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Polycystic Ovary Syndrome

Abortion, Spontaneous

Ovarian Diseases

Syndrome

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Female Urogenital Diseases

Female Urogenital Diseases and Pregnancy Complications

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Genital Diseases, Female

Genital Diseases

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Antineoplastic Agents

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Reproductive Control Agents

Letrozole

Estradiol 17 beta-cypionate

Estradiol 3-benzoate

Estradiol

Polyestradiol phosphate

Dydrogesterone

Progesterone

Estrogens

Hormones

Hormone Antagonists

Aromatase Inhibitors

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Progestins

Polycystic ovarian disease (PCOS) women undergoing frozen embryo transfer (FER) will use Letrozole 5 mg starting on day 3 of spontaneous menstrual period or after progesterone withdrawal bleeding for five consecutive days.

PCOS women will use daily Cetorelix acetate 0.25 mg injections for 5 days from day 1-3 of the menstrual follow or after progesterone (P4) withdrawal bleeding. They will commence daily oral Estradiol Valerate (E2) 2 mg twice daily for 5 days starting from day 3 of the menstrual flow or after P4 withdrawal bleeding, then-after three times daily. When endometrial thickness reaches 7 mm or more, the dose of E2 will be reduced to 4 mg/ day. Women will start using vaginal micronized P4 100 mg three times daily starting from 8PM. After 48 hours of starting the vaginal P4, oral Dydrogesterone 10 mg three times daily will commence.

Letrozole 5 mg starting on day 3 of spontaneous menstrual period or after progesterone withdrawal bleeding for five consecutive days.

Letrozole 2.5mg

One of the indications of freezing is to reduce the risk of ovarian hyperstimulation syndrome particularly in polycystic ovarian disease (PCOS) women. Very few RCTs addressed the issue of optimizing the endometrium for a frozen cycle. Interestingly, Letrozole for ovarian stimulation showed significantly better reproductive outcome when compared with hormone replacement therapy (HRT) cycle. In addition, HRT cycle has been associated with higher miscarriage rate when compared with natural cycle frozen embryo transfer. Nevertheless, there is not yet a well-designed prospective randomized study comparing letrozole and HRT in PCOS women undergoing frozen embryo transfer.

Freezing oocytes and embryos has become an integral part of the daily IVF practice. One of the indications of freezing is to reduce the risk of ovarian hyperstimulation syndrome particularly in polycystic ovarian disease (PCOS) women.

Very few randomized control trials addressed the issue of optimizing the endometrium for a frozen cycle. As PCOS women do not regularly ovulate, most of their frozen cycles are conducted after hormonal replacement therapy (HRT) preparation of the endometrium or after ovulation induction. In HRT cycle the endometrium is prepared using exogenous estradiol and progesterone. While HRT cycles requires less monitoring and easy scheduling, it is costly, associated with increased risk of thrombosis and women must continue using the exogenous hormones up to 10 to 12 weeks of gestation.

Interestingly, Letrozole for ovarian stimulation showed significantly better reproductive outcome when compared with HRT cycles. In agreement with the previous Chinese study, a retrospective Japanese ART registry data that included 110 722 frozen cycles confirmed the superiority of letrozole. Nevertheless, there is not yet a well-designed prospective randomized study.

In addition, HRT cycle has been associated with higher miscarriage rate when compared with natural cycle frozen embryo transfer. HRT is usually used in patients with PCOS. A retrospective study including 2664 PCOS patients showed significant decrease in the pregnancy loss when letrozole was used when compared with HRT in frozen cycles.

Investigators thought of comparing letrozole and HRT in women with PCOS who are undergoing frozen cycles in PCOS women. Live birth and miscarriage rates will be the primary outcomes.

Letrozole Versus Hormonal Preparation in Frozen Cycles of PCOS Patients.

Letrozole Versus Hormonal Preparation in Frozen Cycles of PCOS Patients. Randomized Controlled Study

A birth after 24 weeks gestation with a baby showing signs of life.

loss of pregnancy before 24 weeks gestation

ongoing viable pregnancy (by ultrasound examination at 12 weeks' gestation)

Dubai Fertility Center

Principal investigator

nfertile patients undergoing assisted reproduction were consecutively recruited at the Fertility Clinic, Arhus University Hospital from February 2011 to May 2013. Women aged \< 38 years without endometriosis where more than \> 8 oocytes were retrieved were eligible. Patients were categorized in PCOS and non-PCOS according to the Rotterdam criteria for PCOS, defined by the presence of anovulation and polycystic ovaries.

Ulla B Knudsen, Professor

Polycystic ovary syndrome is one of the most common causes of female infertility. The cause of infertility in PCOS is unknown. Factors other than anovulation, including inherited or induced changes in the embryo quality have been suggested. Time-lapse analysis of embryo development is a sensitive method of detecting reduced embryo viability. Yet, there are no data regarding the embryo development in PCOS assessed by time-lapse analysis.

Method A consecutive cohort of 249 infertile women attending In vitro fertilization (IVF) or Intra-cytoplasmic sperm injection (ICSI) treatment at the Fertility Clinic, Arhus University Hospital was requited from February 2011 to May 2013. During the period, couples undergoing IVF/ICSI treatment were offered blastocyst culture to day 6 and time-lapse imaging (TLI) as part of a study evaluating parameters for embryo selection (Kirkegaard et al. 2013). Women aged \< 38 years without endometriosis and with more than \> 8 oocytes retrieved were eligible. Patients were categorized in two groups. Women with regular menstrual cycles and no clinical signs of PCOS (non-PCOS) and women fulfilling the Rotterdam diagnostic criteria for PCOS detected by the presence of anovulation and polycystic ovaries PCO, which was diagnosed by luteal-phase progesterone testing and trans-vaginal ultrasound, respectively. Biochemical parameters of androgen excess were included in the diagnosis when available, , whereas subjective symptoms of androgen excess (acne, hirsutism, alopecia) were not included.

Ethical approval Written informed consent was obtained from all patients before inclusion. The Central Denmark Region Committees on Biomedical Research Ethics and the Danish Data Protection Agency approved the study.

Ovarian stimulation:

Patients were treated with individual doses of gonadotropin, based on serum AMH and/or antral follicle count. Patients were stimulated by either a GnRH agonist- or antagonist protocol using rec-FSH or HMG for stimulation according to clinical guidelines. A dose of 10,000 IU of hCG was administered when at least 3 follicles measured ≥ 17 mm, and UL guided oocyte retrieval was conducted 36 h later.

Oocyte retrieval and ICSI/IVF Ovarian stimulation and oocyte retrieval were performed according to standard procedures. After fertilization, ICSI embryos were immediately placed in the time-lapse incubator (EmbryoScope™). IVF embryos were cultured for approximately 18 h in a conventional incubator. Before IVF embryos were transferred to the EmbryoScope, adhering cumulus cells were removed to ensure optimal image acquisition. In the EmbryoScope, all embryos were cultured until arrest or removal at day 6.

Embryo assessment. All embryos with 2 pronuclei completing the first cleavage were annotated manually.The following parameters were annotated with time-points: appearance and disappearance of 1st nucleus and 2nd nucleus after 1st division, 1st - 7th divisions, final divisions, compaction, morula, early and full expanded blastocyst, start of hatching and fully hatched blastocyst. All time-points were normalized to first cleavage and treated as durations for further analysis in order to overcome the limitation of inexact starting points, and facilitate comparison between IVF and ICSI populations. For the same reason, no parameters before first cleavage were investigated. Durations of cell cycles and cell stages were subsequently calculated as the interval between two time-points. Two parameters (multi-nucleation and direct cleavage to 3-cell stage) were assessed by binary values yes and no. Embryos were selected for transfer according to conventional measures of morphological quality on day 6 according to the Gardner criteria (Gardner et al. 2004) . No time-lapse parameters were used in the selection process. The observer was blinded to the patient's treatment data and medical history.

Statistics The influence of PCOS on embryo development was tested in regression models for clustered data. A covariance regression model was used to account for potential confounding variables: female age, BMI and fertility treatment. In total, 313 embryos from 43 PCOS women, and 1080 embryos from 175 non-PCOS women were analyzed.

The Influence of Polycystic Ovairan Syndrome on Embryonic Developmental Timing

Timing of Development in Embryos Derived From Women With Polycystic Ovairan Syndrome and Controls

Embryos were cultured in a time-lapse incubator until arrest or removal at day 6. The time-point of an event was annotated and analyzed for the embryos in focus (in order of appearance).The influence of PCOS on embryo developmental timing was tested in regression models for patient-clustered data

University of Aarhus

Consultant

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Letrozole Versus Hormonal Preparation in Frozen Cycles of PCOS Patients.	NCT05168865	Frozen Embryo T... Polycystic Ovar... Letrozole Hormone Replace... Live Birth Miscarriage	Letrozole 2.5mg	20 Years - 40 Years	Dubai Fertility Center
The Influence of Polycystic Ovairan Syndrome on Embryonic Developmental Timing	NCT01953146	Polycystic Ovar...		18 Years - 38 Years	University of Aarhus
The Influence of Polycystic Ovairan Syndrome on Embryonic Developmental Timing	NCT01953146	Polycystic Ovar...		18 Years - 38 Years	University of Aarhus

Spots Global Cancer Trial Database for polycystic ovarian disease