Ovarian hyperstimulation and follicular aspiration. Effect on ovulatory function.

The return of normal function of the reproductive axis immediately after hyperstimulation and follicular aspiration is of both physiologic and clinical interest. These cycles may be utilized for the replacement of cryopreserved embryos, for repeated ovarian stimulation or for any alternative treatment that relies upon normal ovulatory function. Thirty-five women were randomly assigned to be monitored in the first (n = 11), second (n = 13) or third (n = 11) menstrual cycle after in vitro fertilization (IVF). Five of 35 patients (14.3%) failed to ovulate, 2 in each of the first and second menstrual cycles and 1 in the third cycle after IVF. Six (20%) ovulatory cycles demonstrated luteal phase deficiencies. The defective luteal phases were evenly distributed between cycles immediately after IVF and those more remote in time from the procedure.     

Interruption of endometrial maturation without hormonal changes by an antiprogesterone during the first half of luteal phase of the menstrual cycle: a contraceptive potential.

OBJECTIVE: To examine hormonal and endometrial responses to intermittent low-dose RU486 administration in the luteal phase of the menstrual cycle. DESIGN: Prospective open trial in which subjects serve as their own controls. PATIENTS/PARTICIPANTS: Eight normal cycling women. INTERVENTIONS: RU486 (10 mg, orally) was administered 5 and 8 days after urinary luteinizing hormone (LH) surge of treatment cycle. MAIN OUTCOME MEASURES: Daily serum concentrations of LH, follicle-stimulating hormone, estradiol (E2), and progesterone (P) were determined in control, treatment, and recovery cycles (n = 5) or treatment and recovery cycles (n = 3). Changes in endometrial morphology and immunohistochemical staining for P receptor (PR) and E2 receptor (ER) were determined during control (or recovery) and treatment cycles. RESULTS: Cycle length and hormonal patterns were unaltered after treatment with RU486. As demonstrated by reduced stromal edema and delayed glandular development, endometrial dyssynchrony occurred in all eight treatment cycles. In addition, seven of eight treatment cycle endometria demonstrated a decrease in PR staining without consistent change in ER staining. CONCLUSIONS: Two low doses of RU486 given 72 hours apart during the luteal phase of the cycle disrupted ongoing endometrial maturation without altering the hormonal and time course of the menstrual cycle. This study provides a basis for the development of a novel form of luteal contraception.     

Endometrial glycodelin-A expression in the luteal phase of stimulated ovarian cycles

OBJECTIVE: To determine if controlled ovarian hyperstimulation (COH) affects the endometrial expression of glycodelin-A (GdA). DESIGN: Prospective, controlled study. SETTING: Tertiary infertility clinic. PATIENT(S): Fifteen oocyte donors undergoing COH cycles and 19 natural-cycle control patients. INTERVENTION(S): COH, endometrial biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemical scoring of endometrial GdA expression, morphologic endometrial dating, and serum E2, LH, and P4 concentrations. RESULT(S): GdA was detected in all subjects throughout the implantation window period. Immunolocalization was demonstrated in the endometrial glands and not in the stroma or on the surface. A significantly increased proportion of GdA-staining endometrial cells were noted in COH cycle patients as compared with natural-cycling control patients throughout the window of embryo implantation. Both cycle types demonstrated increasing GdA expression throughout the late luteal phase. A significant positive correlation was noted between GdA expression and serum E2 levels (r = 0.5, P<.001) in natural cycles and advanced histology in COH cycles (r = 0.63, P=.01). Neither LH nor P4 were correlated with endometrial GdA expression. CONCLUSION(S): COH cycles have a significantly increased endometrial GdA expression throughout the implantation phase of the luteal cycle when compared with normal menstrual cycles. The increased expression may affect implantation during COH cycles.     

The effect of therapy initiation day on clomiphene citrate therapy

Eighty-seven anovulatory patients were treated with clomiphene citrate (CC) to induce ovulation in 414 cycles. Clomiphene citrate was initiated randomly on the 2nd, 3rd, 4th, or 5th day of the menstrual cycle to evaluate the effectiveness of therapy. The results of therapy were assessed in terms of ovarian response and pregnancy outcome. Ovarian response was evaluated employing basal body temperature (BBT) to define follicular, luteal, and cycle lengths, and a midluteal serum progesterone (P) level and the integrated luteal P to define luteal adequacy. Pregnancy outcome was evaluated in the categories of total pregnancy, live birth, first trimester abortion, and fecundity rates. There were no significant differences noted between the groups who started CC on the 2nd, 3rd, 4th, or 5th day of cycle in terms of anovulation rates (12% to 21%), luteal dysfunction (28% to 39%), and normal ovulation rates (42% to 57%). Pregnancy was achieved in 31% (n = 27/87) of patients with a spontaneous abortion rate of 19% (n = 5/27). The fecundity rates ranged between 5.7% and 9.4%. Pregnancy outcomes also were not significantly different between the groups. Significantly shorter luteal phase length and longer follicular phase length were observed in the cycles with luteal dysfunction. The luteal progesterone parameters, including midluteal serum P concentration, the integrated luteal P, and the luteal P amplitude were significantly lower in the cycles with luteal dysfunction.     

Diagnosis and management of out-of-phase endometrial biopsies among patients receiving clomiphene citrate for ovulation induction

Eighty-seven patients who underwent a late secretory phase endometrial biopsy while taking clomiphene citrate (CC) for ovulation induction were studied. Of the endometrial biopsies, 21 (24%) showed an endometrium greater than 2 days out of phase (OOP) with respect to the subsequent menstrual cycle. All 87 patients were categorized by age, weight, CC dosage, and underlying disease entity. The patients then were evaluated by these categories in relation to the incidence of an OOP biopsy while taking CC. Patients with a diagnosis of hypothalamic amenorrhea were statistically more likely to have an OOP endometrium. No other subgroup showed an increased or decreased incidence of OOP biopsies. Conception and spontaneous abortion rates were similar among patients with in-phase biopsies and those with out-of-phase biopsies, which subsequently were corrected with further medical therapy. An aggressive approach to the diagnosis and treatment of luteal phase insufficiency in patients who receive CC for ovulation induction is recommended.     

Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women

A direct adverse effect of clomiphene citrate on the endometrium has been presumed, and interference with estrogen receptor-mediated endometrial estrogen receptor and progesterone receptor induction has been implicated as the mechanism responsible for an increased incidence of luteal phase deficiency in association with clomiphene citrate treatment. To clarify the net influence of clomiphene administration on endometrial steroid receptor induction, we studied five normal ovulatory women, in both a spontaneous and clomiphene-induced (150 mg/day, cycle days 5 to 9) ovulatory cycle. From cycle day 11 blood samples were obtained daily and urinary luteinizing hormone determinations were performed twice daily. Endometrial biopsy was performed on the day of the urinary luteinizing hormone surge and again 13 days after the surge. Serum levels of follicle-stimulating hormone and luteinizing hormone were determined by immunoradiometric assay, estradiol and progesterone by radioimmunoassay, and clomiphene citrate isomer concentrations in treatment cycles by reversed-phase high-performance liquid chromatography and fluorescence detection. Total, cytosolic, and salt-extracted nuclear endometrial estrogen receptor and progesterone receptor concentrations were determined by enzyme-linked immunoassay. Serum estradiol was threefold to fivefold higher (p less than 0.05) in clomiphene-induced than in spontaneous cycles 8 and 10 days before the luteinizing hormone surge, and progesterone was increased (p less than 0.05) from the day of the surge to end of the cycle. Serum enclomiphene rose to plateau between 12 and 6 days before the luteinizing hormone surge (4.1 +/- 0.8 ng/ml, mean +/- SE, n = 19) and fell thereafter to less than 1.0 ng/ml. Zuclomiphene levels increased rapidly between 14 and 8 days before the surge (53.9 +/- 2.8 ng/ml, mean +/- SE, n = 5) and then decreased gradually but remained elevated throughout the luteal phase (29.0 +/- 1.2 ng/ml, mean +/- SE, n = 33). Late luteal endometrial histology was abnormal in one of four available treatment cycle specimens, but the endocrine characteristics and number and subcellular distribution of estrogen receptor and progesterone receptor in the abnormal cycle were not different from those of normal, in-phase cycles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histochemical localization of endometrial insulin-like growth factor binding protein-1 and -3 during the luteal phase in controlled ovarian hyperstimulation cycles: a controlled study

OBJECTIVE: To determine if controlled ovarian hyperstimulation (COH) affects the endometrial expression of IGFBP-1 and IGFBP-3. DESIGN: Prospective, controlled study. SETTING: Tertiary infertility clinic. PATIENT(S): Eighteen oocyte donors undergoing COH cycles and 17 natural cycle controls. INTERVENTION(S): Controlled ovarian hyperstimulation, endometrial biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemical scoring of endometrial IGFBP-1 and -3 expression, morphological endometrial dating, and serum estradiol (E(2)), LH, and progesterone (P(4)) concentrations. RESULT(S): No statistically significant difference was observed between natural and stimulated cycles in change in IGFBP-1 or -3 over standardized cycle days throughout the window of embryo implantation (days 17-24). The IGFBP-1 and -3 expression was zero or near zero for both the natural and COH cycles until day 12-13. Both IGFBPs showed increased production throughout the secretory phase. Advanced endometrial histology (>/=1 day) in glands and stroma was noted in COH cycles. Significant positive correlations of E(2) and P(4) were noted with IGFBP-1 and -3 but not with advanced endometrial morphology in the COH cycles. CONCLUSION(S): The COH cycles have no significantly increased endometrial IGFBP-1 or -3 expression throughout the implantation phase of the luteal cycle compared with normal menstrual cycles. Both IGFBPs were absent in the proliferative phase and increased throughout the secretory portion of the embryo implantation window.     

Impact of ovarian stimulation on mid-luteal endometrial tissue and secretion markers of receptivity

The objective of this study was to investigate the effect of ovarian stimulation for IVF on endometrial secretion and tissue markers of receptivity in the mid-luteal phase. In 10 oocyte donors, endometrial secretions and biopsies were sampled 5 days after spontaneous ovulation and oocyte retrieval in consecutive cycles. Four subjects received progesterone in the luteal phase of the stimulated cycles. Mid-luteal endometrial maturation in the stimulated cycle was compared with the spontaneous cycle, by histological dating, Ki-67, oestrogen receptor (ER) and progesterone receptor (PR) expression, secretion levels of leukaemia inhibitory factor (LIF), glycodelin A (GdA) and progesterone, and protein profile. No significant differences in histological markers, expression of Ki-67, PR, ER, secretion protein profiles or concentrations of LIF, GdA, or progesterone were observed when comparing natural with stimulated cycles. Progesterone supplementation of stimulated cycles was associated with significantly lower Ki-67 (P = 0.03) and ER (P = 0.04) expression compared with the non-supplemented stimulated cycle. In this pilot study, ovarian stimulation was not demonstrated to alter the studied markers of endometrial maturation in the mid-luteal phase.     

Study on luteal insufficiency by the two-step LH-RH test

To clarify both the releasing function and the self-priming effect of LH-RH on gonadotropins of the anterior pituitary gland, two step administration of 100 micrograms of synthetic LH-RH at a 60 minutes interval (two step LH-RH test) was carried out in 29 women with luteal insufficiency, 10 women in luteal phase just after spontaneous abortion, 12 women in puerperium and 24 women with normal menstrual cycles. Native LH, FSH and their subunits were measured by radioimmunoassay and serum progesterone (P), estradiol (E2) and prolactin (PRL) were also measured before administration of LH-RH. By defining hormone release (1st peak level-0' level) as delta 1, self-priming effect (2nd peak level-60' level) as delta 2 and delta 2/delta 1 as delta 1 delta 2 ratio, in the luteal insufficiency group, especially in the cases with lower of serum P and E2, delta 1 was significantly higher and the delta 1 delta 2 ratio was lower than those in the control group. In the abortion group, delta 1 and delta 2 were similar to those in the control group, indicating rapid recovery of the anterior pituitary function. In the puerperium group (approximately 1 month after delivery), delta 1 was higher and the delta 1 delta 2 ratio was lower than those in the control group. This suggests that the puerperium is more or less similar to the period of luteal insufficiency. The results also indicate that the two step LH-RH test can be one of the useful methods for the study of luteal insufficiency in terms of the pituitary gonadotropin synthesis and release.     

Endometrial biopsy in the infertility investigation. The experience at two institutions

The combined experience at two institutions was reviewed to evaluate endometrial biopsy and the prognosis for pregnancies affected by endometrial sampling during the cycle of conception. In the evaluation of 1,084 patients, 1,174 biopsies were performed. Twenty-seven endometrial biopsies were done during the cycle of conception, with spontaneous abortion occurring in six cases (22.2%). Multiple diagnoses were made (including luteal phase defects, endometritis and polyps), and interruption of pregnancy occurred. Several cases illustrate disturbing complications. Methods of minimizing pregnancy interruption and patient discomfort are available.     

Proliferation kinetics in adenomyosis during the menstrual cycle and during oral contraceptive use.

Our objective was to investigate the presence of focal p53 expression in relation to proliferation rates in adenomyotic lesions during the menstrual cycle and in women on oral contraception. Fifty-nine perimenopausal patients with menorrhagia and adenomyosis were submitted to endometrial resection. The procedure was carried out during menstruation (n = 14), during the proliferative phase (n = 15), during the luteal phase (n = 20) or following the use of oral contraceptives (n = 10). The number of Ki-67-positive cells was low during menstruation, during the luteal phase and following the use of progestins. In the proliferative phase, on the other hand, there was a significant increase in the percentage of Ki-67-positive cells. Focal p53 expression was detected mainly during the proliferative phase of the menstrual cycle when proliferation rates were high. PTEN expression was detected in all cases irrespective of the phase of the menstrual cycle or use of oral contraception. We conclude that proliferation rates in adenomyotic lesions undergo marked cyclic variations and this affects the percentage of cases showing focal p53 expression in the glandular epithelium.     

Unsuspected subclinical pregnancies in patients with luteal phase defects.

Patients with different types of luteal phase defects were studied with the use of the radioimmunoassay for the beta subunit of human chorionic gonadotropin (hCG) to determine if unsuspected subclinical pregnancies were more common in a particular type of defect. A type I luteal phase defect is always characterized by a chronologic lag in endometrial development when repeatedly studied with timed endometrial biopsies. A type II luteal phase defect is always characterized by an in phase endometrium when repeatedly studied by timed endometrial biopsies but always has less than a 14 day luteal span. All blood samples were drawn at least 7 days after ovulation/conception. In 22 cycles in which patients had a type I luteal phase defect, no subclinical pregnancies were detected. In 18 cycles in which a type II luteal phase defect was present, 12 instances of unsuspected subclinical pregnancy were detected and all ended in spontaneous abortion. This study shows that unsuspected subclinical pregnancies ending in abortion do occur and are quite commonly associated with the type II luteal phase defect.     

Transvaginal ultrasonic assessment of endometrial growth in spontaneous and hyperstimulated menstrual cycles

Endometrial thickness and reflectivity were assessed by transvaginal ultrasound in both spontaneous and hyperstimulated menstrual cycles. Two groups of women with ovulatory cycles were examined; women in group 1 had unexplained infertility and women in group 2 were having artificial insemination by donor because of reduced spermatogenesis; a third group (group 3) comprised women with tubal infertility undergoing hyperstimulation for in-vitro fertilization. There was no difference in endometrial thickness or reflectivity between the three groups. A basic pattern of endometrial appearance common to all cycles was found, consisting of hypoechoic, isoechoic and hyperechoic images, occurring in the early follicular, late follicular and luteal phases, respectively. In all three groups a positive correlation was found between proliferative phase plasma oestradiol concentration and endometrial thickness. Group 1 r = 0.403, P less than 0.01; group 2 r = 0.439, P less than 0.01; and group 3 r = 0.617, P less than 0.01. There was a progressive increase in endometrial growth throughout the normal cycle until a plateau was reached 5 days after the LH surge. This pattern was also seen without acceleration of the process in hyperstimulated cycles, despite supranormal levels of oestrogen. Assessment of endometrial thickness is not a useful variable in monitoring hyperstimulated cycles. No aberrations of endometrial growth or pattern were observed in the women with unexplained infertility.     

A short course of menotropin after clomiphene failure in infertile women with luteal phase defects

Twenty-four women with luteal phase defects who were ovulatory on clomiphene therapy with or without human chorionic gonadotropin (hCG) at midcycle for three to eight cycles yet failed to produce a live birth were treated with a short course of menotropin (hMG-S), one to two ampules for five days in the early follicular phase followed or not followed by hCG at midcycle for three to eight cycles. The luteal phase defect was diagnosed with repeat endometrial biopsies with a lag time of three or more days prior to clomiphene therapy. A complete infertility workup revealed only eight patients (33%) with a purely endocrine factor (luteal phase defect). The rest (16 patients, or 67%) had one or two additional infertility factors. Two abortions occurred in this group during clomiphene therapy, while five pregnancies (four live births and one spontaneous abortion) occurred during hMG-S therapy. The ovulation rates were similar for hMG-S (89%) and clomiphene (91%) therapy, but the frequency of a normal ovulatory cycle was significantly greater (P = .026) for hMG-S therapy (71%) than for clomiphene therapy (57%). The midluteal mean serum progesterone level was lower and the mean luteal length shorter in the cycles with less than 130 ng/mL/d of total integrated luteal progesterone. The postcoital test results showed better cervical mucus, with increased mucus volume and better fluidity and spinnbarkeit, in hMG-S cycles than in clomiphene cycles. It appears that hMG-S treatment can improve ovarian function and achieve successful pregnancy in patients with luteal phase defects who fail to produce a live birth during clomiphene treatment.     

An analysis of endometrial biopsies performed for infertility

The authors evaluated 774 endometrial biopsies that were performed for infertility. Complications arose in 3.6%. Lag of more than 2 days was found in 19%; luteal phase defect (LPD) was diagnosed in 5.7%. Most of the incidence of LPD can be predicted from chance occurrence. There was no association between abnormal biopsies and basal body temperature patterns, or between pathology, pregnancy outcome, and treatment. Exceptions included women with multiple spontaneous abortions and patients treated with clomiphene citrate (CC). An endometrial biopsy was performed in a pregnancy cycle in 4.0%, with an abortion rate not significantly different from the total study group. The authors conclude that an endometrial biopsy is relatively safe; however, the diagnostic and therapeutic consequences are limited. Endometrial biopsies may be useful only if performed in cases of habitual abortion or ovulation induction with CC.     

Transvaginal ultrasonic assessment of endometrial growth in spontaneous and hyperstimulated menstrual cycles

Summary. Endometrial thickness and reflectivity were assessed by transvaginal ultrasound in both spontaneous and hyperstimulated menstrual cycles. Two groups of women with ovulatory cycles were examined; women in group 1 had unexplained infertility and women in group 2 were having artificial insemination by donor because of reduced spermatogenesis; a third group (group 3) comprised women with tubal infertility undergoing hyperstimulation for in-vitro fertilization. There was no difference in endometrial thickness or reflectivity between the three groups. A basic pattern of endometrial appearance common to all cycles was found, consisting of hypoechoic, isocchoic and hyperechoic images, occurring in the early follicular, late follicular and luteal phases, respectively. In all three groups a positive correlation was found between proliferative phase plasma oestradiol concentration and endometrial thickness. Group 1 r = 0·403, P<0·01; group 2 r = 0·439, P<0·01; and group 3 r = 0·617, P<0·01. There was a progressive increase in endometrial growth throughout the normal cycle until a plateau was reached 5 days after the LH surge. This pattern was also seen without acceleration of the process in hyperstimulated cycles, despite supranormal levels of oestrogen. Assessment of endometrial thickness is not a useful variable in monitoring hyperstimulated cycles. No aberrations of endometrial growth or pattern were observed in the women with unexplained infertility.     

正常月经周期妇女和自然流产妇女外周血中树突状细胞亚群的变化

目的:探讨正常月经周期妇女和自然流产妇女外周血中髓样树突状细胞(myeloid dendritic cell,MDC)和浆细胞样树突状细胞(plasmacytoid dendritic cell,PDC)的变化。方法:选择正常月经周期妇女30例,分别在每个妇女月经周期卵泡期和黄体期采集外周血;早期自然流产妇女30例流产后清宫前采集外周血,并以正常早期妊娠妇女为对照组。应用流式细胞术,检测各组外周血单个核细胞中MDC和PDC的百分率及MDC/PDC比率。应用放射免疫法检测各组外周血中雌二醇(E_2)和孕酮(P_4)的水平。结果:正常月经周期黄体期外周血中MDC的百分率和MDC/PDC比率显著低于卵泡期(P<0.01),PDC的百分率黄体期与卵泡期无统计学差异(P>0.05)。正常月经周期妇女黄体期外周血中E_2和P_4水平显著高于卵泡期(P<0.01)。早期自然流产妇女外周血中MDC的百分率和MDC/PDC比率显著高于正常早孕组(P<0.01),而PDC的百分率与正常早孕组无统计学差异(P>0.05)。自然流产组E_2和P_4水平显著低于正常早孕组(P<0.01)。结论:早期自然流产妇女外周血中MDC的百分率和MDC/PDC比率显著升高,可能参与了导致母体对胎儿发生免疫排斥。     

Histology of midluteal corpus luteum and endometrium from clomiphene citrate-induced cycles.

OBJECTIVE: To determine the histologic development of midluteal corpus luteum (CL) and endometrium in normal fertile women after induction of ovulation with clomiphene citrate (CC). DESIGN, PATIENTS, INTERVENTIONS: Twelve normally cycling women planning to undergo an elective tubal ligation were treated with 50 to 150 mg of CC daily on days 5 through 9 of the cycle. Luteectomy and endometrial biopsy were performed simultaneously 7 days after the urinary luteinizing hormone surge. RESULTS: Because polyovulation occurred in 10 of the 12 women, 22 CL and 12 endometrial biopsies were studied. Ten women had luteal and endometrial histology that were within 2 days of the ovulation to biopsy interval. The 2 remaining women had endometrial histology that lagged 3 days behind the chronological postovulatory date. In these women, out-of-phase endometrium occurred despite polyovulatory cycles in which two and three histologically normal CL lutea were present and associated with elevated progesterone concentrations. CONCLUSIONS: In CC-induced ovulatory cycles: (1) midluteal CL histology is normal and (2) apparently out-of-phase preimplantation endometrium occurs in midluteal phase.     

Lutealphaseninsuffizienz

Corpus luteum insufficiency belongs to the heterogeneous endocrine disorders characterized by shortened luteal phases (<12 days), decreased progestogen levels in the second half of the menstrual cycle as well as inadequate endometrial differentiation. The prevalence is up to 13.5% in patients with infertility disorders. Replicated low progestogen levels in the luteal phase of the menstrual cycle are mandatory for diagnosis. However, in cases of hyperprolactinaemia or thyroid disorders treatment should focus on adjustment of endocrine dysfunction. Luteal insufficiency due to disturbed follicular genesis with shortened or elongated follicular growing periods can be treated with clomiphene. Recent studies also indicate a benefit of progestogen supplementation in the luteal phase.     

Low-dose follicular-phase cocaine administration disrupts menstrual and ovarian cyclicity in rhesus monkeys

OBJECTIVE: To evaluate the effects of daily low-dose follicular-phase cocaine administration on menstrual cyclicity, ovulation rates, corpus luteum function, and hormone levels in rhesus monkeys. METHOD: Normally cycling, drug-naive, adult rhesus monkeys were randomized to receive either 1 mg/kg of cocaine (n = 7), 2 mg/kg of cocaine (n = 7), or normal saline (n = 7) daily on cycle days 2 to 14. Daily blood samples were obtained through indwelling catheters for measurement of serum gonadotropins and ovarian steroids. Daily vaginal swabs were obtained to determine onset of menses. Laparoscopy was performed 2 days after the midcycle estrogen peak to document ovulation. Daily caloric intakes as well as pretreatment and posttreatment weights were recorded. RESULTS: Two of seven monkeys receiving 1 mg/kg per day and two of seven monkeys receiving 2 mg/kg per day of cocaine had timely ovulation and normal menstrual cycle lengths. One monkey receiving the 2-mg/kg dose ovulated on cycle day 24 and had a short luteal phase (7 days) with a mean progesterone level of 2.4 ng/mL. All seven saline-treated control monkeys ovulated normally; the mean cycle length was 29 days and all had adequate luteal phases. The difference in ovulation rates between cocaine-treated and control monkeys was statistically significant (P = .003). There were no differences in basal levels of LH or FSH between treatment groups. There were no significant differences in weight change or caloric intake among groups. One third of the subsequent menstrual cycles in cocaine-treated monkeys were of abnormal duration. CONCLUSION: Daily low-dose follicular-phase cocaine administration disrupts menstrual cyclicity and folliculogenesis. This effect is independent of weight loss, caloric intake, and basal gonadotropin levels. Cocaine exposure may have a persistent effect on menstrual and ovarian cyclicity in some monkeys.