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FSH co-trigger after ovarian stimulation has been shown to improve oocyte competence and a recent report suggested that the FSH co-trigger can completely prevent OHSS. We report two cases of late OHSS after the FSH co-trigger was administered, underscoring the need for further research on the mechanisms, effects, benefits, and potential risks of FSH co-trigger., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Oral contraceptive pretreatment facilitated scheduling of pure FSH/GnRH antagonist cycles but in a small subset of patients was associated with low serum LH levels, reduced ovarian response, and early pregnancy loss. Supplementation with LH could be examined as a possible way to improve cycle outcome.

Purpose: To assess the effects of using a reduced dose of ganirelix with oral contraceptive pretreatment in a pilot study of COH using pure FSH for intrauterine insemination (IUI) METHODS: Patients received oral contraceptive (OC; 30 microg ethinyl estradiol/150 microg desogestrel) for 14-21 days and rFSH (50-225 IU/day SC) was started on day 4 after OC discontinuation. Ganirelix acetate (125 microg/day) was started with a lead follicle diameter of 14 mm., Results: Of the 25 subjects who started oral contraceptives, one was cancelled due to an excessive response, and one subject was not included in the analysis because she did not receive ganirelix until the lead follicle was 18 mm. Median (range) starting FSH dose was 100 (50-225), cumulative rFSH dose was 1000 (675-2175) IU over 10 (9-17) days. Duration of ganirelix acetate treatment was 4.0 (2-5) days. Seven subjects (30.4%) delivered ten babies (three pregnancies were twins). There were no biochemical pregnancies or miscarriages. Of the 16 subjects with measurement of LH on the day of HCG administration, only one was under 0.5 mIU/ml (0.4), and only one was over 10 mIU/ml (17.7), and that subject delivered twins., Conclusion: OC pretreatment afforded flexibility in scheduling while a reduced dose of ganirelix avoided excessive suppression of LH. The excellent results in this pilot study for IUI suggest this regimen could be further evaluated for scheduling IUI and IVF cycles.

We achieved two ongoing pregnancies in five older recipients with natural cycle oocyte donation from five young donors using a GnRH antagonist, with hMG and hCG to complete oocyte maturation. This provides a new alternative to ovarian stimulation for both oocyte donation and routine IVF.

Objective: To examine possible adverse effects on pituitary function of long-term administration of gonadotropin-releasing hormone agonist (GnRH-a)., Design: Prospective analysis of blood sampling before, during, and after GnRH-a therapy., Setting: Tertiary institutional outpatient care., Patients: Twelve normally ovulatory women with a diagnosis of endometriosis., Interventions: Six-month suppression with GnRH-a., Main Outcome Measures: Serum levels of follicle-stimulating hormone, luteinizing hormone, free thyroxin index, cortisol (F), growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH)., Results: Basal and stimulated values of gonadotropins, PRL, F, TSH, and GH were normal and unchanged by 6 months of GnRH-a after resumption of menses., Conclusions: Utilizing dynamic pituitary function tests, we were unable to demonstrate an adverse effect of long-term GnRH-a therapy on pituitary function.

Objective: The purpose of this study was to determine whether gonadotropin-releasing hormone agonist further increases the prolactin rise accompanying ovarian stimulation., Design: Serum prolactin concentrations were compared between cycles with and cycles without the use of leuprolide acetate (LA) matched for estradiol levels. Relationships of prolactin levels to cycle outcomes were examined., Setting: The study took place at a private fertility center., Patients: Patients were women receiving stimulation for oocyte retrieval using human menopausal gonadotropins., Interventions: No interventions were used., Main Outcome Measures: Serum prolactin level, fertilization rate, embryo quality, and pregnancy were the main outcome measures., Results: Higher serum prolactin was associated with both higher estradiol levels and use of LA but did not have any effects on fertilization rate, embryo quality, or occurrence of pregnancy., Conclusion: LA stimulates prolactin release during ovarian stimulation but without apparent consequence.

The relationship of the circulating level of progesterone (P) on the day of human chorionic gonadotropin (hCG) injection to occurrence of clinical pregnancy was examined in 133 leuprolide acetate human menopausal gonadotropin (hMG) in vitro fertilization cycles in women having at least three embryos transferred. Progesterone concentrations greater than 0.5 ng/mL were associated with a significantly lower rate of pregnancy (12/59, 20%) compared with less than 0.5 ng/mL (40/74, 54%, P less than 0.005). The higher P cycles were associated with greater patient age and hMG dose, although these relationships appeared to be indirect. Luteinizing hormone (LH) concentrations remained suppressed. Ovarian stimulation may cause excessive luteinization and an adverse cycle outcome even in the presence of low LH levels. Prospective use of P levels may be helpful to determine optimal hCG timing.

Highly potent agonists of gonadotropin-releasing hormone (GnRH) have been shown to reduce pelvic pain due to endometriosis and the size and number of implants seen at laparoscopy. The accompanying symptoms and problems associated with the hypoestrogenism induced by the agonist have reduced its acceptability and raised questions about its safety. In an attempt to optimize this form of therapy, we treated eight women with endometriosis with daily subcutaneous injections of a potent agonist of GnRH plus a daily oral dose of 20-30 mg of medroxyprogesterone acetate for 24 weeks. Ovarian estrogen secretion was reduced to levels seen in castrated women throughout the course of treatment. Markers of hypoestrogenism, such as hot flashes and loss of calcium from bone, were diminished with this regimen compared with previous findings with GnRH agonist alone. Blinded evaluation of laparoscopic photographs failed to reveal improvement or suppression of active endometriosis. The results of this pilot study indicate that the addition of medroxyprogesterone acetate decreases the hypoestrogenic effects of GnRH agonist alone but fails to affect pain or endometriotic implants.

Levels of immunoreactive luteinizing hormone (LH), bioactive LH, and testosterone (T) were determined in 52 women receiving human menopausal gonadotropins (hMG). In 26 women receiving leuprolide acetate (LA) preceding hMG, there was a significant suppression of immunoreactive LH and bioactive LH. The characteristic increase in serum levels of bioactive LH and T were absent. Follicular fluid estradiol and T concentrations, and serum progesterone were not different. The lower circulating levels of T may reflect reduced LH-stimulated androgen accumulation in smaller nonaspirated follicles and may account for the enhanced follicle recruitment observed during LA. The lack of premature luteinization despite marked rises of bioactive LH in the absence of LA is consistent with normal events during the menstrual cycle and was due to the early termination of hMG stimulation.

Sixteen women with endometriosis were treated with daily subcutaneous injections of a potent agonist of gonadotropin-releasing hormone (GnRH) for six months. Ovarian estrogen secretion was reduced to castrate levels during most of the course of treatment. Blinded evaluation of laparoscopic photographs confirmed marked suppression of visually apparent disease, but biopsy specimens showed occult, inactive endometriosis in most cases. Marked pain relief was noted by all patients. As a result of this "medical oophorectomy," the women experienced severe hot flashes, and many had insomnia and emotional disturbances. Vaginal cytology showed menopausal changes but related symptoms were generally mild. Calcium excretion rose to menopausal levels. High-density lipoprotein and total cholesterol remained unchanged. These results indicate that GnRH agonist administration has impressive effects on endometriotic implants, and these actions may be enhanced with longer therapy. Further development of this new form of therapy should involve either use of lesser degrees of ovarian suppression or adjunctive therapy to counter the side effects of "medical oophorectomy."

Pituitary suppression with leuprolide acetate (LA) was used before and during ovarian stimulation with human menopausal gonadotropins in 45 consecutive women having their first cycle of in vitro fertilization embryo transfer (IVF-ET). As anticipated, a low rate of cycle cancellation (6.7%) was necessary for poor responses. Follicles were allowed to develop to a larger diameter than with our prior protocol without LA. On the day of human chorionic gonadotropin (hCG), 11.5 + 0.7 follicles of at least 1.0 cm were visualized; 11.7 + 0.9 oocytes were retrieved; 67.5% fertilized and 6.7 + 0.6 normal embryos were available for transfer. Of the 3.4 + 0.1 embryos transferred per patient, 24.6% implanted. The rates of clinical pregnancy per retrieval and per stimulation were 54% and 47%, respectively, of which 23.8% aborted. Routine use of LA resulted in a highly efficient level of ongoing pregnancy per initiated cycle, and therefore may produce a superior first cycle for IVF-ET.

Five women with prior suboptimal ovarian stimulation for in vitro fertilization and embryo transfer (IVF-ET) were pretreated with a long-acting gonadotropin-releasing hormone (GnRH) agonist beginning in the midluteal phase of the preceding menstrual cycle. The four women with normal luteal function had castrate estrogen levels following regression of the corpus luteum, whereas one woman with an abnormal luteal phase and perimenopausal levels of gonadotropins had an agonistic response. In the three women with adequate stimulation, 20 oocytes were obtained and one women became pregnant. Initiation of GnRH agonist therapy during the luteal phase of a normal menstrual cycle may be an efficient way of obtaining ovarian suppression without an agonistic response.

The chemical structure of luteinizing-hormone-releasing hormone (LHRH) was discovered in 1971 after more than a decade of intensive effort. Subsequent physiologic studies in primates and humans showed that the biologic activity of LHRH depends on the way in which the hormone is administered. Pulsatile administration of LHRH, which mimics the natural secretory pattern, causes sustained secretion of the gonadotrophins. This method of administration has been used to induce ovulation in women with hypothalamic amenorrhea and to induce puberty and spermatogenesis in men with hypogonadotrophic hypogonadism. Continuous infusion, however, produces only transient stimulation of gonadotrophin secretion, followed by a "desensitization" response in which gonadotrophin secretion is inhibited. Thus, LHRH can either augment or inhibit gonadotrophin secretion depending on the mode of administration. Recently, long-acting synthetic analogs of LHRH have been shown to desensitize the pituitary gland and inhibit gonadotrophin release when administered as a single daily subcutaneous injection. These LHRH analogs have proved highly effective in the treatment of prostatic carcinoma and central precocious puberty. They are also being studied as a new approach to contraception and to the treatment of endometriosis and polycystic ovary syndrome.

The principal glandular source of increased serum androgens in polycystic ovarian disease (PCO) is controversial), since complete separation of ovarian from adrenal function has not been achieved. The purpose of this study was to determine whether a long-acting GnRH agonist could be used to selectively inhibit ovarian steroid secretion in PCO and ovulatory women. Each of five typical PCO patients and six ovulatory subjects on day 2 of their menstrual cycles received D-Trp6-Pro9-NEt-LHRH (GnRH-a; 100 micrograms) for 28 consecutive days. Their results were compared to basal serum hormone values in eight oophorectomized women. In response to GnRH-a, PCO and normal subjects exhibited sharp and sustained rises of LH and gradual decreases in FSH. These levels were clearly less than basal levels seen in oophorectomized women. Episodic LH release was significantly attenuated in both groups at the end of GnRH-a treatment. After the administration of agonist, serum estradiol (E2), estrone (E1), androstenedione (A), and testosterone (T) were suppressed to castrate levels in both groups. The decrements of E2 and E1 in PCO were gradual and continuous compared to initial dramatic rises, which reached peaks at 14 days, and subsequent abrupt falls in the ovulatory controls. Serum A and T declined steadily in both groups. Basal serum dehydroepiandrosterone and dehydroepiandrosterone sulfate, but not cortisol, levels were elevated in PCO subjects. The 24-h secretion patterns and responses to ACTH of these hormones in PCO and ovulatory subjects were unaltered by GnRH-a administration. These data demonstrate that 1) in PCO subjects, GnRH-a induced complete suppression of ovarian steroid secretion, as circulating levels at the end of treatment were comparable to those seen in our oophorectomy subjects; 2) elevated A and T levels in PCO patients were derived primarily from the ovary; and 3) adrenal steroid secretion was unaltered by GnRH-a in both PCO and normal women.

Five women with endometriosis were given a daily dose of a potent long-acting GnRH agonist, D-Trp6-Pro9-Net-LHRH (GnRH-A) for 28 days in an attempt to suppress ovarian estrogen secretion. The mean level of estradiol (E2) during sampling over 24 hours decreased (P less than 0.01) from 62 +/- 11 to 10 +/- 1 pg/ml at the end of treatment. Mean concentrations of androstenedione, testosterone, estrone and E2 on day 28 of therapy were similar to those measured in oophorectomized women. The level of FSH was decreased (P less than 0.001) during GnRH-a, whereas that of LH was significantly (P less than 0.001) increased, suggesting differing intracellular control mechanisms for release of the two gonadotropins. Desensitization of the pituitary was demonstrated at the end of treatment by a complete lack of acute response of FSH or LH to the daily dose of GnRH-a. "Medical oophorectomy" provides a new approach to the treatment of endometriosis.

The acute gonadotropin and estradiol responses following single subcutaneous injections of 10, 50, 100 and 200 micrograms of [(imBzl)]D-His6,Pro9-NEt]-GnRH were compared to those after 100 micrograms of [D-Trp6, Pro9-NEt]-GnRH. The gonadotropin responses after 50-100 micrograms of the D-His analog of GnRH were equivalent to those following 100 micrograms of the D-Trp analog. The ovarian E2 response, a reflection of the total cumulative secretion of gonadotropins, was similar at 100 micrograms of each analog. The estradiol response paralleled the increasing gonadotropin response accompanying the graded doses of the D-His analog, indicating the lack of a direct inhibitory action of this GnRH agonist on the ovary. Assessment of both gonadotropin and estradiol responses appears to be satisfactory for assessing relative potency among GnRH agonistic analogs.

In eumenorrheic women with endometriosis and in oligo-amenorrheic women with polycystic ovarian disease (PCO), chronic administration of a long-acting GnRH agonist (GnRH-a) reduced the circulating concentrations of estrogens and androgens to levels similar to those of castrated women. The concommittant elevation of LH in both groups suggested that the measured immunoreactive LH had reduced bioactivity. In seven women with endometriosis, bioactive LH (BA LH) measured as the in-vitro secretion of testosterone by dispersed Leydig cells, was significantly (p less than 0.001) reduced from 10.8 +/- 1.2 (SEM) to 4.4 +/- 0.2 mIU/ml at the end of 28 days of GnRH-a therapy. In five women with PCO, BA LH decreased from 44.2 +/- 15.5 to 5.7 +/- 0.6 mIU/ml (p = 0.06). These changes of BA LH appeared to be responsible for the suppression of ovarian androgen secretion during GnRH-a treatment and in turn may have contributed to the profound decreases of estrogen production by reducing the amount of precursor androgen available for aromatization. Free alpha subunit levels increased simultaneously with the decrease of BA LH at the end of therapy, suggesting a post-receptor effect of GnRH-a. Beta subunit levels became undetectable. Cross-reaction of alpha subunit in the RIA for LH was sufficient to only partially account for the LH levels measured. On sephadex G-100 chromatography the excess immunoreactive material was detected at and immediately following the alpha subunit tracer. Further studies will be necessary to elucidate the chemical nature of the immunoreactive LH secreted during GnRH-a therapy.

A long-acting agonist of gonadotropin-releasing hormone (GnRH-a, 100 micrograms/day) was administered daily for 14 days in four patients with polycystic ovarian disease (PCOD) and eight ovulatory women (OW) to determine acute hormone responses. Initiation of GnRH-a treatment in OW on day 5 of their menstrual cycles (OW-day 5) stimulated a greater acute rise of serum follicle-stimulating hormone (FSH) than that seen in OW beginning treatment on day 2 (OW-day 2) or PCOD patients. FSH levels fell to baseline values with repeated injections, whereas luteinizing hormone levels remained elevated in all patients. An acute rise and progressive fall of estradiol (E2) was found in all groups. The OW-day 5 group demonstrated a secondary increase, which by day 14 was clearly greater than that found in the other groups. This secondary increase of E2 in the OW-day 5 group was associated with lower abdominal pain, whereas OW-day 2 and PCOD patients were asymptomatic. For comparison, human menopausal gonadotropin (150 IU/day for 3 days) stimulated a significantly greater increase of E2 in OW-day 5 than in PCOD patients. These studies indicate that daily GnRH-a administration induced variable effects on ovarian function, which depended on when it was begun during the menstrual cycle and whether it was given to ovulatory or PCOD subjects. In addition, abdominal discomfort associated with GnRH-a use in regularly OW can be avoided by commencing agonist administration earlier in their menstrual cycles.

Persistent suppression of gonadotropin and ovarian steroid production can be achieved in women with polycystic ovarian disease (PCO) by daily administration of a long-acting GnRH agonist (GnRHa). This study was designed to determine the patterns of recovery of clinical responses and hormonal secretion after chronic GnRHa administration in women with PCO. Six women with PCO were treated with daily sc injections of [D-His6(imBzl),Pro9-NEt]GnRHa (100 micrograms) for 6 months. Blood samples were obtained at the time of and three times weakly for 90 days after discontinuation of agonist therapy. In five women who did not ovulate, the suppressed serum FSH levels rose to pretreatment values within 10 days. In contrast, a gradual and progressive increase in serum LH (as measured by bioassay and immunoassay) was apparent by day 18. The LH increase coincided with progressive increases in serum estrone (E1), androstenedione, and testosterone. Serum estradiol (E2) began to rise on day 28. All hormones returned to their pretreatment baseline values within the 90-day recovery interval, with the exception of E2. Trend analysis of the slopes of recovery revealed that the incremental secretion patterns of E1, E2, androstenedione, and testosterone differed significantly from that of FSH, but not from those of bioactive or immunoactive LH. Serum progesterone, dehydroepiandrosterone sulfate, and cortisol did not change after withdrawal of GnRHa. One woman ovulated spontaneously on day 52 before which her hormone secretion patterns were indistinguishable from those of the other women. In summary, 1) during recovery after discontinuation of chronic GnRH agonist therapy the patterns of FSH and LH release suggested resumption of endogenous GnRH action on the pituitary with greater release of FSH than LH, a pattern that would be expected in the absence of ovarian steroid influence; 2) the lack of early estrogen production despite the increase in serum FSH concentrations suggests inadequate FSH secretion, abnormal ovarian responsiveness to FSH, or impaired FSH bioactivity; 3) androgen secretion was provoked by the increase in LH secretion; 4) per unit LH measured by bioassay, greater ovarian androgen secretion was stimulated in PCO than ovulatory women; and 5) the likelihood of spontaneous ovulation during recovery was minimal.

To examine the relationship between the occurrence of menopausal hot flashes and the pulsatile release of LH, we have investigated the serum hormone levels and the occurrence of hot flashes by objective recordings in five women with endometriosis given daily injections of a long-acting GnRH agonist (GnRH-a) for 28 days. Results were compared to the findings made in 25 young women 6-8 weeks after bilateral oophorectomy. Serum levels of estrone and estradiol were similar in the subjects given GnRH-a and the women who underwent a surgical castration. In comparison with values before GnRH-a administration, the mean FSH level was lower whereas the mean LH concentration was significantly higher (P less than 0.01) on the last day of therapy. The coefficients of variations of both gonadotropins measured during 4-h sampling periods at 20-min intervals before and at the end of GnRH-a administration were significantly reduced (P less than 0.01) with therapy. During the total of 20 h of frequent sampling in the 5 subjects, 15 pulses (20% rise from nadir) of LH and 12 pulses of FSH were detected before GnRH-a, whereas only 2 and 8 pulses, respectively, were observed on day 28 of treatment. Hot flashes were observed in both groups of patients. The proportion of women experiencing hot flashes, the rate of occurrence/h and the characteristics of the physiological changes were similar in the 2 groups of women. These data indicate that hot flashes can occur in the absence of prominent LH pulses, suggesting the pulsatile release of this hormone is merely associated with the hot flash rather than being etiological.

The time course of suppression of ovarian estrogen production and follicular development with leuprolide was examined in 40 normal women before ovarian stimulation for in vitro fertilization (IVF). Initiation of leuprolide during the midluteal phase caused a significantly more prompt suppression than when treatment was started during the early follicular phase (day 1). Injection of the same total amount of leuprolide in two divided doses also caused a significantly more prompt suppression. These two methods were consistent enough to make routine use of leuprolide practical before ovarian stimulation for IVF.

Previously, we reported that short term administration of a highly potent GnRH agonist (GnRHa) for 1 month to patients with polycystic ovarian disease (PCO) resulted in complete suppression of ovarian steroidogenesis without measurable effects on adrenal steroid production. This new study was designed to evaluate the effects of long term GnRHa administration in PCO patients with respect to their hormone secretion patterns and clinical responses. Eight PCO patients and 10 ovulatory women with endometriosis were treated daily with sc injections of [D-His6-(imBzl]),Pro9-NEt]GnRH (GnRHa; 100 micrograms) for 6 months. Their results were compared to hormone values in 8 women who had undergone bilateral oophorectomies. In response to GnRHa, PCO and ovulatory women had rises of serum LH at 1 month, after which it gradually declined to baseline. In both groups FSH secretion was suppressed throughout treatment. Serum estradiol, estrone, progesterone, 17-hydroxyprogesterone, androstenedione, and testosterone levels markedly decreased to values found in oophorectomized women by 1 month and remained low thereafter. In contrast, serum pregnenolone and 17-hydroxypregnenolone were partially suppressed, and dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol levels did not change. Clinically, hyperplastic endometrial histology in three PCO patients reverted to an inactive pattern, and proliferative endometrium in two other PCO patients became inactive in one and did not change in the other. Regression of proliferative endometrial histology occurred in all ovulatory women. Vaginal bleeding occurred in all women studied during the first month of GnRHa administration, after which all but one PCO patient became amenorrheic. Hot flashes were noted by all ovulatory women and by four of eight PCO patients. All PCO patients noted subjective reduction of skin oiliness, and five had decreased hair growth. We conclude that in premenopausal women: 1) chronic GnRHa administration results in apparently complete persistent suppression of ovarian steroid secretion; 2) adrenal steroid secretion is not influenced directly or indirectly; and 3) its use may be helpful in the treatment of endometrial hyperplasia and ovarian androgen excess in women with PCO.