Ovulation induction and subfertile untreated conception groups offer improved options for interpreting risks associated with ART.

PURPOSE: To identify and characterise appropriate comparison groups for population studies of health outcomes in ART-conceived births: ovulation induction (OI), subfertile untreated and fertile natural conceptions. Our secondary objective was to examine whether known risks of pregnancy complications and adverse birth outcomes in ART births are elevated in comparison with subfertile (untreated and OI) conception groups. METHODS: We linked State and Commonwealth datasets to identify all live and stillbirths (≥ 20 weeks) in Western Australia from 2003 to 2014 by method of conception. Demographic characteristics, maternal pre-existing conditions, adverse obstetric history and pregnancy complications were compared across conception groups. Generalised estimating equations were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CI) for pregnancy complications and birth outcomes in singletons. RESULTS: We identified 9456 ART, 3870 OI, 11,484 subfertile untreated and 303,921 fertile naturally conceived deliveries. OI and subfertile untreated groups more closely resembled the ART group than the fertile group; however, some differences remained across parity, maternal age, pre-existing conditions and obstetric history. In multivariate analyses, ART singletons had greater risks of placental problems (e.g. placenta praevia aRR 2.42 (95% CI 1.82-3.20)) and adverse birth outcomes (e.g. preterm birth aRR 1.38 (95% CI 1.25-1.52)) than the subfertile untreated group, while OI singletons were more similar to the subfertile group with higher risk of preeclampsia and gestational diabetes. CONCLUSION: OI and subfertile untreated conception groups offer improved options for interpreting health outcomes in ART births. Pregnancy complications (particularly placental disorders) and adverse outcomes at delivery are more common following ART.

The Sperm DNA Fragmentation Assay with SDF Level Less Than 15% Provides a Useful Prediction for Clinical Pregnancy and Live Birth for Women Aged under 40 Years.

This retrospective cohort study was conducted on 1148 males who presented along with their partners for infertility management at the PIVET Medical Centre between 2013 and 2022 and had a sperm DNA fragmentation (SDF) assay performed by Halosperm, thereafter participating in 1600 assisted reproductive technology (ART) cycles utilising one of three modalities, namely, IVF-Only, ICSI-Only or IVF-ICSI Split cycles. The outcomes from the ART cycles were then analysed as two groups based on SDF levels <15% and ≥15%. The study showed the unadjusted fertilization rates were not different between the groups, neither across the four female age ranges. However, when the fertilization rates were adjusted for the mature oocytes (metaphase-II oocytes), there was a highly significant difference in fertilization rates in favour of the group with SDF levels < 15% where the women were in the younger age grouping of <35 years (78.4% vs. 73.0%; p < 0.0001). Overall, there was no difference in the rates of blastocyst development nor clinical pregnancy rates between the two SDF groups, but there was a significantly higher pregnancy rate for the younger women (<35 years) with the group of SDF level < 15% (44.1% vs. 37.4%; p = 0.04). Similarly, there was no difference in the miscarriage rates overall with respect to SDF groups, and no clear picture could be deciphered among the women's age groups. With respect to cumulative live births, this reflected the pregnancy rates with no overall difference between the two SDF groups, but there was a significantly higher cumulative live birth rate for women <35 years where the SDF level was <15% (38.6% vs. 28.6%; p < 0.01). Among the three modalities, the highest cumulative live birth rate occurred within the group with SDF level < 15%, being highest with the IVF mode, particularly for women aged <40 years (43.0% vs. 37.7% for IVF-ICSI Split and 27.9% for ICSI; p = 0.0002), noting that the IVF case numbers were disproportionately low.

Male Clinical Parameters (Age, Stature, Weight, Body Mass Index, Smoking History, Alcohol Consumption) Bear Minimal Relationship to the Level of Sperm DNA Fragmentation.

This retrospective cohort study reports on 1291 males who were the partners of women presenting with infertility requiring assisted reproduction and who had sperm DNA fragmentation (SDF) levels measured by the Halosperm test. These men provided clinical and biometric details which included their age, stature, weight, and body mass index (BMI). Of these men, 562 (43.5%) provided detailed historical records of their smoking and alcohol histories. The aim of this study was to determine whether any clinical and biometric parameters, or main lifestyle factors, had any influence on SDF. We found that the only clinical parameter with a direct correlation was that of advancing age (r = 0.064, p = 0.02), but none of the biometric parameters of stature, weight, or BMI showed any significant correlation. In respect to lifestyle, there were significant correlations with smoking history, but not in the way we expected. Our data showed significantly elevated SDF levels among non-smokers (p = 0.03) compared with smokers. We also found that, among the non-smokers, ex-smokers had higher SDF levels (p = 0.03). With respect to alcohol, consumers did not show any significant differences in SDF levels. These lifestyle findings did not show any significant relevance with respect to an SDF level of <15% or ≥15%. Furthermore, logistic regression analysis excluded age as a confounder in these lifestyle findings. It is therefore concluded that, apart from age, both clinical and lifestyle aspects have minimal relevance to SDF.

How Well Do Semen Analysis Parameters Correlate with Sperm DNA Fragmentation? A Retrospective Study from 2567 Semen Samples Analyzed by the Halosperm Test.

Sperm DNA fragmentation (SDF) levels have been measured in the workup for in vitro fertilization (IVF) at PIVET since 2007, with the Halosperm test having replaced the previous sperm chromatin structure assay (SCSA) since 2013. Of 2624 semen samples analyzed for the Halosperm test, 57 were excluded as the sperm concentration was <5 million/mL, a level too low for accurate testing, leaving 2567 samples for assessment within this study. The SDF rates were categorized in 5 sperm DNA fragmentation indices (DFI), ranging from <5% to levels >30%, and these categories were correlated with the respective semen analysis profiles and two clinical parameters, namely the age of the male and the ejaculatory abstinence period prior to the sample. The results showed a significant correlation with male age (r = 0.088; p < 0.0001), the abstinence period (r = 0.076; p = 0.0001), and the semen volume (r 0.063; p = 0.001), meaning an adversely high SDF was associated with advanced age, prolonged abstinence, and raised semen volume parameters. There was a significant negative correlation with sperm morphology (r = -0.074; p = 0.0001), progressive motility (r = -0.257; p < 0.0001), and semen pH (r = -0.066; p < 0.001), meaning these semen anomalies were associated with high SDF values. With respect to abnormal morphology, sperm tail defects had a positive correlation (r = 0.096; p < 0.0001) while midpiece defects showed a negative correlation (r = -0.057; p = 0.004), meaning that tail defects are most likely to associate with adverse DFI values. With respect to motility patterns, the poorer patterns showed a positive correlation with increased DFI, namely C pattern (r = 0.055; p = 0.005) and D pattern (r = 0.253; p < 0.0001). These results imply that raised DFI reflects poor sperm quality and should be investigated in clinical trials involving IVF and the consideration of intracytoplasmic sperm injection (ICSI).

Asthma and allergies in a cohort of adolescents conceived with ART.

RESEARCH QUESTION: Are asthma and allergies more common in adolescents conceived with assisted reproductive technologies (ART) compared with adolescents conceived without? DESIGN: The Growing Up Healthy Study (GUHS) is a prospective cohort study including ART-conceived offspring born between 1991 and 2001 in Perth, Australia. Their long-term health outcomes, including asthma and allergy parameters, were compared with those of their counterparts conceived without ART from the Raine Study Generation 2 (Gen2), born in 1989-1991. At age 14, 152 GUHS and 1845 Gen2 participants completed the following assessments: the International Studies of Asthma and Allergies in Childhood (ISAAC) questionnaire, spirometry, methacholine challenge testing and skin prick testing (SPT). RESULTS: No differences were detected in the prevalence of current asthma (7.7% versus 10.8%, adjusted odds ratio [aOR] 0.82 (95% CI 0.44-1.52), P = 0.530). Spirometry-measured lung volumes were larger in the ART adolescents. Bronchial hyperresponsiveness was less prevalent in the ART cohort (8.8 versus 18.6%, P = 0.006). Current allergic rhinoconjunctivitis (ARC) rates were significantly higher in the ART cohort (32.4% versus 25.2%, aOR 1.52 [95% CI 1.03-2.26], P = 0.036), with no cohort differences in atopic dermatitis. Food allergies were more prevalent in the ART cohort (20.7 versus 10.9%, aOR 1.89 [95% CI 1.17-3.06], P = 0.010) with more adolescents having a positive SPT (68.0% versus 45.4%, aOR 3.03 [95% 1.99-4.63], P < 0.001). CONCLUSIONS: This study reports no differences in asthma prevalence, slightly altered lung function, an increase in ARC, food allergies and positive SPT in the ART-conceived adolescents. These findings are important to families and healthcare providers and may open up possibilities for targeted screening and treatment. Further studies are required to confirm these findings.

Cohort profile: The Growing Up Healthy Study (GUHS)-A prospective and observational cohort study investigating the long-term health outcomes of offspring conceived after assisted reproductive technologies.

Worldwide, over 8 million children and adults are conceived following assisted reproductive technologies (ART), and their long-term health is of consequential public health interest. The objective of this paper is to describe the Growing up Healthy Study (GUHS) cohort in detail, publicise it and invite collaboration. Combining the data collected in the GUHS with other cohorts or databases will improve the much-needed knowledge about the effects of ART, and allow for better understanding of the long-term health outcomes of offspring conceived after ART. The GUHS cohort is a prospective observational study of adolescents and young adults conceived after assisted reproductive technologies (ART). It was established to determine if the long-term health of offspring conceived by ART differs from that of the general population. This was investigated by comparing a substantial number of health parameters to those of a representative population of offspring conceived without ART. The n = 303 GUHS participants were born between 1991-2001 in the two fertility clinics operating at the time in Perth, Western Australia, and undertook assessments at ages 14, 17 and 20, replicating the pre-defined study protocols from the reference cohort-the Raine Study. Participants were comprehensively phenotyped through detailed questionnaires, anthropometry, biochemical analyses, as well as age-specific assessments (asthma, atopy, cardiometabolic health, body composition, mental health, thyroid function, epigenetics and vision). To date the GUHS cohort has been used to study the methylation, cardiometabolic, and thyroid profiles, as well as respiratory and mental health. To summarise, the GUHS cohort provides a valuable addition to the limited knowledge of the long-term health outcomes of ART-conceived offspring.

SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services.

The prolonged lockdown of health facilities providing non-urgent gamete cryopreservation-as currently recommended by many reproductive medicine entities and regulatory authorities due to the SARS-CoV-2 pandemic will be detrimental for subgroups of male infertility patients. We believe the existing recommendations should be promptly modified and propose that the same permissive approach for sperm banking granted for men with cancer is expanded to other groups of vulnerable patients. These groups include infertility patients (eg, azoospermic and cryptozoospermic) undergoing medical or surgical treatment to improve sperm quantity and quality, as well as males of reproductive age affected by inflammatory and systemic auto-immune diseases who are about to start treatment with gonadotoxic drugs or who are under remission. In both scenarios, the "fertility window" may be transitory; postponing diagnostic semen analysis and sperm banking in these men could compromise the prospects of biological parenthood. Moreover, we provide recommendations on how to continue the provision of andrological services in a considered manner and a safe environment. Our opinion is timely and relevant given the fact that fertility services are currently rated as of low priority in most countries.

Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF.

RESEARCH QUESTION: To determine the relationship between vitamin D (VitD) status and embryological, clinical pregnancy and live birth outcomes in women undergoing IVF. DESIGN: Cross-sectional, observational study conducted at a university-affiliated private IVF clinic. A total of 287 women underwent 287 IVF cycles and received a fresh embryo transfer. Patients had their serum 25-hydroxyvitamin D2/D3 (VitD) determined on the day of oocyte retrieval, which was analysed in relation to blastocyst development rate, clinical pregnancy and live birth outcomes. RESULTS: In stepwise, multivariable logistic regression models, increases in blastocyst development rate, number and quality, along with embryo cryopreservation and utilization rates were associated with women with a sufficient VitD status (≥20 ng/ml). For a single increase in the number of blastocysts generated per cycle or embryos cryopreserved per cycle, the likelihood for the patient to be VitD sufficient was increased by 32% (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.10-1.58, P = 0.002 and OR 1.33, 95% CI 1.10-1.60, P = 0.004, respectively). Clinical pregnancy (40.7% versus 30.8%, P = 0.086) and live birth rates (32.9% versus 25.8%, P = 0.195) in the sufficient VitD group versus the insufficient group were not significantly different and VitD sufficiency was not significantly associated with these outcomes. CONCLUSION: A strong relationship was observed between blastocyst development and VitD sufficiency. However, there was no association between VitD and clinical pregnancy or live birth outcomes. Further larger studies are needed to investigate whether the observed effect on blastocyst development may have downstream implications on subsequent clinical pregnancy or live birth rates, and on a potential mechanism where sufficient VitD concentrations are linked to improved IVF outcomes.

Measuring IGF-1 and IGFBP-3 Profiles in Women Seeking Assisted Reproduction; Relationship to Clinical Parameters (Study 1).

This study examines the IGF serum profile (IGF-1, IGFBP-3 and the IGF Ratio) from 1633 women who undertook an Assessment Cycle prior to any treatment by assisted reproduction. The idea is to progressively study the IGF profile with a view to identify those women who may be classified as having adult growth hormone deficiency (AGHD) and who may benefit from specific dynamic endocrinological testing to identify a potential benefit from growth hormone adjuvant treatment. This first study evaluates the IGF profile on clinical parameters, namely age, body mass index (BMI) and stature. The study shows a significant linear reduction in IGF-1 levels across the four age groups (<35 years, 35-39 years, 40-44 years and ≥45 years; p < 0.001). However, there was no variation in IGFBP-3 levels but the IGF Ratio showed a progressive linear elevation with advancing age (p < 0.001). With respect to both BMI and stature, none of the IGF profile parameters showed any variation. We conclude that further studies are warranted to examine the notion of underlying AGHD in the causation of the well-known feature of age-related poor prognosis in assisted reproduction.

MPA given orally during the first trimester for threatened miscarriage carries no specific risk for foetal abnormalities albeit the rate is higher than non-threatened pregnancies.

This observational study examines the outcomes of pregnancies arising in women referred for infertility, where those who experienced threatened miscarriage were treated with medroxyprogesterone acetate (MPA) tablets. The 14-year study period covers comprehensive real-time data entries into the validated electronic database including details of the infertility management, pregnancy outcomes and any foetal anomalies among the infants, each being tracked and recorded. Of 4057 clinical pregnancies, 1343 received MPA for threatened miscarriage; 934 (69.6 %) of which continued to livebirths. These were compared with the remaining 2714 clinical pregnancies without threatened miscarriage or MPA and which resulted in 2075 (76.5 %) livebirths. There were 134 developmental abnormalities recorded among the 3009 livebirths of which 78 (2.6 %) were categorised appropriate for the Western Australian Developmental Abnormalities Register; WARDA. These comprised 55 in the MPA group, 36 of which were categorised as serious (being 2.7 % of clinical pregnancies and 3.9 % of births). In the group without MPA, there were 79 abnormalities, of which 42 were categorised as serious (being 1.7 % of clinical pregnancies and 2.2 % of births). Specifically, there were no cases of androgenisation noted among the female infants. The abnormality rates were low overall and well within the annual WARDA ranges. We cautiously suggest that oral MPA can be considered for studies throughout pregnancy including the early first trimester to assess a potential role in reducing miscarriage, as well as advanced pregnancies to evaluate a potential role in reducing stillbirths and preterm delivery.

Founding pioneers of IVF update: Innovative researchers generating livebirths by 1982.

This commentary adds accuracy and interesting information to the story of the founding pioneers of IVF which was published in this journal in 2018, at the 40th anniversary of the first IVF livebirth, namely Louise Joy Brown born 25 July 1978. Table 1 in that first publication is now updated to reflect extended information about Team 1 comprising the acknowledged "Fathers of IVF", but whose work is better tabulated as Team 1a from the NHS days in Oldham; and Team 1b covering the new period of private practice at Bourn Hall in Cambridge. With the passing of pioneer Ian Craft, co-author of the first article, further information came to light at his memorial service. There has now been some adjustment to the last few months of 1982, with correct inclusion of Israel into the list along with an interesting exposé of the two major pioneer facilities of that country. The previously cited third Australian groups (Team 12) have now been appropriately relegated to 1983, a year which experienced a plethora of IVF facilities around the world and the beginning of the IVF population boom.

Pathogenesis of endometriosis: Look no further than John Sampson.

Rather than consider endometriosis as an enigmatic disease, reading John Sampson's two theories/mechanisms explains virtually all cases affecting the female. It is true that Sampson's most recent publication, in 1940, which talks about retrograde menstruation via the fallopian tubes, clearly fails to explain many types of endometriosis, particularly that located in extra-pelvic sites. However, his earlier publications of 1911 and 1912, on radiographic studies of hysterectomy specimens that had been injected with various gelatin/bismuth/pigment mixtures examining the unique uterine vasculature, were more important. These studies enabled him to describe 'the escape of foreign material from the uterine cavity into the uterine veins' in 1918 and subsequently to demonstrate metastatic or embolic endometriosis in the first of his two important publications in 1927. Later in that same year, in response to 'academic banter' from other historic gynaecologists, he published a second article that indicated his studies had been redirected to explore the retrograde tubal menstruation idea; this required undertaking his hysterectomies during menses. That work led to his 1940 presentation at the invitation of The American College of Obstetricians and Gynecologists to focus on the second theory/mechanism of endometriosis. This appears to have caused his more important first theory/mechanism to have been forgotten.

The Evolving Concept of Poor-Prognosis for Women Undertaking IVF and the Notion of Growth Hormone as an Adjuvant; A Single-Center Viewpoint.

IVF is currently regarded as a successful new technology with the number of IVF children currently well over 8 million worldwide. This has been achieved by an explosive plethora of facilities. However, from its earliest history, IVF has been beset by poor-prognosis on a treatment cycle basis, an aspect which has been a constant feature for the majority of treatments to this stage. The 2019 Australian and New Zealand Assisted Reproduction Database (ANZARD) report shows that IVF clinics have live birth productivity rates (from combined initiated fresh and frozen cycles) ranging from 9.3 to 33.2%. Over the past 40 years there have been a number of innovations which have steadily moved the success rates forward, but progress is held back by an intransigent group of women who can be classified as being poor-prognosis from one or more adverse factors, namely advanced age (>40 years), poor ovarian response (POR) to ovarian stimulation, inability to generate high quality blastocyst-stage embryos, recurrent implantation failure, or recurrent early pregnancy losses. A number of strategies are variously applied including the use of recombinant growth hormone (GH) adjuvant therapy. Our retrospective studies at PIVET over the past decade show a 6.2-fold chance of live birth for fresh cycle embryo transfers following GH injections of 1-1.5 IU daily given for 3-6 weeks in the lead-up to the trigger for ovum pick-up. We have also recently reported the live birth rates from frozen embryo transfers utilizing those blastocyst embryos generated under GH influence and showed the live birth rate was 2.7-fold higher in a carefully matched poor-prognosis group. This experience has been compared to the total 42 GH studies reported since the year 2000, the majority matching those of PIVET with significant increases in both oocyte and embryo utilization rates but only ~50% are followed by elevated live birth rates. We argue that this discrepancy relates to failure in addressing other causes of poor-prognosis along with the wastage of transferring more than a single embryo in the fresh cycle, when ANZARD data indicates a significantly higher chance of live birth from frozen embryo transfers.

Live birth outcomes of vitrified embryos generated under growth hormone stimulation are improved for women categorized as poor-prognosis.

OBJECTIVE: To determine the clinical pregnancy (CP) and live birth (LB) rates arising from frozen embryo transfers (FETs) that had been generated under the influence of in vitro fertilization (IVF) adjuvants given to women categorized as poor-prognosis. METHODS: A registered, single-center, retrospective study. A total of 1,119 patients with first FETs cycle include 310 patients with poor prognosis (109 treated with growth hormone [GH], (+)GH group vs. 201 treated with dehydroepiandrosterone, (-)GH group) and 809 patients with good prognosis (as control, (-)Adj (Good) group). RESULTS: The poor-prognosis women were significantly older, with a lower ovarian reserve than the (-)Adj (Good) group, and demonstrated lower chances of CP (p<0.005) and LB (p<0.005). After adjusting for confounders, the chances of both CP and LB in the (+)GH group were not significantly different from those in the (-)Adj (Good) group, indicating that the poor-prognosis patients given GH had similar outcomes to those with a good prognosis. Furthermore, the likelihood of LB was significantly higher for poor-prognosis women given GH than for those who did not receive GH (p<0.028). This was further confirmed in age-matched analyses. CONCLUSION: The embryos cryopreserved from fresh IVF cycles in which adjuvant GH had been administered to women classified as poor-prognosis showed a significant 2.7-fold higher LB rate in subsequent FET cycles than a matched poor-prognosis group. The women with a poor prognosis who were treated with GH had LB outcomes equivalent to those with a good prognosis. We therefore postulate that GH improves some aspect of oocyte quality that confers improved competency for implantation.

Growth Hormone and Insulin-Like Growth Factor Action in Reproductive Tissues.

The role of growth hormone (GH) in human fertility is widely debated with some studies demonstrating improvements in oocyte yield, enhanced embryo quality, and in some cases increased live births with concomitant decreases in miscarriage rates. However, the basic biological mechanisms leading to these clinical differences are not well-understood. GH and the closely-related insulin-like growth factor (IGF) promote body growth and development via action on key metabolic organs including the liver, skeletal muscle, and bone. In addition, their expression and that of their complementary receptors have also been detected in various reproductive tissues including the oocyte, granulosa, and testicular cells. Therefore, the GH/IGF axis may directly regulate female and male gamete development, their quality, and ultimately competence for implantation. The ability of GH and IGF to modulate key signal transduction pathways such as the MAP kinase/ERK, Jak/STAT, and the PI3K/Akt pathway along with the subsequent effects on cell division and steroidogenesis indicates that these growth factors are centrally located to alter cell fate during proliferation and survival. In this review, we will explore the function of GH and IGF in regulating normal ovarian and testicular physiology, while also investigating the effects on cell signal transduction pathways with subsequent changes in cell proliferation and steroidogenesis. The aim is to clarify the role of GH in human fertility from a molecular and biochemical point of view.

The Concept of Growth Hormone Deficiency Affecting Clinical Prognosis in IVF.

The current understanding of human growth hormone (hGH; here GH) action is that the molecule is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. It can be classified as a protein (comprising more than 50 amino acids) but true proteins have tertiary and quaternary chains creating a more complex structure, hence GH is usually classified as a polypeptide. GH is normally secreted at night during sleep and promotes skeletal, visceral and general body growth through the action of somatomedins or IGFs, notably IGF-1. In some tissues, GH action is directed via specific receptors GHRs; these are most abundant in liver, adipose and muscle tissues but have also been shown in granulosa cells, testicular tissues and on the oocyte, as well as in glandular cells of the luteal phase endometrium and decidua; such findings being recent and minimally researched to now. Following engagement with its receptor, the transduction process activates multiple signaling proteins. These all lead to extensive metabolic and mitogenic (growth promoting) responses. Clinically, GH is known to have an important role in pubertal development and is a key hormone for the vigor associated with adolescence and early adult life stages but has a faded presence and role for later adulthood, beyond age 30 years, and is minimally detected in advanced age, beyond 40 years. In association with the rapidly increasing trend for delaying reproduction beyond age 35 years, GH is being widely researched now as a potential adjuvant for infertility treatment in this group who, studies consistently show, have a poorer prognosis than younger females when relying on autologous oocytes. The idea that the age-related reduction in fertility prognosis is a feature of growth hormone deficiency is supported by our studies showing an elevated binding protein IGFBP-3/IGF-1 ratio and this can be reduced to a normal range (matching younger, good prognosis women) by the administration of GH as an adjuvant.

Advanced fibroid study: paying homage to John Sampson.

A recent article supports our longstanding view that all intramural fibroids can cause disturbance of uterine function. This may be reflected in the symptom of menorrhagia or fertility-related issues, as well as pregnancy losses at all gestational stages. However, it was disappointing that there was no reference to either the mechanism by which fibroids disturb uterine function nor to the gynaecologist who described this more than 100 years ago, namely John Sampson. In fact, Sampson's findings about the unique venous drainage mechanism from the endometrium explains how menstrual loss is contained in normal physiology, but which can be excessive when the protective 'anaemic' zone is disturbed. Two more recent and pertinent observations include the hysteroscopic findings of Osamu Sugimoto, who showed in the 1970s that the endometrium overlying submucous fibroids is actually atrophic, hence the oft-cited reason of hyperplastic or excessive endometrium cannot be the cause of the associated menorrhagia. Furthermore, recent imaging techniques describe an additional 'junctional zone' adjacent to the endometrium in cases of fibroids and adenomyosis. We believe this all adds up to disturbed venous drainage as described by Sampson and needs to immediately enter the educational training of medical students, doctors and gynaecologists worldwide.