Postoperative pelvic adhesions represent a major challenge to the surgeon operating to correct or prevent infertility. Many approaches have been tried, but intraperitoneal treatment seems to be the most efficacious. Some major landmarks led to the development of the intraperitoneal substances currently used to prevent postoperative pelvic adhesions. On comparing the data on both animals and humans we see that high-molecular-weight dextran seems to be superior to other substances. Much work needs to be done to enhance this adjunctive therapy since excellent surgical technique alone seems insufficient. The future emphasis will probably be on these medications in conjunction with precise surgical techniques and adjunctive intraperitoneal therapy.
General OB/GYNGonorrhea and Chlamydia TreatmentSexually Transmitted InfectionsAntibiotic Comparison
We evaluated the effect of treatment of gonorrhea on simultaneous Chlamydia trachomatis infection by randomly assigning 293 heterosexual men and 246 heterosexual women with gonorrhea to receive one of the (1) 4.8 million units of aqueous procaine penicillin plus 1 g of probenecid, (2) nine tablets of trimethoprim-sulfamethoxazole daily for three days, or (3) 500 mg of tetracycline four times a day for five days. Among the men, gonococcal infection was cured in 99 per cent given penicillin plus probenecid, 96 per cent given trimethoprim-sulfamethoxazole, and 98 per cent given tetracycline. Among the women, only 90 per cent given tetracycline were cured, in contrast to 97 per cent given penicillin plus probenecid and 99 per cent given trimethoprim-sulfamethoxazole. Chlamydial infection, present in 15 per cent of the men and 26 per cent of the women, was cured in 30 of 32 patients given trimethoprim-sulfamethoxazole and 27 of 29 given tetracycline, but in only 10 of 23 given penicillin plus probenecid. Among chlamydia-positive patients, postgonococcal urethritis in men and cervicitis in women occurred more often in patients given penicillin plus probenecid. Salpingitis developed in 6 of 20 women given penicillin plus probenecid, but in only 1 of 26 given trimethoprim-sulfamethoxazole and in none of 24 given tetracycline. We conclude that the use of penicillin plus probenecid alone for gonorrhea in heterosexual patients carries an unacceptably high risk of postgonococcal chlamydial morbidity. Trimethoprim-sulfamethoxazole and tetracycline were highly effective against both pathogens and were well tolerated in men, but both drugs caused frequent side effects in women. The failure of tetracycline to cure gonorrhea in 10 per cent of women argues against its use alone; treatment with penicillin followed by tetracycline has been recommended for further trial.
SurgeryHigh Molecular Weight DextranAdhesion ReductionDouble-Blind Study
The use of intraperitoneal 32% high-molecular weight dextran 70 (Hyskon, Pharmacia Inc.) has been reported to reduce the incidence of surgical adhesions in several species. The present study was undertaken to determine the effect of 32% dextran 70 in human females who underwent major abdominal infertility operations. Adhesions were quantitated by means of standardized objective criteria in 44 women in a prospective, randomized, double-blind study, and reevaluated at second-look laparoscopy approximately 6 weeks later. The mean change in the adhesion score for all patients in the 32% dextran 70 group (n = 23) was -2.57 units (i.e., clinically "improved") versus +2.41 units (i.e., clinically "worsened") in the control group (n = 21), p = 0.016. For the subgroup of patients who underwent lysis of adhesions, the 32% dextran 70 group (n = 17) improved significantly, whereas the control group (n = 12) tended not to improve with careful technique alone (-4.2 units versus +0.3 unit, p less than 0.05). These data indicate that 32% dextran 70 not only significantly reduces the formation of adhesions overall in human infertility operations, but also is highly effective in reducing the reformation of adhesions after lysis.
The ovulation method makes women aware of certain changes in their cervical mucus. These modifications help to distinguish the beginning and end of the cycle's fertile period and indicate the time of maximum fertility. In addition to pinpointing the date of ovulation, the method permits the user to know she is not fertile when there is no ovulation. The principle of the method is the state of "basic infertility" which preceeds follicular development. The method cannot be implemented with success unless it is properly acquired. After some preliminary considerations regarding the fertile period, ovluation detection and periodic abstinence, some clinical and hormonal observations are compared in 2 basic studies in order to show to what extent cervical mucus reflects ovarian activity. The application of the method requires an understanding of the "basic infertility profile" and 2 sets of rules regarding the 1st days and the peak sign which indicate respectively the beginning and end of the fertile period. The criteria of an ideal birth control method and the importance of proper teaching are also dealt with. With regard to Natural Family Planning, 2 problems are pointed out--incomplete terminology in data collection and absence of a positive and detailed approach to periodic abstinence. (author's modified)
Microsomal membranes sedimented at 40 000 g were prepared from human myometrium samples. The progesterone binding properties of microsomal suspensions were determined by incubating microsomes and [3H]progesterone at 4 degrees C. Dextran-coated charcoal was used for the separation of bound and free steroids. Membrane-associated progesterone binding sites of high affinity were identified in microsomes prepared from pregnant and nonpregnant uteri. The binding was saturable (Kd approximately 4 X 10(-9) M, concentration of binding sites 400-900 fmol/mg microsomal protein) and specific for natural progesterone. Of 21 steroids tested only 21-hydroxy-4-pregnene-3,20-dione, 17 alpha-hydroxyprogesterone and testosterone showed moderate competition against progesterone with relative affinities between 7.0-20.0% (R.A. of progesterone 100%). 5 alpha-Dihydroprogesterone and 5 alpha-dihydrotestosterone showed weak cross reaction (relative affinities 2.5 and 2.0%, respectively). Corticosteroids, estrogens and the 5 synthetic progestins tested showed only weak competition with relative affinities lower than 1.0%. These microsomal progesterone binding sites of high affinity and limited capacity resemble steroid hormone receptors but they are different from the soluble cytosolic progesterone receptor of human uterus in terms of steroid specificity. The physiological function of this microsomal progesterone receptor is unknown.
PregnancyTocolysis OutcomesInfection BiomarkersC-Reactive Protein Pregnancy
Subclinical intrauterine infection is an important cause of preterm labor, specifically where tocolysis has failed. Fifty patients in preterm labor with singleton pregnancies were studied prospectively to determine whether the presence or absence of C-reactive protein, a nonspecific marker for infection, would correlate with success or failure of tocolysis. Of the 50 patients, tocolysis failed in 11 of 15 women with a positive C-reactive protein determination. Tocolysis succeeded in 33 of 35 cases where C-reactive protein was negative (P less than .0005). Urinary tract infection occurred in 40% of the study patients, but was not a confounding factor in the interpretation of C-reactive protein.
Reproductive EndocrinologyBreast Cancer RiskTestosterone and Breast DiseaseHormonal Risk Factors
Serum testosterone, progesterone, luteinizing hormone, prolactin, and sex hormone-binding globulin levels were measured in 55 normal controls, in 31 patients with hyperplastic alterations of breast epithelium, and in 23 patients with breast cancer. All patients and controls were premenopausal, and they were comparable for age, weight, and body surface. In the controls, the mean level of testosterone [0.47 +/- 0.16 (S.D.) ng/ml] was lower and the mean level of progesterone (17.63 +/- 8.11 ng/ml) was higher than in breast cancer patients [testosterone level, 0.62 +/- 0.22 ng/ml (p less than 0.005); progesterone level, 11.4 +/- 8.0 ng/ml (p less than 0.005)] and in patients with breast epithelial hyperplasia [testosterone level, 0.55 +/- 0.2 ng/ml (p less than or equal to 0.05); progesterone level, 13.9 +/- 8.6 ng/ml (p less than 0.05)]. No difference was found in the mean circulating levels of luteinizing hormone, prolactin, or sex hormone-binding globulin between controls and patients. These results confirm previous findings of increased urinary testosterone excretion in women with anovulatory menstrual cycles and epithelial hyperplasia or cancer of the breast and strongly support the hypothesis that androgens play an important role in both induction and development of breast cancer.
InfertilityAntiestrogen TherapyPostcoital Test TreatmentClomiphene vs Tamoxifen
Twenty-two infertile women with repeated deficient results in the postcoital test received clomiphene citrate or tamoxifen. The patterns of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol (E2), and progesterone were examined during the follicular and periovulatory phases of the menstrual cycle, as were the cervical mucus characteristics. Under clomiphene treatment, an overproduction of E2 was observed (P less than 0.01), which did not result in an improvement of the cervical mucus characteristics. The pH of the endocervical mucus was lower (P less than 0.01). Under tamoxifen treatment, the serum E2 levels were higher (P less than 0.05) and normalized. Higher spermatozoa penetration meter scores were observed during the preovulatory and periovulatory periods, whereas the pH of the endocervical mucus was not lowered. These data support that tamoxifen may be preferential to clomiphene in treating this kind of infertile woman.
InfertilityUltrasound-Guided TherapyFollicular Development AssessmentProgesterone Supplementation
In some series the most appropriate therapy for luteal phase defects is supplemental progesterone in the luteal phase. Clomiphene's efficacy is more controversial since in one series only 8% achieved a successful pregnancy versus 45% in another study. Pelvic sonography was used to evaluate follicular development and release of the ovum in 50 infertile women with luteal phase defects. The results showed that only 40% had "pure" luteal phase defects whereas 52% had immature follicles and 8% had unruptured follicles. Sixty-two percent of the patients had previous therapy for a luteal phase defect and failed to conceive. Sixty-eight percent of this group did conceive when ultrasound was used to determine the appropriate therapy. Thus ultrasound can be employed to determine if the women with a luteal phase defect should be treated with a fertility drug, e.g., clomiphene or just with luteal phase progesterone support. Supplemental progesterone might still be needed with clomiphene based on repeat endometrial biopsy results.
A single dose of micronized oral progesterone was administered to 15 pregnant women immediately prior to elective cesarean section. Levels of progesterone, 17 beta-estradiol, and estrone were measured in the plasma, in the placenta, and at different sites in myometrium obtained during the surgical procedure. Results were compared to those observed in a control group of women who did not receive progesterone. Progesterone levels demonstrated a marked increase in plasma and in the whole myometrium 150 minutes after administration. The levels then decreased rapidly to control values in 1 hour. The concentrations of progesterone in the placenta did not show any changes. No difference appeared in 17 beta-estradiol levels in the plasma or the myometrium, whereas an increase was observed in the placenta. Estrone levels did not change in the plasma, but they decreased in the myometrium and in the placenta.
Reproductive EndocrinologyHypothalamic Control of Menstrual CycleOpioid Peptide ModulationGnRH Pulse Regulation
Thirty-one women with severe premenstrual syndrome had low sex hormone binding globulin (SHBG) binding capacities 30.2 +/- 9.4 nmol DHT bound/l. The SHBG binding capacities rose when they were treated with three different doses of progesterone. On 400 mg (17 women) SHBG level was 45.11 +/- 11.80. On 800 mg (8 women) SHBG binding capacity rose to 64.75 +/- 14.30 and on the six women who took 1200 mg progesterone daily SHBG binding capacity was 78.5 +/- 23.10. These results are discussed.
In 121 women attending the infertility clinic between 1978 and 1982, 127 cycles with luteal phases of 10 days or more were investigated by a complete basal body temperature (BBT) chart, three plasma progesterone assays taken between 11 and 4 days before menses, and a dated endometrial biopsy (EB) taken at the time of the last blood sample. All parameters were normal in 78 women (64.4%) categorized as group I 'normal luteal phases (NLP)'. There were some discordances between the three parameters in the remaining 43 8 had normal BBT but low progesterone levels and delayed EB. They form group II 'inadequate luteal phases'. 29 women (23.9%) had delayed EB despite forming group III 'dysharmonic luteal phases (DLP)'. 6 women had advanced EB group IV. Apart from endometrial maturation, there was no difference between NLP and DLP, neither in clinical parameters (length of the follicular phase, date and duration of the thermal shift, length of the luteal phase), nor in progesterone levels. Fertilization occurred pregnancies went normally to term, giving birth to normal babies. Therefore, the DLP syndrome, characterized by normal midluteal progesterone levels and a delayed endometrial development, is not incompatible with normal nidation and gestation.
The important role of cervical mucus from a reproduction standpoint is the transport and selection of spermatozoa. The study of the fertilizing ability of human spermatozoa by the use of zona-free hamster oocytes has shown that morphologically abnormal sperm can fuse with the zona-free hamster oocyte. The high proportion of morphologically abnormal spermatozoa present in human semen is significantly reduced after sperm migration through cervical mucus. The mucus, while a favorable environment for sperm survival, does not seem to contribute to the occurrence of sperm capacitation and acrosome reaction.
The principal function of muscular tissue is contraction. This is also true for the uterus this function begins with sexual maturation. During pregnancy special conditions are brought about by the increasing distention of the uterine cavity. For clinical practice, external tocography is of importance for the recognition of uterine motility Data in the literature on the normal frequency of contractions during pregnancy vary greatly and caused us to study this topic. Moreover, most cases of prematurity independent of other causes suppose a prematurely increased uterine motility. In order to register this activity a portable recording apparatus was developed. We studied in particular the question for how long and how often uterine contractions should be recorded. A one hour daily recording was found to be sufficient. In order to gain information on the average number of contractions it suffices to record during one week. In 26 healthy primiparous and 28 multiparous women the number of contractions from the 25th to 41st gestation week was recorded. A notable finding was the frequency peak about the 32nd week. The number of pregnancy contractions as a sole parameter for the recognition of impending premature delivery is not sufficient. However, the information may be important when taking in conjunction with the previous history and the state of the cervix. We considered tocolysis indicated when as a weekly average there are more than two contractions per hour with beginning cervical dilation or more than three contractions per hour regardless of cervical findings.(ABSTRACT TRUNCATED AT 250 WORDS)
Fourteen women experiencing early pregnancy failure have been studied during the time of conception and at frequent intervals until spontaneous abortion occurred. Serial measurements of serum estradiol, progesterone, 17 alpha-hydroxyprogesterone, prolactin, human placental lactogen (hPL), and human chorionic gonadotropin (hCG) were determined; regular sonar scanning allowed the time of fetal death to be determined to within 7 days in six patients and a diagnosis of blighted ovum to be made in the remainder. In all patients serum progesterone and estradiol concentrations were within the normal range up to 7 weeks but appeared to decrease from about 8 weeks' gestation whether or not a living fetus was present. The placenta continued to produce hCG and hPL but, despite the continuing presence of hCG, the levels of 17 alpha-hydroxyprogesterone declined to concentrations below those associated with normal pregnancy. These data suggest that the placenta may require a particular stimulus to take over production of progesterone and estradiol.
In women with premenstrual syndrome, negative changes start soon after ovulation gradually increasing as the corpus luteum develops, and reach a maximum during the last 5 days of the luteal phase. They decline rapidly once menstruation starts, disappearing within one or two days of ovarian steroids reaching baseline levels. Positive moods are at maximum when preovulatory estradiol reaches its peak. A comparison of hormone levels in women with high and low degrees of cyclical mood change showed no difference in progesterone, estradiol, testosterone, or androstenedione.
Fertility AwarenessBillings Ovulation MethodSympto-Thermal MethodClinician Role
Despite skepticism on the part of the health care delivery system, increasing numbers of women and couples are relying on natural family planning methods to avoid or achieve pregnancy. Most clients require 2-4 cycles to become familiar with the delineation of the fertile phase. Both the ovulation and the sympto-thermal methods are considered to have a method effectiveness of at least 98%. Teaching-related unplanned pregnancies fall below 5%. Use of the Billings ovulation method requires the couple to abstain from intercourse from the beginning of mucus until the 4th day after peak. The sympto-thermal method is preferred by those desiring a multiple-index approach. 75-80% of users of this method can detect cervical softening and dilatation, and 50% are aware of the change of position of the cervix. Knowledge of mucus buildup patterns can be expecially important for adolescents, lactating women, and premenopausal women in helping them to determine whether cycles are ovulatory. Instruction in interpretation of the mucus cycle is further advised in cases of infertility. Unwillingness of the partners to practice it constitutes the only contraindication to natural family planning. However, couples are advised to wait for the postovulatory infertile phase of the cycle to have intercourse in cases where prgnancy would pose a serious threat to the life of the mother or fetus. Although some groups recommend the use of a barrier method rather than abstinence during fertile periods, this practice makes mucus recognition more difficult and impedes confidence in the method. Attainment of couple autonomy in natural family planning involves 2 1) correct recognition of the signs of fertility and 2) comfort with periodic asbsinence. Successful autonomy is reflected in the high continuation rates found in programs that offer adequate counseling support.
Reproductive EndocrinologyGonadotrope SubtypesLH and FSH StorageCell Separation
The application of centrifugal elutriation to the separation of pituitary cells has produced a fraction that is enriched with LH and FSH gonadotropes. In this study, stains were performed on serial sections of fractions taken from six elutriation experiments with 1:10,000-1:30,000 anti-bLH beta or 1:2,000-1:8,000 anti-hFSH beta and the avidin-biotin-peroxidase complex technique. Over 900 serially sectioned gonadotropes were analyzed. In the initial cell suspensions, 59.6% of the gonadotropes contained both LH and FSH; 18% contained LH, and 23% contained FSH. Fewer than 3% contained ACTH. The elutriation fractions contained several subtypes of gonadotropes. A few small (8 micron), poorly granulated LH or FSH cells were eluted with the smallest cells (10-12%) at flow rates of 15.7 ml/min. Medium sized gonadotropes (10-10.5 micron) that eluted at flow rates of 19.8-30.5 ml/min were infrequent (3-6%) and resembled the larger gonadotrope. An analysis of serially sectioned fields showed that only 15.2%-22% of the small and medium sized gonadotropes contained both LH and FSH, whereas 30-40% contained only LH and 46-50% stored only FSH. The gonadotrope-enriched fraction was eluted at 37-39.5 ml/min; 78% of these gonadotropes (diameter, 14-15 micron) contained both LH and FSH, 10% contained only LH, and 12% contained FSH. Finally, large cells (diameter, 15-16 micron) that contained FSH only were found in the Wash fraction. These studies demonstrate that smaller gonadotropes tend to store only one of the hormones whereas most of the larger cells either store LH and FSH together or FSH alone. These heterogeneous storage patterns may correlate with studies by others who measured different responses to GnRH in gonadotropes separated by size on a unit gravity sedimentation gradient. They may also reflect different secretory phases of gonadotropes from the mixed group of cycling female rats.
Reproductive EndocrinologyExtrapituitary SourcesMyometrial Hormone ProductionMyometrial Function
Human myometrium is shown for the first time to produce prolactin in vitro. This prolactin is similar to pituitary prolactin by criteria of immunologic identity, gel chromatography and bioassay. The de novo synthesis of myometrical prolactin is supported by no detectable prolactin in initial tissue homogenate, nondetectable prolactin production during the first 24 hours of culture, cycloheximide inhibition of prolactin production with recovery of production in control medium, and tritiated leucine incorporation into prolactin. Although human myometrium is capable of producing prolactin without the addition of exogenous hormones, the addition of estrogen and progesterone, respectively, enhances and suppresses prolactin production in contrast to decidualized human endometrium where opposite effects on prolactin production are found.
When properly taught and practised, natural family planning can be a highly effective form of birth regulation. Recent studies indicate low failure rates of less than three pregnancies per 100 women years for couples with a strong motivation to follow the method. Studies show that pregnancy rates are high when the rules for avoiding pregnancy are not adhered to. Successful natural family planning can lead to heightened self esteem and marital enrichment.
This is a survey of 14 placebo-controlled studies regarding the treatment of premenstrual symptoms with bromocriptine. There is no substantial support that bromocriptine is an effective drug in the premenstrual syndrome as an entity. Symptoms such as irritability, depression, and anxiety were not significantly improved during treatment with bromocriptine compared to placebo treatment. Bromocriptine appears to be the treatment of choice in premenstrual mastodynia if the dosage of bromocriptine is at least 5 mg daily. Bromocriptine may therefore have a place in selected cases of the premenstrual syndrome with associated mastodynia.
A prospective study is presented in order to determine the frequency of the luteinized unruptured follicle (LUF) in a population of 66 regularly cycling women. They were monitored by daily ultrasound for a total of 183 cycles, and the LUF was detected in 9 cycles, giving an incidence of 4.9%. The results of daily changes of luteinizing hormone, estradiol, and progesterone provide support for the thesis that the LUF behaves steroidogenically as a corpus luteum and that the luteal phase duration is normal. Continued monitoring in 35 cycles revealed a recurrence in only one case during a fourth subsequent cycle. Thus, the findings indicate that the LUF is a sporadic and infrequent phenomenon. It is therefore an uncommon cause of infertile cycles in potentially fertile women and represents a biologic variable rather than a syndrome. Based on ultrasonic and endocrine observations, a mechanism is proposed for the resolution of the LUF.
Fertility AwarenessMethodology and InterpretationNatural Family Planning EffectivenessOvulation Indicators
Parenteau-carreau S, 1983·Contracept Fertil Sex (Paris)
The symptothermal methods include all those that identify the woman's fertile period through the basal body temperature and the periovulatory signs. Research conducted following the discovery over a century ago of the hyperthermic plateau in the later part of the menstrual cycle has confirmed that under normal conditions, and when the daily temperature is taken under comparable conditions, infertility may be assumed when the high temperature plateau is confirmed. A reliable temperature curve it should be taken upon awakening with a basal thermometer over a sufficient time to obtain an accurate measure, at almost the same time every day, and the graph paper should be appropriately scaled for recording. Various guidelines of interpretation have been developed throughout the world. Serena considers infertility assured from the 3rd consecutive day of elevated temperature as long as other fertility symptoms have disappeared. Among symptoms of ovulation that are perceptible to the woman are cyclic changes in the quantity and consistency of the cervical mucus, which has the advantage of predating and thus forecasting ovulation and of being less sensitive than the basal temperature to nongenital infections, sleepless nights, or other stresses. Use of mucus changes alone as an indicator of fertility carries the risk that such changes may not be noticed or may be due to an estrogen surge not related to ovulation. Other symptoms that are useful for some women in confirming temperature or mucus changes include 4 different alterations in the cervix, abdominal pain or mittelschmerz, intramenstrual bleeding, feeling of heaviness in the breasts, and variations in mood and libido. Many groups that teach the temperature curve and clyclical symptoms also provide instructions or mathematical rules for determining the number of infertile days at the beginning of the cycle. Some programs state that 6-7 days are usually infertile provided that the menses were preceded by a hyperthermic plateau. Many groups recommend the calculation of Ogino or a variant. The symptothermal method of fertility control combines the basal temperature curve with the other signs of fertility to serve as a basis for modification of sexual behavior to enhance or suppress fertility. Different programs stress different elements or combinations. The efficacy of the symptothermal methods depends on precise recordkeeping and observation and on competent instruction and counseling, as well as the willingness of the couple to modify their sexual behavior. Statistical measures of the method's efficacy are complex and unsatisfactory as they attempt to apply rigid rules to actions and decisions that are in fact filled with nuance.
It is generally accepted that laparoscopy should be performed if a woman's basic infertility evaluation reveals no abnormalities. Although it has been shown that a significant number of these patients have unsuspected pelvic pathology that can be detected by laparoscopy, there is concern about the real benefit of this procedure, ie, does the laparoscopic examination truly lead to more pregnancies than otherwise expected? Presented is a review of a series of 50 female patients whose basic infertility evaluation had failed to reveal any abnormalities. Laparoscopy revealed significant pelvic pathology in 28 cases; of the 16 who had appropriate therapy, eight became pregnant.
SurgeryDextran 70 Barrier AgentsTubal and Pelvic SurgerySurgical Interventions
Infertile women of reproductive age requiring an operation for distal tubal disease, endometriosis, or pelvic adhesions were recruited from nine study centers. Prior to closing the peritoneal cavity, 250 ml of 32% dextran 70 (n = 55) or saline (n = 47) was instilled into the dependent portion of the pelvis; 8 to 12 weeks later, laparoscopy was performed on those patients not pregnant. Patients with severe adnexal adhesions at the initial laparotomy had a greater reduction in adhesions if they received 32% dextran 70. Further, patients with a marked reduction in adhesion formation following the initial laparotomy were found to occur more frequently in the 32% dextran 70-treated group (26 of 51 for 32% dextran 70 versus 12 of 40 for saline; P less than 0.05). During second-look laparoscopy, adhesions were found to occur more frequently in control patients than in 32% dextran 70-treated patients at ovary (P less than 0.05); cul-de-sac (P = 0.017); pelvic side wall (P less than 0.001). Thus, in a prospective, randomized, blinded clinical trial, the intraperitoneal high-molecular-weight dextran was found to reduce postoperative adhesion formation effectively.
The concentrations of pregnanediol-3-glucuronide (PGD) and pregnanolone (PN) were measured in daily morning urine specimens from 66 infertile women (40 with varying degrees of endometriosis and 26 control subjects) and correlated with daily changes in basal body temperature (BBT) and with midluteal levels of serum progesterone (P). PN and BBT rose at midcycle in women with endometriosis, as expected, indicating secretion of some P at that time. However, PGD, the major endpoint of P metabolism, was delayed in its excretion. Endometrial biopsies were similarly delayed (out of phase) in women with endometriosis, and a significantly higher incidence of follicular luteinization was seen. It appears that while P secretion begins at midcycle, the bulk of P secretion is delayed, perhaps because of the process of follicular luteinization, and that a shortened functional luteal phase thus exists in women with endometriosis.
Basal body temperature (BBT) charts from three menstrual cycles of 20 normal women and 20 women with biopsy-proven luteal phase defect (LPD) were reviewed. Mean luteal phase length in the normal women was 13.4 days, and that of the women with LPD was 11.8 days (P less than 0.05). Six (30%) of the LPD patients had luteal phases of less than 11 days according to BBT, and five of these patients had severely out-of-phase endometrial biopsies. None of the normal patients had luteal phases of less than 11 days. There was no significant difference in the mean rate of postovulatory BBT rise between the two groups. It is suggested that the slope of postovulatory temperature shift is not helpful in the diagnosis of LPD but that evidence of a luteal phase of less than 11 days on BBT does indicate a high likelihood of LPD.
PregnancyPremature Rupture of MembranesChorioamnionitis PredictionC-Reactive Protein in Pregnancy
A group of 52 patients with premature rupture of the membranes (PROM) before 34 weeks' gestation were evaluated prospectively and managed expectantly. Of 42 patients who were delivered of their infants, 26 (61.9%) had significant chorioamnionitis on histopathology, and 18 had positive microbial cultures at delivery. However, only seven patients (16.7%) developed clinical signs of chorioamnionitis. There were no maternal deaths or perinatal deaths attributable to sepsis. Only two infants (less than 5%) had positive blood cultures. All patients were assessed daily for the development of chorioamnionitis. Amniocenteses were not routinely performed. White blood cell counts, band neutrophil counts, and erythrocyte sedimentation rate determinations were found to be unreliable. C-reactive protein determinations were found most reliable with a high sensitivity and specificity. Elevated C-reactive protein levels correlated better with pathologic confirmation of chorioamnionitis than with the clinical febrile morbidity. Clinical implications for the management of PROM are discussed.
Swiss Webster female mice weighing 25-30 gm were injected subcutaneously on days 6-15 of gestation with the synthetic sex steroid Delalutin (17 alpha-hydroxyprogesterone caproate). Treatment was given daily in doses ranging from 42 to 833 mg/kg body weight, or 10, 100, and 200 times the human therapeutic dose. On day 18 fetuses were removed from the uterus and examined for malformations and other fetotoxic effects. Prenatal treatment with the two higher doses resulted in 8 and 13% maternal deaths, and all doses resulted in a slight increase (4-12% above control) in resorption frequency. Treatment with Delalutin did not significantly affect intrauterine growth, sex ratio, or malformation rate of the offspring. The results of the present study confirm other reports that Delalutin is not androgenic, and that it, like progesterone and certain other sex steroids, does not alter the development of nonreproductive organs.
General OB/GYNVitamin ToxicitySupplement-Induced Neuropathy
We describe seven adults who had ataxia and severe sensory-nervous-system dysfunction after daily high-level pyridoxine (vitamin B6) consumption. Four were severely disabled; all improved after withdrawal. Weakness was not a feature of this condition, and the central nervous system was clinically spared. Although consumption of large doses of pyridoxine has gained wide public acceptance, this report indicates that it can cause sensory neuropathy or neuronopathy syndromes and that safe guidelines should be established for the use of this widely abused vitamin.
InfertilityClomiphene Citrate SafetyCongenital Malformations After Fertility TreatmentClomiphene Teratogenicity
The effect of clomiphene citrate (CC) on the incidence of congenital malformations in newborn infants was assessed from the outcome of 1034 pregnancies after CC-induced ovulation recorded at nine university hospitals in a 5-year period. Of these pregnancies, 14.2% ended in abortion, 0.5% in ectopic pregnancy, 0.1% in molar pregnancy, and 1.6% in stillbirth. In all, 935 infants were born, and 21 (2.3%) showed visible malformations. This incidence of malformations was not significantly different from that in 30,033 infants (1.7%) after spontaneous ovulation (spontaneous ovulation group), and the types of malformations after CC treatment were similar to e those in the spontaneous ovulation group. These data indicate that CC has no teratogenic effect.
Reproductive EndocrinologyEndometrial Response to SteroidsHormonal Effects
Daily estimations of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone were made in the serum of eight infertile patients from day 1 through the follicular phase during menstrual cycles before and after tamoxifen therapy. Tamoxifen therapy was found to shorten the follicular phase from 15.4 +/- 0.8 days (mean +/- standard error of the mean) to 14.0 +/- 0.6 days (difference not significant) and to lengthen the luteal phase from 12.8 +/- 0.4 days to 14.1 +/- 0.8 days (P less than 0.05). The mean estradiol concentration in the eight patients during tamoxifen treatment cycles rose on day 8 (3 days after starting tamoxifen treatment) and increased significantly (P less than 0.05) from day 10 to midcycle. The integrated follicular phase estradiol concentration in the tamoxifen treatment cycle increased to 2450.1 +/- 208.1 pg/ml/cycle, and was significantly higher (P less than 0.025) than that in the nontreatment cycle. In contrast, the concentrations of follicle-stimulating hormone, luteinizing hormone, and prolactin during the follicular phase and at the midcycle peak of tamoxifen treatment cycles were not significantly different from those of the nontreatment cycle. These results suggest that the mechanism of tamoxifen in improving folliculogenesis may involve a direct action on the ovary without intervention of the hypothalamic-pituitary system.
The results of combined ritodrine and indomethacine treatment (RI) in premature labor contractions were compared with ritodrine alone (R). One hundred and twenty patients with threatened premature labor in weeks 26-34 were studied. Sixty RI women received 100 mg ritodrine in infusion followed by 60 mg daily orally until 35 weeks and indomethacine 200 mg on the first day of treatment only. The R group included 60 women with identical tocolysis indices, age of pregnancy and anamnestic parameters who received ritodrine only. The mean prolongation index (PI) was 18.2 in the RI group, against 11.5 in the R patients (P less than 0.05). The mean prolongation of pregnancy was 5.6 weeks in the first and 3.6 in the control group (P less than 0.05). Birthweight and Apgar scores were similar in the two groups. In order to examine the possible early closure of the ductus arteriosus due to the indomethacin therapy, echocardiograms were done the pre-ejection period and right ventricular ejection time ratio was 0.19-0.26 after delivery and 0.17-0.22 1 month later, which excludes pulmonary diastolic hypertension due to premature closure of the duct. The combined RI treatment is more effective that R alone and does not give rise to any complications in the mother or the fetus.
During the five years ending on December 31, 1981, 159 anovulatory and oligomenorrheic patients were treated with clomiphene citrate for induction of ovulation. Overall, 86% of these patients ovulated, and 49% of the patients who ovulated conceived. Life table analysis was employed to investigate factors contributing to reduced conception rates, including abnormal semen analysis, pelvic or tubal abnormalities, and poor cervical mucus. Elevated serum testosterone levels did not affect conception rates. The most significant factor contributing to reduced overall pregnancy rates was patient discontinuation of therapy. Cumulative pregnancy rates corrected for discontinuation approach 100% after ten cycles of therapy. During this period, the monthly probability of pregnancy (monthly fecundability) remained constant. Optimal pregnancy rates are attained if other infertility factors are corrected and treatment is continued for ten to 12 ovulatory cycles.
Thirteen women with luteal phase defects (LPD) confirmed by endometrial biopsies and 14 with histologically normal endometria were studied for early follicular and midfollicular phase follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and for midluteal phase progesterone, estrogen, testosterone, and prolactin levels. The results showed that the women with LPD had significantly lower FSH levels and FSH/LH ratios in the early and midfollicular phases. LH levels, however, were similar in the LPD and normal women. During the midluteal phase, the LPD women showed significantly lower levels of progesterone and estrogen and normal levels of testosterone and prolactin. These findings reaffirm the prevailing concept that events surrounding follicular growth and development can indeed influence the quality of that cycle's corpus luteum. Furthermore, LPD as a result of hyperprolactinemia appears to be a different entity from that due to inadequate follicular phase FSH.
A group of 22 women with anovulatory cycles was treated with tamoxifen in 46 cycles. We elucidated daily hormone profiles in 5 of the 33 tamoxifen-induced ovulatory cycles in order to make a comparison with those found in 5 normal cycles. Serum follicle-stimulating hormone and luteinizing hormone (LH) rose during or a few days after the tamoxifen therapy, and thereafter serum estradiol levels rose gradually over the normal ranges during the follicular phase and reached an extremely high preovulatory peak which triggered an LH surge. This increased estradiol production exerted its usual negative feedback on LH secretion. Following ovulation, serum progesterone rose and fell in a manner similar to that in the normal cycles, with occasional values that exceeded the normal range. The endocrine significance of these findings is discussed.
Reproductive EndocrinologyNutritional EtiologyClassification and SubgroupsVitamin and Mineral Therapy
The premenstrual symptom complex many women experience in a moderate to severe form can be divided into four subgroups. Because there is more than one syndrome and nervous tension is one of the most common symptoms, the term premenstrual tension syndromes (PMTS) is used. The most common subgroup, PMT-A, consists of premenstrual anxiety, irritability and nervous tension, sometimes expressed in behavior patterns detrimental to self, family and society. Elevated blood estrogen and low progesterone have been observed in this subgroup. Administration of vitamin B6 at doses of 200-800 mg/day reduces blood estrogen, increases progesterone and results in improved symptoms under double-blind conditions. Women in this subgroup consume an excessive amount of dairy products and refined sugar, and progesterone may be of value in them. The second-most-common subgroup, PMT-H, is associated with symptoms of water and salt retention, abdominal bloating, mastalgia and weight gain. The severe form of PMT-H is associated with elevated serum aldosterone. Vitamin B6 at high dosage suppresses aldosterone and results in diuresis and clinical improvement. Vitamin E helps the breast symptoms. Methylxanthines and nicotine should be curtailed and sodium limited to 3 gm/day. PMT-C is characterized by premenstrual craving for sweets, increased appetite and indulgence in eating refined sugar followed by palpitation, fatigue, fainting spells, headache and sometimes the shakes. PMT-C patients have increased carbohydrate tolerance and low red-cell magnesium. Adequate magnesium replacement results in improved glucose tolerance tests and decreased PMT-C symptoms. Deficiency of the prostaglandin PGE1 may also be involved in PMT-C. PMT-D is the least common but most dangerous because suicide is most frequent in this subgroup. The symptoms are depression, withdrawal, insomnia, forgetfulness and confusion. In ten PMT-D patients the mean blood estrogen was lower and the mean blood progesterone higher than normal during the midluteal phase. Elevated adrenal androgens are observed in some hirsute PMT-D patients. Two PMT-D patients with normal blood progesterone and estrogens had high lead levels in hair tissue and chronic lead intoxication. This subgroups needs careful medical attention when the symptoms are severe. Therapy should be individualized according to the results of the evaluation.
One hundred thirty-seven premenopausal women with premenstrual tension underwent laparoscopy for bleeding, pain and/or infertility. Endometriosis was the associated gynecologic disease observed most frequently (66 patients). Other associated disorders were primary dysmenorrhea (31), poststerilization syndrome (24), chronic pelvic inflammatory disease (8) and leiomyoma uteri (8). Screening for prolactin and thyroid-stimulating hormone in patients with galactorrhea (74) revealed one patient with pituitary microadenoma and two with primary hypothyroidism. The midluteal progesterone levels were significantly decreased, whereas the midluteal estradiol 17 beta levels were significantly elevated. Because of the frequent association of premenstrual tension with other gynecologic diseases, screening for premenstrual tension in all premenopausal women is recommended.
The physiological requirement for activation of pituitary gonadotrophin secretion by pulsatile LHRH stimulation is discussed, and compared with the effect of pituitary stimulation by LHRH agonists. Initial stimulation is followed by a phase of progressive pituitary and gonadal inhibition. This inhibition is fully reversible at the end of agonist treatment. Clinical applications of high dose suppression are the treatment of precocious puberty and hormone-dependent tumours (mammary and prostatic carcinoma). In women, agonist administration by nasal spray is a reversible method of inhibiting ovulation, and may also be useful in the treatment of endometriosis. Clinical advantages of agonist therapy are favourable biological tolerance, lack of side effects and rapid reversibility.
Body LiteracyNursing and MidwiferySympto-Thermal MethodCycle Interpretation and Signs
All forms of birth control require some motivation, and motivation calls for understanding. If a woman learns to interpret her own cycles, her understanding of her body will be enhanced, and this could have benefits in all aspects of her fertility control. Professional nurses and health visitors are frequently expected to explain the intrigues of the menstrual cycle whether it be in family planning clinics, on gynecology wards, or in a client's home. When information about the monthly cycle is linked with the signs women observe in their own bodies, knowledge will result. With accurate knowledge about the span of the fertile phase, it should be within most women's grasp to control their own fertility, whether they use this knowledge alone or together with some mechanical contraceptive method. The endocrine hormones which control each menstrual cycle come from the pituitary gland and the ovaries, and they work in a feedback system, triggering each other. The start of the cycle is day 1 of the period when the pituitary gland starts the production of follicle stimulating hormone (FSH). This is taken in the bloodstream to the ovary where, as its name implies, it stimulates the ripening of follicles, each of which contains an egg cell. Operating in a feedback system, estrogen is carried back to the pituitary gland where it then causes a lessening in the production of FSH and stimulates the release of the luteinizing hormone (LH). LH proceeds back to the ovary and together with estrogen suppresses the growth of all the follicles except one, which then matures to release an egg at ovulation. If the egg is not fertilized, the pituitary gland detects the high level of progesterone and ceases production of LH, which causes the corpus luteum to die away. The 1st phase of the cycle leading up to ovulation is known as the follicular phase, and its length can vary considerably from month to month. The 2nd phase, leading up to menstruation, is the luteal phase, and its length does not vary more than 12-16 days, normally 14. There are 3 main observations daily temperature; the cervical mucus; and a "calendar" assessment, and after a few months the likely course of the cycle is evident. Each of these 3 ways of interpreting cycles are reviewed in detail. If the motivation and understanding is there, most women can become adept at reading the signs each month. While still learning, it is important to seek advice from those who understand the methods and can ensure accurate interpretation. Encouraging women to discover how their bodies work is not aimed at discouraging the use of mechanical or chemical contraceptive methods. It is simply a way to enhance a woman's understanding of her body which could bring her positive physical and emotional benefits. Practically, if more women could read their body cycles, there would most likely be an increase in motivation to use contraception and an associated reduction in unwanted pregnancies.
The cause of infertility has remained obscure in women with endometriosis in whom the tuboovarian relationship is unaltered. Abnormal corpus luteum function has been one mechanism implicated in the pathophysiology of endometriosis in infertilityl-3 and may also be a possible explanation for the high frequency of spontaneous abortions among women with untreated endometriosis.4 However, we have observed only an occasional occurrence of luteal phase deficiency in women with an ultimate diagnosis of endometriosis. In order to verify this observation, we examined the incidence of luteal phase defects (LPDs) in. our infertility population.
The authors examined the effect of three months' treatment with spironolactone in 34 women with polycystic ovary syndrome. In all patients a significant decrease in hirsutism was noted as well as restoration of a regular although anovulatory menstrual pattern. Plasma luteinizing hormone and follicle-stimulating hormone levels remained unchanged after spironolactone treatment; however, prolactin levels were lowered in both women with normal and those with elevated basal levels. Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate levels were decreased after three months of therapy. No side effects were observed. Plasma electrolytes and liver function tests were normal during the entire time of treatment. This therapy is recommended as initial nontoxic but effective treatment for women with polycystic ovary syndrome who are hirsute and have menstrual disturbances.
Ovarian hormones have been implicated in a number of neoplastic conditions. Chronic anovulation syndrome, a spontaneous biologic experiment of unopposed secretion of estrogen by the ovaries, was identified in a cohort of 1270 patients, and the risk of these patients having neoplasia was studied. Of the 1270 patients studied, 30 had a subsequent malignancy develop; the expected number was 29.8. When the individual types of subsequent malignancy were analyzed, the endometrium was the only site at increased risk. The relative risk of developing carcinoma of the endometrium after the diagnosis of chronic anovulation syndrome is 3.1 (95% confidence interval 1.1 to 7.3). The long-term risk of developing adenocarcinoma of the endometrium might be considered when treating patients who have this syndrome.
Ovarian hormones have been implicated in a number of neoplastic conditions. Chronic anovulation syndrome, a spontaneous biologic experiment of unopposed secretion of estrogen by the ovaries, was identified in a cohort of 1270 patients, and the risk of these patients having neoplasia was studied. Of the 1270 patients studied, 30 had a subsequent malignancy develop; the expected number was 29.8. When the individual types of subsequent malignancy were analyzed, the endometrium was the only site at increased risk. The relative risk of developing carcinoma of the endometrium after the diagnosis of chronic anovulation syndrome is 3.1 (95% confidence interval 1.1 to 7.3). The long-term risk of developing adenocarcinoma of the endometrium might be considered when treating patients who have this syndrome.