Polycystic ovarian syndrome-current pharmacotherapy and clinical implications.

Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism. The treatment in PCOS is mainly symptomatic and involves lifestyle interventions and medications such as Metformin, Oral contraceptives and Antiandrogens. However, the management of PCOS is challenging and current interventions are not able to deal with outcomes of this syndrome. This review encompasses latest pharmacotherapeutic and non-pharmacotherapeutic interventions currently in use to tackle various symptomatic contentions in PCOS. Our focus has been mainly on novel therapeutic modalities for treatment/management of PCOS, like use of newer insulin sensitizers viz., Inositols, Glucagon-like peptide-1(GLP-1) agonists, Dipeptidyl pepdidase-4 (DPP-4) inhibitors, and sodium-glucose transport protein 2 (SGLT2) inhibitors. Also, evidence suggesting the use of vitamin D, statins, and Letrozole as emerging therapies in PCOS have been summarized in this review. Additionally, novel cosmetic techniques like electrolysis, laser and use of topically applied eflornithine to tackle the most distressing feature of facial hirsutism associated with PCOS, non-pharmacological therapy like acupuncture and the role of herbal medicine in PCOS management have also been discussed.

Use of Bao Gui capsule in treatment of a polycystic ovary syndrome rat model.

The present study was designed to elucidate the underlying mechanisms of Bao Gui capsule (BGC) against hyperandrogenism, insulin resistance and leptin resistance of PCOS. Letrozole was used to induce a PCOS model in rats, which were then randomly divided into four groups (n=9): Control, Model, high­dose BGC (BGC­H) and low­dose BGC (BGC­L) group. Serum levels of follicle­stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), insulin, leptin, and interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α (TNF­α) in the hypothalamus were determined by ELISA. Protein levels of cytochrome P450c17α and cytochrome P450 aromatase (P450arom) in ovaries were determined by immunohistochemistry and western blot analysis. Additionally, the expression of GLUT4 in uterus and muscle tissue, and NF­κB, IKKß and SOCS3 mRNA levels in the hypothalamus were evaluated. BGC significantly reduced body weight gain and decreased serum levels of LH/FSH, T, log T/E2, insulin and leptin compared with the PCOS model rats. Furthermore, BGC markedly reduced the expression of P450c17α and significantly increased the expression of P450arom in ovaries, and increased the expression of GLUT4 in uterus and muscle tissues. BGC also effectively reduced the level of IL­6 and TNF­α, and the expression of IKKß, NF­κB and SOCS3 in the hypothalamus of PCOS model rats. These results suggest that BGC may effectively improve hyperandrogenism, insulin resistance, endometrial receptivity and the low­grade chronic inflammation in the hypothalamus.

Female Pattern Hair Loss and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee.

OBJECTIVE: To determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female pattern hair loss (FPHL), a common form of hair loss in women that is characterized by the reduction of hair density in the central area of the scalp, whereas the frontal hairline is generally well conserved. PARTICIPANTS: An expert task force appointed by the Androgen Excess and PCOS Society, which included specialists from dermatology, endocrinology, and reproductive endocrinology. DESIGN: Levels of evidence were assessed and graded from A to D. Peer-reviewed studies evaluating FPHL published through December 2017 were reviewed. Criteria for inclusion/exclusion of the published papers were agreed on by at least two reviewers in each area and arbitrated by a third when necessary. CONCLUSIONS: (i) The term "female pattern hair loss" should be used, avoiding the previous terms of alopecia or androgenetic alopecia. (ii) The two typical patterns of hair loss in FPHL are centrifugal expansion in the mid scalp, and a frontal accentuation or Christmas tree pattern. (iii) Isolated FPHL should not be considered a sign of hyperandrogenism when androgen levels are normal. (iv) The assessment of patients with FPHL is primarily clinical. (v) In all patients with FPHL, assessment of a possible androgen excess is mandatory. Measurement of vitamin D, iron, zinc, thyroid hormones, and prolactin are optional but recommended. (vi) Treatment of FPHL should start with minoxidil (5%), adding 5α-reductase inhibitors or antiandrogens when there is severe hair loss or hyperandrogenism.

Shaoyao-Gancao Decoction alleviated hyperandrogenism in a letrozole-induced rat model of polycystic ovary syndrome by inhibition of NF-κB activation.

Shaoyao-Gancao Decoction (SGD) has been widely used for the treatment of gynopathy. The present study aimed to evaluate the therapeutic effect and potential mechanism of SGD on hyperandrogenism in polycystic ovary syndrome (PCOS) rats. In the present work, SGD was orally administrated to the PCOS rats at the dose of 12.5, 25, and 50 g/kg/d for 14 consecutive days. UPLC-MS/MS was performed to identify the main chemical components of SGD. Body weight, ovarian weight, cystic dilating follicles, and serum levels of steroid hormones were tested to evaluate the therapeutic effect of SGD. In order to further clarify the underlying mechanism, we also measured mRNA and the protein levels of NF-κB, NF-κB p65, P-NF-κB p65, and IκB by RT-qPCR and Western blotting techniques. Our results showed that SGD treatment significantly alleviated hyperandrogenism in PCOS rats as evidenced by reduced serum levels of T and increased E2 and FSH levels. In addition, SGD effectively reduced the phosphorylation of NF-κB p65 and increased the expression of IκB. Results of the present study demonstrated that SGD could ameliorate hyperandrogenism in PCOS rats, and the potential mechanism may relate to the NF-κB pathway.

The effect of alfacalcidiol and metformin on phenotype manifestations in women with polycystic ovary syndrome - a preliminary study.

Aim of this study was to evaluate the effect of vitamin D supplementation in obese, insulin resistant and vitamin D deficient PCOS women on biochemical and clinical hyperandrogenism and menstrual irregularity in comparison to effect of metformin or combined metformin plus vitamin D therapy. Thirty nine PCOS women were randomized into three groups and treated with alfacalcidiol (Group 1), combined alfacalcidiol and metformin therapy (Group 2) and metformin (Group 3) for 6 months. Serum TST, fTST, DHEAS, LH and LH/FSH were measured before and after six months of treatment. Menstrual cycle regularity, hirsutism, acne and pregnancy rate were assessed at the same time. There was a significant decrease in TST levels in the Group 2 and slight but not significant decrease in the Group 3. No significant changes in other parameters (fTST, DHEAS, LH, LH/FSH) have been found after 6 months therapy in all three groups. An improvement of menstrual cycle was detected in 78 % of patients in Group 1 (p<0.04), 80 % in the Group 2 (p<0.03) and in 90 % in the Group 3 (p<0.002), respectively. There was no significant improvement of acne and hirsutism in all three groups (all p not significant). Pregnancy rate was higher in the Group 3 as compared with Groups 1 and 2 (67 % vs. 0 % and 25 %, respectively), however without statistical significance. Vitamin D administration has no significant effect on androgen levels and clinical features of hyperandrogenism in obese vitamin D deficient PCOS women. However, it can potentiate effect of metformin on testosterone levels and LH/FSH ratio but not on clinical hyperandrogenism and pregnancy rate.

Androgen excess: Investigations and management.

Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response.

Effect of oral administration of low-dose follicle stimulating hormone on hyperandrogenized mice as a model of polycystic ovary syndrome.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a widespread reproductive disorder characterized by a disruption of follicular growth and anovulatory infertility. In women with PCOS, follicular growth and ovulation can be induced by subcutaneous injections of low doses of follicle stimulating hormone (FSH). The aim of this study was to determine the effect of oral administration of recombinant human FSH (rhFSH) on follicle development in a PCOS murine model. Moreover, since it is unlikely that intact rhFSH is present into the circulation after oral administration, the biological activity of a peptide fragment, derived from the predicted enzymatic cleavage sites with the FSH molecule, was investigated in vitro on cumulus-enclosed oocytes (COCs). METHODS: Female peripubertal mice were injected with dehydroepiandrosterone (DHEA) diluted in sesame oil for 20 consecutive days and orally treated with a saline solution of rhFSH. A control group received only sesame oil and saline solution. At the end of treatments, blood was analyzed for hormone concentrations and ovaries were processed for morphological analysis. The presumptive bioactive peptide was added during in vitro maturation of bovine COCs and the effects on cumulus expansion and on maturation rate were evaluated. RESULTS: DHEA treatment increased serum levels of testosterone, estradiol and progesterone as well as the percentage of cystic follicles. Orally administered rhFSH restored estradiol level and reduced the percentage of cystic follicles. Despite these results indicating a reduction of the severity of PCOS in the mouse model, the presumptive bioactive peptide did not mimic the effect of rhFSH and failed to induce bovine cumulus expansion and oocyte maturation in vitro. CONCLUSIONS: Although further studies are needed, the present data supports the concept that orally administrated FSH could attenuate some of the characteristic of PCOS in the mouse model.

Roles for the sympathetic nervous system, renal nerves, and CNS melanocortin-4 receptor in the elevated blood pressure in hyperandrogenemic female rats.

Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS.

The effect of atorvastatin and atorvastatin-ezetimibe combination therapy on androgen production in hyperandrogenic women with elevated cholesterol levels.

Statins decreased serum androgen levels in hyperandrogenemic women with polycystic ovary syndrome. No previous study has investigated whether this effect is dose-dependent and observed in patients simultaneously treated with other hypolipidemic agents. The study included 23 premenopausal women with elevated total testosterone levels coexisting with hypercholesterolemia, unsuccessfully treated for at least 6 months with atorvastatin (20 mg daily). These patients were then treated with either an increased dose of atorvastatin (40 mg daily, n=11) or atorvastatin (20 mg daily) plus ezetimibe (10 mg daily) (n=12). Plasma lipids, glucose homeostasis markers and serum levels of androgens, sex hormone-binding globulin and gonadotropins were assessed at baseline and after 3 months of treatment. Although both treatments decreased plasma levels of total and LDL-cholesterol levels, only high-dose atorvastatin reduced serum levels of total testosterone, free testosterone and androstendione. The effect of high-dose atorvastatin on serum androgen levels did not differ between insulin-resistant and insulin-sensitive subjects. The obtained results suggest that atorvastatin reduces serum androgen levels in a dose-dependent manner and that its administration in a higher dose is associated with a more pronounced effect on serum androgens than combination therapy with low-dose atorvastatin and ezetimibe.

Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent, complex endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility. Evidence based medical management emphasises a multidisciplinary approach for PCOS, as conventional pharmaceutical treatment addresses single symptoms, may be contra-indicated, is often associated with side effects and not effective in some cases. In addition women with PCOS have expressed a strong desire for alternative treatments. This review examines the reproductive endocrine effects in PCOS for an alternative treatment, herbal medicine. The aim of this review was to identify consistent evidence from both pre-clinical and clinical research, to add to the evidence base for herbal medicine in PCOS (and associated oligo/amenorrhoea and hyperandrogenism) and to inform herbal selection in the provision clinical care for these common conditions. METHODS: We undertook two searches of the scientific literature. The first search sought pre-clinical studies which explained the reproductive endocrine effects of whole herbal extracts in oligo/amenorrhoea, hyperandrogenism and PCOS. Herbal medicines from the first search informed key words for the second search. The second search sought clinical studies, which corroborated laboratory findings. Subjects included women with PCOS, menstrual irregularities and hyperandrogenism. RESULTS: A total of 33 studies were included in this review. Eighteen pre-clinical studies reported mechanisms of effect and fifteen clinical studies corroborated pre-clinical findings, including eight randomised controlled trials, and 762 women with menstrual irregularities, hyperandrogenism and/or PCOS. Interventions included herbal extracts of Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia. Endocrine outcomes included reduced luteinising hormone (LH), prolactin, fasting insulin and testosterone. There was evidence for the regulation of ovulation, improved metabolic hormone profile and improved fertility outcomes in PCOS. There was evidence for an equivalent effect of two herbal medicines and the pharmaceutical agents bromocriptine (and Vitex agnus-castus) and clomiphene citrate (and Cimicifuga racemosa). There was less robust evidence for the complementary combination of spirinolactone and Glycyrrhiza spp. for hyperandrogenism. CONCLUSIONS: Preclinical and clinical studies provide evidence that six herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism and PCOS. However the quantity of pre-clinical data was limited, and the quality of clinical evidence was variable. Further pre-clinical studies are needed to explain the effects of herbal medicines not included in this review with current clinical evidence but an absence of pre-clinical data.

Therapeutic effects of calcium & vitamin D supplementation in women with PCOS.

OBJECTIVE: To evaluate the efficacy of calcium & vitamin D supplementation in infertile women suffering from polycystic ovary syndrome (PCOS), and to assess levels of 25-hydroxy vitamin D in these patients. METHODS: In a case control study, 100 infertile PCOS women based on a randomly divided into two groups. Group I (n = 50) were treated with metformin 1500 mg/day, and group II (n = 50) treated with metformin 1500 mg/day plus Calcium 1000 mg/day and Vitamin D 100000 IU/month for 6 months. Patients were followed by transvaginal sonography at first, 3 and 6 months later for evaluating dominant follicle. BMI, menstrual regularity, follicle diameter, pregnancy, serum 25-OH-vitamin D level were matured and compared in two groups. RESULTS: BMI decreased almost significantly (25.49 ± 1.88 vs 26.28 ± 2.15, p: 0.054) in group II. A better improvement was gained in regulating menstrual abnormalities (70% vs 58%, p: 0.211), follicle maturation (28% vs 22%, p: 0.698), and infertility (18% vs 12%, p: 0.401) in group II compared with group I, but these results were not statistically significant. Eighty three percent of all the PCOS patients showed vitamin D deficiency while 35% were severely deficient. The serum 25-OH-vitamin D mean levels were 13.38 ± 6.48 ng/ml. Vitamin D deficiency was recompensed in 74% of the PCOS patients who had taken calcium & vitamin D supplementation. There was no correlation between BMI and 25-OH-VD before and after the treatment (p ≥ 0.01). CONCLUSION: This study showed the positive effects of calcium & vitamin D supplementation on weight loss, follicle maturation, menstrual regularity, and improvement of hyperandrogenism, in infertile women with PCOS.

[Treatment of hyperandrogenism and hyperinsulinemia in PCOS patients with essential amino acids. A pilot clinical study]. / Trattamento dell'perandrogenismo e dell'perinsulinemia con aminoacidi essenziali in pazienti affette da sindrome dell'ovaio policistico. Uno studio pilota.

AIM: Women with polycystic ovary syndrome (PCOS) report frequently hyperinsulinemia. The aim of this study was to evaluate the effects of 16-weeks therapy with essential amino acids supplements on metabolic and clinical indices in PCOS. METHODS: For this study ten women with PCOS and fasting hyperinsulinemia were enrolled. The study comprised 16 weeks of therapy with oral essential amino acids (Aminopril, NAMED, Milan, Italy) administered 4 g twice per day. Body mass index, hirsutism score, serum levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, lipoprotein(a), serum adrenal and ovarian androgens, fasting glucose and insulin concentrations, T, DHEAS, gonadotropins, and sex hormone-binding globulin (SHBG), were assessed before and after treatment with essential amino acids. RESULTS: A significant decrease in fasting insulin, total T, luteneizing hormone and follicle-stimulating hormone was reported after amino acids therapy and increase in SHBG, leading to a decrease in the free T index. In addition, a significant reduction in hirsutism score was reported. No significant decrease in mean body mass index and in lipid pattern was reported. CONCLUSION: A decline of insulin after treatment with essential amino acids was observed in women with PCOS as well as total and bioavailable T, leading to significant improvement of clinical symptoms of hyperandrogenism.

[Effects of modified longdan xiegan decoction on hyperandrogenism in patients with polycystic ovary syndrome of stagnant fire in Gan channel type].

OBJECTIVE: To observe the therapeutic effect of modified Longdan Xiegan Decoction (LXD) on hyperandrogenism in patients with polycystic ovary syndrome (POS) of stagnant fire in Gan channel type. METHODS: Forty-eight patients were divided into two groups: the LXD group (25 cases) treated with LXI) for 3 months, and the Diane-35 group (23 cases) with Diane-35. Condition of menstruation, acne, hairiness were observed, basal body temperature (BBT) was measured, and the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), free testosterone (FT), and androstenedione (A) were detected before and after 3 months' treatment. Meanwhile, adverse reaction was observed. RESULTS: After treatment, the condition of menstrual disorder, acne and single-phase BBT were improved significantly, and serum levels of LH, LH/FSH, FT and A decreased in both groups (P < 0.05), showed insignificant difference between them (P > 0.05). The PRL level dropped in the LXD group (P < 0.05), which significantly lower than that in the Diane-35 group (P < 0.05). There were 3 cases with adverse reaction of irregular colporrhagia and 5 cases with nausea and vomiting in the Diane-35 group, while no adverse reaction in the LXD group occurred. CONCLUSION: Modified LXD could significantly improve the condition in hyperandrogenism patients with POS of stagnant fire in Gan channel type.

[Study on treatment of hyperandrogenism and hyperinsulinism in polycystic ovary syndrome with Chinese herbal formula "tiangui fang"].

OBJECTIVE: To observe the efficacy of Chinese herbal formula "Tiangui Fang" (TGF) in hyperandrogenism and hyperinsulinism patients of polycystic ovarian syndrome (PCOS), and compare with western medicine metformin. METHODS: Twenty-two anti-clomiphen citrite patients were divided into two treatment groups: "Tiangui Fang" (n = 10) and metformin (n = 12) for three months. Insulin response during oral glucose tolerance test and serum level of LH, FSH, testosterone (T), estradiol (E2) and waist to hip ratio (WHR), body mass index (BMI) were measured before and after treatment. RESULTS: After treatment for three months with metformin or TGF, fasting and the integrated insulin response to the glucose load decreased. Treated by metformin 4 out of 8 patients had restoration of menstrual cyclicity and 2 of them had double phase bases body temperature (BBT). This was accompanied by lowering in serum logT/E2 but had no significant difference, the BMI, WHR and serum E2, LH:FSH ratio were not changed. Treated by TGF for three months, 6 out of 8 patients had restoration of menstrual cyclicity and double phase BBT. This was accompanied by significant lowering in serum T, logT/E2 and BMI (P < 0.05), serum LH:FSH ratio were not changed. CONCLUSION: Both metformin and TGF can reduce the high concentration of insulin in PCOS patients and induce ovulation, the herbal formula has a better efficacy.

[Ovulation induction with adjuvant antiandrogen treatment in Stein-Leventhal syndrome]. / Az ovulatio inductio kiegészítése adjuváns antiandrogén kezeléssel Stein-Leventhal-syndromában.

Ovulation induction with adjuvant antiandrogen treatment was carried out in 50 cycles of 24 hyperandrogenic anovulatory patients. Besides the clomiphene and gonadotrophin (pure FSH) administration on the bases of antiandrogenic effects of the drugs three treatment groups (dexamethasone, sprinolactone and cyproterone acetate) were established. In 40 cases of 50 cycles ovulation were detected and 11 pregnancies occurred. The authors achieved the highest ovulation and pregnancy rate in the group treated with cyproterone acetate. The highest progesterone and the lowest testosterone levels were measured in the same group. According to our investigations adjuvant antiandrogen treatment with cyproterone acetate advisable in the cases of hyperandrongenic conditions.

[Clinical observation on treatment of hyperinsulinemia and hyperandrogenism anovulatory patient with replenishing kidney-yin drugs].

In order to investigate the effect of Chinese herbal medicine for replenishing Kidney-Yin in treating hyperinsulinemia and hyperandrogenism anovulatory syndrome, 35 patients were treated with replenishing Kidney-Yin drugs for 3 months, basic body temperature, ultrasonic examination and blood levels of sex hormones were taken for monitoring the ovulation, and changes of serum insulin, blood sugar as well as oral glucose tolerence test were observed before and after treatment. Thirty-five patients showed high serum insulin and testosterone levels but normal dehydroepiandrosterone (DHEA) level. Twenty-nine percent of their luteinizing hormone/folliclestimulating hormone (LH/FSH) ratio were in normal range. Twenty four cases completed the regular treatment and 20 of them showed ovulation in the 43 menstrual cycles (59.7%). Seven of 17 (41.2%) infertile cases become pregnant within 6 months. After 3 months of treatment, blood sugar and insulin level significantly decreased but the latter was still slightly higher than normal level. Serum testosterone level decreased significantly and reached normal. Results suggested that replenishing Kidney-Yin Drugs could provide a good microcircumstance for ovarian follicular growth, and resulted in ovulation and pregnancy. The mechanism is remained to be further explored.