[Knowledge, practices and expectations in the management of overactive bladder in general practice and gynecology in France]. / Connaissances, pratiques et attentes pour la prise en charge de l'hyperactivité vésicale en France.

INTRODUCTION: Overactive bladder (OAB) is a clinical syndrome characterized by urgency to urinate, with or without urinary incontinence, often associated with nycturia and pollakiuria. The aim of this practice survey is to identify diagnostic modalities and treatment circuits according to the patient's clinical profile and to practitioner's specialty. MATERIAL AND METHODS: A cross-sectional survey was conducted among 262 physicians practicing in France: 181 general practitioners (GPs) and 81 gynecologists. RESULTS: Urinary disorders were more easily addressed with patients by gynecologists than GPs. Behavioral therapy was the most widely used therapeutic measure, however half of the patients abandoned it. In oldest women and men of all ages, drugs were commonly prescribed, nevertheless only 4 out of 10 patients continued the treatment beyond 6months, according to the physicians. Incontinence was the symptom for which patients were in most need of relief. GPs and gynecologists expressed a need for training, practical tools and recommendations related to OAB. CONCLUSION: Patients and doctors are reluctant to talk about urinary disorders. Non-urologist physicians such as GPs and gynecologists, as health professionals best placed to detect and diagnose OAB, are in demand for training, practical tools and recommendations. LEVEL OF EVIDENCE: 3.

MALDI-TOF MS performance compared to direct examination, culture, and 16S rDNA PCR for the rapid diagnosis of bone and joint infections.

The rapid identification of bacterial species involved in bone and joint infections (BJI) is an important element to optimize the diagnosis and care of patients. The aim of this study was to evaluate the usefulness of matrix-assisted laser desorption ionization mass spectrometry (MALDI-TOF MS) for the rapid diagnosis of bone infections, directly on synovial fluid (SF) or on crushed osteoarticular samples (CS). From January to October 2013, we prospectively analyzed 111 osteoarticular samples (bone and joint samples, BJS) from 78 patients in care at the University Hospital of Rennes, France. The diagnosis procedure leading to the sample collection was linked to a suspicion of infection, inflammatory disease, arthritis, or for any bone or joint abnormalities. Standard bacteriological diagnosis and molecular biology analysis [16S rRNA polymerase chain reaction (PCR) and sequencing] were conducted. In addition, analysis by MALDI-TOF MS was performed directly on the osteoarticular samples, as soon as the amount allowed. Culture, which remains the gold standard for the diagnosis of BJI, has the highest sensitivity (85.9 %) and remains necessary to test antimicrobial susceptibility. The 16S rDNA PCR results were positive in the group with positive BJI (28.6 %) and negative in the group without infection. Direct examination remains insensitive (31.7 %) but more effective than MALDI-TOF MS directly on the sample (6.3 %). The specificity was 100 % in all cases, except for culture (74.5 %). Bacterial culture remains the gold standard, especially enrichment in blood bottles. Direct analysis of bone samples with MALDI-TOF MS is not useful, possibly due to the low inoculum of BJS.

[Screening for carriage of Staphylococcus aureus prior to mammary reconstruction in the prevention of surgical site infection]. / En reconstruction mammaire: intérêt du dépistage du portage de Staphylococcus aureus dans la prévention de l'infection du site opératoire.

The incidence of prosthesis infections after breast reconstruction is of the order of 4% to 13% according to the literature. In surgical patients, Staphylococcus aureus (S. aureus) is the bacterial species most often responsible for surgical site infections. In cardiac surgery, screening for carriage of S. aureus and preoperative decontamination are carried out routinely before prosthetic surgery. We retrospectively reviewed data from patients at our institution between January 2011 and December 2013. Our series showed that the prosthesis infection rates were in the range of 5.92% in 2008 with an ISO rate of S. aureus 3.61%. Routine screening for prosthetic reconstructions was performed to assess the impact of preoperative decontamination patients in carriers of S. aureus. This screening was done in 381 patients: 17.8% of patients were carriers of S. aureus ; 11 patients have an ISO (or an incidence rate of 2.88%) ; 5 patients have an ISO S. aureus (an incidence of S. aureus ISO 1.3%). The introduction of the screening process, allowed a drop of 5.92% ISO rate at 1.46% with a passage of S. aureus SSI rates of 3, 60% to 0.72%. In the near future, studies are needed to confirm these encouraging results, to demonstrate the efficacy of preoperative decontamination in carriers of S. aureus patients before laying prosthesis.

Antibiotic content of selective culture media for isolation of Capnocytophaga species from oral polymicrobial samples.

UNLABELLED: In oral microbiome, because of the abundance of commensal competitive flora, selective media with antibiotics are necessary for the recovery of fastidious Capnocytophaga species. The performances of six culture media (blood agar, chocolate blood agar, VCAT medium, CAPE medium, bacitracin chocolate blood agar and VK medium) were compared with literature data concerning five other media (FAA, LB, TSBV, CapR and TBBP media). To understand variable growth on selective media, the MICs of each antimicrobial agent contained in this different media (colistin, kanamycin, trimethoprim, trimethoprim-sulfamethoxazole, vancomycin, aztreonam and bacitracin) were determined for all Capnocytophaga species. Overall, VCAT medium (Columbia, 10% cooked horse blood, polyvitaminic supplement, 3·75 mg l(-1) of colistin, 1·5 mg l(-1) of trimethoprim, 1 mg l(-1) of vancomycin and 0·5 mg l(-1) of amphotericin B, Oxoid, France) was the more efficient selective medium, with regard to the detection of Capnocytophaga species from oral samples (P < 0·001) and the elimination of commensal clinical species (P < 0·001). The demonstrated superiority of VCAT medium, related to its antibiotic content, made its use indispensable for the optimal isolation of Capnocytophaga species from polymicrobial samples. SIGNIFICANCE AND IMPACT OF THE STUDY: Isolation of Capnocytophaga species is important for the proper diagnosis and treatment of the systemic infections they cause and for epidemiological studies of periodontal flora. We showed that in pure culture, a simple blood agar allowed the growth of all Capnocytophaga species. Nonetheless, in oral samples, because of the abundance of commensal competitive flora, selective media with antibiotics are necessary for the recovery of Capnocytophaga species. The demonstrated superiority of VCAT medium made its use essential for the optimal detection of this bacterial genus. This work showed that extreme caution should be exercised when reporting the isolation of Capnocytophaga species from oral polymicrobial samples, because the culture medium is a determining factor.

Clostridial prosthetic joint infections: A series of 16 cases and literature review.

OBJECTIVES: Prosthetic joint infections (PJIs) due to the Clostridium species have not been widely investigated. We aimed to characterize these uncommon infections. METHODS: We conducted a retrospective study between 2003 and 2020 in six French hospitals combined with a review of the literature. RESULTS: The main conclusions obtained from the 16 patients included were reinforced by the literature analysis: (i) Clostridium perfringens was the most frequently involved species, (ii) patients presented an advanced age at the time of prosthesis placement and infection, (iii) most of the infections were early- or delayed-onset, (iv) the prognosis for these PJIs remains poor, (v) when performed (n = 5), DAIR with 12-week antimicrobial therapy led to a favorable outcome in 80% of cases. CONCLUSIONS: Given the low incidence of this infection, our work represents the largest series of clostridial PJIs reported to date and highlights some specificities of these infections. Further prospective studies are needed to confirm these results.

Bacteroides fragilis prevents Salmonella Heidelberg translocation in co-culture model mimicking intestinal epithelium.

Salmonella Heidelberg is one of the most common serovar causing foodborne illnesses. To limit the development of digestive bacterial infection, food supplements containing probiotic bacteria can be proposed. Commensal non-toxigenic Bacteroides fragilis has recently been suggested as a next-generation probiotic candidate. By using an original triple co-culture model including Caco-2 cells (representing human enterocytes), HT29-MTX (representing mucus-secreting goblet cells), and M cells differentiated from Caco-2 by addition of Raji B lymphocytes, bacterial translocation was evaluated. The data showed that S. Heidelberg could translocate in the triple co-culture model with high efficiency, whereas for B. fragilis a weak translocation was obtained. When cells were exposed to both bacteria, S. Heidelberg translocation was inhibited. The cell-free supernatant of B. fragilis also inhibited S. Heidelberg translocation without impacting epithelial barrier integrity. This supernatant did not affect the growth of S. Heidelberg. The non-toxigenic B. fragilis confers health benefits to the host by reducting bacterial translocation. These results suggested that the multicellular model provides an efficient in vitro model to evaluate the translocation of pathogens and to screen for probiotics that have a potential inhibitory effect on this translocation.

Broad-range 16 s rDNA PCR in synovial fluid does not improve the diagnostic performance of septic arthritis in native joints in adults: cross-sectional single-center study in 95 patients.

OBJECTIVE: To evaluate the diagnostic performance of bacterial identification by broad-range polymerase chain reaction (PCR) of ribosomal DNA (rDNA) 16 s (16S rDNA PCR) for the diagnosis of septic arthritis on native joints. METHODS: Patients with acute mono or oligoarthritis who underwent synovial fluid puncture and prospective follow-up allowing definitive diagnosis (septic arthritis, crystal related disease, chronic inflammatory arthritis, undifferentiated arthritis) were recruited in this single-center study. Systematic analysis of synovial fluid included leukocytes count, search for urate and pyrophosphate crystals with polarized light microscopy, direct bacteriological examination (gram staining), bacteriological culture, and 16S rDNA PCR. RESULTS: Ninety-five patients were included, 34 of which (35.8%) had septic arthritis. Nineteen (20.0%) patients had received probabilistic antibiotic therapy prior to joint puncture. Gram + cocci infection accounted for 79.4% of septic arthritis, of which nearly half (47.1%) was caused by Staphylococcus aureus. Eight (23.5%) septic arthritis patients had a 16S rDNA PCR positive in the synovial fluid with an AUC of 0.618 (95% CI, 0.493-0.742), a sensitivity of 0.24 (95% CI, 0.12-0.40), and a specificity of 1.00 (95% CI 0.94-1.00). The diagnostic performance of 16S rDNA PCR was lower than that of direct examination (AUC at 0.691, CI 95%, 0.570-0.812), blood cultures (AUC at 0.727, CI 95%, 0.610-0.844), and culture (0.925, CI 95%, 0.856-0.994) for the diagnosis of septic arthritis. There was no difference in the positivity of 16S rDNA PCR according to previous exposure to antibiotics. CONCLUSIONS: 16 s rDNA PCR in the synovial fluid does not improve the diagnostic performance of septic arthritis on native adult joints, particularly for Gram-positive cocci infections.

Moxifloxacin-rifampicin combination for the treatment of non-staphylococcal Gram-positive orthopedic implant-related infections.

OBJECTIVE: We aimed to describe the effectiveness and safety of the moxifloxacin-rifampicin combination in non-staphylococcal Gram-positive orthopedic implant-related infections. METHODS: Patients treated with the moxifloxacin-rifampicin combination for an implant-related infection from November 2014 to November 2016 were retrospectively identified from the database of the referral centers for bone and joint infections in Western France. RESULTS: Twenty-three cases of infection due to Streptococcus spp. (n=12), Cutibacteriumacnes (n=6), and Enterococcus faecalis (n=5) were included. Ten patients with hip prosthesis were included. Infection was polymicrobial in 11 cases. According to the MIC, moxifloxacin was 1.5 to 11.7 times as active as levofloxacin against non-staphylococcal Gram-positive bacteria. We reported an 81.8% success rate, and no severe adverse effect. CONCLUSION: The moxifloxacin-rifampicin combination is a valuable alternative for the treatment of non-staphylococcal Gram-positive implant-related infections because of the good activity of moxifloxacin against these bacteria and the potential activity on the biofilm.

Treponema, Iron and Neurodegeneration.

Spirochetes are suspected to be linked to the genesis of neurological diseases, including neurosyphillis or neurodegeneration (ND). Impaired iron homeostasis has been implicated in loss of function in several enzymes requiring iron as a cofactor, formation of toxic oxidative species, inflammation and elevated production of beta-amyloid proteins. This review proposes to discuss the link that may exist between the involvement of Treponema spp. in the genesis or worsening of ND, and iron dyshomeostasis. Proteins secreted by Treponema can act directly on iron metabolism, with hemin binding ability (HbpA and HbpB) and iron reductase able to reduce the central ferric iron of hemin, iron-containing proteins (rubredoxin, neelaredoxin, desulfoferrodoxin metalloproteins, bacterioferritins etc). Treponema can also interact with cellular compounds, especially plasma proteins involved in iron metabolism, contributing to the virulence of the syphilis spirochetes (e.g. treponemal motility and survival). Fibronectin, transferrin and lactoferrin were also shown to be receptors for treponemal adherence to host cells and extracellular matrix. Association between Treponema and iron binding proteins results in iron accumulation and sequestration by Treponema from host macromolecules during systemic and mucosal infections.

Assessment of the automated multiplex-PCR Unyvero i60 ITI® cartridge system to diagnose prosthetic joint infection: a multicentre study.

OBJECTIVES: Prosthetic joint infections (PJI) are responsible for significant morbidity and mortality and their number continues to rise. Their management remains complex, especially the microbiological diagnosis. Besides 'homemade' tests developed by several teams, new molecular biology methods are now available with different analytical performance and usability. METHODS: We studied the performances of one of these tests: ITI® multiplex PCR (mPCR) by the Curetis® company and compared it to either 'optimized' culture or 16S rRNA PCR. We performed a retrospective multicentre study to assess the contributions of mPCR in the diagnosis of PJI. We randomly selected 484 intraoperative specimens among 1252 of various types (biopsy, bone, tissue around the prosthesis, synovial fluid) from 251 patients in seven different hospitals. Each sample was treated according to the recommendations of the manufacturer. RESULTS: In all, 154 out of 164 (93.9%) samples negative in culture were negative with the mPCR. Among the 276 positive samples in culture, 251 (90.9%) were monomicrobial, of which 119 (47.4%) were positive with the mPCR, and 25 (9.1%) were polymicrobial, of which 12 (48%) were positive with the mPCR. The concordance rate of mPCR with culture was 58.1% (53.6%-62.7%) and the concordance rate with 16S rRNA PCR was 70.1% (65.5%-74.6%). CONCLUSION: This new standardized molecular test showed a lack of detection when the bacterial inoculum was low (number of positive media per sample and number of colonies per media) but can be useful when patients have received antibiotic therapy previously.

A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor.

A single natural loss of function mutation of the follicle stimulating hormone receptor (FSHR) has been described to date. Present in the Finnish population it markedly impairs receptor function, blocking follicle development at the primary stage and presenting as primary amenorrhea with atrophic ovaries. When Western European women with this phenotype were examined for FSHR mutations the result was negative, suggesting that other etiologies corresponding to this clinical pattern are markedly more frequent. We now describe a novel phenotype related to mutations provoking a partial loss of function of the FSHR. A woman with secondary amenorrhea had very high plasma gonadotropin concentrations (especially FSH), contrasting with normal sized ovaries and antral follicles up to 5 mm at ultrasonography. Histological and immunohistochemical examination of the ovaries showed normal follicular development up to the small antral stage and a disruption at further stages. The patient was found to carry compound heterozygotic mutations of the FSHR gene: Ile160Thr and Arg573Cys substitutions located, respectively, in the extracellular domain and in the third intracellular loop of the receptor. The mutated receptors, when expressed in COS-7 cells, showed partial functional impairment, consistent with the clinical and histological observations: the first mutation impaired cell surface expression and the second altered signal transduction of the receptor. This observation suggests that a limited FSH effect is sufficient to promote follicular growth up to the small antral stage. Further development necessitates strong FSH stimulation. The contrast between very high FSH levels and normal sized ovaries with antral follicles may thus be characteristic of such patients.

Ghrelin gastrokinetic action in patients with neurogenic gastroparesis.

Ghrelin has been shown to accelerate gastric emptying in animals where its effect appeared mediated through the vagus nerve. We aimed to verify the gastrokinetic capacity of ghrelin in human. Patients with gastroparesis attributed to a neural dysregulation by diabetes (n = 5) or surgical vagotomy (n = 1) were evaluated. The emptying of a test meal (420 kcal) was determined by the C13 octanoic acid breath test. Saline or synthetic ghrelin 1-4 microg/kg were given in 1 min bolus at the end of the meal. T-lag and T-1/2 were shorter during ghrelin than during saline administration [33 +/- 5 min versus 65 +/- 14 min (p < 0.01) and 119 +/- 6 min versus 173 +/- 38 min (p < 0.001)]. Ghrelin injection therefore accelerated gastric emptying of a meal in humans even in presence of a deficient gastric innervation.

Virulence of viable but nonculturable S. Typhimurium LT2 after peracetic acid treatment.

S. Typhimurium LT2 cells suspended in sterilized sewage effluent water (SEW) and in distilled water microcosms were exposed to 0, 7, 15 and 20 mg/l peracetic acid, and tested for viability and virulence. After treatment for one hour, colony forming units decreased by at least 5 log units at peracetic acid concentration of 7 mg/l. In SEW, at peracetic acid concentration of 15 mg/l, the cells were nonculturable (VNC), but retained virulence as demonstrated by invasion assays of HeLa cells. Higher concentrations (greater than or equal to 20 mg/l) resulted in bacterial death, i.e. substrate non-responsive cells. Despite morphological alterations of the bacteria after peracetic acid treatment, visualized by transmission electronic microscopy, conservation of both adhesive and invasive capacities was confirmed by scanning electron microscopy after exposure to 0-15 mg/l peracetic acid. Public health professionals need to recognize that peracetic acid-treated Salmonella is capable of modifying its physiological characteristics, including entering and recovering from the viable but nonculturable state, and may remain virulent after a stay in SEW followed by peracetic acid treatment.

Predictors of failure for prosthetic joint infections treated with debridement.

OBJECTIVE: Prosthetic joint infections (PJI) may be cured in selected patients with debridement and prosthesis retention. We aimed to identify predictors of failure to better target patients most likely to benefit from this conservative strategy. METHODS: Observational study of patients presenting with PJI initially treated at our hospital with debridement between 2008 and 2011, with>6 months of post-treatment follow-up. RESULTS: Sixty consecutive patients presenting with PJI (hip, n=34; knee, n=26) fulfilled the inclusion criteria. Failures (n=20, 33%), predefined as persistence of PJI signs or relapses, were managed with additional surgery (n=17) and/or lifelong suppressive antibiotic treatment (n=6). Variables independently associated with failure: previous surgery on the prosthetic joint (OR: 6.3 [1.8-22.3]), Staphylococcus aureus PJI (OR: 9.4 [1.6-53.9]), post-debridement antibiotic treatment for <3 months (OR: 20.0 [2.2-200]). CONCLUSION: Previous surgery, S. aureus PJI, and short duration antibiotic treatment are associated with an increased risk of failure after debridement.

New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype.

Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12+/-3% residual activity, whereas in patient 1 a 24+/-4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient.

The biological aspects of risks of infertility due to age: the female side.

When women reach their forties, and despite strong inter-individual variations, their fecundity, either spontaneous or assisted, is impaired then falls down from the age of 45 onwards. In humans the size of the ovarian reserve is definitely fixed at birth and decreases drastically with age. Follicles leave the stock of resting follicles in a continuous stream, either disappearing by apoptosis or entering the growth phase. From the age of about 38 years onwards, the rate of follicular depletion accelerates leading to a decreasing number of selectable follicles. As these follicles produce inhibin B, its circulating levels drop, resulting in an increase in circulating FSH concentration. The higher rate of growth of large follicles in women over the age of 40 than in younger women, likely due to high FSH levels, and/or an early selection of the preovulatory follicle seem responsible for the shortening of the follicular phase in women in their late thirties and early forties. An impaired endometrial receptivity and/or a decrease in oocyte quality, or both may be responsible for the increase of the frequency of spontaneous abortion when women reach their forties. In conclusion, it can be predicted that, although apparently inescapable, the fertility impairment due to ageing could be, at least partly, counteracted by the use of molecules preventing attrition of the ovarian reserve.

[Neo-oogenesis in the postnatal ovary: fantasy or reality?]. / Régénération des ovocytes: fantasme ou réalité?

The central dogma of female reproductive biology has long held that oogenesis ceases around birth in almost all mammals. Consequently, the ovarian reserve is definitely fixed and will continuously deplete up to the menopause in humans. New papers by Johnson et al. (2004) and by Bukovsky et al. (2004, 2005) overturn this dogma since they claim that female mice and women, respectively, produce new oocytes during adult life. The following review is mainly devoted to an analysis of the study by Johnson et al. (2004) as well as unpublished data submitted for publication from the same authors. Two bodies of evidence were presented to support their hypothesis: morphologic and experimental. Whereas morphologic data can be easily refuted, experimental data remain disturbing. In conclusion, these recent observations need to be confirmed by others, and extended by additional supporting evidence before they could be considered to question the dogma of a fixed stock of oocytes at birth.

Morphologic and functional determinants of primordial and primary follicles in the monkey ovary.

In mammals, the mechanisms triggering initiation of follicular growth remain largely unknown. The present study constitutes an attempt to relate morphological and functional changes occuring in follicles at the time of transition from the nongrowing to the early growing stage. The population of very small follicles, including both nongrowing and early growing follicles, has been studied in fetal and adult monkey (Macaca fascicularis). Counts of these follicles and immunohistochemical analyses of their content in various intraovarian peptides led to the conclusion that initiation is probably not similar, on a quantitative as well as a qualitative point of view, in the fetal and in the adult ovary. In addition to the recently evidenced stimulatory role of the stem cell factor (SCF) in rats, activation of a nongrowing follicle might imply an arrest in the production of inhibiting factors, such as the transforming growth factor-beta2 (TGF-beta2), occurring simultaneously with the production of stimulatory factors, such as the transforming growth factor-alpha (TGFalpha).

Frequent occurrence of multiovular follicles and multinuclear oocytes in the adult human ovary.

A study of 117 ovaries of adult women showed that multiovular follicles and multinuclear oocytes are found in 98% of 18- to 52-year-old women. The relative frequency of these follicles was not age-dependent and varied between 0.06% and 2.44% of the total follicular population of the ovary. Their frequency was unaffected by gonadotropic hormones, oral contraceptives, pregnancy, or day of the menstrual cycle. Young women with benign cystic teratomas did not have more multinuclear oocytes and multiovular follicles than did other patients. The probability that such follicles will ovulate is very low; therefore they could not be a significant cause of the birth of dizygotic twins or the appearance of triploidy.

Influence of human menopausal gonadotropin on the recruitment of human ovarian follicles.

Human menopausal gonadotropin (hMG) was administered once (225 IU) to 16 women during different phases of the menstrual cycle: either late-luteal, early-follicular, midfollicular, or late-follicular phases before surgical ovarian resection or ablation. The mitotic index (MI) of follicular granulosa cells and the proportion of recruitable healthy follicles were analyzed 4 to 5 days after hMG injection, the findings being compared with those in unstimulated ovaries from 22 normally cycling patients. The percentages of healthy recruitable follicles greater than or equal to 2 mm in diameter was not altered by hMG as compared with controls. The granulosa cell MI was highly stimulated by hMG when administered in late-luteal or early-follicular phases; however, no granulosa cell MI stimulation was noted when hMG was administered in the midfollicular or late-follicular phases. The progressive abolition of the ability of hMG to stimulate follicular growth as ovulation approaches supports the existence of an inhibitory activity (possibly ovarian) designed to suppress the selection and the maturation of the less developed antral follicles from the midfollicular phase of the spontaneous human menstrual cycle.