extent on Day 17 in cows treated with hCG (P < 0.05) and plasma PGFM was also greater in hCG-treated animals (treatment x time interaction; P < 0.05). In Experiment 3, there was a group x period interaction (P < 0.01) for plasma P(4), indicating that less concentrate feeding was associated with greater plasma P(4). Release of PGF(2 alpha) in response to OT was greater for cows receiving less concentrate (group x period interaction; P < 0.05). In conclusion, dairy cows with more elevated blood P(4) concentrations released more PGF(2 alpha) in response to E(2) or OT. (c) 2008 Elsevier B.V. All rights reserved.

Oestrogen and Progesterone Receptor Gene Expression in Canine Oocytes and Cumulus Cells Throughout the Oestrous Cycle

The aim of this research was to analyze oestrogen receptor-alpha (ER alpha), ER beta and progesterone receptor (PR) gene expression in the canine oocyte and cumulus cells throughout the oestrous cycle. Ovaries from 38 bitches were recovered after ovariohysterectomy and sliced. The phase of the oestrous cycle was determined by vaginal cytology, vaginoscopy and serum hormonal measurements. Oocytes were mechanically denuded by repeated pipetting. For each phase of the cycle, a sample was composed by a pool of 50 oocytes (sample number: prooestrus = 3, oestrus = 8, dioestrus = 5 and anoestrus = 5) or a pool of cumulus cells (prooestrus = 4, oestrus = 7, dioestrus = 4 and anoestrus = 6). Oocyte and cumulus cells` total RNA was isolated and reverse transcription was conducted to perform real-time PCR. Oestrogen receptor-alpha was expressed throughout the cycle in the oocyte (33.33%, 25.0%, 20.0% and 60.0% for prooestrus, oestrus, dioestrus and anoestrus, respectively) and cumulus cells (50.0%, 47.14%, 25.0% and 66.67% for prooestrus, oestrus, dioestrus and anoestrus, respectively). In the oocyte, the ER beta was also expressed in all phases of the cycle (33.33%, 50.0%, 20.0% and 60.0% for prooestrus, oestrus, dioestrus and anoestrus, respectively), whereas in cumulus cells, ER beta was only expressed during prooestrus (50%) and oestrus (14.29%). Interestingly, while the oocyte PR was not detected in any phase of the cycle, this receptor was expressed during prooestrus (50%), oestrus (42.86%) and anoestrus (16.67%) in cumulus cells. In conclusion, canine oocytes express ER alpha and ER beta throughout the oestrous cycle, however, there is a lack of PR expression in all these phases. Moreover, in cumulus cells, only ER alpha was expressed throughout the oestrous cycle.

Effect of early luteolysis in progesterone-based Al protocols in Bos indicus, Bos indicus x Bos taurus and Bos taurus heifers

The objective of this study was to evaluate the effects of treatment with an intravaginal progesterone-releasing device (CIDR) and estradiol benzoate (EB) on follicular dynamics in Bos indicus (n = 23), Bos taurus (n = 25), and cross-bred (n = 23) heifers. To assess the influence of reduced serum progesterone concentrations during 8 days of treatment with a progesterone-releasing device on follicular dynamics, half of the heifers received PGF at CIDR insertion (Day 0; 3 x 2 factorial design). Mean ( +/- S.E.M.) serum progesterone concentrations during CIDR treatment varied (P < 0.05) among genetic groups: B. indicus (5.4 +/- 0.1 ng/mL), B. taurus (3.3 +/- 0.0 ng/mL), and cross-bred (4.3 +/- 0.1 ng/mL). Maximum diameter of the dominant follicle (DF) was smaller (P < 0.01) in B. indicus heifers (9.5 +/- 0.5 mm) than in cross-bred (12.3 +/- 0.4 mm) or B. taurus heifers (11.6 +/- 0.5 mm). B. indicus experienced lower (P < 0.01) ovulation rate (39.1%) than did B. taurus (72.7%) and cross-bred (84.0%). Heifers treated with PGF on Day 0 had lower (P < 0.05) serum progesterone concentrations during progesterone treatment. The PGF treatment on Day 0 increased (P < 0.01) the diameter of the DF (11.9 +/- 0.4 mm vs. 10.5 +/- 0.4 mm). Moreover, greater (P = 0.02) ovulation rates (78.8 vs. 54.0%) occurred in heifers treated with PGF on Day 0. In summary, B. indicus heifers had greater serum progesterone concentrations, smaller DF diameter, and a lower ovulation rate compared to B. taurus heifers. Prostaglandin treatment on the day of CIDR insertion reduced serum progesterone during treatment, and resulted in increased maximum DF diameter and ovulation rate. (c) 2008 Elsevier Inc. All rights reserved.

Effects of gonadotropin-exposed medium with high concentrations of progesterone and estradiol-17 beta on in vitro maturation of canine oocytes

During the process of maturation in the oviduct, canine oocytes in the germinal vesicle stage are exposed to decreasing levels of estradiol-17 beta and increasing levels of progesterone. However, hormone concentrations in the microenvironments in which they act are higher than serum concentrations. Therefore, the aim of the present study was to compare the meiotic competence of canine oocytes harvested from anestrous bitches in culture medium containing high concentrations (20 mu g ml(-1)) of estradiol-17 beta and/or progesterone in association to gonadotropins (luteinizing hormone and follicle-stimulating hormone) using three different maturation periods (48, 72, and 96 h). Oocytes were cultured in tissue culture medium (TCM-199) and arranged in four experimental groups: group control, group E2 (estradiol-17 beta), group P4 (progesterone), and group E2 + P4. Regardless of the maturation period, groups P4 and E2 + P4 presented statistically higher rate of germinal vesicle breakdown oocytes compared to the group control and group E2. There were no significant differences among groups on germinal vesicle, metaphase I, metaphase II, and degenerated or unidentifiable oocytes rates. The mean percentage of metaphase II oocytes was higher at 96 h when compared to 72 h. Results of the present research indicate no influence of estradiol-17 beta supplementation, unless in association with progesterone. There is an evidence of the positive effect of progesterone on germinal vesicle breakdown. Results also showed that extended periods of in vitro maturation affect positively maturation rates to metaphase II of low competent oocytes harvested from anestrous bitches, independent of the maturation media. In conclusion, high concentrations of steroids, especially progesterone, have positive effect on in vitro oocyte maturation when the oocytes are derived from the anestrous status.

Effects of estrogen receptor alpha and beta gene deletion on estrogenic induction of progesterone receptors in the locus coeruleus in female mice

Locus coeruleus (LC) is involved in the LHRH regulation by gonadal steroids. We investigated the expression of progesterone and estrogen receptors (PR; ER) in LC neurons of ER alpha (alpha ERKO) or ER beta (beta ERKO) knockout mice, and their wild-type (alpha WT and beta WT). Immunocytochemical studies showed that LC expresses PR and both ERs, although ER beta was more abundant. Estradiol benzoate (EB) decreased ER alpha-positive cells in WT and beta ERKO mice, and progesterone caused a further reduction, whereas none of the steroids influenced ER beta expression. ER beta deletion increased ER alpha while ER alpha deletion did not alter ER beta expression. In both WT mice, EB increased PR expression, which was diminished by progesterone. These steroid effects were also observed in alpha ERKO animals but to a lesser extent, suggesting that ER alpha is partially responsible for the estrogenic induction of PR in LC. Steroid effects on PR in beta ERKO mice were similar to those in the alpha ERKO but to a lesser extent, probably because PR expression was already high in the oil-treated group. This expression seems to be specific of LC neurons, since it was not observed in other areas studied, the preoptic area and ventromedial nucleus of hypothalamus. These findings show that LC in mice expresses alpha ER, beta ER, and PR, and that a balance between them may be critical for the physiological control of reproductive function.

No significant association between progesterone receptor exon 4 Val660Leu G/T polymorphism and risk of ovarian cancer

Epidemiological studies suggest that ovarian cancer is an endocrine-related tumour, and progesterone exposure specifically may decrease the risk of ovarian cancer. To assess whether the progesterone receptor (PR) exon 4 valine to leucine amino acid variant is associated with specific tumour characteristics or with overall risk of ovarian cancer, we examined 551 cases of epithelial ovarian cancer and 298 unaffected controls for the underlying G-->T nucleotide substitution polymorphism. Stratification of the ovarian cancer cases according to tumour behaviour (low malignant potential or invasive), histology, grade or stage failed to reveal any heterogeneity with respect to the genotype defined by the PR exon 4 polymorphism. Furthermore, the genotype distribution did not differ significantly between ovarian cancer cases and unaffected controls. Compared with the GG genotype, the age-adjusted odds ratio (95% confidence interval) for risk of ovarian cancer was 0.78 (0.57-1.08) for the GT genotype, and 1.39 (0.47-4.14) for the TT genotype. In conclusion, the PR exon 4 codon 660 leucine variant encoded by the T allele does not appear to be associated with ovarian tumour behaviour, histology, stage or grade. This variant is also not associated with an increased risk of ovarian cancer, and is unlikely to be associated with a large decrease in ovarian cancer risk, although we cannot rule out a moderate inverse association between the GT genotype and ovarian cancer.