Human follicle-stimulating hormone produced by recombinant DNA technology: a review for clinicians

Human follicle-stimulating hormone (FSH) is now produced in vitro by recombinant DNA technology. FSH being a complex heterodimeric protein, a eukaryotic cell line has been selected for expression work (Chinese hamster ovary cells). The pharmaceutical preparation of recombinant human FSH (r-FSH) differs from that of human menopausal gonadotrophin (HMG) and the first generation of urinary human FSH (u-FSH) in terms of (i) source of bulk materials, (ii) purity and specific activity, (iii) batch to batch consistency, and (iv) complete absence of luteinizing hormone (LH) activity. Pharmacokinetic characterization of r-FSH has shown an absolute bioavailability of approximately 75% after both s.c. and i.m. administration and an apparent terminal half-life of 37 +/- 25 h. These characteristics are very similar to those of u-FSH. Clinical efficacy and safety are currently demonstrated through several randomized, well controlled studies, comparing r-FSH administered s.c. with u-FSH administered i.m. for stimulating follicular development prior to assisted reproduction treatment and in World Health Organization (WHO) group II anovulation. To date, approximately 1000 patients have been treated with r-FSH. Moreover, r-FSH has recently been used successfully in association with recombinant human LH for inducing ovulation and pregnancy in WHO group I anovulatory patients. At this stage of r-FSH preparation assessment, it is likely that r-FSH will replace all urinary-derived FSH preparations for stimulating ovarian follicular development. For clinicians, current experience with r-FSH indicates that it should be used with the regimes and doses applied to u-FSH.     

Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction

The FSH receptor shows three single nucleotide polymorphisms (SNPs), one in the promoter and two in exon 10. In addition, the FSH receptor mRNA undergoes extensive alternative splicing. While no physiological role for the SNP in the promoter and for alternative spliced isoforms has been demonstrated so far, the SNPs in exon 10 result in four discrete allelic variants characterized by the amino acid combinations Thr307-Asn680, Ala307-Ser680, Ala307-Asn680 and Thr307-Ser680. Several studies have demonstrated that the first two allelic variants are very frequent (approximately 60 and 40% respectively) in the Caucasian population. The rarer Ala307-Asn680 and Thr307-Ser680 variants are much less frequent (<5%) in the Chinese. In males the FSH receptor variants are not related to testicular volume, serum FSH or serum inhibin B levels. The two most common receptor variants transiently transfected in COS-7 cells displayed similar functional characteristics. Frequency distribution of the two polymorphisms in normal women and patients with polycystic ovarian syndrome or premature ovarian failure is still under investigation. The homozygous Ala307-Ser680 variant seems to be associated with significantly higher basal serum FSH levels and with a higher amount of FSH required for ovarian stimulation in women undergoing assisted reproduction. This suggests that the FSH receptor genotype can influence the ovarian response to FSH stimulation. The presence of SNPs in the FSH receptor gene capable of modifying FSH action paves the way for future patient-tailored, genotype-based hormone therapies.     

Why does ovarian surgery in PCOS help? Insight into the endocrine implications of ovarian surgery for ovulation induction in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex disorder with heterogeneity of clinical and endocrine features. Ovarian surgery for ovulation induction has been used in the management of clomiphene citrate-resistant anovulatory women with PCOS. Various types of ovarian surgery have been employed (wedge resection, electrocautery, laser vaporization, multiple ovarian biopsies and others) and all procedures result in an altered endocrine profile after surgery. The mechanism behind the reversal of endocrinological dysfunction in PCOS after ovarian surgery remains incompletely understood. This review scans the literature systematically to identify the endocrine changes after ovarian surgery in PCOS, in order to glean some knowledge of the mechanism involved. After ovarian surgery in PCOS, a rapid reduction in serum levels of all ovarian hormones is seen, in combination with increased serum levels of pituitary hormones. Folliculogenesis is then initiated and ovarian hormone production increases, synchronically with a reduction of pituitary hormones. Continuation of follicle growth in subsequent cycles after ovarian surgery occurs in an environment with less androgens and lower LH and FSH levels compared with pretreatment levels. The endocrine changes found after ovarian surgery in PCOS women seem to be governed by the ovaries themselves. Rapid reduced secretion of all ovarian hormones restores feedback to the hypothalamus and pituitary, resulting in appropriate gonadotrophin secretion. Initiation of follicular development seems to be induced by increasing FSH levels following a reduction of the follicle excess and (intra-ovarian) androgen levels. Additionally, anti-Müllerian hormone and gonadotrophin surge attenuating factor probably have a role in the endocrine changes.     

New findings from non-linear longitudinal modelling of menopausal hormone changes

Changes in FSH and estradiol (E2) across the menopausal transition are clearly not linear. The present study utilizes data from 204 women who completed the 13-year prospective Melbourne Women's Midlife Health Project. E2, FSH, symptoms, self-rated health, mood, sexual function and coronary heart disease (CHD) risk were measured longitudinally. We presumed an s-shaped curve for each hormone and estimated five parameters for each hormone curve for each woman: baseline, final value, range, slope at inflexion point and age at inflexion point. These parameters were found to adequately estimate the curve for each hormone. The median age of transition observed for E2 occurs >1 year later than the median age of transition observed for FSH. FSH parameters did not affect any of the health outcomes analysed. Hot flushes, night sweats, sleeping problems, vaginal dryness and to a lesser extent self-rated health were highly significantly associated with E2 range and slope. Sexual response and CHD risk were highly significantly associated with final E2 level (post-menopausally). These findings have clinical relevance in identifying which symptoms will be triggered by steep transitions of E2 such as sudden withdrawal and which health parameters may require a maintenance level of E2.     

Regulation of follicle development and novel approaches to ovarian stimulation for IVF

Current ovarian stimulation regimens for IVF are complex and not without risk. Increasing our knowledge of the physiology of follicle development and dominant follicle selection may enable the design of less complex, safer and cheaper ovarian stimulation regimens for IVF. Decremental serum FSH concentrations during the follicular phase of the menstrual cycle are required for single dominant follicle selection. Only the most mature follicle will continue its development due to increased sensitivity for stimulation by FSH. FSH stimulation becomes insufficient for less mature follicles and remaining cohort follicles will therefore go into atresia. The number of days during which FSH is above the threshold for stimulation of follicle development is limited, resulting in a narrow FSH window. More medium sized and large pre-ovulatory follicles and increased oestradiol output can be induced by the administration of small doses of exogenous FSH during the mid- to late follicular phase, preventing the physiological decrease in FSH stimulation. Intervention with decremental serum FSH concentrations in combination with gonadotrophin-releasing hormone (GnRH) antagonists to prevent a premature rise in serum LH may induce ongoing growth of multiple follicles sufficient for IVF. The benefits and risks of these minimal hyperstimulation protocols require further evaluation.     

Ovarian feedback, mechanism of action and possible clinical implications

The secretion of gonadotrophins from the pituitary in women is under ovarian control via negative and positive feedback mechanisms. Steroidal and non-steroidal substances mediate the ovarian effects on the hypothalamic-pituitary system. During the follicular phase of the cycle, estradiol (E(2)) plays a key role, while circulating progesterone (at low concentrations) and inhibin B contribute to the control of LH and FSH secretion respectively. During the luteal phase, both E(2) and progesterone regulate secretion of the two gonadotrophins, while inhibin A plays a role in FSH secretion. The intercycle rise of FSH is related to changes in the levels of the steroidal and non-steroidal substances during the luteal-follicular transition. In terms of the positive feedback mechanism, E(2) is the main component sensitizing the pituitary to GnRH. Activity of a non-steroidal ovarian substance, named gonadotrophin surge-attenuating factor (GnSAF), has been detected after ovarian stimulation. It is hypothesized that GnSAF, by antagonizing the sensitizing effect of E(2) on the pituitary, regulates the amplitude of the endogenous LH surge at midcycle. Disturbances in the feedback mechanisms can occur in various abnormal conditions or after treatment with pharmaceutical compounds that interfere with the production or the action of endogenous hormones.     

Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy

A great deal of new information has arisen in the recent years concerning inhibin physiology and clinical relevance in reproductive medicine. It is now recognized that the two inhibin isoforms, named inhibin A and inhibin B, are produced by the gonads in the course of gamete maturation and in women have a different pattern of secretion throughout the menstrual cycle. Since inhibins are also produced by placenta and fetal membranes, it has been suggested that there is an involvement in physiological adaptation of pregnancy. Evidence from several sources has underlined the clinical usefulness of the measurement of inhibin-related proteins in the diagnosis and follow-up of different fertility disturbances and early pregnancy viability. In the male, inhibin B is produced in the testis, principally by the Sertoli cells. Inhibin B expression and secretion are positively correlated with Sertoli cell function, sperm number, and spermatogenic status and are negatively correlated with FSH. This review covers the most recent advances on the role of inhibins in human reproductive function. Considerable progress in the understanding of inhibin physiology has resulted from selective measurement of the two inhibin molecular forms, named inhibin A and B. Newly recognized alterations of inhibin levels in gynaecological diseases as well as in normal and pathological pregnancy are discussed, with particular emphasis on the potential clinical usefulness of assessing inhibin levels in serum and other biological fluids.     

The use of LH activity to drive folliculogenesis: exploring uncharted territories in ovulation induction

LH plays critical roles in the control of folliculogenesis and ovarian function in humans. LH activity administration during gonadotrophin ovulation induction can enhance ovarian response and optimise treatment. More specifically, LH activity (both LH and low-dose hCG) can support the growth and stimulate the maturation of larger ovarian follicles as a result of specific granulosa cell receptors that develop after a few days of FSH priming. This action of LH is independent of FSH, and it has been shown recently that the last stages of follicular development can be supported by sole administration of LH activity in the form of low-dose hCG, without causing premature luteinization. Reproductively competent oocytes and pregnancy can be obtained with this regimen. Furthermore, LH activity is capable of reducing the development of small ovarian follicles (<10 mm) that may predispose patients to developing complications such as the ovarian hyperstimulation syndrome. Thus, better understanding of the dynamics and mechanisms that control human folliculogenesis and a more rational and selective use of LH activity administration may allow a reduction in cost and increased safety, while maintaining a high efficacy of the ovulation induction regimens used in assisted reproduction.     

Among patients treated with FSH and GnRH analogues for in vitro fertilization, is the addition of recombinant LH associated with the probability of live birth? A systematic review and meta-analysis

The aim of this systematic review and meta-analysis was to assess whether the addition of recombinant luteinizing hormone (LH) increases live birth rate, among patients treated with follicle stimulating hormone (FSH) and gonadotrophin-releasing hormone (GnRH) analogues for in vitro fertilization (IVF). Eligible studies were randomized controlled trials (RCTs) answering the research question that contained sufficient information to allow ascertainment of whether randomization was true and whether equality was present between the groups compared, regarding baseline demographic characteristics, gonadotrophin stimulation protocol, number of embryos transferred and luteal phase support administered. A literature search identified seven RCTs (701 patients) that provided the information of interest, among which five reported agonist and two antagonist cycles. The reported outcome measure, clinical pregnancy, was converted to live birth using published data in one study. No significant difference in the probability of live birth was present with or without rLH addition to FSH (odds ratio [OR]: 0.92, 95% confidence interval (CI): 0.65-1.31; P = 0.65). This finding remained stable in subgroup analyses that ordered the studies by dose of rLH added, the type of analogue used to inhibit premature LH surge, the time rLH was added during the follicular phase, the age of patients analysed, the presence of allocation concealment and by the way the information on live birth was retrieved. In conclusion, the available evidence does not support the hypothesis that the addition of recombinant LH increases the live birth rate in patients treated with FSH and GnRH analogues for IVF.     

Pituitary-ovarian dysfunction and endometriosis

Significant association between endometriosis, including minor endometriosis, and infertility (or strictly subfertility) is shown by prevalence studies, but a causal relationship has not been established. This review focuses on evidence for pituitary-ovarian dysfunction as a cause for the subfertility. A methodological problem is lack of fertile controls with endometriosis. Group comparison with tubal infertility cases as controls have demonstrated: impaired follicular growth, reduction in circulating oestradiol concentrations during the pre-ovulatory phase and of oestradiol and progesterone during the early luteal phase, and disturbed luteinizing hormone (LH) surge patterns. Reduction in LH concentrations in pre-ovulatory follicular fluid has also been found, and granulosa cells collected at the same time have demonstrated impaired steroidogenic capacity in vitro, but these were not consistently proven findings. Pooled data from published studies show significantly reduced oocyte fertilization rates (49%) compared with controls (69%), even after maximal stimulation with exogenous follicle stimulating hormone (FSH) and human chorionic gonadotrophin (HCG) (54 versus 69%). The implantation rate is also slightly (though significantly) reduced (11 versus 13%). The findings suggest an inherent disorder of follicular function, with LH surge impairment probably being a secondary phenomenon. The resulting reduction in the chance of fertilization of the oocyte would contribute substantially to the subfertility associated with endometriosis. It seems that the benefit of in-vitro fertilization is gained through the excessive number of oocytes obtained by stimulation.     

The sensitivity of the child to sex steroids: possible impact of exogenous estrogens

The current trends of increasing incidences of testis, breast and prostate cancers are poorly understood, although it is assumed that sex hormones play a role. Disrupted sex hormone action is also believed to be involved in the increased occurrence of genital abnormalities among newborn boys and precocious puberty in girls. In this article, recent literature on sex steroid levels and their physiological roles during childhood is reviewed. It is concluded that (i) circulating levels of estradiol in prepubertal children are lower than originally claimed; (ii) children are extremely sensitive to estradiol and may respond with increased growth and/or breast development even at serum levels below the current detection limits; (iii) no threshold has been established, below which no hormonal effects can be seen in children exposed to exogenous steroids or endocrine disruptors; (iv) changes in hormone levels during fetal and prepubertal development may have severe effects in adult life and (v) the daily production rates of sex steroids in children estimated by the Food and Drug Administration in 1999 and still used in risk assessments are highly overestimated and should be revised. Because no lower threshold for estrogenic action has been established, caution should be taken to avoid unnecessary exposure of fetuses and children to exogenous sex steroids and endocrine disruptors, even at very low levels.     

Clinical management of low ovarian response to stimulation for IVF: a systematic review

Poor response is not a rare occurrence in ovarian stimulation. Although not fully accepted, the most dominant criteria for poor ovarian response are small numbers of follicles developed or oocytes retrieved, and low estradiol (E2) levels after the use of a standard stimulation protocol. There is no ideal predictive test as the poor responder is revealed only during ovulation induction; however, increased levels of day 3 FSH and E2 as well as decreased levels of inhibin B can be used to assess ovarian reserve. Several protocols have been proposed for clinical management of low ovarian response in IVF. Although high doses of gonadotrophins have been used by the vast majority of authors, results have been controversial and prospective randomized studies have shown little or no benefit. The few available relevant studies do not indicate that recombinant FSH improves outcome. Flare-up GnRH agonist protocols (including all dosage varieties) produce better results than standard long luteal protocols. Luteal initiation GnRH agonist 'stop' protocols were shown to improve ovarian response according to prospective studies with historical controls, but this was not confirmed by well-designed prospective, randomized, controlled studies. The few available data obtained with GnRH antagonists have not shown any benefits. Adjuvant therapy with growth hormone (GH) or GH-releasing factors results in no significant improvement. The use of corticosteroids reduces the incidence of poor ovarian response in women undergoing IVF treatment. The limited data obtained with nitric oxide donors are encouraging. Pretreatment with combined oral contraceptives prior to stimulation may help ovarian response. No benefit was observed with standard use of ICSI or assisted hatching of zona pellucida. Finally, natural cycle IVF has produced results which are comparable with those obtained with stimulated cycles in true poor responders. Well-designed, large-scale, randomized, controlled trials are needed to assess the efficacy of these different management strategies.     

The LHRH antagonist cetrorelix: a review

In those clinical situations in which an immediate and profound suppression of gonadotrophins is desired, LHRH agonists have the disadvantage of producing an initial stimulatory effect on hormone secretion. Therefore, the use of GnRH antagonists which cause an immediate and dose-related inhibition of LH and FSH by competitive blockade of the receptors is much more advantageous. One of the most advanced antagonist produced to date is Cetrorelix, a decapeptide which has been shown to be safe and effective in inhibiting LH and sex-steroid secretion in a variety of animal species and in clinical studies as well. Clinical trials in patients suffering from advanced carcinoma of the prostate, benign prostate hyperplasia, and ovarian cancer are currently in progress and have already shown the usefulness of this new treatment modality. In particular, the concept that a complete suppression of sex-steroids may not be necessary in indications such as uterine fibroma, endometriosis and benign prostatic hyperplasia represents a promising novel perspective for treatment of these diseases. Following completion of phase III trials in controlled ovarian stimulation for IVF regimens, Cetrorelix was given marketing approval and, thus, became the first LHRH antagonist available clinically.     

The Anti-Mullerian hormone and ovarian cancer

The Anti-Mullerian hormone (AMH), which is produced by fetal Sertoli cells, is responsible for regression of Mullerian ducts, the anlagen for uterus and Fallopian tubes, during male sex differentiation. Ovarian granulosa cells also secrete AMH from late in fetal life. The patterns of expression of AMH and its type II receptor in the post-natal ovary indicate that AMH may play an important role in ovarian folliculogenesis. Recent advances in the physiological role of AMH has stimulated interest in the significance of AMH as a diagnostic marker and therapeutic agent for ovarian cancer. Currently, AMH has been shown to be a circulating marker specifically for granulosa cell tumour (GCT). Its diagnostic performance seems to be very good, with a sensitivity ranging between 76 and 93%. In patients treated for GCT, AMH may be used post-operatively as marker for the efficacy of surgery and for disease recurrence. Based on the physiological inhibitory role of AMH in the Mullerian ducts, it has been proposed that AMH may inhibit epithelial ovarian cancer cell both in vitro and in vivo. These observations will be the basis for future research aiming to investigate the possible clinical role of AMH as neo-adjuvant, or most probably adjuvant, therapy for ovarian cancer.     

Induction of ovulation after gnRH antagonists

The gonadotrophin-releasing hormone (GnRH) antagonist binds competitively to the receptors and thereby prevents endogenous GnRH from exerting its stimulatory effect on the pituitary cells. This causes suppression of gonadotrophin secretion which occurs immediately after administration of the antagonist. When using GnRH antagonist in controlled ovarian stimulation, ovulation or maturation of the oocyte can, therefore, be induced by a variety of drugs, e.g. native GnRH, recombinant LH or short-acting GnRH agonists. Short-acting GnRH agonists were recommended for triggering ovulation in cases with a high risk of developing ovarian hyperstimulation syndrome (OHSS). Since it is evident that GnRH is required to initiate the LH surge and the oestradiol rise, a single administration of GnRH antagonist during the late follicular phase delays the LH surge. Studies showed that a single s.c. administration of 3 or 5 mg of Cetrorelix in the late follicular stage was sufficient to prevent the LH surge for 617 days. This phenomenon can be used in high responder patients who are prone to OHSS. The question whether this delay has any effect on oocyte quality and maturation still remains unanswered. Overall, there are four uses for GnRH antagonist: (i) using short-acting GnRH agonists for triggering ovulation in cases in which the GnRH antagonist is part of the protocol for ovarian stimulation. Recombinant LH and native LHRH could also be used as triggers of LH surge; (ii) delaying the LH surge in cases prone to OHSS by treatment with GnRH antagonist; (iii) to administer GnRH antagonist during the luteal phase to decrease the activity of corpora lutea; (iv) in polycystic ovarian disease with elevated LH the LH/FSH ratio can be corrected with the injection of GnRH antagonist prior to and during ovarian stimulation.     

Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing

The improved long-term survival of adolescents and young women treated for cancer has resulted in an increased focus on the effects of chemotherapy on ovarian function and its preservation. These women may seek advice and treatment regarding their reproductive status, including ways of preserving their fertility and preventing a premature menopause--factors that can have a profound impact on their quality of life. This article comprehensively reviews ovarian reserve testing (ORT) in general. Special emphasis is placed on patients with cancer, including the pathophysiology of gonadal damage following chemotherapy, fertility preservation and the potential role of ORT. Baseline parameters of ovarian reserve [FSH LH, estradiol, inhibin B and anti-Mullerian hormone (AMH)] have not yet performed sufficiently well in predicting poor outcome in assisted reproduction, but biochemical markers of ovarian reserve appear to be better than chronological age. Inhibin B and AMH show potential for future use. Dynamic testing appears to show much promise, especially stimulated levels of inhibin B and estradiol. The most promising tests of ovarian reserve are the biophysical markers, where total antral follicle count was found to be most discriminatory followed by ovarian volume. Combination of biochemical, biophysical and clinical markers of ovarian reserve may also improve predictive capacity. However, there is a lack of data pertinent to ORT in cancer. As yet there is no single clinically useful test to predict ovarian reserve accurately. Patients with cancer represent a distinct cohort who have particular concerns about their future fertility and the possibility of a premature menopause, they can benefit greatly from knowledge of their functional ovarian reserve. Large, prospective, randomized, adequately controlled studies specific to different geographical areas are required in a control population of comparable reproductive age to determine the potential role of ORT in clinical practice.     

Premature ovarian failure

Premature ovarian failure (POF) causing hypergonadotrophic hypogonadism occurs in 1% of women. In majority of cases the underlying cause is not identified. The known causes include: (a) Genetic aberrations, which could involve the X chromosome or autosomes. A large number of genes have been screened as candidates for causing POF; however, few clear causal mutations have been identified. (b) Autoimmune ovarian damage, as suggested by the observed association of POF with other autoimmune disorders. Anti-ovarian antibodies are reported in POF by several studies, but their specificity and pathogenic role are questionable. (c) Iatrogenic following surgical, radiotherapeutic or chemotherapeutic interventions as in malignancies. (d) Environmental factors like viral infections and toxins for whom no clear mechanism is known. The diagnosis is based on finding of amenorrhoea before age 40 associated with FSH levels in the menopausal range. Screening for associated autoimmune disorders and karyotyping, particularly in early onset disease, constitute part of the diagnostic work-up. There is no role of ovarian biopsy or ultrasound in making the diagnosis. Management essentially involves hormone replacement and infertility treatment, the only proven means for the latter being assisted conception with donated oocytes. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation hold promise in cases where ovarian failure is foreseeable as in women undergoing cancer treatments.     

Hyperemesis gravidarum, a literature review

Hyperemesis gravidarum (HG) is a condition causing severe nausea and vomiting in early pregnancy often resulting in hospital admission. The incidence of HG is approximately 0.5% of live births, said to be higher in multiple pregnancies, hydatidiform mole and other conditions associated with increased pregnancy hormone levels. Both the aetiology and pathogenesis of HG remain unknown. We conducted a literature review (1966-now) to summarize the current evidence on the aetiology and pathogenesis of HG. The potential role of pregnancy-related hormones such as progesterone, estrogen and HCG has been widely studied; however, various other hormones such as leptin, placental growth hormone, prolactin, thyroid and adrenal cortical hormones have been implicated in the aetiology of HG. In addition to endocrinological hypotheses, the rationale and evidence considering infectious, immunological, psychological, metabolic and anatomical causes for HG have been analysed here. Many studies suffer from the low number of patients included, the variable definition used for HG and varying assay methodology used in studies of hormone measurement. This review highlights the need for more extensive studies addressing the pathogenesis and aetiology of HG.     

Oxytocin--its role in male reproduction and new potential therapeutic uses

Oxytocin (OT) is traditionally thought of as a "female" neurohypophysis hormone due to its role in parturition and milk ejection. However, OT is recognized as having endocrine and paracrine roles in male reproduction. At ejaculation, a burst of OT is released from the neurohypophysis into the systemic circulation and stimulates contractions of the reproductive tract aiding sperm release. There is conclusive evidence that OT is synthesized within the mammalian testis, epididymis and prostate and the presence of OT receptors (OTRs) through the reproductive tract supports a local action for this peptide. OT has a paracrine role in stimulating contractility of the seminiferous tubules, epididymis and the prostate gland. Interestingly, OT has also been shown to modulate androgen levels in these tissues via stimulation of the conversion of testosterone to dihydrotestostone (DHT) by 5alpha-reductase. The elucidation of OT's role in male reproduction has suggested a number of potential therapeutic uses for this hormone. Exogenous administration of OT has, in some cases, been shown to increase the numbers of ejaculated sperm, possibly by stimulating contractions of the reproductive tract and thus aiding sperm passage. Within the prostate, OT has been shown to affect gland growth both directly and via its interaction with androgen metabolism. Prostate pathologies due to unregulated cell proliferation/growth, such as benign prostatic hyperplasia and cancer, are unfortunately very common and few effective treatments are available. Greater understanding of paracrine growth mediators, such as OT, is likely to provide new mechanisms for treating such pathologies.