1111
Use of gonadotropin releasing hormone analogues suppress the hypothalamic-pituitary-ovarian axis is thought to have increased the frequency of OHSS.s These compounds result in more follicles, higher serum oestradiol concentrations, more high-quality oocytes and embryos, and a better pregnancy rateas well as suppressing the spontaneous protective luteinising hormone surge’ and necessitating exogenous luteal phase support. Whether follicular aspiration and disruption during oocyte retrieval protects against OHSS has been disputed. A prospective trial is needed with accurate recording of the percentage of follicles aspirated and careful exclusion of interoperator variation in retrieval
EDITORIALS
to
techniques.
Ovarian hyperstimulation syndrome The ovarian hyperstimulation syndrome (OHSS) is an important side-effect of treatment with fertility drugs—clomiphene citrate, human chorionic human (hCG), menopausal gonadotropin gonadotropins (hMG, menotropin), follicle stimulating hormone, and luteinising hormone releasing hormone. Any patient who undergoes ovulation induction is at risk. The syndrome is characterised by massive ovarian enlargement and fluid accumulation in peritoneal, pleural, and, rarely, pericardial cavities (third space fluid). Various classifications have been proposed, according to ovarian size (now determined by ultrasound), symptoms, and extent of fluid accumulation; all agree on
mild, moderate,
and
severe
categories. Haning et
aP replaced the assessment of symptoms and fluid accumulation by the patient’s weight gain from the time of hCG injection. Weight increase is a good indicator of fluid accumulation and hence of the severity of the condition. The likelihood and severity of the syndrome are directly related to the extent of ovarian response to stimulation: with hMG, mild cases occur in up to 23 % of cycles and the severe form in less than 5%. OHSS is more common in patients with polycystic ovary syndrome than in eugonadotropic or hypogonadotropic women/ in those treated with hMG than in those receiving clomiphene, and in who become pregnant. Haning and women colleaguesl found a fourfold increase in the syndrome in conception cycles, while Tulandi et aP reported a threefold higher pregnancy rate in patients with OHSS. Nevertheless, irrespective of the degree of ovarian response, OHSS does not occur without the luteinising hormone (or surrogate hCG) preovulatory rise, and is less likely if the corpora lutea are not stimulated by exogenous or endogenous hCG.These two sources of hCG probably account for the biphasic clinical incidence at around day 5 (under the influence of exogenous hCG) and again after day 10 (under the stimulation of endogenous hCG from pregnancy).4 The late form resolves immediately if the pregnancy is
aborted, either spontaneously or therapeutically.4
The biochemical link between the ovary and OHSS remains uncertain. One difficulty is that there is no satisfactory animal model. Oestrogens were suspected because in physiological concentrations they cause slight sodium and water retention and an increased permeability of uterine and ovarian capillaries to plasma proteins. Nevertheless, oestradiol has proved not to be a causal factor.9 What about histamine? Although luteinising hormone induces ovarian hyperaemia and depletes ovarian histamine stores, the value of antihistamine treatment remains unsubstantiated.14 Prostaglandin F 20:’ which causes a decrease in microvascular vasodilatation and permeability, has not been conclusively associated with OHSS, and prolactin has been excluded. Haning and colleagues4 reported that plasma renin, renin activity, and aldosterone were increased in direct proportion to the severity of OHSS and suggested that these rises were homoeostatic; against this is the observation that even though the ovary contains high concentrations of prorenin, only 1 % exists in an active form. 16 Angiotensinogen has been detected immunocytochemically in the corpus luteum of rats, 10 but there is no substantial ovarian outpouring of it or its metabolites in OHSS. Prorenin is predominantly taken up and activated by the kidneys and liver, 11 so it is unlikely that any increase in capillary permeability and angiogenesis would be confined to the peritoneal, pleural, and pericardial cavities. The possibility that a grossly exaggerated angiogenic response induces OHSS merits further investigation. At the time of transition of the normal graafian follicle to the corpus luteum there is intense angiogenic activity in response to the luteinising hormone surge, part of which is a physiological increase in microvascular permeability .12 Peritoneal fluid volume likewise increases in the late proliferative phase, with an abrupt increase at the time of ovulation.13 Fluid accumulation in OHSS may represent a gross exaggeration of these processes. The homoeostatic response to exudation also contributes to the syndrome. The increased capillary permeability results not only in ascites and pleural and pericardial effusions but also in decreased circulating fluid volume, blood pressure, central venous pressure,
1112
and renal perfusion together with increased vascular stasis and coagulation. The diminished circulating volume stimulates secretion of antidiuretic hormone4 and activates the renin-angiotensin-aldosterone system. Fluid retention then causes hyponatraemia; impaired excretion leads to hyperkalaemia and acidosis. Patients with OHSS usually present with the symptoms of third-space fluid accumulation and ovarian enlargement; venous thrombosis is occasionally reported.14 The ovaries may well extend above the umbilicus and are fragile, rupturing even with light pressure. Consequently, examination should be extremely gentle and vaginal examination is contraindicated. Ascites causes pronounced abdominal discomfort, hampers diaphragmatic movement, and can be associated with nausea and paralytic ileus. Concomitant pleural effusions will cause further respiratory embarrassment. Mild and moderate forms of OHSS do not usually require treatment; outpatient surveillance will suffice. Patients with severe OHSS should be admitted to a specialist unit and rehydrated with crystalloids or colloids to increase the intravascular fluid volume, correct electrolyte imbalance, and increase renal perfusion and urine output to a minimum of 30 ml per hour. Management then passes to the chronic phase. It is a mistake to over-infuse to maintain a high renal output because a large proportion of infused fluid will leak into the various cavities and worsen the patient’s discomfort. If the patient is pregnant, this chronic phase may be lengthy; resolution is heralded by the onset of a spontaneous diuresis. Potassium exchange resins, mannitol infusions, or third-space fluid aspiration may be necessary. Diuretics should be avoided unless the patient has haemodilution from over-perfusion because they will remove yet more fluid from the intravascular space. Termination of pregnancy may be the only solution in some cases.
To prevent
OHSS, patients undergoing ovarian hyperstimulation should be monitored carefully; serum oestradiol is closely correlated with the development of OHSS and is a better indicator than the number and size of ovarian follicles. Is Haning and co-workers1 suggested that when hMG is given 12 h before
and
in
the absence of gonadotropin releasing hormone analogues, administration of hCG should be guided by serum oestradiol concentrations. Thus, hCG should be withheld if serum oestradiol concentrations exceed 8870 pmol/1 in hypothalamic amenorrhoea or 13 865 pmol/1 in polycystic ovary syndrome. This policy should give a 5% risk of severe OHSS in conception cycles. Each clinic should establish values for its own dose regimens, concentrations will vary according to intervals between hMG injection, venous sampling, and hCG injection. If the stimulation regimen includes gonadotropin releasing hormone analogues and if hCG has been withheld, the analogues may be
venepuncture,
continued after stopping hMG to allow follicular regression. A second stimulation cycle can then be started, usually after 2 or 3 weeks, with a lower hMG dose.s With assisted reproduction techniques the ovulatory hCG injection can be given, oocytes harvested, any resulting embryos frozen, and the gonadotropin releasing hormone analogues continued until all ovarian cysts have regressed. The embryos can then be replaced in a subsequent cycle.16 1.
Haning RV Jr, Boehnlein LM, Carlson IH, Kuzma DL, Zweibel WJ. Diagnosis-specific serum 17&bgr; estradiol (E2) upper limits for treatment with menotropins using a 125I direct E2 assay. Fertil Steril 1984; 42:
882-89. 2. Tulandi T, Mcinnes RA, Arronet GH. Ovarian hyperstimulation syndrome following ovulation induction with HMG. Int J Fertil 1984; 29: 113-17. 3. Herman A, Ron-El R, Golan A, Raziel A, Soffer Y, Caspi E. Pregnancy rate and ovarian hyperstimulation after luteal human chononic gonadotropin in in vitro fertilization stimulated with gonadotropinreleasing hormone analog and menotropins. Fertil Steril 1990; 53: 92-96. 4. Haning RV Jr, Strawn EY, Nolten WE. Pathophysiology of the ovarian hyperstimulation syndrome. Obstet Gynecol 1985; 66: 220-24. 5. Forman RG, Frydman R, Egan D, Ross, Barlow DH. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for m vitro fertilization: a European series and a proposal for prevention. Fertil Steril 1990; 53: 502-08. 6. Frydman R, Parneix I, Belaisch-Allart J, et al. LHRH agonists in IVF: different methods of utilization and a comparison with previous ovulation stimulation treatments. Hum Reprod 1988; 3: 559-61. 7. Ron-El R, Herman A, Golan A, Nachum H, Soffer Y, Caspi E. Gonadotropins and combined gonadotropin-releasing hormone agonist-gonadotropin protocols in a randomized prospective study. Fertil Steril 1991; 55: 574-78. 8. Golan A, Ron-El R, Herman A, Weinraub Z, Soffer Y, Caspi E. Ovarian hyperstimulation syndrome following D-trp-6 luteinizing hormonereleasing hormone microcapsules and menotropin for in vitro fertilization. Fertil Steril 1988; 50: 912-16. 9. Schenker JG, Polishuk WZ. An experimental model of ovarian hyperstimulation syndrome. Proceedings of the International Congress on Animal Reproduction, 1976; 4: 635-39. 10. Thomas WG, Sernia C. The immunocytochemical localization of angiotensinogen in the rat ovary. Cell Tissue Res 1990; 261: 367-73. 11. Kim S, Hosoi M, Ikemoto F, Murakami K, Ishizuka Y, Yamamoto K. Conversion to renin of exogenously administered recombinant human prorenin in liver and kidney of monkeys. Am J Physiol 1990; 258: 451-58. 12. Cavender JL, Murdoch WJ. Morphological studies of the microcirculatory system of periovulatory ovine follicles. Biol Reprod 1988; 39: 989-97. 13. Maathuis JB, Van Look PFA, Michie EA. Changes in volume, total protein, and ovarian steroid concentrations of peritoneal fluid throughout the human menstrual cycle. J Endocrinol 1978; 76: 123-33. 14. Kaaja R, Siegberg R, Tiitinen A, Koskimies A. Severe ovarian hyperstimulation syndrome and deep venous thrombosis. Lancet 1989; ii: 1043. 15. Haning RV Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS, Zweibel WJ. Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril 1983; 40: 31-36. 16. Amso NN, Ahuja KK, Morris N, Shaw RW. The management of predicted ovarian hyperstimulation involving gonadotropin-releasing hormone analog with elective cryopreservation of all pre-embryos. Fertil Steril 1990; 53: 1087-90.
Partner notification for preventing HIV infection It is only in an atmosphere of discrimination and fear that the concept of partner notification in infectious disease becomes an issue. In the control of sexually transmitted diseases notification and testing of people at risk is widely accepted as means of limiting the spread of infection and treating contacts. In
Use of gonadotropin releasing hormone analogues suppress the hypothalamic-pituitary-ovarian axis is thought to have increased the frequency of OHSS.s These compounds result in more follicles, higher serum oestradiol concentrations, more high-quality oocytes and embryos, and a better pregnancy rateas well as suppressing the spontaneous protective luteinising hormone surge’ and necessitating exogenous luteal phase support. Whether follicular aspiration and disruption during oocyte retrieval protects against OHSS has been disputed. A prospective trial is needed with accurate recording of the percentage of follicles aspirated and careful exclusion of interoperator variation in retrieval
EDITORIALS
to
techniques.
Ovarian hyperstimulation syndrome The ovarian hyperstimulation syndrome (OHSS) is an important side-effect of treatment with fertility drugs—clomiphene citrate, human chorionic human (hCG), menopausal gonadotropin gonadotropins (hMG, menotropin), follicle stimulating hormone, and luteinising hormone releasing hormone. Any patient who undergoes ovulation induction is at risk. The syndrome is characterised by massive ovarian enlargement and fluid accumulation in peritoneal, pleural, and, rarely, pericardial cavities (third space fluid). Various classifications have been proposed, according to ovarian size (now determined by ultrasound), symptoms, and extent of fluid accumulation; all agree on
mild, moderate,
and
severe
categories. Haning et
aP replaced the assessment of symptoms and fluid accumulation by the patient’s weight gain from the time of hCG injection. Weight increase is a good indicator of fluid accumulation and hence of the severity of the condition. The likelihood and severity of the syndrome are directly related to the extent of ovarian response to stimulation: with hMG, mild cases occur in up to 23 % of cycles and the severe form in less than 5%. OHSS is more common in patients with polycystic ovary syndrome than in eugonadotropic or hypogonadotropic women/ in those treated with hMG than in those receiving clomiphene, and in who become pregnant. Haning and women colleaguesl found a fourfold increase in the syndrome in conception cycles, while Tulandi et aP reported a threefold higher pregnancy rate in patients with OHSS. Nevertheless, irrespective of the degree of ovarian response, OHSS does not occur without the luteinising hormone (or surrogate hCG) preovulatory rise, and is less likely if the corpora lutea are not stimulated by exogenous or endogenous hCG.These two sources of hCG probably account for the biphasic clinical incidence at around day 5 (under the influence of exogenous hCG) and again after day 10 (under the stimulation of endogenous hCG from pregnancy).4 The late form resolves immediately if the pregnancy is
aborted, either spontaneously or therapeutically.4
The biochemical link between the ovary and OHSS remains uncertain. One difficulty is that there is no satisfactory animal model. Oestrogens were suspected because in physiological concentrations they cause slight sodium and water retention and an increased permeability of uterine and ovarian capillaries to plasma proteins. Nevertheless, oestradiol has proved not to be a causal factor.9 What about histamine? Although luteinising hormone induces ovarian hyperaemia and depletes ovarian histamine stores, the value of antihistamine treatment remains unsubstantiated.14 Prostaglandin F 20:’ which causes a decrease in microvascular vasodilatation and permeability, has not been conclusively associated with OHSS, and prolactin has been excluded. Haning and colleagues4 reported that plasma renin, renin activity, and aldosterone were increased in direct proportion to the severity of OHSS and suggested that these rises were homoeostatic; against this is the observation that even though the ovary contains high concentrations of prorenin, only 1 % exists in an active form. 16 Angiotensinogen has been detected immunocytochemically in the corpus luteum of rats, 10 but there is no substantial ovarian outpouring of it or its metabolites in OHSS. Prorenin is predominantly taken up and activated by the kidneys and liver, 11 so it is unlikely that any increase in capillary permeability and angiogenesis would be confined to the peritoneal, pleural, and pericardial cavities. The possibility that a grossly exaggerated angiogenic response induces OHSS merits further investigation. At the time of transition of the normal graafian follicle to the corpus luteum there is intense angiogenic activity in response to the luteinising hormone surge, part of which is a physiological increase in microvascular permeability .12 Peritoneal fluid volume likewise increases in the late proliferative phase, with an abrupt increase at the time of ovulation.13 Fluid accumulation in OHSS may represent a gross exaggeration of these processes. The homoeostatic response to exudation also contributes to the syndrome. The increased capillary permeability results not only in ascites and pleural and pericardial effusions but also in decreased circulating fluid volume, blood pressure, central venous pressure,
1112
and renal perfusion together with increased vascular stasis and coagulation. The diminished circulating volume stimulates secretion of antidiuretic hormone4 and activates the renin-angiotensin-aldosterone system. Fluid retention then causes hyponatraemia; impaired excretion leads to hyperkalaemia and acidosis. Patients with OHSS usually present with the symptoms of third-space fluid accumulation and ovarian enlargement; venous thrombosis is occasionally reported.14 The ovaries may well extend above the umbilicus and are fragile, rupturing even with light pressure. Consequently, examination should be extremely gentle and vaginal examination is contraindicated. Ascites causes pronounced abdominal discomfort, hampers diaphragmatic movement, and can be associated with nausea and paralytic ileus. Concomitant pleural effusions will cause further respiratory embarrassment. Mild and moderate forms of OHSS do not usually require treatment; outpatient surveillance will suffice. Patients with severe OHSS should be admitted to a specialist unit and rehydrated with crystalloids or colloids to increase the intravascular fluid volume, correct electrolyte imbalance, and increase renal perfusion and urine output to a minimum of 30 ml per hour. Management then passes to the chronic phase. It is a mistake to over-infuse to maintain a high renal output because a large proportion of infused fluid will leak into the various cavities and worsen the patient’s discomfort. If the patient is pregnant, this chronic phase may be lengthy; resolution is heralded by the onset of a spontaneous diuresis. Potassium exchange resins, mannitol infusions, or third-space fluid aspiration may be necessary. Diuretics should be avoided unless the patient has haemodilution from over-perfusion because they will remove yet more fluid from the intravascular space. Termination of pregnancy may be the only solution in some cases.
To prevent
OHSS, patients undergoing ovarian hyperstimulation should be monitored carefully; serum oestradiol is closely correlated with the development of OHSS and is a better indicator than the number and size of ovarian follicles. Is Haning and co-workers1 suggested that when hMG is given 12 h before
and
in
the absence of gonadotropin releasing hormone analogues, administration of hCG should be guided by serum oestradiol concentrations. Thus, hCG should be withheld if serum oestradiol concentrations exceed 8870 pmol/1 in hypothalamic amenorrhoea or 13 865 pmol/1 in polycystic ovary syndrome. This policy should give a 5% risk of severe OHSS in conception cycles. Each clinic should establish values for its own dose regimens, concentrations will vary according to intervals between hMG injection, venous sampling, and hCG injection. If the stimulation regimen includes gonadotropin releasing hormone analogues and if hCG has been withheld, the analogues may be
venepuncture,
continued after stopping hMG to allow follicular regression. A second stimulation cycle can then be started, usually after 2 or 3 weeks, with a lower hMG dose.s With assisted reproduction techniques the ovulatory hCG injection can be given, oocytes harvested, any resulting embryos frozen, and the gonadotropin releasing hormone analogues continued until all ovarian cysts have regressed. The embryos can then be replaced in a subsequent cycle.16 1.
Haning RV Jr, Boehnlein LM, Carlson IH, Kuzma DL, Zweibel WJ. Diagnosis-specific serum 17&bgr; estradiol (E2) upper limits for treatment with menotropins using a 125I direct E2 assay. Fertil Steril 1984; 42:
882-89. 2. Tulandi T, Mcinnes RA, Arronet GH. Ovarian hyperstimulation syndrome following ovulation induction with HMG. Int J Fertil 1984; 29: 113-17. 3. Herman A, Ron-El R, Golan A, Raziel A, Soffer Y, Caspi E. Pregnancy rate and ovarian hyperstimulation after luteal human chononic gonadotropin in in vitro fertilization stimulated with gonadotropinreleasing hormone analog and menotropins. Fertil Steril 1990; 53: 92-96. 4. Haning RV Jr, Strawn EY, Nolten WE. Pathophysiology of the ovarian hyperstimulation syndrome. Obstet Gynecol 1985; 66: 220-24. 5. Forman RG, Frydman R, Egan D, Ross, Barlow DH. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for m vitro fertilization: a European series and a proposal for prevention. Fertil Steril 1990; 53: 502-08. 6. Frydman R, Parneix I, Belaisch-Allart J, et al. LHRH agonists in IVF: different methods of utilization and a comparison with previous ovulation stimulation treatments. Hum Reprod 1988; 3: 559-61. 7. Ron-El R, Herman A, Golan A, Nachum H, Soffer Y, Caspi E. Gonadotropins and combined gonadotropin-releasing hormone agonist-gonadotropin protocols in a randomized prospective study. Fertil Steril 1991; 55: 574-78. 8. Golan A, Ron-El R, Herman A, Weinraub Z, Soffer Y, Caspi E. Ovarian hyperstimulation syndrome following D-trp-6 luteinizing hormonereleasing hormone microcapsules and menotropin for in vitro fertilization. Fertil Steril 1988; 50: 912-16. 9. Schenker JG, Polishuk WZ. An experimental model of ovarian hyperstimulation syndrome. Proceedings of the International Congress on Animal Reproduction, 1976; 4: 635-39. 10. Thomas WG, Sernia C. The immunocytochemical localization of angiotensinogen in the rat ovary. Cell Tissue Res 1990; 261: 367-73. 11. Kim S, Hosoi M, Ikemoto F, Murakami K, Ishizuka Y, Yamamoto K. Conversion to renin of exogenously administered recombinant human prorenin in liver and kidney of monkeys. Am J Physiol 1990; 258: 451-58. 12. Cavender JL, Murdoch WJ. Morphological studies of the microcirculatory system of periovulatory ovine follicles. Biol Reprod 1988; 39: 989-97. 13. Maathuis JB, Van Look PFA, Michie EA. Changes in volume, total protein, and ovarian steroid concentrations of peritoneal fluid throughout the human menstrual cycle. J Endocrinol 1978; 76: 123-33. 14. Kaaja R, Siegberg R, Tiitinen A, Koskimies A. Severe ovarian hyperstimulation syndrome and deep venous thrombosis. Lancet 1989; ii: 1043. 15. Haning RV Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS, Zweibel WJ. Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril 1983; 40: 31-36. 16. Amso NN, Ahuja KK, Morris N, Shaw RW. The management of predicted ovarian hyperstimulation involving gonadotropin-releasing hormone analog with elective cryopreservation of all pre-embryos. Fertil Steril 1990; 53: 1087-90.
Partner notification for preventing HIV infection It is only in an atmosphere of discrimination and fear that the concept of partner notification in infectious disease becomes an issue. In the control of sexually transmitted diseases notification and testing of people at risk is widely accepted as means of limiting the spread of infection and treating contacts. In
