Cumulative ovulation rate in human menopausal/human chorionic gonadotropin-treated monkeys: "step-up" versus "step-down" dose regimens

Cumulative ovulation rates in monkeys given human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG) on menstrual cycle days 3 to 9 in a "step-up" versus "step-down" protocol were compared with those achieved by hMG only. Using direct ovarian observation to detect sites of follicular rupture, retrograde tubal irrigation to collect eggs or embryos, and serum estradiol and progesterone levels to infer changes in ovarian status, we counted the number of ovulations at intervals of 24, 48, 72, 96, and 120 hours after hCG or comparable intervals without hCG. The data indicate (1) whereas most ovulations occurred on or before day 3 after hCG treatment, when the "step-up" dose regimen was employed additional follicles had ruptured on days 4 and 5; (2) a "step-down" protocol for hMG therapy may better synchronize follicular rupture and reduce susceptibility to delayed ovulations compared with a "step-up" dose regimen; and (3) under hMG stimulation, few follicles would rupture spontaneously (without hCG or luteinizing hormone treatment).     

Effects of sulpiride-induced hyperprolactinemia on human ovarian follicles during the late follicular phase

The effect of hyperprolactinemia during the midfollicular through the late follicular phase of the menstrual cycle on follicular development and follicular fluid hormone concentrations was studied. Fourteen women underwent laparotomy in the late follicular phase for gynecologic reasons; 6 were treated with sulpiride daily from the midfollicular to the late follicular phase (sulpiride group) and 8 received no treatment (control group). Daily administration of sulpiride (150 mg orally) significantly elevated serum prolactin (PRL) levels in all six women. In the small follicles (less than or equal to 8 mm in diameter), follicular fluid 17 beta-estradiol (E2) concentration was significantly lower (P less than 0.01), and testosterone (T) concentration was higher (P less than 0.05) in the sulpiride group. In the large follicles (greater than or equal to 9 mm in diameter), however, follicular fluid E2 and T concentrations showed no significant differences between the sulpiride and control groups. In the sulpiride group, the mean diameters of the follicles were significantly smaller than in the control group (P less than 0.01). These observations suggest that PRL exerts a suppressive effect on the smaller but not the larger follicles during the late follicular phase.     

The use of the GnRH analogue buserelin for IVF--does it improve fertility?

OBJECTIVE--To determine the effect of a short course of the GnRH analogue buserelin and human menopausal gonadotrophin (hMG), for ovarian stimulation in our IVF programme, on reproductive endocrinology and pregnancy rates compared with conventional clomiphene citrate and hMG treatment. DESIGN--Prospective randomized allocation to one of two ovulation stimulation regimens. SETTING--Fertility clinic. SUBJECTS--373 infertile couples with various factors associated with their subfertility. All the women were less than 46 years of age and had normal menstrual cycles. INTERVENTION--The first group (n = 151) was given clomiphene citrate (CC) from days 2-6 of the menstrual cycle and hMG from day 5 onwards (CC/hMG). The second group (n = 222) was given buserelin from days 1-3 and hMG from day 2 (buserelin/hMG). MAIN OUTCOME MEASURES--Concentration of plasma luteinizing hormone (LH), oestradiol (E2) and progesterone, number of ovulatory follicles induced and the occurrence of pregnancy. RESULTS--Plasma LH, E2 and progesterone concentrations were reduced in the late follicular phase after buserelin/hMG compared with CC/hMG. Buserelin/hMG promoted the development of more follicles than CC/hMG. The overall pregnancy rate after buserelin/hMG was not significantly different from that following CC/hMG treatment. CONCLUSION--The chance of pregnancy is not improved by the short-term use of buserelin with hMG, provided adequate follicular phase management is maintained.     

On the effect of an oocyte factor on the formation of cumulus oophorus in human antral follicles

The possible existence of a granulosa cell growth factor (GGF) in the oocyte was investigated by using the mitotic index (%) of granulosa cells (GC) in human antral follicles. 50 follicles (0.4-13 mm in diameter) in 35 ovaries obtained from 35 women were used for the experiments. In each follicle, GC were divided into two groups, cumulus and mural GC, according to the distance from the oocyte. The following results were obtained: The Mitotic Index (MI) of cumulus GC was 8.2 +/- 0.5 (M +/- SE) and was two fold higher than that of mural GC, 4.7 +/- 0.4 (p less than 0.001). As follicles developed, MI of mural GC increased until their diameter reached 3mm but beyond 3mm, MI decreased. On the other hand, there was little relationship between MI of cumulus GC and the follicular size, and MI was constantly high in value. MI of both cumulus and mural GC was higher in the late follicular phase than in other phases of the cycle. These results suggest that the proliferation of GC in growing follicle might be regulated by some unknown substance (GGF) secreted from the oocyte as well as the endocrinological environment. It is also suggested that the presence of the oocyte plays a crucial role in the cumulus oophorus formation in the antral follicles.     

CA-125 levels in human uterine fluid.

OBJECTIVE: To measure uterine fluid CA-125 concentration and to determine if any menstrual cycle phase dependent changes exist in its level. Serum levels are measured for comparison. DESIGN: CA-125 levels in uterine fluid were measured during the follicular and luteal phases of the menstrual cycle. In a sequential study, paired uterine fluid and serum samples were obtained once in both midfollicular and midluteal phases of the same menstrual cycle. RESULTS: CA-125 in uterine fluid during the follicular phase (n = 14) ranged from 16.4 x 10(3) to 616.5 x 10(3) U/mL, and from 6.2 x 10(3) to 567.3 x 10(3) U/mL in the luteal phase (n = 11). In the paired sequential uterine fluid and serum samples, (1) the means (+/- SEM) CA-125 in uterine fluid were 81.5 x 10(3) +/- 37.9 x 10(3) U/mL and 91.4 x 10(3) +/- 56.8 x 10(3) U/mL in the midfollicular and midluteal phases, respectively (P = 0.75); (2) the CA-125 levels in serum increased in the midluteal phase (P less than 0.05); and (3) compared with serum, uterine fluid levels were greater with a wider range. CONCLUSIONS: When compared with serum CA-125, uterine fluid contains high concentrations varying over a wide range without fluctuation between the follicular and luteal phases of the menstrual cycle.     

Atypical response to luteinizing hormone-releasing hormone (LH-RH) agonist (Suprefact nasal) in induction of ovulation in in vitro fertilization (IVF)

Animal and human research has indicated the presence of receptors to luteinizing hormone-releasing hormone (LH-RH) in the ovaries. However, the role of these receptors is not yet clear. Forty-five patients were treated with Suprefact (d-Serg-Des-Gly10-GnRGH), starting in the midluteal phase of a nonstimulatory menstrual cycle. The Suprefact (300 g t.i.d.) was administered as a nasal spray until the administration of human chorionic gonadotropin (hCG). On the third to fifth day of the following menstrual cycle, the patients were treated with a high dose of human menopausal gonadotropin (hMG). hCG was administered when at least two follicles reached a mean diameter of 18 mm. Five of these patients who ovulated spontaneously and had normal menstrual cycles did not respond to the stimulation with hMG. Treatment was stopped after 12 days of hMG administration. During the following cycle of the five patients, levels of gonadotropins were found to be in the normal range, and all of them responded as expected to hMG administered for 3 days only (hMG test). These findings suggest that LH-RH agonist may interfere with ovarian steroidogenesis.     

Interest of growth hormone-releasing hormone administration for improvement of ovarian responsiveness to gonadotropins in poor responder women.

OBJECTIVE: We have investigated the beneficial effect of a somatotroph axis stimulation on ovarian response to gonadotropin. DESIGN: Growth hormone-releasing hormone (GH-RH) was administered in a prospective study in women undergoing an in vitro fertilization protocol. PATIENTS: Twelve patients were selected for their poor ovarian response to previous stimulations using gonadotropin-releasing hormone analog (GnRH-a) and human menopausal gonadotropins (hMG). INTERVENTIONS: Five hundred micrograms of GH-RH1-29 were administered two times daily concomitantly with GnRH-a and hMG from day 2 of the cycle to the time of ovulation. MAIN OUTCOME MEASURES: Stimulation of somatotroph axis was appreciated by measuring over-night urinary growth hormone (GH) output, plasma GH, and insulin-like growth factor I (IGF-I) and follicular fluid (FF) IGF-I. The effects of GH-RH administration on ovarian function were determined by plasma estradiol levels and follicular data. RESULTS: Administration of GH-RH was associated with a significant improvement of urinary (P less than 0.025) and plasma (P less than 0.001) GH concentrations and of the hormonal response to hMG (P less than 0.01). Levels of IGF-I followed a biphasic plasma variation, and a slight increase in recruited follicles, retrieved oocytes, and FF IGF-I content was also observed. CONCLUSIONS: Activation of the somatotroph axis by GH-RH enhances the hormonal ovarian response to hMG and may be an adjunctive therapy to improve follicular maturation.     

Increased salivary chromogranin A in women with severe negative mood states in the premenstrual phase

The present study investigated whether salivary chromogranin A (CgA), a psychological stress marker associated with sympathetic nervous system activity, changes during the menstrual cycle in women with different degrees of premenstrual psychoemotional symptoms. Forty-five women (28.6?±?1.3 years) with regular menstrual cycles participated in this study. Salivary CgA and cortisol were measured during the follicular and late-luteal phases. The authors used the Profile of Mood State (POMS) to assess current mood states of subjects in each menstrual phase and divided the subjects into three groups depending on increase of total mood disturbance (TMD), a global measure of affective states of POMS from the follicular to the late-luteal phase: Low (4.1?±?0.7%), Middle (18.7?±?1.2%) and High (51.7?±?7.4%). Results showed no intramenstrual cycle differences in salivary CgA in the Low and Middle groups. Women in the High group, in contrast, had a significantly higher level of salivary CgA in the late-luteal phase compared to that of the follicular phase. Additionally, salivary CgA level significantly and positively correlated with TMD and four emotional subscales: tension-anxiety, depression-dejection, anger-hostility and confusion in the late-luteal phase. No intergroup or menstrual-cycle difference occurred in the salivary cortisol. This study indicates a significant late-luteal increase in salivary CgA, reflecting an increase of sympathetic nerve activity in women who experience a substantial increase (>30%) in a cluster of negative psychoemotional symptoms premenstrually. Furthermore, salivary CgA, as opposed to salivary cortisol, could serve as a reliable noninvasive biomarker to more sensitively evaluate neuropsychophysiological fluctuations during the menstrual cycle.     

A new model for ovarian follicular development during the human menstrual cycle

OBJECTIVE: To evaluate changes in ovarian follicle dynamics during the human menstrual cycle to test the hypothesis that folliculogenesis occurs in a wave-like fashion. DESIGN: Prospective longitudinal study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Fifty healthy women of reproductive age (range 19-43 years) with a history of regular menstrual cycles not taking medications known to interfere with reproductive function were evaluated. INTERVENTION(S): Transvaginal ultrasonography was performed daily for one interovulatory interval (IOI). MAIN OUTCOME MEASURE(S): Changes in the diameter and number of follicles > or =5 mm were evaluated. RESULT(S): Sixty-eight percent of women exhibited two waves of follicle development during the IOI and 32% exhibited three waves. Waves were characterized by an increase and subsequent decrease in the number of follicles > or =5 mm occurring in association with the growth of > or =2 follicles to > or =6 mm. A day effect and day by wave interaction were detected in the mean diameter of the largest three follicles and the number of follicles > or =5 mm. CONCLUSION(S): The follicular wave phenomenon in women provides a new model for ovarian function during the menstrual cycle and will improve our understanding of the ovarian response to fertility and hormonal contraceptive regimens.     

Localization and cellular distribution of pregnancy-associated plasma protein-a and major basic protein in human ovary and corpora lutea throughout the menstrual cycle

OBJECTIVE: To assess the expression and cellular distribution of pregnancy-associated plasma protein-A (PAPP-A) and major basic protein (MBP) in human ovarian tissue during the menstrual cycle. DESIGN: Ovarian tissues (n = 50) and corpora lutea (n = 18) were obtained from patients undergoing hysterectomy/oophorectomy for benign conditions and tissue sections were immunostained for MBP and PAPP-A. SETTING: University medical center. INTERVENTION(S): Immunostaining of tissue sections using antibodies to PAPP-A and MBP. MAIN OUTCOME MEASURE(S): Microscopic evaluation to assess the presence, distribution, and cellular co-localization of MBP and PAPP-A and to describe any variations in their expression during the menstrual cycle. RESULT(S): Major basic protein (MBP) is found in several ovarian cell types throughout the menstrual cycle. The MBP immunostaining of ovarian follicles varied depending on the size, with primordial follicles staining in the ooplasm with a lack of staining in the granulosa and theca cells. In the intermediate/mature follicles, MBP was immunolocalized in theca, but not in granulosa cells except in the mature follicles. Pregnancy-associated plasma protein-A (PAPP-A) was immunolocalized in primordial follicle ooplasm, theca externa of intermediate/mature follicles, and in granulosa cells with increased intensity as luteinization progressed. The luteal tissue is the major site of MBP and PAPP-A with highest intensity found during the midluteal phase associated with both small and large luteal cells. CONCLUSION(S): The expression and distinct pattern of MBP and PAPP-A cellular localization in human ovarian tissue during folliculogenesis and in luteal tissue suggest that their individual and combined actions in a cell specific fashion may play a role in growth and differentiation of theca, granulosa, and luteal cells.     

Gonadotropin binding sites in human ovarian follicles and corpora lutea during the menstrual cycle

Gonadotropin binding sites were localized by autoradiography after incubation of human ovarian sections with 125I-labeled gonadotropins. The binding sites for 125I-labeled human follicle-stimulating hormone (125I-hFSH) were identified in the granulosa cells and in the newly formed corpora lutea. The 125I-labeled human luteinizing hormone (125I-hLH) binding to the thecal cells increased during follicular maturation, and a dramatic increase was preferentially observed in the granulosa cells of the large preovulatory follicle. In the corpora lutea, the binding of 125I-hLH increased from the early luteal phase and decreased toward the late luteal phase. The changes in 3 beta-hydroxysteroid dehydrogenase activity in the corpora lutea corresponded to the 125I-hLH binding. Thus, the changes in gonadotropin binding sites in the follicles and corpora lutea during the menstrual cycle may help in some important way to regulate human ovarian function.     

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 patients's 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,x ² 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.     

Progress in understanding human ovarian folliculogenesis and its implications in assisted reproduction

Purpose

To highlight recent progress in understanding the pattern of follicular wave emergence of human menstrual cycle, providing a brief overview of the new options for human ovarian stimulation and oocyte retrieval by making full use of follicular physiological waves of the patients either with normal or abnormal ovarian reserve.

Methods

Literature review and editorial commentary.

Results

There has been increasing evidence to suggest that multiple (two or three) antral follicular waves are recruited during human menstrual cycle. The treatment regimens designed based on the theory of follicular waves, to promote increased success with assisted reproduction technology (ART) and fertility preservation have been reported. These new options for human ovarian stimulation and oocyte retrieval by making full use of follicular waves of the patients either with normal or abnormal ovarian reserve lead to new thinking about the standard protocols in ART and challenge the traditional theory that a single wave of antral follicles grows only during the follicular phase of the menstrual cycle.

Conclusions

The understanding of human ovarian folliculogenesis may have profound implications in ART and fertility preservation. Further studies are needed to evaluate the optimal regimens in ART based on the theory of follicular waves and to identify non-invasive markers for predicting the outcome and the potential utilities of follicles obtained from anovulatory follicular waves in ART.     

Effect of a gonadotropin-releasing hormone agonist and gonadotropins on ovarian follicles in cynomolgus monkey: a model for human ovarian hyperstimulation

STUDY OBJECTIVE: To examine the effect on large follicles (greater than or equal to 2 mm) of human menopausal gonadotropin (hMG) and buserelin acetate, a gonadotropin-releasing hormone agonist in monkeys. DESIGN: Experimental. SETTING: Reproductive research laboratory. ANIMALS: Fourteen cyclic cynomolgus monkeys receiving hMG alone for 8 days or buserelin acetate plus 8 (group 1), 12 (group 2), or 16 (group 3) days of hMG administration always starting from day 1 of the cycle. RESULTS: The different treatments were effective in over-riding the specific ovulatory quota of 1, and more large follicles developed in treatments involving long duration and higher doses of hMG. In buserelin acetate plus hMG treatments, the frequency of dissociated follicles and follicles in late atresia were, respectively, lower and higher than in hMG alone treatment. The numbers of recoverable mature oocytes (germinal vesicle breakdown) were similar to the numbers of such oocytes recovered after hyperstimulation performed for human in vitro fertilization and embryo transfer (IVF-ET). However, the number of mature oocytes enclosed in typically preovulatory follicles was very low because there were numerous dysmature follicles. CONCLUSION: These data suggest a deleterious effect of buserelin acetate plus hMG treatments on the recruitable follicles at the time when treatments start. The implications of these observations in the field of human IVF-ET are discussed.     

Increased salivary chromogranin A in women with severe negative mood states in the premenstrual phase

The present study investigated whether salivary chromogranin A (CgA), a psychological stress marker associated with sympathetic nervous system activity, changes during the menstrual cycle in women with different degrees of premenstrual psychoemotional symptoms. Forty-five women (28.6?±?1.3 years) with regular menstrual cycles participated in this study. Salivary CgA and cortisol were measured during the follicular and late-luteal phases. The authors used the Profile of Mood State (POMS) to assess current mood states of subjects in each menstrual phase and divided the subjects into three groups depending on increase of total mood disturbance (TMD), a global measure of affective states of POMS from the follicular to the late-luteal phase: Low (4.1?±?0.7%), Middle (18.7?±?1.2%) and High (51.7?±?7.4%). Results showed no intramenstrual cycle differences in salivary CgA in the Low and Middle groups. Women in the High group, in contrast, had a significantly higher level of salivary CgA in the late-luteal phase compared to that of the follicular phase. Additionally, salivary CgA level significantly and positively correlated with TMD and four emotional subscales: tension-anxiety, depression-dejection, anger-hostility and confusion in the late-luteal phase. No intergroup or menstrual-cycle difference occurred in the salivary cortisol. This study indicates a significant late-luteal increase in salivary CgA, reflecting an increase of sympathetic nerve activity in women who experience a substantial increase (>30%) in a cluster of negative psychoemotional symptoms premenstrually. Furthermore, salivary CgA, as opposed to salivary cortisol, could serve as a reliable noninvasive biomarker to more sensitively evaluate neuropsychophysiological fluctuations during the menstrual cycle.     

Luteinizing hormone receptors in human ovarian follicles and corpora lutea during the menstrual cycle

The binding of 125I-labeled human luteinizing hormone (hLH) to the 2000-g fraction of human ovarian follicles and corpora lutea during the entire menstrual cycle was examined. Specific high affinity, low capacity receptors for hLH were demonstrated in the 2000-g fraction of both follicles and corpora lutea. Specific binding of 125I-labeled hLH to follicular tissue increased from the early follicular phase to the ovulatory phase. Specific binding of 125I-labeled hLH to luteal tissue increased from the early luteal phase to the midluteal phase and decreased towards the late luteal phase. The results of the present study indicate that the increase and decrease in receptors for hLH during the menstrual cycle might play an important role in the regulation of the ovarian cycle.     

The long protocol of administration of gonadotropin-releasing hormone agonist is superior to the short protocol for ovarian stimulation for in vitro fertilization.

OBJECTIVE: To investigate whether pituitary desensitization with the gonadotropin-releasing hormone agonist (GnRH-a), buserelin acetate, before the administration of human menopausal gonadotropin (hMG) for ovarian stimulation in in vitro fertilization (IVF) is superior to the simultaneous administration of both hormones at the beginning of the treatment cycle. DESIGN: Prospective randomized study. PATIENTS: Ninety-one patients having their first attempt at IVF. INTERVENTIONS: Patients in group 1 (long protocol) were administered subcutaneous (SC) buserelin acetate 200 micrograms/d from day 1 of the menstrual cycle, and hMG was started only after pituitary desensitization had been achieved at least 14 days later. Patients in group 2 (short protocol) were administered SC buserelin acetate 200 micrograms/d from day 2 and the same dose of hMG used in the long protocol from day 3 of the menstrual cycle. RESULTS: The median total amount of hMG required in both groups was comparable. There were significantly more follicles (P = 0.0001), oocytes (P = 0.0008), fertilized oocytes (P = 0.0001), and cleaved embryos (P = 0.0001), and a higher fertilization rate (P = 0.0047) in patients in group 1. The pregnancy rates per initiated cycle and per embryo transfer were 19.57% and 25.71% in group 1 compared with 8.89% and 16.67% in group 2. CONCLUSIONS: The long protocol is superior in terms of significantly greater follicular recruitment, oocyte recovery and fertilization rates, and significantly greater number of embryos available for transfer. In general, it is the preferred method when GnRH-a are used for ovarian stimulation in IVF.     

Effect of growth hormone administration on human ovarian function and steroidogenic gene expression in granulosa-luteal cells.

OBJECTIVE: To study the effect of growth hormone (GH) in combination with an ultrashort-term gonadotropin-releasing hormone analogue/human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) regimen in ovarian hyperstimulation for in vitro fertilization (IVF). DESIGN: Prospective randomized placebo-controlled study. SETTING: University-based IVF program. PATIENTS: Fifty-four normally cycling women (27 control and 27 GH-treated) participated in this study. INTERVENTIONS: Human recombinant GH (24 IU)/placebo was given intramuscularly on alternate days starting on cycle day 4 until the day of last hMG injection. RESULTS: Serum estradiol (E2) and progesterone (P) concentrations were slightly lower in the GH group than in the placebo group on the day of hCG injection and 1 day thereafter (P < 0.01 to 0.001). Serum luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone (T), and sex hormone-binding globulin did not differ between the groups. The follicular fluid (FF) concentration of T was higher in the GH group than in the placebo group (15.9 +/- 6.0 nmol/L versus 10.2 +/- 4.9 nmol/L, P < 0.005), and no differences were observed in the FF concentrations of E2, P, and insulin-like growth factor I between the groups. In granulosa cells isolated from patients who received GH treatment, the levels of 3 beta-hydroxysteroid dehydrogenase and aromatase messenger ribonucleic acid were significantly higher than in the patients receiving placebo. The number of hMG ampules needed for follicular development and the number of follicles and oocytes recovered were similar in both groups. CONCLUSIONS: These results indicate that GH administration modifies ovarian steroidogenic response to gonadotropins in IVF patients, suggesting a role for GH in the regulation of human ovarian function.     

Attenuation of ovarian response by low-dose ketoconazole during superovulation in patients with polycystic ovary syndrome.

OBJECTIVE: To investigate the clinical efficacy of mild inhibition of ovarian steroidogenesis by very low-dose ketoconazole during induction of ovulation in patients with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, cross-controlled study in consecutive cycles. SETTING: Large tertiary care center. PATIENT(S): Eighteen patients with PCOS undergoing hMG superovulation with or without ketoconazole. INTERVENTION(S): A fixed hMG dosage was initiated on cycle days 5-9 in both of the study cycles. Further hMG adjustment was done according to serum E2 levels and follicular measurements. Ketoconazole was administered in one of the cycles by two protocols. MAIN OUTCOME MEASURE(S): Serum E2 and P levels, lead follicles, pregnancy rate, and development of ovarian hyperstimulation syndrome. RESULT(S): Although higher daily hMG doses were needed in cycles with ketoconazole compared with cycles without the drug, the peak E2 levels were substantially lower in the ketoconazole cycles. Although the number of lead follicles did not differ between treatments, the addition of ketoconazole significantly reduced the number of hyperstimulated cycles. Consequently, the cancellation rate dropped dramatically, thus yielding a higher pregnancy rate per patient in the ketoconazole protocols. CONCLUSION(S): Use of a very low dose of ketoconazole during ovulation induction effectively attenuates ovarian steroidogenesis in patients with PCOS. This effect may serve as an adjunct to better control the ovarian response in women who are prone to hyperstimulated cycles.     

Human urinary follicle-stimulating hormone and human menopausal gonadotropin in induction of multiple follicle growth and ovulation

Five normally menstruating women were treated, in an attempt to induce development of multiple follicles, with pharmacologic doses of purified human urinary follicle-stimulating hormone (hU-FSH) and (in another instance) with human menopausal gonadotropin (hMG) administered on the second and third days after the onset of menses. All of the cycles were ovulatory: the follicular phase was short and the luteal phase length was normal in both hMG and hU-FSH treatment. No substantial differences were seen between the two types of treatment in regard to plasma values of FSH, luteinizing hormone (LH), estradiol (E2), testosterone, and progesterone (P). FSH, E2, and P increased to supraphysiologic levels, and LH fluctuated within the normal range. On ultrasound examination, a large number of growing and matured follicles were visualized during both treatments: at human chorionic gonadotropin administration, multiple preovulatory follicles (greater than or equal to 15 mm) and only a few small follicles (less than 10 mm) were imaged, without any difference between the two types of treatment. Multiple corpora lutea were often obtained. These data underline that pharmacologic doses of FSH alone are able to induce the growth of multiple preovulatory follicles when the initiation of stimulation is timed early. Besides this, exogenous LH does not seem to interfere with follicular recruitment, and it is not required for follicular maturation and ovarian steroidogenesis when endogenous normal LH mean values are present.