The impact of acute SARS-CoV-2 on testicular function including insulin-like factor 3 (INSL3) in men with mild COVID-19: A longitudinal study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect the male reproductive system as it uses angiotensin-converting enzyme (ACE)2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long-term effects of mild coronavirus disease 2019 (COVID-19) on testicular function, and insulin-like factor 3 (INSL3) levels have not previously been assessed during acute SARS-CoV-2 infection. OBJECTIVES: The aim of the study was to assess the impact of acute SARS-CoV-2 infection on testicular function including INSL3 and the presence of SARS-CoV-2 RNA in semen in non-hospitalised men with mild COVID-19. MATERIALS AND METHODS: This longitudinal study included 36 non-hospitalised SARS-CoV-2-positive men (median age 29 years). Inclusion was within seven days following a positive SARS-CoV-2 reverse-transcription polymerase chain reaction test. Reproductive hormone levels, semen parameters, and the presence of SARS-CoV-2 RNA in oropharyngeal and semen samples were assessed during acute SARS-CoV-2 infection (baseline) and at three- and six-month follow-up. Wilcoxon matched-pair signed-rank (two samples) test was used to assess time-related alterations in reproductive hormone levels and semen parameters. RESULTS: Lower plasma testosterone (T) (total and calculated free (c-fT)) and higher luteinising hormone (LH) concentrations were observed during acute SARS-CoV-2 infection (baseline) compared to three- and six-month follow-up. Consequently, ratios of c-fT/LH were lower at baseline compared to three- and six-month follow-up (p < 0.001 and p = 0.003, respectively). Concomitantly, lower INSL3 concentrations were observed at baseline compared to three-month follow-up (p = 0.01). The total number of motile spermatozoa was also lower at baseline compared to six-month follow-up (p = 0.02). The alterations were detected irrespective of whether the men had experienced SARS-CoV-2-related fever episodes or not. No SARS-CoV-2 RNA was detected in semen at any time point. DISCUSSION AND CONCLUSION: This study showed a reduction in testicular function, which was for the first time confirmed by INSL3, in men mildly affected by SARS-CoV-2 infection. The risk of transmission of SARS-CoV-2 RNA via semen seems to be low. Febrile episodes may impact testicular function, but a direct effect of SARS-CoV-2 cannot be excluded.

Non-pharmacological treatment of reduced quality of life in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is the spontaneous or induced loss of ovarian function in women under the age of 40. POI increases the risk of reduced quality of life. Hormone replacement therapy may be beneficial in POI, but some women have contraindications. Recent studies indicate that exercise, yoga, meditation, acupuncture, and mindfulness may improve quality of life in women with POI. Phyto-oestrogens are not recommended in the treatment of POI since the physiological level of oestrogen cannot be achieved, and phyto-oestrogens should be avoided in women with present or previous breast cancer.

[Intrauterine insemination with or without ovarian stimulation is often a first-choice treatment for infertility].

In Denmark, intrauterine insemination (IUI) with or without ovarian stimulation is a common treatment for infertility. If strict cancellation criteria are met to reduce the risk of multiple pregnancies in ovarian stimulation cycles, IUI can be considered safe, less invasive and less costly compared to in vitro fertilisation. In 2019, a total of 9,322 homologous IUIs and 8,433 IUIs using donor sperm were performed in Denmark, and 2,000 children were expected to be born after the use of IUI. Thus, in this review we conclude that IUI is an effective treatment for infertility in selected patients.

[Presence of SARS-CoV-2 in semen and the impact of COVID-19 on the male reproductive system].

This article reviews the current studies published on the transmission of SARS-CoV-2 in semen and the potential effect of COVID-19 on male fertility. The aim was to provide insight into different possible mechanisms of involvement of the male reproductive system by SARS-CoV-2 infection and to evaluate the studies investigating the presence of virus in semen. It is concluded that the likelihood of SARS-CoV-2 transmission through semen is low and that COVID-19 may negatively affect semen parameters, but that the impairment is probably short-termed.

[Diagnostic criteria for polycystic ovary syndrome].

Since 2004, the Rotterdam criteria have been used in the diagnosis of polycystic ovary syndrome (PCOS), requiring the presence of two of the following three criteria: oligo-/anovulation, hyperandrogenism or polycystic ovaries. Reports of high prevalences of polycystic ovaries in younger women have caused concerns about overdiagnosis. Recently, the international guideline for PCOS has recommended raising the follicle threshold for polycystic ovaries and avoiding ultrasound in adolescents. Anti-Müllerian hormone has been proposed as a substitute marker for polycystic ovaries but is not yet considered adequate for diagnosis.

Individualised gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: A prospective, observational study.

OBJECTIVE: The aim of this study was to evaluate an individualised gonadotrophin starting dose regimen for women with anovulatory infertility. STUDY DESIGN: We included 71 normogonadotrophic anovulatory infertile women in a prospective, observational study. All underwent one ovulation induction cycle in a flexible, low-dose step-up protocol. The gonadotrophin starting dose (75-150IU/day) was individualised according to a nomogram incorporating menstrual cycle pattern (oligo- or amenorrhoea), BMI, and mean ovarian volume. The number of women who fulfilled the criteria for human chorionic gonadotrophin (hCG) administration (one follicle ≥17mm or 2-3 follicles ≥15mm) was assessed. RESULTS: Of the 50 women (70.4%) who fulfilled the hCG criteria and underwent intrauterine insemination, 34 (47.9%) achieved monofollicular growth and 16 (22.5%) developed 2-3 mature follicles. Seventeen (23.9%) cycles were converted to in vitro fertilisation (IVF) due to the development of >3 mature follicles, and one (1.4%) cycle was cancelled due to risk of ovarian hyperstimulation syndrome. Baseline total antral follicle count was found to be significantly associated with fulfillment of the hCG criteria (OR 0.96, 95% CI: 0.92-0.99, P=0.01). CONCLUSIONS: The nomogram-based dose regimen was not considered suitable for ovulation induction due to a tendency to overestimate the gonadotrophin starting dose. However, the model may serve as a mild IVF regimen, especially in women prone to excessive follicle growth.

Mono-ovulation in women with polycystic ovary syndrome: a clinical review on ovulation induction.

Polycystic ovary syndrome (PCOS) affects 5-10% of women of reproductive age and is the most common cause of anovulatory infertility. The treatment approaches to ovulation induction vary in efficacy, treatment duration and patient friendliness. The aim was to determine the most efficient, evidence-based method to achieve mono-ovulation in women diagnosed with PCOS. Publications in English providing information on treatment, efficacy and complication rates were included until September 2015. Systematic reviews, meta-analyses and randomized controlled trials were favoured over cohort and retrospective studies. Clomiphene citrate is recommended as primary treatment for PCOS-related infertility. It induces ovulation in three out of four patients, the risk of multiple pregnancies is modest and the treatment is simple and inexpensive. Gonadotrophins are highly efficient in a low-dose step-up regimen. Ovulation rates are improved by lifestyle interventions in overweight women. Metformin may improve the menstrual cycle within 1-3 months, but does not improve the live birth rate. Letrozole is effective for ovulation induction, but is an off-label drug in many countries. Ovulation induction in women with PCOS should be individualized with regard to weight, treatment efficacy and patient preferences with the aim of achieving mono-ovulation and subsequently the birth of a singleton baby.

Revised criteria for PCOS in WHO Group II anovulatory infertility - a revival of hypothalamic amenorrhoea?

OBJECTIVE: To evaluate revised criteria for polycystic ovarian morphology (PCOM) in the diagnosis of polycystic ovary syndrome (PCOS) in anovulatory infertility. DESIGN: Prospective cohort study. PATIENTS: WHO Group II anovulatory infertile women (n = 75). MEASUREMENTS: Clinical, sonographic and endocrine parameters, including anti-Müllerian hormone (AMH). RESULTS: The Rotterdam criteria for PCOM (antral follicle count (AFC) ≥12 and/or ovarian volume >10 ml) were fulfilled in 93% of the women. The PCOM prevalence was 68% when increasing the threshold to AFC >20 and 76% according to an AMH-based threshold of >35 pmol/l. The most recently proposed AFC ≥ 25 threshold reduced the PCOM prevalence to 52% (n = 39), leaving 48% (n = 36) without features of PCOM. Comparing the 36 women with non-PCOM with the 39 women in the PCOM group according to AFC ≥ 25, 22% vs 59% (P = 0·001) had serum LH >10 IU/l, 11% vs 41% (P = 0·003) had an LH/FSH ratio >2 and 19% vs 41% (P = 0·04) had hirsutism and/or elevated total testosterone, free testosterone, and/or androstenedione. The non-PCOM group included significantly more women with secondary infertility. The median AMH in the non-PCOM group was 47 pmol/l, which was twofold lower than in the PCOM group but above the upper limit of normo-ovulatory women. CONCLUSIONS: According to a revised threshold of 25 follicles, almost half the anovulatory infertile women do not have PCOM. The characteristics of these women may be compatible with hypothalamic anovulation, but according to AMH levels, the ovaries remain multifollicular. PERSPECTIVES: A better distinction between hypothalamic amenorrhoea and PCOS could improve treatment strategies for anovulatory infertility.

Phthalate excretion pattern and testicular function: a study of 881 healthy Danish men.

BACKGROUND: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function. OBJECTIVES: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men. METHODS: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively). RESULTS: The free androgen index was 15% lower [95% confidence interval (CI): -23, -8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: -16, -1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E(2). %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen quality. CONCLUSION: Our data suggest that both testosterone production and pituitary-hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.