Differential effect of exogenous human chorionic gonadotrophin on progesterone production from normal or malfunctioning corpus luteum

To examine whether luteal phase defect is, in part, causally related to insufficient gonadotrophin stimulation, we compared the relation of the increment of serum progesterone concentrations in response to human chorionic gonadotrophin (HCG) with its basal level at mid-luteal phase. Thirty-eight naturally cycling infertile women aged between 27-41 years old were evaluated for hormonal responses to HCG injection at the mid- luteal phase. We measured luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and progesterone concentrations, before and 1, 2 and 3 h after the administration of HCG (5000 IU, i.m.) 7 days after ovulation verified by ultrasonography. Eleven out of 38 women exhibited progesterone concentrations below 10 ng/ml (low progesterone group), and those remaining showed progesterone concentrations of > or = 10 ng/ml (normal progesterone group). The basal LH, FSH and oestradiol concentrations were essentially the same in both groups. Progesterone concentrations rose significantly 1 h after the injection and levelled off thereafter. The increment of progesterone concentrations at 1 h in the normal progesterone group was 5.7 ng/ml on the average, whereas that in low progesterone group was 1.1 ng/ml. Furthermore, the percentage increase in progesterone concentrations at 1 h in the normal progesterone group was significantly greater than that in the low progesterone group. Both groups equally exhibited significant but marginal increases in oestradiol concentrations 1 h after the injection. LH and FSH concentrations at 3 h decreased significantly in both groups. In summary, HCG readily stimulates progesterone production in normally functioning corpus luteum whereas its stimulatory effect is minimal on malfunctioning corpus luteum. This suggests that luteal phase defect is not caused by inadequate gonadotrophin stimulation and, therefore, does not benefit from HCG administration.      

Endocrine responses to gonadotrophins after LHRH agonist administration on cycle days 1-4: prevention of premature luteinization

A treatment regime comprising an intranasally administered luteinizinghormone-releasing hormone (LHRH) agonist analogue (buserelin)on cycle days 1–4, followed by gonadotrophin administration[follicle stimulating hormone (FSH)/human menopausal gonadotrophin(HMG)] resulted in identical oestradiol (E₂) responses comparedwith the reference method using clomiphene citrate (CC) andgonadotrophins. Immediately after analogue administration (day4), buserelin-treated women showed short-lived elevations inserum LH and progesterone concentrations, but in the later follicularphase, the serum LH concentration was lowered compared withthe controls. None of the women treated with analogue displayedelevated serum LH or progesterone concentrations at the timeof injection of human chorionic gonadotrophin. In the earlyluteal phase, these women had higher serum levels of progesteroneand higher progesterone to E2 ratios than the controls, butthe length of the luteal phase was slightly shortened. Hence,in hyperstimulated cycles, 4-day treatment with buserelin causedprofound endocrinological changes: namely, short-term rescueof the corpus luteum, prevention of an endogenous LH rise andpremature luteinization and increased progesterone productionin the early luteal phase     

Induction of follicular growth and production of a normal hormonal milieu in spite of using a constant low dose of luteinizing hormone in women with hypogonadotrophic hypogonadism

This study was designed to examine ovarian performance, i.e.follicular growth, normal steroidogenesis and luteal phase function,following the administration of multiple increasing doses ofhuman follicle stimulating hormone (FSH) with a constant lowdose of luteinizing hormone (LH) in women with isolated hypogonadotrophichypogonadism. Human meno–pausal gonadotrophin (HMG) wasused in the first treatment cycle, starting with 150 IU of LHand 150 IU of FSH per day, for 7 days. The dose was increaseddaily with 75 IU of LH and 75 IU of FSH for another 7 days ifno response was detected by serial ultrasound measurements andserumoestradiol determinations. In the second treatment cycle,a constant dose of 75 IU of LH (using HMG) was administeredper day and up to 150 IU of FSH (using urofollitrophin) wassupplemented. If no response was detected after 7 days of treatment,the dose of FSH was increased. For the final stage of ovulationinduction, human chorionic gonadotrophin (HCG) was administeredin the presence of at least one follicle >17 mm in diameterbut with no more than three follicles >16mm in diameter.To verify the adequacy of the luteal phase, a pharmacokinetic/pharmacodynamicstudy of -HCG, oestradiol and progesterone was performed followingthe second treatment cycle only. Ovarian stimulation using aconstant dose of 75 IU of LH and increasing doses of FSH upto 225 IU, resulted in normal follicular growth and hormonalmilieu. Both women showed normal luteal phase oestradiol andprogesterone production and both women conceived following thesecond treatment cycle     

A bolus of recombinant human follicle stimulating hormone at midcycle induces periovulatory events following multiple follicular development in macaques

The efficacy of follicle stimulating hormone (FSH) as an alternative to luteinizing hormone (LH)/human chorionic gonadotrophin (HCG) for the initiation of periovulatory events in primate follicles is unknown. A single bolus of 2500 IU recombinant (r)-hFSH was compared to 1000 IU r- HCG for its ability to promote oocyte nuclear maturation and fertilization, granulosa cell luteinization and corpus luteum function following r-hFSH (60 IU/day) induction of multiple follicular development in rhesus monkeys. Following the r-hFSH bolus, bioactive luteinizing hormone concentrations were <3 ng/ml. Peak concentrations of serum FSH (1455+/-314 mIU/ml; mean+/-SEM) were attained 2-8 h after r-hFSH, and declined by 96 h. Bioactive HCG concentrations peaked between 2-8 h after r-HCG and remained > or = 100 ng/ml for >48 h, while immunoreactive FSH concentrations were at baseline. The proportion of oocytes resuming meiosis and undergoing in-vitro fertilization (IVF) were comparable for r-hFSH (89%; 47+/-19%) and r- HCG (88%; 50+/-17%). In-vitro progesterone production and expression of progesterone receptors in granulosa cells did not differ between groups. Peak concentrations of serum progesterone in the luteal phase were similar, but were lower 6-9 days post-FSH relative to HCG. Thus, a bolus of r-hFSH was equivalent to r-HCG for the reinitiation of oocyte meiosis, fertilization and granulosa cell luteinization, but a midcycle FSH surge did not sustain normal luteal function in primates.      

Pituitary gonadotrophin secretory capacity during the luteal phase in superovulation using GnRH-agonists and HMG in a desensitization or flare-up protocol.

Pituitary gonadotrophin reserve and basal gonadotrophin secretion were tested during the luteal phase in women superovulated with buserelin/human menopausal gonadotrophin (HMG) in a desensitization (n = 17) or flare-up protocol (n = 7). In the desensitization protocol the luteinizing hormone-releasing hormone (LHRH) stimulated serum LH and follicle stimulating hormone (FSH) concentrations remained impaired at least until day 14 after arrest of the agonist. In the flare-up protocol basal and stimulated LH secretion was still abnormal on days 14 and 15 after human chorionic gonadotrophin (HCG) injection. Normal basal serum FSH concentrations were measured at the end of the luteal phase in the flare-up protocol, but the response of FSH to LHRH injection was still subnormal. We conclude that gonadotrophin function remained impaired until the end of the luteal phase after desensitization and flare-up GnRH-agonist and HMG stimulation protocols. Corpus luteum stimulation with exogenous HCG or substitution therapy using natural progesterone are required to prevent the possible negative effects resulting from pituitary dysfunction after GnRH-agonist treatment.     

Effect of disruption versus continuation of gonadotrophin-releasing agonist after human chorionic gonadotrophin administration on corpus luteum function in patients undergoing ovulation induction for in-vitro fertilization

Previous studies have described the luteolytic effect of gonadotrophin- releasing hormone agonist (GnRHa) administered in the early luteal phase. The present work was undertaken to compare in a prospective and randomized design the effect of disruption versus continuation of daily GnRHa after human chorionic gonadotrophin (HCG) administration on corpus luteum function in patients undergoing ovulation induction for in-vitro fertilization (IVF). Two different studies were designed and a total of 38 ovum donors, aged 23-30 years, were included. In the first study, the effect of GnRHa on the early luteal phase of IVF-stimulated cycles was investigated (n = 27); the patients were divided into two groups, according to whether they stopped (n = 13) or continued with daily GnRHa injections (n = 14) for an additional period of 15 days after HCG administration. Blood was drawn from luteal phase days 2 to 6 (day 0 = day of HCG administration) and oestradiol and progesterone concentrations were analysed. The second study focused on the effects of continuation versus disruption of GnRHa administration in the mid- late luteal phase. A similar design was employed including six patients who stopped GnRH on day 0 and five other women who continued GnRHa for 15 days after HCG administration. In this second study, blood was drawn from days 5 to 11 and oestradiol, progesterone and luteinizing hormone (LH) concentrations were analysed. IVF parameters were similar in both groups. The results indicate that continuous GnRHa administration, after HCG injection, does not produce changes in oestradiol, progesterone and LH concentrations in the early, mid- and late luteal phases compared to those patients in whom GnRHa is discontinued at the day of HCG administration. The present work demonstrates that, when ovulation induction is performed, the corpus luteum is driven primarily by the HCG, regardless of the administration or disruption of GnRHa in the luteal phase. This suggests that the lack of differences between continuation versus disruption of GnRHa may be due to the accumulation of the product over the previous 2-3 weeks of treatment.      

Immunohistochemical localization of the LH/HCG receptor in human ovary: HCG enhances cell surface expression of LH/HCG receptor on luteinizing granulosa cells in vitro

We examined the immunohistochemical localization of luteinizing hormone (LH)/human chorionic gonadotrophin (HCG) receptor (LH-R) in the human ovary using the anti-human LH-R monoclonal antibody, 3B5. In the antral follicles, LH-R was detected on theca interna cells. In pre-ovulatory follicles, granulosa cells also expressed LH-R. During corpus luteum formation, granulosa cells seemed to increase the expression of LH-R, and in corpus luteum of mid-luteal phase, large luteal cells expressed LH-R more intensely than small luteal cells. In the regressing corpus luteum, LH-R was almost undetectable on both luteal cells, whereas in the corpus luteum of early pregnancy, LH-R continued to be expressed on large luteal cells. The granulosa cells obtained from the patients undergoing in-vitro fertilization therapy were cultured for 3 days in serum-free medium, without or with HCG (10 IU/ml) and tumour necrosis factor (TNF)alpha (10 ng/ml). Flow cytometry showed that the expression of LH-R on the cell surface of luteinizing granulosa cells was enhanced by HCG, but was unaffected by TNFalpha. These results suggest that the main target cells for LH/HCG change from theca interna cells/small luteal cells to granulosa cells/large luteal cells during ovulation, corpus luteum formation, and differentiation into the corpus luteum of pregnancy, probably under the influence of LH/HCG.      

Follicular and luteal phase characteristics following early cessation of gonadotrophin-releasing hormone agonist during ovarian stimulation for in-vitro fertilization

Gonadotrophin-releasing hormone agonists (GnRHa) are widely used in in-vitro fertilization (IVF) for the prevention of a premature rise in luteinizing hormone (LH) concentrations. However, the administration of GnRHa during the follicular phase may also impair subsequent luteal function due to retarded recovery of pituitary gonadotrophin secretion. Therefore, luteal supplementation is generally applied. The present study was designed to determine whether a premature LH surge would still be prevented after early cessation of GnRHa during ovarian stimulation and whether subsequent luteal phase LH production would be sufficient to support progesterone synthesis by the corpus luteum. Sixty patients were randomized for three groups: (i) A long GnRHa/human menopausal gonadotrophin (HMG) protocol with luteal support by repeated human chorionic gonadotrophin (HCG) (n = 20), (ii) early follicular phase cessation of GnRHa without luteal support (n = 20), and (iii) a long GnRHa protocol without luteal support (n = 20). Frequent ultrasound and blood sampling was performed during the entire IVF cycle. Forty normo-ovulatory women served as controls. No premature LH surges were found after early cessation of GnRHa. In this group, some pituitary recovery occurred during the late luteal phase, but this did not affect corpus luteum function. Progesterone concentrations were shown to be dependent on disappearance of the pre-ovulatory bolus of HCG. Pregnancies occurred in all three groups. In conclusion, early follicular phase cessation of GnRHa is still effective in the prevention of a premature rise in LH. Although some pituitary recovery was observed thereafter, corpus luteum function is still abnormal due to early luteolysis.     

Inhibin

Inhibin is a glycoprotem which specifically inhibits FSH secretion.In follicular fluid, several forms of inhibin have been identifiedwith mol. wts between 120 and 32 kd. The smallest active formis a glycosylated 32-kd protein with an 18-kd A chain and a13-kd B chain. The secretion of inhibin by granulosa cells ofthe follicle is stimulated by FSH and testosterone, but notLH, and treatment of women with clomiphene and HMG/FSH resultsin an increase In the plasma concentration of inhibin. However,during the follicular phase of the normal menstrual cycle, FSHis inhibited mainly by oestradiol and inhibin levels remainconstant or decline In parallel with those of FSH. It is probablethat inhibin and oestradiol act together to cause the suppressionof FSH. During the luteal phase, the human corpus luteum underthe influence of LH secretes Inhibin as well as oestradiol andprogesterone. This combined negative feedback signal from thecorpus luteum accounts for the suppression of FSH release andthus the failure of follicular growth during the luteal phase.     

Regulation of corpus luteum function

The effects have been studied of different ovulation inductionregimens [either domiphene citrate or buserelin in combinationwith human menopausal gonadotrophin (HMG)] on the circulatingconcentrations of progesterone, oestradiol, relaxin and humanchorionic gonadotrophin (HCG) during the first trimester ofpregnancy. Ovulation induction with clomiphene resulted in elevatedconcentrations of gonadotrophins in both phases of the cycle,while during ovulation induction with buserelin, gonadotrophinconcentrations were elevated in the follicular phase only. Theconcentrations of all corpus luteum products were greater inclomiphene pregnancies compared with spontaneous pregnancies,but only oestradiol and relaxin concentrations were greaterin clomiphene pregnancies compared with buserelin pregnancies.The concentrations of HCG were significantly reduced in clomiphenepregnancies compared to natural pregnancies. Relaxin concentrationswere significantly higher from 7 weeks gestation in buserelincompared with spontaneous pregnancies, while progesterone, oestradioland HCG concentrations were not consistently different. Consistentassociations were found between relaxin and HCG concentrationsin spontaneous pregnancies and between the concentrations ofrelaxin and both progesterone and oestradiol in pregnanciesachieved after ovulation induction. These data suggest that(i) given the similarity in the circulating concentrations ofHCG, the relatively lower circulating gonadotrophin concentrationsduring the luteal phase of the cycle of conception result inreduced circulating concentrations of oestradiol and relaxin;while in the case of relaxin this effect is partially reversible,there is no evidence that this is so for oestradiol; (ii) synthesisof progesterone in the corpus luteum is less affected by lowerconcentrations of gonadotrophins during the luteal phase; (iii)ovulation induction with clomiphene results in pregnancies withlower concentrations of HCG, suggesting that trophoblast functionmay be impaired; and (iv) corpus luteum function is linked withplacental steroidogenesis.     

The benefits of mid-luteal addition of human chorionic gonadotrophin in in-vitro fertilization using a down-regulation protocol and luteal support with progesterone

Luteal support is essential in in-vitro fertilization (IVF)when long-acting gonadotrophin-releasing hormone agonist (GnRHa)is used. Because progesterone lacks luteotrophic stimulation,it seems to be the drug of choice in cases with an increasedrisk of ovarian hyperstimulation syndrome (OHSS). The aim ofthis study was to assess the beneficial effect of the mid-lutealaddition of human choriomc gonadotrophin (HCG) in IVF, usinga down-regulation protocol and luteal support with progesterone,in a prospective randomized study. The study included 170 IVFcycles down-regulated with long-acting GnRHa which were supportedwith 50 mg/day progesterone i.m. during the luteal phase. Patientswere evaluated in the mid-luteal period. Those without clinicalsigns of OHSS, oestradiol concentrations <1000 pg/ml andprogesterone concentrations <50 mg/ml were randomly allocatedto either the addition of 2500 IU HCG (HCG+ group) or no HCG(HCG– group). End luteal phase progesterone concentrationsamong non-pregnant patients were used to assess the contributionof exogenous progesterone and to categorize pregnancies accordingto their corpus luteum function. Similar low OHSS (2.7 and 1.8%)and pregnancy (30 and 29%) rates were observed in the HCG+ andHCG– groups respectively. Of the 26 pregnancies in theHCG+ cases, there was only one case with reduced corpus luteumfunction, compared with 12 of the 25 pregnancies among HCG–patients. Cases with reduced corpus luteum function requiredcontinuous progesterone support and presented lower HCG concentrationsand a higher rate of adverse pregnancy outcome. We concludethat mid-luteal HCG addition does not affect pregnancy rate,but in fact helps to preserve corpus luteum function and avoidsthe need for further supplementation during early pregnancy.     

Severe ovarian hyperstimulation syndrome despite low plasma oestrogen concentrations in a hypogonadotrophic, hypogonadal patient

Ovarian hyperstimulation syndrome (OHSS) is the most serious,life-threatening, iatrogenic complication of ovuia-tion induction.The importance of excessive oestradiol concentrations on theday of human chorionic gonadotro-phin (HCG) administration asa predictor and factor in the pathophysiology of OHSS has beenextensively studied and discussed. We present the case reportof a woman with hypogonadotrophic hypogonadism who developedsevere OHSS during ovulation induction with urinary human folliclestimulating hormone (FSH) and HCG in the presence of low circulatingoestradiol concentrations. The implication of FSH treatmentand complications in hypogonadotrophic hypogonadal patients,and the role of pre-ovulatory oestradiol concentrations in theprediction of OHSS, are discussed.     

Luteal phase support and severe ovarian hyperstimulation syndrome.

The incidence and statistical associations of the ovarian hyperstimulation syndrome (OHSS) were studied in 304 egg retrievals with gonadotrophin-releasing hormone agonist suppression, gonadotrophin administration and follicular aspiration. In addition to preserving corpus luteum function, the luteal phase administration of human chorionic gonadotrophin (HCG) was associated with a higher incidence of severe OHSS than was supplementation with progesterone alone (12 versus 0%, P less than 0.001). Severe OHSS occurred in 3.7% and 12% of retrievals without and with pregnancy respectively (P less than 0.01). Stepwise logistic regression showed that the occurrence of moderate or severe OHSS was statistically predicted by the log of the serum oestradiol on the day the initial HCG was given (P less than 0.0001), treatment with luteal phase HCG (P less than 0.0003), and fetal number (P less than 0.0079). In the late luteal phase of cycles without luteal HCG, the serum oestradiol concentration was one-tenth and the serum progesterone concentration was one-fifth of the luteal phase value with HCG support (P less than 0.001). Without luteal phase HCG, oestradiol was two-fold higher (P less than 0.001) and progesterone was 1.4-fold higher (P less than 0.005) in pregnant than in non-pregnant women. With luteal phase HCG, oestradiol was 1.4-fold higher in pregnant than in non-pregnant women (P less than 0.05), and progesterone was 1.7-fold higher (P less than 0.001). Oestradiol upper limits of 4400 and 14,700 pmol/l (1200 and 4000 pg/ml) for cycles with and without luteal phase HCG respectively correspond to approximately 5% risk of moderate or severe OHSS with a singleton pregnancy under these conditions.     

In-vitro synthesis of steroid hormones in corpora lutea from normal women and women treated with 300 micrograms norethisterone.

The in-vitro oestradiol (E2) and progesterone (P) production by corpora lutea (CL) obtained at sterilization from 30 untreated women and 43 women treated with norethisterone (NET) 300 micrograms daily was measured. The CL were obtained at different stages of the luteal phase in the untreated women [luteinizing hormone (LH) 0 to +3, n = 7; LH +4 to +7, n = 7; LH +8 to +11, n = 9; LH +12 to menses, n = 7] and on days LH +8 to +11 or cycle days 22 to 26 in the NET-treated women. In the treated women, four types of ovarian reaction were identified. Four women showed ovarian reaction Type A (completely inhibited ovarian activity), 14 women Type B (marked follicular activity, but no luteal function), 12 women Type C (normal follicular activity, followed by insufficient luteal function) and 13 women Type D (apparently normal follicular and luteal activity). The CL were incubated in Eagle's medium with and without stimulation by human chorionic gonadotrophin (HCG) for 2 and 4 h. In the untreated women, P and E2 production increased significantly with both incubation time and stimulation by HCG throughout the luteal phase, except in the late luteal phase (LH +12 to menses) where P increased (P less than 0.01) only after 4 h stimulation by HCG. The maximal production of P was found after 4 h incubation with HCG stimulation of CL tissue in the early-mid luteal phase (LH +4 to +7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of gonadotrophin-releasing hormone agonists administered as desensitizing or flare protocols on hormonal function in the luteal phase of hyperstimulated cycles

The incorporation of gonadotrophin-releasing hormone agonist (GnRHa) in in-vitro fertilization (IVF) stimulation protocols has led to doubt about the quality of the subsequent luteal phase. The effects of two GnRHa stimulation protocols on luteal phase concentrations of oestradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were compared with the standard clomiphene stimulation regimen. Subjects receiving clomiphene with human menopausal gonadotrophin (HMG, n = 377) showed essentially similar luteal phase P concentrations to those receiving leuprolide acetate/HMG as a desensitization protocol. Subjects receiving concomitant leuprolide and HMG from day 2 to utilize the flare effect of the GnRHa exhibited significantly lower P levels in the luteal phase compared to clomiphene/HMG and leuprolide desensitization protocols despite the addition of HCG support. This occurred despite equivalent E2 concentrations at the time of ovulation and identical numbers of oocytes recovered. LH concentrations in non-conception cycles were suppressed for at least 14 days in the luteal phase in both GnRHa protocols compared to clomiphene stimulation. Differences were less obvious in cycles where conception occurred suggesting that implantation may proceed more favourably when the luteal endocrinology was optimal. It is concluded that flare methods of GnRHa hyperstimulation are associated with significantly different luteal phases compared with clomiphene or desensitization protocols. It is proposed that the use of the flare type of stimulation may significantly influence the response of the granulosa cells to LH or HCG via gonadotrophin receptors or through altered post-receptor function.     

The human corpus luteum: reduction in macrophages during simulated maternal recognition of pregnancy

It has been shown that immune cells, particularly macrophages, accumulate in the corpus luteum during luteolysis. This study aimed to investigate the effect of maternal recognition of pregnancy on the localization and numbers of macrophages in the human corpus luteum. Corpora lutea (n = 12) were obtained from normally cycling women at the time of hysterectomy and were dated on the basis of serial urinary luteinizing hormone (LH) estimation. In addition, corpora lutea (n = 4) were collected from women who had received daily doubling doses of human chorionic gonadotrophin (HCG) to mimic the hormonal changes of early pregnancy. Macrophages were localized by immunohistochemistry using an anti-CD68 antibody. Steroidogenic cells, steroidogenic cells of thecal origin and endothelial cells were identified on serial sections by immunohistochemistry for 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase and von Willebrand factor, respectively. The luteal cells capable of responding directly to HCG were identified by isotopic in-situ hybridization for messenger RNA encoding LH/HCG receptors. Macrophages were localized primarily to the vascular connective tissue and theca-lutein areas of the corpus luteum, although some were found in the granulosa-lutein cell layer. Macrophage numbers increased throughout the luteal phase to a maximum in the late- luteal phase (P < 0.05). Luteal 'rescue' with HCG was associated with a marked reduction in the numbers of tissue macrophages when compared with those of the late-luteal phase (P < 0.001). One of the effects of HCG during maternal recognition of pregnancy is to prevent the normal influx of macrophages into the corpus luteum. As LH/HCG receptors localized to the steroidogenic cells, this implies a fundamental role for steroidogenic cell products in the control of macrophage influx into the human corpus luteum.      

The corpus luteum

Normal corpus luteum function is determined by function in thefoUicular as well as the luteal phase. In the follicular phaseadequate follicle–stimulating hormone (FSH) and oestrogenstimulation are required for granulosa cell mitosis and luteinizinghormone (LH) receptor synthesis. An increase in LH pulse frequencymay also be necessary for adequate oestrogen synthesis and preparationof follicular cells for luteinization and secretion of progesterone.The nature of LH release may also influence luteal functionand pre–ovulatory progesterone may increase the responsivenessof the follicle to gonado-trophins. The thecal vascular networkbecomes extensive around pre-ovulatory follicles and may influenceaccess of gonadotrophins and/or the ability of follicular cellsto respond to them. Further vascularization is an early featureof luteinization. Angiogenic factors are found in luteal tissueand prostacyclin increases luteal blood flow. The corpus luteumconsists of large cells which secrete most of the progesteroneand have prostaglandin F₂ receptors and small cells which areresponsive to LH. In the luteal phase subnormal luteal functionhas not been associated with a reduction in LH con–centration,pulse frequency or amplitude. The number and occupancy of LHreceptors and adenylate cyclase activity do not appear to bealtered by a reduction in luteal function. Low density lipoproteinprovides the substrate and somatomedin C modulates among otherhormones‘ influences, progesterone production. In additionto the cAMP second messenger system phosphatidyl inositol metabolismmay also be associated with LH stimulation. Luteolysis is anactive process; prostaglandin F₂ or lipoxygenase products andpossibly an endogenous GnRH-like ovarian hormone may mediateit as also may oxytocin in some species.     

Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix

Luteinizing hormone (LH) is mandatory for the maintenance of the corpus luteum. Ovarian stimulation for IVF has been associated with a defective luteal phase. The luteal phases of two groups of patients with normal menstrual cycles and no endocrinological cause of infertility were retrospectively analysed in IVF cycles. Thirty-one infertile patients stimulated with human menopausal gonadotrophins (HMG) for IVF to whom the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix 0.25 mg was also administered to prevent the LH surge (group I) were compared with 31 infertile patients stimulated with HMG alone (group II). Despite differences in the stimulation outcome, luteal LH serum concentrations were similar in the two groups. LH values dropped from 2.3 +/- 1 IU/l on the day of human chorionic gonadotrophin (HCG) administration to 1.1 +/- 0.7 IU/l on day HCG +2 in group I (P < 0.0001) and from 5.1 +/- 3 to 1.2 +/- 1.7 IU/l (P < 0.0001) in group II. In the mid-luteal phase, LH concentrations were low in both groups. Our results suggest that suppressed LH concentrations in the early and mid-luteal phase may not be attributed solely to the GnRH-antagonist administration. Pituitary LH secretion may be inhibited by supraphysiological steroid serum concentrations via long-loop feedback and/or by the central action of the exogenously administered HCG via a short-loop mechanism.     

Initiation of high dose gonadotrophin-releasing hormone antagonist treatment during the late follicular phase in the macaque abolishes luteal function irrespective of effects upon the luteinizing hormone surge

The determination of the efficacy of gonadotrophin-releasing hormone (GnRH) antagonists in blocking the luteinizing hormone (LH) surge and luteal function is important for our understanding of the control of the menstrual cycle and for clinical application. GnRH antagonists have failed to block the LH surge reliably in the non-human primate. The aim of the study was to utilize high dose GnRH antagonist treatment administered during the late follicular phase of the menstrual cycle to block the pre-ovulatory LH surge. It was postulated that the LH surge would be prevented in all animals, but if this failed subsequent luteal function would be blocked by continued suppression of LH, since the early corpus luteum is susceptible to inhibition by GnRH antagonist treatment. A group of 16 adult female stumptailed macaques (Macaca arctoides) with regular menstrual cycles were selected. The GnRH antagonist [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,D-(Hci)6, Lys(iPr)8,D- Ala10]GnRH (Antarelix) (concentration 10 mg/ml) was administered as three daily s.c. injections, at a dose of 1 mg/kg on days 11, 12 and 13 of the follicular phase of the menstrual cycle. Of nine macaques in which it was judged that the treatment was commenced within 1 day of the expected LH surge (serum oestradiol >400 pmol/l), six demonstrated a decline in serum oestradiol concentrations, a total block of the LH/follicle stimulating hormone (FSH) surge and inhibition of ovulation as judged by an absence of a rise in progesterone concentrations. In the three other animals in this category, a partial LH surge occurred, but this failed to result in a functional corpus luteum. In a further three animals treatment was initiated on the day of the LH surge, and again there was absence of a subsequently functional corpus luteum. These results show that GnRH is involved at the time of the mid-cycle LH/FSH surge in the non-human primate. Initiation of high dose GnRH antagonist treatment during the periovulatory period abolishes luteal function irrespective of its effects upon the LH surge because of its long-term action and resultant withdrawal of luteal support.