Inadequate levels of circulating progesterone (P) seen in clinical practice can be increased by P supplementation. When supplementation is via the vaginal route, its presentation may be in many different suppository bases. We have measured circulating P in the follicular phase to compare delivery from the vagina after P was presented in three different bases (glycerinated gelatin, cocoa butter, and polyethylene glycol). The mean peak level achieved and the area under the curve were highest after supplementation from polyethylene glycol-based suppositories. The duration of elevation above baseline was similar with all three suppositories. It is concluded that the suppository base is important in controlling the amount of this steroid absorbed from a given amount presented by this route.
Ultrasonographic measurement of follicle growth and estradiol concentrations have been shown to correlate well in spontaneous and Clomid-induced ovulatory cycles. However, little is known about these changes during human menopausal gonadotropin (hMG) therapy. Twenty-five women who did not ovulate when treated with clomiphene were treated with hMG during 70 treatment cycles. Eleven patients had withdrawal bleeding after progesterone administration (group 1) and 14 did not bleed (group 2). Follicle growth was monitored with intermittent serum estrogen determinations and daily ovarian ultrasound with an ADR Model 2140 real-time sector scanner. The mean dominant follicle size at the time of human chorionic gonadotropin (hCG) injection was 21.2 mm +/- 0.6 (SEM) and was not different between the two groups. Mean serum estrogen level at the time of hCG injection was 1,121 pg/ml and correlated with follicle volume. At the time of hCG injection in group 2, one dominant follicle was present in 65% and two were present in 35% of the patients. Among those in group 1, two or more dominant follicles were present during all cycles. Mean serum estrogen levels were significantly higher in group 1 patients than those in group 2. This "chemical hyperstimulation" was induced in order to delay ovulation until adequate follicular size had been achieved. All cycles were ovulatory. Five patients in group 1 and eight in group 2 conceived. The use of ultrasound enables the physician to evaluate follicular growth and development daily and thus to individualize treatment and to reduce the need for estrogen monitoring.
From 1964 to 1976, a cohort study was performed in West Germany to study the possible influence of various factors on pregnancy and child development. Results of the evaluation of 13,643 pregnancies are given with respect to possible teratogenetic effects of antiemetic drugs and sex hormones administered in early pregnancy. There was no evidence of an increased risk of major malformations following the intake of certain antiemetic drugs and progesterone. Also, the use of a hormonal pregnancy test was not significantly associated with an increase of major malformations.
There is renewed interest in natural family planning (NFP) as the Philippine Population Program enters the 1980s. Much of this interest is due to the realization that, properly practiced, NFP can be a highly effective means of birth spacing. In 1978 the Special Committee to Review the Philippine Population Program recommended that more efforts be made to promote NFP. The different methods of NFP are reviewed. Sex without intercourse, coitus interruptus, and prolonged nursing are not officially recognized as NFP methods by the Program. The rhythm method was first described independently by Drs. Hermann Knaus of Austria and Kyusaku Ogino of Japan in the 1930s. Ogino's method of calculating a woman's fertile period is based on the lengths of the last 12 menstrual cycles which she recorded on a calendar. The advantages of rhythm are that it is inexpensive, it requires only the cost of charts which may be homemade, there are no physical side effects, control is in the woman's hands, and it is acceptable to people who consider it their duty to follow religious teachings. keeping constant, accurate records of cycles for long periods of time; the need for perseverance and correct interpretation of the chart; the possible need for medical advice and help; and the fear that something might upset a woman's cycle and change the time of ovulation. The continuation rates of rhythm acceptors in the Philippines are unimpressive. A study of 142 women revealed a high pregnancy/failure rate--25% for a 12-month period compared to 0 with oral contraception (OC) and the IUD's 2%. The basal body temperature method helps determine the unsafe period with some accuracy. Its premise is that there are slight but detectable changes in a woman's body temperature during her cycle. These changes herald ovulation. A special thermometer must record temperature changes of 0.1 degree Farenheit. This instrument and the charts are the only expenses involved. The reviewers of the Philippine Population Program noted that since the end of the unsafe period can be indicated only by the temperature, the total period of abstinence becomes long, although the basal body temperature method gives more or less 10 successive days for intercourse. The cervical mucus method, also known as the Billings method, takes into account the cervical secretions during the menstrual cycle. Appearance of this mucus is an indication of fertility. All that is required of a practitioner is to learn to distinguish the different sensations of wetness and dryness. The disadvantage is that the method becomes ineffective in areas where there is cervicitis or infection of the cervix. The symptom thermal method is the basal body temperature method combined with other NFP techniques and is widely used. With this method an accurate record of the 6 immediately preceding menstrual cycles is established. The start of the fertile period is set by substracting 20 days plus 1. The woman watches for symptoms like pelvic heaviness, breast softness, and mucus discharge.
The incidence of luteal phase defects in 366 infertility patients was 12.7%. Life-table analysis was used for determination of the conception rate with clomiphene citrate therapy, and with this method, evidence was found for the presence of two subgroups with respect to response. The crude conception rate was 40.9%. In a group of patients with a luteal phase defect and no other infertility factors, those that conceived had a significantly larger mean biopsy delay than those who did not (6.28 days versus 4.32; P less than 0.02). In a group with a histologic delay of 5 days or more, the conception rate was 79%, while the rate was only 8.9% in those with a less severe deficit (P less than 0.001). Theoretic considerations for clomiphene citrate therapy are discussed.
Van der Meer YG et al., 1983·Journal of Psychosomatic Obstetrics & Gynecology
A double-blind cross-over placebo controlled trial was carried out to compare progesterone 200 mg with a placebo, both given in rectal suppositories, in 20 patients with the pre-menstrual syndrome (PMS). Each kind of suppository was used twice daily from mid-cycle to the onset of menstruation during two successive cycles. Six patients did not complete the trial. Daily scores for a number of psychological and somatic symptoms were recorded by the participants. Mean symptom scores in the last seven days of the pre-menstruum did not differ significantly between the two treatment periods. The participants did not express a significant preference for the progesterone therapy. Mean blood levels of FSH, oestradiol, prolactin and LH, determined on the first day of menstruation did not differ between the two periods of treatment. Side effects, in the form of electrolyte abnormalities or hepatic or renal function disturbances, were not seen. In this trial, progesterone 200 mg twice daily by the rectal route was not more effective than the placebo.
Reproductive EndocrinologyAndrogen Excretion in WomenHormonal Risk FactorsUrinary Steroid Analysis
Urinary testosterone and androstanediol were measured by gas chromatography in four groups 22 healthy women (control group), 21 healthy women with a family history of breast cancer (familiality group), 39 patients with breast lumps which consisted of ductal or lobular hyperplasia (hyperplasia group) and 18 patients with infiltrating breast carcinoma (carcinoma group). On the basis of normal values found in our laboratory, steroid levels were above normal in 4.5% of the controls, 4.7% of the familiality group, 38.5% of the hyperplasia group (P less than 0.01 vs controls) and 61.1% of the carcinoma group (P less than 0.001 vs control group). The mean testosterone level in the carcinoma group (11.3 +/- 6.78 S.D.) and the mean androstanediol level in the hyperplasia group (47.25 +/- 31.0 S.D.) were significantly higher than those of the control group (testosterone 6.25 +/- 3.48 S.D., androstanediol 32.55 +/- 20.0 S.D.). No significant difference was found in mean testosterone or androstanediol levels between the control group and the familiality group (testerone 5.41 +/- 3.6 S.D., androstanediol 29.38 +/- 15.89 S.D.). We conclude that increased excretion of androgenic steroids is a hormonal abnormality common to breast cancer patients and to patients with breast epithelial hyperplasia, but not to subjects with a family history of carcinoma of the breast.
Journal Article THE NEUROENDOCRINOLOGY OF OPIOID PEPTIDES Get access ASHLEY GROSSMAN, BA BSc MRCP, ASHLEY GROSSMAN, BA BSc MRCP Departments of Endocrinology and Chemical Endocrinology St Bartholomew's Hospital, London Search for Oxford Academic PubMed Google Scholar LESLEY H REES, MD MSc MRCPath FRCP LESLEY H REES, MD MSc MRCPath FRCP Departments of Endocrinology and Chemical Endocrinology St Bartholomew's Hospital, London Search for Oxford Academic PubMed Google Scholar British Medical Bulletin, Volume 39, Issue 1, 1983, Pages 83–88, //doi.org/10.1093/oxfordjournals.bmb.a071796 01 March 1983
In a double-blind, randomized dose-response study, 75 women with benign breast disease were administered a written questionnaire in which they scored the severity of premenstrual syndrome (PMS) symptoms before and after two months of treatment with placebo or alpha-tocopherol (150, 300, or 600 IU/day). Controlling for age and pretreatment scores, alpha-tocopherol had a significantly greater effect than placebo, improving three of the four classes of PMS symptoms. These findings suggest that vitamin E supplementation may be of value in women with severe PMS symptoms.
Fifteen women with diminished fertility as a result of congenital uterine anomalies were treated by cervical suture (cerclage) in the 11th-12th week of pregnancy without surgical correction of the uterine anomaly. None of these women had either clinical or radiological evidence of cervical incompetence. As a result of the treatment, 13 of the women delivered live full-term mature infants. None of the women aborted, only two women delivered prematurely, and both infants were alive and well. Comparison of these good results to the very poor outcome of previous pregnancies in these women points to a distinct advantage to be gained by cervical suture. As a result of this experience, we recommend cervical suture in cases of diminished fertility as a result of congenital uterine anomaly. We recommend that the suture be performed before considering surgical repair of the anomaly and irrespective of lack of evidence of cervical incompetence. Only in cases where cervical suture is unsuccessful, would we recommend surgical correction according to the accepted techniques.
Twenty-nine consecutive patients with polycystic ovary (PCO) syndrome (defined as hirsutism plus oligomenorrhea or secondary amenorrhea, and excluding Cushing's syndrome, an androgen-secreting adrenal or ovarian tumor or adrenocortical hyperplasia) were treated with ovarian wedge resection leaving normal-sized ovaries. Long-term follow-up from 2.3-9.5 years (mean 5.7 years) showed that 26 of 29 patients (90%) had established normal menstrual cycles. Fertility and normal pregnancies were achieved in all 10 patients (100%) with normal postoperative menstrual cycles who desired to conceive, but not in the 3 patients with remaining postoperative oligomenorrhea. Eight of 9 patients who were obese preoperatively and who had normal postoperative menstrual cycles showed a major weight loss after wedge resection. In contrast, none of the preoperatively obese patients, who remained oligomenorrheic after surgery, lost weight. Hirsutism was not cured by wedge resection. It is concluded that ovarian wedge resection should still be considered useful in patients with PCO.
In studying the structural changes of human cervical mucus during the ovulatory cycle, they have been observed to be directly related to ovarian hormone changes. Mucus structural changes, if taken according to their sequence during the cycle, clearly express the anatomic and functional events occurring in the ovary. If each structure is considered separately, only the mucus of the preovulatory period can be considered an indication of the corresponding ovarian processes, presenting peculiar morphologic characteristics. The observation of a similar morphologic appearance in the mucus of the early follicular and luteal phases leads one to believe, in spite of the influence of totally different hormone levels, in the likely existence of a mechanism of interference between estrogens and progesterone during the postovulatory period of the cycle.
Menstrual CycleBeta-EndorphinMenstrual Cycle RoleEndorphin and Cycle Dynamics
The possibility that beta-endorphin, an endogenous opiate, is involved in the regulation of the menstrual cycle was examined. Daily serum beta-endorphin levels, in conjunction with luteinizing hormone, progesterone, and 17 beta-estradiol were measured during 26 hormonally normal menstrual cycles. Twenty-one cycles showed a preovulatory peak and postovulatory trough of beta-endorphin, 2 cycles had a postovulatory peak, and 3 had a postovulatory peak with sustained elevation. The raw data were standardized by conversion to "Z-scores," and the composite values were computed for each of the three classes described above. Significance within these three classes was assessed using a one-way analysis of variance with an F-ratio at 95% confidence limits. The composite plot of the 26 cycles showed a statistically significant preovulatory peak occurring 2 days prior to the luteinizing hormone surge and a postovulatory trough of beta-endorphin 5 days later. These results suggest that beta-endorphins play a significant role in the neurochemical mechanisms of gonadotropin release.
A push-pull perfusion (PPP) system was used to carry out the first examination of LHRH release from the mediobasal hypothalami (MBH) of conscious, freely moving rats during stages of the estrous (E) cycle and after ovariectomy (Ovx). Female rats received push-pull cannula (PPC) implants into the MBH and then were allowed to recover for 2–10 weeks before PPP experiments. During that time, E cycles were determined by daily inspection of vaginal smears. After exhibiting two consecutive E cycles, rats were fitted with indwelling jugular catheters between 0830–1030 h and subjected to PPP of the MBH and hourly bleeding for more than 6 h. LHRH and LH levels were determined by RIA in perfusates and plasma, respectively. PPP and bleeding sessions were performed on the afternoon of proestrus (Pro; n – 10), diestrous day I (DI; n – 5), diestrous day II (DII; n – 5), estrus (E; n – 5), or more than 28 days after Ovx (n – 5). LHRH output was detectable in at least some samples in all rats whose PPC tips resided within 0.5 mm of the rostrolateral median eminence. Basal LHRH output (<0.2 to 1.2 pg.12 min) appeared to be pulsatile in all groups. During Pro, higher LHRH levels permitted pulse frequency determinations (average Pro interpulse interval, 48.0 min). Overall LHRH output during Pro was elevated (P< 0.01) compared to that in all other groups and was distinctly biphasic; a putative priming pulse (P < 0.05) occurred 2–3 h before the occurrence of a larger main peak (1.6–7.0 pg-12 min) at approximately 1600–1730 h (lights on from 0500–1900 h). Proestrous (Pro) LH levels in rats bearing PPC implants were only 10–30% of those in intact rats regardless of PPP. Nonetheless, these rats did exhibit temporally normal Pro LH surges concident with LHRH release. In DI and DII rats, LHRH pulse amplitude increased moderately for a brief period in the late afternoon (P < 0.01 only when data was normalized to the largest peak). LHRH output in E rats was low and mostly undetectable. Pulse amplitude in ovariectomized (Ovx) rats remained constant and low throughout the afternoon, while LH levels were elevated to typical post-Ovx values. We conclude from this study that (1) a biphasic LHRH surge occurs on the afternoon of Pro which may act to prime and then stimulate pituitary gonadotrophes, (2) small but significant increases in LHRH pulse amplitude occur between 1500–1900 h in DI and DII rats, but not in Ovx or E rats, and (3) LH, but not LHRH, release is increased in Ovx rats, suggesting that the negative feedback effects of ovarian steroids operate primarily at the level of the pituitary gland.
Frequently, when one mentions natural family planning methods, the response is doubt, bewilderment, ridicule, or scorn. Much of this is due to the fact that many people know only of the rhythm method, which depends on a calculation based on the menstrual pattern. What many people do not know, including physicians and nurses, is that in Australia Drs. John and Lyn Billings have been scientifically researching natural methods of family planning for 25 years, and they have pioneered this Ovulation Method of family planning. The Billings Ovulation Method depends only on the mucus sign. It is based on a scientific knowledge of the combined fertility of husband and wife, and an understanding of the physiology of the female body through simple observations. Important facts relating to the ovulation takes place only once in the cycle; mucus is secreted by the cervical mucosa before ovulation; the ovum lives for only 3 days at the most; and the sperms live for 5 days at the most, and only in the presence of this fertile mucus. There a 2 types of mucus. The 1st type to appear is cloudy or white. It is nonslippery, sticky, and breaks when stretched between 2 fingers. The 2nd type is like the part of a hen's egg. It is very slippery, much clearer than the former, and stretches when pulled between 2 fingers. This is fertile mucus, and ovulation occurs on the last day that this is present. Of course, it cannot be recognized as the last day until its absence is observed on the following day. The mucus sign can be both seen and felt. After a few months a woman will readily recognize her fertile time, but daily charting is advocated. Simple signs, representing the various observations, are taught. Once a couple knows and understands their combined fertility through the observation of the mucus sign they can plan their family. Rules of the method are outlined. The self control required by this method can only serve to increase the selfless love and unselfish care and respect between partners.
PCOSOvulation InductionClomiphene ProtocolsDHEA-S and Testosterone
Twelve oligomenorrhic women with polycystic ovary syndrome (PCO) in whom clomiphene (250 mg daily for 5 days) and 10,000 IU human chorionic gonadotropin had failed to induce ovulation were treated with clomiphene and dexamethasone. Eight of the 12 women underwent complete hormonal assessment during treatment. Six of the 12 ovulated and 1 conceived. Serum total and unbound estradiol and testosterone (T), serum dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding-globulin binding capacity (SHBG-BC), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were measured during clomiphene and dexamethasone therapy. SHBG-BC increased in response to clomiphene whether or not ovulation occurred. After treatment with clomiphene and dexamethasone there was a significant decrease in serum T, unbound T, and DHEA-S 2 weeks after dexamethasone administration, but there were no change in LH, FSH, or PRL. In patients who ovulated after clomiphene and dexamethasone, T and unbound T increased again after clomiphene was begun despite the continuation of dexamethasone. The women who ovulated after clomiphene and dexamethasone treatment had significantly higher pretreatment levels of DHEA-S than those who did not ovulate. Clomiphene and dexamethasone treatment may be beneficial to women who have elevated levels of DHEAS and who fail to ovulate with maximum doses of clomiphene.
Whereas follicle rupture never occurred before the 37th hour after an ovulatory stimulus (either the onset of the LH surge or hCG administration) in control patients, ovulation was observed at 26 to 36 h in women submitted to ultrasonography during the late follicular phase. Premature ovulation was observed in 5 out of 23 and 8 out of 19 cycles when ultrasonography occurred during the 3 days preceding or in the 36 h following ovulatory stimulus. This as yet unexplained observation leads us to reconsider the advisability of ovarian scan during the late follicular phase of the menstrual cycle.
The human individual responds as an entire organism to the effect of endurance training. Exercise physiologists have long documented cardiovascular, musculo-skeletal and metabolic effects of conditioning. Only recently are we beginning to understand that there are hormonal and hypothalamic changes which occur with conditioning. These hormonal changes probably serve similar adaptive functions as do the other conditioning responses. Careful controlled studies need to be performed of individuals prior to, early in conditioning, and following extended periods of conditioning looking at hypothalamic function, body morphometric characteristics, psychiatric and psychological testing and menstrual cycle data in order to better understand hormonal conditioning. When hormone changes occurring with endurance training are approached in this light, the complex inter-related alterations will begin to form a pattern. Further studies are needed to document the dynamic and reversible nature of these hormonal adaptations.
Concentrations of beta-endorphin were measured in the venous effluent of the hypothalamus (hypophyseal portal blood) at various phases of the menstrual cycle and after ovariectomy in rhesus and pigtailed monkeys. In the rhesus, beta-endorphin concentrations were high during the mid- to late follicular phase [737 +/- 256 pg/ml (mean +/- SE)] and the luteal phase (1675 +/- 1108) of the menstrual cycle, but were undetectable (less than 133) at menstruation. Concentrations were also high in pigtailed monkeys during stages of the menstrual cycle other than at menstruation (4870 +/- 1090 pg/ml), but undetectable (less than 133) 4--12 months after ovariectomy. These results indicate that beta-endorphin concentrations in hypophyseal portal blood are related to menstrual cycle events, probably changes in ovarian steroids; this in turn suggests that beta-endorphin may participate in the ovarian feedback regulation of gonadotropin secretion.
Fourteen normal women (self-selected from 180 women enrolled) in a marathon training clinic kept basal body temperature (BBT), mileage, and weight records for 48 cycles before the marathon. Age 20-45, gynecologic age greater than 5 years, no hormone use, or weight change in 3 months. The women were 35.2 +/- 5.6 years in age, 22.6 +/- 5.1 years gynecologic age, runners of 4.1 +/- 2.5 years with premenstrual symptoms, previous pregnancy 4/14, no infertility and 2/14 remote amenorrhea. BBT records were obtained and analyzed by Vollman's criteria (1977). There was no weight loss. 32/48 cycles were biphasic but only 16 were normal in the length of the premenstrual phase (PreM = luteal, nl 10 - 16 d) with a mean of 11.1 +/- 1.2 days. The other 16 biphasic cycles had short PreM phase of 6.4 +/- 1.8 days. Monophasic (M = anovulatory) cycles occurred in 16/48 records. Cycles which were abnormal (Short PreM and M) differed only in that usual run length was longer (9.6 - 9.9 miles) than in normal cycles (7.9 +/- 2.4 miles). Marathon training may be associated with normal length but M and short PreM type cycles.
22 physician-providers who serve natural family planning (NFP) programs, mostly in the private sector, gathered to formulate a standard terminology for the field. The Billings and sympto-thermal methods are the 2 methods taught by this group. The sypto-thermal method helps a woman predict ovulation by detecting changes in her cervical mucus and in the cervix itself. Ovulation is confirmed by monitoring the temperature shift as well as by observing the cessation of mucus buildup, closing of the cervix, and firmness of the os. Those women using the Billings ovulation method predict fertility by the appearance of the cervical mucus, its sensation, color, and elasticity. Sperm will only survive if the cervical mucus is of the fertile type. It is also helpful to recognize mucus patterns of anovulation during breastfeeding, weaning, and premenopause. Use-effective rates which only reflect pregnancy are inadequate in evaluating NFP. A series of definitions are presented which in the future will help to analyze NFP data to accurately reflect NFP effectiveness. total pregnancies, planned pregnancy rate, pregnancy avoidance, method effectiveness rate, method-related pregnancies, informed choice pregnancies, teaching-related pregnancies, and unresolved pregnancies. All NPF teaching programs include instruction in basic reproductive physiology and in the recognition of the fertile phase. The cervical mucus factor is emphasized in ovulation method groups while thermal and other parameters are given equal weight in the sympto-thermal groups. It is the intent of NPF to teach couples to distinguish the fertile phase by using the fertility markers and to have them integrate this information into their sexual decision making. Success is dependent on teacher skill and the ability to inspire confidence in the method. Recognition of the mucus patterns of ovulation and anovulation are crucial in assessing infertility. All family providers under Title 10 must by law offer either NFP instruction or referrals to sites which do. A directory of non-Title 10 providers of NFP Services is available for $4.00 from the Human Life and NFP Foundation, 205 South Patrick Street, Alexandria, Virginia, 22314.
The concept of utilizing changes in cervical secretion offers a potentially simple method of natural family planning. A detailed international trial has been conducted to test the effectiveness of the method. 5 Auckland; Bangalore; Dublin; Manila; and San Miguel. The observations provide an indication of the value and success of the method. They also reveal interesting variations between the different centers and between various socioeconomic classes. The work was divided into a teaching phase and an effectiveness phase. The initial phase was designed to teach individual women how to recognize the symptoms in cervical mucus, and it usually covered the first 3 complete cycles. The subjects were ovulatory, of proven fertility, less than 39 years, nonlactating, and with a history of a menstrual cycle of between 23 and 35 days. Data were collected from the patient and returned to the organizers for analysis. Comparisons were then made between different centers on the 2 study phases. In the teaching phase 94% of the women could soon recognize and record their own cervical mucus symptoms. Many women could understand the principle of the method within the 1st teaching cycle. Almost 90% of the subjects completed the teaching phase, and 7% discontinued for various reasons, including 1.3% who failed to learn the method, and 5% who became pregnant. The average number of days of abstinence by the method was 17 in the 3rd teaching cycle, a high proportion of the length of the average menstrual cycle. After the teaching phase, 725 subjects were studied in an effectiveness phase which lasted for 13 cycles. More than 7500 cycles were analysed. High rates of method failures were found in the 2 most socially developed centers, Auckland and Dublin. Pearl rates for method failure ranged from 9.4/100 women years in Auckland to 1.1 in Manila and 0 in Bangalore and San Miguel. The accumulative probability of discontinuation after 13 cycles was 35.6%, more than half of this figure being due to pregnancy. Detailed pregnancy rates/100 woman years, using the modified Pearl Index, conscious departure from the rules of the method, 15.4; inaccurate application of instructions 3.5; method failure 2.8; inadequate teaching 0.4; and uncertain reasons 0.5. Subjects were not selected randomly.
A preliminary study of 'screened' women with two consecutive miscarriages revealed an incidence of abortion in 47.4% in a subsequent pregnancy whilst hCG therapy in a similar group of women where biochemical monitoring with plasma progesterone suggested a potentially jeopardized pregnancy resulted in a continuing pregnancy in 92.3% of treated women. An urgent need for a true randomized double-blind evaluation of this therapy has been established in order to re-examine the therapeutic nihilism which currently pervades the management of women with recurrent abortion.
Two hundred sixty-three patients with a diagnosis of endometriosis or adenomyosis were studied in a retrospective fashion. The association between endometriosis resulted in a spontaneous abortion rate of 44.3%, Patients with adenomyosis spontaneously aborted 35.1% of their pregnancies. These figures are significantly increased in comparison to those pertaining to the general population. Uterine pathology occurring with endometriosis is discussed in relation to secondary infertility. Hypotheses that may explain the relationship between endometriosis and spontaneous abortion are discussed briefly.
A group of 17 patients with suspected luteal phase deficiency was treated with tamoxifen. Tamoxifen therapy was found to lengthen the luteal phase in all patients and resulted in pregnancy in 6 of 17 patients. The integrated luteal phase progesterone (P) concentration in the nontreatment cycle of seven patients was significantly lower (P less than 0.01) than that of five normal women. Therapy with tamoxifen increased the P concentration to 186.0 +/- 24.4 ng/ml/cycle (mean +/- standard error of the mean), i.e., twice that of the control cycle. The mean estradiol (E2) concentration at the midcycle peak was about twice that observed during the nontreatment cycle. The glycogen content of the endometrial tissue at the midluteal phase in the tamoxifen cycle was significantly higher (P less than 0.025) than that of endometrial tissue in the nontreatment cycle, indicating improvement of the endometrial function.
Reproductive EndocrinologyConception Cycle ProfilesConceiving vs Non-ConceivingProgesterone Markers
Hormonal profiles were obtained throughout 26 conception cycles and 27 non-conception control cycles. The pregnancies followed treatment (clomiphene or bromocriptine) in 12 women but were spontaneous in the remaining 14. No sustained significant difference between the various types of conception cycle was found for LH, FSH, oestradiol or progesterone concentrations. Prolactin concentrations varied widely, suggesting that mean cycle prolactin concentrations ranging from 45 to 760 mi.u./l are compatible with conception. Although there were no significant differences in progesterone secretion within the conception cycles, there were highly significant differences between the conception cycles and the non-pregnant control cycles. Mean progesterone concentrations in the conception group were higher (P less than 0.005) than those in the control women over Days 3-8 following the LH peak. This difference could only be partly accounted for by heterogeneity within the control group (15-20% of the control cycles had low progesterone concentrations and were probably subfertile. It is suggested that the higher conception cycle progesterone concentrations during the early part of the luteal phase may constitute a preimplantation component of the maternal recognition of pregnancy in women.
Wade et al.'s report, entitled "A randomized prospective study of the use-effectiveness of 2 methods of natural family planning," contains items worthy of emphasis. 1) less than 5% of the women in the study were prevented from using the method assigned them because of problems in identifying their cervical mucus pattern; 2) those who were unable or unwilling to adhere to the methodology were encouraged to drop out; 3) the largest single category of pregnancies occurred in both groups when the volunteers failed to follow the rules for avoiding pregnancy; 4) it was judged that there were 6 pregnancies in the ovulation method group to be classified as method failures, apparently for a total of 4501 cycles, which gives a method-failure rate of 1.6%; 5) couples were required to sign an informed consent statement of their awareness that the chances of the occurrence of pregnancy could be as high as 25% for the ovulation method; 6) recruiting difficulties constituted an important finding, primarily because they were unexpected by the investigators; 7) the volunteers recruited into the trial were restricted to those women whose menstrual cycles were 24-36 days; 8) the couples who failed to continue with the use of these 2 natural methods--ovulation and temperature rhythm--were on the average younger, more sexually active, and had fewer children; and 9) the ovulation method brings the partners into confrontation with their fertility in each cycle, and this has marked psychological results, including an awakening of the suppressed desire for that fertility to become creative of human life.
General OB/GYNMaternal Mortality StatisticsAbortion Safety DebateMortality Data Interpretation
Thomas W. Hilgers, M.D., testifying to the Australian Royal Commission on Human Relationships in 1975, alleged that liberal abortions laws in the U.S. caused more deaths among women of childbearing age than they prevented. This inference was subsequently challenged because his analysis used a misleading extrapolation of linear regression, applied information from 2 incomparable data sets, and selected unreasonable item intervals for comparisons. On October 14, 1981, Hilgers testified before the U.S. Senate Subcommittee on the Constitution. He stated that America's legal abortion policy has had no measurable beneficial effect on maternal deaths and also implied that "natural pregnancy" was safer than induced abortion. These inferences were based on his recent analysis of abortion mortality with the use of national data from 1940 to 1978. Exception is still taken with Hilgers' inferences neglect of risk associated with the last half of pregnancy; use of provisional 1978 data; selection of inappropriate states and time intervals; absence of the most appropriate references; use of relative frequency rather than absolute numbers; and aggregation of abortion mortality with maternal mortality. Contrary to the statements by Hilgers, the availability of legal abortion has had a measurable impact on deaths among American women of reproductive age. In 1965, even before the availability of legal abortion, deaths of women from all types of abortion (legal, illegal, and spontaneous) began to decline more rapidly than deaths from other pregnancy related causes. In 1970 the decline of abortion mortality rapidly accelerated and generally continued through 1976. In sum, legalized abortion has had a definite impact on the health of American women of childbearing age who are faced with unwanted pregnancies.
Pooled serum from women taking a combined estrogen-progestin oral contraceptive preparation caused significantly greater cell proliferation and incorporation of 3H-thymidine into DNA in both human arterial smooth muscle cells and dermal fibroblasts in tissue culture than did serum from controls. A portion of this mitogenic effect appears to be related to the presence of a factor(s) that is heat stable, nondialyzable, and contained in the lipoprotein-deficient serum fraction. In vitro addition of varying concentrations of mestranol and norethindrone, the two constituents of the oral contraceptive preparation taken by participants in the study, to control serum did not enhance its mitogenicity, suggesting that the effect observed with intact serum was due either to a metabolite of these compounds or to the production of other growth-promoting substances during oral contraceptive treatment. Since smooth muscle cell proliferation is an integral feature of all atherosclerotic lesions, these findings provide some insights applicable to understanding the pathogenesis of vascular disease associated with oral contraceptive use.
Sixty-nine infertile women with a midluteal serum progesterone level of 4 to 14 ng/ml were treated with a graduated dosage schedule of clomiphene citrate until the progesterone level on day 21 was greater than 20 ng/ml. Thirty-one pregnancies occurred, 58% during the first adequate treatment cycle and 19% during the second cycle. The abortion rate was 23%. After 6 adequate treatment cycles, laparoscopic evaluation was performed on 28 of 39 patients who did not conceive. Pathology was noted in 57%. Seven of 17 patients with intraperitoneal causes of infertility conceived after alternative therapy. The corrected pregnancy rate was 60%. Results of this study suggest that low luteal phase progesterone levels may compromise fertility and that clomiphene citrate enhances pregnancy rates.
Many studies have been published on luteal phase deficiency, and the emphasis in most of them is on progesterone deficiency. In this study 144 patients (455 cycles) with infertility were studied. The patients were divided into four groups. Group 1 consisted of patients with high estradiol and high progesterone levels in the midluteal phase. Group 2 consisted of patients with high estradiol and low progesterone levels. Group 3 consisted of patients with low estradiol and low progesterone levels. Group 4 consisted of patients with low estradiol and high progesterone levels. As expected, patients in groups 2 and 3 showed a low conception rate with outphased endometrial biopsy. However, group 4, in spite of the normal progesterone levels, had a low conception rate with an outphased endometrium. We conclude that estradiol deficiency during the luteal phase is a major factor in infertility, and replacement therapy with progesterone alone in these patients may not improve fertility.
The importance of predicting human ovulation for either optimizing or avoiding conception has been considered from an endocrine, morphological and clinical view point. Of the biochemical markers in peripheral blood, a knowledge of the LH peak is the most clearly defined, with a two to four fold increase above baseline levels for a relatively short 24-30 hour preovulatory period. Ovulation is considered to occur 28-36 hours after the beginning of the LH rise or 8-20 hours after the LH peak. Daily assessment of the rise in preovular oestrogen reflects Graafian follicle development but the rise is less distinct and spread over 3-4 days with marked day to day fluctuations. LH induces a marked reduction in oestrogen production some 12 hours prior to ovulation and at the same time induces a two to three fold increase in progesterone production above baseline levels. While these changes in themselves are not great enough for day to day discrimination, a knowledge of their reciprocal relationship may be. The preovular rise in FSH is relatively small compared to LH and the radioimmunoassay technique has not generally been refined to be as rapid and reliable. Monitoring the day to day growth of the preovular follicle ultrasonically is both linear and potentially predictable but there is a wide range of its final diameter (17-26 mm) prior to ovulation making prediction inaccurate. With further refinements in ultrasonic resolution, detection of intrafollicular changes of the cumulus oophorus and granulosal cell layer configuration and thickness may give a closer prediction of the time of ovulation. At a clinical level a knowledge of menstrual cycle length in association with body messages which herald ovulation are useful and may forewarn that ovulation in terms of days is approaching. Such markers as preovulation pain, the detection of periovular cervical mucus and the change in physical character and position of the cervix are reliable signs of preovulation for many well motivated and informed women for either promoting or avoiding conception. A knowledge of the basal body temperature is not a prospective guide to ovulation, but once the thermal shift is established in association with loss of periovular mucus symptoms, the fertile period can be considered to have passed. Because we do not have a precise and simple marker of human ovulation, it is necessary that the most suitable marker of preor postovulation is chosen for the particular need in a given individual.
InfertilityOvulatory DysfunctionFollicular MonitoringEstradiol and Progesterone
A significant portion of human infertility is presumably due to defective ovulation, including patients who fail to conceive despite medical induction of ovulation, those who fail despite repeated timely donor inseminations, and those with "infertility of unknown etiology". All point out the inadequacy of standard criteria for normal ovulation. This investigation correlates preovulatory serum estradiol and gonadotropin concentrations with dominant follicle growth measured ultrasonographically and serum progesterone levels. The data indicate a 35% incidence of cycles with significantly abnormal serum estradiol levels, decreased dominant follicle size, and abnormal progesterone levels despite biphasic basal body temperature curves and normal cycle length. If these cycles represent inadequate or abnormal ovulation, they can be distinguished from adequate cycles prior to follicle rupture and may benefit the treatment of human infertility.
Contraception/ComparisonReturn to FertilityPost-Contraceptive Delayed ConceptionRetrospective Cohort
Interview data from 3,214 married women having planned pregnancies and singleton deliveries who had no history of fertility treatment and who conceived more than two weeks after cessation of contraception were analyzed. The interval from cessation of contraception to conception was 13 months or greater for 24.8% of prior "pill" users vs 10.6% for former users of all other methods. As compared with former users of other methods, pill users had a notably lower monthly percentage of conceptions for the first three months and somewhat lower percentage from four to ten months. Results were not altered when potential confounding variables were controlled by logistic regression. At least 15 months of unsuccessful trials might be a more appropriate working definition of infertility for previous pill users rather than the 12-month interval generally accepted for this purpose.
Pregnant mice were treated with a single subcutaneous injection of either cyproterone acetate (CA) or medroxyprogesterone acetate (MPA). In the first experiment the animals received 5-900 mg/kg of the hormone before implantation (day 2 of pregnancy). CA treatment on day 2 caused a dose-dependent decrease in fetal weight and a significant dose-dependent increase in the rates of cleft palate and urinary tract abnormalities. Exencephaly and heart abnormalities were also significantly more frequent, but this increase was not dose-dependent. MPA treatment on day 2 was followed by sporadic increases in dead and resorbed fetuses, a decrease in fetal weight and an increase in the rates of cleft palate, and malformed or abnormally developed fetuses. None of these effects, however, was dose-dependent. In the second experiment the mice were given one single injection (30 mg/kg) of CA or MPA on any one of days 1-12 of gestation. Treatment with CA on one day between days 1 and 12 revealed that the specific sensitivity for abnormalities of the urinary tract was on days 5 and 6, for the respiratory tract on days 8 and 9, and for cleft palate on days 10 and 11. Treatment with MPA on one day between days 1 and 12 only revealed a high rate of respiratory and urinary tract abnormalities on day 9. After treatment with MPA cleft palate was again significantly more frequent in all treated groups, however, days of peak sensitivity were not detected. The long half-life of CA (60 hours) explains the teratogenic effect of high doses of this progestin after treatment on day 2 and also the pattern of abnormal development found after treatment with a single dose of CA on one of the days between day 1 and day 12.
This review of natural family planning (NFP) components of the fertile phase; sympto-thermal methods; the history and methodology of NFP (calendar rhythm, basal body temperature, cervical mucus--the Billings Ovulation method); special circumstances--periods of erratic ovulation (puberty, lactation, premenopause, discontinuation of ovulation suppression, cervicitis and vaginitis, ovulation suppression by stress and pharmaceuticals); effectiveness of natural family planning; achieving pregnancy; achieving couple autonomy (confidence in the method, periodic abstinence, dynamics of the learning process, and support systems); problem areas; and delivery systems. The number of users of NFP methods increased from 2.8% of currently married couples in 1973 to 3.4% in 1976. In 1979, 75,000 new clients received training in contemporary NFP, while the number increased to over 100,000 in 1980. NFP is planning for achieving or preventing a pregnancy by the timing of intercourse. A couple can, by observing and recording certain natural symptoms and bodily changes that occur in a woman's menstrual cycle and using the information as a guide, learn to identify fertile and infertile phases in the menstrual cycle. Precise prediction of ovulation forms one of the components of delineation of the fertile phase. Billings pioneered the use of cervical mucus as a single parameter for the prediction of ovulation and its application to NFP. Women are instructed to observe their mucus patterns at the vulva, relying primarily on the sensation of wetness and lubrication, the use of the Kegel exercise, palpation with the finger, a "wipe-through" with toilet paper, or a combination of these observations. In the absence of ovulation, the usual changing mucus pattern is also absent. NFP can be used either to achieve or to avoid pregnancy. When NFP is used to avoid pregnancy, one will encounter method-related pregnancies, teaching-related pregnancies due either to poor teaching or poor learning or both. The major use effectiveness studies are listed in table form, and the results are shown under new headings. To achieve pregnancy, it is the general practice of NFP instructors to teach women to recognize and record their fertility signs and to suggest some months of merely concentrating coitus at the time of maximum fertility. Mastery of NFP calls for both identification of the fertile phase and integration of that knowledge into the couple's sexual decision making and behaviors. Studies are reviewed in terms of the spectre of genetically damaged offspring. NFP instruction is available in nearly every country outside the Soviet bloc.
The outcome of pregnancy was studied in all women conceiving after ovulation induction with clomiphene at the gynaecological endocrine clinics operating in 2 Tasmanian cities. In 156 pregnancies where details were available, abortion rate 10.3%; multiple pregnancy rate 4.1%; congenital abnormality rate 3.6%; and perinatal mortality rate 3.5%. The results are compared with other reported series.
This study evaluates the effect of treatment with Proluton-Depot (hydroxyprogesterone hexanoate) in early pregnancy, and the final outcome of pregnancy and fetal status. One hundred and fifty patients received intramuscular injection of Proluton-Depot from 6 weeks to 8 weeks to 16 weeks to 18 weeks gestation. The outcome of this treated group was compared with a similar number of 150 patients with similar problems, but the second group received no hormonal treatment. There was no evidence to suggest that Proluton-Depot had any adverse effect on the infant or the final outcome of pregnancy.