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Human flavin-containing monooxygenase 3 (hFMO3) is a drug-metabolising enzyme that oxygenates many drugs and xenobiotics in the liver. This enzyme is also known to exhibit single nucleotide polymorphisms (SNPs) that can alter the rates of monooxygenation of therapeutic agents. The purpose of this study was to investigate the effect of the three common polymorphic variants of hFMO3 (V257M, E158K and E308G) on the metabolism and clearance of three structurally similar compounds: tamoxifen (breast cancer medication), clomiphene (infertility medication) and GSK5182 (antidiabetic lead molecule). For GSK5182, none of the three variants showed any significant differences in its metabolism when compared to the wild-type enzyme. In the case of clomiphene, two of the variants, V257M and E308G, exhibited a significant increase in all the kinetic parameters measured with nearly two times faster clearance. Finally, for tamoxifen, a mixed behaviour was observed; E158K variant showed a significantly higher clearance compared to the wild type, whereas V257M mutation had the opposite effect. Overall, the data obtained demonstrate that there is no direct correlation between the SNPs and the metabolism of these three hFMO3 substrates. The metabolic capacity is both variant-dependent and substrate-dependent and therefore when testing new drugs or administering already approved therapies, these differences should be taken into consideration., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Clomiphene citrate (CC) is the oldest drug used to regulate the process of ovulation. Considering the great use of CC over the last 40 years, it is important to understand the possible risks associated with its use. The aim of this review was to evaluate the possible teratogenic effects of CC, analyzing results obtained from animal and human studies. The pharmacokinetics of CC and possible mechanisms involved in teratogenesis are examined. Fetal exposure to CC is possible due to the long half-life of CC and its metabolites. Alarming data have emerged from animal studies, although controversial results come from human studies. There is some evidence regarding a possible association of CC exposure and fetal malformations, mainly neural tube defects and hypospadias, which would require further investigation in order to allow safer use of this useful drug.

This study compared the responses shown by lactating dairy cows to four different P4-based protocols for AI at estrus. Cows with no estrous signs 96 h after progesterone intravaginal device (PRID) removal were subjected to fixed-time AI (FTAI), and their data were also included in the study. In Experiment I, follicular/luteal and endometrial dynamics were assessed every 12 h from the beginning of treatment until AI. The estrous response was examined in Experiment II, and fertility was assessed in both experiments. The protocols consisted of a PRID fitted for five days, along with the administration of different combinations of gonadotropin releasing hormone (GnRH), equine chorionic gonadotropin and a single or double dose (24 h apart) of prostaglandin F2α. In Experiment I (40 cows), animals receiving GnRH at the start of treatment showed a significantly higher ovulation rate during the PRID insertion period while estrus was delayed. In Experiment II (351 cows), according to the odds ratios, cows showing luteal activity at the time of treatment were less likely to show estrus than cows with no signs of luteal activity. Treatment affected the estrous response and the interval from PRID removal to estrus but did not affect conception rates 28-34 days post AI. Primiparous cows displayed a better estrous response than multiparous cows. Our findings reveal acceptable results of 5-day P4-based protocols for AI at estrus in high-producing dairy cows. Time from treatment to estrus emerged as a good guide for FTAI after a 5-day P4-based synchronization protocol.

We evaluated perioperative androstenedione levels in laparoscopic ovarian drilling (LOD) for polycystic ovary syndrome (PCOS) and whether an intraoperative androstenedione change was predictive for spontaneous ovulation. In a prospective study, 21 anovulatory women with clomiphene citrate-resistant PCOS who underwent LOD and eight female controls who underwent diagnostic laparoscopy for infertility were included. Perioperatively, blood was drawn one day before surgery, directly before skin incision, ten minutes after surgery, and after two days. Within three months, spontaneous ovulation occurred in 15 women (71.4 %). For both the PCOS and the control group, an androstenedione increase was found from one day before surgery to skin incision (p < 0.05). In PCOS women, there was an intraoperative androstenedione decrease (median 3.5, IQR 2.2-4.8 vs. median 2.6, IQR 1.4-2.6 ng/ml, p = 0.002). In multivariate analysis, only higher preoperative androstenedione (odds ratio, OR 6.53) and luteinizing hormone levels (OR 7.31), as well as secondary infertility (OR 5.40), were associated with higher rates of postoperative spontaneous ovulation (p < 0.001). Androstendione declines significantly during LOD. However, intraoperative kinetics are not useful for the prediction of spontaneous ovulation after LOD, in contrast to preoperative androstenedione and LH levels, as well as a history of previous pregnancies.

The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for the model peptide drug leuprorelin to prove a protective effect against luminal enzymatic metabolism. In order to incorporate leuprorelin into microemulsion droplets (o/w), the commercially available hydrophilic leuprolide acetate was modified by hydrophobic ion paring with sodium oleate. The obtained hydrophobic leuprolide oleate was dissolved in the SMEDDS formulation (30% (m/m) Cremophor EL, 30% (m/m) Capmul MCM, 10% (m/m) propylene glycol and 30% (m/m) Captex 355) in a concentration of 4 mg/g showing a mean droplet size of 50.1 nm when dispersed in a concentration of 1% (m/v) in phosphate buffer pH 6.8. The microemulsion was able to shield leuprolide oleate from enzymatic degradation by trypsin and α-chymotrypsin, so that after 120 min 52.9% and 58.4%, respectively, of leuprolide oleate were still intact. Leuprolide acetate dissolved in an aqueous control solution was completely metabolized by trypsin within 60 min and by α-chymotrypsin within 5 min. Moreover, an in vivo study in rats showed a 17.2-fold improved oral bioavailability of leuprolide oleate SMEDDS compared to a leuprolide acetate control solution. This is the first time, to our knowledge, that hydrophobic ion pairing is utilized in order to incorporate a peptide drug in SMEDDS and evidence of a protective effect of oil-in-water (o/w) microemulsion droplets against enzymatic degradation of a peptide drug was provided. According to these results, the system could be likely a novel platform technology to improve the oral bioavailability of peptide drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study, the effective absorbed dose to human organs was estimated, following intra vascular administration of (111)In-DTPA-Buserelin using biodistribution data from rats. Rats were sacrificed at exact time intervals of 0.25, 0.5, 1, 2, 4 and 24 h post injections. The Medical Internal Radiation Dose formulation was applied to extrapolate from rats to humans and to project the absorbed radiation dose for various human organs. From rat data, it was estimated that a 185-MBq injection of (111)In-DTPA-Buserelin into the human might result in an estimated absorbed dose of 24.27 mGy to the total body and the highest effective absorbed dose was in kidneys, 28.39 mSv. The promising results of this study emphasises the importance of absorbed doses in humans estimated from data on rats.

A novel aqueous progesterone formulation was developed. Study I: Three-way cross-over, open-label study in 24 post-menopausal women. Comparison of the pharmacokinetic profiles of a single 100 mg dose of test product administered by subcutaneous (s.c.) and intramuscular (i.m.) injection and an i.m. reference oily product. Study II: Three-way cross-over open-label study of 25, 50 and 100 mg s.c. single doses of the aqueous formulation in 12 post-menopausal women. Study III: Parallel-group, observer-blinded study in 25 fertile women administered multiple s.c. 25 and 50 mg doses of the aqueous formulation once daily for 11 days. Baseline-corrected pharmacokinetic parameters were evaluated. Aqueous formulation (100 mg) was promptly absorbed, achieving progesterone peak serum levels at an earlier time than the reference (1 h vs. 7 h; p < 0.0001). Test and reference were bioequivalent in the extent of exposure: confidence intervals for AUC(0-t) geometric means ratios were within the pre-specified 80-125% limits. Pharmacokinetics was linear over the range of doses studied. Steady state was reached within 4 days of multiple dose treatment. All treatments were well tolerated. Considering the advantages given by the possibility of self-medication, the s.c. aqueous formulation could offer a convenient alternative for patients on assisted reproductive technology treatments.

Gastrointestinal patches represent a novel multiparticulate drug delivery system able to increase the intestinal absorption of drugs with poor bioavailability. The number of patches to administer is a critical issue since it is related to the surface and drug concentration at the absorption site. The objective of this article is to evaluate the effect of the number of administered patches on the final absorption of leuprolide, a peptide chosen as model drug, assuming complete adhesion of all the devices to the intestinal membrane. The same dose of leuprolide was encapsulated into 2, 4 and 6 patches; the resulting intestinal absorption profiles were measured with the Ussing chamber ex vivo experimental setup and compared between them. The results showed that varying the number of patches, the final absorption does not present statistically significant changes, indicating that changes in concentration are balanced by change in absorption surface. These experimental findings can also be explained considering the equation that links the drug flow to surface and concentration at the absorption site, showing that the drug flow is related only to the geometry of each individual patch., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Latex, a polyisoprene (PI) hydrophobic elastomer, was evaluated in vitro and in vivo as a matrix for intravaginal steroid hormone delivery. Matrices containing hormone were prepared by swelling latex in chloroform that contained soluble progesterone (P4). In vitro studies demonstrate that P4 release from PI follows a zero order model during at least 100 h and depends on initial load up to 10 mg cm(-2). The release of P4 from a PI matrix was found to be two times faster than from a polydimethylsiloxane (PDMS) matrix. FT-IR and X-ray powder diffraction analysis of P4 polymorphs show that when nucleated in PDMS, the hormone crystallizes only in alpha-form while in latex, crystallizes as a mixture of alpha- and beta-form. In vivo studies show that devices with a PI matrix containing 0.5 g of P4 are effective to reach plasma levels above 1 ng ml(-1) that are needed to synchronize estrous in cattle. Altogether, the results show that PI, a vulcanized polymer with a carbon-carbon backbone, can be used as a new matrix for the intravaginal administration of progesterone with improved release profile than silicone and that the matrix can influence the crystalline state of the hormone.

The objective of this work was to investigate the effect of oxygen containing terpenes (carvacrol, menthol and carvone) at 5%w/v in hydroalcoholic mixtures (40% ethanol) on the permeation of LHRH across newborn pig skin in vitro. In addition, the amount of LHRH retained in the skin after 24 h of diffusion was determined. It was found that the passive permeation of LHRH was very limited. Although percutaneous absorption of LHRH improved in the presence of the enhancers, a significant enhancement was observed only with carvacrol, an aromatic terpene. The rank order of enhancement ratio for skin permeation was found to be carvacrol > carvone > menthol. The enhancers also affected the retention of LHRH in the skin. The rank order of enhancement ratio for skin retention was carvone > carvacrol > menthol. The results of the in vitro skin metabolism study of LHRH using fresh newborn pig skin showed that the degradation products were detected and the amount of the degraded LHRH increased with increasing duration of incubation time.

The pharmacokinetics of the zuclomiphene (Zu) and enclomiphene (En) isomers of clomiphene citrate following a single oral dose (50 mg) were characterized for the first time in patients receiving the drug (ie, infertile women with polycystic ovary syndrome). Plasma concentrations of Zu and En were measured in 9 patients from the second day of their menstrual cycle (day 1 of dosing) up to 21 days. The mean (+/- coefficient of variation) of C(max), t(max), and AUC of Zu was 15 +/- 41 ng/mL, 7 +/- 87 h, and 1289 +/- 34 ng/mL.h (AUC(0-456 h)), and that of En was 15 +/- 18 ng/mL, 3 +/- 68 h, and 65 +/- 35 ng/ml.h (AUC(0-72h)), respectively. These parameters appeared to be different for Zu from those reported previously in healthy participants, except for t(max). The pharmacokinetic parameters of En in patients with polycystic ovary syndrome were not generally different from the healthy subjects. The effect of obesity on Zu kinetics was stronger than that on En. The conventional model-dependent pharmacokinetics of clomiphene citrate isomers could not be determined due to a very flat terminal half-life and the long-tailed residence time, signifying the lipophilic nature and potentially extensive distribution of the compound.

Lutropin alfa is the first and only recombinant human form of luteinizing hormone (LH) developed for use in the stimulation of follicular development. Dose-finding studies revealed a significant dose-dependent increase in the rate of optimal follicular development among women with hypogonadotropic hypogonadism and profound LH deficiency (<1.2 IU/L) who received subcutaneous lutropin alfa 0-225 IU/day plus follitropin alfa. Similarly, in a double-blind, randomized study, the rate of optimal follicular development was significantly higher in women with hypogonadotropic hypogonadism and profound LH deficiency receiving subcutaneous lutropin alfa 75 IU/day plus follitropin alfa than in those receiving placebo plus follitropin alfa. Lutropin alfa with follitropin alfa may also be of benefit in certain subgroups of normogonadotropic women (e.g. those with an inadequate response to prior follitropin alfa monotherapy, those aged >or=35 years, and those with profound LH downregulation or who required excessive exogenous follitropin alfa). However, one study in older women (>or=35 years) did not show any advantage of lutropin alfa supplementation. Once-daily subcutaneous lutropin alfa was generally well tolerated in hypogonadotropic hypogonadal women, with the majority of adverse events being of mild to moderate severity.

We have identified differences in transport properties of intestinal epithelia in the marsupial brushtail possum, compared to eutherian mammals. To determine whether differences in its permeability to hydrophilic compounds also occur, the absorption of sodium fluorescein and luteinizing hormone releasing hormone (LHRH) was assessed in vitro and the ability of chemical enhancers and a metabolic inhibitor to promote their absorption investigated. The apparent permeability of colonic and caecal tissues to fluorescein and LHRH and transepithelial resistance (Rt) in the absence or presence of ethylenediamine tetra-acetic acid (EDTA), sodium deoxycholic acid (SDA), dithiothreitol (DTT), polyacrylic acids (PAA), or the inhibitor bacitracin were determined. The effects of SDA and/or DTT on adherent mucus and the release of lactate dehydrogenase (LDH) were also assessed. In the absence of treatment, both tissues had comparable amounts of adherent mucus, Rt and low permeabilities to fluorescein and LHRH. All chemical enhancers increased fluorescein permeability, but SDA at concentrations >0.5 mM also induced LDH release. DTT alone and in combination with SDA reduced the amount of adherent mucus. Bacitracin inhibited LHRH metabolism and increased LHRH permeability. These data indicate that the possum hindgut epithelium represents a significant barrier to the uptake of hydrophilic compounds, similar to that in eutherians., ((c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.)

The introduction of recombinant gonadotrophins for the treatment of infertility has been an important advance in improving the quality and consistency of therapeutics offered to patients seeking care from fertility specialists. Over the past decade, a number of investigators have discovered small molecules that mimic the effects of FSH and LH. Despite extensive medicinal chemistry efforts from many institutes, including Serono Research Institute, and reasonable in-vitro activity, receptor-targeted agonists have not yet been successfully developed for clinical use, based upon results generated in animal models of follicular stimulation (FSH-like) or ovulation induction [human chorionic gonadotrophin (HCG)-like]. A different approach to gonadotrophin mimicry was identified that modifies intracellular signalling pathways common to gonadotrophins. Phosphodiesterase type 4 enzyme inhibitors and selective prostaglandin E receptor (EP2/EP4) agonists have been demonstrated to mimic the effects of HCG to induce ovulation following oral administration. Multiple approaches with small molecules have been attempted to activate the FSH receptor and initiate cAMP-dependent mechanisms. Pharmacodynamic effects of FSH on follicular growth were demonstrated by inhibiting a different enzyme pathway with a small molecule, albeit in the presence of very low concentrations of circulating FSH. These results raise the possibility that in the future orally active agents can be used in combination with injectable gonadotrophins or perhaps independent of gonadotrophins for first-line interventions for infertility.

Poor absorption and stability of peptides are the major obstacles concerning the development of therapeutically relevant iontophoretic devices for the transdermal delivery of peptides. The present study examined the impact of constant and pulsed (direct/alternating) current profiles on the transport and stability of two decapeptides LHRH and Nafarelin. The stability of these peptides was studied in a physiological buffer solution, with electrical current, and when the peptide solution was exposed to the stratum corneum or to the epidermal/dermal side of human skin. Pulsed direct current profile was shown to be the most efficient in transporting both LHRH and Nafarelin across the human epidermis. Furthermore, the percentage of intact LHRH in the receiver phase was slightly higher when a pulsed current profile was used. Both the peptides were stable in a physiological buffer and under the influence of current, but LHRH was degraded especially in contact with the dermal side of the skin. Altogether five hydrolytic degradation products of LHRH were observed, and they were identified by LC-ESI/MS and LC-ESI/MS/MS. No degradation products of Nafarelin were observed. It is concluded that the pulsed direct current profile may provide at least a partial solution for the transdermal delivery of peptides in terms of improved transport efficacy and peptide stability.

A vast literature documents the role of melatonin in human reproductive function including: a) the relation between melatonin and the menstrual cycle in relation to the peak time of luteinizing hormone in the middle of the cycle; b) the varying concentrations of melatonin in the control of puberty; c) the fewer conceptions in some artic populations where melatonin is connected significantly to seasonal photoperiodicity during the months of the polar nights. The aim of this paper is to report our findings on the pharmacological action of this molecule on reproduction in which gonadal activity is clearly connected to photoperiodicity. We used polymer bioimplants programmed for the sustained release of melatonin for experimental gynecologic protocols. These implants had beneficial results with respect to the use of progestinics because melatonin allowed ovarian activity to be induced for at least two to three consecutive cycles with one single bioimplant. We thought it indispensable to use pharmacological systems with a sustained release because different preliminary tests showed that the half-life of melatonin is limited at maximum to two to three hours and, consequently, any other tested modalities of administration would not provide any appreciable results for our study. As a model for our research we used goats to administer melatonin via targeted programs since these animals clearly respond (even against the rule of the light/dark relation) in contrast to humans in whom response is less evident. For controls, after inserting bioimplants in the animals, we tested their efficiency in vitro and subsequently in vivo, evaluating blood parameters and pharmacological effects of melatonin occurring during the treatment. The final results proved to be interesting in relation to reproductive activity in that regular and programmed births were achieved.

Clomiphene can be used to treat anovulation due to hypothalamus or pituitary gland dysfunction, and it normalizes the luteal phase in stimulated patients. It can be used to estimate ovarian follicle reserve, and may be predictive of ovulation in women aged >/=35 years or with failed IVF. Contraindications include risk of congenital anomalies, chronic liver disease and visual disorders. Clomiphene may impair fertility through its effects on cervical mucus and in causing various endometrial dysfunctions. However, if clomiphene is administered in 50 mg doses, side-effects are avoided and efficacy is similar to that of a 100 mg dose, although daily dosages of 200 mg/day over 5 days can induce ovulation in approximately 70% of treated patients. Gonadotrophin concentrations increase up to days 5-9 when follicles are selected, and clomiphene is effective in patients with polycystic ovary syndrome (PCOS). Fifty percent of normal patients conceive, a value perhaps biased by the antagonistic effects of clomiphene on cervical mucus in some women. Clomiphene is valuable for IVF, and is used by some clinics in combination with HMG or recombinant FSH. Resistance to clomiphene can develop, and human chorionic gonadotrophin may be needed to induce ovulation in clomiphene cycles. Corticosteroids and human menopausal gonadotrophin (HMG) can be combined with clomiphene for stimulation, its combination with HMG long having been a standard protocol in assisted reproduction. PCOS patients may become insulin resistant, a condition improved by the administration of metformin. Other adverse effects include multiple pregnancies, an increase in the rate of multiple births, ovarian hyperstimulation and unsubstantiated claims of ovarian cancer.

The in vitro permeability and in vivo absorption of leuprolide in different intestinal regions were measured to investigate the feasibility for site-specific delivery of leuprolide in the gastrointestinal (GI) tract. In vitro permeability of leuprolide in the rabbit GI tract was performed using a side-by-side diffusion apparatus and the permeability coefficients in the jejunum, ileum and colon were 0.27x10(-7), 2.96x10(-7) and 7.85x10(-7)cm/s, respectively. Varying the donor drug concentrations from 2 to 10 mg/ml, the permeability coefficients were independent of the donor concentration, suggesting the transport mechanism of passive diffusion. Using an intestine loop model in anesthetized rats, bioavailabilities of leuprolide in the jejunum, ileum and colon were 1.28, 5.62 and 9.59%, respectively. Drug recovery from the loop 5 h after dosing was 10.7% in jejunum, 24.5% in ileum and 40.7% in colon. Additional in vivo studies using conscious rats showed that the bioavailability of leuprolide was less than 1% for both ileal and colonic administration. In vivo absorption of leuprolide from ileum was not significantly different from colon in conscious rats. Sodium salicylate, a permeation enhancer, was co-administered with leuprolide to the rat ascending colon, and results showed a 4-fold increase in the bioavailability in conscious rats. Thus, in vivo studies indicate that both absorption and enzymatic degradation of leuprolide in the GI tract is site-dependent and the lower intestine may be an advantageous region for oral delivery of leuprolide.

Objective: To determine the serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate treatment in anovulatory infertile women., Design: Prospective cohort., Setting: Tertiary institutional infertility clinic., Patient(s): Fourteen consenting anovulatory infertile women receiving standardized, cyclic, incremental treatment with clomiphene citrate for ovulation induction., Intervention(s): Clomiphene citrate treatment (50-150 mg/d, cycle days 5-9), titrated to the minimum effective ovulation-inducing dose, was administered for three to six total cycles. Blood samples were obtained on cycle days 3 and 10 in each treatment cycle., Main Outcome Measure(s): Serum concentrations of enclomiphene and zuclomiphene., Result(s): Cycle day 3 zuclomiphene levels were below assay limits in all initial cycles, increased progressively across three consecutive cycles, and thereafter plateaued. Cycle day 3 enclomiphene concentrations were uniformly undetectable. Cycle day 10 enclomiphene levels increased with dose administered, but these observations were not statistically significant., Conclusion(s): Clomiphene citrate induction of ovulation results in an isomer-specific systemic accumulation of zuclomiphene across consecutive cycles of treatment. The combined maximum concentration of enclomiphene and zuclomiphene attained in practice approximates 100 nmol/L and is generally well below levels previously demonstrated to have adverse effects in vitro.

Recently, several new urinary gonadotrophin preparations have been developed, containing less luteinizing hormone (LH) activity than human menopausal gonadotrophin. Normegon is a gonadotrophin preparation with a follicle stimulating hormone (FSH)/LH ratio of 3:1; Follegon and Metrodin-HP are purified FSH preparations. The aim of the present randomized study was to compare pharmaco-dynamics, -kinetics and local tolerance of these preparations after repeated s.c. administration. Thirty-six healthy female subjects were treated with Lyndiol contraceptive pills for 5 weeks to suppress endogenous gonadotrophin concentrations. After 3 weeks of Lyndiol treatment, 150 IU of Normegon, Follegon or Metrodin HP were administered once daily, s.c. for 7 days. Blood samples were collected once daily during the fourth and fifth weeks of the study and assayed for FSH and oestradiol. After the last gonadotrophin injection, blood samples were collected more frequently to determine pharmacokinetic parameters of FSH. During the fourth and fifth study weeks, daily ultrasound measurements of follicular growth were performed. Endogenous FSH and LH values were extremely suppressed during Lyndiol treatment. Serum FSH values showed similar patterns in the three groups. The maximum FSH concentration was reached 9-11 h post-injection, the terminal half-life was 43-47 h. The preparations were bioequivalent with respect to FSH immunoreactivity. The number of follicles tended to be larger after Normegon than after Follegon and Metrodin HP treatment, though this was not statistically significant. Serum oestradiol concentrations were significantly higher after Normegon treatment. In general, s.c injections were well tolerated. In conclusion, the three preparations were bioequivalent with respect to FSH immunoreactivity. Nevertheless, the biological activity of Normegon tended to be higher than that of Follegon and Metrodin HP in Lyndiol-suppressed women.

This review describes the development and pharmacology of clomiphene and those specific characteristics of both drug and patients which determine its clinical efficacy. The studies reviewed describe clinical observation of patient characteristics (age, additional infertility diagnosis, semen quality), vaginal ultrasound observations of ovaries (number and size of pre-ovulatory follicles) and endometrial lining (thickness, pattern) in 2841 clomiphene cycles in patients who required intrauterine insemination (IUI) because of poor sperm quality or an unsatisfactory postcoital test. They show that (i) conception in clomiphene cycles is related to the number and size of pre-ovulatory follicles, endometrial thickness, patient age, pelvic adhesions, type of anovulatory disorder and semen quality; (ii) pregnancy rates per clomiphene-IUI cycle are constant through at least six cycles; (iii) multiple births cannot be prevented by withholding human chorionic gonadotrophin or advising against coitus when multiple pre-ovulation follicles are present unless all follicles down to 10-12 mm diameter are counted. We also reviewed pregnancy outcome (number of gestational sacs, babies, preclinical and clinical abortion, ectopic pregnancy and birth sex) in 1744 clomiphene pregnancies from our clinic. We found that (i) preclinical and clinical abortions are increased only slightly by clomiphene use, compared to spontaneous pregnancy; (ii) clinical abortions are decreased in patients with polycystic ovaries and luteal insufficiency who use clomiphene; (iii) conception and preclinical abortions are related to endometrial thickness prior to ovulation; (iv) ectopic pregnancies are not increased by clomiphene and (v) the ratio of male births is not altered by clomiphene, except possibly in timed insemination cycles. These studies repudiate many misconceptions regarding clomiphene. They also show that clinical outcome may be improved by pre-ovulation ultrasound monitoring of ovarian and endometrial response.