The plasma concentration of progesterone (P) has been measured by radioimmunoassay in maternal peripheral vein (M.P.V.) at early pregnancy and in M.P.V. umbilical artery (U.A.) and umbilical vein (U.V.) at term pregnancy. In early preganacy marked hour-to-hour fluctuation of plasma progesterone was noted. At term pregnancy plasma P levels of U.V. were higher than those of U.A. and the umbilical venous arterial differences of plasma P did not differ between male and femal fetuses. Administration of hydrocortisone and ACTH to patients scheduled to undergo cesarean section had no effect on M.P.V., U.A., and U.V. plasma P concentration. On the basis of the differences between U.V. and U.A. plasma P concentrations and reported umbilical flow it was estimated that the secretion rate of P into the fetal circulation is approximately 23 mg. per 24 hr. and would amount to approximately 10 per cent of the reported total daily production rate of P at term pregnancy. The fraction of P which is unbound to the plasma proteins was estimeated by equilibrium dialysis at 37 degrees C. The per cent unbound P in M.P.V. plasma of pregnant patients at term was not different from that of nonpregnant patients but was 40 per cent lower than that in umbilical cord plasma (P LESS THAN 0.01), and the ratio between the concentrations of unbound P and estradiol in M.P.V. increased as pregnancy progressed. Plasma P in re-eclamptic patients who subsequently sustained intrauterine fetal death had no value in assessing placental function.
5alpha-Pregnane-3,20-dione and progesterone were isolated from a pregnancy plasma pool and were identified by using a combination of chromatographic techniques and mass spectrometry. Antibodies to progesterone were obtained in rabbits by immunization with progesterone-1alpha-carboxyethyl-thioether-thyroglobulin. The raised antibodies were of high affinity and one of them cross-reacted (137%) with 5alpha-pregnane-3,20-dione. This property was used to develop radioimmunoassays for measuring circulating levels of both progesterone and 5alpha-pregnane-3,20-dione in pregnancy plasma. The levels of both progesterone and 5alpha-pregnane-3,20-dione increase throughout pregnancy, but a highly significant increase is observed only after the 32nd week of gestation.
To develop a practical yet statistically valid means of indicating ovulation and adequacy of corpus luteum function concentrations of plasma progesterone (P) were measured daily during the luteal phase of 30 normal and abnormal menstrual cycles. During a normal cycle any 3 P measurements taken from 11 days before the first day of the following menses (M) to Day M-4 gave a total equal to or greater than 15 ng/ml. An abnormal cycle was considered one in which the total P (for 3 measurements) was less than 15 ng. Individual levels were often at 3 ng/ml in normal cycle and above 3 ng/ml in abnormal cycles indicating that the single P measurement proposed by Israel et. al. would not always be valid.
PregnancyGestational Trophoblastic DiseaseProgesterone in Abnormal PregnancyProgesterone
Swain MC et al., 1974·J Obstet Gynaecol Br Commonw
The luteal phase plasma progesterone levels of 341 control patients were compared with those in 25 patients with early and 12 patients with advanced breast cancer. There was a significant increase of ovulatory failure and luteal deficiency in patients with advanced breast cancer.
The use of clomiphene in gradually increasing doses, in cases of infertility due to anovulation, oligo-ovulation and inadequate luteal phase, led to a high pregnancy rate, particularly in the initial stages of treatment. Although clomiphene is a relatively safe and inexpensive drug, there is a possibility that high doses in repeated cycles may adversely affect fertility by its anti-oestrogenic effect. It is therefore suggested that therapy be commenced with a lower dosage than that generally recommended.
Reproductive EndocrinologyLuteal Phase DeficiencyOligomenorrhea Hormonal ProfileHormonal Evaluation of Ovulatory Dysfunction
The irregular menses experienced by obese and/or hirsute women were studied by daily measurement of serum LH, FSH, estradiol (E2) and progesterone (P). During 8 cycles of 24 to 157 days, each episode of menstrual bleeding was preceded by hormonal evidence of follicular maturation and corpus luteum formation. The premenstrual fluctuations of LH and E2 were not different from those observed in normal cycles. Although the luteal phase was of more than 10 days' duration, progesterone secretion was subnormal during each cycle. Serum FSH was low throughout the time preceding the LH/FSH surge. These data suggest that inadequate corpus luteum progesterone secretion may be characteristic of the menstrual cycles in oligomenorrheic, obese infertile women.
Plasma concentration of estrogen and progesterone were measured during the last 6 days of the menstrual cycle in women with premenstrual tension, and compared with a group of healthy women. Those women with anxiety as the main symptom (PMT-a) had significantly higher estrogen levels on days 5-2 before the onset of menstruation. On days 6-4 they had lower levels of progesterone. Estrogen-progesterone ratios were significantly higher on days 6-3 before menstruation. The PMT-a group also showed increases in body wt. during the last days of the menstrual cycle.
Reproductive EndocrinologyExogenous Progesterone EffectsLuteal Phase Progesterone SupportLuteal Phase Dating
A group of infertility patients were evaluated by an endometrial biopsy, timed with a basal body temperature chart, serum luteinizing hormone radioimmunassay to pinpoint ovulation, and daily serum progesterone values during a control and a treatment cycle. Progesterone in the suppository or intramuscular form and 17-hydroxyprogesterone caproate* were administered during the luteal phase to a group of volunteer patients with normal corpus luteum function to determine if these compounds would depress serum progesterone levels as do certain progestational agents. There was no apparent inhibition of corpus luteum function as no decrease in progesterone production occurred. Despite the additive effect of progesterone administration demonstrated by elevated serum levels, endometrial biopsies remained in phase when dated from the estimated day of ovulation.
PregnancyHormonal Initiation of LaborProgesterone WithdrawalEstradiol-Progesterone Ratio at Term
Lindberg BS et al., 1974·Acta Obstet Gynecol Scand
Plasma progesterone levels were estimated by competitive protein binding in 815 samples from healthy pregnant women with uncomplicated pregnancies. This series includes 32 patients who were followed serially throughout pregnancy. The mean level increased from 47 ng/ml in week 22 to 148 ng/ml in week 41. The spread was large. Individual patients showed very large variations between two consecutive weeks.
Diurnal variations were examined in 7 patients and short-time variations during one hour in 5 patients. Large but non-systematic variations were found in most cases. The maximal difference between values observed over a 24-hour-period was 123 ng/ml and during one hour 150 ng/ml.
Plasma progesterone levels were studied in 87 cases of toxemia of pregnancy, 6 cases of hypertension, 54 cases of Rh-immunization, 37 cases of diabetes and 5 cases of fetal growth retardation of unknown origin. The results indicate that no constant changes occur in plasma progesterone levels in these groups or in cases of impending fetal death.
As the normal limits are very wide, the intraindividual variations large, and the progesterone values in high risk pregnancies are inconclusive, plasma progesterone estimates during the latter part of pregnancy seem to be of limited value.
During human pregnancy large amounts of progesterone are produced by the placenta (1, 14). The production rate during the third trimester lies between 200 and 300 mg/day (9). Part of the progesterone produced is metabolized to pregnanediol and excreted in the urine as the 3-glucuronidate (16). The percentage of conversion to pregnanediol seems to vary with the stage of gestation and is influenced by pathological alterations in risk pregnancies (2, 5).
Large day to day variations in the urinary pregnanediol levels have been found. It is thus hardly surprising that the clinical value of serial determinations of urinary pregnanediol in late pregnancy has been limited.
Recently useful methods for the assay of progesterone in plasma have been developed and applied to physiological and clinical studies. A number of reports dealing with the prognostic value of progesterone determinations in complicated pregnancies have been published (8, 12, 17). The number of cases investigated is, however, small and the results are, in many respects, inconclusive. The aim of the present investigation was to determine the normal limits during the latter half of uncomplicated pregnancies, circadian and short-time variations, and to evaluate the prognostic value of progesterone determinations in plasma in high risk pregnancies.
The levels of prostaglandins in the human endometrium throughout the normal menstrual cycle were measured by bioassay. The identity of prostaglandin F2alpha and prostaglandin E2 in endometrial tissue extracts was established by combined gas chromatography/mass spectrometry. The levels of prostaglandin F2alpha and prostaglandin E2 are low during the proliferative phase of the cycle (10-25 ng/100 mg tissue). Prostaglandin F2alpha rises significantly during the luteal phase to levels of 65-75 ng/100 mg of tissue. Prostaglandin E2 levels are similar to prostaglandin F2alpha levels in the proliferative phase but remain lower during the luteal phase. The prostaglandin E2 level is highest at menstruation (52 ng/100 mg tissue). The implications of these findings are discussed in relation to the menstrual process and to the steroid hormonal changes during the cycle.
Reproductive EndocrinologyHistory of DiscoveryHormone Research
This paper gives in narrative style those phases of the corpus luteum story in which the author was an active participant. The first part deals with the exciting days at the University of Rochester where the pure hormone was isolated in 1933 and where many of the effects of the hormone on target tissues were elucidated. The origin of the name, progesterone, is given as a fine example of international cooperation in the selection of a name which has been universally accepted. The accidental discovery of the ‘Blue Color Test’ for DHIA and the development of the Allen-Correction at Washington University in St. Louis are recounted as sideline adventures in science. The final part recounts the steps, extending over a period of 40 years, which have clarified the role of the human corpus luteum in pregnancy.
The ovulation method of family planning relies on self-recognition of physiological changes occuring around time of ovulation rather than a calendar to enable a couple to avoid sexual intercourse during the fertile period. The most practical signs are elevated basal body temperature, changes in the amount and physicochemical properties of cervical mucus, and ovulation pain. The basal body temperature rises about .3 degrees C following ovulation. The problem with this method is that it is retrospective. The mucus symptoms, as described by Billings and associates in Melbourne, Australia, 1) a variable number of days with no vaginal discharge following menstrual bleeding; 2) onset of mucus symptoms characterized by increasing quantities of ''cloudy'' or ''sticky'' secretion; 3) a clear, slippery lubricative mucus having the characteristics of raw white of egg (spinnbarkeit), which is an immediate forwarning of ovulation; 4) a variable period of thick, opaque, diminished volume discharge followed by dry days. The clear ''peak symptom'' mucus lasts 1-2 days; in a study of 22 women followed for 27 cycles this symptom occurred .9 days +3 or -2 days before ovulation. The problem is that 2 of the 22 cycles reported in detail had ovulation 3 days after the peak symptom and 1 had ovulation 4 days after. Intercourse on the 4th day, therefore, would have had a significant risk of pregnancy. Weissman and associates collected data on 282 women on the Pacific island of Tonga who used the mucus symptoms alone to control conception. In the 2503 cycles there were 53 unplanned pregnancies, 25.4 per 100 woman-years using the Pearl formula. 50 resulted from the couples ''taking a chance,'' 2 misunderstood the method, 28 abandoned the method because they wanted more children, and 1 woman became pregnant even though she thought she understood the method. Field trials with groups who are more motivated than those in the Tongan trial are needed.
Progesterone levels in the human fetoplacental unit at term were determined by a competitive protein binding method. Progesterone levels in the umbilical vein were always higher than in the umbilical artery. The concentration of progesterone in the umbilical vein of male and female fetuses was identical. However, the umbilical venous-arterial difference in progesterone levels was significantly greater in female than in male fetuses. The fetal genotype therefore may affect the fate of progesterone available to the fetus.
SurgeryCorticosteroid ProtocolsPostoperative OutcomesReproductive Surgery Outcomes
A combination of Decadreon (dexamethasone) and Phenergan (promethazine) was tested in this collaborative study of 240 infertility patients as a means of preventing postoperative adhesion formation after simple pelvic surgery. 24 patients were lost to follow-up. The overall pregnancy rate among the 240 patients was 51.7% (124): 49% with primary infertility and 58% with secondary infertility conceived after surgery. 90 full-term deliveries were recorded, 27 spontaneous abortions occurred, and 7 ectopic gestations were conceived. In all, 31 cases were reinspected for various reasons after the drug treatment postsurgery; 42% showed no adhesions, 23% showed minimal adhesions, and 35% had significant adhesions. Complications coincident with use of the combined medication were seen in 2.2% (11 of 240) patients. Though this study lacked controls, the authors feel thta the use of corticosteroids postoperatively after pelvic intervention may control the numbers of adhesions which form postoperatively.
Ten ovulating women were studied to assess the interrelationships of various systemic, hormonal, and reproductive tract changes during normal menstrual cycles. Samples of blood, 24 hour urine specimens, vaginal smears, and cervical mucus were obtained every 2 days preand post-menstrually and daily in mid-cycle. Endometrial biopsies were performed at the onset of or immediately before menstruation, and the basal body temperature was recorded. Data for 10 cycles were fed into a computer, and mean reciprocal relationships were determined. (1) All endometrial biopsies reflected the late secretory phase; (2) there was a simultaneous mid-cycle surge of luteinizing hormone (LH) and folliclestimulating hormone (FSH), and serum concentrations of FSH and LH were significantly lower in the luteal phase compared to the follicular phase; (3) urinary peaks of estrone, estradiol and total estrogens occurred on the day before and that of estriol occurred on the day of the LH surge; (4) serum progesterone began to rise just before the LH peak, reached a high level 7 days after the LH peak, declined precipitately on Day 9, and rose again on Day 10, to decrease slowly until the onset of menstruation; (5) a significant relationship was observed between the LH peak and the basal body temperature; (6) urinary pregnanediol levels closely paralleled serum progesterone concentrations; (7) vaginal cytology revealed a karyopyknotic index peak the day following the LH peak; (8) properties of cervical mucus showed a remarkable relationship to the ovulatory estrogen peak.
Reproductive EndocrinologyGnRH DiscoveryFSH and LH RegulationGnRH Therapy
This article has been designed to review recent developments in the field of hypothalamic hormones involved in the control of reproductive functions. A brief resume of early physiologic and anatomic studies was presented initially to give a better understanding of the concept of hypothalamic regulation of the release of gonadotropic hormones from the pituitary gland. Recently, an advance was achieved with the isolation from porcine hypothalami of a decapeptide which has both FSH-releasing hormone (FSH-RH) activity and LH-releasing hormone (LH-RH) activity. Its amino acid sequence was determined to be (pyro) gluhis-trp-ser-tyr-gly-leu-arg-pro-gly-NH2. The decapeptide corresponding to this structure was synthesized and shown to stimulate the release of LH and of FSH in laboratory and domestic animals and human beings. Natural and synthetic FSH-RH/LH-RH also stimulated the synthesis of both gonadotropins in tissue cultures of rat pituitaries in vitro. It was postulated that this decapeptide represents the hypothalamic hormone which regulates the release of both LH and FSH from the anterior pituitary gland. Complex effects of sex steroids on the release of LH and FSH were reviewed briefly. It was suggested that the over-all control of secretion of FSH and LH is most likely mediated by the interaction of hypothalamic FSHand LH-releasing hormone with sex steroids. Clinical studies performed with natural and synthetic LH-RH/FSH-RH were reviewed. These studies, particularly induction of ovulation, suggest that LH-RH should find practical application in the treatment of sterility. Subsequent synthesis of LH-RH/FSH-RH by several laboratories and drug houses should provide enough material for large-scale clinical evaluation of this hormone. Some comments were made concerning probable clinical use of LH-RH. Finally, some speculations were offered about the possibility of developing new birth control methods based on LH-RH/FSH-RH, its analogues, or its derivatives.
Studies on pituitary and ovarian function as assessed by the urinary output of total gonadotrophic activity, the three classical oestrogens, pregnanediol and, in some cases, testosterone and epitestosterone, were conducted in eight patients suffering from premenstrual tension. Major abnormalities in endocrine function were not a feature of the condition. Ovulation, as judged by pregnanediol assays, was absent in seven out of the fifteen cycles investigated. Contrary to traditional belief, the symptoms of premenstrual tension could exist in the presence of cycles with anovulatory hormonal patterns.
Eighty-six women reached at least 20 weeks' pregnancy in 96 instances, after ovulation induced by clomiphene citrate. Although 37 of the women had 44 previous pregnancies, there had been a high pregnancy wastage (70.5%) producing only 13 live infants prior to the successful clomiphene therapy. After clomiphene therapy, pregnancies were normal except for a high incidence of toxemia (16.7%) and a possibly increased incidence of prediabetes. The pregnancies resulted in 88 single and 8 twin births. The total fetal and neonatal loss was 6.7%. The loss of single births (3.1%) included two stillbirth infants of prediabetic mothers. The twin loss of 25% was due to prematurity. The incidence of congenital malformations was within normal limits.
Fertility AwarenessUser FactorsEffectiveness and ComplianceFamily Planning Adherence
To describe normal relationships between the various plasma unconjugated estrogens and progesterone during the second half of human pregnancy, the plasma concentrations of progesterone, 17-hydroxyprogesterone (17-OHP), and unconjugated estrone (E1), estradiol (E2), and estriol (E3) were measured in 126-310 normal women. Progesterone and unconjugated E1, E2, and E3 increased gradually throughout later pregnancy; 17-OHP increased only after the thirty-third week. At term the mean value of progesterone was 9 times higher than that 17-OHP. Throughout pregnancy the mean value of E2 was higher than that of E1 or E3. During the second half of pregnancy the ratios of progesterone to estradiol and estriol and of estradiol to estriol remained unchanged, indicating no preferential increase of plasma concentration of maternal or fetal hormones.
A study was undertaken to determine whether solitary progesterone as says performed on serum samples obtained in the midluteal phase would provide the clinician with a convenient indicator that ovulation had occurred in that cycle. After a normal luteal-phase range was establish ed, single luteal-phase serum progesterone sampling was performed in 51 infertile women with regular menses and 35 oligomenorrheic women undergoing clomiphene citrate therapy. In the follicular phase of the cycle, progesterone levels were consistently less than 2 ng/ml. Between 11 and 4 days prior to the onset of menses in presumptively ovulatory cycles, serum progesterone levels were always 3 ng/ml or greater. Progesterone values in this range were always accompanied by a secretory endometrium and can be considered presumptive evidence of ovulation. This rapid, easily performed technique enables 1 technician to assay 30 or more samples for progesterone in a single working day and the results are available within 24 hours. This assay technique is easier to perform and more reproducible than a urinary pregnanediol assay, and it is expected that clinical laboratories will soon perform serum progesterone assays as a routine procedure.
Following the total removal of luteal tissue, circulating plasma progesterone, intrauterine pressure, oxytocin response, and clinical progress in abortion were determined sequentially in 12 first-trimester pregnant patients. 3 patients were ovariectomized for the removal of ovarian cysts and 9 were luteectomized during tubal ligation in an attempt to terminate pregnancy in spontaneous abortion. 7 patients had corpora lutea which averaged 21 plus or minus 1mm in diameter at operation when performed at Day 49 plus or minus 2 (mean S.E.) of pregnancy. These patients responded to ovariectomy or luteectomy by a continuing decrease in progesterone, evolution in intrauterine pressure, oxytocin response, progress in cervical dilitation and, abortion. Abortion occurred with a mean lapse time of 5 plus or minus 1 days after operation. In contrast, 5 patients whose corpora lutea averaged only 11 plus or minus 1mm in diameter when removed at Day 61 plus or minus 4 of pregnancy showed only transient decrease in progesterone after operation. This decrease was followed by an increase in progesterone; no progress in the evolution of intrauterine pressure, oxytocin response, cervical dilatation, and abortion. It appears that so long as the corpus luteum serves as the major source of progesterone, it is indispensable in the maintenance of pregnancy in human subjects as it is in the clinical model animal, the rabbit. However, with the shift of progesterone production from the corpus luteum to the placenta (the luteoplacental shift) the human corpus luteum becomes dispensable. These findings identify the corpus luteum and its secretory product, progesterone, as feasible targets of fertility control strategy.
Fertility AwarenessHormonal CorrelationSymptoms and SignsOvulation Detection
PROSTAGLANDINS (PGs) are being used increasingly as abortifacients although their precise mechanism of action is uncertain. One of the compounds frequently used is PGF2α, which has been shown to stimulate the myometrium in vitro1 and in vivo2. Whether or not the direct action of this agent on the uterine muscle alone is responsible for the interruption of pregnancy is not clear, but the long interval between infusion and abortion3 suggests that other mechanisms might be involved; for example, a luteolytic effect4–6. The prompt increase in uterine activity after treatment with prostaglandin, however, argues that the direct effect plays some part in the abortifacient action. Little is known of the influence of other myometrial regulatory agents such as the ovarian steroids on the uterine response to PGs. Accordingly we examined the influence of progesterone on myometrial responses to prostaglandin F2α in the rabbit, a species in which progesterone is known to have a blocking action on the uterine muscle7.
A METHOD IS DESCRIBED FOR ANALYZING THE ASSOCIATION OF THE OPIATE NARCOTIC LEVORPHANOL WITH BRAIN nonsaturable, saturable nonspecific, and saturable stereospecific. The method may be of general applicability for the study of the interaction of drugs with body tissues. In mouse brain the stereospecific binding of levorphanol represents only 2% of the total association of drug with tissue, and it was found only in certain membrane fractions. The material responsible for the stereospecific binding might be the opiate receptor.
The use-effectiveness of oral contraception and intrauterine contraception was studied in 3 family planning Grady Memorial Hospital in Atlanta, Georgia; State University of New York, Downstate Medical Center, in Brooklyn; and the Planned Parenthood Center in Buffalo, New York. In each locality 1000 women were selected for the study. 2900 women accepted intrauterine devices (IUDs) or oral contraceptives (OCs) as their first method of contraception. In Brooklyn 3 out of 4 women chose OCs; in Atlanta and Buffalo roughly equal numbers selected each method. The mean age of admission was 25.7 years in Buffalo, 24 years in Brooklyn, and 23.8 years in Atlanta. IUD acceptors were older than those choosing OCs. The difference was greatest in Buffalo (3.3 years) and smallest in Atlanta (.8 years). A special one-page, self-coding questionnaire was designed to collect the information required. In all 3 clinics contraceptive termination rates were markedly lower for the IUDs than for OCs. At 1 year of use for the first method only about one-fourth the women who chose the IUD had discontinued its use. Women on OCs terminated at rates from 10-20% higher. Termination rates for all contraception, both first-method and substitution, were lower than for first-method alone and lower for IUDs than for OCs. The highest continuation rate for all contraception was 92.5% for IUD users in Brooklyn while OC users in Atlanta were at the lowest level at 60.5%. Pregnancy rate studies demonstrated higher failure rates with OCs than with IUDs in all 3 clinics. Statistics by age showed that termination rates for both IUD and OC users declined with age. Women who selected IUDs as their method of contraception were more persistent users of contraception. Even after discontinuing IUD use, they were more likely to adopt another contraceptive method.
PregnancyProgesterone LevelsPregnancy and LaborHormonal Changes
Some of the psychological influences on contraceptive misuse and rejection are presented, ranging from denial (of the possibility of pregnancy), guilt, sexual identity conflicts, to fear, opportunism (desperation) and iatrogenesis (influence of medical personnel. It is suggested that more attention be focused on these psychological factors as a means to successful population control rather than on the development of the "ideal" contraceptive. In discussion 4 doctors varied in their reactions to the authors' premise that social systems which require or allow volitional and individually initiated contraceptive use - as the sole method for population control - will fail to accomplish that goal.
The extended use-effectiveness of IUD and oral pills as measured by 1) their theoretical effectiveness 2) consistency of use and 3) continuation of use in preventing unwanted pregnancies was studied for 2900 women who had chosen either method as their first contraceptive in family planning clinics in Atlanta Georgia and in Brooklyn and Buffalo New York for a 12-18 month period. The greater persistence among IUD users to continue the method or use another method and the less likelihood there was of these women to have an unplanned pregnancy (the difference between IUD users and pill users increasing with months of exposure) suggest the necessity of greater support from the clinics to help women using pills prevent unwanted pregnancies. IUD users were generally older than pill acceptors and among IUD contraceptors the greater tendency to continue using the IUD and contraception may indicate that older women use contraception to terminate rather than to space childbirth.