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Biomedical subjects

K Oktay

Publications and source records attributed to K Oktay.

At least 19 recordsLinked to original sources
PubMed2003

Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen.

BACKGROUND: Breast cancer chemotherapy commonly causes premature ovarian failure and infertility. Because increased estrogen levels are thought to be potentially risky in breast cancer patients, natural cycle IVF (NCIVF) has been used to preserve fertility and treat infertility in these women. METHODS: Twelve women with breast cancer received 40-60 mg tamoxifen for 6.9 +/- 0.6 days beginning on days 2-3 of their menstrual cycle (15 cycles), and had IVF (TamIVF) with either fresh embryo transfer (six cycles) or cryopreservation (nine cycles). They were compared to a retrospective control group (n = 5) who had natural cycle IVF (NCIVF, nine cycles). RESULTS: Cycle cancellation was significantly less frequent in TamIVF, compared with NCIVF (1/15 versus 4/9, P < 0.05). Compared with NCIVF, TamIVF patients had a greater number of mature oocytes (1.6 +/- 0.3 versus 0.7 +/- 0.2, P = 0.03) and embryos (1.6 +/- 0.3 versus 0.6 +/- 0.2, P = 0.02) per initiated cycle. TamIVF resulted in the generation of embryo(s) in every patient (12/12) while only three out of five patients had an embryo following NCIVF. Two out of six patients in TamIVF, and 2/5 in NCIVF conceived. One patient in the TamIVF group delivered a set of twins. After a mean follow up of 15 +/- 3.6 months (range 3-54), none of the patients had a recurrence of cancer. CONCLUSIONS: Tamoxifen stimulation appears to result in a higher number of embryos and may provide a safe method of IVF and fertility preservation in breast cancer patients.

Adult↗
PubMed2001

Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm.

CONTEXT: In reproductive-age women, one of the common adverse effects of chemotherapy and radiotherapy is premature ovarian failure. In addition, a significant number of women experience early menopause due to oophorectomy performed for benign indications. OBJECTIVE: To develop an ovarian transplantation technique to preserve endocrine function in women undergoing sterilizing radiotherapy and/or chemotherapy, or oophorectomy. DESIGN AND SETTING: Case study of 2 patients in New York who received autologous ovarian transplantation (patient A, November 1999; patient B, April 2000) to the forearm prior to pelvic radiotherapy or after oophorectomy. PARTICIPANTS: Patient A is a 35-year-old woman with stage IIIB squamous cell cervical carcinoma and patient B is a 37-year-old woman with recurrent benign ovarian serous cysts. MAIN OUTCOME MEASURES: Follicular development evident by ultrasound examination; cyclical production of estradiol and progesterone; restoration of serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels to nonmenopausal range; and disappearance of menopausal symptoms. RESULTS: Menopause was confirmed immediately after the transplantation in both patients by serum follicle-stimulating hormone measurements (patient A, 47 mIU/mL; patient B, 50.7 mIU/mL). In patient A, follicle development was noted by physical and ultrasound examinations approximately 10 weeks after the transplantation. The mean (SE) follicle-stimulating hormone and luteinizing hormone levels decreased to 8.6 (0.4) mIU/mL and 12.8 (0.8) mIU/mL, respectively. The peripheral estradiol levels showed cyclical variation (mean [SE], 115 [9.2] pg/mL [422 (33.8) pmol/L), and during the 18-month follow-up, a dominant follicle developed each month. The estradiol levels from the right cubital vein were consistent with ovarian vein measurements (mean [SE], 1069 [269] pg/mL [3924 (987.5) pmol/L]). Percutaneous oocyte aspirations yielded a mature oocyte. In patient B, ovarian function was demonstrated by ultrasound visualization of a 9-mm follicle by 6 months after transplantation. Thereafter, the patient had spontaneous menstruation every 25 to 28 days. Ovulation was further confirmed by midluteal progesterone measurements (range, 7-10.1 ng/mL; mean [SE], 8.5 [0.9] ng/mL). Patient B's ovarian graft was still functional 10 months after the transplantation. CONCLUSIONS: Subcutaneous ovarian transplantation appears to be a relatively simple, novel technique to preserve endocrine function in women undergoing sterilizing cancer therapy or surgery.

Adult↗
PubMed2001

A technique for laparoscopic transplantation of frozen-banked ovarian tissue.

OBJECTIVE: To describe a laparoscopic technique for transplanting frozen-banked ovarian tissue. DESIGN: Case study. SETTING: Academic medical center. PATIENT(S): A patient whose ovarian tissue was previously frozen with the slow-freeze technique. INTERVENTION(S): Microsurgical reconstruction of ovarian cortex and its laparoscopic transplantation to the ovarian fossa. MAIN OUTCOME MEASURE(S): Blood flow to the grafts by doppler, follicle development and ovulation by ultrasound, E(2) and progesterone production, and resumption of spontaneous menses. RESULT(S): The patient ovulated and menstruated 4 months after the transplant in response to ovarian stimulation with menopausal gonadotropins. CONCLUSION(S): Laparoscopic transplantation of frozen-banked ovarian tissue beneath the pelvic peritoneum can restore ovarian function.

Adult↗
PubMed2001

Recent progress in oocyte and ovarian tissue cryopreservation and transplantation.

Ovarian tissue cryopreservation and transplantation is an experimental technique that has been developed to sustain the reproductive function of women and children who are faced with sterilizing chemotherapy, radiotherapy, or radical reproductive surgery. Oocyte cryopreservation, on the other hand, is less feasible in the context of cancer because there is usually inadequate time to complete an ovarian stimulation cycle. The main promise of oocyte cryopreservation is that it offers an alternative when embryo freezing is not possible for technical, regulatory, or religious reasons. Oocyte freezing is more suitable for a single woman when the concern is age-related decline in fecundity. There have been significant scientific advances in the field of cryopreservation of ovarian tissue and oocytes, especially within the past few years. Ovarian function has been reported after the first cases of ovarian transplantation, and the number of pregnancies from cryopreserved oocytes has grown. Ovarian tissue and oocyte freezing can now be recommended in a carefully selected group of patients, provided that these options are offered under protocols that are approved by an institutional review board.

Cryopreservation↗
PubMed2000

Ovarian cryopreservation and transplantation: basic aspects.

Animal studies and studies using human ovarian xenografts in immunodeficient mice have shown that ovarian transplantation is feasible. In this manuscript, we present the first and limited experience with ovarian tissue cryopreservation and transplantation in the human. Despite the progress, more basic studies are needed to improve the survival of primordial follicles during and after the cryopreservation process.

Animals↗
PubMed2000

Transplantation of cryopreserved human ovarian tissue results in follicle growth initiation in SCID mice.

OBJECTIVE: To determine the long-term survival of frozen-thawed human ovarian tissue as xenografts in severe-combined-immunodeficiency (SCID) mice. DESIGN: Animal study. SETTING: Animal and laboratory facilities at an academic center. PATIENT(S): Ovarian tissue obtained from a 27-year-old woman. INTERVENTION(S): Grafting of frozen-thawed ovarian tissue in SCID mice for 22 weeks. MAIN OUTCOME MEASURE(S): Follicle counts and growth by morphology and PCNA staining in frozen-thawed grafts and fresh controls. RESULT(S): All three grafts were recovered intact after 22 weeks. Their stroma was devoid of necrotic cells and contained healthy follicles. The ratio of primordial-total follicles decreased significantly after grafting (0.94 +/- 0.02 to 0.87 +/- 0. 01, control vs. grafting). Compared with controls, after 22 weeks of grafting, a higher percentage of follicles had initiated growth (5.6 +/- 2.4 vs. 12.5 +/- 1.9), but there was still a significant number of primordial follicles/graft (75 +/- 6.8). Follicle stages were similar between two groups; only primordial and one-layer follicles were seen in the xenografts. In the controls, except for one two-layer follicle, the most advanced follicle was at the one-layer stage. CONCLUSION(S): Human primordial follicles survive freeze-thaw and long-term xenografting procedures and retain their capacity to initiate growth. These findings encourage future attempts for human autologous ovarian transplantation.

Adult↗
PubMed2000

Interaction of extracellular matrix and activin-A in the initiation of follicle growth in the mouse ovary.

The precise mechanism for the initiation of follicle growth and progression through the earliest stages of follicle development remains largely unknown. Activins play a role during early follicle development, and evidence suggests that the extracellular matrix plays a role during later stages of follicular growth. We investigated the role of activin-A and extracellular matrix in follicle growth initiation and early follicular development in the mouse ovary. Ovaries were collected from 5-day-old mice and cultured for 10 days on polylysine, collagen, or laminin in the presence or absence of recombinant human activin-A. Follicle density, indices of follicle growth initiation (primary:primordial follicle [PY:PD] and primary:total follicle [PY:TF] ratios), ratios of multilayer follicle:total follicle (ML:TF), and follicle growth rates were compared between groups. Follicle densities were significantly higher in the extracellular matrix treatment group compared with the polylysine group (P < 0.01). Also, compared with polylysine, both collagen and laminin significantly increased indices of follicle growth initiation (PY:PD ratio: P < 0.001, odds ratio of 3.3; PY:TF ratio: P < 0.001, odds ratio of 2.5), and these were not altered by activin treatment. In the absence of activin-A, exposure to neither collagen nor laminin had an effect on multilayer follicle development. When activin-A was added, collagen and laminin had opposing effects on multilayer follicle development. Activin-A stimulated multilayer follicle development in the presence of laminin (ML:TF ratio: P = 0.01, odds ratio of 10.8), whereas it suppressed follicle growth in collagen (P = 0.01). Activin-A did not affect the ML:TF ratio in the polylysine-treated groups. These results strongly suggest that extracellular matrix components and activin-A interact with each other, and that they regulate follicle growth initiation and multilayer follicle development.

Activins↗
PubMed1998

Cryopreservation of immature human oocytes and ovarian tissue: an emerging technology?

OBJECTIVE: To review the potential for cryopreserving immature follicles either in situ or after isolation from ovarian stroma and to consider the options for fertility by transplantation or in vitro follicle growth. DESIGN: The problems of storing embryos and mature (metaphase II) oocytes were considered in light of the needs of patients to protect fertility before undergoing potentially sterilizing therapy for cancer. The evidence from the experimental biology literature showing that immature oocytes (prophase I) in primordial follicles can be cryopreserved successfully and transplanted to produce fertile eggs was reviewed. The review, which was compiled from MEDLINE and other bibliographic databases, is intended to emphasize the practical opportunities for this technology and the need for future research rather than to be a comprehensive treatment of the subject. CONCLUSION(S): The disappointing results obtained with the cryopreservation of oocytes at metaphase II and ethical concerns about embryo storage are giving impetus to the banking of ovarian tissue for patients who require conservation of fertility. The numbers of needy patients are growing as long-term survivorship after high-dose chemotherapy and bone marrow transplantation rises. More speculatively, if ovarian tissue banking becomes a proven effective method, young, healthy women may request storage of ovarian biopsy samples to keep their reproductive options open in midlife when oocyte fertility is declining. Although the cryotechnology is not yet perfected, the major question now is how to use the tissue most effectively after thawing. For the present, ovarian tissue cryopreservation is still at the experimental stage, but it holds the promise of valuable applications.

Cellular Senescence↗
PubMed1998

Development of human primordial follicles to antral stages in SCID/hpg mice stimulated with follicle stimulating hormone.

In contrast to the many detailed studies of Graafian follicles, the biology of small follicles in the human ovary is poorly understood and the trigger for follicular growth initiation remains unknown. No practical model exists to study preantral follicle growth in the human because of their slow growth rate and lack of an effective culture system. We therefore tested ovarian xenografts as a new strategy to study the early stages of ovarian follicular growth in vivo. Mice homozygous for severe combined immunodeficiency (SCID) and hypogonadism (hpg) received human ovarian xenografts under their kidney capsules. Follicle growth was assessed by morphology and proliferating cell nuclear antigen (PCNA) immunostaining. The grafts were recovered after 11 (short-term) and 17 weeks (long-term), and serially sectioned. During the last 6 weeks of long-term grafting, mice were randomized to receive either placebo or 1 IU of purified follicle stimulating hormone (FSH) s.c. on alternating days. After 11 weeks of grafting, the most advanced follicles had a maximum of two granulosa cell layers. In the absence of FSH administration, follicles did not progress beyond the two-layer stage even after 17 weeks of grafting, and the oestradiol levels remained undetectable. In the FSH-treated long-term grafts, follicles had grown to antral stages and resulted in oestradiol levels as high as 2070 pmol/l. Growth initiation indices did not differ between control and FSH-treated grafts. This study demonstrates that follicles can survive and grow in human ovarian tissue grafted under the renal capsules of immunodeficient mice for at least 17 weeks, and indicate that xenograft models are potentially useful for studying human follicle development. Using this physiological model, we showed that FSH is required for follicle growth beyond the two-layer stage, although growth initiation is independent of gonadotrophin stimulation.

Animals↗
PubMed1997

Isolation and characterization of primordial follicles from fresh and cryopreserved human ovarian tissue.

OBJECTIVE: To develop an efficient isolation technique for human primordial follicles. DESIGN: Prospective, experimental study of ovarian biopsies collected from healthy women undergoing elective cesarean section. Ovarian blocks either were fixed for histology and follicle counting or partially disaggregated with type 1A collagenase before or after cryopreservation. After partial disaggregation, follicles were isolated by microdissection. SETTING: Leeds General Infirmary. MAIN OUTCOME MEASURE(S): Follicle viability was assessed with live-dead stains using 5-(and 6-) carboxyfluorescein diacetate, succinimidyl ester and propidium iodide, respectively, and using electron microscopy. The numbers recovered were expressed as a percentage of the numbers of primordial follicles in comparable blocks of tissue and the viability of the whole follicle and oocyte were scored separately. RESULT(S): On average, 18.0 +/- 3.8 and 15.9 +/- 2.2 (mean +/- SEM) follicles per block were recovered from fresh and cryopreserved ovarian tissue, respectively, corresponding to recovery rates of 57.9% +/- 8.8% and 56.2% +/- 16.7%. In the fresh group, the percent viability of whole follicles and oocytes were 71.6% +/- 2.4% and 91.3% +/- 2% compared with 71.5% +/- 4.7% and 95% +/- 4.3% in the frozen-thawed group. Electron microscopy confirmed that the majority of the cells lacked ultrastructural signs of damage after isolation and cryopreservation. CONCLUSION(S): Primordial follicles can be isolated from fresh and cryopreserved human ovarian tissue with similar high efficiency and viability rates.

Adult↗
PubMed1997

Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles.

FSH stimulates antral follicles to grow, but its role in earlier stages, if any, is obscure. Our aim was to determine the follicle stage at which the FSH receptor (FSHr) gene is first expressed. We used a PCR-based strategy to analyze single follicles ranging from primordial to multilaminar stages after isolation from human ovaries. Ovarian tissue was obtained from 11 women (age range, 25-33 yr) undergoing elective cesarean section. Tissue was partially disaggregated in medium containing 1% collagenase, and follicles were manually dissected free of stroma. Follicle stages were confirmed microscopically as primordial (nongrowing), primary (1 layer of cuboidal granulosa cells), or having 2 or more layers of granulosa cells. Rectus muscle and stromal tissue were used as negative controls. Messenger ribonucleic acid (mRNA) from each follicle was reverse transcribed, and the resulting cDNA was amplified by nested PCR using primers for FSHr and actin. None of the 9 primordial follicles expressed FSHr mRNA. Thirty-three percent of the primary and 2-layer follicles were positive for FSHr mRNA (4 of 12 and 3 of 9, respectively), as were 100% (n = 4) of the multilaminar follicles. The difference in FSH expression between the growing and primordial follicles was significant. This study shows for the first time that transcription of the FSHr gene begins at the earliest stages of follicular growth and indicates that FSH may have a hitherto unsuspected physiological role in preantral follicle development. In addition, this study demonstrates the practical feasibility of investigating the expression of other genes during human folliculogenesis.

Adult↗
PubMed1996

[Follicle freezing and autografting. A new method of medically assisted procreation?].

Although frozen human follicles were shown to be viable after thawing, more than forty years, the low yield of primordial follicles after cryopreservation has greatly limited research in this area. The aim of freezing follicles is to stock a patient's ovocytes before potentially destructive therapy for cancer then to reimplant the follicular tissue after successful treatment. The patient's ovulatory capacity would then theoretically be restored, allowing natural or possibly in vitro fertilization. As have other teams, we recently renewed work in cryopreservation of follicles in experimental models in search for a better cryopreservation agent and have had encouraging results suggesting that primordial human follicles or ovarian fragments can be grafted successfully after cryopreservation. Questions still under study include the optimal site for implantation, the survival time for grafts and the quantity of follicles needed to achieve pregnancy. Work on large animal models or xenografts of human tissues on immunotolerant animals may provide further insight. The possibilities of grafting primordial follicles, either alone or within ovarian tissue, may raise hope for many women, although new questions such as an age limit for reimplantation and use of allografts requiring preparation with major immunosuppressive therapy require further debate.

Animals↗
PubMed1995

Proliferating cell nuclear antigen marks the initiation of follicular growth in the rat.

Despite expanding knowledge on the kinetic aspects of folliculogenesis, the question of what initiates follicle growth remains unanswered. Efforts to solve this problem have been thwarted by the absence of sensitive markers to identify the onset of follicular growth. In this study, we determined whether increased proliferating cell nuclear antigen (PCNA) correlates with initiation of follicle growth and might therefore be useful for studying early events in this process. Paraffin sections of ovaries from cycling adult rats, prepubertal eCG+hCG-primed rats, and prepubertal control rats were processed for immunocytochemistry by use of a PCNA primary antibody. In primordial follicles, neither granulosa cells nor oocytes stained for PCNA. PCNA immunoreactivity coincided with the earliest sign of follicle growth, appearing in pregranulosa cells of early primary follicles just beginning to grow. In all primary follicles, some granulosa cells were PCNA-positive. PCNA immunoreactivity in oocytes first appeared in primary follicles, preceding oocyte enlargement. In preantral and antral follicles, granulosa cell PCNA staining was uniform throughout the granulosa cell layers. Oocytes were positive for PCNA in both preantral and antral follicles. PCNA expression diminished in atretic follicles. In CL, granulosa cell PCNA expression was also decreased. Theca cell PCNA expression was first evident in the transitional follicle (1-2-layer granulosa cells) and was present in all stages thereafter. The pattern of PCNA expression did not differ among adult cycling, prepubertal eCG+hCG-stimulated, and control rat ovaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗