Premenstrual syndrome.

Within the past decade, premenstrual syndrome (PMS) has become the subject of rigorous scientific scrutiny. As a result, diagnostic criteria have been developed, and the pathophysiology of the disorder has been partially elucidated. The preponderance of evidence suggests that the disorder is the result of the interaction of cyclic changes in estrogen and progesterone with specific neurotransmitters. Serotonin and gamma-amino butyric acid (GABA) appear to be especially important in this regard. Increased understanding of PMS has enabled the development of specific treatment modalities that, unlike previous prescriptions, have demonstrated efficacy in rigorous and reproducible studies.

The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women.

To discern the pharmacological effects of dehydroepiandrosterone (DHEA) in older women with low endogenous DHEA and DHEA sulfate (DS), 1600 mg/day (in four divided doses) were administered orally to six postmenopausal women for 28 days in a double blind placebo-controlled cross-over study. Serum concentrations of androgens after the first 400-mg dose of DHEA increased rapidly and reached a maximum at 180-240 min, resulting in increases over baseline of 6-fold for DHEA (5.8 +/- 2.1 to 28.8 +/- 5.5 nmol/L), 12-fold for DS (3.0 +/- 1.6 to 28.2 +/- 4.6 mumol/L) and androstenedione (1.4 +/- 0.3 to 19.5 +/- 9.8 nmol/L), 2.5-fold for testosterone (0.7 +/- 0.1 to 2.2 +/- 0.6 nmol/L), and 15-fold for dihydrotestosterone (0.2 +/- 0.06 to 2.73 +/- 1.0 nmol/L), but estrone, estradiol, and sex hormone-binding globulin (SHBG) were unchanged. Assessment at weekly intervals revealed a further increase in all androgens which was maximal at 2 weeks and remained markedly elevated, although it declined somewhat by 4 weeks. The increments observed after 2 weeks of DHEA administration reached 15-fold for DHEA (71.9 +/- 14.2 nmol/L), 9-fold for testosterone (6.5 +/- 1.7 nmol/L), and 20-fold for DS (65.1 +/- 14.9 nmol/L), androstenedione (30.5 +/- 11.5 nmol/L), and dihyrotestosterone (3.8 +/- 1.5 nmol/L). Both estrone and estradiol showed a progressive increase to 2-fold the basal value at 4 weeks. Integrated SHBG and thyroid binding globulin levels decreased (P less than 0.05) during DHEA treatment. However, LH, FSH, body weight, and percent body fat, as measured by underwater weighing, were unaltered during the 4-week experiment. A marked decline of 11.3% (P less than 0.05) in serum cholesterol and 20.0% (P less than 0.05) in high density lipoprotein noted within the first week of DHEA administration persisted for the 28-day period and was accompanied by a nonsignificant downward trend in low density lipoprotein, very low density lipoprotein, and triglycerides. Peak insulin levels during the 3-h oral glucose tolerance test were significantly higher (P less than 0.05) after the 28 days of DHEA (1126 +/- 165 vs. 746 +/- 165 pmol/L) and were accompanied by a 50% increase in the integrated insulin response (P less than 0.01) without a significant change in fasting glucose insulin or glucose-6-phosphate dehydrogenase values.(ABSTRACT TRUNCATED AT 400 WORDS)

Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin.

Although abolishment of ovarian cyclicity by the use of a long-acting GnRH agonist (GnRH-a) provides effective treatment for premenstrual syndrome (PMS), its use is limited by sequellae of the resultant hypoestrogenism. In this study the effects of estrogen/progestin replacement on the symptomatic improvement afforded by GnRH-a were evaluated in eight women with severe PMS. The 8-month study design included 2 months of control, 2 months of GnRH-a alone, and 4 further months in which the exogenous steroids were replaced in randomized, double blind, placebo-controlled cross-over fashion using 1 month each of 1) conjugated equine estrogen (CEE) on days 1-25, 2) 10 mg medroxyprogesterone acetate (MPA) on days 16-25, 3) CEE (days 1-25) plus MPA (days 16-25), and 4) placebo alone. Mood and physical symptoms were measured daily on a valid and reliable instrument, the Calendar of Premenstrual Experiences. As expected, administration of GnRH-a alone resulted in a 75% improvement in luteal phase symptom scores (17.8 +/- 4.8 vs. 4.2 +/- 1.6; P less than 0.01). Combined sequential administration of CEE and MPA in addition to GnRH-a was effective in maintaining the reduced symptom scores seen after GnRH-a alone and was superior to the addition of CEE alone, MPA alone, or placebo. This combination of CEE and MPA resulted in a 60% improvement (P less than 0.05) compared to the luteal phase of control months in both behavioral (14.1 +/- 3.9 vs. 4.2 +/- 0.8) and total (17.8 +/- 4.8 vs. 6.5 +/- 1.8) symptoms. We conclude that the undesirable consequence of ovarian steroid deficiency in the treatment of PMS by GnRH-a can be overcome by the addition of sequential estrogen and progestogen replacements without significantly reducing the effectiveness of GnRH-a in this disorder.

Role of endogenous opioid peptides in the initiation of the midcycle luteinizing hormone surge in normal cycling women.

While compelling evidence indicates a pivotal role for endogenous opioids in the regulation of GnRH-LH pulsatile activity during the late follicular and luteal phases of the menstrual cycle, the participation, if any, of the opioidergic mechanism in the initiation of the midcycle surge has not been examined. Accordingly, we measured serum LH, FSH, estradiol (E2) and progesterone (P4) levels daily during 2 consecutive cycles in 12 normal cycling women. After a control cycle, each woman was infused with naloxone (30 micrograms/kg.h) for 24 h starting 3 days before the anticipated spontaneous midcycle surge. Blood samples were obtained at 15-min intervals for 8 h before, during, and 16 h after the naloxone infusion. Serum LH and FSH concentrations were measured in all samples, and serum E2 and P4 concentrations at 2-h intervals. Pulsatile LH secretion was analyzed using the cluster program. The opioidergic blockade elicited a robust increase in LH pulsatile activity and a 3-fold rise in serum FSH levels in 6 of the 12 women. This increased gonadotropin secretion lasted more than 24 h and was characterized by a progressive increase in LH pulse amplitude, which was 9-fold greater during the last 8 h of naloxone infusion [mean LH pulse amplitude, 36.5 +/- 4.5 (+/- SE) vs. 4.1 +/- 0.4 IU/L; P less than 0.001]. This increase was accompanied by a corresponding increase in transverse mean serum LH levels (83.3 +/- 13 vs. 20.7 +/- 3.2 IU/L; P less than 0.001), but no alteration of the interpulse interval (93 +/- 11 vs. 85 +/- 4 min). The peak serum LH concentrations exceeded 100 IU/L in all 6 of these women. This naloxone-advanced gonadotropin surge, resembling closely the spontaneous midcycle surge, resulted in a significantly shortened (P less than 0.001) follicular phase and a more than 2-fold elevation of serum P4, followed by assumed ovulation and normal luteal function. These 6 women had serum E2 levels immediately before naloxone infusion that were comparable to those during the preovulatory peak during the control cycle. In the 6 women who did not have a naloxone-induced increase in gonadotropin secretion the preinfusion serum E2 levels were substantially lower (P less than 0.001) than the values during the control cycle. These findings suggest that a transient decrease in opioidergic activity may contribute to the initiation of the midcycle gonadotropin surge in women.

Alterations in the hypothalamic-pituitary-ovarian and the hypothalamic-pituitary-adrenal axes in athletic women.

The functional integrity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes was assessed by determining pulsatile LH, ACTH, and cortisol secretion during the early follicular phase in athletic women with regular menstrual cycles (CA; n = 9), athletic women with amenorrhea (AA; n = 9), and regularly cyclic sedentary women (CS; n = 8). The CA and AA women were not significantly different in body composition, exercise training, psychometric tests, or dietary consumption. The CA women had shorter luteal phases (P less than 0.05) and lower urinary excretion of pregnanediol glucuronide than the CS women. In the AA women, urinary estrone glucuronide, pregnanediol glucuronide, and LH excretion were low throughout a 30-day period. The CA women had a 24-h pattern of pulsatile LH secretion characterized by reduced frequency (P less than 0.05) and increased amplitude (P less than 0.05), yielding an overall increased 24-h mean level (P less than 0.05), but interpulse intervals similar to those in the CS women. During sleep, LH pulse frequency slowed in the CS and CA women, while pulse amplitude increased and the mean serum LH level decreased in both groups. The AA women had even fewer pulses (P less than 0.05) of normal amplitude occurring at much more variable (P less than 0.01) interpulse intervals. Sleep-associated changes in LH pulsatility were absent. Responses to a 10-microgram bolus GnRH dose revealed blunted (P less than 0.05) FSH release in CA and augmented (P less than 0.05) LH release in AA women. The groups did not differ in any 24-h ACTH pulse pattern parameter or in cortisol pulse frequencies. Yet, early morning (0200-0800 h) serum cortisol levels were higher (P less than 0.05) in both groups of athletes, and this elevation was extended through the day (0800-2000 h; P less than 0.001) and evening (2000-0200 h; P less than 0.05) in the AA women. The plasma ACTH and serum cortisol responses to bolus human CRH administration were blunted in the CA and AA women [change from baseline (delta) in ACTH, P less than 0.05 and P less than 0.01; delta cortisol, P less than 0.01 and P less than 0.01, respectively], but adrenal sensitivity (delta cortisol/delta ACTH ratio) was increased (P less than 0.05). The plasma ACTH and serum cortisol responses to meals also were blunted in the athletic groups (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Alterations of the adrenocorticotropin-cortisol axis in normal weight bulimic women: evidence for a central mechanism.

We studied pituitary-adrenal function in eight women with normal weight bulimia and seven normal women by measuring plasma ACTH and serum cortisol levels at 20-min intervals for 24 h and the responses to human CRH (hCRH) and to a noon meal. The bulimic women had increased 24-h transverse mean plasma ACTH [1.09 +/- 0.06 (+/- SE) vs. 0.75 +/- 0.14 pmol/L; P less than 0.05] and serum cortisol (235 +/- 21 vs. 152 +/- 9 nmol/L; P less than 0.005) concentrations. While the 24-h ACTH and cortisol pulse frequencies were unaltered, the bulimic women had higher (P less than 0.05) mean peak ACTH (1.46 +/- 0.09 vs. 1.03 +/- 0.15 pmol/L) and cortisol values (331 +/- 33 vs. 239 +/- 17 nmol/L). Despite having higher mean and peak plasma ACTH and serum cortisol values, the bulimic women had a blunted response of both ACTH (P less than 0.001) and cortisol (P less than 0.005) to hCRH, which included a lower mean maximal plasma ACTH response, decreased (P less than 0.05) integrated area under the ACTH response curve (161 +/- 12 vs. 231 +/- 23 pmol/min.L), a lower (P less than 0.05) maximum cortisol response (284 +/- 35 vs. 413 +/- 19 nmol/L), and decreased (P less than 0.05) area under the cortisol curve (11.1 +/- 1.9 vs. 15.9 +/- 1.3 X 10(3) nmol/min.L). The circadian variations of both ACTH and cortisol were maintained in the bulimic women; the nadir and acrophase times were similar to those of the normal women. However, the rise in serum cortisol that occurred within 1 h after the lunch meal in the normal women (104 +/- 35 nmol) did not occur in the bulimic women (P less than 0.05). These data demonstrate that marked changes in hypothalamic-pituitary-adrenal function occur in bulimia in the absence of weight disturbance and suggest central activation of CRH and/or synergistic factors as well as alterations in signals from gut to brain in this syndrome.

Amplification of nocturnal melatonin secretion in women with functional hypothalamic amenorrhea.

Plasma melatonin levels were determined by a sensitive RIA at 30 min intervals for 24h in 7 women with functional hypothalamic amenorrhea (HA) and in 7 age and season matched normal cycling women in the early follicular phase (NC). While daytime melatonin concentrations were nondetectable in both groups, the integrated nocturnal levels were 3-fold greater in HA (244 +/- 58 (SE) vs 74 +/- 32 pmol-min/Lx10(3), p less than 0.005). This melatonin increase in HA was due to an elevated peak amplitude (p less than 0.01) and extended duration (p less than 0.05). The latter was mostly due to a significant delay in the offset time of the amplified nocturnal melatonin secretion.

A circadian rhythm of serum follicle-stimulating hormone in women.

While a nocturnal decline in serum LH levels in the early follicular phase of the menstrual cycle has been well established, a diurnal variation in serum FSH levels in women has not been demonstrated. We addressed this issue by determining serum LH and FSH levels at 15-min intervals for 24 h in the early follicular phase (EFP; n = 16) and late follicular phase (LFP; n = 10) of the menstrual cycle and in postmenopausal women (PMW; n = 10). Serum estradiol was simultaneously measured at hourly intervals. As expected, EFP, but not LFP and PMW, women had a 15% nocturnal decline (P less than 0.01) in transverse mean LH levels compared to values in the daytime hours. In contrast, nocturnal FSH transverse mean values were significantly lower than daytime values in all groups studied, demonstrating an 18% decline in EFP (P less than 0.001), a 17% decline in LFP (P less than 0.00001), and a 4.3% decline in PMW (P less than 0.01). Cosinor analysis revealed a circadian rhythm for FSH, with acrophases in the afternoon and nadirs at night in all three groups. The circadian amplitudes were 1.43 +/- 0.22, 1.02 +/- 0.16, and 8.42 +/- 1.31 IU/L for EFP, LFP, and PMW, respectively. The EFP nocturnal decline in LH did not conform to a cosine rhythm. A diurnal variation in estradiol was not present in any of the groups of women. These data constitute the first demonstration of a robust circadian rhythm of serum FSH in women. The comparable timing of the acrophase in all groups of subjects and its presence in the postmenopausal years suggest a central, rather than peripheral, feedback mechanism(s) for the circadian rhythmicity. This observation provides strong evidence for a dissociation in the hypothalamic regulation of pituitary LH and FSH secretion in women. The circadian peak and nadir of circulating FSH may prove to be determining for appropriate follicular development.

Melatonin rhythms in women with anorexia nervosa and bulimia nervosa.

To discern whether the multiple neuroendocrine-metabolic dysfunctions observed in women with anorexia nervosa (AN) and bulimia nervosa (BN) are associated with altered diurnal variations in serum melatonin profiles, we compared cycling and amenorrheic women with normal weight BN (n = 8) and AN (n = 7) to 21 normal cycling controls. Endogenous depression, which has confounded prior studies of melatonin profiles in women with eating disorders, was excluded in all subjects. Serum samples for melatonin measurements were obtained at frequent intervals (every 20 min) in a controlled light-dark environment, and cycling women were studied in the early follicular phase of the menstrual cycle. Mean (+/- SE) peak melatonin levels were similar in AN, BN, and controls (325 +/- 43, 310 +/- 33, and 334 +/- 30 pmol/L, respectively). The time of melatonin peak, the time of onset and offset of the nocturnal serum melatonin excursion, and the duration of the nocturnal elevation were also similar in the three groups. Analysis of covariance revealed no independent effects of age or time of year on the data. Moreover, when subjects were separated into those with and without menstrual cyclicity, no significant differences in any parameter of melatonin diurnal variation were observed. Taken together, these data suggest that pineal melatonin secretion is unaltered in women with eating disorders, in whom depression is excluded, and that the frequent occurrence of amenorrhea in this population is not mediated by melatonin.

Gonadotropin-releasing hormone receptor gene expression in human ovary and granulosa-lutein cells.

GnRH regulates gonadotropin biosynthesis and release in the anterior pituitary via specific receptors. Although extrapituitary expression and action of GnRH have been shown in some species, in the human it is not clear whether GnRH has a peripheral action. In this study we sought to determine whether the human ovary expresses GnRH receptor (GnRHR) messenger ribonucleic acid (mRNA). Ovarian tissues from 11 women (32-61 yr old) and granulosa-lutein (GL) cells purified from follicular aspirates of 51 women undergoing oocyte retrieval for in vitro fertilization were analyzed by ribonuclease protection assay and reverse transcriptase-polymerase chain reaction (RT-PCR). Human pituitaries, lymphocytes, and placenta were also studied. Measurable levels of GnRHR mRNA were found by ribonuclease protection assay in 2 of 10 ovaries, in 2 of 4 GL cells preparations from women whose ovarian hyperstimulation involved a GnRH agonist, in GL cells from 3 women whose ovarian hyperstimulation involved a GnRH antagonist, and in human pituitaries. Relative to the total amount of RNA analyzed, the level of GnRHR mRNA was about 200-fold lower in the ovary than in the pituitary. A sequence of 314 basepairs of GnRHR mRNA was amplified by RT-PCR in the pituitary, in 9 of 10 ovaries, and in 4 of 5 GL cell preparations. No message could be amplified in human lymphocytes, and placental specimens showed a weak signal. The relative GnRHR mRNA levels in GL cells from 13 women analyzed by quantitative RT-PCR showed a wide range of individual differences. These results suggest that GnRHR mRNA is expressed in GL cells and the human ovary across different functional stages, implying that multiple ovarian compartments may express GnRH receptors. The administration of GnRH analogs may have a further direct action on the human ovary.

Dopaminergic control of circadian and pulsatile pituitary thyrotropin release in women.

Dopamine (DA) inhibits pituitary TSH release, but its role as a regulator of circadian and pulsatile TSH secretion is not clear. Accordingly, we studied the 24-h TSH secretory patterns in seven normal women in the early follicular phase of their cycles before and during DA receptor blockade by metoclopramide (MCP). Serum TSH was measured by a highly sensitive (0.05 mU/L) RIA at 15-min intervals for 48 h during sequential 24-h saline and 24-h MCP infusions (30 micrograms/kg.h). Sleep was confirmed by electroencephalogram between 2300-0700 h. All women had a nocturnal rise of TSH, independent of sleep, which began in the late afternoon and reached a peak (acrophase) after midnight during the saline infusion. This circadian periodicity was composed of a series of TSH pulses with greater magnitude and frequency during nocturnal hours. Infusion of MCP had no effect on pulse frequency, but the pulse amplitude increased (P less than 0.05), especially at night. As a consequence, the circadian excursion of TSH, as assessed by cosinor function, was exaggerated. The mean acrophase amplitude and mesor levels increased (P less than 0.05), but the nadir and acrophase times did not change. These findings suggest that DA is an inhibitor of TSH pulse amplitude throughout the 24-h biological clock. By inference, the neuroendocrine mechanism(s) that underlies the nocturnal increase in TSH secretion is not due to decreased dopaminergic inhibition.

Pulsatile rhythms of adrenocorticotropin (ACTH) and cortisol in women with endogenous depression: evidence for increased ACTH pulse frequency.

Plasma ACTH and serum cortisol levels were measured at 20-min intervals for 24 h in six young women with unipolar endogenous depression and in eight normal women during the early follicular phase of the menstrual cycle. The women with depression had a marked increase (P less than 0.005) in mean ACTH pulse frequency [14.5 +/- 0.6 (+/-SE) pulses/24 h] compared with normal women (9.9 +/- 0.7 pulses/24 h), while mean ACTH pulse amplitude and 24-h transverse mean ACTH levels were similar in the two groups. In contrast, 24-h transverse mean cortisol levels were higher (P less than 0.02) in the depressed women (242 +/- 28 nmol/L) than in the normal women (163 +/- 10 nmol/L). This hypercortisolemia in the depressed women was accompanied by markedly increased (P less than 0.001) episodic cortisol secretion (286 +/- 24 X 10(2) nmol/L X min) compared with that in normal women (155 +/- 17 X 10(2) nmol/L X min), and the secretory episodes were both longer in duration (P less than 0.05) and of higher amplitude (P less than 0.05) in the depressed women. The circadian variations in ACTH and cortisol were maintained in these depressed women, and the times of the circadian nadir, as determined by cosinor analysis, were similar to those in the normal women. However, the mean length of the evening quiescent period of cortisol secretion was far shorter (P less than 0.005) in the depressed women (27 +/- 8 vs. 202 +/- 40 min). Moreover, the postlunch rise in serum cortisol was significantly higher (P less than 0.02) in the depressed women (204 +/- 29 vs. 111 +/- 15 nmol/L). These results provide evidence that the hypercortisolism in depressed women is associated with an increase in ACTH pulse frequency, expanded cortisol secretory episodes, including a greater postlunch rise in cortisol, and a shortened evening quiescent period of cortisol secretion. Our findings provide evidence for centrally mediated activation of the ACTH-cortisol system in women with depression without a phase shift in circadian rhythm.

Neuroendocrine aberrations in women with functional hypothalamic amenorrhea.

To further elucidate the neuroendocrine regulation of anterior pituitary function in women with functional hypothalamic amenorrhea (FHA), we measured serum LH, FSH, cortisol, GH, PRL, TSH concentrations simultaneously at frequent intervals for 24 h in 10 women with FHA and in 10 normal women in the early follicular phase (NC). Using the same data, we separately analyzed the cortisol-PRL responses to meals in these women. In addition, the pituitary responses to the simultaneous administration of GnRH, CRH, GHRH, and TRH were assessed in 6 FHA and 6 normal women. The 24-h secretory pattern of each hormone except TSH was altered in the women with FHA. Compared to normal women, the women with FHA had a 53% reduction in LH pulse frequency (P less than 0.0001) and an increase in the mean LH interpulse interval (P less than 0.01); LH pulse amplitude was similar. The 24-h integrated LH and FSH concentrations were reduced 30% (P = 0.01) and 19% (P less than 0.05), respectively. The mean cortisol pulse frequency, amplitude, interpulse interval, and duration were similar in the two groups, but integrated 24-h cortisol secretion was 17% higher in the women with FHA (P less than 0.05). This increase was greatest from 0800-1600 h, but also was present from 2400-0800 h. Cortisol levels were similar in the two groups from 1600-2400 h, resulting in an amplified circadian excursion. In contrast, the 24-h serum PRL levels were markedly lower at all times (P less than 0.0001), the sleep-associated nocturnal elevation of PRL was proportionately greater (P less than 0.05), and serum GH levels were increased at night in the women with FHA (P less than 0.05). Although 24-h serum TSH levels were similar at all times, T3 (P less than 0.05) and T4 (P less than 0.01) levels were lower in the FHA women. The responses of serum cortisol to lunch (P less than 0.01) and dinner (P less than 0.05) and those of serum PRL to lunch (P less than 0.05) and dinner (P = 0.08) were blunted in the women with FHA. Pituitary hormone increments in response to the simultaneous iv administration of GnRH, CRH, GHRH, and TRH were similar in the two groups, except for a blunted PRL response to TRH in the women with FHA (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic-pituitary-thyroidal function in eumenorrheic and amenorrheic athletes.

The impact of chronic high volume athletic training on thyroid hormone economy has not been defined. We investigated the status of the hypothalamic-pituitary-thyroid axis (H-P-T) in women athletes with regular menstrual cycles (CA) and with amenorrhea (AA). Their data were compared with each other and with those derived from cyclic sedentary women (CS) matched for a variety of confounding factors including the intensity of exercise, caloric intake, and body weight. Alterations of the H-P-T axis were observed in women athletes compared to CS. While serum levels of T4, T3, free T4, free T3 and rT3 were substantially reduced (P less than 0.01) in AA, only serum T4 levels were significantly decreased in CA. Further, remarkable differences were found between CA and AA in that serum levels of free T4 (P less than 0.01), free T3 (P less than 0.01), and rT3 (P less than 0.05) were significantly lower in AA than in CA. Thyroid binding globulin and sex-hormone binding globulin concentrations were within their normal ranges for all groups of subjects. Both 24-h mean TSH levels and the circadian rhythm of TSH secretion were also comparable. However, the TSH response to TRH stimulation was blunted (P less than 0.01) in AA when compared to CA, but not to CS. Whereas the underlying mechanism(s) to account for the "global" reduction of circulating thyroid hormone in the face of normal TSH levels in AA is presently unknown, these observations provide information of clinical significance: 1) chronic high volume athletic training in women athletes with menstrual cyclicity is accompanied by an isolated T4 reduction; 2) an impaired H-P-T axis occurs selectively in athletic women in whom chronic high volume athletic training is associated with compromised hypothalamic-pituitary-ovarian function and amenorrhea.

Pulsatile cosecretion of estradiol and progesterone by the midluteal phase corpus luteum: temporal link to luteinizing hormone pulses.

Using recently defined analytical tools that permit quantitative and integrated assessments of pulsatile activities of two or more hormones, we have examined the coincidence of pulses of estradiol (E2), progesterone (P4), and LH determined in blood withdrawn at 15-min sampling intervals for a duration of 24 h in each of 15 women during the midluteal phase of the human menstrual cycle. The occurrence of E2 and P4 pulses is simultaneous, as their peaks were maximally correlated at zero time lag (P less than 10(-4], and there were comparable periodicities for E2 (13.5 +/- 0.7 pulses/24 h) and P4 (11.2 +/- 0.7 pulses/24 h). This coupling of E2 and P4 pulses suggests cosecretion by the mature corpus luteum. These E2 and P4 pulses are significantly coupled with LH pulses, with a lag time of about 30 min and/or 45 min for P4 (P = 0.029) and 0 min and/or 15 min for E2 (P = 0.032). Further, when considered together, LH, E2, and P4 are found to be triply copulsatile (P = 0.0066). However, significant numbers of discrete pulses of P4 and E2 are observed without antecedent LH pulses, suggesting some degree of corpus luteum autonomy. In conclusion, orchestrated synchrony of pulsatile pituitary and ovarian (corpus luteum) signaling can be demonstrated by the coordinated temporal release of LH, E2, and P4 in normal cycling women.

Diagnosis of premenstrual syndrome by a simple, prospective, and reliable instrument: the calendar of premenstrual experiences.

To establish a quantitative method for the diagnosis of premenstrual syndrome (PMS), a simple prospective inventory, the calendar of premenstrual experiences, was constructed. The validity and reliability of this instrument were assessed by administering it throughout two consecutive ovulatory cycles to 36 rigidly screened women with PMS and to 18 controls. To establish concurrent validity, scores on behavioral items were correlated with simultaneously obtained scores on lengthier, well-validated psychiatric inventories designed to measure depression rather than PMS, the Beck Depression Inventory and the Profile of Mood States. The results showed that the calendar of premenstrual experiences luteal phase score distinguished PMS women from controls correctly in 104 of 108 cycles, with a 2.8% false-negative rate and no false positives when used for two consecutive cycles. An upper limit follicular phase score was observed beneath which all PMS and normal control subjects fell, suggesting that a higher score is not consistent with PMS. Correlation coefficients of calendar item scores with Profile of Mood States scale scores were 0.58 for tension, 0.51 for depression, 0.46 for anger, 0.61 for fatigue, and 0.57 for confusion (P less than .0001 for all correlations). The correlation of the calendar depression item with the Beck Depression Inventory score was 0.56 (P less than .0001). The test-retest reliability of the calendar given in the same phase of two consecutive menstrual cycles was high (r = 0.78, P less than .0001). We conclude that this instrument is a valid, reliable, and practical PMS inventory, applicable to clinical and some research settings.

Treatment of premenstrual syndrome with fluoxetine: a double-blind, placebo-controlled, crossover study.

OBJECTIVE: Although its etiology is unknown, it has been hypothesized that premenstrual syndrome (PMS) is linked to a deficiency of central serotoninergic activity. In the present study, we evaluated the effect of fluoxetine, a specific serotonin uptake inhibitor, on PMS symptoms. METHODS: Following extensive screening, including several psychological inventories, eight women with severe persistent PMS participated in a 6-month double-blind, placebo-controlled, crossover study which included three months each of daily fluoxetine 20 mg or placebo, administered in a randomized order. Symptoms were evaluated using the Calendar of Premenstrual Experiences and other psychometric measures. RESULTS: Compared with placebo, treatment with fluoxetine was associated with an improvement in PMS symptoms as judged by highly significant decreases in behavioral (P less than .005), physical (P less than .05), and total (P less than .005) Calendar of Premenstrual Experiences scores; Beck Depression Inventory scores (P less than .005); Profile of Mood States subscales scores including depression (P less than .005), tension (P less than .005), and anger (P less than .01); and State-Trait Anxiety Inventory scores. The use of fluoxetine was associated with a greater mean reduction in behavioral (75%) than in physical scores (40%), with a mean decrease in total Calendar of Premenstrual Experiences scores of 62%, which rendered these scores similar to follicular phase values. Thus, the luteal phase symptomatology of PMS was effectively abolished. At this dose, no significant side effects or complications were noted during treatment. CONCLUSION: Fluoxetine appears to be a highly effective, well-tolerated treatment for the psychological and physical symptoms accompanying severe PMS.

Persistence of premenstrual syndrome during low-dose administration of the progesterone antagonist RU 486.

OBJECTIVE: To test whether progesterone or progesterone receptors are important mediators of premenstrual syndrome (PMS) and whether progesterone antagonist RU 486 would alleviate symptoms. METHODS: Following extensive screening including physical and psychological assessment, seven women with severe PMS participated in a 6-month, randomized, double-blind, placebo-controlled, crossover study. The treatment included 3 months of low-dose RU 486 (5 mg alternate days for four doses, beginning 3 days after the urinary LH surge) or placebo, administered in a similar fashion. Symptoms were evaluated using the Calendar of Premenstrual Experiences, Beck Depression Inventory, State-Trait Anxiety Inventory, and the Profile of Mood States. RESULTS: Symptoms of PMS were similar during RU 486 and placebo treatments. CONCLUSION: Luteal-phase administration of low-dose RU 486 does not significantly reduce the physical or behavioral manifestations of PMS.

A risk-benefit appraisal of drugs used in the management of premenstrual syndrome.

Recent advances in the understanding of the pathogenesis of premenstrual syndrome (PMS) have allowed the development of appropriate pharmacological interventions. Although at the present time there are no approved medications for this indication in the US, several well-designed studies have been conducted that guide the clinician's treatment of PMS. As a result, less-proven nonpharmacological modalities, such as dietary modification, exercise regimens and psychotherapy, are more quickly supplanted by the use of medication. Three classes of agents have been proven efficacious and are widely used to treat the disorder. These include benzodiazepines (especially alprazolam), selective serotonin reuptake inhibitors (especially fluoxetine), and gonadotropin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] agonists. In addition to these medications which are used to treat the generalised syndrome of PMS, a variety of other drugs are used in the treatment of specific aspects of this disorder. Despite the success of these treatments, each has a substantial adverse effect profile which modulates their use in some patients. Knowledge of these potential adverse effects and their management should help optimise therapy. In addition, a variety of less well-proven pharmacological remedies are commonly in use. The adverse effects of these medications may well outweigh their benefits.

Alterations in immune responsiveness in women exposed to diethylstilbestrol in utero.

In order to study the effect of in utero diethylstilbestrol (DES) exposure on the immune system of adult women, the blastogenic response of peripheral blood lymphocytes to two mitogens was compared in eight DES-exposed patients and in eight age-matched controls with normal menstrual cycles and proven fertility. As measured by the uptake of 3H-thymidine (mean [+/- standard error]), response to the T-cell mitogen phytohemagglutin (PHA) was significantly higher (P less than 0.002) in cells of DES-exposed women (88.6 +/- 5.7 X 10(3) cpm) than in controls (44.0 +/- 8.9 X 10(3) cpm) at the lowest dose of mitogen tested (0.125 microgram/ml). Moreover, lymphocytes of DES-exposed subjects showed maximal blastogenic response to PHA at a concentration (0.125 microgram/ml) two to four times lower (P less than 0.002) than controls (0.25 microgram/ml to 0.5 microgram/ml). Cells of both DES-exposed subjects and controls were maximally responsive to pokeweed mitogen (PWM) at the lowest dose tested (0.625 microgram/ml). These findings suggest that in utero DES exposure is associated with a hyper-reactive immune response during the reproductive years.