Physiology of the menstrual cycle.

Modern techniques of bioassay have permitted correlation of hormonal secretion with genital tissue changes during the normal menstrual cycle. During the follicular phase, estrogen secretion rises while other hormone levels are low. At ovulation luteinizing hormone and follicle-stimulating hormone surges are associated with falling estrogen levels. Secretions of progesterone and estrogen again are characteristic of the luteal phase ending with menstruation. Gonadotrophin-releasing hormones are detectable just before the luteinizing hormone and follicle-stimulating hormone surges. Basal body temperature rises with ovulation and is still the most reliable clinical indicator, although ferning and spinnbarkeit (when present) are also quite helpful. Vaginal smears are probably less useful except in the hands of experienced observers.

PIP: The correlation of hormonal secretion with genital tissue changes during the normal menstrual cycle has been made possible employing modern techniques of bioassay. Estrogen secretion rises and other hormone levels are low buring the follicular phase. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges are associated with decreasing estrogen levels at ovulation. The luteal phase ending with menstruation is characterized by the secretion of progesterone and estrogen. Prior to LH and FSH surges gonadotrophin-releasing hormones are detectable. The rise of basal body temperature with ovulation is the most reliable indicator of ovulation although ferning and spinnbarkeit are also useful. Vaginal smears may be of use when handled by experienced people.

Steroids and related products. XLI. (1) the synthesis of 11-oxa steroids. III. (2) 17-acetoxy-11-oxaprogesterone (3).

The synthesis of 17-acetoxy-11-oxaprogesterone, the 11-oxa analogue of the orally active progestational and anti-fertility agent 17-acetoxyprogesterone, is described. An intermediate in the synthesis of 11-oxaprogesterone, 11-oxa-5alpha-pregnane-3,20-dione, available from hecogenin, was used as starting material and the 17-hydroxy function was introduced by a modified Barton oxidation. The new hormone analogue shows only extremely weak progestational activity in the oral Clauberg assay.

Direct evidence that 17 alpha,20 beta-dihydroxy-4-pregnen-3-one functions as a goldfish primer pheromone: preovulatory release is closely associated with male endocrine responses.

This study directly tested the hypothesis that 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P) is a goldfish preovulatory pheromone (pheromone released at peak levels during oocyte final maturation) which increases blood gonadotropin (GtH) and milt volume in males. During spontaneous ovulation, GtH and 17,20 beta-P in female blood and 17,20 beta-P released to the water increased dramatically 7-10 hr prior to ovulation, peaked 1-4 hr prior to ovulation, and then rapidly declined. Males held with these females, or exposed to their odors, had increased GtH levels and milt volumes at approximately the time when increased 17,20 beta-P release by ovulatory females commenced. Although these findings strongly support the hypothesis that 17,20 beta-P is a preovulatory female sex pheromone in goldfish which stimulates male GtH levels and milt production prior to spawning, the milt increases occurred earlier than predicted, suggesting either that preovulatory 17,20 beta-P release begins earlier than the data indicate or that other steroids known to have pheromonal activity are released before 17,20 beta-P.

Luteal function in ectopic pregnancy.

Human chorionic gonadotropin, estradiol, progesterone, and 17-hydroxyprogesterone have been measured in the serum of 46 patients with ectopic pregnancy. All these hormones were significantly lower than in normal pregnancy. Unruptured ectopic pregnancy differed from the ruptured state by a lower serum human chorionic gonadotropin concentration, a slower human chorionic gonadotropin increment, a higher incidence of metrorrhagia, and an earlier diagnosis. The concentration of estradiol, progesterone, and 17-hydroxyprogesterone in the serum of patients with ectopic pregnancy was lower than could be expected from the decrease of human chorionic gonadotropin, often lower than in a normal luteal phase. It is suggested that, as long as ultrasonography fails to show an intrauterine pregnancy, the simultaneous determination of serum human chorionic gonadotropin and progesterone could aid in the early diagnosis of ectopic pregnancy and in the improvement of subsequent fertility; to that regard any progesterone level below 15 ng/ml in the presence of detectable amounts of human chorionic gonadotropin is highly suggestive of either a threatened abortion or an ectopic pregnancy, whatever the gestational age.

Experimental studies on the positive feedback effect of progesterone, 17 alpha-hydroxyprogesterone and 20 alpha-dihydroprogesterone on the pituitary release of LH and FSH in the human female. The estrogen priming of the progesterone feedback on pituitary gonadotropins in the eugonadal woman.

Administration of progesterone eugonadal women during the midfollicular phase of the menstrual cycle failed to induce a positive feedback effect on the serum concentrations of LH and FSH. The levels of estradiol in serum decreased following the injection of progesterone without a parallel change in LH and FSH concentrations indicating a direct ovarian effect of the exogenous progesterone. In the late follicular phase of the cycle, when preovulatory levels of estradiol were present in serum, or under a ethinyl estradiol treatment progesterone was able to induce an LH discharge indicating the requirement of an estradiol priming of the positive feedback of progesterone in eugonadal women. In order to establish the time required for a sufficient estrogen priming with preovulatory levels of estradiol in serum 3 mg of estradiol-benzoate were administered i.m. 1, 12 and 24 h prior to the administration of 30 mg of microcristalline progesterone in the midfollicular phase of the menstrual cycle, when progesterone alone did not cause an LH surge. Only when estradiol-benzoate was injected 24 h prior to the progesterone administration an LH surge reproducible in time course and magnitude occurred. Administration of estradiol-benzoate alone under these conditions did not cause an LH surge within the elapse of time after the injection when the progesterone induced LH surge occurred. Thus, these experiments demonstrate that a defined estrogen priming is required for the positive feedback effect of progesterone on the gonadotropin release in eugonadal women. Furthermore, progesterone levels in serum of about only 1--2 ng/ml were required for the induction of an LH surge indicating that under physiological conditions progesterone may have an supplementory effect on the primarily estradiol induced LH midcycle peak. 17-hydroxyprogesterone administered during the mid follicular phase of the menstrual cycle and under pretreatment with ethinyl estradiol failed to induce a positive feedback effect on the serum concentrations of LH and FSH, indicating that this steroid does not play a regulatory role on the midcycle LH release in women. 20alpha-dihydroprogesterone administered under the same experimental conditions as 17-hydroxyprogesterone seems to be able to induce an LH surge in serum provided there is an adequate estrogen priming.

PIP: The hypothesis that progesterone (P) is involved in the regulation of the estradiol-induced midcycle surge of luteinizing hormone (LH) was investigated in eugonadal women. The administration of P during the midfollicular phase did not exert a positive feedback effect on serum levels of LH and follicle stimulating hormone (FSH). Serum estradiol levels fell after the administration of P, though levels of LH and FSH were not altered. This indicates a direct ovarian effect of P. Administration of P, in the presence of preovulatory levels of estradiol or exogenous ethinyl estradiol, induced an LH discharge indicative of the necessity of estradiol priming for the positive feedback effect of P. It was found that estradiol benzoate had to be adminstered at least 24 hours prior to the administration of P during the midfollicular phase for the LH surge to occur. In his latter experiment, neither P nor estradiol by themselves were able to produce an LH surge, thus indicating the estrogen priming is required for the positive feedback effect of P on LH release. 20alpha-dihydroprogesterone, but no 17-hydroxyprogesterone, was able to induce an LH surge with adequate estrogen priming.

Stimulation by 17 alpha-hydroxyprogesterone of glycoprotein and glycosaminoglycan synthesis in human placenta in vitro.

The incorporation of 14C-glucosamine into glycoproteins (GP) and glycosaminoglycans (GAG), of 3H-leucine into protein, and the hexuronic acid (HA) content of polymerized GAG was determined in incubated placental tissue. In placentae of earlier gestational age (GA), incorporation of 14C-glucosamine was 2.6 times greater than other at 38-39 weeks GA. 19 of 26 placentae at 38-39 weeks GA responded by one or more parameters when incubated with 0.5-3 microM 17 alpha-OH-progesterone (17OHP). Those which did not respond were all of earlier GA; the placental content of GAG decreased in these from 31.1 +/- 1.8 nmol HA/mg protein to 16.4 +/- 1.5 nmol in placentae of GA 38-39 weeks. In the latter, 17OHP increased GAG by 42.5% to 24.4 +/- 2.5 nmol HA/mg protein in a 2-hour incubation. Progesterone, oestriol, cortisol and testosterone were without effect. It is concluded that synthesis of placental GAG decreases toward the end of gestation, but can be increased by 17OHP specifically. This indicates that 17OHP is a biologically active steroid and might have a role in maintaining placental function.

Cytodifferentiation of ovarian follicle cells during oocyte growth and maturation.

Inasmuch as 17 alpha,20 beta-diOHprog was identified as the maturation-inducing hormone, we now have two known biologically important mediators of oocyte growth and maturation in salmonids, estradiol-17 beta and 17 alpha,20 beta-diOHprog. It is now established that the granulosa cells are the site of production of these two mediators, but production by the ovarian follicle depends on the provision of precursor steroids by the thecal cell (two-cell type hypothesis). A dramatic switch in the steroidogenic pathway from estradiol-17 beta to 17 alpha,20 beta-diOHprog occurs only in ovarian follicle cells immediately prior to oocyte maturation. This switch is a prerequisite step for the growing oocyte to enter the maturation phase. Resolution of the molecular events regulating this switch will provide new insight into the hormonal events regulating oocyte growth and maturation.

[Origin, variations and physiological role of steroid hormones during the menstrual cycle]. / Origine, variations et rôle physiologique des stéroïdes hormonaux au cours du cycle menstruel.

PIP: The biosynthesis of specific steroids by the theca, granulosa, corpus luteum (CL), and stroma of the human ovary, and their roles in the menstrual cycle and in ovarian disorders are reviewed in detail. Before luteinization, the theca interna and granulosa are separated by a lamina propria. The theca of the Graafian follicle synthesizes estradiol-17beta and 17-hydroxyprogesterone. The granulosa secretes progesterone after the CL is formed. The ovarian stroma releases the androgens dihydroepiandrosterone, androstenedione, and testosterone as well as lesser amounts of estrogens. During the cycle, estradiol rises from 50 pg/ml to 250-400 pg/ml at the preovulatory peak, and remains moderately high until menstruation. 40% of plasma estrone derives from peripheral conversion of androstenedione and estradiol; 50% comes from the adrenal. Hydroxyprogesterone increases from 2 ng/ml in late follicular phase to 1.6 ng/ml at the ovulatory peak and in luteal phase. Progesterone plateaus at 8-10 ng/ml in luteal phase. The physiology of androgens is complicated by the fact that only free testosterone, converted locally to dihydrotestosterone, is androgenic. Premenstrual syndrome, short luteal phase, and polycystic ovarian dystrophy are increasing degrees of low LH, limited FSH (invariant in polycystic ovary), resulting in low estradiol and hydroxyprogesterone. There is no qualitative difference in ovarian biochemical capability in polycystic ovary, but androgen synthesis by stroma overshadows the deficient estrogens.^ieng