Table 1 Summary of evidence for the reproductive endocrinological effects of six herbal medicines in oligo/amenorrhoea, hyperandrogenism and PCOS

Vitex agnus-castus

Eight studies investigated gonadotropic hormone concentration effects of Vitex agnus-castus.

Three RCTs investigate clinical effectiveness for Vitex agnus-castus for oligo/amenorrhoea and PCOS [61, 62, 64]. One RCT demonstrated equivalence for Bromocriptine and Vitex agnus-castus[63].

Ethanol extracts

Strontan®, Mastodynon®, Phyto-hypophyson®, Agnacaston®

1. Investigation for equivalence of dopaminergic effects for Vitex agnus-castus and the pharmaceutical Lisuride using rat pituitary cell cultures (basal and stimulated cells) [41]

1. Lowers prolactin due to dopaminergic effects [38–41, 63]

2. Brain (calf, guinea pig and rats) receptor tissue cultures including DA2, histamine and 5HT transporters. Radio ligand and super-fusion experiments [40]

2. No change for serum prolactin [64]

3. Three investigations found affinity for Vitex agnus-castus and β oestrogen receptors [38, 43, 69]

3. FSH no change [39]

4. Using recombinant human dopamine (DA2) receptor proteins [38]

4. LH no change [39]

5. The affinity of Vitex agnus-castus extract (with and without fatty acids) for human μ opoid receptor cells cloned and transfected into hamster ovary cells [70]

5. LH lowered [49]

6. The endocrine effects for Vitex agnus-castus were investigated in normal and ovariectomised rats [49]

6. Binds to β oestrogen receptors [38, 43, 69]

7. Corpus striatum membrane including D2 receptors to assess the inhibitory properties of Vitex agnus-castus on prolactin, FSH and LH [39]

7. Increased serum oestradiol [49, 64]

8. Increased serum progesterone [49, 62]

9. Improved pregnancy rates [61, 62]

Cimicifuga racemosa

Four laboratory studies investigated pituitary oestrogen receptor binding and gonadotropin concentrations following exposure to Cimicifuga racemosa.

Three RCTs demonstrate positive fertility effects for Cimicifuga racemosa in women with PCOS [65, 67, 68]

Ethanol extract

Klimadynon®

1. One study investigated a constituent flavonoid of Cimicifuga racemosa, discovered during the course of the study for reduction for LH in ovariectomised rats [37]

1. Binds with α oestrogen receptors [44] in the pituitary and reduces LH secretion [45, 52, 68].

2. Oestrogen receptor binding affinity for Cimicifuga racemosa was studied using pituitary cell cultures from ovariectomised rats. This study followed a clinical study demonstrating significantly lowered LH in post-menopausal women following administration of Cimicifuga racemosa (2 mg for two months) against placebo control (n = 110) [45]

2. Increases luteal progesterone concentration [65, 67, 68]

3. Binding affinity for oestrogen receptors (ERα) for Cimicifuga racemosa examined using MCF7 cell cultures [44]

3. Improves endometrial thickness for infertile women with PCOS [65, 67, 68].

4. Chronic and acute dosage effects of Cimicifuga racemosa and oestradiol on oestrogen receptors, gene expression, uterine and bone tissue of ovariectomised rats [52]

4. Lowers LH in women with PCOS [65, 67, 68]

5. Improves FSH:LH ratio for women with PCOS [67]

6. Limits anti-oestrogen effects when used in combination with Clomiphene citrate for women with PCOS [65, 68]

Cinnamon cassia

One animal study compared the effectiveness of Cinnamomum cassia with metformin against controls in rats with PCOS. Hormone concentration was measured at 15 and 30 days [48]

One pilot RCT demonstrated positive effects for metabolic parameter’s (HOMO and QUICKI) for Cinnamomum cassia in overweight women with PCOS [66]

1. Equivalence for metformin for reduced testosterone in PCOS [48]

Aqueous extract (animal study)

2. Equivalence for metformin for reduced LH in PCOS [48]

Ethanol extraction (Human trial)

3. Equivalence for metformin for reduced LH in PCOS [48]

4 Equivalence for metformin for reduced insulin resistance [48]

5. Improved metabolic profile for overweight women with PCOS [66]

Herbal medicine

Evidence

Physiological effects in oligo/amenorrhoea, hyperandrogenism and/or PCOS

Pre-clinical in vitro and in vivo

Data from clinical studies (non RCTs)

Botanic name

Herbal extract

Tribulus terrestris

Three animal studies investigated the effects of Tribulus terrestris, two for polycystic ovaries and one on oestrogen sensitive tissues in rats.

Two clinical studies

Ethanol extracts

1. One study examined the oestrogenic effects of Tribulus terrestris on uterine and vaginal tissue of ovariectomised rats [51].

1. Healthy women n = 8 early menstrual cycle (follicular phase) Pre and post serum hormone concentration for FSH, LH testosterone and oestradiol at 8 am and 12 pm. Intervention consisted of Tribulus Terrestris 250 mg per day over five days. Results showed significant increase in FSH and rise in LH (not significant), an increase in oestradiol and no change in testosterone concentration [56]

1. Ovulation induction in polycystic ovaries [46, 47].

2. Two studies investigated the ovulation rates, number of corpus luteum and follicle characteristics in rats with polycystic ovaries following exposure to various doses of Tribulus terrestris[46, 47].

2. Equivalence of Tribulus terrestris and three ovulation induction pharmaceuticals evaluated ovulation in women with oligo/anovular infertility (n = 148) [60].G

2. No oestrogenic effects in female reproductive tissues [51].

3. Increased FSH in healthy women [56].

4. Equivalence for ovulation induction for Tribulus Terrestris and Clomiphene for women with oligo/anovular infertility [60].

Glycyrrhiza glabra (European liquorice)

Two preclinical studies investigated the effects of Glycyrrhiza spp. for steroid hormone concentration and in polycystic ovaries.

Two clinical trials

1. Steroid hormone concentration in sterilised and oophrectomised rats following exposure to Glycyrrhiza spp. (kanzo) [53].

1. Single arm clinical trial investigating serum androgen concentration in healthy women aged 22–26, (n = 9) following administration of Glycyrrhiza spp. 7grams per day [55].

1. Increased aromatisation of testosterone to 17 beta oestradiol shown by significantly dose dependent reduced testosterone and increased oestradiol [53].

Glycyrrhiza uralensis (Chinese liquorice)

Ethanol extract

Aqueous extract used in two pre-clinical studies

2. Morphological features of polycystic ovaries of rats following exposure to two Chinese herbal compounds with only Glycyrrhiza spp. as a common ingredient [50].

2. Single arm clinical trial including women with PCOS (n = 32) taking Spirinolactone [54].

2. Reduced free and total testosterone [53].

3. Reduced serum androgens in healthy women [55].

4. Reduced androgen flare for women with PCOS using the anti-androgen pharmaceutical Spirinolactone [54].

5. Improved ovulation rates in polycystic ovaries [50].

Paeonia lactiflora in combination with Glycyrrhiza spp. Aqueous extract Shakuyaku- kanzo-to (TJ-68)

One laboratory study examined the effects for the combination Paeonia lactiflora and Glycyrrhiza uralensis on testosterone, oestradiol, FSH and LH in sterilised female rats [53].

Two single arm clinical trials examined androgen concentrations Following treatment with Paeonia lactiflora and Glycyrrhiza uralensis in the Chinese herbal combination Shakuyaku-kanzo-to. One included infertile oligomenorrhoeic women with hyperandrogenism (n = 8) [58] and the other included women with oligo/amenorrhoea and PCOS (n = 34) [59].

1. Reduced total and free testosterone [53, 58, 59].

2. Increaed SHBG [59].

3. Reduced LH [53].

4. Reduced LH:FSH ratio [59].

5. Oestradiol slight increase (not significant) [53].

6. Improved ovulation in women with PCOS [58].

Paeonia lactiflora in combination with Cinnamomum cassia Aqueous extract Unkei-to

Paeonia lactiflora and Cinnamomum cassia combination was investigated for steroid hormonal effects on cultured human granulosa cells (obtained from women undergoing IVF). Cells were incubated with different doses for 48 hours [42]

One clinical trial investigated the effects of Paeonia lactiflora and Cinnamomum cassia combination (Unkei-to) [57]. This single arm study included amenorrheic women aged 17–29 years (n = 157) with a sub group of women with hyper-functioning oligo/amenorrhoea (n = 42). Ovulation occurred in 61.3% of primary amenorrheic women and in 27.3% of secondary amenorrheic women following two months of treatment [57].

1. Increased granulosa production of oestradiol [42].

2. Increased granulosa production of progesterone [42].

3. Reduced LH in oligo/amenorrhoea [57].

4. Improved ovulation rates in oligo/amenorrhoea [57].