Short-term changes in hormonal profiles after laparoscopic ovarian laser evaporation compared with diagnostic laparoscopy for PCOS.

STUDY QUESTION: Which reproductive endocrine changes are attributed exclusively to laparoscopic ovarian drilling in polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Laser evaporation-specific endocrine effects were the prevention of an immediate increase in inhibin B and a sustained decrease in testosterone, androstenedione and anti-Müllarian hormone (AMH). WHAT IS KNOWN ALREADY: All ovarian drilling procedures result in reproductive endocrine changes. It is not known which of these changes are the result of ovarian drilling and which are related to the surgery per se. STUDY DESIGN, SIZE, DURATION: This prospective controlled study was performed at an outpatient academic fertility clinic. Between 2007 and 2010, a total of 21 oligo- or amenorrheic PCOS patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were oligo- or amenorrheic PCOS patients with all three of the Rotterdam criteria and luteinizing hormone (LH) >6.5 U/l. All PCOS patients had an indication for diagnostic surgery due to subfertility. There were 12 PCOS patients who chose to undergo ovarian laser evaporation (CO2 laser, 25 W, 20 times/ovary) and 9 PCOS who chose a diagnostic laparoscopy only (controls). Reproductive endocrinology was measured before, and until 5 days after, surgery, and four gonadotrophin-releasing hormone (GnRH) 'double pulse' tests were included. The main outcome measures were changes in reproductive endocrinology and pituitary sensitivity/priming to GnRH after laser evaporation compared with diagnostic laparoscopy only. MAIN RESULTS AND THE ROLE OF CHANCE: In the first hours after surgery, both groups showed an increase in LH, follicle stimulating hormone, estrogen and a decrease in testosterone, androstenedione, AMH and insulin growth factor-1 (P < 0.05). Inhibin B increased in the laparoscopy only group (P < 0.05). In the first days after surgery, testosterone, androstenedione and AMH remained at lower than baseline levels exclusively in the laser group (P < 0.05). Pituitary sensitivity/priming to GnRH was not altered after either laser evaporation or laparoscopy only. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study are the short follow-up period and the relatively small groups. WIDER IMPLICATIONS OF THE FINDINGS: The strength of this study is the integrally measured endocrine profiles in combination with an optimal control group of PCOS patients undergoing diagnostic laparoscopy only. Interestingly, most of the immediate endocrine changes after laser evaporation could be related to the surgical context and not to the ovarian drilling procedure itself. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Foundation of Scientific Research in Obstetrics and Gynaecology and the study medication, Lutrelef, was donated by Ferring, The Netherlands, Hoofdorphe There were no conflicts of interests mentioned by the authors.

Influence of ovarian manipulation on reproductive endocrinology in polycystic ovarian syndrome and regularly cycling women.

OBJECTIVE: Little is known about the function of the ovarian neuronal network in humans. In many species, copulation influences endocrinology through this network. As a first step, the possible influence of ovarian mechanical manipulation on pituitary and ovarian hormones was evaluated in polycystic ovarian syndrome (PCOS) and regularly cycling women. DESIGN: Prospective case-control study (2008-2010). METHODS: Ten PCOS women (Rotterdam criteria) undergoing ovulation induction with recombinant-FSH and ten normal ovulatory controls were included in an academic fertility clinic. In the late follicular phase blood was drawn every 10 min for 6 h. After 3 h the ovaries were mechanically manipulated by moving a transvaginal ultrasound probe firmly over each ovary ten times. Main outcome measures were LH and FSH pulsatility and ovarian hormones before and after ovarian manipulation. RESULTS: All PCOS patients showed an LH decline after the ovarian manipulation (before 13.0 U/l and after 10.4 U/l, P<0.01), probably based on a combination of a longer LH pulse interval and smaller amplitude (P=0.07). The controls showed no LH change (before 9.6 U/l and after 9.3 U/l, P=0.67). None of the ovarian hormones (estradiol, progesterone, anti-Müllerian hormone, inhibin B, androstenedione and testosterone) changed in either group. CONCLUSIONS: Ovarian mechanical manipulation lowers LH secretion immediately and typically only in preovulatory PCOS patients. The immediate LH change after the ovarian manipulation without any accompanying ovarian hormonal changes point to nonhormonal communication from the ovaries to the pituitary. A neuronal pathway from the ovaries communicating to the hypothalamic-pituitary system is the most reasonable explanation.

Insulin-induced capillary recruitment is impaired in both lean and obese women with PCOS.

BACKGROUND: Insulin resistance, i.e. impaired insulin-mediated glucose uptake (IMGU), is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). Insulin-induced capillary recruitment (IICR) is considered a significant determinant of IMGU. We investigated whether IICR is a determinant IMGU in obese and lean women with and without PCOS. METHODS: The study included 36 women with PCOS (20 lean, BMI 21.9 ± 2.3 kg/m(2) and 16 obese, BMI 35.9 ± 6.0 kg/m(2)) and 27 age-matched healthy controls (14 lean, BMI 22.2 ± 1.8 kg/m(2) and 13 obese, BMI 40.5 ± 7.0 kg/m(2)). IICR was evaluated by capillary microscopy during an isoglycemic-hyperinsulinemic clamp. IMGU was expressed as M/I value. RESULTS: The M/I value was significantly lower in obese PCOS women compared with obese controls [0.5 (0.2-1.1) versus 0.8 (0.3-1.4) (mg kg(-1) min(-1) pmol l(-1)) × 100, P < 0.01], whereas the small difference between lean PCOS and lean control women was non-significant [1.5 (0.5-2.6) versus 1.7 (1.0-3.7) (mg kg(-1) min(-1) pmol l(-1)) × 100, P = 0.17]. Hyperinsulinemia increased capillary recruitment in lean controls (53.5 ± 20.3 versus 64.9 ± 27.4 n/mm(2), P < 0.05), but not in either PCOS group nor in obese controls. IICR and androgens were a determinant of M/I value only in lean women with or without PCOS. CONCLUSIONS: PCOS per se is associated with impaired IICR. Obese women with PCOS, in part independent of obesity, demonstrated a profound insulin resistance, whereas the difference between lean PCOS women and healthy controls was small and statistically non-significant. IICR was a determinant of IMGU in lean, but not in obese, women regardless of the presence of PCOS.

Pituitary sensitizing effect of GnRH antagonists: a mechanism explaining LH escape during IVF?

BACKGROUND: GnRH antagonists have been introduced to induce persistent LH suppression. Many studies show a gradual increase of LH levels after several days of GnRH antagonist administration, the so-called escape or rebound effect. We hypothesize that, under chronic GnRH antagonist administration, a higher pituitary response to GnRH could be an underlying mechanism explaining the escape phenomenon. METHODS: In a prospective study, pituitary response to a supramaximal test dose of GnRH was tested in 12 post-menopausal women before and 8 days after daily treatment with 0.5 mg GnRH antagonist (ganirelix). The same strategy was applied, after a wash-out period, in 11 of the same women using daily 0.5 mg GnRH antagonist in combination with daily estradiol (E(2), 50 microg) administration. The main outcome measure was the LH response 30 min after GnRH administration (Delta LH 30) after the various GnRH tests. RESULTS: The Delta LH 30 increased significantly after antagonist administration [Median (range): from 65.5 (32-85) to 77.5 (47-122) IU/l; P = 0.002]. During E(2) administration, the LH response to the GnRH test did not change significantly. CONCLUSIONS: Pituitary response increases after 8 days of GnRH antagonist administration. An escape/rebound phenomenon may result from increased pituitary response to endogenous GnRH.

Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population.

The aim of this study was to investigate the prevalence of diabetes mellitus, hypertension and cardiac complaints in a Dutch population with polycystic ovarian syndrome (PCOS) and to compare the results with the prevalence of these conditions in the Dutch female population, as retrieved from the Netherlands Health Interview Survey of Statistics Netherlands. A total of 346 PCOS patients were interviewed by telephone, with a mean age of 38.7 years (range 30.3--55.7) and a mean body mass index of 24.4 (range 17.5--55.8). Diabetes occurred in eight (2.3%), hypertension in 31 (9%) and cardiac complaints in three (0.9%) of the women. The prevalence of diabetes and hypertension differed significantly from the prevalence of these conditions in the Dutch female population (both P < 0.05). In PCOS women aged 45--54 years (n = 32) the prevalence of diabetes was four times higher (P < 0.05) and of hypertension 2.5 times higher (P < 0.01) than the prevalence of these conditions in the corresponding age group of the Dutch female population. Hypertension also occurred significantly (P < 0.05) more in the younger (35--44 years) PCOS group (n = 233), but this age group was significantly more obese (P < 0.01) when compared with figures of obesity of the Dutch female population. In conclusion, our data show that in a follow-up study of a relatively lean PCOS population, the prevalence of diabetes mellitus and hypertension was increased when compared with the Dutch female population, especially in women aged 45--54 years.

Obesity, rather than menstrual cycle pattern or follicle cohort size, determines hyperinsulinaemia, dyslipidaemia and hypertension in ageing women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to investigate if ageing women with polycystic ovary syndrome (PCOS) who gained regular menstrual cycles differed from women who continued to menstruate irregularly with regard to risk factors for developing diabetes mellitus and atherosclerosis. DESIGN AND PATIENTS: In the original study of a population of 346 PCOS patients, defined in the past as having oligo- or amenorrhoea and elevated LH concentrations, we had sent out a questionnaire to investigate changes in the pattern of their menstrual cycles while ageing. From this cohort of patients, a significantly older group of 53 women (mean age: 41.3 years, range: 33.3-49.4) who were not using oral contraceptives or other hormones visited the outpatient clinic. These women did not differ from the non-participating group in BMI, ethnic origin, the proportion with regular menstrual cycles by age group, parity or the use of clomiphene citrate or gonadotrophins in the past. MEASUREMENTS: A physical examination and a transvaginal ultrasound were performed. The size of the follicle cohort was determined by counting the number of small follicles in the ovaries. Thirty-four women were also willing to give two fasting blood samples for measuring their glucose, insulin and lipid status. RESULTS: Forty-one of the 53 (77.4%) women had a regular menstrual cycle (shorter than 6 weeks) and 12 (22.6%) had an irregular cycle (longer than 6 weeks). The body mass index (BMI), waist: hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of diabetes (1-9%) and hypertension (11.3%) did not differ between the two menstrual cycle groups. Also, the fasting glucose, insulin, glucose/insulin ratio, total cholesterol, HDL-c, and LDL-c concentrations did not show any significant difference between the two groups. Instead, these parameters all were significantly higher in women with a BMI > 27 kg/M2 compared to women with a BMI < or = 27 kg/m2. Regularly menstruating PCOS women were older (P < 0.01), showed less follicles in their ovaries (n = 48, P < 0.01) and had lower androgens (n = 34, P < 0.05) than the irregularly menstruating women. Logistic regression analysis showed a second significant influence, after age, of the BMI on the menstrual cycle pattern (age, P < 0.01; BMI, P < 0.05). If age was excluded from the analysis, only the follicle count significantly predicted the menstrual cycle pattern (P < 0.02). CONCLUSIONS: We conclude that hyperinsulinaemia, dyslipidaemia and hypertension in our population of ageing women with polycystic ovary syndrome are not related to the menstrual cycle pattern but rather to obesity. Age and the size of the follicle cohort are the main factors determining the menstrual cycle pattern in ageing women with polycystic ovary syndrome, although an association with the BMI was also found.

Women with polycystic ovary syndrome gain regular menstrual cycles when ageing.

The aim of this study was to investigate if previously oligo- or amenorrhoeic polycystic ovary syndrome (PCOS) patients gain regular menstrual cycles when ageing. Women registered as having PCOS, based on the combination of oligo- or amenorrhoea and an increased LH concentration, were invited by letter to participate in a questionnaire by telephone. In this questionnaire we asked for the prevalent menstrual cycle pattern, which we scored in regular cycles (persistently shorter than 6 weeks) or irregular cycles (longer than 6 weeks). We interviewed 346 patients of 30 years and older, and excluded 141 from analysis mainly because of the use of oral contraceptives. The remaining 205 patients showed a highly significant linear trend (P < 0.001) for a shorter menstrual cycle length with increasing age. Logistic regression analysis for body mass index, weight loss, hirsutism, previous treatment with clomiphene citrate or gonadotrophins, previous pregnancy, ethnic origin and smoking showed no influence on the effect of age on the regularity of the menstrual cycle. We conclude that the development of a new balance in the polycystic ovary, solely caused by follicle loss through the process of ovarian ageing, can explain the occurrence of regular cycles in older patients with PCOS.

The effects of levonorgestrel, desogestrel and gestodene on the pulsatile release of luteinizing hormone in oral contraceptive users.

The dynamics of luteinizing hormone (LH) and follicle stimulating hormone (FSH) release were investigated in 60 long-term oral contraceptive (OC) users. Five different types of OC, all containing the same amount of estrogens were studied: three monophasic preparations containing levonorgestrel, desogestrel and gestodene, respectively, and two triphasic formulations, containing levonorgestrel or gestodene. Thirteen healthy, normally cycling volunteers served as controls. Blood sampling was performed at 10-min intervals during a 6-h period to determine the pulsatile release of LH. LH and FSH were measured using a sensitive immunoradiometric assay. Pulse patterns were classified on the basis of the overall LH level, as well as on the character of the LH pulses, according to both frequency and amplitude characteristics. Pulsatile LH release was maintained during OC use. After the 7-day pill-free interval, FSH levels as well as the LH pulse patterns were comparable to those of early follicular-phase controls. FSH levels and FSH release in response to a gonadotropin releasing hormone (GnRH) challenge were profoundly suppressed in all OC users, as early as day 8 of the pill cycle. LH release during the pill cycle was characterized by either a low frequency (median 1 pulse/6 h), high amplitude (median 2.5 IU/l) pulse pattern or by a pattern of low-amplitude pulses (median 0.2 IU/l) and low basal LH levels (median 0.2 IU/l). The distribution of these pulse patterns showed marked differences between different OC preparations and depended on both the type and dose regimen of the gestagenic component of the OC.

Pulsatile luteinizing hormone secretion during the first and the fourth cycle on two different oral contraceptives containing gestodene.

Oral contraceptives inhibit ovarian follicular growth by suppressing the release of gonadotropins from the pituitary. We studied basal and gonadotropin-releasing hormone-stimulated gonadotropin release, as well as pulsatile luteinizing hormone (LH) secretion, in ten healthy volunteers who had not used oral contraceptives before. Subjects received either a monophasic preparation containing 30 micrograms of ethinylestradiol and 75 micrograms of gestodene (group 1) or a triphasic formulation containing 30-40 micrograms of ethinylestradiol and 50, 70 and 100 micrograms of gestodene (group 2). Blood sampling at 10-min intervals during 6-h periods was performed on days 1, 8, 15 and 21 of both the first and fourth pill cycle. Thirteen healthy volunteers with regular ovulatory cycles served as normal controls. Both LH and follicle-stimulating hormone (FSH) were measured by a sensitive immunoradiometric assay. Pulsatile LH secretion was observed in all oral contraceptive users. Mean serum LH and FSH levels, number of pulses/6 h and the amplitude of LH pulses on day 1 in both the first and fourth pill cycle did not differ from early follicular phase controls in both groups. The FSH levels were suppressed rapidly in both groups, even in first cycles, while LH serum levels progressively declined in all cycles studied. In both groups, amplitudes of LH pulses decreased from day 8 onwards, with a substantial number of low-amplitude pulses (< 0.75 U/l) interspersed between large-amplitude pulses. On day 1 of the fourth pill cycle a significant number of pulses were of low amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulsatile luteinizing hormone patterns in long term oral contraceptive users.

Oral contraceptives (OC) inhibit folliculogenesis by a central suppressive action on the release of gonadotropins. To characterize the nature of these central effects, we studied 40 long term OC users on 3 different OCs: two monophasic preparations with 30 micrograms ethinyl estradiol and 150 micrograms l-norgestrel (group 1; n = 15), 150 micrograms desogestrel (group 2; n = 10), and a triphasic formulation containing 30-40 micrograms ethinyl estradiol and 50, 75, and 125 micrograms l-norgestrel (group 3; n = 15). Blood sampling at 10-min intervals during 6-h periods was performed at different moments in the pill cycle. Thirteen healthy volunteers with regular ovulatory cycles served as normal controls. FSH and LH were measured by a sensitive immunoradiometric assay. Pulsatile LH release was observed in all OC users. Mean serum LH and FSH levels, number of LH pulses per 6 h, and the amplitude of LH pulses on day 1 of the pill cycle did not differ from early follicular phase control values. FSH levels were rapidly suppressed from day 2 onward in all three groups, whereas LH levels progressively declined in groups 1 and 2 from day 8 onward. In group 3, however, LH levels were only significantly suppressed after day 13. The number of LH pulses per 6 h decreased in all groups starting on day 2, whereas the amplitude of LH pulses increased. A substantial percentage of LH pulses observed in OC users after day 1 were of low amplitude (< 0.75 IU/L). From these results, we conclude that 1) pulsatile release of LH is maintained during OC use; 2) FSH levels are suppressed equally early and equally effective by all OCs studied; 3) during OC use, the number of LH pulses per 6 h is reduced; 4) modulation of LH pulse amplitudes, and subsequently of serum LH levels, is mainly mediated by a dose- and time-dependent effect of the gestagenic component of the OC; and 5) after the 7-day pill-free interval, a normal early follicular phase pulse pattern is found, even in long term OC users, suggesting that in this period, most of the steroidogenic feedback effects wear off.

PIP: Oral contraceptives (OCs) inhibit folliculogenesis by a central suppressive action on the release of gonadotropins. To characterize the nature of these central effects, the authors studied 40 long-term OC users different OCs: 2 monophasic preparations with 30 mcg ethinyl estradiol and 150 mcg 1-norgestrel (group 1, n + 15), 150 mcg desogestrel (group 2; n = 10), and a triphasic formulation containing 30-40 mcg ethinyl estradiol and 50, 75, and 125 mcg 1-norgestrel (group 3; n = 15). Blood sampling at 10-minute intervals during 6-hour periods was performed at different moments in the pill cycle. 13 healthy volunteers with regular ovulatory cycles served a normal controls. FSH and LH were measured by a sensitive immunoradiometric assay. Pulsatile LH release was observed in all OC users. Mean serum LH and FSH level,s number of LH pulses per 6 hours, and the amplitude of LH pulses on day 1 of the pill cycle did not differ from early follicular phase control values. FSH levels were rapidly suppressed from day 2 onward in all 3 groups, whereas LH levels progressively declined in groups 1 and 2 from day 8 onward. In group 3, however, LH levels were only significantly suppressed after day 13. The number of LH pulses per 6 hours decreased in all groups starting on day 2, whereas the amplitude of LH pulses increased. A substantial percentage of LH pulses observed in OC users after day 1 were of low amplitude (0.75 IU/L). From these results, the authors conclude that 1) pulsatile release of LH is maintained during OC use; 2) FSH levels are suppressed equally early and equally effective by all OCs studied; 3) during OC use, the number of LH pulses per 6 hours is reduced; 4) modulation of LH pulse amplitudes, and subsequently of serum LH levels, is mainly mediated by a dose--and time-dependent effect of the gestagenic component of the OC; and 5) after the 7-day pill-free interval, a normal early follicular phase pulse pattern is found, even in long-term OC users, suggesting that in this period, most of the steroidogenic feedback effects wear off.

Ovulation induction with pulsatile luteinizing hormone-releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: endocrine results.

The pituitary and gonadal response to pulsatile luteinizing hormone-releasing hormone (LH-RH) administration during the first and consecutive second treatment unit (TU) was studied in nine women with clomiphene citrate-resistant polycystic ovary-like disease (PCOD). The control group consisted of eight eumenorrheic women. Luteinizing hormone levels, LH amplitudes, and total urinary excretion/24 hours did not differ between ovulatory and anovulatory TUs, but were significantly higher compared with the control group. Follicle-stimulating hormone (FSH) in PCOD did not differ from normal cycles. Androgen values in the anovulatory TUs were significantly higher compared with the ovulatory TUs (P = 0.001). We conclude that LH-RH therapy may result in ovulation; however, it does not redress the intrinsic abnormality in PCOD and FSH, and androgen levels do not seem to be critical in ovulation induction.

Pituitary response during pulsatile luteinizing hormone-releasing hormone ovulation--induction in patients with clomiphene citrate-resistant polycystic ovary-like disease.

The pituitary response to pulsatile luteinizing hormone-releasing hormone (LRH) was studied in 6 women with clomiphene-resistant polycystic ovary-like disease (PCOD). PCOD was defined as oligomenorrhea, elevated luteinizing hormone (LH), normal follicle-stimulating hormone (FSH), and, in general, elevated androgens. LRH was administered in a pulsatile way, chronically, with a pulse dose of 20 micrograms and a pulse interval of 60, 90 and 120 minutes. Blood was drawn every 10 minutes for 6 hours, at the start of therapy (pulse study 1) and 9-15 days after the start of therapy (pulse study 2). Five patients ovulated within 10 days of therapy, which meant that pulse study 2 was performed during the luteal phase. One patient remained anovulatory. The follicular and luteal response during LRH therapy was comparable to that of normal cycles, although the pituitary response was enhanced in PCOD at the start of therapy, which might be related to the state in which the ovary finds itself with respect to follicular development. Desensitization for LH to LRH occurred only incidentally during pulse study 1. Desensitization for FSH to LRH already developed during pulse study 1 and continued to existed during therapy. The 60, 90 and 120 minute LRH pulse interval regimes resulted in LH nadir intervals with wide ranges, although the medians were 60, 90 and 120 minutes respectively.

Induction of first cycles in primary hypothalamic amenorrhea with pulsatile luteinizing hormone-releasing hormone: a mirror of female pubertal development.

During pubertal development in girls, the attainment of regular ovulatory menstrual cycles usually is preceded by cycles that are either anovulatory or show a defective luteal phase. It is not known whether these defective cycles are caused by inadequate luteinizing hormone-releasing hormone (LH-RH) secretion or by an inadequate response of the pituitary-ovarian axis to LH-RH stimulation. To shed new light on this matter, the authors analyzed endocrine data from 12 menstrual cycles induced by pulsatile LH-RH therapy in five women with primary amenorrhea of hypothalamic origin. Anovulatory cycles occurred with and without an increase in estrogen excretion and with and without a luteinizing hormone surge. In addition, ovulatory cycles with and without deficient corpus luteum function were observed. Most of these types of anovulatory and ovulatory menstrual cycles also have been described during normal puberty. Therefore, these observations suggest that, during normal pubertal development, maturation of the pituitary gonadotropes and of the ovary occurs, as well as the increased secretion of LH-RH from the hypothalamus, which the overall process depends upon.

Patterns of LH and FSH in men during high-frequency blood sampling.

The aim of the study was to test the hypothesis that in serial determinations of concentrations of LH and FSH involving blood samples taken every minute, the observed pulses of LH and FSH which last less than 3-4 min might not be a physiological phenomenon but part of the 'noise' of the radioimmunoassay or blood-sampling technique. Blood was sampled every minute for a period of 90 min in six men. During the first 45 min, blood was sampled by means of vacuum tubes only. During the second 45 min, sampling took place with a syringe via a rubber stopper, either using a tourniquet (n = 3) or flushing the cannula with heparinized saline. Three criteria were used to identify variations in the patterns of LH and FSH as true hormonal changes. First, a threshold was used which had to be exceeded by the difference between nadir and maximum values before a pulse could be identified. An average of approximately six pulses per 90 min was found in both the LH and FSH series. The majority of these pulses lasted less than 3-4 min. In two subjects, larger LH pulses of longer duration were measured. Secondly, differences between duplicate measurements of nadir and/or maximum values of more than one-third of the amplitude of a pulse were considered unacceptable. This involved about 75% of the pulses. Thirdly, the reproducibility of the hormone variations was estimated. In one subject, concentrations of LH were measured four times in four separate assays.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term pituitary desensitization to luteinizing hormone-releasing hormone (LH-RH) after pulsatile LH-RH administration in women with amenorrhea of suprapituitary origin.

The existence of a short-term pituitary desensitization in luteinizing hormone (LH) release to single doses of luteinizing hormone-releasing hormone (LH-RH) in the ovariectomized rat was recently disclosed. The purpose of the present study was to investigate whether this refractoriness is also present in humans. Blood from six women with amenorrhea of suprapituitary origin was sampled every 10 minutes for 300 minutes for determination of LH and follicle-stimulating hormone (FSH). A pulse of 20 micrograms LH-RH was given intravenously 90 and 210 minutes after the first blood sample, and 2 micrograms LH-RH was given 30, 150, 240, and 270 minutes after t0. The mean maximal increments of LH and FSH were compared. The LH response to a 2-micrograms LH-RH bolus given 30 (t240) or 60 (t150) minutes after a 20-micrograms LH-RH pulse was significantly decreased, compared with the initial response to this dose at t30. For both LH and FSH, the response to 2 micrograms LH-RH given 30 minutes after the 20-micrograms pulse (t240) was almost absent, compared with 60 (t150) minutes after the 20-micrograms dose. We conclude that a short-term pituitary refractoriness to LH-RH is present after administration of single pulses of LH-RH in women with amenorrhea of suprapituitary origin and pulses of LH-RH in the physiologic range (2 micrograms) given to these women do not always generate LH and FSH increments that are identifiable as significant hormone pulses.

Ovulation induction with pulsatile luteinizing releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: clinical results.

Eighty-four treatment units were given to 11 women with clomiphene citrate-resistant polycystic ovarian disease (PCOD). PCOD was defined as oligomenorrhea elevated luteinizing hormone (LH), normal follicle-stimulating hormone (FSH), and preference-elevated androgens. Luteinizing-releasing hormone (LRH) was administered intravenously via a portable infusion pump. Doses varied between 5 and 40 micrograms/pulse given at 60-, 90-, or 120-minute intervals. In 11 women, 85 treatment units (TUs) were completed, of which 74 were ovulatory, showing no specific advantage of any particular pulse dose or pulse interval. Five pregnancies occurred in three women. Two women did not ovulate during 52 and 284 consecutive days of therapy, respectively. Oligomenorrheic patients with PCOD can be made more regular by means of LRH, not necessarily leading to a regular menstrual cycle. In general, LRH is sufficient for luteal support. No signs of hyperstimulation were observed, although two patients incidently developed unilocular cysts with a maximum diameter of 8 cm. Ovulation induction with LRH in PCOD is possible, although the disease itself does not change during therapy. This may be further evidence that altered hypothalamic LRH secretion is more the result, rather than the cause, of the phenomenon of PCOD.

Pulsatile luteinizing hormone patterns in the follicular phase of the menstrual cycle, polycystic ovarian disease (PCOD) and non-PCOD secondary amenorrhea.

To characterize the oscillations of plasma LH in normally cycling and amenorrheic women, three groups of women were studied: I, normal women during the follicular phase of the cycle (n = 9); II, women with polycystic ovarian disease (PCOD; n = 11); and III, women with non-PCOD secondary amenorrhea (n = 12). Blood samples were obtained at 10-min intervals for 6 h on 2 separate days. A pulse was defined as an increase in LH at least 20% over the preceding lowest value (nadir). Since LHRH release immediately follows the nadir of the LH levels, the nadir interval (NI) was used for analysis. For analysis, the results from 1 day were selected at random from each subject, and from each day, the same number of NIs also were randomly selected. When two NIs from each patient were selected, the median NI was 75 min in group I, 45 min in group II, and 45 min in group III. When three or four NIs were chosen, the median NI was 60 min in group I, 50 min in group II, and 40 min in group III. The differences between the groups were statistically significant. When three NIs were selected, the mean of the corresponding LH amplitudes was 2.8 U/liter in group I, 6.0 U/liter in group II, and 1.5 U/liter in group III. The differences between these groups were statistically significant. Thus, the NI in PCOD patients was shorter than that during the follicular phase of the cycle, but this short NI is not unique for PCOD, since the NI in non-PCOD secondary amenorrhea patients was even smaller. The LH amplitude was higher in PCOD and lower in non-PCOD secondary amenorrhea compared to that during the follicular phase of the cycle. The decrease in NI in PCOD and/or non-PCOD secondary amenorrhea vs. the NI of the follicular phase could be explained by either a higher frequency of LHRH pulses from the hypothalamus or an increased sensitivity of the pituitary leading to a greater response of the pituitary to LHRH pulses.