Is endometriosis due to evolutionary maladaptation?

Similar to diabetes and unlike many pathogen-induced diseases, endometriosis is likely a result of maladaptation to the evolutionary heritage of humans. The objective of this article is to review the literature and improve understanding of the evolutionary factors behind endometriosis, leading to more effective prevention and treatment approaches. In primates, spontaneous decidualization of the endometrium evolved to ensure optimal implantation of a limited number of early embryos, unlike many non-primates which depend on early embryos to induce decidualization and subsequent pregnancy. Spontaneous decidualization results in menstrual bleeding when embryo implantation does not occur, and endometriosis is commonly believed to be caused by retrograde menstruation. Although direct evidence is lacking, it is likely that hunter-gatherer women experienced fewer menstrual periods due to pregnancy shortly after menarche, followed by repeated pregnancies and lactation. However, the mismatch between the evolved uterine physiology and rapid societal changes has led to modern women delaying pregnancy and experiencing numerous menstrual periods, potentially increasing the incidence of endometriosis. The symptoms of endometriosis are often managed by suppressing menstruation through systemic hormonal treatments, but these may have side effects. For patients with a family history of endometriosis or in the early stages of the disease, intrauterine devices releasing progesterone locally could prevent uterine bleeding and the development of endometriosis while preserving fertility and minimizing side effects.

Gonacin: A germ cell-derived hormone with glucogenic, orexigenic, and gonadal activities.

Fish require abundant nutrients to generate a large number of eggs for spawning. Based on the evolutionary conservation of human FBN2 and its C-terminal placensin-like sequences in fish, we identified a peptide hormone gonacin (GONAdal Cell placensIN) and found its high expression in early-stage germ cells in the ovary and testis of zebrafish. We demonstrated that gonacin is essential for food intake, glucose release, and ovarian development in zebrafish. Similar expression patterns and functions of gonacin were also demonstrated in rainbow trout. Gonacin represents the first hormone secreted by germ cells with endocrine functions in vertebrates, bridging the energy homeostasis and reproduction.

Out of step societal and Darwinian adaptation during evolution is the cause of multiple women's health issues.

During human evolution, major changes in our societal conditions and environment took place without sufficient time for concomitant genetic alterations, leading to out of step adaptation and diseases in women. We first discuss recent societal adaptation mismatch (menstrual bleeding; increases in cancers of reproductive organs, endometriosis; mother's nursing; polycystic ovarian syndrome; transgenerational epigenetic modifications), followed by Darwinian out of step adaptation (labor difficulties; sex chromosomes, human diseases and sex disparity in genomic DNA). We discuss the evolutionary basis of menstrual bleeding, followed by recent increases in cancers of reproductive organs and endometriosis. The importance of breastfeeding by mothers is also emphasized. Earlier onset of menarche, decreased rates of childbirths and breastfeeding resulted in increased number of menstrual cycles in a lifetime, coupled with excess estrogen exposure and incessant ovulation, conditions that increased the susceptibility to mammary and uterine cancers as well as ovarian epithelial cancer and endometriosis. Shorter lactation duration in mothers also contributed to more menstrual cycles. We further discuss the evolutionary basis of the prevalent polycystic ovary syndrome. During the long-term Darwinian evolution, difficulties in childbirth evolved due to a narrowed pelvis, our upright walking and enlarged fetal brain sizes. Because there are 1.5% genomic DNA differences between woman and man, it is of significance to investigate sex-specific human physiology and diseases. In conclusion, understanding out of step adaptation during evolution could allow the prevention and better management of female reproductive dysfunction and diseases.

Whole-Ovary Laparoscopic Incisions Improve Hormonal Response and Fertility in Patients with Extremely Poor Ovarian Response.

STUDY OBJECTIVE: Recent findings have shown mechanical fragmentation of ovarian cortex and ovarian drilling could promote follicle growth in patients with premature ovarian insufficiency and polycystic ovarian syndrome, respectively. A common element shared by these treatments is the mechanical disturbance of ovarian extracellular matrix tissues. We thus hypothesized a simplified whole-ovary laparoscopic incision (WOLI) procedure may provide the intrinsic stimuli needed to activate resting follicles in patients with an extremely poor ovarian response (EPOR) who had negligible chance of becoming pregnant with their own oocytes via modern in vitro fertilization practice. DESIGN: Retrospective pilot study. SETTING: The study was conducted in a research medical center in Taiwan. PATIENTS: Women who had multiple canceled ovarian stimulation cycles due to the lack of follicle growth were recruited. A total of 6 patients with EPOR received the WOLI procedure, which covers the whole surface of ovaries, in 2015 to 2017. INTERVENTIONS: After receiving an outpatient WOLI procedure, ovarian response and follicle growth were monitored for 90 days with or without gonadotropin stimulation. Embryo quality and clinical outcomes were analyzed. MEASUREMENTS AND MAIN RESULTS: After the WOLI treatment, 5 of 6 patients had significant increases in serum estradiol level and improved follicle growth (p = .001). Multiple oocytes were retrieved from each of these patients, and it led to thawed embryo transfer (ET) cycles in 4 patients (p = .010). On average, the duration from the WOLI procedure to the first ovum pickup was 24 days (11 to 58 days). After ET, 2 patients became pregnant and delivered healthy babies. Two other patients received ET, and 1 led to a chemical pregnancy. One patient had cryopreserved embryos with pending transfer. CONCLUSION: The standardizable WOLI procedure restored hormonal responses in a majority of patients with EPOR. Further validation of this novel and yet simple laparoscopic procedure, which requires only 1 laparoscopic surgery, may provide a practical option to reactivate the aging ovarian environment in patients with EPOR and premature ovarian insufficiency.

A kaleidoscopic view of ovarian genes associated with premature ovarian insufficiency and senescence.

Ovarian infertility and subfertility presenting with premature ovarian insufficiency (POI) and diminished ovarian reserve are major issues facing the developed world due to the trend of delaying childbirth. Ovarian senescence and POI represent a continuum of physiological/pathophysiological changes in ovarian follicle functions. Based on advances in whole exome sequencing, evaluation of gene copy variants, together with family-based and genome-wide association studies, we discussed genes responsible for POI and ovarian senescence. We used a gene-centric approach to sort out literature deposited in the Ovarian Kaleidoscope database (http://okdb.appliedbioinfo.net) by sub-categorizing candidate genes as ligand-receptor signaling, meiosis and DNA repair, transcriptional factors, RNA metabolism, enzymes, and others. We discussed individual gene mutations found in POI patients and verification of gene functions in gene-deleted model organisms. Decreased expression of some of the POI genes could be responsible for ovarian senescence, especially those essential for DNA repair, meiosis and mitochondrial functions. We propose to set up a candidate gene panel for targeted sequencing in POI patients together with studies on mitochondria-associated genes in middle-aged subfertile patients.

Parental methylome reprogramming in human uniparental blastocysts reveals germline memory transition.

Uniparental embryos derived from only the mother (gynogenetic [GG]) or the father (androgenetic [AG]) are unique models for studying genomic imprinting and parental contributions to embryonic development. Human parthenogenetic embryos can be obtained following artificial activation of unfertilized oocytes, but the production of AG embryos by injection of two sperm into one denucleated oocyte leads to an extra centriole, resulting in multipolar spindles, abnormal cell division, and developmental defects. Here, we improved androgenote production by transferring the male pronucleus from one zygote into another haploid androgenote to prevent extra centrioles and successfully generated human diploid AG embryos capable of developing into blastocysts with an identifiable inner cell mass (ICM) and trophectoderm (TE). The GG embryos were also generated. The zygotic genome was successfully activated in both the AG and GG embryos. DNA methylome analysis showed that the GG blastocysts partially retain the oocyte transcription-dependent methylation pattern, whereas the AG blastocyst methylome showed more extensive demethylation. The methylation states of most known imprinted differentially methylated regions (DMRs) were recapitulated in the AG and GG blastocysts. Novel candidate imprinted DMRs were also identified. The production of uniparental human embryos followed by transcriptome and methylome analysis is valuable for identifying parental contributions and epigenome memory transitions during early human development.

Spatial topological analysis of sympathetic neurovascular characteristic of acupoints in Ren meridian using advanced tissue-clearing and near infrared II imaging.

Acupuncture has been used for treating various medical conditions in traditional Chinese medicine. Both manual and electro-acupuncture stimulate specific acupoints to obtain local and systemic biological effects, but the underlying mechanisms remain unclear. Here, we used three-dimensional tissue-clearing technology to study acupoints on the Ren meridian of mice to reveal the distribution, density, branching, and relationships between blood vessels and nerves. Using topological Mapper methods, we found that sympathetic neurovascular networks were denser in the CV 4 acupoint compared with surrounding non-acupoints. Furthermore, high resolution in vivo real-time vascular imaging using the near infrared-II probe LZ-1105 demonstrated increased blood flow in the CV 4 acupoint compared with neighboring non-acupoints after manual or electro-acupuncture. Consistent with earlier findings, our research indicated that acupuncture could enhance local blood flow, and our high-resolution 3D images show for the first time the important role of sympathetic neurovascular networks in the CV 4 acupoint.

First-in-class humanized FSH blocking antibody targets bone and fat.

Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHß subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing.

Surgical approaches of drug-free in vitro activation and laparoscopic ovarian incision to treat patients with ovarian infertility.

OBJECTIVE: To demonstrate our procedures of drug-free in vitro activation (IVA) for treating patients with premature ovarian insufficiency (POI) or diminished ovarian reserve (DOR), as well as the laparoscopic ovarian incision (LOI) procedure for treating patients with resistant ovary syndrome (ROS). DESIGN: Step-by-step video demonstration of the surgical procedures. SETTING: Fertility clinic and reproductive medicine department. PATIENTS: Women were diagnosed with POI based on recent amenorrhea before 40 years of age or with DOR according to the Bologna criteria, showing growth of a few antral follicles after ovarian stimulation. ROS patients were diagnosed based on amenorrhea with hypergonadotropic hypoestrogenism but showing age-appropriate number of antral follicles under transvaginal ultrasound. INTERVENTIONS: The drug-free IVA consists of the following 4 steps: removing a part of the cortex from one or both ovaries; cutting ovarian cortical pieces into small cubes in vitro; making pockets for ovarian tissue grafting; and grafting ovarian cortical cubes. The LOI procedure consisted of only one step: cutting ovarian cortex in situ. Both procedures were followed by ovarian hyperstimulation for at least 1 year. Informed consent was obtained from patients and approval was granted by the Biomedical Ethics Committee of the International University School of Medicine and the Rose Ladies Clinic. The present clinical trial was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). MAIN OUTCOME MEASURE: Follicle growth. RESULTS: These procedures can be completed within 1 hour under laparoscopic surgery. There were no complications. In 13 of 15 patients treated with drug-free IVA, increases in antral follicle numbers were found, followed by a higher number of retrieved oocytes for in vitro fertilization. In addition to one spontaneous pregnancy, embryo transfer allowed four live births and one ongoing pregnancy. Five additional patients and one miscarriage patient have cryopreserved embryos for future transfer. We also found follicle growth to the preovulatory stage in seven of 11 ROS patients who have not responded to any endogenous and exogenous follicle-stimulating hormone stimulations for follicle growth prior to LOI treatment, allowing the retrieval of mature oocytes for in vitro fertilization. Four ROS patients became pregnant, followed by the delivery of three healthy infants and one ongoing pregnancy. CONCLUSION: A drug-free IVA approach provided an infertility treatment for recent POI or DOR patients. This procedure promoted growth of residual ovarian follicles following ovarian tissue fragmentation in vitro, leading to Hippo signaling disruption. Although ROS patients exhibited symptoms of hypergonadotropic hypoestrogenism similar to that of POI patients, they still had multiple secondary follicles. Hippo signaling disruption in vivo based on cutting ovarian cortex using LOI could promote follicle growth. UMIN CLINICAL TRIALS REGISTRATION NUMBER: UMIN000029807.

Hippo signaling disruption and ovarian follicle activation in infertile patients.

The Hippo signaling pathway, which is important in organ size regulation, is present in organisms from the fly to mammals. Disruption of the Hippo signaling pathway leads to increased nuclear translocation of the effector Yes-associated protein (YAP), resulting in the expression of cystein-rich 61, connective tissue growth factor, and nephroblastoma overexpressed (CCN) growth factors and baculoviral inhibitors of apoptosis repeat containing (BIRC) apoptosis inhibitors to increase organ sizes. Furthermore, genome-wide knockdown of genes in insect cells demonstrated that actin polymerization promoted nuclear translocation of YAP. In the mammalian ovary, we demonstrated the expression of Hippo signaling pathway genes and showed that ovarian fragmentation increased actin polymerization, leading to YAP nuclear translocation and increased expression of cystein-rich 61, CCN growth factors and BIRC apoptosis inhibitors, followed by enhanced follicle growth. Here we summarize evidence suggesting the role of mechanical stress on follicle growth in the ovary and describe recent use of ovary-damaging procedures to treat ovarian infertility. Ovarian fragmentation, together with in vitro incubation with Akt-stimulating drugs, formed the basis of an in vitro activation (IVA) therapy to treat patients with premature ovarian insufficiency, whereas ovarian fragmentation alone (drug-free IVA) was successful in treating patients with premature ovarian insufficiency with recent menses cessation. For middle-aged women with poor ovarian responses and diminished ovarian reserve, drug-free IVA was also effective in promoting follicle growth for infertility treatment. In addition, an in vivo follicle activation approach based on laparoscopic ovarian incision showed promise for patients with resistant ovary syndrome. With initial success using mechanical disruption approaches, future investigation could evaluate possibilities to refine mechanical methods and to locally administer actin polymerization-enhancing drugs for ovarian infertility treatment.

Increasing ovarian NAD+ levels improve mitochondrial functions and reverse ovarian aging.

Loss of follicles together with decreased oocyte quality and quantity contribute to age-associated ovarian senescence and infertility. Although underlying mechanisms for ovarian senescence are still unknown, mitochondrial dysfunctions have been reported. Here, we showed age-dependent decreases in ovarian Nicotinamide Adenine Dinucleotide (NAD+) levels in mice whereas supplementing aging mice with nicotinamide riboside (NR), an NAD+ precursor, increased ovarian NAD+ content. We found that increases in ovarian NAD+ levels in aging mice led to increased number of ovarian follicles and ovulatory potential as well as increased live birth rate. NR supplementation also reduced levels of reactive oxygen species and decreased spindle anomalies in aging oocytes, together with increased mitochondrial membrane potential (ΔΨm) and decreased mitochondrial clustering. In addition, NR supplementation improved ovarian mitochondrial energy metabolism. Our data suggested that supplementation with NAD+ precursors in vivo and in vitro could be potential therapeutic approaches for treating age-related ovarian infertility.

Discovery of polypeptide ligand-receptor pairs based on their co-evolution.

Sequencing diverse genomes allowed the tracing of orthologous and paralogous genes to understand the co-evolution of polypeptide ligands and receptors. This review documents the discovery of several polypeptide ligands and their cognate receptors mainly expressed in the reproductive tissue using evolutionary genomics. We discussed the sub-functionization of paralogs and co-evolution of ligand-receptor families. Based on the conserved signaling among paralogous receptors and common knock-out phenotypes of ligand-receptor pairs, relationships between relaxin family peptides and leucine-rich repeat-containing, G protein-coupled receptors (LGR) were revealed. We also described the identification of a novel paralogous glycoprotein hormone thyrostimulin and design of a long-acting FSH. Human stresscopin and stresscopin-related peptide, paralogous to CRH, were also identified based on the conserved signaling pathways. Recently, a novel ligand placensin expressed in human placenta was found based on the paralogous relationship with a metabolic hormone asprosin. Placensin likely contributes to stage-dependent increases in insulin resistance during human pregnancy and its elevated secretion was associated with gestational diabetes mellitus. Although many ligands were predicted based on sequence signatures, ligands of shorter sequences have not been identified, together with many "orphan" receptors without known ligands. Future development of tools for predicting ligands and high throughput assays to identify ligand-receptor pairs based on ligand binding and/or signal transduction could advance hormone-based physiology and pathophysiology.

Drug-free in-vitro activation of follicles for infertility treatment in poor ovarian response patients with decreased ovarian reserve.

RESEARCH QUESTION: The recently developed in-vitro activation (IVA) approach provides a promising infertility treatment for patients with premature ovarian insufficiency. The IVA method promotes growth of residual ovarian follicles following ovarian tissue fragmentation leading to Hippo signalling disruption, together with in-vitro incubation with Akt stimulators. As poor ovarian response (POR) patients with decreased ovarian reserve (DOR) have multiple secondary follicles, this study tested whether Hippo signalling disruption alone using in-vitro ovarian cortical fragmentation, followed by autologous grafting, was sufficient to promote follicle growth. DESIGN: A case series study. RESULTS: In 9 out of 11 POR patients with DOR treated with a simplified IVA procedure, increases in antral follicle numbers in multiple growth waves were detected following FSH treatment. Subsequent injection with human chorionic gonadotrophin allowed retrieval of more mature oocytes for IVF (median antral follicle counts before and after IVA per ovarian stimulation: 1.0 versus 2.6) with 68.7% fertilization rates and 56.9% showing high-quality embryonic development. One natural conception and 16 embryo transfers in five patients resulted in one live birth, two ongoing pregnancies and one miscarriage. Three additional patients and the miscarriage patient have cryopreserved embryos for future transfer. CONCLUSIONS: The present drug-free IVA approach may be suitable for POR patients with DOR, as it increased the number of antral follicles. The procedure also eliminated the need for 2-day incubation with drugs and required only one surgery. This approach could allow the retrieval of more oocytes in middle-aged women to achieve higher pregnancy rates and deserves proper evaluation in future randomized controlled trials.

Forty years of IVF.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.

Imaging the ovary.

During each reproductive cycle, the ovary exhibits tissue remodelling and cyclic vasculature changes associated with hormonally regulated folliculogenesis, follicle rupture, luteal formation and regression. However, the relationships among different types of follicles and corpora lutea are unclear, and the role of ovarian vasculature in folliculogenesis and luteal dynamics has not been extensively investigated. Understanding of ovarian physiology and pathophysiology relies upon elucidation of ovarian morphology and architecture. This paper summarizes the literature on traditional approaches to the imaging of ovarian structures and discusses recent advances in ovarian imaging. Traditional in-vivo ultrasound, together with histological and electron microscopic approaches provide detailed views of the ovary at organ, tissue and molecular levels. However, in-vivo imaging is limited to antral and larger follicles whereas histological imaging is mainly two-dimensional in nature. Also discussed are emerging approaches in the use of near-infrared fluorophores to image follicles in live animals to detect preantral follicles as well as visualizing ovarian structures using CLARITY in fixed whole ovaries to elucidate three-dimensional interrelationships among follicles, corpora lutea and ovarian vasculature. Advances in ovarian imaging techniques provide new understanding of ovarian physiology and allow for the development of better tools to diagnose ovarian pathophysiology.

Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion.

OBJECTIVE: To assess if infusion of human bone marrow-derived stem cells (BMDSCs) could promote follicle development in patients with impaired ovarian functions. DESIGN: Experimental design. SETTING: University research laboratories. ANIMAL(S): Immunodeficient NOD/SCID female mice. INTERVENTION(S): Human BMDSCs were injected into mice with chemotherapy-induced ovarian damage and into immunodeficient mice xenografted with human cortex from poor-responder patients (PRs). MAIN OUTCOME MEASURE(S): Follicle development, ovulation, and offspring. Apoptosis, proliferation, and vascularization were evaluated in mouse and human ovarian stroma. RESULT(S): Fertility rescue and spontaneous pregnancies were achieved in mice ovaries mimicking PRs and ovarian insufficiency, induced by chemotherapy, after BMDSC infusion. Furthermore, BMDSC treatment resulted in production of higher numbers of preovulatory follicles, metaphase II oocytes, 2-cell embryos, and healthy pups. Stem cells promoted ovarian vascularization and cell proliferation, along with reduced apoptosis. In xenografted human ovarian tissues from PRs, infusion of BMDSCs and their CD133+ fraction led to their engraftment close to follicles, resulting in promotion of follicular growth, increases in E2 secretion, and enhanced local vascularization. CONCLUSION(S): Our results raised the possibility that promoting ovarian angiogenesis by BMDSC infusion could be an alternative approach to improve follicular development in women with impaired ovarian function. CLINICAL TRIAL REGISTRATION NUMBER: NCT02240342.

Epitope-specific monoclonal antibodies to FSHß increase bone mass.

Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that FSH inhibition reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHß was found not only to rescue bone loss postovariectomy, but also to display marked antiobesity and probeiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance--osteoporosis and obesity--we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHß. Hf2 has already been shown to reduce body weight and fat mass and cause beiging in mice on a high-fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on microcomputed tomography. This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild-type mice. We also reconfirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat.

3D NIR-II Molecular Imaging Distinguishes Targeted Organs with High-Performance NIR-II Bioconjugates.

Greatly reduced scattering in the second near-infrared (NIR-II) region (1000-1700 nm) opens up many new exciting avenues of bioimaging research, yet NIR-II fluorescence imaging is mostly implemented by using nontargeted fluorophores or wide-field imaging setups, limiting the signal-to-background ratio and imaging penetration depth due to poor specific binding and out-of-focus signals. A newly developed high-performance NIR-II bioconjugate enables targeted imaging of a specific organ in the living body with high quality. Combined with a home-built NIR-II confocal set-up, the enhanced imaging technique allows 900 µm-deep 3D organ imaging without tissue clearing techniques. Bioconjugation of two hormones to nonoverlapping NIR-II fluorophores facilitates two-color imaging of different receptors, demonstrating unprecedented multicolor live molecular imaging across the NIR-II window. This deep tissue imaging of specific receptors in live animals allows development of noninvasive molecular imaging of multifarious models of normal and neoplastic organs in vivo, beyond the traditional visible to NIR-I range. The developed NIR-II fluorescence microscopy will become a powerful imaging technique for deep tissue imaging without any physical sectioning or clearing treatment of the tissue.

Gonadotropins and their receptors: coevolution, genetic variants, receptor imaging, and functional antagonists.

Gonadotropins belong to the family of dimeric glycoprotein hormones and regulate gonadal physiology mediated by G protein-coupled, seven-transmembrane receptors. These glycoprotein hormones are widely used in the clinic to promote ovarian follicle development and for treating some cases of male infertility. We traced the coevolution of dimeric gonadotropin hormones and their receptors, together with thyrotropin and its receptor. We updated recent findings on human genetic variants of these genes and their association with dizygotic twining, polycystic ovarian syndrome, primary ovarian insufficiency, male-limited precocious puberty, and infertility. In addition to the known physiological roles of gonadotropin-receptor signaling in gonadal tissues, we also discussed emerging understanding of extragonadal functions of gonadotropins in bones and adipose tissues, together with recent advances in in vivo imaging of gonadotropin receptors in live animals. Recent development of gonadotropin receptor agonists and antagonists were summarized with an emphasis on the development of functional antagonists for FSH receptors to alleviate osteoporosis and obesity associated with menopause.