Professional Documents
Culture Documents
1
Centre for Neuroendocrinology, University of Pretoria, Pretoria 0001, South Africa; 2Department of
Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; 3Department of
Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; 4MRC Centre for
Reproductive Health, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ,
United Kingdom; 5Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of
Cape Town, Cape Town 7700, South Africa; and 6Institute of Infectious Diseases and Molecular Medicine,
University of Cape Town, Cape Town 7700, South Africa
ABSTRACT The gonadotropin receptors LH receptor and FSH receptor play a central role in governing reproductive competency/fertility.
Gonadotropin hormone analogs have been used clinically for decades in assisted reproductive therapies and in the treatment of various
infertility disorders. Though these treatments are effective, the clinical protocols demand multiple injections, and the hormone preparations
can lack uniformity and stability. The past two decades have seen a drive to develop chimeric and modified peptide analogs with more
desirable pharmacokinetic profiles, with some displaying clinical efficacy, such as corifollitropin alfa, which is now in clinical use. More
recently, low-molecular-weight, orally active molecules with activity at gonadotropin receptors have been developed. Some have excellent
characteristics in animals and in human studies but have not reached the market—largely as a result of acquisitions by large pharma.
Nonetheless, such molecules have the potential to mitigate risks currently associated with gonadotropin-based fertility treatments, such as
ovarian hyperstimulation syndrome and the demands of injection-based therapies. There is also scope for novel use beyond the current
remit of gonadotropin analogs in fertility treatments, including application as novel contraceptives; in the treatment of polycystic ovary
syndrome; in the restoration of function to inactivating mutations of gonadotropin receptors; in the treatment of ovarian and prostate
cancers; and in the prevention of bone loss and weight gain in postmenopausal women. Here we review the properties and clinical
application of current gonadotropin preparations and their analogs, as well as the development of novel orally active, small-molecule
nonpeptide analogs. (Endocrine Reviews 39: 911 – 937, 2018)
ESSENTIAL POINTS
· Urinary gonadotropin analogs have been used clinically for decades in assisted reproductive therapies and in the
treatment of various infertility disorders
· Issues with the gonadotropin peptide hormones include clinical protocols requiring multiple injections, nonuniformity of
preparations, protein stability, and increased risk of ovarian hyperstimulation syndrome
· More recently, recombinant gonadotropin preparations have been favored as a result of their improved purity and batch-
to-batch consistency
· Gonadotropin hormones with differing half-lives and oral bioavailability may mitigate the need for repeated injections
anterior pituitary stimulate the production and secre- and females. Whereas LH pulse frequency remains
tion of the gonadotropin hormones LH and FSH, which constant in males, it varies over the female menstrual
are released into the general circulation to stimulate cycle with low-frequency pulses during the luteal
gonadal steroidogenesis, peptide hormone secretion phase of the cycle and higher-frequency pulses in the
(inhibin and activin), and gametogenesis. Gonadal follicular phase. FSH pulsatility is less discernible, as
steroids and peptide hormones then feed back in unlike LH, FSH is not stored in secretion granules and
negative and positive modalities at the hypothalamus has a longer half-life in the circulation. In females, FSH
and/or pituitary (, ). activity in the late-luteal/early-follicular phases of the
cycle is responsible for recruitment of five to seven
The actions of gonadotropins in the HPG axis Graafian follicles into the menstrual cycle and drives
The gonadotropin glycoproteins exert their effects on follicular development. Estradiol, produced by the
the HPG axis through interaction with and activation developing follicle, feeds back negatively to the hy-
of their cognate receptors, the LH receptor (LHCGR/ pothalamus, resulting in suppressed LH secretion.
LHR) and FSH receptor (FSHR). Whereas a number of Through poorly defined mechanisms, an estradiol
studies have documented the presence of LHR and threshold is reached, at which point estradiol switches
FSHR in extragonadal tissues (, ), physiologically, to positive feedback, resulting in a midcycle increase in
their primary site of activity is the gonads. FSHR LH pulse frequency and surge of LH, which are re-
activation stimulates follicular development in females sponsible for initiating ovulation and luteinization of
and the initiation of spermatogenesis in males whereas the ruptured follicle. The luteinized follicle, or corpus
LHR stimulation is responsible for steroidogenesis and luteum, subsequently produces progesterone that
follicular/gamete maturation, as well as the induction prepares the uterine endometrium for implantation.
of ovulation in females. LH regulates expression of Progesterone also feeds back negatively at the hypo-
steroidogenic enzymes and the subsequent production thalamus, suppressing LH secretion, resulting in at-
of androgens within the interstitial Leydig and thecal rophy of the corpus luteum should implantation not
cells of the testes and ovaries, respectively. Steroido- occur.
genesis is also dependent on the activity of FSH in The importance of both glycoprotein hormones
testicular Sertoli cells and the granulosa cells of the and their receptors in gonadal function is highlighted
ovaries, supporting gonadal development and facili- by the pathophysiologies attributed to inactivating (or
tating the conversion of androgen to estrogen via the constitutively activating) mutations that affect the LH/
enzyme aromatase. Activation of FSHR additionally LHR and FSH/FSHR signaling modalities. Loss of
results in the production of the TGF-b family functional LH and FSH in males and females can
members activin and inhibin, which positively and result in impaired fertility/infertility phenotypes and in
negatively feed back to the pituitary and hypothalamus the case of LH, a lack of pubertal development (, ).
to regulate FSH production/activity (). The severity of the phenotype attributed to muta-
The gonadotropin-secretion profiles are also sex- tions in the LHR correlates with the degree of receptor
ually dimorphic, differing dramatically between males inactivation and a resultant spectrum of phenotypes from
912 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
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pseudohermaphroditism and hypogonadism through and both activate the LHR with similar potencies in
to the less severe micropenis and oligomenorrhea (). vitro (). However, the CTP confers an increased half-
Interestingly, loss of FSH/FSHR signaling in females life to hCG. The a- and b-subunit heterodimers form
results in infertility, in contrast to males, where through noncovalent interactions, whereas the intra-
homozygous-inactivating FSH/FSHR mutations appear subunit tertiary structure is largely governed by
to result in a qualitative and quantitative reduction in disulfide bonds (), with the a- and b-subunits
spermatogenesis without rendering the patient com- containing and cysteine residues, respectively
pletely infertile, implying a level of redundancy in FSHR (). The resolution of the crystal structure of hCG
signaling with regard to male fertility (–). These demonstrated that the a- and b-subunit interaction is
findings appear to be supported by an FSH-deficient stabilized by a cysteine loop of the b-subunit that
(reduced sialylation) display higher binding affinities and glycoprotein hormones interact with this large N-
biopotencies in heterologous cell-assay systems than the terminal domain (). The LRRs have been demon-
acidic isoforms, and some of the most basic isoforms strated to form a slightly curved solenoid, with the
(pH . .) have antagonistic activity (–). In- hormone binding to the curved inner surface.
triguingly, antagonism of GnRHR has been shown to The receptor wraps around the central portion of the
result in elaboration of a greater proportion of these basic hormone through both hormone subunits and occurs
forms of FSH, which act as antagonists (). Differentially over a large interface, described as a “hand clasp.” This
glycosylated FSH isoforms appear to have physiological interaction is mediated via a number of charge in-
relevance, as during puberty and the transition from teractions, salt bridges, and aromatic ring-stacking
early-to-late follicular phase, there is a progressive increase interactions (, ). A region proximal to the ECL/
914 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
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Figure 1. Two-step FSH/FSHR recognition and activation. The ECD LRRs of FSHR, in a putative orientation relative to the seven
transmembrane (7TM) domain, are shown as a magenta block with a hinge, and the 7TM domain is shown as a cylinder, with the
inactivated state colored gray and the activated state colored green. Sulfated Y335 is shown as a yellow ball, residue S273 is shown as
a green star, and disulfide bonds are shown as a brown stick. Heterotrimeric Gs or b-arrestin protein is shown as a green ellipsoid. FSH
heterodimer is represented in purple, with carbohydrates at N52a shown as a yellow, Y-shaped stick. (a) Inactive receptor is bound by
hormone, (b) resulting in Y335 in the receptor hinge lifting via interaction with the hormone, permitting (c) activation of the 7TM
domain. HBSD, hormone-binding subdomain; SSSD, signal-specificity subdomain. Reproduced with permission from Jiang X, Liu H,
Chen X, et al. Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. Proc Natl Acad Sci USA
2012; 109(31):12491–12496. [© 2018 Illustration Presentation ENDOCRINE SOCIETY]
Gynogen HP (Sanzyme)
Merional/Eigenorm/Meriofert (IBSA)
Normegon (Organon)
Puregraf (GUFIC)
Endogen HP (Sanzyme)
Follicare (GUFIC)
Folliova (Sanzyme)
Fostimon/Fostipur/Altermon (IBSA)
Orgafol (Organon)
916 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
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Table 1. Continued
Hormone Source Generic Name Example Brand Names (Manufacturer)
Cinnal-F (CinnaGen)
FSH/LH mix (2:1 ratio) Recombinant Follitropin alfa:lutropin alfa Pergoveris (EMD Serono/Merck Serono)
A.P.L. (Wyeth-Ayerst)
Choriomon/Gonasi HP (IBSA)
Endocorion (ELEA)
Materna-hCG (Emcure)
Pubergen HP (Sanzyme)
Puretrig (GUFIC)
Table 1. Continued
Hormone Source Generic Name Example Brand Names (Manufacturer)
918 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
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positive prognostic indicator of response, as is previous with testosterone and with similar final testicular
treatment with gonadotropins, whereas cryptorchi- volumes (). Thus, in keeping with a meta-analysis in
dism is an important negative predictor. The long- adult men (), previous testosterone therapy was not
acting version of FSH, corifollitropin alfa, has also been found to be disadvantageous, although a possible
used in hypogonadotropic men, and in a small open advantage of gonadotropin-induced puberty would be
label trial, spermatogenesis was established in % of that spermatogenesis can subsequently be more rap-
men who remained azoospermic after treatment with idly induced in men previously treated with gonad-
hCG alone (). Administration of this long-acting otropins when fertility is desired.
analog, once every weeks, greatly reduces the
treatment burden, and on the basis of this limited Gonadotropin therapy in women
(with a higher cycle cancellation rate reflecting a higher The initial approach to more rapid-onset FSH
multifollicular response), and a lower pregnancy rate is administration involved luteolysis with the use of a
achieved. Therefore, such women are ideally treated GnRH antagonist (), but it subsequently became
with pulsatile GnRH (whereby the involvement of clear that FSH administration could be started at al-
physiological feedback pathways contribute to high most any stage of the cycle, other than in the im-
rates of mono-ovulation), but this is of very limited mediate periovulatory period. This approach gives
availability. comparable oocyte number and apparent de-
velopmental competence to those obtained after
Superovulation routine ovarian stimulation, and whereas data on
The use of high doses of FSH for controlled super- pregnancy rate remain limited as a result of the nature
920 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
REVIEW
N linker (FSHb-N-a) or CTP (FSHb-CTP-a) also had greater bioavailability compared with the
linkers, there was only a modest improvement in non-PEGylated control in rats ().
clearance rates for the FSHb-N-a analog (). In- Another strategy for increasing FSH half-life was
terestingly, despite a plateau in elimination half-life the creation of a fusion-protein consisting of FSH a-
and comparable augmentation of ovarian weight and b-subunits fused to a binding partner (e.g., im-
following injection of FSHb-CTP-a, FSHb-N-a, and munoglobulin Fc fragments) of the neonatal Fc
FSHb-N-a analogs, there were increases in the receptor (FcRn). FSH fusion proteins containing
number of antral follicles and substantial increases in immunoglobulin Fc fragments had increased stability
inhibin A following treatment with all the N-linked and serum half-life. In addition, these fusion proteins
analogs (). The in vivo bioactivities of FSHb-N-a are protected from endosomal degradation by binding
922 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
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compared with one of FSH dissolved in an alternative often result in incomplete deglycosylation, which may
adjuvant, polyvinylpyrrolidone, but superovulation confound the interpretation of data ().
was found to be much more effective when FSH was
administered in the aluminum hydroxide preparation
(). Nonpeptidic Low-Molecular-Weight
Whereas these modified analogs with improved Gonadotropin Receptor Agonists
bioactivity/bioavailability have not been tested clini- and Antagonists
cally, they do offer an exciting possibility for possible
future development of improved or less invasive go- Whereas the development of polypeptide gonado-
nadotropin therapeutics. tropin analogs with increased serum half-life/bioactivity
mechanism (Fig. ). Therefore, it is difficult to imagine gonadotropin receptors, and a number of cell-based
orthosterically binding LMW molecules that could screening assays have been used over the last years,
simultaneously occupy and induce the structural resulting in the identification of various lead
changes within the glycoprotein hormone receptor compounds/chemical scaffolds, with specific in vitro
ECDs to attain full efficacy of activation with low cellular and in vivo physiological activity profiles.
potency. However, this concern has been overcome The most frequently targeted of the glycoprotein
with allosterically binding LMW molecules (see later). hormone receptors for LMW drug discovery is the
Thirdly, promising lead compounds, identified through FSHR. This is perhaps unsurprising, given the multiple
in vitro screening, have been found to have little/no injections of hormone necessary for ovarian hyper-
in vivo efficacy (), as is a common feature of small- stimulation in assisted reproductive therapy protocols.
924 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
REVIEW
Diketopiperazines
A high-throughput screen in by Pharmacopeia
(since acquired by Ligand Pharmaceuticals) and Or-
ganon [since acquired by Schering-Plough and then
merged with Merck & Co./Merck Sharpe & Dohme
(MSD)] of approximately two million compounds,
identified a number of biaryl agonists of the
FSHR with different substituents on the phenyl rings.
The most potent compounds contained heterocyclic
diketopiperazine substituents (). Lead optimiza-
tion, aimed at modification of the diketopiperazine
core side-chains, increased their potency from the low
micromolar to the low nanomolar range in both lu- Figure 2. Top view of the LHCGR, with a partially clipped
ciferase reporter gene and cAMP assays (). How- backbone of the ECLs, visualizing the potential binding region
ever, these compounds do not appear to have been for small allosteric LMW ligands (magenta). This ligand-binding
developed further, and there is no information re- region can be subdivided further into a major and a minor
pocket. TMH, TM helix. Reproduced with permission from
garding specificity or in vivo activity of these hit
Heitman LH, Kleinau G, Brussee J, et al. Determination of different
compounds. At a similar time, Serono also filed a putative allosteric binding pockets at the lutropin receptor by
patent describing substituted piperazine compounds using diverse drug-like low molecular weight ligands. Mol Cell
with FSHR agonistic activity in the low micromolar to Endocrinol 2012;351(2):326–336. [© 2018 Illustration Presentation
low nanomolar range (). ENDOCRINE SOCIETY]
926 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
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https://academic.oup.com/edrv
Table 3. Selected LMW Gonadotropin Analog Structures
doi: 10.1210/er.2018-00052
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928 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
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benzamide analogs were subsequently identified by (Table ), which displayed nanomolar potency at the
Addex, corroborating the description of biased antag- LHR (EC of . nM; % efficacy compared with
onism identified for ADX and further sub- LH), no activity at the TSHR, and reduced activity at
stantiating the requirement for blockade of both arms of the FSHR (-fold reduced potency than at the LHR)
the FSHR steroidogenic signaling pathway to inhibit (). Interestingly, this study also highlighted biased
follicular maturation and ovulation in rats (). signaling properties of Org . Whereas LH ac-
tivation of the LHR stimulated both cAMP (EC
Other FSHR antagonists pM) and phospholipase C (PLC; EC . nM), no
Pyrrolobenzodiazepine and acyltryptophanol LMW substantial activation of the PLC pathway by Org
FSHR antagonists were identified through luciferase was measured, suggestive of biased agonism
tolerated up to a maximum dose of mg (). binding (, ). Several analogs were synthesized,
The GnRH analog, Ganirelix, was administered SC for including the potent allosteric inhibitor, compound
pituitary suppression in conjunction with recombi- (LUF; Table ). In a luciferase reporter assay, this
nant FSH to stimulate follicular growth. Adminis- compound reduced the potency of LH or Org
tration of mg Org resulted in ovulation stimulation of the receptor by approximately threefold
induction in .% of patients, as determined by ().
transvaginal ultrasound and a midluteal rise in pro-
gesterone (). Analogs with dual-receptor activity
Org has activity at the FSHR, in addition to The high degree of sequence conservation among the
the LHR, and this lack of selectivity could be an issue glycoprotein hormone receptors frequently translates
930 Anderson et al Peptide and Nonpeptide Gonadotropin Analogs Endocrine Reviews, December 2018, 39(6):911–937
REVIEW
hMG and hCG, the latter are still widely used, as they are compounds offer subtle advantages over traditional
less expensive and effective. agonist and antagonist ligands, such as improved
Good progress has been made in development of specificity and thus, reduced side-effects. Therefore,
LMW orally active LHR and FSHR agonists and development of PAMs/NAMs that target the go-
antagonists, and three have been evaluated in clinical nadotropin receptors would be an exciting develop-
studies. The allosteric LHR agonists Org and ment in this field and is one currently being pursued
Org displayed excellent bioavailability, safety, by companies, such as Addex Therapeutics.
and pharmacokinetic and pharmacodynamic prop- Another exciting development in the arena of
erties, and both demonstrated good efficacy in in- LMW gonadotropin analogs is their ability to restore
duction of ovulation protocols. Therefore, these function to inactivating mutations in human gonad-
on this subject (, ). Despite an increasing body for FSH/FSHR in ovarian cancer (–) open up an
of evidence supporting a role for FSH in bone and fat even wider spectrum of potential novel applications for
regulation, there are contradictory findings in both LH and FSH agonists and antagonists.
human and rodent studies, and robust conclusions are Although these observations are compelling, the
difficult to tease out in view of the relation of estrogen extent of gonadotropin receptor expression in extra-
to FSH and the often-opposed effects of the two gonadal tissues and the effects of gonadotropins on
hormones, such as on osteoclasts (). diverse tissues remain to be fully explored, using a
Elevated LH may also exert neurodegenerative range of experimental approaches and advanced ep-
effects, such as those seen in Alzheimer’s disease idemiological studies. Therefore, it remains to be seen
(, ). Additionally, increased FSH and FSHR ex- whether gonadotropin analogs may have use in these
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the b-subunit of FSH prevents bone loss by of Physiology, Faculty of Health Sciences, University of Pre-
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14574–14579. Lauchlan SC, Pike MC. Ovarian epithelial tumor Disclosure Summary: R.A.A. and R.P.M. undertake
208. Liu P, Ji Y, Yuen T, Rendina-Ruedy E, DeMambro VE, growth promotion by follicle-stimulating hormone consultancy work for KaNDy Therapeutics Ltd. The
Dhawan S, Abu-Amer W, Izadmehr S, Zhou B, Shin and inhibition of the effect by luteinizing hormone. remaining authors have nothing to disclose.