Symptoms and General Pathology

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Gland and Hormone Related Diseases

Syndrome

Hemorrhage

Infertility

Polycystic Ovary Syndrome

Genital Diseases

Urogenital Diseases

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Ovarian Cysts

Ovarian Diseases

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Genital Diseases, Female

Female Urogenital Diseases

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Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Anticoagulants

All Drugs and Chemicals

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Other Dietary Supplements

Citric Acid

Sodium Citrate

Progestins

Clomiphene

Enclomiphene

Zuclomiphene

Medroxyprogesterone Acetate

Medroxyprogesterone

Contraceptive Agents

Contraceptives, Oral

Contraceptives, Oral, Hormonal

Contraceptive Agents, Female

Contraceptive Agents, Hormonal

Contraceptive Agents, Male

Antineoplastic Agents, Hormonal

Hormones

Hormone Antagonists

Citrate

No progestin prior to ovulation induction with clomiphene citrate

Progestin prior to beginning ovulation induction with clomiphene citrate (standard care)

The experimental group will have no progestin prior to ovulation induction with clomiphene citrate, while the comparison group will have progestin medication prior to ovulation induction with clomiphene citrate, as per usual care.

Progestin

Jon Havelock, MD

Women with polycystic ovary syndrome (PCOS) can suffer from infertility because they do not produce an egg each month, resulting in irregular periods. As a result, these women often need a medication called clomiphene citrate (clomiphene) to induce ovulation. A traditional 'clomiphene protocol' begins with a short course of progestin treatment to bring on a period (termed a 'withdrawal bleed') before starting the clomiphene medication. Newer evidence, however, has suggested that this progestin-induced shedding of the uterine lining (i.e., withdrawal bleed) may decrease the chances of pregnancy. The purpose of our study is to determine whether withdrawal bleeding has an impact on pregnancy rates for patients with PCOS undergoing a clomiphene cycle.

It is hypothesized that patients who undergo ovulation induction with clomiphene citrate without prior endometrial shedding will have higher clinical pregnancy rates than those who begin with a progestin-induced withdrawal bleed.

Effect of Progestin-Induced Withdrawal Bleed on Ovulation Induction Cycles With Clomiphene Citrate

Effect of Progestin-Induced Endometrial Shedding on Ovulation Induction Cycles With Clomiphene Citrate: A Randomized Study

clinical pregnancy rate (gestational sac seen on ultrasound approximately 6-7 weeks after starting clomiphene) per ovulation

ovulation rate (progesterone \>10nmol/L per clomiphene cycle)

ongoing pregnancy rate (pregnancy with a fetal heartbeat \>12 weeks gestational age)

multiple pregnancy rate (twins and higher order multiples)

endometrial thickness (assessed via transvaginal ultrasound)

University of British Columbia

Infertility, Female

Abortion, Spontaneous

Micronutrients

Hematinics

Vitamins

Inositol

Folic Acid

Vitamin B Complex

Trace Elements

Folinic Acid

Folate

Vitamin B9

Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Inositol (Myo-inositol and D-chiro-inositol at 40:1 ratio) plus Folic acid for 6 months.

Couples are required to have regular intercourse with the aim to achieve a spontaneous conception.

Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Folic acid for 6 months.

Couples are required to have regular intercourse with the aim to achieve a spontaneous conception.

Daily oral supplementation of for 6 months or until pregnancy conception:

Myo-Inositol: 1100 mg D-chiro-inositol: 27.6 mg Folic acid: 400 mcg

Inositol + Folic acid

Daily oral supplementation of for 6 months:

Folic acid: 400 mcg

Folic acid

Couples are required to have regular intercourses with the aim to achieve a spontaneous conception.

Regular intercourses

Antonio Simone Laganà, M.D.

Simone Garzon, M.D.

Fabio Ghezzi, M.D.

Massimo Franchi, M.D.

Polycystic ovarian syndrome (PCOS) is a heterogeneous, multifaceted and complex disorder characterized by insulin resistance (IR), hyperinsulinemia, and hyperandrogenism leading ovarian disfunction and infertility. Given the central pathogenic role of IR in the endocrine, reproductive, and metabolic disturbances of PCOS, several pharmacological and non-pharmacological approaches have been proposed to counteract the hyper insulinemic IR typical of the syndrome. Two Inositol stereoisomers, Myo-Inositol (MI) and D-chiro-inositol (DCI), captured the attention of researchers for their insulin-sensitizing actions, which configure them as proper candidates for the treatment of PCOS.

Very few studies reported on spontaneous clinical pregnancy rates, none were powered for this outcome, and none reported on the clinically relevant outcome of live birth. Therefore, data about clinical pregnancy rate, live birth rate, and miscarriage rate comparing inositols with placebo are limited.

Conversely, about infertility and assisted reproduction techniques (ART), improvements have been reported in PCOS women who underwent fertility treatment using inositol in different forms, combinations or doses. This data, considering the different tissue-specific ratios (i.e., 100:1 in the ovary) and the different physiological roles of inositol stereoisomers, suggest that DCI supplementation alone might not be the optimal or appropriate approach for improving IVF outcomes in PCOS patients, and drawn attention to the importance of MI and DCI supplementation in a physiological ratio in order to restore normal ovary functionality. Indeed, the combination of MI and DCI, at a more physiological ratio of 40:1, was able to more quickly restore to normal the hormonal and metabolic parameters in PCOS women than MI treatment alone or DCI treatment alone, improving the endocrine profile and IR of women with PCOS.

Nevertheless, regarding infertility the primary outcomes that should be considered are clinical pregnancy rate, miscarriage rate and live birth rate. Although many studies showed improved hormonal and metabolic profile and improved ovulation rate and higher quality and number of oocyte retrieved in ART in PCOS women after inositols administration, data about clinical pregnancy rate, live birth rate, and miscarriage rate are limited with several concerns regarding interpretation of the studies.

Randomized multi centre double-blind controlled trial

The patients, care provides, investigators and outcome assessors are blinded for the treatment: Inositol + Folic acid versus Folic acid alone. The treatment allocation is identified by code number before the study start, and will be revealed only after data analysis.

Spontaneous Reproductive Outcomes After Oral Inositol Supplementation in Infertile Polycystic Ovarian Syndrome Women.

Effects of Oral Inositol Supplementation on Spontaneous Reproductive Outcomes in Infertile Polycystic Ovarian Syndrome Women.

Number of spontaneous pregnancies conceived per women diagnosed by transvaginal ultrasound. Diagnosis is based on the identification of intrauterine gestational sac with embryo and/or yolk sac.

Number of spontaneous abortion per women diagnosed by positive pregnancy test with subsequent spontaneous interruption of the pregnancy.

Number of spontaneous pregnancies per women resulted in a delivered viable fetus.

Spontaneous ovulation activity evaluated by menstrual cycle regularization. Menstrual cycles evaluated by intervals between menstruations (days), day of menstrual blood flow. Rate evaluate considering the number of women with restored regular menstrual cycles per women with irregular menstrual cycles.

OGTT: values of oral glucose tolerance test. Impaired glucose metabolism is diagnosed if fasting glucose values were abnormal (100-125 mg/dl) or glucose tolerance is impaired (2 h plasma glucose within OGTT range of 140-199 mg/dl), and when glucose values exceed threshold values for gestational diabetes (fasting glu- cose value ≥92mg/dl, 1-hour glucose value ≥180mg/dl or 2- hour glucose value ≥153mg/dl)

Lipid profile assessed by evaluation the high density lipoprotein level and triglycerides level.

Serum free testosterone, dehydroepiandrosterone sulfate, and serum SHBG serum concentrations.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Effect of Progestin-Induced Withdrawal Bleed on Ovulation Induction Cycles With Clomiphene Citrate	NCT01966575	Polycystic Ovar... Infertility	Progestin	18 Years - 38 Years	University of British Columbia
Spontaneous Reproductive Outcomes After Oral Inositol Supplementation in Infertile Polycystic Ovarian Syndrome Women.	NCT03598374	Polycystic Ovar... Infertility, Fe...	Inositol + Foli... Folic acid Regular interco...	18 Years - 40 Years	Università degli Studi dell'Insubria

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