Hum Reprod Research Articles

Fertility Treatment and Cancers—The Eternal Conundrum: A Systematic Review and Meta-analysis

(Abstracted from Hum Reprod 2021;36:1093–1107) Given the increased risk of ovarian, breast, and endometrial cancers associated with nulliparity, there is a higher inherent cancer risk among patients pursuing fertility treatment (FT) than the general population. Endometrial and breast are hormone-sensitive cancers that carry elevated risk associated with estrogen predominant states including ovarian stimulation.

Validity of Self-Reported Endometriosis: A Comparison Across Four Cohorts

(Abstracted from Hum Reprod 2021;36:1268–1278) Approximately 10% of reproductive-aged women are affected by endometriosis, a condition in which endometrial-like tissue is found outside of the uterus causing severe pain and infertility. Diagnosis requires surgical visualization resulting in many studies relying on medical record abstraction or insurance claim information for diagnosis.

Expression Patterns of Analgesic Metabolising Machinery in 1st and 2nd Trimester Human Fetal Liver and Gonads

Use of over-the-counter analgesics during pregnancy is widespread globally. Most analgesic compounds can freely diffuse through the placental feto-maternal interface and reach the developing fetus. Current literature suggests an endocrine disruptor (ED) potential of in utero exposure to these compounds. The liver is the primary site of contact with EDs in the fetus. Exposure of the fetal gonads can also alter reproductive function with potential intergenerational effects. We aimed to characterise the metabolic capability of these fetal organs. RNA sequencing was performed in 80 second trimester human fetal livers and 48 fetal gonads (balanced for fetal age and fetal sex). Samples were collected from elective terminations of normal pregnancies (liver 11-19 weeks, FeGo study: REC 04/S0802/21, and gonads 6-17 weeks, as previously described1. RNA was extracted and Illumina NextSeq was used to produce 76 bp single end (liver) or paired end 2x50 bp (gonads) sequencing reads. Reads were quality controlled, aligned to the human reference genome and quantified at gene regions. Statistical analyses involved an ANOVA model of two-way interactions between fetal sex and fetal age. All organs expressed phase I and II metabolising enzymes and drug transporters involved in the pharmacokinetic and pharmacodynamic pathways of over-the-counter analgesics. The human fetal liver expressed ABCC2, ABCC3, ABCC4 and ABCG2 receptors at similar levels between males and females. Expression of cytochrome p450 enzymes CYP2A6, CYP2C8, CYP2C9, CYP2E1, CYP3A4 involved in metabolism of the analgesics paracetamol and ibuprofen, all increased with gestational age in the liver. Expression of GSTM1, GSTP1, GSTT1, SULT1A1, SULT1A3, SULT1A4, SULT1E1, SULT2A1, UGT2B4, UGT2B7 and UGT2B15 metabolising enzymes also increased during gestation, while fetal hepatic GSTP1 expression showed a significant 2-way interaction between both sex and age. Fetal gonads expressed ABCC4 and ABCG2 transporters, with transcript levels demonstrating significant sex-specific and gestational age differences. Fewer analgesic metabolising enzymes were expressed in the gonads than the fetal liver, including CYP2E1, GSTP1 and SULT1A1, all significantly altered by gestation and fetal sex. Our results reveal expression of major analgesics metabolic and transport components within the human fetal liver, ovaries and testes between gestation weeks 7-19. Significant sex alterations in transcript levels also suggest sexually dimorphic metabolic activity of these organs during fetal life. In conclusion, analgesics can be transported into fetal liver and gonad cells and metabolised into bioactive forms, posing toxicity risks for the developing fetus.1. Lecluze E, Rolland AD, Filis P, et al. Dynamics of the transcriptional landscape during human fetal testis and ovary development. Hum Reprod. 2020;35(5):1099-1119.

A Novel Mouse Model for Studying the Effects of Cyp17 Overexpression in a Temporal- and Spatial-Specific Manner

Background: Cyp17 plays a key role in theca cells (TCs) to produce androgens, which, in turn, are converted to estrogens in granulosa cells. Intrinsic alterations in ovarian steroidogenesis contribute to excessive ovarian androgen production that characterizes polycystic ovary disease (PCOS)1,2. Hyperandrogenism has been associated with higher levels of Cyp17 in TCs, and correlate with increased numbers of antral follicles3. While androgen excess is one of the hallmark features of PCOS, its putative role in the follicular development and function remains poorly known. Most efforts have used androgen administration or Cyp19 blockade approach to study how androgens prolong folliculogenesis4. Although some insights have been made, it is not clear if these models accurately address the cascade of effects that follow ovarian hyperandrogenism. Aim: Here, we aim to study the specific effects of hyperandrogenemia on ovarian morphology, follicle function and fertility with a new transgenic (TG) mouse model expressing elevated Cyp17 levels exclusively in TCs. Methods: We generated a breeding line of triple TG mice using a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. Specifically, we used Cyp17 promoter-iCre mice crossed with trans-activator mice (R26-STOP-rtTA-IRES-EGFP transgene, Jackson Lab) and with a responder mouse carrying the TRE-Cyp17 transgene. Cyp17 promoter-iCre mice were used to ensure rtTA/EGFP is expressed specifically in TCs of secondary follicles. After the DNA segment between the two LoxP sites is excised by Cyp17iCre specifically in TCs, the R26-STOP-rtTA gene remains activated in all daughter TCs. Only upon treatment with Doxycycline (DOX) can suppression be relieved and active transcription of TRE-Cyp17 be induced in a dose-dependent manner. Results: Cyp17 mRNA expression levels in TCs of TG mice treated with 20, 100 or 200 mg/Kg DOX compared with corresponding untreated control mice showed a modulation in a dose-dependent manner (P=0.01 ANOVA). Confocal and RNAscope analysis validated (i) the effective combination of the Cyp17iCre/rtTA expression system visualizing the rtTA/EGFP specifically expressed in ovarian TCs and (ii) the DOX-induced increase of Cyp17 expression compared with the WT mice. DOX treated TG females were acyclic, being mostly arrested in diestrus. Analysis of estrous cycle stages revealed that treated TG females spent significantly more time in diestrus than control females (P=0.007, ANOVA). Conclusions: Our new in vivo model is the first that analyzes androgen impact independent of any extraovarian source of androgen, complementing current clinical efforts to study the occurrences of TCs elevated androgen levels in normal and PCOS women. 1 Rosenfield, R. L. et al. Endocr Rev (2016)2 Azziz, R. et al. Nat Rev Dis Primers (2016)3 Comim, F. V., et al. Hum Reprod (2013)4 Stener-Victorin, E. et al. Endocr Rev (2020)

Acute Ischaemic Stroke With Hyperprolactinemia:A Case Report

Background: Macroincidentalomas were reported in 0.2% of patient underwent imaging (CT scans) for central nervous symptoms (1). In acute ischaemic stroke with hyperprolactinemia, the diagnosis of a double pathology of ischemic stroke and sellar tumour especially prolactinoma need to be considered. Hyperprolactinemia itself may be considered as a risk factor for ischemic stroke due to its thrombogenic effect (3). Clinical Case: A 47-year old man underlying hypertension and diabetes mellitus for 5 years presented with sudden onset of right sided body weakness associated with facial asymmetry and aphasia. No history of fever or trauma. Asymptomatic of hyperprolactinemia previously. On general examinations Glasgow Coma Scale 11/15 Eye 4 Verbal 1 Motor 6, blood pressure was unstable with readings of systolic 244mmHg and diastolic 142mmHg. Neurological examinations showed expressive aphasia, right hemianopia, right facial nerve palsy and absence of gag reflex. Cerebellar signs were negative. Motor function examinations of right upper and lower limbs showed hypertonia, reduce power of 2/5, normal reflexes and up going plantar response. Sensory functions of right upper and lower limbs were reduced. Clinically diagnosed as stroke with hypertensive emergency. CT brain showed multiple hypodensities due to recent infarct and incidental finding of an aggressive sellar mass. MRI brain showed left Middle Cerebral Artery territory infarct and an aggressive sphenoid sinus mass with suprasellar and bilateral cavernous sinus extension possibility of a macroadenoma. Serum prolactin level showed markedly hyperprolactinemia (21146 ng/ml, n 4.04 – 15.2 ng/ml) which level of 500ng/ml or greater is diagnostic of a macroprolactinoma (2). FSH level (0.929 IU/L, n 1.5-12.4 IU/L) and LH level (1.11 IU/L, n 1.7-8.6 IU/L) were low in this patient due to suppression of GnRH secretion from hypothalamus by prolactin. Testosterone level (0.15 nmol/L, n 8.64-29.0 nmol/L) was low secondary to low LH. Serum cortisol, growth hormone and TSH were normal. Platelet count and coagulation profiles were normal. The patient was treated conservatively in ward for acute ischaemic stroke and later was started on dopamine agonist cabergoline for hyperprolactinemia. Conclusion: This is a case report of acute ischaemic stroke with markedly hyperprolactinemia secondary to incidentaloma macroprolactinoma. Reference: (1)Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96 (4): 894-904.(2)Abha Majumdar and Nisha Sharma Mangal. Hyperprolactinemia. J Hum Reprod Sci. 2013 Jul-Sep; 6(3): 168–175.(3)Sankalp Kumar Tripathi, Pallavi Kamble, M.G. Muddeshwar. Serum Prolactin Level in Patients of Ischemic stroke. International Journal of Contemporary Medical Research 2016; 3(12): 3459-3460.

Self-management Factors Associated With Quality of Life Among Women With Endometriosis: A Cross-sectional Australian Survey

(Abstracted from Hum Reprod 2021;36(3):647–655) Endometriosis is a chronic inflammatory condition characterized by endometrial tissue growing outside of the uterus, resulting in chronic pain and reduced quality of life requiring long-term multimodal management including surgery, analgesic medications, and hormonal therapy. Self-management of one's chronic disease is a concept defined as the active participation of the patient in planning decision-making and undertaking tasks to manage the symptoms, treatment, and physical and psychological changes involved in living with a chronic disease.

The Association between Dietary Inflammatory Index and Sex Hormones among Men in the United States.

This study investigated the association between Dietary Inflammatory Index and sex hormones in a large, nationally representative adult male sample. We utilized data from the 2013-2014 and 2015-2016 National Health and Nutrition Examination Survey. Males aged ≥20 years who provided a 24-hour dietary intake history and underwent serum sex hormone testing were included in analysis. Weighted proportions and multivariable analysis controlling for age, race, energy, smoking status, education level, body mass index and time of venipuncture were used to evaluate the associations between Dietary Inflammatory Index and sex hormones. For 4,151 participants, Dietary Inflammatory Index ranged from -5.05 to 5.48. Mean±SD total testosterone was 419.30±176.27 ng/dl. Mean±SD total testosterone was lower among men in the highest tertile compared with men in the lowest tertile group (410.42±171.97 vs 422.71±175.69, p <0.001). A per unit increase in Dietary Inflammatory Index was related to 4.0% (95% CI 0.5-7.6) higher odds of testosterone deficiency. In the fully adjusted multivariable model, males in Dietary Inflammatory Index tertile 3 (the most pro-inflammatory) had 29.6% (3.1-63.0) higher odds of testosterone deficiency than those in tertile 1 (p trend=0.025). Interaction tests revealed no significant effect of body mass index on the association of Dietary Inflammatory Index with testosterone deficiency and all sex hormone parameters. Men adhering to a more pro-inflammatory diet appear to have a higher risk of testosterone deficiency, indicating the important role of diet in male reproductive health.

Scientometric Analysis of The Research on The Abortion: 2015-2019

Nowadays the researchers have found the Finale the soundless virus of unsafe abortion is an imperative public-health and human-rights authoritative. Furthermore, noticeable global-health issues related to abortion constitute an important debate in medical ethics. Each year, approximately 19–20 million abortions are completed by personalities lacking the necessary bits of help or in situations lower lowest medical ethics or both. As a result, we found that the greatest productive author in standings of the total number of articles, the highest mean of total citation per articles 10.02 registered in the year 2015 against 1684 number of the citation with five citable years, Foster DG is the most remarkable writer according to M-index which is the median number of cited publications. While the author only started to create in 2015, the top two journals with highly (4143 and 4110 cited a Fertil Steril, and Hum Reprod) related to abortion services research.

Streamlining Follicular Monitoring During Controlled Ovarian Stimulation: A Data-Driven Approach to Efficient IVF Care in the New Era of Social Distancing

(Abstracted from Hum Reprod 2021;36(1):99–106) During controlled ovarian stimulation (COS) as part of in vitro fertilization (IVF), routine monitoring using transvaginal ultrasound is indicated in order to identify the most appropriate time to trigger final follicular maturation and to identify signs of overresponse. Evidence regarding the ideal protocol and frequency of monitoring COS patients in order to maximize live birth rate and minimize morbidity has been inconclusive.

SARS-CoV-2 in First Trimester Pregnancy: A Cohort Study

(Abstracted from Hum Reprod 2021;36(1):40–47) Pregnant women are at an increased risk of viral infections and increased risk of serious morbidity such as severe pneumonia, particularly during the first trimester. COVID-19 (coronavirus disease 2019) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

AIUM Practice Parameter for the Performance of Sonohysterography and Hysterosalpingo-Contrast Sonography.

AIUM Practice Parameter for the Performance of Sonohysterography and Hysterosalpingo-Contrast Sonography.

Maternal Plasma Genome-Wide Cell-Free DNA Can Detect Fetal Aneuploidy in Early and Recurrent Pregnancy Loss and Can Be Used to Direct Further Workup

(Abstracted from Hum Reprod 2020;35(5):1222–1229) Traditional diagnostic investigations of recurrent pregnancy loss (RPL) identify an etiology in fewer than half of cases. The single most common etiology is random chromosomal anomalies, and it has been established that 50% to 70% of early pregnancy losses (EPLs) are caused by numeric chromosomal anomalies.

Prospective analysis of progesterone exposure in programmed single thawed euploid embryo transfer cycles and outcomes.

In the era of personalized medicine and the increased use of frozen embryo transfer (FET), assay of the endometrium's receptivity prior to transfer has gained popularity, especially among patients. However, the optimal timing for single thawed euploid embryo transfers (STEET) in a programmed FET has yet to be determined Mackens et al. (Hum Reprod. 32(11):2234-42, 2017). We sought to examine the outcomes of euploid FETs by length of progesterone (P4) exposure. Prospective cohort study of programmed FETs of single euploid embryos between June 1, 2018, and December, 18, 2018, at our center. Subjects reported the exact start time for initiating progesterone. The transfer time was noted to calculate the primary independent variable, duration of progesterone exposure. Statistical analysis included ANOVA and Spearman's rho correlation, with p < 0.05 considered significant. Inclusion criteria were met for 253 programmed STEET cycles in the analysis. There was no significant difference in P4 duration when comparing outcome groups (112.8 ± 3.1 ongoing pregnancy (OP), 112.4 ± 4.4 spontaneous abortion (SAB), 111.6 ± 1.7 biochemical pregnancy (BP), 113.9 ± 5.7 no pregnancy (NP), F 1.76, df 3, p = 0.16). An ROC curve assessing the ability of P4 duration to predict ongoing pregnancy (OP) had an area under the curve of 0.467 (p = 0.38). Duration of P4 was not associated with outcome. Of the cycles, 65.6% resulted in ongoing pregnancy with our center's instructions resulting in an average progesterone exposure of 112.8h, with a range of 98.3-123.7h. With growing popularity for individualized testing, these results provide evidence for patient counseling of the high likelihood of ongoing pregnancy without personalized testing.

Septum Resection in Women With a Septate Uterus: A Cohort Study

(Abstracted from Hum Reprod 2020;35(7):1578–1588) The septate uterus has an estimated prevalence of 0.2% to 2.3% in women of reproductive age and is associated with impaired reproductive outcomes, the biologic basis of which is unclear. The standard-of-care treatment for septate uterus is hysteroscopic septum resection.

Multiple Vitrification-Warming and Biopsy Procedures on Human Embryos: Clinical Outcome and Neonatal Follow-up of Children

(Abstracted from Hum Reprod 2020;35(11):2488–2496) Despite advances in preimplantation genetic testing (PGT), inconclusive diagnoses following aneuploidy screening, chromosomal rearrangement, or monogenic testing do occur regularly. With PGT these days shifting toward more and more trophectoderm (TE) biopsy, test failures inevitably involve a second round of biopsy and blastocyst vitrification.

Mullerian Malformations and Reconstructive Surgery: Clinicians' Approach.

Mullerian malformations are not uncommon. Overall incidence ranges widely between 1 in 200 women and 4 in 100 women (Chan et al. in Hum Reprod Update 17:761-771, 2011; Grimbizis et al. in Hum Reprod 28:2032-2044, 2013). Other way, these observations suggest presently an increased number of Mullerian abnormalities are diagnosed with more details, following the use of newer diagnostic modalities. Most classifications that are available have limitations. Diagnosis was based on imaging studies that had low diagnostic accuracy. It was focused mainly on the anomalies of the uterus. Less is known about the anomalies of the cervix or the vagina in isolation or in combination with the utero-cervical and vaginal malformations. Improved diagnostic modalities and incorporation of assisted reproductive technology have improved the outcome further. Therefore, a more expanded classification needs to be introduced with wider criteria for the clinicians. This will make clinicians' approach for the management more simple.

Endometriosis-associated pain in women undergoing hysterectomy.

Pain is a cardinal symptom of endometriosis and its management can be challenging. Analgesics are commonly used as first line treatment for endometriosis-associated pain, despite there being a paucity of evidence regarding their use for this indication. Clinicians are advised to consider NSAIDs or other analgesics to reduced endometriosis-associated pain due to the known benefit of NSAIDs in primary dysmenorrhea (ESHRE guideline "Management of women with endometriosis." Dunselman et al., Hum Reprod. 2014; 29(3):400-12). Women who fail to respond to conservative treatments and who have completed their family may be offered hysterectomy with removal of the ovaries and all visible endometriosis lesions, alongside advice that hysterectomy will not necessarily cure the symptoms or the disease.

Polycystic ovary syndrome and assisted reproduction: splitters versus lumpers.

In 2003, the Rotterdam ESHRE/ASRM consensus updated the criteria for diagnosing polycystic ovary syndrome (PCOS), requiring, after the exclusion of other etiologies, at least two of the following: oligo-anovulation, hyperandrogenism, and polycystic ovaries. This change was driven by the awareness that PCOS is a syndrome with a broad spectrum of signs and symptoms of ovarian dysfunction (The Rotterdam PCOS consensus workshop group. Hum Reprod. 2004;19:41-47).

Associations Between Polycystic Ovary Syndrome and Adverse Obstetric and Neonatal Outcomes: A Population Study of 9.1 Million Births

(Abstracted from Hum Reprod 2020;35(8):1914–1921) Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology that may be associated with an increased risk of requiring cesarean section (C/S), experiencing preterm delivery (PTD), having small-for-gestational-age (SGA) infants, and undergoing induction of labor. This syndrome is commonly associated with insulin resistance (IR) and is indicated to be independently associated with gestational diabetes mellitus, hypertensive disorders of pregnancy, and preeclampsia.

Late Follicular Phase Progesterone Elevation During Ovarian Stimulation Is Not Associated With Decreased Implantation of Chromosomally Screened Embryos in Thaw Cycles

(Abstracted from Hum Reprod 2020;35:1889–1899) Although the physiologic mechanism remains unclear, late follicular phase progesterone elevation (LFPE) commonly occurs during controlled ovarian hyperstimulation (COH) for assisted-reproductive technology (ART) such as in vitro fertilization (IVF). Late follicular phase progesterone elevation has been associated with patient body mass index (BMI), ethnicity, ovarian reserve metrics, ovarian response to exogenous gonadotropins, number of follicles recruited during COH, dosage/duration of stimulation cycles, and other factors.