Rising trends towards the development of oral herbal male contraceptive: an insight review

Acknowledging population control to be an essential step for global health promotes wide research study in the area of male contraception. Although there are a great number of synthetic contraceptives available in the market, they have plenty of adverse effects. Different potential strategies for male contraception were investigated over a long period time consisting of hormonal, chemical, and immunological interventions, although these methods showed good antifertility results with low failure rates relative to condoms. This review is based upon the concept of herbal contraceptives which are an effective method for controlling the fertility of animals and humans. This review has highlighted herbal medicinal plants and plant extracts which have been reported to possess significant antifertility action in males. The review considers those plants which are used traditionally for their spermicidal and antispermatogenic activities and imbalance essential hormones for fertility purposes and plants with reported animal studies as well as some with human studies for antifertility effect along with their doses, chemical constituents, and mechanism of action of the antifertility effect of the plants. This review also explains the phases of sperm formation, hormone production, and the mechanism of male contraceptives. As far as the relevance of the current review is discussed, it might be quite useful in generating monographs on plants and recommendations on their use. A lot of the plant species listed here might appear promising as effective alternative oral fertility-regulating agents in males. Therefore, significant research into the chemical and biological properties of such less-explored plants is still needed to determine their contraceptive efficacy and also to possibly define their toxic effects so that these ingredients can be utilized with confidence to regulate male fertility. The new inventions in this field are necessary to concentrate on modern, more potent drugs with less harmful content and that are self-administrable, less costly, and entirely reversible.

the USA, the unwanted pregnancy rate is approximately 45% with the help of the various contraceptive options provided to women [7]. Although female contraceptives are much effective in preventing unplanned pregnancy, giving high yielding results, it cannot be used by a greater proportion of sex due to their profuse adverse effects [8].
Talking about extreme measures, the World health Organization has initiated a population control program that includes trials linked to traditional medical activities [2]. Many methods for induction of infertility are implemented over a long period that involves biochemical, biological, and immunological pathways [9] with the least impact but minimal inadequacy [5]. During ancient times, the human reproduction system was not fully established. Hence, the progress in research could not be put into practice due to unclear mechanisms related to human hormones [10].

Methods and materials
The present study has been geared up with wide-ranging facts of curative plants inhabiting all over the world concerning their accepted tradition by countless ethnic groups for fertility regulation in males. To date, no examination has analyzed the dose, constituents of elements, and mechanism of action of the antifertility effect of plants.
So, information concerning this article has been systematically gathered from the sources of scientific literature, including PubMed, Google Scholar, Science Direct, and Scopus. Simply applicable studies available in the English language were considered. The botanical and English names are considered after validation from available text and database. The criteria followed for the choice of information in this evaluation deliberate folk plant: 1. Found in Ancient Indian medicines 2. With recorded animal studies for effects on infertility as well as those with human studies of antifertility effect Plants, their parts, or their extracts traditionally used for spermicidal and antispermatogenic activities and those that imbalance essential hormones for fertility purposes have been considered as antifertility agents. Furthermore, compounds isolated from plants with attributed potential for fertility regulation are also classified into 6 categories: 1. Phytoconstituents with spermicidal activity 2. Phytoconstituents with antispermatogenic activity 3. Phytoconstituents acts through Sertoli cells 4. Phytoconstituents acts through Leydig cells 5. Phytoconstituents with antimotility activity 6. Phytoconstituents acts by unbalancing hormones The following keywords were used to search the literature in the data sources: oral male contraceptives, herbal contraceptives, antifertility, and male contraception.
The need of male contraceptives-a boon for society!!! Acknowledging population control to be an essential step for global health promotes an opportunity for a large-scale research study in the field of male contraceptives [11]. Male contraceptives originated with the use of a condom in ancient times in Imperial Rome. Researches on male contraception initiated with the sole objective of taking easy targets to the male reproductive system by stopping either the sperm or the testis to function [10]. Although there are a great number of synthetic contraceptives available in the market, they have plenty of adverse effects [5].
Moreover, there is a rise in the need for male contraceptives to avoid unwanted pregnancies because not many men wish to take responsibility for family planning [8]. Also due to the adverse effects of synthetic male contraceptives, the quest for a modern, more effective, more reliable, and less expansive approach is the priority as well as objectives for the pharmaceutical and medical sciences not to forget an unusual self-administration and long-lasting effect of male contraceptives [9]. The new inventions in this field often concentrate on modern, more potent drugs with less harmful content and that are self-administrable, less costly, and entirely reversible [12].
Since ancient times, plants are always regarded as a potent source of nourishment that we require for staying healthy along with their valuable components commonly used for food and nutrition, beverages, cosmetics, dyes, medicines, etc. Herbs are excellent examples of being one of the richest sources of nutrients that aim at protecting and restoring a healthy life [13]. As specified by the World Health Organization (WHO) statistics, almost 65-80% of the world's population relies on plant species and their health care products due to the lack of modern facilities and poor conditions. There is a total of 422,000 plant species that have been recorded all over the world, out of which 20,000 species are acclaimed as wild edible species and less than 20,000 of the same community is consumed as a food supplement for 90% of people around the world, contributing to almost 25% of drug formulations from plants or their extracts [14]. The herbal preparations have been used as an oral tradition. It is becoming more popular and useful in modern times as demand for natural remedies/medicines is increasing every day because of the belief of people that they do not have any adverse effects, a boon in disguise [15]. Continuing the traditional system of medicines, more than 35,000 plant species are being used worldwide for medicinal purposes. Following which, more than 80% of the world population is turning to herbal preparations that contain plant extracts for primary health care [2]. Herbal contraceptives are plant-based contraceptives which are effective methods for controlling the fertility of animals and humans [16]. The chemical constituents of plants such as flavonoids, terpenes, tannins, quinines, diterpenoids, and lactones are apprehended to possess antifertility action through a different mechanism [17]. Different potential mechanisms for male contraception have been studied over a long period of time consisting of hormonal, chemical, and immunological strategies [2,18] though these methods have shown better results of antifertility effects with minimum failure rates than condoms.
In recent years, plants have been reported to be used in the regulation of male fertility because of the better compatibility with the human body, better cultural acceptability, and lesser adverse effects giving it an upper hand [19]. As a result, herbal products attract scientists as a primary source of naturally occurring antifertility agents due to little or negligible adverse signs [17]. For instance, in India, several herbal plants have been reported to have antifertility effects that act through the mechanism by suppression of spermatogenesis or by prevention of implantation [20].

Phases for sperm formation
Testicular carries out two primary goals: 1. Testosterone production 2. Spermatogenesis (origin of haploid germ cells) [8] ( Fig. 1) Flow sheet for production of hormones [21] (Fig. 2) Pituitary gonadotrophins regulate the functions of the testicles, with luteinizing hormones (LH) acting on the testosterone and producing interstitial cells and the folliclestimulating hormone (FSH) affecting the cells of the seminiferous tubules. Including the seminiferous epithelium's structural elements, the movement of nutritional growth factor to the haploid germ cells with a near junction in the epithelium for consecutive cells is known as the "bloodtestis barrier." Well-performing Sertoli cells supply sufficient mitogens, distinct factors, and energy sources to the growing germ cell, as well as shielding them from the host's own immune system from harmful agents. The number and function of the present Sertoli cells define the spermatogenesis rate and quality [22].
Male contraceptives might work as follows:

Phytoconstituents with spermicidal agents
Ideal spermicidal characteristics include the following: would rapidly and irreversibly achieve sperm immobilization, are not harmful to the vaginal and penile mucosa, do not have any side effects on the growing fetus that are free from long-term topical and systemic toxicity, and should not be ingested systemically [23]. A typical lipid bilayer consisting of outer, intra, and transmembrane proteins is a key component of the plasma membrane of sperms. This lipid bilayer associate with saponin molecules, impacting cell membrane glycoproteins and altering ionic movement across the membrane, resulting in many plants (Phytolacca dodecadra, Calendula officinalis, and Acacia caesia) differing [24]. Sperm immobilization can be caused by the acid pH of lemon juice through the denaturation of ATPase dyein [23].

Phytoconstituents with antispermatogenic activity
The spermatogenesis process involves a complex process: 1. Spermatocytogenesis

Spermatidogenesis 3. Spermiogenesis
A diploid spermatogonium undergoes mitotic division in the process of spermatocytogenesis and develops two diploids known as primary spermatocytes. Every primary spermatocyte divides into two haploid secondary spermatocytes by meiosis. Spermiogenesis is the process of spermatid differentiation into mature sperm. It indicates interference in the steroidogenesis when the cholesterol level rises and sudanophilic lipid accumulates [25].

Phytoconstituents acts through Sertoli cells
Sertoli cells are columnar with oval or pear nuclei and thin mitochondria; at the base of their cytoplasm, they have lipofuscin and lipid droplets. The main feature of Sertoli cell structural support for germ cell development is the blood test barrier, which is situated between neighboring Sertoli cells in close junctions. Sertoli cells play an important part in the process of spermatogenesis and adult life as a whole. The plant extracts kill the viability and work of Sertoli cells and have various effects on spermatogenesis, such as reducing the nuclear and cytoplasmic volume and vacuolizing Sertoli cells [26].

Phytoconstituents acts through Leydig cells
Leydig cells are polyhedral with a large prominent nucleus, an eosinophilic cytoplasm, and various vesicles packed with lipids. The hormone-releasing gonadotropin, secreted and synthesized by the hypothalamus, produces and releases LH and FSH from the pituitary gland. LH induces the production of testosterone in the testis Leydig cells [27].

Phytoconstituents with antimotility activity
The sperm passes through three sections of the caput, corpus, and cauda epididymis that are important for sperm maturation [28]. Therefore, the production and secretion of proteins through the epididymis and the completion of various morphological, biochemical, and motile properties during the transformation from epididymis are important for the spermatozoa's full capacity to fertilize [29].

Phytoconstituents acts by unbalancing hormone
Hypothalamus, pituitary gland, and testis secrete the various hormones which regulate spermatogenesis [30]. The Leydig cells synthesize and secrete the major male sex hormone testosterone under the influence of pituitary gonadotropin luteinizing hormone (LH). Several plant products are considered to contain enzymes that are used in androgen synthesis [31]. Quassia Amara's blunt methanol extract shows lower levels of testosterone, LH, and hormone-stimulating follicles (Fig. 3) ( Table 1) Epidemiological studies have shown that the use of combination oral contraceptives increases the possibility of brain thrombosis; enhances the serum triglyceride, high-density lipoprotein (HDL), and cholesterol levels; and also increases family mortality related to cardiovascular diseases as well as malignant tumors in any organ, low resistance to glucose or insulin, diarrhea, abdominal pain, fatigue, hypertension, and menstrual shifts [2].
Patents available are shown Table 2.       use. Therefore, this review has highlighted the significant antifertility activity of herbal medicinal plants and their extracts. Moreover, this review can concentrate the interest of researchers on toxicity studies of phytoconstituents and their clinical trials, which may serve as an alternate potential antifertility agents with milder or fewer side effects and can be developed into suitable contraceptive formulations. Therefore, significant research into the chemical and biological properties of such lessexplored plants is still needed to determine their contraceptive efficacy and also will possibly define their toxic effects so that these ingredients can be utilized with confidence to regulate male fertility.