Tamoxifen Breast cancer drug could treat infertility
Researchers say the breast cancer drug tamoxifen may help cancer patients retain their fertility after a woman who took it to stimulate egg production gave birth to twins.
According to doctors at Cornell University in New York, this is the first recorded case of a successful pregnancy and birth arising from the use of tamoxifen as an in vitro fertilisation (IVF) treatment.
In a study looking at its effectiveness as a fertility drug, researchers discovered it boosted egg production in 12 women who had survived breast cancer.
Although tamoxifen has been known to be an ovarian stimulant for the past 30 years, its use in IVF treatment has been neglected because of its success as a breast cancer therapy, according to the report.
The new findings, published in the journal Human Reproduction, suggest it could play a key role in helping breast cancer patients who want to freeze embryos because they risk ovarian failure due to the toxic effects of chemotherapy.
"Sometimes the best ideas are the obvious ones and tamoxifen seemed the obvious choice of drug to test, although to my knowledge no one has tried it before in breast cancer patients," lead researcher Professor Kutluk Oktay said in a statement.
"We hypothesised that tamoxifen stimulation would result in higher numbers of embryos compared with natural cycle IVF, while theoretically shielding breast cancer cells against oestrogen." Many doctors are reluctant to use traditional methods to stimulate the ovaries of breast cancer patients to produce more eggs, for fear that the drugs could trigger cancer growth.
Tamoxifen was originally developed back in the mid-1960s as a contraceptive before finding favour in Europe as an ovarian stimulant. But after its anti-cancer properties were discovered in 1976, its use as a fertility aid declined.
Oktay, from the Center for Reproductive Medicine and Infertility at Cornell's Weill Medical College, said the study arose from a desire to find a safe way of preserving fertility among the 15% of breast cancer patients who are still of reproductive age when diagnosed with the disease.
Even if their fertility survives chemotherapy, many of these women can simply run out of time to have a child because they are advised to wait up to five years before trying to conceive.
"These women can try natural cycle IVF without ovarian stimulation, but typically, no more than a single embryo can be achieved for immediate use or freezing," said Oktay. "So we need to find a safe way of increasing the number of embryos."
Twelve breast cancer patients were given 40 to 60 milligrams of tamoxifen for seven days, starting two or three days into their menstrual cycle, and monitored for egg production.
To gauge the effects, researchers compared them with a group of five cancer patients who had undergone natural cycle IVF.
The results showed the women taking tamoxifen produced an average of 1.6 mature eggs compared to 0.7 in the non-tamoxifen group, or control group. All 12 then went on to generate embryos to freeze for later attempts at pregnancy, compared to three out of the five controls. None of the women has since suffered a recurrence of their cancer.
One patient who had two embryos transferred has successfully given birth to twins, the researchers announced.
Oktay added: "We exploited tamoxifen's dual action as an ovarian stimulant and an anti-cancer agent.
"It would be especially fitting if a drug that has saved so many women's lives should also turn out to be a means of preserving their fertility."
Dr. Mark Johnson, a specialist in assisted conception at the Imperial College of Science, Technology and Medicine in London, said tamoxifen's benefits as an IVF treatment came as no big surprise. Other doctors in the UK, he said, have used the drug to stimulate the ovaries in women with polycystic ovary syndrome but this was the first documented case of a successful birth. Polycystic ovary syndrome is a condition marked by infertility, excess facial hair and obesity.
"I'm sure they are right to say that but the numbers of women who will benefit are quite small," Johnson said. "The numbers of people with breast cancer who have fertility problems are not that great."
How does tamoxifen work?
Twenty patients with ultrasound diagnosed polycystic ovaries and high luteinizing hormone levels who failed to respond to clomiphene citrate were given tamoxifen to induce ovulation. Tamoxifen 20 mg daily (group 1, n = 10) and 40 mg daily (group 2, n = 10) was given for 5 consecutive days from the third to seventh day of the cycle. Treatment was monitored by serial ultrasound scans and assessment of serum estradiol. Human chorionic gonadotrophin (hCG) was administered when at least one follicle was > 16mm and serum estradiol level was > 300 pg/ml per follicle. Ovulation was confirmed with detection of the follicular rupture ultrasonographically 2 days after hCG and midluteal progesterone levels. The ovulation rate achieved in group 2 patients was significantly higher (p = 0.01) than group 1. Three pregnancies were achieved in group 2 patients while there was no pregnancy in group 1. The only side effect was ovarian cyst formation in one patient in group 1. As a result, tamoxifen might be a good choice for clomiphene resistant patients prior to treatment with surgery or hMG.
The anti-oestrogens clomiphene and tamoxifen are successful therapeutic agents in the induction of ovulation but the associated pregnancy rates are low. One cause for this may be a direct anti-oestrogenic effect on cervical mucus, reducing its sperm penetrability. This potentially adverse effect has been shown to occur with clomiphene. In this study the effects of clomiphene and tamoxifen on the cervical factor are compared in women who were anovulatory or had defective ovulation. Forty fully investigated infertile women were randomly allocated to different treatment sequences after being observed for three control cycles. A double-blind placebo technique was used with four different treatment regimes. Serial serum progesterone and oestradiol were assayed. Cervical mucus from the periovulatory phase was assessed by means of the cervical score and in vitro sperm penetration tests. Both these anti-oestrogens can affect cervical mucus but their effect seems to be related more to the end-organ sensitivity of the individual than to a specific action of the drug per se.
Twenty-two infertile women with repeated deficient results in the postcoital test received clomiphene citrate or tamoxifen. The patterns of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol (E2), and progesterone were examined during the follicular and periovulatory phases of the menstrual cycle, as were the cervical mucus characteristics. Under clomiphene treatment, an overproduction of E2 was observed (P less than 0.01), which did not result in an improvement of the cervical mucus characteristics. The pH of the endocervical mucus was lower (P less than 0.01). Under tamoxifen treatment, the serum E2 levels were higher (P less than 0.05) and normalized. Higher spermatozoa penetration meter scores were observed during the preovulatory and periovulatory periods, whereas the pH of the endocervical mucus was not lowered. These data support that tamoxifen may be preferential to clomiphene in treating this kind of infertile woman.
Fourteen pregnancies were achieved with tamoxifen therapy in 12 women who failed to conceive with clomiphene citrate. There were no side-effects and fewer treatment cycles were required than with clomiphene citrate treatment. Ovulation and cervical score with tamoxifen therapy were significantly higher (p less than 0.005).
Antiestrogens are widely used to treat eugonadal anovulation, luteal phase deficiency (LPD) and oligospermia. This paper reviews the rationales, endocrine effects, profertility effects and side effects of these treatments. Furthermore, we present our own experience of the use of antiestrogens in this field. We have compared the results of clomiphene citrate (CC) to those of tamoxifen (TAM) in a randomized study including 66 infertile women presenting eugonadal anovulation (n = 26) or LPD (n = 40). Both drugs obtained the same pregnancy rate of 80% at 9 months in the anovulatory patients. Conversely, CC was superior to TAM in the LPD cases (pregnancy rates at 6 months of respectively 40 and 11%). The abortion rates were of 11% on CC versus 36% on TAM. Both drugs significantly increased the luteal phase length and plasma progesterone level to the same extent. The results of endometrial biopsies suggest that the difference in their effects on female fertility could result from a detrimental effect of TAM on endometrium. The rates of the side effects proved to be almost identical on both drugs. Thus the use of TAM is not justified as a first-step treatment on ovulation disturbances. TAM should be reserved for patients who experience severe visual side effects on CC. We have also tested TAM in 100 subfertile males. In the 92 oligospermic males, TAM significantly increased the mean sperm count only in the normogonadotropic patients, but as much whether oligospermia was idiopathic or not. Sperm improvement was not significantly related to any hormone criterion except basal serum FSH. The cumulative pregnancy rate was of 41.2% at 1 year. Whether TAM actually improves male fertility, and is superior to CC in this indication, remains to be confirmed in controlled studies.
Twenty-five infertile women conceived while taking tamoxifen (TMX). Daily serum profiles of 5 of the 25 TMX-induced conception cycles were elucidated and compared with those found in 5 normal cycles. In spite of lower levels of follicle-stimulating hormone and luteinizing hormone during the follicular phases, estradiol concentrations were higher in the TMX-induced conception cycles. It is suggested that this may be due to a direct ovarian effect of TMX as one of its major mechanisms in the course of folliculogenesis. On the other hand, progesterone concentrations on days 6 and 7 during the luteal phases were also higher in the TMX-induced conception cycles. It is suggested that this may be due to a luteotropic influence at the blastocyst stage.
Tamoxifen at a dose of 10 mg/day for 5 days was given to five infertile women in the luteal phase. Daily serum samples were obtained during the luteal phase for radioimmunoassay of progesterone (P), estradiol (E2), follicle-stimulating hormone, luteinizing hormone (LH), and prolactin levels. The integrated luteal phase concentrations of serum P and E2 before and after cycles of tamoxifen treatment increased from 87.8 +/- 16.2 ng/ml and 1120 +/- 164.4 pg/ml to 131.6 +/- 18.9 ng/ml and 1461 +/- 205.2 pg/ml, respectively (P less than 0.01 and P less than 0.05). No apparent increase in circulating LH levels was seen in one of the five cases, but this patient's serum P and E2 levels rose nonetheless. This suggests that the significant increase in circulating P and E2 induced by tamoxifen is not consistently associated with an increase in serum LH concentration.
Daily estimations of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone were made in the serum of eight infertile patients from day 1 through the follicular phase during menstrual cycles before and after tamoxifen therapy. Tamoxifen therapy was found to shorten the follicular phase from 15.4 +/- 0.8 days (mean +/- standard error of the mean) to 14.0 +/- 0.6 days (difference not significant) and to lengthen the luteal phase from 12.8 +/- 0.4 days to 14.1 +/- 0.8 days (P less than 0.05). The mean estradiol concentration in the eight patients during tamoxifen treatment cycles rose on day 8 (3 days after starting tamoxifen treatment) and increased significantly (P less than 0.05) from day 10 to midcycle. The integrated follicular phase estradiol concentration in the tamoxifen treatment cycle increased to 2450.1 +/- 208.1 pg/ml/cycle, and was significantly higher (P less than 0.025) than that in the nontreatment cycle. In contrast, the concentrations of follicle-stimulating hormone, luteinizing hormone, and prolactin during the follicular phase and at the midcycle peak of tamoxifen treatment cycles were not significantly different from those of the nontreatment cycle. These results suggest that the mechanism of tamoxifen in improving folliculogenesis may involve a direct action on the ovary without intervention of the hypothalamic-pituitary system.
The effectiveness of tamoxifen and clomiphene in inducing ovulation was compared in 46 women with anovulatory infertility. All the women were given both the drugs in an alternate way. If one cycle was treated by tamoxifen the next was treated by clomiphene and vice versa. Forty-one out of the 46 women (89.1%) ovulated at least once during the study. Similar ovulation rates were achieved by tamoxifen (56.2%) and clomiphene (62.9%). The lengths of the ovulatory cycles and their luteal phases and the mid-luteal phase serum progesterone levels did not differ significantly between the two compounds. Nor did the occurrence of luteal phase defects during the tamoxifen and clomiphene treatment cycles differ. Thirty-seven of the 46 women (80.4%) responded similarly to both drugs. Thus, tamoxifen is just as effective as clomiphene in inducing ovulation in women with anovulation.
