PMS is a condition, which is associated with somatic, emotional and behavioral symptoms during the women menstruation. Anxiety, depression, acne, fatigue, and headache are common symptoms of PMS. Insomnia and suicidal thoughts are severe symptoms of premenstrual dysphoric disorders. Menstruating women of 85% are affected by these symptoms. PMS is characterized by over 150 clinical symptoms (behavioral, psychological, and physical) including cyclical mastalgia, headache, backache, irritability, depression, food carving, and irritable bowel syndrome during the luteal phase of menstrual cycles. Low level of prostaglandin E₁, as the result of a deficiency in essential fatty acids causes high sensitivity to prolactin, which produces at ovulation time and increases the high level during the luteal phases [9].

The therapeutic potency of evening primrose oil in the management of PMS is the subject of many clinical trials (Table 1). Linoleic acid promotes prostaglandin synthesis and alleviates PMS. The first report on the efficacy of evening primrose oil in PMS returned to a meta-analysis in 1994. This meta-analysis was performed on seven placebo-controlled clinical trials, which five trials had clear randomization. From these seven randomized clinical trials, only two clinical trials were well-controlled studies, but the small and modest sample size of these two studies limited the conclusion on the efficacy of evening primrose oil in PMS. The only best finding of this meta-analysis article is the safety of 3 to 6 g daily dose of evening primrose oil in volunteers with PMS [10]. In a randomized double-blind placebo controlled parallel design, the alleviating effect of 180 mg/d γ-linoleic acid was compared with the placebo on clinical symptoms of 28 women suffering from PMS in three luteal phases. The patients in the placebo group received edible oil without γ-linolenic acid. The blood samples in three cycles, duration and severity of symptoms were compared in groups. The levels of stearic acid, oleic acid and dihomo-γ-linolenic acid, palmitic acid and γ-linolenic acid in plasma phospholipids had a significant reduction in follicular and luteal phases. Irritable bowel syndrome was the most common symptom of women with PMS, followed by breast swelling, drowsiness, avidity, and facial eruption. After treatment, the patients in γ-linolenic acid group had higher γ-linolenic acid and dihomo-γ-linolenic acid in plasma phospholipids compared to the placebo group. The severity and duration of PMS (physical, mental, and social), irritability improved in the γ-linolenic acid group compared to the placebo group (P < 0.05) [11]. In another randomized placebo-controlled trial, evening primrose oil was evaluated on 80 women with PMS according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) criteria. The randomized patients of two groups received a daily dose of 1.5 g evening primrose oil or placebo for three months. Compared to before intervention, evening primrose oil significantly changed the PMS severity scores after the intervention, while no significant difference was observed in PMS scores after treatment with placebo. The symptom severity scores reduced from 53.2 ± 14.31 to 33.62 ± 16.94 after three months administration of evening primrose oil, while these amounts were 53.38 ± 13.93 and 50.27 ± 16.94 in placebo groups. A significant difference in PMS symptom severity scores was observed between placebo and evening primrose groups after three months of interventions (P < 0.001) [12]. The results of the above clinical studies showed the efficacy and safety of evening primrose oil in the management of PMS during menstruation.

The women of 70% complain of breast pain at some stages of their life. Breast pain or mastalgia is a common distressing ailment among ladies in reproductive ages. Cyclical breast pain is as the result of changing in hormone during the menstrual cycle, while noncyclical breast pains are not linked to menstrual cycle [13]. The deficiency in γ-linolenic acid or its derivatives makes the breast tissues sensitive to sex hormones, which is associated with breast pain [14].

The most clinical trials on women ailments have been focused on the efficacy of evening primrose oil in cyclical mastalgia (Table 2). One-hundred women (15–35 years old) with moderate to severe mastalgia were recruited for an open, non-randomized, comparative clinical study, and were evaluated according to Cardiff breast pain score (CBS). The patients received 100 mg oral danazol, or 500 mg evening primrose oil, twice daily for a period of three months. The responses to treatments were evaluated at baseline, 4 and 12 weeks after treatments. There was no significant difference between the two groups after 4 and 12 weeks of treatments. The reported distressing adverse effects were reported in 32% and 12% of women in danazol and evening primrose oil, respectively [15].

In single-blinded clinical study on 61 women suffering from cyclical mastalgia (18–40 years old), who were randomly divided in two groups of 3 g daily oral evening primrose oil (n = 31) or 600 mg daily oral vitamin E (n = 30) and were evaluated according to CBS and the severity of pain. The patients received medications, three times a day for one month at the beginning of their menstruation cycle. Intervention with evening primrose oil or vitamin E significantly reduced the severity of pain (61.3% vs. 26.7%; P < 0.05) [16].

Eighty-five women with cyclical mastalgia were randomly divided into four groups of 1,200 IU/d vitamin E (n = 21), 3 g/d evening primrose oil (n = 21), 1,200 IU/d vitamin E plus 3 g/d evening primrose oil (n = 21), or placebo (n = 22) for 6 months and were evaluated by modified McGill pain questionnaire. The results of this pilot study showed no significant reduction in cyclical mastalgia in three intervention groups but showed a trend toward a benefit with evening primrose oil, vitamin E or their combination [17].

In another prospective clinical trial on sixty-six women (17–49 years) with disturbing cyclical mastalgia, and having single breast surgeon, the patients were recommended to use six evening primrose oil capsules for 3 months. Treatments continued for 3 and 6 months in patients with unresolved mastalgia. The median duration of pain before treatment was 12 months on the base of CBS, and 40% of women experienced mastalgia for more than 12 months, while, only 18% administered analgesics for their mastalgia. After treatment, the overall response to evening primrose oil was 97% after 6 months of treatments [18].

The efficacy of evening primrose oil was evaluated on 100 women with cyclic mastalgia and the patients were divided into four groups (n = 25) and received 2 g daily evening primrose oil, or 400 IU vitamin E, or 2 g daily evening primrose oil plus 400 IU vitamin E or placebo for 6 months. The difference between the three treatment groups was not significant (P > 0.05), but the difference between intervention groups and placebo was statistically significant [19].

In a double-blind clinical study on 80 Egyptian women with cyclical mastalgia, who were randomly divided into two groups and received 5 mg daily bromocriptine plus 2 g daily evening primrose oil (n = 36) or low-intensity laser therapy (helium-neon laser plus infra-red diode laser) (n = 40). The visual analogue score (VAS) and plasma cortisol level were evaluated in patients. The response to treatment by evening primrose oil plus bromocriptine and laser therapy was 63.9% and 82.5%, respectively. Patients of 37.5% reported adverse effects (nausea, epigastric discomfort, vomiting, and dizziness) after administration of bromocriptine [20].

A double-blind placebo-controlled parallel multicenter clinical trial on 555 women with moderate to severe mastalgia, the patients randomly allocated in four groups of γ-linolenic acid plus antioxidants or placebo γ-linolenic acid plus antioxidants, or γ-linolenic acid plus placebo antioxidant or placebo γ-linolenic acid and placebo antioxidants for four menstrual cycles. The γ-linolenic acid of 320 mg daily was prepared by 4 g daily evening primrose oil capsule. Evening primrose oil capsule was containing 10 mg natural vitamin E. The antioxidant capsule was containing 3 mg β-carotene, 100 mg vitamin C, 25 mg vitamin B₆, 10 mg zinc, 10 mg niacin, and 455 µg selenium. After 1-month wash-out period, the patients received evening primrose oil for eight menstrual cycles, randomized to active or placebo antioxidants according to the parallel phase. From 555 patients, 77% and 69% completed the blinded and open phases of a clinical study, respectively. Breast pain scores improved in 4 groups at the end of treatments. The difference among the four groups was not significant (P > 0.05). The patient's VAS measurements and patients assessments showed improvement in two phases. Nausea was the most common adverse event during treatment [21].

In another randomized clinical trial on 135 patients with mastalgia, who randomly received 30 mg centchroman (ormeloxifene; n = 67) or 3 g/d evening primrose oil (n = 68) for 6 months. After 6 months, 68% and 23% of patients had a complete response to treatment (P < 0.05) and centchroman had a significant effect on breast pain relief and nodularity higher than evening primrose oil group [22].

A randomized, double-blind factorial controlled trial on 120 women with severe chronic mastalgia, who were randomly divided into four groups of 1) fish oil-control oil, 2) evening primrose oil- control oil, 3) fish oil-evening primrose oil, and 4) both control oils (wheat germ oil plus corn oil). The decrease in percentage days with mastalgia after 6-month treatment were 12.3%, 13.8% for evening primrose oil and its control (P = 0.73), while these amounts were 15.5%, 10.6% for fish and its control (P = 0.28) [23]. In another study, the efficacy, safety, and response of evening primrose oil in the treatment of mastalgia was compared with topical non-steroidal anti-inflammatory drugs (NSAIDs). Fifty women (15–50 years) with moderate to severe mastalgia were divided into two groups of piroxicam gel 0.5% (twice a day for 3 months) and 1 g daily evening primrose oil. After 12 weeks of treatment with NSAIDs, 56%, 35% and 8% of patients had excellent, substantial and poor responses, respectively. In evening primrose oil, 64% and 32% of patients had substantial or poor responses to treatment. Patients of 4% reported side effects with evening primrose oil (nausea and altered taste) [24]. Among 10 clinical studies, 7 clinical studies showed the priority of evening primrose oil than other treatments in the management of mastalgia. Therefore, evening primrose oil can be used as a safe and effective treatment for mastalgia in women.

Evening primrose oil is the most popular treatment as complementary and alternative medicine among 1,296 menopausal women in Sydney. Women of 66.3% found it as an effective treatment in menopause symptoms [25]. The most commonly experienced symptom of menopause is hot flash.

The efficacy of 500 mg evening primrose oil capsule or placebo was evaluated in a randomized, double-blind placebo-controlled trial on 56 menopausal women (45–59 years old) with hot flashes on the base of Hot Flash Related Daily Interference Scale (HFRDIS) questionnaire before and after treatments. The patients received 90 capsules 500 mg for 6 weeks. The hot flash frequency, severity and duration percent were 39%, 42%, and 19% for evening primrose oil, while these amounts were 32%, 32%, and 18% in the placebo group, respectively. The significant difference was observed between the hot flash severity percent of evening primrose oil and placebo groups (P < 0.05). HFRDIS scores improved in two groups, but the social activities, sexuality, and relation with others were significantly higher in evening primrose oil than that of placebo (P < 0.05) [26]. Small sample size influences the result of the study, so it can be the limitation of the above study, also hot flashes is highly dependent the self-evaluation, therefore, conclusion on response to treatment is difficult.

Fibroadenomas is benign noncancerous tumor in breast, which occurs often in women with the age of 15 to 35 years old. These solid breast lumps are usually painless, round with distinct smooth borders, which can easily move. The etiology of fibroadenomas is unknown, but the reproductive hormones may be involved in fibroadenomas. No treatments are required in many cases, but some patients choose surgical removal of breast lumps. In one clinical study on women with fibroadenomas (22–49 years old), who received a daily dose of 4 g evening primrose oil (n = 23) or placebo (n = 16) for 6 months, the clinical size of breast lump was measured by surgeon and ultrasound measurement after and before treatments. In spite of satisfying the patients from treatment with 4 g evening primrose oil for 6 months, there was no significant difference in means of fibroadenomas size between evening primrose oil and control group after measuring by ultrasound (P = 0.6). The reduction in fibroadenomas size was 52% and 42% in evening primrose oil and control groups, respectively [27]. The results of the only clinical study disapproved the efficacy of evening primrose oil in the treatment of fibroadenomas.

Gestational diabetes develops during pregnancy. The high blood sugar in gestational periods of pregnant women can effect on pregnancy and baby's health. After delivery, gestational pregnancy returns to normal level soon.

In a randomized double-blind placebo controlled clinical trial, the efficacy of 1 g evening primrose oil and 1,000 IU vitamin D supplements (n = 30) in comparison with placebo for 6 weeks on women with gestational diabetes was evaluated on biochemical variables at baseline and after treatment. The results showed supplement with evening primrose oil and vitamin D caused a significant reduction in serum high sensitivity C-reactive protein level and malondialdehyde, while the increase in plasma nitric oxide and total antioxidant capacity level was observed in evening primrose oil plus vitamin D compared with placebo [28]. Therefore, women with gestational diabetes can benefit from the antioxidant activities of evening primrose oil during their pregnancy.

Pre-eclampsia is a common dangerous complication of pregnancy, which is associated with high vasoconstriction, plate aggregation, reduction in uteroplacental blood flow and premature delivery. A hundred and fiftiy pregnant primiparous and multiparous women in the first 4 months of pregnancy were randomly divided into three groups of placebo group, evening primrose oil plus fish oil and magnesium oxide group. The patients in the experimental group received 8 capsules of evening primrose oil plus fish oil per day for 30 days, which each capsule was containing 37 mg γ-linolenic acid, 18 mg eicosapentaenoic acid and 10 mg docosahexaenoic acid. The placebo groups received olive oil and the patients in the magnesium group received daily two tablets 500 mg for 30 days. Pre-eclampsia was defined as simultaneous occurrence of edema, hypertension, or proteinuria during the pregnancy. Vomiting and diarrhea were significantly greater in fatty acid supplement and magnesium oxide groups, respectively. The patients in group's fatty acid and magnesium oxide had greater qualitative improvement conditions in 6 months of pregnancy, compared to the placebo group. The weight gain between 1st and 3rd trimesters was significantly higher in fatty acid supplemented and placebo groups than that of magnesium oxide. The pregnancy-associated hypertension was lower in magnesium supplemented group, while the placebo group had more cases of hypertension. The lower cases of edema were observed in fatty acid supplemented group (n = 13) or magnesium oxide group (n = 12) compared to the placebo group (n = 29). Proteinuria was distributed among three groups. Pre-eclampsia was occurred in 5 cases of placebo groups, followed by fatty acid supplemented group (n = 2) and magnesium oxide (n = 2). There was no significant difference between baby's conditions (skin color, heart rate, respiratory effort, and muscle tone) among the three groups. Birth weight was better in fatty acid supplemented group and magnesium oxide group [29]. Evening primrose oil is suitable for pre-eclampsia during pregnancy without any adverse effects.

Midwives used evening primrose oil as a cervical ripening agent for shortening the labor and reducing the incidence of postdates pregnancies. Evening primrose oil with prostaglandins E₁ and E₂ precursors has relaxant activity on smooth muscle, which changes cervical vascular tone and consistency. The cervical dilation and effacement affected by prostaglandins [30]. The efficacy of evening primrose oil capsule as the cervical ripening agent was evaluated on thirteen patients with an average age of 27 ± 6 years and mean age of gestation 40 ± 1 weeks by evaluating Bishop's score before and 4 hours after intervention. The interventions were performed by intra-vaginal insertion of six capsules of 500 mg evening primrose oil. Women of 54%, 15% and 31% were nulliparous, primiparous, and multiparous, respectively. The Bishop's scores were changed 4 hours after insertion of evening primrose oil capsules and these changes were significant (P = 0.001). The patients of 85% had an improvement in Bishop scores 4 hours after intra-vaginal insertion of evening primrose oil. Bishop scores for 31% of patients were higher than 4. Dilation (P = 0.027), effacement (P = 0.006), and consistency (P = 0.002) were the specific components of Bishop scores with significant changes, other components of Bishop scores, such as position (P = 0.08), and station (P = 0.17) had no changes. The patients of 85% had significant cervical dilation and effacement, based on the clinical changes. The patients of 31% had vaginal delivery, while 69% of patients had cesarean section, including nonreassuring fetal status (46%), arrest in cervical dilation (15%), and intra-amniotic infection (8%) [31]. The other clinical study, the efficacy of oral evening primrose oil was evaluated on length of pregnancies and intrapartum outcomes of 108 low-risk nulliparous women in retrospective quasi-experimental clinical study. The patients were divided into two groups of 500 mg evening primrose oil or control groups and the patients received evening primrose oil or nothing from 37th gestational weeks until child delivery. The results of the study showed oral feeding with oral daily of evening primrose oil did not reduce the length of labor time, and also increased the risk of the protracted active phase, the arrest of descent and vacuum extractor utilization. The use of patients' records to asses outcome variables, no strict procedure for defining the onset of labor or latent phase is the limitation of this study [32].

The efficacy of 500 mg evening primrose oil on cervical ripening and dilatation of thirty-six non-menopausal patients and 14 menopausal patients was evaluated before hysteroscopy. The patients were randomly divided into two groups of evening primrose oil or placebo. The patient received 1 g soft capsules 6 to 8 hours before hysteroscopy via posterior vaginal fornix. The total dilation time, uterine cervicovaginal complication and the adverse effects related to treatments were evaluated. Application of evening primrose oil reduced the total cervical dilation time (P = 0.003), also, evening primrose oil caused a greater first Hegar size or force for cervical dilation compared to the placebo group (P = 0.002). No adverse effects or uterine cervicovaginal complications were reported during the study [33].

The effect of intra-vaginal evening primrose oil was compared with intra-cervical laminaria in ease of cervical dilation prior to hysteroscopy. The patients in the laminaria group received treatment 12 hours before hysteroscopy, while the patients in evening primrose oil received 6 soft capsules 6 hours prior and 4 capsules 1 hour before hysteroscopy. Cervical dilation and time to reach Hegars 10 mm were recorded for two groups. The initial cervical dilations were 5 and 7 mm in laminaria and evening primrose oil group and median time to Hegars 10 mm were 5 minutes and 45 seconds for laminaria, while the corresponding time for evening primrose oil was 1 minute and 57 seconds. Cervical dilation was good and easy for laminaria and evening primrose oil groups, respectively. The patients in evening primrose oil group had no pain, while the other group had tolerable pain. The results of this clinical trial showed better cervical dilatation and required less time for evening primrose oil group, rather than laminaria [34]. The use of intra-vaginal evening primrose oil has cervical ripening effects in women and can be used prior to hysteroscopy or childbirth.