Compensating human subjects providing oocytes for stem cell research: 9-year experience and outcomes.

PURPOSE: Human oocytes are arguably one of the most important cell types in humans, yet they are one of the least investigated cells. Because oocytes are limited in number, the use of high-quality oocytes is almost entirely in reproduction. Furthermore, regulatory hurdles for research on gametes and regulations on funding related to research on gametes present significant obstacles to research and the advancement of reproductive treatments. Here we report the outcomes of the largest compensated oocyte donation program for research in the USA to date, and probably worldwide. METHODS: Women who participated in oocyte donation for research between 2008 and 2017 were contacted in a phone interview and completed a standardized questionnaire. RESULTS: Of 114 participants, 98 oocyte donors completed donation, donating 1787 mature MII oocytes and a total of 86 skin biopsies. Complication rate, including minor complications, of oocyte donation was 8/98, or 8.1%, for which two involved follow-up. Fifty-seven donors answered questions about their experience. Participants were incentivized primarily by money and a desire to help others and reported an overall favorable experience. Most, but not all, human subjects recalled that they had donated for research, and approximately half recalled that their oocytes were being used specifically for stem cell research. CONCLUSIONS: Compensated oocyte donation provides a reliable path to obtaining high-quality oocytes for research and is reviewed favorably by oocyte donors. The continuation of programs that offer compensation for oocyte donation is invaluable to continued progress and advancements in stem cell research and human embryology, and for the advancement of novel reproductive treatments.

Providing assisted reproductive care to male haemophiliacs infected with human immunodeficiency virus: preliminary experience.

Outlined is our experience with couples in whom the male was both human immunodeficiency virus (HIV) seropositive and a haemophiliac who underwent assisted reproductive technologies (ART) in order to attain family goals while minimizing the risk of HIV transmission. We report their demographics, attitudes towards assisted reproduction, and ART performance and outcomes. The study included HIV serodiscordant couples (n = 11) who underwent ART at a university-based infertility practice from August 1997 to May 2002. Prior to treatment, couples prospectively completed a survey regarding their demographics and attitudes towards assisted reproduction. All couples underwent ART and pregnancy outcomes were analysed. The majority of the patients were fully employed, college-educated, in good health, married and motivated to have a child while minimizing the risk of HIV transmission. Eleven couples underwent 25 cycles of ART [19 in vitro fertilization (IVF) cycles; five frozen embryo transfer cycles; and one oocyte donation cycle] resulting in nine successful pregnancies. The ongoing/delivered pregnancy rate per initiated IVF cycle was 42.1% per embryo transfer. Eight of 11 (72.7%) couples achieved a successful pregnancy. More than half (six of 11; 54.5%) the couples conceived during their initial attempt. Four of nine (44.4%) pregnancies were multiple gestations, including three sets of triplets. All female recipients tested seronegative for HIV at 3 and 6 months post-embryo transfer. All delivered babies (n = 8) tested seronegative for HIV at birth and 3 months postpartum. Four pregnancies are currently ongoing. ART should be considered for HIV serodiscordant couples with haemophilia who desire to have children in order to minimize the risk of viral infection.

Understanding the effects of age on female fertility.

This review focuses on age-related changes occurring in the female reproductive system and their effect on reproductive material. Aging significantly impact the female reproductive system but, despite this fact, there is nowadays a trend to postpone pregnancy to pursue educational and vocational goals. Therefore a remarkable effort is now being made by the medical establishment to understand the effects of aging in women. The assessment and treatment of this decline in fertility is discussed, as well as assisted reproductive techniques and new therapeutic options.

Development and characterization of a long-acting recombinant hFSH agonist.

BACKGROUND: Fusion of the carboxyterminal peptide (CTP) of hCG to FSH results in a follitropin agonist with an extended half-life, presumably due to the four O-oligosaccharides on the CTP. Alternatively, an rhFSH analogue containing additional N-linked carbohydrate is described in this report. METHODS: A DNA sequence containing two N-oligosaccharide signal sequences was ligated into a vector containing hFSHbeta- and alpha-subunit encoding cDNA, and expressed in CHO-K1 cells. In-vitro bioactivity of the single-chain hormone was assessed in CHO cells expressing the hFSH receptor. Pharmacokinetic values were derived from serial serum assays of the analogue in immature female rats following a single i.v. injection. In-vivo bioactivity was assessed by measuring ovarian weight gain 3 days post-injection. RESULTS: rhFSH-N2 and native rhFSH induced comparable levels of cAMP in vitro. t(1/2) for native rhFSH, rhFSH-CTP and rhFSH-N2 were 3.7, 7.1 and 7.3 h respectively. Rats receiving rhFSH-N2 had a mean +/- SD ovarian weight 3 days post-i.v. injection (22 +/- 3.6 mg) significantly greater than rats receiving rhFSH and saline (16.7 +/- 1.5 and 15.3 +/- 0.47 mg respectively, P < 0.05). CONCLUSIONS: rhFSH-N2 has prolonged half-life and increased bioactivity compared with native rhFSH. This rhFSH agonist, and other analogues containing additional N-oligosaccharides may have important clinical applications.

Assessing the influence of payment on motivations of women participating as oocyte donors.

We report on the motivations of potential ovum donors entering an assisted reproduction program and discuss the potential ramifications of escalating payments to donors. From July 1995 to July 1998, recruitment of ovum donors was directed at healthy women between 21 and 34 years of age. Financial remuneration for services rendered was USD 2,500 from July 1995 through March 1998 and increased to USD 5,000 after that. Donors were screened and consented according to established SART guidelines. The demographic background of the women was similar for women paid USD 2,500 to those receiving USD 5,000. The financial motivation was greater in those receiving USD 5,000 (68%) than USD 2,500 (39%). Some form of expressed altruism was similarly present in both groups (USD 5,000 90%, and USD 2,500 91%). However, altruism expressed as the sole motivation occurred more in those receiving USD 2,500 (61%) compared to USD 5,000 (32%). Financial reimbursement has escalated for the services of ovum donors in order to maintain the increasing demand. While money has become a dominant factor motivating ovum donors, its seductive nature requires even greater attention to adequate informed consent. Young donors may be unable to adequately weigh the risks of ovarian hyperstimulation and oocyte retrieval against the monetary reward.

Assessing fertility in women of advanced reproductive age.

Reproductive capacity in women declines dramatically beyond the fourth decade of life. Oocyte quality seems to be the primary determinant of reproductive potential, although age-related uterine changes may also contribute. Underlying reasons for reproductive decline in women remain unclear, and both ovarian and neuroendocrine mechanisms have been proposed.A number of age-related endocrinologic changes precede menopause and predict diminished reproductive capacity. Thus, "ovarian reserve" screening may identify patients in whom attempts at conventional assisted reproduction is warranted before proceeding with ovum donation. Techniques to preserve the maternal genetic contribution to offspring (in lieu of egg donation), including germinal vesicle transfer and donor ooplasm, are under investigation.

Controlled ovarian hyperstimulation. Relationship of early serum E2 levels to the ultimate response of oocyte donors.

OBJECTIVE: To assess the predictive value of measuring serum day 5 E2 and in vitro fertilization (IVF) cycle outcome of oocyte donors undergoing controlled ovarian hyperstimulation (COH). STUDY DESIGN: Retrospective data analysis. RESULTS: Day 5 E2 significantly correlated with the peak serum E2 and number of retrieved mature oocytes. The pregnancy rates associated with stimulated day 5 E2 > 70 pg/mL were significantly greater than in cycles with levels < 70 pg/mL (58%, 71/123, versus 25%, 15/60; P < .05). CONCLUSION: The cycle performance of an oocyte donor can be predicted by measuring cycle day 5 serum E2 during COH. Poor-prognosis cycles can be identified and discontinued, saving patients and the program unnecessary exspense.

Posthumous reproduction in a human immunodeficiency virus-discordant couple.

A human immunodeficiency virus-discordant couple failed to conceive through in vitro fertilization and intracytoplasmic sperm injection of cryopreserved semen banked by the human immunodeficiency virus-positive partner. The husband subsequently had acquired immunodeficiency syndrome and died. The subsequent transfer of cryopreserved embryos resulted in pregnancy. Both mother and child are human immunodeficiency virus negative.

On the association between valproate and polycystic ovary syndrome.

Recent studies by Isojärvi et al. have raised the issue of an increased incidence of polycystic ovary syndrome (PCOS) in women with epilepsy treated with valproate (VPA) and have proposed replacement with lamotrigine (LTG). Polycystic ovaries (PCO) are a common finding, with a prevalence >20% in the general population, and are easily detected by pelvic or vaginal ultrasonography, whereas PCOS is comparatively rare: few women with PCO have fully developed PCOS, which includes hirsutism, acne, obesity, hypofertility. hyperandrogenemia, and menstrual disorders. From an extensive review of the current literature, it appears that there are no reliable data on the actual prevalence of PCOS in normal women and in women with epilepsy. The pathogenesis of PCO is multifactorial, including genetic predisposition and the intervention of environmental factors, among which weight gain and hyperinsulinism with insulin resistance may play a part. The roles of central (hypothalamic/pituitary), peripheral, and local ovarian factors are still debated. PCO and PCOS appear to be more frequent in women with epilepsy, but there are no reliable data showing a greater prevalence after VPA. The recent studies by Isojärvi et al. may have been biased by the retrospective selection of patients. To date, there is no reason to contraindicate the use of VPA in women with epilepsy. However, patients should be informed about the risk of weight gain and its consequences.

Oocyte donation treats infertility in survivors of malignancies: ten-year experience.

Women who are survivors of malignancy may achieve pregnancy through oocyte donation. The largest obstacle to successful reproduction in cancer patients relates to iatrogenic damage to the primary reproductive organs associated with their primary oncology treatment. Reactive damage from surgery, radiation, or chemotherapy may render these organs nonfunctional and irreparable. In cases where the ovary is primarily affected, oocyte donation provides a logical alternative for childbearing.

Prolonged inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates the circadian rhythm of human TSH secretion.

OBJECTIVE: Originating from the pituitary gland, TSH secretion is regulated predominantly by thyroid-releasing hormone (TRH) neurons located in the hypothalamus. Norepinephrine and dopamine have important effects in modulation of TSH secretion. An inhibitor of catecholamine synthesis, alpha-methyl-para-tyrosine (AMPT) has been used in several studies of the regulation of human TSH secretion. The short-term effects (<8 hours) of low doses of AMPT include stimulation of pituitary TSH secretion by selective lowering of brain dopamine levels. After prolonged administration of AMPT (>24 hours), theoretically both dopamine and norepinephrine levels are lowered significantly in the brain, although this has not been reported previously. METHODS: Nine subjects (five women and four men) received a total of five 1-g doses of AMPT or five 50-mg doses of promethazine (active placebo) over 28 hours in a randomized, double-blind, placebo-controlled crossover design in which the active and control tests were separated by 4-6 weeks. Blood samples were obtained over 24 hours (18 time points) on day 2 of each condition. RESULTS: Changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion indirectly showed the effects of AMPT on dopamine and norepinephrine. The typical circadian rhythm of TSH secretion was blunted by AMPT throughout the night; at ten time points, the difference between the two groups was statistically significant (P <.01). The long-term effects of repeated doses of AMPT were inhibition of TSH secretion and significant attenuation of the circadian rhythm of TSH. Additionally, AMPT induced low norepinephrine levels, which counteracted the stimulatory effect of low dopamine levels on TSH. CONCLUSION: Through its inhibitory effect on TRH, norepinephrine appeared to be involved in the regulation of TSH.

Preovulatory treatment of mice with anti-VEGF receptor 2 antibody inhibits angiogenesis in corpora lutea.

Adult mammalian angiogenesis occurs predominantly in female reproductive organs: the ovary and the uterus. Angiogenesis is very active during corpus luteum formation. A key regulator of angiogenesis is vascular endothelial growth factor (VEGF), which is highly expressed during corpus luteum formation. Inhibition of VEGF activity can block the formation and function of the corpora lutea by preventing angiogenesis. The VEGF receptor 2 (VEGF-R2) mediates the angiogenic action of VEGF and is expressed during corpus luteum formation. We hypothesized that treatment with an antibody against VEGF-R2 would inhibit luteal angiogenesis by blocking VEGF/VEGF-R2 interaction. Immature mice were induced to superovulate with PMSG/hCG resulting in neovascularization in the corpora lutea, as evidenced by abundant staining for the endothelial-specific adhesion molecule PECAM. Multiple doses of a monoclonal antibody against the VEGF-R2 (DC101) were administered to immature mice. Treatment was initiated 2 days prior to the induction of superovulation with PMSG/hCG. This antibody inhibited luteal angiogenesis as evidenced by the lack of PECAM staining in the center of the corpora lutea. Multiple dose treatment with antibody initiated prior to gonadotropin administration could not dissociate the luteal inhibition from the consequences of inhibition of angiogenesis in the developing follicle. Administration of a single, preovulatory dose of anti-VEGF-R2 antibody, such that follicular angiogenesis would not be affected, also inhibited luteal development, demonstrating that luteal angiogenesis is required for corpus luteal development. We conclude that VEGF acting through VEGF-R2 has an obligatory role in luteal angiogenesis and corpus luteum formation.

Testicular sperm aspiration (TESA) and its application in oocyte donation.

This study was conducted to assess the outcomes of TESA in women undergoing oocyte donation. Descriptive reports from a university IVF practice were reviewed to evaluate the outcomes of women (n = 10) who underwent 12 cycles of ovum donation and required testicular sperm aspiration due to obstructive azoospermia (n = 6) and nonobstructive azoospermia (n = 4). Percutaneous needle aspiration of the testes was performed prior to oocyte retrieval to recover sperm, and intracytoplasmic sperm injection was subsequently performed on the donated oocytes. Fertilization was documented 16-18 h later and transcervical embryo transfer performed 72 h postretrieval. Successful retrieval of testicular spermatozoa utilizing the percutaneous technique was achieved in all 12 cycles. All cycles resulted in an ET with the achievement of 7 (58%) pregnancies, of which 5 (42%) are ongoing or delivered. The individual embryo implantation rate was 18.4% (9/49). Two cycles (16.6%) produced supernumerary embryos for cryopreservation. TESA represents a simple procurement technique associated with minimal morbidity. It may be offered even in cases of nondestructive azoospermia.

Defining the incidence of serious complications experienced by oocyte donors: a review of 1000 cases.

A review of 1000 aspirations of oocyte donors was performed. Only witnessed events necessitating hospitalization or emergent intervention were considered significant. Seven (0.7% incidence) cases were noted, including severe ovarian hyperstimulation syndrome (n = 3), adverse reaction to intravenous anesthesia (n = 2), intra-abdominal bleeding after aspiration (n = 1), and bladder atony with hematuria after aspiration (n = 1).

Short-term administration of antivascular endothelial growth factor antibody in the late follicular phase delays follicular development in the rhesus monkey.

Indirect evidence in the nonhuman primate and human suggests that angiogenesis and regulators of angiogenesis such as vascular endothelial growth factor (VEGF) may play an active role in cyclic folliculogenesis. Indeed, the follicle selected for maturation and ovulation possesses a denser microvascular network, and VEGF messenger ribonucleic acid and its protein have been identified in granulosa cells of the developing follicle during the mid- and late follicular phases, with a more intense signal in the mature follicle. The objective of this study was to obtain direct evidence in the nonhuman primate for an active role of VEGF in follicular growth and maturation by studying the effect of VEGF-blocking antibodies in this process. After documenting two normal ovulatory cycles, female rhesus monkeys (n = 7) received iv injections of anti-VEGF antibodies (0.5 mg) twice on successive days in the late follicular phase. Three monkeys also received nonspecific goat IgG (0.5 mg) twice on successive days in the late follicular phase. Daily measurements of estradiol, progesterone, LH, and FSH were obtained during the two control cycles, the anti-VEGF treatment and posttreatment cycles, and the IgG treatment cycle. Anti-VEGF antibody administration significantly lengthened the follicular phase in six of seven monkeys to 17.8 +/- 1.7 vs. 10.0 +/- 0.7 and 9.8 +/- 0.6 in control cycles and 10.7 +/- 0.3 days (mean +/- SE) in IgG-treated cycles. The expected late follicular phase rise in estradiol, as documented in the control cycles (day 0, 96.1 +/- 6.0; day 1, 125.5 +/- 20.0; day 2, 165.5 +/- 24.9; day 3, 183.8 +/- 11.0 pg/mL), was interrupted by anti-VEGF antibody treatment (99.3 +/- 5.0, day 0, preinjection control) to 63.3 +/- 12.2 (day 1), 48.5 +/- 8.7 (day 2), and 57.6 +/- 9.0 (day 3). Mean FSH levels were significantly increased by day 2 of anti-VEGF antibody treatment. After a variable delay, estradiol concentrations increased to reach a preovulatory peak in all anti-VEGF-treated animals, followed by ovulation, normal luteal function, and a normal posttreatment cycle. The data clearly demonstrate that short-term inhibition of angiogenesis with an anti-VEGF-blocking antibody during the later growth phase of the dominant follicle interferes with normal follicular development. Persistence of estradiol secretion and delayed resumption of its rise also suggest recovery of the follicle. We conclude that the angiogenic regulator VEGF is a crucial component in the process of follicular growth in the primate.