Attempts to induce ovulation have been made since the early 1920s, but the major breakthrough came in the early 1960s with the introduction of clomiphene citrate and the gonadotropins. Additional progress was made in the early 1970s with the introduction of bromocriptine and in the early 1980s with the introduction of pulsatile GnRH. At the present, 'pure' FSH and GnRH agonists are being evaluated as adjuncts to HMG for induction of ovulation. As more insight is gained in the neuroendocrine control of the ovulating cycle, we may soon be able to induce ovulation by direct manipulation of the central nervous system.
ovulation induction history clomiphene citrate gonadotropins, pulsatile GnRH ovulation induction anovulation, bromocriptine ovulation induction hyperprolactinemia, FSH pure gonadotropins HMG ovulation induction adjunct, GnRH agonist ovulation induction protocol, neuroendocrine control ovulatory cycle manipulation, clomiphene citrate versus gonadotropins anovulatory women, ovulation induction review past present future Jewelewicz, central nervous system ovulation induction approaches, anovulation treatment historical review pharmacological agents
PMID 3146532 3146532 DOI 10.1159/000293679 10.1159/000293679 Jewelewicz et al. 1988, Jewelewicz 1988
Cite this article
Jewelewicz, R., & Gindoff, P. R. (1988). Induction of ovulation--past, present and future. Gynecologic and obstetric investigation, 26(2), 89-103. https://doi.org/10.1159/000293679
Jewelewicz R, Gindoff PR. Induction of ovulation--past, present and future. Gynecol Obstet Invest. 1988;26(2):89-103. doi:10.1159/000293679
Jewelewicz, Raphael, and Paul R. Gindoff. "Induction of ovulation--past, present and future." Gynecologic and obstetric investigation, vol. 26, no. 2, 1988, pp. 89-103.
Induction of ovulation is indicated for anovulatory and amenorrheic women as well as for women who have an inadequate luteal phase. It is also indicated as a strategy for recruiting multiple follicles for women with unexplained infertility and those who are undergoing assisted reproductive technologies. The use of various agents and detection of ovulation are described. This includes a discussion of clomiphene citrate, bromocriptine, human menopausal gonadotropins, urinary follicle stimulating hormone and pulsatile gonadotropin releasing hormone therapy. Regimens, success rates and potential complications of each form of therapy are reviewed. Also discussed is the use of combination therapy and partial ovarian destruction.
In an effort to diminish the incidence of multiple pregnancy, ovarian hyper-stimulation syndrome, and the excessive cost of human menopausal gonadotropin (HMG) administration, a sequence of Clomid-HMG-human chorionic gonadotropin (HCG) was used in 80 patients with infertility due to prolonged amenorrhea. Criteria for this therapeutic regimen were: (1) normal seminal fluid analysis and postcoital test; (2) lack of withdrawal bleeding from progesterone following amenorrhea of more than 6 months' duration; (3) normal x-ray of the sella turcica and visual fields; (4) low serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; (5) normal endoscopic examination; and (6) lack of response to clomiphene in excessive dose (200 mg daily for 5 days) or prolonged dose (100 mg daily for 10 days) with or without HCG, or apparent ovulatory response to the above sequence for five or six consecutive cycles without pregnancy. Clomiphene was administered in a dose of 100 mg daily for 7 days. HMG was then given in the following manner: two ampules daily for 4 days, then one ampule daily for 2 days (75 IU of FSH and 75 IU of LH/ampule). After a 24-hour interval without treatment, 10,000 IU of HCG were given and 2000 IU of HCG 4 days later. Twenty-three pregnancies occurred in 80 patients. However, 15 of the first 25 patients became pregnant--in these patients the only abnormality noted was lack of ovulation. Six additional pregnancies occurred subsequent to one or more unsuccessful cycles. Multiple pregnancies occurred in only two patients (twins delivered at 32 weeks in one and an abortion of five fetuses at 20 weeks in another). However, multiple pregnancy did not occur in any patient whose urinary estrogen level was monitored and in whom the level was 100 mug or less when the HCG was given. The ovarian hyperstimulation syndrome did not occur in any patient.
Reimão Miller KA et al., 2026·Reproductive biomedicine online
This review explores whether the clomiphene citrate stair-step protocol (SSP) for ovulation induction in patients with polycystic ovary syndrome (PCOS) outperforms the traditional protocol. The following databases were searched: PubMed, Cochrane Library, ClinicalTrials.gov, EMBASE and Google Scholar from inception to 15 June 2025, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and with PROSPERO registration (CRD420251050294). Of 847 screened records, five randomized controlled trials were included (n = 520: n = 255; traditional protocol: n = 265). Analyses were conducted in Review Manager 5.4 using random-effects models. Risk ratios, mean differences and 95% confidence intervals were calculated. Heterogeneity was assessed with I², risk of bias with RoB2, certainty with GRADE and robustness with leave-one-out sensitivity analysis. The SSP increased ovulation rates compared with the traditional protocol (RR 1.28, 95% CI 1.10 to 1.49; five randomized controlled trials [RCTs], n = 520, I² = 0%). Clinical pregnancy also favoured SSP (RR 1.46, 95% CI 1.04 to 2.05; four RCTs, n = 460; I² = 0%), although this result was largely driven by one study. The SSP shortened treatment duration (mean difference -32.59 days, 95% CI -38.66 to -26.52 days; three RCTs, n = 320, I² = 83%). Endometrial thickness was similar (mean difference 0.32 mm, 95% CI -0.95 to 1.59 mm; four RCTs, n = 460, I² = 91%). SSP improves ovulation rate and shortens treatment without affecting endometrial thickness and may increase clinical pregnancy rates.
Clomiphene citrate (CC) is the first-line medication for inducing ovulation in women with polycystic ovary syndrome (PCOS). However, approximately 20% of patients with PCOS are resistant to CC. This study aims to identify reliable baseline predictors of CC resistance in infertile women with PCOS. A post-hoc analysis of a large, multicenter randomized controlled trial (PCOSAct trial) conducted in China. The current analysis comprised the 471 participants who were randomized to the active CC arm and completed the requisite follow-up. To identify potential candidate variables, we employed multivariable logistic and LASSO regression analyses. Within the framework of a multivariable logistic regression model, we also estimated the independent associations between the identified candidate variables and resistance to CC. Additionally, we plotted the Receiver Operating Characteristic (ROC) curve and utilized the DeLong method to compare the statistical differences in the area under the curve (AUC). Finally, we constructed a restricted cubic spline (RCS) logistic regression model to illustrate the dose-response relationship between continuous predictor variables and CC resistance. CC resistance was identified in 32 (6.8%) participants. Body Mass Index (BMI), Total Testosterone (TT), and Anti-Müllerian Hormone (AMH) were useful predictors of ovarian response to CC. The "T+BMI" dual-factor model demonstrated high discriminative power (AUC = 0.801) and was statistically comparable to the three-factor model including AMH (AUC = 0.818; P = 0.347). TT was the strongest individual predictor (OR = 2.73 per 1-unit), while BMI was the most significant modifiable risk factor (OR = 2.49 per 1-SD). A simplified "T + BMI" assessment provides comparable prognostic utility without the need for AMH testing. For patients at high risk of CC resistance, we recommend upfront use of aromatase inhibitors or low-dose gonadotropins. This strategy avoids ineffective treatment cycles and enables personalized ovulation induction. The study was registered on ClinicalTrials.gov under the identification number NCT01573858 on July 6, 2012.