Hormonal Changes in Clomiphene Citrate Cycles in Unexplained Infertility Can Predict Follicle Development?

AbstractClomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17β-estradiol (E2), 11-deoxycortisol (11 S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.

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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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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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