Drug delivery for in vitro fertilization: Rationale, current strategies and challenges

Advanced Drug Delivery Reviews 61 (2009) 871–882

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Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Drug delivery for in vitro fertilization: Rationale, current strategies and challenges ☆ Margit M. Janát-Amsbury, Kavita M. Gupta, Caroline D. Kablitz, C. Matthew Peterson ⁎ Department of Obstetrics and Gynecology, Health Science Center, University of Utah, 30 North 1900 East, Suite 2B200, School of Medicine, Salt Lake City, Utah 84132, USA

a r t i c l e

i n f o

Article history: Received 8 October 2008 Accepted 28 April 2009 Available online 5 May 2009 Keywords: In vitro fertilization (IVF) Luteal phase support Controlled ovarian hyperstimulation Gonadotropins Progesterone GnRH analogues

a b s t r a c t In vitro fertilization has experienced phenomenal progress in the last thirty years and awaits the additional refinement and enhancement of medication delivery systems. Opportunity exists for the novel delivery of gonadotropins, progesterone and other adjuvants. This review highlights the rationale for various medications, present delivery methods and introduces the status of novel ideas and possibilities. © 2009 Published by Elsevier B.V.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hormone interplay in the natural menstrual cycle . . . . . . . . . . . . . . Stimulated cycles in IVF . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Controlled Ovarian Hyperstimulation (COH). . . . . . . . . . . . . . 3.1.1. Gonadotropin releasing hormone (GnRH) analogues . . . . . 3.1.2. Gonadotropins for growing multiple follicles: FSH, LH, and HCG 3.1.3. Gonadotropins for triggering preovulatory maturation; hCG . . 3.1.4. Technological gaps in delivery methods for gonadotropins. . . 3.2. Luteal phase support . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Progesterone . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Delivery routes . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Progesterone delivery systems . . . . . . . . . . . . . . . . 3.3. Additional adjuvant infertility treatments for women . . . . . . . . . 4. Eye to the future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In vitro fertilization (IVF) is increasingly pursued as a treatment for infertility that affects nearly 70 million couples globally [1]. Three million babies have been born worldwide through IVF treatment cycles [2] since the first successful IVF in 1978 [3]. The IVF procedure ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “The Role of Gene- and Drug Delivery in Women's Health – Unmet Clinical Needs and Future Opportunities”. ⁎ Corresponding author. Tel.: +1 801 587 8303 fax: +1 801 585 9295. E-mail address: [email protected] (C.M. Peterson). 0169-409X/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.addr.2009.04.019

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involves stimulated development and maturation of multiple oocytes through exogenous hormonal stimulation, transvaginal retrieval of oocytes from the follicles, fertilization of the eggs in vitro with sperm collected from the male counterpart, transfer of the in vitro fertilized embryo(s) into the patient's uterus or fallopian tube (zygote intrafallopian tube transfer-ZIFT) and finally, hormonal support post-implantation for 30–70 days to sustain the pregnancy. Numerous advancements have been made in IVF including surgical techniques, protocols and in development of synthetic/recombinant hormonal analogues [2]. However, approaches for long duration delivery of peptide and steroidal hormones to meet the demands of IVF treatment cycles remain as major technological gaps. IVF protocols

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entail daily injections of multiple agents that extend for weeks to months; yet the majority of delivery methods utilized for IVF procedures are limited to often-painful intramuscular (i.m.) or subcutaneous (s.c.) injections. Furthermore, IVF treatments are expensive due to the high cost of medications used and the necessity for frequent monitoring. Novel delivery systems that will minimize patient-to-patient variation, improve efficacy of embryo implantation and live birth rates, reduce the dose and frequency of medications required, eliminate injections and complex monitoring, and overall decrease the cost of IVF treatments will be welcomed by IVF patients and physicians. This review attempts to provide a background and rationale for the various pharmacological agents and treatment protocols utilized in IVF. Emerging delivery technologies applied in IVF procedures are briefly discussed and potential areas that would benefit from more extensive research endeavors focusing on more efficient and patient friendly drug delivery strategies are highlighted. 2. Hormone interplay in the natural menstrual cycle The natural female reproductive endocrinology involves a delicate balance and an intricate interplay of hormones (see Figs. 1 and 2) resulting in cyclic changes in the endometrium along with the development of a mature oocyte each cycle [4–7]. The hypothalamus secrets gonadotropin releasing hormone (GnRH), a decapeptide, in a pulsatile manner to stimulate the pituitary to secrete the gonadotropins: luteinizing hormone (LH) and follicle stimulating hormone (FSH) (Fig. 1) [7]. GnRH has a short half-life of 2–5 min due to rapid cleavage by serum proteases. The frequency of GnRH pulses contributes to modulation of LH and FSH released and hence the LH: FSH ratio in blood (Fig. 2) [8]. LH and FSH synergistically regulate the menstrual cycle through stimulating production of estrogen and progesterone from the ovarian follicles. FSH stimulates the granulosa cell compartment and is essential for the development of mature oocytes capable of fertilization. While higher amounts of FSH in the early follicular phase

Fig. 2. Hormone levels in natural menstrual cycle and the corresponding states of follicular development.

promotes growth of 6–8 follicles (follicular cohort), the diminished levels occurring in the late follicular phase usually restrict the number of fully developed preovulatory follicles to a single follicle with highest sensitivity to FSH among the cohort [6]. The growing follicle secretes high levels of estrogens, which is produced by conversion of cholesterol to androgens in theca cells followed by aromatization of androgens to estrogen in granulosa cells. When elevated estrogen levels persist for more than 2 days, a positive feedback signal to the hypothalamus and pituitary initiates a preovulatory LH surge (Figs. 1 and 2). The LH surge initiates resumption of meiosis in the oocyte up to metaphase II, causes extrusion of the ovum from the follicle and results in luteinization of the follicle to form corpus luteum. The luteal phase is characterized by transformation of the follicle into a corpus luteum post-ovulation in response to the LH surge. The secretory cells of the follicle are converted to mainly progesterone secreting cells. The progesterone secretion in the luteal phase increases dramatically from 1 mg/day in the follicular phase to 25 mg/day in the luteal phase and promotes changes in the endometrium that are essential to sustain pregnancy [9]. The corpus luteum secretes estrogen and mainly progesterone and is responsible for sustaining pregnancy in the first trimester. If fertilization occurs, the growing embryo and placenta start secreting human chorionic gonadotropin (hCG) that prolongs the life of corpus luteum [9]. Human chorionic gonadotropin has molecular structure and function similar to LH and is secreted by the embryo and the placenta after conception [10]. FSH, LH and hCG are about 40 kD dimeric glycoproteins with identical α subunits consisting of 92 amino acids. The unique β subunits that determine the specific biological activity vary between 118 (FSH), 121 (LH) and 152 (hCG) amino acids. The initial and terminal half-life's vary depending on the degree of glycosylation of the glycoprotein hormones (LH: 1 h and 12 h [11]; FSH: 2 h and 17 h [12]; and hCG: 5 h and 30 h [13]). 3. Stimulated cycles in IVF

Fig. 1. Hormonal interplay in natural menstrual cycle.

In early IVF treatments, including the first successful IVF in 1978 [3], a single mature oocyte retrieved from the patient's natural

M.M. Janát-Amsbury et al. / Advanced Drug Delivery Reviews 61 (2009) 871–882

menstrual cycle was fertilized in vitro and a single embryo was transferred into the uterus [14,15]. However, natural cycle IVFs are clinically inefficient and result in much lower pregnancy rates (7.2% per cycle) [14]. Moreover, the requirement for frequent monitoring to assess maturation of oocytes and the lack of control over time of ovulation render natural IVF cycles less practical. It is clear that pregnancy rates per IVF cycle correlate with the number of embryos transferred [16] and consequently on the number of oocytes retrieved per cycle [17,18]. Therefore, the objective of stimulated cycles in IVF is to induce ‘superovulation’ by increasing the number of mature oocytes to 10–20 per treatment cycle. This is achieved by the administration of exogenous hormones and/or manipulating the feedback loops of the menstrual cycle [19]. The natural hormonal balance is disturbed with the intake of exogenous hormones in stimulated cycles and may necessitate hormonal support after embryo transplantation i.e. in the luteal phase [20,21]. With respect to the delivery of exogenous hormone and synthetic pharmaceutical agents, IVF treatment can be divided into two major phases: 1) controlled ovarian hyperstimulation (COH), and 2) luteal phase support. The rationale and protocols utilized for each step are explained below. 3.1. Controlled Ovarian Hyperstimulation (COH) Various exogenous hormones are administered in different protocols to maximize the recruitment of follicles, sustain the growth of multiple follicles and synchronize the maturation of the follicular cohort. The resulting exaggerated hormone levels can potentially lead to premature ovulation and cancellation of the treatment cycle. Therefore, care is taken to prevent premature ovulation while inducing ‘superovulation’. In order to achieve better control on hormone levels, current stimulated IVF protocols favor suppression of the endogenous hormone cycle in the patient [22]. Also, close monitoring of the patient's response to COH and individualized exogenous hormone intake is practiced in order to minimize the risk of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening condition [23,24]. The different protocols and pharmaceutical agents/hormones employed in COH are described in this section. 3.1.1. Gonadotropin releasing hormone (GnRH) analogues GnRH analogues are utilized in IVF stimulated cycles to reversibly inactivate the pituitary–ovarian axis of the natural hormone cycle so that all the events in the treatment cycle, from follicular recruitment until ovulation, can be controlled by exogenous hormones [22]. The rationale of inhibiting the endogenous gonadotropin secretion is to prevent premature ovulation resulting from an endogenous LH surge and to achieve better synchronization of the follicular cohort. 3.1.1.1. GnRH agonists. Continuous delivery of GnRH leads to desensitization of the receptors in the pituitary gland and halts its FSH and LH secretion [25,26]. GnRH agonists utilize this mechanism to suppress the endogenous LH and FSH release. GnRH agonists are synthetic derivatives of GnRH with longer half-life's and prolonged binding to the receptors in the pituitary glands [22]. They provide a scenario of continuous delivery of GnRH and thereby curtail the endogenous hormonal cycle. Synthetic modifications include a Damino acid at the 6th position to circumvent the short half-life due to enzymatic degradation and ethylamide or azaglycine substitutions at the 10th position (C-terminus), which in combination increase the activity 60–200 times, when compared to the natural hormone (Fig. 4) [27,28]. Introduction of GnRH agonists in IVF treatment cycles has been viewed as a landmark step in improving the efficacy of IVF treatments [29]. Employment of GnRH agonists has reduced the cycle cancellation rates due to premature ovulation from 20% to less than 2% [30]. An increased secretion of gonadotropins in the initial 2–3 days of starting GnRH agonists, generally referred to as the ‘flare’ effect, [31] is followed by a shut down of gonadotropin secretion and quiescent

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ovaries within 7–14 days. The duration of pituitary desensitization correlates with the length and dosage of the GnRH agonists. Two different regimens of GnRH agonists are employed [32]. In the ‘long’ protocol (Fig. 3), the GnRH agonist is prescribed daily starting from the mid-luteal phase of the preceding menstrual cycle until the day follicular maturation is triggered after gonadotropin stimulation in the IVF treatment cycle [33,34]. In the ‘short protocol’ (Fig. 3), the pituitary is suppressed in the late follicular phase by GnRH agonist administration starting from day 2–3 of the IVF treatment cycle and continued until the day follicle maturation is triggered. In both “short” and “long” protocols, exogenous gonadotropins are prescribed from day 1 of the treatment cycle until the day of triggering follicle maturation. The ‘short protocol’ utilizes the initial stimulatory ‘flare effect’ of GnRH agonists during which an increased secretion of FSH and LH occurs. The longer the pituitary needs to be suppressed, the higher is the cost of IVF treatment in order to meet the increased dosage requirement of exogenous gonadotropins. However, the ‘long’ protocol is predominantly favored due to better efficacy, which is based on reduced cycle cancellation rates and larger number of oocytes recovered per treatment cycle [35]. Additionally, scheduling egg retrieval by manipulating the treatment cycle is more convenient in the ‘long protocol’ [36,37]. The dosage forms of GnRH agonists available include: nasal sprays, s.c. injections and one-month subcutaneous depots (Table 1). In general, nasal delivery is limited by the size of peptide/protein drug utilized for systemic treatment [38]. As a decapeptide, GnRH agonist can permeate across the nasal mucosal membranes thereby offering the opportunity for non-invasive nasal delivery [39]. Synarel® nasal Solution containing nafarelin acetate, a synthetic GnRH agonist, is commercially available and provides the advantage of convenient usage and improved patient compliance [40]. However, the lower bioavailability of peptides in nasal delivery limits widespread adoption as compared to injectable systems. Chaplin et al. reported the systemic bioavailability for intranasal nafarelin to be 2.82% ± 1.23%. Considerable loss of the peptide occurs through proteolysis and swallowing, giving a fluctuating pituitary desensitization level [41]. Still, the bioavailability of nafarelin acetate is capable of achieving the desired therapeutic effect because of its inherent high biologic potency and its pharmacokinetic properties [42]. Implantation and pregnancy rates per embryo transfer were not significantly different in IVF cycles using nafarelin acetate as nasal spray when compared to leuprolide acetate s.c. injection [43]. Nevertheless, daily s.c. injections are preferred because of their more reproducible and stable effect. After s.c. injection, the agonist is rapidly absorbed and blood concentrations remain elevated for many hours. Controlled release delivery systems that ensure delivery over extended periods of time would also provide alternative options for GnRH agonist delivery. Biodegradable poly(D, L-lactide-co-glycolide) microsphere

Fig. 3. Typical protocols utilized in stimulated IVF cycles.

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Table 1 GnRH agonist and antagonist. Drug class

INN

Brand name

Dosage form

Route of administration

Dose

GnRH agonist

Triptorelin pamoat Goserelin Buserelin acetate Nafarelin acetate Leuprolide acetate Abarelix Cetrorelix Ganirelix acetate

Trelstar® depot Zoladex® Suprefact® Synarel® Eligard®, Lupron®, Procrin® Plenaxis® Cetrotide® Ganirelix®, Antagon®, Orgalutran®

Aqueous Implant Aqueous Aqueous Aqueous Aqueous Aqueous Aqueous

i.m. s.c. nasal, s.c. nasal s.c. /i.m. i.m. s.c. s.c.

3.75 mg/injection 3.6 mg/implantation According to individual response 2–3 times daily (400–600 µg/d) 1 mg/d According to individual response According to individual response According to individual response (≈ 250 µg/d)

GnRH antagonist

formulations such as microsphere preparations of leuprolide acetate (i.e. Lupron®, Takeda-Abbott Pharmaceutical) enable continuous delivery of small doses over 30 days, with a well defined dose after the initial burst release. Due to sustained release kinetics, the subsequent amount delivered daily could be kept lower than the amount required from multiple injections. However, depot preparations are not used as the first choice in IVF due to their long duration of action. A hypogonadotrophic and hypogonadal state can be sustained for more than 7 weeks after a single depot in regularly cycling women. Thus, the suppression lasts longer than actually needed and the effect would endure into the first weeks of pregnancy [44]. 3.1.1.2. GnRH antagonists. GnRH antagonists, synthetic derivatives of GnRH (Table 1) that competitively bind to GnRH receptors, are recent alternatives to GnRH agonists. GnRH antagonists have five or more amino-acid substitutions (Fig. 4). Modifications involving position 6 hinder cleavage by serum proteases; substitutions at positions 2 and 3 affect gonadotropin release; and changes at positions 1, 6 and 10 affect receptor binding [45]. In contrast to the agonists, GnRH antagonists bind immediately and competitively to GnRH receptors in the pituitary gland. Within 8 to 24 h after the initial dose, LH concentrations are reduced by 51–84%, and the FSH concentrations are reduced by 17 to 42%. The competitive blocking of the GnRH receptor results in a rapid, but reversible, decrease in LH and FSH without any ‘flare’ response [46]. Owing to immediate onset of action, GnRH antagonists are administered once the follicular response has commenced and need to be delivered for a much shorter period compared to agonist administration. GnRH antagonists are generally prescribed in the late follicular phase of the IVF treatment cycle to prevent premature LH surge: either single dose on day 8/9 (3 mg cetrorelix) [47] or as a daily dose of 0.25 mg from day 6 until the day of triggering follicle maturation [48,49]. Exogenous gonadotropins are prescribed daily until the day of triggering follicle maturation (Fig. 3). Although GnRH antagonist protocols are lower in cost due to the lesser demand of exogenous gonadotropins compared to the GnRH agonists protocols, there is a debate regarding the cause of the lower success rates compared to agonist protocols [50,51]. There is some evidence that high doses of GnRH antagonists may interfere with processes associated with folliculogenesis, implantation and endometrial development [52]. More dose-defining studies are needed to improve current protocols

Fig. 4. Amino-acid sequence of GnRH and its substitutions of GnRH agonists and antagonists. Arrows represent the positions at which amino acids are modified to obtain agonist and antagonist GnRH analogues. The solid arrows represent required modifications while the dotted arrows represent optional modifications.

suspension solution solution solution solution solution solution

utilizing GnRH antagonists. Patients with polycystic ovarian syndrome (PCOS), that have a higher risk of OHSS using GnRH agonists treatment, have been considered potential candidates for a GnRH antagonist stimulated cycle [53,54]. Currently available dosage forms of GnRH antagonists are s.c. or i.m. injections (Table 1). Both administration routes (i.m. and s.c.) are efficient with regards to the treatment; however, patients prefer s.c. injections since they are less painful and can be administered easily without any assistance. It is documented that the aqueous solution applied through intramuscular or subcutaneous injections may gel post-application and provide some level of extended release which does not effect the efficiency of the treatment [55,56]. A recently developed non-peptide GnRH antagonist delivered orally is being evaluated in clinical trials as a therapeutic agent for endometriosis, and may provide a potential alternative to peptide GnRH antagonists in IVF stimulated cycles [57]. 3.1.2. Gonadotropins for growing multiple follicles: FSH, LH, and HCG The goal of multiple oocytes in stimulated IVF cycles mandates the use of exogenous gonadotropins. The normal hormonal interplay to release single oocytes is overridden by administration of continuous and higher levels of FSH. The supra-physiological concentrations of gonadotropins achieved in IVF stimulated cycles amplify follicular recruitment and sustain the growth of multiple follicles. Additionally, the occurrence of an untimely LH surge, due to high FSH and estrogen levels obtained in stimulated cycles, is prevented by the use of GnRH analogues by suppressing the pituitary. This LH surge blockade enables the delivery of exogenous gonadotropins until the desired number of mature follicles is attained. Extensive ultrasound monitoring of follicular growth to prevent premature or postmature egg collection and individualized dosing with assessment of blood hormone levels to prevent OHSS are required in all gonadotropin treatment protocols [10]. Gonadotropins are mainly delivered by administrating human menopausal gonadotropins (hMGs), which contain FSH, LH and/or hCG. Alternatively, purified FSH obtained from urine samples of postmenopausal women or produced via recombinant technologies is prescribed with or without supplementation of LH activity [24]. 3.1.2.1. Human menopausal gonadotropins (hMG). Cessation of the estrogen feedback loop in menopausal women results in elevated serum levels of LH and FSH, which are secreted in the urine and serve as the source of hMGs [58]. Highly purified hMGs are concentrated from urine by adsorption on kaolin followed by a series of extraction and column chromatography steps, including cationic and anionic exchange, and hydrophobic interaction column chromatographies [59]. FSH and LH in clinical products are standardized against reference preparations using in vivo bioassays. Differences in bioand immmunoreactivity occur because of molecular heterogeneity that differs according to the method of preparation or synthesis [60]. Human menopausal gonadotropins are prepared so that equal numbers of international units (IU) activity of FSH and LH are present per unit volume. Because FSH bioactivity exceeds LH activity in purified hMG preparations, hCG derived from the urine of pregnant women is

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added as an LH surrogate to achieve the desired equivalency of FSH and LH activities. Human chorionic gonadotropin may account for 95% of the LH activity in such preparations [61,62]. Preparations with hCG, to confer LH activity, will cause an increase in LH activity over successive days because of the long half-life of hCG. Since LH activity can contribute to follicular growth in intermediate and a larger follicle, this characteristic likely has pharmacodynamic implications and also poses the theoretical risks of premature ovulation and OHSS. Human menopausal gonadotropin administration is initiated on the second or third day of the treatment cycle and continued daily until the follicles reach a threshold size (minimum N15 mm). A high dose is often given in the beginning maximizing the recruitment of follicular cohorts. Some centers follow a step-down regimen of hMGs for synchronized maturation of multiple follicles in the cohort, as supported by studies in non-human primate models [63]. The formulations of hMGs are available as i.m. injections which are painful to receive, and frequently cause local inflammatory reactions [64]. Recently, s.c. injections of hp-hMGs were shown to be equally effective and more tolerable. Moreover, s.c. injections offer the convenience of self-administration and therefore improved patient compliance [65,66]. Some trials, and meta-analyses of trials do show small differences in clinical outcomes according to the gonadotropin preparation used [67–69]. 3.1.2.2. Follicle stimulating hormone (FSH). Administration of FSH alone in the form of highly purified urine FSH (uFSH) [70] or recombinant FSH (rFSH) [71] is employed in stimulated IVF cycles for maximizing the recruitment of follicular cohorts. Higher specific activity and far fewer impurities of these hormonal preparations enable a delivery through s.c. routes with its improved safety profile [66,72]. Since 2004, the FDA has approved the administration of rFSH by using a pen device. The pen is a safe, effective, and easy to use, thereby enabling self-administration of rFSH during ovarian stimulation [71,73]. The main advantages for patients includes reduced pain, reliability of dosing mechanism and the minimization of dosing errors [74]. In a study evaluating a fully automated injection device (Softinject™), Greco et al. stated that it would be feasible for any subcutaneously administered drug employed in ovarian stimulation [75]. Clinical studies compared serum FSH after single-dose administration of uFSH and rFSH and observed a higher Cmax following uFSH administration [76]. The biological activity and clearance rates of FSH is dependent on the degree and pattern of glycosylation which varies between uFSH and the different rFSH preparations, thereby causing the observed difference between the pharmacokinetic profiles in vivo [77]. Despite differences in bio- vs. immunoreactivity of FSH pharmacokinetics between traditional highly purified urinary preparations and recombinant products, clear evidence of practical clinical significance for these differences is yet to be achieved [11,12,76,78–80]. There is significant controversy regarding the advantages and disadvantages of FSH monotherapy versus a “mixed protocol” including LH [24]. In practice, cost, access, and route of administration required are often the major factors in the choice of product(s) utilized. When mixed protocols of FSH and LH are used, the dosing devices presently available often require multiple injections impairing reproducibility, reliable dosing, convenience and patient acceptance. Some programs further complicate the stimulation regimen with split daily dosages of mixed protocols adding to the complexity and disadvantages noted above. 3.1.2.3. Luteinizing hormone (LH) and human chorionic gonadotropin (hCG). There is an ongoing debate regarding a beneficial ceiling level of LH activity required for folliculogenesis as FSH induced LH receptors are present on the granulosa cells of the growing follicles [81,82]. Folliculogenesis appears to be suboptimal in the absence of a minimum LH level while atresia of follicles results if the threshold LH level is surpassed [82]. Furthermore, there is a theoretical risk of

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premature ovulation due to increased LH activity. Recent studies have shown significantly better outcomes in terms of live birth rates [83] and embryo quality associated [84–86] with hMG compared to rFSH, suggesting a beneficial role of LH activity, which is absent in FSH-only regimens. Therefore protocols utilizing pure FSH often supplement LH activity in the form of hCG or recombinant LH as the follicles mature [81]. Low dose hCG (50–200 IU/d) is also used for folliculogenesis along with FSH. Concerns of increased OHSS risk due to the much longer terminal half-life of hCG (~30 h) compared to LH motivated the development of recombinant LH. Lutropin alfa is the first and only recombinant human form of LH developed for concomitant administration with Follitropin alfa (rFSH) to stimulate follicular development. Once-daily s.c. lutropin alfa was generally well tolerated in hypogonadotropic hypogonadal women, with the majority of adverse events being of mild to moderate severity [87]. Lutropin alfa with follitropin alfa may be of benefit in certain subgroups of normogonadotropic women (e.g. those with an inadequate response to prior follitropin alfa monotherapy, those aged ≥35 years, and those with profound LH down-regulation and/or those who required excessive exogenous follitropin alfa) [87]. 3.1.3. Gonadotropins for triggering preovulatory maturation; hCG Maturation of oocytes is triggered in stimulated cycles after documenting adequacy of the size of the leading follicles, endometrial development and serum estrogen levels. Injecting hCG simulates an LH surge. Purified hCG extracted from the urine of pregnant women (uhCG) is utilized to simulate the preovulatory LH surge in IVF treatment cycles. A single dose of 5000 to 10,000 IU of hCG is injected i.m. to trigger follicle maturation [88]. Eggs are retrieved 34–36 h after hCG injection through an ultrasound guided transvaginal procedure. Alternatives to i.m administration are limited because of the high MW of hCG and the presence of multiple impurities in the urinary derived protein. The development of recombinant hCG (rhCG) offers the feasibility of s.c. administration [89] and thereby the convenience of self-administration. The pharmacodymanics of hCG are altered by the route of administration wherein s.c. administration has been demonstrated to achieve higher blood plasma levels and follicular fluid levels compared to i.m. injections [90]. Although used in majority of IVF cycles for triggering preovulatory maturation, hCG increases the risk of ovarian hyperstimulation syndrome (OHSS) [91]. The increased risk of OHSS may stem from the prolonged pharmacokinetics: higher receptor affinity and half-life of hCG compared to LH. Use of rLH or hCG modified by desialization to closely mimic the half-life of LH has been attempted to reduce the risk of OHSS [92]. In GnRH antagonist's cycles, a single dose of GnRH agonist for triggering preovulatory maturation through an endogenous LH surge was recently explored. This alternative protocol for triggering preovulatory oocyte maturation instead of the commonly used hCG may be advantageous in reducing the risk of OHSS (see Section 3.1.3) [93]. 3.1.4. Technological gaps in delivery methods for gonadotropins The delivery options of gonadotriopins are limited to i.m. or s.c. injections (Table 2). New opportunities to deliver these hormones via alternative routes including oral, transmucosal or transdermal have not been developed, to date. But, there are several challenges, which need to be overcome in order to develop less painful and more patient friendly delivery options. First, maintaining stability of the active structure, adequate absorption and bioavailability is difficult because of their high MW (~ 40 kD). Second, the dosage of gonadotropins administered usually varies between individual IVF programs with further minor variations between patients, depending on the number of follicles growing and body mass index. For example, obesity is associated with an increase in dose requirements in WHO type II patients [94,95].

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Table 2 Gonadotropins: FSH, LH and hCG. Drug class

International Nonproprietary Name (INN)

Brand name

Ovulation stimulants

Lutropin Alfaa (rLH)

Luveris®

b

b

®

Route of administration

Dose

Aqueous solution

s.c.

Aqueous solution

s.c.

According to individual response (≈ 75–450 units/d) According to individual response (≈ 75–450 units/d) According to individual response (≈ 5000–10,000 units) According to individual response (≈ 250 µg) According to individual response (≈ 37.5–75.0 units/d) According to individual response According to individual response

Menotropins (hMG)

Menopur (hp-hMG), Repronex

Human Chorionic Gonadotropin (uhCG) Choriogona-dotropin Alfa (rhCG) Follitropin Alfa (rFSH)

Novarel®, Pregnyl®, Profasi®

Aqueous solution

s.c.

Ovidrel®

Aqueous solution

s.c.

Aqueous solution

i.m.

Aqueous solution Aqueous solution

s.c., i.m. s.c.

Follitropin Beta (rFSH) Urofollitropin (uFSH) a

®

Dosage form

®

Gonal-f /Gonal-f RFF Pen

®

Follistim AQ®/Puregon® Bravelle®, Fertines®, Metrodin HP®, Neo-fertinorm®

Lutropin alfa is coadministered with follitropin alfa for stimulation of follicular development in infertile, hypogonadotropic, hypogonadal women with profound LH deficiency. In conjunction with hCG for COH.

Third, the usual practice of daily dosing of gonadotropins results in gonadotropin dynamics that are markedly inconsistent with normal ovulatory physiology. In normal menstrual cycles, LH and FSH are secreted in pulses that occur at a frequency of 30 to 180 min depending on the phase of the menstrual cycle. The gonadotropins applied though injections lack pulsatility, achieve a single maximum approximately 12 h after injection, and gradually accumulate levels over the multiple days of follicle recruitment. Despite these drawbacks, it should be mentioned here that daily injections have not been shown to be inferior to regimens using more frequent, (including split dosing) or pulsatile administration [96–98]. Fourth, minimal efforts have been undertaken to match the delivery of hCG to the amplitude and duration of the natural LH surge [92]. In a natural cycle, blood plasma LH levels increase prior to ovulation and peak in 16 h at 6–8 times the basal level (Fig. 2), which is maintained for about 14 h and then decreases to the basal level within 24 h [99]. Final maturation of the oocyte (meiosis up to metaphase II) occurs in a 36 hr gap between the initiation of the LH surge and rupture of the follicle to release the ovum [7]. The pharmacokinetics of the LH surge plays an important role in follicle maturation, release of the ovum and formation of corpus luteum [100]. Finally, the use of hCG for triggering preovulatory maturation has primarily been associated with an increased risk of OHSS [91], possibly due to prolonged biological activity and half-life as compared to LH [92]. The use of modified hCG through desialization to reduce the halflife to more closely mimic the half-life of LH has been attempted to reduce the risk of OHSS [92]. It is known that LH does not increase the risk of OHSS irrespective of the high estradiol levels achieved in stimulated cycle [101,102]. However, utilization of rLH is hampered by the requirement for a high dose ranging from 15,000 to 30,000 IU to yield comparable results [102]. This high dosage requirement is likely due to a lower availability of rLH to the follicles despite high systemic concentrations. This fact suggests that local delivery to the ovaries might potentially be more efficacious. Overall, research efforts should be employed to devise better delivery technologies that overcome the above-mentioned challenges for the administration of gonadotropins.

3.2. Luteal phase support Contents of the follicles are aspirated in IVF cycles to retrieve the eggs. It was postulated that this aspiration potentially removed a majority of the secretory cells of the follicle leading to insufficient progesterone secretion in the luteal phase [21]. These concerns regarding luteal phase insufficiency initiated empiric progesterone supplementation in the luteal phase in patients undergoing IVF treatment.

Despite numerous studies showing no benefit in combination clomiphene citrate and hMG IVF stimulation cycles [103–105], and a meta-analysis which also failed to substantiate the necessity of progesterone supplementation [106], it became a routine practice in IVF. However, when GnRH agonists routinely complimented IVF stimulation protocols in order to prevent a premature LH surge, the rationale for progesterone supplementation of the luteal phase was based on the fact that pituitary gonadotropins remained suppressed for up to 2 to 3 weeks after discontinuation of the agonist. LH pulse suppression in the luteal phase from GnRH agonist activity could inhibit endogenous progesterone and estradiol production resulting in endometrial inadequacy. Ample clinical trials have now demonstrated the need for luteal phase supplementation in IVF cycles stimulated with GnRH agonist/gonadotropin protocols [107,108]. The subsequent introduction of GnRH antagonists in IVF stimulation protocols followed the same rationale and studies also support the need for luteal phase supplementation in GnRH-antagonist cycles [109]. Despite the initial introduction of progesterone supplementation in IVF without adequate clinical evidence to justify its use, the advent of IVF stimulation protocols utilizing GnRH agonists or antagonists now includes progesterone supplementation based on evidence for its need. Although, the duration of progesterone supplementation is controversial and poorly studied, it is usually started after oocyte retrieval and continued until 8–10 weeks of gestation [21]. It should be mentioned here that for IVF treatment only progesterone is used and not any other progestin. 3.2.1. Progesterone Progesterone is a C-21 steroid hormone synthesized inside the follicle from pregnenolone, a derivative of cholesterol. The main functions of progesterone include preparation of the uterus for pregnancy, transforming breast tissue for lactation and maintenance of the pregnancy. In the luteal phase, progesterone promotes secretory changes in the endometrium that facilitates implantation of the blastocyst and provides nutrients for the growing embryo. Blood progesterone levels increase from less than 3 nmol/L (0.9 ng/mL) in the follicular phase to about 60 nmol/L (18 ng/mL) in the luteal phase, and continue to increase with peak levels to about 1000 nmol/L (300 ng/mL) at 36–38 weeks of gestation [9]. The progesterone required during pregnancy is supplied initially by the corpus luteum during the first 6–8 weeks of pregnancy and is progressively supplemented and eventually replaced, at ten weeks, by the growing placenta as the predominant source of progesterone. About 98% progesterone is bound to plasma proteins (especially albumin) and is rapidly released to tissues within 30 min [110]. Within minutes of secretion, progesterone is degraded by the liver into inactive steroids, which are excreted via renal and biliary elimination.

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Table 3 Progesterone. Drug class

INN

Brand name

Dosage form

Route of administration

Dose

Progestin

Progesterone Progesterone Progesterone Progesterone Progesterone Progesterone

Prometrium®, Utrogestan® Prometrium®, Cyclogest® Prochieve®, Crinone® Endometrin® Progesterone injection USP Gestone®

Capsules Suppositories Aqueous emulsion-gel Insert Oil solution Aqueous suspension

p.o. vaginal vaginal vaginal i.m. i.m.

According to individual response (200 mg/d) According to individual response (200–400 mg/d) According to individual response (1–2 × 90 mg/d) According to individual response (2–3 × 100 mg/d) According to individual response (25–100 mg/d) According to individual response (25–100 mg/d)

3.2.2. Delivery routes Progesterone can be administered orally, vaginally, or through i.m. injection (Table 3) and all these routes of administration have demonstrated characteristic endometrial histological changes [111]. Oral dosing requires a higher concentration in order to compensate for “first-pass” liver metabolism. The bioavailability of the orally administered progesterone can be as low as 10% [112]. Micronized dosage forms of progesterone are utilized to increase efficiency of delivery. Micronization decreases particle size and shortens its dissolution time according to the equation of Noyes–Whitney (see Eq. (1)). Since absorption of micronized progesterone can be enhanced two-fold if the hormone is taken with food, some dosage forms have incorporated peanut oil in the formulation e.g. Prometrium® soft gelatin capsules [113]. However, oral administration may result in noticeable sedative and anxiolytic effects due to progesterone metabolites that enhance inhibitory neurotransmission by binding to the GABAA receptor complex [114]. Patients may also report fatigue, headache and urinary frequency [115]. This formation of sedating metabolites limits the dosing that can be achieved orally. Thus, the oral administration is compromised by bioavailability issues, varying metabolic rates in different individuals, rapid clearance times (6 h), and sedating side effects. Consequently, other routes of administration have supplanted oral administration in the case of progesterone delivery for IVF. dc D•A ðcs − cÞ = dt h

ð1Þ

where dc/dt = rate of drug dissolution at time t; D = Diffusion rate constant; A = surface area of the particle; cs = concentration of the dissolved drug (equal to the solubility of the drug) in the stagnant layer; c = concentration of the drug in the bulk layer; h = thickness of stagnant layer. By increasing the total surface area (A) through micronization, the rate of drug dissolution at time t (dc/dt) will increase leading to a faster delivery of progesterone. Intramuscular injections of micronized progesterone in oil result in a higher peak and longer lasting plasma concentrations when compared to aqueous solutions. But, a daily administration is required due to a rapid metabolism. Progesterone in oil (USP) is formulated with sesame oil (50 mg/ml) and 10% v/v benzyl alcohol that functions as preservative. Intramuscular injections are difficult to self-administer and are often painful. A common practice is to warm up the oil solution in order to decrease its viscosity in an attempt to reduce pain with injection. Transdermal progesterone administration has evolved into a nonFDA supervised activity. As a steroid hormone with a small molecular weight and lipophilic character, progesterone has the ability to penetrate through the skin immediately into to the vascular system bypassing the hepatic first pass effect. Transdermal drug delivery offers the advantage of a controlled release of the medicament and avoids the peaks and troughs in the absorption kinetics. However, a significant dosage is required to overcome the low skin permeability and loss due to enzymatic degradation in order to meet the high progesterone demands of the IVF cycle's mid-luteal phase [116]. Bulletti et al. first described a preferential trafficking of vaginally delivered progesterone to the uterus leading to a higher progesterone

concentration in the endometrial tissue compared to the blood serum [117]. Therefore, targeted delivery of progesterone directly to the uterus is thus achievable through utilizing this ‘uterine first pass effect’ [118]. The anatomy of the vagina with its rich vascular plexus provides an ideal environment for absorbing drugs. The rugae of the vaginal wall increase the total available surface area. The vascular system around the vagina and the venous drainage of the vagina does not initially pass through the liver, and thus bypasses the first pass hepatic effect [119]. By avoiding the hepatic first pass effect, vaginal progesterone does not create high concentrations of metabolites that cause undesired side effects. Vaginal administration of progesterone results in more consistent serum levels, which can remain elevated for up to 48 h. Minor complaints associated with vaginal administration include: vaginal irritation, discharge, dyspareunia, bleeding disturbances and reproductive tract infections [120]. 3.2.3. Progesterone delivery systems 3.2.3.1. Vaginal gels. Crinone® 8%, (Columbia Laboratories, Inc., Livingston, NJ) is a vaginal progesterone formulation containing 90 mg of progesterone that is inserted up to three times a day. The carrier vehicle is an oil-in-water emulsion containing polycarbophil, a bioadhesive and water-swellable polymer [121]. The water phase bypasses dependence on the local vaginal moisture, which is highly variable. The progesterone is sparingly soluble in oil (1:30 w/w) and practically insoluble in water (1:10,000 w/w) therefore the majority of the progesterone exists in a suspended form. The emulsion containing both dissolved and suspended progesterone adheres to the vaginal epithelial cells and thereafterdissolved progesterone permeates through the mucosal tissue. The depletion of dissolved progesterone in the formulation is replenished by the dissolution of suspended progesterone particles. This results in a sustained drug release following zero order kinetics until all progesterone particles are dissolved (Fig. 5). Although vaginal gels provide painless administration, the messiness caused by leakage is a major drawback. Engineering vaginal gels to enhance mucoadhesion and efficiency of progesterone delivery through mucosal penetration has the potential to address above mentioned problems. Polymer properties such as surface chemistry, hydrophilicity and charge in response to the vaginal pH, play a significant role in the

Fig. 5. Drug release of suspension-emulsion [122].

878

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interactions with the vaginal epithelial cells and the mucosal layers adhering to the epithelium [121]. Mucoadhesion is facilitated by interpenetration of polymer chains across the vaginal mucus layer (Fig. 6), resulting in adhesion due to entanglement or intermolecular forces such as ionic and hydrogen bonding [123]. Several synthetic and natural polymers such as synthetic polyacrylates, hydroxypropyl cellulose, chitosan, and carragenan or sodium alginate exhibit mucoadhesive properties [124]. Due to its penetration enhancement capabilities, biocompatibility, biodegradability, bioadhesivity, and bacteriostatic effects Chitosan appeared promising for vaginal delivery of medical and pharmaceutical applications [123]. The mechanism of absorption enhancement lies in the combination of its mucoadhesive capability and its effect on tight junctions proteins [125–128]. High molecular weight chitosans derivatives (e.g. 5-methyl-pyrrolidinone chitosan) are promising for delivering hydrophilic drug as they can enhance absorption via the vaginal mucosa [129].

3.2.3.2. Vaginal suppositories: Endometrin® and Cyclogest®. Endometrin® (Ferring Pharmaceuticals, Parsippany, NJ) is an FDA approved, micronized, naturally derived vaginal progesterone tablet insert. Endometrin® tablets adsorb the vaginal secretions and disintegrate into an adhesive powder that adheres to the vaginal epithelium, thus facilitating sustained absorption and reduced perineal irritation [130]. Each Endometrin® vaginal insert delivers 100 mg of progesterone in a base containing excipients conventionally used for solid oral dosage forms: lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide. Endometrin® vaginal inserts provide reproducible serum levels and show less variability than vaginal progesterone gel in pharmacokinetic studies measuring serum concentrations over time [131]. Endometrin® 100 mg administered twice or three times per day was compared with Crinone® 8% in women undergoing IVF. In that study, biochemical, clinical, and ongoing pregnancy rates, as well as live birth rates were not significantly different [132]. Pharmacokinetic studies comparing Endometrin® applied twice or three times daily compared to Crinone® 8% showed that peak serum progesterone concentrations could be achieved more rapidly with Endometrin®. Dosing of Endometrin® three time daily showed the lowest between-subject serum progesterone variability. In case-matched comparisons, Endometrin® 100 mg and Crinone® 8% delivered twice or three times daily were compared to i.m. progesterone. Clinical analyses demonstrated similar pregnancy, miscarriage, and live birth rates from each route [133]. Adverse reaction rates such as breast tenderness, bloating, mood swings, irritability, and drowsiness were similar with Endometrin® when compared to other dosage forms. Cyclogest®, another vaginal suppository mainly used in the U.K., contains semi-synthetic glycerides produced from interesterification of hydrogenated vegetable oil. Comparing Cyclogest® and Endometrin® in clinical trials demonstrated, comparable serum progesterone concentrations could be demonstrated in both. Though there was a difference in the accompanying progesterone dose. The Cyclogest® group received

Fig. 6. Interpenetration of vaginal gel into mucus.

800 mg and the Endometrin® group received 200 mg progesterone [120]. Cyclogest® suppositories can lead to a bothersome vaginal discharge as they melt at body temperature [134]. 3.2.3.3. Vaginal rings. Another vaginal delivery formulation for progesterone is an intravaginal ring (IVR) fabricated from polymers such as ethenyl-vinyl acetate, silicone and polyurethanes [135]. IVRs are torus-shaped polymeric devices that are placed in the vaginal canal near the cervix to provide a sustained delivery of the loaded drugs with duration ranging from 1 week to 1 year [136,137]. IVRs have been successfully employed for the delivery of hormones including applications such as contraception, e.g. Nuvaring [137], or for post-menopausal hormone replacement therapy [138], e.g. Estring and Femring. Progestin-only IVRs providing one year sustained delivery have previously investigated for contraception in lactating women [136,139]. The precedence of effective steroid delivery using IVRs has motivated the development of similar products for luteal phase supplementation. Besides painless delivery compared to i.m. injections, the cosmetic acceptability of IVRs, due to the lack of leakage that commonly occurs in the case of vaginal gels and suppositories, favors their future as a new method for the delivery of progesterone. The overall performance of a vaginal ring depends on its drug release profile, mechanical behavior, and biocompatibility. IVRs can either be loaded with drug throughout the polymer matrix (monolithic or matrix type [140]) or in the core which then is surrounded by a non-medicated sheath of polymer (core or reservoir type [141]). Typically, the reservoir devices are loaded with large quantities of drug in the core to provide a zero order release rate controlled by the membrane, whereas the release rate is proportional to the drug loading and also varies with time in matrix devices [142]. Once placed in the vagina, the drug is absorbed via transcellular, paracellular and/ or receptor mediated routes. Largely, the transport of small molecular weight lipophilic steroids occurs through transcellular pathways at rates correlating with their water/lipid diffusion coefficients similar to general transepithelial absorption at any site. Changes in the vaginal epithelium during the menstrual cycle may affect the absorption of drugs; with the effect on the absorption of lipophilc drugs through transcellular route being less pronounced [143]. The flexible elastomeric backbone enables the compression of the IVR for insertion inside the vaginal cavity. The ring retracts back to an oval shape post-application and is retained in the vagina until removed by the user manually [144]. The position of the ring in the vaginal cavity is not critical for its performance as long as it is in the upper 1/3rd portion of the vaginal cavity close to the cervix. It is held in place by the vaginal muscles and is engineered to have a minimimal involuntary expulsion rate [145]. The ring shape helps in retention and minimizes trauma to the vaginal tissue due to absence of sharp edges or other pronounced structures. Current IVRs for progesterone delivery follow the reservoir type design fabricated from poly(dimethyl siloxane) i.e. silicone. IVRs evaluated for luteal phase support consisted of 1–2 g of progesterone and provided sustained delivery (10–20 nmol/L) for duration of 90 days [135]. Evaluating the silicone ring compared to i.m. progesterone injections (50 mg/day), the IVF-embryo transfer trial showed equal efficacy while the oocyte recipient trial showed a higher implantation rate using the IVR [135]. Although the peripheral progesterone concentrations in the IVR arm (10–20 nmol/L) was significantly lower than that observed in the i.m. arm (N 80 nmol/L), the efficacy in terms of implantation rate was significantly higher in the IVR arm with exogenous delivery being the only source of progesterone for oocyte recipients due to their lack of a corpus luteum.. Therefore, the significantly higher implantation rates observed with IVRs in oocyte recipients illustrate the distinct advantage of sustained delivery through the vaginal route, which was likely attributed to steady-state tissue levels similar to natural pregnancies. Since progesterone requires a diffusion time from the

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cervix to the fundus of the uterus of approximately 4 to 5 h [146], sustained delivery from IVRs are able to utilize the full benefit of vaginal administration by maintaining steady state delivery in a contiguous space. The progesterone IVR for luteal phase supplementation is currently undergoing clinical trials and not available in the U.S. [135]. 3.3. Additional adjuvant infertility treatments for women Potential benefits from additional adjuvants such as oral contraceptives, acetylsalicylic acid, glucocorticoids, and metformin for the treatment of infertile women are extensively discussed in the literature. Oral contraceptives (OC) are established as adjuvant treatment for women undergoing IVF. They are used to regulate the timing of the IVF cycle. Furthermore, OC's prescribed in pretreatment cycles prior to starting the individual GnRH analogue protocol demonstrate an improvement in follicular synchronization [147]. Acetylsalicylic acid (e.g. Aspirin®, Bufferin™, Ecotrin®, Ascripitin®) is widely used as a vasoactive substance. Studies have reported that acetylsalicylic acid may increase uterine perfusion, and it is hypothesized that acetylsalicylic acid may increase endometrial receptivity and ovarian response to gonadotropin stimulation in IVF cycles [148]. However, both hypothesis have not been clinically confirmed and controversial results have been published [149,150]. Conclusions regarding an effect or lack of effect of acetylsalicylic acid treatment never led to firm guidelines for use. Clinical trials are ongoing to prove the effect of low-dose Aspirin in gestation and reproduction [151] Until results prove the use of acetylicsalicylic acid is beneficial in certain pregnancy conditions its use should be deferred. Glucocorticoids suppress androgen levels improving follicle development and increase the production of growth factors, which are known to enhance the action of gonadotropins [152]. They also induce changes in the levels of follicular cytokines, which may be important in determining an individuals' response to ovarian stimulation. Although evidence to support the empirical use of glucocorticoids to improve implantation is insufficient, it has been used in selected patient groups [153]. It is described in literature that the use of metformin by women suffering from PCOS may positively influence the opportunity to conceive in a natural way. However, due to the lack of homogeneity in the duration of therapy and dosages in different clinical trials, the interpretation of the variable results is problematic and a true benefit remains questionable, except for a reduction in the incidence of OHSS [152]. Up to now, no recommendation have been made for the administration of any of the above mentioned adjuvant modalities, except for OCs. with regard to timing and synchronous follicular recruitment, and metformin's potential to reduce OHSS in patients with PCOS. 4. Eye to the future Although significant progress has been made in the past three decades following the first successful IVF procedure in 1978, limited research has been directed towards the development of long duration delivery vehicles for the pharmaceutical agents utilized in IVF treatments. Gonadotropin (FSH; LH; hCG) administration is still limited to s.c. and i.m. injections. Alternative ways of delivery are challenging due to the size and peptide structure of gonadotropins. On the other hand, several novel delivery systems have been evaluated in terms of insulin delivery, which is a smaller but very similar peptide hormone compared to gonadotropins. For example, an inhalation device is available on the market (Exubera®). Additionally, nasal delivery for insulin loaded nanoparticles described in literature seem to provide a promising alternative [154]. Although challenging, the models employed for insulin delivery may also be exploited for the delivery of gonadotropins in the future. Similarly, there are shortfalls in luteal phase progesterone supplementation, which become readily apparent when patients are provided

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a forum regarding luteal phase progesterone supplementation. A recent industry-sponsored survey ‘Progesterone Therapy: The Patient Perspective’, was supported by an educational grant from Ferring Pharmaceuticals, which markets Endometrin®. It surveyed 350 patients visiting the American Fertility Association (AFA) Web site [155]. The survey showed that 86% of patients were dissatisfied with their current progesterone formulations. They reported that progesterone suppositories were leaky and messy, and progesterone-in-oil i.m. injections caused pain and inconvenience. Progesterone gels were noted to routinely leave a vaginal build-up. Oral and vaginal tablets were perceived to be less efficacious than other forms without clear evidence. The majority of the respondents (86%) were not completely satisfied with their progesterone treatment, and 80% felt there was a need for more effective and patient-friendly options. While the survey is subject to obvious bias, physician directed communications with patients tends to support the views reported. The survey described above, confirms an urgent need for improved drug delivery techniques and herald a new era for drug regimens in assisted reproductive technology. The specialties of assisted reproduction, gynecology, obstetrics and gynecological oncology offer numerous opportunities for novel delivery systems that enhance bioavailability, patient compliance and reduce cost of treatment. Improving existing dosage forms by utilizing new polymers engineered to complement drug delivery performance can provide promising drug delivery vehicles. For example, thiolated mucoadhesive tablet formulations are under investigation for vaginal delivery applications and exhibited controlled release properties and efficient mucoadhesion [156]. Other routes are also being explored for hormone delivery; for example, nasal gels were tested as a delivery platform for progesterone [157]. It should be mentioned here that sustained delivery vehicles developed for hormone delivery should also provide the feasibility of aborting the drug treatment immediately upon adverse effects. This is easily achievable in topical delivery systems such as vaginal rings and transdermal patches by removing them from the body. Additionally, smart delivery systems engineered to be responsive to physiological feed-back loops can be designed by utilizing innovative piezoelectric approaches with polymer technology. Thus, polymeric drug delivery and nanotechnology offer tremendous potential in providing solutions to current needs in IVF.

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