Search

This study was intended to correlate different clinical and biologic parameters to better define luteal insufficiency (LI) and to contribute to a better understanding of its origin. Endometrial patterns were used as the basis for classification of clinical cases. Of 328 outpatients with menstrual disorders and/or infertility, 88 were considered to have LI. Their cycles were compared with 79 normal cycles. Two different principal endometrial patterns of LI are described: pure LI, when the endometrium is more than 2 days out of phase; and LI with persistent estrogenic influence, when the histologic estrogenic stigmata are excessive during the luteal phase. Basal body temperature charts demonstrated menstrual cycle disturbances: either ovulation delay or a slow increase in temperature (longer than 2 days). Plasma steroid concentrations also demonstrated a perturbation of the entire menstrual cycle: progesterone levels were statistically significantly lower in LI than in normal cycles and this defect was worse when the estrogenic influence was persistent; the preovulatory estradiol peak was disturbed in all circumstances, as was the concentration of endometrial steroid receptors. These simultaneous abnormalities strongly suggest a central origin of LI.

Estradiol and progesterone receptor sites (empty or filled with endogenous hormone)have been measured in the cytoplasm and nuclei of human endometrium. Receptor changes have been observed throughout the normal menstrual cycle. During the preovulatory phase the cytoplasmic estradiol receptor sites do not change while the nuclear receptor sites more than double. Cytoplasmic estradiol receptor sites decrease very early in the secretory phase, whereas the decrease in nuclear sites occurs later. Cytoplasmic progesterone receptor sites more than double during the preovulatory phase and show a large decrease immediately after ovulation, when the concentration of nuclear receptor is at its highest. Thus the total cellular concentrations of both estradiol and progesterone receptors are lowest in the late secretory phase. It was found that they are positively correlated with the concentration of plasma estradiol only during the proliferative phase. The concentration of cytoplasmic progesterone receptor is negatively correlated with 17 beta-hydroxysteroid oxidoreductase activity during the secretory phase. In anovulatory cycles the concentrations of estradiol and progesterone receptors are high, similar to those of the late proliferative phase. "luteal insufficiency" is characterized by a very low concentration of estradiol receptor. Early pregnancy endometrium (8 to 10 weeks' gestation) is characterized by a large concentration of progesterone receptor, exceeding those of any period of the menstrual cycle.In the present study receptor measurements have been obtained in 101 cases of normal menstrual cycles, and receptor changes correlated with microsomal 17-beta-hydroxysteroid-dehydrogenase activity and the concentration of plasma estradiol. During preovulatory phase estradiol receptor sites do not change, while they decrease very early in the secretory phase. Progesterone receptor sites more than double during preovulatory phase, and decrease immediately after ovulation. Cellular concentrations of both estradiol and progesterone are positively correlated with the concentration of plasma estradiol during the proliferative phase. Anovulatory cycles are characterized by high concentrations of estradiol and progesterone receptors. A large concentration of progesterone receptors characterizes early pregnancy endometrium.

Nonhormonal drugs—diphenylhydantoin and nialamide, which act on the central nervous system and have no known endocrine activity—were given to two groups of women with distinct types of electroencephalographic patterns in an effort to regulate menstrual disorders. Equalization of the lengths of both the follicular phase and the luteal phase to the normal range was observed during the drug therapy. Forty-five per cent of the pregnancy rate was achieved in 36 of the 80 infecund patients within 4 months of treatment. The mode of action of these drugs is still unknown.

RU 16117, the 11α-methoxy derivative of ethynyl estradiol, is an orally active weak estrogen potentially effective in the treatment of estrogen-deficiency in postmenopausal women (climacteric symptoms and severe osteoporosis). Biochemical studies have shown that RU 16117, like estriol, possesses the properties characteristic of a partial estrogen agonist/antagonist. RU 16117 binds to the cytosol estrogen receptor (ER) to form a complex which dissociates much faster than the estradiol complex. This explains its lower nuclear uptake. Furthermore, the nuclear RU 16117 complex also dissociates faster than the estradiol complex. Consequently, although low doses of RU 16117 can induce the majority of the effects of estradiol (increased polymerase A and B activities, cytosol ER replenishment, progestin receptor induction, increased uterine weight), these effects are long-lived only if the dose is considerably increased or if the compound is administered repeatedly or continuously. Since RU 16117 transiently occupies available estrogen binding sites, it can prevent the full response of estradiol. Thus, under appropriate kinetic conditions, it acts as an estrogen antagonist on the above parameters and also on DMBA-induced mammary tumors in the rat. At a daily dose of 24μg for a period of 4 weeks RU 16117 led to 65% reduction in the number of already-established tumors. RU 16117 inhibits basal gonadotropin secretion and decreases the LH response to LHRH. Injection of 5 μg s.c. to the rat in estrus markedly inhibited the spontaneous peaks of LH, FSH and PRL measured on the afternoon of expected proestrus. Low doses which block ovulation by 100% had no detectable effect on vaginal comification, thus suggesting a greater sensitivity at the hypothalamo-pituitary level. In postmenopausal women, daily oral administration of 1, 3 or 10 mg RU 16117 led to a progressive decrease of basal serum LH levels to 60 ± 17, 35 ± 9 anda 20 ± 3% of control, respectively, after 4 weeks of drug administration. EEG profiles have confirmed the central activity of RU 16117. After 56 days treatment with a total weekly dose of 3.5–5 mg of RU 16117, postmenopausal women with predominantly α waves at pretreatment (N = 4) showed a profile with decreased α waves and increased δ + θ waves, whereas women with predominantly δ + θ waves at pretreatment (N = 5) had increased α waves and decreased δ + θ waves. The effect of the estrogen is thus to minimize the differences between the two populations as already observed with tranquilizers. Parallelly, an alleviation of symptoms such as hot flushes, fatigue, insomnia, and headache was noted in several patients. These reappeared on discontinuation of treatment.

Although Wentz noticed the higher frequency of articles on luteal defect (LD)1, the effects of this disorder, its influence on fecundity, its physiopathology, and its therapy are still uncertain and debated. Following Jones2–4, we have used endometrial biopsy (EB) as the reference criterion for investigation of LD. Two different patterns of the progesterone insufficient influence on the endometrium have been previously described: the first is a delay or a lack of progesterone effect which induces an out of phase endometrium (Figure 1(a) and (b)), while a persistent oestrogenic influence (PEI) is associated to luteal defect in the second pattern, as if progesterone effect was too weak to blunt the oestrogenic one (Figure 1(c) and (d)). These endometrial patterns were correlated to ovarian steroid plasma values5.

Alkaline phosphatase was considered as evidence of estrogen-induced protein synthesis in the endometrium. Biochemical and histochemical determinations of alkaline phosphatase activity have been made on human endometrium during the whole cycle, with simultaneous histologic appraisal. Fifty-four cases were used to compute a curve of alkaline phosphatase activity during the menstrual cycle, the peak of which appears to be on the eighteenth day. Although the data are preliminary and the observations few, the results suggest that such a method would be accurate to estimate estrogen action upon the endometrium.

Immunoassayable β-endorphin is present in samples of amniotic fluid obtained in the last two weeks of pregnancy. Average concentration is approximately 300 pg. per milliliter. In all cases of suspected or recognized fetal distress, striking elevations of the β-endorphin concentrations (twofold to 20-fold) were observed. The degree of elevation correlated with the degree of fetal distress.

Mathematical analysis of electroencephalographic (EEG) variations during the normal menstrual cycle or during different endocrine situations demonstrates the bioelectric reactivity of the central nervous system under different hormonal influences. 3 different investigations were performed: 1) normal menstrual cycle; 2) contraceptive therapy with ethinyl estradiol (50 mcg) + norgestrel (.5 mg) or ethinyl estradiol (50 mcg) + norethisterone (2 mg); and 3) a very weak dose of ethinyl estradiol (10 mcg) in a castrated patient. Patterns of EEG variations appear quite different in cases of contraceptive ovulation blockade (negative feedback) and under the stimulatory influence on follicle stimulating hormone (FSH) secretion of weak doses of estrogen. Although individual differences are to be expected these results may clarify neuroendocrine feedback mechanisms; the negative feedback mechanism might be attested by the collapse of both alpha and theta rhythms power spectra variations. A positive feedback mechanism confirmed by the significant variations of FHS level might be demonstrated by a wide amplitude of alpha rhythm variation and a rather moderate amplitude of theta waves variation. Such a correlative investigation might lead to a better understanding of clinical situations concerned with the control of the hypothalamic gonadal axis and new therapeutic prospects. (FULL TEXT)