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Human gonadotrophins are follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotrophin (HCG). All three gonadotrophins are new produced in vitro by recombinant DNA technology. Being complex heterodimeric proteins, an eukaryotic cell line, has been selected for expression and large scale production (Chinese hamster ovary cells). The advantages of producing the gonadotrophins in vitro rather than extracting them from human fluids are : (i) a fully controlled production process from bulk to finished product; (ii) high purity and specific activity; (iii) batch-to-batch consistency; and (iv) complete absence of contamination by the other gonadotrophins. Pharmacokinetic characterization of recombinant human gonadotrophins has shown that this first generation have pharmacokinetic characteristics very similar to the extractive gonadotrophins with an apparent terminal half-life after s.c. administration of ∼37 h, 12 h and 32 h for recombinant FSH (rHFSH), recombinant LH (rhLH) and recombinant HCG (rhHCG) respectively. Clinical efficacy and safety have been demonstrated in several randomized, well-controlled studies, comparing rhFSH administered s.c. with uhFSH administered i.m. for stimulating follicular development prior to assisted reproductive technology and in WHO Group II anovulation. To date, ∼1300 patients have been treated with rhFSH. Moreover, rhLH has recently been successfully used in association with rhFSH for inducing ovulation and pregnancy in WHO I anovulatory patients and rhCG has been successfully used for triggering final follicular maturation prior to assisted reproductive technology.

'Pure' follicle stimulating hormone (FSH) and luteinizing hormone (LH) are expected shortly to become available for pharmaceutical use in the clinical setting. To test the contribution of LH to optimal ovarian responsiveness to FSH, 21-day-old hypophysectomized, immature, female rats received four s.c. injections of recombinant human LH (rhLH; total dose 1-10 IU) and/or rhFSH (total dose 30-72 IU) given at 12-hourly intervals. At 48 h after the first injection, ovaries were removed, weighed and used to isolate granulosa and thecal/interstitial cells for assessment of basal and gonadotrophin-responsive steroidogenesis in vitro, or homogenized to extract total RNA for Northern analysis of 17-hydroxylase/C17-20-lyase (cytochrome P-450c17 alpha) mRNA. Serum oestradiol and uterine weight were measured as indices of ovarian oestrogen production; androstenedione was measured to reflect ovarian androgen production. Consistent with the two-cell, two-gonadotrophin model of oestrogen synthesis, increased ovarian oestrogen secretion only occurred if both rhFSH and rhLH were given simultaneously. Treatment with rhFSH alone stimulated ovarian weight gain and granulosa cell aromatase activity without oestrogen secretion, whereas rhLH alone stimulated thecal androgen synthesis and androgen secretion. When the total rhLH dose was fixed at 1 IU, giving rise to an unmeasurably low serum concentration of rhLH, additional treatment with rhFSH (30-72 IU) dose-dependently stimulated serum androgen concentrations as well as oestrogen concentrations. The approximately 2.0 kb-sized P-450c17 alpha mRNA transcript was undetectable in the ovaries of untreated control animals but was abundant in the ovaries of positive controls treated with 15 IU of pregnant mare serum gonadotrophin.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary: A first case of successful induction of ovulation with recombinant human FSH administered subcutaneously to a WHO group II anovulatory patient is reported. Using a chronic low-dose protocol, recombinant human FSH, a preparation with no LH activity, led to a clear and even supraphysiological increase of inhibin and E 2 and the development of four follicles among which one was dominant. The treatment cycle resulted in an ongoing pregnancy.

A pharmacological approach was used to study the involvement of opioid peptides and dopamine in mediating the suckling-induced release of prolactin in the lactating ewe (10-20 days post partum). To promote reliable and predictable suckling activity lambs were fitted with elasticated masks to prevent sucking for 4.5 h. After a 1-hour control period of frequent blood sampling, ewes were treated (i.v. injections every 5 min) for a further 75 min with either saline vehicle, an opioid antagonist (naloxone; 4.17 mg/5 min), a dopamine antagonist (metoclopramide; 1.25 mg/5 min), a mixture of naloxone + metoclopramide or a dopamine agonist (apomorphine; 6.6 mg/5 min). Blood was withdrawn at 5-min intervals for determination of plasma prolactin and luteinizing hormone (LH) by radioimmunoassay. Plasma LH concentrations (less than or equal to 1 microgram/l) were not significantly affected by any of the drug treatments and there was no evidence for an acute fall in LH associated with suckling- or TRH-induced increases in prolactin secretion. Naloxone significantly (p less than 0.05) reduced the mean incremental change in prolactin concentration (delta PRL) in response to suckling (+7 +/- 18 micrograms/ml) compared with saline-infused controls (+79 +/- 26 micrograms/ml), an effect which was completely reversed by combined treatment with naloxone and metoclopramide (+146 +/- 56 micrograms/ml). Metoclopramide alone raised basal prolactin levels by 46% (p less than 0.01) but did not affect delta PRL in response to suckling (+115 +/- 52 micrograms/ml). Neither naloxone, metoclopramide nor a combination of the two drugs affected the subsequent prolactin to TRH (10 micrograms). Apomorphine, however, completely abolished both the suckling- and TRH-induced release of prolactin.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-one patients superovulated with clomiphene citrate (CC) and human menopausal gonadotrophin (HMG) were given a single injection of 25 mg progesterone (P group) 6 h prior to injection of human chorionic gonadotrophin (HCG). Levels of urinary and plasma luteinizing hormone (LH) were significantly higher (P less than 0.001) immediately prior to HCG in the P group compared with thirty-one control patients who had HCG on the same night. Plasma levels of progesterone remained significantly elevated (P less than 0.02) for 80 h after injection in the P group, thereafter the level was similar to controls. The number of oocytes recovered, fertilized and replaced per patient was identical in both groups. However, four control patients had no embryos replaced due to failed fertilization. It is concluded that in the majority of P patients the timing of ovulation induction by HCG injection was appropriate as an LH surge was elicited thus reflecting a physiological stage of readiness, and elevated plasma progesterone levels around the time of oocyte recovery and in the early luteal phase do not increase the likelihood of the establishment of pregnancy in patients stimulated for in-vitro fertilization and embryo replacement (IVF/ER) with CC and HMG.

Successful in-vitro fertilization (IVF) requires the generation of a number of healthy embryos and adequate priming and maintenance of a receptive endometrium. Both of these factors are influenced by ovarian stimulation regimes and are responsive to endocrine manipulation. Detailed analysis of follicular phase patterns of hormone secretion have established an inverse relationship between luteinizing hormone (LH) and egg/embryo quality which is not discernible on microscopic examination. The advent and extensive use of LHRH agonists in ovarian stimulation has gone some way towards optimizing embryo fitness by suppressing LH secretion and this has exposed the endometrial contribution to a failure of implantation to closer examination. The supraphysiological production of oestradiol and progesterone from the large numbers of follicles developed during ovarian stimulation cannot be without effect on the endometrium. Data presented in this brief review show how our understanding of ovarian stimulation and its influence on the outcomes of IVF has advanced and highlights the opportunities for manipulation of the endometrium to encourage implantation.

Two-hundred patients, half of whom had on-going pregnancies, were examined in terms of follicular growth, urinary oestrogen and LH output, oocytes recovered and embryos replaced. The two groups were identical in all parameters measured except that urinary LH output was significantly higher (P less than 0.01) in non-pregnant patients on the two days prior to HCG administration. During the early to mid-luteal phase, plasma progesterone concentrations were related to the number of follicles aspirated at oocyte recovery, but the overall pattern of secretion was similar in both groups. It is concluded that monitoring urinary LH output, a non-invasive technique, may be of great value for assessing oocyte quality and predicting the outcome of in-vitro fertilization and embryo replacement.

Over a period of 4 months, 262 infertile couples participated in a prospective pseudorandom trial of a novel short-term luteinizing hormone-releasing hormone/human menopausal gonadotropin (LH-RH/hMG) treatment; the short-Buserelin-gonadotropin (Hoechst, Hounslow, United Kingdom) regimen. Patients treated with the short-Buserelin-gonadotropin regimen had a significantly higher likelihood of achieving pregnancy than patients treated with the standard clomiphene citrate (CC)/hMG regimen (respectively, 35.5% and 18% per treatment cycle). A significantly higher number of eggs were collected after short-Buserelin-gonadotropin treatment than CC/hMG, but the proportion of patients having a given number of embryos replaced was similar in the two groups. The short-Buserelin-gonadotropin-treated patients were distinguished from the CC/hMG-treated group by significantly lower levels of LH in the late follicular phase and a lower plasma level of estradiol. A detrimental relationship between elevated endogenous LH secretion and failure of implantation has been established. The nature of the short-Buserelin-gonadotropin regimen provokes high levels of endogenous gonadotropin secretion in the early follicular phase and induces a suppression of gonadotropin secretion in the late follicular phase. This may be the physiologic basis of the greater implantation rate after short-Buserelin-gonadotropin treatment than is seen with conventional CC/hMG treatment.