Abstract: The review provides updated scientific information of medicinal plants with proven female anti-fertility activity. The objective is to highlight the fertility regulating agents from plant origin for females. This review is a result of conduction of a literature search from different sources viz., the library of our institution, pubmed, google search and other personal sources. A total of 317 references were found using 204 plants for fertility regulation in females for the period of 68 years (1947-2015). The biological name, plant part, type of extract, dose, mode of administration, animal model and pharmacological action of these plants have been reviewed in this study to explore some of the ways in which phytotherapy may contribute and focus on research into potential herbal tools for population control.
INTRODUCTION
Global population has severely disturbed the ecological balance and has forced mankind to develop new fertility regulating techniques. Although, considerable progress has been made in the field of chemically formulated contraceptive methods but many of them have adverse effects. Therefore, it is necessary to screen biologically active fertility regulating agents which are safe. Plants have been used worldwide for screening of various human ailments since ancient times. About 325 extracts from 75 plants with anti-fertility actions were screened by Garg et al.1. Kulshreshtha and Srivastava2 recognized anti-fertility action in 43 folkloric traditional plants. The Task Force on Plants for Fertility Regulation set up by the World Health Organization (WHO) identified approximately 30 plants with anti-implantational activities but none of these have reached the stage of clinical examination3. Hence, the detailed information including plants scientific name, part, extract, dose, administration mode, animal model and pharmacological action have been reviewed in this study (Table 1).
The status of the plant products which have undergone clinical trials and have shown promising results is briefly reviewed.
Pippaliyadi vati: It has been used in combination of powdered fruit berries of Embelia ribes, Piper longum and borax, as an ayurvedic contraceptive, since ancient times. Phase I clinical trials have been completed at the Postgraduate Institute of Medical Education and Research, Chandigarh, the JIPMER, Pondicherry and at the KEM Hospital, Mumbai. The trial was preceded in Central Council for Research in Ayurveda and Sidha, Kolkata and Hyderabad and acute, subacute toxicology and teratological examination carried out at the National Institute of Immunology, New Delhi3. The researchers concluded that in utero exposure to pippaliyadi did not exhibit any adverse effects on postnatal development and reproductive performance of the F1 progeny4.
Consap: Saponins (obtained from Sapindus mukorossi) have spermicidal activity. Saponins caused alterations in the glycoproteins associated with the lipid bilayer of plasma membrane of spermatozoa, observed under scanning electron microscope5. Plant extracts altered biochemical and biophysical changes in the sperm membrane during sperm maturation without changing the testicular and epididymal morphology6. A contraceptive cream known as consap was developed under CDRI’s contraceptive development programme. It has passed through phase I, II and III clinical trials and proved to be an effective fertility regulating agent. Hindustan Latex Limited, Mumbai licensed the cream to market as non-hormonal herbal spermicidal contraceptive7.
Praneem: Praneem, combination of seed extract of Azadirachta indica, fruit extract of Sapindus mukorossi and Mentha citrata oil has emerged as an intravaginal polyherbal (PPH) cream and pessary at the National Institute of Immunology, Delhi, India. The formulation was safe under sub-acute toxicity studies in monkeys and has effective contraceptive efficacy in rabbits and monkeys after intravaginal application8. This has undergone phase II clinical trials9 and was accepted by the study participants in a phase II safety and acceptability study done in Pune, India10,11. Clinical trials were carried out in 3 centres in India, viz., Postgraduate Institute of Medical Education and Research, Chandigarh; Safdarjang Hospital, New Delhi and Kamla Nehru Memorial Hospital, Allahabad. No toxic effects were observed on intravaginal use during clinical investigations12. A microbicide praneem polyherbal tablet has successfully passed through phase III clinical trials and licensed to M/s Panacea Biotec.
Carica papaya: As a male contraceptive, a series of experiments have been conducted by Lohiya and associates with various extracts, fractions and sub-fractions with varying dose and duration in male rats, rabbits and langur monkeys. The chloroform extract exerted maximum antifertility activity in rats and rabbits, mainly due to its mild estrogenic property. The benzene chromatographic fraction of chloroform extract produced inhibition of cauda epididymal sperm motility in rats with reduced sperm density and morphological changes of the spermatozoa and azoospermia in rabbits. The methanol and ethyl acetate sub-fractions obtained from the benzene chromatographic fraction also showed motility inhibition properties in rats following 30-60 days of treatment and azoospermia in rabbits within 15 days of treatment13,14.
Apart from effective male contraceptive, it has been equally screened as a fertility regulating agent in females. Carica papaya seeds and fruits exerted abortion in women15. In countries like Indonesia, Malaysia and Myanmar papaya have been used indigenously as abortifacients16-18. About 82% of females avoided papaya consumption during pregnancy in Tamil Nadu, India19.
Extensive toxicological investigations have also been carried out with Methanol Sub Fraction (MSF) of the benzene chromatographic fraction of the chloroform extract of papaya seeds following a single high dose administration or daily administration upto 10 times of contraceptive dose for a period of 28 and 90 days and long-term daily administration upto 10 times for a period of 52 weeks and 2 years in rats indicated no associated health hazards.
| Table 1: | Summary of plants with reported anti-fertility activity in female |
a1: Alcoholic extract, a2: Alcoholic extract (arjunalone), a3: Aqueous extract, a4: Abridin, a5: Aristolic acid, a6: Alkaloid, a7: Alkaloid (aroborinine), a8: Alkaloid (binsindole), a9: Alkaloid (vasicine), a10: Acetone, b1: Benzene extract, b2: n-butanol extract, b3: Butanol fraction, c1: Chloroform extract, c2: Chloroform extract (chalepensin), c3: Coumarin, c4: Coronaridine hydrochloride, c5: Crude fraction, d1: Distilled water extract, d2: Dichloromethane, e1 : Embelin, e2: Ether extract, e3 : Ethanolic extract, e4: Ethyl acetatem, f1: Fruit oil, f2: Flower extract, f3: Flavones (apigenin and luteolin), f4: Flavones (acacetin and luteolin), f5: Fatty acids, g1: Gossypol, g2: Glycosides, h1: Hexane extract, h2: Hydroalcoholic extract, h3: Hexane fraction, ip: Iso-propanolic extract, l1: Leaf juice, l2: Latex extract (aqueous), m1: Methanolic extract, m2: Methanolic extract (andrographolide), m3: Montanol, m4: Methanol:methylene chloride 1:1, m5: Methanol fraction, n1: Nut oil, n2: Neem oil, n3: Non-proteinaceous extract, o1: Oleoresin (acidic fraction), o2: Oleonolic acid,3-β Glucoside, p1: Plant extract, p2: Phenol and flavonoids, p3: Physalinx, p4: Petroleum ether extract, p5: P-coumaric, p6: Powder, r1: Resin, s1: Saponin fraction, s2: Steroidal extract, s3: Steroidal lactone (dq1), s4: Steroidal lactone, s5: Steroidal fraction, s6: Seed extract, s7: Seed oil, t1: Triterpenoid glycoside, u1: Uterotonic fraction, w1: Water soluble fraction of ethanolic extract, x1: Xylohydroquinone, z1: Zoapatanol, A1: Anti-implantation, A2: Abortifacient, A3: Anti-oestrogenic or interrupt oestrous cycle, A4: Antifertility or 100% sterility or inhibited fertility, A5: Anti-ovulatory, A6: Abrogate pregnancy (10%), A7: Alteration in reproductive organ weight, A8: Anti-conceptive, A9: 100% Activity, A10: Anti-zygotic, B1: Blocked pregnancy (pre-implantation block), B2: Blocked the uterotropic responses of exogenous estrogen, B3: Blastocidal, C1: Cyclicity disrupted in virgin, C1: Changes in biochemical profile of ovary and uterus, C3: Completely annulled the biological potency of hCG, C4: Complete inhibition of chorionic gonadotropin, C5: Cycle length prolonged, C6: Cholesterol, ascorbic acid of ovary is elevated, C7: Contraceptive efficacy, D1: Decrease in fertile mating and number of offspring, D2: Decrease no. of graafian follicle and corpora lutea, D3: Decrease in litter size, E1: Estrogenic activity or oestrogenic or estrogenicity, E2: Encouraging antifertility activity, E3: Estrogen induced alkaline phosphatase activity in the endometrium of immature rabbits, E4: Enhanced uterine contractibility, E5: Embryotoxic perinatally, F1: Follicular degeneration, F2: Reduction in No. of viable fetuses, F3: Fetal toxicity, G1: Altered gonadotropin release and estradiol secretion, H1: Histopathological changes in the ovary and uterus, l1: Inhibition of progesterone production (abortifacient), I2: Implantation sites decreased, I3: Increase in uterine, cervical and vaginal weights, I4: Irregular oestrous cycle, I5: Influences the sexual maturity of immature female rats, I6: Inhibited the action of hormone in hCG, I7: Inhibition of uterine activity, I8: Inhibition of delta 5, 3- β hydroxy steroid dehydrogenase and glucose-6-phosphodehydrogenase, I9: Inhibition of heat, I10: Increased progesterone concentration, I11: Inhibited uterine contractility, L1: Lower plasma level of oestradiol, L2: Lower body weight of pups, M1: Mild oestrogenic activity, N1: No effect, N2: No effect on progesterone response of uterus, P1: Prevent or protected or inhibit or interrupt pregnancy, P2: Partial to complete vaginal cornification, P3: Prolonged diestrous phase (prolonged oestrus cycle ), P4: Pregnant mare’s serum gonadotropin, P5: Post-coital contraceptive efficacy, R1: Resin- Rs: Reversible on withdrawal of treatment, R2: Reduction in weight of ovaries, uterus and cervix, R3: Resorption of implants, R4: Reversible on exogenous administration of hydroxy progesterone, R5: Reduction in fertility index, S1: Significant increase in body weight, Ts: Tetanic spasm, U1: Uterotonic, U2: Uterine stimulant, U3: Uterotropic activity, V1: Vagina open, showed cornified and epithelial cells, Pl: Whole plant, Ae Pl: Aerial plant part, Rt: Root, St: Stem, Lf: Leaves or leaf, Bk: Bark, Rt-Bk: Root bark, Bk: Stem bark, Rt Xy: Root xylem, Ep: Epigeal part, Fl: Flowers, Fr Pl: Fruit peel. Pe: Petals, Be: Berries, Fr: Fruit, Ri Fr: Ripe fruit, Ri Fr Ep: Ripe fruit epicarp, Gr Fr Ep: Green fruit epicarp, Un Fr Pu: Unripe fruit pulp, Un Fr Lx: Unripe fruit latex, Sl Fr: Stale fruit, Sd: Seed, sp: Serial part, Rh: Rhizome, Rg: Bulb, Bu: Resinous gum, Tu: Tuber, Ct: Crude papaya latex, Pc: Post-coitally, Ivg: Intravaginal, Iu: Intrauterine, Sc: Subcutaneous, Or: Oral, Ov: Overiectomised, b.wt.: Body weight, Ip: Intraperitoneum, d: Days, c: Cycle, gd: Gestation day, mc: Menstrual cycle |
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The study suggested that MSF was administered at doses of 50, 100, 250 and 500 mg kg–1 b.wt., day–1 for 4 weeks had no developmental toxicity and teratogenicity during implantation and gestation20. The MSF treatment at various dose regimens did not show significant changes in body and organs weight, feeding habit and pre-terminal deaths. Chromosomal aberrations were investigated in spermatogonial cells of albino rats and rabbits, following oral administration of Methanol Sub Fraction (MSF) of papaya seeds. The chromosomal fragments, rings, dicentrics, exchanges, damaged chromosomes and total chromosomal aberrations in MSF treated rats and rabbits did not showed any alterations21. Moreover, oral administration of Methanol Sub-Fraction (MSF) of benzene chromatographic fraction of the chloroform extract of papaya seeds had no lethal effect when administered at 20x CD (Contraceptive dose) for 5 consecutive days in albino rats and rabbits22.
CONCLUSION
The review showed that study for female fertility regulation is being carried out on a large number of plants and derived products. Consap as a spermicide has been licensed to the Hindustan Latex Limited, Mumbai to market the product. Clinical trials are on going with pippaliyadi vati. A microbicide praneem polyherbal tablet (PPHT), as a contraceptive and for management of abnormal vaginal discharge syndrome has been licensed to M/s Panacea Biotec. Carica papaya products may take a great lead as a dual contraceptive which has been found effective for both sexes. At last, for developing a contraceptive from a natural source, a well defined time-bound approach should be adapted.
SIGNIFICANT STATEMENT
| • | The ancient literature described how plant and their derived products contributed in regulating fertility in females |
| • | In this review, status of research on plant derived agents is highlighted |
| • | The plant kingdom stills an essentially unused source of new fertility regulating agents |
ACKNOWLEDGMENT
The authors are thankful to the Head, Department of Zoology, University of Rajasthan, Jaipur, India for providing facilities.