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.

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.

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.

Infertility and ovarian follicle reserve depletion are associated with dysregulation of the FSH and LH receptor density in human antral follicles.

The low take-home baby rate in older women in Australia (5.8%) undergoing IVF (5.8%) is linked to the depletion of the ovarian reserve of primordial follicles. Oocyte depletion causes an irreversible change to ovarian function. We found that the young patient FSH receptor and LH receptor expression profile on the granulosa cells collected from different size follicles were similar to the expression profile reported in natural cycles in women and sheep. This was reversed in the older patients with poor ovarian reserve. The strong correlation of BMPR1B and FSH receptor density in the young was not present in the older women; whereas, the LH receptor and BMPR1B correlation was weak in the young but was strongly correlated in the older women. The reduced fertilisation and pregnancy rate was associated with a lower LH receptor density and a lack of essential down-regulation of the FSH and LH receptor. The mechanism regulating FSH and LH receptor expression appears to function independently, in vivo, from the dose of FSH gonadotrophin, rather than in response to it. Restoring an optimum receptor density may improve oocyte quality and the pregnancy rate in older women.

PIVET rFSH dosing algorithms for individualized controlled ovarian stimulation enables optimized pregnancy productivity rates and avoidance of ovarian hyperstimulation syndrome.

The first PIVET algorithm for individualized recombinant follicle stimulating hormone (rFSH) dosing in in vitro fertilization, reported in 2012, was based on age and antral follicle count grading with adjustments for anti-Müllerian hormone level, body mass index, day-2 FSH, and smoking history. In 2007, it was enabled by the introduction of a metered rFSH pen allowing small dosage increments of ~8.3 IU per click. In 2011, a second rFSH pen was introduced allowing more precise dosages of 12.5 IU per click, and both pens with their individual algorithms have been applied continuously at our clinic. The objective of this observational study was to validate the PIVET algorithms pertaining to the two rFSH pens with the aim of collecting ≤15 oocytes and minimizing the risk of ovarian hyperstimulation syndrome. The data set included 2,822 in vitro fertilization stimulations over a 6-year period until April 2014 applying either of the two individualized dosing algorithms and corresponding pens. The main outcome measures were mean oocytes retrieved and resultant embryos designated for transfer or cryopreservation permitted calculation of oocyte and embryo utilization rates. Ensuing pregnancies were tracked until live births, and live birth productivity rates embracing fresh and frozen transfers were calculated. Overall, the results showed that mean oocyte numbers were 10.0 for all women <40 years with 24% requiring rFSH dosages <150 IU. Applying both specific algorithms in our clinic meant that the starting dose was not altered for 79.1% of patients and for 30.1% of those receiving the very lowest rFSH dosages (≤75 IU). Only 0.3% patients were diagnosed with severe ovarian hyperstimulation syndrome, all deemed avoidable due to definable breaches from the protocols. The live birth productivity rates exceeded 50% for women <35 years and was 33.2% for the group aged 35-39 years. Routine use of both algorithms led to only 11.6% of women generating >15 oocytes, significantly lower than recently published data applying conventional dosages (38.2%; P<0.0001). When comparing both specific algorithms to each other, the outcomes were mainly comparable for pregnancy, live birth, and miscarriage rate. However, there were significant differences in relation to number of oocytes retrieved, but the mean for both the algorithms remained well below 15 oocytes. Consequently, application of both these algorithms in our in vitro fertilization clinic allows the use of both the rFSH products, with very similar results, and they can be considered validated on the basis of effectiveness and safety, clearly avoiding ovarian hyperstimulation syndrome.

Higher ß-HCG concentrations and higher birthweights ensue from single vitrified embryo transfers.

To examine the effect of cryopreservation on developmental potential of human embryos, this study compared quantitative ß-HCG concentrations at pregnancy test after IVF-fresh embryo transfer (IVF-ET) with those arising after frozen embryo transfer (FET). It also tracked outcomes of singleton pregnancies resulting from single-embryo transfers that resulted in singleton live births (n = 869; with 417 derived from IVF-ET and 452 from FET). The initial serum ß-HCG concentration indicating successful implantation was measured along with the birthweight of the ensuing infants. With testing at equivalent luteal phase lengths, the median pregnancy test ß-HCG was significantly higher following FET compared with fresh IVF-ET (844.5 IU/l versus 369 IU/l; P < 0.001). Despite no significant difference in the average period of gestation (38 weeks 5 days for both groups), the mean birthweight of infants born following FET was significantly heavier by 161 g (3370 g versus 3209 g; P < 0.001). Furthermore, more infants exceeded 4000 g (P < 0.001) for FET although there was no significant difference for the macrosomic category (≥4500 g). We concluded that FET programme embryos lead to infants with equivalent (if not better) developmental potential compared with IVF-ET, demonstrated by higher pregnancy ß-HCG concentrations and ensuing birthweights.

The effect of cigarette smoking, alcohol consumption and fruit and vegetable consumption on IVF outcomes: a review and presentation of original data.

BACKGROUND: Lifestyle factors including cigarette smoking, alcohol consumption and nutritional habits impact on health, wellness, and the risk of chronic diseases. In the areas of in-vitro fertilization (IVF) and pregnancy, lifestyle factors influence oocyte production, fertilization rates, pregnancy and pregnancy loss, while chronic, low-grade oxidative stress may underlie poor outcomes for some IVF cases. METHODS: Here, we review the current literature and present some original, previously unpublished data, obtained from couples attending the PIVET Medical Centre in Western Australia. RESULTS: During the study, 80 % of females and 70 % of male partners completed a 1-week diary documenting their smoking, alcohol and fruit and vegetable intake. The subsequent clinical outcomes of their IVF treatment such as quantity of oocytes collected, fertilization rates, pregnancy and pregnancy loss were submitted to multiple regression analysis, in order to investigate the relationship between patients, treatment and the recorded lifestyle factors. Of significance, it was found that male smoking caused an increased risk of pregnancy loss (p = 0.029), while female smoking caused an adverse effect on ovarian reserve. Both alcohol consumption (ß = 0.074, p < 0.001) and fruit and vegetable consumption (ß = 0.034, p < 0.001) had positive effects on fertilization. CONCLUSION: Based on our results and the current literature, there is an important impact of lifestyle factors on IVF clinical outcomes. Currently, there are conflicting results regarding other lifestyle factors such as nutritional habits and alcohol consumption, but it is apparent that chronic oxidative stress induced by lifestyle factors and poor nutritional habits associate with a lower rate of IVF success.

Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement.

This study explores the relevance of mid-luteal serum hormonal concentrations in cryopreserved embryo transfer cycles conducted under hormone replacement therapy (HRT) control and which involved single-embryo transfer (SET) of 529 vitrified blastocysts. Widely ranging mid-luteal oestradiol and progesterone concentrations ensued from the unique HRT regimen. Oestradiol had no influence on clinical pregnancy or live birth rates, but an optimal progesterone range between 70 and 99 nmol/l (P < 0.005) was identified in this study. Concentrations of progesterone below 50 nmol/l and above 99 nmol/l were associated with decreased implantation rates. There was no clear interaction between oestradiol and progesterone concentrations but embryo quality grading did show a significant influence on outcomes (P < 0.001 and P = 0.002 for clinical pregnancy and live birth rates, respectively). Multiple comparison analysis showed that the progesterone effect was influential regardless of embryo grading, body mass index or the woman's age, either at vitrification or at cryopreserved embryo transfer. The results support the argument that careful monitoring of serum progesterone concentrations in HRT-cryopreserved embryo transfer is warranted and that further studies should explore pessary adjustments to optimize concentrations for individual women to enhance implantation rates.