Impact of letrozole co-treatment during ovarian stimulation on oocyte yield, embryo development, and live birth rate in women with normal ovarian reserve: secondary outcomes from the RIOT trial.

STUDY QUESTION: Does letrozole (LZ) co-treatment during ovarian stimulation with gonadotropins for in IVF impact follicle recruitment, oocyte number and quality, embryo quality, or live birth rate (LBR)? SUMMARY ANSWER: No impact of LZ was found in follicle recruitment, number of oocytes, quality of embryos, or LBR. WHAT IS KNOWN ALREADY: Multi-follicle stimulation for IVF produces supra-physiological oestradiol levels. LZ is an aromatase inhibitor that lowers serum oestradiol thus reducing negative feedback and increasing the endogenous gonadotropins in both the follicular and the luteal phases, effectively normalizing the endocrine milieu during IVF treatment. STUDY DESIGN, SIZE, DURATION: Secondary outcomes from a randomized, double-blind placebo-controlled trial (RCT) investigating once-daily 5 mg LZ or placebo during stimulation for IVF with FSH. The RCT was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018 and pregnancy outcomes of frozen-thawed embryo transfers (FET) registered until May 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred fifty-nine women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) were randomized to either co-treatment with LZ (n = 80) or placebo (n = 79). In total 1268 oocytes were aspirated developing into 386 embryos, and morphology and morphokinetics were assessed. One hundred twenty-nine embryos were transferred in the fresh cycle and 158 embryos in a subsequent FET cycle. The effect of LZ on cumulative clinical pregnancy rate (CPR), LBR, endometrial thickness in the fresh cycle, and total FSH consumption was reported. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of usable embryos of retrieved oocytes was similar in the LZ group and the placebo group with 0.31 vs 0.36 (mean difference (MD) -0.05, 95% CI (-0.12; 0.03), P = 0.65). The size and number of aspirated follicles at oocyte retrieval were similar with 11.8 vs 10.3 follicles per patient (MD 1.5, 95% CI (-0.5; 3.1), P = 0.50), as well as the number of retrieved oocytes with 8.0 vs 7.9 oocytes (MD 0.1, 95% CI (-1.4; 1.6), P = 0.39) in the LZ and placebo groups, respectively. The chance of retrieving an oocyte from the 13 to 16 mm follicles at trigger day was 66% higher (95% CI (24%; 108%), P = 0.002) in the placebo group than in the LZ group, whilst the chance of retrieving an oocyte from the ≥17 mm follicles at trigger day was 50% higher (95% CI (2%; 98%), P = 0.04) in the LZ group than in the placebo group. The proportion of fertilized oocytes with two-pronuclei per retrieved oocytes or per metaphase II oocytes (MII) (the 2PN rates) were similar regardless of fertilization with IVF or ICSI with 0.48 vs 0.57 (MD -0.09, 95% CI (-0.24; 0.04), P = 0.51), and 0.62 vs 0.64 (MD -0.02, 95% CI (-0.13; 0.07), P = 0.78) in the LZ and placebo groups, respectively. However, the MII rate in the ICSI group was significantly lower with 0.75 vs 0.88 in the LZ vs the placebo group (MD -0.14, 95% CI (-0.22; -0.06), P = 0.03). Blastocysts on Day 5 per patient were similar with 1.5 vs 2.0, P = 0.52, as well as vitrified blastocysts per patient Day 5 with 0.8 vs 1.2 in (MD -0.4, 95% CI (-1.0; 0.2), P = 0.52) and vitrified blastocysts per patient Day 6 with 0.6 vs 0.6 (MD 0, 95% CI (-0.3; 0.3), P = 1.00) in the LZ vs placebo group, respectively. Morphologic evaluation of all usable embryos showed a similar distribution in 'Good', 'Fair', and 'Poor', in the LZ vs placebo group, with an odds ratio (OR) of 0.8 95% CI (0.5; 1.3), P = 0.68 of developing a better class embryo. Two hundred and ninety-five of the 386 embryos were cultured in an embryoscope. Morphokinetic annotations showed that the odds of having a high KIDscore™ D3 Day 3 were 1.2 times higher (CI (0.8; 1.9), P = 0.68) in the LZ group vs the placebo group. The CPR per transfer was comparable with 31% vs 39% (risk-difference of 8%, 95% CI (-25%; 11%), P = 0.65) in the LZ and placebo group, respectively, as well as CPR per transfer adjusted for day of transfer, oestradiol and progesterone levels at trigger, progesterone levels mid-luteal, and number of oocytes retrieved (adjusted OR) of 0.8 (95% CI (0.4; 1.6), P = 0.72). Comparable LBR were found per transfer 28% vs 37% (MD -9%, 95% CI (-26%; 9%), P = 0.60) and per randomized women 24% vs 30% (MD of -6%, CI (-22%; 8%), P = 0.60) in the LZ group and placebo group, respectively. Furthermore, 4.8 years since the last oocyte aspiration, a total of 287 of 386 embryos have been transferred in the fresh or a subsequently FET cycle, disclosing the cumulative CPR, which is similar with 38% vs 34% (MD 95% CI (8%; 16%), P = 0.70) in the LZ vs placebo group. LIMITATIONS, REASONS FOR CAUTION: Both cleavage stage and blastocyst transfer and vitrification were permitted in the protocol, making it necessary to categorize their quality and pool the results. The study was powered to detect hormonal variation but not embryo or pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The similar utilization rate and quality of the embryos support the use of LZ co-treatment for IVF with specific indication as fertility preservation, patients with previous cancer, or poor responders. The effect of LZ on mature oocytes from different follicle sizes and LBRs should be evaluated in a meta-analysis or a larger RCT. STUDY FUNDING/COMPETING INTEREST(S): Funding was received from EU Interreg for ReproUnion, Sjaelland University Hospital, Denmark, Ferring Pharmaceuticals, and Gedeon Ricther. Roche Diagnostics contributed with assays. A.P. has received grants from Ferring, Merck Serono, and Gedeon Richter, consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, speakers fees from Gedeon Richter, Ferring, Merck A/S, Theramex, & Organon, and travel support from Gedeon Richter. The remaining authors declare that they have no competing interests in the research or publication. TRIAL REGISTRATION NUMBERS: NCT02939898 and NCT02946684.

The Impact of Suppressing Estradiol During Ovarian Stimulation on the Unsupported Luteal Phase: A Randomized Controlled Trial.

CONTEXT: Supraphysiological sex steroid levels at the follicular-luteal phase transition are implicated as the primary cause of luteal insufficiency after ovarian stimulation (OS) for in vitro fertilization. OBJECTIVE: We aimed to determine the impact of suppressing estradiol levels during OS of multiple dominant follicles on the unsupported luteal phase and markers of endometrial maturation. METHODS: At 2 university hospitals, 25 eligible egg donors were randomized to undergo OS using exogenous gonadotropins with or without adjuvant letrozole 5 mg/day. Final oocyte maturation was triggered with a GnRH agonist. No luteal support was provided. The primary outcome was the duration of the luteal phase. Secondary outcomes were luteal phase hormone profiles and the endometrial transcriptomic signature 5 days after oocyte pick up (OPU + 5). RESULTS: The median (interquartile range [IQR]) luteal phase duration was 8.0 (6.8-11.5) days compared with 5.0 (5.0-6.8) days in the intervention and control group, respectively (P < 0.001). Estradiol levels were effectively suppressed in the letrozole group with a median of 0.86 (0.23-1.24) nmol/L at OPU compared to 2.82 (1.34-3.44) nmol/L in the control group. Median (IQR) progesterone levels at OPU + 5 were 67.05 (15.67-101.75) nmol/L in the letrozole group vs 2.27 (1.05-10.70) nmol/L in the control group (P < 0.001). In the letrozole group, 75% of participants revealed endometrial transcriptomic signatures interpreted as post-receptive. In the control group, 40% were post-receptive and 50% noninformative. CONCLUSION: Suppressing estradiol levels in the follicular phase with adjuvant letrozole significantly reduces the disruption of the unsupported luteal phase after OS.

Does adjuvant letrozole reduce uterine peristalsis prior to fresh embryo transfer?

STUDY QUESTION: Does adjuvant letrozole in ovarian stimulation for IVF decrease the uterine peristalsis frequency (UPF) prior to fresh embryo transfer (ET)? SUMMARY ANSWER: Adjuvant letrozole in ovarian stimulation for IVF does not reduce the UPF significantly prior to fresh ET. WHAT IS KNOWN ALREADY: Throughout the cycle, uterine peristalsis aids spermatozoa transport to the fallopian tube and may affect implantation. At fresh ET, UPF is negatively correlated with implantation and clinical pregnancy rates and is believed to be modulated by oestradiol and progesterone. High levels of oestradiol, from multiple follicular development, in ovarian stimulation have been reported to increase UPF, whereas progesterone is considered to be an utero-relaxant. The influence of androgens is unclear. Co-treatment with letrozole during gonadotropin ovarian stimulation limits the supra-physiological oestradiol rise and may therefore reduce UPF prior to fresh ET. STUDY DESIGN SIZE DURATION: This study was carried out on subjects participating in a single-centre double-blinded randomized controlled trial of the impact of letrozole on follicle development and endocrine profiles, and investigated the impact of adjuvant letrozole in ovarian stimulation for IVF on UPF prior to fresh ET and the correlations of UPF with endocrine markers. Between 2016 and 2017, 39 women expected to be normal responders were randomized to co-treatment with letrozole or placebo. Of these, 33 women completed this element of the study. The study was carried out according to the Helsinki Declaration and the ICH-Good-Clinical-Practice. PARTICIPANTS/MATERIALS SETTING METHODS: Eligible women were randomized 1:1 to adjuvant treatment with letrozole 5 mg/day or placebo in an antagonist protocol using a fixed dose of recombinant (r) FSH 150 IU/day. Final maturation was triggered with hCG 6500 IU and luteal support with vaginal progesterone was administered from the day following oocyte aspiration. Less than 1 h prior to fresh ET, 6-min duration transvaginal ultrasound recordings of the uterus in sagittal section were performed and blood samples were drawn. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 33 women completed the study (letrozole n = 17; placebo n = 16). Age, BMI and ovarian reserve markers were similar between the groups. On the day of ET, serum oestradiol levels were significantly suppressed in the letrozole group to a mean of 867 ± 827 pmol/l compared to 3110 ± 1528 pmol/l in the placebo group (P < 0.001). Mean UPF prior to fresh ET did not differ between the intervention and placebo group (3.3 ± 0.36 versus 3.5 ± 0.51 per minute respectively, P = 0.108). UPF was assessed and agreed by two observers who were blinded to adjuvant treatment. Two patients were excluded due to poor quality of the ultrasound recordings. Supra-physiological serum oestradiol in the placebo group were negatively correlated with UPF (P = 0.014; R = -0.62), but the more physiological serum oestradiol levels in the letrozole group showed no correlation with UPF (P = 0.567; R = 0.15). Serum progesterone levels were similar in both groups and did not show any significant correlation with UPF. Testosterone levels were significantly higher in the letrozole group (P = 0.005) and showed a non-significant trend that negatively correlated with UPF in the placebo group (P-value = 0.071, R = -0.48). LIMITATIONS REASONS FOR CAUTION: Limitations of the study included the limited sample size and the lack of a power calculation specifically determined for this endpoint. WIDER IMPLICATIONS OF THE FINDINGS: The supra-physiological levels of oestradiol generated during ovarian stimulation were significantly suppressed in the intervention group. However, UPF prior to fresh ET was similar in both groups. Modulating the luteal phase sex steroids with adjuvant letrozole had little measured impact on UPF. Any beneficial effect of adjuvant letrozole during ovarian stimulation is unlikely to be due to significant modulation of UPF. STUDY FUNDING/COMPETING INTERESTS: M.D.H.'s salary was funded by an unrestricted research grant from Gedeon Richter. The expenses of the study were funded by a scientific collaboration: ReproUnion, co-financed by the European Union, Interreg Öresund-Kattegat-Skagerrak and Ferring Pharmaceuticals. The assays for the analyses were funded by Roche Diagnostics and an unrestricted research grant from Merck Life Science AS, Denmark. The authors have no competing interests to declare regarding this study. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT02939898, EudraCT no.: 2015-005683-41.

Co-treatment with letrozole during ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis.

Letrozole reduces serum oestradiol by inhibiting the aromatase enzyme and has growing clinical indications in fertility. The available evidence of letrozole's role in ovarian stimulation for IVF and intracytoplasmic sperm injection (ICSI) and clinical outcomes was assessed. Medline, Cochrane, and ClinicalTrials.gov databases were systematically searched up until August 2021, including 31 studies (n = 16 randomized controlled trials [RCTs]; n = 15 observational studies). Live birth rate (LBR) in poor responders significantly increased by 7% (95% CI, 1% to 13%, P = 0.03) with letrozole co-treatment. Concomitantly, the gonadotrophin consumption was significantly reduced, without decreasing the number of retrieved oocytes. In normal responders, number of oocytes increased with 1.8 oocytes (95% CI 0.35 to 3.27, P = 0.01) with letrozole co-treatment. No significant effect on LBR, clinical pregnancy rate (CPR), or ovarian hyperstimulation syndrome rate was demonstrated. Only two studies reported on high responders and revealed no effect on LBR or CPR. Overall, the endometrium thickness was slightly affected, where as the, miscarriage rate and cancellation rate were unaffected by letrozole co-treatment. None of the included studies reported on neonatal outcomes. The quality of evidence was high or moderate in the RCTs and low in the observational studies. In conclusion, poor responders may benefit from co-treatment with letrozole during ovarian stimulation for IVF, whereas letrozole for normal and high responders requires further investigation with larger, high-quality studies.

Impact of letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF: a multicentre, randomized, double-blinded placebo-controlled trial.

STUDY QUESTION: Does letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF reduce the proportion of women with premature progesterone levels above 1.5 ng/ml at the time of triggering final oocyte maturation? SUMMARY ANSWER: The proportion of women with premature progesterone above 1.5 ng/ml was not significantly affected by letrozole co-treatment. WHAT IS KNOWN ALREADY: IVF creates multiple follicles with supraphysiological levels of sex steroids interrupting the endocrine milieu and affects the window of implantation. Letrozole is an effective aromatase inhibitor, normalizing serum oestradiol, thereby ameliorating some of the detrimental effects of IVF treatment. STUDY DESIGN, SIZE, DURATION: A randomized, double-blinded placebo-controlled trial investigated letrozole intervention during stimulation for IVF with FSH. The trial was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: A cohort of 129 women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) completed an IVF cycle with fresh embryo transfer and received co-treatment with either 5 mg/day letrozole (n = 67) or placebo (n = 62), along with the FSH. Progesterone, oestradiol, FSH, LH and androgens were analysed in repeated serum samples collected from the start of the stimulation to the mid-luteal phase. In addition, the effect of letrozole on reproductive outcomes, total FSH consumption and adverse events were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of women with premature progesterone >1.5 ng/ml was similar (6% vs 0% (OR 0.0, 95% CI [0.0; 1.6], P = 0.12) in the letrozole versus placebo groups, respectively), whereas the proportion of women with mid-luteal progesterone >30 ng/ml was significantly increased in the letrozole group: (59% vs 31% (OR 3.3, 95% CI [1.4; 7.1], P = 0.005)). Letrozole versus placebo decreased oestradiol levels on the ovulation trigger day by 68% (95% CI [60%; 75%], P < 0.0001). Other hormonal profiles, measured as AUC, showed the following results. The increase in LH in the letrozole group versus placebo group was 38% (95% CI [21%; 58%], P < 0.0001) and 34% (95% CI [11%; 61%], P = 0.006) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, testosterone increased by 79% (95% CI [55%; 105%], P < 0.0001) and 49% (95% CI [30%; 72%], P < 0.0001) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, the increase in androstenedione was by 85% (95% CI [59%; 114%], P < 0.0001) and 69% (95% CI [48%; 94%], P < 0.0001) in the follicular and luteal phases, respectively. The ongoing pregnancy rate was similar between the letrozole and placebo groups (31% vs 39% (risk-difference of 8%, 95% CI [-25%; 11%], P = 0.55)). No serious adverse reactions were recorded in either group. The total duration of exogenous FSH stimulation was 1 day shorter in the intervention group, significantly reducing total FSH consumption (mean difference -100 IU, 95% CI [-192; -21], P = 0.03). LIMITATIONS, REASONS FOR CAUTION: Late follicular progesterone samples were collected on the day before and day of ovulation triggering for patient logistic considerations, and the recently emerged knowledge about diurnal variation of progesterone was not taken into account. The study was powered to detect hormonal variations but not differences in pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Although the use of letrozole has no effect on the primary outcome, the number of women with a premature increase in progesterone on the day of ovulation triggering, the increased progesterone in the mid-luteal phase due to letrozole may contribute to optimizing the luteal phase endocrinology. The effect of letrozole on increasing androgens and reducing FSH consumption may be used in poor responders. However, the effect of letrozole on implantation and ongoing pregnancy rates should be evaluated in a meta-analysis or larger randomized controlled trial (RCT). STUDY FUNDING/COMPETING INTEREST(S): Funding was received from EU Interreg for ReproUnion and Ferring Pharmaceuticals, and Roche Diagnostics contributed with assays. N.S.M. and A.P. have received grants from Ferring, Merck Serono, Anecova and Gedeon Richter, and/or personal fees from IBSA, Vivoplex, ArtPred and SPD, outside the submitted work. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBERS: NCT02939898 and NCT02946684. TRIAL REGISTRATION DATE: 15 August 2016. DATE OF FIRST PATIENT'S ENROLMENT: 22 August 2016.

Oestrogen-free oral contraception with a 4 mg drospirenone-only pill: new data and a review of the literature.

Purpose: The contraceptive pill is an effective and safe method of preventing pregnancy. The progestins used for contraception either are components of a combined hormonal contraceptive (tablets, patches or vaginal rings) or are used alone in progestin-only formulations. Progestin-only contraceptives are available as daily oral preparations, subcutaneous or intramuscular injectables (every 1-3 months), subdermal implants (every 3-5 years) and intrauterine systems (every 3-5 years). Long-acting progestins are highly effective in typical use and have a very low risk profile and few contraindications.Material and Methods: A new progestin-only, oestrogen-free contraceptive, drospirenone, in a dosage of 4 mg/day in a 24/4 regimen, has received regulatory approval in the USA and the EU. The molecule has antigonadotropic, antimineralocorticoid, antiestrogenic and antiandrogenic properties.Results: The regimen was chosen to improve the bleeding profile; maintain plasma oestradiol levels at those of the early follicular phase, to avoid hypoestrogenism; and preserve efficacy even with a missed pill, as drospirenone has a half-life of 30-34 h.Conclusions: Clinical studies have shown good efficacy, very low cardiovascular side effects and a favourable bleeding pattern, as well as maintenance of ovulation inhibition after scheduled 24 h delays in pill intake.

Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial.

INTRODUCTION: Despite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome. METHODS AND ANALYSIS: Multicentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18-41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed. ETHICS AND DISSEMINATION: The study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated. TRIAL REGISTRATION NUMBER: The study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.

The Impact of the Biological Variability or Assay Performance on AMH Measurements: A Prospective Cohort Study With AMH Tested on Three Analytical Assay-Platforms.

This study examined longitudinal, age-related and intra-individual variation in Anti-Müllerian Hormone (AMH) in regular menstruating women and correlated the hormonal levels to the antral follicle count (AFC). The impact of variations on an algorithm for calculation of follitropin-dose for ovarian stimulation were also tested. The study was carried out at a fertility clinic of a tertiary university hospital and had a prospective trial design. Twenty-six healthy women not receiving infertility treatment aged 22 to 50 years participated. Blood sampling for hormonal analysis was done every fifth day throughout three consecutive menstrual cycles, AFC was determined with 3-dimentional ultrasound and AMH measured by different assays from Beckman Coulter, Roche and Ansh Labs. Outcome measures were maximum and minimum difference in absolute and relative terms for each study subject during the test-period, coefficient of variation (Cv) for AMH for each cycle and cycle-day and correlation between AMH and AFC. The impact from variable AMH levels on an algorithm calculating follitrophin-delta dose in ovarian stimulation was explored. A significant longitudinal age-independent variation in AMH-levels and coefficient of variation in cycles and cycle days was found. A strong correlation between AMH-levels and AFC was confirmed and a case of significant divergence between assays was seen. Variations in AMH had a significant impact on an algorithm calculated dosage of gonadotrophins in ovarian stimulation. The finding of a substantial longitudinal variation in AMH question one recording being sufficient in quantifying gonadotrophins for ovarian stimulation, decision making and prognostication related to infertility treatment and counseling. Occasionally, commercial assays may fail to recognize specific AMH cleavage-products.

Semen Quality as a Predictor of Subsequent Morbidity: A Danish Cohort Study of 4,712 Men With Long-Term Follow-up.

Semen quality has been suggested to be a biological marker of long-term morbidity and mortality; however, few studies have been conducted on this subject. We identified 5,370 men seen for infertility at Frederiksberg Hospital, Denmark, during 1977-2010, and 4,712 of these men were followed in the Danish National Patient Registry until first hospitalization, death, or the end of the study. We classified patients according to hospitalizations and the presence of cardiovascular disease, diabetes, testicular cancer, or prostate cancer. We found a clear association between sperm concentration below 15 million/mL and all-cause hospitalizations (hazard ratio = 1.5, 95% confidence interval: 1.4, 1.6) and cardiovascular disease (hazard ratio = 1.4, 95% confidence interval: 1.2, 1.6), compared with men with a concentration above 40 million/mL. The probabilities for hospitalizations were also higher with a low total sperm count and low motility. Men with a sperm concentration of 195-200 million/mL were, on average, hospitalized for the first time 7 years later than were men with a sperm concentration of 0-5 million/mL. Semen quality was associated with long-term morbidity, and a significantly higher risk of hospitalization was found, in particular for cardiovascular diseases and diabetes mellitus. Our study supports the suggestion that semen quality is a strong biomarker of general health.

Validation of spontaneous abortion diagnoses in the Danish National Registry of Patients.

PURPOSE: The purpose of this study is to validate the diagnosis of spontaneous abortion (SA) recorded in the Danish National Registry of Patients (DNRP). METHODS: We randomly selected patients registered in the DNRP with a diagnosis of SA between 1980 and 2008 from hospitals in the county of North Jutland and searched for their discharge records in hospital files. We estimated positive predictive value (PPV) of the DNRP diagnosis and stratified the analysis by period (1980-1994 versus 1995-2008), hospital type (regional versus local), and International Classification of Diseases revisions (ICD-8 versus ICD-10). RESULTS: We could identify hospital files of 117/174 (67%) sampled registration records. Of those, the diagnosis was confirmed in 114 patients, yielding a PPV of 97.4% (95% confidence interval = 92.7%-99.5%). The PPV did not markedly vary by period, hospital type, or ICD revision. Among the three patients with available data who did not fulfill the criteria for SA, one had an induced abortion and two had threatened abortion but did not miscarry. CONCLUSION: Registration of SA in the DNRP accurately reflects the diagnoses recorded in medical charts. The DNRP is a suitable source of data on SAs for epidemiologic research.

[Increased morbidity risk in female athletes]. / Risiko for øget sygelighed hos kvindelige idraetsudøvere.

The female athlete triad refers to the interrelationships among energy availability, menstrual function and bone mineral density which may have clinical manifestations including eating disorders, functional hypothalamic amenorrhea and osteoporosis. The potentially irreversible consequences of these clinical conditions emphasize the critical need for prevention, early diagnosis and treatment. Nutritionally correct food ensuring optimal energy balance is a premise to improve these conditions. Alternative treatment is oestrogen replacement therapy which can prevent progressive bone loss.

[Polycystic ovary syndrome and comorbidity]. / Polycystisk ovariesyndrom og komorbiditet.

Polycystic ovary syndrome (PCOS) is the most frequent endocrinological disorder among women in the reproductive age. It is by its very nature a heterogeneous juxtaposition of clinical and biochemical features. In women with PCOS, the most common clinical manifestations - obesity, hirsutism and oligomenorrhoea - are associated with insulin resistance, dyslipidaemia, hypertension, vascular dysfunction involving chronic inflammation and also reduced cardiopulmonary function. The focus of this overview is therefore on PCOS comorbidity with the metabolic syndrome, type 2 diabetes and cardiovascular diseases.