The hormonal response to clomiphene citrate (CC) has been used to evaluate ovarian reserve. In the current study, we tested the reproducibility of response to 100 mg of CC administered for 5 days in a group of 20 women, 35 to 40 years of age, with regular menstrual cycles who completed 57 cycles during the study. Individual hormonal responses to repeated stimulation were not identical. When ovarian responsiveness to CC was categorized as “low” (E2 and E2/FSH ratios ≤200 pg/mL and ≤20, respectively) or “high” (E2 ≥400 pg/mL and E 2/FSH ≥61), however, responses of individual subjects seldom spanned both categories. Specifically, only 3 of 20 subjects had both low and high E2 and low and high E2/FSH ratios (P<0.001). In addition, seven subjects were identified as FSH hyperresponsive in at least one cycle (post-CC FSH ≥10 IU/L). Only 2 of 21 cycles in these seven subjects had post-CC E2/FSH ratios ≥61, in comparison with 20 of 36 cycles in the other 13 subjects (P<0.01). Thus, despite the cycle-to-cycle variations, the hormonal response of an individual subject could usually be categorized as occurring at one or the other end of the spectrum of ovarian function, these two extremes probably signifying good and poor ovarian reserve. This prediction is further strengthened by the observation of a significant negative correlation between the FSH and E2 responses after administration of CC (P≤0.05). (Endocr Pract. 1995; 1:335-337)

Adult rats exposed to prenatal alcohol were evaluated for their susceptibility to either hormone- or chemical-inducing tumors. In the first study, rats exposed to prenatal alcohol displayed an increased propensity to beta-estradiol (E2)-induced adenohypophyseal prolactinoma. The susceptibility was manifest as a potentiated increase in anterior pituitary weight as well as in serum prolactin levels after 1 and 3 weeks but not 5 weeks of hormone treatment. Two weeks after withdrawing the E2-implant, the prolactinoma underwent involution and serum prolactin reversed to baseline levels. The high concentrations of serum corticosterone were also reduced but did not return to baseline levels after E2 removal. In the second study, nitrosomethylbenzylamine (NMBA) was utilized to induce esophageal cancer in adult rats. There were no significant differences in tumor incidence or size between the prenatal alcohol-exposed and the pair-fed cohorts. However, the NMBA-treated prenatal alcohol-exposed rats displayed a marked decrease in thymus: body wt ratio as well as adrenal gland hyperplasia. The results suggest that no single mechanism can account for the variable susceptibility displayed by the prenatal alcohol-exposed rats to chemical carcinogens. Some of the observed changes, however, may be attributable to the long-lasting adverse effects of prenatal alcohol exposure on the well-being of the adult host.

The existence of inhibitory short- and ultrashort-loop feedback mechanisms for luteinizing hormone (LH), while documented in animals, has been questioned in humans. Since human chorionic gonadotropin (hCG) binds to LH receptors but can be distinguished from LH in immunoassays, it is possible to identify LH surges in the face of exogenously administered hCG. The present study demonstrates LH surges at midcycle in normal volunteers and in women undergoing controlled ovarian hyperstimulation, given hCG. This provides further evidence for lack of loop feedback control of LH secretion in humans.

We compared the gonadotrophin and oestradiol responses to clomiphene citrate (CC) in women aged 18–25 versus 35–40 years. Despite similar baseline hormone concentrations and the attainment of similar concentrations of the E and Z isomers of clomiphene, higher follicle stimulating hormone (FSH) concentrations were observed in the older women, possibly indicative of their ageing ovaries. Furthermore, diminished oestradiol responses occurred in a subgroup of women showing FSH hyper-responsiveness to CC. These preliminary results support the concept that the hormonal response to CC may be an indicator of approaching perimenopause.

The pharmacokinetics of human chorionic gonadotropin (hCG) was studied in 15 normal volunteers and 15 patients undergoing in vitro fertilization (IVF). Each subject received 6000 IU hCG, intramuscularly (im), at midcycle, and serum was assayed for hCG frequently for 16 hr. All 30 subjects achieved hCG concentrations ≥10 IU/liter within 2 hr and 19 (63%) did so within 1 hr of injection. The time taken to attain concentrations of ≥20 and ≥40 IU/liter correlated positively with the subjects' weight and/or surface area, but the correlation was not strong. Eleven of the 15 IVF patients had oocytes retrieved 34–35+hr post hCG. Three of the 11 showed evidence of prior “undetected ovulation” at the time of surgery (definite in one, presumed in two). Taking into consideration the pharmacokinetics of hCG and other factors that could lead to undetected ovulation, the authors conclude that (1) hCG is rapidly absorbed in the majority of subjects following im injection, (2) ovulation may occur earlier than 36 hr following hCG in some individuals, and (3) implementation of a shorter (than 35 hr) hCG-to-oocyte retrieval interval would be advised if undetected ovulation is to be avoided.

A study was undertaken to compare the hormonal parameters [serum concentrations of estradiol (E2), and progesterone (P) and P/E2 ratios] of patients undergoing in vitro fertilization/embryo transfer to whom either progesterone in oil or human chorionic gonadotropin (hCG) was administered as luteal support. Seventeen patients were studied in 20 cycles. In 10 randomly assigned cycles 25 mg of intramuscular progesterone in oil was administered daily from the day of embryo transfer (day +4) until day +18. In the other 10 cycles, 1500 IU of hCG was given intramuscularly on days +4, +7, +10, and +13. Even when accounting for the differences in recruitment in the two groups, the hCG-treated group had significantly higher concentrations of serum P (P<0.01) and E2 (P<0.05) during the luteal phase. The luteal P/E2 ratios were higher in the progesterone-treated group because of the lower E2 levels in that group, although the difference was not statistically significant. The ratio of the mean luteal P to the preovulatory serum E2 was significantly higher in the hCG-treated group (P<0.01). There were three clinical pregnancies in the hCG-treated group. We conclude that (1) higher P concentrations are achieved with hCG treatment than with progesterone treatment during the luteal phase; (2) high luteal P/E2 ratios per se may not be an important determinant of implantation; (3) progesterone production by the corpus luteum is not maximal in progesterone-treated cycles; and (4) the usefulness of hCG as a luteal support agent should be further evaluated.

The in vitro fertilization and cleavage rates of oocytes obtained from patients exhibiting two different patterns of increase in serial serum concentrations of estradiol (E2) in response to ovarian stimulation were compared. Forty-two cycles (from 38 stimulated patients) were evaluated because they fulfilled requirements from two predefined patterns of E2 response to ovarian stimulation. In 16 cycles, serial serum E2 concentrations followed a “plateau” pattern (group A), viz., the rate of increase in the serum concentration of E2 decreased prior to the administration of human chorionic gonadotropin (hCG). In 26 cycles, serial serum E2 concentrations followed a “leap” pattern (group B), in which the rate of increase in serum concentrations of E2 increased progressively up to and including the day of hCG administration. There was no significant difference in the fertilization rate of oocytes obtained from patients exhibiting either pattern A or pattern B (78 versus 74%) but the cleavage rate was significantly higher in ova obtained from patients who exhibited pattern A rather than pattern B (72 vs 50%; P ⩽ 0.01). In addition, embryos resulting from fertilized ova obtained from women in group A were of better quality morphologically than those obtained from women in group B (mean embryo grades, 3.9 vs 3.2; P ⩽ 0.005). We conclude that cycles in which serial serum concentrations of E2 follow pattern A in response to stimulation give rise to oocytes that, when fertilized, yield higher cleavage rates and better-quality embryos than oocytes obtained from women in whom serial serum E2 concentrations follow pattern B. This finding is in keeping with the hypothesis that plateau and leap patterns of serial serum E2 concentrations are reflective of synchronous and asynchronous follicular recruitment, respectively.

Melatonin initially inhibited FSH secretion from superfused adult male hamster anterior pituitary glands obtained at 8:30 a.m. However, there was a gradual rebound during melatonin superfusion followed by an overshoot above baseline when melatonin was discontinued (morning response). Melatonin continuously inhibited FSH secretion during superfusion of hamster anterior pituitary glands obtained at 3:30 p.m., with a rebound evident only when melatonin was withdrawn (afternoon response). Melatonin continuously inhibited LH secretion from these superfused pituitaries, with a return to baseline levels only upon melatonin withdrawal. Prior pinealectomy or constant light could reverse the FSH morning response to an afternoon response, and late-morning melatonin injections could reverse the FSH afternoon response to a morning response. Neither prior pinealectomy, constant light nor melatonin injections affected melatonin inhibition of LH secretion from superfused pituitary glands. These results suggest that melatonin differentially inhibits FSH and LH secretion from isolated superfused hamster anterior pituitary glands.

The effect of chronic daily afternoon injections of melatonin upon basal and melatonin-modulated release of FSH and LH was investigated in supervised hamster anterior pituitary glands. The basal release rate of both FSH and LH began to decline following the beginning of melatonin injections, and reached a nadir after six weeks. Basal release rate of FSH and LH then began to spontaneously increase and reached a plateau at 13 weeks of injections. The inhibition by melatonin upon FSH and LH release in vitro gradually declined during the period of melatonin injections. After six weeks of melatonin injections the release rate of FSH was no longer suppressed by melatonin superfusion, while the release rate of LH became refractory to melatonin suppression in vitro after nine weeks of melatonin injections. These results demonstrate a change in the release rates of both basal and melatonin-inhibited gonadotropin release during melatonin-induced testicular regression and recrudescence in hamsters.

A combination of clomiphene citrate and human menopausal gonadotropin was employed for enhanced follicular recruitment in an in vitro fertilization program. All patients received 50 mg of clomiphene and 1 ampule of human menopausal gonadotropin daily from cycle day 5 through cycle day 9. Follicular monitoring was begun on day 10 using a combination of ultrasound measurement of follicular size and number and determination of peripheral estradiol levels. Based on the size and number of follicles, the peirpheral levels of estradiol, and the rate of follicular growth and increase in estradiol, human menopausal gonadotropin was continued at a dosage of 1 to 3 ampules/day through the day of human chorionic gonadotropin administration. Human chorionic gonadotropin was administered on the evening of the day the largest follicle reached or exceeded 20 mm in mean diameter if the estradiol levels had been rapidly rising or reaching a plateau and had exceeded a minimal level of 300 pg/ml. Using this protocol, 30 of 33 patients underwent laparoscopy, 29 patients had successful oocyte recovery, and 23 patients underwent embryo replacement, with the establishment of six clinical pregnancies.