Clomiphene citrate does not affect the secretion of alpha3, alphaV and beta1 integrin molecules during the implantation window in patients with unexplained infertility

Background: Balance between endometrial cell proliferation and apoptosis is crucial for successful embryo implantation. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a pro-apoptotic factor, is proposed to be one of the signaling proteins through which estrogen and progesterone act to affect cellular homeostasis. Although reports in literature have suggested role of PTEN in regulating endometrial cell proliferation and apoptosis during window of implantation, its involvement in women with unexplained infertility is not clear. In the present study, we examined expression, cellular distribution and activation status of PTEN, cell proliferation, and apoptosis in midsecretory endometrium from women with unexplained infertility as compared to fertile controls.Methods: Endometrial biopsies from infertile (n=11) and fertile women (n=22) were used for immunohistochemical evaluation of PTEN, phospho-PTEN and Ki67. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay was performed for detection of apoptotic cells.Results: Biopsies from infertile women as compared to fertile controls demonstrated statistically significant: i) decrease in nuclear PTEN (P < 0.001), increase in nuclear phospho-PTEN (P < 0.05), increase in nuclear and cytoplasmic phospho-PTEN/PTEN ratio (P < 0.001 and P < 0.05 respectively) in endometrial stroma, ii) increase in cytoplasmic phospho-PTEN (P < 0.001) and phospho-PTEN/PTEN ratio (P < 0.05) in glandular epithelium (GE), iii) increase in Ki67 labeling in GE (P < 0.01) and stroma (P < 0.05) and, iv) decrease in (P < 0.001) apoptosis.Conclusions: Altered PTEN expression and associated modulation in cellular homeostasis during the implantation window might contribute to mechanism underlying unexplained infertility.

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The effects of clomiphene citrate upon ovulation and endocrinology when administered to patients with unexplained infertility

Human Reproduction ◽

10.1093/oxfordjournals.humrep.a137401 ◽

1991 ◽

Vol 6 (5) ◽

pp. 659-664 ◽

Cited By ~ 20

Author(s):

John M. Randall ◽

Allan Templeton

Keyword(s):

Clomiphene Citrate ◽

Unexplained Infertility

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A Randomized Clinical Trial to Evaluate Optimal Treatment for Unexplained Infertility

50 Studies Every Obstetrician-Gynecologist Should Know ◽

10.1093/med/9780190947088.003.0045 ◽

2021 ◽

pp. 246-250

Author(s):

Stephanie Rothenberg ◽

Joseph Sanfilippo

Keyword(s):

Ovulation Induction ◽

Treatment Approach ◽

Intrauterine Insemination ◽

Clomiphene Citrate ◽

Unexplained Infertility ◽

Additional Benefit ◽

Multiple Gestation ◽

Time To Pregnancy ◽

Vitro Fertilization

The treatment of unexplained infertility has traditionally been comprised of a stepwise treatment approach, first with ovulation induction combined with intrauterine insemination (IUI) and then with in vitro fertilization (IVF). Ovulation induction is first attempted with clomiphene citrate, and, if unsuccessful, injectable gonadotropins are used. The value of ovulation induction with injectable gonadotropins in couples with unexplained infertility has been questioned, however, given the high risk of multiple gestation and the increasing efficacy of IVF. To address this, the FASTT trial randomized couples with unexplained infertility to a treatment arm that either included or omitted gonadotropin/IUI. They found that an accelerated treatment approach that involved 3 cycles of clomiphene citrate/IUI and then progressed immediately to IVF resulted in a decreased time to pregnancy compared to the group who underwent gonadotropin/IUI for 3 cycles, as well as decreased cost per live birth. Therefore, it was concluded that treatment of couples with unexplained infertility with gonadotropin/IUI was of no additional benefit.

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Assessment of endometrial receptivity during implantation window in women with unexplained infertility

Gynecological Endocrinology ◽

10.1080/09513590.2020.1727433 ◽

2020 ◽

Vol 36 (10) ◽

pp. 917-921

Author(s):

Li Wang ◽

Shulan Lv ◽

Wenjun Mao ◽

Meili Pei ◽

Xiaofeng Yang

Keyword(s):

Endometrial Receptivity ◽

Unexplained Infertility ◽

Implantation Window

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IVF and IUI in couples with unexplained infertility (FIIX study): study protocol of a non-inferiority randomized controlled trial

Human Reproduction Open ◽

10.1093/hropen/hoaa037 ◽

2020 ◽

Vol 2020 (3) ◽

Author(s):

Lucy Prentice ◽

Lynn Sadler ◽

Sarah Lensen ◽

Melissa Vercoe ◽

Jack Wilkinson ◽

...

Keyword(s):

Live Birth ◽

Ovarian Stimulation ◽

Lower Cost ◽

Controlled Trial ◽

Clomiphene Citrate ◽

Multiple Pregnancy ◽

Unexplained Infertility ◽

Live Births ◽

Randomized Controlled ◽

Natural Conception

Abstract STUDY QUESTIONS In couples with unexplained infertility and a poor prognosis of natural conception, are four cycles of IUI with ovarian stimulation (IUI-OS) non-inferior to one completed cycle of IVF for the outcome of cumulative live birth? Are four cycles of IUI-OS associated with a lower cost per live birth compared to one completed cycle of IVF? Will four cycles of IUI-OS followed by one complete cycle of IVF result in as many live births at lower cost per live birth, than two complete cycles of IVF? Will four cycles of IUI-OS followed by two complete cycles of IVF result in more live births at lower cost per live birth, than two complete cycles of IVF alone? WHAT IS KNOWN ALREADY IUI is widely used in the USA, the UK and Europe as a low cost, less invasive alternative to IVF for couples with unexplained infertility. Although three to six cycles of IUI were comparable to IVF in the three major studies carried out to date, gonadotrophin ovarian stimulation was used in the majority of cases, and this also resulted in a high multiple pregnancy rate in some studies. Ovarian stimulation with clomiphene citrate is known to have lower multiple pregnancy rates. STUDY DESIGN, SIZE, DURATION The FIIX study is a multicentre, open label, parallel, pragmatic non-inferiority randomized controlled trial of 580 couples with unexplained infertility comparing four cycles of IUI-OS with clomiphene citrate and one completed cycle of IVF. Variable block randomization stratified by age and clinic with electronic allocation will be used. PARTICIPANTS/MATERIALS, SETTING, METHODS Couples with poor prognosis for natural conception and who are eligible for publicly funded fertility treatment in six fertility clinics in New Zealand. STUDY FUNDING/COMPETING INTEREST(S) Auckland Medical Research Fund (3718892/1119003), A+ Trust, Auckland District Health Board (A + 8479), Maurice and Phyllis Paykel Trust (3718514). No competing interests. TRIAL REGISTRATION NUMBER ACTRN12619001003167. TRIAL REGISTRATION DATE 15 July 2019 DATE OF FIRST PATIENT’S ENROLMENT 02/08/2019

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