20 April 2009.

Polycystic ovarian disease (PCOD) is associated with elevated serum LH and (sub)normal FSH levels, while serum androgen levels are often elevated. To clarify the role of androgens in this abnormal pattern of gonadotropin secretion, LH secretion was studied in 1) 9 eugonadal female to male transsexual subjects before and during long term (6 months) testosterone (T) administration (250 mg/2 weeks, im), and 2) in a woman with an androgen-secreting ovarian tumor both before and after surgical removal of the tumor. Finally, we studied the effects of high serum androgen levels on ovarian histology in 3) 26 transsexual subjects after long term (9-36 months) T administration (250 mg/2 weeks, im) to assess whether T-induced ovarian abnormalities are similar to those that occur in women with PCOD. Long term T treatment in the nine female to male transsexual subjects resulted in increases in the mean serum T level from 1.7 +/- 0.8 (+/- SD) to 40.8 +/- 31.9 nmol/L (P less than 0.01), the mean serum dihydrotestosterone level from 0.6 +/- 0.2 to 3.3 +/- 1.5 nmol/L (P less than 0.02), and the mean serum free T level from 9.5 +/- 5.2 to 149 +/- 46 pmol/L (P less than 0.02). Mean serum estrone and estradiol levels were similar before and during T treatment. The mean serum LH level decreased from 6.3 +/- 2.0 to 2.9 +/- 1.1 U/L (P less than 0.01), and the mean FSH levels decreased from 6.6 +/- 2.0 to 3.7 +/- 2.2 U/L (P less than 0.02). Pulsatile LH secretion before and during T treatment was studied in five subjects. Neither the mean nadir LH interval nor the LH pulse amplitude changed significantly in these five subjects. The serum T level in the woman with the androgen-secreting ovarian tumor was 9.6 nmol/L, and it declined to normal after removal of the tumor. Her mean serum LH and FSH levels, the mean nadir LH interval, and LH pulse amplitude were in the normal range before and after removal of the tumor. Studies of ovarian histopathology in 26 transsexual subjects after long term androgen treatment revealed multiple cystic follicles in 18 subjects (69.2%), diffuse ovarian stromal hyperplasia in 21 subjects (80.8%), collagenization of the tunica albuginea in 25 subjects (96.2%), and luteinization of stromal cells in 7 subjects (26.9%). Findings consistent with criteria for the pathological diagnosis of polycystic ovaries, that is 3 of the 4 findings listed above, were present in 18 of the 26 subjects (69.2%).(ABSTRACT TRUNCATED AT 400 WORDS)

STUDY QUESTION Does septum resection improve reproductive outcomes in women with a septate uterus? SUMMARY ANSWER Hysteroscopic septum resection does not improve reproductive outcomes in women with a septate uterus. WHAT IS KNOWN ALREADY A septate uterus is a congenital uterine anomaly. Women with a septate uterus are at increased risk of subfertility, pregnancy loss and preterm birth. Hysteroscopic resection of a septum may improve the chance of a live birth in affected women, but this has never been evaluated in randomized clinical trials. We assessed whether septum resection improves reproductive outcomes in women with a septate uterus, wanting to become pregnant. STUDY DESIGN, SIZE, DURATION We performed an international, multicentre, open-label, randomized controlled trial in 10 centres in The Netherlands, UK, USA and Iran between October 2010 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with a septate uterus and a history of subfertility, pregnancy loss or preterm birth were randomly allocated to septum resection or expectant management. The primary outcome was conception leading to live birth within 12 months after randomization, defined as the birth of a living foetus beyond 24 weeks of gestational age. We analysed the data on an intention-to-treat basis and calculated relative risks with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE We randomly assigned 80 women with a septate uterus to septum resection (n = 40) or expectant management (n = 40). We excluded one woman who underwent septum resection from the intention-to-treat analysis, because she withdrew informed consent for the study shortly after randomization. Live birth occurred in 12 of 39 women allocated to septum resection (31%) and in 14 of 40 women allocated to expectant management (35%) (relative risk (RR) 0.88 (95% CI 0.47 to 1.65)). There was one uterine perforation which occurred during surgery (1/39 = 2.6%). LIMITATIONS, REASONS FOR CAUTION Although this was a major international trial, the sample size was still limited and recruitment took a long period. Since surgical techniques did not fundamentally change over time, we consider the latter of limited clinical significance. WIDER IMPLICATIONS OF THE FINDINGS The trial generated high-level evidence in addition to evidence from a recently published large cohort study. Both studies unequivocally do not reveal any improvements in reproductive outcomes, thereby questioning any rationale behind surgery. STUDY FUNDING/COMPETING INTEREST(S) There was no study funding. M.H.E. reports a patent on a surgical endoscopic cutting device and process for the removal of tissue from a body cavity licensed to Medtronic, outside the scope of the submitted work. H.A.v.V. reports personal fees from Medtronic, outside the submitted work. B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. M.G. reports several research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the scope of the submitted work. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER Dutch trial registry: NTR 1676 TRIAL REGISTRATION DATE 18 February 2009 DATE OF FIRST PATIENT’S ENROLMENT 20 October 2010

Study question Does septum resection improve reproductive outcomes in women with a septate uterus? Summary answer In women with a septate uterus, septum resection does not increase live birth rate nor does it decrease the rates of pregnancy loss or preterm birth, compared with expectant management. What is known already The septate uterus is the most common uterine anomaly with an estimated prevalence of 0.2–2.3% in women of reproductive age, depending on the classification system. The definition of the septate uterus has been a long-lasting and ongoing subject of debate, and currently two classification systems are used worldwide. Women with a septate uterus may be at increased risk of subfertility, pregnancy loss, preterm birth and foetal malpresentation. Based on low quality evidence, current guidelines recommend removal of the intrauterine septum or, more cautiously, state that the procedure should be evaluated in future studies. Study design, size, duration We performed an international multicentre cohort study in which we identified women mainly retrospectively by searching in electronic patient files, medical records and databases within the time frame of January 2000 until August 2018. Searching of the databases, files and records took place between January 2016 and July 2018. By doing so, we collected data on 257 women with a septate uterus in 21 centres in the Netherlands, USA and UK. Participants/materials, setting, methods We included women with a septate uterus, defined by the treating physician, according to the classification system at that time. The women were ascertained among those with a history of subfertility, pregnancy loss, preterm birth or foetal malpresentation or during a routine diagnostic procedure. Allocation to septum resection or expectant management was dependent on the reproductive history and severity of the disease. We excluded women who did not have a wish to conceive at time of diagnosis. The primary outcome was live birth. Secondary outcomes included pregnancy loss, preterm birth and foetal malpresentation. All conceptions during follow-up were registered but for the comparative analyses, only the first live birth or ongoing pregnancy was included. To evaluate differences in live birth and ongoing pregnancy, we used Cox proportional regression to calculate hazard rates (HRs) and 95% CI. To evaluate differences in pregnancy loss, preterm birth and foetal malpresentation, we used logistic regression to calculate odds ratios (OR) with corresponding 95% CI. We adjusted all reproductive outcomes for possible confounders. Main results and the role of chance In total, 257 women were included in the cohort. Of these, 151 women underwent a septum resection and 106 women had expectant management. The median follow-up time was 46 months. During this time, live birth occurred in 80 women following a septum resection (53.0%) compared to 76 women following expectant management (71.7%) (HR 0.71 95% CI 0.49–1.02) and ongoing pregnancy occurred in 89 women who underwent septum resection (58.9%), compared to 80 women who had expectant management (75.5%) (HR 0.74 (95% CI 0.52–1.06)). Pregnancy loss occurred in 51 women who underwent septum resection (46.8%) versus 31 women who had expectant management (34.4%) (OR 1.58 (0.81–3.09)), while preterm birth occurred in 26 women who underwent septum resection (29.2%) versus 13 women who had expectant management (16.7%) (OR 1.26 (95% CI 0.52–3.04)) and foetal malpresentation occurred in 17 women who underwent septum resection (19.1%) versus 27 women who had expectant management (34.6%) (OR 0.56 (95% CI 0.24–1.33)). Limitations, reasons for caution Our retrospective study has a less robust design compared with a randomized controlled trial. Over the years, the ideas about the definition of the septate uterus has changed, but since the 257 women with a septate uterus included in this study had been diagnosed by their treating physician according to the leading classification system at that time, the data of this study reflect the daily practice of recent decades. Despite correcting for the most relevant patient characteristics, our estimates might not be free of residual confounding. Wider implications of the findings Our results suggest that septum resection, a procedure that is widely offered and associated with financial costs for society, healthcare systems or individuals, does not lead to improved reproductive outcomes compared to expectant management for women with a septate uterus. The results of this study need to be confirmed in randomized clinical trials. Study funding/competing interest(s) A travel for JFWR to Chicago was supported by the Jo Kolk Studyfund. Otherwise, no specific funding was received for this study. The Department of Obstetrics and Gynaecology, University Medical Centre, Groningen, received an unrestricted educational grant from Ferring Pharmaceutical Company unrelated to the present study. BWM reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, other payment from Guerbet and grants from Merck, outside the submitted work. The other authors declare no conficts of interest. Trial registration number N/A

We investigated the effects of long term testosterone (T) administration on pulsatile gonadotropin secretion in agonadal women and the effects of estradiol (E2) on gonadotropin secretion in eugonadal women in the follicular phase of the menstrual cycle. We studied 4 groups: A) 28 eugonadal women in the early follicular phase of the menstrual cycle, B) 11 hypogonadal women, C) 13 agonadal female to male (f-t-m) transsexuals treated for at least 3 months with 120-160 mg T undecanoate (TU)/day, orally, and D) 5 agonadal f-to-m transsexuals treated for at least 6 months with 250 mg of a mixture of testosterone esters, im (im T-esters), every 2 weeks. The eugonadal women in the early follicular phase had a mean serum E2 level of 193 +/- 94 (+/- SD) pmol/L, significantly higher (P less than 0.01) than that in the hypogonadal women (60 +/- 24 pmol/L), whereas there was no difference in the mean serum T levels (1.8 +/- 0.7 vs. 2.3 +/- 1.5 nmol/L). the higher serum E2 level in the eugonadal women was associated with a significantly lower mean serum LH level (6.9 +/- 2.6 vs. 44.6 +/- 17.6 U/L; P less than 0.01) and LH pulse amplitude (2.8 +/- 1.0 vs. 12.6 +/- 4.8 U/L; P less than 0.01), whereas the mean nadir LH interval did not differ between the two groups (75 +/- 29 vs. 81 +/- 49 min). The mean serum T level in the agonadal f-to-m transsexuals treated with oral TU was significantly higher (P less than 0.01) than that in the hypogonadal women (9.7 +/- 4.7 vs. 2.3 +/- 1.5 nmol/L). In spite of this elevated T level there was no difference in the mean serum LH level (38.4 +/- 14.7 vs. 44.6 +/- 17.6 U/L), LH pulse amplitude (14.3 +/- 5.7 vs. 12.6 +/- 4.8 U/L), or nadir LH interval (72 +/- 27 vs. 81 +/- 49 min) in these groups. Also, the mean serum E2 (64 +/- 16 vs. 60 +/- 24 pmol/L and FSH levels (62 +/- 17 vs. 64 +/- 28 U/L) did not differ between these groups. Treatment of the agonadal f-to-m transsexuals with im T-esters resulted in mean serum T and E2 levels of 34.4 +/- 27.0 nmol/L and 121 +/- 54 pmol/L, respectively, both significantly higher (P less than 0.01) than those in groups B and C.(ABSTRACT TRUNCATED AT 400 WORDS)