Is Metformin the Answer for Distressed Females with Menstrual Irregularities?

This literature review is aimed to determine if metformin alone improves menstrual irregularities in females with the polycystic ovarian syndrome. The current literature review involves females with polycystic ovarian syndrome experiencing menstrual irregularity. The data was collected in PubMed and inclusion criteria included articles published in the past 10 years, articles involving only humans, articles written in the English language and considering women age 19 or more. The number of discovered articles was 1550 after the first search and only 25 articles that met the inclusion criteria were selected after quality assessment. The selected 25 articles that met the inclusion criteria after a review showed evidence for regulating menstrual cycles with metformin therapy alone among females with the polycystic ovarian syndrome. When metformin was used in addition to other pharmacologic agents, there was a more significant restoration of menstrual cycles. Monotherapy with metformin is found to be highly effective in treating menstrual irregularities experienced among patients with the polycystic ovarian syndrome. Greater improvement was noted with the addition of another agent to metformin.


Introduction And Background
The polycystic ovarian syndrome affects women of childbearing age and is a clinical diagnosis. The etiology of the polycystic ovarian syndrome is unknown but may be attributed to insulin resistance. Patients frequently present with symptoms such as menstrual irregularities, androgen excess, and polycystic ovaries. While androgen excess often presents with acne and hirsutism, menstrual irregularities often lead to infertility. Treating menstrual irregularities is a crucial component to the polycystic ovarian syndrome. Menstrual irregularities caused by polycystic ovaries leads to infertility, resulting in distress among women trying to conceive [1][2][3].
Hormonal pharmacologic therapies such as oral contraceptives have been used for the treatment of menstrual irregularities in polycystic ovarian syndrome. In addition to hormone therapy, metformin was used to treat irregular menses in females with a history of oligomenorrhea or amenorrhea. The exact mechanism of metformin in regulating menstrual cycle is still unknown. However, it may be attributed to insulin sensitization thereby targeting the insulin resistance caused by androgen excess [1][2][3]. This literature review is aimed to determine the effectiveness of metformin in regulating menstrual cycles among females with the

Review Method
The data was collected from PubMed using regular keywords "polycystic ovary" and "metformin." The following inclusion criteria were applied in the following order -literature published within 10 years, articles involving only human subjects, articles published only in English language and the age of the subjects 19 years or more. The collection of the articles for the study was done ethically.

Results
After using regular keywords on PubMed, a total of 1550 articles were identified. Among the 1550 articles, 347 were obtained with the application of filters. Table 1 shows the total number of articles obtained in order after applying inclusion criteria in PubMed.

Total articles found 1550
After inclusion criteria 10 years 890 Humans 706 English language 658 Age 19 or more 347

TABLE 1: Keywords search after applying inclusion criteria in PubMed
Of the 347 articles obtained, each article was individually reviewed based on the abstract content. Three hundred and twenty-two articles were not selected for review due to one or more of the following reasons: -lack of disease of interest; -lack of menstrual irregularities; -lack of metformin use for menstrual irregularity; -studies with no possible derivation of information with quality assessment.
The number of articles obtained after removal of 322 articles was 25, among which 16 were free abstracts available online for review and nine were free with full text available online for review. Of the articles included in the data, there were 21 randomized controlled trials, two literature reviews, and one systemic review.
The 25 selected articles showed evidence for metformin therapy to be efficacious in regulating menstrual cycles of females with the polycystic ovarian syndrome. When metformin was used with other pharmacologic agents, there was a recovery of menstrual cycles as well. Of the articles collected, the randomized clinical trials involving metformin showed improvement in menstrual cycle irregularity with metformin [3,[10][11][12][13][14][15][16][17]. Table 2 shows the analysis of various parameters seen in the randomized clinical trials.  Irrespective of the dosage, it is observed that even at a 500 mg dosage, metformin therapy showed improvement in regulating menstrual cycles. In addition, metformin also showed a decrease of hormone levels such as luteinizing hormone (LH), luteinizing hormone/folliclestimulating hormone (LH/FSH) ratio, testosterone, estradiol, dehydroepiandrosterone sulfate 2019  (DHEA-S) and progesterone. Furthermore, metformin was effective in weight reduction and hirsutism [15,[18][19].

Conclusions
The objective of the current literature review is to determine the effectiveness of metformin in regulating menstrual cycles among women diagnosed with the polycystic ovarian syndrome experiencing irregular menses. The use of metformin has demonstrated an improvement in regulating menses significantly with a greater improvement when metformin is used as an adjunctive to another pharmacologic agent. It is to be determined whether these patients will require lifelong metformin therapy or if insulin sensitization can be achieved at a specific number of doses required thereby leaving room for speculation if metformin can be halted after a certain number of doses. One wonders if metformin's effect at regulating menses is tied with insulin sensitization and if serum testosterone plays a role.