Maximum Follicle-stimulating Hormone Research Articles

O-185 A clinically robust machine learning model for selecting the first FSH dose during controlled ovarian hyperstimulation: incorporating clinical knowledge to the learning process

Abstract Study question Can we improve the selection of the first dose of follicle stimulating hormone (FSH) for IVF patients by incorporating clinical evidence with machine learning? Summary answer A significant improvement in correct dose prescription is achieved when using a FSH dosing model that integrates a novel machine learning methodology with clinical knowledge. What is known already The appropriate selection of the initial FSH dose during controlled ovarian hyperstimulation (COH) is key for ART success. An optimal number of oocytes should be obtained for achieving pregnancy, while also avoiding complications for the patient. While clinical protocols achieve good results for the majority of patients, further refinements in individualized FSH dosing may improve safety while reducing the risk of poor response. Machine learning techniques have been applied to dose/response problems with promising results. However, the observational datasets used to train the models are often incomplete and biased, leading to less clinically robust predictions. Study design, size, duration We used a database of 2713 first cycles performed between January 2011 and December 2019, across five clinics to train the model. Predictors included age, body mass index (BMI), anti-Müllerian hormone (AMH) levels and antral follicle count (AFC). First FSH dose and number of mature oocytes retrieved were also recorded. Another 273 cycles performed between January 2020 and September 2021 were used for validation. Dosing was performed by 41 clinicians (mean 12 years of experience). Participants/materials, setting, methods The model was developed in Python and trained while incorporating available clinical evidence. The relationship between FSH dose and response (number of mature oocytes) was specified by assuming a positive linear function. Rules were incorporated to penalize dose changes that resulted in poorer outcomes compared to the clinician, and to discourage large dose modifications by the model. These same rules were applied during the validation phase. Comparisons were assessed by Chi-squared test with Bonferroni correction. Main results and the role of chance Mean maternal age was 37.1 ± 4.9 years. Patients had a mean BMI of 23.8 ± 4.2, AFC of 11.9 ± 7.7 and AMH of 2.4 ± 2.3. They were prescribed a first dose of 247.0 ± 59.0 IU of FSH and obtained 7.3 ± 5.3 mature oocytes after pick-up. An optimal outcome was defined as 10-15 mature oocytes retrieved, and 300 IU was the maximum FSH dose allowed. In the validation dataset, we observed that 22.9% patients could have received a higher FSH dose (<10 mature oocytes collected), 69.3% were correctly prescribed (10-15 mature oocytes or no change in dose was required), while 7.9% needed a decrease in FSH dose (>15 mature oocytes). In the machine learning model 9.4% of patients required a dose increase, 80.5% were correctly prescribed and 7.9% needed a decrease in dose. Accordingly, the model rescued 11.6% of patients that would have otherwise achieved suboptimal outcomes. Ultimately, when compared to the clinicians, the model significantly reduced the number of patients that required a dose increase, and significantly improved the number of patients that were prescribed a correct dose (p < 0.05). Limitations, reasons for caution The model assigned a non-conservative dose increase to 2.3% of patients, potentially leading to a risk of ovarian hyperstimulation syndrome. Moreover, hyper-responders were underrepresented in the database, resulting in no significant improvements in the dose/outcome relationship for this subgroup. Wider implications of the findings Coding clinical knowledge into the training of clinically relevant machine learning models ensured adherence to scientific evidence, and improved model performance while making conservative changes. This approach is critical for the safe and robust clinical implementation of interventional models. Trial registration number not applicable

ANTI-MÜLLERIAN HORMONE AND FOLLICLE STIMULATING HORMONE ARE POOR INDEPENDENT PREDICTORS OF LIVE BIRTH AFTER ASSISTED REPRODUCTIVE TECHNOLOGY

To query if anti-Müllerian hormone (AMH) and/or follicle stimulating hormone (FSH) predict live birth at University of Colorado Advanced Reproductive Medicine (CU ARM). We used the 2017-2019 Society for Assisted Reproductive Technology Clinical Outcomes Reporting System to identify all CU ARM autologous oocyte cycles. Donor gametes and frozen oocytes were excluded. The pregnancy outcome was recorded from the initial fresh or frozen embryo transfer. Multivariable linear regression was used to compare log AMH or FSH levels across pregnancy outcomes after adjusting for age categories including <35 years, 35-37 years, 38-40 years, 41-42 years, and >42 years. AMH or FSH values (n=988 cycles from 457 patients) were recorded for 255 transfers. The live birth (L/B) rate was 57.3% (146/255), which declined with increasing age group (p=0.008). Spontaneous abortion (SAB) rate was 12.9% (33/255), and the remaining 29.8% of transfers (76/255) were unsuccessful (N/E). The average AMH values did not differ among pregnancy outcomes after adjusting for age groups (p=0.51). FSH values, on the other hand, were on average 15% lower in the SAB group (geometric mean ratio=0.85, 95% CI: 0.75-0.97, p=0.014). Minimum observed AMH achieving a L/B increased with increasing age groups. Maximum FSH achieving a L/B had no trend across age groups. AMH and FSH are poor independent predictors of L/B after assisted reproductive technology (ART).

Differential impact of controlled ovarian hyperstimulation on live birth rate in fresh versus frozen embryo transfer cycles: a Society for Assisted Reproductive Technology Clinic Outcome System study

To study the impact of both controlled ovarian hyperstimulation (COH) length and total gonadotropin (GN) dose individually and in concert on live birth rates (LBR) in both fresh and freeze-all invitro fertilization embryo transfer (IVF-ET) cycles. Historical cohort study. Not applicable. The U.S. national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System from 2014 to 2015 was used to identify patients undergoing autologous GN stimulation IVF cycles with the use of GnRH antagonist-based suppression protocols where a single embryo transfer was performed as part of a fresh IVF-ET cycle (fresh, n = 14,866) or the first frozen embryo transfer after a freeze-all cycle (frozen, n = 2,964), and not including preimplantation genetic testing cycles. The patients' demographic and cycle characteristics, duration of COH, total GN dose, and pregnancy outcomes were extracted. Binomial regression models estimated trend and relative risk of live birth with respect to days of stimulation and total GN dose singularly, and after adjustment for a priori confounders including age, parity, body mass index, diagnosis, and maximum follicle-stimulating hormone in both fresh and frozen embryo transfer cycles. Both days of stimulation and total GN dose were then added to the multivariate model to show whether they were independently associated with LBR. Not applicable. Live birth rate. In both fresh and frozen cycles, length of COH was significantly associated with total GN dose. On univariate analysis, LBR decreased significantly with increasing length of stimulation and increasing total GN dose in both fresh and frozen cycles. On multivariable analysis including both days of stimulation and total GN dose, days of stimulation was no longer significantly correlated with LBR, whereas total GN dose remained significantly correlated with LBR in fresh cycles only. When total GN doses ranging from <2,000 IU through 5,000 IU to >5,000 IU were compared, a significant improvement in live birth rate was noted with lower total GN doses. Specifically, GN doses <2,000 IU had a 27% higher rate of live birth compared with GN dose >5,000 IU. For GN dose groups up to 4,000 IU, the estimated effect on LBR was similar. There was a marginal improvement (13%) in LBR with GN doses of 4,000 IU to 5,000 IU compared with >5,000 IU. When the multivariate model was applied to the frozen cycles, neither total GN dose nor days of stimulation was significantly associated with LBR. High total GN dose but not prolonged COH is associated with decreasing LBRs in fresh cycles, whereas neither factor significantly affects LBR in frozen cycles. Consideration should be given to minimizing the total GN dose when possible in fresh autologous cycles, either by decreasing the daily dose or by limiting the length of stimulation to improve LBRs. In freeze-all cycles, the use of higher GN doses does not seem to adversely affect the LBR of the first frozen embryo transfer. High total GN dose likely exerts a negative impact on the endometrium and/or oocyte/embryo unrelated to the length of stimulation. The differential effect of total GN dose on LBR in fresh and frozen cycles may imply a greater impact exerted on the endometrium rather than the oocyte.

Maximum basal FSH predicts reproductive outcome better than cycle-specific basal FSH levels: waiting for a "better" month conveys limited retrieval benefits.

BackgroundElevated follicle stimulating hormone (FSH) is associated with poor vaginal oocyte retrieval (VOR) outcomes and cycle cancellations but intercycle variability in basal FSH reportedly does not predict ovarian response.MethodsWe conducted a retrospective cohort study of basal FSH (n = 15573 cycles) in couples (n = 9132) who initiated IVF cycle(s) with basal estradiol (E2) <100 pg/mL between 2002 and 2014 to reevaluate this hypothesis.The most recent (current) FSH, maximum FSH (Max FSH) and prior cycle maximum basal FSH (PMax FSH) were computed for each cycle. Metaphase II (MII) oocyte counts were modeled by age, stimulation type, prior peak E2 level, prior MII count, Max FSH, PMax FSH and current FSH. Antral follicle counts, pregnancy, clinical pregnancy and live birth rates were modeled as secondary outcomes.ResultsMax FSH level distinguished completed cycles from cancelled cycles better than PMax FSH or current FSH (AUC of 0.72, 0.71 and 0.61, respectively, p < 0.001). Fewer MIIs were retrieved (5.7 ± 3.8) in cycles with Max FSH >13 mIU/mL (n = 1475) than those with ≤13 mIU/mL (n = 11978) (11.6 ± 7.1) (p < 0.001). Max FSH was a better predictor of MII count than PMax FSH or current FSH after controlling for age, stimulation type, prior peak E2 level and prior MII count.Additional MIIs were retrieved on average in cycles with PMax FSH >13 mIU/mL (n = 1930) whose current FSH was ≤13 mIU/ml rather than >13 mIU/ml (p < 0.01) after controlling for age, cycle number and stimulation type. However, no improvement in pregnancy or live birth rate was detected.ConclusionsMax FSH is the best FSH-based predictor of ovarian reserve. Retrieval benefits from waiting for a "better" month appear to exist but are limited.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0078-0) contains supplementary material, which is available to authorized users.

Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer.

Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5-28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36-9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated palliatively with ADT for advancing prostate cancer. Further clinical investigation in a larger cohort of men is required to determine any clinical utility of FSH as a biomarker of progression or target for therapy.

Prenatal diethylstilbestrol exposure and reproductive hormones in premenopausal women.

Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-1900s, is a potent endocrine disruptor. Prenatal DES exposure has been associated with reproductive disorders in women, but little is known about its effects on endogenous hormones. We assessed the association between prenatal DES exposure and reproductive hormones among participants from the Harvard Study of Moods and Cycles (HSMC), a longitudinal study of premenopausal women aged 36-45 years from Massachusetts (1995-1999). Prenatal DES exposure was reported at baseline (43 DES exposed and 782 unexposed). Early follicular-phase concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured at baseline and every 6 months during 36 months of follow-up. Inhibin B concentrations were measured through 18 months. We used multivariable logistic and repeated-measures linear regression to estimate odds ratios (OR) and percent differences in mean hormone values (β), respectively, comparing DES exposed with unexposed women, adjusted for potential confounders. DES-exposed women had lower mean concentrations of estradiol (pg/ml) (β=-15.6%, 95% confidence interval (CI): -26.5%, -3.2%) and inhibin B (pg/ml) (β=-20.3%, CI: -35.1%, -2.3%), and higher mean concentrations of FSH (IU/I) (β=12.2%, CI: -1.5%, 27.9%) and LH (IU/I) (β=10.4%, CI: -7.2%, 31.3%), than unexposed women. ORs for the association of DES with maximum FSH>10 IU/I and minimum inhibin B<45 pg/ml--indicators of low ovarian reserve--were 1.90 (CI: 0.86, 4.22) and 4.00 (CI: 0.88-18.1), respectively. Prenatal DES exposure was associated with variation in concentrations of FSH, estradiol and inhibin B among women of late reproductive age.

Urinary Follicle-Stimulating Hormone as a Measure of Natural Fertility in a Community Cohort

High serum follicle-stimulating hormone (FSH) levels have been associated with diminished ovarian reserve; however, the association between high urinary FSH and reduced natural fertility has yet to be established. We sought to characterize the relationship between a single or multiple measurements of early follicular phase urinary FSH and fertility. Women (n = 209), 30 to 44 years old with no history of infertility, who had been trying to conceive for less than 3 months, provided early follicular phase urine. Participants subsequently kept a diary to record bleeding and intercourse and conducted standardized pregnancy testing for up to 6 months. A subset of women (N = 95) collected urine on cycle day 3 for up to 6 cycles. Urine was analyzed for FSH and creatinine (cr) corrected. Proportional hazard models were used to calculate fecundability ratios (FRs). Urinary FSH levels across cycles from the same woman were highly correlated (adjusted intraclass correlation = .77); within-woman variance was 3-fold lower than variance among women. Women with an initial urinary FSH level <7 mIU/mg cr exhibited a nonsignificant reduction in the probability of pregnancy (adjusted FR 0.71, 95% confidence interval [CI]: 0.45-1.13), as did women with elevated urinary FSH (≥12 mIU/mg cr; adjusted FR 0.78, 95% CI: 0.46-1.32). Using the most recent or maximum urinary FSH value did not strengthen the association. In the general population, urinary FSH levels appear to be nonlinearly associated with fertility; however, broad CIs indicate a lack of statistical significance. Repetitive testing appears to be of little benefit.

Overnight Levels of Luteinizing Hormone, Follicle-Stimulating Hormone and Growth Hormone before and during Gonadotropin-Releasing Hormone Analogue Treatment in Short Boys Born Small for Gestational Age

Aims: To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone (GH) profiles and fasting insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels after 3 months of GnRHa treatment with those at baseline. Methods: After measurement of baseline overnight profiles and IGF-I and IGFBP-3 levels, 14 short pubertal SGA boys received leuprorelide acetate depots of 3.75 mg subcutaneously, every 4 weeks. Results: At baseline, mean GH levels were comparable with those of controls, whereas IGF-I and IGFBP-3 standard deviation scores (SDS) were significantly lower than zero SDS. After 3 months of GnRHa treatment, all boys showed clinical arrest of puberty. The area under the curve above zero, mean and maximum LH and FSH had significantly decreased to prepubertal levels. Peak LH during the GnRH agonist test, however, indicated insufficient pubertal suppression in 43% of boys. Overnight GH profile characteristics and IGF-I and IGFBP-3 levels did not significantly change. Conclusions: Puberty was sufficiently suppressed by GnRHa treatment, as shown by the prepubertal LH and FSH profiles. After 3 months of GnRHa treatment, overnight GH profile characteristics had not significantly changed, reflecting that GH levels are comparable for prepubertal and early pubertal boys.

Adaptation of Chinese hamster ovary cells to high potassium ion-containing medium for enhancement of follicle-stimulating hormone production

In this study, a suspension culture of recombinant Chinese hamster ovary (CHO) cells producing follicle-stimulating hormone (FSH) was used to investigate the effects of potassium ion (K+) on cell growth and FSH production. Cell growth was significantly suppressed at a K+ concentration higher than 60 mM, but specific FSH productivity (q FSH) was enhanced more than 2-fold compared to the value obtained at 4 mM K+. In an attempt to alleviate the cell growth suppression at a high K+ concentration, the cells were adapted at 60 mM K+ in a repeated batch mode. During adaptation, the growth rate increased from 0.010 to 0.020 h−1, andq FSH also gradually increased and reached 11.1 ng/(106 cells h), which was even higher than that of the unadapted cells at 60 mM K+. The adapted cells showed a 2.6-fold increase in maximum FSH titer at 80 mM K+ compared to the unadapted cells at 4 mM K+. Taken together, these results demonstrate the potential of using culture media containing cells adapted to high K+ concentrations, for the enhancement of recombinant protein production.

Effect of culture temperature on follicle-stimulating hormone production by Chinese hamster ovary cells in a perfusion bioreactor

Follicle-stimulating hormone (FSH) was produced in Chinese hamster ovary (CHO) cells using a perfusion bioreactor. Perfusion culture at 37 degrees C yielded a high cell density but a low FSH production. To investigate the effect of culture temperature in the range of 26-37 degrees C on cell growth and FSH production, batch cultures were performed. Lowering culture temperature below 32 degrees C resulted in growth suppression. However, specific productivity of FSH, q (FSH), increased as culture temperature decreased, and the maximum q (FSH) of 43.4 ng/10(6) cells/h was obtained at 28 degrees C, which is 13-fold higher than that at 37 degrees C. Based on the results obtained from batch cultures, we performed perfusion cultures with two consecutive temperatures. CHO cells were grown up to 3.2 x 10(7) cells/ml at 37 degrees C and culture temperature shifted down to 28 degrees C to obtain a high FSH titer. Soon after the maximum FSH titer of 21 mug/ml was achieved, a rapid loss of not only viable cell concentration but also cell viability was observed, probably due to the low activities of enzymes related to cell growth. Thus, the extension of production period at 28 degrees C is critical for the enhancement of FSH production, and the use of antiapoptotic genes seems to be promising.

Lamprey GnRH‐III Stimulates FSH Secretion in Barrows

Although studies have indicated that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release can be dissociated in the pig, the underlying mechanisms are still to be answered. Since it was demonstrated that lamprey gonadotropin-releasing hormone (l-GnRH-III) has preferential FSH-releasing potency in several mammalian species, we have investigated the gonadotropin-releasing activity of l-GnRH-III in barrows. Each of nine barrows (body weight: 85-90 kg; age: 207 days) received 2 ml saline (S-barrow), followed by 150 microg l-GnRH-III (1.6-1.7 microg/kg body weight) dissolved in 2 ml saline intramuscularly 7 days later. Three pre-treatment and 13 post-treatment blood samples were taken at intervals of 30 min to 8 h to assess basal and treatment-associated concentrations of FSH and LH, respectively, by radioimmunoassay. Animals were defined as having responded to treatment if, 2 h post-treatment, plasma FSH and/or LH levels were >3 SD of the respective basal concentrations. There was no treatment-associated FSH response after saline treatment, but a clear FSH response in all l-GnRH-III-injected barrows. On average, the maximum FSH level (205% of the basal concentration) was observed at 1 h post-treatment. Mean FSH values were elevated until 10 h post-treatment. There was no LH response either to saline or to l-GnRH-III. In conclusion, this study demonstrates a selective FSH-releasing activity of 150 microg l-GnRH-III in barrows. Further studies are needed to investigate whether this effect is ubiquitous in the pig and what the physiological relevance is.

Endocrine control of estrous cycle in mithun ( Bos frontalis)

The objective of the present study was to establish the profiles of luteinising hormone (LH), follicle stimulating hormone (FSH), estradiol 17β (E2) and progesterone (P4) secretion and their interrelationships during the natural estrous cycle of mithun ( Bos frontalis). Daily blood samples were collected from second or third postpartum estrous cycles for determination of plasma concentrations of LH, FSH, E2 and P4. Concentration of P4 was found to be lowest on the day of estrus. It increased following estrus, attained the highest concentration on day 11 and decreased thereafter. Concentrations of LH and FSH varied significantly ( p < 0.01) during the first and last 6 days of the cycle and their variations were found to be synchronised. Both LH and FSH attained a biphasic peak during the estrous cycle. This biphasic peak lasted on from day −5 to day 3 of the cycle. The variations in maximum LH and FSH concentrations of both the phases did not differ significantly. During the entire estrous cycle, the E2 concentrations attained either one peak or two peaks. The first peak, approximately on day 4 before estrus was common in all animals. One additional peak was found on the day of estrus in 45% animals. A significant ( p < 0.01) negative relationship was found between P4 and, LH and FSH during the first and last 6 days of cycle. But a significant ( p ≤ 0.01) negative relationship between E2 and, LH and FSH was found only during the last 6 days of cycle. The results suggest a negative feedback mechanism on LH and FSH release by E2 and P4 during the respective phases of cycle. A sustained increase in LH and FSH levels during the period before estrus was probably necessary for the final maturation of ovulatory follicle and subsequent ovulation.

Ovarian follicular dynamics and endocrine profiles in Polwarth ewes with high and low body condition

AbstractIn this investigation we tested the hypothesis that static body condition (BC) of the ewe affects oestradiol and FSH with implications for subsequent follicular growth and turn-over. Sixteen Polwarth ewes were selected from a flock according to their BC score (scale: 1 emaciated; 5 obese). High BC (HBC) ewes (no. = 8) had a BC score of 4·1 (s.e. 0·1) and low BC (LBC) ewes (no. = 8) had a BC score of 1·9 (s.e. 0·1). Daily ultrasound examinations were performed and blood samples for progesterone, oestradiol and follicle-stimulating hormone (FSH) determination were collected. All HBC ewes (8/8) exhibited three waves of follicular development, while four LBC ewes (4/8) had two waves and the other four (4/8) had three waves of follicular development (P ≤ 0·05) during the interovulatory period. Overall, the emergences of 33 out of 44 follicular waves were preceded by significant increases in FSH concentrations. Maximum FSH concentrations were detected 0·9 ± 0·2 days before wave emergence. Oestradiol concentrations increased significantly during the growing phase in 38 out of 44 large follicles. A negative correlation between oestradiol and FSH was observed in HBC ewes. A similar inhibitory effect of oestradiol on FSH was observed in LBC ewes, irrespective of whether they developed two or three follicular waves. However, a longer period with high FSH was needed to promote the emergence of the second follicular wave in two-wave LBC ewes. Four HBC ewes had twin ovulations but no LBC ewes did (P ≤ 0·05). In HBC ewes, the follicular phase was characterized by lower oestradiol (6·5 (s.e. 1·0) pmol/l) but higher mean FSH concentrations (2·4 (s.e.0·4) μg/l) than in LBC ewes (8·9 (s.e. 1·2) pmol/l and 2·0 (s.e. 0·3) μg/l, respectively; P ≤ 0·05). The present results suggest that BC influences the pattern of follicular dynamics through changes in the endocrine milieu. Higher FSH concentrations during the follicular phase in HBC ewes, which allowed an extended period of follicular recruitment from a significantly larger pool of small antral follicles could explain the higher ovulation rate observed in this group.

Follicle development during the normal menstrual cycle

An understanding of the factors which determine initiation of follicle growth, recruitment and dominant follicle selection may increase our understanding of the underlying process of ovarian aging. In this article, these aspects of the normal menstrual cycle are reviewed. The morphological and endocrinological development in the early follicle is described from the primordial follicle stage. The degree of follicle-stimulating hormone (FSH) dependency is discussed, as is the relationship of estradiol (E 2) production to follicle diameter. The principles governing mono-follicular selection are outlined, and the FSH `threshold' and `window' concepts are highlighted. Maximum FSH levels in the early follicular phase are shown to be variable between individuals. The relevance of this and the means by which individual sensitivity to FSH may be altered at the ovary in the context of ovarian aging are discussed.

Lack of correlation between maximum early follicular phase serum follicle stimulating hormone concentrations and menstrual cycle characteristics in women under the age of 35 years.

The gradual increase in follicle stimulating hormone (FSH) concentrations in women approaching menopause results from the depletion of the ovarian follicular pool, a process referred to as 'ovarian ageing'. This study investigates whether variable endogenous FSH concentrations, as have been observed in normo-ovulatory young women, are related to menstrual cycle characteristics, including predictors of ovarian ageing. Serum concentrations of immunoreactive FSH, oestradiol, and inhibin-A and inhibin-B were measured, and follicular growth was assessed by transvaginal ultrasound throughout the follicular phase in 39 healthy volunteers (20-35 years) with regular menstrual cycles. Median serum FSH concentration on cycle day 3 was 5.1 IU/l (range 3.6-11.2), and median maximum follicular phase FSH was 6.2 IU/l (range 4.3-11.2), observed on cycle day 6 (range 2-15). Maximum FSH concentrations were not correlated with age or cycle length, nor with maximum inhibin-B. The number of small (<10 mm) antral follicles on cycle day 3 was 11 (range 4-21) and was not correlated with age, nor with maximum FSH. Inhibin-A remained low until a significant rise on cycle day 9 (range 3-12), which was significantly correlated with the late follicular rise in oestradiol (r = 0.56, P = 0.01). These observations indicate a lack of correlation between maximum follicular phase serum FSH concentrations and parameters of ovarian ageing in women under the age of 35 years. In addition, FSH concentrations assessed on cycle day 3 represent an underestimation of maximum early follicular phase FSH. Distinct individual differences in intra-ovarian modification of FSH action, resulting in differences in the FSH threshold for stimulation of ovarian function, may be operative.

Are there any predictive factors for successful testicular sperm recovery in azoospermic patients?

Recovery of testicular spermatozoa from azoospermic patients with testicular failure followed by intracytoplasmic sperm injection (ICSI) is a recent advance in the treatment of male infertility. This study aimed at investigating which parameter(s) may predict successful testicular sperm recovery. We reviewed 395 testicular sperm recovery procedures and analysed the most frequently available parameters for clinical decision-making in azoospermic patients: (i) presence of at least one single spermatozoon in at least one preliminary semen analysis; (ii) maximum testicular volume; (iii) serum follicle stimulating hormone (FSH); and (iv) presence of spermatozoa in the histology of a randomly-taken testicular biopsy. Sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio and accuracy were calculated for the above index parameters in different clinically relevant subgroups using receiver operating characteristic (ROC) curves whenever possible. Spermatozoa were always successfully recovered in patients with normal testicular histological findings (n = 173) or hypospermatogenesis (n = 16) but not in some patients with tubular sclerosis (seven out of 18), Sertoli cell-only pattern (55 out of 112) or maturation arrest (39 out of 76). Histopathology was the best test for predicting successful sperm recovery in the whole population (sensitivity: 86%, specificity: 93%, accuracy: 0.87). In patients with secretory azoospermia, histopathology was again the most accurate parameter (accuracy: 0.74), especially in patients showing Sertoli cell-only pattern (accuracy: 0.83) but not in patients showing maturation arrest (accuracy: 0.55). In patients with serum FSH concentrations > 12 IU/l and maximum testicular volume < 15 ml, histopathology was not found to be accurate. Semen analysis, maximum testicular volume and serum FSH were not highly predictive in all subgroups studied. Our analysis shows that no strong predictors for successful testicular sperm recovery are available except for testicular histopathology.

Age-related variation of follicle-stimulating hormone-stimulated cAMP production, protein kinase C activity and their interactions in the rat testis

To study further the ontogeny of hormonal regulatory mechanisms in the testis, we measured follicle-stimulating hormone (FSH)- and protein kinase C (PKC)-stimulated cAMP production, PKC activity, and messenger (m)RNA levels of the PKC isoenzymes α, β and γ in rat testes between day 19 of fetal life and day 90 postpartum. Human FSH (30 mg/1) stimulated slightly but significantly cAMP production of fetal testes (57%; p < 0.05). A higher response (3-fold; p < 0.01) was observed on the day of birth, and the maximum FSH effect on cAMP (23-fold) was observed on day 10 postpartum. Thereafter, a gradual decline of FSH response occurred towards adult age. Concerning testicular PKC, the soluble (inactive) form had its maximum at the age of 1 day and this PKC form declined gradually thereafter. The particulate (active) form was low at birth, increased 6-fold on days 8–11 of age, and declined thereafter. A significant age-dependent variation was also found in the mRNA level of the PKC α isoenzyme (maximum on day 10), whereas those of PKC γ and PKC β were undetectable at all ages in Northern blots. When the in vitro modulation of basal and FSH-dependent cAMP production by the PKC activator 12- O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/1) was studied, the substance alone was without effect at all ages studied. The TPA effect on FSH-stimulated cAMP production displayed age-dependent variation: a slight stimulation in fetal testes, no effect at birth, decrease between days 8 and 11, and no effect on day 30. In conclusion, the FSH-stimulated cAMP production is at its maximum in rat testicular tissue on days 8–11 postpartum. The age of maximum cAMP production is associated with a sharp peak in the active form of PKC and in the mRNA level of PKC isoenzyme α. At the same tune, a transition appears to occur from stimulation to inhibition in the modulatory effect of PKC on FSH-stimulated cAMP production. Thus, clearcut developmental changes occur in testicular FSH action and its modulation by the PKC-related signal transduction systems.

Dose and time-course evaluation of a redox-based estradiol-chemical delivery system for the brain. II. Pharmacodynamic responses.

Clinically, brain-enhanced delivery and sustained release of estradiol (E2) are desirable for effective treatments of menopausal hot flushes and prostatic adenocarcinoma and for fertility regulation. Thus, we conducted studies to determine the dose- and time-dependent effects of a brain-enhanced estradiol-chemical delivery system (E2-CDS) on anterior pituitary hormones secretion in ovariectomized (OVX) rats. The E2-CDS has consistently demonstrated preferential retention of its intermediate metabolite (E2-Q+), with slow release of E2 in the brain but rapid clearance from peripheral tissues. Animals received a single iv injection of E2-CDS at doses of 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg on day 0. The responses of plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL) were then evaluated at 1, 7, 14, 21, or 28 days after drug administration. The E2-CDS caused a dose- and time-dependent suppression of LH and FSH throughout the time course studied. The maximum LH and FSH reduction occurred at 7 days postinjection. Plasma LH and FSH were significantly suppressed by 86 and 58% on day 7, respectively, and were suppressed by 35% (LH) or were at preinjection levels (FSH) at 28 days following the single injection of a 1.0-mg E2-CDS dose. An equimolar E2 dose suppressed LH and FSH by only 29 and 20% on day 7, respectively which were not significantly different from time 0 values. Plasma PRL increased significantly on day 14 with the 1.0-mg E2-CDS dose but levels returned to preinjection values by 28 days after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum levels of prolactin, TSH and gonadotrophins following LRH/TRH--double stimulation tests during the menstrual cycle.

Abstract. The objective of this study was to re-investigate the capacity of pituitary prolactin (Prl) and thyrotrophin (TSH) secretion throughout the normal menstrual cycle to respond to repeated thyrotrophin releasing hormone (TRH) stimulation analogous to the double luteinizing hormone-releasing hormone (LRH) stimulation test. This test has been shown to be a sensitive parameter for oestrogenic effects on the gonadotrophs. In addition, the volunteers were selected carefully on the basis of ovulatory cycles and otherwise normal endocrine function. In 9 women a combined LRH/TRH double stimulation test was performed during the early follicular, periovulatory and mid-luteal phases. TRH (200 μg) and LRH (25 μg) each were given iv twice, 2 h apart. Basal and LRH stimulated luteinizing hormone (LH) and follicle stimulating hormone (FSH) were found to follow characteristic cyclic response patterns. The LH responses after both LRH stimulations were greatest in the periovulatory phase; Δ1 and Δ2 were higher in the mid-luteal phase than in the follicular phase. Maximum FSH response to LRH was found during the periovulatory phase, but the FSH response in the early follicular phase was greater than that found in the mid-luteal phase. In contrast, basal and TRH stimulated serum concentrations of TSH and Prl remained constant throughout the cycle. The gonadotrophin ratios Δ2:Δ1 were generally greater than 1. They increased from 1.4 in the early follicular phase to 3.0 in the late follicular phase, concomitant with the rise in oestrogens. The Δ2: Δ1 ratios for TSH and Prl were less than 1, ranging from 0.66 to 0.98 for TSH and from 0.26 to 0.99 for Prl. They did not show any cyclic changes. Thus, this study shows that after LRH/TRH double stimulation, the gonadotrophin but not the Prl and TSH responses vary with the physiological changes in oestrogens during the menstrual cycle. The supposed mechanism of oestrogen effects on pituitary hormone secretion and their possible clinical significance are discussed.

Inhibition of ovulation in women by chronic treatment with a stimulatory lrh analogue — A new approach to birth control?

A stimulatory luteinizing hormone-releasing hormone (LRH) analogue D-Ser (TBU) 6-EA 10-LRH was administered subcutaneously once daily in a dose of 5 ug to four regularly menstruating women. Treatment was instituted within the first three days of the menstrual bleeding and continued for 22 – 30 days. Ovulation was inhibited in all the women during the treatment cycle. The treatment resulted in disturbances in the pituitary gonadotropin secretion which presumably led to disordered follicular maturation and anovulation. The maximum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to the LRH analogue were obtained during the first few days of treatment. The gonadotropin responses then rapidly decreased during the prolonged treatment. This change in the pituitary responsiveness probably prevented the release of a normal preovulatory LH surge. After the treatment, all the women resumed normal ovulatory menstrual cycles. The results suggest that it might be possible to use stimulatory LRH analogues for birth control.