Administration of luteinizing hormone-releasing hormone analogs delays ovulation without affecting the luteal function in rhesus monkeys

Regularly cycling rhesus monkeys received, from days 1 to 6 of the menstrual cycle (1) the potent luteinizing hormone-releasing hormone (LH-RH) agonist D-Trp6-LH-RH, 20 micrograms/day; (2) the potent LH-RH antagonist [N-Ac-D-Trp1,3,D-p-Cl-Phe2,D-Phe6-D-Ala10]-LH-RH, 1 mg/day; or (3) vehicle. Whereas control animals showed normal menstrual cycles, as determined by dates of ovulation, length of luteal phases, and hormonal profiles, animals treated with either analog of LH-RH exhibited disruption of the cycles. In animals from both groups, delayed ovulation was observed (LH-RH agonist, 22, 23, 17, 19, and 20 days of the cycle; LH-RH antagonist, 22, 22, 24, and 10 days of the cycle, and one animal remained anovulatory for 65 days). Monkeys treated with either LH-RH analog showed normal luteal phase lengths (15, 15, 16, 14, and 15 days, and 15, 16, 16, and 13 days, respectively) and serum progesterone concentrations. The results of this study suggest that, in the rhesus monkey, the administration of LH-RH analogs during the early follicular phase induces a temporary cessation of folliculogenesis demonstrated by a delay of ovulation, with subsequent normal luteal function.     

Paradoxical effects of D-Trp6-luteinizing hormone-releasing hormone on the hypothalamic-pituitary-gonadal axis in immature female rats.

The effect of administration of a superactive and long-acting analog of luteinizing hormone-releasing hormone (LH-RH), D-Trp6-LH-RH, in doses of 0.05 or 1 microgram/day for 10 days on the hypothalamic-pituitary-gonadal axis was studied in immature female rats. Treatment with a 0.05-microgram dose of analog produced few changes as compared with the control group. Treatment with 1 microgram of D-Trp6-LH-RH did not affect the body weight or the pituitary weight, but increased ovarian weight and decreased uterine weight; elevated serum gonadotropin levels; and lowered the pituitary LH content. This depletion of pituitary LH content was associated with a low pituitary responsiveness to LH-RH. Serum estradiol levels were not modified, suggesting that decreased uterine weight reflects a direct and extrapituitary effect of this analog. The hypothalamic LH-RH content was higher, indicating a possible inhibition of the release of endogenous LH-RH. A delay in vaginal opening was also observed. This indicates that large doses of D-Trp6-LH-RH may interfere with the process of puberty in rats. These findings extend other reports about the paradoxical antifertility effects of large doses of stimulatory analogs of LH-RH.     

Endocrinology of gonadotropin-releasing hormone induced cycles in hypothalamic amenorrhea: the role of the pulse dose.

OBJECTIVE: To find the treatment regimen giving a maximum chance of ovulation and a minimal chance of multiple follicular development in pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with hypothalamic amenorrhea. DESIGN: We propectively studied the endocrinology of cycles induced with 5, 10, and 20 micrograms GnRH pulse doses, randomly assigned per patient, comparing this with the endocrinology of spontaneous menstrual cycles. SETTING: All patients were treated at the Academic Hospital of the Vrije Universiteit, Division of Reproductive Endocrinology and Fertility. PATIENTS: Fifteen patients with hypothalamic amenorrhea were treated for one to three cycles; 14 normally cycling volunteers were studied for one cycle. MAIN OUTCOME MEASURE: Number of ovulations per pulse dose; luteinizing hormone, follicle-stimulating hormone, total urinary estrogens (Es), and pregnanediol were measured per cycle day and per stimulation day. RESULTS: The endocrinology of all ovulatory cycles remained within the normal range. First treatment cycles showed significantly higher ovulation rates compared with subsequent cycles. Significantly more anovulation was observed in cycles with 5-micrograms pulse doses. Luteal Es were significantly higher in induction cycles compared with controls. CONCLUSIONS: The optimum treatment regimen should be to start induction with 5 micrograms/pulse in the first cycle and to raise the dose to 10 micrograms/pulse in subsequent cycles, regardless of the outcome of the first cycle. After ovulation, the pulse interval should be changed to 240 minutes.     

Long-acting agonists of LH-RH in the treatment of large ovarian endometriomas

Reversible temporary medical oophorectomy using long-acting agonist analogs of LH-RH was tried in three infertile patients suffering from large endometriomas of the ovary. These patients had stage IV disease according to the revised 1985 classification of the American Fertility Society. D-Ala6-des-Gly10-LH-RH propylamide (D-Ala6-LH-RH PA), in a dose of 125 micrograms, was administered intramuscularly every 48 hours to one patient, and daily to the other two patients, for 22, 17, and 14 weeks, respectively. Two patients subsequently received 100 micrograms of D-Trp6-LH-RH for 4 weeks in order to compare its efficacy with D-Ala6-LH-RH PA. Clinical controls, pelvic ultrasonography, and routine laboratory tests and hormone assays were done periodically. Ultrasonography images showed a reduction in the size of endometriomas after the second or third week of treatment. This reduction was maintained throughout and continued after the period of treatment. Suppression of the pituitary and estrogen responses was obtained rapidly, but some transient increments were occasionally found. Progesterone levels always decreased and remained in the range of the early follicular phase. Most intervals of uterine bleeding were prolonged. An evident improvement of abdominal pain, dysmenorrhea, and dyspareunia was found. Administration of D-Trp6-LH-RH was more effective than D-Ala6-LH-RH PA in most of the parameters tested. After discontinuation of treatment, all three patients had a prolonged follicular phase with a normal luteal phase during the first cycle. One woman became pregnant in the fourth cycle after discontinuation of D-Ala6-LH-RH PA and delivered a normal baby.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased potency of four analogues of LH-releasing hormone in man

Four analogues of LH-releasing hormone (LH-RH) were injected iv. in normal men at a dose of 25 mug: des-Gly-10NH2-LH-RH ethylamide (9-EA-LH-RH); des-Gly-10-NH2-LH-RH propylamide (9-PA-LH-PH), d-ala-6-LH-RH; and D-Ala-6, des Gly10-NH2-LH-RH ethylamide (D-Ala-6,9-EA-LH-RH). Each peptide tested was found to be more potent than LH-RH in releasing LH and, to a lesser extent, FSH. The times of the peak values of LH after the analogues were similar to LH-RH (about 20 minutes). However, LH as well as FSH levels were considerably delayed in returning to baseline after administration of D-Ala-6,9-EA-LH-RH. The half-time disappearances of the 9-EA and 9-PA analogues could be tested and were found to be similar to that of LH-RH. The increased potency and prolonged duration of action of D-Ala-6,9-EA-LH-RH suggest the potential usefulness of this compound in stimulating ovulation and perhaps spermatogenesis.     

Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study.

Secondary amenorrhea in women with normal estrogen levels increases the risk of endometrial carcinoma. Cyclical dydrogesterone induces regular withdrawal bleeding and effectively protects the endometrium of postmenopausal women receiving estrogens. In order to assess the efficacy of dydrogesterone in inducing regular withdrawal bleeds in premenopausal women with secondary amenorrhea or oligomenorrhea and normal estrogen levels, a double-blind, randomized, placebo-controlled, multicenter study was conducted in 104 women using cyclical dydrogesterone as is used for estrogen replacement therapy. Treatment consisted of dydrogesterone (10 mg/day on days 1-14 followed by placebo on days 15-28 of each cycle) given for six cycles of 28 days. The control group received placebo throughout the six cycles. Bleeding was documented by the patient on diary cards. The number of women with withdrawal bleeding during the first cycle was twice as high in the dydrogesterone group as in the placebo group (65.4% vs. 30.8%; p = 0.0004). Superiority of dydrogesterone was also observed for regularity of bleeding over the six cycles (p < 0.0001), although endometrial thickness after six cycles did not differ between the groups. In conclusion, dydrogesterone is significantly superior to placebo in inducing withdrawal bleeding, and maintaining regular bleeding, in women with secondary amenorrhea and normal estrogen levels.     

Depo-provera as a long-term contraceptive

Clinical experiences with depo-provera (trimonthly injections of 150 mg) as a contraceptive in over 2000 women are reported. 37 pregnancies have been observed in the 4-year period of the study; most occurred when the injection was given after the 6th day of the cycle. A variable (4-21 months) period of infertility follows the last injection. Side effects included headache, weight gain, amenorrhea, spotting, breakthrough bleeding, and cycle irregularity. Hemorrhage and spotting were successfully treated with estrogens or estrogen-gestagen combinations. The method is highly acceptable when patients have been informed about possible side effects.     

Induction of ovulation with subcutaneous pulsatile administration of human menopausal gonadotropin

Induction of ovulation with subcutaneous pulsatile (every 90 min.) administration of HMG (Pergonal) 75 or 150 IU/day using a portable pump (Nipro SP-3I) was performed in 3 PCO patients (6 cycles), 4 first grade amenorrhea (Am-I) patients (7 cycles) and 4 Am-II patients (4 cycles). All patients ovulated except one cycle of Am-I patients and one PCO woman conceived. In regard to the duration of administration and the total dose of HMG until ovulation, the administration of 150 IU/day (M +/- SD=15.2 +/- 5.0 days, 2280 +/- 774 IU) is superior to 75 IU/day (39.5 +/- 11.4 days, 3900 +/- 1357 IU), and there was no significant difference between this method and the daily intramuscular injection of HMG. The group treated with HCG in the luteal phase revealed a longer luteal phase (14.0 +/- 2.3 days) than the nontreated group (12.6 +/- 1.5 days). Ovarian hyperstimulation was observed in one case and subsided spontaneously after admission. There were no other side effects. In conclusion, this method has the following advantages: A high ovulation rate, comparable with daily intramuscular administration. It is a less painful procedure than daily intramuscular injection. It is possible for the patient to lead normal life, insertion and removal being easily done by herself.     

Plasma gonadotropin response to D-Ala6-LH-RH propylamide.

A long-acting analog of LH-RH, D-Ala6-desGly10-LH-RH propylamide (D-Ala6-LH-RH PA) was administered intramuscularly in a dose of 250 micrograms to 11 women with amenorrhea in whom the determinations of urinary steroid secretion, progesterone challenge, clomiphene, HMG, and LH-RH tests had been performed previously. Blood samples were taken twice before the injection and at 0.5, 1, 2, 4, 8, 12, 24, 26, 28, 30, and 32 h. No visible side effects were observed. Plasma levels of LH and FSH were determined by radioimmunoassays and expressed in mIU/2nd-IRP HMG/ml. The analog caused a great elevation in plasma LH and FSH levels. The maximal absolute increment for LH was between 3.93 and 115.89 mIU/ml, and the maximal increment in percentage was between 220 and 4,300. The time of the LH peak varied between 0.5 and 12 h. For FSH, the maximal absolute increment was between 6.45 and 50.92 mIU/ml and the maximal increment in percentage was between 63 and 1,442. The peak of FSH occurred in most cases at 4 to 8 h.     

Administration of L-thyroxine does not improve the response of the hypothalamo-pituitary-ovarian axis to clomiphene citrate in functional hypothalamic amenorrhea

OBJECTIVE: To investigate the hypothalamo-pituitary-ovarian axis in women with functional hypothalamic amenorrhea to determine whether the combination of L-thyroxine and clomiphene citrate produces a qualitative and quantitative increase in induced ovulatory cycles. SETTING: Gynecological Endocrinology Research Center, University of Siena (Italy). PATIENTS: 16 young women with functional hypothalamic amenorrhea and 15 women with normal cycles in early follicular phase. DESIGN: Administration of 50 microgram GnRH and 200 microgram TRH. The women with functional hypothalamic amenorrhea were divided into groups A (n=8) and B (n=8). Both groups were given 100 mg/day clomiphene for 5 days/month for 3 months. Women in group A were also given 75 mcg/day thyroid hormone (L-thyroxine) for 3 months. MAIN OUTCOME MEASURES: Comparison of basal and stimulated levels of gonadotropins, TSH and Prl, in groups A and B. Qualitative and quantitative comparison of ovulatory cycles induced in the groups. Results: Administration of clomiphene and clomiphene plus L-thyroxine was evaluated in the second and third months of treatment and was followed by a total of 11 ovulatory cycles, six in group A and five in group B. No significant difference was found between groups. Mean progesterone concentrations measured 16 days after the last clomiphene tablet were 5.5+/-1.2 ng/ml in group A and 5.1+/-1.3 ngl/ml in group B. CONCLUSIONS: Administration of L-thyroxine with clomiphene does not improve the response of the hypothalamo-pituitary-ovarian axis to clomiphene citrate or the number of ovulatory cycles and does not reduce luteal phase defects.     

Effects of clomiphene citrate on cervical mucus: analysis of some influencing factors

A multicenter study was performed to investigate the effects of a standard dose of clomiphene citrate (100 mg/day from day 5 of the cycle for five days) on the quality of cervical mucus. A total of 82 cervical mucus samples from 60 infertile patients (15 with secondary amenorrhea, 16 with delayed ovulation, 15 with anovulatory cycles, 14 with oligomenorrhea) was examined on the day of maximum follicular diameter. As a control we studied 54 cervical mucus samples from 47 patients with documented tubal sterility or infertile partners, who had spontaneous cycles with normal rhythm. Cervical mucus was unfavorable in 59% of the treatment cycles compared with 11% of the control cycles. Clomiphene citrate's antiestrogenic effect on cervical mucus was found to be related to the length of time between the last drug administration and the day of maximum follicular diameter (delta days), since cervical mucus was favorable in 64% of the cycles with a delta days more than 6 and in only 16% of the cycles with a delta days of 6 or less. Clomiphene citrate thus seems able to decrease cervical mucus quality. This could be one of the causes of the discrepancy between the rates of ovulation and pregnancy reported in patients treated with this drug.     

New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea.

OBJECTIVE: To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. DESIGN: This was an open-label study. PATIENTS: Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. MAIN OUTCOME MEASURES: Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. RESULTS: Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. CONCLUSIONS: The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.     

Serum LH, FSH and testosterone response to the administration of a new LH-RH analog, D-Trp6-LH-RH, in normal men.

A long-acting superactive analog of LH-RH, D-Trp6-LH-RH was given to 23 normal men by several routes of administration (iv, im, sc, continuous infusion) and in increasing doses of 1 to 50 microgram. LH and FSH responses were obtained at doses as low as 2.5 microgram. The maximal absolute LH and FSH increment in response to a 10 microgram iv bolus injection of this analog was similar to 100 microgram of LH-RH. In addition, after administration of the analog the LH and FSH level was maintained at a higher than basal level for at least 8 hours. With a 50 microgram iv bolus injection, from 30 minutes onwards the increases in LH levels were significantly greater (P less than 0.05) than those elicited by the 10 microgram dose for at least 8 hours. Maximum release of LH and RSH was observed when this same dose was given as continuous infusion for 8 hours (P less than 0.05). There seemed to be no significant differences between the im and sc routes. Following the administration of the D-Trp6-LH-RH, testosterone levels were maintained above the normal values (P less than 0.02). The high potency and prolonged duration of action of this compound suggest its potential usefulness for increasing testosterone levels and for stimulation of spermatogenesis in men.     

A comparison of clomiphene/menotropins and D-Trp6-LH-RH/menotropins cycles of IVF-ET in the same patients.

Pituitary suppression by long-acting D-Trp6-LH-RH and concomitant hMG ovarian stimulation for in vitro fertilization and embryo transfer (ET) has been used in 19 patients who previously failed to conceive, following ovarian stimulation by clomiphene citrate and hMG. When available, up to five embryos were transferred. Compared with the previous CC/hMG cycles, D-Trp6-LH-RH/hMG cycles were associated with significantly more embryos (P less than .002), lower follicular-phase basal LH levels (P less than .05), and a higher early luteal progesterone level (P less than .05). Following D-Trp6-LH-RH/hMG cycles, 11 patients had a clinical pregnancy. The multiple pregnancy rate was 18% and the abortion rate, 18%. Thirty percent of the cycles (6/20) were associated with the ovarian hyperstimulation syndrome. These promising results warrant a further trial of D-Trp6-LH-RH-hMG stimulation.     

Amenorrhea following oral contraception

In 21 patients with amenorrhea after taking oral contraceptives, the urinary excretion of estrogens and the plasma concentrations of LH, FSH and prolactin were determined. In five of these women the amenorrhea was accompanied by galactorrhea. Ten of the 21 patients had had origomenorrhea before contraceptive therapy. The progesterone test was negative in 9 patients and clomiphene test was negative in 10 patients. The urinary excretion of estrogens and plasma LH and FSH values were low normal while the prolactin concentration in group A (amenorrhea without galactorrhea) amounted to 12.8 +/- 2.4 micrograms/l of plasma and in group B (amenorrhea with galactorrhea) to 85.4 +/- 15.8 micrograms/l (p < 0.01). The pituitary response to 100 micrograms synthetic LH-RH i.m. was similar to that found in the early follicular phase of the ovulatory cycle and showed that the pituitary was capable of synthesizing and secreting LH and FSH. Two of the three women from group A who wanted to become pregnant conceived under the therapy with Clomid and HCG. In all women from group B, in response to Parlodel (bromocriptine) therapy administered in 5-mg dose daily, the plasma concentration of prolactin decreased to a normal level, galactorrhea ceased within 15-62 days, and menstruation resumed within 38-75 days. In three women it is very probable that the cycle became biphasic, and a previously clomiphene negative patient became a clomiphene responder.     

Ovulation induction with luteinizing hormone--releasing hormone in amenorrheic, infertile women.

Thirteen women with infertility thought due to anovulation were treated with LRH. Etiologic diagnoses of amenorrhea included hypothalamic or "idiopathic" and PCOD. All patients had normal gonadotropins and otherwise normal endocrinologic and infertility evaluations; none had ovulated with clomiphene. Patients were studied for six 35 day cycles, single blind, and received LRH or placebo by subcutaneous injections for 28 days/cycle (LRH dosage 1.0 mg 2 or 3 times each day). Frequent assessments of physical status, cervical mucus, vaginal cytology, and serum LH, FSH, estrogen, and progesterone were performed. Ovulation was documented by basal temperature, serum progesterone and, on occasion, endometrial biopsy. Follow-up was continued for 6 months after therapy. Of the 13 patients treated, eight have ovulated and five have conceived. There were no complications of therapy.     

Inhibition of progesterone secretion during the luteal phase by two luteinizing hormone-releasing hormone agonists in Macaca fascicularis

The administration of 200 microgram of the potent luteinizing hormone-releasing hormone (LHRH) agonist [D-Leu6,des-Gly-NH2(10)]LHRH ethylamide on day 6 following the plasma estradiol peak to 11 female monkeys (Macaca fascicularis) during two consecutive menstrual cycles decreased plasma progesterone levels by 40.0% +/- 3.9% as compared with previous control cycles. The plasma estradiol profile and the cycle length were not affected significantly by the treatment. Similar results were obtained with 25 microgram of [D-Ser(TBU)6,des-Gly-NH2(10)]LHRH ethylamide administered to one monkey at the same period of the cycle, such treatment leading to a 41% inhibition of circulating progesterone levels. Although plasma progesterone levels were still reduced in the two post-treatment cycles in monkeys treated with the high dose (200 microgram) of [D-Leu6,des-Gly-NH2(10)]LHRH ethylamide, the recovery cycle was normal after the administration of a lower dose (25 microgram) of [D-Ser(TBU)6, des-Gly-NH2(10)] LHRH ethylamide. The M. fascicularis monkey thus appears as a valid model with which to study the inhibitory effects of LHRH agonists on luteal function.     

Studies of a controlled-release microcapsule formulation of an LH-RH agonist (D-Trp-6-LH-RH) in the rhesus monkey menstrual cycle

It has been shown that continuous administration of LH-RH agonists inhibits ovulation in many species, including human and nonhuman primates. However, the need of daily injections or intranasal application of the LH-RH agonists makes this contraceptive approach impractical. In addition, due to the repeated daily administration of the LH-RH analogues and their bioavailability, serum levels of gonadotropins and estradiol present wide variations and are often associated with irregular bleeding and/or endometrial hyperplasia. This experiment was designed to study the effects on ovulation and the hormonal profile during the rhesus monkey menstrual cycle of a system that continuously delivers a potent agonist of LH-RH (D-Trp-6-LH-RH encapsulated in poly [DL-lactide-co-glycolide]). Subjects were divided into two groups: On day 1 of the cycle, monkeys received a single subcutaneous injection of microcapsules containing D-Trp-6-LH-RH at a release rate of 13.6 micrograms/day (Group 1) or placebo microcapsules (Group 2). Ovulation dates were significantly delayed in animals from Group 1 (50 +/- 3 days) as compared to those in group 2 (20 +/- 2 days). Luteal phases following ovulation were normal in animals of both groups, as determined by length and serum progesterone levels. No significant differences on baseline levels of FSH and LH were observed between the two groups of animals. Post-treatment cycles were ovulatory and presented normal luteal phases and hormone concentrations as compared to the non-treated animals of our colony. The present data show for the first time that a controlled-release microcapsule formulation that delivers an agonist of LH-RH can effectively suppress ovulation when injected in a single dose in non-human primates.     

Effects of a low-dose estrogen-antiandrogen combination (Diane-35) on clinical signs of androgenization, hormone profile and ovarian size in patients with polycystic ovary syndrome

This study evaluates the effect of an oral contraceptive containing 35 micrograms of ethinyl estradiol and 2 mg of cyproterone acetate (Diane-35) on hormone dynamics, clinical signs of androgenization and ovarian size in patients with polycystic ovary syndrome (PCOS). Forty-six patients with PCOS were treated with Diane-35 for between 9 and 30 cycles without interruption (a total of 688 cycles). Clinical and hormonal evaluations were performed before treatment and every 3rd cycle during the treatment period while ultrasonographic assessment of ovaries was carried out every 6th cycle. A highly significant decrease in the LH/FSH ratio (p less than 0.001) as well as testosterone levels (p less than 0.001) was noticed after the 3rd cycle of Diane-35 administration. The mean serum androstenedione level decreased significantly (p less than 0.025) after the 3rd cycle, and showed a lowering trend thereafter. A significant reduction in serum DHEA-S levels was observed after the 6th cycle of treatment and they also showed a subsequent lowering trend. A highly significant increase in SHBG concentrations (p less than 0.001) was noticed after the 3rd cycle. Most of the patients noticed improvement in hirsutism between the 8th and 12th cycles of treatment. Mean ovarian size decreased significantly (p less than 0.001) after the 6th cycle, the normal size being reached after the 12th cycle of treatment. After the 4th cycle treatment was discontinued in 1 patient due to secondary amenorrhea, and in another 3 patients because of an increase in diastolic blood pressure. In a few patients side-effects such as weight gain, breast tenderness and mood changes in mild form were reported. Three out of 7 patients conceived in the 2nd or 3rd cycle after discontinuing Diane-35 therapy. The results of this study show that a combination of low-dose estrogen and cyproterone acetate (Diane-35) successfully reduces the hormonal disturbances which characterize PCOS. Apart from the normalization of the hormonal profile and the decrease in ovarian size, beneficial effects of Diane-35 were also observed on acne, hirsutism and regulation of the menstrual cycle. Favourable effects were also seen in terms of the pregnancy rate after discontinuation of Diane-35 therapy.     

Luteolytic activity of LHRH and [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide: a new and physiological approach to contraception in women

The administration of five subcutaneous 250-microgram doses of luteinizing hormone-releasing hormone (LHRH) at 4-hour intervals on 1 or 2 consecutive days between days 1 and 9 following the spontaneous LH surge in normal women shortened the luteal phase from 1 to 4 days in 16 out of 17 treatment cycles. Treatment appeared to be more efficient when LHRH was administered on days 6 to 9 after the LH surge as compared with days 1 to 5. In fact, the luteal phase was shortened from 3.3 +/- 0.2 versus 1.4 +/- 0.2 days (P < 0.01) and the serum progesterone level was decreased to 44 +/- 5 versus 71 +/- 6% of control levels (P < 0.01) when the neurohormone was injected late as compared with early in the luteal phase. A similar luteolytic effect has been obtained after intranasal administration of 500 microgram of [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide at 0800 and 1700 h on one day between days 4 and 9 following the LH peak. In six women treated with the LHRH analogue during two consecutive cycles, the luteal phase was shortened by 2.6 +/- 0.4 days (range 0.5-4.5 days) and plasma progesterone levels were reduced to 61.3 +/- 9.2% of control. As determined by daily blood sampling for LH, FSH, estradiol, and progesterone, normal cycles occurred immediately after treatment. The present data indicate the luteolytic effect of treatment with LHRH or a LHRH agonistic analogue in normal women and support the interest of such a new and physiological approach for the control of corpus luteum function and menstrual cycle in women.