Erik Schoute

The importance of endogenous feedback for monofollicular growth in low-dose step-up ovulation induction with follicle-stimulating hormone in polycystic ovary syndrome: a randomized study*

OBJECTIVE To evaluate the role of endogenous feedback in monofollicular growth during low-dose gonadotrophin therapy in polycystic ovary syndrome (PCOS) by measuring FSH levels in a group of patients cotreated with a GnRH agonist (GnRH-a) (group B) compared with patients not cotreated with an agonist (group A). DESIGN Prospective randomized study. SETTING University tertiary care Reproductive Endocrinology Unit. PATIENTS Women with clomiphene citrate-resistant PCOS. MAIN OUTCOME MEASURES Follicle-stimulating hormone, E2, and inhibin levels, follicular growth. RESULTS In group A, FSH levels decreased significantly from 7.3 mIU/mL (conversion factor to SI unit, 1.00) at day -5 to 5.9 mIU/mL at day 0 (day that hCG was administered) despite a constant dose, whereas they remained at a level of 7.4 mIU/mL in group B. The rate of monofollicular growth was significantly higher in group A (80%) than in group B (22%). No significant differences in E2 levels or inhibin levels were found between the groups. CONCLUSIONS The absence of a decrease of FSH during GnRH-a treatment in association with a lower rate of monofollicular growth suggests that endogenous feedback during low-dose step-up ovulation induction in PCOS plays an important role. The absence of this feedback mechanism in the presence of normal inhibin levels suggests that negative feedback control by inhibin during follicular stimulation is minimal.

Serum procollagen I carboxyterminal propeptide (PICP) levels through puberty: relation to height velocity and serum hormone levels

The synthesis of type I collagen, the major component of the organic bone matrix, is reflected by procollagen I carboxyterminal propeptide (PICP) levels. Conflicting reports have been made about the relationship between PICP levels and puberty. We have studied PICP levels in serum in relation to pubertal stage, height velocity, oestradiol, testosterone, androstenedione, dehydroepiandrosterone sulphate, insulin‐like growth factor I and growth hormone levels in 32 healthy boys aged 7.2–15.8 years and 32 healthy girls aged 7.2–14.8 years. The PICP levels in girls tended to be higher during midpuberty; in boys the levels were higher at the end of puberty. The PICP levels correlated strongly with height velocity in boys and girls. In conclusion, PICP correlates especially with height velocity. The variation of PICP between subjects during puberty is considerable. The PICP levels may predict growth at a certain moment, especially in cases where only one height measurement is available.

The GnRH challenge test: a quantitative measure of pituitary desensitization during GnRH agonist administration

OBJECTIVE The use of GnRH agonists for desensitization of the pituitary is widespread in gynaecological practice. For indications such as contraception and treatment of uterine leiomyomata partial desensitization may suffice. With respect to partial desensitization of the pituitary we have addressed three basic questions: (1) Is the degree of pituitary desensitization dependent on the dose of agonist used? (2) What is the optimal way to measure the degree of pituitary desensitization? (3) Is it possible to create a standard to express the degree of pituitary desensitization?

The reliability, acceptability and applications of basal body temperature (BBT) records in the diagnosis and treatment of infertility

The possibilities and limitations of basal body temperature (BBT) records as an adjunct in the management of infertility were re-evaluated. To assess its accuracy as an index of ovulation, 172 charts were analyzed by three different physicians. While the average true positive rate was 90%, the false negative rate was only 2%. The remaining graphs (8%) were classified as non-interpretable, probably reflecting measurement problems. Retrospective assessment of 210 biphasic records showed the thermal nadir to occur within 1 day of the urinary luteinizing hormone (LH) surge in 75% of the cases, and in 90% when 2 days where considered. This confirms BBT as a relatively accurate guide for retrospective identification of the periovulatory period. Moreover, results of a study conducted to investigate how patients experienced daily recording of BBT graphs suggest that the method is well accepted by a high proportion of women. From all these it appears that there are many indications where BBT graphs can still be applied. Development of new electronic devices may further improve the reliability, acceptability and applications of the BBT records in the fertility investigation.

The relationship between follicle-stimulating hormone dose and level and its relevance for ovulation induction with adjuvant gonadotropin-releasing hormone-agonist treatment *

OBJECTIVE To investigate the effect of a GnRH agonist (GnRH-a) on the FSH threshold level and the relationship between the FSH dose and the FSH level of patients suffering from polycystic ovarian syndrome (PCOS). DESIGN The stimulation with low-dose FSH in PCOS (group 1) was compared with the subsequently performed stimulation with low-dose FSH combined with GnRH-a in another group of patients suffering from the same syndrome (group 2). SETTING Specialist Reproductive Endocrine Unit. PATIENTS Suffering from clomiphene citrate-resistant PCOS. MAIN OUTCOME MEASURES The FSH threshold level for ongoing follicular growth and the relationship between dose and level of FSH. RESULTS In 15 patients in group 1 and in 13 patients in group 2, respectively, 39 and 32 stimulation cycles were performed. Below and above threshold values of FSH of group 1 and 2 did not differ significantly. For the equation stable level of FSH (Y mIU/mL) = A X infusion rate of FSH (X IU/24 h) + basal level of FSH (B mIU/mL), the median A of group 1 was 0.027 and A of group 2 was 0.055 (significant difference). CONCLUSIONS In PCOS, a change of the FSH threshold level for ongoing follicular growth induced by the GnRH-a could neither be proven nor ruled out. The use of a GnRH-a resulted in larger FSH level increases per IU/24 h of FSH administered and might therefore interfere with the effect of low-dose FSH treatment.

Predictive value of serum follicle-stimulating hormone levels in the differentiation between hypogonadotropic hypogonadism and constitutional delay of puberty.

Objective: Gonadotropin secretion was evaluated to predict hypogonadotropic hypogonadism (HH) in 36 children suspected of having HH. Methods: LH was measured for 24 h at 10-min intervals, and FSH and estradiol or testosterone at 1-hour intervals. Twenty boys (age 15.7, range 13.2–19.3 years) and 16 girls (age 16.1, range 13.0–20.6 years) were studied. Results: LH pulses were detected in 9 boys and 5 girls. HH was confirmed in all 11 LH apulsatile boys and in 8 of 11 LH apulsatile girls. Random FSH values of ≤1.11 and ≤2.86 IU/l in boys and girls, respectively, discriminated patients with LH pulses from patients without (sensitivity for lack of LH pulses 97 and 100%, respectively). In boys testicular volume was not discriminatory. In 1 girl LH pulses were observed without estradiol production, suggesting LH neurosecretory dysfunction. Conclusions: Low FSH levels in adolescence are strongly related to a lack of LH pulses. Lack of LH pulses is highly suspect for HH. FSH may be a tool in the differentiation between HH and delayed puberty.

Androstenedione, Dehydroepiandrosterone Sulfate, and Estradiol Levels throughout Female Puberty: Relation to Height Velocity

Sex steroids are important contributors to the pubertal growth spurt. Both androgens and estrogens have been related to this moment of rapid growth, but the role of estrogens is thought to be the most important one. Since exogenous estrogens are not capable to induce an appropriate growth spurt in girls, there might be an additional contributing factor involved. In a recent pilot study of 32 healthy pubertal girls, we found that the peak height velocity (HV) is preceded by relatively high levels of dehydroepiandrosterone sulfate and androstenedione (delta4A) as compared with the end-pubertal level. In the present study we evaluated HV in relation to dehydroepiandrosterone sulfate and delta4A levels in 149 healthy girls of various Tanner stages. HV was correlated with delta4A and estradiol levels in Tanner stages I-III. These results suggest that, like estrogens, delta4A might be an important stimulator of the female growth spurt.

Exploring the recovery phase after treatment with a gonadotrophin-releasing hormone-agonist for ovulation induction in polycystic ovary syndrome: three pilot trials

OBJECTIVE Guided by the favorable results of pulsatile gonadotrophin-releasing hormone (GnRH) in the recovery phase after GnRH agonist (GnRH-a) in PCOS, two hypotheses concerning the recovery phase were tested: (1) The resistance to clomiphene citrate will be broken in the recovery phase. (2) Stimulation with (i) a fixed dose of follicle stimulating hormone (FSH) or (ii) with the GnRH-a itself is equally effective in inducing ovulation as pulsatile GnRH. DESIGN After discontinuation of a 17-21 days GnRH-a treatment, ovulation induction was attempted with clomiphene citrate (CC) or with a fixed dose of FSH or with GnRH-a itself in three separate pilot trials. A previously reported group of 12 patients, treated with pulsatile GnRH in the recovery phase served as control. PATIENTS Three groups of six patients having PCOS. The group treated with CC was a selected CC-resistant group. RESULTS No CC-treated patient ovulated. After FSH stimulation two patients ovulated, and one patient ovulated on stimulation with a low dose of the GnRH-a. Endocrine observations in the recovery phase showed an early rise of FSH as compared to the rise of LH and androgens. CONCLUSION This study could not demonstrate any effect of the recovery phase with respect to facilitation of follicular growth in PCOS. Both tested hypotheses were rejected: (1) The resistance to CC appeared not to be broken by the GnRH-a treatment and (2) subsequent stimulation with FSH or with the GnRH-a itself were not as effective as stimulation with pulsatile GnRH. An extensive further study of the mentioned modalities did not seem feasible.