Drugs Used For Anovulation
This list also comprises most of the drugs used for ovulation induction and IVF treatments

The medication which is most commonly used to treat anovulation is clomifene citrate (or clomid), which has been used since the 1960s. It was first used to treat cases of oligomenorrhea, and it was then applied to the treatment of anovulation. It is relatively easy and convenient to use: factors which contributed to its success. Clomifene citrate has an anti-estrogenic role, and it appears to stimulate the pituitary and therefore affect the ovarian function.It also has an effect on cervical mucus quality and uterine mucosa, which might affect sperm penetration and survival, hence its early administration during the menstrual cycle. Clomifene citrate is a very efficient ovulation inductor, and has a success rate of 67%. Nevertheless, it only has a 37% success rate in inducing pregnancy. This difference may be due to the anti-estrogenic effect which clomifene citrate has on the endometrium, cervical mucus, uterine blood flow, as well as the resulting decrease in the motility of the fallopian tubes and the maturation of the oocytes.

Another anti-estrogenic molecule called tamoxifen is often used in the prevention and treatment of breast cancer. It can therefore also be used to treat patients that have a reaction to clomifene citrate. A third anti-estrogenic compound

Femara (Letrozole) is used also as a substitute for Clomid . Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Letrozole blocks production of estrogens in this way by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids. In contrast, the antiestrogenic action of tamoxifen, the major medical therapy prior to the arrival of aromatase inhibitors, is due to its interfering with the estrogen receptor, rather than inhibiting estrogen production.

Human chorionic gonadotropin (hCG) is a molecule which is structurally similar to luteinizing hormone (LH). LH is secreted by the pituitary just before ovulation occurs, whereas hCG is released during pregnancy. On its own, hCG is not very effective in inducing ovulation, but when combined with clomifene citrate, it is much more effective. HCG should only be administered at certain points in the cycle, around the time of ovulation. A Recombinant version of hCG is available commercially and it is called Ovidrel. Ovidrel works just like hcg but it si more convenient because it does not require mixing.

Human menopausal gonadotropin (hMG) is a very powerful treatment for infertility. It consists of a combination of LH and FSH. From menopause onwards, the body starts secreting LH and FSH in large quantities due to the slowing down of the ovarian function. This excess of hormones is not used by the body and is expelled in the urine. HMG is therefore collected from the urine of menopausal women. The urine then undergoes purification and a chemical treatment. The resulting hMG induces the stimulation of several ovarian follicles. This increases the risk of producing several oocytes during the same cycle, and thus the risk of multiple pregnancies. Commercial names of hMGs are Menopur, Repronex.

Follicle-stimulating hormone (FSH or recombinant FSH) is now used as a replacement for hMG. Although hMG is a combination of FSH and LH, FSH is the main active component that has an effect on ovulation.

Metformin is an oral biguanid used to treat type 2 diabetes that has shown very promising results in the treatment of patients with PCOS. However, some experts question the efficacy of metformin. Though the results from early treatment with metformin were promising, its role and the roles of other similar molecules in reducing insulin levels among patients suffering from PCOS is not very clear.

Several studies indicate that in some cases, a simple change in lifestyle could help patients suffering from anovulation. Consulting a nutritionist, for example, could help a young women suffering from anorexia to put on some weight, which might re-start her menstrual cycle. Conversely, a young overweight woman who manages to lose weight could also relieve the problem of anovulation (losing just 5% of body mass could be enough to re-start ovulation). However, it is widely acknowledged by doctors that it is usually very difficult for PCOS patients to lose weight.

Elevated DHEA and PCOS

Good article from Medscape below:

PCOS is characterized by menstrual irregularities and hyperandrogenism. Androgens (testosterone, androstenedione, DHEA, and DHEA sulfate [DHEAS]) are produced by the ovaries and the adrenal glands. In addition, androgens are derived from the peripheral conversion of estrogens. A fraction of the total androgens consists of androgen bound to proteins in the circulation; it is the free, unbound fraction that is responsible for the clinical effects. The adrenal gland produces about 25% of the circulating testosterone, 50% of androstenedione, and 90% of DHEAS. Most patients with PCOS will have increased testosterone levels, but 25% to 50% of them will also have elevated DHEAS.

The exact etiology of adrenal androgen excess is not known. Increased adrenocorticotropic hormone (ACTH) production, increased adrenal sensitivity to ACTH, altered steroidogenic enzyme activity (17-20 lyase, 3-beta-hydroxysteroid dehydrogenase activity), and an overproduction of androgens in response to hyperprolactinemia have all been implicated as potential mechanisms. Others have suggested a role for abnormal glucose metabolism (hyperinsulinemia; insulin resistance is a characteristic feature of PCOS) in the adrenal androgen excess.

A connection between ovarian estrogen production and adrenal androgen synthesis has also been evaluated. Estrogens could have a direct adrenal effect or their effect could be mediated via prolactin. Estrogens are known to increase pituitary prolactin secretion, which in turn will augment adrenal DHEAS output. The induction of hypoestrogenism with gonadotropin-releasing hormone agonist reduces DHEAS levels. Some of these metabolic characteristics may have a genetic background.

These potential pathways leave us with numerous possibilities for medical intervention. Before choosing the treatment, we need to decide what symptom we are planning to manage (eg, infertility, recurrent miscarriage, hirsutism, acne, or menstrual irregularity). If our goal is to restore ovulatory cycles, then selective estrogen receptor modulators (eg, clomiphene citrate [CC]), insulin-sensitizing agents (eg, metformin), gonadotropins, bromocriptine (in the case of hyperprolactinemia), glucocorticoids, aromatase inhibitors, or ovarian drilling could all be offered. Most of these drugs have been shown to be effective in restoring menstrual cyclicity, although their efficacy varies. In addition, they are associated with different risk-benefit profiles. The agent with the least side effects and best safety profile should be chosen first. Because hyperinsulinemia has been suggested as a possible mechanism leading to increased adrenal DHEAS production, the use of metformin is likely to lower DHEAS levels as well. However, it is my opinion that metformin should not be administered with the sole indication to lower high DHEAS levels; treatment should address the patient's complaint. During metformin administration, androgen levels will be reduced, and in over 50% of the patients, ovarian cyclic function will be restored. Metformin administered in early pregnancy will lower miscarriage rates as well.

Glucocorticoids (eg, dexamethasone 0.5-2.0 mg) have been shown to improve menstrual regularity in up to 60% of women with PCOS. However, success rates significantly vary from study to study. The combination of CC and dexamethasone also has been shown to be effective for CC-resistant women with PCOS. At this point, it is unclear which patient might benefit from additional dexamethasone therapy. Biochemical parameters (various baseline androgen levels) were mostly shown not to be predictive of response. It is also unclear which dose of dexamethasone leads to the best results, and for how long it should be administered. Long-term steroid administration is associated with significant side effects (eg, weight gain, osteoporosis, gastrointestinal problems, and glucose intolerance); therefore, its use should be limited. As there are numerous, safer treatment options that are available to manage the various problems that arise among women with PCOS, the use of glucocorticoids should be reserved for those who fail other interventions.

What are the most appropriate treatments for patients with Polycystic Ovary Syndrome (PCO) who desire fertility?

Well ASRM and ESHRE had a consensus meeting last year and here is the abstract (most important points highlighted in bold by me):

Consensus on infertility treatment related to polycystic ovary syndrome.

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. On the basis of the currently available evidence, a group of experts reached a consensus regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counseling should be provided emphasizing the importance of lifestyle, especially weight reduction and exercise in overweight women, smoking, and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotropins is associated with increased chances for multiple pregnancy, and, therefore, intense monitoring of ovarian response is required. Laparoscopic ovarian surgery alone is usually effective in less than 50% of women, and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC-gonadotropin paradigm) is reported to be highly effective with a cumulative singleton live-birth rate of 72%. Recommended third-line treatment is in vitro fertilization (IVF). More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-line, second-line, or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.

Source : Fertility And Sterility via MEDLINE

I think it is very important to note that this consensus document confirms what most reproductive endocrinologists already know and that is that Metformin (Glucophage) is a lousy fertility drug. For a while it seemed to be very promising and at some point it was being prescribed (by some) to all PCOS patients. But today it is quite clear that only a subgroup of patients will benefit from this drug. More on this in the future!