A combination of plant extracts and amino acids, designated as PACR, consisting of 20mg French maritime pine bark extract (Pycnogenol®, Horphag Research Ltd.), 200mg of L-arginine and 200mg L-citrulline 50mg rose hip extract (ROSVITA®, Horphag Research Ltd.) per tablet (Lady Prelox®, Horphag Research Ltd.), has been tested in 3 clinical trials. Aim of the studies was to evaluate the effects of PACR on relief of symptoms of female sexual disorder (FSD) in pre-menopausal, peri-menopausal and post-menopausal women, with the aim of the Female Sexual Function Index (FSFI) self-reporting questionnaire.

The results of all studies indicated a significant improvement of sexual functions by PACR. No adverse effects were observed.

Oxidative stress was significantly reduced in two studies.

The proposed non-hormonal mechanism of action is based on NO-mediated vasculogenic and neurogenic effects.

PACR (Lady Prelox®) seems to provide a safe, natural supplement for relief from female sexual disorder for women of all ages.

Rohdewald P (2018) Non-Hormonal Improvement of FSD by a Combination of Plant Extracts and Amino acids (Lady Prelox®). JSM Sexual Med 3(1): 1013.

• FSD; PACR; Pycnogenol®; Lady Prelox®; NO-synthase

FSD: Female Sexual Dysfunction; FSAD: Female Sexual Arousal Disorder; HSDD: Hypoactive Sexual Desire Disorder; FOD: Female Orgasmic Disorder; FSFI: Female Sexual Function Index; PACR: Pine Bark Extract, L-Arginine, L-Citrulline, Rose Hip Extract

Sexual dysfunction is defined by the WHO as follows: “The various ways in which an individual is unable to participate in a sexual relationship as she or he would wish” [1].

Female sexual dysfunction (FSD) especially was defined as “disorder of libido, arousal, orgasm and sexual pain that lead to personal distress and interpersonal difficulties” [1]. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [2] and the International Consultation of Sexual Medicine Committee on Definitions [3] introduced more specific classifications of the diverse female sexual dysfunctions as Female Sexual Arousal Disorder (FSAD), Female Orgasmic Disorder (FOD) and Hypoactive Sexual Desire Disorder (HSDD).

The problem of FSD has been neglected by the scientific community for a long period of time. It was the successful treatment of male sexual dysfunction with sildenafil, which generated the interest for sexual female problems.

World-wide epidemiological research revealed that FSD affects 41% of premenopausal women [4]. Remarkably, this percentage has been found with little variation in Europe, Asia, USA, South America and Australia as follows from the metaanalysis of 95 studies [4].

As FSD increases with age, starting with the onset of menopause, the overall prevalence of FSD for women will exceed the 41% rate, so it is a widespread, but underestimated health problem. According to the meta-analysis [4], FSD was associated with lubrication problems at a rate of 20.6% and 28.2% of the women reported HSSD symptoms. Therefore, main target for therapy is the improvement of women’s desire and arousal.

The evaluation of FSD was done in the cited clinical studies by the self-reporting questionnaire based on the Female Sexual Function Index, FSFI ,which was re-validated in 2016 [5-7].

Etiology of FSD comprises of a complex network of psychological and biochemical reactions. Women seeking for assistance from their physicians for their sexual problems are examined first of all for psychological and physiological obstructions hindering a healthy sexual relationship. The following pharmacotherapy will be directed individually to the various aspects as HSDD, FSAD, FOD and dyspareunia.

The International Consultation on Sexual Medicine Report [8] lists the types of pharmacologic interventions for HSDD and FSAD.

Pharmacotherapy of FSAD

Hormone replacement therapy: Endocrine hormones exert a strong influence on FSAD. Declining production of hormones in menopause or androgen hormone deficiency may lead to FSAD.

Fading production of estradiol, causing alterations in vaginal structure and acidity, results in sexual discomfort [7]. Consequently, Hormone Replacement Therapy (HRT) is indicated. However, many women are reluctant to HRT because of serious unwanted effects. The topical application of sex hormones avoids the systemic problems of HRT and improves FSAD effectively [9- 11].

Low levels of testosterone have a negative impact on desire, arousal and orgasm [12]. Androgen deficiency is treated with testosterone patches and a transdermal cream, thereby increasing local testosterone levels, resulting in enhanced sexual arousal [13-17].

As a non-prescriptional supplement, Dehydroepieandrosterone (DHEA) is frequently recommended as its metabolisation delivers precursors to androgens and estrogens. It increases testosterone levels more than estrogen concentrations [16]. Use of DHEA is limited though by unwanted androgenic effects at high doses. However, DHEA applied intravaginally was effective in improving dyspareunia and libido without systemic androgenic effects [18-19].

Tibolone, a synthetic hormone, is metabolized to androgens as well as to estrogens. It improves FSAD and improves vaginal lubrication [20-25].

As there are frequently concerns about hormonal treatment, a variety of approaches aim at vasculogenic and neurogenic causes of FSD.

The neurogenic approach: Flibanserin inhibits serotonin secretion, which depresses sexual activity, and stimulates liberation of dopamine and noradrenaline [26-27]. Clinical trials with large numbers of women demonstrated statistically significant, but modest improvements in sexual desire [28]. Significant side effects as somnolence, dizziness, nausea and fatigue were observed in all clinical studies listed in the review of Lodise [29].

Further neurogenic pharmacological treatments with Bupropion, Trazodone, Melanocortin and Apomorphin have been reviewed by Kingsberg et al [8].

The vasculogenic approach: In analogy to treatment of male sexual disorder, the erectile dysfunction, numerous attempts were directed to increase the blood flow to female sexual organs.

Sildenafil relaxes smooth muscles by prolonging the stability of GMP, thereby increasing blood flow in clitoris and vagina. However, results of clinical studies were not absolutely convincing. Arousal and orgasm were improved in two studies, but no beneficial effects were reported in a third, larger study [30-32].

Following topical application, prostaglandin PGE1 [33] or a combination of vasodilators causes smooth muscle relaxation and improves arousal and orgasm [34].

The NO donor L-arginine, contained in ArginMax®, yielded positive results in treatment of FSD in clinical trials [35-36].

The vascular approach to stimulate arousal by enhancement of blood flow is not fully satisfying in treatment of FSD as the neurogenic component, desire, was not convincingly improved. A successful therapy of FSD has to consider the neurogenic and the vasculogenic approach simultaneously.

Combination of the neurogenic and vasculogenic approach: The branded extract from bark of the French maritime pine, Pycnogenol® (Horphag Research Ltd.), exerts vasculogenic effects by stimulating the NO producing endothelial nitric oxide synthase (e-NOS). Vasorelaxation and increased blood flow following oral intake of Pycnogenol® has been demonstrated in young volunteers [37].

Furthermore, neurogenic effects of the pine bark extract has been observed in clinical studies directed to climacteric disorders. In a randomized, double-blind, placebo-controlled study with 155 perimenopausal women (mean age 46), scores for sexual behavior from the Women Health Questionnaire [38] improved significantly (p<0.001) over a period of 6 months vs placebo after intake of 200mg/day Pycnogenol® [39]. Furthermore, libido improved significantly (p<0.05) according to the Menopause Symptoms Questionnaire after 100mg/day Pycnogenol® for 8 weeks in 38 women (mean age 46 years), whereas no changes were noted in the control group of 32 women with the same age [40].

Based on these improvements of sex life of menopausal women, a proprietary combination of 20mg Pycnogenol® with 200mg of the NO donors L-arginine and L-citrulline was developed to improve women’s sex life and sexual function. 50mg rose hip extract was added to the combination to counteract oxidative stress. This combination, designated as PACR, tradename Lady Prelox® (Horphag Research Ltd), was successfully tested in 3 clinical studies. The evaluation of the efficacy of PACR was performed with the aid of the FSFI questionnaire, translated into Italian and Bulgarian language.

A study evaluating sexual function with the FSFI questionnaire with 100 premenopausal women, age between 37-45 years, was performed over a period of 8 weeks at the University of Siena, Italy [41]. All participants were instructed to follow a strict healthy lifestyle with diet, exercises and regular sleep. Half of the women received additionally 4 tablets Lady Prelox® daily. The total FSFI scores of the PACR group were significantly (p<0.05) higher compared to control. Scores under PACR increased from 15 at start to 28.5 and to 34 after 8 weeks. In the control group, the increase of FSFI was limited: From 15 at start to 23 at 4 and 8 weeks. Oxidative stress, expressed as plasma free radicals, decreased significantly with PACR intake. Reduction of oxidative stress in controls did not reach levels of significance.

In a randomized, double-blind, placebo-controlled study with 80 premenopausal women (age 40-50 years), the increase of female sexual function was evaluated at the University of Sofia by the FSFI, following oral intake of 4 tablets Lady Prelox® [42]. Sexual function scores increased by 60% after 1 month and ending with a total score of 73% after 2 months. According to Rosen et al., [5] the value of 26.5 delineates functional from dysfunctional sexual function, so that the treatment for 2 months with Lady Prelox® normalized the sexual function of the participants.

The elevation of scores for the diverse domains as desire, arousal, lubrication, orgasm, satisfaction and pain reduction varied in a narrow range between 71 and 76%.

Further evaluation of women’s health with the Women’s Health Questionnaire [38] revealed an increase of scores for sexual behavior by 71% under PACR, in agreement with the results obtained by the FSFI questionnaire.

Total plasma antioxidant capacity increased significantly (p<0.05) versus placebo after 4 and 8 weeks of intake of PACR thus indicating a reduction of oxidative stress

In a single-blinded, placebo-controlled study at the University of Siena with 80 postmenopausal women, age 47-53 years, the PACR group received 4 tablets Lady Prelox® daily [43]. The scores from the nine item FSFI questionnaire increased in the PACR group from 44 to 70.9 after 4 weeks with a further small increase to 71.7 after 8 weeks. The scores for orgasm, satisfaction and diminished pain were almost doubled from 6 to 11 after 4 weeks.

No adverse effects exceeding climacteric symptoms were reported or observed in all 3 studies.

The positive effect of PACR on FSD is based mainly on the activity enhancement of e-NOS [37,44]. The higher activity of e-NOS, coupled with a surplus of NO-donors (L-arginine and L-citrulline), delivers a high quantity of NO following neural stimulation of e-NOS. Result is a long lasting vasodilation in female organs after arousal. The vasculogenic effect of PACR on female sexual orgasm is in perfect agreement with the effect of Prelox®, consisting of Pycnogenol and L-arginine, on erectile dysfunction (ED) in men. Two randomized, double-blind, placebo-controlled, cross-over studies with patients suffering from ED demonstrated a tremendous, significant (p<0.01) improvement of erectile function [45,46].

The positive effects on desire could be related to the general enhancement of cognitive functions by Pycnogenol. The pine bark extract promotes learning and memory in animal experiments as well as in clinical studies [47-48]. The mechanisms for these neurogenic effects could be an improved blood circulation in brain as result of vasodilatation or an increase of neuronal activity by a NO-mediated biochemical reaction.

Pycnogenol does not influence hormonal secretion in women, as plasma concentrations of estradiol, follicle-stimulating hormone or dehydro-epiandrosterone are not significantly changed following intake of Pycnogenol [49,50]. Therefore, the improvement of FSD by PACR does not relate to hormonal effect.

The benefits of PACR result most probably from the combined action of the vasculogenic effects, mediated by NO, and the neurogenic effects.

Although the studies with PACR seem to offer an option for women looking for a non-hormonal, natural alternative to hormone therapy or pharmacotherapy with drugs, more well designed double-blind, placebo-controlled studies are needed to extend the basis of knowledge about PACRs actions and clinical effects. Studies on other non-caucasian populations or on women with defined problems as diabetes, hypertension or depression are needed to enlarge the data base for safety and efficacy.

In conclusion, the clinical studies with Pycnogenol and PACR suggest that PACR offers a safe and non-hormonal option for relieving FSD in pre-menopausal, peri-menopausal and post-menopausal women.

1. Basson R, Berman J, Burnet A, Derogatis L, Ferguson D, Fourcroy J, et al. Report of the international consensus development conference of female sexual dysfunction: definitions and classifications. J Urol. 2000; 163: 888-893.

2. American Psychiatric Association, Diagnostic and statistical manual of mental disorders. 4th ed, text rev. Washington, DC; American Psychiatric Association; 2013.

3. McCabe MP, Sharlip ID, Atalla E, Balon R, Fisher AD, Laumann E et al. Definitions of sexual dysfunctions in women and men: a consensus statement from the Fourth International Consultation on Sexual Medicine 2015. J Sex Med. 2016; 13: 135-143.

4. Mc Cool ME, Zuelke A, TheurichMA, Knuettel H, Ricci C, Apfelbacher C. Prevalence of Female Sexual Dysfunction Among Premenopausal Women: A Systematic Review and Meta-Analysis of Observational Studies. Sex Med Rev. 2016; 4: 197-212.

5. Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, et al . The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000; 26: 191-208.

6. Stephenson KR, Toorabally N, Lyons L, Meston C. Further Validation of the Female Sexual Function Index: Specificity and Associations with Clinical Interview Data. J Sex Marital Ther. 2016; 42: 448-461.

7. Berman JR. Physiology of female sexual function and dysfunction. Int J Impot Res. 2005; 17: 44-51.

8. Kingsberg SA, Althof A, Simon JA, et al. Female Sexual Dysfunction – Medical and Psychological Treatments, Committee 14. J Sex Med. 2017; 14: 1463-1491.

9. Labrie F, Cusan L, Gomez JL, Cote I, Berube R, Belanger P, et al. Effect of one-week treatment with vaginal estrogen preparations on serum estrogen levels in postmenopausal women. Menopause. 2009; 16: 30- 36.

10. Davis SR, Braunstein GD. Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. J Sex Med. 2012; 9: 1134-1148.

11. Fernandes T, Costa-Paiva LH, Pinto-Neto AM. Efficacy of vaginally applied estrogen, testosterone, or polyacrylic acid on sexual function in postmenopausal women: a randomized controlled trial. J Sex Med. 2014; 11: 1262-1270.

12. Davis SR. Androgens and female sexuality. J Gend Specif Med. 2000; 3: 36-40.

13. Braunstein GD, Sundwall DA, Katz M, Shifren JL, Buster JE, Simon JA, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch Intern Med. 2005; 165: 1582-1589.

14. Davis SR, van der Mooren MJ, van Lunsen RH, Lopes P, Ribot C, Rees M, et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause. 2006; 13: 387-396.

15. Hayslett RL, Nykamp D. Sexual Dysfunction in Women. US Pharm. 2015; 40: 46-49.

16. Panjari M, Davis SR. DHEA for postmenopausal women: a review of the evidence. Maturitas. 2010; 66: 172-179.\

17. Tuiten A, Van Honk J, Koppeschaar H, Bernaards C, Thijssen J, Verbaten R. Time course of effects of testosterone administration on sexual arousal in women. Arch Gen Psychiatry. 2000; 57: 149-153.

18. 18. Labrie F, Archer DF, Koltun W, Vachon A, Young D, Frenette L, et al. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause. 2016; 23: 243-256.

19. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, et al. Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause. 2009; 16: 923-931.

20. Nijland EA, Weijmar Schultz WC, Nathorst-Boos J, Helmond FA, Van Lunsen RH, Palacios S, et al. Tibolone and transdermal E2/NETA for the treatment of female sexual dysfunction in naturally menopausal women: results of a randomized active-controlled trial. J Sex Med. 2008; 5: 646-656.

21. Nappi RE, Cucinella L. Advances in pharmacotherapy for treating female sexual dysfunction. Expert Opin Pharmacother. 2015; 16: 875- 887.

22. Biglia N, Maffei S, Lello S, Nappi RE. Tibolone in postmenopausal women: a review based on recent randomized controlled clinical trials. Gynecol Endocrinol. 2010; 26: 804-814.

23. Davis SR. The effects of tibolone on mood and libido. Menopause. 2002; 9: 162-170.

24. Laan E, van Lunsen RH, Everaerd W. The effects of tibolone on vaginal blood flow, sexual desire and arousability in postmenopausal women. Climacteric. 2001; 4: 28-41.

25. Uygur D, Yesildaglar N, Erkaya S. Effect on sexual life – a comparison between tibolone and continuous combined conjugated equine estrogens and medroxyprogesterone acetate. Gynecol Endocrinol. 2005; 20: 209-212.

26. Reviriego C. Flibanserin for female sexual dysfunction. Drugs Today9(Barc). 2014; 50: 549-556.

27. Stahl SM, Sommer B, Allers KA. Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med. 2011; 8: 15-27.

28. FDA News Release: FDA Approves First Treatment for Sexual Desire Disorder. US Department of Health and Human Services: Food and Drug Administration (FDA); 2015.

29. Lodise NM. Female sexual dysfunction: a focus on flibanserin. Int J Womens Health. 2017; 9: 757-767.

30. Berman JR, Berman LA, Lin H, Flaherty E, Lahey N, Goldstein I, et al. Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther. 2001; 27: 411-420.

31. Caruso S, Intelisano G, Lupo L, Agnello C. Premenopausal women affected by sexual arousal disorder treated with sildenafil: a doubleblind, cross-over, placebo-controlled study. BJOG. 2001; 108: 623-628.

32. Basson R, McInnes R, Smith MD, Hodgson G, Koppiker N. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J Womens Health Gend Based Med. 2002; 11: 367-377.

33. Liao Q, Zhang M, Geng L, Wang X, Song X, Xia P, et al. Efficacy and safety of alprostadil cream for the treatment of female sexual arousal disorder: a double-blind, placebo-controlled study in Chinese population. J Sex Med. 2008; 5: 1923-1931.

34. Gomaa AA, Abdel Aziz NM, Thabet RH, Fouly HA, Altellawy SH, Gomaa GA. A pilot study of a topical intervention for treatment of female sexual dysfunction. J Clin Psychopharmacol. 2017; 38: 60-67.

35. 35.Ito TY, Polan ML, Whipple B, Trant AS. The enhancement of female sexual function with ArginMax, a nutritional supplement, among women differing in menopausal status. J Sex Marital Ther. 2006; 32: 369-378.

36. 36.Ito TY, Trant AS, Polan ML. A double-blind placebo-controlled study of ArginMax, a nutritional supplement for enhancement of female sexual function. J Sex Marital Ther. 2001; 27: 541-549.

37. 37.Nishioka K, Hidaka T, Nakamura S, Umemura T, Jitsuiki D, Soga J, et al. Pycnogenol, French Maritime Pine Bark Extract, augments endothelium-dependent vasodilaton in humans. Hypertens Res. 2007; 30: 775-780.

38. 38.Hunter M. The Women’s Health Questionnaire: A Measure of MidAged Women’s Perceptions of their emotional and physical health. Psychol & Health. 1992; 7: 45-54.

39. 39.Yang H-M, Liao M-F, Zhu S-Y, Liao M-N, Rohdewald P. A randomized, double-blind, placebo-controlled trial on the effect of Pycnogenol® on the climacteric syndrome in peri-menopausal women. Acta Obstet Gynecol. 2007; 86: 978-985.

40. 40.Errichi S, Bottari A, Belcaro G, Cesarone MR, Hosoi M, Cornelli U, et al. Supplementation with Pycnogenol® improves signs and symptoms of menopausal transition. Panminerva Med. 2011; 53: 65-70.

41. 41.Bottari A, Belcaro G, Ledda A, Luzzi R, Cesarone MR, Dugall M. Lady Prelox® improves sexual function in generally healthy women of reproductive age. Minerva Ginecol. 2013; 65: 435-444.

42. 42.Stanislavov R, Rohdewald P. PACR (Pine Bark Extract, L-Arginine, L-Citrulline, Rose Hip Extract) improves emotional, physical health and sexual function in peri-menopausal women. J Women’s Health Care. 2014; 3: 3-6.

43. 43.Bottari A, Belcaro G, Ledda A, Cesarone MR, Vinciguerra G, Di Renzo A, et al. Lady Prelox® improves sexual function in post-menopausal women. Panminerv Med. 2012; 54: 3-9.

44. 44.Fitzpatrick DF, Bing B, Rohdewald P. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol. 1998; 32: 509-515.

45. 45.Stanislavov R, Nikolova V. Treatment of Erectile Dysfunction with Pycnogenol and L-arginine. J Sex Marital Ther. 2003; 29: 207-213.

46. 46.Stanislavov R, Nikolova V. Sperm quality in men is improved by supplementation with a combination of L-arginine, L-citrulline, roburins and Pycnogenol. Minerva Urol Nefrol. 2014; 66: 217-223.

47. 47.Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol®), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther. 2002; 40: 158-168.

48. 48.Rohdewald P. Update on the clinical pharmacology of Pycnogenol®. Med Res Arch. 2015; 3: 1-11.

49. 49.Kohama T, Herai K, Inoue M. Effect of French maritime pine bark extract on endometriosis as compared with leuprorelin acetate. J Reprod Med. 2007; 52: 703-708.

50. 50.Kohama T, Negami M. Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women. J Reprod Med. 2013; 58: 39-46.