WO2016123650A1 - Methods and compositions for extending reproductive life using beta-cryptoxanthin - Google Patents

Abstract

Methods and compositions for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve are disclosed. The methods may involve administering a therapeutically effective amount of beta-cryptoxanthin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof to a female subject. The bCX may be administered in combination with a contraceptive agent and/or a multivitamin agent.

Description

METHODS AND COMPOSITIONS FOR EXTENDING REPRODUCTIVE

LIFE USING BETA-CRYPTOXANTHIN

TECHNICAL FIELD

[0001 ] The present invention relates to methods and compositions for delayin the onset of .menopause and/or slowing the rate of loss of ovarian reserve.

PRIORITY DOCUMENT

[00021 The present application claims: priority from Australian Provisional Patent Application No 201590034 titled "Method and. composition for extending teproctactive life" filed on 4 February 2015, the content of which is hereby incorporated by reference in its entirety,

BACKGROUND

[0003] A woman is born with her total oocyte compliment (ie a pool of approximately 1 -2 million primordial follicles) and cannot generate an new oocytes from this time forward.. The total compliment of oocytes within a woman's ovaries is termed the "ovarian reserve" (te Velde and Pearson, 2002).

[00041 Typically, only a few hundred oocytes will ever reac maturity and be lost through Ovulation. The remaining primordial follicles (oocytes) are lost through natural apoptotic (programmed cell death) attrition. Once the primordial pool of oocytes is totally depleted, a woman will enter menopause and become sterile. The rate of loss of rimordial follicles by apoptotic attrition varies amongst individuals, resulting in widel varying differences in the age of onset of menopause (and a .corresponding onset of sterili ty) . While the average age of menopause in the Caucasian population is 51 years, 10% of the female population will be menopausal by 45 years, \% by 40 years and approximately S in a 1000 women will be menopausal by 3 years of age (te Velde and Pears on, 2002) .

[0005) Epidemiological surveys in populations that do not use any form of contraception have reported that the average age of a woman at the birth of her last child is 40 years. That is, half of all non- contraeepting women are unable- to conceive any more children at the age: of 40, despite being fertile in the past (Tietze, 1957; te Velde and Pearson, 2002). This onset of secondary infertili ty is due to a reduction in ovarian reserve, both from a quantitative and qualitative perspective. Interestingly, the vast majorit -of these women still have a regular menstrual cycle an are othenvise wiaware of their critical loss of ovarian reserve_* Therefore, there appears to be at least a decade of disconnect between the average age of onset of menopause and terminal, loss of ovarian reserve from a fertility perspective. If the rate of loss of ovarian reserve- can be slowed, then it may be pos sible to delay the onset of menopause, thereby resulting In atv extension of a woman's reproductive lire.

[0006 ] Loss of ovarian reserve is a relatively new cause for primary infertility, with its onset being linked to the development of safe and effective reversible contraception and the professional/educational enianc i patiofl of women that occurred from the 1960's . Before this time, the a verage age of a woman at the time of the birth of her first child was around 23-25 years in tire developed world. No . with the advent of better education and career advancement for women, and empowered by effectiv

contraception, the average age of a woman at the birtli of her first child is aro nd 28-30 years, depending on the country surveyed (Tremelle and Savuleseu, 2014). While loss of ovarian reserve may have limi ted a pre-:! 960's woman from having her third or subsequent child, it was highly unlikely to produce ^•primary infertility as only 0.1% of the population have terminal loss of ovarian reserve in their early 20's, However, since 10% of the population, are menopausal by 45 years, thereby experiencing "terminal loss" of ovarian reserve from a fertility perspective by thei mid-30's, a ver significant proportion of women today will experience difficulties in having a child if they delay conception until their earl to mid-30's. This is especially a major concern for the professional eiass, as the majority of these women have not started their family by 30 years of age. involuntary childlessness from age related loss of ovarian reserve is a significant concern for many wome and their partners. j 00071 An early onset of menopause has also been linked with increased risk: of cardiovascular disease, atherosclerosis, stroke and osteoporosis. Overall, ail-cause mortality has been found to be reduced b 2% with, each increasin year of age at natural menopause (Schoenaker et at, 2014). Thus, any dela in the onset of menopause, even by just a couple of years, has significant potential to protect reproductive capacity in mid-life, while also improving_. general physical and mental health and reducing mortality later in life.

[0008] Given the strong association between mothers' and daughters' age at natural menopause (Mishra et ciL, 2007, Torgerson et «/., 1997), there would appear to be a significant genetic component determining the time of onset of menopause, which is of course not open to modification. Ho wever, siiidies suggest that somewhere ^'between 1.5 and 70% of the variabil ity in the age of onset of menopause is non-genetie in origin and therefore potentiall modifiable (Gold, 201 .1 ). Previous studies have examined, the correlations between lifestyle factors such as diet, exercise and smoking on age of onset of menopause. The relationship between diet and onset of menopause is reported to be complex and, in many instances, the findings are inconsistent or even contradictory. For example, one study reported an earlier onset of menopause in vegetarians compared to omni vores (Baird et at, 1 S8). A high intake of fat was associated with a later onset of menopause in one German study (Nagel. et at, 2005), yet. no

relationship was seen between fat intake and menopause in two large Asian studies (Dorjgochoo et^'at. 2008, Nagata et af, 2000). However, the majority of studies appear to report a consistently positive correlation between protein intake and delayed onset of menopause (Dorj ochoo ei at.. 2008, Gold, 2 1 1. Nags! at int., 2005). One study found no significant correlations between dietary intake of Vitamin A, Vitamin C, Vitamin E, carotene and calcium micronutrietits and onset: of menopause (Nagata ei a/., 2000),

[0009] There is thus a need to provide a means of delaying the onset of menopause and/Or slowing: the rate of loss of ovarian reserve to extend a ^'woman's reproductive life.

SUMMARY

[001 ] According to a first aspect, provided herei is a method of delaying the onset of menopause and/or slowing the rate of loss of ovariao reserve, said method comprising administering a therapeutically effective amount of beta-crypto artthirt (bCX) or a pharinaeeutieally acceptable salt, solvate or prodru thereof to a female subject.

[001 1 1 in certain embodiments, the method comprises administering from about 5 micrograms (pg) to about 10.000 pg per day or about 400 jig. to about 1200 pg pe d ay of bCX or a pharmaceutically acceptable salt solvate or prodrug thereof to the female subject.

10012] Ift certain embodiments, the method comprises administering from about 140 pg to aboiit 310,000 pg per month of bCX or a phannaceutic y acceptable salt, solvate or prodrug thereof to the female subject.

[0013] In certain embodiments, the bCX or phamiaeeutiealiy acceptable salt., solvate or prodrug thereof i administered in combinatio with a contraceptive agent. Alternatively, or in addition, in other certai embodiments the bCX or pharmaceutically acceptable salt, solvate o prodrug thereof is administered in combination with a iBuiuvitatniri agent.

[ 00141 The bCX may be administered by way of a composition comprising bCX.

10013] Accordingly, in a second aspect also provided herein is a composition for delayin the onset of menopause and/or slowing the rate of loss of ovarian reserve comprising a therapeutically effective amount of a therapeutic agent comprising beta-cryptoxantlHn (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof wherein,_; upon administration to a female subject, the composition delays the onset of menopause and/or slows the rate of loss f ovarian reserve. [0016 ] in certain embodiments of the second aspect, the therapeutical iy effective amount of bC or phanTsaceufically acceptable salt, solvate or prodrug thereof in the composition is from about 5 pg to about 5 grams (g), from about 160 ^ig to about 4800 p.g or from about 400 §· to about 1200 ig.

[0017 ) In certain embodiments of the second aspect, the therapeutic agent consists of bCX or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In other words, there are no other therapeutically acti ve agents hi the CompositiOn. 0018] In certain embodimen ts of the second aspect, the composition is in the form of a non- contraeeptive sugar pill for use in a dail contraceptive regime. In other certain embodiments of the second aspect, the composition further comprises at least one contraceptive agent.

[00 9] In certain embodiment of the second aspect, the composition is in the form of a dosage form that provides a dose of bCX or a pharmaceutically aceeptable salt, solvate or prodrug thereof that i equivalent to a dail dose of from about 5 pg to about 1.0,000 .

[ 0020] The composition may be a pharm aceutical preparati on comprisi n g the composi tion of the second aspect and one or more pharmaceutically acceptable carriers and/or excipients. The pharmaceutical preparation may comprise a plurality of dosage unit Suitable for consecutive daily oral administration.

[ 0021 1 In a third aspect., provided herein is a. combination product for oral contraception and delaying the onset of mcnopan.se and/or slo wing the rate of loss of ovarian reserve, comprising;

21 to 24 contraceptive dosage units, each comprisin an effecti ve amount of at least one contraceptive agent and an effective amount of beta-cryptoxanthin (bCX) or a

phannaeeuttcally acceptable salt, solvate or: prodrug thereof; and

7 to 4,. respectively, .contraceptive agent-free placebo dosage units each comprising an effective amount of bCX or a pharmaceutically aceeptable salt, solvate or prodrug thereof; and, optionally, instructions or indications to show that the daily administration of the 21. to 24 contraceptive dosage. units, is to be followed by daily administration, of 7 to 4, respectively, contraceptive agent-free placebo dosage units,

[0022] In a fourth aspect, provided herein is an injectable dosag form comprising bCX or a

pharmaceutically acceptable salt, solvate or prodrug thereof and one: or more pharmaceutically acceptable carriers and exeipients for del ayin the onset of menopause and/or .slowing, the rate of loss of ovarian reserve,; wherein the dosage form delivers from about 50 p to about 10,000 pg of eta-cryptoxanthm. (bCX) or pharmaceutically acceptable salt solva te or prodrug thereof per dosage form or per day,

[0023 ] In a fifth aspect, provided herein is a subcutaneous implantable dosag form, comprising beta- cryptoxanthin (bQC) or a pharmaceutically acceptable salt, solvate or prodrug thereof and one orraoie pharmaceutically acceptable carriers: and excipients fo delaying the onset of menopause and/or sl owing th e rate of loss of varian reserve, wherein the dosage fbnn delivers from about 50 pg to abou t .10,000 pg of bCX or pharmaceutically acceptabl salt, solvate or prodrug thereof per dosage form or per day,

[0024] In a sixth aspect provided herein is rise of beta-cryptoxanfhin. (bCX) or a pharmaceutically acceptable salt, solvate or prodrug, thereof for delaying the onset of menopaus and/or slowing the rat of loss of o varian reserve in a female subject and/or in the preparation of a medicament tor delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve in a female subject.

[0025] In certain embodiments of the sixth aspect, the bCX or pharmaceutically acceptable salt, solvate or prodru thereof is administered in combination with a contraceptive agent,

[0026] In certain embodiment of the sixth aspect, the bCX is administered in combination with, a multivi amin agent,

[00271 In a sevent aspect, provided herein is a kit comprising beta-ciyptoxanthin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof, at least one contraceptive agent and instructions, for the us e of said kit in a method for delayin the onset of menopause and/or slo wing the rate of loss of ovarian reserve,

[0028] In an. eighth aspect, provided herein is a kit comprising: beia-eryptoxanihin . (bCX) or a

pharmaceutically acceptable salt, solvate or prodrug thereof, at least one multivitamin arid instructions for the use of said kit in. a method for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve.

[0029] hi further aspects, pro ided herein is a method, use, composition, injectable dosage tbrf¾ subcutaneous implantable dosage form and kit for enhancing fertility in a female subject such as an

"older" female subject of≥ 35 years of age. BRIEF DESCRIPTION OF FIGURES

[0030] Figure 1 provides graphical results of a rat study showing the litter size and rat of sterile matiogs in dams mated at 7 months of age. Animals of the. hCX implant group received subcutaneously administered bCX (5 pg/day) from 3 months of age ; and j 0031 ] Figure 2 provides further graphical results of the rat study; this time showing' the lifter size and rate of sterile mat ings in dams m ated at 9 months of age.

DETAILED DESCRIPTION j 003^:2j The present inventors h ve surprisingly found that beta-eryptoxsnthin (structure show below) ean be used to protect arian reserve and delay the o nse t of menopause.

[00331 Thus, in a first aspect, provided herein is a method of delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve, wherein said method comprises administering a therapeutically effective m u t of beta-cryptoxanthin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof to a female subject.

[0034] The term "administering" as used herein includes all means of introducing bCX to the female subject including, but not limited to, oral, intravenous, intramuscular, subcutaneous, transdermal, inhalation, buccal, ocular, sublingual and -rectal, routes.

[0035] Beta-eryptoxanthin ((iQ-3,5,5~triffiethyl-4

J -enyl)-oetadeca-l, 3,5,7,9 ,.1,1, 1.3, 15,17-n^'Qnaenyl]-cyclohex-3-enol) belongs to the class of earotenoids, more specifically the xanthophyils. In plants, earotenoids are involved in light harvesting in

photosynthesis and in protecting chlorophyll from photodamage. In humans, eaiOtenoids act

as anti oxidants and ma inhibit the oxidation of fats (ie lipid peroxidation) under certai conditions, but their actions may also be dependent upon their interaction with other eoantioxidanis, such as vitamins E and C (Young

of D A oxidation^' damage in addition to acting as an antioxidant in huma cells which prevents free radical damage to the cells and DNA (Lorenzo et a!,, 2008). Beta-cryptoxa»min. efficiently deactivates singlet oxygen and has also been. found to stimulate gap junctional communication (Stahl etal, 1997). [0036] The caroten ids alpha-carotene, ^'beta-carotene and bCX also have

vitamin A activity as they are converted to rctinai (Institute of Medicine, Food and Nutrition Board, 2000). Vitamin A is essential for normal growth and development, inumme system function, and vision. The vitami A. activity of bCX and alpha-carotene are both. I /24th thatof tetinol

(ie preformed vitamin A), while the vitamin A activi ty of beta-carotene is 1/ 1.2th thai of rettnoii (institute of Medicine, .Food and Nutrition B oard, 2000) . j 00.371 Two recent studies have raised concerns that: vitamin A may potentiall have an. adverse effect on ovarian reserve if consumed in ^'high quantities (Abali a ., 2013, Sikar Aktiirk ef L, 2013). That .is, isotretinoin, synthetic analogue of vitamin A, commonl used to treat severe acne, has recentl been reported to result in a significant loss of ovarian reserve in both, rodent and human studies (Abali t, 2013, Sikar Aktiirk et l, 2013). There is a concern that long term consumption of high amounts of vitamin A in food or vitamin supplements,, or vitamin A precursors, could potentially result in damage to a woman's ovarian reserve. Nevertheless, the structurally related bCX can be used to protect ovarian, reserve and delay the onset of menopause.

[0038 ] Beta-ctyptoxanthin can be found in many vegetables and . ruits, including papaya, mango, peaches, oranges, tangerines:, bell peppers, com and watermelon. BCX is also found in some yellow coloured animal products such as egg yolk and batter. Further, bCX is found in petals arid flowers of plants in the nus Phymlti and in bovine blood serum.

10039 J The therapeutically effective amount of b K administered to the female subject according to the method described herein should be sufficient to cause a beneficial response in the subject over time. In certain embodiments, the therapeutically effective amount of bCX is between 5 micrograms (pg) and 10 grams (g). in certain specific embodiments, the therapeutically effective amount of bCX is- between 5 ug and 5 g, 10 pg: and 4 g., 25 pg and 3 g, 50 fig and 2 g, 100 pg and 1 g, 200 p and 500 milligrams (nig), 300 pg and 250 mg, 400 pg and 1 0 mg, 500 pg and 50 mg, 600 pg and 25 mg, 700 pg and 10 mg, 700 p.g and 5 mg, 700 and 2500 pg, 80 ug and 200 pg, 800 and 1600 pg, 80 pg and 120 pg, and 900 pg and 11 0 pg, ί 00 and 1100 pg, 1,000 and 5000 pg or any sub-range of these specified ranges, in certain embodiments, the therapeutically effective amount of bCX is about 5, 1 , 25, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200. 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, .2300, 2400, 2500, 2600, 2700, 800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 400, 9500, 9600, 9700, 9800, 9900 or 10,00 ug, about 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 rag, or about 2, 3, 4, 5, 6, 7, 8, 9 or 10 g, an amount between any of these amounts or a range between any of these amounts.

[0040] In certain embodiments, the method relates to administerin a therapeutically effective amount of bCX to the female subject each. day. ^'In these embodiments, the fliefapeutically effecti v amount of bCX administered to the female subject, per day ma be between 5 pg and 10,000 . . In. certain embodiments, the therapeutically effective amount of bCX administered to the female subject per day is: between^{' "}10 and 9000 ug, 25 and 800 μ& 50 and 7000 μ& 100 and 5000 μ_& 200 and 2500 μ& 300 and 1800 μ& 400 and 1200 ug, 600 and 1200 ug, 800 and 11 0 pg, 1 00 and 5000 pg or any sub-range of these specified ranges.

[0041] In certain embodiments, the method relates to administering a therapeutieali effective amount of bCX to the female subject each month, in these embodiments, the therapeutically^' effective amount of bC administered to the female subject per month is about 140 ug (ie the equivalent of 5 μα per day in a 28 day month) and 310 mg fie the equivalent of 10,000 pg per day i a.31 day month). j 00421 The method, may comprise admini stering the dverapeutieaily effective amoun t of bCX to the female subject on. consecutive days or every 2, 3, 4, 5, 6 days, each week, each month, each year, each decade or according to any schedule, provided that the femal subject is administered a dose equivalent to a dail dose of between 5 μ and 1.0,000 of bCX. j 0043 j The bCX may be administered n combination with a contraceptive agent. The contraceptive agent may be se lec ted from any contraceptive agents known to those skilled in the- art. The contraceptive agent may be a single agent or a combination of agents, as is known in the art in certain, embodiments;, the contraceptive agent comprises any one or more of an oestrogen and a progestogen. In certain embodiments, the at least one oestrogen is selected from 1.7-beta-estradiol and ethmyleStTadiol, estradiol, estrop ate, natural conjugated equine estrogens, conjugated syn the lie estrogens, esterified estrogens, estroge suiphamate, estrone sulfate, piperazine estrone sulfate, tnestranol, esttioi, estrone, estradiol valerate, dinestrol, or any combinations: thereof In certain embodiments, the at least one progestogen is selected from gestodene, levonorgestrel, etonogesteroi, desogestreL dienogest, 3-ketodesogestrel, drospirenone, cyproterone acetate, norgestirnate, narelgestromm, nomegestrol acetate, norethisterone, dydrogestcrone, medroxyprogesterone, norgcstrel and nomegestrol acetate.

£0044^') In certain embodiments, the amount of contraceptive, agent administered in combination with the bC is equivalent to daily dose of between 0.001 mg and 200 mg of the contraceptive agent, in certain embodiments, the amount of contraceptive agent administered in combination with the bCX is equivalent to a daily dose of between 0.001 mg and 10 mg, 0.001 mg and 50 mg, 0.001 mg and 25 mg, 0.0 1 and 10 mg, 0.01 and 5 mg, 0.01 and 3 mg, 0.01 and 2 mg, 0.01 and 1 mg or any sub-range of these specified ranges. In. alternative embodiments, the am unt of contraceptive agent administered in combination with the hCX is selected from 0.1 to 6,0 mg of estradiol and 0.0 1 nig to 3 nig of ethinyiestradioi, and 0,01 to 3 mg of gestodene, 0.02 to 0.25 mg of levonotgestrel, 0.02 to 0.5 mg of desogestrel, 0.01 to 0.5 mg of 3- ketodesogestrel, 0. 1. to 6 nrg of drospirenone, 0. 1 to 3 ig of eyproterone acetate, 0.01 to.2 mg of norgestimate, 0,1 to 60 mg of norethisterone, 0,1 to 20 mg ofdydrogesterone, 0,J. to .150 nig of medioxypKjgesterone and 0.1 to 5 mg of norgestrel,

J 00 51 In certain embodiments, the bCX is administered in eombination with a multivitamin agent. The multivitamin agent may comprise any one or more of alpha-carotene,, beta-car oicne, biotin, calcium, chloride, chaudroitin, chromium, copper, coenzyme QiO, a fatty acid such as ome a-3 (eg

eieosapentaenoic acid (EPA.) or docosahexaenoic acid (DHA) or deri vatives thereof) or omega- fatty acid, folic acid, glucosamine, iodine, iron, lutein, magnesium, malic acid, manganese,

methylsolxbnyimeiharie, moi ybdenum, niacin, nicotinamide, pantothenic acid, phosphorus, potassium, riboflavin., selenium, thiamine, vitamin B6, vitamin Sl 2, vitamin C, vitamin D, vitamin E, resveratol (which has been found to protect ovarian reserve in mice; Liu ei l, 2 13), N*acetyl cysteine (NAQ (which has been found to delate oocyte aging in mice; Liu el al 201 ) and zinc. In certain embodiments, the amount of the muiiivitanun agent is about 5, 10, 25, 50. 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1 00, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000. 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4.900, 5000, 5100, 5200, 5300,.5400, 5500, 5600, 5700, 5800, 5900, 6000, 61 0, 6200, 6300, 400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 81.00, 8200, 8300, 8400, 8.500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900 or 1 ,000 ug, about 100, 00, 300, 400, 500, 600, 700, 800, 900 or 1 00 mg, or about 2, 3, 4, 5, 6, 7, 8, 9 or ,1 g, an amount between any of these amounts or a range: between any

0 f these amounts, 0046 j The amount of alpha-carotene administered may be between 1 and 5000 iU, the amount of beta- carotene administered may be between 1. and 5000 IU,. the amount of bi otin administered may be between

1 fi and 5 rag, the amount of calcium adliiinistered may be between 1 mg and 5000 mg, the amount of chl oride administered may be between I nig and 5 g, the amount of chondroitin administered, may be between 1 mg and g, the amount of chromium administered may be between 1 p,g and 1 0 jr , the amount of copper, coenzyme QI O, fatty acid or folic acid administered may be between 5 ^tg and 5 mg each, th e amount of glucosamine, i odine, i ron , lutein, magnesium , malic ac id, manganese,

methylsuifonyimethane, molybdenum, niacin, nicotinamide, pantothenic acid, phosphorus, potassium or riboflavin administered may be between 100 pg and 5 mg each, and the amount of selenium or thiamine administered may be between 1 0 tig and 5 mg each. The amount of vitamin B6 administered may be between 0.1 and 1 0 mg. The amount of vitamin B I administered ma be between 1 and 2.4 . The amount of folic acid administered may be ^'between 200 and 1000 pg„ The amount of vitamin. £

administered may be between 1 and 300 rag. The amount of vitamin C ascorhate or ascorbyi palmitate administered may be between 10 and 500 nig, more preferabl 2 to 200 mg. There may be between 1 and 400 IU of vitamin D . There may be between 1 and 6 of seleni um. There ma be b e tween 1 and 8 ni of zinc. There ma be between 1 and 18 rug of iron , There may be between 500 nd 1 ,000 mg of calcium. There. may be between 50 and 320 mg of magnesium. There may be between.200 and 2000 mg ofresveratol, more preferably between 500 and 1000 mg. There may be between 60 and 1800 nig. of N- aeetyl cysteine.

[0047] In some embodiments (eg where the composition is intended for use in. a subject with a vitamin A deficiency), it may be particularly advantageous for the b. to be administered in combination with vitamin selected from the group consisting of vitamin A, pre-vitami A carotenoids (such as alpha- carotene and beta-carotene) and combinations thereof, in such embodiments, the vitamin A .may be administered in an amount of 1.00 to 5000 IU, more preferably 1500 to 300 Hj. One example of a particularly suitable dose of vitami A is 2600 IU (ie about 770 pg/day). Those skilled in the art will understand that where a pre-vitamin camtenoid is used instead of vitamin A₍ then ecjiii valents amounts (eg in the range of 100 to 5000 IU, more preferably 1500 to 3000 IU) should be suitable.

(00481 if will be evident from the foregoing discussion that i a second aspect, also provided herein is a composition for delay ing the onset of menopause and/or slowing the fate of loss of ovarian reserve. The composition comprises a therapeutically effective amount of a therapeutically effective agent optionally in combination with one or more pharmaceutically acceptable carriers and/or excipients., wherein the therapeutically effective agent, is bC or pharmaceutically acceptable salt, solvate or prodrug thereof and wherei n the composition delays the onset of menopause and or slows the rat of loss of ovarian reserve.

[0049] The composition may be available in. dosage form. The dosage form may be an oral dosage form, a fortified drink product, a fortified food product, a topical dosage form, an injectable dosage form, a subcutaneous implantable dosage form (which may be effective for a period within the range of, for example, 3 months to 3 years), a vaginally iusertabJe dosage form, a transdermal dosage form or a spray.

[0050] The dosage form may contain anywhere from about 0.1 % to about 99.9% of bCX, depending upon the selected dose and dosage form. Dosage forms can be prepared in accordance with generally accepted procedures for the preparation of pharmaceutical preparations as described in Remington'* Mmrma tftt l Sci c&s, 17 th Ed,, 1985.

[005 J. ) In addition to any specific dosages and dosing protocols exemplified herein, it is to be understood that an effective amount of any one or a mixture of the compounds described herein can be readil π

determined by the attending physician by the use of known techniques and/or by observing results obtained under analogous circumstances. In. determining the effective amount of dose, a number of factors are considered by the attending diagnostician or physician, including, but not limited to the female subject's size, age, and general health, the response of the individual patient, the particular compound administered, the mode of administration, die bioavailability characteristics of the preparation

administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances.

[0052 J hi certain embodiments, the bCX is administered in the form of an oral dosag form. The oral dosage form may ^'be a tablet, pill, dragee, capsule, pellet, cap let, gel-cap, multi-particles i sachet, encapsulated form, lozenge, emulsion, lipophilic and liydrophilie suspensions, liquid, gel, syrup, slurry, suspensions and the like, for oral ingestio by the female subject.

[ 0053 ] Optionally., the oral dosage form comprises either one or both of carriers and exeipients. Suitable carriers include but are not limited to starch, sodium lauryl sulphate, Polysorbate 80. Polysorbate 20, pre- geiatinised starch, nonionto surfactants, polyethylene glycol, carnauba wax, water, corn oil, sesame oil, and/or peanut oil Suitable excipients include but are not limited to lactose, lactose monohydrate, macrocrystalline cellulose, methyleelhilose, ethylceOuIose. hydroxypropyimethyleellulose, hydroxypropyi. cellulose, sugar alcohols such as xylitol, sorbitol and/ maltitttL 0054] In embodiments, the oral dosage form further comprises any one or more of additives such as binders, adjuvants, giidants/lubricants, disintegrants, colouring agents, ©pacifiers, flavouring agents, preservati ves, fillers and anti-adherents. Examples of these additives include: binders such as guirt tragacaiith, acacia, com starch or gelatine; adjuvants such as povidone; g ants lubricailts, such as silica or stearic acid and stearic acid salts such as magnesium stearate, sodium stearyl fomarate, leucine, sodium benzoate or oloxamers; disintegrants such as crosslinked sodium carboxymethyi starch, crosslinked sodium earboxymethylcelMose (croscarmellose sodium) and crosslinked poiwinylpyrrolidone; colouring agents, pigments and food grade dyes; opacifiers, such as titaniu dioxide; flavouring agents, suc as sucrose, fructose, corn syrup, vanilla, mint, cherry, anise, peach, apricot, liquorice, or raspberry;

preservatives, such as citric acid, sodium citrate or propyl paraben, fillers such, as macrocrystalline cellulose, cellulose., calcium hydrogen phosphate, mannitol, sorbitol, xylitol, lactose, dicalcium phosphate, calcium phosphate tribasic, calcium sulfate and trietiryl citrate; and anti-adlierents such as magnesium stearate.

[00551 In general, an oral dosage form is prepared b uniformly and intimatel admixing the bQi and any other active agents (if present) with liquid carriers and/or excipients or finely divided solid carriers and/or excipients, or both, and then, .if necessary,, shaping the produc t into the desired presentation.

Compresse tablets can be prepared by compressing in a suitable machine the bCX i a. free-flowing form such as powder or granules,, option ally mixed with an exeipient, a. binder, a lubricant, a filler and/or a disiniegrant Moulded tablets can be made b moulding i a suitable machine a mixture of the powdered compound moistened with a inert liquid diluent.

}0⁽⁾S6) The oral dosage form may be adapted for any one or more of immediate release, sustained release and delayed rel ease. For example, tablets may be monolithic, have a compressed core or he of .-multi -layer construction, wherein the layers may be arranged in a sandwich-like fashion or concentrically. Tablets may be- uneoatcd or they may be coated using conventional techniques, such as those described in Encyclopedia of Pharmaceutical Technology, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period. The coating may be adapted to release the bCX and any otlier active agents (if present) in. a predetermined patter (e in order to achieve a controlled release- formulation) or it may be adapted not to release the bCX and any other active agents (if present) until after passag of the stomach (enteric coating). For example, a time delay material such as glyceryl, monostearate or glyceryl distearate can be employed to delay tablet disintegration. Illustrative sustained release formulations are described in United States Patent ^"Nos, 3,847,770, 3, 16,11 9, 3,536,809, 3,598,123, 3,630,200, 4,008,719, 4,687,610, 4,76:9,027, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,566, and 5,733,566, the disclosures of which are incorporated herei by reference, j 00571 Othe oral dosage forms include; hard gelatin capsules (ie push-fit capsules) wherein the-bCX is mixed with an inert solid diluent, for example, calci um carbonate, calcium phosphate or kaolin, and a filler such as lactose, binders suc as starches,, and/or lubricants such: as talc or magnesium stearate; and soft gelatin capsules made of gelatin and a plastieiser, such, as glycerol or sorbitol, wherein the bCX is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil, j 0058 ] in certain embodimen ts, tire bCX is administered in the form of a fortified drink or food product. As used herein, die term "drink" includes any solution which is suitable for a person to drink. As would be known to those skilled in the art, a fortified drink product is any drink that contains biologically active components that provide health benefits or desirable physiological effects: beyond basse nutrition.

Similarly, and as would. ^'be known to those skilled in the art, a fortified food product is any food or part thereof that contains biologically active components that provide health benefits or desirable

physiological effec ts beyond basic nutrition. Fortified drink and food products are usually of plant origin, but may also be of, for. example, animal, fungal, or microbial origin, or from expression in plants, animals or microbial organisms, using recombinant DMA techniques, A fortified drink product may comprise a processed product, a fermented product, an extract or an fortified drink. Examples of fortifie drink products are water, fruit j uice, plant and animal based milks, and soft drinks such as cola. A fortified food product may comprise a processed product, fermented product, an extract, a beverage or a whole food. Examples of possible fortified food products are bread and other baked products, pasta, flour, breakfast cereals, snack foods such as muesli bars, yoghurt., ice cream, butter, margarine arid torn. In embodiments, either or both of the fortified drink product and fortified food produc t is adapted for any one or more of immediate release, sustained release and delayed release.

[0059] As used herein, "topical dosage form" includes any therapeutically effective pharmaceutical dosage form, for administering topically on the skin for percutaneous a sor tion. Topical dosage forms include water-in- oil emulsions such as: ointments, and oil-in water emulsions such as: creams, balms-, lotions, liniments, foams, gels, hydrogeis, solutions, s spensions, sticks, sprays, pastes, piasters, tinctures and other kinds of transdermal drug delivery systems. The topical dosage .form may additionally comprise conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes, emulsifying agents, antioxidants, buffering agents, preservatives, humeetants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes,_, and skirt protective agents, in embodiments, the topical dosage form includes a patch. In embodiments, the topical dosage for is adapted for any one or more of immediate release, sustained release and delayed release.

10060] As used herein, an "injectable dosage: form" includes a dosage form, adapted for parenteral administration. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intramuscular and subcutaneous, as well as any other con ventional, routes of parenteral administration. Suitable means of parenteral administration include needle (including microneedle) injectors, needle-free injectors an infusion tec!miques, as well as airy other means of parenteral

administration. In embodiments, the injectable dosage form includes -a liquid, a solid, or a Jow^rable composition. In embodiments, the injectable dosage form is adapted for any one or more of immediate release, sustained release and delayed release. Injectable dosage forms are typically aqueous solutions which ma additionally comprise appropriate proportions of: excipients such as water, saline, dextrose, glycerol, ethanol, or the like:; stabilisers such as chelating agents like ethylenediaminetetraacetic acid (EDTA) and its salts, citric acid and its salts or mtrilo acetic acid derivatives and its salts; antioxidants such as sodium bisulphite, sodium metabisulphite, cysteine hydrochloride, thiol acetic acid or phenolic grou derivatives., butyktecl hydroxy anisole arid its derivatives, parabeiis and its salts; wetting or emulsifying agents and pH bufferin agents (preferably at a pH in the range from about 3 to about 9), but, fo some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-frce water. The preparation of injectable dosage forms under sterile conditions, for example, by lyophilisation, may readily be accomplished using conventional pharmaceutical techniques,

[0061 ] As used herein, a "subcutaneous implantable dosage form" includes a biodegradable flowabk composition (eg .as disclosed in United States Patent No. 8,921,387), a biodegradable rod or similar shaped dosage form or a nondegradable reservoir such as a polymeric material (eg as disclosed in United States Patent No, 5,088,505), osmotically driven device (eg as disclosed in United States Patent Kos. 3,987,790, 4,865,845, 5,057,318, 5,059,423, 5.112,61.4, 5,137,727, 5,234,692 and 5,234,693, the disclosures of which are incorporated herein by reference) or an impermeable reservoir with a semipermeable plug. In embodiments, the implantable dosage form is adapted for any one or more of immediate release, sustamed release and delayed release. Accordingly, in embodiments, the implantable insatiable dosage form is capable of the controlled release of the bCX over a period of ti me. In accordance with the above described daily dose ofhCX, if an implantable insertable dosage form is administered once per year, the implantable insertable dosage form comprises at least 365 times the minimum daily dose of bCX. Similarly, if the implantable insertable dosage form, is administered at any other interval, such as monthly, biamiually or every three years, the implantable dosage form will contain sufficient bCX to administer the minimum daily dose.

[0062] As used herein., a 'Vaginally insertable dosage form" includes a dosage form adapted for insertion into the vagina or the uterus of a female such as a vaginal tampon, dissolvin or non-dissolving, intrauterine device (lUD), degfadable or non-degradable vaginal foam, tampon-like foam, or any other vaginal device, such as pessary, sponge, iabletj suppository, pellet, ring but also a vaginal applicator or any other structure generally insertable into vagina. In embodiments, the vaginally insertable dosage form is adapted for any one or more of immed iate release, sustained release and delayed release. Accordingly, in embodiments, the vaginally insertable dosage form' comprises: a core of suitable polymeric matrix, impregnated with the bCX and enveloped by a perraeable membrane for controlling sustained release of the bCX into the uterus cavity ov er a prolonged time, in accordance with the above described daily dose of bCX, if a vaginally insertable dosage form: is administered once per year, the vaginally insertable dosage form, comprises at least 365 times the minimum daily dose of bCX. Similarly, if the vaginally insertabie dosage form is administered at any othe interval such as monthly, biamiuall or e er ' three years, the implantable dosage form will contain sufficient bCX^'to administe the minimum daily dose.

[00631 The therapeutically effective amount of bCX in the dosage form may be between 5 micrograms: (ug) and 10 grams (g). in certain embodiments, the thera entically effective amount of bCX is between 5 pg and 5 g, 10 pg and 4 g. 25 pg and 3 g, 50 pg and 2 g, 100 ug and g, 200 μ-g and 500 milligrams (mg), 300 pg and 250 m _* 400 pg and 100 mg, 500 pg and 50 mg, 600 pg and 25 mg, 700 ug and 10 mg, 700 pg and 5 mg, 700 and 2500 pg, 800 pg and 2000 pg, 00 and 1600 pg, 800 pg and 1200 pg, and 900 pg and 100 p , 1 0 and 1 100 pg, 1600 and 4800 pg, 400 and 1200 pg, 1000 and 5000 pg or any sub-range of these specified ranges, in certain embodiments, the therapeutically effective amount of bCX is about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, J 700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600. 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5 00, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, ί>000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 8100, 8200, 8300, 8400. 8500, 8600, 8700, 8800, 8900, 9000, 9 00, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900 or 10,000 ¾ about 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 nig, or about 2, 3, 4, 5, , 7, 8. or 10 g. an amount: betwe en any of these amouats or a range be tween any of t hese amounts.

1 0641 In embodiments, the composition further comprises one or more pharmaceutically acceptable carriers and/or excipients. In alternative embodiments, the composition, docs not comprise one or more pharmaceutically acceptable carriers aad'or excipients. Accordingly, in embodiments, pharmaceutically acceptable carriers and/or excipients are optional. In embodiments, the composition further comprises additives.

J006 J In certain embodiments, the only therapeutically effective agent present in the composition is bCX. Fo example, the composition may take the form, of a non-contraceptive sugar pill for use in a daily contraceptive regime. Therefore, in certain embodiments, tire composition will not comprise any other therapeutically effective agents such as hormones, hormone agonists (eg GnRB agonists such as

desloreim)- or antagonists (eg GnRH agonists such as cetrorelix), antibiotics, antibodies, antiinflammatories, sedatives or pain killers. j 0066 ] In certain embodiments, the dosage form provides a dose of^'bCX equivalent to daily dose of between 5 and 10,000 p.g. In alternative embodiments, the dosage form provides a dose of bCX equivalent to a daily dose of between 10 and 9000 pg, 25 and 800 , 50 and 7000 ug, 100 and 5000 pg, 200 and 2500 pg, 30 and 1800 μ§, 400 and 1200 μ§, 600 and 1200 μ¾ 800 arid .1.100^' pg, 1000 and 5000 pg or any sub-range of these specified ranges, hi certain embodiments, the dosage form provides a dose ofbCX equivalent, to a daily dose of between 400 and 1200 ug.

[0067] In certain embodiments, the dosage form provides a dose ofbCX each month that is equivalent to a daily dose of between 5 and 10,000 ug. Accordingly, in certain embodiments:, the dosage form provides a dose o CX each month that is betwee about 140 ug (!e the equivalent of 5 g;pef day in 28^' day month) and 31 mg (ie the equivalent of 10,000 pg per day in. a 31 day month),

(00681 in certain embodiments, the dosage form is adapted to. provide a dose of bCX on consecuti ve days or every 2, 3, 4, 5, days, each week, each month, eac year, each decade or according to any schedule provided that the dosage form. is adapted to provide dose equivalent to a daily dose of between S and 10,000 pg of bCX.

100691 In certain embodiments, the composition further comprises a contraceptive agent. The contraceptive agent ma be selected from an contraceptive agents known in the art I embodiments, the contraceptive agent comprises any one or more of an oestrogen and a progestogen. In embodiments, an at least one oestrogen, is selected from t7befa-estradial and etlnnylesi^'radiai, estradiol, estropipate, natural conjugated equine estrogens, conjugated synthetic estrogens, este.rifi.ed estrogens, estrogen sulphaniate, estrone sulfate, piperazine estrone sulfate, mestranol, esftriol, estrone, estradiol valerate, dinestroi, or any combinations thereof,: in certain embodiments, the at least one progestogen is selected from gestodeiie, levonorgestrel, eionogssterol, .desogestrel,. dienogest, 3-ketodesogesirel, drospirenone, cyproterone acetate, norgestimate, norelgestromm, nomegestroi acetate, norethisterone, dydrogesterone,

medroxyprogesterone, norgestrel and nomegestroi acetate, j 0070] In certain embodiments, the. composition comprises a contraceptive agent in an amount that provides- a daily dose of between 0,001 mg and 200 mg of the contraceptive agent. In certain

embodiments, the amount of contraceptive agent in the composition is equivalent to a daily dose of between 0.001 mg and 100 mg, 0.001 mg and 50 mg, 0.001 mg and 25 mg, 0,001 and 1 ø mg, 0.01 and 5 mg, 0.01 and 3 mg, 0.0.1 and 2 mg, 0,01 and 1 mg or an sub-range of these specified ranges. In alternative embodiments, the amount of contraceptive- agenda the composition is selected from 0.1 to 6.0 mg of estradiol arid 0.001 mg to 3 mg of ethinyl estradiol, and 0.01 to 3 mg of gestodene, 0.02 to 0.25 mg of levonorgestrel, 0,02_: to 0.5 mg of desogestrel, 0.01 to 0.5 mg of S-kefodcsogestrel, 0.01 to 6 mg of drospirenone, 0.01 to 3 mg of cyproterone acetate, 0,01 to 2 m of norgestimate, 0,1 to 60 mg of norethisterone, 0,1 to 20 mg of dydiOges terone, 0.1 to 150 mg^' of medroxyprogesterone and- 0.1, to 5 m of norgestxel.

[0071 j In certain embodiments, the composition farther comprises a multivitamin agent. The multiv itamin agent may comprise any one or more of alpha-carotene, beta-carotene, biotin, calcium, chloride, chondroitin, chromium, copper, coenzyme Q10, a fatt acid such as omega-3 (eg.

eieosapentaenoie acid (EPA) or doeosahexaenoie acid (DHA) or derivati ves thereof) or omega-6 fatty acid, folic acid, glucosamine, iodine, iron, lutein, magnesium, malic acid, manganese,

methylsnlfonyimethane, molybdenum, niacin, nicotinamide, pantothenic acid, phosphorus, potassium, riboflavin,, selenium, thiamine, vitamin B6, vitamin B 12, vitamin C, vitamin D, vitamin E, resveratol, N- acetyi cysteine (NAG) aad zinc. In certain embodiments, the amount of the multivitamin agent is about 5, 10, 25, 50, 100, 200, 300, 400, 00, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600,. 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 81.00, 8200, 8300, 8400, 8.500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 93.00, 9400, 9500, 9600, 9700, 9800, 9900 or .10,000 ug, about 1 0, 200, 300, 400, 500,_.600, 700, 800, 900 or 1000 mg, or about 2, 3, 4, 5, 6, 7, 8, 9 or 10 g, an amount betwee any of these amounts or a range between any of these amounts. [0072 ] The: amount of alpha-carotene administered m y be between 1 and 5000 lU, the amount of beta- carotene administered may be between 1 and 5000 113, the amount of hiotin administered ma be between 1 jig and 5 mg, the amount of calcium administered may be between 1 nig and 5000 mg, the amount of chloride administered may b between 1 rag and 5 , the amount: of chondroitin administered may be between 1 mg and 5 g, the amount of chromiiiin administered may be between 3 g and 100 g, the amount of copper, coenzyme QIO, fatty acid or folic acid administered may be- etween 5 ₍ug and 5 rag each, the amount of glucosamine,, iodine, iron, lutein, magnesium, malic acid, manganese,

methylsulfonylmethane, molybdenum, niacin, nicotinamide, pantothenic acid, phosphorus, potassium or riboflavin administered may be between 100 ug and 5 mg each, and the amount of selenium or thiamine administered may be betwee 100 pg and 5 mg each. The amount of vi tamin B6 administered may be between 0.1 and 100 mg. The amount of vitamin B 1.2 administered may be be tween 1 and 2.4 μ§. The amount of folic acid administered may be between 200 and 1000 pg. The amount of vitamin E administered may he between 1 and 300 mg. The amount of vitamin C aseorbate or ascorbyl palmitate administered may be betwee i and 45 mg. There may be between i and 400 ID of vitamin D, There may be between 1 and 60 pg of selenium. There may be between 1 and 8 mg of zinc. There may be between 1 and 38 mg of iron. There may be- between 500 and 1,000. mg of calcium. There may be between 50 and 320 nig of magnesium. There may be between.200 and 2000: m of resveratol, more preferably between 500 and 1 00 mg. There may be between 600 and 1800 rag of -acetyl cysteine.

[0073] Also provided herein is a pharmaceutical preparation which comprises the composition as described herein, in combination with one or more pharmaceutically acceptable carriers and/or exeipienis. .in. certain embodiments, the pharmaceutical preparation further comprises additives. In certain embodiments, the pharmaceutical composition further comprises any one or both, of at least one contraeeptiv¾ agent: and at least one multivitamin agent as: described herein. 0074] in certain embodiments, the pharmaceutical preparation is an oral dosage form. Accordingly, the pharmaceutical, preparation may take the form, of a tablet, pill, dragee, capsule, pellet, multi-particles in sachet, encapsulated form, lozenge, emulsion, lipophilic and hydrophilie suspensions, liquid;, gel, syrup, slurry, suspensions and the like, f r Oral ingestion.

1 0751 In embodiments, the pharmaceutical preparation consists of a number of daily dosage units adapted for consecutive daily oral administration. Accordingly, the pliarmaceUtical preparation may form a number of daily dosage units that are part of a daily dosing regimen, in embodiments, the daily dosage uni s are non-contraceptive sugar pills for use in a daily contraceptive regime. In embodiments, the daily dosage units are contraceptive pills for use in a daily contracepti ve regime, In embodiments, the daily dosage units ma be separately packed and individually removable. In embodiments, the daily dosage units comprise at least 28 separately packed and individually removable dosage units adapted for consecutive daily oral administration for a period of at least 28 consecutive days. Accordingly, the daily dosage units ma form part of a 28-day ki t. In embodiments, the 28-da.y kit is a daily contraceptive regime. Moreover, the daily dosage units may be provided in a produet comprising multiple dosage unils comprising the composition of the invention, wherein each dosage unit is adapted for daily oral administration.. Accordingly, the product may comprise biisterpack comprising a card, one or more blisters on at least, one side of the card and one or more dosage units in each blister. In alternative embodiments, more than one dosage unit may be stored together with instructions for daily oral

administration. In embodiments, the dosage units can be numbered. In embodiments,, the dosage units can be designated by days of the week. The product can include a weekly, biweekly, monthl or annual supply of dosage units. I : other embodiments, the product comprises at least one dosage unit comprising the composition of the invention in combination with a Contraceptive agent and at least one dosage unit comprisin the composition of tile in ention., wherein the dosage units are adapted for daily oral administration. Accordingly, the product may comprise at least one- contraceptive pill and at least one non-contraceptive sugar pill, for use in a dail contraceptive regime,

}0(i761 In a third aspect, provided herein is. a combination product for oral contraception and delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve, comprising:

2_.1 to 24 contraceptive dosage units, each comprisin an effective amount of at least one contraceptive agent and an effective amount of beta-cryptoxa thin (bCX) o a

pharmaceutically acceptable salt, solvate or prodrug ^'thereof; and

7 to 4, respectively, contraceptive agent-free placebo dosage units eaeh comprising an effective amount of bCX or a pharmaceutically acceptahk salt, solvate or prodrug thereof; and, optionally, instructions or indications to show that the daily administration of the 21 to 24 contraceptive dosage units, is to be followed by daily administration of the 7 to 4, respectively, contraceptive agent-free placebo dosage units.

[0077] In a fourth aspect, the present invention relates to an injectable dosage form comprising beta- cryptDxan in (bCX) or a pharraaceutieaily acceptable salt, sol vate or prodrug thereof and one or more pharmaceutically acceptable carriers and e cipients for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve,- wherein the dosage form delivers 50 to 1 ,000 pg of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or per day.

[0078] In a fifth aspect, provided herein is a subcutaneous implantable dosage form comprising beta- erypfoxanthm (bCX) or a pharmaceutically acc eptable salt, solvate or prodrug thereof and one or more pharmaeeuti caliy acceptable carriers and excipients for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve, wherein the dosage form delivers from about 50 pg to about 1⁽ ,0⁽M⁾ p of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage fprra or per day.

[0079 ] In a sixth aspect, provided ^'herein, is the use of beta-er ptoxanthm (bCX) or a pharniacevitieaily acceptable salt, solvate or prodrug thereof for delaying the onset of menopause and/or slowing the rate of lo ss of o varian res erve in a female subjec t aftd/dr in t he preparation of a medicament for delaying the onset of menopause and/of slowing the rate of loss of ovarian reserve in a- female subject.

[0080] in certain embodiments of the sixth aspect, the beta-eryptoxaothm (bCX) or pharmaceutically acceptable salt, solvate or prodrug thereof is administered in combination with a contraceptive agent.

[0081] n certain embodiments of the sixth aspect, the bC or pharoiaeeutically acceptable salt, sol vate or prodrug thereof is administered in combination with a multivitamin agent.

[0082] In a. sevent aspect, provided herein is a kit comprising beta-eryptoxanthm. (bCX) or

pharmaceutically acceptable salt, sol ate or prodrug thereof, at least one contraceptive agent and instructions for the use of said kit in a method for delaying the onset of menopaus and/or slowing the rate of loss of ovarian reserve.

[0083 J in an eighth aspect, provided herein is a kit comprising beta-eryptoxanth i (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof, at least one - multivitamin and instructions for the use of said kit i a method for delaying the onse of menopause and/or slo wing the rate of loss of ovarian reserve.

[0084] It is considered, that the inventors' finding that bCK. can be used to protect ovarian reserve and delay the onset of menopause, and the results provided i di examples provided herein, tarther support the use of bCX for enhancing fertility in "older" female subjects (eg female subjects o£> 35 years of age). The effect of the bCX in this context may include, for example, tire preservation of primordial follicles (eg through reduction of natural apoptoti c attrition) and/or an increase in the rate of oocyte maturation and ovulation.

[0⁽3851 Thus, i a ninth aspect, provi ded herein is a method of enhancing future fertility potential in a female subject, said method comprising administering daily or substantially daily a therapeuticall effective amount of beta-cry toxanthin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof to the female subject for a period of 3 years preceding a planned pregnancy or older age at which she desires to preserve the possibility of a pregnancy. [0086 ] The: metho d of the ninth aspect may be suitable for a female subject pl anning, a . pregnancy, or wishing to preseve the possibilit of a pregnancy, as an " older" female subject of > 35 years of age (eg female subjects planning a pregnancy at 35-45 years of age, 40-45 years of age and 45 years of age). Preferably, the daily or substantially daily administration o f the bCX or a pharmaceutically acceptable salt, solvate or prodrug thereof, is for a period of > 5 years, more preferabiy > 7 years and, still axo preferably, 10 years preceding a. planned pregnancy or older age at which she desires to preserve the possibility of a pregnancy. Ideally, the daily or substantially daily administration of the bCX or a pharmaceutically acceptable salt, solvate, or prodrug thereof, will commence when the female subject is of 20-25 years of age.

[0087] The method may be performed in accordance with certain embodiments as described above in. respect of the method of the fi st aspect. Accordi gly, the method of enimncing future fertility potential in a female subj ect may comprise administering from about 5 micrograms (ug) t about 10,000 pg_: per day or about 400 pg to about 1200 g per day of bCX or a pharmaceutically acceptable salt, solvate or prodrug thereof to the female subject. Also, the method ma for example, involve administering the bCX o pharirsaeeutically acceptable salt, solvate or prodrug thereof in combination wit contraceptive agent and/o multivitamili agent.

(00881 To tenth aspect, provided herein is a composition for enhancing future fertility potential in a female subject comprising- a therapeutically effective amount of a therapeutic agent comprising beta- cryptoxantliin (bCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00891 In certain, embodiments' of the tenth aspect, the therapeutically effective amount: ofbCX or a pharinaceuticaiiy acceptable salt, solvate or prodrug thereof in the composition is front about 5 ug to about 5 grams (g), from about 1600 pg to about 4800 pg or from about 400 ug to about 1200 ¾. Also, in certain embodiments of the tenth aspect, the therapeutic agent consists of bCX or a pharmaceuticall acceptable salt, sol vate or prodrug thereof. In other words, there are no other therapeutically active agents in the composition.

[0090] The composition may be provided, for example, in an injectable dosage .form (which may deli ver, fo example, from about 50 ug to about 10,000 pg of bO£ or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or pe day) or in a .subcutaneous implantable dosage form (which may deliver, for example, from about 50 pg to about 10,000 pg of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or per day).

[0091] in an eleventh aspect, provided herein is a use of beta-cryptoxant n (bCX) or a phannaceuticaliy acceptable salt, solvate or prodrug thereof for enhancing foture fertility potential in a female subject and/o in the preparation of medicament for enhancing future fertility- potential.. in. female subject. [0092] The use may be made in accordance with certain embodiments as described above in respect of the method of the sixth aspect. Thus, tor exam le, the medicament may comprise hC in combination w th a contraceptive agent and/or multivitamin agent

} 0093 ) In a twelfth aspect, provided herein is a kit comprising beta-cryproxanthin (bCX) or a phitrmaceutiealJy acceptable salt, solvate or prodrug thereof at least one contraceptive agent and/or multivitamin and ins raetions for the use of said kit in a method for enlmncing future fertilit potential in a female subject.

[0094 ] The inventio is hereinafter described by way of the following, non-Hmiting examples and accompanying figures,

EXAMPLES

Example 1

[0095 j Raw data were obtained from the Melbourne Collaborative Cohort Study, a large prospective cohort study consisting of 24,469 women aged 2? to 69 years recruited from the. metropolitan area of Melbourne, Victoria, Australia, between 1990 and 1994, whose primary aim was to prospectively investigate the link between diet . nd incidence of cancer (Giles eiaL, 2002). Reproductive life span was not a primary goal of the study., but women were asked about their age of menopause since this is a significant covariant for cancers such as breast carcinoma. Of the women in this study, 1458 provided an age at menopause at follow up intervie where participants ranged from 42 to 64· years: of age. Worsen consuming vitamin supplements (n-3i i) were removed from the data set as it was felt that vitamin supplement use was likely to be sporadic and not. represent average nutrient intake over a prolonged period.

Materials an ' Methods f 00961 Data regarding age, medication, vitamin usage and smoking status were collected. Nutrient intake was assessed using a validated Food Frequenc Questionnaire (Hodge i al., 2000), and then reduced to average daily intakes for the various macro and micro-nutrients. Body height was measured to the nearest 0.1 cm with subjects barefoot in the free-standing position. Body weight was measured to the nearest, 0, 1 kg with subject wearing lightweight clothing and barefoot, BMI was calculated as weight (kg) divided by height squared (m). Descriptive statistics including the mean and standard deviation were calculated using the software IBM SPSS Statistics 20 (version 20,0, 2011; IBM Corporation, Armonk NY, United States of America). A one-way ANOVA was employed to detennine statistical differences age of menopause quiniiies. Pearson's correlation coefficient was computed to identify correlations between, age of menopause a n d. dietary components. Partial correlations were also performed adjusting for BMI, smoking status, total. ener y intake, amount of alcohol consumed- daily and total exercise index.

Regression analysis was. performed using energy intake, BMI, age at baseline, physical activity level, smoking status and amount of alcohol consumed as variables,

Results ami Discussion j 0 7 { Characteristics of t he- study population

Participants had an average age at baseline of 50.7 y ears and reported an -average age of menopause of 51 .7 + 3.2 years with a range of 42 to 64 years. The average BMI of 27.8+5,3 (kg/rrt) as: classified as overweight. The majority of participants were- of Caucasian descent (60.1% Australian, 15.4% Greek. 16.3% Italian). Only 24% of the participants had a tertiary degree or diploma, with the majority of women completing some high school or technical school (39%). Exercise levels suggested thai the population was generall sedentary, with onl 21 % being invol ved in strenuous exercise more than 3 times per week. None of the participants in this group were taking vi tamin supplements as this was an exclusion criterion and 70% were non-smokers, 9% current smokers (more than 7 cigarettes/week) and 21 % had previousl smoked. Full details are contained in Table 1.

(^'0098] Habitua dietar analysi

Overall, the average composition of the diet was 1-9% (E) protein, 46%: (E) carbohydrate, 36% (E) fat representing an average daily intake of 8600+_3263¾. Participants also consumed on. average 4.6+3,7 serves of fruit and 5.1+3.4 serves of vegetables per day. The weekly intake of cereals, dairy, egg, total meat, chicken and fish was 31,7+16,3, 36,2+19.9, 1.9+2.3, 7.7+5.0, 2.4+2,0, J .7+2,2 times per day respectively, and 50.1±64.S ml of vegetable oils or oil blends.

[0099 ] Correlation to the age of menopause

Overall a positive correlation was observed between age of onset of menopause and BMI (r=0.09, p-0.003). Smokers had an average onset of menopause that was 9 months earlier than non-smokers, a difference that was statistically significant (r=0.1 12, p:<0,00.1). No correlation was seen between levels of physical exercise and daily alcohol intake and the onset of menopause. Protein intake (g day) also correlated with age of menopause (r=0.⁽⁾6, p= 0.04), but no significant relationship was noted for other maeronutrients (p>0 ,05 for all). Once adjusted for BMI, the relationship between protein intake and onset of menopause became insignificant.

[00100] in regard to roicromitrients, the age of menopause was only posi ti vely correlated with dietary intake of bCX (pg/day; r-0.105, p<0,0 1;), vitamin C (Γ-Ο,ΟΟ^', p^:-0.04), lutein and zeoxanthin (r-0.06, 0=0.03) and lycopene (r-0,06, p=O.03). Has can be seen in Table 3 , which shows that when the study cohort was divided into cjuintiles based on age of menopause, a clear relationship was seen between bCX intake and age of menopause, with early menopause being associated with the lowest intake of bCX.

[001011 Table 1 ttietar intake vs. age of onset of menopause; subjects were divided

into quintiles based upon their age of onset of menopause, and then the difference in dietary intake (macro- and micro-nutrients)

compared. Results displayed as mean + standard deviation. ^ap<u.&5,

Q 243 Q2 289 Q3 50 Q4 ^ 29 QS .228 iwai- 1146

Sid Sid Srd ^■Sid

Mean Dcv Meaa D*v Mean X>?v Dev Mean IJev Mean Dev

¾ge i!KiH!psmse 47,3 1,8 50.4 0,5 52.0 0, 53.5 0.5 50,1 ! 4 51,7^' 3,2· B I(kgi!iij 5,3 3,0 27.4 5,3 ?.7 7 4. 29.1 6.0 27. s ^■5.3

T'hymai activity

3.6 3.4 3.9 3.7 3.7 3,6 4:0 3.9 3.4 3.3 3.7 3 score

Energy intake

S4 i 3191: 3056 88:7» 324» 8472 imi 8860 3840 8600 3263 • ki <i :

IVot.-m (g/dj

90.8 30.9 ¾!8 32.3 97.J 42 x 92.7 32.8 97.9 41.2 93 5 35.7

Carbohydrates H.IN.

2.33.2 229.9 99.fi 240,0 93.7 232.3 95.7 240.9 122.1 234.7 tf S

9

Γ.ι> (g-'ti) 77.2 30.8 '7₇ *! 30.2 82.3 34. 76.8 30.9 80.4 38.1 78.4 32.»

Saturated fei {g/di

3i.fi •4 2 31.0 13,2 32,9 14.5 31 . 13.5 ? 18.1 1.7 14.7 onounssfcirated

27,3 J 0.7 27.7 11.4 29.6 12 9 27. 11 29.4 13.6 28.2 12.0 fat ( d ;

! i >; S.4 12,0 5,4 12.8: 6.1 11.3 S. l 12.0 6.0 1 1.9 5,6

1st ¾.·' si)

"Fibre (ji/ l) 28,7 13,2 29.5 11.3 31.2 12. i 29.4 10.8 3:2, 1 • I. I 39.1 12.4

Ch lesterol iiiis; dj 2»2 1 17 2«2 136 318 243 283 129 304 158 291 155

Sotiiuai (jiigiti)

2934 1074 2908 930 3117 1208 2919 1082 3067 1298 2976 11 !

Potassium img d)

3727 101:3 ¾7(i8 1839 3860 18) 3739 1702 3956 2217 3789 1907

Calcium (t«g¾)

411 S49 373 891 413 3») m(, 511 864 418

!i.54 739 1638 741 1722 78''. 1663 700 1 35 9® 1677 W

()Hg¾|

Magnesiu

43 271 422 2¾) 433 258 425 257 442 335 430 282 {«¾·<3)

Ireii (tag d)

2T 16 20 17 21 15 2,1 15 21 20 21. I? .'.!¾

12 5 12 13 5 12 5 13 7 12

Thiamin (ittg/d) 2 1 ? 2 7

j^'OGT02j After adjustment for total energy intake, BMl, age at baseline, daily alcohol intake, physical activity levels and smokin status, the. relationship between bCX intake and age of menopause still remained significant (p=Q,03_¾ r=C),07), but was rendered insignificant for vitamin C, lutein and zeoxanthin and lycopene (p>0.05 for all). Overall, no statistically significant relationship was observed between dietary intake of Retinoi. equivalents (ug day),. a-carotene (^tg/day), -earotene.(^g day) and β- carotene equivalent (fig/day) and age of menopause (p 0.05 for all) either before- or after- adjustment.

[00103] Multiple linear regression analysis

Multiple linear regression analysis was used to develop a model for predicting age of menopause from bCX intake, B l at baseline, age at baseline, physical activity level, smoking status, energy intake and alcohol intake. Beta-erypiaxanthin intake predicted the age of menopause when controlling for BM! at baseline, age at baseline, physical activity level, smoking status, energy intak and alcohol intake (p<0. Ol„ r2=0..3?9_? CI [0.000, 0.002] with a j 0 μβ intake/day associated with a 6 week delay in the age of menopause. As shown in Table 2, whe n the bCX intake ug/ ay was split into uiatilcs there was a difference of 1.3 years between those with, the lowest and highest intakes of the nutrient No other micro- nutrient appeared to be significantly associated with age of onset of menopause. [001 4] Table 2 Age of onset of menopause presented as quintiies split by levels of

faCX, Dietary intake of bCX presented as quintiies; dietary in ake assessed using a seif-adiiimistered food frequency questionnaire.

Results displayed as mean + standard deviation. ° <©,0J, ^bp<0.001.

J ^'001 51 The findings are surprising and contrary to what would have been expected based on. the available literature, Beta-cryptoxanthin is a carotenoid that can be converted into Vitamin A within the body (Burri, 2014). As outlined above, two recent studies have raised concerns that Vitami A ma potentially have an adverse effect on ovarian reserve if consumed in high quantities (Abali et at, 2013, Sikar Akturk ei !., 2013); certainly not a protective effect. That is, isotretinoin, a synthetic analogue of Vitamin A commonly used to treat severe acne., has been reported to result in. a significant loss of ovarian reserve in bot rodent and human studies (Abali et a 2 13, Sikar Akturk et at, 2 13). While it is acknowledged that: isotretinoin is a significantly more powerful retinoid form of Vitamin A than that present in a natural diet , there is a theoretical concern that l ong term consumption of high amounts of Vitamin A in food or vitamin supplements, or vitamin A precursors such as bCX, could potentiall result in damage to a woman's ovarian reserve. The present findings teach the opposite; that is, that bCX protec ts o varia reserve and delays the onset of menopause .

[00106] Dosage calculations

The desired dose of bC should be sufficient to render women with low dietary intakes ofbCX replete (ie at the high end of normal consumption levels), without supplementation being excessive so as to cause potential toxicity or .harm.

[00107] The average daily intake ofbCX varies between countries, as would be- expected due to.

differences in food preference and availability of foods rich in bCX (principally citrus and yellow/orange coloured vegetables). Table 3 outlines mean daily bCX intake in various countries, in the Melbourne Collaborative Cohort Study, the mean bCX level was 98± 63 ^ig/day, but in. a much smaller stud of 73 infertile women {unpublished o erviftm iS), the mean bCX level was much lower (1 8±20 pg/day). [001 8] Table 3 Average daily intake of bCX. Average bCX dietary intake from eight

published studies.

[00109] Given the data in table 3 , it would appear that in eounteies such as the United States of America,, bC intake is quite tow (~150 pg/day), requiring an additional 500 pg/day supplement to reach levels see in countries such as Japa and Spain. A previous randomised cross over stud has reported that daily supplementation with 750 pg/day ofbCX at least doubled serum bCX levels (Granado-Lorencio ei al., 2014). A similar doubling in serum bCX levels can be achieved by eating just two Satsuma mandarins per week (Sugiura et al, 2002). Suppienientation with 4.7 mg (4700 pg) ofbCX per day increased serum levels 4-fold in another interventional study (t amoto et /., 20 2).

[0 1. 0 f ^'There does not appear to be any reported adverse effect of bC intake . Se veral studies suggest that bCX may protect against various forms of cancer (revi ewed in .Donaldson 2004), and al so provide some protection against osteoporosis and cardiovascular disease (Ford and Giles 2000, Voutilainen et aL, 2006, Granado-Lorencio et al., 2014). Further, the top tertik of bCX intake i a Japanese population (Sugiura et aL., 2011) was at least 1.0-fold higher than that seen in a typical American diet (1200-7910 pg/day; cf 150 μ§ in typical. American diet), yet this high intake appears to have no adverse

consequences.

[00111 J Taking all of the infonnation contained above, i t is considered that an ide al supplement of^'bCX to protect against ovarian senescence fie slow die rate of loss of ovarian reserve) would contain between 50 and 1000 pa per day. In the present study, there was nearly a 900 pg/day difference in bCX intake between .the lowest a d highest qninti^'le of intake, with a resulting 16 months difference in. age of nset of menopause, Therefore, a preferred supplemental dose would be approximately 1.000 μ§/ day (1 mg day).

Example 2

[00112] A study was conducted where bCX was administered to group of five (3) female albino Wistar rats (sub-cutaneous implant) for a period of three months . The■ administration of the bCX commenced when the rats were at 3 months of age. Making the assumption that a likely therapeutic dose for a 70 kg oman was 1 mg pe day (equivalent to 14 rrtg kg woman/ day), this dose was replicated in the rat model usmg an identical, dosage schedule (subcutaneous implant deli vering 14 mg of bCX per kg of rat per day). With, an average rat weight at sexual, maturity being estimated to be 350 gm, this equated to

approximately dosage of 5 jig bCX /day. The source o f bC X used in th se implants was pharmaceutical, grade ( 97% purity) bC purchased from Sigma-Aldrich (St Louis,. MD, United States of America) and was administered as a sub-cutaneous infusion using an osmotic pump (AlzetS; Dureet Corporation, Cupertino, CA, United States of America) changed monthly for 3 months in total A control group of ten (10) rats was used as a comparator; with control animals receiving an osmotic pump filled with water. All rats were then bred at 7 months and 9 months of age.

Results and Dis mion

[001 .13] All rats were supplied at 2 months of age. with their being no significant difference in their weights as was expected. After allowin the rats to acclimatise to their setting, subcutaneous implants containing bCX or control (water) were inserted at 3 months of age and then replaced monthly fo 3 months; i n total. The surgical wound was allowed to heal fo one month after removal of the third implant before commencing breeding at 7 months of age. Dams were allowed to nurse their youn for 3 weeks after birth, before the young: were removed and the dams allowed to mate again at 9 months of age. The results of the 7 month and 9 mont matings are shown in. Figures 1 and 2,

(ΌΟί 14J At 7 months there were no significant differences in mean (S:D) Sitter size between the study groups (control 10,7 ± 4.4; bCX implant 1 1.6 + 4.7) . Howe ver, 10% of the matings were sterile (no pups) in. the control group, versus no sterile matings in the bCX group. By 9 months of age, material differences in litter size and rates of sterile matings became apparent. The rats administered with bCX had significantly larger litter sizes than the controls (control 7.9 + 6.6; bC impant 1 . + 2.1), and a lower rate of sterile matings (control 30%; bCX implant 0%). These results indicate that the administration of bCX i s capable of preventing the loss of ovarian, reserve: with increasing age, as well as boosting natural fertility. PROPHETIC EXAMPLES rop etic Example I Daily contraceptive tablet including bCX

10 1 15] A two compartment tablet consisting of a core layer of a sustained releas contraceptive agent and h X overeoated wi th a layer of an immedia te release contraceptive agent can be formed by blending the core ingredients and the outer layer ingredients separately, compressing to produce core tablets and then overcoating with the compressed outer layer blend using a suitable -coating. ress- (Table 4).

[00 16] Table 4 Possible composition of a daily contraceptive tablet

Prophetic Example 2 Contraceptive sugar/placebo pill including bCX

[00 171 A contraceptive sugar pill or placebo pill containin bC can be form d using known ingredients and the same amount of bCX listed above.

Prophetic Exanipie 3 Drink product fortified with bCX

[00118] A fibre-based dry beverage- mix may be prepared with components list in Table 5. [001 1 ] Table 5 Possible composition of a fortified drinfc product

[001 0] All ingredients can be combined and processed in a flash-flo mixer to yield granules which can then, be dissolved in water to prov ide a fortified juice drink

Prophetic Esainpie 4 Subcutaneous contraceptive implant including bCX

[00121] A long-acting (ie up to 3 years) subcutaneous contraceptive implant can be formed by the methods disclosed in United States Patent No. 4,244,949 using, for example, 68 mg of the etonogestrel and bC iii an amount of 900 to 1200 mg.

[00122] It will be appreciated by those skilled in the art that the invention, is not restricted in its use to the particular application described. Neither is the present ..indention restricted in. its preferred embodiment with regard to the particular elements and/or features described or depicted herein. It will be appreciated that the invention is not limi ted to the embodiment or embodiments disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the scope of the invention as set forth and defined by the following claims, j 01)1231 As used herein, ranges are used herein in shorthand, to avoid/having to list and describe each and. every value within the range. Any appropriate value within a given range can be selected, where appropriate., as the upper value, lower value, or the -terminus of the range.

[00124] As used herein, the singular form of a word includes the plural, and vice verm, unless the context clearly dictates otherwise. Thus, the references "a", "an", and "the" are generally inclusive of the plurals of the respective terras. For example, reference to "a compound" or "a method" includes a plurality of such "compounds" or "methods". Similarly, the words "comprise", "comprises" and

"comprising" are to be interpreted inclusively rather than exclusively. Likewise the term "include", "including" and "or" should all be construed to be inclusive, unless such a construction: is- clearly prohibited from the context.

[001251 The term "and/or" is a shorthand term for the alternative arid the inclusi ve. Accordingly, the term "and/or" as used herein means one or the. other, or one and the other.

[00126] Throughout the specification, and the claims that follow, unless the context. requires otherwise, the words "comprise" and "include" and variations such as "compri ing" and "including" will be understood to imply the inclusion of a stated i nte ger or group of integers , but not the exclusion of any other integer or group of integers,

[00127] The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement of any form of suggestion that such prior art forms part of the common general knowledge. REFERENCES

AMiKeta ep d.Biomed^'C⁾nline27(2)i -l9l (2013).

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BumBJ. J Sci Food Agric doi:10.1 02/jsfa,6942. [Epub aliead of prtntj (2014).

Donaldson MS. NutrJ 3:19 (2004).

Dorjgochoo T el al Menopause 15(5): 24-933 (2008).

Ford ES, and Giles WH. Awn Epidemiol 10(2): 106-116 (2000).

Garcia-Closas R et al, Br JNurr 9I(6);1005-]0] 1 (2004).

Giles GO, and English DR. The Melbourne Collaberatoe Cohort Study. lARC Sci Publ 156:69-70 (2002).

Gold EB. Ohsiet Gynecol Clin North Am 38(3):425-440 (2011).

GraMdo-Lorencio F etal NutrMetub Canlim c Dis 24(1 ): 1090-1096 (2014).

Hodge A etal AmlNZJPtMic Health 24(6):576-583 (2000).

Institute of Medicine, Food and Nutrition Board. Beta-carotene and other earotenoids. Dietary reference inakes for vitamin C, vitamin E, sdewum, and carotenoids_i Washington, D.C.: National Academy Press: 2000:325-400.

irwtgMS etal. J Nirtr 132(10):316]-31 7 (2002).

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Trcmelien.K, and Savulescu J. Hum Reprod 29(12);2m6-2614 (2014). Voutilainen S el at. Am J Clin NiUr 83(6): 1265-1271 (2006).

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Claims

1. A method of delaying the onset of menopause and/or^' slowing the rate of loss of ovarian: reserve comprising administerin a therapeutically effective amount of heta-cryptoxanth i (bCX) or a pharmaceutical iy acceptable sal t, solvate or prodrug thereof to a female subjec t.

2. The method of claim I, wherein the. method comprises administering from about 5 micrograms (μ ) to about 10,000: g per day ofbCX or pharmaceutically acceptable salt, solvate or prodrug thereof to the female subject.

3. The method of claim 1 , wherein the method comprises administerin from about 400 ,ug to a bout 1 00 μ per day of bCX or phaimaeeuiicaliy aceeptable salt, solva te or prodrug thereof to the female subject.

4. The method of claim. 1 , where in the method comprises admi n istering from about 1000 g and 5000 pg per day of bCX or pharmaceutically aceeptable salt, solvate or prodrug thereof to the female subjec

5. The method of claim 1, wherein the method comprises administering from about 140 μg to about 310,000 μ per month of bCX or phanriaceuticail acceptable sal t, solvate or prodrug thereof to the female subject

6. The method of any one of claims 1 to 5 , wherein the bCX or pharmaceutically aceeptable salt, solvate or prodrug thereof i administered in. combination with a contraceptive agent,

7. The method of any one of claims 1 to 6, wherein the bCX or pirarmaeeirficaliy acceptable salt, solvate or prodrug thereof is administered in combination with a multivitamin agent,

8. The method of any one of cl aims 1 to 7, where in the bCX or pharmaceutically acceptable salt, solvate or prodrug thereof is admi nistered i n the form of an oral dosage form, a fortified drink product, a fortified food product, a topical dosage form, an injectable dosage form, a subcutaneous im lantable dosage form or a vaginally tnsertable dosage form.

9. A. composition for delaying the onset of menopause^■■and or stowing the rate of loss: of ovarian reserve comprising a therapeutically effective amount of a therapeutic agent comprising beta- cryptoxanthln (bCX) or a phamiaeeutically acceptable salt, solvate or prodrug thereof, wherein, upon administration to a female subject the composition delays the onset of menopause and or slows the rate of loss of ovari an reserve.

10. The composition of claim 9, when used to delay onset of menopause.

1 ί . The composition of claim 9. when used to slow the rate of loss: of ovari an .reserve.

12. The composition of any one of claims ^c> to 1 wherein the therapeutically effective- amount of hCX or pharmaeeolicaUy acceptable salt, solvate .or prodrug thereof is from about 5 fi to about 5 grams (g).

13. The composition of any one of claims 9 to J .1. wherein the therapeutically effective amount of bCX. or ^pharmaceutically aeceptabk salt, solvate or prodrug thereof is from abou t 1600 ug to about 4800

14. The composition of an one of claims to 1 1 , wherein the t erapeuticall effective amount of bCX. or pharmaceutically acceptable salt, solvate or prodrug thereof is from about 400 .g to about 1200 H .

15. The composition of an one of claims 9 to 11 , wherein the therapeutic agent consists of hCX o a pliarmaeeutically acceptable salt, solvate o prodrug thereof:

16. The composition of claim 15, wherein the composition is i the form of a non-contraceptive sugar pill for use in a daily contraceptive regime.

17. The composition of any one of claims- 9 to 15, wherein the composition is in a dosage form selected from the group consisiing of an oral dosage: form, a fortified drink product, a fortified food product, a topical dosage form, an injectable dosage form, a ubcutaneous implantable dosage form, and a vaginally hiseriabk dosage form

18. The composition of claim. 7, wherein the dosage form provides a dose of bCX or pharmaceutical ly aeceptabk salt, solvate or prodrug thereof that is equivalent to a daily dose of from about 5 p to about 10,001) pg.

19. The composition of any one of claims 9 to 15, further comprising at least one contraceptive agent.

20. The composition of any one of -claims 9 to , ftjrther comprising any one or more of alpha- carotene, biotin, calcium, chloride, chromium, copper, coenzyme Q UI folic acid, iodine, iron, lutein, magnesium, malic acid, manganese, molybdenum, niacin, nicotinamide, pantothenic acid, phosphorus, potassium, riboflavin, selenium, thiamine, vitamin B6, vitamin B 12, vitamin C, vitamin D, vitamin £, resveratol, -acetyl cysteine (MAC) and zinc.

21. A pharmaceutical preparation comprising the composition of any one of claims to 20 and one or more pharmaceutically acceptable carriers and/or excipients,:

22. The pharmaceutical preparation of claim 21, wherein the pharmaceutical preparation is an oral dosage form.

23. The pharmaceutic al preparation of claim 21 or 22, wherein the pharmaceutical preparation comprises a plurality of dosage units suitable for consecutive daily oral administration.

24. The pharmaceutical preparatio of claim 23, wherein the dosage units are separately packed and individual iy removable.

25. A. product comprising a package containing the phammceutical preparation of claim 22 or 23.

26. The product of claim 25 comprisin at least one dosage unit of the pharmaceutical preparatio in the form of a non-eontmceptive sugar pill and at least one dosage un it of A pharmaceutical, preparation which further comprises at least one contraceptive agent.

27. The product of claim 26 comprising at least 28 separately packed and indi vidually removable dosage units adapted for consecutive daily oral administration for a period of at least 28 consecutive days.

28. A combination product for oral contraception and delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve, compri sing:

21 to 24 contraceptive dosage units, eac comprising an effective amount of at least one contraceptive agent and an effective amount of beta-cryptoxanthin (bCX) or a

pharmaceutically acceptable salt, solvate or prodrug thereof; and

7 to 4, respectively, contraceptive agent-free: placebo dosage units each comprising an, effective amount of bCX or a pharmaceutically acceptable salt, solvate or prodrug thereof; and, optionally, instructions or indications to show that the daily administration of the 21 to 24 contraceptive dosage units, is to be followed by daily administration of 7 to 4,

respectively, contraceptive agent-free placebo dosage units.

29. An injectable dosage form comprising beta-eiyptoxanthin (bCX) or a pharmaceuticall acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable carriers and excipients for delayin the onset of menopause and/or slowin the rate of loss of ovarian reserve, wherein the dosage form delivers from about 50 μ§ to about 10,000 jig of bCX or pharmaceutically acceptable salt, solvate or prodrug thereof per dosage form or per day,

30; Use of beta-cry toxanthin (bCX) or a pharmaceuticall acceptable salt, solvate or prodrug thereof for delaying the onset of ^'menopause and/or slowing the rate of loss of ovarian reserve in a feraale subject and or in the preparation of a medicament for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve in a female subject.

31. The use of cl im 30, wherein the bC or pharmaceutically acceptable salt, solvate or prodrug thereof is administered in combination with a contracepti ve agent.

32. The use of claim 30 or 31, wherein the bCX is administered in combination with a multivitami agent.

33. A kit comprising. besta-cryptoxanthm (bCX) o a pharmaceuticall acceptable salt, solvate o prodrug tiiereof, at leas one contraceptive ageilt; and instructions for the use of said kit in a method for delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve.

34. A kit comprising- beta-cr^imant i (bCX) or a pban.naee«ticaliy acceptable salt, solvate o prodrug thereof, at least one multivitami and instructions for the use of said kit in a -method fo delaying the onset of menopause and/or slowing the rate of loss of ovarian reserve,

35. A method of eiitencing future fertility potential in a female subject, said method comprising administering daily or substantially daily a therapeutically effective amount of beta-cryptoxanihin (hCX) or a pharmaceutically acceptable salt, solvate or prodrug thereof to the female subject for a period of > 3 years preceding a plann ed pregn ancy or older age at w hi ch sh e desires to preserve the possibility of a pregnancy.

36. The method of claim 35, wherein the daily or substantially daily administration of the bCX or a pharmaceutically acceptable salt, solvate or prodrug thereof, is fo a period of > 7 years preceding a lanned pregnancy or older age at which she desires to preserve the possibility of a pregnancy.

37. The method of claim 35 or 36, wherein the method comprises administerin from about 5 micrograms (μ to about 10,000 ug per day of hCX or pharmaceutically acceptable salt, solvate or prodrug thereof to (he female subject

38. A composition for enhancing future fertility potential in a female subject compris ng a therapeutically e fective amount of a therapeutic agent comprising bet -e^toxantbin (bCX) or a. pharmaceutically acceptable salt, solvate or prodrug thereof.

3 . The composition o f claim 3 wherein the therapeutically effective amount of bCX- or pharmaceutically acceptable salt, solvate or prodrug thereof is from about 5 LIS to about 5 grams (g).

40. The composition of ci aim 39 provided as an injectable dosage form or subcutaneous implantable dosage form. 1. Use of beta-ciyptoxainhin (bCX) or a pharmaceutically acceptable salt, solvate: or prodrug thereof for eahancing future- fertility potential in a female subject . and/or in the preparation of a medicament for enhancing future fertility potential in a female sub ect.

42. A kit comprising .beia-cryptp&anlbin (bCX) o a pharmaceittiealiy acceptable salt, solvate o prodrug thereof, at leas one contraceptive agent; and/or multivitamin and instructions for the us© of said kit in a method for enhancing .future- fertility potential in a female subject.