Vrbicky, K. W., Baumstark, J. S., Wells, I. C., Hilgers, T. W., Kable, W. T., & Elias, C. J. (1982). Evidence for the involvement of beta-endorphin in the human menstrual cycle. Fertility and Sterility, 38(6), 701-704. https://doi.org/10.1016/s0015-0282(16)46697-5
Vrbicky KW, Baumstark JS, Wells IC, Hilgers TW, Kable WT, Elias CJ. Evidence for the involvement of beta-endorphin in the human menstrual cycle. Fertil Steril. 1982;38(6):701-704. doi:10.1016/s0015-0282(16)46697-5
Vrbicky, K. W., et al. "Evidence for the involvement of beta-endorphin in the human menstrual cycle." Fertility and sterility, vol. 38, no. 6, 1982, pp. 701-704.
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RRM Academy Synopsis
Serum beta-endorphin peaks before ovulation in most normal cycles
Blood beta-endorphin peaked before ovulation in 21 out of 26 normal menstrual cycles, a 1982 study of 15 women found. They charted their cycles and gave daily blood samples. In those 21 cycles, levels then fell after ovulation. Across all cycles combined, the peak came 2 days before the luteinizing hormone surge.
Key Findings
In 21 of 26 cycles from 15 women, beta-endorphin showed a preovulatory peak and a postovulatory trough.
Two cycles showed a postovulatory peak, and 3 cycles showed a postovulatory peak with sustained elevation.
The composite of all 26 cycles showed a statistically significant preovulatory peak 2 days before the luteinizing hormone surge and a postovulatory trough 5 days later.
Every woman who contributed two or three cycles had at least one cycle with a preovulatory peak.
Interpretation
The study is a small observational series: 15 women aged 20 to 38 and 26 cycles, each with an ovulation surge. Researchers measured beta-endorphin, luteinizing hormone, progesterone and estradiol daily from the follicular phase through several days after the peak mucus day. The authors call their reading of a link to the luteinizing hormone surge speculative. They say the pattern may play a role in gonadotropin release. Only hormonally normal cycles were analyzed, so women with irregular cycles or ovulation problems are not covered.
RRM Context
Each woman charted her mucus, temperature and symptoms while following the ovulation method of natural family planning. The peak mucus day set the end of her daily sampling window. Charting timed the sampling around each woman's own peak mucus day. A Creighton University School of Medicine team ran the work in 1982.
Our editorial summary of this paper, not the article's abstract.
Abstract
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.
Hilgers TW, 2020·Linacre Q·Free full text on PubMed Central
This study reports on 632 cycles from 105 women who were using the CREIGHTON MODEL FertilityCare™ System to avoid pregnancy and had either a serious reason to avoid pregnancy or some degree of a lack of confidence. A progesterone level was drawn on the third day after the Peak Day as they were charting, and if the progesterone level was 2.3 ng/mL or greater, then ovulation was determined to have passed. If the level was greater than 3.0 ng/mL, this indicated that an absolute period of infertility had begun. In these cases, no pregnancies were observed. In the 27 cycles in which a specific follow-up relative to pregnancy could not be definitively determined, the progesterone levels in all cases were 2.3 ng/mL or greater with 23 of the 27 cycles being 3.1 ng/mL or greater. It is highly unlikely that any of those became pregnant as well. These cycles were collected over thirteen years (2004-2016). Two case presentations are also a part of this article of two families in which the couples had very serious reasons to avoid pregnancy. In these two couples, each of the women was multi-gravid and had no evidence of subfertility or infertility. They used the family planning progesterone level (the Peak Day +3 progesterone level) for a total of 167 cycles over a number of years successfully without a subsequent pregnancy.
This article presents a thirteen-year effort to evaluate the serum progesterone level on the third day after the Peak Day as observed by women charting the CREIGHTON MODEL FertilityCare™ System. It is known that the Peak Day is associated with ovulation, and if the progesterone reaches a certain level, then an absolute period of infertility should follow. In fact, this is what this study reflects.
Chang CP et al., 2020·Paediatr Perinat Epidemiol·Free full text on PubMed Central
Previous research has demonstrated that women instructed in fertility awareness methods can identify the Peak Day of cervical mucus discharge for each menstrual cycle, and the Peak Day has high agreement with other indicators of the day of ovulation. However, previous studies enrolled experienced users of fertility awareness methods or were not fully blinded. To assess the agreement between cervical mucus Peak Day identified by fertile women without prior experience on assessing cervical mucus discharge with the estimated day of ovulation (1 day after urine luteinising hormone surge). This study is a secondary analysis of data from a randomised trial of the Creighton Model FertilityCare(TM) System (CrM), conducted 2003-2006, for women trying to conceive. Women who had no prior experience tracking cervical mucus recorded vulvar observations daily using a standardised assessment of mucus characteristics for up to seven menstrual cycles. Four approaches were used to identify the Peak Day. The referent day was defined as one day after the first identified day of luteinising hormone (LH) surge in the urine, assessed blindly. The percentage of agreement between the Peak Day and the referent day of ovulation was calculated. Fifty-seven women with 187 complete cycles were included. A Peak Day was identified in 117 (63%) cycles by women, 185 (99%) cycles by experts, and 187 (100%) by computer algorithm. The woman-picked Peak Day was the same as the referent day in 25% of 117 cycles, within ±1 day in 58% of cycles, ±2 days in 84%, ±3 days in 87%, and ±4 days in 92%. The ±1 day and ± 4 days' agreement was 50% and 90% for the expert-picked and 47% and 87% for the computer-picked Peak Day, respectively. Women's daily tracking of cervical mucus is a low-cost alternative for identifying the estimated day of ovulation.
Daly KD et al., 2019·Linacre Q·Free full text on PubMed Central
A special course on Marriage, the Family and Human Sexuality was established at Kenrick-Glennon Seminary in St. Louis so as to assist the seminarians in their better understanding of the Church's teaching relative to natural methods of family planning and women's health care. This article compares the response at the beginning of this three-credit semester course to the same seven-item questionnaire given at the conclusion of the course. The preand postcourse scores were calculated for each of the questions. The scores obtained after the course were all significantly higher than they were before the course with p values ranging from 0.01 to <0.0001. Four of the items showed marked improvement including an understanding of the church's teaching related to natural methods, current methods of natural family planning, the impact of a natural method on a couple's marriage, and also the impact of a natural method on family life. Statistically significant improvement was also seen in their understanding of the topic of natural family planning and the Creighton Model System and its relevance toward the seminarian's vocation, the use of the methods to either achieve or avoid pregnancy, and how contraception and abortion are linked. In these last three items, the level of statistical significance was quite high, although not as high as the other four items. There were 104 seminarians over an eight-year period of time, who provided answers to these questions, both before and after the course. This course was modeled after a course that was initiated at the Pope Paul VI Institute for the Study of Human Reproduction, which was for priests, seminarians, and Catholic leaders, titled Love & Life Unlimited. NONTECHNICAL This is an evaluation of a ten-point, seven-question questionnaire that was utilized at the beginning of a course at Kenrick Seminary in Marriage, Sexuality, Creighton Model and NaProTECHNOLOGY. The same questionnaire was given to the students at the beginning of the course and then two to three months later at the conclusion of the three-credit course. The results show that there is a significant improvement in the seminarians' knowledge and general attitude about natural methods of family planning and suggests that such courses would be beneficial to establish in seminaries throughout the country.
Progesterone support in pregnancy has been in use for over 60 years, having received its start in the 1940s. Its initial use was in patients who had habitual spontaneous abortion caused by luteal phase deficiency. More recently, the administration of progesterone later in pregnancy has been considered to be justified because of an observed decrease in circulating progesterone with the onset of labor, an association of premature labor with decreased progesterone concentrations, and the observation that progesterone has a tocolytic effect. A considerable boost to the use of progestational agents to reduce preterm delivery was received with the publication of two papers which showed a significant reduction in preterm delivery rates with the prophylactic administration of either progesterone or 17-a hydroxyprogesterone caproate. Recently it has been shown, however, that its use is not universal. This may be related to the significant late sequelae that were documented following the in utero exposure of the fetus to the potent steroid diethylstilbestrol (DES) and that this bad experience cast “a long shadow,” In spite of this, the use of progesterone, at least in early pregnancy, is widespread in the various artificial reproductive programs and is growing in its use as an agent to reduce prematurity. Over the years, there has been an extraordinary amount of confusion related to the use of progesterone support in pregnancy. The Food & Drug Administration (FDA) created some of this confusion. In various labeling of progesterone products by the FDA, one of the contraindications to the use of oral progesterone is listed as “known or suspected pregnancy.” And, yet, no such contraindication is identified for the use of progesterone gel. In fact, progesterone gel is indicated for progesterone supplementation or replacement as a part of an assisted reproductive technology (ART) treatment program for infertile women with a progesterone deficiency. To make this even more confusing, oral progesterone, while it was contraindicated in “known or suspected pregnancy,” its official labeling stated that it “should be used during pregnancy only if indicated (see contraindications).” Also, up until very recently, there was a dire “warning” contained in the labeling for USP progesterone injection in sesame seed oil regarding an increased possibility of birth defects. An analysis of the fetal safety of isomolecular progesterone (Pregn-4-ene-3,20-dione) administration during the course of 1,310 pregnancies over a 35-year period of time (1979-2014) was undertaken to address this confusion.
In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin-releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post-naloxone. The LH response to naloxone in individual subjects showed a significant (P less than 0.01) quadratic (U-shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.
beta-Endorphin has a role in the regulation of the normal menstrual cycle and possibly in the onset of puberty. We have reviewed the evidence pointing to an alteration in this neuropeptide that may contribute to the pathogenesis of various reproductive dysfunctions. Elevated or high levels of beta-endorphin have been associated with exercise-associated amenorrhea, stress-associated amenorrhea, and polycystic ovarian syndrome. Depressed or low levels of beta-endorphin have been associated with PMS and menopause. Alterations in the levels of beta-endorphin may change the pulsatile release of GnRH via noradrenergic and/or dopaminergic pathways. We have primarily focused on beta-endorphin as representative of the endogenous opioid peptides, but other opioid peptides may also contribute to the pathogenesis of various types of reproductive dysfunction. Perhaps it will become possible to characterize and hone our understanding of the function of beta-endorphin and the other substances composing the endogenous opioid peptides. A better understanding of their role in physiological as well as pathophysiological processes may allow for the development of rational approaches to the treatment of specific disorders pertaining to reproduction. Many questions remain unanswered. Among the most relevant are: what is the precise mechanism of action by which beta-endorphin exerts its influence on pulsatile GnRH release? Is there a functional relationship between CNS and peripheral (serum) levels of beta-endorphin? Are the detected changes in beta-endorphin levels merely associated, or are they a cause of a particular disorder? Since it took almost 40 years between the time prostaglandins were first discovered and eventual realization of their clinical application, it may take some time before the beta-endorphin story is complete.
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.
To test the postulate that endogenous opioid peptides may be involved in the neuroendocrine mechanisms controlling the frequency and amplitude of LH pulses, saline and an opioid receptor antagonist, naloxone, were infused sequentially, each for 6-h intervals, in six normal cycling women during the luteal phase of the menstrual cycle. During naloxone infusion (1.6 mg/h), there was a significant (P less than 0.01) increase in both the frequency and amplitude of LH pulses compared to those in saline controls. FSH pulses were not discernible in individual subjects; however, a significant increment in FSH levels occurred concomitantly with the increase in LH. These data strongly suggest that endogenous opiates, through an inhibition of hypothalamic LRF, participate in the endocrine events leading to the low frequency of episodic LH secretion characteristic of the luteal phase of the human menstrual cycle.
PMID 6292005 6292005 DOI 10.1016/s0015-0282(16)46697-5 10.1016/s0015-0282(16)46697-5 Vrbicky et al. 1982, Vrbicky 1982
Cite this article
Vrbicky, K. W., Baumstark, J. S., Wells, I. C., Hilgers, T. W., Kable, W. T., & Elias, C. J. (1982). Evidence for the involvement of beta-endorphin in the human menstrual cycle. Fertility and Sterility, 38(6), 701-704. https://doi.org/10.1016/s0015-0282(16)46697-5
Vrbicky KW, Baumstark JS, Wells IC, Hilgers TW, Kable WT, Elias CJ. Evidence for the involvement of beta-endorphin in the human menstrual cycle. Fertil Steril. 1982;38(6):701-704. doi:10.1016/s0015-0282(16)46697-5
Vrbicky, K. W., et al. "Evidence for the involvement of beta-endorphin in the human menstrual cycle." Fertility and sterility, vol. 38, no. 6, 1982, pp. 701-704.
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