RELATIONSHIPS BETWEEN THE CHARACTERISTICS OF ENDOGENOUS LUTEINIZING HORMONE SURGE AND THE DEGREE OF OVARIAN HYPERSTIMULATION DURING SUPEROVULATION INDUCTION IN WOMEN

Ovarian hyperstimulation was induced in 17 normally cycling women undergoing in-vitro fertilization (IVF) and embryo transfer with clomiphene (9 cycles), clomiphene followed by pulsatile hMG (12 cycles) or clomiphene followed by pulsatile FSH (11 cycles). Hyperstimulation was greater with the combined treatments than with clomiphene alone. In all 32 cycles an endogenous LH surge occurred. The peak values and the duration of the LH surge showed significant negative correlations with the plasma oestradiol levels, the number of the follicles and the total follicular fluid volume aspirated at laparoscopy. We suggest that during superovulation induction for IVF, the endogenous LH surge is attenuated by factors which are related to the degree of ovarian hyperstimulation.     

HORMONAL CHANGES IN PATIENTS WITH POLYCYSTIC OVARIAN DISEASE AFTER OVARIAN ELECTROCAUTERY OR PITUITARY DESENSITIZATION

Eleven patients with polycystic ovarian disease (PCO) were treated by laparoscopic ovarian electrocautery and nine with a long-acting luteinizing hormone releasing agonist (LHRH-A) for 8 weeks. Both groups showed equivalent significant decreases in their 6-h mean values of luteinizing hormone (LH) and testosterone (T) measured in 25 samples collected every 15 min. Patients treated with ovarian electrocautery showed significant increases in their 6-h mean values of follicle stimulating hormone (FSH) and insulin with variable oestradiol (E2) responses. The magnitude of change following treatment was significantly greater for LH than for FSH. Buserelin medication did not cause persistent significant changes in the levels of insulin or FSH but it did cause a significant reduction in the 6-h mean values of E2. We conclude that LH is the gonadotrophin primarily affected after pituitary desensitization and ovarian electrocautery. Furthermore, there is no direct correlation between the levels of circulating insulin and testosterone in patients with PCO.     

Ovulation induction in clomiphene-resistant anovulatory women: differential follicular response to purified urinary follicle-stimulating hormone (FSH) versus purified urinary FSH and luteinizing hormone

We studied 15 anovulatory women undergoing ovulation induction with purified human urinary FSH or purified human urinary FSH and LH [human menopausal gonadotropins (hMG)]. All patients had either sporadic or no vaginal bleeding after progesterone therapy and failed to ovulate after receiving clomiphene (250 mg for 5 days) plus hCG. Other causes of infertility were ruled out. Sixteen cycles of FSH and 12 cycles of hMG were administered according to a standard protocol. Estradiol, progesterone, androstenedione, testosterone, LH, and FSH concentrations were quantitated by RIA. Follicular diameter was determined using ultrasound. There was no significant difference in the amount of FSH or hMG used per patient, in the duration of therapy before hCG administration, or in the length of the luteal phase in any patient. There was a difference in the number of follicles greater than 1000 mm3 per cycle in those patients receiving FSH compared to the number in those receiving hMG [2.8 +/- 1.3 (+/- SEM) vs. 4.4 +/- 1.5 follicles; P = 0.026). The maximum follicular phase serum estradiol (18.3 vs. 34.8 ng/ml) and maximum luteal phase progesterone concentrations (1289 vs. 2808 pg/ml; P = 0.026) were also different between the FSH and hMG groups. Linear regression analysis revealed a significant correlation between the peripheral serum estradiol levels and the total follicular volume of follicles in the hMG-treated group which was not apparent in the FSH-treated group. These findings suggest that exogenous LH may not be required to induce folliculogenesis in anovulatory patients.     

Ovulation stimulation and induction.

Evaluation of gonadotropins, prolactin, and thyroid function in anovulatory women directs subsequent therapy. Treatment should be initiated with the agent that is the safest and least costly for the specific indication. Except in cases of FSH elevation, pregnancy rates should approximate those of normally ovulating women. Bromocriptine, the drug of choice for hyperprolactinemia, restores ovulation in greater than 90% of women treated. Clomiphene citrate remains the drug of choice for normoestrogenic anovulation. Although drug-resistant women may respond to extended regimens, failure to ovulate or to conceive within six ovulatory cycles with clomiphene is an indication for menotropin therapy. Menotropins and pulsatile GnRH should be considered first line therapy for women with hypogonadotropic anovulation. When using hMG or pulsatile GnRH in clomiphene-resistant patients, pretreatment with GnRH analogs may normalize their response and result in higher pregnancy rates. GnRH analogs prevent premature luteinization in hMG-induced in vitro fertilization and gamete intrafallopian transfer cycles, resulting in lower cancellation rates and improved oocyte quality. Superovulation with clomiphene citrate should be attempted in patients with unexplained infertility prior to using menotropin therapy.     

Urinary luteinizing hormone testing and prediction of ovulation in spontaneous, clomiphene citrate and human menopausal gonadotropin-stimulated cycles. A clinical evaluation

A urinary luteinizing hormone test was utilized to predict ovulation in 99 spontaneous, 122 clomiphene citrate, and 82 human menopausal gonadotropin stimulated cycles. Tests were performed in early morning and evening specimens and follicular development was monitored by daily ultrasonography. A positive detection rate of 98, 97, and 94%, respectively, was obtained. Evidence of luteinized unruptured follicles was seen more frequently in stimulated cycles, concurring with negative test results. In 2 spontaneous, 1 clomiphene citrate and 5 hMG induced cycles two distinct LH surges were detected concomitant with a pattern of follicular atresia and subsequent new follicular development. Most ovulations occurred between 16 and 28 h after LH detection, significantly earlier in spontaneous than in clomiphene citrate stimulated cycles (p less than 0.02), whereas pre-ovulatory follicles were larger in the clomiphene citrate group (p less than 0.001). The mean duration of the follicular and luteal phases, as calculated from the LH peak, was substantially shorter in the hMG cycles than in the other two groups (p less than 0.001).     

Ovarian electrocauterization causes LH-regulated but not insulin-regulated endocrine changes

OBJECTIVE We studied the effects of ovarian electrocauterization on the serum levels of luteinizing hormone (LH), testosterone, insulin, sex hormone-binding globulin (SHBG) and insulin-like growth factor binding globulin-1 (IGFBP-1) in women with polycystic ovarian disease (PCOD). DESIGN Prospective. PATIENTS Ten women with PCOD admitted to a University Infertility Clinic. MEASUREMENTS Fasting blood samples for determination of hormone levels were taken during the follicular phase before and one month after laparoscopic ovarian electrocauterization. RESULTS One month after electrocauterization the serum mean ± SE LH levels had decreased from 14 4 ± 1 9 to 10 9 ± 1 1 U/l (P<0 05), while the serum insulin levels showed no significant change (10 3 ± 2 0 and 8 1 ±1 3 μ/l). The levels of IGFBP-1 (33 9 ± 8 2 and 38 4 ± 13 7 μg/l) and SHBG (48 ± 10 4 and 43 ± 5 7 nmol/l) showed no significant changes. Testosterone decreased from 3 9 ± 2 6 to 2 9 ± 0 3 nmol/l (P<0 001) and androstenedione from 15 0 ± 1 2 to 12 0 ± 1 5 nmol/l (P= 0 05). After electrocautery seven out of ten PCOD patients ovulated either spontaneously (n= 3) or with clomiphene citrate (n= 4), and two of them conceived. CONCLUSIONS Ovarian electrocautery leads to resumption of ovulatory cycles in some but not all PCOD patients. This effect seems to be mediated by reduction of serum LH and androgen levels, while the insulin-driven pathway via SHBG and IGFBP-1 remains unaffected.     

Ovulation induction in normogonadotropic anovulation (PCOS)

Treatment of normogonadotropic anovulatory infertility (World Health Organization class 2, or WHO2) is by induction of ovulation using clomiphene citrate (CC), followed by follicle-stimulating hormone (FSH) in cases of treatment failure. Not all patients will become ovulatory or will conceive with this treatment. Others, exhibiting multifollicular instead of monofollicular development, may encounter complications such as ovarian hyperstimulation and multiple pregnancy. Recently introduced alternative treatment interventions-such as insulin-sensitizing drugs, aromatase inhibitors, or laparoscopic electrocautery of the ovaries-may offer the possibility of improving the efficacy of the classical ovulation induction algorithm. Based on initial patient characteristics, it may be possible to identify specific patient subgroups with altered chances of success or complications while using one of these interventions. Regarding CC and FSH ovulation induction, this has been performed using multivariate prediction models. This approach may enable us to improve safety, cost-effectiveness, and patient convenience in future ovulation induction.     

TREATMENT OF POLYCYSTIC OVARIAN DISEASE BY INDUCING OVULATION WITH PULSATILE SUBCUTANEOUS ADMINISTRATION OF HUMAN MENOPAUSAL GONADOTROPHIN ASSOCIATED WITH LUTEINIZING HORMONE-RELEASING HORMONE ANALOGUE

Treatment with a combination of luteinizing hormone-releasing analogue (GnRHa, Buserelin) and pulsatile administration of hMG (Group I) were used to induce ovulation in nine patients with polycystic ovary syndrome (PCO). The same patients were also treated with pulsatile hMG administration alone (Group II). Ovulation was observed in all twelve treatment cycles in Group I, and there were two pregnancies. In Group II, ovulation occurred in 22 of 26 treatment cycles. Ovarian hyperstimulation occurred in one cycle of Group I and in 5 of 26 cycles of Group II. The total dose per cycle of hMG to induce ovulation in Group I was significantly lower than that needed when only pulsatile hMG administration was used. In response to Buserelin administration, the concentrations of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) increased transiently and then declined to the normal range observed in the early follicular phase. The concentrations of FSH increased in response to hMG administration, resulting in a normal LH/FSH ratio. The present data demonstrated that pulsatile subcutaneous administration of hMG in addition to Buserelin was effective in inducing follicular maturation and ovulation in patients with PCO with a lower incidence of serious side-effects.     

Scanning electron microscopy of postovulatory human endometrium in spontaneous cycles and cycles stimulated by hormone treatment

The ultrastructure of the luminal surface epithelium was compared in endometrial samples taken from 23 normally cycling women and from 22 patients submitted to ovarian stimulation with clomiphene citrate (100 mg/day for 5 days), human menopausal gonadotrophin (hMG) and human chorionic gonadotrophin (hCG). On day 2 after ovulation, only four out of nine specimens taken from the women in the hormone-treated group were identical to those of normally cycling women. On day 6 after ovulation, only two out of the 13 biopsy specimens from the treated group were the same as those from normally cycling women at that stage. Apical protrusions (pinopodes), typical for this period of the cycle, were missing in 11 of the 13 endometrial samples from the treated group. These observations suggest that the hormonal treatment applied to induce ovulation (clomiphene citrate, hMG and hCG) can modify the normal development of the prenidatory endometrium, and may thus have a negative effect on the rate of egg implantation.     

A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol

Extending the FSH window for multifollicular development by administering FSH from the midfollicular phase onward constitutes a novel mild protocol for ovarian stimulation for in vitro fertilization (IVF) based on the physiology of single dominant follicle selection in normo-ovulatory women. We compared outcomes from this protocol with two other stimulation protocols. One hundred and forty-two normo-ovulatory patients with an indication for IVF (or IVF/ICSI) were randomized to a GnRH agonist long protocol (group A; n = 45) or one of two GnRH antagonist protocols commencing recombinant FSH on cycle d 2 (group B; n = 48) or cycle d 5 (group C; n = 49). A fixed dose (150 IU/d) of rFSH was used for ovarian stimulation, and GnRH antagonist cotreatment was initiated on the day when the leading follicle reached 14 mm diameter. Group C showed a shorter duration of stimulation (median duration, 11, 9, and 8 d for groups A, B, and C, respectively; P < 0.001), reflected in a significantly lower total dose of rFSH used (median amount of rFSH, 1650, 1350, and 1200 IU for groups A, B, and C, respectively; P < 0.001). In group C more cycles were cancelled during the stimulation phase due to insufficient response, resulting in a lower percentage of oocyte retrievals (84%, 73%, and 63% for groups A, B, and C; P = 0.02). However, women in group C obtained better quality embryos (percentage of embryo score of 1 for best embryo, 29%, 37%, and 61% for groups A, B, and C, respectively; P = 0.008), resulting in more transfers per oocyte retrieval (68%, 71%, and 90% for groups A, B, and C, respectively; P = 0.04). After profound ovarian stimulation (groups A and B) only 7% of the patients who retrieved four oocytes or less conceived, whereas after mild stimulation (group C) 67% of these patients conceived (P < 0.01). Overall, no differences were found among the three groups comparing pregnancy rate per started IVF cycle. In conclusion, application of the described mild ovarian stimulation protocol resulted in pregnancy rates per started IVF cycle similar to those observed after profound stimulation with GnRH agonist cotreatment despite shorter stimulation and a 27% reduction in exogenous FSH. A higher cancellation rate before oocyte retrieval was compensated by improved embryo quality concomitant with a higher chance of undergoing embryo transfer. A relatively low number of oocytes retrieved after mild ovarian stimulation distinctly differs from the pathological reduction in the number of oocytes retrieved after profound ovarian stimulation (poor response) associated with poor IVF outcome. The relatively small number of oocytes obtained after mild ovarian stimulation may represent the best of the cohort in a given cycle.     

A novel method for assessing assisted female fertility: bioelectric impedance

Early detection of declining female fertility is important for effective prevention and treatment of infertility. Age, serum concentration of FSH in the early follicular phase (basal FSH), and the clomiphene citrate (CC) challenge test correlate only with large declines in fertility. We serendipitously discovered that by a novel mechanism bioelectric impedance (BEI) sensitively reflects early fertility decrements. BEI was measured between the right and left arms by the tetrapolar method before and during ovarian stimulation for in vitro fertilization (IVF). In a stepwise multiple logistic regression analysis of five factors (BEI on luteal day 4 prior to the IVF cycle [BEI-L4], age, basal FSH, body height, and body mass index), BEI-L4 alone was a significant predictor (P<0.05) of achievement of pregnancy by IVF in 148 women (74 pregnant and 74 nonpregnant). BEI showed a nadir on the day of administration of hCG in the pregnant but not the nonpregnant group. Serum concentrations of VEGF during ovarian stimulation were significantly higher in the pregnant group, but not those of 17beta-estradiol and progesterone. The CC challenge test revealed no significant difference between 11 pregnant and 15 nonpregnant women. The clinical usefulness of BEI was evaluated in 272 consecutive IVF cycles. Rate of pregnancy was significantly higher (P<0.01) in IVF cycles with BEI-L4 > or =600 Ohms than <600 Ohms (44% and 26% in 149 and 123 cycles, respectively). When BEI-L4 was > or =600 Ohms, pregnancy rates were constantly high irrespective of age and basal FSH. In prediction of nonpregnancy, sensitivity of BEI-L4 (0.52) was significantly (P<0.05) higher than those of age and basal FSH (0.39 and 0.046, respectively). BEI, which is easy, noninvasive, and inexpensive, predicts female fertility more sensitively than age and basal FSH, probably reflecting angiogenic capacity of reproductive organs.     

Correlation of human follicular fluid inhibin activity with spontaneous and induced follicle maturation

We sought to correlate the inhibin activity of individual ovarian follicles (greater than 16 mm in diameter) from untreated (7 patients; 7 follicles), clomiphene-stimulated (150 mg/day; menstrual cycle days 5-9; 9 patients, 14 follicles), and human menopausal gonadotropin (hMG)-stimulated (150 IU/day; menstrual cycle days 3-11; 8 patients; 23 follicles) ovarian cycles and to correlate these results with the follicular fluid (FF) steroid concentration. Follicular aspirates were obtained via laparoscopy from 24 regularly menstruating patients when the diameter of the largest follicle reached 20 mm, as determined by serial ultrasonography. FF concentrations of estradiol, progesterone, testosterone, 17-hydroxyprogesterone, and androstenedione were determined by RIA. Inhibin activity was determined using the inhibition of basal 24-h FSH secretion by dispersed rat anterior pituitary cells. Inhibin values were highest among the follicles aspirated from those patients who received hMG [277 +/- 31 (+/- SE) U/ml] compared to untreated subjects (51 +/- 13 U/ml) or those who received clomiphene (96 +/- 14 U/ml). Estradiol was highest in FF from untreated patients (2295 +/- 1155 ng/ml) compared to levels in patients who received hMG (368 +/- 1.76 micrograms/ml) or clomiphene (1049 +/- 174 ng/ml). FF progesterone values were highest in untreated patients (9.4 +/- 2.59 micrograms/ml) compared to those in hMG-treated (5.04 +/- 1.76 micrograms/ml) and clomiphene-treated patients (7.82 +/- 1.24 ng/ml). FF 17-hydroxyprogesterone values (7.82 +/- 1.24 ng/ml). FF 17-hydroxyprogesterone values were similarly higher in the untreated (1.55 +/- 0.21 micrograms/ml) and clomiphene-treated (2.54 +/- 0.27 micrograms/ml) patients than in the hMG-treated group (0.73 +/- 0.09 micrograms/ml). FF androstenedione (untreated, 50.7 +/- 30 ng/ml; clomiphene-treated, 73.4 +/- 23.4 ng/ml; hMG-treated, 60.2 +/- 19.8 ng/ml) and testosterone (6.66 +/- 2.45, 5.98 +/- 1.46, and 6.39 +/- 2.16 ng/ml, respectively) concentrations in all three patient groups were similar. In untreated patients, there was a highly significant positive correlation between intrafollicular inhibin activity and FF estradiol, testosterone, and androstenedione concentrations and a statistically significant negative correlation between intrafollicular inhibin activity and FF progesterone concentrations. Patients receiving clomiphene therapy demonstrated at least two different response patterns, one with a positive and one a negative correlation between intrafollicular inhibin activity and FF steroid concentrations. The patients receiving hMG therapy had no statistically significant correlation between intrafollicular inhibin     

氯菧酚胺疗效及失败的内分泌因素

应用氯蔗酚胺(CC)治疗33例无排卵性不孕的83个周期中,32例64个周期出现排卵反应,妊娠12例(37.5％)。采用BBT、宫颈评分、生殖激素和B超等项监测指标,发现64个有排卵反应周期中,确实排卵的仅37个周期(51.8％),发生LUF的27个周期(42.2％)。重复治疗周期中LUF重演率达83.3％。未发现CC在宫颈部位的抗雌激素效应及黄体不健,LUF是妊娠失败的主要原因。通过各项参数和生殖激素测定,分析了CC成功诱发排卵的关键及发生LUF的机理。     

Ovulation induction with human menopausal gonadotropin compared to human urinary follicle-stimulating hormone results in a significant shift in follicular fluid androgen levels without discernible differences in granulosa-luteal cell function

Follicular fluid estradiol, progesterone, testosterone, and androstenedione levels were compared in 2 groups of spontaneously ovulatory women undergoing ovulation induction with human menopausal gonadotropin (hMG; which contains equal amounts of LH and FSH) or human urinary FSH (huFSH). The results were correlated with the ratios of embryo cleavage and pregnancy. Although significantly more FSH [1268 +/- 38 (+/- SEM) vs. 953 +/- 38 IU; P less than 0.05] was required for equivalent hyperstimulation in hMG compared to huFSH cycles, the number of oocytes retrieved and fertilized and the number of embryos transferred were similar for the 2 ovulation induction protocols. Forty-two follicles from 21 women stimulated with hMG and 38 follicles from 15 women stimulated with huFSH were examined and found to be representative of the total cohort of aspirated follicles. Follicular fluid estradiol and progesterone levels were similar, but hMG-stimulated follicles contained significantly more testosterone [7.83 +/- 0.52 (+/- SEM) vs. 6.30 +/- 0.42 ng/ml; P less than 0.03] and less androstenedione (24.4 +/- 3.6 vs. 37.8 +/- 5.0 ng/ml; P less than 0.03) than did huFSH-stimulated follicles. Embryonic cleavage rates were similar for all fertilized oocytes from both hMG- and huFSH-stimulated cycles, although pregnancy rates were significantly higher in huFSH cycles (40% vs. 9.5%; P less than 0.05). In addition, aromatase activity, progesterone production, and [125I]hCG-binding activity were compared in granulosa-luteal cells isolated from some of these women. Cells from 21 follicles from 9 women stimulated with hMG and 24 follicles from 9 women stimulated with huFSH were studied. There were no significant differences in aromatase activity, progesterone production, or [125I]hCG binding. Thus, the presence or absence of exogenous LH during ovulation induction with FSH has little direct effect on granulosaluteal cell function. However, the presence of LH during ovulation induction with FSH does appear to alter thecal androgen metabolism, resulting in higher testosterone and lower androstenedione levels in follicular fluid. Such a shift in androgen milieu may impair oocyte development and successful implantation.     

GONADOTROPHIN RELEASE IN OVARIECTOMIZED PATIENTS

Administration of clomiphene citrate (150 mg/day) for 5 days to twenty-four ovariectomized patients and seven normal female patients evoked a significant release of FSH and LH in the normal control group and suppressed the gonadotrophin secretion in the castrated patients. A similar suppressive effect on gonadotrophin secretion was noted in eight ovariectomized patients treated for 10 days with low doses (50 μg/day) of ethinyl oestradiol. It is suggested that in the ovariectomized hypoestrogenic patients, clomiphene acted as an oestrogen, suppressing by a negative feedback action gonadotrophin release in a way similar to ethinyl oestradiol. In the normal control group with an adequate steroid environment, clomiphene acted (probably at the hypothalamic level) as an oestrogen antagonist and stimulated gonadotrophin secretion. In view of our findings, it seems as if the ability of anovulatory patients to respond to clomiphene treatment by increased gonadotrophin secretion depends upon the absolute concentration of the compound in the different organs and by the quantitative relation of clomiphene to the endogenous oestrogens. There is still a considerable degree of uncertainty about the exact mode of action of clomiphene (1-[p-β-diethyl-aminoethoxyphenyl]-1,2, dipheny1-2 chloroethylene citrate) a non-steroidal oestrogen antagonist. However, it appears increasingly evident that this compound which possesses antioestrogenic properties acts probably in an indirect manner, by competing with oestradiol for the receptor sites at the hypothalamic centres regulating gonadotrophin secretion, thus stimulating gonadotrophin releasing hormone (LHRH) secretion, with a subsequent release of FSH and LH (Igarashi et al., 1967; Seki et al., 1970). By contrast, in prepubertal children, a paradoxical suppression of both LH and FSH release was demonstrated following administration of clomiphene (Kelch et al., 1971). The explanation offered for this phenomenon was that the immature hypothalamic gonadostat is hypersensitive to sex steroids, and as clomiphene has intrinsic oestrogenic properties, it could account for the unexpected gonadotrophin suppression rather than stimulation in the prepubertal child. A similar effect could be obtained in prepubertal children by administration of low doses of oestrogens (Kelch et al., 1971). In order to gain additional information on the mode of action of clomiphene at the hypothalamic and pituitary levels, we studied the effect of clomiphene and of low doses of oestrogens on LH and FSH release in ovariectomized patients. These patients provide a suitable model for the investigation of the mode of action of clomiphene on a normal hypothalamic-pituitary system in an environment free of gonadal steroid (Tepperman, 1973).     

Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.

The present prospective follow-up study was designed to identify whether clinical, endocrine, or ultrasound characteristics assessed by standardized initial screening of normogonadotropic oligo/amenorrheic infertile patients could predict conception in 160 women who reached ovulation after clomiphene citrate (CC) medication. Additional inclusion criteria were total motile sperm count of the partner above 1 million and a negative history for any tubal disease. Daily CC doses of 50 mg (increasing up to 150 mg in case of absent ovarian response) from cycle days 3-7 were used. First conception (defined as a positive urinary pregnancy test) was the end point for this study. A cumulative conception rate of 73% was reached within 9 CC-induced ovulatory cycles. Patients who did conceive presented more frequently with lower age (P < 0.0001) and amenorrhea (P < 0.05) upon initial screening. In a univariate analysis, patients with elevated initial serum LH concentrations (>7.0 IU/L) had a higher probability of conceiving (P < 0.01). In a multivariate analysis, age and cycle history (oligomenorrhea vs. amenorrhea) were identified as the only significant parameters for prediction of conception. These observations suggest that there is more to be gained from CC ovulation induction in younger women presenting with profound oligomenorrhea or amenorrhea. Screening characteristics involved in the prediction of ovulation after CC medication in normogonadotropic oligo/amenorrheic patients (body weight and hyperandrogenemia, as shown previously) are distinctly different from predictors of conception in ovulatory CC patients (age and the severity of cycle abnormality). This disparity suggests that the FSH threshold (magnitude of FSH required for stimulation of ongoing follicle growth and ovulation) and oocyte quality (chances for conception in ovulatory cycles) may be differentially regulated.     

Bromocriptine induced pregnancy in two cases of euprolactinemic hypothalamic amenorrhea.

Two euprolactinemic women with hypothalamic amenorrhea, previously unsuccessfully submitted to clomiphene citrate therapy, were treated with bromocriptine. PRL secretion was studied in basal conditions and under dynamic tests: TRH and chlorpromazine. Serum FSH, LH and 17-beta-estradiol were determined before and during the treatment. Both patients conceived, and one delivered a healthy baby at term. Bromocriptine appears to be an effective drug for treating women with hypothalamic amenorrhea, particularly those unresponsive to clomiphene.     

Conventional dose intravenous pulsatile GnRH therapy does not induce ovulation in polycystic ovarian disease

The value of pulsatile GnRH therapy for induction of ovulation in patients with polycystic ovarian disease remains unclear. Intravenous pulsatile GnRH therapy was administered to a defined group of 5 patients with polycystic ovarian disease; all were infertile, had an LH:FSH ratio of greater than 2:1 on two or more occasions, and had multiple cysts on ovarian ultrasonography. All had failed to respond to clomiphene citrate. The 5 patients received increasing doses of GnRH (5-40 micrograms/pulse) continuously for up to 6 weeks. The response was evaluated by serial hormone levels and ovarian ultrasonography. During nine treatment periods no patient ovulated, and in only one did the LH:FSH ratio revert to normal. Four patients have subsequently had wedge resection of the ovaries and in each case the diagnosis of polycystic ovarian disease was confirmed. Pulsatile GnRH therapy was of no value in the management of this group of infertile patients with strictly defined polycystic ovarian disease.     

Fertility in women with late-onset adrenal hyperplasia due to 21-hydroxylase deficiency.

Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency. The majority of patients (n = 33) were seen for isolated postpubertal hirsutism, 9 patients consulted for sterility, and 11 for irregular menstrual cycles. At the time of diagnosis, the ages of patients ranged from 15-40 yr (mean +/- SD, 24.6 +/- 5.2). No patient had major signs of virilization. The plasma 17-hydroxyprogesterone level was higher than normal in all patients (26.8 +/- 18.9 nmol/L; range, 3.4-139.4) and dramatically increased to 140.1 +/- 80.6 nmol/L (range, 35.2-324.2) after ACTH treatment. Plasma androgen levels were high (testosterone, 3.25 +/- 2.03 nmol/L; delta 4-androstenedione, 13.65 +/- 5.60 nmol/L). Plasma basal and LHRH-stimulated values were normal for FSH and high for LH. Basal and TRH-stimulated plasma PRL levels were normal. Among these 53 LAH patients, only 20 desired a pregnancy. These had a total of 38 pregnancies. Ten patients became pregnant before the diagnosis of LAH and without any treatment; they had a total of 18 pregnancies, 12 of which were successful. Moreover, 19 normal pregnancies without any spontaneous abortion were carried to term by 14 of 16 hydrocortisone-treated patients. One patient needed the association of one cure of clomiphene citrate. Hypofertility in LAH patients seems, therefore, to be relative. Its mechanism is hormonal, with anovulation or dysovulation, due to the continuous steroid feedback of adrenal origin on the hypothalamo-pituitary axis. Hydrocortisone is the appropriate treatment in most cases, reducing adrenal androgen overproduction and relieving hypothalamic-pituitary gonadotropin function, thereby making possible cyclic ovarian activity and ovulations.     

Direct enhancement of gonadotropin-stimulated ovarian estrogen biosynthesis by estrogen and clomiphene citrate

The biosynthesis of ovarian aromatases and hence estrogen production are under the control of the gonadotropins, FSH and LH. Using a primary culture of rat granulosa cells, we now report that estrogens (diethylstilbestrol and 17 beta-estradiol) augment the stimulation of aromatase activity by FSH and LH. Moreover, clomiphene citrate, a drug widely used to induce ovulation in anovulatory women, also enhances gonadotropin-stimulated aromatase activity. These in vitro findings suggest that estrogens within the microenvironment of the ovarian follicles may exert a local autoregulatory effect on their own production via an ultra-short loop, positive feedback mechanism. In addition, the clinical efficacy of clomiphene citrate may derive partially from its direct augmentation of the gonadotropin-stimulated estrogen production at the ovarian level.