|Year : 2017 | Volume
| Issue : 4 | Page : 216-220
Induction of ovulation with clomiphene citrate combined with bromocriptine in polycystic ovary syndrome patients with infertility: A prospective, randomized, and controlled clinical trial
Hai-Yun Guan1, Wei Zhang1, Bing-Qing Huang2
1 Department of Reproductive Endocrinology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
2 Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tong Ji University, Shanghai 200040, China
|Date of Submission||17-Nov-2017|
|Date of Web Publication||7-Feb-2018|
Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011
Source of Support: None, Conflict of Interest: None
Background: To investigate the therapeutic effects of bromocriptine (BCT) combined with clomiphene citrate (CC) in the induction of ovulation in polycystic ovary syndrome (PCOS) patients with infertility.
Methods: A prospective, randomized, and controlled clinical trial was performed on 100 PCOS patients with infertility. Patients were randomly divided into two groups (n = 50), patients in control group were treated with 50 mg CC from day 3 to day 7 of the menstrual cycle, and those in observation group (CC + BCT) were given 50 mg of CC from day 3 to day 7 of the menstrual cycle along with 2.5 mg of BCT daily for the full cycle. Patients in both groups were treated for one cycle. Blood was extracted from patients on day 3 of the menstrual cycle, the day of human chorionic gonadotrophin (hCG) injection, and day 7 after hCG injection to measure serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2), total testosterone (T) and progestin (P). Vaginal ultrasound was used to determine the thickness of endometrium and follicle size and count.
Results: There was no significant difference in basal hormone levels between two groups. The success rate of ovulation induction in control group and observation group was 72.0% and 75.4%, respectively, no significant difference was found between two groups (P > 0.05). The ongoing pregnancy rate (18.4%) in observation group was significantly higher than that in control group (8.0%). On the day of hCG injection, no significant differences in the levels of FSH, E2, and P were found between two groups, while LH was lower, and levels of PRL and T were significantly lower in observation group than those in control group (all P = 0.00). On day 7 after hCG injection, no significant differences in the levels of E2 and P were found between two groups, while PRL level was significantly lower in observation group than that in control group, and the endometrial thickness in observation group (10.20 ± 1.92 mm) was significantly higher than that in control group (9.22 ± 1.88 mm) (P = 0.01).
Conclusions: Compared with the use of CC alone, BCT combined with CC can increase the success rate of ovulation induction-assisted pregnancy in PCOS patients, decrease the levels of PRL, LH, and T and increase the endometrial thickness in implantation window. Those data suggest that dopamine agonist BCT may reduce the pituitary hormone and androgen levels, reduce endometrial vascular resistance, and increase endometrial blood supply to improve the infertility outcomes of PCOS patients with infertility.
Keywords: Bromocriptine; Clomiphene; Infertility; Ovulation Induction; Polycystic Ovary Syndrome
|How to cite this article:|
Guan HY, Zhang W, Huang BQ. Induction of ovulation with clomiphene citrate combined with bromocriptine in polycystic ovary syndrome patients with infertility: A prospective, randomized, and controlled clinical trial. Reprod Dev Med 2017;1:216-20
|How to cite this URL:|
Guan HY, Zhang W, Huang BQ. Induction of ovulation with clomiphene citrate combined with bromocriptine in polycystic ovary syndrome patients with infertility: A prospective, randomized, and controlled clinical trial. Reprod Dev Med [serial online] 2017 [cited 2021 Jan 20];1:216-20. Available from: https://www.repdevmed.org/text.asp?2017/1/4/216/224917
| Introduction|| |
Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disease that affects about 5%–10% females. Main clinical manifestations of PCOS are oligoovulation or anovulation, oligomenorrhea or amenorrhea, hyperandrogenism, and polycystic ovary. Hormonal disorders involved in this disease include elevated luteinizing hormone (LH), elevated androgen (total testosterone [T]), elevated insulin or insulin resistance, and increased prolactin (PRL). About 20%–30% of patients with PCOS show a slight increase in PRL levels., In addition, studies have shown that PCOS patients with hyperprolactinemia also showed higher serum PRL in follicular phase and ovulation cycle compared with normal healthy people. However, the mechanism of the effect of elevated PRL on the development of PCOS remains unclear.
The pathogenesis of PCOS is complex and its mechanism remains unclear. One hypothesis is that neurotransmitter disorders in the regulation of release of the hypothalamic gonadotrophin-releasing hormone by dopamine (DA) may lead to abnormal secretion of pituitary gonadotropin and PRL in patients with PCOS. Studies have shown that DA agonists such as bromocriptine (BCT) can significantly inhibit LH levels and improve the recovery of menstrual cycle in some patients,, suggesting the existing of hypothalamic DA deficiency in PCOS patients, which is responsible for abnormal level of LH and increased level of PRL.
About 50% of PCOS patients suffer from infertility due to ovulation dysfunction, and the main treatment of those patients is to promote ovulation. Clomiphene citrate (CC) is a first-line drug for ovulation, and the success rate can be as high as 70%–80%. About 20%–30% of patients are not sensitive to ovulation induction drugs. In addition, the pregnancy success rate is only about 20% in a cycle, pregnancy after ovulation is the main challenge. Ovulation outcomes in PCOS patients are affected by many factors, including hormone disorders, insulin resistance, and so on. Increased PRL is a type of hormone disorder in patients with PCOS, about 20%–30% of PCOS patients show elevated PRL levels. The role of increased PRL in the development of PCOS is unclear. There was a study reported that BCT can directly inhibit pituitary PRL secretion, which is conducive to the recovery of normal central nervous system-pituitary gonadotropin secretion and function, as well as ovarian response to gonadal hormones in PCOS patients.
Based on findings in those previous studies, we hypothesized that the use of DA agonists may improve ovulation induction in patients with PCOS. Therefore, further studies on the role of DA and PRL in ovulation induction in PCOS patients are necessary. To understand the effects of BCT adjuvant treatment on ovulation induction in PCOS patients with infertility, we carried out a multicenter, randomized, open, and controlled clinical study to compared the therapeutic effects of CC alone and CC + BCT on ovulation rate and ovulation outcomes with the expectation of improving treatment outcomes of PCOS patients with infertility.
| Methods|| |
This study was a randomized, open, and controlled trial. A total of 100 PCOS patients with infertility were enrolled from January 2014 to December 2016 in Obstetrics and Gynecology Hospital of Fudan University, and Shanghai First Maternity and Infant Hospital, Tong Ji University. Those patients were randomly divided into observation group (CC + BCT) and control group (CC), 50 patients in each group. Inclusion criteria: (1) <38 years of age; (2) diagnosed as PCOS according to Rotterdam standards; (3) experienced more than 1 year of infertility after marriage; (4) body mass index (body weight/height 2) <25 kg/m2. Exclusion criteria: (1) patients with infertility caused by other factors (tubal factors and male factors); (2) patients with serious cardiovascular, pulmonary, liver, and kidney disease; (3) patients with alcoholism, drug addiction, or uncured venereal diseases; (4) pregnant female; (5) patients with or previously with hormone-related tumors; (6) patients known allergies to research drugs and control drugs; (7) patients were undergoing neuropsychiatric drug treatment or receiving any medication that may affect normal reproductive function (e.g., neuroleptics, and DA receptors Antagonists); and (8) with unexplained gynecological bleeding. This study was approved by the Ethics Committee of Obstetrics and Gynecology Hospital of Fudan University. All patients signed the informed consent and were willing to cooperate with researcher and to finish follow-up.
Patients in observation group were subjected to oral intake of CC (Codal Synto Ltd.,) at a dose of 50 mg/d for 5 days from the day 3 to day 7 of menstrual cycle. At the same time, those patients were also subjected to oral intake of BCT (Gedeon Richter Ltd.,) at a dose of 2.5 mg/d until pregnancy. Patients in control group were only subjected to oral intake of CC at a dose of 50 mg/d for 5 days from the day 3 to day 7 of menstrual cycle. Patients in both groups were injected with 10,000 IU of human chorionic gonadotrophin (hCG, Livzon, China) to induce ovulation when dominant follicles were developed to ≥18 mm in diameter. Their sexual activities were guided and oral intake of Dydrogesterone Tablets (Abbott Laboratories, USA) was performed from the day 3 after the raise of basal body temperature at a dose of 20 mg/d for 10 days.
(1) Blood estradiol (E2), follicle stimulating hormone (FSH), LH, T, and PRL levels were measured on the day 3 to day 5 of menstrual cycle. (2) Blood E2, FSH, LH, T, and PRL levels were measured on the 10th day of menstrual cycle. (3) Blood levels of E2, FSH, LH, T, PRL, and progesterone were measured, and the size of the follicles and the thickness of the endometrium were monitored by transvaginal ultrasonography on the day of hCG injection. (4) Blood levels of E2, FSH, LH, T, PRL, and progestin (P) were measured, and thickness of endometrium was monitored by transvaginal ultrasonography on the 7th day after hCG injection. Pregnancy test: blood hCG was detected for patients did not show menstruation to determine pregnancy. Pregnant patients confirmed by ultrasonography were further confirmed by B-ultrasound on the 30th day after ovulation, and the number of fetal sacs and fetal heart rate were recorded.
Main efficacy indicators: (1) at least one follicle diameter ≥18 mm; (2) serum E2 level on the day of hCG injection >109 ng/L; (3) progesterone (P4) level at middle luteal phase >7.9 μg/L; (4) biochemical pregnancy and clinical pregnancy. Secondary efficacy indicators: (1) changes in FSH, LH, PRL, T, and E2 levels; (2) endometrial thickness.
All data were analyzed by SPSS 13.0 software package (SPSS Inc., Chicago, IL, USA). Measurement data were expressed as mean ± standard deviation (x¯ ± s), and comparison between two groups were performed by t- test. Count data were expressed as percentage and compared by Chi-square test. P < 0.05 indicated the difference was statistically significant.
| Results|| |
Comparison of baseline data
There were 50 patients in observation group and control group, respectively. One patient in observation group was lost during follow-up. Before ovulation induction, there was no significant difference in hormone levels and endometrial thickness between two groups [Table 1].
|Table 1: Comparison of hormones and endometrial thickness before ovulation induction between the two groups (x¯ ± s)|
Click here to view
Comparison of related factors on the day of hCG injection
Androgen and PRL levels in observation group on the day of hCG injection were significantly lower than those in control group (P < 0.01). LH level was lower in experimental group than in control group; however, no statistical difference was found. There was no significant differences in other hormone levels were found between two groups [Table 2].
|Table 2: Comparison of hormones and endometrial thickness on hCG injection day between the two groups (x¯ ± s)|
Click here to view
Comparison of related factors on the 7th day after hCG injection
There was no significant difference between two groups in E2 and P levels on the 7th day after hCG injection. Compared with control group, PRL level dropped significantly but thickness of endometrium increased significantly in observation group (P < 0.05) [Table 3].
|Table 3: Comparison of hormones and endometrial thickness on hCG injection day 7 between the two groups (x¯ ± s)|
Click here to view
Comparison of ovulation and pregnancy rates
There was no significant difference in ovulation rate between two groups (P > 0.05) [Figure 1]. Compared with control group, single-cycle pregnancy rate was significantly higher in observation group. In observation group, the biochemical pregnancy rate was 20.4%, the ongoing pregnancy rate was 18.4%, one patient only showed the biochemical pregnancy. Single pregnancy rate in control group was only 8%, and significant differences were found between two groups (P < 0.01) [Figure 2].
|Figure 1: Comparison of ovulation rate between CC group and CC + BCT group. CC: Clomiphene citrate; BCT: Bromocriptine.|
Click here to view
|Figure 2: Comparison of pregnancy rate between CC group and CC + BCT group. CC: Clomiphene citrate; BCT: Bromocriptine.|
Click here to view
| Discussion|| |
CC is the first-line drug for ovulation induction in the treatment of patients with PCOS. However, about 20% of PCOS patients show CC resistance. The sensitivity of PCOS patients to ovulation induction drugs are affected by many factors, such as androgen, elevated LH levels, insulin resistance, and so on. Therefore, adjustment of LH and androgen levels and insulin sensitizers were usually used to assist ovulation induction therapy.
The function of the hypothalamic-pituitary-ovarian axis is regulated by central neurotransmitter. DA is an important neuroendocrine regulator that inhibits the production and release of pituitary PRL and regulates FSH and LH secretion. Studies have shown that increased LH and PRL levels were common in PCOS due to the existing of DA deficiency. Increased LH and PRL levels can inhibit the growth and maturation of follicles and ovulation. Therefore, DA agonist-assisted ovulation induction has also been used to treat PCOS patients combined with infertility.,
BCT is a DA-receptor agonist that currently has been clinically used in the treatment of hyperprolactinemia. Control of PRL can restore ovulation in 95% of patients. Studies in the last several decades have shown that BCT has no embryotoxicity, and the used of this drug before and during pregnancy does not increase fetal malformations, thus the safety is satisfactory. Since PCOS patients usually experience DA deficiency and increased PRL level and other pathological changes, BCT as a DA-receptor agonist may improve ovulation and pregnancy outcome of PCOS patients. In our study, a randomized, controlled trial was carried out to treat patients with PCOS. Ovulation induction in control group was performed by oral intake of CC, while CC + BCT was sued in observation group, a total of 100 patients were enrolled, 50 cases in each group, and only one patient in observation group was lost during follow-up. Results showed that ovulation rate was 75.4% in observation group and 72.0% in control group, no significant difference was found between two groups. Single-cycle pregnancy rate was 20.4% in observation group, which was higher than that in control group (8%). Although no significant difference was observed, those results suggest treatment with BCT may improve efficacy of CC in ovulation induction for PCOS patients.
To investigate the effect of BCT on hormone levels in patients with ovulation induction, we measured hormone levels on the day of hCG injection. Results showed that LH level decreased and levels of T and PRL decreased significantly in observation group compared with control group, while there was no significant difference in the levels of E2 andP between two groups. Determination of PRL, E2, P levels on the 7th day after hCG injection showed that PRL level was significantly lower in observation group than in control group, but no significant differences in the levels of estrogen and P were found. Our results suggest that BCT can reduce PRL, L, and androgen levels in patients with PCOS, thereby improving hormone disorders and increasing the success rate of ovulation induction. The previous study has shown that long-term use of DA agonists can reduce PRL and T levels in PCOS patients and improve menstrual cycle. Studies also showed that DA agonists reduced LH levels in patients with PCOS and improved menstrual cycle., These results are consistent with our findings, suggesting that use of DA agonists may improve pituitary hormone LH and PRL disorders and inhibit androgen production. The use of DA agonists for ovulation induction in PCOS still has not been well studied. However, some studies have shown that the application of the DA agonist Cabergoline can restore regular menstrual cycles in patients with PCOS, suggesting that DA agonists indeed have the effect of regulating endocrine disorder in PCOS patients to improve ovulation, which indirectly supports our findings.
Studies have confirmed the existing of endometrial blood flow resistance in PCOS patients,, which can affect endometrial receptivity and reduce the chance of conception. DA receptors can be expressed on endometrium. DA agonist Cabergoline can increase endometrial perfusion and improve menstrual cycles in women with PCOS., In addition, DA agonist can also improve endometrial receptivity possibly by stimulating the synthesis and release of nitric oxide (NO) by endometrial glandular epithelial cells. In our study, endometrial thickness on the 7th day after hCG injection was compared. Results showed that endometrial thickness in the observation group was significantly higher than in control group, which indirectly suggest that DA agonists could locally improve endometrial receptivity and thus increase the rate of pregnancy and improve ovulation and pregnancy outcomes.
In summary, our study suggests that the use of DA agonist BCT to assist ovulation induction can reduce levels of LH and PRL, inhibit T secretion, and improve endometrial receptivity, thereby improving the outcomes of ovulation induction.
Financial support and sponsorship
This study was supported by the project of Shanghai Association for Science and Technology (KXSH021311).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Corenblum B, Taylor PJ. The hyperprolactinemic polycystic ovary syndrome may not be an distinct entity. Fertil Steril 1982;38:549-52. doi: 10.1016/S0015-0282(16)46633-1.
Işik AZ, Gülekli B, Zorlu CG, Ergin T, Gökmen O. Endocrinological and clinical analysis of hyperprolactinemic patients with and without ultrasonically diagnosed polycystic ovarian changes. Gynecol Obstet Invest 1997;43:183-5. doi: 10.1159/000291850.
Doldi N, Papaleo E, De Santis L, Ferrari A. Hyperprolactinemia in IVF cycles: treatment vs. notreatment and outcome of ovarian stimulation, oocyte retrieval and oocyte quality. Gynecol Endocrinol 2000;14:437-41. doi: 10.3109/09513590009167716.
Leblanc H, Lachelin GC, Abu-Fadil S, Yen SS. Effects of dopamine infusion on pituitary hormone secretion in humans. J Clin Endocrinol Metab 1976;43:668-74. doi: 10.1210/jcem-43-3-668.
Paoletti AM, Cagnacci A, Depau GF, Orrù M, Ajossa S, Melis GB, et al.
The chronic administration of cabergoline normalizes androgen secretion and improves menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril 1996;66:527-32. doi: 10.1016/s0015-0282(16)58563-x.
Hernández I, Parra A, Méndez I, Cabrera V, Cravioto MC, Mercado M, et al.
Hypothalamic dopaminergic tone and prolactin bioactivity in women with polycystic ovary syndrome. Arch Med Res 2000;31:216-22. doi: 10.1016/s0188-4409(00)00059-x.
Murdoch AP, Dunlop W, Kendall-Taylor P, Watson MJ. The acute effects of a dopamine antagonist (domperidone) on luteinising hormone, follicule stimulating hormone, prolactin and thyrotrophin secretion in polycystic ovarian syndrome: Differential effect of ovulation. Clin Endocrinol (Oxf) 1984;21:611-9. doi:10.1111/j.1365-2265.1984.tb01403.x.
Tripathy S, Mohapatra S, M M, Chandrasekhar A. Induction of ovulation with clomiphene citrate versus clomiphene with bromocriptine in PCOS patients with normal prolactin: A Comparative study. J Clin Diagn Res 2013;7:2541-3. doi: 10.7860/JCDR/2013/7617.3605.
Polson DW, Mason HD, Franks S. Bromocriptine treatment of women with clomiphene-resistant polycystic ovary syndrome. Clin Endocrinol (Oxf) 1987;26:197-203. doi: 10.1111/j.1365-2265.1987.tb00777.x.
Elsersy MAM. Efficacy of combined cabergoline and metformin compared to metformin alone on cycle regularity in patients with polycystic ovarian disease with hyperprolactinemia: A Randomized clinical trial. J Obstet Gynaecol India 2017;67:363-9. doi: 10.1007s13224-017-1022-3.
Ajossa S, Guerriero S, Paoletti AM, Orrù M, Melis GB. The antiandrogenic effect of flutamide improves uterine perfusion in women with polycystic ovary syndrome. Fertil Steril 2002;77:1136-40. doi: 10.1016/s0015-0282(02)03101-1.
Lam P, Johnson I, Raine-Fenning N. Endometrial blood flow is impaired in women with polycystic ovarian syndrome who are clinically hyperandrogenic. Ultrasound Obstet Gynecol 2009;34:326-34. doi: 10.1002/uog.7314.
Yanagawa T, Kishimoto Y, Tada K, Arai F, Kondo Y, Kudo T, et al.
Presence of dopamine DA-1 receptors in human decidua. Placenta 1997;18:169-72. doi:10.1016/s0143-4004(97)90089-8.
Ajossa S, Paoletti AM, Guerriero S, Floris S, Mannias M, Melis GB, et al.
Effect of chronic administration of cabergoline on uterine perfusion in women with polycystic ovary syndrome. Fertil Steril 1999;71:314-8. doi: 10.1016/s0015-0282(98)00462-2.
Mohammadbygi R, Yousefi SR, Shahghaybi S, Zandi S, Sharifi K, Gharibi F, et al.
Effects of cabergoline administration on uterine perfusion in women with polycystic ovary syndrome. Pak J Med Sci 2013;29:919-22. doi: 10.12669/pjms.294.3558.
Tseng L, Mazella J, Goligorsky MS, Rialas CM, Stefano GB. Dopamine and morphine stimulate nitric oxide release in human endometrial glandular epithelial cells. J Soc Gynecol Investig 2000;7:343-7. doi: 10.1177/107155760000700605.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]