Alexander M. Dlugi

Lupron * depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study †

The safety and efficacy of leuprolide acetate (LA) for depot suspension (Lupron depot; TAP Pharmaceuticals, North Chicago, IL), 3.75 mg versus placebo, in the treatment of pain associated with endometriosis was assessed in a randomized, double-blind, multicenter study involving 52 patients. Dysmenorrhea, pelvic pain, and pelvic tenderness all responded significantly to LA treatment in comparison with placebo. Menses were suppressed in all of the LA patients. Estradiol decreased significantly to menopausal levels in the LA group. There were small to moderate changes in a variety of laboratory parameters, but these were not clinically significant. The most common adverse event was vasodilatation, occurring significantly more frequently in the LA group. Lupron depot was shown to be safe and effective in inducing a hormonal and menstrual suppression in patients with endometriosis, resulting in alleviation of pain symptoms.

The use of high-dose human menopausal gonadotropin in an in vitro fertilization program

Sixty-three normal ovulatory women suffering from obstructive tubal disease not corrected by previous surgery were enrolled in an in vitro fertilization (IVF) program. To achieve a large number of mature follicles, a relatively high dose of human menopausal gonadotropin (hMG) was administered (19 +/- 4 ampules/cycle). Monitoring consisted of daily follicular ultrasonography and serum estradiol measurements. Human chorionic gonadotropin (10,000 IU) was administered when more than two large follicles (1.6 to 1.8 cm in diameter) were visualized. Fifty-five laparoscopies for oocyte retrieval were performed. A mean of 4.3 follicles per woman were aspirated, and 3.2 oocytes per woman were recovered. The oocytes were preincubated for 8 or 24 hours according to the morphologic degree of mucification and dispersal of the oocyte-corona-cumulus complex. Seventy-seven percent of the oocytes were fertilized and were transferred into the uterus 38 to 40 hours after insemination. Fifty-two women received one to eight embryos (mean, 3.5 +/- 1.9), and 9 (17%) conceived. This regimen of high-dose hMG precludes the need for serum or urine luteinizing hormone monitoring, because the occurrence of spontaneous ovulation is low. It is valuable in increasing the number of fertilizable oocytes, the percentage of women undergoing embryo transfer, and compensates with multiple oocyte transfer for the high embryonic loss involved in IVF.

The periovulatory and luteal phase of conception cycles following in vitro fertilization and embryo transfer

The pattern of periovulatory and luteal phase levels of serum estradiol (E2) and progesterone (P) were compared between 8 conception and 28 nonconception cycles of patients undergoing in vitro fertilization (IVF). Ten additional women served as control subjects and did not undergo follicular aspiration. Follicle growth was induced with an individualized Pergonal (human menopausal gonadotropin) regimen, and laparoscopy was performed 36 hours after human chorionic gonadotropin administration. The length of the luteal phase did not differ significantly among the three groups and was between 14 and 15 days in duration. When IVF conception cycles were compared with nonconception cycles, although no difference in the number of large follicles was observed (4.25 +/- 0.45 versus 3.6 +/- 0.25), the patterns of E2 and P differed significantly. Daily serum E2 levels tended to be higher in the periovulatory phase in conception cycles when compared with nonconception cycles, and were significantly (P less than 0.05) higher in the early, mid, and late luteal phases. Serum P levels were significantly higher (P less than 0.05) in conception cycles from the midluteal phase onward. A decline in both serum E2 and P in the midluteal phase in conception cycles suggested some degree of corpus luteum deficiency. It is suggested that high E2 levels in the periovulatory phase may be an indicator of better follicular development under human menopausal gonadotropin stimulation and that the deficiency observed in the late luteal phase is overcome with the establishment of pregnancy.

Human in vitro fertilization employing individualized ovulation induction by human menopausal gonadotropins

One hundred six women suffering from obstructive tubal disease not corrected by previous surgery were treated in an in vitro fertilization (IVF) program. Ovulation was induced by 3 amps of human menopausal gonadotropin (HMG)/day starting on the third day of the cycle for 5 days. In most of the patients the regmmen was continued for another 1–3 days, depending on the individuals ovarian response (means, 20±5 amps/cycle). Monitoring consisted of daily follicular ultrasonography and serum estradiol measurements. Human chorionic gonadotropin (HCG), 10,000 IU, was administered when more than two large (1.5 to 1.8 cm in diameter) follicles were visualized. Using this regimen, a mean of five follicles per woman was aspirated, from which a mean of 3.9 over was recovered. The oocytes were pre-incuted for 8 or 24 hr. according to the morphological degree of inucification and dispersal of the oocyte-corona-cumulus complex. Following exposure to washed spermatozoa for 16 hr, a 68% fertilization rate was obtained. Oocytes were transferred into the uterus 48 hr after laparoscopy. Ninety-nine transfers (93% of the women) of 1–8 embryos (mean, 2.9/woman) were performed and resulted in 16 clinical pregnancies. No pregnancies occurred in 14 women transferred with one to three oocytes in the pronuclear stage and only one pregnancy (7.1%) was obtained in 14 women transferred with one cleaved oocyte. Over 70% of the women were transferred with two or more cleaved oocytes: in this group the pregnancyl transfer rate was 21%. Of thee pregnant women 5 of 16 (31%) aborted between 6 and 10 weeks of gestation and 1 (6%) had an ectopic pregnancy. The individualized regimen of HMG is valuable in increasing the number of fertilized oocytes and compensates with multiple-embryo transfers for the high early embryonic loss occurring in IVF.

Delaying human chorionic gonadotropin administration in human menopausal gonadotropin-induced cycles decreases successful in vitro fertilization of human oocytes

Correct timing of human chorionic gonadotropin (hCG) administration in induced cycles for in vitro fertilization is of crucial importance to oocyte maturation and normal luteal function. The purpose of this work was to compare the effect of hCG timing on follicular development, oocyte maturation, and fertilization in vitro, as well as on the pattern of luteal phase hormone secretion. Ovulation was induced in 32 normally cycling women by human menopausal gonadotropin (hMG)/hCG administration. In the first group (17 women) 10,000 IU hCG was administered 24 hours after the last injection of hMG and in the second group (15 women) 48 to 72 hours after the last hMG injection. Serum estradiol levels prior to oocyte aspiration were similar in both groups, as were the numbers of large follicles on the day of hCG administration (4.5 +/- 2.3 versus 4.1 +/- 1.9 follicles/woman, respectively). The distribution of oocyte-corona-cumulus complexes was similar in both groups and was comprised of 11% immature, 43% intermediate, and 45% mature complexes. The fertilization rate, however, was significantly (P less than 0.001) reduced in the group treated by delayed hCG injection (57% versus 84%), and the percentage of degenerated oocytes was increased (9% versus 1%). Luteal phase length as well as progesterone and estradiol levels were comparable in both groups. It is concluded that an interval longer than 24 hours between the last injection of hMG and the administration of an ovulatory dose of hCG does not affect follicular and luteal phase serum steroid patterns but may result in a decreased oocyte fertilization rate, possibly due to atretic changes in the follicles.

Altered follicular development in clomiphene citrate versus human menopausal gonadotropin-stimulated cycles for in vitro fertilization

The pattern of periovulatory and luteal phase serum estradiol (E2) and progesterone (P) as well as follicular fluid (FF) E2, P, androgen, gonadotropin, and prolactin concentrations of eight women undergoing clomiphene citrate (CC)/human chorionic gonadotropin (hCG) stimulation and eight women undergoing human menopausal gonadotropin (hMG)/hCG stimulation of follicular development for the purpose of in vitro fertilization were compared. Ovulation was induced with either a 5-day course of CC (100 mg/day beginning on day 5 of the cycle) or an individualized hMG regimen, and laparoscopy was performed 36 hours after hCG administration. The length of the luteal phase was significantly longer (P less than 0.05) in the CC-treated group as compared with the hMG-treated group. The pattern of serum E2 levels differed significantly (P less than 0.01) in that E2 levels were lower in the early and midluteal phase in CC-stimulated cycles; in addition, a delayed second E2 peak was observed in the late luteal phase in these women. Serum P levels, however, were lower in the hMG-stimulated group. Analysis of FF hormone concentrations revealed significantly (P less than 0.05) higher concentrations of E2 and androsterone in the FF of hMG-treated patients. It is concluded that follicular development in CC-stimulated cycles differs markedly from that in hMG-stimulated cycles. These differences may reflect either an altered follicular maturational process or may represent a direct inhibitory effect of CC on follicular steroidogenesis.

The day of initiation of human menopausal gonadotropin stimulation affects follicular growth in in vitro fertilization cycles

The attainment of synchronous follicular development in human menopausal gonadotropin/human chorionic gonadotropin-stimulated cycles for in vitro fertilization (IVF) continues to be a perplexing problem. Two regimens of follicle stimulation for IVF cycles were, therefore, compared. Twenty-nine patients commenced human menopausal gonadotropin (hMG) therapy on day I of the menstrual cycle (Group I), while 30 women received hMG from the third day of the cycle (Group II). The hMG therapy was tailored to the individual patientss response, based on ultrasonographic measurements of follicular size and serum estradiol (E2) levels. Both groups of patients received a mean of 19.6±1.4 ampules of hMG over a mean of 6.1±0.2 days. The pattern of serum E2 and progesterone levels in the periovulatory and luteal phase was not affected by the day of initiation of hMG therapy, although Group I patients demonstrated lower (P<0.05) E2 levels on the 2 days prior to human chorionic gonadotropin (hCG) administration. In terms of follicle growth, Group II follicles consistently demonstrated a significantly (P<0.01,x2 test) larger proportion of medium- and large-sized follicles compared to Group I follicles on almost all of the days when ultrasonographic measurements were taken. In addition. Group II follicles demonstrated an earlier shift (day—1) to the larger follicles than Group I follicles (day 0). Significantly (P<0.001) more oocytes were recovered per uspirated follicle in Group II patients, but the fertilization rate per oocyte was greater (P<0.003) for Group I oocytes. Nevertheless, pregnancy rates did not differ between the two groups. It is suggested that a difference between the two groups of patients in the quantity or quality of gonadotropin receptor sites in the early part of the follicular phase may account for both the diminished E2 production in the follicular phase and the persistent depressed follicular growth in Group I patients.