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Plasma levels of progesterone after vaginal, rectal, or intramuscular administration of progesterone

Nillius SJ et al., 1971·Am J Obstet Gynecol

Progesterone and 20 alpha-dihydroprogesterone in human myometrium during pregnancy

Runnebaum B et al., 1971·Acta Endocrinol Suppl (Copenh)

Experience with induction of ovulation

MacLeod SC et al., 1970·Am J Obstet Gynecol

One hundred and thirty-five patients diagnosed as ovulatory failure have been treated in our clinic since 1966. One hundred and eighteen of these have been treated with clomiphene citrate, or more recently, its cisisomer, and 17 patients with long-standing secondary amenorrhea or primary amenorrhea have been treated with human menopausal gonadotropins, in combination with human chorionic gonadotropins. Of the latter group, 14 of the 17 were shown to be capable of response to exogenous gonadotropins and 12 of these ovulated and 7 (50 per cent) became pregnant. The over-all ovulatory rate with clomiphene citrate or its cisisomer was 78 per cent, with a pregnancy rate of 31 per cent. The results of our present investigation with clomiphene citrate in 10 and 20 mg. dosage are presented in detail, and compared with our previous experience with clomiphene. It appears that cisclomiphene 20 mg. is as effective as clomiphene citrate 100 mg., but has the decided advantage of fewer side effects associated with its use. With the human menopausal gonadotrophins, no major complications, such as ovarian overstimulation or multiple pregnancies, were encountered, and we feel this is attributed to careful selection of patients and daily tracking of total urinary estrogens.

Plasma progesterone secretion by the corpus luteum of term pregnancy

LeMaire WJ et al., 1970·Am J Obstet Gynecol

Plasma progesterone concentration was determined in the maternal peripheral vein, umbilical vein, uterine vein, and both ovarian veins at elective cesarean section in term pregnancy. In 10 cases plasma from both ovarian veins was analyzed. In all but one the ovarian vein draining blood from the corpus luteum contained greater concentrations of progesterone than did the blood from the side without the corpus luteum. It has been suggested for some time that the corpus luteum of pregnancy continues to function throughout pregnancy. Our data appear to support this concept.

Neonatal estrogen stimulation nd aggressive behavior in female mice

Edwards DA et al., 1970·Physiol Behav

The short luteal phase

Strott CA et al., 1970·J Clin Endocrinol Metab

From among a group of women with apparently normal menstrual cycles, 7 cycles with short luteal phases were identified. These cycles were characterized by grossly normal FSH and LH patterns although the FSH/LH ratio was below normal. Mean plasma progesterone increased to less than 2 ng/ml shortly after the LH peak; thus, the peak level was lower and the peak occurred earlier than in the normal cycle. Plasma 17-hydroxyprogesterone increased at the time of the LH peak although the mean peak level was only 60% that of normal cycles. There was no secondary increase of 17-hydroxyprogesterone during the luteal phase. These observations are consistent with the hypothesis that a relative deficiency of FSH during the follicular phase results in diminished follicular development and subsequent inadequate corpus luteum formation or function.

Psychologic aspects of the basal body temperature method of regulating births

Marshall J et al., 1970·Fertil Steril

Outcome of pregnancy after induced ovulation. Follow-up of pregnancies and children born after gonadotropin therapy

Hack M et al., 1970·JAMA

Plasma levels of progesterone in pregnancy measured by a rapid competitive protein binding technique

Johansson ED, 1969·Acta Endocrinol (Copenh)

Plasma levels of progesterone* were measured during normal human pregnancy by a sensitive and rapid competitive protein binding technique. During the first half of gestation 440 determinations in 321 women and in the second half of gestation, 209 determinations in 160 women were performed. The average plasma level of progesterone in the 5th week of gestation was 24.8 ± 7.3 (s) ng/ml which is above the normal range of the luteal plateau of the menstrual cycle (10–20 ng/ml). Between the 5th and the 9th week of gestation the plasma concentration decreased significantly. From the 9th to the 32nd week of gestation the plasma level of progesterone increased from 16.7 ± 7.4 (s) to 125.2 ± 37.9 (s) ng/ml. During the last 8 weeks of gestation the plasma levels of progesterone did not show any significant rise. One woman was followed up from the day of ovulation to the 8th week of gestation. An increase in progesterone levels was observed about 10 days after ovulation. Morning samples of progesterone, which were taken before the 20th week of gestation, when the woman was still in bed, were found to be somewhat higher than levels found during the remainder of the day. Progesterone concentrations in a few abnormal pregnancies are also reported.

Evaluation of a new ovulatory stimulating agent: clomiphene citrate (clomid)

No Authors Listed, 1968·JAMA

Clomiphene citrate, in selected patients, is an effective agent for the treatment of infertility due to anovulation. An adequate laboratory and physical evaluation of each individual patient is essential for proper use of the drug. The major adverse reactions encountered are ovarian enlargements and cysts; in most patients, these conditions regress spontaneously after withdrawal of the drug.

Plasma progesterone levels in normal pregnancy, labor, and the puerperium. I. Method of assay

Yannone ME, 1968·Am J Obstet Gynecol

A method to measure plasma progesterone by gas-liquid chromatography is presented. The procedure allows for the preparation of a plasma progesterone extract clean enough for accurate submicrogram quantification by gas-liquid chromatography. In a gas chromatograph equipped with a hydrogen flame detector, the instrument modifications and operating conditions as outlined make possible the measurement of 0.001 μg (1 ng.) of progesterone standard on a stable recorder base line. In biologic samples the sensitivity of the assay is in the order of 0.01 μg (10 ng.) of progesterone.

Plasma progesterone levels in normal pregnancy, labor, and the puerperium. II. Clinical data

Yannone ME et al., 1968·Am J Obstet Gynecol

One hundred and seventy-two plasma progesterone determinations were performed in normal pregnancy, labor, and the puerperium. One hundred and nineteen of the assays were done on isolated samples; 53 of the assays were done in 11 serial studies. While the concentration of progresterone in peripheral blood increased progressively with advancing pregnancy, no apparent decrease in the hormone level occurred at or near the onset of labor or during its progress. A significant decrease in plasma progesterone one hour after the delivery of the placenta continued to decline to menstrual cycle levels by 72 hours post partum.

A field trial of the basal-body-temperature method of regulating births

Marshall J, 1968·Lancet

502 couples used the basal-body-temperature method of regulating births through 8294 cycles. The overall failure-rate in those confining coitus to the postovulatory phase of the menstrual cycle was 6·6 pregnancies per 100 women-years, while in those having coitus in the preovulatory and postovulatory phases it was 19·3 pregnancies per 100 women-years. The biological effectiveness of the method was greater than this, and was achieved by certain subgroups in the survey.

Further clinical experience with clomiphene citrate

Macgregor AH et al., 1968·Fertil Steril

Statistical evaluation of contraceptive methods: Use-effectiveness and extended use-effectiveness

Lewit S et al., 1968·Demography

The recent advent of national family planning programs and the expansion of local programs have created an acute need for accurate statistical evaluation of contraceptive methods. Effectiveness in terms of pregnancy rates and continuation or discontinuation of use of the contraceptive method or methods under study have emerged as the major criteria in such evaluations.

Pregnancy after clomiphene citrate treatment

Karow WG et al., 1968·Fertil Steril

For years the gynecological endocrinologist has been seeking an effective gonadotrophin for the treatment of ovarian dysfunction and anovulation in the human. 7 Animal preparations have been self-limiting because of allergic reactions, antihormone formation, failure to obtain a uniform response from a standard dose, and the absence of data on animal specificity. A breakthrough occurred in 1958 when Gemzell et al. reported a human pituitary gonadotropin which induced follicular growth and estrogen production in the ovaries of amenorrheic women. The human source does not permit widespread application of this material. A few years later, Pergonal (HMG ),* a human menopausal urine gonadotropin which had similar effects,16 was developed; but standardization of HMG has been difficult and the extraction process complicated and expensive. A most important contribution was made in 1959 by Tyler et al., who were able to induce ovulation in 6 patients with severe anovulatory problems, and in 1960 by Kistner and Smith, who successfully induced ovulation in 4 patients with the Stein-Leventhal syndrome, by using the estrogen antagonist MER 25.t Related compounds were further investigated and clomiphene citrate (Clomidt) proved more effective and had fewer side effects. 5, 12 The exact mechanism of action of the drug is stilI in doubt. It is postulated that clomiphene acts either directly on the hypothalamic-pituitary axis, causing an increase in gonadotropin output,9, 12, 17 or sensitizes the ovary to respond more readily to endogenous gonadotropins. 6 Smith and Kistner believe that Clomid directly influences the enzyme systems involved in ovarian steroidogenesis, or merely acts as a potentiator of gonadotropins. Pildes believes that there is a change in the synthesis of estrogen in both the adrenals and ovaries at the pre-estradiol phase of steroid synthesis. Dickey et al. postulate a direct anti-estrogen effect in the system involved in estrogen metabolism, with subsequent stimulation of the hypothalamic-pituitary axis due to a fall in estrogen levels. Probably more than one mechanism of action is responsible for the response to the drug. We first used clomiphene in the treatment of infertile patients with impaired ovarian function in May 1962. Because of the frequent side effects such as large ovarian cysts, reported by the early investigators, its use was limited to women with major endocrine defects and in cases where all other treatments had failed. With more experience and smaller dosages, 50-200 mg. daily for a short period of time, 3-5 days of each cycle, the drug was effective and most of the side effects were eliminated.14 With a program of at least monthly checkups, the drug proved safe and we have extended its use to infertile patients with only minor problems of ovarian dysfunction. All patients, prior to treatment, have a thorough infertility and endocrine evaluation. The patient who is a proper candidate for this drug should be one with a moderately intact pituitary-ovarian axis and norm~or low total urinary gonadotropin levels, although we have had several patients with mildly elevated total gonadotropin who have responded. The patient should have a fair endogenous estrogen production. Thyroid function is usually normal or mildly subnormal. The 17-ketosteroid concentration is usually normal, although 32.5% of our patients who conceived did show levels of 13.0 mg. 24 hr. or more. Several of these decreased to normal levels after treatment with clomiphene; Pildes has reported a similar finding. Of our patients who conceived, 35.5% showed a diabetic or a prediabetic glucose tolerance curve on initial evaluation. Pituitary tumors should be ruled out. Patients with ovarian damage due to chronic infection are not likely to respond. Since clomiphene citrate is detoxified in the liver, one should be hesitant to prescribe the drug to a patient with chronic liver disease. Visualization of the ovaries by culpotomy with ovarian biopsy or culdos-copy is helpful in establishing the diagnosis, especially in patients who fail to respond.

Biophysical composition of cervical mucus and spermigration during treatment with Conluten and Conlunett

Odeblad E, 1968·Acta obstetricia et gynecologica Scandinavica

The functional structure of human cervical mucus

Odeblad E, 1968·Acta Obstet Gynecol Scand

Clomiphene citrate for improvement of ovarian function

De Moraes-Ruehsen MD et al., 1967·Am J Obstet Gynecol

Some aspects of the clinical communication of pain

J C Prior, 1967·J Am Med Womens Assoc

Hormonal therapy for control of the incompetent os of pregnancy

Sherman AI, 1966·Obstet Gynecol

The concept that a cervix could be inadequate or incompetent for retaining a normal pregnancy was publicized by Lash and Lash in 1950. It did not catch the fancy of the majority of obstetricians to any extent until the introduction of the relatively simple corrective procedure advocated by Shirodkar in 1955 and publicized by Barter et al. Since then there has been a constantly increasing number of reports discussing this problem. Incompetent cervical os is estimated to represent only a small percentage of all causes of fetal wastage …

An instrument for transcervical treatment of the oviducts and uterine cornua

Corfman PA et al., 1966·Obstet Gynecol

A new instrument has been designed to treat the primate uterine cornua and oviducts. 2 versions of the instrument are described. Both versions are 12 cm long. One is 3 mm in diameter, and the other is 3.5 mm. Tips may be manufactured to hold different volumes of fluid. The Teflon piston which is moved inside the tip, forces the fluid out through a small hole at the end. The piston is actuated from the proximal (operator's) end of the strument. Silicon rubber tubing may be filled with air or fluid from the stopcock at the operator's end through a fine tube which runs inside the instrument. In an attempt to determine if the instrument will locate fluids reliably and accurately, a vital stain, cresyl violet, has been used to inject normal sized uteruses in 6 patients prior to operation for various conditions. In 3 patients, both cornua were successfully stained with dye. In 2 patients, the cornu on only 1 side was seen to be stained, and in 1 patient, no stained areas were identified. Suggested applications 1) investigation of oviduct physiology; 2) temporary sterilization; and 3) permanent sterilization.

Prevention of postoperative intestinal adhesions with combined promethazine and dexamethasone therapy: experimental and clinical studies

Replogle RL et al., 1966·Ann Surg

This study, combining experimental and clinical data, attempted to develop methods to prevent formation of adhesions in the highly susceptible infant undergoing abdominal surgery and to inhibit reformation of adhesions after surgical division of those which had appeared after some previous operation. Rats were treated with a combination of dexamethasone (Decadron) and promethazine (Phenergan). This series showed that the inflamma tory phase that follows trauma to intestinal serosa can be minimized and the organization of inflammatory exudate into fibrous adhesions can be delayed with this combination treatment (antihistamine plus adrenal cortex hormones). An addendum notes that so far 81 patients have been treated with the drug combination, and the results are characterized as very satisfactory, with no complications related to treatment. 2 1) since adhesion formation begins within minutes of peritoneal trauma, prevention requires a high level of drug saturation at the time of injury; and 2) large doses of drugs are required for maximum benefit. Experimentally, this study used 1 mg/kg of each drug, intramuscularly, 6-3 hours preoperatively, with dose repetetion via intraperitoneal saline as the abdomen is being closed for 2-36 hours postoperatively.

Habitual Abortion Treated with 17 Alpha-Hydroxyprogesterone Caproate

Cope E et al., 1966

Reconstructive tubal surgery

McEwen DC, 1966·Fertility and sterility

Double-Dash Blind Controlled Trial of 6-Methyl, 17-Acetoxyprogesterone in Threatened Abortion

Møller K et al., 1965

Hormones in Recurrent Abortion

Klopper A et al., 1966·BJOG

FURTHER OBSERVATIONS ON THE EFFECTS OF CLOMIPHENE CITRATE IN ANOVULATORY FEMALES

Kistner RW, 1965·Am J Obstet Gynecol

The clinical use of clomiphene citrate

Rivo E et al., 1965·Pac Med Surg

The clinical use of clomiphene citrate

Rivo E et al., 1965·Pacific medicine and surgery

Clomiphene citrate: Its uses and observations on its probable action

Whitelaw MJ et al., 1964·Am J Obstet Gynecol

CLOMIPHENE CITRATE IN THE MANAGEMENT OF ANOVULATORY UTERINE BLEEDING

Puebla RA et al., 1964·J Clin Endocrinol Metab

Clomiphene citrate [1-p(β-diethylaminoethoxy) phenyl-1,2-diphenyl-2-chloroethylene citrate], because of its ability to induce ovulation, was administered to 26 patients with excessive anovulatory uterine bleeding. Of the 129 menstrual cycles during which the drug was administered, 105 cycles (81.3%) were ovulatory and were followed by normal uterine bleeding. After clomiphene was discontinued, observations made in 52 cycles showed that only 20 (38.4%) were ovulatory

ACTION OF PROGESTERONE AS A CLEAVAGE INHIBITOR OF RABBIT OVA IN VITRO

Daniel JC Jr et al., 1964·J Reprod Fertil

Summary. The manner whereby progesterone acts as an inhibitor of cleavage of mammalian ova was studied using rabbit ova in vitro. Progesterone blocked cleavage when it was present in the culture medium at concentrations of 10 µg/ml more, and exerted this same effect on all stages up to the morula. The growth of blastocysts was not affected. ova resumed cleavage within 2 to 3 hr after removal to progesterone-free media. The reversal was time-specific and was used to phase the subsequent cleavage of ova inhibited for varying periods of time. The inhibition was overcome by increasing the concentrations of amino acids or of the serum component in the medium. Supplementing the progesterone media with oestradiol did not reverse the inhibition. Autoradiographs of sections of ova that were kept in C-labelled progesterone for 8 hr, showed silver grains concentrated on the surface of the ovum and the zona pellucida. It is concluded that progesterone blocks cleavage by limiting the supply of protein or amino acids and thus inhibiting protein synthesis within the ovum. Presumably this is done by the progesterone aggregating on the surface of the cell or its protective coating. The inhibitory action appears to be timed in relation to some event that precedes mitosis by an hour or two. It is therefore suggested that the protein synthesis involved is related to formation of the mitotic apparatus or to chromosome condensation.

THE EFFECT OF PROVERA ON THE FETUS

Burstein R et al., 1964·Obstet Gynecol

239 women received medroxyprogesterone during their pregnancies; they received no other hormone therapy. Of the 203 who went to term 172 were treated prior to the 12th week; the latter are discussed. Average daily dose varied from 5-50 mg or more orally with or without injectable supplements. Sex distribution of infants was 92 male to 82 female there were 2 sets of twins 1 stillborn and 1 newborn with congenital heart disease. The authors report a case of transient masculization of a female infant born with an enlarged clitoris which persisted until age 6 months. Masculization of the female fetus may occur if the fetus is subjected to some source of androgen prior to the 12th week of gestation after which the female generative tract is well differentiated and not likely to be affected. Other studies have reported up to 18% masculization using exogenous hormones with abnormalities as extreme as labial fusion and cloacal formation necessitating surgical correction.

DOUBLE-BLIND TRIAL OF A PROGESTIN IN HABITUAL ABORTION

Goldzieher JW, 1964·JAMA

Study of 54 habitual aborters with low or normal pregnanediol excretion, in a double-blind trial, revealed the spontaneous-salvage rate and the possible benefit of therapy with medroxyprogesterone acetate. The salvage rate in the placebo group with the worst prognosis (never a term pregnancy, low pregnanediol in the current pregnancy) was ten of 13, and the salvage rate in the other placebo groups showed no statistically significant difference. In view of this high spontaneous salvage rate, the numbers required to demonstrate a therapeutic effect of progestin administration are prohibitively large. This indicates the need for new criteria to pinpoint cases with a poor prognosis, and it raises the question whether habitual abortion is a disease entity or a statistical coincidence.

INDUCTION OF OVULATION WITH CLOMIPHENE CITRATE

Naville AH et al., 1964·Fertil Steril

Spontaneous Abortion Risks in Man: Data from Reproductive Histories Collected in a Medical Genetics Unit

Fraser FC et al., 1964·Am J Hum Genet

SPONTANEOUS ABORTION is one of the most common and least understood pathological processes. Because it is so difficult to obtain reliable information about abortion, even the basic facts about its frequency, familial distribution, and relation to parity and parental age are largely unknown or disputable. Such information is needed to provide a basis for advising women with several abortions about their chances of successfully completing another pregnancy, to evaluate measures for the prevention of abortion, as well as to provide clues to the etiology of the condition. Reproductive histories taken by personal interview with a random series of women would probably be the best available data for estimating spontaneous abortion statistics. These would include very early terminations of pregnancy, recognized as spontaneous abortions by the women concerned but not receiving medical attention, which are under-represented in series of consecutive hospital admissions or in consecutive cases from private obstetrical practice. They would allow estimation of abortion risks in women with given numbers of previous abortions and at given ages. Some reservations must be held about the validity of self-diagnosis of early abortion, but this source of error should not affect comparisons within the sample.

PURIFICATION OF GONADOTROPHIN FROM HUMAN MENOPAUSAL URINE

Donini P et al., 1964·Acta Endocrinol (Copenh)

Gonadotrophins were prepared from human postmenopausal urine with the kaolin-acetone method and purified by adsorption of impurities on diethylamine ethyl cellulose (DEAE-C). The last step, namely chromatography on the column of permutit, resulted in a significantly improved specific activity. The immunoelectrophoresis showed that the purified HMG is not homogeneous and that the constituents are glycoproteins which migrate into the region α1, α2and β globulins.

LIPOTROPIN, A NEW ACTIVE PEPTIDE FROM PITUITARY GLANDS

Li CH, 1964·Nature

Duration of fertility following ovarian wedge resection--Stein-Leventhal syndrome

Stein IF Sr, 1964·West J Surg Obstet Gynecol

DETERMINATION OF PLASMA PROGESTERONE DURING PREGNANCY

van der Molen HJ, 1963·Clin Chim Acta

A modification of Short's method for the determination of plasma progesterone is described, which allows the estimation of 0.5–1.0 μg per sample. The reliability of the method is tested and plasma levels in cord and peripheral blood during pregnancy are reported.

CLOMIPHENE CITRATE: FURTHER OBSERVATIONS ON ITS USE IN INDUCTION OF OVULATION IN THE HUMAN AND ON ITS MODE OF ACTION

Roy S et al., 1963·Fertil Steril

Induction of ovulation in the human has been of considerable research interest for several decades. Various hormonal regimens and other procedures have been tried in the past.1 • 2 In spite of all these trials, the problem of ovulatory failure remains a frustrating dilemma for the physician. Recently, the induction of ovulation with clomiphene citrate in about 70% of anovulatory women was reported by our group.3- 6 It was felt that an important breakthrough in this difficult field of endeavor was at hand. 7- 9 Our observations have been confirmed by other groups of investigators.10- 12 The present report embodies a detailed analysis of the results of administration of this agent to 200 women, of whom 179 were anovulatory. The results of our studies on the probable mode of action of this drug are also discussed.

Action of MER-25 and of clomiphene on the human ovary

Smith OW et al., 1963·JAMA

IT APPEARS TO BE WELL ESTABLISHED that the synthetic nonsteroidal analogue of chlorotrianisene (Tace), which has been given the generic name of clomiphene citrate (MRL/41)*, is capable of stimulating ovarian secretory activity in women.1-4 Perhaps the most convincing evidence for this is found in the high incidence of cystic ovaries observed among treated patients, together with the associated microscopic ovarian and endometrial changes, indicating that the cystic structures produced are functional.2,3 The striking similarity between the histopathology of this response to clomiphene and the ovarian response to administered gonadotropins of both human and animal origin has been pointed out by Southam and Janovski.2 With both forms of treatment, the degree of ovarian response to a given dosage appears to be unpredictable and all patterns of atypical stimulation have been observed. In view of this analogy, it has been logical to assume that the ovarian response

Double-blind study of effect of 17-hydroxyprogesterone caproate on abortion rate

Shearman RP et al., 1963·Br Med J

After many years of use and a large number of publications there is still no good evidence to indicate that progestogens have a valid role in the treatment of patients with a history of abortion. In many of the published series the amount of material administered has been inadequate in the light of current concepts of progesterone secretion in pregnancy (Zander, 1959) and inadequate control observations have invalidated much published data. To assess the salvage rate in treated pregnancies and then compare it with that found for previous untreated pregnancies in the same patients ignores the number of pregnancies that would have reached viability if no treatment had been given at all. Malpas (1938) produced a theoretical estimate that any woman with a history of three consecutive abortions. . .

[PHYSIOLOGY AND PATHOLOGY OF CERVICAL MUCUS. II. PATHOLOGY]

ODEBLAD E, 1963·Hormoner

[PHYSIOLOGY AND PATHOLOGY OF CERVICAL MUCUS]

ODEBLAD E, 1963·Hormoner

In vitro inhibitory effect of progesterone on extrauterine human smooth muscle

Kumar D, 1962·American Journal of Obstetrics and Gynecology

Plasma progesterone in mother and foetus in the second half of human pregnancy

Greig M et al., 1962·J Obstet Gynaecol Br Emp

Induction of ovulation

GREENBLATT RB et al., 1962·American journal of obstetrics and gynecology

Comparison of the acetophenone derivative 16alpha,17alpha-dihydroxyprogesterone with other progestational steroids for masculinization of the ratfetus

Lerner LJ et al., 1962·Endocrinology

A new progestational steroid, the acetophenone derivative of 16α,17α;- dihydroxyprogesterone, was compared with several progestogens for masculinizing effects on the offspring of rats treated during pregnancy. The results were similar to those obtained with progesterone and 17α-hydroxyprogesterone this new steroid female sex ratio and did not virilize the internal or external sex structures of the newborn. The present results confirm those of others in finding that 6α-methyl-17α-hydroxyprogesterone acetate, 17α-ethinyl-19-nortestosterone and 17aethinyl- 19-nortestosterone acetate increased the number of male and intersex offspring, as determined by ano-genital measurements and masculinization of internal and external sex organs.