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The role of steroid hormone supplementation in non–assisted reproductive technology treatments for unexplained infertility

  • Alexander M. Quaas
    Correspondence
    Reprint requests: Alexander M. Quaas, M.D., Ph.D., Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, PO Box 26901, WP 2540, Oklahoma City, OK 73126-0901.
    Affiliations
    Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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  • Karl R. Hansen
    Affiliations
    Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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      Fertility treatment strategies are evolving, with a more rapid transition to assisted reproductive technology (ART) treatments after unsuccessful non-ART treatments. This trend increases the potential importance of adjuvant treatments in non-ART cycles, such as steroid hormone supplementation. It has been established that success rates of ART treatments are increased with the use of luteal support with progesterone. In the setting of non-ART cycles, however, the evidence is less clear, and clinical practices vary widely between providers and clinics. In this review, we aimed to provide an overview of the current evidence for the use of steroid hormone supplementation, including progesterone for luteal support, estrogens, androgens, and mineralocorticoids, in the setting of non-ART treatments for ovulatory women.

      Key Words

      The evaluation and treatment of unexplained infertility is evolving (
      • Diamond M.P.
      Future evaluation and treatment of unexplained infertility.
      ,
      • Gunn D.D.
      • Bates G.W.
      Evidence-based approach to unexplained infertility: a systematic review.
      ). The diagnosis is made in ∼10%–30% of couples presenting with infertility, when no etiology is identified after assessment of ovulatory function, tubal patency, and semen (
      • Gunn D.D.
      • Bates G.W.
      Evidence-based approach to unexplained infertility: a systematic review.
      ,
      • Athaullah N.
      • Proctor M.
      • Johnson N.P.
      Oral versus injectable ovulation induction agents for unexplained subfertility.
      ,
      • Collins J.A.
      • van Steirteghem A.
      Overall prognosis with current treatment of infertility.
      ). Treatment paradigms for this diagnosis have typically involved ovarian stimulation (OS) with intrauterine insemination (IUI), first with oral agents such as clomiphene citrate (CC), then with injectable gonadotropins (GND) with IUI (
      • Gunn D.D.
      • Bates G.W.
      Evidence-based approach to unexplained infertility: a systematic review.
      ). For those unsuccessful in achieving pregnancy with OS-IUI, this is followed by treatments involving assisted reproductive technology (ART) such as in-vitro fertilization (IVF) (
      • McClamrock H.D.
      • Jones Jr., H.W.
      • Adashi E.Y.
      Ovarian stimulation and intrauterine insemination at the quarter centennial: implications for the multiple births epidemic.
      ). According to the definition by the Centers for Disease Control and Prevention based on the 1992 Fertility Clinic Success Rate and Certification Act (
      United States Fertility Clinic Success Rate and Certification Act of 1992: Public Law 102-493.
      ), ART includes “all fertility treatments in which both eggs and sperm are handled,” not treatments involving ovarian stimulation without the intention of egg retrieval, or those in which only sperm are handled.
      Recent prospective studies have cast doubt on the above traditional strategy of progressing from CC + IUI to GND + IUI followed by IVF for couples with unexplained infertility, given low per-cycle pregnancy rates (
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      ) and alarming multiple pregnancy rates (
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      ,
      • Diamond M.P.
      • Legro R.S.
      • Coutifaris C.
      • Alvero R.
      • Robinson R.D.
      • Casson P.
      • et al.
      Letrozole, gonadotropin, or clomiphene for unexplained infertility.
      ,
      • Guzick D.S.
      • Carson S.A.
      • Coutifaris C.
      • Overstreet J.W.
      • Factor-Litvak P.
      • Steinkampf M.P.
      • et al.
      National Cooperative Reproductive Medicine Network. Efficacy of superovulation and intrauterine insemination in the treatment of infertility.
      ) in patients treated with GND + IUI. Per-cycle live birth rates for OS-IUI treatments with the use of oral agents were similar to those conducted with the use of injectable agents in several prospective randomized clinical trials (
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      ,
      • Dankert T.
      • Kremer J.A.
      • Cohlen B.J.
      • Hamilton C.J.
      • Pasker–de Jong P.C.
      • Straatman H.
      • et al.
      A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility.
      ), with lower associated multiple pregnancy rates. Although the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial demonstrated higher live birth rates following GND-IUI treatments compared with CC- or letrozole-IUI, the majority of the additional pregnancies were multiple gestations (
      • Diamond M.P.
      • Legro R.S.
      • Coutifaris C.
      • Alvero R.
      • Robinson R.D.
      • Casson P.
      • et al.
      Letrozole, gonadotropin, or clomiphene for unexplained infertility.
      ). In addition to concerns regarding multiple gestations associated with GND-IUI treatment, a cost-effectiveness analysis in the Fast Track and Standard Treatment (FASTT) trial has suggested that proceeding directly from CC-IUI treatment to IVF is associated with cost savings and a shorter time to delivery (
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      ). Given these findings, practice patterns are shifting toward a faster transition from relatively low-cost low-intervention non-ART treatments to high-cost high-intervention ART treatments including IVF. With this trend in mind, even small improvements in per-cycle pregnancy rates in non-ART treatments including CC-IUI become more clinically relevant.
      Luteal phase abnormalities have been described in women undergoing treatment with GND in the setting of ART, including treatment cycles involving GnRH agonists and antagonists and those involving no down-regulation (
      • Kolb B.A.
      • Paulson R.J.
      The luteal phase of cycles utilizing controlled ovarian hyperstimulation and the possible impact of this hyperstimulation on embryo implantation.
      ,
      • Macklon N.S.
      • Fauser B.C.
      Impact of ovarian hyperstimulation on the luteal phase.
      ,
      • Pritts E.A.
      • Atwood A.K.
      Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.
      ). Randomized studies have demonstrated that luteal support with the use of progesterone (P) significantly improves outcomes in IVF cycles (
      • Pritts E.A.
      • Atwood A.K.
      Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.
      ). It is hypothesized that P supplementation corrects the luteal phase abnormalities found in ART cycles that may result from suppression of GnRH activity, loss of granulosa cells associated with follicle aspiration, suppression of GND associated with supraphysiologic levels of E2 and/or P, or a combination of the above factors.
      Multiple studies suggest luteal phase alterations also occur in non-ART ovulation stimulation treatments with the use of GND and CC, with reported prevalence rates of 13%–50% (
      • Cook C.L.
      • Schroeder J.A.
      • Yussman M.A.
      • Sanfilippo J.S.
      Induction of luteal phase defect with clomiphene citrate.
      ,
      • Duffy D.A.
      • Manzi D.
      • Benadiva C.
      • Maier D.
      • Saunders M.
      • Nulsen J.
      Impact of leuprolide acetate on luteal phase function in women undergoing controlled ovarian hyperstimulation and intrauterine insemination.
      ,
      • Homburg R.
      • Pap H.
      • Brandes M.
      • Huirne J.
      • Hompes P.
      • Lambalk C.B.
      Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome.
      ,
      • Keenan J.A.
      • Herbert C.M.
      • Bush J.R.
      • Wentz A.C.
      Diagnosis and management of out-of-phase endometrial biopsies among patients receiving clomiphene citrate for ovulation induction.
      ,
      • Olson J.L.
      • Rebar R.W.
      • Schreiber J.R.
      • Vaitukaitis J.L.
      Shortened luteal phase after ovulation induction with human menopausal gonadotropin and human chorionic gonadotropin.
      ). Even though there is a significant amount of controversy surrounding the diagnosis of “luteal phase defects” (discussion of which is beyond the scope of this review), these findings lead to the question: Does luteal-phase P treatment improve outcomes of OS-IUI treatment cycles?
      In addition to the effect of P supplementation, little is known about the impact of supplementation with the use of other steroid hormones, such as estrogens, androgens, and mineralocorticoids in the setting of non-ART fertility treatments. The role of steroid hormone supplementation in non-ART treatment cycles, particularly as it relates to OS-IUI treatment in the setting of unexplained infertility, is covered in this review.

      Luteal-phase progesterone supplementation in gonadotropin–intrauterine insemination treatment cycles for unexplained infertility

      Duffy et al. reported that 13.9% of women undergoing OS with the use of hMG experienced luteal phase deficiencies (
      • Duffy D.A.
      • Manzi D.
      • Benadiva C.
      • Maier D.
      • Saunders M.
      • Nulsen J.
      Impact of leuprolide acetate on luteal phase function in women undergoing controlled ovarian hyperstimulation and intrauterine insemination.
      ). Similarly, Olson et al. documented altered luteal phases as assessed by serum steroid levels, luteal phase length, or both in 18.4% of women following hMG treatment for ovulation induction (
      • Olson J.L.
      • Rebar R.W.
      • Schreiber J.R.
      • Vaitukaitis J.L.
      Shortened luteal phase after ovulation induction with human menopausal gonadotropin and human chorionic gonadotropin.
      ). OS with ovulation-inducing agents can result in significantly higher concentrations of E2 and P than would be experienced in a natural cycle (
      • Kolb B.A.
      • Paulson R.J.
      The luteal phase of cycles utilizing controlled ovarian hyperstimulation and the possible impact of this hyperstimulation on embryo implantation.
      ,
      • Fauser B.C.
      • Devroey P.
      Reproductive biology and IVF: ovarian stimulation and luteal phase consequences.
      ). It has been hypothesized that these high concentrations of sex steroids in the late follicular and early luteal phases may result in negative feedback on the hypothalamic-pituitary axis, thus inhibiting the secretion of luteal LH necessary for continued progesterone production from the corpora lutea (Fig. 1) (
      • Fauser B.C.
      • Devroey P.
      Reproductive biology and IVF: ovarian stimulation and luteal phase consequences.
      ,
      • Tavaniotou A.
      • Albano C.
      • Smitz J.
      • Devroey P.
      Impact of ovarian stimulation on corpus luteum function and embryonic implantation.
      ,
      • Jones Jr., H.W.
      What has happened? Where are we?.
      ).
      Figure thumbnail gr1
      Figure 1Luteal-phase progesterone trajectory according to degree of ovarian stimulation.
      Adapted from (
      • Jones Jr., H.W.
      What has happened? Where are we?.
      ), with permission.
      Multiple investigations have addressed the impact of luteal-phase P supplementation in GND-IUI treatments. A prospective randomized study that included 200 couples undergoing up to four treatment cycles with the use of FSH-IUI identified significant differences in clinical pregnancy rates (CPRs) and live birth rates (LBRs) in women treated with luteal-phase P (39.4% and 35.8%, respectively) compared with untreated control women (23.8% and 18.1%, respectively) (
      • Erdem A.
      • Erdem M.
      • Atmaca S.
      • Guler I.
      Impact of luteal phase support on pregnancy rates in intrauterine insemination cycles: a prospective randomized study.
      ). That study was neither placebo controlled nor double blinded. Similarly, a prospective study by Maher that included 71 patients reported a higher LBR per treatment cycle after OS with the use of FSH-IUI for women who were treated with the use of luteal-phase P supplementation (18.9%) than for women who did not receive supplemental P (5.5%) (
      • Maher M.A.
      Luteal phase support may improve pregnancy outcomes during intrauterine insemination cycles.
      ).
      In contrast, a prospective randomized study from Spain by Romero Nieto et al. which included 398 patients undergoing a total of 893 GND-IUI cycles, did not find significant differences in LBR (10.2% vs. 8.3%; P=.874), CPR (13.8% vs. 11.0%; P=.248), and early miscarriage rate (3.6% vs. 2.7%) between cycles supported with the use of micronized vaginal P (200 mg once daily) and unsupported cycles (
      • Romero Nieto M.I.
      • Lorente J.
      • Gonzalez J.E.
      • Arjona-Berral M.
      • del Munoz–Villanueva M.
      • Castelo-Branco C.
      Luteal phase support with progesterone in intrauterine insemination: a prospective randomized study.
      ). Those authors stated that lack of homogeneity existed between the different studies on this topic, and that varying stimulation characteristics may have been responsible for different results and conclusions. When studying subgroups of cycles, it appeared that the difference in CPR between intervention and control groups was correlated with the degree of ovarian stimulation, as demonstrated by stimulation characteristics and multiple pregnancy rates. The studies showing a difference in outcomes (
      • Erdem A.
      • Erdem M.
      • Atmaca S.
      • Guler I.
      Impact of luteal phase support on pregnancy rates in intrauterine insemination cycles: a prospective randomized study.
      ,
      • Maher M.A.
      Luteal phase support may improve pregnancy outcomes during intrauterine insemination cycles.
      ,
      • Agha-Hosseini M.
      • Rahmani M.
      • Alleyassin A.
      • Safdarian L.
      • Sarvi F.
      The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial.
      ) were associated with a higher number of dominant follicles on the day of hCG trigger and a higher multiple pregnancy rate than the studies that did not show a difference (
      • Romero Nieto M.I.
      • Lorente J.
      • Gonzalez J.E.
      • Arjona-Berral M.
      • del Munoz–Villanueva M.
      • Castelo-Branco C.
      Luteal phase support with progesterone in intrauterine insemination: a prospective randomized study.
      ,
      • Ebrahimi M.
      • Asbagh F.A.
      • Dervish S.
      The effect of luteal phase support on pregnancy rates of the stimulated intrauterine insemination cycles in couples with unexplained infertility.
      ,
      • Kyrou D.
      • Fatemi H.M.
      • Tournaye H.
      • Devroey P.
      Luteal phase support in normo-ovulatory women stimulated with clomiphene citrate for intrauterine insemination: need or habit?.
      ). Similarly, in a prospective study of 149 patients with unexplained infertility, Seckin et al. demonstrated no difference in outcomes following OS-IUI with the use of GND with and without P supplementation in the setting of a monofollicular response. However, the clinical pregnancy rate was higher in the setting of a multifollicular response with P support (28.2%) compared with no support (11.4%; P=.04) (
      • Seckin B.
      • Turkcapar F.
      • Yildiz Y.
      • Senturk B.
      • Yilmaz N.
      • Gulerman C.
      Effect of luteal phase support with vaginal progesterone in intrauterine insemination cycles with regard to follicular response: a prospective randomized study.
      ). Therefore, it is feasible that patients undergoing more aggressive OS as part of their IUI cycle represent a subgroup that may benefit from luteal-phase P supplementation, although definitive evidence for this hypothesis does not exist.

      Luteal-phase progesterone supplementation in clomiphene citrate–intrauterine insemination treatment cycles for unexplained infertility

      Similarly to OS-IUI cycles with the use of injectable GND, high rates of abnormal luteal phases (16%–50% of treatment cycles) have been reported in women undergoing treatment with CC (
      • Cook C.L.
      • Schroeder J.A.
      • Yussman M.A.
      • Sanfilippo J.S.
      Induction of luteal phase defect with clomiphene citrate.
      ,
      • Homburg R.
      • Pap H.
      • Brandes M.
      • Huirne J.
      • Hompes P.
      • Lambalk C.B.
      Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome.
      ,
      • Keenan J.A.
      • Herbert C.M.
      • Bush J.R.
      • Wentz A.C.
      Diagnosis and management of out-of-phase endometrial biopsies among patients receiving clomiphene citrate for ovulation induction.
      ). It is unclear whether luteal-phase P supplementation affects success rates in CC-IUI treatments. Although the majority of investigations have evaluated hMG-IUI treatments or combinations of hMG and CC-IUI rather than CC-IUI alone, several studies have attempted to address this question.
      In studies limited to CC-IUI treatments, Kyrou et al. did not detect a significant difference in ongoing pregnancy rate in 468 couples undergoing a single cycle of CC-IUI with (8.7%) or without (9.3%) P supplementation (
      • Kyrou D.
      • Fatemi H.M.
      • Tournaye H.
      • Devroey P.
      Luteal phase support in normo-ovulatory women stimulated with clomiphene citrate for intrauterine insemination: need or habit?.
      ). However, that investigation included a large number of women undergoing therapeutic donor insemination rather than women with true unexplained infertility. Furthermore, the study was underpowered and neither blinded nor placebo controlled and used a dose of CC (50 mg) that did not induce the development of multiple follicles (1.2 and 1.3 follicles ≥17 mm on the day of hCG in the treatment and control groups, respectively).
      Conversely, a more recent retrospective cohort study by Elguero et al. investigating empiric luteal-phase P supplementation in CC-IUI cycles for unexplained infertility did find a significantly increased CPR in those receiving supplementation compared with those that did not (odds ratio 2.04, 95% confidence interval 1.01–4.14) (
      • Elguero S.
      • Wyman A.
      • Hurd W.W.
      • Barker N.
      • Patel B.
      • Liu J.H.
      Does progesterone supplementation improve pregnancy rates in clomiphene citrate and intrauterine insemination treatment cycles?.
      ). When the investigators used a multivariate logistic regression model to identify potential demographic and clinical predictors of clinical pregnancy, their results suggested that patients with an endometrial thickness in the 6–8 mm range appeared to receive the greatest benefit from P supplementation.
      An alternate method to examine the potential impact of luteal-phase P supplementation on outcomes following CC-IUI treatment in women with unexplained infertility is to evaluate pregnancy and live birth outcomes from prospective randomized studies that used effective doses of CC that did not empirically supplement P in the luteal phase (
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      ,
      • Dankert T.
      • Kremer J.A.
      • Cohlen B.J.
      • Hamilton C.J.
      • Pasker–de Jong P.C.
      • Straatman H.
      • et al.
      A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility.
      ,
      • Al-Fozan H.
      • Al-Khadouri M.
      • Tan S.L.
      • Tulandi T.
      A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation.
      ,
      • Berker B.
      • Kahraman K.
      • Taskin S.
      • Sukur Y.E.
      • Sonmezer M.
      • Atabekoglu C.S.
      Recombinant FSH versus clomiphene citrate for ovarian stimulation in couples with unexplained infertility and male subfertility undergoing intrauterine insemination: a randomized trial.
      ,
      • Fouda U.M.
      • Sayed A.M.
      Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial.
      ) with those that did (
      • Abu Hashim H.
      • El Rakhawy M.
      • Abd Elaal I.
      Randomized comparison of superovulation with letrozole vs. clomiphene citrate in an IUI program for women with recently surgically treated minimal to mild endometriosis.
      ,
      • Badawy A.
      • Elnashar A.
      • Totongy M.
      Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial.
      ) (Table 1). Although this approach appears to suggest a beneficial impact of P supplementation on pregnancy and LBR in this setting, it is flawed by directly comparing investigations from different centers using different protocols. Currently there is no consensus regarding the impact of P supplementation in the luteal phase of OS-IUI treatments with the use of CC.
      Table 1Progesterone supplementation and clomiphene citrate–intrauterine insemination outcomes.
      AuthorYearNo. of subjectsNo. of cyclesPregnancy rate per cycle (%)Live birth rate per cycle (%)Miscarriage rate (%)
      No progesterone supplementation
       Dankert et al.
      • Dankert T.
      • Kremer J.A.
      • Cohlen B.J.
      • Hamilton C.J.
      • Pasker–de Jong P.C.
      • Straatman H.
      • et al.
      A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility.
      20077119913.51025.9
       Al-Fozan et al.
      • Al-Fozan H.
      • Al-Khadouri M.
      • Tan S.L.
      • Tulandi T.
      A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation.
      2004801238.95.736.4
       Berker et al.
      • Berker B.
      • Kahraman K.
      • Taskin S.
      • Sukur Y.E.
      • Sonmezer M.
      • Atabekoglu C.S.
      Recombinant FSH versus clomiphene citrate for ovarian stimulation in couples with unexplained infertility and male subfertility undergoing intrauterine insemination: a randomized trial.
      1997939311.89.718.2
       Reindollar et al.
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      20104751,2949.57.620.3
       Fouda et al.
      • Fouda U.M.
      • Sayed A.M.
      Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial.
      201110521011.49.516.6
      Total1,91910.28.021.4
      Progesterone supplementation
       Badawy et al.
      • Badawy A.
      • Elnashar A.
      • Totongy M.
      Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial.
      200920740418.315.316.2
       Abu Hashim et al.
      • Abu Hashim H.
      • El Rakhawy M.
      • Abd Elaal I.
      Randomized comparison of superovulation with letrozole vs. clomiphene citrate in an IUI program for women with recently surgically treated minimal to mild endometriosis.
      20126721314.612.712.9
      Total6171714.415.2

      Luteal-phase progesterone supplementation in combination GND and CC treatment cycles for unexplained infertility

      A prospective randomized trial by Ebrahimi et al. including 200 couples with unexplained infertility undergoing OS-IUI with a combination of hMG and CC did not demonstrate a statistically significant improvement in clinical pregnancy rate with luteal-phase P supplementation compared with control couples over three treatment cycles (30.6% P group, 25.5% control group) (
      • Ebrahimi M.
      • Asbagh F.A.
      • Dervish S.
      The effect of luteal phase support on pregnancy rates of the stimulated intrauterine insemination cycles in couples with unexplained infertility.
      ). However, that investigation was underpowered and not placebo controlled. Similarly, a prospective trial by Hossein Rashidi et al. that randomized 253 couples to luteal-phase P supplementation versus placebo demonstrated no difference in CPR in supported versus unsupported cycles (15.75% vs. 12.69%; P=.03) following OS-IUI with combined GND and CC. However, that trial included a combination of women with unexplained and anovulatory infertility (
      • Hossein Rashidi B.
      • Davari Tanha F.
      • Rahmanpour H.
      • Ghazizadeh M.
      Luteal phase support in the intrauterine insemination (IUI) cycles: a randomized double blind, placebo controlled study.
      ).
      Another prospective study from Iran by Agha-Hosseini et al. sought to analyze the efficacy of vaginal luteal-phase P supplementation in 290 patients with unexplained or mild male-factor infertility undergoing OS-IUI treatment cycles with the use of CC, letrozole, or a combination of either oral medication with hMG (
      • Agha-Hosseini M.
      • Rahmani M.
      • Alleyassin A.
      • Safdarian L.
      • Sarvi F.
      The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial.
      ). When all four subgroups of ovarian stimulation regimens (CC, letrozole, CC + hMG, letrozole + hMG) were analyzed together, the CPR per cycle was higher for supplemented than for unsupplemented cycles (24.3% vs. 14.1%; P=.027). However, when subgroups were analyzed separately (with decreased respective cycle numbers and resulting decreased power), statistically significant differences were no longer observed.

      Luteal-phase progesterone supplementation in letrozole–intrauterine insemination treatment cycles for unexplained infertility

      The above-mentioned trial by Agha-Hosseini et al. (
      • Agha-Hosseini M.
      • Rahmani M.
      • Alleyassin A.
      • Safdarian L.
      • Sarvi F.
      The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial.
      ) is the only currently published study examining the effect of luteal-phase P supplementation in OS-IUI cycles containing letrozole as part of the ovarian stimulation in the setting of unexplained infertility. When the analysis was limited to the 96 letrozole-only cycles in the trial, pregnancy rates with and without supplementation were 23.2% and 12.5%, respectively, a difference that did not achieve statistical significance. Further well designed studies are needed to determine the impact of P supplementation when letrozole is used as part of OS-IUI treatments.

      Meta-analyses on luteal-phase progesterone supplementation in ovarian stimulation–intrauterine insemination treatment cycles for unexplained infertility

      Two systematic reviews and meta-analyses evaluating the effect of P luteal phase support in the setting of OS-IUI cycles have been conducted (
      • Hill M.J.
      • Whitcomb B.W.
      • Lewis T.D.
      • Wu M.
      • Terry N.
      • de Cherney A.H.
      • et al.
      Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis.
      ,
      • Miralpeix E.
      • Gonzalez-Comadran M.
      • Sola I.
      • Manau D.
      • Carreras R.
      • Checa M.A.
      Efficacy of luteal phase support with vaginal progesterone in intrauterine insemination: a systematic review and meta-analysis.
      ). Both included the studies by Erdem et al. (
      • Erdem A.
      • Erdem M.
      • Atmaca S.
      • Guler I.
      Impact of luteal phase support on pregnancy rates in intrauterine insemination cycles: a prospective randomized study.
      ), Kyrou et al. (
      • Kyrou D.
      • Fatemi H.M.
      • Tournaye H.
      • Devroey P.
      Luteal phase support in normo-ovulatory women stimulated with clomiphene citrate for intrauterine insemination: need or habit?.
      ), Ebrahimi et al. (
      • Ebrahimi M.
      • Asbagh F.A.
      • Dervish S.
      The effect of luteal phase support on pregnancy rates of the stimulated intrauterine insemination cycles in couples with unexplained infertility.
      ), Maher et al. (
      • Maher M.A.
      Luteal phase support may improve pregnancy outcomes during intrauterine insemination cycles.
      ), and Agha-Hosseini et al. (
      • Agha-Hosseini M.
      • Rahmani M.
      • Alleyassin A.
      • Safdarian L.
      • Sarvi F.
      The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial.
      ) and constructed Forrest plots of primary pregnancy outcomes on the efficacy of P supplementation with a priori subgroup analysis to compare methods of OS. Only the meta-analysis by Miralpeix et al. (
      • Miralpeix E.
      • Gonzalez-Comadran M.
      • Sola I.
      • Manau D.
      • Carreras R.
      • Checa M.A.
      Efficacy of luteal phase support with vaginal progesterone in intrauterine insemination: a systematic review and meta-analysis.
      ) contained a separate analysis on the effect of P supplementation in cycles containing letrozole for OS, but the data used for it consisted of the single small trial described above (
      • Agha-Hosseini M.
      • Rahmani M.
      • Alleyassin A.
      • Safdarian L.
      • Sarvi F.
      The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial.
      ).
      Regarding CC and GND OS, both meta-analyses concluded that based on the available data, P luteal phase support was of benefit in GND-IUI cycles but not in patients undergoing OS with the use of CC (Fig. 2).
      Figure thumbnail gr2
      Figure 2Forrest plot of clinical pregnancy rates with and without supplemental progesterone in subgroup analysis based on method of ovulation induction with the use of (A) gonadotropins, (B) clomiphene citrate, and (C) clomiphene citrate and gonadotropins combined.
      Reprinted from (
      • Hill M.J.
      • Whitcomb B.W.
      • Lewis T.D.
      • Wu M.
      • Terry N.
      • de Cherney A.H.
      • et al.
      Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis.
      ), with permission.
      The authors of the meta-analyses pointed out that there was significant heterogeneity in the included studies and that no study included a placebo control arm. In addition, no study evaluating CC alone included the outcome of live birth, and the largest study, by Kyrou et al. (
      • Kyrou D.
      • Fatemi H.M.
      • Tournaye H.
      • Devroey P.
      Luteal phase support in normo-ovulatory women stimulated with clomiphene citrate for intrauterine insemination: need or habit?.
      ), was not blinded, used a dose of CC that did not result in the development of multiple follicles, and included many patients undergoing donor inseminations rather than infertility patients. It should also be noted that the investigations by Romero Nieto et al. (
      • Romero Nieto M.I.
      • Lorente J.
      • Gonzalez J.E.
      • Arjona-Berral M.
      • del Munoz–Villanueva M.
      • Castelo-Branco C.
      Luteal phase support with progesterone in intrauterine insemination: a prospective randomized study.
      ), Seckin et al. (
      • Seckin B.
      • Turkcapar F.
      • Yildiz Y.
      • Senturk B.
      • Yilmaz N.
      • Gulerman C.
      Effect of luteal phase support with vaginal progesterone in intrauterine insemination cycles with regard to follicular response: a prospective randomized study.
      ), and Hossein Rashidi et al. (
      • Hossein Rashidi B.
      • Davari Tanha F.
      • Rahmanpour H.
      • Ghazizadeh M.
      Luteal phase support in the intrauterine insemination (IUI) cycles: a randomized double blind, placebo controlled study.
      ) were not included in either meta-analysis owing to their later publication dates.
      Investigators have attempted to explain why there may be a difference in pregnancy outcomes with respect to OS protocol. A plausible explanation is that although elevated follicular phase estrogen levels in GND-IUI cycles produce a reduced luteal phase length (Fig. 1) (
      • Fauser B.C.
      • Devroey P.
      Reproductive biology and IVF: ovarian stimulation and luteal phase consequences.
      ,
      • Jones Jr., H.W.
      What has happened? Where are we?.
      ,
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • et al.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ), CC has a greater half-life, acting directly on the hypothalamus to induce FSH and LH pulses (
      • Hill M.J.
      • Whitcomb B.W.
      • Lewis T.D.
      • Wu M.
      • Terry N.
      • de Cherney A.H.
      • et al.
      Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis.
      ,
      • Hammond M.G.
      • Talbert L.M.
      Clomiphene citrate therapy of infertile women with low luteal phase progesterone levels.
      ).

      Estrogen supplementation in fertility treatments not involving assisted reproductive technology

      Factors thought to be important to success for couples undergoing OS-IUI treatment cycles include the number of follicles that ovulate, with higher success rates being reported with greater follicle number and the preparation and receptivity of the endometrium for implantation (
      • Dickey R.P.
      • Olar T.T.
      • Taylor S.N.
      • Curole D.N.
      • Rye P.H.
      Relationship of follicle number and other factors to fecundability and multiple pregnancy in clomiphene citrate–induced intrauterine insemination cycles.
      ,
      • Ghesquiere S.L.
      • Castelain E.G.
      • Spiessens C.
      • Meuleman C.L.
      TM d’Hooghe. Relationship between follicle number and (multiple) live birth rate after controlled ovarian hyperstimulation and intrauterine insemination.
      ,
      • Park S.J.
      • Alvarez J.R.
      • Weiss G.
      • von Hagen S.
      • Smith D.
      • McGovern P.G.
      Ovulatory status and follicular response predict success of clomiphene citrate-intrauterine insemination.
      ). Whereas CC is useful in inducing the development and ovulation of multiple follicles through its antagonism of the estrogen receptor, this same mechanism of action may be associated with a reduced pregnancy rate by interfering with the normal development of the endometrium in the follicular phase and causing abnormalities of P secretion and effects in the luteal phase (
      • Cook C.L.
      • Schroeder J.A.
      • Yussman M.A.
      • Sanfilippo J.S.
      Induction of luteal phase defect with clomiphene citrate.
      ,
      • Homburg R.
      • Pap H.
      • Brandes M.
      • Huirne J.
      • Hompes P.
      • Lambalk C.B.
      Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome.
      ,
      • Keenan J.A.
      • Herbert C.M.
      • Bush J.R.
      • Wentz A.C.
      Diagnosis and management of out-of-phase endometrial biopsies among patients receiving clomiphene citrate for ovulation induction.
      ,
      • Adashi E.Y.
      Clomiphene citrate: mechanism(s) and site(s) of action—a hypothesis revisited.
      ,
      • Massai M.R.
      • de Ziegler D.
      • Lesobre V.
      • Bergeron C.
      • Frydman R.
      • Bouchard P.
      Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment.
      ).
      In natural menstrual cycles, the rise in serum levels of E2 from the developing ovarian follicle stimulates endometrial proliferation in preparation for implantation. Some studies have suggested that endometrial thickness is decreased in treatment cycles with the use of CC compared with natural cycles (
      • Dickey R.P.
      • Holtkamp D.E.
      Development, pharmacology and clinical experience with clomiphene citrate.
      ,
      • Haritha S.
      • Rajagopalan G.
      Follicular growth, endometrial thickness, and serum estradiol levels in spontaneous and clomiphene citrate-induced cycles.
      ,
      • Yagel S.
      • Ben-Chetrit A.
      • Anteby E.
      • Zacut D.
      • Hochner-Celnikier D.
      • Ron M.
      The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate.
      ), possibly through competitive antagonism of estrogen receptors in the endometrium (
      • Dickey R.P.
      • Holtkamp D.E.
      Development, pharmacology and clinical experience with clomiphene citrate.
      ). This finding has been used to explain a potential discrepancy between ovulation and pregnancy rates in women undergoing ovulation induction with the use of CC (
      • Massai M.R.
      • de Ziegler D.
      • Lesobre V.
      • Bergeron C.
      • Frydman R.
      • Bouchard P.
      Clomiphene citrate affects cervical mucus and endometrial morphology independently of the changes in plasma hormonal levels induced by multiple follicular recruitment.
      ,
      • Drake T.S.
      • Tredway D.R.
      • Buchanan G.C.
      Continued clinical experience with an increasing dosage regimen of clomiphene citrate administration.
      ). Although a few investigations have suggested that supplementation of E2 in the late follicular phase may increase endometrial thickness and improve subsequent pregnancy rates, these studies involved women with oligo-ovulation rather than unexplained infertility (
      • Elkind-Hirsch K.E.
      • Darensbourg C.
      • Creasy G.
      • Gipe D.
      Conception rates in clomiphene citrate cycles with and without hormone supplementation: a pilot study.
      ,
      • Gerli S.
      • Gholami H.
      • Manna C.
      • di Frega A.S.
      • Vitiello C.
      • Unfer V.
      Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study.
      ).
      In the setting of unexplained infertility, a single trial comparing a phytoestrogen (Cimicifuga racemosa) with the use of follicular-phase E2 supplementation in women with unexplained infertility undergoing treatment with the use of CC did not demonstrate a significant difference in pregnancy rates between treatment groups (14% vs. 21%, respectively) (
      • Shahin A.Y.
      • Ismail A.M.
      • Shaaban O.M.
      Supplementation of clomiphene citrate cycles with Cimicifuga racemosa or ethinyl oestradiol—a randomized trial.
      ). That study did not include IUI or an untreated control group.
      Although a beneficial effect of E2 supplementation in women with unexplained infertility undergoing treatment with the use of CC-IUI may clinically exist, there is no current evidence for the use of supplemental E2 in CC-IUI cycles or other types of OS-IUI cycles in patients with unexplained infertility.

      Androgen supplementation in non-ART fertility treatments

      It has been demonstrated in laboratory and clinical studies that ovarian testosterone (T) concentrations play a role in the ability of follicles to respond to FSH (
      • Meldrum D.R.
      • Chang R.J.
      • Giudice L.C.
      • Balasch J.
      • Barbieri R.L.
      Role of decreased androgens in the ovarian response to stimulation in older women.
      ). Serum T decreases with age (
      • Sowers M.F.
      • Beebe J.L.
      • McConnell D.
      • Randolph J.
      • Jannausch M.
      Testosterone concentrations in women aged 25–50 years: associations with lifestyle, body composition, and ovarian status.
      ), likely secondarily to decreased responsiveness of ovarian theca cells (
      • Piltonen T.
      • Koivunen R.
      • Ruokonen A.
      • Tapanainen J.S.
      Ovarian age-related responsiveness to human chorionic gonadotropin.
      ). Although clinical trials examining the effect of T administration on ovarian response in poor responders in the setting of ART have been conducted (
      • Balasch J.
      • Fabregues F.
      • Penarrubia J.
      • Carmona F.
      • Casamitjana R.
      • Creus M.
      • et al.
      Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH.
      ,
      • Fabregues F.
      • Penarrubia J.
      • Creus M.
      • Manau D.
      • Casals G.
      • Carmona F.
      • et al.
      Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial.
      ,
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders.
      ,
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Galey-Fontaine J.
      • Wolf J.P.
      • Hugues J.N.
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique—a prospective, randomized, double-blind study.
      ), no high-quality human studies examining the role of androgen supplementation for non-ART fertility treatments of unexplained infertility exist. Pretreatment with the use of the synthetic androgen danazol for unexplained subfertility was examined in two randomized clinical studies (
      • Iffland C.A.
      • Shaw R.W.
      • Beynon J.L.
      Is danazol a useful treatment in unexplained primary infertility?.
      ,
      • van Dijk J.G.
      • Frolich M.
      • Brand E.C.
      • van Hall E.V.
      The “treatment” of unexplained infertility with danazol.
      ), but a Cochrane systematic review on the topic concluded that there was no benefit (
      • Hughes E.
      • Brown J.
      • Tiffin G.
      • Vandekerckhove P.
      Danazol for unexplained subfertility.
      ). The latter authors added that “the need for contraception during treatment and the adverse effects and costs of danazol make its use for this problem unwarranted.”

      Glucocorticoid supplementation in non-ART fertility treatments

      Glucocorticoid medications have been used extensively in ART and non-ART fertility treatments, with conflicting evidence to support its use. In the ART setting, the use of peri-implantation glucocorticoids to improve embryo implantation in IVF/intracytoplasmic sperm injection has been advocated, but a recent Cochrane systematic review examining the practice found no clear evidence for significantly improved clinical outcomes (
      • Boomsma C.M.
      • Keay S.D.
      • Macklon N.S.
      Peri-implantation glucocorticoid administration for assisted reproductive technology cycles.
      ).
      In non-ART fertility treatments, glucocorticoids have been used for ovulation induction in patients with polycystic ovarian syndrome, although consensus guidelines do not recommend their routine use as first-, second-, or even third-line treatment (
      Thessaloniki ESHRE/ASRM–Sponsored PCOS Consensus Workshop Group
      Consensus on infertility treatment related to polycystic ovary syndrome.
      ). In ovulatory patients with infertility, the effect of adjunct glucocorticoid supplementation in non-ART treatment cycles is largely unknown. In a clinical trial from Saudi Arabia, Moradan et al. examined the addition of dexamethasone as adjunct therapy to CC-IUI (n = 42) versus CC-IUI alone (n = 66) in patients undergoing one treatment cycle for the indication of unexplained infertility (
      • Moradan S.
      • Ghorbani R.
      Dexamethasone in unexplained infertility.
      ). The pregnancy rate in the intervention group (21.4%) was higher than in the control group (4.5%), with a significant statistical difference between the groups (relative risk 4.71, 95% confidence interval 1.35–16.42; P=.0085). However, it is unclear whether that study was conducted prospectively, no details on randomization methods were given, and it is uncertain whether investigators were blinded to the treatment arm. In addition, the authors state that “16 cases were excluded, because they were unresponsive to the induction ovulation regimen,” which casts doubt on the assertion that the study population consisted of patients with unexplained infertility (
      • Moradan S.
      • Ghorbani R.
      Dexamethasone in unexplained infertility.
      ). Large-scale high-quality prospective clinical trials on glucocorticoid supplementation in non-ART fertility treatments are lacking.

      Summary

      The treatment of unexplained infertility is evolving (
      • Diamond M.P.
      Future evaluation and treatment of unexplained infertility.
      ). Recent prospective studies have cast doubt on the traditional strategy of progressing from CC-IUI to GND-IUI followed by IVF for couples with unexplained infertility, given the comparatively low per-cycle pregnancy rates, high multiple pregnancy rates, and low cost-effectiveness of GND-IUI (
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      ,
      • Diamond M.P.
      • Legro R.S.
      • Coutifaris C.
      • Alvero R.
      • Robinson R.D.
      • Casson P.
      • et al.
      Letrozole, gonadotropin, or clomiphene for unexplained infertility.
      ,
      • Guzick D.S.
      • Carson S.A.
      • Coutifaris C.
      • Overstreet J.W.
      • Factor-Litvak P.
      • Steinkampf M.P.
      • et al.
      National Cooperative Reproductive Medicine Network. Efficacy of superovulation and intrauterine insemination in the treatment of infertility.
      ). These findings are likely to prompt providers to move sooner from more affordable non-ART treatments, such as CC-IUI or letrozole-IUI, to potentially expensive ART treatments. In this context, the identification of adjuvant therapies that improve outcomes in non-ART treatments is both important and timely.
      The current body of evidence suggests that luteal-phase P supplementation in GND-IUI cycles is beneficial (
      • Hill M.J.
      • Whitcomb B.W.
      • Lewis T.D.
      • Wu M.
      • Terry N.
      • de Cherney A.H.
      • et al.
      Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis.
      ,
      • Miralpeix E.
      • Gonzalez-Comadran M.
      • Sola I.
      • Manau D.
      • Carreras R.
      • Checa M.A.
      Efficacy of luteal phase support with vaginal progesterone in intrauterine insemination: a systematic review and meta-analysis.
      ). Although some investigations have suggested that luteal-phase P supplementation in other types of OS-IUI may improve CPRs and LBRs in couples with unexplained infertility, studies on this topic have methodologic weaknesses, are underpowered, and, with one exception, are not placebo controlled. In the setting of OS with CC, current evidence suggests no clear benefit, with limited data, no studies evaluating the outcome of live birth, no placebo control in any study, and use of a dose of CC in the largest study that did not result in the development of multiple follicles (
      • Kyrou D.
      • Fatemi H.M.
      • Tournaye H.
      • Devroey P.
      Luteal phase support in normo-ovulatory women stimulated with clomiphene citrate for intrauterine insemination: need or habit?.
      ). Even fewer data are available for P supplementation after OS with the use of aromatase inhibitors, with all available evidence coming from subgroup analysis of a single study (
      • Agha-Hosseini M.
      • Rahmani M.
      • Alleyassin A.
      • Safdarian L.
      • Sarvi F.
      The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial.
      ).
      Although the largest studies have been focused with the use of GND, where P luteal-phase support may be of benefit (
      • Hill M.J.
      • Whitcomb B.W.
      • Lewis T.D.
      • Wu M.
      • Terry N.
      • de Cherney A.H.
      • et al.
      Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis.
      ), there is consensus that fewer of these treatments should be conducted owing to the risk of multiples and lack of cost-effectiveness (
      • Reindollar R.H.
      • Regan M.M.
      • Neumann P.J.
      • Levine B.S.
      • Thornton K.L.
      • Alper M.M.
      • et al.
      A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the Fast Track and Standard Treatment (FASTT) Trial.
      ,
      • Diamond M.P.
      • Legro R.S.
      • Coutifaris C.
      • Alvero R.
      • Robinson R.D.
      • Casson P.
      • et al.
      Letrozole, gonadotropin, or clomiphene for unexplained infertility.
      ,
      • Guzick D.S.
      • Carson S.A.
      • Coutifaris C.
      • Overstreet J.W.
      • Factor-Litvak P.
      • Steinkampf M.P.
      • et al.
      National Cooperative Reproductive Medicine Network. Efficacy of superovulation and intrauterine insemination in the treatment of infertility.
      ). Future studies should therefore focus on the treatments that are more likely to be performed and therefore to have the greatest potential impact. Although ART will continue to be the most effective treatment we have, improving success rates in these less expensive and less invasive treatments, such as CC- and letrozole-IUI cycles, may reduce the need for ART.
      As the presented evidence in this review suggests, well designed multicenter prospective clinical trials evaluating the impact of steroid supplementation in the setting of non-ART fertility treatments will be timely and beneficial.

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