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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 2  |  Page : 433-439

Effects of metformin alone and in combination with spironolactone on hyperandrogenism in polycystic ovarian syndrome


1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, Al-Shohadaa Hospital, Menoufia, Egypt

Date of Submission07-Mar-2019
Date of Decision14-Apr-2019
Date of Acceptance26-Apr-2019
Date of Web Publication27-Jun-2020

Correspondence Address:
Shaza S Maklad
Al-Shohadaa, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_61_19

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  Abstract 


Objective
To evaluate the efficacy of combined therapy with metformin and low-dose spironolactone as compared with metformin alone on the clinical and endocrine-metabolic alterations of patients with polycystic ovarian syndrome (PCOS).
Background
PCOS is the most common endocrinological disorder in reproductive-age women. Thus, at least theoretically, metformin plus spironolactone therapy may be an effective and safe combination for PCOS.
Patients and methods
A prospective randomized comparative study was carried out on 48 patients with the PCOS in Obstetrics and Gynecology Department, Menoufia University Hospital, and Al-Shohadaa Hospital, Egypt, from the period of May 2016 till January 2018. Detailed history, laboratory investigations, obstetric examination, and follow-up were done.
Results
Mean hirsutism score and BMI (kg/m2) were 10.8 ± 3.9 and 26.8 ± 2.2, respectively, before treatment, which decreased significantly to 7.6 ± 2.4 and 22.10 ± 1.92, respectively, after 6 months of treatment. Luteinizing hormone, follicle-stimulating hormone, free testosterone, dehydroepiandrosterone sulfate, fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance were decreased significantly after 6 months of treatment as compared with before treatment among women who received metformin + hypocaloric diet and received metformin + spironolactone + hypocaloric diet before treatment. Free testosterone was decreased in group B (58.2 ± 9.1) more than group A (73.6 ± 12. 9).
Conclusion
The results confirm the beneficial effects of metformin in patients with PCOS. It also proves that the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism in patients with PCOS present with hyperandrogenic conditions.

Keywords: combined therapy, metformin, polycystic ovarian syndrome, spironolactone


How to cite this article:
Abd Elaal NK, Ellakwa HE, El Halaby AE, Maklad SS. Effects of metformin alone and in combination with spironolactone on hyperandrogenism in polycystic ovarian syndrome. Menoufia Med J 2020;33:433-9

How to cite this URL:
Abd Elaal NK, Ellakwa HE, El Halaby AE, Maklad SS. Effects of metformin alone and in combination with spironolactone on hyperandrogenism in polycystic ovarian syndrome. Menoufia Med J [serial online] 2020 [cited 2020 Sep 29];33:433-9. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/433/287809




  Introduction Top


Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in reproductive-age women. The prevalence of this disorder is 5.6–10% in the general population[1]. The main clinical features of PCOS are abnormal menstrual cycles, hyperandrogenism, and typical polycystic appearance of the ovaries by ultrasound[2]. The insulin resistance and compensatory hyperinsulinemia are frequently associated with PCOS, not only in the obese but also in normal-weight patients, and are believed to have a pathogenic role in PCOS. However, visceral obesity is commonly present in patients with PCOS and may exacerbate insulin resistance. Therefore, women affected by PCOS develop impaired glucose tolerance and type 2 diabetes mellitus. Hyperinsulinemia contributes toward stimulating hyperandrogenism by multiple mechanisms, including direct effects on ovary thecal cells and adrenal cells, and inhibition of the hepatic synthesis of sex hormone-binding protein (SHBG), which increases free testosterone levels[3]. The clinical presentations of hyperandrogenism in PCOS are hirsutism, acne, seborrhea, and alopecia. The most common manifestation of clinical hyperandrogenism in women with PCOS is hirsutism[4]. The therapeutic approach of overweight/obese patients with PCOS is currently based on lifestyle intervention. Several studies have shown that these patients benefit from caloric restriction and weight loss, especially when associated with a constant and moderate aerobic physical activity. These lifestyle changes reduce insulin resistance and hyperandrogenism and may restore ovulation[5]. As insulin resistance and hyperandrogenemia are among the main interacting causes, as well as overproduction of luteinizing hormone (LH) and androgenic hormones, in PCOS, a combination of insulin sensitizers and antiandrogens may have complementary effects in the treatment of PCOS[6]. It has been shown that metformin (insulin sensitizers) improves insulin resistance, increases the number of cycles in patients with PCOS, and may improve hirsutism. Spironolactone, one of the antiandrogenic and aldosterone antagonist medicines, has been used to treat hirsutism and acne in women with PCOS. It ameliorates hyperandrogenism by inhibiting both synthesis and receptor binding of androgens[7]. It has been shown to decrease sebum production and improve acne. The therapeutic dose range is 25–200 mg/day. It appears to be safe, even after long-term use; however, it may cause hypokalemia, breast tenderness, diuretic effect, and menstrual disturbances, particularly with high doses. Thus, at least theoretically, metformin plus spironolactone therapy may be an effective and safe combination for PCOS[8].

This study aimed to evaluate the efficacy of combined therapy with metformin and low-dose spironolactone as compared with metformin alone on the clinical and endocrine-metabolic alterations of patients with PCOS.


  Patients and Methods Top


A prospective randomized comparative study was carried out on 48 patients with the PCOS in Obstetrics and Gynecology Department, at Menoufia University Hospital, and Al-Shohadaa Hospital, Egypt, from May 2016 till January 2018.

Ethical consideration

All participants were volunteers. All of them signed a written informed consent before study initiation, after explaining to them the aim of the study. Approval was obtained from the ethics committee in the Faculty of Medicine, Menoufia University.

Method of recruitment

Forty-eight overweight/obese women were recruited for the study, from those referred to the gynecologic outpatient clinic complaining of hyperandrogenic conditions such as hirsutism, acne, and/or androgenic alopecia. The diagnosis of PCOS was based on Rotterdam Revised criteria (2003). Those who fulfilled two out of the following were recruited into our study: oligo- or anovulation, such as amenorrhea (absence of menstruation >180 days) or oligomenorrhea (menstrual periods occur at intervals of >35 days), and clinical and/or biochemical signs of hyperandrogenism. Polycystic ovaries on ultrasound are defined as an ovary containing 12 or more follicles measuring 2–9 mm in diameter or an ovary that has a volume of greater than 10 ml.

Exclusion criteria

Pregnancy was ruled out by human-chorionic gonadotropin measurement. Normal serum prolactin and normal thyroid function were established by hormonal evaluation. Late-onset nonclassical congenital hyperplasia was excluded by values of basal 17-hydroxy progesterone less than 2 ng/ml. Cushing syndrome was also ruled out by hormonal evaluation. Drugs included oral contraceptive, antihypertensive agents, anti-diabetic drugs, and agents for weight loss. Method of randomization was as follows: 48 patients were randomized into both groups using a block of six randomization method, which was produced by a computer-generated random number list. The allocation sequence was concealed in sequentially numbered, opaque, sealed and stapled envelopes. Group A had 24 patients who were taking metformin (1700 mg/day) plus hypocaloric diet. Group B had 24 patients who were taking metformin (1700 mg/day) plus spironolactone (25 mg/day) plus hypocaloric diet. Metformin was started at a dose of 500 mg twice a day and it was increased after a week to the final dose of 850 mg twice a day. Both patient groups were treated for 6 months.

Dietary intervention was as follows: all patients were prescribed the same energy-restricted, high-protein diet (1500–2000 kcal/day) for a planned weight loss of 8–12 kg over the study period. The diet provided 30% of energy as protein, 40% as carbohydrate, and 30% as fat (<8% saturated fat). To facilitate compliance, the diet included specific daily quantities of foods in a checklist that patients completed daily. Patients met with a dietician in small groups or individually fortnightly throughout the study to discuss dietary issues, nutrition guidelines, and the importance of compliance with the diet to promote weight loss. All patients were subjected to the following clinical and laboratory evaluation during the mid-follicular phase of spontaneous menstrual cycles, both at baseline and the end of the 6-month treatment period. History taking included personal history, with emphasis on the name, age, occupation, residency, and special habits; present history, including symptoms that are usually associated with PCOS such as clinical hyperandrogenism such as hirsutism, acne, or alopecia; menstrual irregularities such as oligomenorrhea, menorrhagia, or amenorrhea; past history with particular emphasis on the history of medical disorders, abdominal surgeries, drug therapy or allergy or history of intake of other tocolytic drugs; and family history, for any similar condition. Physical examination included anthropometric parameters (height, weight, and BMI), as well as measurements of blood pressure, pulse, and temperature. Thyroid examination, chest and heart examination, and hirsutism (hirsutism was diagnosed by modified Ferriman–Gallwey scale, where a score of 8 or more is considered hirsutism) were also done. The ovarian ultrasound examination is carried out for assessment of criteria of a polycystic ovary. Laboratory investigations included hormonal level [follicle-stimulating hormone (FSH) and LH], free testosterone level, dehydroepiandrosterone sulfate level (DHEAS) for hyperandrogenism, and fasting glucose and insulin levels to assess insulin resistance, according to the homeostasis model assessment of insulin resistance (HOMA-IR) technique. It was calculated according to the following formula: HOMA-IR = glucose (mg/dl)×insulin (mU/ml)/405.

Statistical analysis

Results were analyzed and tabulated using Microsoft Excel version 7 (Microsoft Corporation, New York, New York, USA) and SPSS, version 16. (SPSS Inc., Chicago, Illinois, USA). Two types of statistics were done: descriptive, for example, percentage, mean, median, and SD, and analytical, which includes paired t test, Wilcoxon test, and independent t test of variance for comparing categorical data. A value of P less than 0.05 was indicated as statistically significant.

Plasma insulin was measured by RAB0327/1KT Human Insulin enzyme-linked immunosorbent assay (ELISA) kits (Advia Centaur XPT Immunoassay System, Cairo, Egypt). Estimations of serum T3, T4, cortisol, 17-OHP, and T were done by ELISA using commercial kits in duplicates and according to supplier protocol. Measurements of TSH, PRL, LH, and FSH were done by solid-phase ELISA using commercial kits. The kits were supplied by Centaur XPT Immunoassay system. Plasma glucose was measured by Advia1800. Sensitivity, specificity, and interassay and intraassay coefficients of variation were within the prescribed limits prescribed in the manufacturer's protocol.


  Results Top


In total, 21 patients were randomized to metformin (group A) and 22 patients were randomized to metformin plus spironolactone (group B), and they completed 6 months of treatment. Five patients (three in group A and two in group B) dropped out because of noncompliance to the treatment (three patients after 3 months because of desire of pregnancy and two after 1 month because of change of residence).

In the current study, the age of the studied patients ranged from 20 to 28 years, with mean age of 25.40 ± 2.37 years. Regarding BMI (kg/m2), it ranged from 25 to 38 kg/m2 (overweight and obese women), with a mean of 29.03 ± 3.5 kg/m2. However, hirsutism score ranged from 8 to 21, with mean of 11.6 ± 4.99. FSH and LH of the studied groups before treatment ranged from 1 to 10 and 3.3–30, with mean of 5.37 ± 2.14 and 15.7 ± 5.9, respectively. Free testosterone and DHEAS for them ranged from 20 to 110 and 1.4–8, with mean of 79.9 ± 17.4 and 2.46 ± 1.07, respectively. Regarding fasting glucose and insulin, it ranged from 75–123 and 10–43 with a mean of 97.3 ± 12.7 and 22.3 ± 8.8, respectively, whereas HOMA-IR ranged from 1.1 to 9, with mean of 4.6 ± 2.1 [Table 1].
Table 1: Age, BMI, hirsutism score, and laboratory investigations of the studied group before treatment

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Additionally, the mean hirsutism score and BMI (kg/m2) were 10.8 ± 3.9 and 26.8 ± 2.2 kg/m2, respectively, before treatment, which decreased significantly to 7.6 ± 2.4 and 22.10 ± 1.92 kg/m2, respectively, after 6 months of treatment. The mean FSH and LH (mIU/ml) were 3.5 ± 2.3 and 13.3 ± 6.3 mIU/ml, respectively, before treatment, which decreased significantly to 5.4 ± 1.6 and 7.8 ± 2.4 mIU/ml, respectively, after 6 months of treatment. Moreover, mean free testosterone and DHEAS (μmol/l) were 7.85 ± 3.76 and 2.5 ± 0.70 μmol/l, respectively, before treatment, which decreased significantly to 4.73 ± 1.96 and 1.81 ± 0.54 μmol/l, respectively, after 6 months of treatment. Moreover, mean fasting glucose, fasting insulin (mU/ml), and HOMA-IR were 93.5 ± 13.1, 22.08 ± 11.8, and 3.8 ± 1.7 mU/ml, respectively, before treatment, which decreased significantly to 84.6 ± 4.6, 19.7 ± 2.6, and 2.42 ± 0.91 mU/ml, respectively, after 6 months of treatment [Table 2].
Table 2: Comparison of clinical data and laboratory investigations in women who received metformin + hypocaloric diet before treatment and 6 months after treatment

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Furthermore, mean BMI (kg/m2) and hirsutism score were 31.1 ± 3.3 and 12.4 ± 5.8 kg/m2, respectively, before treatment, which decreased to 26.7 ± 3.1 and 7.3 ± 2.2 kg/m2, respectively, after 6 months of treatment among women who receive metformin + spironolactone + hypocaloric diet before treatment. Moreover, mean FSH and LH (mIU/ml) were 3.1 ± 1.8 and 18.06 ± 4.4 mIU/ml, respectively, before treatment, which decreased significantly to 5.2 ± 1.8 and 8.2 ± 1.6 mIU/ml, respectively, after 6 months of treatment. In addition, mean free testosterone and DHEAS (μmol/l) were 9.62 ± 4.27 and 2.4 ± 1.3 μmol/l, respectively, before treatment, which decreased significantly to 3.11 ± 0.67 and 1.73 ± 0.66 μmol/l, respectively, after 6 months of treatment. Mean fasting glucose, fasting insulin (mU/ml), and HOMA-IR were 101.1 ± 11.4, 22.6 ± 5.7, and 5.3 ± 2.2 mU/ml, respectively, before treatment, which decreased significantly to 83.7 ± 16.5, 16.8 ± 5.5, and 1.8 ± 0.60 mU/ml, respectively, after 6 months of treatment [Table 3].
Table 3: Comparison of clinical data and laboratory investigation women who receive metformin + spironolactone + hypocaloric diet before treatment and 6 months after treatment

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Hirsutism score was significantly decreased in group B (6.3 ± 2.2) more than group A (7.6 ± 2.4) 6 months following treatment. On the contrary, there was no statistically significant difference (P > 0.05) between the studied groups regarding their BMI (kg/m2) after 6 months of treatment. Moreover, free testosterone was decreased in group B (58.2 ± 9.1 kg/m2) more than group A (73.6 ± 12.9 kg/m2). However, there was no statistically significant difference (P > 0.05) between the studied groups regarding FSH, LH, DHEAS, fasting glucose, fasting insulin, and HOMA-IR after 6 months of treatment [Table 4].
Table 4: Comparison between studied groups regarding clinical data and laboratory investigation in women after 6 months of treatment

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  Discussion Top


PCOS is the most common form of the WHO type II anovulatory infertility and is usually associated with hyperandrogenemia. It is also the most common endocrine abnormality in reproductive-age women. With the introduction of the current Rotterdam diagnostic criteria, the prevalence of PCOS has been shown to be higher (11.9 ± 2.4%) than that previously determined by the National Institute of Health (10.2 ± 2.2%) and the Androgen Excess Society (8.7 ± 2.0%)[9]. As insulin resistance and hyperandrogenemia are among the main interacting causes, as well as overproduction of LH and androgenic hormones, in PCOS, a combination of insulin sensitizers and antiandrogens may have complementary effects in the treatment of PCOS. It has been shown that metformin improves insulin resistance, increases the number of cycles in patients with PCOS, and may improve hirsutism in some patients[10]. In this prospective, randomized study, we evaluated the efficacy of a pharmacological treatment with metformin as compared with metformin plus low-dose spironolactone in overweight/obese patients with PCOS. Our study revealed that there was a statistically significant difference (P ≤ 0.05) among women who received metformin (1.7 g/d) before treatment and 6 months after treatment regarding their hirsutism score and serum free testosterone levels. This finding was found in agreement with that of Ganie et al.[6] who found that administration of metformin (1 g/d) to women with PCOS decreased their hirsutism score and serum testosterone levels at 3 and 6 months of therapy. Moreover, we have demonstrated a significant effect on weight and BMI after 6 months of treatment in both groups. These results were similar to those of Mazza et al.[3]. On the contrary, these findings were at variance with some authors[6], who demonstrated no significant benefit on BMI of patients in both treatment groups. In the current study, it was found that there was a statistically significant difference (P ≤ 0.05) among women who received metformin plus spironolactone before treatment and 6 months after treatment regarding their hirsutism score and serum free testosterone. The magnitude of fall was significantly higher in the combination group than in the metformin group at 6 months of follow-up. These results are in agreement with the finding of Mazza et al.[3] who showed that hirsutism score significantly decreased in both groups, although more markedly in the combination group (−27%) than in the metformin group (−13%). Noteworthy, insulin sensitivity calculated by HOMA-IR was improved after 6 months in both treatment groups, but the benefit was superior in the combination group. This interesting observation of improved insulin sensitivity with spironolactone, although to a lesser extent than metformin, was found similar to what has been confirmed before by Ganie et al.[6]. On the contrary, some authors demonstrated no effect on insulin sensitivity[11]. In addition, previous studies combining metformin with other antiandrogens failed to demonstrate this important finding[12],[13]. As a routine practice in our clinics, the diet and exercise counseling was administered to all the patients before randomization and was reinforced at each visit throughout the study period. Because there was no placebo arm in the present study, it is possible that some of the clinical benefits were owing to lifestyle modification. Because the lifestyle modification was similar in both groups, its effects could be similar. In our study, we used a very low-dose spironolactone (25 mg/day) to maximize drug safety and tolerability. Previous studies have used doses of 100 mg/day, which were associated with hypotension, tachycardia, and menstrual spotting[14]. No such adverse effects were observed in our patients.


  Conclusion Top


To conclude, the present study confirms the beneficial effects of metformin in patients with PCOS. It also proves that the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism in patients with PCOS present with hyperandrogenic conditions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Diri H, Karaburgu S, Acmaz B, Unluhizarci K, Tanriverdi F, Karaca Z, et al. Comparison of spironolactone and spironolactone plus metformin in the treatment of polycystic ovary syndrome. Gynecol Endocrinol 2015; 32 :1–4.  Back to cited text no. 7
    
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Conway G, Dewailly D, Diamanti-Kandarakis E. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 2014; 171 :1–29.  Back to cited text no. 8
    
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Gambineri A, Patton L, Vaccina A. Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab 2006; 91 :3970–3980.  Back to cited text no. 12
    
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Ibáñez L, Valls C, Ferrer A, Ong K, Dunger DB, De Zegher F. Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. J Clin Endocrinol Metab 2002; 87 :2870–2874.  Back to cited text no. 13
    
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Zulian E, Sartorato P, Benedini S. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity, and lipid profile. J Endocrinol Invest 2005; 28 :49–53.  Back to cited text no. 14
    



 
 
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