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Ovarian blood flow measurements were carried out in pseudopregnant anesthetized rabbits in order to compare three different techniques. Direct measurement by venous cannulation and flow determination by 15-mum radioactive microspheres resulted in values 5 and 10 times higher, respectively, than indicator fraction technique using -86Rb. The direct method inevitably involves surgical handling of the ovary and its vessels, which may account for the lower values found with this method than with microspheres. A comparison between the dynamics of -86Rb uptake in the luteal ovary and the hindleg tissues, mainly consisting of striated muscle, indicated that this technique will underestimate ovarian blood flow due to a low ovarian extraction of the radionuclide. In the preparation for direct measurement the relation between blood pressure and flow was linear. This lack of autorgeulation is an important factor to consider in studies of ovarian steroid secretion rates. Theradioactive microsphere technique appears to reflect physiological blood flow in the ovary and corpus leteum of the rabbit and can be useful in studies of vascular mechanisms in this gland.

The pituitary-ovarian relationship was studied in a 26-year-old patient with uterovaginal atresia. The plasma levels of luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol were determined daily for a month's period. They showed cyclic variations similar to those of normally menstruating women.

There exists a well documented age-related loss in the coordination of hypothalamic-hypophysial-ovarian function in the female rat but the initial cause of this dysfunction is unclear. A compelling case for the involvement of a central pacemaker in age related neuroendocrine dysfunction has been made but changes in ovarian steroid secretion with age and the demonstrated detrimental effects of long-term steroid exposure on hypothalamic structure and function also suggests that the ovary is an initiator or at least an important modulator of neuroendocrine change associated with aging.

The clinical and pathological features of 63 steroid cell tumors, not otherwise specified, were reviewed. The patients ranged in age from 2 1/2 to 80 years. The most common initial manifestation was virilization (41%); four patients had estrogenic manifestations, and four had hypercortisolemia with Cushing's syndrome. The tumors, 6% of which were bilateral, ranged from 1.2 to 45 cm in greatest dimension. Microscopic examination revealed two types of cells, which had overlapping features: those with abundant eosinophilic cytoplasm and those with vacuolated cytoplasm. Fat stains were positive in 75% of the 16 cases in which they were performed. Follow-up data ranging from 1 to 19 years (average 5.2 years) in duration were available for 50 patients. In 24 cases, the tumor was designated probably benign (no evidence of spread beyond the ovary within 3 or more years postoperatively). In 18 patients, the tumor was clinically malignant. The best pathological correlates of malignant behavior were: the presence of two or more mitotic figures per 10 high power fields (92% malignant); necrosis (86% malignant); a diameter of 7 cm or greater (78% malignant); hemorrhage (77% malignant); and grade 2 or 3 nuclear atypia (64% malignant).

The establishment of mammalian pregnancy involves a complex series of events in which the uterine environment is prepared to accept and allow implantation of the embryo. Continuation of the pregnancy depends on rapid recognition by the mother, so that the hormonal support of the endometrium, provided by the corpus luteum, can be maintained until the time of the luteoplacental shift (Csapo et al. 1973). There is considerable variation in the mechanisms by which different species achieve this end with respect both to the systemic, hormonal changes and to the local morphological and biochemical adaptations of the endometrium (Finn 1983; McLaren 1985; Hearn 1986) However, underlying this complexity are certain basic similarities between species, including the ovarian steroids, oestradiol and progesterone, and the need for adaptive changes of the endometrium, termed decidualisation.

Ovarian steroid hormones are frequently used in clinical practice. Postmenopausal replacement therapy and oral contraception are both based on the effects of the ovarian steroids. Mental side effects have often been reported, especially in relation to oral contraceptives. In that context it is of course of importance to collect knowledge about the influence ovarian steroid hormones have on the brain. The present review discusses the natural hormones estradiol and progesterone and some of their metabolites. Knowledge of the effects of synthetic estrogen and progestagen derivatives is very limited and will be mentioned only briefly.

Available evidence indicates that the motility of the oviduct is markedly influenced by adrenergic hormones and ovarian steroids (Coutinho, 1973). The relationship between these two regulatory mechanisms is thought to play an important role in the control of ovum transport. Although the effects of the ovarian steroids on the oviduct are not as striking as those on the uterus, there is a tendency to consider estrogens as activators and progestins as inhibitors of oviduct contractility (Coutinho, 1973). Ovarian steroid hormones also influence the reactivity of the oviduct to adrenergic compounds. Estrogens render the oviduct more sensitive to the α-adrenergic effects of catecholamines, while progestins apparently potentiate the response of the oviduct to β-adrenergic activation (Coutinho et al., 1971; Coutinho, 1973).

The ability of prostaglandin (PG) E2 treatment to stimulate luteinizing hormone (LH) release was compared in cyclic (4-day) and ovariectomized rats. PGE2 (500 μg) was injected sc and plasma LH concentration was determined in serial jugular blood samples. Administration of PGE2 at 13.30 h on each day of the oestrous cycle resulted in a significantly greater increase in plasma LH levels at pro-oestrus and oestrus than at dioestrus 1 and 2. This differential response by the hypothalamo-hypophyseal axis during the oestrous cycle implicates regulatory activity by ovarian steroid feedback. In oestrogen-primed ovariectomized rats, PGE2 administration stimulated a significant increase in plasma LH, but similar treatment in non-primed castrates decreased plasma LH levels. This finding suggests a major role for oestrogen in regulating this response.

SummarySteroid 17α-hydroxylase was measured, using a tritium exchange assay, in the microsomal fraction of ovaries from immature intact or hypophysectomized rats exposed to 20IU pregnant mare's serum gonadotropin. The hypophysectomized animals were pretreated with diethylstilbestrol (DES) to increase the ratio of granulosa:theca + interstitium in the ovary; controls received oil vehicle. In intact animals hydroxylase levels decreased within 8 hr after injecting PMS but by 48 hr the concentration was more than 3 times that found in starting controls; after 48 hr the enzyme level decreased drastically and remained low through 120 hr. In oil-treated hypophysectomized rats hydroxylase activity decreased within 12 hr after PMS but in DES-treated animals the enzyme was already extremely low. In both, the enzyme level reached much higher levels than in intact animals and it did not decrease significantly through 72 hr after PMS. The results indicate that 17-hydroxylase activity is induced by PMS treatment but th...

Publisher Summary This chapter discusses the roles played by the ovary in the initiation, maintenance, and termination of pregnancy in viviparous vertebrates. Having formed and discharged the egg, the ovary reverts to an intermediary role so that a consideration of its function falls naturally into two parts: (1) the factors that influence or control ovarian activity and (2) the effects of that activity upon other organs. The delay in the recurrence of estrus is associated with the persistence of the corpus luteum beyond its duration in the normal cycle. The relation between this organ and the maintenance of pregnancy was first appreciated in the early years of the century. The chapter describes the ovarian changes in pregnancy and the formation of the corpus luteum in eutherian mammals. The outstanding ovarian change involved in pregnancy is the increased functional survival of the corpus luteum and, as a consequence, the predominance of progesterone in the ovarian steroid output. Progesterone is described as the hormone of pregnancy for without a source of progesterone, no pregnancy can be maintained.

Cyclical ovarian function is totally dependent on the secretion of gonadotropic hormones from the anterior pituitary. The synthesis and release of these tropic hormones is controlled on the one hand by hypothalamic releasing hormones, and on the other by the feedback of steroid hormones secreted by the ovary. This paper will review briefly the hormones secreted by the hypothalamus, pituitary and in particular the ovary and discuss the interrelationships between these hormones (i.e. the HP0 axis).

The secretion rate of oestradiol and the peripheral concentration of luteinizing hormone (LH) were measured during anoestrus in six Merino cross ewes. The basal concentration of LH remained low (

Bilateral lesions that destroyed the amygdaloid nuclear complex failed to alter either serum concentrations of luteinizing hormone (LH), estradiol (E2), progesterone, and testosterone or sexual behavior in female rhesus monkeys. In 3 of 5 females ovulation occurred in the postoperative cycle, and in 4 of 5 females exogenous E2 treatment released a surge of LH whose pattern was indistinguishable from the normal preovulatory surge. A postcastration rise in serum LH also occurred in the 5 lesioned monkeys, and E2 again induced an LH release. The data suggest that the amygdala does not play a major role in regulation of LH or ovarian steroid secretion during the menstrual cycle. Moreover amygdaloid lesions in female monkeys do not alter their sexual behavior.

We have correlated the concentrations of serum LH, estradiol and progesterone with the activities of 2 ovarian steroid biosynthetic enzymes during the rat estrous cycle. Ovarian 3 beta-hydroxysteroid dehydrogenase isomerase (3-beta HSD) activity decreased from 29 +/- 6 nmol/mg protein/min (mean +/- SEM) in diestrus, to 7 +/- 0.4 nmol/mg protein/min in late proestrus (p less than 0.005), and subsequently increased to 36 +/- 9 nmol/mg protein/min in metestrus (p less than 0.01). Ovarian 17-hydroxylase (17-OH) activity decreased from early to late proestrus (3.3 +/- 0.2 vs 2.2 +/- 0.2 nmol/mg protein/min, p less than 0.0025), and subsequently increased to 3.9 +/- 0.2 in metestrus (p less than 0.001). Serum LH, estradiol and progesterone peaked during proestrus, and reached a nadir during estrus. We conclude that the activities of 3-beta HSD and 17-OH in the rat ovary vary markedly during the estrous cycle. These changes may underlie the pattern of steroid secretion characteristic of this process.

Breed and seasonal effects on LH release, ovarian steroid secretion, and ovulation were evaluated in mature Finnish Landrace (Finn) and Hampshire ewes that received either a progestogen-PMSG treatment in May, July and November (experiment 1) or estradiol-17β (50 μg) in May and July (experiment 2). The progestogen-PMSG treatment increased plasma estradiol within 12 hr after the PMSG injection at all three treatment periods and resulted in plasma LH and estradiol profiles similar to those during proestrus in cyclic ewes. Season, but not breed, affected the time from PMSG injection to preovulatory LH surge (56.5±1.4 hr in November vs 77.1±3.4 hr in July). Ovulation rate was higher in Finn than Hampshire ewes except in July when it decreased in Finn ewes. Magnitude of the estradiol-mediated LH release was decreased in July in Finn but not Hampshire ewes. Seasonal effects on reproduction in progestogen-PMSG treated ewes appear to be mediated through pituitary gonadotropin secretion with breed differences as to time and/or intensity of the seasonal effect(s).

PRL secretion induced by cervical stimulation (CS) in the intact rat is characterized by a daily diurnal surge (1900 h) which recurs for 10 days and a daily nocturnal surge (0500 h) which lasts for 11 days. In ovariectomized (OV) rats, CS induces attenuated PRL surges which last for only 6 days. This study describes the effect of SC Silastic implants of estradiol (E2) or progesterone (P) on the magnitude and persistence of PRL surges in OV-CS rats. Placement of P at 1500 h and CS at 1900 h day 0 (D-0) resulted in nocturnal surges of PRL on D-2 which were significantly greater than those of blank-implanted rats. Diurnal surges of PRL on D-2 were equivalent in P and blank-implanted rats. Placement of E2 at 0800 h on the day before CS at 1900 h on D-0 resulted in an enhanced diurnal surge and extinction of the nocturnal surge of PRL on D-2 compared to blank-implanted rats. In the absence of CS, OV rats presented diurnal but no nocturnal surges of PRL in response to E2. When steroid implantation was delayed u...

Three ovarian tumors occurring in patients 35–52 years of age resulted in clinically typical and biochemically documented Cushing's syndrome. All three tumors were of steroid cell (lipid cell) type and had metasta-sized within the abdomen by the time of presentation.

Female Wistar-derived rats with regular oestrous cycles were injected s.c. at 15.00 h on pro-oestrus with difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase. The drug (10–100 mg/rat) caused a dose-related reduction in the concentration of LH in plasma taken at 19.00 h (the time of the peak of the LH surge in this colony). There was also a dose-related reduction in the pituitary content of total polyamines. The reduction in the plasma concentration of LH was not due to the shifting of the time of the peak of the surge, as concentrations were significantly lower than control from 17.00 to 21.00 h, the overall reduction in total LH release being approximately 50%. The number of ova in the oviducts at 06.00 h next morning was significantly reduced by treatment with 50 mg DFMO/rat, by an average of 70%. Injection of DFMO enhanced the fall in plasma oestradiol concentrations seen between 15.00 and 19.00 h, in a dose-related manner. It also prevented the rise in progesterone concentrations seen in control animals during this period. The ability of DFMO to prevent the rise in plasma concentrations of LH was not secondary to the effects of the drug on ovarian steroid production because DFMO also significantly reduced the LH surge in animals ovariectomized on dioestrus and given appropriate replacement injections of oestradiol and progesterone. It seems possible that part of the action of DFMO is exercised at the hypothalamus, since when 50 mg DFMO/rat was given either 2 or 4 h before the expected peak of the LH surge, the LHRH content of the hypothalamus was significantly reduced at that time. These results suggest that activation of ornithine decarboxylase is a necessary prerequisite for a normal LH surge, and that this activation is steroid-dependent. This conclusion is borne out by results from direct observations on the activity of the enzyme in pituitary tissue incubated in vitro. J. Endocr. (1988) 117, 447–453

Pro-oestrous-type LH surges were induced by treating ovariectomized rats (day 0) with either oestradiol benzoate (OeB, 40 μg/rat) or oestrogen (10 μg/rat followed by progesterone (4 mg/rat, day 2, OeBP). To characterize the temporal changes associated with the LH surge on day 2, LH-RH levels in the medial basal hypothalamus (MBH) and the pre-optic area (POA) were analyzed by RIA in rats sacrified at hourly intervals between 10.00–19.00 h. Following these treatments the LH-RH content of POA fluctuated somewhat but no definite pattern was observed. In OeB rats, the MBH LH-RH levels were unchanged through the initial LH surge period (13.00–15.00 h) declining significantly, as in the OeBP group, near the end of the surge period (19.00 h). However, in OeBP rats, the MBH LH-RH contents decreased at 14.00 h and these were followed by markedly elevated levels between 15.00–17.00 h coincident with maximal increments in serum LH. The OeBP group alone showed a surge of serum FSH.

The effects of the diabetes (D) mutation on utero-ovarian structure and function were examined in match-paired D and control (C) C57BL/KsJ mice between 2 and 16 weeks of age. Between 4 and 8 weeks of age, the uterine epithelium of D mice exhibited a remarkable increase in the amount of cytoplasmic lipid stores as compared with that of C animals. Associated with progressive hyperglycemia between 8 and 16 weeks of age, uterine atrophy and continued lipid accumulation occurred. Both serum progesterone and estradiol levels were lower in D than C mice between 8 and 16 weeks of age. In addition, the uteri of D mice failed to accumulate as much 3H-estradiol as C uteri at 16 weeks of age. These data demonstrate that changes in uterine structure that are attributable to depressed ovarian activity in diabetics underlie the reproductive failure in these animals. The temporal association between the onset of reproductive tract involution and the expressed hyperglycemic condition suggests a causal association between these events in the genetically diabetic C57BL/KsJ mouse.

We examined blood concentrations of ovarian steroid hormones (E2, P) and serum LH concentrations to establish that the Ovu-STICK assay reliably reflects endocrine events in the periovulatory period. In all 16 cycles studied, which included 2 cycles in which the women received CC, the ovulatory surge of LH was detected with the use of the Ovu-STICK assay. In contrast, BBT monitoring correctly predicted the ovulatory event in only half the cycles.

Infusion of LRF (0.2 μg/min × 3.5 hrs) and injection of LRF-agonist (50 μg, SC) elicited a prompt and sustained PRL release by the pituitary. This effect is independent of ovarian steroid environment as observed in both normal cycling women and hypogonadal subjects with similar time course and magnitude of PRL release.

The importance of cervical mucus in the physiopathology of reproduction is considerable. It is the first barrier encountered by the spermatozoa on their route towards the ovum. The mechanisms which render the mucus permeable to the spermatozoa are still not clear; they probably depend upon variations in the number and quality of chemical bindings between the proteic macromolecules that constitute the structure of the mucus under the influence of the ovarian steroids.

The levels of cytosol receptors for both oestradiol and progesterone were simultaneous monitored in the uterus at various stages of the rat oestrous cycle. The use of the synthetic gestagen R-5020, with its high specificity and affinity for the progesterone receptor, eliminated interference arising from corticosteroid binding globulin (CBG) contamination of uterine extracts. The results show that the patterns for both receptors are markedly different over the cycle. The variation can be correlated with changes in ovarian steroid output. The results also suggest that oestradiol and progesterone interact not only with their specific receptor, but also influence the other receptor system.

Treatment of GnRH-deficient (hpg) female mice with oestradiol-17 beta (E2) for 7 days increased GnRH receptors from 4.1 +/- 0.4 fmol/pituitary (control) to 7.2 +/- 0.7 fmol/pituitary (GnRH-treated), and consistently increased pituitary FSH content. Treatment of hpg female mice with E2 plus progesterone (P) for 14 days stimulated GnRH receptors more than did E2 alone, although values still remained lower than those of normal intact female mice. In contrast, GnRH treatment of intact hpg female mice alone, or combined with E2 + P, increased GnRH receptors to values similar to those of intact normal female mice. In contrast, the receptor rise after GnRH treatment alone of ovariectomized hpg mice was significantly less than in intact hpg mice similarly treated. However, the combination of GnRH + E2 + P treatment of ovariectomized hpg mice increased GnRH receptors to normal intact female values, indicating the synergistic actions of these hormones on GnRH receptor up-regulation at the pituitary. Oestradiol treatment of ovariectomized normal female mice prevented the receptor fall after ovariectomy, and when combined with exogenous GnRH further increased receptors to values identical to those of intact female mice receiving GnRH alone. Ovariectomy of hpg mice had no effect on GnRH receptor, serum or pituitary LH and FSH values. There was no change in serum LH concentration after GnRH treatment of hpg female mice, but serum FSH increased and this was accentuated by ovariectomy, indicating that in intact mice an ovarian factor(s) normally inhibits GnRH-stimulated FSH release. This factor did not appear to be an ovarian steroid since serum FSH was not suppressed in intact or ovariectomized GnRH-treated hpg mice concurrently receiving E2 + P treatment. These results suggest that: (1) gonadal steroids alone have a major direct stimulatory action on the pituitary to increase GnRH receptors; (2) the oestrogen-induced increase in GnRH receptors is enhanced in the presence of GnRH; (3) steroids exert inhibitory feedback on gonadotrophin secretion that is mediated at some cellular regulatory locus other than the GnRH-receptor complex.

Discovery of intracellular hormonal receptors has permitted histologic interpretation of the action of ovarian steroids on the endometrium. Research carried out by biochemists and physiologists has led to a better understanding of the histologic effects of hormonal disturbances and isolated or combined hormonal treatments.

The present study examined the ovarian progesterone levels in rats during the normal 5-day oestrous cycle and in rats with an experimentally induced delayed or advanced ovulation. Ovarian androgen and oestrogen concentrations were also studied in rats with an advanced ovulation. The ovarian progesterone concentrations during the normal cycle showed two peaks: one during metoestrus and dioestrus 1 and the second during the afternoon of pro-oestrus. Rats treated with pentobarbitone sodium (35 mg/kg body weight) at 13.00 h on the day of pro-oestrus showed no increase in ovarian progesterone levels on that day, but did show an increase during the afternoon of the next day. Rats injected intraperitoneally with an ovulation-inducing bolus of human chorionic gonadotrophin (hCG; 20 i.u.) at 15.00 h on the day before pro-oestrus (dioestrus 2) showed increased ovarian progesterone levels as early as 0·5 h after hCG injection. Lowered levels of ovarian androgen and oestrogen values compared with saline-injected rats were first found 2 and 6 h respectively after hCG injection. In conjunction with data obtained previously these findings show that normal, delayed and advanced ovulations are preceded by an increase in ovarian progesterone concentrations and a subsequent decline in ovarian androgen and oestrogen levels.

The plasma patterns of ocstrogens, progesterone and 17α-hydroxyprogesterone were studied during 18 normal menstrual cycles in 15 rhesus monkeys. Radioimmunoassays and competitive protein binding were used for the determination of the plasma levels of the steroids. The average patterns of the steroids in plasma and their relation to ovulation, menstruation and normality of the cycles studied are described.

Publisher Summary This chapter discusses the role of the adrenocortical hormones in mammary differentiation. It has been reported that desoxycorticosterone stimulates ductal growth in the ovariectomized, and the injections of cortisol can enhance alveolar development in intact female rats. While ovarian steroids seem to act as permissive factors in hypothalamic lactation, the role of the adrenal corticosteroids in perphenazine-induced lactation is still unknown. The absence of both ovarian and adrenocortical steroids results in the involution of the mammary tissue of the untreated rats as well as the impairment of the mammotropic effect of perphenazine. In vivo adrenocortical hormones seem to be essential for milk secretion but they are not necessary for the first stages of mammary growth. This holds true also in perphenazine-induced hypothalamic lactation—at least for the rat; other species may have different requirements.

1. When ovulation is prevented by the injection of pentobarbitone on the day of pro-oestrus in female rats, the expected increases in thyroid-serum concentration ratio (T/S ratio) for 131I and in the uptake of 113I by the thyroid on the day of oestrus do not occur. 2. Ovulation induced by human chorionic gonadotrophin or ovine luteinizing hormone in rats treated with pentobarbitone at pro-oestrus is not associated with an increase in T/S ratio or 131I uptake at oestrus. 3. These results support the view that it is the neuro-endocrine changes at the hypothalamic or pituitary level that lead to ovulation rather than changes in the pattern of ovarian steroid secretion before or at ovulation that are responsible for the increased thyroid activity at oestrus in the female rat. 4. Experimental evidence of an increase in thyroid activity after ovulation in mice and hamsters also supports this view.

SUMMARY A comparison has been made between the steroids present in equine follicular fluid and luteal tissue. Follicular fluid was found to contain progesterone, 17α-hydroxyprogesterone, androstenedione, epitestosterone, 19-norandrostenedione, oestrone, oestradiol-17β and 6α-hydroxyoestradiol-17β, in confirmation of previous studies. On the other hand, luteal tissue contained large amounts of progesterone and 20α-hydroxypregn-4-en-3-one, and a small quantity of 17α-hydroxyprogesterone. No C18 or C19 steroids could be detected. These findings are therefore interpreted as evidence in favour of a 'two-cell type' theory of steroid formation in the ovary. One type, possibly the theca interna cell, has the ability to convert progesterone into oestrogens; the other type, possibly the luteinized granulosa cell, has a diminished 17-hydroxylating ability and is unable to cleave the C21 side chain to make C18 and C19 steroids. However, it does have an active 20-reductase enzyme system present.

Plasma levels of estradiol estrone 17-hydroxyprogesterone (17-HP) progesterone (P) 20alpha-dihydroprogesterone (20alpha-DHP) and luteinizing hormone (LH) were measured in blood continuously withdrawn at a rate of 4 ml/hour over a period of 48 hours from 10 normally menstruating women during the periovulatory period. LH was estimated in 3-hourly plasma samples. 1 patient showed a continuous parallel increase in estradiol and estrone 2 days prior to the LH surge without a concomitant change in LH and 17-HP. Another patient showed a sudden drop in estradiol 1 day before the LH peak which was accompanied by the beginning of a major increase in LH and 17-HP and 6-9 hours later by a small but marked rise in P. In 3 women studied for the LH surge a constant decline in estradiol was observed beginning at least 12 hours before the peak in the presence of unchanged estrone. All subjects showed biphasic LH peaks which were strongly correlated with similarly changing levels of 17-HP. P levels increased at the time of the sharpest rise in LH. 2 subjects showed a parallel decrease in estradiol LH and 17-HP on the day after the LH peak until a plateau was reached. Once this plateau was reached a new increase in P and 20alpha-DHP was observed. A 2nd increase in 17-HP was observed on the 2nd day after the LH peak which was accompanied by a parallel increase in P and 20alpha-DHP and decreasing levels of LH. The findings strongly suggest that different control mechanisms are involved in the regulation of ovarian steroid secretion during the periovulatory period.

A SERIES of experiments concerned with the influence of prolactin on spermatogenesis and on the accessory reproductive structures in mice led to the suggestion that prolactin can stimulate the production of testicular androgens1. In the female, prolactin is known to affect the synthesis of ovarian steroid hormones; its luteotropic action in the mouse and the rat is particularly well established. The results obtained in the rat2,3, the rabbit4 and in the perfused bovine ovary5 indicate that the prolactin effects on ovarian steroidogenesis may be mediated, at least in part, by changes in cholesterol storage and perhaps discharge. The present work investigates the influence of prolactin on cholesterol stores in the mouse testis.

Among women with acute intermittent porphyria (AIP) a small group exists whose clinical symptoms are precipitated by menses or pregnancy. In three such cases studied, the cyclical use of the oral progestational agents was apparently successful in preventing the appearance of symptoms. The individual administration of androgen, estrogen, and a progestin preparation to one patient showed the same protective effect. This suggests that inhibition of gonadotropin secretion, with stabilization of endogenous ovarian steroid production at a low level, may be the effective mechanism. Use of the progestins is occasionally associated with signs and symptoms of hepatotoxicity. Such side effects constitute the main limitation in the use of these drugs. Untoward effects can be minimized by the use of alternative preparations and lower dosage.