CC/AIs in PORs Prof. Dr. Mesut Oktem, Gazi Universitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum Anabilim Dalı Reprodüktif Endokrinoloji ve İnfertilite Bilim Dalı

cc On February 1, 1967, the U.S. Food and Drug Administration (FDA approved the sale and marketing of clomiphene citrate (Clomid) for the ‘‘treatment of ovulatory dysfunction in women desiring pregnancy Sponsored by the William S. Merrell Company Synthesized in 1956 by Frank P. Palopoli, M.S., a chemist with the William S. Merrell Company

On October 14, 1961, Dr. Greenblatt reported in the pages of JAMA that clomiphene citrate (then code-named MRL/41) reestablished ovulation in 28 of 36 patients afflicted with secondary amenorrhea . Four ongoing pregnancies were noted as well.

CC nonsteroidal triphenylethylene derivative a selective estrogen receptor modulator (SERM) competitive inhibitors of estrogen binding to estrogen receptors (ERs) and have mixed agonist and antagonist activity, depending upon the target tissue The two clomiphene isomers have mixed estrogenic and antiestrogenic effects that vary among species. En-clomiphene is the more potent isomer with greater antiestrogenic activity and the one primarily responsible for inducing follicular development

CC Most evidence suggests that the primary site of clomiphene action is the hypothalamus, where it appears to bind to and deplete hypothalamic ERs, thereby blocking the negative feedback effect of circulating endogenous estradiol This results in an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency and increased serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

CC In vitro data suggest that clomiphene citrate also has a pituitary site of action where it causes an increase in the gonadotropin response to GnRH The ovarian actions of clomiphene are for the most part secondary to the effects of elevated FSH and LH on ovarian follicular development Clomiphene is an estrogen agonist in the absence of estrogen, thereby enhancing FSH stimulation of LH receptors in granulosa cells. Clomiphene acts primarily as an antiestrogen in the uterus, cervix, and vagina

CC- Teratogenic ? Most but not all , studies suggest that the frequencies of congenital malformations and spontaneous abortion are notincreased in pregnancies after clomiphene therapy. In one report of 1034 pregnancies and 935 newborns after clomiphene-induced ovulation , spontaneous abortion and visible congenital malformations occurred in 14.2 and 2.3 percent, respectively; rates were comparable with those in mothers who spontaneously ovulated. In contrast, a newer report by the National Birth Defects Prevention Study of the Centers for Disease Control and Prevention (CDC) examined 30 different birth defects in a multicenter, case-control study of deliveries between 1997 and 2005 The exposure of interest was clomiphene citrate use for two months before conception through the first month of pregnancy. Several significant associations between clomiphene use and birth defects were observed, but because of the small number of cases in several categories and the inability to assess the effects of clomiphene separately from subfertility, these results should be interpreted with caution. There is no evidence of developmental delays or learning disabilities in children whose mothers took clomiphene 

AIs Third-generation AIs that are commercially available in North America, Europe, and other parts of the world include: two nonsteroidal preparations: anastrozole (Arimidex) letrozole (Femara) one steroidal agent: exemestane (Aromasin).

AIs Letrozole and anastrozole are reversible, competitive agents. At a dosage of 1 to 5 mg/day, they reduce estrogen levels by 97% to more than 99%. mean terminal half-life of approximately 45 hours (range: 30–60 hours). AIs work both centrally (at the level of the hypothalamus and pituitary) and peripherally (at the level of the ovaries).

AIs At the central level, AIs suppress estrogen production by directly, specifically, and potently inhibiting the aromatase enzyme AIs suppress estrogen production in all of those tissues, leading to a low serum estrogen level and low local estrogen level. Low estrogen levels are thought to release the hypothalamus and pituitary gland from their negative feedback mechanism, thereby increasing production of endogenous gonadotropins from the pituitary gland and stimulating ovarian follicular development and ovulation

AIs At the peripheral level, the aromatase enzyme catalyzes the terminal step in the steroidogenesis cascade that converts androgens into estrogen. When that enzyme is inhibited, enzyme substrate (androgens) is thought to accumulate. Studies in primates have demonstrated that androgens actually upregulate the expression of gonadotropin receptors, particularly follicle-stimulating hormone (FSH) receptors.

Are AIs teratogenic? When used for ovarian stimulation,the short half-life of AIs and administration in the early follicular phase (several days before ovulation and fertilization occur) should ensure clearance of the drugs before implantation. Nevertheless, it is important to confirm that the patient is not pregnant before an AI is given.

The first was a cohort study comparing outcomes of 394 pregnancies achieved after treatment with letrozole (133 pregnancies) and other ovarian-stimulation agents, including clomiphene citrate (113 pregnancies) and gonadotropins (110 pregnancies), with a control group of 38 pregnancies achieved without ovarian stimulation. The study encompassed three tertiary referral centers over 2 years Pregnancies conceived after treatment with an AI had rates of miscarriage and ectopic pregnancy comparable to all other groups. In addition, letrozole was associated with a significantly lower rate of multiple gestation than was clomiphene citrate.

The third study, which is more recent, compared the incidence of congenital malformation in 911 newborns conceived after treatment with letrozole (n = 514) or clomiphene citrate (n = 397).37 It found no statistically significant difference between the groups. Congenital malformation was diagnosed in 2.4 and 4.8% of the letrozole- and clomiphene-treated groups, respectively, and major malformation occurred in 1.2% and 3% of the letrozole- and clomiphene- treated groups, respectively. These differences were not statistically signifi cant, but there was a sevenfold increase in overall cardia anomalies in the clomiphene treated group, compared with the letrozole-treated group and this difference was statistically significant

Minimal stimulation protocol Minimal stimulation protocol utilizes CC in conjunction with human menopausal gonadotropin (HMG), which is more effective compared to administering HMG alone (46% vs. 25.9%) In this treatment protocol , administration of CC occurs on the 6th day, or earlier depending on LH level rise, and continues until HCG administration. Letrozole, an aromatase inhibitor is used alternative to clomiphene for minimal stimulation protocol in some clomiphene resistant patients. Letrozole is used at 2.5 mg starting on day 2 or 3 of menstruation for 5 days in conjunction with gonadotropin. However, letrozole was developed to treat metastatic breast cancer and is still not approved for use in ovulation induction.

Effectiveness of the minimal stimulation protocol The number of gonadotropin ampoules used in this protocol is significantly lower than agonist (5.7 vs. 25) . This protocol has resulted in less mature oocytes; consequently, lower chance of obtaining viable frozen embryos. However, the pregnancy rate appeared to be similar with the agonist protocol.

Minimal stimulation protocol This protocol is cost-effective for women with advance age or for those with poor ovarian reserve compared to agonist or antagonist protocols.

Aıs vs. CC Potential advantages of letrozole over clomiphene citrate include; A high rate of monofollicular development, which should theoretically reduce the risk of multiple pregnancies. No direct antiestrogenic adverse effects on the endometrium, due to an absence of peripheral estrogen receptor blockade. A shorter half-life (48 hours, versus two weeks for clomiphene citrate), which would predict a lower risk of teratogenicity. Lower serum estradiol levels – This is a particular advantage for women with breast cancer undergoing ovarian stimulation prior to gonadotoxic therapy and possibly for women with endometriosis undergoing in vitro fertilization (IVF), but this is speculative

F&S,2017

RCT 77 PORs ,CC+HMG / HMG JFRH,2016

Conclusion Mild stimulation Friendly approach Low cost Similar live birth rate Similar pregnancy rate Similar implantation rate Low gonadotropin ampoules used High cancellation rate Low mean oocytes retrieved